VBCC March 2012, VOL 3, NO 2 by Value-Based Cancer Care

MARCH 2012 VOL 3 NO 2

www.ValueBasedCancerCare.com

AMA Delegates and Oncologists Wilshire Oncology Medical Home Balk at ICD-10 Implementation and insurance coverage major concerns Pilot: Reengineering Cancer Care Cost By Caroline Helwick BEST PRACTICES

Provider-payer collaboration

Interview with Linda Bosserman, MD, Clinical Oncologist and President of Wilshire Oncology Medical Group, La Verne, CA

Over the past several years, Wilshire Oncology has transformed its patient care to patient-centered medical home management, working with the largest payer in California. Value-Based Cancer Care (VBCC) asked Dr Bosserman to describe the new pilot and what has led to this reengineering of cancer care. VBCC: Can you briefly describe your practice and the recent transformation in care management? Linda Bosserman, MD: Our group has been in southern California for 54 years, starting in Los Angeles, then moving east to now serve what is referred to as the Inland Empire—eastern Los Angeles County, San Continued on page 10

Everolimus Has Minimal Economic Impact on Treatment of Pancreatic NETs Model shows a $22,000 overall increase for typical health plan By Caroline Helwick San Francisco, CA—Using a prediction model to analyze the impact of adding targeted agents to the treatment of pancreatic neuroendocrine tumors (pNETs), everolimus (Afinitor) had a minimal overall impact on

healthcare expenditures, by reducing infusions and surgical procedures costs, according to a study presented at the 2012 Gastrointestinal Cancers Symposium. Continued on page 18

New Orleans, LA—According to the American Medical Association (AMA) and many oncologists, the International Classification of Diseases, Tenth Revision (ICD-10) diagnostic coding system will be a needless and expensive burden to oncology practices, without enhancing patient care. ICD-10 is being developed by the World Health Organization. The Centers for Medicare & Medicaid Services (CMS) ordered the switch in 2009 as part of carrying out the Health Insurance Portability and Accountability Act. At their 2011 interim meeting last

fall, the House of Delegates of the AMA voted to “work vigorously” to stop the implementation of ICD-10 to “reduce its unnecessary and significant burdens on the practice of medicine.” With that goal in mind, James L. Madara, MD, Executive Vice President and CEO of the AMA penned a letter to Health and Human Services (HHS) Secretary Kathleen Sebelius, MPA, on February 2. Citing the government’s intention to streamline regulations, Dr Madara said that, “This is a perfect opportunity for HHS to make good on its comContinued on page 22

External Beam Radiation More Toxic, Costlier than Brachytherapy or Prostatectomy By Wayne Kuznar San Francisco, CA—In a retrospective long-term comparative analysis of 3 prostate cancer treatment strategies, treatment with external beam radiation therapy (EBRT) was more toxic and costlier than prostatectomy and brachytherapy, according to Cleveland Clinic researchers who presented their data at the 2012 annual

Genitourinary Cancers Symposium. In most other studies, the reported treatment-related toxicity data cover a follow-up period of only 5 years, said lead investigator Jay P. Ciezki, MD, Staff Physician, Cleveland Clinic. By contrast, the Cleveland Clinic study involved a median follow-up of 71 Continued on page 13

INSIDE IN THE LITERATURE

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Family history of gastric cancer increases survival in advanced disease Ruxolitinib boosts QOL outcomes in myelofibrosis VALUE PRoPosITIoNs

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NICE misapprehending value of cancer drugs MEETING HIGHLIGHTs

GU cancer symposium . . . . . . . . . . .13 GI cancer symposium . . . . . . . . . . . .18 ASH annual meeting . . . . . . . . . . . . .26

BREAsT CANCER

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Drug costs versus total cost of care Oncotype DX assay cost-effective in ER-positive cancer HEALTH PoLICY

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The costs of implementing ICD-10 in oncology

VBCC PERsPECTIVE . . . . . . . . . . . . .32

Specialty pharmacy and value-based cancer care CHEMoTHERAPY 2.0

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Chemotherapy sequencing chart

NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

SC (n=148) IV (n=74)

ORR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. †

Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

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

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. 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 PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. 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(5):431-440.

