VBCC September 2012, VOL 3, NO 6

SEPTEMBER 2012 VOL 3 NO 6

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com

Living Life to the Fullest, with Cancer The fight for quality: the Niagara Fall trajectory Interview with Amy J. Berman, BS, RN Senior Program Officer, The John A. Hartford Foundation, New York, NY

2nd Annual Conference

Defining Value in Cancer Care: AVBCC 2012 Steering Committee Report

A

pproximately 200 oncologists, payers, employers, managed care executives, pharmacy benefit managers, and other healthcare stakeholders convened in Hous-

Amy J. Berman, BS, RN, was diagnosed with incurable stage IV breast cancer almost 2 years ago. In the following interview, she discusses with Value-Based Cancer Care (VBCC) her recent experience, and why she chose to focus on quality of life rather than on the length of her life.

VBCC: Can you share with us your professional background, and how this relates to your cancer diagnosis and treatment decisions, and how this may also relate to other patients with cancer?

Continued on page 9

ton, TX, on March 28-31, 2012, for the Second Annual Conference of the Association for Value-Based Cancer Care (AVBCC).

Continued on page 12

Economics Impede Growth of Supportive Care Services Cost-effectiveness does not equal cost-saving

By Phoebe Starr

New Calculator Shows Financial Impact of Poor Quality of Care to an Institution, and How to Correct It

New York, NY—Supportive care is effective in improving outcomes, but the growth of supportive care programs is hampered by economics,

Toronto, Canada—A Healthcare Quality Calculator (HQCal) created by researchers at Vanderbilt University School of Medicine, Nashville, TN, allows decision makers to determine which investments are the most costefficient for improving quality of care, according to a new study presented at the 2012 International Conference on Head and Neck Cancer.

The HQCal was created to calculate the financial impact of poor quality of care for a specific institution or hospital, which allowed them to highlight issues that would have the most financial benefit by improving their quality and preventing potential complications associated with a poor quality of care. For example, in a hospital with a Continued on page 46

©2012 Engage Healthcare Communications, LLC

Continued on page 30

INSIDE FDA UPDATE . . . . . . . . . . . . . . . . .4

By Rosemary Frei, MSc

explained Eduardo Bruera, MD, Chair, Palliative Care & Rehabilitation Medicine, University of Texas

Bosulif approved for Ph+ CML Xtandi for prostate cancer Zaltrap for metastatic colorectal cancer

IN THE LITERATURE . . . . . . . . . . .8

Anastrozole-fulvestrant combination improves survival in breast cancer Intermittent versus continuous androgen deprivation after radiotherapy

PROSTATE CANCER . . . . . . . . . .11

Observation a good strategy in low-risk prostate cancer

MASCC SYMPOSIUM . . . . . . . . .30 G-CSF agents prevent neutropenia, but cost limits utilization

HEALTH POLICY . . . . . . . . . . . . .32 Medicare proposes rewarding quality, cutting payments for oncology

DRUG UPDATE . . . . . . . . . . . . . .34 Carfilzomib a new option for myeloma

CONTINUING EDUCATION . . . . .38 Considerations in lymphoma

IV R FO AND D S ON E V OU TI O R NE TRA P AP UTA INIS C M B SU AD

VELCADEHCP.COM

If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated Closely monitor patients with risk factors for, or existing heart disease Acute diffuse infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

FDA Update Bosulif Approved for Ph+ CML The US Food and Drug Administration (FDA) approved the tyrosine kinase inhibitor bosutinib (Bosulif; Pfizer) for the treatment of patients with chronic, accelerated, or blastphase Philadelphia chromosome– positive (Ph+) chronic myelogenous

leukemia (CML) who are resistant to or who cannot tolerate other therapies.

The approval was based on a single clinical trial of 546 patients with chronic, accelerated, or blast-phase CML. All patients were treated with bosutinib; their disease had progressed after treatment with imatinib (Gleevec) or

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia.

The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

with imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna), or they could not tolerate the side effects of previous therapy.

In patients with chronic-phase CML, 34% of those who had previously received imatinib achieved major cytogenetic response (MCyR) after 24 weeks

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%).

Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients.

However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

V-12-0095

6/12

2:17 PM

4

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

with bosutinib therapy; of those who achieved MCyR at any time, 52.8% responded for at least 18 months.

Among patients previously treated with imatinib followed by dasatinib and/or nilotinib, approximately 27% achieved MCyR within the first 24 weeks of treatment with bosutinib; of those achieving MCyR at any time, 51.4% responded for at least 9 months.

In patients with accelerated CML previously treated with at least imatinib, 33% had complete hematologic response and 55% achieved overall hematologic response within the first 48 weeks of treatment with bosutinib; the rates were 15% and 28%, respectively, in those with blast-phase CML. The most common side effects with bosutinib were diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, fever, and fatigue. (September 4, 2012)

FDA Expedited Approval of Xtandi for Prostate Cancer The FDA expedited the approval of the androgen inhibitor enzalutamide (Xtandi; Astellas Pharma/Medivation) for the treatment of metastatic castration-resistant prostate cancer (CRPC) that has spread or recurred in patients previously treated with docetaxel chemotherapy or with surgery. Enzalutamide is designed to interfere with the ability of testosterone to bind to prostate cancer cells.

Enzalutamide was approved 3 months ahead of its scheduled review.

The approval was based on a study of 1199 patients with metastatic CRPC who had received previous treatment with docetaxel. The median overall survival was 18.4 months for patients receiving enzalutamide compared with 13.6 months with placebo.

The most common side effects were weakness or fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, headache, upper respiratory infections, dizziness, spinal cord compression and cauda equina syndrome, muscular weakness, difficulty sleeping, lower respiratory infections, blood in urine, tingling sensation, anxiety, and hypertension. Approximately 1% of those receiving enzalutamide had a seizure and stopped taking it.

Enzalutamide is currently being tested in patients with early-stage prostate cancer. (August 31, 2012)

Zaltrap Newest Drug for Metastatic Colorectal Cancer The FDA approved the angiogenesis inhibitor ziv-aflibercept (Zaltrap; sanofiaventis/Regeneron) for use in combination with a FOLFIRI (folinic acid, Continued on page 7

VOL. 3

I

NO. 6

VALUE PROPOSITIONS The Number of Cancer Survivors on the Rise in the United States

NCCN Awards 5 Grants to Study Afatinib Efficacy in Several Solid Tumors

A recent report titled “Cancer Treatment & Survivorship—Facts & Figures, 2012-2012” was released earlier this year by the American Cancer Society, in association with the National Cancer Institute. According to this report, approximately 13.7 million Americans are alive in 2012 who have survived cancer. The researchers suggest that this number will reach 18 million by 2022. For this analysis, everyone who has ever been diagnosed with cancer by January 1, 2012, was counted as a cancer survivor.

Overall, according to this report, the numbers of new cases of cancer are decreasing, and the numbers of people who survive a cancer diagnosis are increasing in the United States, in part as a result of the aging population and the overall growth of the US population, and in part thanks to improved anticancer treatments. The authors of the report urge cancer CARE providers to pay greater attention to the needs of cancer survivors and their caregivers, including medical, psychological, and social needs.

“As more people survive cancer, it is vital that healthcare providers are aware of the special needs of cancer patients and caregivers,” said senior author of the report Elizabeth R. Ward, PhD, National Vice President of Intramural Research.

The most common types of cancer survivors among men are prostate cancer (43%), colorectal cancer (9%), and melanoma (7%). The 3 most common cancers among female survivors are breast cancer (41%), uterine cancer (8%), and colorectal cancer (8%).

The median age of patients at the time of cancer diagnosis is 66 years.

This may explain why the majority of cancer survivors are older people: 45% of all cancer survivors are aged ≥70 years. By contrast, only 5% are aged <40 years. Childhood cancer represents only <1% of new cancer diagnoses; however, it is the second leading cause of death in children, after accidents. In 2012, there are 58,510 survivors of childhood cancer in the United States, and 12,060 new cases are expected to be diagnosed by the end of the year. American Cancer Society; June 14, 2012.

The Oncology Research Program (ORP) of the National Comprehensive Cancer Network (NCCN) has recently awarded 5 grants to study the clinical efficacy of the investigational oral drug afatinib in various settings in solid tumors, including breast, non–small-cell lung (NSCLC), and head and neck cancers. The NCCN awards were funded through a $2-million grant provided by Boehringer Ingelheim Pharmaceuticals, the drug developer. Afatinib is currently in phase 3 clinical trials of patients with NSCLC, head and neck, and breast cancers.

“NCCN ORP is pleased to announce the funding of 5 new afatinib investigator-initiated clinical research studies to be conducted at NCCN Member Institutions,” said Diane Paul, MS, RN, Vice President of the NCCN ORP. “These 5 new studies add to the more than 60 studies that are currently enrolling through the NCCN Oncology Research Program. These studies, conducted by NCCN Member Institutions, not only create opportunities for patients to participate in important clinical research, but also make scientific discoveries more attainable.” NCCN; September 4, 2012.

A New Molecular Cervical Cancer Test Will Aid Accurate Diagnosis Quest Diagnostics, the leading provider of diagnostic testing, has introduced a new laboratory test that identifies molecular changes to cervical cells that may signal increased risk for cervical cancer. “Given that medical guidelines now advise less frequent cervical cancer screening for women, it is more important than ever that testing for this cancer be highly reliable,” said Daniel M. Jones, MD, PhD, Medical Director, Cancer Diagnostics Services, Quest Diagnostics. “Testing for abnormalities of the TERC gene is based on the most advanced scientific knowledge available of the molecular changes that turn cervical dysplasia into malignancy. It can potentially act like a ‘second opinion’ for the thousands of women whose Pap and HPV test results produce an indeterminate picture of cancer risk each year.”

This Cervical Cancer TERC test is based on the TERC gene marker that is under patent license from the National Institutes of Health (NIH). NIH research has shown that the TERC gene is amplified, indicated by an abnormal number of copies of the gene on chromosome arm 3q, in the precursor cells of cervical cancer; therefore, it may be useful in the identification of women at risk.

The test is designed as an adjunct to conventional Pap and human papillomavirus tests, and is performed on residual samples from Pap tests. The test may be particularly helpful in evaluating the 1.5 million American women whose Pap test shows low-grade squamous intraepithelial lesions. Because cervical cancer is often not symptomatic until advanced disease, accurate screening is crucial to detect early cellular abnormalities. Quest Diagnostics; August 30, 2012.

VOL. 3

I

NO. 6

Physical Activity Can Lower Risk of Invasive Breast Cancer The largest research to date on the potential link between diet, lifestyle, and cancer prevention shows that being physically active, including through activities such as brisk walking, exercising, and gardening can help to reduce the risk of invasive, estrogen-receptor/progesterone-receptor–positive breast cancer. This information is based on data from 257,805 women in the European Prospective Investigation of Cancer (EPIC) study that collects information on occupational, recreational, and household physical activity. After a median of 11.6 years of follow-up, more than 8000 cases of invasive breast cancer were identified. Analysis showed that women who were the most physically active had a 13% reduced risk of developing invasive breast cancer compared with those who were physically inactive. Moderate physical activity was associated with an 8% risk reduction for developing invasive breast cancer.

Previous research has estimated that <150 minutes weekly of at least moderate intensity physical activity was associated with increased risk of various types of cancer. Commenting on this new EPIC study, coinvestigator Timothy J. Key, MD, Director of Cancer Research, Epidemiology Unit, University of Oxford, UK, said, “This large study further highlights the benefits of being active—even moderate amounts. There is also a lot of evidence that exercise reduces the risk of bowel cancer. More research is needed on other types of cancer, and to investigate the mechanisms which could explain the links.”

Sara Hiom, Director of Information at Cancer Research UK, said, “While maintaining a healthy body weight and cutting back on alcohol remain 2 of the best ways of reducing our risk of breast cancer, being active can clearly play a role too—but doesn’t have to cost you money or too much time.” She noted that “Keeping active could help prevent more than 3000 cases of cancer in the UK every year.” Cancer Research UK; September 4, 2012.

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

5

In This Issue

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1882 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895

PALLIATIVE CARE

IN THE LITERATURE

Living life to the fullest, with cancer

Anastrozole-fulvestrant combination improves survival in metastatic breast cancer Newer, more effective anticancer drugs increase toxicity Intermittent androgen deprivation as effective as continuous therapy after radiotherapy

CONFERENCE Defining value in cancer care: AVBCC 2012 Steering Committee report

MASCC SYMPOSIUM Economics impede growth of supportive care services G-CSF agents prevent febrile neutropenia, but high cost limits utilization More….

Associate Publisher Cristopher Pires cris@engagehc.com 732-992-1896

Bosulif approved for Ph+ CML FDA expedited approval of xtandi Zaltrap newest drug for metastatic CRC More….

National Accounts Manager Zach Ceretelle Director, Creative & Design Robyn Jacobs

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments.

This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL Past President, ACCC Past Chair, NCCN Board of Directors

Contact Information: For subscription information please contact: circulation@valuebasedcancercare.com Telephone: 732-992-1538 Fax: 732-992-1881

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881

Craig Deligdish, MD Chief Medical Officer Oncology Resource Networks Orlando, FL

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved.

Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs eviti, Inc

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher.

Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

VALUE-BASED CANCER CARE

DRUG UPDATE

CONTINUING EDUCATION Considerations in lymphoma

VBCC Editorial Board

Quality Control Director Barbara Marino Business Manager Blanche Marchitto

6

Medicare proposes rewarding quality, cutting payments for oncology providers

Carfilzomib a new option for the treatment of patients with relapsed, refractory multiple myeloma

FDA UPDATE

Associate Publisher Joe Chanley joe@greenhillhc.com Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536

HEALTH POLICY

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

I

Ira Klein, MD, MBA Aetna Hartford, CT

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy Aetna, Hartford, CT

Mark J. Krasna, MD Medical Director, The Cancer Institute Principal Investigator, NCI Community Cancer Centers Program Towson, MD

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Crystal Kuntz, MPA Astellas Pharma US Washington, DC John L. Marshall, MD Director, The Ruesch Center for the Cure of GI Cancers Chief, Hematology and Oncology Associate Director, Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region Portland, OR

David Hom, MBA Solucia Farmington, CT

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Naimish Pandya, MD University of Maryland Baltimore, MD

SEPTEMBER 2012

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY Section Editor Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

VOL. 3

I

NO. 6

FDA Update Zaltrap Newest Drug...

Continued from page 4

fluorouracil, and irinotecan) chemotherapy regimen for the treatment of adults with metastatic colorectal cancer (CRC) whose tumors are resistant to or progressed after an oxaliplatincontaining chemotherapy regimen.

The approval was based on a randomized clinical trial of 1226 patients with metastatic CRC whose cancer grew while receiving oxaliplatin-based combination chemotherapy, or whose cancer was removed but returned within 6 months. Patients who received the ziv-aflibercept plus FOLFIRI combination lived an average of 13.5 months compared with 12 months in those receiving FOLFIRI plus placebo; tumor size reduction was 20% versus 11%, respectively. Progression-free survival was 6.9 months versus 4.7 months, respectively.

Zaltrap was approved with a boxed warning regarding the potential for severe internal bleeding and the development of holes in the gastrointestinal tract. The most common side effects were decreased white blood cell count, diarrhea, mouth ulcers, fatigue, hypertension, increased amount of protein in the urine, weight loss, decreased appetite, abdominal pain, and headache. (August 3, 2012)

tane (Aromasin) for the treatment of postmenopausal women with advanced hormone-receptorâ&#x20AC;&#x201C;positive, HER2-negative breast cancer, who had disease recurrence or progression after receiving letrozole (Femara) or anastrozole (Arimidex). The approval was based on a study of 724 postmeno-

pausal women with estrogen-receptorâ&#x20AC;&#x201C;positive, HER2-negative advanced breast cancer that had spread despite previous therapy with letrozole or anastrozole. Patients randomized to the everolimus plus exemestane combination had a 4.6-month improvement in the median time to dis-

ease progression or death compared with those receiving placebo plus exemestane.

Everolimus is already FDA approved for the treatment of patients with advanced renal-cell carcinoma that has progressed after treatment with other cancer therapies. (July 20, 2012) â&#x2013;

Carfilzomib Added to Multiple Myeloma Therapies The FDA approved the proteasome inhibitor carfilzomib (Kyprolis; Onyx Pharmaceuticals) for the treatment of patients with multiple myeloma who have received at least 2 previous therapies that include the proteasome inhibitor bortezomib (Velcade) and one of the immunomodulatory drugs, thalidomide (Thalomid) or lenalidomide (Revlimid).

The approval was based on a clinical trial with 266 patients with relapsed and/or refractory myeloma who had received at least 2 previous treatments, including bortezomib and one of the immunomodulatory drugs, thalidomide or lenalidomide. The overall response rate in this study was approximately 23%, with a median duration of 7.8 months.

Serious side effects included heart failure and shortness of breath. The FDA notes that patients should be closely monitored for these serious side effects and that treatment with carfilzomib should be withheld when such effects occur. (July 22, 2012)

Afinitor Gets the Nod for Metastatic Breast Cancer The FDA approved the mTOR inhibitor everolimus (Afinitor; Novartis) for use in combination with exemes-

VOL. 3

I

NO. 6

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

7

In The Literature Anastrozole-Fulvestrant Combination Improves Survival in Metastatic Breast Cancer The addition of fulvestrant—which downgrades the estrogen receptor—to the aromatase inhibitor anastrozole enhances progression-free survival (PFS) and overall survival (OS) in

postmenopausal women with hormone-receptor (HR)-positive metastatic breast cancer compared with anastrozole monotherapy, according to results of a new study (Mehta RS, et al.

N Engl J Med. 2012;367:435-444).

The Southwest Oncology Group (SWOG) study randomized 707 post-

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other.

Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation.

System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim.

Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim.

The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading.

Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta.

• Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity.

Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice.

Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

menopausal patients with previously untreated HR-positive metastatic breast cancer to anastrozole alone (N = 345) or to a combination of anastrozole plus fulvestrant (N = 349). All patients received 1 mg of anastrozole; those in the combination therapy group also received a 500-mg loading dose of ful-

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred.

Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).

Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk.

Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11).

The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

65481-R1-V1

vestrant on day 1, followed by 250 mg on days 14 and 28, and every 28 days thereafter. Patients in the anastrozolealone group whose disease progressed were strongly encouraged to cross over to receive fulvestrant alone. Early in 2011, when the higher group (500 mg) of fulvestrant was approved by the US Food and Drug Administration (FDA), all patients were allowed to receive the 500-mg dose as well.

In the SWOG study, the median PFS was 15.0 months with the combination therapy and 13.5 months with anastrozole alone, representing a significant difference (P = .007); the OS was 41.3 months with anastrozole alone and 47.7 months with the combination therapy, also a significant difference (P = .049), even though 41% of these patients crossed over to fulvestrant after progression. This is the first study of first-line hormone therapy used for HR-positive metastatic breast cancer that shows an improvement in OS, not just PFS. It is also the first study to show the superiority of concurrent therapy with 2 hormonal modulators over monotherapy, especially an improvement in OS. Toxic effects were mild and similar between the 2 groups. However, more patients who received the combination therapy discontinued treatment because of toxicity.

Newer, More Effective Anticancer Drugs Increase Toxicity, Requiring Individualized Approach to Therapy The FDA approval of new drugs for advanced solid tumors is relying heavily on demonstration of increased survival duration in phase 3 clinical trials.

Most trials, however, are not designed to detect differences in quality of life (QOL) or in toxicity levels. A new metaanalysis reviewed pivotal clinical trials that have led to FDA approval of new anticancer drugs focusing on QOL outcomes in 3 areas—treatment-related differences in grade 3 or 4 adverse events (AEs), treatment discontinuation, and toxic deaths (Niraula S, et al. J Clin Oncol. 2012;30:3012-3019).

This meta-analysis included 38 randomized controlled trials of targeted drugs or chemotherapeutic drugs approved by the FDA for the treatment of cancer in the United States between 2000 and 2010, excluding supportive care drugs. Overall, the newer drugs had greater odds of resulting in toxic deaths than the comparator therapy of nontargeted drugs (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.15-1.70; P <.001) and greater odds of treatment discontinuation (OR, 1.33; 95% CI, 1.22-1.45; P <.001). Grade 3 or Continued on page 22

8

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

VOL. 3

I

NO. 6

Palliative Care

Living Life to the Fullest, with Cancer...

Ms Berman: I am a registered nurse and a senior program officer at The John A. Hartford Foundation in New York, which is focused on improving the healthcare of older Americans by providing experts who are capable of supporting good quality care for older adults and by developing models of care that look at how the healthcare system supports good care. We focus on supporting good quality care, and examine the ways that we need to reconfigure, for example, transitions between hospital care and home-based primary care.

I lead the foundation’s area called Integrating and Improving Services, which is focused on developing, testing, and disseminating innovative and cost-effective models of patient care that improve both health and cost outcomes related to older adults.

Approximately 22 months ago a red spot appeared on my right breast. I immediately went to my primary care physician. I had read an article long before that red spot appeared, and therefore I thought that I might have inflammatory breast cancer. My primary care physician was equally concerned when she saw what I saw, and she made an appointment for me to have a biopsy and a localized scan.

The results came back that I did in fact have inflammatory breast cancer.

When they did a body scan, they found that it had already metastasized to my lower spine.

Most people are diagnosed with cancer at an early stage, but I was diagnosed at the final stage, which is stage IV. Although we have preventive measures and breast self-examinations, this particular type of cancer does not appear as a lump and therefore is hard to diagnose. It is “floating,” so to speak, and only when it aggregates and clogs up the lymphatic system does it begin to appear on the skin. That is why my cancer, which is a rare form of cancer, is typically only diagnosed at stage III or IV. I am fortunate that I feel good, even 22 months after my diagnosis. I am, indeed, very fortunate, and these 22 months have been tremendous. But if I had made different decisions in the past 22 months, it would not have been a very pleasant period.

When I was first diagnosed, I read about this particular cancer and had discussions with my oncologist in New York. There are no cures for this type of cancer. My cancer has particularly poor prognosis, with the worst outcomes among the different types

VOL. 3

I

NO. 6

of breast cancers. The literature suggests that 87% of all patients with breast cancer survive for 5 years or more. Yet only 40% of all patients with inflammatory breast cancer live for 5 years. And for those, like me, diagnosed with stage IV inflammatory breast cancer, only 11% live 5 years.

So, unfortunately, my cancer is the one type that skews the statistics for breast cancer.

Once diagnosed, I had 2 very different oncologists. I have the ability to seek out treatment anywhere in the country, and I had read the research literature. With the support and blessing

Continued from cover

I wanted: to live the best possible life for as long as possible, and not to ruin my quality of life. I wanted what I call the “Niagara Falls trajectory”—good, good, good, and then drop off the cliff.

I want to maintain the ability to work, to enjoy my family, to travel, and to live life well for as long as possible. I am a quality-of-life person. I think that comes from working in geriatrics, where we see what it means to have poor function, pain, and poor quality of life. What these people want is someone to attend to those needs, not just to focus on the outcome in terms of days of life.

“I wanted what I call the ‘Niagara Falls trajectory’—good, good, good, and then drop off the cliff. I want to maintain the ability to work, to enjoy my family, to travel, and to live life well for as long as possible. I am a quality-of-life person. I recently climbed the Great Wall of China.

I bike, I ride, and I swim.” of my own oncologist, I decided that I would leave her and visit an oncologist who was focused on this particular type of cancer, because it is so rare; only approximately 1% to 2% of all breast cancers are of this particular type. My local oncologist and I wanted to see whether there were treatments that perhaps were not yet in the literature. It takes a while for findings to make it into the literature, and reading the literature is not necessarily going to provide the best picture of everything that may be in the early state of research.

