VBCC February 2012, VOL 3, NO 1 by Value-Based Cancer Care

february 2012 VOL 3 NO 1

www.ValueBasedCancerCare.com

BEST PRACTICES

Ventura County Hematology Oncology Specialists: Efficiencies Crucial for Economic Viability Interview with Kooros Parsa, MD, FACEP, and Marissa M. Rivera, MBA Dr Parsa is Medical Oncologist, and Ms Rivera is Practice Administrator, Ventura County Hematology Oncology Specialists, CA (http://venturaoncology.com)

Ventura County Hematology Oncology Specialists has so far managed to avoid many of the financial difficulties facing a large number of community cancer practices. Value-Based Cancer Care asked Dr Parsa and Ms Rivera to discuss what makes their practice successful from a clinical and a business perspective.

VBCC: When was the practice established, and what are some of the services you offer? Dr Parsa: I was the first medical oncologist in the western Ventura County area when I started the practice in 1971. Rosemary McIntyre, MD, joined me in 1980, and by the time the third physician joined us we were operating in 2 Continued on page 10

ASH ANNUAL MEETING

Bosutinib Shows Superior Results in CML

The Cost of Cancer Care: How Can We Spend Better? By Caroline Helwick San Antonio, TX—One of the few clinical science symposia at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium focused not on clinical issues but on delineating the economic issues facing oncologists. Elena B. Elkin, PhD, Center for Health Policy and Outcomes, Memorial Sloan-Kettering Cancer Center, New York, reviewed the unprecedented concerns regarding health expenditures, calling for more cost-effectiveness analyses and more realistic thresholds for cost-effectiveness. Breast cancer specialist Eric P. Winer, MD, Dana-Farber Cancer Institute, Boston, introduced the presentation by commenting, “If we don’t take control

What Does Breast Cancer Cost? In 2010, the United States spent $16.5 billion on breast cancer care (Table 1). “Most of the money, by far, is spent at the end of life,” Dr Elkin observed. An earlier investigation based on 2002 US dollars (Warren et al. J Natl Cancer Inst. 2008;100:888-897) showed that the initial phase of cancer care averages $21,000, although the cost goes much higher for many patients: chemotherapy averages $12,800; surgery, $5700; radiation, $4500; and Continued on page 28

VBCC PERSPECTIVE

The Promise of Molecular Profiling A conversation with Al B. Benson, III, MD, FACP By Caroline Helwick At the 2012 Gastrointestinal Cancers Symposium, Value-Based Cancer Care (VBCC) asked Al B. Benson, III, MD, FACP, Professor of Medicine, Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Immediate Past President, ACCC, and editorial board member of VBCC, to discuss the growing importance of molecular profiling in cancer care.

May soon join first-line TKIs

VBCC: Where is the field of molecular profiling at this point, and where is it heading? Dr Benson: Comprehensive molecular profiling of a tumor will help us distinguish subtypes within cancers. We have been doing this with breast cancer for some time now, and at this meeting we heard more about several distinct types of gastric cancer including those that express HER2. In colon cancer, for example, oncoloContinued on page 15

INSIDE

By Neil Canavan San Diego, CA—The newest data presented from the BELA (Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia) trial show a superior cumulative complete cytogenetic response rate (CCyR) for bosutinib versus the standard-of-care agent, imatinib, when used as frontline treatment for patients with chronic

as the people providing the cancer care, we will lose all control.”

myeloid leukemia (CML), with 87% and 81% response rates at 24 months. “Given these results, bosutinib may soon offer a new therapeutic option for patients with newly diagnosed chronic-phase CML,” said lead investigator Jorge E. Cortes, MD, of the University of Texas M.D. Anderson Cancer Continued on page 22

FDA UPDATE

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Erivedge first drug ever for advanced basal-cell carcinoma Inlyta for advanced renal-cell carcinoma MEETING HIGHLIGHTS

HEALTH POLICY

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Paying for quality: increasing shift toward value-based healthcare Americans willing to pay OOP for cancer screening

GI cancers symposium . . . . . . . . . . . . . .12 ASH annual meeting . . . . . . . . . . . . . . . . .22 GU cancers symposium . . . . . . . . . . . . .40

PATIENT ADVOCACY

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PROSTATE CANCER

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BREAST CANCER

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Mammography use up when copay down

Patient advocacy: a physician’s perspective Array of treatments, but can we afford them?

38 41

New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

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.

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

MP (n=338)

0 0

Kaplan-Meier estimate.

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ 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

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 next page.

FDA UPDATE Erivedge First Drug Ever for Metastatic Basal-Cell Carcinoma The US Food and Drug Administration (FDA) approved vismodegib (Erivedge; Hoffmann–La Roche), a hedgehog pathway inhibitor, for the

treatment of basal-cell carcinoma (BCC) in adults with locally advanced disease who are not candidates for surgery or radiotherapy and in those with metastatic disease. Approved under a priority review, oral vismodegib is the first FDA

approved drug with an indication for this condition. “Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose 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.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. 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. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. 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, the incidence of any treatmentemergent 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, 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.

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, the safety profile of VELCADE 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%). 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) m 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, the drug 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 VELCADE 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 VELCADE.com.

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:: VELCADE is metabolized by liver enzymes. VELCADE 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.

VALUE-BASED CANCER CARE

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 © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

FEBRUARY 2012

V-11-0264

12/11

Pazdur, MD, Director, FDA’s Office of Hematology and Oncology Products. The approval was based on a single, multicenter clinical trial of 96 patients with locally advanced or metastatic BCC. After a median treatment of 10.2 months, 30% of patients with metastatic BCC and 43% of those with locally advanced disease had a complete or partial response, the study’s primary end point. The most common adverse effects were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, dysgeusia, decreased appetite, constipation, and vomiting. The recommended dose is 150 mg/day. Vismodegib has a boxed warning about the risk for death or severe birth defects to a fetus. Pregnancy status must be checked before beginning treatment with this drug. (January 30, 2012)

FDA Approves Axitinib for Advanced Renal-Cell Carcinoma The FDA approved the newest oral kinase inhibitor axitinib (Inlyta; Pfizer) for the treatment of patients with advanced renal-cell carcinoma that has failed to respond to previous therapy. Axitinib selectively inhibits vascular growth factor receptors 1, 2, and 3 that promote tumor growth, vascular angiogenesis, and tumor progression. The approval was based on the phase 3 AXIS trial, an open-label study of 723 patients with advanced renalcell carcinoma that had progressed after 1 previous round of systemic therapy with sunitinib, bevacizumab, temsirolimus, or a cytokine. Patients were randomized to receive axitinib 5 mg twice daily or to sorafenib 400 mg twice daily. The primary end point was progression-free survival (PFS). Treatment continued until disease progression, unacceptable toxicity, or withdrawal. Axitinib resulted in a 6.7month PFS compared with 4.7 month with sorafenib, representing a 43% improvement in median PFS (P <.001). The objective response rate was 19.4% in the patients receiving axitinib compared with 9.4% in those receiving sorafenib. The most frequent adverse events (≥20%) with axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmarplantar erythrodysesthesia syndrome, weight loss, vomiting, asthenia, and constipation. The recommended dose is 5 mg twice daily, administered approximately 12 hours apart. (January 27, 2012)

VOL. 3

NO. 1

FDA UPDATE Subcutaneous Bortezomib a New Therapeutic Option The FDA approved a new, subcutaneous route of administration for the proteasome inhibitor bortezomib (Velcade; Millennium) as an alternative method to the previously approved intravenous (IV) form of the drug in all the FDA indications. Bortezomib is indicated for the treatment of multiple myeloma (MM) and of mantle-cell lymphoma in patients who have received at least 1 previous therapy. The FDA approval of bortezomib for injection is based on a randomized, phase 3, open-label, noninferiority trial in 222 bortezomib-naïve patients with relapsed MM. The study met its primary end point, to demonstrate at least 60% overall response rate with subcutaneous bortezomib relative to IV bortezomib. The overall safety profile was similar between the 2 forms of the drug, with the subcutaneous form showing reduced (6%) grade 3 peripheral neuropathy versus the IV form (16%). (January 23, 2012)

Topical Gel for Actinic Keratosis The apoptotic topical gel ingenol mebutate (Picato; Leo Pharma) has received FDA approval for the treatment of actinic keratosis, a precancerous condition that can progress to squamous-cell carcinoma. In 4 phase 3 studies involving >1000 patients with actinic keratosis, 60% to 68% of those with lesions on the face and scalp and 44% to 55% of those with lesions on the trunk and extremities demonstrated ≥75% clearance after receiving ingenol. Among those who received placebo, only 7% to 8% demonstrated ≥75% clearance. The recommended dose is 0.015% applied to lesions on the face or scalp once daily for 3 consecutive days and 0.05% applied to lesions on the trunk and extremities once daily for 2 days. (January 23, 2012)

Boxed Warning, New Contraindication Added to Brentuximab’s Label The FDA has issued a boxed warning for brentuximab vedotin (Adcetris, Seattle Genetics) related to the risk of John Cunningham virus infection, leading to progressive multifocal leukoencephalopathy (PML) and death in patients who take brentuximab to treat Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. This warning is in response to 2 cases of PML that occurred since the drug’s

VOL. 3

NO. 1

expedited approval in August 2011. At that time, 1 fatal case had already been noted in the label. The FDA has also added a new contraindication against the concomitant use of brentuximab with the cancer drug bleomycin, because of an increased risk for pulmonary toxicity. (January 13, 2012)

Bosutinib NDA Accepted for CML

leukemia (CML). The submission was based on efficacy and safety data from a single-arm study of bosutinib in more than 500 patients with previously treated Ph+ CML, including those who were resistant or intolerant to imatinib or had previously received dasatinib or nilotinib. (January 27, 2012) ■

The FDA has accepted a New Drug Application (NDA) for bosutinib (Pfizer), an oral dual Src and Abl tyrosine kinase inhibitor, as a second-line therapy for adult patients with previously treated Philadelphia chromosome–positive (Ph+) chronic myeloid

Call for Papers Cancer Care Theme Issue American Health & Drug Benefits Readers are invited to submit cancer-related articles to American Health & Drug Benefits, focusing on the clinical, business, and policy aspects of cancer care. The type of articles sought varies considerably: all original research, comprehensive reviews, cost and utilization evaluations, surveys, white papers, call to action, perspectives, and case studies will be considered for publication in this theme issue in May 2012. The growing focus on targeted therapies and diagnostics, and the ever-growing cost of cancer care, require a thorough examination of current and emerging trends in oncology, focusing on benefit design, utilization, and health outcomes. Areas of particular interest include: ➤ Benefit design to enhance cancer-related

outcomes

➤ Management and health policy issues in

oncology

➤ Best practices in oncology

➤ Managing toxicities of cancer therapies

➤ Comparative effectiveness research

➤ Patient navigation initiatives

➤ Cost comparisons in cancer drug therapy

➤ Pathways and practice guidelines: role in

patient care

➤ Emerging trends in cancer therapy

➤ Personalized medicine in oncology

➤ End-of-life costs of care issues

➤ Programs for cancer survivors

➤ Health plan initiatives in oncology ➤ Initiatives to control the cost of and/or

➤ Targeted cancer therapies ➤ Value-based approaches to cancer care

improve access to cancer therapies

TH E PE ER

-R EV IE NOVEM W ED FO BER/DE RU M FO CEMBE R 2011 R EV ID EN

C E IN BE N EF

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VOLUM E 4, NU MBER 7

FOR PA YERS,

Submission deadline: March 14, 2012. All articles will undergo AHDB’s standard peer-review process.

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HEALTH

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Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) For more information contact editorial@AHDBonline.com, or call 732-992-1889

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IN THIS ISSUE

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editors Brett Kaplan Lara J. Lorton Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896 Sales Assistant Zach Ceretelle Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto 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. Contact Information: For subscription information please contact: circulation@valuebasedcancercare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 7 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. 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. 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, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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GI CANCERS SYMPOSIUM

HEALTH POLICY

Molecular profiling for stage II colon cancer Novel TKI, regorafenib, extends survival in advanced CRC New assay may detect pancreatic cancer early More….

Paying for quality: increasing shift toward valuebased healthcare Americans willing to pay hundreds of dollars for cancer screening

VBCC PERSPECTIVE

Mammography use increases when copayment is removed Eribulin linked to less neuropathy than ixabepilone More….

The promise of molecular profiling

ASH ANNUAL MEETING

BREAST CANCER

Future directions in myeloma Cost of treating myeloproliferative neoplasms is significant Cost of managing NHL Ponatinib overcomes hard-to-treat T315I mutation More….

Comparative effectiveness analysis of 3 radiation therapies Two distinct new agents show impressive results in prostate cancer More….

PATIENT ADVOCACY

NOISE-CANCELING INFORMATION

Building a national patient advocacy network in oncology More….

GU CANCERS SYMPOSIUM

See article online or submit your questions at www.valuebasedcancercare.com/submit-noise.

VBCC Editorial Board 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 Immediate Past President, ACCC Past Chair, NCCN Board of Directors Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Craig Deligdish, MD Florida Comprehensive Cancer Network, Melbourne, FL Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

Ira Klein, MD, MBA Aetna Hartford, CT

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX

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

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Crystal Kuntz, MPA Astellas Pharma US Washington, DC Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Lynn Nishida, RPh RegenceRX Portland, OR

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

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

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

Naimish Pandya, MD University of Maryland Baltimore, MD

David Hom, MBA Solucia Farmington, CT

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

FEBRUARY 2012

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

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IN THE LITERATURE Pertuzumab Prolongs PFS in Patients with HER2 Metastatic Breast Cancer The addition of pertuzumab to trastuzumab and docetaxel as first-line therapy for women with HER2-positive metastatic breast cancer significantly prolongs progression-free survival (PFS) compared with the use of the 2 agents without pertuzumab, according to results of a new phase 3 clinical trial (Baselga J, et al. N Engl J Med. 2012;366:101-119). These results from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study suggest that using the 2 HER2 inhibitors, trastuzumab and pertuzumab, together provides a complementary activity that enhances HER2 blockade, thereby increasing antitumor activity in patients with HER2-positive breast cancer, as has been demonstrated in earlier studies. In CLEOPATRA, 808 patients from 25 countries with HER2-positive metastatic breast cancer were randomized to trastuzumab (6 mg/kg every 3 weeks or until progression) plus docetaxel (75 mg/m2) plus either pertuzumab (420 mg every 3 weeks or until progression or unmanageable toxicity) or to placebo. The primary end point was PFS. The median duration of treatment was 18.1 months in the pertuzumab group and 11.8 months in the placebo group. At approximately 34 months, PFS was 6.1 months longer in the pertuzumab group (18.5 months vs 12.4 months, respectively; P<.001). In addition, after a median follow-up period of 19.3 months, the objective response rate, a secondary end point, was 80.2% with pertuzumab versus 69.3% with placebo (P = .001). The rates of grade ≥3 febrile neutropenia and diarrhea were ≥2% higher in the pertuzumab group (13.8% and 7.9%, respectively) than in the placebo group. The rates of cardiac dysfunction did not increase in the pertuzumab group, however.

Bevacizumab Delays Progression, May Extend Survival in Ovarian Cancer Two phase 3 international clinical studies show that initiating therapy with bevacizumab in combination with standard chemotherapy extends progression-free survival (PFS) in women with advanced ovarian cancer, and women at high risk for disease progression may live longer with the addition of bevacizumab to standard therapy (Burger RA, et al. N Engl J Med. 2011;365:2473-2483; Perren TJ, et al. N Engl J Med. 2011;365:2484-2496). In the Gynecologic Oncology Group (GOG)-0218 study, 1873 women with

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newly diagnosed stage III or stage IV ovarian cancer who had undergone debulking surgery were randomized to 1 of 3 treatments for 22 cycles of 3 weeks each: standard chemotherapy (carboplatin plus paclitaxel, cycles 1-6) followed by placebo (cycles 7-22); standard chemotherapy plus bevacizumab 15 mg/kg followed by placebo; or stan-

dard chemotherapy plus bevacizumab 15 mg/kg, followed by an additional course of bevacizumab 15 mg/kg. The primary end point was PFS. After a median follow-up of 17.4 months, the median PFS was 14.1 months in those who received bevacizumab for the entire study period versus 11.2 months in those receiving

bevacizumab only in the initial cycles, and 10.3 months in those who received only standard chemotherapy. The difference in overall survival (OS) between the groups was not significant. Hypertension (grade ≥2) was the only adverse event occurring significantly more often in patients receiving Continued on page 8

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: Q 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2 Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta ®-treated patients as compared with placebotreated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2011 Amgen. All rights reserved.

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IN THE LITERATURE Bevacizumab Delays Progression... Continued from page 7 bevacizumab for the entire study (22.9%) or in the initial cycles (16.5%) than in those receiving standard chemotherapy (7.2%). The second study, the International Collaboration on Ovarian Neoplasms (ICON7), was similar in design to

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegﬁlgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically signiﬁcant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

GOG-0218, but only 91% of the 1528 women had stage III or IV ovarian cancer; 9% had high-risk early-stage disease; and 30% were at high risk for disease progression. Patients were randomized to standard chemotherapy every 3 weeks for 6 cycles or to standard chemotherapy plus bevacizumab 7.5 mg/kg every 3

(n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) ADVERSE REACTIONS reported frequency of the reaction, or (3) strength of causal The following serious adverse reactions are discussed in relationship to Neulasta. greater detail in other sections of the Brief Summary: Gastro-intestinal disorders: Splenic rupture [see Warnings • Splenic Rupture [See Warnings and Precautions] and Precautions] • Acute Respiratory Distress Syndrome [See Warnings Blood and lymphatic system disorder: Sickle cell crisis and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Use in Patients with Sickle Cell Disorders [See Warnings including anaphylaxis, skin rash, and urticaria, generalized and Precautions] erythema and flushing [see Warnings and Precautions] • Potential for Tumor Growth Stimulatory Effects on Malignant Respiratory, thoracic, and mediastinal disorder: ARDS Cells [See Warnings and Precautions] [see Warnings and Precautions] The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: Injection site reactions in the pegfilgrastim arm in placebo controlled clinical trials Skin and subcutaneous tissue disorders: Sweet’s syndrome, are bone pain and pain in extremity. Cutaneous vasculitis Clinical Trials Experience Because clinical trials are conducted under widely varying DRUG INTERACTIONS conditions, adverse reaction rates observed in the clinical trials No formal drug interaction studies between Neulasta and other of a drug cannot be directly compared with rates in the clinical drugs have been performed. Increased hematopoietic activity trials of another drug and may not reflect the rates observed in of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider clinical practice. Neulasta clinical trials safety data are based upon 932 patients these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The USE IN SPECIFIC POPULATIONS population was 21 to 88 years of age and 92% female. The Pregnancy ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy Category C 1% Asian. Patients with breast (n = 823), lung and thoracic There are no adequate and well-controlled studies in pregnant tumors (n = 53) and lymphoma (n = 56) received Neulasta women. Pegfilgrastim was embryotoxic and increased after nonmyeloablative cytotoxic chemotherapy. Most patients pregnancy loss in pregnant rabbits that received cumulative received a single 100 mcg/kg (n = 259) or a single 6 mg doses approximately 4 times the recommended human dose (n = 546) dose per chemotherapy cycle over 4 cycles. (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta

weeks for 5 or 6 cycles and continuation with bevacizumab for an additional 12 cycles or until disease progression occurred. At a median follow-up of 19.4 months, median PFS was 19.0 months in the bevacizumab group and 17.3 months in the chemotherapy group. In patients at high risk for progression,

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 © 2011 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

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PFS was 15.9 months with bevacizumab versus 10.3 months with standard chemotherapy; at 42 months, OS was 36.6 months versus 28.8, respectively. Adverse events were similar to those in the GOG-0218 study.