FDA UPDATE FDA Updates Imatinib’s Label to 36 Months of Use after Removal of GIsT The US Food and Drug Administration (FDA) approved an updated label for imatinib (Gleevec; Novartis) for the use of the drug in adults after the surgical removal of CD117-positive gastrointestinal stromal tumors (GIST). The FDA now recommends extending treatment with imatinib to 36 months instead of the current standard of 12 months. This approval, processed under a priority review, highlights the new data from a phase 3 clinical trial showing an increased overall survival (OS) in patients using imatinib for 36 months compared with 12 months. The use of the drug for 36 months significantly reduced (by 54%) relapsefree survival compared with the 12month use (P <.001). In addition, 36 months of treatment reduced the risk of death by 55% compared with 12 months of treatment. The median time of follow-up was 42 months for relapse-free survival and 48 months for OS. At 60 months, 92% of patients who received 36 months of imatinib were alive compared with 82% of those who received the drugs for 12 months. “Although originally approved in the metastatic disease setting, this subsequent trial has demonstrated that longer use of Gleevec can prolong patients’ lives in earlier disease settings,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA. (January 31, 2012)

House Introduces Bill to Expedite FDA Drug Review A new House bill—the Drug Shortage Prevention Act (H.R. 3839)— received bipartisan support to expedite the FDA review of drugs in shortage, improve communication within the agency and with stakeholders about possible shortages, and increase Drug Enforcement Administration (DEA) quotas for medications in short supply. This legislation includes the following short-term fixes to the drug shortages: • Requiring the FDA to identify drugs that are vulnerable to shortages and mandate expedited review and approval; the FDA would be required to expedite review of changes to manufacturing processes of drugs in shortage, and expedite approval of an alternative supplier • The FDA will notify distributors of an imminent critical drug shortage, while allowing the agency to withhold notification to a distributor determined to be stockpiling, price gouging, or engaging in other illegal activities related to distribution of a drug in shortage; furthermore, the FDA would have to develop a sys-

tem to notify the public when a drug is added to the drug shortage list • Mandating closer communications between the FDA’s regulatory staff and its drug shortage team and communicating any new concern identified about a critical drug, including possible manufacturing problems,

within 1 business day to the FDA drug shortage office, and within 5 business days to manufacturers • The Attorney General will determine whether it is appropriate to increase ≥1 DEA quotas to address a drug shortage, and mandate that the DEA and FDA increase the quota for con-

trolled substances on the shortage list • The Secretary of Health and Human Services will determine the logistics associated with creating a national contingency plan in the event of a critical drug shortage, including the creation of a national stockpile for these drugs. (January 31, 2012) ■

Brief Summary INDICATIONS: 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.

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

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/ postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been

VALUE-BASED CANCER CARE003399_milpro_schcp_ahdb_fa1.indd I MARCH 2012

isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. (continued)

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IN THE LITERATURE BRAF Inhibitors Linked to squamous-Cell Carcinoma in Patients with RAS Mutations As many as 15% to 30% of patients who receive BRAF inhibitors (eg, vemurafenib, dabrafenib) for the treatment of metastatic melanoma develop nonmelanoma skin cancers. Data from

a new study suggest that this paradoxical effect may be caused by squamous-cell carcinoma cell lines with RAS mutation that proliferate on exposure to these drugs (Su F, et al. N Engl J Med. 2012;366:207-215). A molecular analysis identified oncogenic mutations, including HRAS,

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). 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.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/ prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

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KRAS, NRAS, CDKN2A, and TP53, in lesions of patients in 3 phase 1-3 studies. All patients had metastatic melanoma with BRAF V600 mutation, and all received vemurafenib therapy; the analysis included 11 initial patients plus a validation set of 14 samples from 12 patients. All samples were analyzed