My oncologist in New York knew that if what I had read in the literature held true, my focus would be on what

So I got a set of slides containing my biopsied cancer cells from my oncologist and went to visit the specialist oncologist. He performed a physical examination, and suggested that I have a very intensive course of chemotherapy, as much as the body could stand. After that he suggested that I undergo a mastectomy, followed by radiation, and then return once again to that very, very intensive chemotherapy. He said that this is what he did for all of his patients with this type of cancer.

I asked him, “If it’s already spread to my spine, why are we doing a mastectomy? You can’t remove it at this point. If it’s in the bone, every drop of

SEPTEMBER 2012

I

my blood is perfused through the area. It’s already spread.” He said, “Well, you don’t want to look at the cancer, do you?”

To me, whether I look at the cancer is not very important. I worry more about having lymphadenopathy and not being able to use my right arm or my right hand, because I rely on them for my work. Removing the cancer is not a cosmetic issue for me. I am more concerned with what the treatment outcomes would be.

I asked him why he would do this very aggressive version of treatment.

Again, he said this is what he did for all his patients. This, to me, is not a patientcentered oncologist. I didn’t find him to care about what my values are. Still, I am sure that he was doing what he felt was the best possible medicine. It just was not the best possible care.

VBCC: Did he ask you what your preferences were? Was this open to discussion?

Ms Berman: No, it was not. This physician believed that his aggressive approach was the best that he could offer. I do not believe that it was done for any reason other than that he believes this is the best that one could do in fighting the cancer. But this is not necessarily the best that one could do in supporting the patient. If my values are different—if I really want to maintain my quality of life—then following his suggestions would mean that I would be stripping down the quality of life that I have now and, according to the research, would not benefit later.

A brilliant physician colleague provided a great analogy. If this were a bank account containing my quality of life, I would be withdrawing everything that is in my account now. If I am doing that knowing that I am going to have deposits coming back in later, that’s a really good plan. But if I don’t believe that that is going to happen, or if the science does not show that I am likely going to get a benefit from this, then I have basically emptied out my account of quality of life and I have nothing to show for it, which to me is not a good plan.

VBCC: What happened then?

Ms Berman: Based on the information that I had and my goals, I determined that the best approach for me was one that would support optimizing my quality of life for as long as possible. I returned to my oncologist in New York, who put me on a different treatment regimen.

Continued on page 10

www.ValueBasedCancerCare.com

9

Palliative Care

Living Life to the Fullest, with Cancer...

I am not foregoing treatment. I am receiving treatment, but that treatment does not have the same level of side effects and the kinds of problems I would have if I opted for the treatments suggested by the other oncologist. My treatment involves hormonedepletion therapy. I am taking a pill at night. I also receive infusions to support the health of my bones.

I am doing very well with this treatment, and the side effects are very much under control. I recently climbed the Great Wall of China. I bike, I ride, and I swim. Life is really quite good, and I think it would not have been had I chosen a different option. People go through those other forms of intensive treatment to get a benefit down the line, but there is nothing in the literature to suggest that I would gain any better benefit down the line. The tradeoff now would be the only thing that would occur, and that would not be a good option to me.

I have been very happy with the plan that my doctor in New York laid out. I am able to speak and write about this on behalf of many people, patients in my situation who do not have enough information to make the kinds of decisions that are really important.

When patients are grappling with serious illness, they need to be able to understand what the trade-offs are for the different treatments. They need to understand what the impact would be on their current health status. Many patients who are grappling with these problems—63% of patients with cancer—are older adults. They have other problems as well, and typically 45% of them have multiple chronic diseases.

A patient who already has other health problems and then cancer is being added as well, that patient must understand both the potential benefits and negative impacts of the different treatment options to make a choice based on the patient’s goals and values. For me, who has no other health issues, but simply because of the nature of the advanced state of my disease, it was very clear what the decision would be.

VBCC: What is missing from the treatment paradigm today for patients with cancer?

Ms Berman: Palliative care must be an integral component of cancer care.

Oncologists must understand what the main needs of their patients are. We cannot assume that people necessarily want to pursue a curative approach in a noncurative situation. We often create a mismatch by supporting the

10

patient’s fight, but perhaps the wrong fight. Oncologists need to ask patients what their goals of care are, talk honestly about their health, and understand all aspects of their health.

Patients need to understand what the prognosis is for them, what is the likely outcome of chemotherapy, radiation, and all the other curative components of care.

Amy J. Berman, BS, RN

“Palliative care must be an integral component of cancer care. Oncologists must understand what the main needs of their patients are.

The healthcare system treats a diagnosis, but it typically does not treat the patient.”

If patients are not given a clear picture of all the options surrounding their care, including the financial aspect, it is very hard for them to be part of that decision and to ensure that their decisions will actually meet their needs.

VBCC: You are clearly very resourceful, and you have access to information that many patients do not have.

How should oncologists provide the information that would allow patients to make the best decisions?

Ms Berman: It would be helpful for patients to have very clear information about their diagnosis, which I think most patients do get, as well as much clearer information about their prognosis and the likely course of the disease, which many patients do not get.

We then move into even muddier territory, which is what the different types of treatment protocols are that each patient could have, and what would be the likely impact of each treatment on their health now, what

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Continued from page 9

would be the benefits later, as well as what the costs are.

We need to give enough information so that patients can participate in making the choice about which path is right for them. In today’s medical record, electronic or paper, there is typically no place to note what a person’s goal of care is. What are we trying to do? What is important to us?

The healthcare system treats a diagnosis, but it typically does not treat the patient.

For patients to participate fully in making the treatment decisions—and there’s nothing more important than this—patients and providers need a shared understanding of 3 key pieces of information: the diagnosis, the prognosis, and the patient’s values.

Then patients and providers need to discuss the different pathways of treatment. Patients must be provided with basic information. What is the treatment going to do for me and how is it going to make me feel now? What is it going to mean later? And what will the cost be? If we don’t provide this information, then we are denying the patient the ability to make informed decisions.

In my case, the particular choice that I made follows one of the treatment options recommended by the National Cancer Institute (NCI) on their website (www.cancer.gov/cancertopics/fact sheet/Sites-Types/IBC). This option is there, as is the other, more aggressive pathway. The NCI lists several treatment options for a patient with inflammatory breast cancer.

I believe that there are no wrong decisions, only informed decisions.

Not everyone should choose what I chose, but people need to be supported so they can make informed choices. Today, healthcare often lacks attention to the patient’s choice and to quality of life in general. Success in cancer care is viewed in terms of 3month increments of longevity. We measure whether we have a longer life: everything is focused on the length of life. Although those are important data, they are not everything. If we have stripped quality of life from people, and we give them an extra 3 months of bad life, that may not be a good trade-off.

VBCC: What needs to happen to promote a paradigm change in oncology?

Ms Berman: At the beginning of any serious illness, palliative care needs to be an integral partner in the care plan. Typically, palliative care providers are going to be concerned

with that person’s goal and with the needs of the family. They are going to be focused on pain and on symptom management, and they are going to be more focused on the person than on the disease. Some people will opt to go for an entirely palliative approach. Other people simply need palliative care as a companion toward that curative care. Palliative care should be brought in at the very beginning of any serious illness.

Today, 80% of large hospitals have palliative care services. Palliative care in the community can be found online at www.GetPalliativeCare.org. On that site, one can choose a state and find local palliative care teams in the community. It does not necessarily have to be in an oncology center; it could be related to other disease states.

Whether the care is provided in partnership with curative care or with support of problems that are not necessarily going to be resolved, palliative care should be brought on at the onset of any serious illness.

An article published in the New England Journal of Medicine (Temel JS, et al. N Engl J Med. 2010;363:733-742) concerning lung cancer showed that when palliative care consultation started at the beginning of treatment, patients had better outcomes. They had a better quality of life, and they also lived longer, which was a surprise to many oncologists; they did not understand that palliative care could actually lengthen life.

That reason may be that palliative care keeps people out of the hospital.

Immunosuppressed people who go into the hospital can acquire secondary infections. It could be for different reasons, but simply addressing people’s pain and symptoms is supportive of a better and longer life. I am certainly proof of that.

Palliative care is an extra layer of support that helps people manage their pain and symptoms. Palliative care can happen with curative care to help resolve nausea or pain that may be attributed to the treatment itself, not just the disease. Palliative care goes hand in hand with any serious illness that has accompanying pain and symptom issues. It focuses on the needs of the patient and optimizing that patient’s functioning.

VBCC: There is evidence in other fields that when a person feels well or the quality of life is better, people do better overall. Has this been your experience?

Continued on page 11

VOL. 3

I

NO. 6

Prostate Cancer

Observation as Good as Radical Surgery for Localized Prostate Cancer, Especially Low-Risk Cancer

By Phoebe Starr

I

n this era of upwardly spiraling healthcare costs, the management of low-risk prostate cancer is changing. Although approximately two thirds of men with a diagnosis of prostate cancer have a low prostatespecific antigen (PSA) value or lowrisk disease, approximately 90% of these men receive early intervention, with surgery or with radiation.

Findings from a new study from the Minneapolis Veterans Affairs Health Care System suggest that localized prostate cancer, especially low-risk cancer, can be safely managed by observation alone.

Radical prostatectomy was not significantly better than observation in preventing death from any cause, including prostate-specific death, in men with localized prostate cancer that was detected by PSA, according to the large, randomized Prostate Cancer Intervention Versus Observation Trial (Wilt TJ, et al. N Engl J Med. 2012;367: 203-213).

“Our findings add to evidence supporting observation, and possibly active surveillance, for most men who receive a diagnosis of localized prostate cancer, especially those with a low

PSA value or low-risk disease,” wrote the investigators.

Between November 1994 and January 2002, 364 patients were assigned to radical prostatectomy and 367 to observation. All patients (aged ≤75 years) had histologically confirmed localized prostate cancer of any grade diagnosed within the previous year, PSA <50 ng/mL (median at baseline, 7.8 ng/mL), a negative bone scan, and a life expectancy of at least 10 years from randomization. All the men underwent a biopsy to confirm the PSA-based diagnosis. Men assigned to observation were offered palliative therapy or chemotherapy for disease progression.

Based on review of biopsy specimens, 48% of the patients had Gleason scores of ≥7 and 66% had intermediate- or high-risk cancers.

Over a 12-year period (median follow-up, 10 years), 47% of the men who were assigned to radical prostatectomy died versus 49.9% of those assigned to observation alone, for a nonsignificant absolute risk reduction of 2.9% for surgery. The rates of prostate-specific cancer death were 5.8% for surgery versus 8.4% for observation alone, a non-

significant 2.6% absolute risk reduction favoring surgery.

The effect of radical prostatectomy did not differ by age, race, performance status, coexisting illness, or histologic features of the tumor. Radical prostatectomy appeared to be superior

This study adds to the evidence supporting observation, and possibly active surveillance, for most patients with localized prostate cancer, especially those with low-risk disease.

to observation in reducing death from any cause among men with a PSA value >10 ng/mL and in those with intermediate- or high-risk tumors.

“Our study was conducted in the early era of PSA testing. The current practices of performing repeated PSA testing, using a lower PSA threshold for biopsy, obtaining more tissue-biop-

Living Life to the Fullest, with Cancer...

Ms Berman: Certainly. If somebody is having very difficult pain and symptoms, it further compromises them. It is detrimental to their body, and it is also protective when people are able to work, to socialize, and to feel well. So, yes, palliative care is extraordinarily important, and it should be a very basic part of advanced illness care. But today it is not a requirement in cancer care. It should be.

VBCC: Has palliative care received enough attention by cancer organizations and by oncologists?

Ms Berman: There is a growing recognition of its importance. I was recently asked to speak to the Institute of Medicine. They are doing a study on cancer and older adults, and this was a big part of their discussions. There is a growing recognition of the need for palliative care to be part of routine cancer care. The American Society of Clinical Oncology has recently issued recommendations to that effect (Smith

VOL. 3

I

NO. 6

TJ, et al. J Clin Oncol. 2012;30:880-887.

Epub 2012 Feb 6).

VBCC: Is there anything else that oncologists and other team members should consider in this context?

Ms Berman: I have not mentioned that many of the medications and the approaches that we take are not well tested on older adults. We need to do more research in this area to ensure we address the needs of people with multiple chronic diseases, and to recognize that this population is the eye of the storm. Of all patients with cancer, 63% are older adults. This group is doubling and will skew older in the next decade. This is the baby boom generation, with 10,000 people turning 65 years old every day. We are not doing a good job in clinical trials of testing treatments on people with cancer coupled with other comorbidities. This is the norm for cancer. Why is it an exclusion in trials? We need to look at the medications and ap-

sy cores, and performing a repeat biopsy…increase the detection of smaller volume indolent cancers,” the investigators wrote. These factors lead to overdiagnosis and overtreatment, they noted.

Among men with intermediaterisk (ie, PSA of 10.1-20 ng/mL; a Gleason score of 7; or a stage T2b tumor) or high-risk prostate cancer, surgery reduced all-cause mortality by 10.5% compared with observation; however, in patients with low-risk disease, observation was favored over surgery.

For prostate cancer–specific mortality, surgery had an advantage compared with observation in men with a PSA value >10 ng/mL at diagnosis and among men with high-risk prostate cancer. No advantage was found with surgery versus observation in men with a PSA value <10 ng/mL. Perioperative complications in the first 30 days after surgery were reported in 21.4% of men who underwent a radical prostatectomy. At 2 years, urinary incontinence and erectile dysfunction rates were significantly higher with surgery than with observation. ■

Continued from page 10

proaches to manage those multiple conditions and cancer.

When diagnosed with cancer, many people forget everything else and only focus on the cancer. That is not helpful to them. It does not support good quality of life or good quality of care.

We need to focus on the needs of the whole human being. Cancer is a part of the picture, but it is never the whole picture.

And last, I would like to take this opportunity to personally thank oncologists, radiologists, palliative care providers, nurses, and anyone involved in cancer care for what they do for people like me. I know that their efforts are focused on doing the best they can for their patients. But the world is changing. Patients want to take a bigger role in their care. It is important to provide more information rather than less; this will give patients the ability to make the choices that are right for them. The one-on-one patient and provider dialogue usually

SEPTEMBER 2012

I

goes in one direction only. Providers need to ask questions about what the patients want. They align care with those values.

We must make sure that every patient is fully informed to the degree that they want information. Some will not want to know. Some may want it conveyed to their families. Your job is to invite the patient into the conversation. This is vitally important, especially with the aging demographic.

Many patients are not going to benefit from their treatments. We may be putting physical and financial burdens on them that may not be necessary. Oncologists must ensure that they are informing patients as much as possible so that they make choices that are good for them. This sounds simple, and yet I know that this is a very difficult thing; it is a change for many providers. “Fight, fight, fight” should be “fight, fight, for what?”

In my case, it’s going to be fight for quality. ■

www.ValueBasedCancerCare.com

11

2012 Conference

AVBCC 2012 Steering Committee CO-MODERATORS

STEERING COMMITTEE MEMBERS

Gene Beed, MD President and CEO Horses, Zebras, and Unicorns Irvine, CA

Gary M. Owens, MD President Gary Owens Associates Glen Mills, PA

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern Univ.

Ira M. Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Oncology Strategy Hartford, CT

Samuel M. Silver, MD, PhD, FACP Professor of Internal Medicine Hematology/Oncology Associate Director, Faculty Group Practice, University of Michigan Medical School, MI

Roy A. Beveridge, MD Chief Medical Officer McKesson Specialty Health/The US Oncology Network The Woodlands, TX

Jennifer Malin, MD, PhD Manager and Medical Director of Oncology WellPoint Los Angeles, CA

John D. Sprandio, MD, FACP Chief Physician Consultants in Medical Oncology and Hematology Drexel, PA

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL

Matthew Mitchell, PharmD, MBA Manager Pharmacy Services SelectHealth Salt Lake City, UT

F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Co-Founder, Bentelligence Sharon, MA

John Fox, MD, MHA Associate Vice President for Medical Affairs Priority Health Grand Rapids, MI

Lee N. Newcomer, MD Senior Vice President of Oncology Services UnitedHealthcare Minneapolis, MN

Defining Value in Cancer Care: AVBCC 2012...

The mission of the conference was to align the various perspectives around the growing need of defining value in cancer care and developing strategies to enhance patient outcomes. The AVBCC conference presented a forum for the various viewpoints from all the stakeholders across the cancer care continuum, featuring more than 20 sessions and symposia led by nearly 30 oncology leaders. The discussions focused on current trends and challenges in optimizing value in oncology by reducing or controlling cost while improving care quality and patient outcomes, introducing

12

emerging approaches to management and tools that providers and payers are using to enhance cancer care collaboratively.

The AVBCC Second Annual Conference was opened by a Steering Committee discussion of 11 panel members who attempted to define value in cancer care and articulated action steps that can help to implement value into cancer care delivery. The following summary represents highlights from the Steering Committee discussion, which was moderated by Gene Beed, MD, and Gary M. Owens, MD.

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Gary M. Owens, MD: The 2 target concepts we need to consider during this Steering Committee discussion are “value” and “action.” Our goal is to define what is value in cancer care, and how is that value different for a payer, a clinician, and, of course, the patient. But we also must include other stakeholders, such as employers and the government, who pay for the care. In addition, we want to develop concepts and ideas that are actionable, ones that we can ultimately transfer into true action steps.

One thing that complicates the approach to cancer is that it is not a single disease but a collection of very different diseases.

Heterogeneity is the hallmark of cancer. At the same time, there are similarities in the issues that concern patients with cancer, related to costs and outcomes. Currently, the most robust area in the drug pipeline is oncology. There are almost twice as many specialty oncology agents in the pipeline as there are other specialty agents for all of the

Continued from cover

other diseases combined. So we are on this cusp of innovation. We are seeing innovation in cancer diagnostics, which parallels the types of therapies being developed, and we are now able to do testing to tailor treatment for certain genetic mutations and expression of genes.

We need to mold that innovation into what it means for patient care, what it means to those who pay for it, and what it means for those who provide that care.

That is how we are going to open the discussion for the Second Annual AVBCC Conference.

Gene Beed, MD: We are going to discuss the changing epidemiology of cancer toward patient-centered medicine. This means personalized medicine and the economics of cancer care. For example, what does this mean in terms of innovation, or when cancer becomes a chronic disease?

Our overarching mission today is to focus

VOL. 3

I

NO. 6

2012 Conference

on the issues that are most important to promoting value-based cancer care—quality, costs, policy, regulation, and patient access.

What is value in cancer care? I can say that it is quality divided by cost, but those are not quantifiable terms that we can all agree on. What is quality, and quality in the eyes of whom? If there are barriers related to cost, then the question arises who will pay for the care. Are we just all going to pay more for healthcare, or spend less on other conditions? Are we going to indebt the next generation, stifle innovation, ration care? What are our options?

Perceptions of value differ throughout the healthcare industry. For manufacturers, efficacy, total patient outcomes, and unmet medical needs determine value. This is in marked contrast to how health insurance companies, employers, and regulators define value, which concerns longevity, quality of life (QOL), and cost. Cost is a key part of the value equation, regardless of what part of the healthcare industry is involved. Why is defining value in cancer care more challenging than defining value in other areas of medicine?

Value in cancer care is challenging for 2 reasons.

One reason is the clinical situations in which patients present. And the second reason is the cost of drugs.

—John D. Sprandio

John D. Sprandio, MD, FACP: Value in cancer care is challenging for 2 reasons. One reason is the clinical situations in which patients present, depending on their state and their variable frame of reference in terms of their goals and their understanding of the situation. And the second reason is the cost of drugs. Cancer care is uniquely complex. This is not to say that in other areas of medicine cost is not complex, but cancer presents a uniquely complex situation.

VOL. 3

I

NO. 6

Samuel M. Silver, MD, PhD, FACP: I agree wholeheartedly that there are 2 issues here. One issue is indeed the complexity of oncology.

When I talk about quality-of-care issues to nononcology audiences, they say, “So what is the problem? We talked to our cardiovascular colleagues, and we have it down.” And, they partly have it down.

If you have to treat a myocardial infarction (MI), that involves a single organ.

It does not make a difference how the patient got the MI, only that that patient has MI. There are not 4 stages of the disease. It is not estrogen receptor– positive or progesterone receptor–positive; it is not HER2-negative or HER2positive. It is not all of these various silos. The science of cancer is complex, with multiple diseases and with multiple presentations of a single disease.

Second, because we have so many silos and our cardiovascular colleagues do not, they can have hundreds or even thousands of patients in randomized trials looking at a single point. In cancer, we do not have these numbers of patients. Therefore, the science becomes more difficult for comparative effectiveness analyses.

It is very difficult to determine the degree of improved efficacy and total patient outcomes in oncology. It also depends on where and how we are looking. What does cost mean for the patient? Value is not about the total cost of management, it is about the cost that we bear personally. Some of us are only seeing a part of the costs, and some of us see more of them.

This also varies from patient to patient, depending on their insurance.

The value equation changes depending on the outlook of just that one variable.

Improved patient QOL—whether we define that in terms of years of life or quality per se—is the metric that has to be the most important. And the next is total patient outcomes.

Craig K. Deligdish, MD: For the purpose of this discussion, I would disagree with my colleagues for a couple of reasons. We have been treating cancer for many years. I think we must ask, “What has changed during this time?”

Why would the definitions of value, quality, or outcomes be different today from what they were 10, 20, or even 30 years ago?

The difference today is in the cost of treatment. The cost of treatment today is drastically different from what it was 10, 20, or 30 years ago. By contrast, I do believe that we have made a dramatic impact on the survival of patients with cancer. At the end of the day, one of the

important questions that a physician and a patient need to answer is, “Do I have a curable form of cancer? Can the patient be cured?” And a second important question is indeed about QOL, which is even more important when the patient does not have a curable disease. That question must be answered in the context of defining “quality” and “value.”

Next, we need to consider all of the treatment and diagnostic tools that are available to us today, compared with those that were available 10 or 20 years ago. What have they contributed in terms of value, quality, and cost? We also need to talk about how we define efficacy. We need to factor all of this information into what ultimately is the definition of value. Is a diagnostic tool or a treatment efficacious if it extends survival by 1 or 2 months? Clearly, taking a pill that has few side effects and cures an otherwise terminal disease (eg, Gleevec) has high value, whereas a drug that costs $30,000 a month and allows us to live 1 month longer has less value.

In terms of value, the definition is to some degree based on whether value is being defined by the patient or by the payer. As we all know, it frequently is neither the provider nor the patient who is paying for treatment. Is the government paying, the employer, or the insurance company, or is the patient paying for the treatment? And this is tantamount to defining the issue of value. We must also consider whether it is going to result in an improvement in QOL, make the patient feel better, or cure the patient’s disease.

Al B. Benson, III, MD, FACP: I would agree that in terms of value, the central focus must be on the patient’s perspective. For patients whose disease could be cured, the goal is cure and living a long, productive life. I think that is how most patients would define value. Financially, this is very difficult from a patient’s perspective, because in many cases the patient is divorced from the outlay of funds that cover the true cost. Although we are talking about tremendous problems with uninsured patients, copays, and so forth, over time most patients with cancer end up in a situation that they would not experience in any other aspect of their daily life in terms of potential catastrophic costs and life-threatening illness.

Normally, if you purchase any product, you have to cover that cost.

Within the overall complexity of oncology, value is somehow distorted for many patients, because they are not paying the full cost of the service.

Another fundamental problem with

SEPTEMBER 2012

I

Within the overall complexity of oncology, value is somehow distorted for many patients, because they are not paying the full cost of the service. Another fundamental problem with value is that over time we are seeing significant technological advances in all aspects of care that may not be optimally defined in terms of utilization.

—Al B. Benson, III

value is that over time we are seeing significant technological advances in all aspects of care, whether it is in diagnosis, in imaging, or in treatments, that may not be optimally defined in terms of utilization yet can drive up costs and at the same time have the potential to extend life.

There is so much we do not understand about cancer biology, and, as the technology advances, we have been unable to study the technology at its maximum to truly define value. For example, for cancer surveillance, we now talk about survivorship and how we monitor patients over time. The literature is very sparse in terms of defining what is appropriate surveillance. In my area of expertise, which includes colon cancer, there have been some metaanalyses done, but that is the exception.