33 States Not Prepared to Cover Patients in Clinical Trials by 2014 In an attempt to eliminate insurance coverage status as a barrier to clinical trial enrollment, the Affordable Care Act of 2010 (ACA) requires that by January 2014, all payers in all states must cover routine medical costs associated with patient participation in approved clinical trials. A new study reveals, however, that most states either have laws that do not properly comply with these regulations or have no laws or agreements regarding clinical trial (phases 1-4) insurance coverage (Kircher SM, et al. J Clin Oncol. Epub December 27, 2011). In April 2011, investigators from cancer treatment centers in Chicago, IL, and Rockville, MD, reviewed databases from the National Cancer Institute, the American Cancer Society, and the National Conference of State Legislatures to identify the state mandates and current agreements for clinical trials involving patients with cancer. This study shows that: • 18 states currently meet the ACA requirements for clinical trial coverage, either through state law or through voluntary agreements with payers • 33 states have laws that are not compliant with the 2014 ACA mandate • Of those, 15 states have no laws addressing trial participation coverage: Alabama, Arkansas, Hawaii, Idaho, Kansas, Minnesota, Mississippi, Montana, New York, North Dakota, Oklahoma, Pennsylvania, South Dakota, Utah, and Washington. The most common problem was the lack of coverage for phase 1 trials, followed by coverage for therapeutic studies only. The difficulty in determining the true benefit of the 2014 ACA mandate is compounded by the “grandfather” provision in the ACA, which exempts health plans and other payers from covering patients enrolled in trials on or before March 23, 2010. Rather than wait years for the effects of the grandfather regulation to pass, the governments of 6 states—Florida, Georgia, Michigan, Nebraska, New Jersey, and South Carolina—have already initiated their own voluntary agreements directly with insurers for covering routine medical care for patients enrolled in clinical trials. Continued on page 14

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VALUE PROPOSITIONS A New Vision for Drug Development “We can no longer think of cancer as one disease. Even something like lung cancer could be hundreds of distinct cancers, each defined by specific molecular characteristics requiring different treatment approaches. This makes research more challenging, but the payoff for patients will be enormous.”—Michael P. Link, MD, ASCO President, Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research, November 2011

Key Driver of Metastasis Uncovered, Important for Drug Development “We used to think that the only cells that mattered in a tumor were the cancer cells and that’s it, but now we are beginning to see that other cells must collaborate with cancer cells to drive tumor growth and permit an evolution of the cancer cells into metastatic cells. This change is what causes poor prognosis and ultimately what kills the patient,” said David Waisman, PhD, Professor of Biochemistry and Molecular Biology and Pathology, and Canada Research Chair in Cancer, Dalhousie University, Halifax, Nova Scotia. Explaining this new understanding on the key role that the macrophage cell surface protein S100A10 has in tumor development, Dr Waisman suggested that this finding is but one example of the complicated nature of cancer biology, and hence its cure. He and his colleagues suggest that a tumor cannot grow without this “support” from the macrophages, which come from the blood or other tissues in the body and not from the tumor itself. How the macrophages move into the tumor remains unclear. The next step, according to Dr Waisman, is to demonstrate exactly how S100A10 functions as a “molecular scissor” and to identify drugs that can block its activity—the key to preventing metastasis.

Potential Therapeutic Value in Linking Cancer and Inflammatory Processes AB Science, the French drug developer, is one of several companies that are investigating the link between cancer and other inflammatory/ immunologic processes in their development of new therapies with novel mechanisms of action. One such example is the company’s drug masitinib, which is currently in a phase 2 clinical trial that compares it with sunitinib in 44 patients with inoperable, metastatic, imatinib-resistant gastrointestinal stromal tumors (GISTs). Masitinib has been shown to significantly extend overall survival. After a median follow-up of 18 months, 79% of patients treated with masitinib were still alive versus 20% for patients treated with sunitinib. After 2 years, 53% of those receiving masitinib were still alive versus 0% in the other group. “In addition to killing cells that make up the tumors, masitinib has a complementary mode of action that may also kill cancer stem cells and trigger an immune response, which may further enhance its efficacy,” said Olivier Hermine, MD, PhD, President of the Scientific Committee of AB Science. Masitinib received an orphan drug designation for GISTs by the US Food and Drug Administration. Masitinib’s activity on the mast cell and certain kinases essential to the activation of the inflammatory cells can have an

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effect on the symptoms associated with some inflammatory and central nervous system diseases. GISTs are diagnosed in approximately 5000 to 6000 new patients annually in the United States. In 2010, the global market for drugs for GISTs was $920 million.

Merging of Biotechnology Companies to Bolster Innovation in Cancer Therapies Two large biotechnology companies announced in January that they would be buying smaller firms that are incorporating new technologies for the development of drugs for leukemia and lymphoma. The 2 companies are Amgen, which is buying Micromet for $1.16 billion, and Celgene, which is buying Avila Therapeutics for $350 million. Micromet is developing a drug that utilizes the bispecific T-cell engager (BiTE) antibodies, which bind to a tumor, as well as to a T cell of the immune system. When the T cell is near the tumor, the BiTE can kill it. Celgene’s acquisition of Avila is in line with its focus on hematologic therapies. Avila’s most advanced drug is AVL-292, which is currently in phase 1 clinical trials. The drug inhibits the activity of the Bruton’s tyrosine kinase protein, which may slow the development of diseases that involve the activity of immune B cells, such as non-Hodgkin lymphoma or B-cell chronic lymphocytic leukemia.

GE-ACCC Collaboration Enhances Innovation in Oncology The Association of Community Cancer Centers (ACCC) announced in February that GE Healthcare will sponsor the annual ACCC Innovator Awards, which supports innovation in the approach to cancer care. “GE’s sponsorship of the ACCC Innovator Awards will help catalyze cancer innovation in the community setting,” said ACCC President Thomas Whittaker, MD, FACP. “ACCC Innovator Awards recognize transformational change and honor community cancer programs for their will, drive, and spirit to leverage technology…and empower their patients as well as their staff.”

GE Invests in Ingestible Imaging Capsule for CRC GE Capital and GE Healthcare, the financial services and healthcare divisions, respectively, of GE Company, announced their investment in CheckCap, an Israeli developer of imaging capsules for ingestion that could help in the diagnosis of colorectal cancer (CRC). The capsule will be capable of 3-dimensional imaging of the colon when the patient swallows it, and it will not require bowel cleansing before ingestion or a hospital visit. This lessinvasive procedure could remove some of the barriers preventing patients from undergoing colonoscopies. “Check-Cap’s technology is not only innovative, but it presents great promise to change the standard of patient care and to help them avoid the discomfort of traditional colonoscopies,” said Mike Harsh, Vice President of GE and Chief Technology Officer at GE Healthcare. CRC is the third most common and the second leading cause of cancerrelated death in the United States.

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BEST PRACTICES

Ventura County Hematology Oncology... sites—Oxnard and Ventura. When our sixth physician joined in 2008, we opened our third site, in Camarillo. Currently we have 7 physicians, who are all hematologists-oncologists. In addition, we have 1 physician assistant and 10 nurses working in the 3 sites. In late 2010, the Ventura site expanded its infusion capacity, and in mid2011 the Camarillo site began to provide infusions. Currently all 3 offices provide infusion services. The 3 offices are located within 8 miles of each other. We serve a very large population of about 700,000 people in Ventura County, which encompasses many cities, including Santa Paula, Fillmore, Ojai, Port Hueneme, Somis, Ventura, Oxnard, and Camarillo, as well as the Thousand Oaks and Simi Valley areas. We also have a pharmacy technician who dispenses oral medications inhouse, a licensed clinical laboratory scientist to oversee laboratory services in-house, and full-time research services that allow us to enroll patients in National Cancer Institute–approved clinical trials so patients do not have to go to university centers in Los Angeles, which is about 50 miles south. These enhance our patient care and ensure that we can offer patients important services within the context of our practice. Ms Rivera: We have been using an oncology-specific electronic medical record (EMR) system since 2006 and started prescribing electronically (eprescribing) in 2009. These are important features to have in any oncology practice. Being efficient is very important to us, because it is directly related to our ability to survive economically as a practice. Our hope is that our EMR system will help us be even more efficient, so we could concentrate our efforts on improving patient care. Each of our 3 sites is located either in the hospital’s medical office building, or in close proximity to the hospital. Although not part of our practice, radiation and imaging services are available in the same facilities at our Oxnard and Ventura sites. Patients who need radiation and chemotherapy can have these done on the same day, in the same building. It is very convenient to our patients.

VBCC: Why do you need 3 separate infusion centers in such close proximity? Ms Rivera: The 3 sites serve very different demographics. Our Ventura center covers the neighboring cities. We expanded our infusion center in late 2010 to accommodate the demand.

This makes it very convenient to these patients rather than traveling to Oxnard. The Oxnard center is in the middle, and it serves the largest population. Camarillo has many senior residents, who often prefer to see physicians and be treated within the city limits. Offering infusions close to people’s homes is an important feature of our practice. Having 3 smaller infusion centers rather than a large one gives them a noninstitutional, neighborhood feel. We are also lucky to have very skilled and compassionate oncology nurses. Our patients love them. In fact, there are other physician specialists, such as rheumatologists, from Ventura County, who send their patients to us for infusion. This service also generates additional revenue.

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trial directly through our office. Approximately 10% of our patients participate in clinical trials. Our research coordinator informs us during our weekly meetings which trials are open, and we coordinate this based on the type of patients we have.

Being efficient is very important to us, because it is directly related to our ability to survive economically as a practice. As overhead costs continue to rise and with reimbursement going in the other direction, we strive to be as efficient as possible to stay in business for our patients in the community.

VBCC: You mentioned that you are involved in research. Could you elaborate on this? Dr Parsa: We have a full-time research coordinator, and we are continuously involved in approximately 10 or 20 clinical trials at one time. In the past we were associated with the University of California, Los Angeles, for clinical trials, but this involved a long drive for patients.

Approximately 10% of our patients participate in clinical trials. Our research coordinator informs us during our weekly meetings which trials are open, and we coordinate this based on the type of patients we have. Once we switched to US Oncology, we are now able to provide all the research coordination directly at our practice. Having such a large population of patients allowed us to coordinate the research with US Oncology. Our patients like being able to join a

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Oncology Alliance, I am also active in advocacy efforts to educate members of Congress about the current crisis in cancer care access. Our Congress members need to understand that keeping cancer care delivery in the community setting costs the system less.

The research coordinator then matches the patients with the trials, and if the patients agree, they are being signed up.

VBCC: Many community cancer centers today are struggling with economic issues and competition from neighboring hospitals. Are you worried about this?

VBCC: What are your main financial concerns?

Dr Parsa: We are not experiencing these issues yet; we are still doing fairly well. Many of our patients have insurance, and we keep close contact with the primary care physicians in the area, who are very satisfied with us and keep referring patients to us, once a cancer diagnosis is made. Approximately 90% of the patients we have come to us after an initial cancer diagnosis was made or suggested. Although there are 3 hospitals in the area, and the county hospital has its own oncologist, we are the major community practice in the area offering hematology oncology services. We have approximately 500 or 600 patients under our care on an ongoing basis, and the majority of them come from our area physicians. Because we are the main oncology practice in our area, we get the majority of the patients from the primary care physicians in the area. Therefore, the area hospitals do not present a threat at this point. Having a strong connection with the area physicians is crucial and is probably the main reason for our success. In addition, we run an excellent business office under the leadership of our business manager, Marissa. She handles all the business decisions. Ms Rivera: We are aware that last year 199 community cancer centers closed or were sold to hospitals. Even

Ms Rivera: Our single largest expense is drugs. One main concern is not recovering the cost of purchasing, administering, and billing for the drugs. It is also difficult to get reimbursed for many drugs, considering how expensive cancer drugs are. Certain insurance companies require a long turnaround time for prior authorizations, which often makes the treatment process very inefficient. Many patients are also not fully insured, and some employers have been opting for lower-premium, higher out-of-pocket cost plans. Our group cannot sustain a practice when patients are unable to afford their share of the treatment costs that are not reimbursed by their insurance. This is why we have staff members who find help for patients through foundations and manufacturers’ copay assistance programs. We find financial help for patients so that they can afford their cancer therapy. Patients are treated with generics when these are available and are equivalent in efficacy. As overhead costs continue to rise and with reimbursement going in the other direction, we strive to be as efficient as possible to stay in business for our patients in the community. Through the help of Community

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Ventura County Hematology Oncology... here, in Southern California, I see a growing trend. Oncologists are tired of taking the risk of fronting the cost of drugs without the certainty of getting reimbursed properly. So far we are in a different situation. Our group has the biggest presence in western Ventura County. Our physicians played a major role in developing cancer programs in our area in conjunction with the community hospitals. We are an integral part of the community and the major provider of cancer care in our area. Every year our physicians provide free talks to the public regarding cancer prevention. They have touched on genetic disposition as well. Recently, they have expanded the talks to discuss available cancer treatments and the importance of follow-up after active treatment is over. Obviously, we have to be financially viable to be able to offer oncology services. As the business manager, I believe that our physicians should focus on providing the best cancer care to patients. That is why I focus on running an efficient office—to free the physicians to focus on the clinical aspects of the practice.

VBCC: Can you discuss some of the business aspects of running a successful cancer practice today? Ms Rivera: We are all doing more these days. To survive, we have to maintain a very lean staff, and we all have to do our part. The following points represent the main aspects of our success:

We have the biggest presence in the area, which is an important factor in our success. Our flexibility and adaptability to changing times also allow us to survive.

Another important factor is efficiency. We are running a very efficient practice. We run a lean staff and are not “top heavy.” Everyone is now doing more, including the physicians. Some responsibilities, which probably could be performed by medical assistants, are being done by our physicians. We expect everyone—the physicians, the nurses, the billing office, the laboratory, the back and the front offices—to do their part, as costs continue to rise and reimbursement continues to be “flat,” or even go down.

Another example is that those working in the front office know how important it is to collect the copayments upfront, so we do not

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have to waste time on collecting it later. Or, if patients do not have full coverage, we help them get money from different foundations to pay for their bills. This way, we help them pay their bills, and we help ourselves to get paid for our services. We do not just leave it to patients to figure it out on their own.

We have been participating in the Physician Quality Reporting Initiative (PQRI) since 2007. We have been successful every year in reporting the PQRI quality measurements to the Centers for Medicare & Medicaid Services (CMS). Each year we select quality measures to report on, and we report them to CMS. This means we have been getting the bonuses from CMS for the past several years, which helps financially.

We have also met the requirements for e-prescribing since this program was instituted by CMS. We have been encouraging the physicians to do e-prescribing. We participate in all the programs that offer incentives by CMS, and we have been doing this for many years. We participated in past demonstration projects by CMS. The business aspect of a practice is very important to the success of the practice. We do not take anything for granted, and we realize how important it is to take advantage of such programs.

This year, we plan on attesting for the EHR (electronic health record) Meaningful Use Incentive Program. Successful attestation gives each physician the opportunity to receive a bonus totaling $44,000 payable in 5 years.

This is also true about technology. We use technology to improve our efficiency. The EMR system, for example, is very important, especially because we have more than 1 location. Having paper charts is not efficient, and it can interfere with providing the best care for patients. If the chart is in one office, and the nurses need it in the other office, this is not efficient. Moving to EMRs was very important to improve our efficiency. Now everyone has access to the patient’s medical record regardless of office location. We also use technology to automate certain processes for our practice management system, which also allows us to manage with a smaller staff at a high productivity level.

Billing is also part of our EMR. When nurses enter the start and stop times for each drug, the EMR knows which Current Procedural Terminology (CPT) codes to bill. Our billing specialist imports the physician and treatment charges electronically through an interface instead of manually entering them in our practice management system. Before submitting claims, we use claim edit software to make sure that all the diagnoses, CPT, and Healthcare Common Procedure Coding System codes needed are not missed, because it is more efficient to send the claims when they are correct and clean than to fix them later. Going through hundreds of claim lines daily is taxing for a person, but technology assists to ensure that the claims are correct before submitting them. We send claims every day. Some practices wait and submit claims once a week or every 2 weeks, but we process and submit claims every day.

Our physicians meet every week to discuss clinical cases. In addition, we have a business meeting every month. Keeping the communication open between the physicians and the business administrator is very important.

As one of our physicians, Ann Kelley, MD, commented, the secret to our practice’s success is excellent office management with fiscal discipline, experienced and dedicated nurses and staff, caring physicians, rare turnover, and above all—great team work. I believe these are some of the main reasons that we are able to survive as a practice.

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VBCC: Finally, you have mentioned that you have patient education programs. Can you elaborate? Ms Rivera: We provide support programs for patients and the community. Our physicians are very active in educational and support programs in the community. For example, one physician is always attending the prostate cancer support group. Because we have a big presence in the community, when any organization, such as the American Cancer Society or one of the community hospitals has an event for the public regarding cancer, one of our physicians usually speaks at that event. Recently we hosted and sponsored our own series of educational events for the community. We had a series of talks related to breast and prostate cancers. Topics include risk factors, prevention, early detection, treatments available, and what to do after treatment. Many of the people who attend these meetings are not necessarily our patients but rather people from the community who are interested in the topic. The goal is to keep the community informed about cancer prevention and treatments, and of course these are free events. We plan on hosting more educational community events for other types of cancer. In addition, we provide a symposium about once every other year to physicians in the area—such as surgeons, gastroenterologists, dermatologists, urologists, pulmonologists, neurologists, cardiologists, hospitalists, nephrologists, gynecologists, and the primary care physicians in the community...to educate them on the latest advances in cancer care. Our community cancer practice is truly an important part of our community at large. ■

www.ValueBasedCancerCare.com

GI CANCERS SYMPOSIUM

Molecular Profiling for Stage II Colon Cancer

VBCC Perspective, page 1

The benefits and limits of current testing By Caroline Helwick San Francisco, CA—Approximately 80% of patients with stage II colon cancer will be cured by surgery alone, but 20% will still relapse. Oncologists struggle with the question of which patients could benefit from adjuvant chemotherapy to reduce this risk, and which patients can be safely observed, without further treatment. Molecular factors of the tumor can help define high-risk stage II disease; however, no agreement exists about which of the currently available molecular assays are most useful for this purpose. At the 2012 Gastrointestinal Cancers Symposium, George J. Chang, MD, FACS, Associate Medical Director, Colorectal Center, University of Texas M.D. Anderson Cancer Center, Houston, and Neal J. Meropol, MD,

Table

“What matters is the absolute benefit of chemotherapy at each level of risk. The available tests also do not obviate the need for consideration of patient preferences in adjuvant therapy decision-making.” —Neal J. Meropol, MD Chief, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, debated this question. Dr Chang described the current assays, by risk (Table). In all the assays, prognosis is independent of standard high-risk clinical criteria. But molecular profiling does improve treatment efficiency, he said.

Molecular Tests for Stage II Colon Cancer

Oncotype DX Colon Cancer Assay (Genomic Health) A 12-gene signature, RT-qPCR assay using paraffin-embedded tumor tissue. Yields a continuous recurrence score that stratifies patients into low-, intermediate-, and high-risk groups ColoPrint (Agendia) 18-gene signature derived from fresh tumor blocks, yielding 2 risk groups: high risk and low risk. A prospective validation study is under way Colorectal Cancer DSA (Almac Diagnostics) A 634-gene transcriptome-based microarray assay using formalin-fixed paraffin-embedded samples, which stratifies patients by high or low risk Previstage GCC Colorectal Cancer Staging Test (DiagnoCure) Utilizes RT-qPCR to quantify expression of guanylyl cyclase C (GCC) in lymph nodes. GCC is an enzyme found only found in the intestinal epithelium, and its presence within lymph nodes may indicate that the tumor will behave aggressively. A ratio of GCC-expressing nodes to total lymph nodes >1.0 indicates high risk. A prospective validation study is under way RT-qPCR indicates real-time reverse transcription polymerase chain reaction.

Limitations of the Assays “Although these assays are emerging as tools that can classify patients with stage II colon cancer based on their risk for recurrence, an inherent limitation of each is its lack of predictive ability,” Dr Chang noted. “In an ideal world, we could identify patients who can be predicted to benefit from chemotherapy. But in the real world, we can identify patients at high risk for recurrence, and, therefore, those who have the greatest need for adjuvant chemotherapy benefit. And, we can identify patients at low risk for recurrence who may safely be observed.” The number needed to treat for a low-risk patient with stage II cancer is 50 compared with 20 for high-risk patients. In the latter case, the benefit is similar to that obtained by oxaliplatin in a patient with stage III cancer, which is considered very reasonable, Dr Chang said. According to Dr Meropol, “What matters is the absolute benefit of chemotherapy at each level of risk.” This is hard to determine, especially when the estimated relapse risk varies in each of the assays. Although he did not dismiss the benefit of these assays, he did note their limitations: • Validation sets are small or not representative of real patient populations

• No well-validated genetic platforms identify patients at “very high risk” • There is a small or uncertain impact of chemotherapy in the “high-risk” groups • The predictive value of the assays has not been demonstrated • The impact of oxaliplatin in “highrisk” groups is uncertain • It is unclear how to integrate testing for microsatellite stability status (another determinant of favorable/ unfavorable prognosis) into the classifier • It is unclear how to address discordance between clinical and molecular results.