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

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

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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for RAS mutations. Among the 23 patients, 78% had a history of chronically sun-damaged skin, and 17% had a history of cutaneous squamous-cell carcinomas or keratoacanthomas. Of all samples, 60% had RAS mutations. Among these, 12 of the 13 initial specimens and 4 of the 8 validation samples had HRAS mutations, with HRAS Q61L being most prevalent. The effects of BRAF inhibitors on these HRAS mutations were analyzed by comparing the murine cell line B9, which harbors the HRAS Q61L mutation. In each of the 3 studies, exposure to vemurafenib led to an increased proliferation of HRAS Q61L mutant cell lines caused by a paradoxical increase in oncogenic MAPK-pathway signaling in those cells. Vemurafenib, which was recently approved by the US Food and Drug Administration for malignant melanoma, appears to exacerbate preexisting nonmelanoma skin cancer. The authors of the study outlined the mechanism by which vemurafenib paradoxically potentiates skin cancers. It appears that the drug enhances MAPK activity leading to RAS gene mutations, a driver oncogene in approximately one third of cancers. This effect, however, can be blocked with the use of MEK inhibitors. This discovery may lead to the development of BRAF inhibitors that do not stimulate MAPK and RAS mutations.

statins Have Protective Effects Against Hepatocellular Cancer in HBV Infection Several studies have suggested that statins may have protective effects against cancer. The results of the first study to investigate the association between statin therapy in patients with chronic hepatitis B virus (HBV) infection and the risk for hepatocellular carcinoma (HCC) were recently published (Tsan YT, et al. J Clin Oncol. 2012;30:623-630). This population-based study involved 33,413 patients with HBV infection who were tracked between 1997 and 2008 to identify those who developed HCC. Data were collected on statin prescriptions (simvastatin, lovastatin, atorvastatin, fluvastatin, pravastatin, and rosuvastatin) for all patients before a diagnosis of HCC. A total of 1021 cases of HCC were diagnosed among the patients with HBV infection during the follow-up period. Results showed a dose-response relationship between statin use and the risk for HCC, indicating a reduced risk with a statin. Furthermore, there was a trend (P for trend <.001) toward risk reduction with increasing cumuContinued on page 7

2:18 PM www.ValueBasedCancerCare.com I3/5/12

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 Editor 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

GU CANCERS SYMPOSIUM

HEALTH POLICY

Vigorous exercise reduces prostate cancer risk, long-term vitamin E increases risk More….

The costs and complications of implementing ICD-10 in oncology The end of health insurance companies?

GI CANCERS SYMPOSIUM

BREAST CANCER

For pancreatic cancer, neoadjuvant chemoradiation cost-effective versus surgery first Oncotype DX assay and colon cancer More….

Nab-paclitaxel requires less growth factor support in metastatic disease, reducing total costs Oncotype DX assay: cost considerations More….

ASH ANNUAL MEETING Burden of febrile neutropenia in NHL exceeds $11,000 per episode Novel B-cell receptor inhibitor effective in CLL First-line choices for high-risk MDS not always supported by evidence More….

CHEMOTHERAPY 2.0 A sequencing chart for administering chemotherapy

CANCER DRUGS Vismodegib: a new treatment option for basalcell carcinoma

VBCC PERSPECTIVE The challenges of specialty pharmacy in oncology

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.

VALUE-BASED CANCER CARE

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

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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 statins Have Protective Effects Against... Continued from page 5

lative daily dose of statin. In addition to overall use of statins, individual statin use (except for pravastatin) also had a significant protective effect in patients with HBV after adjusting for risk of HCC. The mechanism related to the protective effects of statins in HCC risk reduction is not yet understood.

therapy with ruxolitinib or to best available therapy. The primary end point was the proportion of patients reaching a ≥35% spleen volume reduction by week 48; the main secondary end point was the percentage of patients achieving this reduction by week 24. Imaging was used to assess spleen volume reduction.