Overall, we need evidence to decide how to maximally use imaging, how to define risk, which patients are at risk, and how to monitor patients over time.

And if we diagnose a tumor recurrence, for example, what can we do to help that patient further?

The same is true for drugs—the way we study most drugs now remains empiric. We do not have the selection tools Continued on page 14

www.ValueBasedCancerCare.com

13

2012 Conference

Defining Value in Cancer Care... that we need to demonstrate true value.

As we develop markers, we are certainly making some progress. We have seen this in diseases such as leukemia, breast cancer, and to some extent, colon cancer.

When we talk about value and cost, survival benefit demonstrated in clinical trials shows proof of principle, that this given intervention works, but we cannot define how it works maximally in each individual patient. Because of the way we design these large trials—in most of them we are giving treatment to a large proportion of patients who will absolutely not benefit from that treatment—we cannot select out the patients who, in fact, truly benefit from the therapy, thereby reaching the ultimate goal for the individual patient.

Roy A. Beveridge, MD: The topic of adjuvant therapy versus palliative therapy is directly relevant here. The value for these types of therapy is different. I do not know of many biopharmaceutical companies that believe that improved longevity of a patient is not very important, because everything related to drug design right now is related to making patients live longer. In terms of personalized medicine, identifying particular patient populations is among the major goals.

By contrast, the US Food and Drug Administration (FDA) has indicated a lack of interest in QOL improvements.

That may be something that the FDA may aspire to in the future, but this has not been relevant so far to any major drug development approvals.

Dr Beed: From the payer’s perspective, how do you respond to what people have said so far about value, and how is it perhaps different from that of clinicians?

Dr Silver: Fundamentally, value relates to people agreeing that something has equivalent value; there is an exchange that goes on. But in cancer care, that equation does not work, because the consumer is not the payer.

I may not agree that this has the same value as something else, but I am constrained, because I cannot set the prices. I cannot decide on the prices of treatment, and I am restrained by state laws that force me to pay for something, even though I do not think it has value.

Therefore, we have a fundamental challenge in defining what value is in cancer care.

We have a challenge defining value in all of medicine. For example, there are new transaortic valve replacements that cost $35,000 for a valve—$60,000 total compared with $8000 for a typical

14

valve replacement. These new valves provide an additional 18 months of life for a patient who has less than 1 year of life expectancy. We have the ability to negotiate those prices. But in cancer care, we do not have the ability to negotiate that, because there are typically monopolies, at least early on, with the release of a new drug and a new drug category.

There is hope that in the era of biomarkers there would be enhanced value, because at least we would not be spending money on drugs that were not going to benefit a patient. But with tumor biology that involves escape mechanisms, it is not clear that it is going to provide a long-term benefit. Even with the recent study that was published in the New England Journal of Medicine showing that there is a lot of tumor heterogeneity, within any given tumor there may be multiple tumor types. We just happened to pick one, because that is what we biopsied. So even the role of biomarkers is now coming into question, especially in relation to the current economy.

The challenge is that we do not compare the value in producing 1 year of life or a QOL year in the same way that we compare it to people with heart disease. We may pay $80,000 a year to a patient with multiple myeloma, which is now a chronic disease, and that person may live for another 2, 3, or 4 years, but we do not have discussions about this—what is 1 year of life worth?

At the same time, we are making tradeoffs as a society, because in the state of Michigan we are closing schools and are not paying for teachers. This is a challenge for us as oncologists, because at the end of the day we have to make choices on where we put our money, and we are not having a dialogue about where we should spend those dollars.

Dr Beed: You raise a very good point.

One way that oncology is different from the rest of medicine is that just a generation ago we did not even use the word “cancer” with our patients. This is very different from most diagnoses. We did not talk about cancer, and we did not mention the diagnosis.

Now we want to talk about the value of 1 year of life, QOL, and what the patient’s out-of-pocket copay is.

Matthew Mitchell, PharmD, MBA: You asked what makes cancer different from other categories of management.

From my perspective, some of the biggest issues are the regulatory and government mandates in oncology. Nothing comes close to cancer care, and when we tie that with the amount of money that is tied to oncolytics, that is where the

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Continued from page 13

think we can define value in many different ways, but that is the basic premise.

Dr Beed: There is some disconnect between, “The value of an extra month of life in a clinical study does not show what this drug can really do in the real world in my hands,” versus “It’s not a free market.

There is no ability to negotiate.” What is the value for the cost that is being paid with someone else’s money?

We have to ask what is efficacy, or what is the treatment effectiveness in real-world outcomes. We may need to consider allowing coverage of products within a certain regimen even if the exact regimen was not studied in a specific cancer type.

—Matthew Mitchell

difference is between oncology and other clinical areas.

Dr Beed: So cost has been the main change.

Dr Mitchell: Cost is what gets on the radar, but much of this is semantics, that is, the way the question is asked. We have to ask what is efficacy, or what is the treatment effectiveness in real-world outcomes. I am surprised that we are not discussing adverse events or safety issues in relation to value. From a management perspective, these issues have to enter into the quality of care and the value proposition. We may need to consider allowing coverage of products within a certain regimen even if the exact regimen was not studied in a specific cancer type. One example may be allowing the substitution of cisplatin/carboplatin therapies into a regimen in which both products have demonstrated efficacy in separate regimens, but one may produce fewer adverse events, leading to better patient experience and lower cost with the reduced adverse events.

Ira M. Klein, MD, MBA, FACP: My role at Aetna for the past several years has been to be the clinical leader for our oncology strategy, and in that position we have wrestled with the issue of value. I would say that the standard definition of value is quality over cost. I

Lee N. Newcomer, MD: By the time our 5-year-old children graduate from college, their healthcare premium will be equal to the average US salary.

Based on current cost trends, we are 1 generation away from spending our entire salary to cover healthcare, if we do not change something. We can have many discussions about how we ought to tweak this, but we have to make some changes in the system, and they have to be made in the next 2 or 3 years.

We need to make some decisions about whether, as a society, we can spend any time treating people with drugs that get a 1- or 2-month response, until we find out how those drugs work in a combination that gets us a much more meaningful response, such as 4 to 6 months or 6 to 8 months. And we have to decide as a society how much those months are worth.

By the time our 5-year-old children graduate from college, their healthcare premium will be equal to the average US salary. Based on current cost trends, we are 1 generation away from spending our entire salary to cover healthcare, if we do not change something.

—Lee N. Newcomer

We know that England has done that.

It came up with the number of $40,000 per life-year. I do not know if that is the right number for the United States, and at UnitedHealthcare I will not be making that decision, but as a society we have to do that, because we simply cannot afford to continue the way we are spending today. It is not sustainable.

Dr Beed: In the Affordable Care Act, the discussion about comparative effectiveness explicitly says that a calculation of Continued on page 19

VOL. 3

I

NO. 6

THE AFINITOR® (everolimus) TABLETS DUAL BENEFIT CO-PAY CARD FROM NOVARTIS PHARMACEUTICALS CORPORATION Designed to help make treatment more affordable for your eligible AFINITOR patients h The AFINITOR Dual Benefit Co-Pay Card With this co-pay assistance card, most eligible patients will pay $25 per 28-day prescription of AFINITOR® (everolimus) Tablets when they visit their pharmacy. The card also provides up to $50 off their co-pay for generic exemestane when prescribed with AFINITOR.

601341 RxBIN: OHCP RxPCN: RxGrp: [OHXXXXXXX] RxID: [000000000000] 01 Suf:

THE AFINITOR DUAL BENEFIT CO-PAY CARD

Novartis Pharmaceuticals Corporation will pay the balance of your eligible patient’s out-of-pocket expenses, up to a maximum of $1200 per month for the AFINITOR prescription and up to $50 per month for generic exemestane when prescribed with AFINITOR. Not valid for prescriptions for which payment may be made in whole or in part under federal or state healthcare programs, including, but not limited to, Medicare or Medicaid. The exemestane offer is not valid in Michigan. Patients can obtain the co-pay card at their physician’s office or at www.AFINITOR.com. This program will expire on June 30, 2014.

Helping make access to AFINITOR easier Novartis Oncology shares your commitment to helping patients living with cancer receive the medicines they need. Patient Assistance Now Oncology offers quick and easy access to information about the broad array of support and reimbursement programs available for patients.

For more information about AFINITOR access services, please visit www.AFINITOR.com.

Please see accompanying Important Safety Information and Brief Summary of Prescribing Information for AFINITOR on the following pages.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

9/12

AFB-1046627

AFINITOR速 (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively.

Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve. For grade 3 cases, interrupt AFINITOR until resolution to ) grade 1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered.

Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment.

Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR. Geriatric Patients: In the randomized advanced hormone receptorpositive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients * 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent discontinuation occurred in 33% of patients * 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids,

and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Drug-Drug Interactions: Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments.

Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Adverse Reactions: The most common adverse reactions (incidence * 30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%) and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence * 2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%) and diarrhea (2%).

Laboratory Abnormalities: The most common laboratory abnormalities (incidence * 50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%). The most common grade 3/4 laboratory abnormalities (incidence * 3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%).

Please see accompanying Brief Summary of Prescribing Information for AFINITOR on the following pages.

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information.

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information].

Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information].

For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose.

Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions].

Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] .

Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].

Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information].

For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy.

Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4.

Table 4: Key Laboratory Abnormalities Reported in â&#x2030;Ľ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: O >8GB6BA4MB?8 4 FGEBA: 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L 4A7

9B?7 E8FC86G<I8?L

O 8ELG;EB@L6<A 4 @B78E4G8 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L

4A7

9B?7 E8FC86G<I8?L

O I8E4C4@<? 4 @B78E4G8 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L 4A7

9B?7 E8FC86G<I8?L

Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions].

Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions].

Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers "A ;84?G;L FH5=86GF 6B 47@<A<FGE4G<BA B9 "'",(* J<G; E<94@C<A 4 FGEBA: <A7H68E B9 CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared GB 8I8EB?<@HF GE84G@8AG 4?BA8 BA F<78E 4 7BF8 <A6E84F8 B9 "'",(* J;8A 6B 47@<A<FG8E87 J<G; FGEBA: 0) <A7H68EF <9 4?G8EA4G<I8 treatment cannot be administered. St. Johnâ&#x20AC;&#x2122;s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information].

Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions 58GJ88A "'",(* 4A7 G;8 !& B E87H6G4F8 <A;<5<GBEF 4GBEI4FG4G<A 4 0) FH5FGE4G8 4A7 CE4I4 FG4G<A 4 ABA 0) FH5FGE4G8 4A7 CBCH?4G<BA C;4E@46B kinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. FGH7L <A ;84?G;L FH5=86GF 78@BAFGE4G87 G;4G 6B 47@<A<FGE4G<BA B9 4A BE4? 7BF8 B9 @<7 4MB?4@ F8AF<G<I8 0) FH5FGE4G8 J<G; 8I8EB?<@HF E8FH?G87 <A 4 <A6E84F8 <A @<7 4MB?4@ max and a 30% increase in @<74MB?4@ - <A9 .

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%.

However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse 8I8AGF E8?4G87 GB 8K8@8FG4A8 J4F B5F8EI87 <A C4G<8AGF J<G; ;BE @BA8 E868CGBE CBF<G<I8 ! * A8:4G<I8 47I4A687 5E84FG 64A68E E868<I<A: G;8 6B@5<A4G<BA

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. ,;8E8 4E8 AB 478DH4G8 4A7 J8?? 6BAGEB??87 FGH7<8F B9 "'",(* <A CE8:A4AG JB@8A ;BJ8I8E 54F87 BA the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

I8EB?<@HF 64HF87 8@5ELB 98G4? GBK<6<G<8F <A 4A<@4?F 4G @4G8EA4? 8KCBFHE8F G;4G J8E8 ?BJ8E G;4A ;H@4A exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the 7EH: G;8 C4G<8AG F;BH?7 58 4CCE<F87 B9 G;8 CBG8AG<4? ;4M4E7 GB 4 98GHF /B@8A B9 6;<?7584E<A: CBG8AG<4? should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating and G;EBH:; BE:4AB:8A8F<F <A7H687 8@5ELB 98G4? GBK<6<G<8F <A6?H7<A: <A6E84F87 E8FBECG<BA CE8 <@C?4AG4G<BA 4A7 CBFG <@C?4AG4G<BA ?BFF 786E84F87 AH@58EF B9 ?<I8 98GHF8F @4?9BE@4G<BA 8 : FG8EA4? 6?89G 4A7 retarded skeletal development. These eff86GF B66HEE87 <A G;8 45F8A68 B9 @4G8EA4? GBK<6<G<8F @5ELB 98G4? toxicities in rats occurred at doses â&#x2030;Ľ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC ;) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

"A 4 CE8 4A7 CBFG A4G4? 78I8?BC@8AG FGH7L <A E4GF 4A<@4?F J8E8 7BF87 9EB@ <@C?4AG4G<BA G;EBH:; ?46G4 tion. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or F<:AF B9 @4G8EA4? GBK<6<GL ;BJ8I8E G;8E8 J8E8 E87H6G<BAF <A 5B7L J8<:;G HC GB E87H6G<BA 9EB@ G;8 6BAGEB? 4A7 <A FHEI<I4? B9 B99FCE<A: N 7<87 BE @<FF<A: ,;8E8 J8E8 AB 7EH: E8?4G87 89986GF BA G;8 developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use AFINITOR is recommended for use only in patients with SEGA who are aged â&#x2030;Ľ 3 years.

CEBFC86G<I8 BC8A ?458? F<A:?8 4E@ GE<4? J4F 6BA7H6G87 GB 8I4?H4G8 G;8 F498GL 4A7 899<646L B9 "'",(* <A C4G<8AGF J<G; + 4FFB6<4G87 J<G; ,+ "A GBG4? C4G<8AGF E868<I87 GE84G@8AG J<G; "'",(* @87<4A 4:8 J4F L84EF E4A:8 "'",(* ;4F ABG 588A FGH7<87 <A C4G<8AGF J<G; + L84EF B9 4:8

Geriatric Use "A G;8 E4A7B@<M87 47I4A687 ;BE@BA8 E868CGBE CBF<G<I8 ! * A8:4G<I8 5E84FG 64A68E FGH7L B9 "'",(* GE84G87 C4G<8AGF J8E8 â&#x2030;Ľ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients â&#x2030;Ľ 65 years of age compared to 2% in C4G<8AGF L84EF B9 4:8 7I8EF8 E846G<BAF ?847<A: GB C8E@4A8AG GE84G@8AG 7<F6BAG<AH4G<BA B66HEE87 <A 33% of patients â&#x2030;Ľ L84EF B9 4:8 6B@C4E87 GB <A C4G<8AGF L84EF B9 4:8 [see Warnings and Precautions].

"A GJB BG;8E E4A7B@<M87 GE<4?F 47I4A687 E8A4? 68?? 64E6<AB@4 4A7 47I4A687 A8HEB8A7B6E<A8 GH@BEF B9 pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and LBHA:8E FH5=86GF "A G;8 E4A7B@<M87 47I4A687 * FGH7L B9 "'",(* GE84G87 C4G<8AGF J8E8 â&#x2030;Ľ 65 L84EF B9 4:8 J;<?8 J8E8 4A7 BI8E "A G;8 E4A7B@<M87 47I4A687 )' , FGH7L B9 "'",(* treated patients were â&#x2030;Ľ 65 years of age, while 7% were 75 and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out 1F88 ?<A<64? );4E macology (12.3) in the full prescribing information].

'B 7BF4:8 47=HFG@8AG <A <A<G<4? 7BF<A: <F E8DH<E87 <A 8?78E?L C4G<8AGF 5HG 6?BF8 @BA<GBE<A: 4A7 4CCEBCE< ate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal <@C4<E@8AG <F ABG 8KC86G87 GB <A9?H8A68 7EH: 8KCBFHE8 4A7 AB 7BF4:8 47=HFG@8AG B9 8I8EB?<@HF <F E86 ommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose FGH7L B9 8I8EB?<@HF <A FH5=86GF J<G; <@C4<E87 ;8C4G<6 9HA6G<BA E8?4G<I8 GB FH5=86GF J<G; ABE@4? ;8C4G<6 9HA6 tion. KCBFHE8 J4F <A6E84F87 <A C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF @B78E4G8 ;<?7 )H:; 6?4FF 4A7 F8I8E8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 1F88 ?<A<64? );4E@46B?B:L <A G;8 9H?? CE8 scribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the E<F> BE C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF BE @B78E4G8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 4 dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

BE + C4G<8AGF J<G; F8I8E8 ;8C4G<6 <@C4<E@8AG ;<?7 )H:; 6?4FF "'",(* <F ABG E86B@@8A787

BE + C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF BE @B78E4G8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 47=HFG@8AG GB G;8 FG4EG<A: 7BF8 @4L ABG 58 A88787 ;BJ8I8E FH5F8DH8AG 7BF<A: F;BH?7 58 <A7<I<7H4? <M87 54F87 BA G;8E4C8HG<6 7EH: @BA<GBE<A: [see Dosage and Administration (2.4 <A G;8 9H?? CE8F6E<5 ing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Novartis Pharma Stein AG +G8<A +J<GM8E?4A7 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Š Novartis ,

July 2012

2012 Conference

Defining Value in Cancer Care... cost per quality-adjusted life-year shall not be used.

Dr Newcomer: Exactly, and the way that Medicare balances its budget is by simply paying the physician and the hospital less and less each year, because it is not bringing enough money in.

Medicare simply lowers the reimbursement and tells providers that it is something they have to accept. Very few people can walk away from Medicare.

But, we cannot take that all the way down to zero.

I have just attended a hospital board meeting to discuss reimbursement. Each year we have to find $30 million worth of new profits just to cover what Medicare is not going to pay us, because their fee schedule went down. We have to do that year after year, and now we are laying off people to get it done. That the government will not address this tells us how difficult the discussion is, but we cannot use their approach of down-pricing to zero.

Dr Beed: If the US government will not address it, who will? Where is the area of agreement between clinicians who are caring for patients with cancer and the payers who are trying to manage this pot of money?

Jennifer Malin, MD, PhD: My alma mater, the University of California Los Angeles (UCLA), has the dubious honor of being the most expensive academic center in the country, according to the Dartmouth Group. At the same time, California is in a budget crisis.

The 3 primary state budget expenses are healthcare, education, and prisons.

I do not see any efforts to try to rein in costs at UCLA, even though the educational mission of the university is suffering—our faculty and the entire staff have mandatory furloughs, essentially a 2-week salary cut per year. The cost of tuition has increased by 30% over the past year. Our public education system is in shambles.

Therefore, what we are talking about in a theoretical way is actually very real. It is happening now: 1 in 3 of us is going to get cancer, so what do we see as worth putting our money away for in terms of treatments? Realistically, being in the position of being able to not have cancer, but thinking about ourselves as potential patients, what is a meaningful improvement in QOL and in length of life that is worth mortgaging our children’s future for?

F. Randy Vogenberg, RPh, PhD: There are so many different perspectives in this issue. Looking at it from

VOL. 3

I

NO. 6

the perspective of the commercial payer, the self-funded plan sponsor, whether it is an employer, a union, or a municipality, they are all feeling the squeeze as well. The research that I have been involved with recently is demonstrating very clearly that employers in particular are very much engaged in this debate, more than many people realize. They are trying to grapple with the value question not only in economic terms but also with how the whole healthcare system that they are paying for is performing to deliver outcomes.

As one of the biggest areas that is so visible to everybody, cancer is a very emotional disease. Everybody has been touched one way or another by cancer, including me. And there are many dollars involved. Employers are concerned about cost, but their primary interest has been performance. There is a big gap between what we are paying for today and the results or the performance that we expect to see. It is not just about cost.

Employers are looking for the performance that is related to the cost of therapy, whether it is a drug or a diagnostic test, extending life, or curing disease.

We are now also dealing with severe drug shortages. Employers are very inter-

Continued from page 14

There are probably employers who are seeing this as an urgent issue. They are looking at a 2- to 3-year window, as well as a time for very rapid innovation and change, to try and shift not only the cost curve but also the performance curve among all of the vendors that they are paying for.

No one would question that we should be investing more in early detection when there is good evidence that makes a difference in outcomes. In metastatic disease, we have to ask questions about how long to treat.

—John D. Sprandio

Dr Beed: We were just talking about the meaning of value and about how the demographics have changed. Personalized medicine, biomarkers, and resource allocation are where the rubber hits the road in many cases. Should we spend more money on cancer care going forward? Are we willing to take money from other diseases and spend less on them and more on cancer?

Dr Vogenberg: That is all part of the discussion. There’s a finite amount of financial resources.

What we are talking about in a theoretical way is actually very real. It is happening now: 1 in 3 of us is going to get cancer, so what do we see as worth putting our money away for in terms of treatments?

—Jennifer Malin

ested in more of a 360-degree view of what is happening with the dollars that they are spending. That is unlike what we see typically with the Centers for Medicare & Medicaid Services (CMS) because of some of the congressional budget rules that CMS has to play by.

Dr Sprandio: Cancer therapies are valuable if they are potentially curative.

In the metastatic setting, there is value, and it is reasonable as a society to support 1 or 2 lines of therapy. Regarding biologics, especially biomarkers, if we can convince patients that we are using the best drug from the beginning, and the second-best drug for the second round of chemotherapy, we would have a much better chance of telling patients that there is no sense in doing the second, third, fourth, or fifth lines of therapy. But today we cannot say that. We can just say that based on a population and a probability, we are going to choose the best drug, but we do not know what is best for the specific patient’s tumor.

No one would question that we should be investing more in early detection when there is good evidence that makes a difference in outcomes. In metastatic disease, we have to ask questions about how long to treat.

Dr Klein: Because this is an epidemiologic discussion, we should point out that we do not have the granular data that we know how to get to the

SEPTEMBER 2012

I

answers we are seeking. Clearly, there is a lead time bias. One of the reasons that we do not know whether we are doing better than we were doing 20 years ago (except in some select diseases, such as chronic myelogenous leukemia) is that Medicare and most of the private payers do not capture the elements that we need to figure out whether we are comparing like to like.

So we might have a diagnosis, but we do not have a stage. We do not have tumor histology. We do not have biomarkers. And we do not have performance status. Until we get that information, we cannot make an informed epidemiologic decision. Once that information is available, I think we will be able to make much better decisions regarding the value of treating a metastatic disease, and who is getting the best chemotherapy.

And if we are comparing like to like, then we just eliminated the lead time bias, because we can get rid of the disease through our ability to granularly bucket different patient categories.

Dr Beed: So when it comes to actionable things that need to happen in terms of value in cancer, I have heard about watchful worrying and the early detection lead time bias. You point out that we need to have more robust informatics that look at cancer, and that may integrate clinical trial data, claims data, and other data to get some ideas of what happens in the population. Dr Newcomer, what else would you add to this in terms of making value-based cancer care a reality, considering the increasing numbers of expensive therapies, better early detection, and better survivability that may be real or may be related to lead time bias?

Dr Newcomer: I want to underscore the need for starting to collect some registries, so we can truly find out whether your statements are true. One of the things I am struck with in my discussions with practicing oncologists is that they do not get the same response that was shown in the registration trials, because the patients are different.

Patients entered into a registration trial have a performance status of zero. The patients we see in the office often cannot do half the things as patients who are enrolled in clinical trials.

Only about 2% to 3% of all patients with cancer enter into clinical trials. If we are going to accelerate the pace of making these kinds of value-based decisions with cancer, we need registries.

I think they are very possible. At UnitedHealthcare, we have 35,000 Continued on page 24

www.ValueBasedCancerCare.com

19

Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the JakafiÂŽ (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

130T BSF BO JNQPSUBOU NFBOT UP EFNPOTUSBUF USFBUNFOU benefits in clinical trials. 6TF PG B 130 JOTUSVNFOU DBO evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. *ODPSQPSBUJOH 130T JOUP B DMJOJDBM USJBM QSPHSBN QSPWJEFT B means for evaluating the impact of therapy from the patientâ&#x20AC;&#x2122;s perspective and helps patients and clinicians make betterinformed decisions.