“Although these assays are emerging as tools that can classify patients with stage II colon cancer based on their risk for recurrence, an inherent limitation of each is its lack of predictive ability.” —George J. Chang, MD, FACS

“The available tests also do not obviate the need for consideration of patient preferences in adjuvant therapy decision-making,” Dr Meropol added. Future research should focus, he said, on expanding the identification of patients who will not relapse, improving the identification of those at highest risk, improving adjuvant therapy, and predicting the harms of chemotherapy for individual patients, so that the impact on quality-adjusted survival can be estimated. ■

Promising Data for New DNA Stool Testing, at Low Cost May replace invasive procedures for CRC San Francisco, CA—The “eradication” of colorectal cancer (CRC) may be a step closer, based on promising data for stool DNA testing, said David A. Ahlquist, MD, Mayo Clinic, Rochester, MN, at the 2012 Gastrointestinal Cancers Symposium. Suggesting that his claim is “not too bold, and not hyperbole,” Dr Ahlquist explained that stool DNA testing using next-generation technology is: • Based on rational biology

• Has an “extraordinarily” high detection rate for curable cancers and precancers likely to progress • Detects lesions on both sides of the colon with equal accuracy • Picks up flat, or serrated, polyps likely to be missed not only by fecal occult blood tests but also by colonoscopy. Broad application of stool DNA testing in longitudinal screening programs has the potential to effectively prevent CRC by cumulatively high

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FEBRUARY 2012

precancer detection, he claimed. The noninvasive DNA test, currently in development, involves no diet or medication restrictions and no bowel preparation, and it is performed at home using a stool sample. It works by detecting tumor-specific DNA alterations in cells that are shed into the stool from precancerous and cancerous lesions. Richard M. Goldberg, MD, Ohio State University Medical Center, chair of the meeting’s steering committee,

commented, “The data are very impressive. I’m surprised and delighted at how good it is.” He said that if the DNA stool test could substitute for screening colonoscopy, the cost-savings would be substantial. “This is potentially a very exciting development,” he said. “I would like to see it cost less than $300. And this will be just the tip of the submerged iceberg. The reduction in false-positives and the effect of canContinued on page 15

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NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse 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 • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 109/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 • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi 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 • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Brief Summary of Full Prescribing Information on the following page.

RUX-1004C

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IN THE LITERATURE Continued from page 8

Chemotherapy-Induced Structural Brain Changes Linked to Cognitive Function Findings from a longitudinal study of impaired cognitive functioning and cerebral white matter integrity in women who receive chemotherapy for breast cancer suggest that chemothera-

py-induced structural changes in the brain are correlated with impaired cognitive functioning (Deprez S, et al. J Clin Oncol. 2012;30:274-281). In a Dutch study involving 69 premenopausal women, 34 women with early-stage breast cancer who were exposed to chemotherapy were com-

pared with 16 women with early-stage breast cancer who were not exposed to chemotherapy, and with 19 matched healthy controls. Before treatment was started and at 3 to 4 months afterward, all participants underwent neuropsychological testing for attention, concentration, memory,

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Gradesb Grade 3 Parameter BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk 69.7 9.0 3.9 30.5 1.3 0 Thrombocytopenia myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential 96.1 34.2 11.0 86.8 15.9 3.3 Anemia thrombocythemia myelofibrosis. 18.7 5.2 1.9 4.0 0.7 1.3 Neutropenia 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). 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 Reactions Gradesa 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 d Urinary Tract Infections 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.

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FEBRUARY 2012

executive functioning, cognitive/psychomotor-processing speed, and selfreported cognitive functioning. Baseline testing revealed similar results between all 3 groups, but paired t-test analyses showed that the chemotherapy group scored significantly worse (P <.05) on attention, concentration, psychomotor speed, and memory tests at 3 to 4 months after treatment initiation. The 2 control groups, however, performed significantly better at the later points than at baseline in those domains, which is consistent with a learning effect. The decline in the attention and verbal memory domains in the neuropsychological tests in the chemotherapy group correlated with the changes in fractional anisotropy.

BCL2 Inhibitor Navitoclax Shows Antileukemic Activity in CLL Results of a phase 1 study show that navitoclax, a new BH3 mimetic that targets BCL2 and related antiapoptotic intracellular proteins in cancer cells, inhibits the development of lymphocytosis in patients with chronic lymphoyctic leukemia (CLL; Roberts AW, et al. J Clin Oncol. Epub December 19, 2011). CLL is characterized by overexpression of BCL2, whose antiapoptotic effects lead to the accumulation of mature leukemic lymphocytes. The BH3 mimetic is a new class of anticancer drugs that focus on the mitochondrial apoptotic pathway for destroying cancer cells and target BCL2. In this early-stage study, 29 patients with relapsed or refractory CLL received oral navitoclax once daily in 21day cycles. Exploratory efficacy end points included progression-free survival (PFS), overall response rate (ORR), time to disease progression, and duration of overall response. After a median treatment of 7 months, peripheral blood lymphocyte count dropped by 50% in 19 of 21 patients who had lymphocytosis at baseline. A significant reduction was observed within days of starting the first cycle, and the maximum reduction occurred after 3 cycles. Among 26 patients who received ≥110 mg of navitoclax daily, 9 achieved a partial response and 7 maintained stable disease for >6 months; the ORR was 35%. The median PFS was 25 months. Durable responses were seen in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. The low expression of MCL1, which mediates resistance to navitoclax in vitro, was significantly correlated with a maximum reduction in lymphocytosis. ■

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VBCC PERSPECTIVE

The Promise of Molecular... gists are now ordering tests for the KRAS mutation, if they are considering anti-EGFR (epidermal growth factor receptor) therapy. But there are other potential markers, such as BRAF. Recently, the drug vemurafenib, an inhibitor of BRAF kinase, was approved by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation. Although BRAF mutations are also seen in colon cancer, it is unclear whether a drug with the same target that works in melanoma will also have efficacy for patients with colorectal cancer. So we cannot assume that an observation in one tumor type will apply to another. We will have to investigate mutations across tumor types, particularly if we are to more precisely develop treatments linked to biologic profiles within a disease spectrum. We are also learning that the biologic profile of the primary tumor may be very different from the metastatic tumor. As mutations develop over time, we need to be able to track these. This should help inform drug development, telling us which strategies we need for which disease setting. This is a complex endeavor. Most of us who are involved in cancer care believe that a patient will not have a single mutation (or marker), but a collection of markers. It may, therefore, take a combination of different types of drugs to address these markers.

Continued from cover

VBCC: How do you envision molecular profiling will improve the clinical trial process? Dr Benson: Currently, in our clinical trials, we typically identify 1 biomarker (to be targeted by a specific drug) that will be the focus of the trial. What we have to do is independently screen a number of patients, until we obtain that particular subset of trial participants that test positive for that marker. Perhaps in the future we will need a subset of patients with 3 or more, not 1, mutations. What will help this whole process is for our clinical trial candidates to have a molecular profile already available as part of routine assessment. This will make screening for clinical trials much more efficient, because a diagnostic profile or panel, such as a gene profile, would already be available from which patients could be selected for a specific molecularly driven trial.

VBCC: Will molecular profiling aid in drug development? Dr Benson: One of the goals is to enhance drug development. Historically, our conventional approach to study relatively unselected patients with a given disease has worked to a certain extent. However, under our current methods, many patients are not being treated optimally. To create a tighter link between a particular biologic characteristic and a targeted drug that addresses this characteristic will be much more beneficial to the indi-

The development of molecular principles that guide cancer therapy is massively complex. It is going to be very expensive. And we need everyone on board. —Al B. Benson, III, MD, FACP vidual patient. That is why there is so much emphasis on biomarkers in drug development.

VBCC: When do you expect that molecular profiling will become advanced enough to reach these goals? Dr Benson: We are getting closer. Companies are developing mutation panels. But some of these cannot fully be utilized now. Although they are increasingly identifying larger numbers of mutations, currently we are not able to use them for treatment decisions. If these continue to evolve,

however, and they prove to be economical as commercial diagnostic tests, it will certainly help speed up the process of developing molecularly based treatments based on specific gene profiles as an example. What is exciting about gene signature work is that it represents what will become a continuum. It will allow researchers to build on a body of work and move us closer to where we want to be—which is not only to identify patients who are most likely to have a recurrence, but to identify those who will be most likely to benefit from a particular intervention. The message we need to get out is that the development of molecular principles that guide cancer therapy is massively complex. It is going to be very expensive. And we need everyone on board: the insurers, regulators, funding agencies, diagnostic and pharmaceutical industries, and patients, who will be asked, for example, to undergo repeat biopsies. This is very exciting, because we are beginning to have the tools that can actually do this work. But there is a high level of complexity involved, and the challenge is to identify these biologic profiles for individual patients. Being able to segregate out the various mutations and treatment strategies would revolutionalize cancer care. It is hard to predict just when we will get there. There is huge promise that it could occur within the next 5 years, but it is difficult to know for sure. ■

GI CANCERS SYMPOSIUM

See also page 21

Promising Data for New DNA Stool Testing... cer prevention are all downstream cost burdens that are enormous,” Dr Ahlquist said. Test Detects 85% of Cancers A multicenter case-control study of 678 patients, including 253 with CRC and 130 with advanced adenomas, detected 85% of nonmetastatic CRCs and 64% of adenomas (in pooled analysis of the training and validation sets; Ahlquist D, et al. Gastroenterology. 2012;142:248-256). “When you apply the 64% sensitivity rate for precancerous lesions, repeated over time, by the third time you have an aggregate 95% sensitivity,” Dr Ahlquist said. Detection increased with adenoma size: 64% for adenomas >1 cm, 77% for those >2 cm, and 90% for those >3 cm; fewer than one third of adenomas

VOL. 3

NO. 1

<1 cm were picked up. “This is most important,” he said. “As a polyp

“I would like to see it cost less than $300. And this will be just the tip of the submerged iceberg. The reduction in false-positives and the effect of cancer prevention are all downstream cost burdens that are enormous.” —David A. Ahlquist, MD

grows, the risk of transformation to cancer increases, and the sensitivity of

Continued from page 12

this test increases in proportion.” Lesions were detected in the proximal and distal colons with equal accuracy: 87% and 83%, respectively, for cancerous lesions and 55% and 53% for adenomas. Dr Ahlquist mentioned that the emerging plasma-based tests, one of which, plasma Septin 9, is commercially available, have not been shown to reliably detect adenomas. Using paired samples from the same patients in a direct comparison of stool DNA testing with the Septin 9 plasma test, he and his colleagues found that 82% of large adenomas were detected by stool DNA testing compared with just 14% by the plasma test, with false-positive rates of 7% and 23%, respectively. For CRC, the stool DNA test detected 87% compared with 60% by the plasma test.

FEBRUARY 2012

at a glance Next-generation stool DNA testing provides: ➤ Rational biological basis for test ➤ High detection rates for CRC and precancers, on both sides of the colorectum ➤ User-friendly, affordable, unlimited access by the public ➤ Potential to prevent CRC through screening

Final validation of the test’s accuracy is under way in a multicenter study, the results of which should support US Food and Drug Administration approval, he said.—CH ■

www.ValueBasedCancerCare.com

Indication ZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

Important Safety Information ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient. In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose. Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breast-feed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby. In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, and a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lowerlimb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain. Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs. Patients should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily. Please see the brief summary of full Prescribing Information on the following pages.

October 2011

ZOM-1030926

HELPS REDUCE ELIGIBLE PATIENT OUT-OF-POCKET COSTS—UP TO $2500 Program benefit

A free program that may help eligible patients manage the cost of ZOMETA treatment.

Program limit

Covers 100% of the out-of-pocket cost of the first ZOMETA treatment and any amount over $25 for subsequent treatments (up to $2500 covered each year). This benefit can be applied to the cost of ZOMETA only; it will not cover the cost of administration services or office visits.

Eligibility

For a patient to qualify for medical benefits under the ZOMETA Card Program, they should be on commercial insurance. They: CANNOT be on Medicare, Medicaid, or any other publicly funded program CANNOT live in Massachusetts MUST be prescribed an on-label indication MUST have a diagnosis for which ZOMETA is indicated

GET STARTED TODAY! Register your office by calling 1-888-966-3826 or by visiting www.ZOMETACARD.com —The process takes less than 5 minutes and activation takes less than 24 hours

The ZOMETA Card is issued by The Bancorp Bank pursuant to license by MasterCard® International and this card may not be used everywhere Debit MasterCard is accepted. The ZOMETA Card is not a credit card and no cash or ATM access is available. This card cannot be used in any capacity outside of the ZOMETA Card Program. MasterCard and the MasterCard Brand Mark are registered trademarks of MasterCard International Incorporated. The Bancorp Bank; Member FDIC.

For more information about the ZOMETA Card Program, ask your ZOMETA representative or Clinical Nurse Educator.

Zometa® (zoledronic acid) Injection Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL patient albumin (g/dL)). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 µmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 µmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Pregnancy Zometa should not be used during pregnancy. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose if 4 mg based on an AUC comparison) resulted in pre- and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. 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 [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Patients Studied Total No. of Patients Studied Total No. of Patients with any AE Body as a Whole Fever Progression of Cancer Cardiovascular Hypotension Digestive Nausea Constipation Diarrhea Abdominal Pain Vomiting Anorexia Hemic and Lymphatic System Anemia Infections Moniliasis Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia Musculoskeletal Skeletal Pain Nervous Insomnia Anxiety Confusion Agitation Respiratory Dyspnea Coughing Urogenital Urinary Tract Infection

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

38 14

(44) (16)

34 21

(33) (20)

(11)

(2)

25 23 15 14 12 8

(29) (27) (17) (16) (14) (9)

28 13 17 13 17 14

(27) (13) (17) (13) (17) (14)

(22)

(18)

(12)

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

(12)

(10)

13 12 11 11

(15) (14) (13) (13)

10 8 13 8

(10) (8) (13) (8)

19 10

(22) (12)

20 12

(19) (12)

(14)

(15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4 1Grade

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4

Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].

Laboratory Parameter

Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13) Musculoskeletal Bone Pain 569 (55) Myalgia 239 (23) Arthralgia 216 (21) Back Pain 156 (15) Pain in Limb 143 (14) Neoplasms Malignant Neoplasm Aggravated 205 (20) Nervous Headache 191 (19) Dizziness (excluding vertigo) 180 (18) Insomnia 166 (16) Paresthesia 149 (15) Hypoesthesia 127 (12) Psychiatric Depression 146 (14) Anxiety 112 (11) Confusion 74 (7) Respiratory Dyspnea 282 (27) Cough 224 (22) Skin Alopecia 125 (12) Dermatitis 114 (11)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

(15) (9) (11) (9)

105 61 59 45

(23) (13) (13) (10)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

(62) (16) (16) (9) (11)

(17)

(20)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

(11) (13) (16) (8) (10)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

155 129

(28) (23)

107 65

(24) (14)

80 74

(14) (13)

36 38

(8) (8)

n (%)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8. Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 3 Laboratory Parameter

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg n/N (%) 7/529 6/973 115/973 19/971 1/971

(1%) (<1%) (12%) (2%) (<1%)

Pamidronate 90 mg n/N (%) 4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

Placebo n/N 4/241 0/415 14/415 8/415 1/415

1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L)

(%) (2%) — (3%) (2%) (<1%)

Zometa 4 mg n/N (%) 2/529 7/973 5/973 0/971 2/971

Pamidronate 90 mg n/N (%)

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

Placebo

(<1%) (<1%) — — (<1%)

n/N

(%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenzalike illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Normal Abnormal Total Solid Tumors Normal Abnormal Total Prostate Cancer Normal Abnormal Total

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

(11%) (8%) (11%)

23/246 2/22 25/268

(9%) (9%) (9%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

(11%) (9%) (11%)

10/143 1/20 11/163

(7%) (5%) (7%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

8/68 2/10 10/78

(12%) (20%) (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials.

7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Zometa should not be used during pregnancy. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia. 8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman.

8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. 16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 T2011-01 ©Novartis

GI CANCERS SYMPOSIUM

Regorafenib Extends Survival in Advanced CRC First small-molecule TKI showing efficacy in this disease By Caroline Helwick San Francisco, CA—The novel tyrosine kinase inhibitor (TKI) regorafenib, used as a single agent to treat treatment-refractory metastatic colorectal cancer (CRC), significantly improved survival and delayed disease progression in an international phase 3 trial presented at the 2012 Gastrointestinal Cancers Symposium. Regorafenib is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. “Regorafenib will likely join the list of useful therapeutics for metastatic colorectal cancer,” commented Herbert I. Hurwitz, MD, Duke Cancer Institute, Durham, NC, who was asked to discuss the findings at the meeting, “although efforts to improve its efficacy, ie, biomarkers, are still needed.” Axel Grothey, MD, Mayo Clinic, Rochester, MN, presented the results of the CORRECT trial, which randomized 760 patients with advanced (ie, treatment-refractory) disease from 105 centers at a 2:1 ratio to best supportive care plus either regorafenib (160 mg/day every 3 weeks) or to placebo. The primary end point was overall survival (OS). “This drug was tested in a setting in which many companies shy away from drug development. These patients are more difficult to treat. But

this is a patient population that is truly in need,” Dr Grothey said. At the second interim data analysis, the median OS was 6.4 months with regorafenib and 5.0 months with placebo, a 29% increase in OS (P = .005).

“Regorafenib is the first small molecular kinase inhibitor showing proof of efficacy in colorectal cancer, and it thereby identifies itself as a potential new standard of care.” —Axel Grothey, MD

“Regorafenib is the first small molecular kinase inhibitor showing proof of efficacy in colorectal cancer, and it thereby identifies itself as a potential new standard of care in metastatic patients who have progressed on other treatments,” Dr Grothey said. “For patients who are running out of treatment options, who have a very poor prognosis, regorafenib added 1.4 months of benefit, a 29% improvement in survival, that I think is statistically and clinically significant.” The median progression-free sur-

vival was 1.9 months for regorafenib and 1.7 months for placebo (P <.001), which translated to a 51% reduction in progression risk. “The median difference of only 0.2 months demonstrates that medians are not the best way to show efficacy,” Dr Grothey said. “The main emphasis,” he added, “is that the drug delayed disease progression. Although response rates were low in both arms [1.6% with regorafenib, 0.4% with placebo], regorafenib produced a much higher rate of disease control [44% vs 15%, respectively],” he said. “This drove the efficacy of the drug,” he observed. “I personally have treated 35 of the 78 patients who received regorafenib. I have had one patient on the drug for 12 months, with excellent performance status, and virtually no side effects.” Other Small Molecules Have Not Worked in CRC Dr Grothey acknowledged that up to now, small-molecule TKIs have not yet made an impact in CRC. “So far, in drug development, sorafenib, gefitinib, and PTK/ZK [vatalanib], which were all added to first-line or secondline chemotherapy, have not produced the desired result,” he said in a press briefing.

at a glance ➤ Regorafenib was tested in a setting in which many companies shy away from drug development—metastatic disease ➤ This is a patient population that is truly in need ➤ At this analysis, median OS was 6.4 months in the regorafenib arm and 5.0 months in the placebo arm—a 29% increase in OS ➤ Regorafenib is the first smallmolecule TKI with demonstrated efficacy in advanced CRC ➤ Regorafenib may become a new standard of care for this patient population

By contrast, regorafenib was evaluated as a single agent in a treatmentrefractory population, which Dr Grothey credits with providing the treatment effect. “We know that tumors change over time and activate multiple pathways and resistance mechanisms. It could be that we need more promiscuous multikinase inhibitors in later lines of therapy,” he suggested. ■

Serum-Based Immunoassay May Detect Pancreatic Cancer Early San Francisco, CA—A serum-based enzyme immunoassay using the PAM4 antibody, combined with the serum marker CA19-9, detected stage I pancreatic cancer in nearly two thirds of patients analyzed in a study presented at the 2012 Gastrointestinal Cancers Symposium. It also demonstrated high discriminatory power with respect to benign pancreatitis. “The PAM4-based assay to quantify antigen in patients’ sera shows high sensitivity and specificity for the detection of pancreatic ductal adenocarcinoma (PDAC),” said David V. Gold, PhD, Director of Laboratory Administration, Garden State Cancer Center, Morris Plains, NJ. “The results provide a basis for future studies of a combined PAM4 plus CA19-9 biomarker analysis for surveillance of patients at high risk for

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the development of PDAC, which makes up approximately 90% of all pancreatic cancers, and is highly lethal,” Dr Gold said. Certain populations of patients, including persons with a family history of pancreatic cancer, are considered at risk for the disease. The assay was evaluated in more than 600 tissue specimens, including 234 with PDAC. Combining PAM4 with CA19-9 led to greater sensitivity, while maintaining a high level of specificity. When used individually, PAM4 detected 74% of positive PDAC cases and CA19-9 detected 77%, but combined they detected 84%, a significant (P < .001) improvement over the single tests. For patients at high risk for PDAC, long-term follow-up for the PAM4positive patients may help detect early PDAC, Dr Gold said. “The combined

use of PAM4 and CA19-9 biomarkers gave enhanced detection of PDAC versus either alone and…achieved high specificity.”