At week 48, 28% of patients receiving the JAK inhibitor achieved at least a 35% reduction in spleen volume compared with 0% in the best available therapy cohort. At week 24, these percentages were 32% and 0%, respectively. The median palpable spleen length decreased by 56% at week 48 with JAK inhibition compared with a 4%

Ruxolitinib Boosts Qualityof-Life outcomes in Myelofibrosis The treatment options for myelofibrosis are very limited, with ruxolitinib the potent Janus kinase (JAK) 1 and 2 inhibitor, being the first and only drug approved specifically for this condition late last year. This study compared its efficacy and safety with the best available therapy for patients with myelofibrosis (Harrison C, et al. N Engl J Med. 2012;366:787-798). A total of 219 patients with primary myelofibrosis were randomized to

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

Family History of Gastric Cancer Associated with Improved survival in Patients with Advanced Cancer Family history of gastric cancer increases the risk for the disease and its recurrence. Different studies provided conflicting evidence regarding the impact of family history of the disease on the chance for survival after gastrectomy. A new study has now investigated the prognosis of patients with gastric cancer who have a family history of the disease and have undergone gastrectomy (Han MA, et al. J Clin Oncol. 2012;30:701-708). This retrospective review included 1273 patients with gastric cancer who had undergone gastrectomy between 2001 and 2005 and had a first- or second-degree relative with a family history of the disease. Patients were followed up through 2009 for death or recurrence. A total of 263 patients (20.6%) had first-degree relatives with a history of gastric cancer. Firstdegree family history of gastric cancer was associated with significant improvements in disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS) (P = .012, .006, and .005, respectively) compared with those without family history of the disease. In patients with stage III or IV gastric cancer, firstdegree family history was associated with a significant risk reduction of recurrence or mortality and significant improvements in DFS, RFS, and OS. However, family history did not improve the prognosis of patients with stage I or II disease.

increase in the best available therapy. The median duration of response has not yet been reached with ruxolitinib; 80% of patients in that group are still showing a response at 12-month follow-up. Quality-of-life (QOL) measures were improved and the myelofibrosis-relat-

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 Ruxolitinib Boosts Quality-of-Life outcomes... Continued from page 7

ed symptoms were reduced in the ruxolitinib group compared with the other cohort. The most common grade ≥3 adverse events in each group were thrombocy-

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.

topenia and anemia; 1 patient in each group discontinued treatment because of thrombocytopenia. Nonhematologic events were mild and rare; 2 cases of myeloid leukemia occurred in the best available therapy group. Although overall survival has not been documented yet with ruxolitinib

(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

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therapy in this study, JAK inhibition in this patient population improves patients’ QOL and significantly reduces disease symptoms. Additional studies are needed to investigate potential survival benefit and other safety and efficacy issues with this new drug therapy.