.ZFMPĂĽ CSPTJT .'

JT B MJGF UISFBUFOJOH QSPHSFTTJWF EJTFBTF characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEZ $0.'035 * GPS +BLBĂĽ 4QMFFO SFEVDUJPO BT NFBTVSFE CZ JNBHJOH .3* PS $5

was the primary and biologic endpoint, and a reduction in total TZNQUPN TDPSF 544 UIF 130 NFBTVSF XBT B LFZ TFDPOEBSZ endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 5P JODMVEF 130T JO UIF USJBM B OPWFM JOTUSVNFOU IBE UP CF specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version NPEJĂĽ FE .'4"' W XBT ĂĽ OBMJ[FE BT QBSU PG UIF 4QFDJBM 1SPUPDPM "TTFTTNFOU QSJPS UP UIF JOJUJBUJPO PG $0.'035 * Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyteâ&#x20AC;&#x2122;s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDAâ&#x20AC;&#x2122;s draft guidance on 130T XBT ĂĽ OBMJ[FE JO

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postâ&#x20AC;&#x201C;polycythemia vera myelofibrosis and postâ&#x20AC;&#x201C;essential thrombocythemia myelofibrosis.

Important Safety Information t 5SFBUNFOU XJUI +BLBĂĽ DBO DBVTF IFNBUPMPHJD BEWFSTF reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required t 5IF UISFF NPTU GSFRVFOU OPO IFNBUPMPHJD BEWFSTF reactions were bruising, dizziness and headache t 1BUJFOUT XJUI QMBUFMFU DPVOUT ¨ 9/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered t 1BUJFOUT EFWFMPQJOH BOFNJB NBZ SFRVJSF CMPPE USBOTGVTJPOT Dose modifications of Jakafi for patients developing anemia may also be considered t /FVUSPQFOJB "/$ ¨ 9/L) was generally reversible and was managed by temporarily withholding Jakafi t 1BUJFOUT TIPVME CF BTTFTTFE GPS UIF SJTL PG EFWFMPQJOH serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before TUBSUJOH +BLBĂĽ 1IZTJDJBOT TIPVME DBSFGVMMZ PCTFSWF QBUJFOUT receiving Jakafi for signs and symptoms of infection JODMVEJOH IFSQFT [PTUFS BOE JOJUJBUF BQQSPQSJBUF treatment promptly t " EPTF NPEJĂĽ DBUJPO JT SFDPNNFOEFE XIFO BENJOJTUFSJOH +BLBĂĽ XJUI TUSPOH $:1 " JOIJCJUPST PS JO QBUJFOUT XJUI

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patientâ&#x20AC;&#x2122;s response.

50

WORSENING

20

100

IMPROVEMENT

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patientâ&#x20AC;&#x2122;s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MFâ&#x20AC;&#x201D;this is an important consideration when evaluating and treating patients.9 5IF '%" BQQSPWBM JODMVEFE QBUJFOUT XJUI JOUFSNFEJBUF SJTL BOE IJHI SJTL BT XFMM BT QBUJFOUT with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and BDBEFNJD FYQFSUT UP EFWFMPQ SFMFWBOU BOE WBMJEBUFE 130 JOTUSVNFOUT UIBU DBO CF JODPSQPSBUFE JOUP DMJOJDBM USJBMT 1,8 The approval PG +BLBĂĽ NBSLT B TJHOJĂĽ DBOU NJMFTUPOF JO XIJDI WBMJEBUFE 130 JOTUSVNFOUT DBO QSPWJEF TZNQUPN EBUB BOE EFNPOTUSBUF DMJOJDBM CFOFĂĽ U 5IF FYQFSJFODF XJUI +BLBĂĽ NBZ QSPWJEF B NPEFM GPS UIF GVUVSF VTF PG 130T JO NBSLFUJOH BQQMJDBUJPOT 8

renal or hepatic impairment [see Dosage and Administration].

1BUJFOUT TIPVME CF DMPTFMZ NPOJUPSFE BOE UIF EPTF UJUSBUFE based on safety and efficacy t 5IFSF BSF OP BEFRVBUF BOE XFMM DPOUSPMMFE TUVEJFT PG +BLBĂĽ in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus t 8PNFO UBLJOH +BLBĂĽ TIPVME OPU CSFBTU GFFE %JTDPOUJOVF nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials.

3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.

6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011.

10. Data on File, Incyte Corporation.

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a â&#x2030;Ľ35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a â&#x2030;Ľ50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms â&#x20AC;&#x153;absentâ&#x20AC;? and 10 representing â&#x20AC;&#x153;worst imaginableâ&#x20AC;? symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a registered trademark of Incyte Corporation. Š 2012, Incyte Corporation. All rights reserved.

RUX-1130A 05/12

In The Literature Newer, More Effective Anticancer Drugs...

Continued from page 8

4 AEs, especially nonhematologic AEs (eg, diarrhea, skin reactions, and neu ropathy),

common

the were more with newer agents (OR, 1.52; 95% CI, 1.351.71; P <.001).

The increased toxicity was not limited to targeted drugs and applied to new chemotherapeutic agents as well.

Indeed, targeted therapies are overall less toxic than chemotherapy; when targeted drugs used as monotherapies were compared with new chemotherapeutic agents, treatment discontinua-

tion and hematologic toxicity rates were lower with the targeted agents.

However, because patients in clinical practice are “less selected” than in clinical trials, the likelihood of newer therapy-related toxicity is greater in the real world than in a clinical trial, the investigators suggest. Therefore, they

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved.

Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

22

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

conclude, the use of newer agents and newer chemotherapy must be selective and individualized; oncologists must consider the health status of the individual patient when prescribing therapy with newer agents.

Intermittent Androgen Deprivation as Effective as Continuous Therapy after Radiotherapy Many studies have shown that cyclic androgen deprivation is associated with a reduction in toxic effects in patients with prostate cancer.

Results of a new international study show that the use of intermittent androgen treatment after radiotherapy in patients with elevated prostate-specific antigen (PSA) levels is noninferior to continuous androgen treatment and leads to improvements in some QOL measures (Crook JM, et al. N Engl J Med. 2012;367:895-903).

This is the first randomized trial to compare intermittent androgen deprivation treatment with continuous androgen treatment in patients with rising PSA levels after radiotherapy for prostate cancer, using OS as the primary end point. A total of 1368 patients with a PSA level >3 ng/mL more than 1 year after radiotherapy for localized prostate cancer were randomized to intermittent treatment with a luteinizing hormone–releasing hormone agonist combined with a nonsteroidal antiandrogen (N = 690) or to continuous treatment with the combination or with an orchiectomy (N = 696). The intermittent therapy was administered in 8-month cycles; nontreatment periods were determined by the patient’s PSA level.

The median follow-up was 6.9 years.

No significant differences were seen between the groups. A total of 268 prostate cancer–related deaths occurred in the intermittent-treatment group and 256 in the continuous-treatment group; the median OS was 8.8 years versus 9.1 years, respectively (hazard ratio for death, 1.02; 95% CI, 0.86-1.21).

In addition, some QOL measures were better with intermittent than with continuous treatment—symptom-related items were significantly improved, including hot flashes (P <.001), the desire for sexual activity (P <.001), and urinary symptoms (P = .006), with a trend toward improvement in fatigue level (P = .07); by contrast, although functional domain scores were slightly higher, the difference was not significant.

Toxicity events were not significantly different between the groups. The study was terminated early when the prespecified noninferiority threshold for intermittent treatment was met. ■

VOL. 3

I

NO. 6

NOW AVAILABLE

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1111-CARF-147a July 2012 Printed in USA

KYPROLIS.com

2012 Conference

Defining Value in Cancer Care...

I want to underscore the need for starting to collect some registries, so we can truly find out whether your statements are true. One of the things I am struck with in my discussions with practicing oncologists is that they do not get the same response that was shown in the registration trials, because the patients are different.

—Lee N. Newcomer

patients now with breast, colon, and lung cancers, and we have the data that were requested. We have information on stage, genetics, and current status— everything but performance status. We are starting to try to mine that data now to see if we can find what delivers value, and what does not.

Dr Beed: How do we apply these to individual patients? How do we make sure we are using the treatments that are really of value? Is this just the art of medicine, or is there something more to it than that?

Dr Benson: This gets back to the point about how we expand our knowledge base in terms of understanding how to use these drugs for appropriate people.

It is going to take many shifts in what we do. Clinical trials are designed to determine efficacy, to see whether the drug works. They are critical in that regard, but what we are increasingly arguing now is that we have to change the way we design clinical trials. Even if we do not have the correct biological profile, since we often do not know that at the beginning of the trial, we need to prepare an information database, including tumor banking, so that in the future we could go back to that database and tissue to explore links encompassing biological profiles, treatment, and outcome.

24

A good example of that is the KRAS marker in colon cancer. When some of the colon cancer trials were designed and the researchers were looking at markers, KRAS was not even one of the markers in the original design. But because the researchers had collected tissue, they had excellent clinical data and banked tissue from which exploration of markers could be pursued.

They had a methodology that was consistent with the need to test the marker.

We were therefore able to go back to the data and combine a number of different trials to come up with a marker that transformed the treatment strategy.

These databases are going to be increasingly important, provided that we are putting the appropriate information in the databases. One reason that the database concept is especially attractive is that we are moving away from an empiric approach to one looking for patient selection based on more precise criteria. We now know that most malignant diseases, because of tumor heterogeneity, are a collection of different biological profiles. And as we start subsetting, we are going to need larger populations to look at these small population subsets. For example, in patients with lung cancer, there is a marker that defines a 4% population that will benefit from a given intervention; in patients with gastric cancer, there is a marker that identifies 20% of the gastric cancer population that will potentially benefit from a targeted therapy. If we are going to do comparative effectiveness analyses in oncology with these databases, we have to make sure, in an ongoing way, that we are populating these databases with ongoing information as it evolves, so that we can look at these subpopulations with meaningful data over time.

It is also going to require cultural shifts in trying to convince more people to participate in clinical trials. These trials are going to be even more complex, because as the National Cancer Institute has recently stated at the American Society of Clinical Oncology (ASCO) GI Symposium, “No tissue, no marker, no study.” The point is that if we are going to truly demonstrate marked improvement in efficacy, we have to define the population that is most likely to respond to a given treatment. This changes the landscape in how we conduct oncology clinical research. It changes the landscape in real need for population-based databases. It asks less, “Does it work in the real world?” and asks more, “Will this enable us to capture the subpopulations in sufficient numbers of patients that

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Continued from page 19

we could actually show that there is efficacy and appropriate intervention for the subpopulation?”

Dr Sprandio: What we are getting at is that we are going to change the epidemiologic description of disease from a histopathologic diagnosis to a genomic or epigenomic diagnosis. That will give us much more potential, I think, to observe changes in outcomes.

Additional clinical studies that Dr Benson mentioned are critical to driving guidelines, and it is the oncologist’s job to follow guidelines. The question is how do we devise innovative practices to impact the changing clinical and economic burdens of cancer? What can we control in terms of the economics?

We can control unnecessary resource utilization. At the core of what we have done in this model that is still evolving is that we have minimized unnecessary resource utilization on a consistent basis over the past 6 years.

Consider the National Committee for Quality Assurance guidelines; each of the guidelines and requirements include a quality of service and a value component. The guidelines help to focus on patients as a central target, streamlining the standardizing treatment, which is what we do as oncologists.

Dr Beed: In your oncology delivery system, how is my experience as a patient going to be different from another center or from the old way of care delivery?

Dr Sprandio: Patients notice improvement in service. They also recognize better coordination and communication, which are major concerns. The physicians are different silos. That is noticeable in the patient’s eyes. Access, engagement, and responsibility are important, and making patients understand that they have a responsibility to communicate and report information to their providers. The whole thing about patient-centered medical homes (PCMHs) is tracking chronically ill patients over time to be in a better position to avert the acute exacerbations of their symptoms or issues, and then not only provide a decrease in resource utilization but also to improve their QOL. The PCMH was geared and developed for primary care, initially pediatrics, and then adopted by primary care. It is a model that also fits very well for oncology care. At my practice, we are now saving money delivering care this way. I run a 9-man practice, and we have shown that we were able to reduce our annual emergency department utilization per patient receiv-

ing chemotherapy by 68% since 2005.

We have reduced our annual hospital rate for patients receiving chemotherapy by 51%, and we have reduced the length of hospital stay for admitted patients by 21%.

Dr Beed: Does that drive every insurer to your doorstep?

Dr Sprandio: Yes, it is starting to.

We created many efficiencies; for example, we went down from 8.3 fulltime equivalents (FTEs) to 5.5 FTEs. There was a lot of internal infrastructure that we had to build, and that was costly. The programming was done by trial and error. There was instruction and handholding. It cost a lot of money to develop this model, but now our practice has stabilized—we are still independent, and we are hopeful.

Dr Beed: Have the capital expenditures been laid out, and are you going to start seeing a return on investment?

Dr Sprandio: If there is no return on investment, it means that there is no payer response to this. Reforming payment methodology is harder than reforming care delivery.

Dr Beed: If somebody does something that decreases emergency department use and other resource use, it saves money in terms of patients with cancer. They spend some money, they save some money, and they have an ongoing process that’s saving money in caring for cancer patients. Does that mean that we should then, as a system or as a payer, be spending less on patients with cancer going forward and realizing those savings? Or does it mean that we should reward people for saving money and spend more on cancer, and then the ultimate burden on the system is negligible?

One of the elephants in the room that we have not talked about is how oncology care is paid for, and the fact that most of the revenue for oncology practices comes from the margin on drugs.

—Jennifer Malin

Dr Malin: One of the elephants in the room that we have not talked about is how oncology care is paid for, and the Continued on page 26

VOL. 3

I

NO. 6

Serving Your Oncology Needs Our Generics Lineup Just Expanded—Again.

At Pfizer Injectables, we’re dedicated to delivering customer-focused solutions that can help drive your business. One measure of our commitment is an expanding oncology portfolio and a growing selection of oncology products in CYTOSAFE® plastic vials. Backed by our heritage of commitment to quality and reliable manufacturing, we stand ready to leverage the proven resources of Pfizer and execute with the high level of service that today’s generics marketplace demands.

Pfizer Injectables also offers products in other key therapeutic areas, including:

Anesthetics Anticoagulants Anti-infectives Anti-inflammatories

Hemostatics

To learn about our full range of solutions for your business, contact us today.

For Ordering Information, call 800.533.4535.

For Pfizer Medical Information, call 800.438.1985 or visit www.pfizermedicalinformation.com.

For more information, visit www.pfizerinjectables.com.

CYTOSAFE is a registered trademark of Pfizer Inc, New York, NY. USI00227E-01

© 2011 Pfizer Inc.

All rights reserved.

July 2011

www.pfizerinjectables.com

2012 Conference

Defining Value in Cancer Care... fact that most of the revenue for oncology practices comes from the margin on drugs. If we are going to make the decisions about which treatments to use on which patients as cost-neutral to the practice, we have to reward those innovative practice models and start to reimburse providers for offering care that is patient-centered and well-coordinated rather than reimbursing them for selecting the most expensive, highest technology-based novel therapy, if that therapy is not going to have a dramatic improvement in patient outcomes.

Dr Beed: What do you think about the way we pay oncologists, and the incentives that are a part of it?

Dr Mitchell: I am unable to think of another specialty that brings in revenue based on billing for drug therapy to the degree that is done in oncology. Part of the elephant in the room is the potential for treatment decisions, and more specifically medication selection, based on potential clinic revenue. One possible solution is to reevaluate the way cancer centers are reimbursed. One option would be allowing a management fee, similar to a medical home but more comprehensive, because the sophisticated centers do have interdisciplinary teams. Knowing that it costs more to deliver that type of care, this removes the revenue out of the drug side completely, and puts it into a management fee.

Dr Beed: We have mentioned personalized medicine: what do payers think of this approach? Are they going to only pay for people who have the biomarker? Does personalized medicine direct therapy, or do people just become a little more comfortable or a little less comfortable with what they have decided they are going to do? If all we have done is add the cost of a test, that really did not change anything. Is personalized medicine the Holy Grail? Are we going to test for biomarkers in everyone?

Dr Beveridge: One of the main problems is that with International Classification of Diseases, Ninth Edition (ICD9) coding, the insurers do not know whether a patient with lung cancer had small-cell or non–small-cell lung cancer, localized versus metastatic, first-line therapy or fifth-line therapy. Payers were in the dark. In the next couple of years, ICD-10 will address some of that.

The inability to compare groups throughout the country has been a fundamental problem in terms of assessing quality in one area versus the other.

Peter Ellis, MD, Kathy Lokay, and others

26

first started using pathways, and then the US Oncology Network and McKesson Specialty Health have continued with pathways in the past 7 years.

I suspect that some of the criticism that

At some point we need to address the issues of end of life, corporate use of hospice, and futile therapy. These are all crucially important for the management of the patient. That is what we should discuss when we talk about true patient-centered principles and personalized medicine.

—Roy A. Beveridge Dr Ellis remembers is that we (the US Oncology Network) were converting over to “cookbook medicine,” that all people were being treated the same, and that the goals of pathways were to render the least expensive care. As we look at the evolution of pathways in the past 6 to 7 years, we recognize that it allows for true personalization of care. Because the treatment algorithm does specify, and probably all pathways in the country do now, whether this is for a patient with breast cancer who is HER2-positive, HER2-negative, estrogen-receptor–positive, triple-negative, and so on.

But this is not the “be all and end all” as far as where we need to go. In terms of truly personalized care, the answer is more than just pathways. We need to begin to take into account radiation, which we have not yet discussed. Today, radiation is a significant component of our cancer care delivery system.

We keep talking about drugs, because most of us are medical oncologists, but hospitalization and emergency department rates are very important in terms of costs.

At some point we need to address the issues of end of life, corporate use of hospice, and futile therapy. These are all crucially important for the management of the patient. That is what we should discuss when we talk about true patient-centered principles and personalized medicine.

VALUE-BASED CANCER CARE

Dr Vogenberg: I have recently had

I

SEPTEMBER 2012

Continued from page 24

discussions with employers about personalized medicine. One of the common responses I hear is, “If you cannot prove or show me that what you are doing is better than what we did before using a newer product versus an older product, then the only difference is cost.” All of these other quality parameters we talk about are considered to be irrelevant by the true payer (ie, the employer as benefits purchaser). We have seen this with CMS, and we are seeing it now with employers. I have never heard an employer say, “I’m not willing to pay.” All employers are willing to pay, but they want to see that this cost is making a difference. That value is going to be key to the focus of personalized medicine.

We are increasingly moving toward personalized medicine, which will be a large conundrum. A key issue will be whether we can differentiate between the performance of one product and all of the surrounding services.

Dr Sprandio: Ultimately we are going to get to a point where we are using genomic diagnosis. But with tumor genomics sequencing, any escape mechanism creates a significant challenge for the oncologist in trying to decide how to use that wealth of information to figure out which therapy is best. And there are probably going to be a number of tumors for which no markers exist.

We can most likely all accept that our current system is not sustainable. If we look to the past, at least in the area of cancer treatment, some fairly dramatic mistakes were made when it came to value and cost. We cannot continue to make these types of mistakes, but we continue to make them.

—Craig K. Deligdish

Dr Deligdish: Payers think there is value in information related to clinical utility, if that information helps the physician to decide on an optimal therapy. But if this information does not help

in the decision-making process, then that information has limited value. For example, if the cost of tumor genome sequencing is in the $2000 range in the next several years, and the cost of treatment is between $5000 and $15,000 monthly, the cost of genome sequencing may be a good investment if it impacts the decision-making process. However, if some patients can be cured by the information gleaned from this test, the value may be priceless.

We can most likely all accept that our current system is not sustainable. If we look to the past, at least in the area of cancer treatment, some fairly dramatic mistakes were made when it came to value and cost; one example is the use of high-dose chemotherapy and autologous bone marrow transplantation for women with breast cancer. That treatment was very popular and was even performed at tertiary medical centers and in the community setting. Indeed, billions of dollars were spent before it was recognized that the treatment had no true value and was associated with significant morbidity and mortality. Similar examples occurred in the past couple of years, when treatments that were promoted without proven benefit were approved and implemented on a fairly large scale. We cannot continue to make these types of mistakes, but we continue to make them.

As we move toward healthcare reform, we continue to see consolidation in the number of providers and payers.

But as we continue with this consolidation, we are realizing that it does not reduce cost and does not make the system more efficient. Indeed, it makes the system less efficient and more costly.

Unless we, as a society, are willing to address those issues, we will end up in a place where there probably is only 1 payer, because no other payers will be able to afford to be in that space, and patients may no longer be able to afford treatment.

We need to think about where we are going to be in 5 years, because, as Dr Newcomer said, we cannot afford to be where we would end up in 10 years unless some of these issues are addressed.

Dr Beed: If we are going to spend more money on cancer, how are we going to finance it? Are we going to spend less money on other diseases, hold down innovation, or borrow from the next generation? What are the appropriate steps, that could be accepted by providers, that we have to take as a society?

Dr Silver: I have heard at an oncology panel that we spend more money on Continued on page 27

VOL. 3

I

NO. 6

2012 Conference

testing now than we do on chemotherapy drugs and radiation.

Dr Newcomer: That is correct, and that is on genetic testing alone. However, genetic testing includes all diseases.

When you do parse it down by cancer, it will come down. But, the point is that when we look at spending, it is clear that we are enamored with genetic testing, and we are spending large amounts of money on it. In fact, we are seeing significant spending for genetic testing in areas without evidence to support use yet.

Dr Silver: Hematologists have been working with these kinds of advanced personalized medicine tests for the past 20 years. These tests have been getting more specific and more advanced. But, it is much easier to obtain tissue in hematologic malignancies than in solid tumors, which is why this has been in the forefront.

Overuse in the very expensive diagnostic testing for personalized medicine typically takes place for several reasons.

First, there are many perverse incentives financially for doing this. Second is the lack of impediments for use.

—Samuel M. Silver

Overuse in the very expensive diagnostic testing for personalized medicine typically takes place for several reasons.

First, there are many perverse incentives financially for doing this. Second is the lack of impediments for use. For example, Oncotype DX for women with breast cancer does decrease the amount of adjuvant chemotherapy when used appropriately. However, we have reviewed cases when the Oncotype DX showed a highrisk score and the women did not receive adjuvant chemotherapy, or when women had a low-risk score and received adjuvant therapy.

One question that I cannot answer is who was ordering the tests. We can have an 85-year-old woman who should never get adjuvant chemotherapy, but if the test is being ordered reflexively by a pathologist (who does not meet the

VOL. 3

I

NO. 6

woman), is that reasonable? We end up spending $5000 on a test that no one is going to look at.

We have excellent tests, but they have to be used in the right context. We are ordering too many things, because we can do it. There are certainly overuse issues that must be addressed.

Dr Beed: Does the PCMH model address the need to keep the pathologists from ordering something when they have never seen the patient?

Dr Sprandio: It does. Among the goals of the PCMH model is assuming complete control of everything related to cancer diagnosis, orchestrating the appropriate response, and coordinating patient care.

Dr Beed: With regard to negative consequences of personalized medicine on drug innovation—should we continue to develop the same innovative products that only approximately 4% of the population will benefit from?

Dr Benson: One of the hallmarks of selecting a marker to become a clinical test is that in the end it must benefit the patient. Part of the problem with technologic innovations—whether it is a diagnostic test, an interventional radiology procedure, or now positronemission tomography (PET) or magnetic resonance imaging (MRI)—because of the way they are being developed and get reimbursed, they enter the marketplace without the true testing that is required to understand their clinical benefit. We have been talking about drugs, but if we look at PET scans alone, the amount of money being spent on them is mindboggling, and most of it is inappropriate use.