“The combined use of PAM4 and CA19-9 biomarkers gave enhanced detection of PDAC versus either alone.” —David V. Gold, PhD Low False-Positive Rate The specificity of PAM4 was significantly greater than that of CA199, which detected more than twice as many benign conditions (ie, chronic pancreatitis). Combined, of 50 cases of chronic pancreatitis, 9 (18%) were labeled positive by the assay, but that

FEBRUARY 2012

18% rate of positivity does not represent “false-positives,” Dr Gold said. The investigators examined 32 chronic pancreatitis specimens and identified 10 preneoplastic lesions. PAM4 reacted with these lesions but not with the completely benign, nonneoplastic tissue. “Our results indicate that PAM4 is not reactive with inflamed pancreatic tissue but rather [with] neoplastic tissue that develops within the inflamed chronic pancreatitis parenchyma,” he concluded. “We speculate that chronic pancreatitis patients, and perhaps others having disease that places them at high risk for the development of PDAC, who are PAM4-positive, may harbor occult PDAC or have significant numbers of precursor lesions producing the PAM4 biomarker.”—CH ■

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ASH ANNUAL MEETING

Bosutinib Shows Superior Results... Center, Houston, at the ASH 2011 annual meeting. The way was not always so clear for bosutinib, the most clinically advanced, investigational second-generation tyrosine kinase inhibitor in the pipeline. The initial report of the pivotal BELA trial was a sensation for the wrong reason; the trial failed to meet its primary end point. The reason that the 12-month data (presented in 2010) fell short of expectations was not for the drug’s lack of efficacy, but because of a conflict between the planned intent-to-treat (ITT) analysis, and because the trial was conducted in more than 100 locations, where some clinicians failed to proactively manage treatment-related adverse events. This suboptimal care led to an inordinate number of patient discontinuations, thereby driving down the otherwise encouraging treat-

ment response rates. This critical issue has been addressed, and results at 24 months have improved significantly.

“Bosutinib may soon offer a new therapeutic option for patients with newly diagnosed chronic-phase CML.” —Jorge E. Cortes, MD BELA Trial at 24 Months The BELA trial was designed to look at the use of bosutinib versus imatinib

Continued from cover

in 502 patients with treatment-naïve, chronic-phase CML. The study’s primary end point was CCyR at 12 months, with secondary end points including major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. The planned follow-up period for BELA is 8 years. At 24 months, the initial ITT analysis for CCyR indicated that the response to both drugs was nearly identical: 79% for bosutinib and 80% for imatinib. However, when patients who discontinued unnecessarily were excluded from the calculation, the cumulative CCyR was 87% for bosutinib versus 81% for imatinib. Further analysis showed a complete response rate plus MMR of 67% for bosutinib versus 52% for imatinib, Dr Cortes reported. Although median PFS and OS

have not yet been reached, at 24 months bosutinib has a lower rate of treatment failure: 4% versus 13% for imatinib. Regarding adverse events, as expected (and now effectively managed), individuals in the bosutinib cohort had more grade 3/4 diarrhea, whereas patients in the imatinib arm had more edema and myalgia. Hematologic events were more common in the imatinib treatment arm, especially for neutropenia (24% vs 10% for bosutinib). On January 27, 2011, the US Food and Drug Administration accepted a New Drug Application for bosutinib for a standard review as a treatment option for patients with previously treated Philadelphia chromosome– positive CML; the drug was already submitted for approval in Europe last year. ■

Future Directions in Myeloma By Caroline Helwick

ith so many new myeloma drugs of various classes in the pipeline (Table), “myeloma is going to become a chronic illness, with sustained complete responses in a significant fraction of patients,” according to Kenneth C. Anderson, MD, of DanaFarber Cancer Institute and Harvard Medical School, Boston. In his ASH 2011 presentation about treatment targets and niches, Dr Anderson predicted that the future direction of multiple myeloma management will include: • Development of immune treatments (vaccine and adoptive immunotherapy); these may be very personalized • Development of novel agents aimed at the myeloma cell in the bone marrow microenvironment; these will target cell growth, survival, and drug resistance • Development of rationally based combination therapies, such as bortezomib plus histone deacetylase inhibitors • Utilization of genomics for improved classification; microRNA profiles can already identify clinical subgroups with different survival outcomes • Personalized treatment based on tumor genetics. Sonja Zweegman, MD, PhD, of VU University Medical Center, Amsterdam, and Erasmus University,

Table

Novel Investigational Agents for Multiple Myeloma

Agent

Mechanism of action

Carfilzomib,a MLN9708, marizomib

Proteasome inhibitor

Pomalidomidea

Immunomodulatory drug

Daratumumab, elotuzumab,a siltuximab,a cetuximab

Monoclonal antibody

BT062

Immunotoxin a

With so many new myeloma drugs of various classes in the pipeline, “myeloma is going to become a chronic illness, with sustained complete responses in a significant fraction of patients.” —Kenneth C. Anderson, MD Rotterdam, the Netherlands, moderated the session on new agents in myeloma. She elaborated on the future of personalized treatment for myeloma: “We need many drugs to prolong the life of these patients, and what you will increasingly see hap-

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FEBRUARY 2012

Perifosine, GSK 2110183

Akt inhibitor

Vorinostat,a panobinostat,a romidepsin, ACY-1215

Histone deacetylase inhibitor

ARRY-520

Kinesin spindle protein inhibitor

PD 0332991

Cyclin-dependent kinase 4/6 inhibitor

BMS-833923

Hedgehog pathway inhibitor

Everolimus

mTOR

Hydroxychloroquine

Aggresome/autophagy

Selumetinib (AZD6244)

MEK inhibitor

Currently in phase 3 clinical trials.

pen is the use of biologically determined treatment.” For example, she said, we heard here at ASH 2011, that with the MEK (mitogen-activated protein kinase kinase) inhibitor AZD6244 (selumetinib), only patients with activation of the signaling transduction pathway will respond. “It will help to have a biological determination of the malignant plas-

ma cells, and a predictive model to help select the most appropriate treatment for a particular patient. That will be the future,” said Dr Zweegman. Dr Anderson agreed. “With whole genome sequencing coming, and with so many novel agents—including many in phase 3 trials, as we saw discussed at this meeting—I know the future is bright in myeloma.” ■

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ASH ANNUAL MEETING

Guidelines for Molecular/Cytogenetic Tests Can Eliminate Overordering, Reduce Costs Vanderbilt hematologists institute new standards, improve outcomes By Caroline Helwick

nstituting guidelines-based test ordering could lead to more effective, accurate, and complete diagnosis and monitoring of hematolymphoid malignancies, while reducing costs, according to hematopathologists at Vanderbilt University Medical Center, Nashville, who said that tests were frequently overordered by their hematologists. Molecular and cytogenetic testing is critical in the diagnosis and management of hematologic malignancies, but these can be complex and expensive. No comprehensive guidelines exist for the disease- and patient-specific selection of these tests. The Hematopathology Diagnostic Management Team explored the hypothesis that there is significant variability in test-ordering patterns, including overordering of unnecessary tests and underordering of necessary tests. They established evidence-based standard operating procedures for molecular and cytogenetic test ordering, which pathologists would apply after a review of the patient’s clinical history and bone marrow morphology. These standards were then compared with current practices at Vanderbilt.

“We found that if we followed the guidelines in all cases, and eliminated excess testing, we would save our payers $1.25 million a year,” said Adam C. Seegmiller, MD, PhD, a hematopathologist who led this study.

“We found that if we followed the guidelines in all cases, and eliminated excess testing, we would save our payers $1.25 million a year.” —Adam C. Seegmiller, MD, PhD

“Before we instituted this, we found that clinicians had a tendency to

overorder tests, when doing molecular cytogenetic testing before the bone marrow biopsy was done,” Dr Seegmiller said. “We created a standard operating procedure based on current guidelines, best evidence, and best clinical practice. We decided what tests should be ordered for 6 categories of disease and their stages. It’s a very simple chart.” They evaluated 3007 ordered tests on 804 bone marrow biopsy specimens; this included 769 karyotypes, 1790 fluorescence in situ hybridization assays, and 448 molecular tests. Comparing how clinicians ordered (or did not order) tests with this new standard operating procedure showed that: • Only 1927 tests (64%) were concordant with the new guidelines • 1080 tests (36%) were discordant • 307 tests were omitted that would have been recommended by the new guidelines. “Over one third were tests that the guidelines would not have recommended [ie, overordered], while 307 tests should have been ordered but were not,” Dr Seegmiller noted. By stage and clinical scenario, for

example, there was 99% concordance between clinicians’ ordering and guidelines for the diagnosis of myeloma, but 0% concordance for testing during follow-up, and 0% posttransplant. For lymphoma, concordance was 81% for diagnosis, 41% for staging, 13% for follow-up, 70% pretransplant, and 32% posttransplant. “Among discordant tests, only 4% came back positive [ie, detected a mutation], but more than one third of these were redundant. They were positive, but we would have caught these cases elsewhere,” he said. Only 1% of cases were true positives that would have been missed. “We think we are not only eliminating unnecessary tests, but also increasing the effectiveness of the tests we are using,” Dr Seegmiller added. “We have now given hematologists the option to turn over all the testing decisions to the hematopathologists, and about 80% of the time our clinicians do that,” he said. Using this new standard, “the hematopathologist makes a decision for testing based on the patient’s clinical history, the appearance of the bone marrow morphology, and the guidelines.” ■

Significant Cost of Treating Myeloproliferative Neoplasms By Neil Canavan

new cost analysis of the management of the 3 subtypes of myeloproliferative neoplasms (MPNs)—myelofibrosis, polycythemia vera, and essential thrombocythemia—shows that associated medical and pharmaceutical expenses for patients with these hematologic disorders in patients with cancer are 2 to 6 times that of matched patients without cancer. Outpatient visits for MPN accounted for more than 50% of the total costs incurred by patients with cancer. “Some symptomatic treatment options exist, but with the exception of hematopoietic stem-cell transplant, none are curative. And little is known about healthcare costs associated with these diseases,” according to Gregory L. Price, MPH, who presented the data at ASH 2011. The median survival in these MPN subtypes ranges from months to years for myelofibrosis, and as long as a

decade or more for patients with polycythemia vera and essential thrombocythemia. To perform this cost analysis, data for the years 2005-2008 were extracted from the Thomson Reuters MarketScan database, which includes claims data from more than 100 US payers. Patients eligible for analysis had to have an MPN diagnosis code for the study period. Data on matched patients with no cancer (ie, the control group) were selected based on sex, year of birth, geographic region, and insurance type. Calculated costs were based on total gross payments to the provider. Total costs were defined as the sum of MPN- and non–MPN-related medical costs, including inpatient, outpatient, and emergency department services and pharmacy. Costs related to pharmacy included chemotherapy (injectable and otherwise) and other prescription supportive care.

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FEBRUARY 2012

Table

Mean Costs for MPNs: Patients with Cancer versus Controls

Costs

Patients with cancer and MF

Control group with MF

Patients with cancer and PV

Control group with PV

Patients with cancer and ET

Control group with ET

Outpatient cost

$18,395

$3053

$5688

$2541

$8598

$2714

Pharmaceutical cost

$7803

$1881

$2540

$1474

$2855

$1426

$34,690

$6899

$11,927

$5510

$19,672

$5683

Total cost

ET indicates essential thrombocythemia; MF, myelofibrosis; MPNs, myeloproliferative neoplasms; PV, polycythemia vera.

A total of 25,145 patients with MPN were included in the analysis. As expected, all MPN-related costs for the parameters selected exceeded those of noncancer controls. Results for outpatient care cost, pharmaceutical cost, and total cost are highlighted in the Table. In November 2011, ruxolitinib (Jakafi), a Janus kinase (JAK) inhibitor,

was the first drug to be approved by the US Food and Drug Administration for myelofibrosis and related diseases. New JAK inhibitors are currently in development. LY2784544, a JAK2 inhibitor, is currently in phase 1 clinical trials. Preliminary data for the current 19 patients enrolled have been presented at the meeting. ■

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ASH ANNUAL MEETING

A Large Study Sheds Light on the Cost of Managing NHL By Caroline Helwick

large, ongoing Canadian study provides an overview of the cost of managing nonHodgkin lymphoma (NHL). “Our study provides total and stage-specific cost estimates for NHL, where attributable costs were 3- to 7-fold higher than those for non-NHL controls, and increased by stage,” said Pierre K. Isogai, BSc, of Sunnybrook Health Sciences Centre in Toronto. Mr Isogai and colleagues identified 13,336 patients with NHL in the Ontario Cancer Registry (2005-2009) and compared them with 65,668 matched controls from the Institute for Clinical Evaluative Sciences database who were demographically similar and used healthcare resources but did not have cancer. Resources for the analysis included physician visits, hospitalizations, emergency department visits, drugs,

home care, and same-day surgeries. Costs were inflated to 2009 Canadian dollars ($0.88 US) and were presented as the mean annual cost for all patients and by clinical stage. A public payer’s perspective was used. The participants’ median age was 68 years, and 55% were male. Geographically, 86% of both groups were from urban areas. The mean cost difference between the NHL and the control groups represents the mean cost attributable to NHL diagnosis and treatment. The mean annual cost of managing NHL was $16,778; the cost by stage at diagnosis ranged from $9575 for stage I to $26,099 for stage IV. “So, for a typical patient, we spent about $16,000 extra per year,” Mr Isogai noted. “By stage, end of life was the most expensive, costing up to $25,000 versus less than $10,000 for stage I patients.”

Table

Mean Annual Costs of Managing Patients with NHL versus Controls Patients with nonHodgkin lymphoma, $

Control group, $

Difference, $

Ontario Health Insurance Plan

3509

1375

2134

Hospitalization

10,401

1811

8590

Same-day surgery

384

189

195

Drugs

6283

1174

5109

Home care

667

260

407

21,244

4809

16,435

Cost category

Total NHL indicates non-Hodgkin lymphoma.

Five cost categories were analyzed by the time for reporting at the meeting: health insurance plan, hospitalization, same-day surgery, drug costs, and home care (Table).

The study is ongoing; the re searchers will be analyzing additional data, including cancer clinic visits, other drugs, and radiation therapy. ■

Ponatinib Overcomes Hard-to-Treat T315I Mutation in Patients with CML/ALL By Neil Canavan

reliminary data from the phase 2 PACE (Ponatinib Ph+ALL and CML Evaluation) trial show that ponatinib (Ariad Pharmaceuticals) can overcome the difficult-to-treat T315I mutation in patients with chronic myeloid leukemia (CML). Currently, patients with this genetic mutation have no effective treatment options. In PACE, the tyrosine kinase inhibitor (TKI) ponatinib achieved a 47% major cytogenetic response (MCyR). For patients with the T315I mutation, ponatinib induced a 65% MCyR. This drug was specifically designed to overcome the T315I mutation. “Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory/relapsed CML,” said PACE lead investigator Jorge E. Cortes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston. This open-label study enrolled 499 patients with CML or with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) who had previously been treated with nilotinib or dasatinib, but their disease was resistant or intolerant to those drugs, or they had the T315I mutation. Patients were stratified into 1 of 6 groups, according to disease, disease phase, and mutation status. All patients were treated with the same dose and

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schedule. The primary end points were MCyR for chronic-phase (CP)-CML, and major histologic response for accelerated-phase (AP)-CML, blast-phase (BP)-CML, or Ph+ALL. After a median follow-up of 5 months, Dr Cortes reported high levels of response being observed in all patient types. Patients with AP-CML achieved a major histologic response of 74%, and MCyRs ranging up to 53%. For patients with the most severe

prognosis, the BP-CML and Ph+ALL cohorts, both groups achieved a major histologic response of 37%, and MCyRs of 34% and 37%, respectively. A major molecular response rate of 33% was reported in patients with the T315I mutation and those with CP-CML/T315I. Treatment-related adverse events were generally mild; the most common serious events were thrombocytopenia and neutropenia.

“Extremely exciting,” said Tim Brümmendorf, MD, of the University Hospital, Aachen, Germany, in response to the ponatinib data. “It is the most promising approach to target the most problematic mutation that we currently see—the T315I mutation. This mutation confers absolute resistance to all TKIs that we currently have approved in clinical use. So, from what I have seen, it [ponatinib] looks extremely promising.” ■

Investigational Blinatumomab Puts BiTE on Acute Lymphoblastic Leukemia

he novel agent blinatumomab more than doubled the complete response (CR) rate in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) compared with standard therapies. Blinatumomab is a member of the BiTE (bispecific T-cell engager) drug class, a bispecific monoclonal antibody designed to direct the cytotoxic T-cells of the host’s immune system, via CD3, to attack CD19-expressing cancer cells. In this open-label, single-arm, doseranging, phase 2 clinical trial, 25 patients with ALL were randomized to 1 of 3 doses of blinatumomab. Results for all tested doses showed that 68% (17) of the patients achieved a CR or a

CR with partial hematologic recovery with blinatumomab. For the 12 patients who received the dose selected for further investigation, 9 achieved a CR or partial hematologic recovery. All responders achieved minimal residual disease status, meaning that there were no detectable leukemic cells in their blood or bone marrow. Treatment effect with blinatumomab was lasting, with a median complete hematologic remission of 7.1 months. At a median follow-up of 9.7 months, median survival time has not been reached. This ongoing measure already exceeds median survival times typically seen in ALL. The most common adverse events

FEBRUARY 2012

observed were mild, predominantly flulike symptoms of fever and headache. More serious, but reversible, events occurred in 7 patients and were managed with treatment interruption, after which all 7 patients continued the trial at event resolution. “Blinatumomab as single agent induced an unprecedented high rate of complete hematological and minimal residual disease responses in adult patients with relapsed/refractory Bprecursor ALL,” said the study’s lead investigator, Max S. Topp, MD, at Wuerzburg University Medical Center, Wuerzburg, Germany, where phase 2 studies are under way.—NC ■

www.ValueBasedCancerCare.com

ASH ANNUAL MEETING

Next-Generation Proteasome Inhibitors Cause Less Peripheral Neuropathy First oral agent in the pipeline elicits excitement By Caroline Helwick

he first-generation proteasome inhibitor bortezomib changed the treatment paradigm of multiple myeloma. Data are now maturing for the next-generation agent carfilzomib, with US Food and Drug Administration approval expected soon. Several novel agents in this class are also in the pipeline. These secondgeneration agents appear to be as effective as bortezomib but less neurotoxic, according to studies presented at ASH 2011. High Response Rates with Carfilzomib Regimen High response rates and minimal toxicity were seen when carfilzomib was combined with lenalidomide and low-dose dexamethasone in a phase 2 clinical trial presented by Andrzej Jakubowiak, MD, of the University of Chicago Medical Center. “The carfilzomib/lenalidomide/ dexamethasone [CRd] regimen is well tolerated and highly active, demonstrating rapid and deep responses in newly diagnosed myeloma,” Dr Jakubowiak said. This study included 53 patients who received 8 cycles of CRd and at least 9 additional cycles for maintenance. The 24 patients who were transplant candidates received 4 cycles before their transplant and 4 afterward. Partial responses or better were observed in 94% of patients after 1 cycle:

• 53% achieved complete response (CR) or stringent complete response (sCR) • After 12 treatment cycles, 79% achieved a near-CR, CR, or sCR • High response rates were not affected by stage or cytogenetics. “These response rates compare favorably to our best frontline regimens, and the study is still early. Responses continue to improve with time. I think this is going to be one of those regimens that will potentially change the landscape of what we can do,” Dr Jakubowiak predicted. First Oral Agent in Early Development The first oral proteasome inhibitor, MLN9708, has “similar selectivity and potency, it dissociates from the proteasome faster, and has greater tissue penetration compared with bortezomib,” said Paul G. Richardson, MD, of Dana-Farber Cancer Center, Boston, who has led some of the trials. “The activity of MLN9708 is dramatic,” he said. “Upfront, we are seeing 100% response rates, which is amazing; and in the relapsed/refractory setting, where we expect to see nothing because patients are so ill, we are seeing response rates, including some very good partial responses, and stable disease. That’s the signal we need in the advanced disease population.”