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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Adding Bevacizumab to Neoadjuvant Chemotherapy Increases Complete Response Rates Findings from 2 separate studies have shown that adding the vascular endothelial growth factor inhibitor bevacizumab to adjuvant chemotherapy regimens improves response rates in patients with early-stage breast cancer (Bear HD, et al. N Engl J Med. 2012;366:310-320; von Minckwitz G, et al. N Engl J Med. 2012;366:299-309). In the first study, 1206 women with primary operable HER2-negative breast cancer were randomized to receive docetaxel, alone or in combination with capecitabine or gemcitabine, every 3 weeks, followed by doxorubicin plus cyclophosphamide every 3 weeks, for 4 cycles. In addition, 604 of these patients also received bevacizumab with each of the first 6 chemotherapy cycles. The primary end point was the pathologic complete response (pCR). In the German Breast Group study, 1948 women with untreated HER2negative breast cancer were randomized to receive neoadjuvant epirubicin and cyclophosphamide every 3 weeks, followed by docetaxel every 3 weeks, for 4 cycles. Half of this group also received bevacizumab for 8 cycles, beginning with the first cycle of epirubicin and cyclophosphamide. In the first study, 59% of the tumors were hormone receptor (HR)-positive. Among 1186 evaluable patients, the addition of capecitabine or gemcitabine to docetaxel therapy did not increase the pCR rate over docetaxel alone, but both were associated with increased toxicities. Compared with patients who did not receive bevacizumab, however, those who received bevacizumab had significant improvement in pCR in the breast (28.2% vs 34.5%, respectively) but not in the breast and nodes. The pCR with bevacizumab was more pronounced in women with HR-positive tumors (23.2% vs 15.1%, respectively). In the second study, a similar overall benefit of bevacizumab was demonstrated. The pCR was greater in patients who received bevacizumab than in those who did not (18.4% vs 14.9%, respectively). However, the benefit of bevacizumab was significantly greater only in patients with triple-negative tumors (39.3% vs 27.9%, respectively), not in those with HR-positive tumors. The improvement in the pCR rate implies that more women would be spared primary surgery for their breast cancer. In both groups, pCR was higher in the bevacizumab group. However, it is unclear whether this increased response will translate into prolonged survival. ■

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VALUE PROPOSITIONS UK Researcher Charges NICE of Misapprehending Value of Costly Cancer Drugs

Despite Lack of Value, Many Providers Recommend Ovarian Cancer Screening

Professor Jonathan Waxman, of Imperial College London, an expert in prostate cancer who founded the Prostate Cancer Charity in England and helped garner support for cancer treatment, has denounced the refusal of the UK National Institute for Health and Clinical Excellence (NICE) to approve the 2 new and expensive prostate cancer drugs approved last year in the United States, saying that NICE “has overregulated and proscribed drugs that offer real advances to people with cancer.” He charges that NICE has blocked the approval of several new cancer drugs because of the agency’s faulty assessment of cost-effectiveness of cancer therapies. Prof Waxman said the way NICE evaluates cost is wrong. He told the BBC, “I would argue that they [the 2 prostate drugs] have been disallowed—banned—by NICE on the basis of assessment which is not a true financial costing of the worth of the drugs.” He warned that drug companies may soon stop seeking approval for their medications in the United Kingdom, which will be a disaster for patients. Agreeing with Prof Waxman, GlaxoSmithKline’s Chief Executive Officer Sir Andrew Witty said that delaying approval of innovative new drugs was “a false economy,” suggesting that “the drug bill is only 8% to 10% of the total healthcare bill, and what is being lost in this stampede for cost cuts is any kind of strategic thoughtfulness.” BBC Radio 4; February 25, 2012.

Results of a new survey of primary care physicians (PCPs) show that 1 in 3 PCPs believe that ovarian cancer screening is safe and effective, contrary to current evidence. The survey was published in the February 7, 2012, issue of Annals of Internal Medicine. Substantial evidence suggests that such universal screening is unnecessary and may involve risks associated with surgeries and other procedures because of frequent false-positive test results, as well as the associated unnecessary costs of such testing. A total of 65% of providers indicated that they sometimes or often order ovarian screening test for women at medium-risk level, and 29% of physicians said they did so for women at low risk. “These findings are cause for concern, given that the risks of ovarian cancer screening outweigh the benefits,” said lead investigator Laura-Mae Baldwin, University of Washington. NCI Cancer Bulletin, Vol 9, No 4; February 21, 2012.

Prostate Cancer Foundation Promotes Innovation in Young Investigators The Prostate Cancer Foundation (PCF) is expanding its efforts to encourage innovation in prostate cancer research. Its 2012 Young Investigator Awards have already funded 15 research grants internationally in the attempt to attract best innovations in the field. Each award recipient receives $225,000 during a 3-year period. In addition, each recipient institution matches the funding dollar for dollar, bringing each award to a total of $450,000 for every recipient. “PCF-supported young investigators have changed the scope of prostate cancer research, advancing treatment sciences and improving the lives of patients worldwide,” said Howard Soule, PhD, Chief Science Officer and Executive Vice President, PCF. Santa Monica, CA; February 22, 2012.