There are important clinical trials addressing the use of PET scans, but they are lagging behind in defining the optimal use of this technology, which is also an evolving technology. Because PET scanning is readily available across the country, it impedes the prospective collection of the essential information needed to answer, “Does this work, or does it not work?”

Part of the perversity of our reimbursement system is the way these products get on the market. They are paid for before we clearly define the appropriate clinical use. We need to make a better investment and say, “We are going to order this test, but the only way the test is going to get reimbursed is that it will be entered into a database or a prospective clinical trial, to try to define what the real use should be.”

At Aetna, we have tried to approach some of the more egregious misuses of technology through clinical policy bulletins and sometimes on claims table edits.

Nobody likes to get a precertification for an MRI. And yet, because we have collected systematic data, we know that radiology benefit management works and formulary management works.

—Ira M. Klein

How to get around that is a major problem. For example, I was on the ASCO panel that was going to create a guideline for radiofrequency ablation use for patients with colon cancer and liver metastasis. This is a procedure used every day around the world. It has been used for years. In doing a systematic review, we found that there was not even 1 prospective randomized trial on this. It was, therefore, impossible to create a guideline, and we were left defining a group of research questions that are yet to be addressed. But there are currently no incentives for these types of trials to be done; there are certainly no reimbursement disincentives.

Dr Beed: When a new diagnostic test or a new therapy becomes available, we would expect that the coverage will be contingent on these data points, so that we get an answer and can revisit it with real data. Does that appeal to an insurer? Is it doable?

Dr Klein: In many ways, CMS has punted on much of this by saying, “We will give coverage with evidence development.” But the majority of coverage decisions are made at the local or the regional level. Therefore, from a national perspective, CMS has not necessarily

SEPTEMBER 2012

I

taken the bull by the horns.

At Aetna, we have tried to approach some of the more egregious misuses of technology through clinical policy bulletins and sometimes on claims table edits. Nobody likes to get a precertification for an MRI. And yet, because we have collected systematic data, we know that radiology benefit management works and formulary management works. Benefit design changes do drive behavior on the member side.

We have already been doing this, but not enough. If we (ie, payers) are always being looked at as those who are not doing something or are withholding something, then it is hard to get our message out that we are really trying to address overuse. As with the Oncotype DX, for example, there is overuse, underuse, and misuse.

There are 2 ways we can reduce cost.

First, we can make the individual practices more efficient as entities that have a product. Second, we can better connect the system with data. The discussion about overuse of genetic tests speaks to a fragmented system in which nobody talks to one another. If we all talked to one another, we would have much less misuse and overuse of testing, because the communication will solve these problems. Those are 2 areas where we may have a glimmer of hope in reducing the cost of cancer care.

Dr Beed: Do we have mechanisms to encourage collection of data and connection of practices?

Employers have invested quite heavily in wellness and in preventive services. They are now “getting it,” and they are seeing the return on their investment in employee satisfaction and in the difference in employee performance and productivity.

—F. Randy Vogenberg

Dr Vogenberg: Yes, companies have gotten involved very rapidly, particularContinued on page 28

www.ValueBasedCancerCare.com

27

2012 Conference

Defining Value in Cancer Care... ly the larger Fortune 500 companies.

They are looking at the sharing of information that Dr Klein talked about, and are trying to promote better use of information technology, as well as linking it to benefit design. From the employer’s perspective, all they can do is look at changing some of the coverage parameters through their benefit design. They are not going to get involved, and they are not going to “touch” patients. But they are trying to drive many types of behavior.

There are gaps in their success; up until a few years ago, most employers did not pay attention to any of this, because drugs were cheap. Now that drugs are expensive and are getting more expensive, employers are now looking at the cost of healthcare.

What they still do not see is the spending on diagnostics and devices, which is going to force even more interest around the integration of information and a better coordination of care delivery. We are seeing that with some of the larger employers.

Dr Beed: What will the reimbursement mechanism be for employers who invest money and provide better care?

Dr Vogenberg: We are back to how employers perceive performance of their vendors—the health plans and other providers of services. It is rare to see a very clearly differentiated performance, which is why I think we keep going back to this cost issue. Some employers are trying to drive the discussion, as well as partner and collaborate with their plans and with their other vendors to encourage that kind of innovation. Employers are looking to drive innovation with their partners.

What has changed is the cost.

Whether it is the patient or the employer as a payer, the dollars at stake today are so significant that it makes it worth their while.

Dr Beed: How does cancer prevention fit into our value-based care discussion?

Dr Vogenberg: Employers have invested quite heavily in wellness and in preventive services. They are now “getting it,” and they are seeing the return on their investment in employee satisfaction and in the difference in employee performance and productivity as a result of catching disease earlier.

Dr Beed: Are we going to prevent cancer? Is that something we should be investing our money in?

28

Continued from page 27

Dr Beveridge: I do not think that medical oncologists see patients early enough to prevent cancer. The numbers of my patients who start a “brown rice and broccoli diet” after they have had colon cancer are quite a few, but they started it approximately 25 years too late. Breast cancer genetics programs are going to be increasingly widespread. I think we should continue to invest in some expensive tests in the relatives of our patients with breast cancer as a preventive measure.

Dr Malin: I would not say that prevention focused specifically on cancer is how we are going to bend the cost curve; rather, the issue of obesity, and it is affecting not only cancer prevalence rates but also all other diseases.

Dr Newcomer: I could come up with a list of 10 things that we could get rid of without hurting the patient. For example, 20% of our patients with stage I breast cancer get PET scans. Why? There is no reason to do that, as Dr Benson mentioned.

I would look for that “list of 10,” and then try and make sure that that is consistently applied throughout my entire practice, that every one of my partners signs off on this list, and that we monitor it carefully.

I could come up with a list of 10 things that we could get rid of without hurting the patient. For example, 20% of our patients with stage I breast cancer get PET scans.

Why? There is no reason to do that, as Dr Benson mentioned.

—Lee N. Newcomer

We will pick our 10 habits, and get rid of them. As soon as we are consistent on those 10 things, we will move to the next 10 things. We have to start finding things today that we are going to stop doing, so that we could leave some funds for therapies that truly work. The last thing any of us wants to say to a patient with Hodgkin lymphoma is, “There’s not enough money in the system to treat you anymore.” That would be a travesty.

There is plenty of waste in the system that we could and should start eliminating, and that budget could be very viable.

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Waste, and often harm, occur when we provide treatments to patients that they would not have wanted had they known all their options. There is compelling evidence that having advance care planning discussion improves health outcomes.

—John Fox

Dr Owens: No matter where we went in our value discussion, the elephant in the room remains cost. Every road leads back to cost. So the reality is that value and costs are inextricably linked together. We cannot take them apart. But one of the things that we can do vis-à-vis action is take waste out of the system. Another thing we can do is change the way care is delivered. The only true mistake is to keep doing the same thing we always did, and hope to get a different outcome.

Dr Beveridge: It is worth noting that Dartmouth College has a new institute, the Center for Health Care Delivery Science. Its goal is to change the way we think about the importance of the actual execution of care. The president of Dartmouth College has been quoted as saying that the real rocket science in medicine over the next 10 years is in the delivery of, and in the execution of, care. This is true. It is one way of wringing out the waste.

Dr Owens: The other piece of this is certainly changing the payment methodology. In oncology in particular, a lot is driven by drug cost and the way we reimburse for drugs. To change the system, we have to change the way we pay for it. That is another action item. We cannot be afraid to experiment with new payment methodologies and truly change them.

John Fox, MD, MHA: One of the things that Dr Beveridge brought up was the need to have processes for advance care planning. The National Comprehensive Cancer Network (NCCN) guidelines and the ASCO guidelines document the importance of advance care planning and trying to understand, through conversations with patients, what their goals, preferences, and priorities are for care at the end of life. Yet we don’t do advance care planning, not because we do not think it has value, but because it is uncomfortable, and we do not know how to integrate it into practice. The hard work this requires is not rocket science, just social science.

Oncology practices need to achieve consensus among the oncologists, develop the competence to have these discussions, and implement them through a process into the practice.

Waste, and often harm, occur when we provide treatments to patients that they would not have wanted had they known all their options. There is compelling evidence that having advance care planning discussion improves the patient experience in the healthcare system, improves health outcomes, and reduces cost of care—not because of denied care, but because we have provided the care that the patient truly wanted.

Dr Silver: My practice is an outlier, in that many of the patients I see have very low-prevalence diseases. Therefore, there are no guidelines, and there are no randomized trials for these diseases. In addition, because I am in Michigan, many of my patients work for ERISA corporations, and their insurance company is an administrator. Because the insurance says no, and because there is no evidence for the treatment, when I see a patient I call the human resources (HR) department of that patient’s company to check on insurance. We end up having a good conversation about their employee, about what the employee needs, and about this rare disease. The HR department, the patient, and I feel good about the next step, but I think that is unusual.

Dr Newcomer: At UnitedHealthcare, we are piloting a 6 medical group experiment that starts with an episode payment. We have created an episode payment that covers all of the patient care involved. As the physician group gets more effective in improving an outcome or in reducing the total cost of care, their amount of the episode payment will increase. And we are trying to reduce cost by having one third of the Continued on page 29

VOL. 3

I

NO. 6

2012 Conference

savings go to the group, roughly one third goes to UnitedHealthcare, and one third goes back to the employer in the form of a lower premium.

By now we know that we can get enough data to start figuring this out.

The 6 groups just met recently. We looked at 64 measures of cost, quality, and operational efficiencies and came back with some projects that we think will begin to reduce care in a number of areas. The reason I mention this is that it is an example of a payer sitting with 6 medical groups, and I never saw a finger pointed at someone the entire day. The questions were, “I wonder how we can fix this. We saw this problem in the data.

Now, how can we solve it? What do you do over here? How did you get such good results? What are you doing here that maybe makes you so variant, and how can we bring it down?”

The point is that we are all going to have to roll up our sleeves and probably work together. I do not think any of us can do this alone. We need to start more of the little projects that we have heard all day about—literally a dozen different attempts at trying to do this, but we need 100. Some of them will fail. A lot of them will succeed. But we are going to have to start faster and begin to collaborate and look at each other as partners. We need to figure out how we can get it done.

Dr Beed: How do we integrate survivorship services into the definition of value?

Dr Benson: This is a fundamental element of personalized medicine. It is not just the markers. The NCCN, for example, has created a partnership in terms of employers. What are the fundamental aspects of a cancer program that truly provide comprehensive care? We have talked about the absurd way drugs have been reimbursed for oncologists, but that has created the margin so that programs could integrate many of these other services that are otherwise not paid for. One of the enormous challenges is how do we fairly reimburse these essential services that are hallmarks for appropriate care?

Another challenge is access. Someone who is in a rural community, for example, may not even have an oncologist. How can we make these services available to much larger populations? It is one thing to be a patient at my cancer center, where we have all of these services on the same floor, so the day patients are being seen, they can get insurance counseling, nutrition counseling, or psychosocial support, for example, if they need them. We can quickly

VOL. 3

I

NO. 6

get all of that integrated, but that is not true in many situations.

A freestanding practice may not be able to provide all of those services right in its own facility; this gets us into the referral mechanisms. It is also an issue when we talk about accountable care organizations and bundled payments for

Another challenge is access.

Someone who is in a rural community, for example, may not even have an oncologist.

How can we make these services available to much larger populations?

—Al B. Benson, III

care. Not everyone needs all of the services we may have available, such as nutrition services or psychological support. But how do we make sure, when we are talking about episodic care reimbursement, that we are integrating all these other essential services that we now have to pay for, often in a way that comes from philanthropy or from other sources, but not because we are billing for these services?

Dr Beed: Is this just another sign of the toxicity of our à-la-carte system of billing?

Dr Malin: This gets at the issue we were getting at earlier of early detection versus surveillance. When we talk about survivorship care, we need to think about who are the people at risk in the transition. It should not be one-size-fitsall survivorship care anymore than it should be for active treatment. We need to think about when to integrate people back into primary care, who are the people who truly need the extra support, and what are the best models to deliver that kind of care.

Dr Sprandio: One of the things that would be very helpful is if we all agreed on a core set of services that are inherent to providing good patient-centered care that everyone would reimburse. That is not restricted to cancer only. Any patient who has a chronic disease would benefit from that. There is no patient mechanism for that today, because there are no margins on drugs.

That is one challenge, and I agree that when we look at whole person care, there are a set of services that we could all agree are important to that patient’s care but that we do not pay for today.

Dr Beed: Can anybody argue that there are not significant dollars to be saved by removing futile care?

Dr Beveridge: We have had 9 pilot studies in the US Oncology Network looking at end of life. We have piloted putting palliative care physicians in practices. We have trained nurses in palliative care. We have trained nurse practitioners. We have a large number of palliative care physicians in our 1400-physician network at this point.

But the common theme is—when providers can speak to the patient with metastatic disease early, which our data clearly support, there is a higher use of palliative care; there is a greater use of appropriate hospice treatment; the days in hospice increase significantly; and the number of days using a drug therapy decrease.

The number of physicians trained in palliative care in the country is so small that they cannot even begin to take up the slack. The average reimbursement for a palliative care physician across the country is less than $210,000, and on the East Coast, in Washington, DC, in particular, the average compensation for a palliative care physician is less than $145,000.

The other thing we have not talked about is the waste that exists when we continue chemotherapy in the face of progressive disease. I have had many oncologists say, “The patient wants to continue treatment, even though their disease has progressed.” Is that a waste, because we are not willing to have a

conversation with the patient?

Therefore, not only do we need guidelines on disease surveillance and disease progression, but we also need clear guidelines on when to stop therapy, what to do when patients progress, and whether we should add fourth- or fifthline therapy.

Dr Deligdish: We do not need guidelines about treating or not treating a patient when a patient’s disease is progressing. This is intuitively obvious, and it is a very small minority of oncologists, I hope, who are treating patients with the same treatment when a patient’s disease is progressing. If we cannot accept that, then the problem is that we do not have access to data that can demonstrate that either way.

We need to be very clear on this; we have talked a lot about advanced illness programs and a little bit about palliative care programs. It is very important to differentiate between these 2 entirely different approaches.

Advanced illness programs have been around for more than a decade. We have all heard about the number of successful pilots that have been conducted.

However, there are many examples in which payers have adopted these programs, but they have failed to educate patients or providers as to their availability. In these situations, the programs are not utilized.

Palliative care is quite different.

Palliative care can extend survival in patients with cancer, in addition to enhancing QOL.

Call to Action In closing, the amount of information that we covered is very impressive. We did our best to define value from the different stakeholders’ points of view, and we decided it is inextricably linked to cost and action.

Based on this discussion, I have formed the following 7 actionable steps needed to develop a highly valuable cancer care system: 1. Get rid of waste 2. Change the systems of care, and do not be afraid to experiment with multiple new systems of care, because no one answer is going to be the right answer 3. Change the payment systems; ultimately, the payment systems have to be changed to reward value, however we define it 4. Use new technology judiciously; we heard some examples of where technology was not used wisely—newer

SEPTEMBER 2012

I

is not always better, until it is proved better, but it is generally more expensive 5. Introduce data collection and data integration improvements across the system, whether real-world or clinical trial data: ultimately we cannot manage a system that we cannot measure; that is almost axiomatic 6. Improve communication across all stakeholders 7. Finally, do not be afraid to try new things and be willing to try multiple things. ■

www.ValueBasedCancerCare.com

29

MASCC Symposium

Economics Impede Growth of Supportive...

M.D. Anderson Cancer Center, Houston, speaking at the 2012 Multinational Association of Supportive Care in Cancer International Symposium. “Financial distress is a huge elephant in the room,” Dr Bruera stated.

More studies are needed to demonstrate dollar savings achieved by supportive care, but the optimal design of these studies is not clear. Direct costs and revenues have been identified, but the savings achieved by supportive care are not well known, Dr Bruera told the audience. Research in supportive care needs to be independent, so that the design of studies does not lead to bias.

The Economic Analysis Conundrum “Some misconceptions related to economic analyses are that ‘cost-effective’ means cost-saving, low cost is economically attractive, large cost is economically unattractive, and that preventive therapies save money,” Dr Bruera commented.

The ideal design of studies to show

cost-effectiveness of supportive care could include several outcomes—cost per life saved, cost per death averted, and reduction in symptom domains.

“Financial distress is a huge elephant in the room….We are moving to clinical outcomes that will have a dollar value. We are being told what those outcomes are, and we need to develop a way to show savings.”

—Eduardo Bruera, MD

The less expensive supportive care program may not turn out to be the best approach from an economic point of view. “A cheaper program could end up costing more in healthcare resource utilization in the end,” Dr Bruera stated.

Other considerations in demonstrating economic benefits include cost-

utility analysis, outcomes, refractory symptoms requiring sedation, and hospitalization.

A cost-benefit analysis measures costs and health outcomes by assigning a dollar value to someone’s life or to symptoms.

Economic analyses should include the perspectives for the analysis (ie, society, the patient, and the institution), the rationale for costs included in the analysis, a description of the benefits and harms, discounting if costs and benefits accrue during different periods, an incremental cost analysis, and a sensitivity analysis.

When supportive care is initiated early, clinical outcomes are improved, which is economically attractive for payers, such as hospitals, health plans, and government agencies.

“We are moving to clinical outcomes that will have a dollar value.

We are being told what those outcomes are, and we need to develop a way to show savings. But economic studies need to be done in the context of a specific healthcare system,” Dr Bruera noted.

See also page 32 Continued from cover Need for Comprehensive Inpatient Supportive Care Program Dr Bruera emphasized that the environment in which supportive care is delivered is place-specific, and what works in one setting may not be a good fit in another. M.D. Anderson Cancer Center, where he works, is the only comprehensive inpatient supportive care program in the United States, he said.

In general, the environment in comprehensive cancer centers is more favorable for supportive care clinics than in noncomprehensive cancer centers. A recent survey suggested that approximately 50% of comprehensive cancer centers plan to increase supportive care services compared with 25% of noncomprehensive cancer centers.

In the United States, payment for services is being increasingly linked to outcomes. The National Quality Forum recently identified 4 important outcomes related to payment—intensive care unit deaths, reduced admissions to the emergency department in the past 30 days, chemotherapy administered ≤14 days before death, and a reduction of overall payment. ■

Use of G-CSF Agents Prevents Febrile Neutropenia, but High Cost Limits Their Utilization

By Phoebe Starr New York, NY—Two major advances over the past decades have improved the management of febrile neutropenia (FN)—the MASCC (Multinational Association of Supportive Care in Cancer) scoring system for predicting the risk of FN, and the use of granulocyte colony-stimulating factors (GCSFs) for the prevention of FN. However, the need for improvement still exists, said Jean Klastersky, MD, Professor, Institut Jules Bordet, Brussels, Belgium, at the 2012 MASCC International Symposium. Among the remaining challenges is refining the optimal use of these agents.

According to Dr Klastersky, current guidelines restricting the use of prophylactic G-CSFs to high-risk patients are based on economic, not on scientific, considerations. He believes that the criteria should be expanded to incorporate patients at a lower risk of developing FN, because when FN develops, costly and lifethreatening complications are similar in all risk groups. Furthermore, stud-

30

ies show that the benefits of preventing FN are similar in low-risk and high-risk patients.

mortality rate is about 5%, but even a 5% mortality rate is too high, Dr Klastersky said.

Treating low-risk patients on an outpatient basis reduces the cost of FN treatment by approximately 50%. The mean cost of treating 1 episode is $7700 in an outpatient setting and $15,231 in the inpatient setting. Growth factors account for a good part of the costs associated with hospitalization.

Over the past 3 decades, FN-related mortality and morbidity have declined, and therapies are less toxic and more appropriately geared toward risk status. The complications of FN can include hypotension, respiratory failure, intensive care unit admission, and confusion; 30 years ago, these complications were fatal for many patients. Currently, the rate of complications is 10% to 20%, and the

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Treating low-risk patients on an outpatient basis reduces the cost of FN treatment by approximately 50%. The mean cost of treating 1 episode is $7700 in an outpatient setting and $15,231 in the inpatient setting.

Growth factors account for a good part of the costs associated with hospitalization, Dr Klastersky said.

The MASCC scoring index for FN predicts the risk for complications,

which is calculated based on total symptom burden and on individual symptoms. A MASCC index score >20 predicts a 5% (ie, low) risk for complications. Low-risk patients can be effectively treated as outpatients, with oral antibiotics after a 24-hour observation period in the hospital.

Patients with a MASCC score <15 are at higher risk of severe sepsis and mortality if FN develops. According to Dr Klastersky, the management of this group of patients should be more aggressive. Protocols are needed and treatment should be initiated with intravenous antibiotics before several hours elapse.

Because of the high cost associated with the G-CSFs, their use is typically recommended in patients with a ≥20% risk for FN, and growth factors are typically withheld from patients with a 10% risk of developing FN. Dr Klastersky said that further study is needed to determine whether the criteria for G-CSF prophylaxis should include lower-risk patients. ■

VOL. 3

I

NO. 6

Image: Colored scanning electron micrograph (SEM) of a lymphoma cancer cell.

One focus: discovering and delivering breakthrough medicines to combat cancer.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers.

Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation.

We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

To learn more, visit us at millennium.com. ©2012 Millennium Pharmaceuticals, Inc. All rights reserved.

Health Policy

Medicare Proposes Rewarding Quality, Cutting Payments for Oncology Providers

By Ross D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPH Mr Margulies is an Associate at Foley Hoag, LLP, Washington, DC; Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC

O

n July 6, 2012, the Centers for Medicare & Medicaid Services (CMS) issued the Physician Fee Schedule (PFS) and Hospital Outpatient Prospective Payment System (HOPPS) proposed rules for fiscal year 2013. These rules include a number of proposed changes aimed at improving quality and promoting value in cancer care in the Medicare program. Although many of these changes are positive, a number of proposed cuts to payment rates, particularly to services performed by radiation oncologists, could have a devastating impact on oncology providers and patients.

In this article we highlight some of the major proposals that will impact the entire oncology team. Of particular note is the addition of a new oncology group in the Physician Quality Reporting System (PQRS), as well as a

Ross Margulies

Jayson Slotnik

new G-code for postdischarge transitional care management services.

These 2 additions highlight an increased focus on paying for value and for quality in the oncology space. The final rules are expected to be published later this fall.

The 2013 PFS Proposed Rule The 2013 PFS proposed rule takes several major steps toward increasing the value and the efficiency of oncology care. Specifically, CMS continues the

process of implementing the valuebased payment modifier required by the Affordable Care Act (ACA), including the addition of a new oncology group in the PQRS. Furthermore, CMS proposes to create a new Healthcare Common Procedure Coding System G-code that would be used to describe postdischarge transitional care management services furnished within 30 days after the date of discharge from an inpatient facility.

This new oncology group encompasses 8 quality measures, including hormone therapy for estrogen receptor/progesterone receptor–positive breast cancer; chemotherapy for stage III colon cancer; influenza immunization; documentation of current medications in the medical record; quantification of pain intensity for patients with cancer who are treated with chemotherapy or radiation therapy;

plan of care for pain for patients with cancer who are treated with chemotherapy or radiation therapy; documentation of cancer stage for patients with breast, colon, and rectal cancers; and screening and cessation counseling for tobacco use. These measures promise to further reward (or negatively adjust) payment rates for groups of eligible providers who meet the proposed criteria for satisfactory reporting of data. The addition of a new oncology group opens a new pathway for oncology providers to successfully participate in the PQRS, which is a positive step toward rewarding better cancer care.

CMS also proposes to create a new G-code for calendar year 2013 that specifically describes postdischarge transitional care management services, including all non–face-to-face Continued on page 33

See also page 30

MASCC Symposium

Molecularly Targeted Agents Have Lower Rates of Severe Diarrhea than Standard Chemotherapy

By Phoebe Starr New York, NY—Diarrhea is a common side effect of standard chemotherapy, but the risk is less well characterized with molecularly targeted agents, which may add to the risk of diarrhea when combined with standard chemotherapy, according to Lowell Anthony, MD, Professor of Medicine, University of Kentucky, and Chief of Medical Oncology, UK HealthCare, Lexington, who discussed this topic at the 2012 Multinational Association of Supportive Care in Cancer International Symposium.