“The activity of MLN9708 is dramatic. Upfront, we are seeing 100% response rates, which is amazing, and in the relapsed/refractory setting... we are seeing response rates…and stable disease.” —Paul G. Richardson, MD

Dr Richardson reported the results of a phase 1 dose-escalation expansion cohort study of 56 patients who averaged 3.5 previous therapies; 88% had previous bortezomib therapy. MLN9708 was given orally twice weekly in 21-day cycles at a dose of 2 mg/m2. Of the 46 patients evaluable for response, 6 achieved partial responses or better, including 1 CR. One patient achieved a minimal response, and 28 patients experienced stable disease. Five responders had previously received bortezomib. Disease stabilization has lasted nearly 16

months in many cases, and encouraging activity has been seen in bortezomib-resistant patients. The drug activity in previously untreated patients is even more striking. Jesus G. Berdeja, MD, of Sarah Cannon Research Institute in Nashville, reported that of 10 treatment-naïve patients enrolled in a phase 1 and 2 study, 9 achieved partial responses or better, including 1 CR and 3 very good partial responses. Comparing MLN9708 to carfilzomib, Dr Richardson said that although carfilzomib is a welcomed agent in myeloma, “you must give carfilzomib intravenously and weekly 2 days in a row, on days 1 and 2, 8 and 9, and 15 and 16. It is a great drug, and it is associated with less neurotoxicity, but its delivery is inconvenient for the patient. MLN9708 has the advantage of being an oral drug that produces very little neuropathy,” he said in an interview. Dr Richardson said that this agent has “an excellent tolerability profile.” Fatigue, thrombocytopenia, and nausea are the most common adverse events reported, along with skin rash, especially as first-line treatment, “which patients find quite manageable.” No peripheral neuropathy grade ≥3 has been reported. Dose reductions as a result of adverse events have been uncommon. Phase 1 and 2 clicnial trials are evaluating oral and intravenous formulations, using different dosing schedules in a variety of tumor types. Phase 3 trials will begin next year. ■

First Cost Analysis of Long-Term Management of CML Will newer TKIs change the economic landscape? By Neil Canavan

ew analyses to date have assessed the long-term costs associated with the management of chronic myeloid leukemia (CML). At ASH 2011, Shrividya Iyer, PhD, of Pfizer, presented results of a retrospective analysis performed by a group of researchers at Pfizer and the Eliassen Group that looked at information from the Thomson Reuters MarketScan Commercial Claims and Encounters Database, and the Medicare Supplemental Database. Medical claims for the years 20022009 were used for 2583 patients with CML who had ≥2 claims associated with a CML diagnosis.

Costs for the entire CML cohort were analyzed first, followed by a subanalysis of costs related to patients with ≥4 years of postdiagnosis followup. The average follow-up for the entire cohort of 2583 patients was 2.7 years, with 509 (20%) patients having ≥4 years of follow-up (mean age, 59 years). More than 50% of the patients had a point-of-service health plan with capitation coverage. The proportion of patients with ≥1 CML-related outpatient, inpatient, or emergency department visit annually were: • 94.9% for outpatient visits (55.1 actual outpatient and office visits com-

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bined, per patient-year) • 32.4% for inpatient visits (1.3 average number of actual visits) • 15.1% for emergency department visits (1.6 visits). The average number of drug prescriptions for the entire CML cohort was 6.7 per year, with the tyrosine kinase inhibitor (TKI) imatinib accounting for 85% of those claims. The average annual costs for CMLrelated healthcare utilization per patient were: • $24,391 for outpatient care • $24,462 for inpatient care • $15,588 for prescription drugs (CML drugs accounted for 73% of overall prescription costs).

Data for patients with ≥4 years of follow-up indicated an increase in outpatient visits, but with nearly equivalent rates for inpatient and emergency department care; for patients with ≥1 CML-related visit, 98% had an outpatient visit, 31% had inpatient care, and 15% had presented to the emergency department on an annual basis. This analysis did not address the potential cost and utilization impact of the newer TKIs; improved efficacy and reduced side effects may have a positive impact on overall healthcare utilization and costs in the long-term management of CML, but this remains to be seen. ■

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ASH ANNUAL MEETING

First Randomized Comparison of Catheter-Directed Thrombolysis versus Standard Care for DVT Prophylaxis By Neil Canavan

n the first comparative trial of its kind, the Catheter-Directed Venous Thrombolysis (CaVenT) study determined that treating a clot directly with the recombinant, antithrombotic agent alteplase reduced the frequency of postthrombotic syndrome (PTS) and improved long-term outcome in patients with proximal deep-vein thrombosis (DVT) compared with standard anticoagulation methods. PTS can greatly affect a patient’s quality of life: 1 in 4 patients with DVT will experience PTS, despite having been treated according to current clinical guidelines. To offset the risk of PTS, alteplase has been used in this setting. “This interventional therapy is expensive,” said CaVenT lead investigator Tone Rønnaug Enden, MD, PhD, of Oslo University Hospital in Norway. “It is also associated with life-threatening

“This interventional therapy is expensive. However, it has become standard care in some centers, despite a complete lack of evidence.” —Tone Rønnaug Enden, MD, PhD bleeding. However, it has become standard care in some centers, despite

a complete lack of evidence from randomized, controlled trials.” This multicenter investigation enrolled 209 adults who had experienced an objectively verified DVT within 21 days of study entry and who met other entry criteria. Patients were randomized to standard treatment (ie, control group) with heparin/warfarin anticoagulation for 6 months, in addition to the use of elastic compression stockings for 24 months, or to standard treatment plus catheter-directed thrombolysis (CDT) with alteplase for up to 96 hours, but not exceeding 20 mg/day. “This is a minimally invasive percutaneous technique performed with local anesthesia,” said Dr Enden. End points included measures of outcome for patient-rated criteria of pain, cramps, heaviness, pruritus, and clinician-rated criteria of edema, skin

induration, hyperpigmentation, venous ectasia, and ultrasound examination. At 24-month follow-up, 37 (41.1%) patients in the CDT group had PTS compared with 55 (55.6%) patients in the control group, an absolute risk reduction of 14.4%. Regarding adverse events, 20 bleeding complications were reported—3 were classified as major and 5 as clinically relevant. The majority of bleeds were related to the puncture site, and no bleeding related to CDT led to a permanently reduced outcome. Dr Enden concluded that the addition of CDT to standard treatment improved long-term outcomes and should be considered for patients with iliofemoral DVT when there is no contraindicating risk of bleeding. “These results should be taken into account when guidelines are revised.” ■

VTE Prophylaxis during Chemotherapy Cost-Effective Venous thromboembolism a common, costly adverse event

enous thromboembolism (VTE) is a common cause of serious morbidity and mortality, and patients with cancer are at particular risk. “VTE has a substantial burden on the current US medical system. Its preventable costs and indirect costs from premature deaths are substantial,” said Alex C. Spyropoulos, MD, of McMaster University, Hamilton, Canada. Dr Spyropoulos and colleagues developed a decision tree and cost model to estimate the national healthcare costs for pulmonary embolism (PE), total hospital-acquired PE, and total preventable PE. The model demonstrated annual savings of $4.6 billion to $14.3 billion in the base model, and as high as $12.8 billion to $42.2 billion when adjusted to 2011 US dollars in the sensitivity analysis. The authors concluded that “appropriate type, dose, and duration of prophylaxis is cost-effective.”

VTE Prophylaxis Is Cost-Effective Other investigators from the University of Pittsburgh agreed that VTE prophylaxis is cost-effective. As background, they noted that despite evidence that low-molecular-weight heparin (LMWH) has antitumor effects and improves short-term sur-

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vival, the cost-effectiveness of anticoagulation in ambulatory cancer patients is unknown. Allyson Pishko, BS, and colleagues constructed a Markov model to evaluate prophylactic anticoagulation with enoxaparin in such patients with no previous VTE during 4 months of chemotherapy. The model used data

minor bleeding, $73. Death was calculated at $5000. Compared with no LMWH, 4 months of primary prophylaxis with enoxaparin was associated with a relative mortality risk of 0.92 over 24 months, at a gain of 0.0484 QALY, for an ICER of $76,922 per QALY gained. The relative risk for deep-vein thrombosis was 0.55.

“Prophylactic anticoagulation appears to be cost-effective in ambulatory cancer patients during the first 4 months of chemotherapy.” —Allyson Pishko, BS

from a 2011 Cochrane Review of 9 randomized controlled studies of cancer patients with no indication for anticoagulation prophylaxis. The researchers measured medical costs, effectiveness (measured by mortality reduction), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over a 24-month period. Enoxaparin 40 mg/day was estimated to cost $1132 per month. The cost of treating a major bleeding event was $5317 and the cost of a

“This is well within the accepted $100,000/QALY threshold,” Ms Pishko said. However, if the ICER increases to >$100,000 per QALY, it may no longer be considered cost-effective. “Prophylactic anticoagulation appears to be cost-effective in ambulatory cancer patients during the first 4 months of chemotherapy. If the suggested mortality benefit is confirmed by additional randomized controlled studies, administering anticoagulation to ambulatory cancer patients during

FEBRUARY 2012

high-risk chemotherapy treatments should be considered,” she concluded. Electronic Reminder Enhances VTE Prophylaxis The use of an electronic “smart order set” to remind physicians about VTE risk boosted the use of VTE prophylaxis within Johns Hopkins Hospital. The intervention also dramatically reduced the rate of symptomatic VTEs, reported Amer M. Zeidan, MD, of Johns Hopkins University. A review of patient records showed that risk-appropriate prescribing rates rose from 68% to 86% when the smart order set was added to the institution’s decision support (P <.001). The rate of VTE episodes within 90 days of admission fell from 2.5% to 0.7% (P = .002), as a result of VTEs that occurred postdischarge: the rates of major bleeding did not increase with the use of VTE prophylaxis. This intervention was developed after an internal review showed that VTE prophylaxis was not being prescribed for many patients deemed eligible by national guidelines. “Our results support the use of a mandated risk-adaptive strategy for consideration of VTE prophylaxis for every hospitalized patient,” Dr Zeidan said.—CH ■

www.ValueBasedCancerCare.com

BREAST CANCER

The Cost of Cancer Care... other inpatient expenditures total $16,700. Of these, surgery accounts for the highest percentage (25%) of the total cost, topping $261 million. Chemotherapy accounts for 15% and reaches $157 million. “Altogether, extrapolating to total spending, breast cancer costs the country $1.06 billion” annually, she said.

“What is considered a good value for the money depends on the willingness to pay for the health gain.” —Elena B. Elkin, PhD It is no surprise that the rising price of new drugs contributes to the escalating costs of cancer care. Translated into 2010 dollars, that increase over time is stark. Tamoxifen, approved in 1977, costs $100 per month in today’s dollars, whereas letrozole, approved in 1997, costs double that amount. Paclitaxel, approved in the 1992, costs $3000 a month, but nab-paclitaxel increased the taxane expenditure to about $7000. “Why are costs increasing?” Dr Elkin asked. “Price of drugs and quantity are both factors.” New technology results in more expensive treatments and more patients eligible for treatment, largely because the associated toxicity and risks are diminished as treatments evolve. The projected spending for 2020 shows that breast cancer is still associated with the highest cost of care among the common tumor types. “How high that goes depends on assumptions about trends, incidence, survival, and cost,” she said. Are the Drugs Worth the Cost? She described an example in which ixabepilone, added to capecitabine in taxane/anthracycline–resistant metastatic breast cancer, has been shown to

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increase response rates, reduce disease progression by 25%, and extend progression-free survival by 1.6 months. However, it adds $4200 (in 2008 dollars) to each cycle of treatment; therefore, for the average 5 cycles in the metastatic setting, ixabepilone provides a very small—although significant—benefit, costing payers $21,000. “Do you think this drug is worth the cost?” she asked oncologists. “Healthcare spending must be prioritized,” she suggested. Value-Based Decisions To make good decisions, information about value is needed. A costeffectiveness (or cost-utility) analysis can help estimate value for the money, she said. It measures effectiveness in quality-adjusted life years (QALYs) and produces an incremental costeffectiveness ratio (ICER). The costeffectiveness of various breast cancer interventions varies tremendously (Table 2). “What is considered a good value for the money depends on the willingness to pay for the health gain,” Dr Elkin said. “In the United States, there are no strict criteria, but the common perception is that less than $50,000 per QALY is a low ICER and a good value, $50,000 per QALY to $100,000 per QALY is a judgment call, and more than $100,000 per QALY is a high ICER that must be justified on clinical grounds.” “But should we adjust for inflation?” she asked. The $50,000 cut-point proposed in 1982, and adjusted to 2007 dollars, would equal $197,000 per QALY. “The $100,000 as a benchmark may also be keeping people resistant to the notion of cost-effectiveness analysis,” she suggested. “The rule of thumb is probably too low, and it is certainly outdated.” Dr Elkin noted that cost-effectiveness analyses are not used much for decision-making in the United

Table 1 Average Annualized Net Costs of Care for Breast Cancer, by Phase Average annual costs Phase of disease

Age <65 yrs, $a

Age ≥65 yrs, $a

27,700

23,000

2200

94,300

62,900

Initial Continuing b

Last year of life

In 2010 dollars. Among women whose cause of death was cancer. Source: Mariotto AB, et al. J Natl Cancer Inst. 2011;103:117-128. Epub 2011 Jan 12. a

Table 2 Cost-Effectiveness Analysis in Breast Cancer Intervention

ICER (cost per QALY), $

BRCA1/2 testing (age ≥35 yrs, family history of breast/ovarian cancer)

5400

Raloxifene risk reduction (white race, age 55 yrs)

22,000

Letrozole vs anastrozole (postmenopause, ER-positive)

26,000

Lapatinib/capecitabine vs capecitabine (HER2-positive, metastatic breast cancer)

170,000

Annual MRI screening vs film mammography (BRCA1)

210,000

Bevacizumab + paclitaxel vs paclitaxel (HER2-negative, metastatic breast cancer)

280,000

Partial breast irradiation vs whole breast radiotherapy (stage 1, ER-positive, postmenopause)

730,000

All-digital screen mammography vs film (age, ≥40 yrs)

930,000

ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2; ICER, incremental costeffectiveness ratio; MRI, magnetic resonance imaging; QALY, quality-adjusted life-year.

States, but they are used in many other countries. “But let’s be clear,” she said; “cost-effective does not necessarily mean cost-saving. Most medical interventions do not save money, and most result in net monetary expenditure.”

Dr Elkin insists that the questions that must still be answered are: • “Do we spend too much?” • “How can we control cost without jeopardizing quality of access?” • “Who should decide what we spend, and how we spend it?” ■

Mammography Use Increases When Copays Are Dropped By Caroline Helwick San Antonio, TX—When copayments were eliminated, annual screening mammography rates among insured rural women improved significantly, researchers from Duke University Comprehensive Cancer Center reported at the 2011 CTRC AACR San Antonio Breast Cancer Symposium. “Cost-sharing for high-value healthcare services may have unintended

negative consequences,” said Jeffrey M. Peppercorn, MD, MPH, Associate Professor, Duke University School of Medicine, Durham, NC. Because of declining rates of screening mammography, the National Rural Electric Cooperative Association (NRECA), a national nonprofit health plan for rural electrical workers and their families, eliminated copayments

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for screening mammography in January 2006. The NRECA provides health insurance coverage to more than 100,000 members across the United States, more than 80% of whom live in rural areas. Dr Peppercorn and colleagues evaluated the impact of eliminating copayments on the utilization of annual screening mammography among wom-

en aged 40 to 64 years, based on claims data for screening mammography between 1999 and 2009. Changes in use over time were assessed before and after the policy change in 2006. From 1999 to 2009, an average of 20,825 eligible women received health insurance each year through the NRECA. During that time, annual Continued on page 30

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BREAST CANCER

Eribulin Associated with Less Neuropathy than Ixabepilone

Figure. Waterfall graphs of percent change in summed longest diameter of target lesions from baseline to nadir in patients receiving a) eribulin or b) ixabepilone according to RECIST (ITT population)

By Caroline Helwick San Antonio, TX—In a randomized phase 2 study of patients with metastatic breast cancer, peripheral neuropathy was less likely to occur in patients receiving eribulin mesylate than with ixabepilone. “Peripheral neuropathy is a big problem in the treatment of breast cancer. Across the spectrum, patients have it, and we don’t know how to treat it,” said Linda T. Vahdat, MD, Weill Cornell Medical College in New York, who presented the study at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. “If we want to be able to identify patients at risk for peripheral neuropathy and develop strategies to manage it, we need to characterize it better. This trial was conceived and started after the close of the EMBRACE trial. It gave us the opportunity to get a better handle on how eribulin performed from the perspective of side effects. The end point was the incidence of neuropathy.” EMBRACE demonstrated that eribulin treatment significantly improved median overall survival by 2.5 months compared with standard treatments in patients with heavily pretreated metastatic breast cancer. The overall incidence of peripheral neuropathy in patients who received eribulin was 35% and was mostly mild; grade 3 was seen in 8% of patients and grade 4 in <1%. The current study prospectively evaluated peripheral neuropathy in

Figure courtesy of Prash Krishna, MBBS, MRCS.

101 patients with heavily pretreated metastatic breast cancer who were randomized to receive either eribulin or ixabepilone as a single agent in 3week cycles; the mean number of

“Peripheral neuropathy is a big problem in the treatment of breast cancer. Across the spectrum, patients have it, and we don’t know how to treat it.” —Linda T. Vahdat, MD treatment cycles was 6.2 cycles in the eribulin group and 4.8 cycles in the ixabepilone group. Almost one third

of patients in each arm had received ≥6 previous agents. “We found the incidence of neuropathy was about 13% lower with eribulin,” Dr Vahdat reported. Peripheral neuropathy of any grade occurred in 31% of the eribulin group and 44% of the ixabepilone group. Grade 3/4 peripheral neuropathy occurred in 10% versus 20%, respectively. The difference numerically favored eribulin, although it was not statistically significant, she added. “Most importantly,” she said, “the median time to the onset of treatmentemergent neuropathy was longer in the eribulin group: 36 weeks versus only about 12 weeks with ixabepilone. By cycle 4, only 24% of patients receiving eribulin had developed neuro-

Mammography Use Increases When Copays... screening mammography increased from 38.1% in 1999 to 49.5% in 2009. In 2007, the year after the copayment was eliminated, screening rates jumped to 48%, from 43% in 2006. The rates increased in all age-groups by about ≥5%. “We saw that in 2006, when we eliminated the copay, there was a significant bump in the screening rate, possibly in contrast to national trends. If you look at the age-group 45 to 49 in 2005, the screening rate was about 40% and now is close to 50%,” Dr Peppercorn said in an interview. “We think that this is a striking finding in this rural population, but still only 40% to 60% of women, depending on the age-group, are having annu-

al mammography. Yes, the drop in the copay eliminated one barrier, but there is still work to be done to determine why other women are not getting mammograms,” he added.

“When we eliminated the copay, there was a significant bump in the screening rate, possibly in contrast to national trends.” —Jeffrey M. Peppercorn, MD, MPH The incidence of advanced breast cancer—determined, as a surrogate, from the number of women receiving chemotherapy or mastectomy—

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pathy, compared to 44% receiving ixabepilone.” In addition, safety end points, including objective response rate and progression-free survival, based on Response Evaluation Criteria in Solid Tumors, showed greater reduction in the longest diameter of target lesions (ie, reducing tumor size) with eribulin (~80%) compared with ixabepilone (~70%) from baseline to nadir, as well as a faster rate of change with eribulin (Figure). Dr Vahdat acknowledged that if ixabepilone were given weekly, as it often is, the incidence of peripheral neuropathy would be lower. The study followed the US Food and Drug Administration–approved dosing schedule. ■

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at a glance ➤ Cost-sharing may have unintended negative consequences on patient adherence to prevention ➤ Eliminating the copayment for screening mammography significantly increased the screening rate among rural women in this study ➤ At 1 year after the copayment was eliminated, the screening rate increased by ≥5% in all age-groups

seemed to decrease, dropping from 7.2% before the policy change to 3.7% afterward. The investigators attribute this to early detection, at least in some patients. Dr Peppercorn noted that temporal trends unrelated to copayment elimination may explain the increase in the mammography rate and the increase in breast cancer treatment. In addition, some NRECA members may have obtained screening outside of the health plan. Further research will evaluate biannual screening rates, sociodemographic associations with screening, the impact of recent controversies over screening guidelines, and additional barriers in this rural population. ■

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

goal One goal: 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.