Online Genetic Testing Registry New Tool from NIH An online tool launched by the National Institutes of Health (NIH) will help patients, providers, and researchers navigate the rapidly growing landscape of genetic testing, many of them associated with cancer therapy. The Genetic Testing Registry (GTR) is available at www.ncbi.nlm. nih.gov/gtr/ and can be accessed by the public. “It is a tremendous resource for all who are struggling to make sense of the complex world of genetic testing,” said NIH Director Francis S. Collins, MD, PhD. The GTR will be updated frequently, using data submitted by genetic test providers. The GTR can be searched by tests, conditions, genes, genetic mutations, and laboratories; it will also have links to practice guidelines and a variety of genetic and literature resources through the National Library of Medicine. NIH News, National Institutes of Health; February 29, 2012.

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Cancer Center Launches Personalized Medicine Institute Moffitt Cancer Center in Tampa, FL, has announced it is launching its Personalized Medicine Institute to advance the fight against cancer, and implementing the promise of personalized cancer care medicine by focusing on innovative biotechnology with its biotechnology subsidiary M2Gen. Moffitt’s Board Chairman Robert Rothman said that “the time is now, because cancer research and treatment is at an inflection point that requires the right mix of visionary leadership and collaboration to realize the promise of personalized cancer care for patients everywhere.” Moffitt’s Chief Executive Officer William S. Dalton, PhD, MD, will focus on the establishment of the institute, highlighting the value of such an approach. “Moffitt’s investment in Total Cancer Care has positioned us to realize the dream of cancer therapy based on the right treatment, for the right patient, at the right time. Our unique clinical trial matching process has been recognized by an issued patent. M2Gen is partnering with Merck and other pharmaceutical and biotechnology companies to launch the first clinical trials in which patients have been recruited using the world’s largest cancer-focused biorepository,” Dr Dalton said. Moffitt Cancer Center press release; February 22, 2012.

Novel Biologics Will Reshape Cancer Therapy by 2018, Affordability Key Challenge Researchers at Espicom Business Intelligence, a medical and pharmaceutical market analysis company, predict that the development of novel biologic approaches to drug therapy will bring “a sea change” to the approach to cancer therapy, by focusing on controlling solid tumors and the introduction of new drugs that target new pathways. These drugs could be on the market in the next 5 years, the researchers suggest, and that is expected to change the face of cancer therapy, based on current directions in biologic drug research. “Novel approaches in the development of new drugs along with broader mechanism of action for existing therapeutic approaches will bring real clinical benefits to patients and will have fewer side effects. The challenge for industry and for society alike will be the affordability of these products,” said Sue Viney, Senior Oncology Analyst at Espicom. Chichester, UK; Targeted Cancer Drugs; February 9, 2012.

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BEST PRACTICES

Wilshire Oncology Medical Home Pilot... Bernardino County, and Riverside County. Many hospitals and small oncology groups serve different medical groups and medical populations throughout this region. Initially our group came together around clinical research. As managed care came in and dominated the Inland Empire, we began to work in the managed care space. It is a long learning process for doctors, who are often rugged individuals, to effectively interact with colleagues and their different payment systems, particularly trying to articulate what the oncology needs are and what quality oncology care is. This happened over a time, when it became possible to implement electronic medical records (EMRs). We began using EMRs in 2000. In 2003, we put it in an oncology-specific system, then in 2005, we converted to a customizable oncology-specific EMR. We initiated monthly group meetings to ask, “What are the standards of care we need programmed? What information would we enter? How would we enter it? Who would enter it? What is important? What data could we study and understand about our care delivery?” We implemented our findings with the EMR and reengineered our practice as a result. We reconstructed staff positions to contribute to quality care, patient experience, and collecting a dataset that could be used to understand what we were doing and how we were doing it. We asked whether the right person was getting the right cancer care for the right disease, and what the associated outcomes and costs were. Our group developed a vision of what these records could look like. We began to think of medical care as something you could define, prove, and understand the outcomes and cost of. Our goal is also to ensure that patients have satisfaction with personalized care: by being educated honestly about their choices and outcomes, relieving side effects, and lowering their cost of care. Many EMRs do not have the detailed reporting capabilities that we all need to keep improving and looking at where we are spending money. With the new pilot and data from other large national networks, we will eventually be able to know what adjuvant therapies work for different tumors and for different age-groups of people with different comorbidities; things that clinical trials are not large enough or powerful enough to tell us. We can keep improving our care in America through data and analytics and outcomes.