Diarrhea induced by any treatment can increase morbidity and mortality, leading to increased resource utilization and costs of care, if not controlled at the outset, Dr Anthony stated.

“Grade 1 and 2 diarrhea can quickly spiral downward to grades 3 and 4 if not controlled, requiring hospitalization and even causing death,” he told listeners. “Only you can really prevent the spiral of diarrhea.”

Diarrhea, especially when it is severe, requires increased healthcare

32

resources to manage sequelae, such as fatigue and malaise, abdominal cramping, incontinence, increased anxiety, perineal pain, malnutrition, weight loss, and immobility.

“Targeted therapies can cause diarrhea, but nowhere near the amount that is associated with irinotecan.”

—Lowell Anthony, MD

Chemotherapy-induced diarrhea is seen with 5-fluorouracil, irinotecan, paclitaxel, high-dose epirubicin, and other standard chemotherapies. Molecularly targeted therapies, such as bortezomib, bevacizumab, epidermal growth factor receptor inhibitors, and the multitargeted tyrosine kinase inhibitors sunitinib and sorafenib, also cause diarrhea.

“Targeted therapies can cause diar-

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

rhea, but nowhere near the amount that is associated with irinotecan,” noted Dr Anthony. “With targeted therapy, the only good news is that the rates of serious grade 3 and 4 diarrhea are under 10%, but they do cause grades 1 and 2 diarrhea. In general, treatment delays are not necessary, and we don’t stop treatment.”

Dr Anthony cited the following rates of diarrhea associated with molecularly targeted agents that have been reported in various clinical trials: • Bortezomib—45%, any grade • Cabozantinib—57%, grades 1-4 • Lapatinib—48%-64%, any grade • Regorafenib—32%, grades 1-4 • Vandetanib—56%, grades 1-4.

Diarrhea is treated in the context of other side effects associated with molecularly targeted agents, Dr Anthony noted, such as peripheral neuropathy or cardiovascular side effects (eg, QTc prolongation, hypertension, and heart failure).

Dr Anthony emphasized the importance of a differential diagnosis and

identifying the correct etiology for diarrhea. Etiology can include an infection on top of toxic injury, increased motility, or hyperthyroidism, he pointed out. Chemotherapy-induced diarrhea is secretory and continues after patients stop eating.

Risk factors for chemotherapyinduced diarrhea include previous chemotherapy, previous pelvic irradiation, performance status, the presence of chemotherapy-induced diarrhea on a previous treatment cycle, increased age, and female gender.

Three drugs or drug classes are guideline-recommended for chemotherapy-induced diarrhea, including loperamide, opium derivatives, and octreotide. The treatment of grades 1 or 2 uncomplicated diarrhea entails the ingestion of adequate fluids and dietary intervention with the BRAT (bananas, rice, applesauce, and toast) diet. Patients with grade 3 or 4 diarrhea may require hospitalization, antibiotics, octreotide, and intravenous fluids. ■

VOL. 3

I

NO. 6

Health Policy services related to transitional care management that are provided by a community physician or by a qualified nonphysician practitioner within 30 calendar days after the date of discharge to community-based care from an inpatient acute-care hospital, psychiatric hospital, long-term care hospital, skilled nursing facility, inpatient rehabilitation facility, hospital outpatient for observation services, or partial hospitalization services. This new code is a dramatic step forward in rewarding a healthcare system that provides a continuum of quality care.

Oncology providers will play an important role in ensuring appropriate transitions to and from facilities.

The PFS and HOPPS proposed rules signal an increasing shift in paying for value. Although a number of cuts to providers are concerning, the focus paid to rewarding quality cancer care is encouraging.

Among the most criticized of proposals from CMS in the 2013 PFS rule relates to a dramatic reduction in payment for 2 radiation therapy services.

In the proposed rule, CMS indicated that based on patient experience information obtained about the length of intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), it will reduce the procedure time for both treatments to more accurately take into account actual patient experiences. As a result, CMS proposes to reduce the procedure time for delivery of IMRT from 60 minutes to 30 minutes and for delivery of SBRT from 90 minutes to 60 minutes (a 40% and 28% reduction, respectively).

Under this proposal, total payments to radiation oncologists would be reduced by 7%, and payments to radiation therapy centers would decline by 8%. When combined with other proposed changes to the PFS, payments to these providers would be reduced by 15% and 19%, respectively.

The 2013 HOPPS Proposed Rule Among the most significant of proposals in the 2013 HOPPS rule for the cancer community is a continuance of a hospital-specific payment adjustment for cancer hospitals to reflect the higher costs associated with cancer hospitals. This positive payment adjustment builds on the

VOL. 3

I

NO. 6

policies adapted in the 2012 HOPPS rule, and it is determined to address the concerns of many providers and patients that the outpatient costs incurred by cancer hospitals exceed the costs incurred by other hospitals.

The ACA directed the Secretary of Health and Human services to study this concern, and, if costs were found

to be higher, directed the secretary to adjust payment to appropriately reimburse cancer hospitals for the higher cost burden. For 2013, CMS proposes to continue the policies adopted in last year’s final rule, including adopting a target payment-to-cost ratio of 0.91 for eligible cancer hospitals.

Overall, both the PFS and HOPPS proposed rules signal an increasing shift in paying for value. Although a number of cuts to providers are concerning (and a looming cut to the sustainable growth rate remains on the horizon), the focus paid to rewarding quality cancer care is encouraging. ■

ts and Providers with the Reimburse n e i t a P ment g Proc Helpin ess 1-888-587-3263 www.TevaCORE.com

Our C RE commitment CORE Hotline Offers Assistance Related to: Benefit verification and coverage determination Precertifications / prior authorization support Coverage guidelines and claim requirements of payers Personalized support through the claims and appeals process Templates for letters of medical necessity Cephalon Oncology Patient Assistance Program

To enroll in CORE Phone 1-888-587-3263 Monday through Friday, 9 AM to 8 PM (ET), fax 1-866-676-4073, or visit www.TevaCORE.com

Supporting Teva Oncology Products Reimbursement Assistance and Support through CORE - the Comprehensive Oncology Reimbursement Expertise Program

CephalonCares® Foundation offers a Patient Assistance Program to provide FDA-approved products free of charge for patients who qualify.

Teva Oncology also partners with patient advocacy organizations, such as the Leukemia & Lymphoma Society, and others that have programs designed to help patients access the treatment they need.

© Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved, ONC-2139, Printed in USA

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

33

Drug Update

Carfilzomib a New Option for the Treatment of Patients with Relapsed, Refractory Multiple Myeloma Previously Treated with Bortezomib and an Immunomodulatory Agent

By Lynne Lederman, PhD, Medical Writer

M

ultiple myeloma (MM), a clonal malignancy of plasma cells, is responsible for 10% to 15% of all hematologic malignancies and for 20% of deaths resulting from hematologic cancers.1,2 In most patients, MM evolves from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic plasma-cell disorder.

In some patients, MGUS progresses through an intermediate, asymptomatic, premalignant stage, smoldering MM, before the disease is diagnosed.1,2 Although the cause of MM is not known, it is more common in older individuals aged >65 years than in younger persons, is more common in blacks than in whites, and is slightly more common in men than in women. Other factors associated with MM include exposure to certain chemicals, being overweight or obese, having been exposed to radiation, or having another plasmacell disorder.3

The Burden and Impact of Multiple Myeloma In 2012, the American Cancer Society estimated that there would be 21,700 patients diagnosed with MM and 10,710 deaths would occur from MM.4 Patients with MM frequently experience fatigue, bone pain, osteolytic bone lesions, and/or compression fractures.5 End-organ damage, including hypercalcemia, anemia, renal dysfunction, or bone lesions caused by proliferation of myeloma cells, is considered diagnostic of symptomatic MM.6 Patients with MM experience leukopenia and thrombocytopenia in addition to anemia, and they are at risk for recurrent infections. Also, peripheral neuropathy (PN) can be present at diagnosis. This is important, because cytopenias and PN are significant toxicities associated with some antimyeloma therapies.2 The median survival for patients with MM was less than 1 year before the introduction of alkylating agents in the 1960s. Median survival increased with the introduction of high-dose chemotherapy and autologous stem-cell transplant (ASCT) in the 1980s.7 Supportive therapies, such as growth factors, bisphosphonates, and improved modalities to treat frac-

34

tures, have also played a role in increasing survival.2,7 Much of the increased survival for patients with MM since approximately 2000 can be attributed to the development of novel, targeted therapies, including the immunomodulatory agents thalidomide and lenalidomide, and the proteasome inhibitor bortezomib.7 Current treatment approaches for newly diagnosed or relapsed MM are based on patient-specific factors, such as eligibility for ASCT and the presence of comorbidities, and diseaserelated factors, such as high-risk characteristics.2 Almost all patients with MM will eventually experience a relapse. The duration of remission in patients with relapsed MM is shorter with each successive treatment regimen.8 Once MM relapses, it tends to become more resistant to chemotherapy over time, and patients are likely to require continuous treatment with one regimen after another as their disease progresses.2 Therefore, despite the progress in developing novel, targeted therapies, MM remains incurable.7

“Carfilzomib is an exciting new option for our patients with progressive disease after receiving treatment with bortezomib and lenalidomide.”

—Jamie Shapiro, PharmD, BCOP

Carfilzomib Fills an Unmet Need On July 20, 2012, the US Food and Drug Administration (FDA) granted accelerated approval for carfilzomib for injection (Kyprolis; Onyx Pharmaceuticals), which is indicated for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (thalidomide or lenalidomide), and have demonstrated disease progression on or within 60 days of the completion of the last therapy.9 Currently, the median survival for patients with MM that is refractory to bortezomib is 9 months; for those with MM refractory to lenalidomide,

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Table 1

Disease Characteristics and Patient Baseline Demographics

Patient characteristic Total patients, N

266

Median age, yr (range) Sex, N (%) Male Female Race, N (%) White Black Asian Other Years since diagnosis, median, N (range)

63 (37-87)

Prior regimens, median, N (range)

5 (1-2)

Prior transplants, N (%)

198 (74.4)

155 (58.3) 111 (41.7) 190 (71.4) 53 (19.9) 6 (2.3) 17 (6.4) 5.3 (0.5-22.3)

Adapted from Kyprolis (carfilzomib) for Injection [prescribing information].

South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012. the median survival is only 5 months.8 As the second-in-class– approved proteasome inhibitor, carfilzomib should provide a new option for patients whose MM has become resistant to bortezomib, the first-approved proteasome inhibitor for MM.10 The approval of carfilzomib was based on the response rate determined in a single-arm clinical trial and is not based on survival. Furthermore, a clinical benefit (eg, increased survival or improved symptoms) has not been confirmed.9,11 As a condition of the accelerated approval, Onyx Pharmaceuticals will submit the results of an ongoing phase 3 randomized trial comparing lenalidomide plus low-dose dexamethasone with lenalidomide plus low-dose dexamethasone plus carfilzomib in patients with MM that has relapsed or is refractory after 1 to 3 prior therapies. The primary end point of this phase 3 trial is progression-free survival.9 Carfilzomib is not currently indicated for the treatment of newly diagnosed MM. According to Jamie Shapiro, PharmD, BCOP, Clinical Coordinator at H. Lee Moffitt Cancer Center, Tampa, FL, “Carfilzomib is an exciting new option for our patients with progressive disease after receiving treatment with bortezomib and lenalidomide.

Carfilzomib is an important addition to our antimyeloma therapies and meets an unmet need in our patients with

progressive multiple myeloma.”

Page Bertolotti, RN, BSN, OCN, of Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, commented that, “Carfilzomib is an important treatment option for our patients with refractory multiple myeloma. We had several patients who missed the clinical trial enrollment and waited anxiously for the approval.”

Clinical Pharmacology

Mechanism of Action Carfilzomib is in the epoxyketone class of proteasome inhibitors and irreversibly binds to the proteolytic core particle within the 26S proteasome.

Carfilzomib has selectivity for the chymotrypsin-like activity of proteasome, and in preclinical studies it has induced cell-cycle arrest and programmed cell death and activated stress response pathways.10,11 Pivotal Phase 2 Clinical Trial Carfilzomib was approved by the FDA based on the results of a singlearm, multicenter phase 2 clinical trial enrolling 266 patients with relapsed MM who had received at least 2 previous therapies that included bortezomib and either thalidomide or lenalidomide.9 The results of this trial have recently been published.12

Trial Design The trial included patients with MM Continued on page 36

VOL. 3

I

NO. 6

www.avbcconline.org

MAY 2-5, 2013

THIRD ANNUAL CONFERENCE

Influencing the Patient-Impact Factor May 2-5, 2013 Westin Diplomat Hollywood, Florida

For more information please visit

www.AVBCConline.org

!

Drug Update

Carfilzomib a New Option for the Treatment... who had a response rate of ≤25% to the most recent therapy or had disease progression during or within 60 days of the most recent therapy they received before enrolling in the trial.

Patients received carfilzomib by intravenous (IV) infusion over 2 to 10 minutes on 2 consecutive days weekly for 3 weeks followed by a 12-day rest period (one 28-day cycle) until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. The carfilzomib dose was 20 mg/m2 for the first cycle and was escalated to 27 mg/m2 for subsequent cycles.

Premedication with 4 mg of dexamethasone was administered before each dose during cycle 1 and during the first dose escalation cycle and subsequently, when needed, to reduce the incidence and severity of infusion reactions.11

Patient Population Key baseline patient demographic and disease characteristics are listed in Table 1.

Safety Profile The most common adverse reactions experienced by ≥30% of patients in clinical trials included fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

The safety of carfilzomib as monotherapy or with premedication with dexamethasone has been assessed in 526 patients with relapsed and/or refractory myeloma.

This patient population includes the 266 patients treated in the phase 2 approval trial. Patients received a median of 4 treatment cycles of carfilzomib.

Of the total population, there were 37 deaths (7%) within 30 days of the

Table 2

last carfilzomib dose, including 21 from disease progression; 5 from cardiac issues (eg, acute coronary syndrome, cardiac arrest, and cardiac disorder); 4 from end-organ failure (ie, multiorgan, hepatic, and renal); 4 from infection; and 1 each from dyspnea, intracranial hemorrhage, and unknown causes.11 Serious adverse reactions were reported in 45% of patients receiving carfilzomib—the most common being pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). In addition, 15% of the patients had serious adverse reactions that led to the discontinuation of carfilzomib monotherapy.11 Peripheral neuropathy. PN is often associated with MM therapies. Anygrade PN occurred in 14% of patients enrolled in carfilzomib clinical trials, but only 1% of patients experienced grade 3 PN. Serious PN events resulting in dose reductions or treatment discontinuations occurred in <1% of patients.11 The incidence of PN associated with carfilzomib is lower than that associated with thalidomide or with bortezomib, and the low rate of new-onset or worsening PN suggests that patients with PN associated with other therapies may be able to tolerate treatment with carfilzomib.12 Commenting on carfilzomib, Dr Shapiro noted that, “One of the most beneficial aspects with carfilzomib is the low incidence of peripheral neuropathy.”

Renal events. The most common renal adverse reactions of any grade were increased blood creatinine (24%) and renal failure (9%). Grade 3 renal events occurred in 6% of patients and grade 4 in 1%. Discontinuations result-

Carfilzomib Dosing Regimen

Dosing for cycle 1 Week 1 Week 2 Week 3 Week 4 Carfilzomib Day Day Days Day Day Days Day Day Days Days 20 mg/m2 1 2 3-7 8 9 10-14 15 16 17-21 22-28 20

20

No dosing

20

No dosing

20

20

20

No No dosing dosing

Dosing for cycles 2 and beyonda Week 1 Week 2 Week 3 Week 4 Carfilzomib Day Day Days Day Day Days Day Day Days Days 27 mg/m2 1 2 3-7 8 9 10-14 15 16 17-21 22-28 27

27

No dosing

27

No dosing

27

27

27

No No dosing dosing

a

If previous cycle dosing is tolerated.

Adapted from Kyprolis (carfilzomib) for Injection [prescribing information].

South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

36

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

Table 3

Continued from page 34

Carfilzomib Warnings and Precautions

Warnings and precautions Description Cardiac events

• Cardiac failure in 7% of patients • Death resulting from cardiac arrest within 1 day of administration reported • Patients with heart failure, myocardial infarction within preceding 6 months, and uncontrolled conduction abnormalities may be at increased risk

Pulmonary arterial hypertension

• Reported in 2% of patients • ≥Grade 3 in <1%

Pulmonary complications

• Dyspnea in 35% of patients in clinical trials • Grade 3 in 5% • 1 death reported

Infusion reactions

• Characterized by fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina • Can occur immediately or up to 24 hours after administration • Premedication with dexamethasone reduces incidence and severity

Tumor lysis syndrome

• Occurred in <1% of patients • High tumor burden may increase risk • Ensure patients are well hydrated before administration

Thrombocytopenia

• Occurred in 36% of patients • Grade 4 in 10% • Platelet nadirs around day 8 of each cycle, recover to baseline by start of next cycle • Monitor platelet counts frequently

Hepatic toxicity and hepatic failure

• Hepatic failure including deaths in <1% of patients • Carfilzomib can cause elevated serum transaminases and bilirubin • Monitor liver enzymes frequently

Adapted from Kyprolis (carfilzomib) for Injection [prescribing information].

South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

ing from increased blood creatinine and acute renal failure, each, occurred in 1% of patients. Furthermore, 1 patient died from concurrent sepsis and worsening renal function.11

OS of 9 months in similar settings.

Response and survival may have been affected by treatment discontinuation resulting from progressive disease in almost 23% of patients in the first 2 treatment cycles.12

Response Response rates for the phase 2 approval trial population were determined by an independent review committee.11 The overall response rate was 22.9% (n = 61); of these, 17.7% of patients (n = 47) achieved a partial response (PR); 4.9% (n = 13) achieved a very good PR, and 0.4% (n = 1) achieved a complete response. The median duration of response was 7.8 months.11 Overall survival (OS) was 15.6 months in this group of patients with heavily pretreated MM refractory to or intolerant of bortezomib and lenalidomide, and compares favorably to an

Dosing and Administration Carfilzomib is administered intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks on days 1, 2, 8, 9, 15, and 16, followed by a 12-day rest period from days 17 to 28. These 28 days constitute 1 treatment cycle.11 This dosing regimen is shown in Table 2.

The dose for cycle 1 is 20 mg/m2 using the baseline patient’s body surface area. If this dose is tolerated, the dose is increased to 27 mg/m2 beginning at cycle 2, and the dose is maintained at this level for subsequent cycles.11 Continued on page 37

VOL. 3

I

NO. 6

Drug Update

Carfilzomib a New Option for the Treatment...

Hydration and Premedication Patients should be hydrated with IV normal saline or with another appropriate IV fluid before each dose of carfilzomib in cycle 1 and after administration, as needed, to reduce the risk of renal toxicity and tumor lysis syndrome. Maintaining adequate hydration and monitoring blood chemistries is recommended.

Hydration can be continued for subsequent cycles if needed.11 To reduce the incidence and severity of infusion reactions, patients should receive premedication with 4-mg oral or IV dexamethasone before all doses in cycle 1 and the first cycle of escalation to the higher dose. Premedication with this dose of dexamethasone may be administered if infusion reactions occur or recur during treatment.11

6. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol.

2003;121:749-757.

7. Kumar SK, Rakjumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

Continued from page 36

8. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2010;86:57-65.

9. US FDA Drug Approvals and Databases. Carfilzomib. www.fda.gov/Drugs/Information OnDrugs/ Approved Drugs/ucm312945.htm. Accessed July 21, 2012.

10. Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years later.

Blood. 2012;120:947-959.

11. Kyprolis (carfilzomib) for Injection [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Jul 25. [Epub ahead of print.]

RJ Health Systems The Creators of ReimbursementCodes.com

Dose Modifications Based on Toxicity

RJ Health Systems — the pharmaceutical specialists that healthcare

The dose of carfilzomib may be modified if hematologic or nonhematologic toxicities occur, including grade 3 or grade 4 cytopenias; cardiac, hepatic, or renal toxicities; pulmonary complications; PN; or other toxicities.

In general, carfilzomib is withheld until resolution, followed by restarting therapy at the same or at a reduced dose, depending on the type of toxicity and whether it was attributable to carfilzomib.11

professionals have turned to since 1983 for their drug information.

Warnings and Precautions A number of adverse reactions associated with carfilzomib are discussed in the “Warnings and Precautions” section of the prescribing information (Table 3).11 These reactions, which may require dose modification, include cardiac arrest, congestive heart failure, myocardial ischemia, pulmonary hypertension and other complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, and hepatic toxicity and failure.11 Women of child-bearing potential are advised to avoid becoming pregnant during treatment with carfilzomib, because it has been shown to cause fetal harm in animal studies.11 ■

ReimbursementCodes.com incorporates the CMS HCPCS and AMA

We work with over 170 Payor organizations that touch approximately 110 million lives.

RJ Health Systems has established and continuously maintains a Library of Drug Intelligence that provides the most comprehensive, trusted, and up-to-date coding and reimbursement information in the industry.

CPT Drug codes into a system that crosswalks each drug code with the drug’s NDC and brand/generic name.

Please visit www.rjhealthsystems.com to learn more about our products and services listed below:

>> >> >> >> >> >> >> >> >>

References 1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood.

2008;111:2962-2972.

2. Laubach J, Richardson P, Anderson K. Multiple myeloma. Ann Rev Med. 2011;62:249-264.

3. American Cancer Society. Multiple myeloma overview.

2011. www.cancer.org/acs/groups/cid/documents/ webcontent/003065-pdf.pdf. Accessed August 28, 2012.

4. American Cancer Society. Cancer Facts & Figures 2012.

Atlanta, GA: American Cancer Society; 2012. www.cancer. org/acs/groups/content/@epidemiologsurveilance/ documents/document/acspc-031941.pdf. Accessed August 28, 2012.

5. Rajkumar SV. Multiple myeloma. Curr Probl Cancer.

2009;33:7-64.

VOL. 3

I

NO. 6

ReimbursementCodes.com Drug Diagnosis Coding CMAC PartBorPartD.com NDC Conversion Database Min/Max Dosing Advisories Notations Clinical Consulting

rjhealthsystems.com

1

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com 1

37

CONTINUING EDUCATION SEPTEMBER 2012 • VOLUME 4 • NUMBER 2

4th Annual

CONSIDERATIONS

Lymphoma

™

IN

ASK THE EXPERTS: Follicular Lymphoma LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

According to recent estimates from the American Cancer Society, approximately 70,130 individuals will be diagnosed with non-Hodgkin lymphoma (NHL) in 2012 and about 18,940 deaths will be attributed to the disease. There has been significant progress in the treatment of these hematologic malignancies, including the development and approval of new, highly effective therapies. However, more progress is needed and numerous questions remain unanswered regarding the application and interpretation of recent clinical advances.

The goal of our 4th annual “Considerations in Lymphoma” newsletter series is to provide clinicians with the latest evidence-based strategies for managing NHL in the era of novel agents. To address the needs of key members of the interdisciplinary team, frequently asked questions have been posed to physicians, midlevel providers, and pharmacists from leading cancer centers specializing in the treatment of lymphoma. In this second issue, experts from Winship Cancer Institute at Emory University discuss the effective management of follicular lymphoma. It is our hope that the insight, knowledge, and professional experience offered by these professionals will facilitate the optimal care of your patients with NHL.