HEALTH POLICY

Paying for Quality: Increasing Shift Toward Value-Based Healthcare By Ross D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPH Mr Margulies is a Health Policy Specialist, Foley Hoag, LLP, Washington, DC Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC

n November 30, 2011, the Office of the Inspector General (OIG) of the US Department of Health and Human Services issued an advisory opinion (No. 1118) to the web-based physician practice service provider athenahealth, tacitly approving the company’s new online service athenaCoordinator. The athenaCoordinator is a cloud-based physician referral tool that monetizes, in some instances, the “referral transaction” between a referring physician and a “trading partner.” Important for members of the oncology team, the OIG opinion offers precedent in the cost-value debate, particularly with regard to arrangements that may offer costsaving, value-enhancing benefits that fall outside the bounds of what has traditionally been viewed as appropriate arrangements between referring health professionals. Despite the acknowledgment by the OIG that the proposed arrangement could generate prohibited referrals under the federal Anti-Kickback Statute, the OIG stated it would not impose administrative sanctions in connection with the proposed arrangement. The OIG acknowledged the

“laudable goal” of the “efficient exchange of health information between health professionals” in determining that the proposed arrangement would be unlikely to influence an ordering physician’s referral decisions. The athenaCoordinator service offers current athenahealth subscribers the opportunity to transmit referrals through a cloud-based network, with options for insurance precertification

The Affordable Care Act brought us accountable care organizations and valuebased purchasing. and patient registration among physicians and hospitals, surgical centers, and imaging centers. To avoid obvious violations of the Anti-Kickback Statute and to offer a more robust network of trading partners (those who receive the referrals), there would be no cost for a health professional to be listed in the athenaCoordinator service. As a result, a nonparticipating health professional may receive a referral

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from an athenahealth subscriber, with no out-of-pocket cost. Instead, the transmission fee in this instance would be placed on the referring physician. However, should health professionals choose to become official trading partners with athenahealth, they would receive an enhanced profile on the cloud-based network. Although there would be no cost to health professionals to become a trading partner, trading partners would be charged for any services provided by athenahealth. Moreover, once a health professional becomes an official trading partner, the cost of the referral transmission is borne by the trading partner, not by the referring physician. As acknowledged by the OIG, such an arrangement clearly implicates the Anti-Kickback Statute, because a referring physician has an incentive (however slight: the transmission fee is $1) to choose paying trading part-

ners over health professionals who list for free in the network. In addition, although the possibility has not been addressed by the OIG, one must assume that the “customized” network profiles provided to paying trading partners may attract more referrals than health professionals who are receiving a free ride. The OIG concluded that the facts and circumstances of the proposed arrangement would “adequately reduce” the risk that the remuneration provided through athenaCoordinator could be an improper payment for referrals, or for arranging for referrals of federal healthcare program business. The OIG’s advisory opinion has received quite a bit of press among the legal community. Because this arrangement offers clear cost-value benefits, it is conjectured that the OIG approved of the arrangement in spite of a clear violation of the Anti-Kickback Statute. This transition to a healthcare system in which cost and value are integral to the treatment decision is not a new phenomenon but an emerging trend. The Affordable Care Act brought us accountable care organizations and value-based purchasing, which are increasingly relied on by payers, both public and private, to ensure that each receives the most value for each healthcare dollar. The oncology community is aware of this trend and should be prepared for a continued shift toward value, as this OIG opinion demonstrates. ■

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PROGRAM OVERVIEW

CO-CHAIRS

This is the first global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on the treatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice. • Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatment-related adverse events.

TARGET AUDIENCE This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

Rüdiger Hehlmann, MD Chief and Professor of Medicine University of Heidelberg Mannheim, Germany

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.0 contact hours. REGISTERED PHARMACY DESIGNATION Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.0 contact hours (0.12 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-11-088-L01-P.

Early registration of $425 ends January 13, 2012!

COMMERCIAL SUPPORT ACKNOWLEDGMENT This activity is supported by educational grants from Genentech, Inc. and Millennium Pharmaceuticals, Inc.

HEALTH POLICY

VALUE-BASED CANCER CARE

FEBRUARY 2012

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AY D TO 0 R E $10 T S GI AVE E R S

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery March 29-31, 2012 • JW Marriott • Houston, Texas

REGISTER TODAY at www.regonline.com/avbcc2012 TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

CONFERENCE CO-CHAIRS Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University

EDUCATIONAL OBJECTIVES • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery • Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively • Examine the current trends in personalized care and companion diagnostics • Analyze the patient issues around cost, quality, and access to care

Gary Owens, MD

DESIGNATION OF CREDIT STATEMENTS Physician Accreditation – Joint Sponsor

Burt Zweigenhaft, BS

President Gary Owens Associates

President, CEO OncoMed

The Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 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 accordance 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 Association for Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit. This activity is jointly sponsored by Medical Learning Institute, Inc., and the Association for Value-Based Cancer Care

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.

HEALTH POLICY

Direct-to-Consumer Genetic Testing: Concerns Trump Benefits at This Point By Caroline Helwick Miami, FL—Direct-to-consumer (DTC) marketing of genetic tests represents personalized medicine in evolution. High-throughput genetic technologies have made it possible to evaluate individuals at a relatively affordable price, but a number of technologic, social, regulatory, and ethical issues must first be settled before DTC genetic testing takes personalized medicine to new heights. At the 2011 Best of ASCO meeting, Gary H. Lyman, MD, MPH, Director of Comparative Effectiveness and Outcomes Research, Duke University School of Medicine, Durham, NC. DTC genetic testing may provide clinical benefits, but there are real concerns, he said. DTC testing may promote better patient awareness. It has been shown, for example, to increase patient awareness of genetic-associated risks (eg, BRCA mutations in breast cancer) and access to care in the way of referral for professional genetic testing and counseling. “But the benefits are clearly limited by the complexity of genetic information, the social context of genetics, and the questionable utility of these tests,” Dr Lyman said. Available genomic products range from tests that genotype a small set of genetic variants to those that provide whole genome sequencing. Currently, the most popular health-related consumer products rely on singlenucleotide polymorphism chips to simultaneously examine thousands of

small changes found across the genome. These typically target about 1 million sites of known genetic variations, at a retail cost of $200 to $2000. Two Main Dilemmas Dr Lyman sees 2 “dilemmas” presented by DTC testing: the “evidence” dilemma and the “provider” dilemma.

“Patients still require protection from misleading, false information, that medical device regulation must keep up with science and technology.” —Gary H. Lyman, MD, MPH DTC testing, he explained, “challenges current thresholds for the introduction of medical innovations.” That is, the availability of these tests should be based on professional recommendations founded on empirical evidence, not just on the tests’ technical feasibility or commercial potential, he said. The provider dilemma pertains to the burden that DTC testing places on oncologists: to order tests of questionable clinical utility, to explain the results

of tests already obtained, to correct the tests’ inaccuracies or patients’ expectations, to understand a variety of services, and to rely on the company’s own materials and information, he said. “Many consumers of DTC genetic tests share the results with providers and believe it is their duty to interpret these,” he observed. “This is a real problem. It not only adds time to your day, it could compromise the physician/patient relationship as well as patient care.” It Boils Down to a Mixed Message “All this comes down to the mixed message that DTC testing sends,” he concluded. There are indications that DTC testing triggers an interest in cancer screening, such as colonoscopy, mammography, and prostate-specific antigen testing. However, should the tests actually prove valuable, their uptake will be among the wealthy and better educated, with little potential for uptake among the lower socioeconomic classes. Company websites are complex and often unbalanced, which can lead to a misunderstanding of the reasons for the tests, as well as the results. DTC testing also has the potential to harm. In one study, for example, 15% of persons changed their medications as a result of testing. Much of this is hypothetical, however. “Currently, we have virtually no data on the actual utilization or impact on outcomes from these ap-

proaches,” Dr Lyman said. In addition to the need for evidence of the accuracy and utility of DTC genetic tests, oversight is needed; numerous committees and agencies have said so, according to Dr Lyman. There is also consensus that the DTC industry would benefit from greater standardization, especially the development of a standard format for returning genomic data and for interpreting and reporting those data. “The fundamental tension is how to enhance oversight to ensure public health and safety while still promoting personal genomics innovation and autonomy,” he said. The current status of such oversight is “in limbo.” In 2011, the US Food and Drug Administration has been holding public meetings regarding DTC testing and having private dialogues with industry. “In summary, we can agree that patients still require protection from misleading, false information; that medical device regulation must keep up with science and technology; and that the healthcare community requires more training in how to use the rapidly emerging genetic information,” he said. “A wide variety of genetic information is out there of varying usefulness.” Meanwhile, one thing is certain: although these tests are proliferating, their price is dropping. The cost of whole DNA gene sequencing will be only approximately $1000. ■

Americans Willing to Pay Hundreds of Dollars Out of Pocket for Cancer Risk Tests Prostate cancer tops the list By Rosemary Frei

merican adults would be willing to pay a median of $263 for a perfect prostate cancer prediction test and $232 for a perfect breast cancer prediction test, according to a recent survey (Neumann PJ, et al. Health Econ. 2012;21:238-251). This is even when—according to this hypothetical scenario presented to participants in the survey—respondents were told that if the test results were positive the disease could not be prevented, but the person could access treatments when the disease occurred. “The results show that people value having information about their disease

risk, whether or not they have any symptoms or can do anything about it. People may feel empowered by the information,” noted lead investigator Peter J. Neumann, ScD, Director, Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston. Dr Neumann and his colleagues presented the 1463 survey respondents 1 of 16 hypothetical scenarios in which their physician told them in the course of a regular checkup that they were healthy, but they had a probability—either 10% or 25%—of one day contracting either

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“The results show that people value having information about their disease risk, whether or not they have any symptoms or can do anything about it. People may feel empowered by the information.” —Peter J. Neumann, ScD prostate cancer, breast cancer, Alzheimer’s disease, or arthritis. The physician offered a new blood test that would tell them—with either perfect or imperfect accuracy— whether they would develop the dis-

ease. They were also told they would have to pay for it themselves, because insurance did not cover it. Prostate cancer was the condition male respondents were most inclined to be tested and pay for, with 85.4% to 88.0% of respondents saying they would take the test, depending on the risk level and the level of test accuracy. The median amount respondents would be willing to pay for a prostate cancer test was $263, with a perfect test and a disease risk of 25%. Breast cancer testing was not far behind, with 79.0% to 82.4% of respondent women being inclined to take the test and being willing to pay a median of $232 for a perfect test and if they had a 25% disease risk. ■

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“Managing patients with myeloma means staying current.”

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

Value-Based Care in Myeloma !"'&1"-. "3 '0.&1" &)/"-1&"2. )! +"-.+" /&1". -"' /"! /* *./ ,0 '&/4 )! ".. &..0". +" & ' ." /&*). #*."! '&)& & ). !1 ) "! +- /& " )0-.". )! +% -( &./. 2&'' '.* #* 0. *) /%" 0)&,0" % ''")$". &) /%" ( ) $"(")/ *# (0'/&+'" (4"'*(

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PATIENT ADVOCACY

Patient Advocacy: A Physician’s Perspective By Richard Frame, MD Dr Frame is a Medical Oncologist, Utah Cancer Specialist, Salt Lake City

never thought it would happen in the United States, but it has. We are critically close to running out of some chemotherapy drugs. It came as a shock to all of us, when we realized how severely the problem of drug shortages has started to affect our patients. The following case is but one example.

Drug Shortages: Brenda’s Story My patient Brenda was diagnosed with the BRCA1 gene mutation and was treated for breast cancer in the 1990s, with a lumpectomy and radiation therapy. Brenda was in remission, until she was diagnosed with stage IIIC ovarian cancer in May 2006. She could not tolerate chemotherapy given directly into her abdominal cavity. By November 2006 she had completed 6 cycles of standard aggressive chemotherapy. Her ovarian cancer required abdominal surgery in May 2009, followed by more chemotherapy. By March 2011, Brenda had started treatment with a fifth chemotherapy drug, doxorubicin (Doxil). Her disease was responsive to Doxil, which controlled her disease and symptoms, with minimal side effects for 6 months. Brenda is one tough patient. However, later in 2011 I had to tell Brenda that Doxil was no longer available, and that her treatment would need to be changed. She had no option but to return to drugs she had tried before. Brenda was mad, frustrated, angry, and dying for a solution to the drug shortage. When Brenda started receiving Doxil, there was no hint that the drug would become unavailable. In 2008, 3 cancer drugs were in short supply; in 2011, 23 cancer drugs were in short supply. As a result of the Doxil shortage, Brenda and I have discussed that her life would likely be shortened. As luck would have it, toward the end of January 2012, Doxil became available again, and Brenda received her first Doxil treatment on January 30, 2012. We hope that we would be able to maintain the same level of disease control she had previously with Doxil. This has been a medical roller coaster that runs the gamut of disease progression, treatment symptom control, unavailability of drug, disease progression, and drama— plenty of drama.

Patient advocacy is just coming of age. I see a time when the patient matters more than the finances. Trying to get that message out is our challenge. Policy Concerns and Patient Advocacy Network Six years ago, I was asked to serve on the Board of Directors of Community Oncology Alliance (COA). I would sit in meetings and listen to very intelligent, motivated, compassionate physicians fight on behalf of patients with cancer; fight to make sure that the new treatments are available; fight that the new therapy could be paid for; and fight for access to care for the uninsured and indigent. I looked around the room and wondered, “Where are the cancer patients in our fight on their behalf?” The Board of Directors listened and directed us to create an advocacy program on behalf of COA, which we have named CPAN: COA Patient Advocacy Network. CPAN is a network of patients and survivors who are identified through oncology practices. Every oncologist has a few special patients who want to help in that capacity. They want the opportunity to ensure that their cancer treatments are available for other patients who come after them. CPAN is providing an opportunity for patients who want to carry the message to other practices, to their legislators, to their senators, and to the media, to raise the awareness of the serious challenges facing community oncology these days. In our inaugural meeting in February 2011 in Las Vegas we had more than 40 advocates from across

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the country. We have been trying to promote to patients the opportunity to work with their oncologists toward preventing the deterioration in cancer care. There is no stronger relationship between patient care and patient advocacy than the topic of drug shortages. At COA and CPAN we are trying all routes to address the issue of drug shortages. COA has been represented at several congressional hearings, trying to make Congress members aware that in part it is the legislative policies that have gotten us into this situation. The reasons for the generic drug shortage are multiple and complex. It relates to the way the government has priced the reimbursement for different chemotherapy drugs, as well as the manufacturers’ “race to be the lowestcost producer.” The margin for profit has become so low that manufacturers elect not to produce certain drugs. From a business perspective, manufacturers will not make an older chemotherapy drug that costs so much to produce and for which there is little reimbursement. Rather, they would elect to produce a new, expensive drug that would produce a profit. Production delays in the manufacture of delicate toxic drugs and government regulatory panels do not make things any easier. It is not clear if Congress understands the issue well enough to come up with a solution. At COA we are trying to explain the way we see the problem: it will take a pricing guarantee or some government oversight to ensure that these drugs continue to be made by companies that do a good job. Getting Patients Involved In the past 3 years, 199 community cancer practices have closed or have moved their operations to the hospital. Oncologists are being directed to hospitals, where the cost of patient care is much more expensive than in a private practice. One of our challenges is to try to help people recognize the value of a community oncology clinic, where you can get these drugs at a lower rate than in the hospital, and where the treatment is closer to the physician. When patients are directed to receive their cancer care in an expensive hospital environment rather than in local clinics, this is bad for cancer care, and it is bad for the country. We want to make patients aware that our community oncology practices may not exist if we do not promote them and ask patients to help.

We are looking for patients who understand the issues, who have been through cancer treatment. We are particularly interested in patients who work in cancer clinics. We want CPAN to provide an opportunity for these patients to join with us and participate in getting the message out about current cuts, clinics closing, drug shortages, and the threat to cancer care in the United States. How should you try to engage patients? Nobody does anything unless they are asked. We recommend that each COA practice identifies at least 1 patient who will serve as a point person for disseminating the information about current events, affairs, and bills to the other patients in that practice. That person is likely an administrator or a nurse working in the cancer clinic who also happens to have had cancer. It is common that 10% or 20% of the people have direct exposure to our cancer clinics, and many of them are already working in our clinics. This is a very valuable, untapped resource to advocate for the prevention of cancer care deterioration. The staff working in oncology practices who also happen to have cancer already get the message we need to spread. Utilizing Resources the Smart Way This is a very exciting time to be an oncologist. There are new treatments, new protocols, new regimens, and drugs that would have been impossible to imagine 5 or 10 years ago. So oncology has gone a long way. But we need to be smarter and better about utilizing the resources we have. For example, the amount of resources that are spent on end-of-life care for patients with cancer in intensive care units could be spent elsewhere. There are ways that we can educate everyone, including physicians, that there is only so much in the pie. How much do we want to use on one program, and how much do we want to use on another? We could be much better at making these decisions. Patient advocacy is just coming of age. I see a time when the patient matters more than the finances. Trying to get that message out is our challenge. Patients do a much better job than we oncologists do at getting this message out. A patient like Brenda and her story speaks more volumes than any physician ever could. We can help get the message out, but the story is all about the patients. ■

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PATIENT ADVOCACY

Building a National Patient Advocacy Network in Oncology By Rose Gerber Ms Gerber is an 8-year breast cancer survivor and Director of Patient Advocacy, Community Oncology Alliance, Washington, DC

ormed in 2003, the Community Oncology Alliance (COA), led by Executive Director Ted Okon, has been well established nationally as the only nonprofit organization advocating solely for community oncologists and their patients. As a result, COA has a very strong presence on Capitol Hill, representing its physicians and community center practice administrators from all across the country. Yet even in this context of advocating for oncologists and patients, it took a few years before it was realized that the patient’s voice was missing, and that led to the formation of the Community Oncology Alliance Patient Advocacy Network (CPAN).

The Patient’s Voice Although COA members had presented their concerns to Congress and the media about threats to cancer care in the community, they understood that what resonates best with people is the patient’s experience. I was hired by COA in 2009 as the Director of Patient Advocacy. Although I joined COA with extensive local and national advocacy experience and a professional background in marketing and public relations, it was my experience as a cancer survivor (treated primarily in a community cancer setting) combined with advocacy program development, which lent an additional level of understanding of how CPAN could appeal to patients and survivors. With the full support of COA’s board (physicians, nurses, and practice administrators) and the CPAN Medical Chairman, Rick Frame, MD (who initiated the idea of the patient voice and a patient advocacy network), we have successfully reenergized CPAN’s national presence. Building a Patient Advocacy Network I am often asked about how to develop a cancer advocacy program. One of the first things I would recommend to any cancer practice or a community group is to start with a market assessment. It is important to assess what is already in the community. Most likely, other patient advocacy programs are already in existence, which is good news for patients, but a challenge when trying to develop a new program. One of our biggest tasks was to identify how to differentiate CPAN from other advocacy groups. What

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would distinguish CPAN, a new, small organization compared with wellestablished groups, such as the American Cancer Society, Susan G. Komen for the Cure, and Lance Armstrong, which are all wonderful organizations in their own right? The answer was clear. Our strength was our unique membership: patients, survivors, nurses, practice administrators, and oncologists. Few patients will ever see their providers in a role outside the clinic. With CPAN, our advocate volunteers will partner with oncologists in advocating for cancer care. Engaging the Cancer Community One of our goals at CPAN is to alert the cancer community about how policy changes in Washington, DC, can have a negative impact in our local communities. For example, a staggering number of community cancer clinics are closing across the country. This directly affects patients’ access to care. In my case, for example, although it is 8 years after my primary diagnosis, I am still under the care of an oncologist; if my community practice closed, this would be devastating for me. I share this, because cancer survivors currently remain under an oncologist’s care longer as a result of increased survivorship. The continuum of care is long today, and we want to make sure that community cancer centers are there to treat newly diagnosed patients and longterm survivors. Because CPAN represents all types of cancer, we can deal with legislative advocacy in broad terms. CPAN membership is open to all members of the cancer community: patients in active treatment, survivors, caregivers, family members, nurses, oncology professionals, and interested members of the general community. After a primary treatment, many patients want to get involved in cancer advocacy. At CPAN we offer that opportunity. As a survivor, I am greatly concerned that all patients with cancer may lose access to cancer care in their communities. CPAN offers patients the ability to get involved in advocating for cancer care at the local and national level. Nurses’ Unique Role Patients often form close bonds with their nurses. This is what happened in my case, and this can happen in any practice. As a result of my extensive

treatment period, I gradually developed a close bond with my community cancer center and with my nurse. In addition to the patient’s medical history, nurses often learn about the patient’s personal life, skills, and interests. As a result, nurses are among the best liaisons for alerting administrators or physicians to patients who may be ideal CPAN patient advocates. We are very interested in working with nurses, and I invite all nurses to reach out to me to discuss patient advocacy opportunities with CPAN.