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Sincerely, Director, Production and Manufacturing Alaina Pede

Stephanie A. Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University Chicago, IL

Director, Creative and Design Robyn Jacobs

Quality Control Director Barbara Marino

Director, Digital and Media Anthony Romano

FACULTY

Web Coordinator Jose Valentin

Christopher R. Flowers, MD, MS Associate Professor of Hematology and Medical Oncology Emory School of Medicine Winship Cancer Institute Atlanta, GA

Digital Content Specialist David Maldonado

Business Manager Blanche Marchitto

Bookkeeper Teresa Torgersen

Executive Administrator Jackie Luma

Center of Excellence Media, LLC 1249 South River Road Suite 202B Cranbury, NJ 08512

VALUE-BASED CANCER CARE

Nassoma King, PA-C Physician Assistant Winship Cancer Institute Emory University Atlanta, GA

Lisa Anderson, RN, BSN, OCN Clinic Nurse Emory Bone Marrow and Stem Cell Transplant Center Winship Cancer Institute Atlanta, GA

Supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals

Circulation Department circulation@greenhillhc.com

38

Loretta J. Nastoupil, MD Hematology/Oncology Fellow Emory School of Medicine, Winship Cancer Institute Atlanta, GA

This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

I

SEPTEMBER 2012

VOL. 3

I

NO. 6

CONSIDERATIONS IN LYMPHOMA Sponsor This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with follicular lymphoma.

Educational Objectives Upon completion of this activity, the participant will be able to: • Review current and novel treatment approaches for optimizing clinical outcomes in patients with follicular lymphoma (FL) • Summarize expert guideline recommendations and clinical trial data to determine appropriate treatment plans for patients with newly diagnosed and relapsed/refractory FL • Formulate strategies for incorporating consolidation and maintenance therapy in appropriate patients with FL • Discuss clinical issues of importance in the treatment paradigm for FL, including the timing of initial therapy, the role of transplantation, and the management of adverse events Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12031.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records.

For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or cgusack@mlicme.org.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accor-

dance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the ACCME to provide continuing medical education for physicians.

and has received research support from Celgene, Gilead Sciences, Janssen Biotech, and Millennium: The Takeda Oncology Company.

Loretta Nastoupil, MD, is a consultant for Genentech/Roche.

Lisa Anderson, RN, BSN, OCN, has nothing to disclose.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.

Registered Pharmacy Designation Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-12-027-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted

by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Ryan Sims, CRNA, MS, MLI Reviewer, has nothing to disclose.

Shelley Chun, PharmD, MLI Reviewer, has nothing to disclose.

Nassoma King, PA-C, has nothing to disclose. *Content will include non–FDA-approved uses.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months.

Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred.

Agenda: 1 hour Articles/Commentaries: 45 minutes Evaluation/Posttest: 15 minutes Date of original release: September 14, 2012 Valid for CME/CE credit through: September 14, 2013

SCAN HERE to Download the PDF or Apply for Credit.

Faculty Disclosures Stephanie A. Gregory, MD, is on the advisory board for Genentech/ Roche, and Spectrum Pharmaceuticals, and on the data safety monitoring board for Genentech/Roche. *Christopher R. Flowers, MD, MS, is a consultant for Celgene, Genentech/Roche, and Millennium: The Takeda Oncology Company,

To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

New Treatment Paradigms in Follicular Lymphoma Christopher R. Flowers, MD, MS 1 and Loretta Nastoupil, MD 2 1

Associate Professor of Hematology and Medical Oncology, Emory School of Medicine, Winship Cancer Institute, Atlanta, GA; 2 Hematology/Oncology Fellow, Emory University, Winship Cancer Institute, Atlanta, GA

Introduction Over the past several years, the treatment paradigm for patients with follicular lymphoma (FL) has undergone significant changes, with the development of effective new agents that are now being used in the frontline, maintenance, and relapsed settings. Although these new therapies have led to improvements in patient outcomes, numerous questions remain regarding their optimal use. In this article, Christopher Flowers, MD, MS and Loretta Nastoupil, MD, discuss results from recent clinical trials evaluating novel agents and combination regimens for FL and provide their professional insights on future directions related to the management of this disease.

Is there a standard approach to the initial treatment of patients with FL?

The American Cancer Society estimates that 70,130 new cases of nonHodgkin lymphoma (NHL) and 18,940 NHL-related deaths will occur in 2012 in the United States.1 FL is the second most frequently occurring NHL subtype worldwide, with an increasing incidence in Western nations over the

VOL. 3

I

NO. 6

last 2 decades.2 It accounts for approximately 22% of all NHLs.2 Most patients with FL have stage III or IV disease at the time of diagnosis.3,4 Depending on stage and presenting characteristics, there are numerous available options for the initial management of FL. These include observation (ie, watchful waiting), radiation alone, single-agent chemotherapy, singleagent rituximab, and rituximab-chemotherapy combinations (ie, immunochemotherapy).5 According to data from the National LymphoCare Study (NLCS), there is no single standard of care for frontline management of FL in the United States.6 Stage I/II FL is often managed with radiation therapy, based on observational studies indicating long-term disease-free survival for select patients.5 For example, a British National Lymphoma Investigation study reported that, following radiation therapy for stage I FL, relapse was rare after 10 years of follow-up.7 However, emerging data on practice patterns from the NLCS suggest that other management strategies for patients with localized disease may produce outcomes similar to those achieved with radiation.8 Regarding stage III/IV disease, preliminary NLCS data also indicate that outcomes for patients with high-risk scores on the Follicular Lymphoma International Prognostic Index (FLIPI) differ depending on the type of immunochemotherapy selected.9,10 For high-risk FLIPI patients, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves progression-free survival (PFS) and overall survival (OS) compared with rituximab plus cyclophosphamide, vincristine, and prednisone (RCVP).9,10 A third combination, rituximab plus fludarabine, produces a significantly longer PFS and time to next treatment compared with R-CVP; however, it is also associated with more frequent treatment discontinuation.10 The

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

39

CONTINUING EDUCATION

Figure. Comparison of immunochemotherapy regimens for frontline therapy of advanced FL: results of FOLL05.12

100

P=0.021

P=0.007

98% 95% 93%

P=0.969

Patients (%)

80 60 40

64%

R-CVP R-CHOP R-FM

61%

46%

20 0

3-Year TTF

3-Year OS

FL indicates follicular lymphoma; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, prednisone; R-FM, rituximab, fludarabine, mitoxantrone; TTF, time to treatment failure.

above findings have been corroborated by a secondary analysis of the Primary Rituximab and Maintenance (PRIMA) trial, which reported that R-CHOP produces both higher response rates and longer PFS than does R-CVP, with comparable tolerability.11 Recent findings from the FOLL05 study, a clinical trial evaluating frontline immunochemotherapy regimens, provided a definitive comparison.12 In this study, previously untreated patients with advanced-stage FL (N=534; 178/arm), the majority of whom had high-risk FLIPI scores, were randomly assigned to receive R-CVP, R-CHOP, or rituximab plus fludarabine and mitoxantrone (R-FM), with no maintenance therapy. Significant differences between regimensâ&#x20AC;&#x201D;favoring R-CHOP and R-FMâ&#x20AC;&#x201D;were observed in terms of 3-year time to treatment failure (TTF), the primary endpoint (Figure). The trial also showed superior 3-year PFS with R-CHOP and R-FM compared with R-CVP; 3-year OS rates, on the other hand, were comparable among groups.

Unfortunately, R-FM was associated with a higher rate of grade 4 neutropenia than R-CVP or R-CHOP (64%, 28%, and 50%, respectively).

Rummel and colleagues investigated a regimen of bendamustine plus rituximab (BR) versus R-CHOP for indolent lymphomas (FL and other subtypes, N=549), with favorable outcomes.13,14 At a median follow-up of 45 months, median PFS was 69.5 in the BR group versus 31.2 months in the R-CHOP group, representing a significant prolongation of PFS with BR (P<.001).14 In the FL subgroup, PFS benefit was independent of FLIPI risk.14 In comparison to R-CHOP, BR was associated with less hematologic toxicity and no alopecia greater than grade 1.13 No significant difference in OS was reported between groups, although the authors suggest that interpretation of OS may be confounded by the fact that 21% of patients treated with R-CHOP also received BR as a salvage treatment.14 Although the FL cohort undergoing collection in this trial was small, results showed that stem cells could be harvested adequately from patients treated with either regimen. In addition, the occurrence of second malignancies, including myelodysplastic syndromes and acute myeloid leukemia, were similar in both groups.

What are the latest data on maintenance and consolidation strategies in FL?

Results from the PRIMA trial showed significant improvements in PFS with rituximab maintenance versus observation following first-line induction with a

40

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

variety of immunochemotherapy regimens.15 Although BR was not one of the induction regimens offered in PRIMA, an ongoing trial by the Eastern Cooperative Oncology Group (ECOG) is evaluating the safety and efficacy of this combination, followed by maintenance rituximab with or without lenalidomide.16 This randomized phase 2 trial (ECOG E2408) is enrolling high-risk patients with FL who will be randomized to either BR followed by rituximab maintenance; bortezomib, bendamustine, and rituximab (VBR) followed by rituximab maintenance; or BR followed by maintenance with lenalidomide plus rituximab (RR).16 Study results should be available for analysis by August 2016.

The phase 3 ECOG 4402 RESORT trial was designed to determine whether a maintenance rituximab strategy following induction rituximab could improve TTF compared with a rituximab retreatment strategy in patients with low tumor burden FL.17 At 3 years of follow-up, 95% of patients receiving maintenance rituximab and 86% of patients randomized to rituximab retreatment remained free of cytotoxic chemotherapy. However, the authors reported that rituximab retreatment was as effective as maintenance rituximab in terms of TTF, which was the primary endpoint of this study, and was the preferred strategy for this patient population.

Radioimmunotherapy (RIT), which combines a radiation-emitting radionuclide with an antibody, continues to be evaluated as consolidation in FL. In the FIT trial, 414 patients with advanced-stage FL, who had achieved a complete response (CR)/unconfirmed complete response (CRu) or partial response (PR) to frontline chemotherapy (with or without rituximab), were randomized to either 90Y-ibritumomab tiuxetan (90Y-IT) or observation. In this trial, only 31 patients received rituximab-based frontline therapy.

Despite the substantial improvements in PFS with frontline immunochemotherapy and maintenance regimens, nearly all patients with FL eventually relapse.

Patients in the 90Y-IT consolidation arm had a high conversion rate from PR to CR/CRu (77%) and a high overall CR rate (89%). RIT consolidation also significantly prolonged median PFS compared with no further treatment in patients who were responsive to frontline therapy.18 For all patients, at 8 years of follow-up, 41% who received consolidation were still free of relapse compared with 22% in the control group. There was no statistically significant difference between groups regarding the occurrence of secondary malignancies. There was also no difference in OS. What treatment options are available for patients in the relapsed setting?

Despite the substantial improvements in PFS with frontline immunochemotherapy and maintenance regimens, nearly all patients with FL eventually relapse. Therefore, strategies aimed at treating relapsed disease are the focus of numerous investigations. Allogeneic stem cell transplantation (alloSCT) is the only approach that is demonstrably curative.5 However, it carries significant morbidity and mortality risks and is therefore reserved for young, highly motivated patients with relapsed or resistant FL. Alternatively, reduced intensity conditioning (RIC) regimens are associated with lower transplantrelated mortality. For example, single-center studies and registry analyses indicate that long standing disease control can be achieved in 40% to 75% of patients with FL following RIC and allo-SCT.19 Therefore, this appears to be a promising approach for select populations of patients.19,20

VOL. 3

I

NO. 6

CONSIDERATIONS IN LYMPHOMA

Regimens using molecularly targeted agents, such as bortezomib and lenalidomide, have also emerged as useful options in the management of relapsed FL. For example, in the phase 2 VERTICAL trial, treatment with VBR was shown to be active in previously treated patients, producing an 88% overall response rate (ORR), a 53% CR rate, and a median PFS of 14.9 months.21 A randomized trial in recurrent FL from the Cancer and Leukemia Group B (CALGB 50401) reported that RR yielded a greater response rate and a longer event-free survival than single-agent rituximab (Table).22 In addition, several novel antibody therapies are being studied in FL. Recent trials include a phase 1/2 study of veltuzumab in relapsed/refractory B-cell NHL, including 55 FL patients, showing good response with no adverse events grade 3 or higher, despite short infusion times.23 Subcutaneous dosing of this agent is also being explored.24 Ofatumumab has shown activity in patients with rituximab-refractory FL25 and has also yielded promising results in frontline use with CHOP.26 It is still uncertain as to whether the efficacy of adding an antibody to chemotherapy is a class effect common to all B-cell–targeted antibodies. This question will remain unanswered pending randomized trials comparing the monoclonal antibody rituximab to other antibodies plus chemotherapy.

In addition, defining the mechanisms of action and resistance for emerging antibodies across lymphoma subtypes will become increasingly important.

Another intriguing approach to the treatment of FL is the use of drugs that target B-cell receptor signaling. CAL-101 (GS-1101) is an orally bioavailable, small-molecule inhibitor that selectively targets phosphatidylinositol 3kinase-delta, which regulates survival and proliferation of normal and malignant B cells.27 An early phase 1 study of this inhibitor demonstrated substantial clinical activity in patients with hematologic malignancies.27 In a subsequent phase 1 study that evaluated CAL-101 in combination with rituximab, bendamustine, or both drugs in patients with extensively pretreated indolent NHL, all evaluable patients had reductions in lymphadenopathy, resulting in an ORR of >65% for all regimens.7 CAL-101 is thus an attractive agent, given its reported favorable safety profile28 and lack of overlapping toxicity, allowing delivery at a full single-agent dose even when coadministered with immunochemotherapy in heavily pretreated patients.

PCI-32765 is an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, a downstream mediator of B-cell receptor signaling.29 A phase 1 study of PCI-32765 in patients with relapsed/refractory B-cell malignancies reported a 43% ORR.29 Durable responses occurred at all dose levels and across various histologic subtypes, irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase levels, or disease burden.

With its good safety profile and lack of cumulative hematologic toxicities, PCI-32765 warrants further studies in patients with FL. It is hoped that these studies, along with those of other novel agents, will reveal new strategies that continue to enhance outcomes in FL. ◆ References 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.

2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma: The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909-3918.

3. Smith SM. What is the best strategy for incorporating new agents into the current treatment of follicular lymphoma? ASCO Educational Book. 2012:481-487.

4. Solal-Céligny P, Roy P, Colombat P, et al. Follicular Lymphoma International Prognostic Index.

Blood. 2004;104:1258-1265.

5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-Hodgkin’s Lymphoma. Version 3.2012. www.nccn.org. Accessed May 14, 2012.

6. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the National LymphoCare Study. J Clin Oncol. 2009;27:1202-1208.

7. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, Anderson L, Linch DC. Clinical stage 1 non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer. 1994;69:1088-1093.

8. Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study [published online ahead of print August 20, 2012). J Clin Oncol. doi:10.1200/JCO.2011.40.6546.

9. Nastoupil L, Sinha R, Byrtek M, et al. A comparison of the effectiveness of first-line chemoim-

VOL. 3

I

NO. 6

Table. Efficacy and Tolerability of Lenalidomide Alone or With Rituximab in Recurrent FL: Results of CALGB 5040122 Regimens

Lenalidomide

Lenalidomide + Rituximab

P Value

OR rate

49%

75%

NR

CR rate

13%

32%

NR

1.2 years

2.0 years

.0063

49% 16% 9% 16%

52% 19% 14% 4%

Median EFS Grade 3/4 AEs • Overall • Neutropenia • Fatigue • Thrombosis

NS

AEs indicates adverse events; CALGB, Cancer and Leukemia Group B; CR, complete response; EFS, event-free survival; FL, follicular lymphoma; NR, not reported; NS, not significant; OR, objective response.

munotherapy regimens for follicular lymphoma (FL) used in the United States. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 97.

10. Nastoupil L, Sinha R, Byrtek M, et al. Effectiveness of first-line chemoimmunotherapy regimens for patients diagnosed with follicular lymphoma (FL) in the US: data from the National LymphoCare Study (NLCS). Haematologica (EHA Annual Meeting Abstracts). 2012;97:Abstract 0800.

11. Morschhauser F, Seymour J, Feugier P, et al. Impact of induction chemotherapy regimen on response, safety and outcome in the PRIMA Study. Ann Oncol (ICML Annual Meeting Abstracts). 2011; 22(suppl 4):Abstract 022.

12. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8006.

13. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405.

14. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 3.

15. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42-51.

16. National Cancer Institute. Bendamustine hydrochloride and rituximab with or without bortezomib followed by rituximab with or without lenalidomide in treating patients with high-risk stage II, stage III, or stage IV follicular lymphoma (E2408). www.clinicaltrials.gov. Accessed August 10, 2012.

17. Kahl BS, Hong F, Williams ME, et al. Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): a randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Blood (ASH Annual Meeting Abstracts). 2011;118:LBA 6.

18. Morschhauser F. Y-90 Ibritumomab tiuxetan consolidation in follicular lymphoma: the 7-year update of the FIT trial. Oral presentation at: 17th Congress of the European Hematology Association (EHA); June 14-17, 2012; Amsterdam, the Netherlands.

19. Dreger P. Role of allotransplantation for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Ann Oncol. 2011;22(suppl 4):iv36-iv39.

20. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008;111;5530-5536.

21. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389-3395.

22. Leonard J, Jung S-H, Johnson JL, et al; Alliance for Clinical Trials in Oncology. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8000.

23. Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol. 2009;27:3346-3353.

24. Negrea GO, Elstrom R, Allen SL, et al. Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin’s lymphoma.

Haematologica. 2011;96:567-573.

25. Czuczman M, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119:3698-3704.

26. Czuczman MS, Hess G, Gadeberg OV, et al. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157:438-445.

27. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 , in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 1777.

28. de Vos S, Schreeder MT, Flinn IW, et al. A phase 1 study of the selective phosphatidylinositol 3kinase-delta (PI3K ) inhibitor, CAL-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 2699.

29. Fowler N, Porte Sharman J, Smith SM, et al. The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity in patients with relapsed/refractory B-cell malignancies: results from a phase I study. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 964.

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

41

CONTINUING EDUCATION

Managing Treatment-Related Adverse Events in Follicular Lymphoma Lisa Anderson, RN, BSN, OCN Clinic Nurse Emory Bone Marrow and Stem Cell Transplant Center Winship Cancer Institute, Atlanta, GA

Introduction Follicular lymphoma (FL), one of the most common forms of nonHodgkin lymphoma (NHL), comprises approximately 1 in 5 of all cases of the disease.1 FL is slow growing and incurable, and it typically must be treated over a period of several years. As a result, effective management of patients requires that nurses be aware of the latest treatment approaches as well as effective strategies for the prevention and management of adverse events (AEs). In this article, Lisa Anderson, RN, BSN, OCN, discusses these key issues related to the administration of newer therapies for FL.

What are some of the toxicities and risks related to the use of bendamustine?

Hematologic toxicities are common AEs associated with the alkylating agent bendamustine. In a recent multicenter study by Kahl and colleagues, the efficacy and toxicity of this agent as monotherapy was evaluated in patients with rituximab-refractory indolent B-cell lymphoma.2 Among 100 patients aged 31 to 84 years who received bendamustine 120 mg/m2 (days 1 and 2 every 21 days for 6-8 cycles), 61% experienced grade 3/4 neutropenia, resulting in filgrastim or pegfilgrastim administration in 38% of cases; grade 3/4 thrombocytopenia occurred in 25% of patients (Figure).2 Combination therapy with bendamustine plus rituximab (BR) is associated with less hematologic and nonhematologic toxicity than is a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). In the phase 3 study by Rummel and colleagues, which included patients with FL and other indolent lymphomas, serious AEs were less frequent with BR than with R-CHOP. The rate of grade 3/4 neutropenia was 10.7% with BR versus 46.5% with R-CHOP (P<.0001).3 Incidence rates of alopecia, infectious complications, peripheral neuropathy (PN), and stomatitis were also lower with BR, although this regimen produced more skin reactions.

Bendamustine has been associated with tumor lysis syndrome (TLS) in both clinical trials and postmarketing reports.3,4 If TLS occurs, it generally appears within the first treatment cycle and may be life-threatening if clinicians do not intervene.3 To prevent TLS, it is crucial to maintain adequate volume status and closely monitor blood potassium, uric acid, and other chemistries.3,5 In addition, allopurinol or rasburicase can be used prophylactically at the start of bendamustine therapy to help prevent TLS.5 If a TLS event should occur, management requires aggressive hydration, diuresis, and treatment with allopurinol or rasburicase.5,6 Caution must be used, however, as there may be an elevated risk of potentially fatal skin toxicity when bendamustine and allopurinol are coadministered; toxicity syndromes include Stevens-Johnson syndrome and toxic epidermal necrolysis.3

42

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

How do you monitor and manage AEs related to the use of bor tezomib and lenalidomide?

Hematologic toxicities, including neutropenia, thrombocytopenia, and anemia, may occur with other agents being used to treat FL, including bortezomib and lenalidomide.7,8 Management of these AEs may require dose interruption and/or dose reduction.7,8 At our center, we ensure that patients have complete blood counts weekly for the first 8 weeks of treatment, and then monthly thereafter. Since neutropenia increases infection risk, patients receiving lenalidomide or bortezomib are given sulfamethoxazole/trimethoprim (for pneumonia prophylaxis) on Monday, Wednesday, and Friday of the treatment week. We also reinforce bleeding precautions at each patient visit, and thrombocytopenic patients receive transfusions when their platelet count falls to 20,000 cells/mm3. For anemia, we transfuse patients at hematocrit 26% to 27%.

Neuropathy is a common AE among patients receiving bortezomib-based therapy.7 Preexisting neuropathic symptoms are a potential but unconfirmed risk factor for treatment-induced PN,9,10 with a recent animal model demonstrating a more marked effect of bortezomib on peripheral nerves when baseline neuropathy is moderate or severe.10 Following a baseline neuropathy assessment, we monitor all of our bortezomib-treated patients for symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, neuropathic pain, or weakness. If we identify PN, we follow recommendations for reducing, interrupting, or discontinuing the dose, depending on the severity.

Our goal is amelioration of bortezomib-induced PN, which can be reversible when promptly managed.7,11

Caution must be used, however, as there may be an elevated risk of potentially fatal skin toxicity when bendamustine and allopurinol are coadministered.

Herpes zoster reactivation has been documented in patients receiving bortezomib, but the occurence of this AE can be reduced with antiviral prophylaxis.7,12,13 For example, in a trial of bortezomib in combination therapy for multiple myeloma, incidence of zoster reactivation was 13% before but 7% after the introduction of antiviral prophylaxis into the protocol.13 At our institution, patients are given acyclovir 400 mg BID while receiving bortezomib treatment, with dose adjusted for renal insufficiency.

Risk of venous thromboembolic events (VTEs)â&#x20AC;&#x201D;deep vein thromboses and pulmonary emboliâ&#x20AC;&#x201D;may be elevated in patients treated with lenalidomide, and the drug carries a boxed warning for this AE.8,14 Therefore, we administer prophylactic aspirin at either 81 mg or 325 mg daily for patients receiving this agent.14,15 Hormone-containing medications, such as oral contraceptives, should be avoided in female patients to minimize the risk of VTE.16 Lenalidomide also has a boxed warning for human birth defects risk.8 Specific risk evaluation and mitigation strategies for nurse/pharmacist counseling, pregnancy prevention, and avoidance of sperm donation are offered via the manufacturerâ&#x20AC;&#x2122;s RevAssist program.8

VOL. 3

I

NO. 6

CONSIDERATIONS IN LYMPHOMA

Figure. Incidence of Grade 3/4 Hematologic Adverse Events in a Multicenter Study of Single-Agent Bendamustine (N=100)2 38%

40

Grade 3 Grade 4

Patients (%)

30 23%

Table. Serious Mucocutaneous Reactions Associated with Rituximab Use18 Reactions Lichenoid dermatitis Paraneoplastic pemphigus Stevens-Johnson syndrome Toxic epidermal necrolysis Vesiculobullous dermatitis

Symptom patterns that raise suspicion Blistering Painful sores/ulcers on skin, lips, mouth Peeling skin Pustules Rashes

19%

20

10

7%

tologic toxicities, notably skin reactions, TLS, PN, and VTEs. Best nursing practices include frequent counseling, preventive strategies, and prompt intervention to minimize AEs, maintain quality of life, and allow for continuation of therapy. ◆

6% 3%

0 Anemia

Thrombocytopenia

Neutropenia

References

What are necessary precautions that need to be discussed with patients receiving rituximab maintenance therapy?