A staggering number of community cancer clinics are closing across the country. This directly affects patients’ access to care. Defining Patient Advocacy The terms “patient” and “advocate” can have many different meanings. Most practices have staff members who are “patient advocates,” but they are often employed by practices to work on reimbursement or insurance issues, which is a form of advocacy. Other types of advocacy can include peer-to-peer support, and legislative advocacy. CPAN’s focus is legislative advocacy. The first thing for the practice to understand is what type of advocacy they are seeking. If I ask administrators and oncologists to identify a patient advocate for CPAN, they will immediately think of a patient who is in treatment. This is fine, but a patient could also be someone who is 10 years out of treatment, a family member, or an active member of the community. It is therefore helpful to expand your line of thinking when using the term “patient.”

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What CPAN Can Offer Practices and Patients We are actively recruiting patients nationally, and we would love to have volunteers in every state. Community oncology practices have a great opportunity to contribute to CPAN growth. We have members in more than 15 states. Scott Parker, Executive Director of Northwest Georgia Oncology Centers, was one of the first practice administrators to step up and say, “I can help you develop this program.” Mr Parker introduced me to several potential volunteers. One of them, Susanne Johnson-Berns, now serves as our Georgia State Chapter President. When an administrator such as Mr Parker is talking to other administrators, they are excited to get involved in CPAN. When an oncologist such as Dr Frame is serving as CPAN Medical Chairman, it inspires other oncologists to get involved in advocacy. And, of course, our advocate survivors inspire each other. We introduce advocates gradually to policy issues, by bringing them to Capitol Hill and helping them understand that what happens in Congress is ultimately going to affect them in their local community. We ask our volunteers to alert the members in their communities about how national issues affect them locally. In turn, we invite them to stand side by side with an oncologist, a nurse, and a cancer practice administrator and share their concerns with their legislators. With CPAN we give volunteers the opportunity to become cancer care advocates by assisting year round with our outreach and by joining us during our annual trips to Washington, DC, and special member events. Join Our Annual Conference On March 30-31, 2012, during COA’s 7th annual conference, we are offering a patient advocacy program, with several educational advocacy sessions planned. Nurses, practice administrations, volunteer advocates, and representatives from national organizations are featured speakers. Our distinguished guest is the Honorable Mark Shurtleff, Utah Attorney General, a colon cancer survivor. I invite any advocates who may be interested in learning more about CPAN and/or attending our conference to visit www.coaAdvocacy.org or contact me by e-mail at roseg@ coacancer.org. ■

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GU CANCERS SYMPOSIUM

Comparative Effectiveness Analysis of 3 Radiation Therapies for Prostate Cancer IMRT proves to be current standard, proton beam therapy costliest, no improved outcomes By Wayne Kuznar San Francisco, CA—A new, large comparative effectiveness analysis of 3 techniques for delivering radiation therapy for the treatment of localized prostate cancer supports intensity-modulated radiation therapy (IMRT) as the current standard, said Ronald Chen, MD, MPH, Assistant Professor of Radiation Oncology, University of North Carolina (UNC), Chapel Hill, and Research Fellow, Sheps Center for Health Services Research, UNC at the 2012 annual Genitourinary Cancers Symposium. Men treated with IMRT were less likely to have cancer recurrence or significant adverse effects than those who received conventional conformal radiation therapy (CRT). The analysis also revealed no advantage with proton beam radiation, the newest and costliest radiation technique, over IMRT. “Proton radiation is receiving a lot of attention as a new way to treat prostate cancer, and it is the most expensive radiation technique to date,” said Dr Chen. “However, it is unclear if new treatments actually improve patient outcome, and, therefore, comparative effectiveness research is needed.” Since 2000, the use of IMRT has increased dramatically, from essentially 0% to 96%, practically replacing the older CRT.

“More recently there has been a rapid increase in the number of proton radiation centers built in the United States, suggesting that a similar phenomenon may be seen with an increased use of proton radiation in the near future,” Dr Chen said.

“Proton radiation is receiving a lot of attention as a new way to treat prostate cancer, and it is the most expensive radiation technique to date. IMRT causes fewer side effects and achieves better cancer control compared with the older CRT.”

at a glance ➤ Evidence from this large comparative study shows that men treated with IMRT were less likely to have cancer recurrence than those who received CRT ➤ Side effects were also reduced with IMRT compared with the other modalities ➤ Proton beam therapy is attracting attention as a new way to treat prostate cancer, but its cost is prohibitive ➤ It is also unclear if proton therapy results in better clinical outcomes than the other radiation modalities

—Ronald Chen, MD, MPH Dr Chen and colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER)Medicare database of more than 12,000 patients with localized prostate cancer who received 1 of the 3 forms of radiation therapy between 2002 and 2007. The number of patients in each group who required additional cancer treatments after radiation was used as an indicator for cancer recurrence.

Compared with patients who received CRT, those who received IMRT suffered fewer bowel adverse events. The rates of bowel adverse events were 14.7 events per 100 patient-years for CRT versus 13.4 events per 100 person-years for IMRT, corresponding to a 9% relative reduction in events from IMRT. The IMRT group also had 22% fewer hip fractures than the CRT group, although hip fractures were a very uncommon event after radiation (0.8

events per 100 patient-years in the IMRT group vs 1 event per 100 patientyears in the CRT group). Patients who received IMRT also required 19% fewer additional cancer treatments than those who received CRT, “suggesting that there’s better cancer control with IMRT,” said Dr Chen. However, the IMRT group had a relative increase of 12% in the frequency of erectile dysfunction versus CRT—5.9 events versus 5.3 events per 100 patient-years, respectively. Compared with IMRT, patients who received proton beam therapy had a 66% higher rate of bowel side effects: 12.2 events per 100 patient-years versus 17.8 events, respectively. There was no significant difference between IMRT and proton therapy in the rates of other adverse effects and additional cancer treatments. “This study supports the use of IMRT as the current standard radiation technique for prostate cancer,” said Dr Chen. “IMRT causes fewer side effects and achieves better cancer control compared with the older CRT. Currently, there is no clear evidence that proton therapy is better than IMRT.” Two additional comparative effectiveness studies of radiation therapy technique in patients with prostate cancer are ongoing. ■

Two Mechanistically Distinct Agents Lead to Impressive Survival Improvements in Advanced Prostate Cancer Combining these therapies may add even more value San Francisco, CA—Two treatments significantly extended survival in men with metastatic castration-resistant prostate cancer (CRPC) in separate phase 3 clinical trials reported at the 2012 Genitourinary Cancers Symposium. The hope is that the 2 treatments, one an injectable alpha pharmaceutical (radium-223 chloride) and the other a novel antiandrogen drug (MDV3100), can be used either sequentially or in combination to further boost survival in men with CRPC and bone metastases. Alpha Emitter Reduces Skeletal Events, Improves Mortality In the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, radium-223 chloride improved overall survival (OS) by 30% compared with

placebo. Mean survival in men randomized to radium-223 chloride was 14.0 months compared with 11.2 months in the group receiving placebo. Radium-223 chloride also cut the risk of pathologic bone fracture and spinal cord compression in half while also reducing the need for external beam radiation by one third, reported A. Oliver Sartor, MD, Professor of Cancer Research at Tulane University and Medical Director of the Tulane Cancer Center, New Orleans. “We believe this novel alpha-pharmaceutical—the very first one to be tested in phase 3 in all of medicine— may provide a new standard of care for the treatment of patients with bone metastases in advanced prostate cancer,” said Dr Sartor.

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FEBRUARY 2012

Radium-223 is an alpha particle emitter that binds to stroma adjacent to bone metastases. The short range of the alpha emitters enables highly localized tumor cell death with minimal damage to surrounding normal tissue. The ALSYMPCA investigators randomized 922 men with confirmed symptomatic CRPC and at least 2 bone metastases, but no visceral metastases, in a 2:1 ratio to radium-223 chloride or placebo. Most participants had disease progression after treatment with docetaxel or were considered unfit for docetaxel, a group often excluded from clinical trials, noted Dr Sartor. Both groups received best supportive care. After a planned interim analysis, the Independent Data Monitoring Committee recommended stopping the trial

early because of evidence of a significant benefit with radium-223 treatment. The time to a first skeletal-related event (SRE) was extended from 8.4 months in the placebo group to 13.6 months in the radium-223 chloride group, corresponding to a 39% relative improvement. Compared with placebo, treatment with radium-223 resulted in a 55% reduction in pathologic bone fracture (6.7% vs 3.6%), a 56% reduction in spinal cord compression (6.0% vs 3.1%), and a 35% reduction in the need for external beam radiation (26.9% vs 22.6%). There was no significant difference between the 2 groups in the rate of surgical intervention for SREs. Radium-223 chloride was “very well Continued on page 41

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Two Mechanistically Distinct Agents... tolerated,” said Dr Sartor. The rates of grade 3 or 4 events, including anemia and other hematologic events, were not different with radium-223 than with placebo, except for a lower rate of bone pain in those treated with radium-223. The lack of toxicity is evidence that the short tract of the radium particle spares the bone marrow, he said. Based on the ALSYMPCA results, the US Food and Drug Administration has agreed to a fast-track review of radium-223. MDV3100: Next-Generation Antiandrogen The other phase 3 data presented here involved MDV3100, the first in a new class of oral hormonal agents that affects multiple steps in androgenreceptor signaling, a key driver of prostate cancer growth. It was studied in 1199 patients with progressive CRPC in whom docetaxel chemotherapy failed. The patients were randomized in a 2:1 ratio to daily MDV3100 or placebo. The double-blind trial was unblinded early after the Independent Data Monitoring Committee determined that the risk:benefit ratio with MDV3100

was favorable. OS, the primary end point of the trial, was extended by an average of 4.8 months in the MDV3100 arm, from 13.6 months in the placebo group to 18.4

“We believe this novel alphapharmaceutical [radium-223 chloride]—the very first one to be tested in phase 3 in all of medicine—may provide a new standard of care for the treatment of patients with bone metastases in advanced prostate cancer.” —A. Oliver Sartor, MD months in the MDV3100 group—a 37% relative reduction in the risk of death, said lead investigator Howard I. Scher, MD, Chief of the Genitourinary Oncology Service and Chair in Urologic Oncology at Memorial Sloan-Kettering Cancer Center, NY. A significantly higher proportion of patients treated with MDV3100 had shrinkage of soft tissue tumors dem-

Continued from page 40

onstrated on imaging studies—28.9% of patients randomized to MDV3100 versus 3.8% of patients randomized to placebo. The median progression-free survival on imaging was extended by approximately 60% with MDV3100. A higher proportion of patients also had a decline of at least 50% in their blood level of prostate-specific antigen (PSA). A ≥50% reduction in PSA level from baseline was seen in 54.0% of patients randomized to MDV3100 and only 1.5% of placebo recipients. A ≥90% reduction in PSA level from baseline occurred in 25% of the MDV3100 group and 1% of the placebo group. MDV3100 increased the time to PSA progression by 5.3 months—from 3.0 months with placebo to 8.3 months with MDV3100. The time to disease progression was 5 months longer on average in those receiving MDV3100 versus placebo. MDV3100 was well tolerated. Mild fatigue, diarrhea, and hot flushes were more common with MDV3100 but did not necessitate a reduction in dosage. “The benefit:risk profile [of MDV3100] will likely position it as the first frontline agent after docetaxel therapy,” said Dr Scher.

An 18.4-month median survival rate, with 25% of patients having a 90% decline in PSA is “unprecedented,” commented Nicholas J. Vogelzang, MD, Medical Director of the Developmental Therapeutics Committee of US Oncology. Synergy between Therapies? These drugs will probably be used in sequence, said Dr Vogelzang. “In a simple, additive way, we would expect the survivals to be fairly dramatically pushed forward,” but it is impossible to know because they have not yet been tested in sequence. The drugs are mechanistically different and both have favorable safety profiles and have shown a survival benefit. “Seeing these effects and effects on survival in drugs that seem like they can be given in sequence or even together…will clearly benefit patients going forward,” Dr Scher pointed out. “These mechanistically distinct therapies will probably be combined,” agreed Dr Sartor, and combinations or sequences “may add even more value than what we see here.”—WK ■

PROSTATE CANCER

Array of Treatments for Metastatic Prostate Cancer, See also page 42 but Can We Afford Them? By Phoebe Starr New York, NY—Men with castrationresistant prostate cancer (CRPC) now have several different treatments that improve their survival—docetaxel (Taxo-tere), cabazitaxel (Jevanta), abiraterone (Zytiga), and sipuleucel-T (Provenge). The newest potential therapy to improve survival in this group of patients is the radiopharmaceutical radium-223 (Alpharadin), which is currently under US Food and Drug Administration review. Alpharadin In the pivotal phase 3 ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, radium-223 improved survival in metastatic CRPC and had “remarkable” effects on bone scans, with a safety profile that was as good as that of placebo. Data are less mature for a second drug, cabozantinib (XL-184), which also may be another “transformative” drug for CRPC, according to experts who spoke at the 2011 Chemotherapy Foundation Sympo-

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sium in November. “Radium-223 promises to become a new standard of treatment for men with CRPC who have bone metastasis,” said A. Oliver Sartor, MD, Professor of Cancer Research at Tulane University and Medical Director of the Tulane Cancer Center, New Orleans. “We now have a variety of agents that prolong survival. In the future, we will need to learn how to combine them and sequence them. But the question is, can we afford this?” ALSYMPCA enrolled 922 patients with CRPC and at least 2 bone metastases but without visceral metastasis who were randomized to receive radium-223 or placebo. A definite survival benefit for radium-223 was shown at a preplanned interim analysis, after which the study was stopped and men in the placebo group were allowed to cross over to the radiopharmaceutical arm. The median overall survival was 14.0 months with radium-223 versus

11.2 months with placebo. The risk for time to a first skeletal-related event was reduced by 39% in patients who received radium-223. Radium-223 was of benefit in all prespecified subgroups, including those who had received docetaxel previously. The adverse effect rate associated with radium-223 was less than that with placebo, and more patients in the placebo group discontinued treatment. Cabozantinib Cabozantinib, the second drug for CRPC discussed at the meeting, showed promising results in a phase 2 trial. Cabozantinib is a dual inhibitor of MET and vascular endothelial growth factor receptor 2, explained David C. Smith, MD, Professor of Medicine, University of Michigan, Ann Arbor, who discussed studies of the drug at the meeting. The phase 2 randomized discontinuation trial compared cabozantinib versus placebo in 171 men (median age, 68 years) with metastatic CRPC that was progressing. Among this group, 54% had bone pain, 42% were

FEBRUARY 2012

taking narcotics for their pain, and approximately 40% had received docetaxel previously. Randomization was discontinued after 12 weeks, because cabozantinib led to controlled disease (ie, complete response, partial response, or stable disease) in 68% of patients. Bone scans showed some evidence of activity of cabozantinib in almost all of the patients, Dr Smith commented. The major toxicities were fatigue (63%), thrombocytopenia (8%), and gastrointestinal perforation (1%); 50% of patients required dose reductions. No significant effect was observed in patients who received docetaxel previously. The moderator of the session, William K. Oh, MD, Mount Sinai School of Medicine, New York, NY, said that both radium-223 and cabozantinib target the microenvironment. “Radium-223 will be transformative, because of its efficacy and favorable toxicity. Cabozantinib should also be transformative. It had a remarkable effect on bone scans, but we need to see more studies,” he stated. ■

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Physician-Led Approach Can Cut Unnecessary Testing in Prostate Cancer By Caroline Helwick

eedback from their peers helped physicians refrain from ordering unnecessary tests for patients with newly diagnosed cancer, according to a recent study (Miller DC, et al. J Urol. 2011;186:844-849. Epub 2011 Jul 23). Physicians ordered fewer tests after becoming more aware of practice guidelines and being presented with comparative data on tests they and their colleagues ordered. The program also improved the quality of care by reducing variations in practice patterns. “The study is a great example of a new solution for an old problem,” said David C. Miller, MD, MPH, a urologist at the University of Michigan School of Medicine, Ann Arbor, and lead investigator. “Physicians are at the heart of the solution.” The study was conducted by the Urological Surgery Quality Collaborative, a consortium of 150 urologic surgeons in several Midwestern states

and Virginia that formed in 2009 to find ways to improve healthcare quality and consistency. Investigators examined the diagnostic practices of physicians treating 858 patients with early-, middle-, or latestage prostate cancer. Among men with newly diagnosed cancer, 44% were classified as having low-risk cancer, 39% had intermediate-risk cancer, and 17% had high-risk cancer. To look for metastases, overall urologists initially ordered bone scans for 25% of patients and computed tomography (CT) scans for 22%. Among the patients with low- or medium-risk cancer, for whom the benefits of these interventions are less established, bone scans were ordered initially for 31% of patients and CT scans for 28%. The urologists then participated in a quality assurance intervention. They received comparative performance feedback and review, the results of the

imaging studies, and the American Urological Association and National Comprehensive Cancer Network guidelines for staging evaluations in men with early-stage prostate cancer.

“The study is a great example of a new solution for an old problem. Physicians are at the heart of the solution.” —David C. Miller, MD, MPH Ultimately, they began using an information collection form that included a summary of the practice guidelines. At the program’s end, only 13% of patients received CT scans and 16% received bone scans. The reduction in testing was espe-

cially notable among patients with low-risk cancer. Use of CT scans dropped from 14% to 2%, and the use of bone scans dropped from 10% to 1%. In patients with early-stage cancer, for whom metastases are highly unlikely, screening tests can create more stress by uncovering benign findings that lead to further testing and can expose patients to radiation unnecessarily, the authors pointed out. Dr Miller suggested that physicians may not practice in accordance with guidelines because they are unfamiliar with them or because they are comfortable with their own practice patterns, which may differ from the guidelines. He said the study demonstrates that positive changes can come from within medical practices through “physician-led approaches,” and that peer counseling may be better accepted than mandates from third-party payers and policymakers. ■

Which Patients with Prostate Cancer Should Receive Hormone Therapy in Addition to Radiation? By Phoebe Starr Miami, FL—Although several studies have shown that the addition of androgen-deprivation therapy (ADT) to radiation improves disease-free survival (DFS) in men with intermediaterisk prostate cancer, this is a heterogeneous group of patients, and it is not clear whether they should all receive ADT plus radiation, or whether the benefit is confined to a specific subset of patients. A nonrandomized retrospective study presented at the 2011 American Society for Radiation Oncology meeting suggests that the additive benefit of ADT in men with intermediate-risk prostate cancer treated with radiation is confined to those with a poor prognosis (Gleason score ≥4 + 3), whereas no such benefit is seen in those with a favorable prognosis. “ADT was clearly of benefit in patients with Gleason scores of 4 + 3 and higher-volume disease. We need randomized trials to support these data, but in the interim, these findings may help clinicians identify a favor-

able subset of intermediate-risk patients who can be treated with radiation alone,” said Katherine Castle, MD, University of Texas M.D. Anderson Cancer Center, Houston.