There is concern that maintenance rituximab therapy has the potential for causing additional hematologic and nonhematologic toxicities.17 At our center, each patient who starts or resumes rituximab therapy receives written and verbal education from the nurse and outpatient pharmacist at the time of the first clinic visit, followed by reinforcement education on the day of the first treatment in the infusion center. Potential AEs related to the use of rituximab are reviewed with the patient at each additional clinic visit.

Mucocutaneous reactions, some with fatal outcome, may occur with rituximab (Table).18 We are vigilant in monitoring for these reactions because of their potential severity. Serious reactions of this kind require discontinuation of rituximab.18 We also carefully observe rituximab-treated patients for blood-count changes and other signs of infection. Serious infections may occur during and after rituximab-based therapy18; postmarketing reports have documented infections in some patients, with prolonged hypogammaglobulinemia >11 months after exposure to rituximab.19 The 5 most frequent infections reported in the rituximab maintenance arm of the PRIMA trial were bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, and nasopharyngitis.20 Vaccination with live-virus vaccines is not recommended in patients receiving rituximab.18 For example, in a study of NHL patients in remission who had been treated with rituximab-containing immunochemotherapy, humoral response to influenza vaccine was significantly reduced for a prolonged period versus healthy controls.21 Conclusion

Novel and targeted therapies have enhanced outcomes in FL, but they present unique challenges in the occurrence and management of AEs. Newer therapies are associated with myelosuppression and potentially elevated infection risks. Patients may also be at risk for potentially serious nonhema-

VOL. 3

I

NO. 6

1. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89: 3909-3918.

2. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study.

Cancer. 2010;116:106-114.

3. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405.

4. Treanda [package insert]. Frazer, PA: Cephalon Inc; July 2010.

5. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26: 2767-2778.

6. Hummel M, Buchheidt D, Reiter S, Bergmann J, Adam K, Hehlmann R. Recurrent chemotherapy-induced tumor lysis syndrome (TLS) with renal failure in a patient with chronic lymphocytic leukemia—successful treatment and prevention of TLS with low-dose rasburicase.

Eur J Haematol. 2005;75:518-521.

7. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals Inc; June 2012.

8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012.

9. Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593-1599.

10. Bruna J, Alé A, Velasco R, Jaramillo J, Navarro X, Udina E. Evaluation of pre-existing neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model. J Periph Nerv Syst. 2011;16:199-212.

11. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

J Clin Oncol. 2006;24:3113-3120.

12. Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy. Cancer. 2009; 115:229-232.

13. Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study.

Blood. 2006;108:2165-2172.

14. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group.

Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008; 22:414-423.

15. Niesvizky R, Martínez-Baños D, Jalbrzikowski J, et al. Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide of lenalidomide in myeloma. Leuk Lymphoma. 2007;48:2330-2337.

16. Koopman K, Uyttenboogaart M, Vroomen PC, van der Meer J, De Keyser J, Luijckx GJ. Risk factors for cerebral venous thrombosis and deep venous thrombosis in patients aged between 15 and 50 years. Thromb Haemost. 2009;102:620-622.

17. Fowler NH. Role of maintenance rituximab (Rituxan) therapy in the treatment of follicular lymphoma. P T. 2011;36:590-598.

18. Rituxan [package insert]. South San Francisco, CA: Genentech Inc; July 2012.

19. US Food and Drug Administration. Rituxan (rituximab) intravenous injection: detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER).

FDA Web site. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm296234.htm. Updated March 28, 2012. Accessed August 29, 2012.

20. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42-51.

21. Bedognetti D, Zoppoli G, Massucco C, et al. Impaired response to influenza vaccine associated with persistent memory B cell depletion in non-Hodgkin’s lymphoma patients treated with rituximab-containing regimens. J Immunol. 2011;186:6044-6055.

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

43

CONTINUING EDUCATION

Improving Patient Outcomes in Follicular Lymphoma Nassoma King, PA-C Physician Assistant,Winship Cancer Institute Emory University, Atlanta, GA

Introduction Despite recent advancements, the management of follicular lymphoma (FL) remains challenging for many reasons. Physician assistants (PAs) play an essential role in improving patient outcomes by provid-

From Cancer Patient to Cancer Survivor: Lost in Transition,1 cancer patients who have finished primary therapy should be given a summary of their treatments and a comprehensive plan for follow-up.2 To achieve this goal at our center, we have instituted survivorship clinics, where we provide patients with treatment summaries detailing their chemotherapy and/or radiation schedules (including specific doses), as well as any complications that may have occurred and information regarding short- and long-term AEs. We also give these summaries to the patient’s PCP and referring oncologist, which helps to close the communication gap posttreatment.

ing continuity of care before, during, and after treatment. In this article, Nassoma King, PA-C, responds to questions pertaining to the care

What are the greatest challenges patients face during therapy?

of patients with FL, including the need for pretreatment assessments, education and counseling, follow-up care, and the prevention and management of treatment- and disease-related complications.

What is the role of the PA in the management of patients with FL?

As members of the interdisciplinary care team, PAs can be involved in all aspects of care for patients with FL. Working collaboratively with the supervising physicians, we order and review tests, set up treatment schedules and follow-up visits, and arrange appropriate restaging studies. PAs also enhance care by performing health assessments and physical examinations, ordering chemotherapy and other medications, and helping patients cope with the numerous challenges related to their diagnosis and treatment. At our institution, we provide individuals with counseling and education and work with them to set realistic expectations both during and after therapy. Our center also offers patients and their families a “pretreatment” visit, which gives us the opportunity to discuss treatment-related adverse events (AEs), nutrition and exercise, potential drug–drug interactions, and sexuality/fertility issues.

During this meeting, a social worker, a nutritionist, and a pharmacist are also available to provide more in-depth evaluation if necessary. These visits are instrumental in identifying additional needs as well as any possible barriers to successful outcomes.

PAs also assume the role of “coordinator of care.” Frequently, after their initial visit with the oncologist, patients may feel overwhelmed by a diagnosis of lymphoma. As a result, it may be difficult for them to process all of the information they have received. Regardless of whether the oncologist prescribes a “watch and wait” approach or active treatment, the PA will review the established plan of care and schedule necessary visits and studies. For patients who are scheduled to undergo active therapy, all required testing must be ordered and evaluated prior to the first treatment cycle. During follow-up visits, PAs will address treatment-related AEs and other concerns and arrange appropriate referrals. We encourage our patients’ caregivers to attend clinic visits to help reiterate instructions and information. Our institution also provides additional assistance in the way of caregiver support groups, massage therapy sessions, and social worker services.

After a patient has completed therapy, PAs continue to manage several aspects of care. In particular, they are an important bridge between the primary care physician (PCP) and the oncology team. As recommended in

44

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

With FL, the goal of therapy is to maintain optimal quality of life and to treat only when patients develop symptoms. Any alteration to this approach requires demonstration of improved survival with early institution of therapy, or identification of criteria that define patients at a sufficiently high risk to merit early intervention.3 Numerous therapeutic options for FL are now available, ranging from radiotherapy to single-agent chemotherapy to combination regimens.3 For patients who undergo active treatment, the greatest challenges are often related to physical and psychosocial changes.

It is well known that certain chemotherapeutic agents destroy normal cells as well as malignant cells, resulting in numerous AEs, including nausea and vomiting, reduced appetite, hair loss, and mouth sores.4 Damage to healthy immune cells may also place patients at greater risk for infection.4 Single-agent rituximab is generally well tolerated but may cause infusion-related complications and myelosuppression.5,6 Radioimmunotherapy may also result in the development of AEs such as transient bone marrow depression, fatigue, fever, chills, sweating, rash, arthralgias, erythema, and edema.7 It is therefore critical for PAs and other members of the oncology care team to be familiar with the toxicity profiles associated with these therapies so they can initiate appropriate interventions, including growth factor support to manage infection, erythropoietin to treat anemia, and antiemetics to relieve nausea and vomiting.

Psychosocial changes, which are often triggered by the AEs described above, may cause patients to feel emotionally distraught.8 Interpersonal relationships may become strained due to disruptions in everyday life, job loss, decreased finances, and changes in family dynamics. Depression, fatigue, and changes in physical appearance often lead to sexual dysfunction and poor body image. Chemotherapy is often associated with loss of libido and decreased physical intimacy for both men and women. Combining psychosocial therapy with treatment for the disease itself can help to alleviate emotional distress. Our team, which includes a social worker and a psychiatrist, provides individual and family counseling, as well as support groups geared toward addressing many of the psychosocial issues related to chemotherapy.

We offer an in-house boutique that provides hair and make-up classes, as well as hair prostheses and accessories.

Elderly patients may be more difficult to treat due to preexisting comorbidities, diminished organ function, altered drug metabolism, and irregular drug clearance rates.9 They may often present with poor performance status and underlying cardiac or renal dysfunction. In addition, the risk of developing treatment-related AEs and the inability to tolerate full doses of therapeutic

VOL. 3

I

NO. 6

CONSIDERATIONS IN LYMPHOMA

agents generally increases with age, and cure and remission rates usually decrease.9 The key to maintaining quality of life and helping patients reap the optimal benefits of therapy involves good communication between members of the oncology team and their patients regarding AEs and other complications.

What special considerations are necessary for patients who undergo transplantation?

Although patients with FL typically demonstrate good response to induction therapy, most will eventually relapse. When this occurs, cure is very unlikely; the median survival after disease recurrence is approximately 4.5 years.10 There are several options available to patients who relapse, including chemotherapy, radioimmunotherapy, and stem cell transplant.

Investigators addressed the role of autologous stem cell transplantation (ASCT) in the European CUP trial, which randomized patients with relapsed FL to undergo chemotherapy alone (C), ASCT with an unpurged autograft (U), or ASCT with a purged autograft (P).11 The 2-year progression-free survival (PFS) rates were 26% (C), 58% (U), and 55% (P), whereas 4-year overall survival (OS) rates were 46% (C), 71% (U), and 77% (P). No difference in PFS or OS was seen between the transplant groups. However, a significant reduction in hazard ratios for both PFS and OS was observed in the combined groups of patients undergoing ASCT compared with the chemotherapy group.

Allogeneic stem cell transplantation (allo-SCT) may be a viable option for patients whose lymphoma is behaving in an aggressive fashion (ie, early recurrence after intensive frontline or salvage therapy). However, due to relatively high treatment-related mortality, patients must have an excellent performance status, minimal comorbidities, and an human leukocyte antigen–identical donor (related or unrelated) to be considered for this procedure.12 For transplant-eligible patients, it is important to consider factors such as nutritional status prior to transplant, neutropenic precautions during transplant, and posttransplant changes. Patients must undergo a rigorous pretransplant evaluation, which includes testing to assess organ function and disease status. It is also necessary to arrange a meeting with a social worker to address psychosocial needs. At our institution, patients typically meet with a nutritionist to help improve their performance status prior to transplant, because disease status, the amount of time since the last cycle of chemotherapy, infection, and anorexia can all significantly impact nutritional status.13 Malnutrition prior to transplantation has been reported to increase the length of hospital stay and can be a negative prognostic factor for survival.13 Opportunistic infections remain a significant cause of morbidity and mortality related to transplant.14 The conditioning regimen causes pancytopenia, impaired phagocytosis, and damaged mucocutaneous barriers.15 Venous access devices may also place patients at an increased risk for infection, as they serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (eg, coagulase-negative staphylococci, Staphylococcus aureus, Candida species, and enterococci).15 At our center, we start patients on prophylactic antibiotics on day 1, continuing until engraftment of white blood cells. If patients develop fever, we order a culture and initiate broad spectrum antibiotics until the pathogen is identified. Upon discharge from the hospital, patients who have undergone ASCT will usually continue acyclovir for herpes simplex virus prophylaxis; whereas patients who have undergone alloSCT will continue with both acyclovir and fluconazole. The Centers for Disease Control and Prevention has established extensive guidelines for the prevention of opportunistic infections following transplantation, including hospital infection control, food safety, pet and travel safety, vaccinations, and general infection precautions.15

VOL. 3

I

NO. 6

It is important to be cognizant of the fact that patients and families may have unrealistic expectations after transplant. For example, they may be under the impression that life will return to normal as soon as the procedure is complete. Some of the common difficulties that patients face posttransplant include the inability to resume social roles, concerns about the future, work-related problems, infertility, fear of relapse, and anxiety and depression.16 In addition, fatigue may last anywhere from 3 to 6 months posttransplant for recipients of ASCT and up to 2 years or more for recipients of alloSCT. For patients who develop graft-versus-host disease, fatigue may last even longer. As a result, they may be unable to return to their jobs or may need to perform their responsibilities in a limited capacity, causing additional financial stress. At our center, an oncology supportive care team consisting of social workers and psychiatrists works collaboratively with the medical team to help patients and caregivers address physical, emotional, and financial stressors.

Conclusion

Because many patients with FL face physical, financial, and emotional challenges before, during, and after treatment, it is essential that they feel comfortable contacting the nurse practitioner or PA regarding any and all concerns. In addition to providing information on external support groups, we employ an interdisciplinary approach to tackle issues preemptively. It is critical to recognize that each patient has specific needs and that each should be cared for in a way that addresses those needs appropriately. ◆ References 1. Hewitt M, Greenfield S, Stovall E, eds. From Cancer Patient to Cancer Survivor: Lost in Transition.

Washington, DC: The National Academies Press; 2005. www.nap.edu/catalog.php?record_id= 11468. Accessed August 29, 2012.

2. Bhatia S, Landier W; on behalf of the Children’s Oncology Group (COG) Nursing Discipline and Late Effects Committees. Appendix F: treatment summary forms developed by the Children’s Oncology Group (COG). In: A National Coalition for Cancer Survivorship and Institute of Medicine National Cancer Policy Forum Workshop, The Lance Armstrong Foundation and The National Cancer Institute, Hewitt M, Ganz PA, eds. Implementing Cancer Survivorship Care Planning. Washington, DC: The National Academies Press; 2007. www.nap.edu/openbook.php?record_id=11739&page=288. Accessed August 29, 2012.

3. Gribben JG. How I treat indolent lymphoma. Blood. 2007;109:4617-4626.

4. American Cancer Society. Chemotherapy principles: an in-depth discussion. American Cancer Society Web site. www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/ Chemotherapy/ChemotherapyPrinciplesAnIn-depthDiscussionoftheTechniquesanditsRolein Treatment/chemotherapy-principles-indepth-toc. Accessed August 29, 2012.

5. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomized controlled trial. Lancet. 2011;377:42-51.

6. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28:4480-4484.

7. Buchegger F, Antonescu C, Helg C, et al. Six of 12 relapsed or refractory indolent lymphoma patients treated 10 years ago with 131I-tositumomab remain in complete remission. J Nucl Med. 2011;52:896-900.

8. Bergeson B. Emotional effects of chemotherapy. Livestrong.com Web site. www.livestrong. com/article/143086-emotional-effects-chemotherapy/#ixzz23NwEZ4LT. Updated June 8, 2010.

Accessed August 29, 2012.

9. Cabanillas ME, Lu H, Fang S, Du XL. Elderly patients with non-Hodgkin lymphoma who receive chemotherapy are at higher risk for osteoporosis and fractures. Leuk Lymphoma.

2007;48:1514-1521.

10. Thieblemont C, Coiffier B. Lymphoma in older patients. J Clin Oncol. 2007;25:1916-1923.

11. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol. 2003;21:3918-3927.

12. van Besien K. Allogeneic stem cell transplantation in follicular lymphoma: recent progress and controversy. Hematology Am Soc Hematol Educ Program. 2009:610-618.

13. Horsley P, Bauer J, Gallagher B. Poor nutritional status prior to peripheral blood stem cell transplantation is associated with increased length of hospital stay. Bone Marrow Transplant.

2005;35:1113-1116.

14. Nevill TJ, Shepherd JD, Nantel SH, et al. Stem cell transplant-related mortality (TRM) 19851996: the Vancouver experience. Blood. 1997;90(10)(suppl 1 [part 2 of 2]):4426.

15. Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49:1-125.

16. Hjermstad MJ, Evensen SA, Kvaløy SO, Fayers PM, Kaasa S. Health-related quality of life 1 year after allogeneic or autologous stem-cell transplantation: a prospective study. J Clin Oncol.

1999;17:706-718.

SEPTEMBER 2012

I

www.ValueBasedCancerCare.com

45

Head & Neck Cancer

New Calculator Shows Financial Impact of Poor Quality...

Continued from cover

3.2% rate of postoperative airway complications, the savings from preventing each such complication are $48,000. Therefore, a quality improvement investment in this area would pay off handsomely, according to the team of researchers.

“Hospital administrators could see that it would be profitable, for example, to hire a nurse practitioner to follow only surgical-airway patients,” noted lead investigator Andrew B. Sewell, MD, of Vanderbilt University School of Medicine. “In fact, they could spend up to $480,000 and still break even if they are able to prevent half of the complications.”

The team used data from billing records at Vanderbilt University Medical Center to create the calculator and also examined patients’ charts for relevant complications.

HQCal can be made specific to each institution by inputting its cost and

payment data based on diagnosisrelated group payment rates. This

“Hospital administrators could see that it would be profitable, for example, to hire a nurse practitioner to follow only surgical-airway patients. In fact, they could spend up to $480,000 and still break even if they are able to prevent half of the complications.”

—Andrew B. Sewell, MD

allows administrators to see what would happen if certain changes are implemented.

The investigators focused on 2 examples; the first was postoperative surgical airway complications, which are relatively rare events but cause significant morbidity (and hence high cost). They calculated the cost of each case, including legal costs, at $48,000. Hence, preventing a minimum of 1 case by investing $40,000 would be cost-neutral, as would preventing at least 10 cases by investing $480,000.

The second example involved infections after major abdominal surgery, which represent the opposite of the previous example in being “high-frequency and low-impact” events. The investigators calculated 90-day inpatient costs and payment information for 600 patients, which yielded an overall saving of $108,000 from decreasing the infection rate by 20%, but a per-patient saving would occur only if the cost of the product used to

reduce infections was less than $182 per patient.

The researchers also highlighted HQCal’s ability to help administrators determine optimal strategies in light of changes in the healthcare environment. They calculated the changes in government reimbursement involving no payment for infection-related readmissions. They found in 1 example that preventing 1 abdominal surgery– related infection increased profit by $8909 compared with $5440 before the reimbursement change. In a second example, reducing the length of stay by 1.5 days for patients readmitted for such an infection increased profit by a total of $107,273.

“The calculator provides a tool to improve transparency regarding both short- and long-term financial consequences of funding, or failing to fund, initiatives to close gaps in quality,” the investigators noted. ■

Use of Intensity-Modulated Radiotherapy Increasing and Costly in the Management of Head and Neck Cancers, but Value Unknown

By Rosemary Frei, MSc Toronto, Canada—The popularity of intensity-modulated radiotherapy (IMRT) for head and neck cancer has climbed rapidly in recent years. However, the extra cost associated with this treatment modality may not equate with improved value, according to researchers from the University of California at Los Angeles (UCLA), who presented their analysis at the 2012 International Conference on Head and Neck Cancer.

The results showed that IMRT treatment was associated with approximately 3-fold higher costs to Medicare than the costs of standard treatment. The team of researchers is calling for studies to investigate whether this increased cost correlates with significantly improved patient outcomes.

“Whereas IMRT has theoretical advantages, and there is some evidence for this, more prospective, randomized, and controlled studies are required to justify its wide use given the high cost,” lead investigator Ali Razfar, MD, Head and Neck Surgery

46

resident at UCLA Medical Center, told Value-Based Cancer Care. “If there is no difference in overall quality of life and survival, then it may not justify the cost.”

A recent systematic review of 15 articles involving 1555 patients showed that IMRT is better than ex-

“If there is no difference in overall quality of life and survival, then it may not justify the cost.”

— Ali Razfar, MD

ternal-beam radiotherapy (EBRT) at avoiding xerostomia, osteoradionecrosis, and blindness, but that there are insufficient data to show that IMRT provides better treatment-related outcomes (O’Sullivan B, et al. Clin Oncol.

Epub 2012 June 18).

In this new analysis, Dr Razfar and

VALUE-BASED CANCER CARE

I

SEPTEMBER 2012

colleagues reviewed data of 2817 patients who were diagnosed with a head and neck cancer between 2000 and 2007 and were included in the SEER (Surveillance, Epidemiology and End Results)-Medicare database. A total of 1359 patients were treated with traditional EBRT and 335 were treated with IMRT. The 2 groups had similar demographics and disease stages. Patients undergoing EBRT were less likely to have oral-cavity cancer and more likely to have laryngeal cancer than their IMRT counterparts.

Between 2000 and 2007, the use of IMRT increased from 2% to 60%, whereas EBRT decreased from 98% to 40% (P <.001). No significant changes were observed over that time in the use of surgery alone, radiation alone, or surgery with adjuvant radiation, with the latter option dominating in each year.

The odds ratio (OR) of women receiving IMRT versus EBRT was 1.4; for patients who were also receiving chemotherapy, the OR was 3.3. In con-

trast, patients aged ≥80 years had an OR of 0.69 for receiving IMRT. Cost Comparison The mean total cost per case was $183,452 with IMRT compared with $63,618 for EBRT (P <.001). Oropharyngeal cancer is one of the most costly head and neck cancers to treat.

The average cost per oropharyngeal cancer was $200,907 with IMRT and $70,736 for EBRT (P <.001).

For treatment of early-stage tumors, surgery alone cost Medicare an average of $61,994 per case; in comparison, the average cost of EBRT was $66,123 per case compared with $183,294 with IMRT. This makes IMRT 2.9-fold more expensive than surgery and 2.7-fold more expensive than EBRT. “We ended our analysis at 2007, because that was the last year of available data from the SEER-Medicare linked database,” noted Dr Razfar.

“IMRT is even more widely used in 2012 than in 2007, and so the total cost to Medicare is likely much more than it was 5 years ago.” ■

VOL. 3

I

NO. 6

“Managing patients with myeloma means staying current.”

Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

7

Value-Based Care in Myeloma !"'&1"-. "3 '0.&1" &)/"-1&"2. )! +"-.+" /&1". -"' /"! /* *./ ,0 '&/4 )! ".. &..0". +" & ' ." /&*). #*."! '&)& & ). !1 ) "! +- /& " )0-.". )! +% -( &./. 2&'' '.* #* 0. *) /%" 0)&,0" % ''")$". &) /%" ( ) $"(")/ *# (0'/&+'" (4"'*(

www.ValueBasedMyeloma.com Value-Based Care in Myeloma &.

+0 '&

/&*) *# )$ $"

" '/%

-"

*((0)&

/&*).

("( "- *# %" 4)3

-*0+ 6

'' -&$%/. -"."-1"! .&5" )$ $"

Get connected to the perspectives of 100 stakeholders who manage 143 million covered lives Connecting you with relevant information is part of our commitment to you.

Thatâ&#x20AC;&#x2122;s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: É? &RYHUDJH DQG UHLPEXUVHPHQW RI RQFRO\WLFV É? 2QFRORJ\ PDQDJHPHQW VWUDWHJLHV É? &OLQLFDO SDWKZD\V The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Managerâ&#x20AC;&#x201C;Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services.

Visit www.lillyoncology.com.

|

Creating better connections.

7KH LQGH[ LV DQ LQGHSHQGHQW VWXG\ XQGHUWDNHQ E\ 7KH =LWWHU *URXS D PDQDJHG FDUH FRQVXOWLQJ Ę&#x2030; UP VSHFLDOL]LQJ LQ PDUNHW UHVHDUFK ON74961

12/11

PRINTED IN USA

Š 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.