“These findings may help clinicians identify a favorable subset of intermediate-risk patients who can be treated with radiation alone.” —Katherine Castle, MD

Dr Castle recommended a personalized approach to management that considers tumor and patient characteristics in the decision of whether to use radiation alone or radiation plus shortcourse ADT. The study included patients with intermediate-risk prostate cancer who received intensity-modulated radiation therapy or 3-dimensional

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FEBRUARY 2012

conformal radiation between 1993 and 2008. A total of 327 patients received radiation alone (in doses ranging from 75.6 Gy to 78.0 Gy) and 218 received radiation plus up to 6 months of ADT.

at a glance ➤The additive benefit of ADT in intermediate-risk prostate cancer treated with radiation applies only to men with a poor prognosis ➤ Tumor and patient characteristics should be considered in the decision whether to use radiation alone or with short-course ADT ➤ In this study, disease-free survival was 94% in men with an unfavorable prognosis who received radiation plus ADT versus 74% with radiation alone

Prognosis was categorized as favorable, unfavorable, or marginal according to the patient’s Gleason score, T-stage, and pretreatment prostatespecific antigen level. Patients with a favorable prognosis had either a Gleason score of 6 and stage T1b-T2b disease or a Gleason score of 3 + 4 and stage T1b-c disease. Those with marginal prognosis had a Gleason score of 3 + 4 and stage T2a-b disease, and those with an unfavorable prognosis had a Gleason score of 4 + 3 or stage T2c disease. The biochemical DFS at 5 years was 94% for men with an unfavorable prognosis who received radiation plus ADT versus 74% with radiation alone (P = .005). Patients with a favorable prognosis received no benefit from radiation plus ADT versus radiation alone; the DFS was 94% and 95%, respectively. In patients with a marginal prognosis, the DFS at 5 years was 91% for radiation alone and 100% for radiation plus ADT. ■

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The Health Burden of Multiple Myeloma: Subcutaneous Bortezomib a New, Convenient Route of Administration Option By Rhonda Williams

n 2011, the American Cancer Society projected there would be 20,520 cases of newly diagnosed multiple myeloma (MM) and 10,610 deaths from the disease that year.1 MM is an incurable hematologic cancer marked by great heterogeneity, in terms of its biology and clinical course. Morbidity and survival rates vary widely, even in the age of novel, molecularly based targeted therapies. Many factors account for differences in prognoses among patients with MM, including genomic aberrations in the plasma cells of the myeloma neoplasm. Survival outcomes range from <1 year in patients with aggressive disease to >10 years in those with indolent disease.2 A variety of patient-, disease-, and therapy-related characteristics have been identified to predict the disease course and outcomes among patients with MM. Evaluation of prognostic factors and risk stratification is important in defining appropriate treatment strategies and comparing therapeutic outcomes, to predict survival.2

The Approach to Therapy in MM Use of the proteasome inhibitor bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid),

Table 1

and bisphosphonates such as zoledronic acid (Zometa) and pamidronate (Aredia) has revolutionized the management of patients with MM. These therapies, however, are all associated with potentially serious side effects, which can negatively affect a patient’s quality of life. The majority of preferred regimens for initial therapy are 3-drug combinations, although some 2-drug combinations are also recommended in the current guidelines from the National Comprehensive Cancer Network, because these multidrug regimens are associated with the best response rates.3 New Treatment Option The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, bortezomib disrupts biologic pathways related to the growth and survival of cancer cells.4 Bortezomib was approved by the US Food and Drug Administration (FDA) in 2003 for intravenous (IV) injection for the treatment of patients with MM who had received at least 2 previous therapies and had demonstrated disease progression on their last therapy.4

Summary of Efficacy Analyses in the Relapsed MM Study of Bortezomib SC versus IV Bortezomib SC (N = 148)

Intent-to-treat population

Bortezomib IV (N = 74)

In 2008, the FDA approved an expanded indication for bortezomib for the first-line treatment of patients with previously untreated MM. The approval was based on data from the VISTA trial, which compared the addition of bortezomib to melphalan plus prednisone (MP) versus MP without bortezomib (ie, control group) in 682 patients with newly diagnosed MM. At a median follow-up of 16.3 months, the addition of bortezomib to the MP regimen resulted in significantly improved outcomes, including improved response rates, increased time to disease progression, overall survival (OS), and progression-free survival.5 The trial was stopped early and patients in the control group were permitted to cross over to the bortezomib regimen. In December 2011, results of 5-year median follow-up of the VISTA trial confirmed a >13-month OS advantage of the bortezomib plus MP regimen for patients with previously untreated MM. Bortezomib is also indicated for the treatment of patients with mantlecell lymphoma who have received at least 1 previous therapy.5 In January 2012, the FDA approved a new route of administration for bortezomib; the new subcutaneous (SC) form of bortezomib for injection offers patients an easier mode of administration, with a safety profile comparable to the IV form but with significantly reduced peripheral neuropathy (6% vs 16%, respectively),5 providing patients with MM a new option in the choice of the route of administration.

Primary end point Response rate at 4 cycles ORR (CR+PR), N (%)

63 (43)

31(42)

Ratio of response rates (95% CI)

1.01 (0.73, 1.40)

CR, N (%)

11 (7)

6 (8)

PR, N (%)

52 (35)

25 (34)

nCR, N (%)

9 (6)

4 (5)

ORR (CR+PR), N (%)

78 (53)

38 (51)

CR, N (%)

17 (11)

9 (12)

PR, N (%)

61 (41)

29 (39)

nCR, N (%)

14 (9)

7 (9)

Median time to progression, months

10.4

9.4

Median progression-free survival, months

10.2

8.0

72.6

76.7

Secondary end points Response rate at 8 cycles

1-year overall survival, %

Median duration of follow up is 11.8 months. CI indicates confidence interval; CR, complete response; IV, intravenous; MM, multiple myeloma; nCR, near-complete response; ORR, overall response rate; PR, partial response; SC, subcutaneous. Source: Reference 5. a

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FEBRUARY 2012

Clinical Pharmacology of Bortezomib Mechanism of action. Bortezomib is a reversible inhibitor of the chymotrypsinlike activity of the 26S proteasome in mammalian cells; the 26S proteasome degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of this pathway can therefore affect multiple signaling cascades within the cell and can lead to cell death.5 Pharmacodynamics. After twiceweekly administration of bortezomib 1 mg/m2 and 1.3 mg/m2, the maximum inhibition of 20S proteasome activity, relative to baseline, occurred 5 minutes after drug administration.5 Pharmacokinetics. After IV administration of bortezomib 1 mg/m2 and bortezomib 1.3 mg/m2 in 24 patients

with MM, the maximum plasma concentrations (Cmax) of bortezomib were 57 ng/mL and 112 ng/mL, respectively. The mean elimination half-life of bortezomib with multiple dosing ranged from 40 to 193 hours after administration of the 1-mg/m2 dose and 76 to 108 hours after administration of the 1.3-mg/m2 dose. After an IV or a SC bolus injection of a 1.3-mg/mL dose in patients with MM, the total systemic exposure with a repeat-dose administration was equivalent for the SC and the IV routes of administration. The Cmax after SC administration (20.4 ng/mL) was lower than that after IV administration (223 ng/mL).5 In vitro studies suggest that bortezomib is primarily oxidatively metabolized via the cytochrome P450 enzymes 3A4, 2C19, and 1A2.5 Phase 3 Clinical Trials: Bortezomib SC versus IV The FDA approval of SC bortezomib was based on a randomized, openlabel, phase 3, noninferiority trial that compared the efficacy and safety of SC versus IV administration of bortezomib in patients with relapsed MM. A total of 222 bortezomib-naïve patients were randomly assigned, in a 2:1 ratio, to receive bortezomib 1.3 mg/m2 by either SC injection (N = 148) or IV infusion (N = 74) for 8 cycles. Patients were stratified according to the number of lines of previous therapy they had received (1 previous line vs >1 previous line of therapy) and stage of disease, using International Staging System (ISS) stage I, II, or III.5 The primary study end point was to demonstrate noninferiority of singleagent SC bortezomib with respect to overall response rate (ORR)—complete response (CR) plus partial response. In this study, noninferiority was defined as retaining at least 60% of the ORR relative to single-agent IV bortezomib after 4 cycles of therapy.5 Patients who did not obtain an optimal response (less than CR) to treatment with bortezomib alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after bortezomib administration (N = 82 in the SC treatment group; N = 39 in the IV treatment group). Patients with baseline grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/L, were excluded from trial participation. A total of 218 patients were evaluable for response.5

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CANCER DRUGS The baseline demographic and other characteristics of the 2 treatment groups were similar. The median patient age was approximately 64 years (range, 38-88 years), and the majority of patients were male (SC, 50%; IV, 64%). The primary type of myeloma was immunoglobulin G. ISS stage I/II/III was 27%, 41%, and 32%, respectively, with both SC and IV routes of administration. The Karnofsky performance status score was ≤70% in 22% of SC-treated patients and 16% of IV-treated patients. Creatinine clearance was 67.5 mL/min in the SC group and 73 mL/min in the IV group. The median years from diagnosis were 2.68 years and 2.93 years in the SC and IV groups, respectively. The proportion of patients with >1 prior line of therapy was 38% with SC treatment versus 35% with IV treatment.5 This study met its primary (noninferiority) objective that treatment with single-agent SC bortezomib retains at least 60% of the ORR after 4 cycles relative to IV bortezomib (Table 1).5

Table 2

Most Common Adverse Events (≥10%) in the Relapsed MM Study of Bortezomib SC versus IV

MedDRA system organ class MedDRA preferred term

Warnings and Precautions Peripheral neuropathy. Peripheral

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Total N (%)

N (%)

Total N (%)

Bortezomib IV (N = 74)a toxicity grade 3 grade ≥4 N (%)

N (%)

Blood and lymphatic system disorders Anemia

53 (36)

14 (10)

4 (3)

26 (35)

6 (8)

Leukopenia

29 (20)

9 (6)

16 (22)

4 (5)

1 (1)

Neutropenia

42 (29)

22 (15)

4 (3)

20 (27)

10 (14)

3 (4)

Thrombocytopenia

52 (35)

12 (8)

7 (5)

27 (36)

8 (11)

6 (8)

5 (3)

1 (1)

8 (11)

Gastrointestinal disorders Abdominal pain Abdominal pain upper

3 (2)

8 (11)

Constipation

21 (14)

1 (1)

11 (15)

1 (1)

Diarrhea

35 (24)

2 (1)

1 (1)

27 (36)

3 (4)

1 (1)

Nausea

27 (18)

14 (19)

Vomiting

17 (12)

3 (2)

12 (16)

1 (1)

General disorders and administration site conditions Asthenia

23 (16)

3 (2)

14 (19)

4 (5)

Fatigue

17 (12)

3 (2)

15 (20)

3 (4)

Pyrexia

28 (19)

12 (16)

16 (11)

2 (1)

7 (9)

1 (1)

22 (15)

2 (3)

1 (1)

14 (10)

7 (9)

Infections and infestations Herpes zoster

Safety Profile: Reduced Peripheral Neuropathy with SC Option The safety data reported herein are from the randomized, open-label study that compared the SC administration of bortezomib with IV administration of bortezomib at the recommended dose of 1.3 mg/m2 in 222 patients with relapsed MM. Overall, the safety data were similar between the SC and IV treatment groups (Table 2), but with significant differences in some adverse events (AEs) favoring the SC form of bortezomib. Differences of ≥5% between the 2 groups favoring the SC administration were reported for neuralgia (3% SC vs 9% IV), peripheral neuropathy grade ≥3 (6% SC vs 16% IV) and all grades (38% vs 53%), and thrombocytopenia (13% SC vs 19% IV).5 In the SC treatment group, local reactions, primarily redness, were reported in 6% of patients; 2 patients (1%) experienced local reactions that were considered severe (1 case of pruritus and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to study discontinuation in 1 patient and reduction in dose concentration in 1 patient.5 Dose reductions associated with drug-related AEs were reported in 31% of patients in the SC group compared with 43% of patients in the IV group. The most common AEs leading to dose reduction included sensory peripheral neuropathy (17% SC vs 31% IV) and neuralgia (11% SC vs 19% IV).5

Bortezomib SC (N = 147)a toxicity grade 3 grade ≥4

Investigations Weight decreased Metabolism and nutrition disorders Decreased appetite

Musculoskeletal and connective tissue disorders Back pain

21 (14)

1 (1)

8 (11)

1 (1)

Pain in extremity

8 (5)

1 (1)

8 (11)

2 (3)

5 (3)

8 (11)

35 (24)

5 (3)

17 (23)

7 (9)

56 (38)

8 (5)

1 (1)

39 (53)

11 (15)

1 (1)

18 (12)

8 (11)

11 (7)

2 (1)

9 (12)

2 (3)

14 (10)

3 (2)

3 (4)

Nervous system disorders Headache Neuralgia b

Peripheral neuropathies NEC Psychiatric disorders Insomnia

Respiratory, thoracic, and mediastinal disorders Dyspnea Vascular disorders Hypertension

Safety population: 147 patients in the SC treatment and 74 patients in the IV treatment who received at least 1 dose of study medication. Represents MedDRA high-level term. IV indicates intravenous; MedDRA, Medical Dictionary for Regulatory Affairs; NEC, not elsewhere classified; SC, subcutaneous. Source: Reference 5. a

neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. The peripheral neuropathy associated with bortezomib use is primarily sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported with use of the agent. Patients with such preexisting symptoms as numbness, pain, or a burning sensation in the feet or hands, and/or signs of peripheral neuropathy, may experience worsening of peripheral neuropathy, including grade ≥3, during treatment with bortezomib.5 A paradigm shift regarding bortez-

omib use currently exists, with recent data suggesting that changing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. The results of a phase 3 study by Moreau and colleagues, which included patients with relapsed MM who had received 1 to 3 previous lines of therapy, concluded that SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.6 The protocol of this study provided

FEBRUARY 2012

for a robust comparison of the 2 routes of administration, since it specified 4 cycles of single-agent bortezomib with the addition of oral dexamethasone 20 mg to enhance response at the end of cycle 4 in patients who achieved a suboptimum response.6 In this trial, the incidence of grade ≥2 peripheral neuropathy was 24% in patients who received SC bortezomib and 41% in those who received IV bortezomib (a significant difference).5,6 Also in this trial, grade ≥3 peripheral neuropathy occurred in 6% of patients in the SC treatment group and 16% of those in Continued on page 46

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CANCER DRUGS

The Health Burden of Multiple Myeloma... the IV treatment group.5,6 When initiating bortezomib therapy, SC administration may be considered for patients with preexisting peripheral neuropathy or those who are at high risk for developing peripheral neuropathy. In patients with preexisting, severe peripheral neuropathy, the risk-benefit should be carefully assessed prior to beginning bortezomib therapy.5 Prevention is the best approach to use when addressing bortezomibrelated neuropathy. One advantage of bortezomib is that most episodes of grade 3/4 neuropathy can be prevented by closely adhering to the algorithm for dose modification and interruption provided in the prescribing information (Table 3). By following these recommendations, the severity of peripheral neuropathy can usually be decreased to grade 1 or 2, and in many cases, patients may resume bortezomib therapy.5 Hypotension. The incidence of hypotension, which included postural hypotension, orthostatic hypotension, and hypotension not otherwise specified, reported with the use of bortezomib was 13%. These events occurred throughout treatment. Caution should be used when administering bortezomib to patients with a history of syncope, those receiving medications known to be associated with hypotension (eg, antihypertensive agents), and persons who are dehydrated.5 Cardiac disorders. Exacerbation or acute development of congestive heart failure and new onset of decreased left ventricular ejection fraction (LVEF) have been reported in patients receiving treatment with bortezomib, including those with no known risk factors for

Table 3

decreased LVEF. Thus, patients at risk for the development of heart disease or those with a history of existing heart disease should be monitored closely.5 Pulmonary disorders. Reports of acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, acute respiratory distress syndrome, and lung infiltration, have been noted among patients receiving treatment with bortezomib.5 Reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome (RPLS), a rare, reversible neurologic disorder that can present with seizure, hypertension, lethargy, headache, blindness, confusion, and other visual and neurologic disturbances, has been reported in patients receiving bortezomib therapy. Bortezomib should be discontinued in patients who develop RPLS that has been confirmed by brain imaging, preferably magnetic resonance imaging.5 Gastrointestinal events. Nausea, diarrhea, constipation, and vomiting, at times requiring the use of antiemetic therapy and antidiarrheal agents, have been reported in patients receiving bortezomib. In order to prevent dehydration, fluid and electrolyte replacement should be administered to these patients.5 Thrombocytopenia and neutropenia. Bortezomib is associated with the development of thrombocytopenia and neutropenia that follows a cyclical pattern, with nadirs that generally occur following the last dose of each cycle and typically recover prior to initiation of the next cycle of therapy. This cyclical pattern remained consistent over 8 cycles of twice-weekly

Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy

Severity of peripheral neuropathy signs and symptomsa

Modification of dose and regimen

Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia), without pain or loss of function

No action

Grade 1 with pain or grade 2 (moderate symptoms; limiting instrumental ADL)b

Reduce bortezomib to 1 mg/m2

Grade 2 with pain or grade 3 (severe symptoms; limiting self-care ADL)c

Withhold bortezomib therapy until toxicity resolves; when toxicity resolves, reinitiate with a reduced dose of bortezomib at 0.7 mg/m2 once weekly

Grade 4 (life-threatening consequences; urgent intervention indicated)

Discontinue bortezomib

Grading is based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money. c Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. ADL indicates activities of daily living; NCI, National Cancer Institute. Source: Reference 5. a

VALUE-BASED CANCER CARE

FEBRUARY 2012

Continued from page 45

therapy, with no evidence of cumulative thrombocytopenia or neutropenia observed. In patients experiencing thrombocytopenia, platelet counts should be monitored prior to the administration of each dose; an adjustment in dose and/or schedule may be required. There have been reports of gastrointestinal and intracerebral hemorrhage associated with the use of bortezomib.5 Tumor lysis syndrome. Tumor lysis syndrome may occur with the use of bortezomib because the agent is cytotoxic and can rapidly kill malignant cells. Patients with a high tumor burden prior to therapy may be at a higher risk for the development of tumor lysis syndrome.5 Hepatic events. Acute liver failure has occurred in bortezomib-treated patients receiving multiple concomitant medications and in those with serious underlying medical conditions. Other hepatic events reported with the use of bortezomib include elevations in liver enzymes, hyperbilirubinemia, and hepatitis.5 Hepatic Impairment Because bortezomib is metabolized by the liver, exposure is increased in patients with moderate or severe hepatic impairment. Therefore, such patients should be started on reduced doses of bortezomib and closely monitored for the development of toxicities.5 Use in Pregnancy Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib.5 Dosing Bortezomib is for IV or SC administration only and should not be administered by any other route. The recommended starting dose of bortezomib is 1.3 mg/m2 for both SC and IV forms of administration. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume of drug to be administered. With IV administration, the recommended concentration of bortezomib is 1 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL.5 Patients with previously untreated MM. In patients with previously untreated MM, bortezomib is administered in combination with oral melphalan and oral prednisone for a total of nine 6-week treatment cycles. In cycles 1 through 4, bortezomib is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5

through 9, bortezomib is administered once weekly (on days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of bortezomib.5 Patients with relapsed MM or mantle-cell lymphoma. In patients with relapsed MM or mantle-cell lymphoma, bortezomib 1.3 mg/m2 per dose is administered twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21). For extended therapy of more than 8 cycles, bortezomib may be administered according to the standard schedule or on a maintenance, once-weekly schedule for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period.5 Dose modifications. A patient’s platelet count should be ≥70 ⳯ 109/L and his or her absolute neutrophil count should be ≥1.0 ⳯ 109/L before receiving any cycle of therapy with bortezomib in combination with melphalan and prednisone. All nonhematologic toxicities should have resolved to grade 1 or to baseline level.5 Dose modification guidelines for patients with relapsed MM or mantle-cell lymphoma state that bortezomib therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hematologic toxicities excluding neuropathy, which is discussed separately. Once the symptoms of the toxicity have resolved, bortezomib therapy may be reinitiated at a 25% reduced dose.5 Administration Precautions When the SC route of administration is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.5 If local injection-site reactions occur after SC bortezomib administration, a less-concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be used for SC administration. Alternatively, the IV route of administration may be considered.5 ■ References 1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. 2. Munshi NC, Anderson AC, Bergsagel PL, et al; for the International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696-4700. 3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Multiple Myeloma, Version 1. 2012. www.nccn.org. February 5, 2012. 4. CenterWatch. Drug information. Velcade (bortezomib). www.centerwatch.com/drug-information/fda-approvals/ drug-details.aspx?DrugID=830. Accessed February 5, 2012. 5. VELCADE prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012. 6. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

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NO. 1

April 20-22, 2012 • Le Westin Montreal Montreal, QC, Canada CO-CHAIRS

PROGRAM OVERVIEW The goals of this interactive, CME/CE-certified meeting are to update participants on advances in the field of cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, and ongoing research. In addition to didactic lectures, this program will also include debates and discussions of controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, question-and-answer sessions, poster sessions, as well as workshops focusing on future strategies for the treatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This is the inaugural meeting of what is envisioned as an annual global forum to facilitate integration of contemporary and evolving standards of care for the optimal management of patients with cutaneous malignancies into clinical practice for oncologists and dermatologists.

Kim A. Margolin, MD

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, Washington

TARGET AUDIENCE This global educational program is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to attend.

ACCREDITATION INFORMATION Teresa Petrella, BSc, MD, MSc, FRCPC

SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.5 contact hours. REGISTERED PHARMACY DESIGNATION Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.5 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-089-L01-P.

Medical Oncologist Chair, National Cancer Institute of Canada Melanoma Group Chair, Melanoma Site Group Odette Cancer Centre Assistant Professor, University of Toronto Toronto, Ontario, Canada

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.

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