VBCC: What is the approximate size of your center or clinic? Dr Bosserman: We are a part of US Oncology McKesson Specialty Health now. The network sees approximately 800,000 new patients annually, and we see 4500 new patients annually. We have many small centers in southern California. Over these years, we developed 6 private cancer center offices, 2 of which have radiation therapy, 1 has a PET CT, and all the offices have clinical research trials. Approximately 5 years ago, we took over all of the care for patients with cancer—inpatient and outpatient—for San Bernardino County, which is the largest geographic county in America, as well as one of the poorest. Then, approximately 3 years ago, we were asked to take over cancer care for Riverside County patients, because we had a proven program of data reporting and team work that we could integrate with their nursing, pharmacy, and medical staff to meet their growing patient care needs. We have standardized all treatment protocols to be cost-effective, reengineered all of our staff, and developed an extensive training and partnering program with mid-level providers at private sites which we extended to both county programs. We have 10 doctors and 8 mid-level clinicians (nurse practitioners and physician assistants) and are in the process of hiring 2 more physicians and 2 more mid-level providers. We run the county programs with 2 midlevel providers per doctor, plus a clerk. We standardized all of the charts; we work with the county pharmacists, nurses, and healthcare staff. We have brought private-practice efficiencies and data reporting to county medicine. In our first 2 years, we were up 450% in patient volume in the inpatient setting and 250% in the outpatient setting at the Riverside site alone. Both counties are experiencing significant growth because of the region’s high 26% uninsured rate and the ongoing 12% to 14% unemployment rates. VBCC: Who pays for all this? Dr Bosserman: In California, indigent care is most often paid for by the counties. It is provided most often by academic centers. We used all of our learning on the private side and our managed care experience to be able to serve the indigent patients cost-effectively. We help them with free care programs and all of the generic drug regimens and standardization we use in our private sites.

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In our first 2 years, we were up 450% in patient volume in the inpatient setting and 250% in the outpatient setting at the Riverside site alone. —Linda Bosserman, MD

VBCC: Was your EMR a big help in terms of efficiency? Dr Bosserman: Actually we have learned that EMRs do not save time or make doctors more efficient. Rather, they allow us to meet multiple needs at once. When we look at EMRs, they are very structured ways to collect data and generate reports. They help us take better care of the patient by our programming to prompt correct decision-making at the time of care and recording disease and patient details, warranted variations, symptoms and their management, triage and interval care, as well as end-of-life care. There is also a patient component to that, which for now we have patients fill out standardized reports and plan to move to electronic patient entry. VBCC: What is involved in standardized reports by patients? Dr Bosserman: We try to find out everything about new patients before they even come into the clinic. Then, patients on therapy are given forms to fill out before they return or on the day of the visit. The on-therapy form is a standard report that tells us everything that happened to him/her since the last treatment. Was the patient in the hospital, the emergency department, urgent care? What was it for? What are the patient’s current medications? Are there any new medications? What medications were stopped or started? What side effects did the patient experience? What does the patient want addressed or treated? Usually there are 3- to 4-week inter-

vals between therapy cycles. Our ontherapy reports ask patients about a standardized list of toxicities and their impact. This is a standardized way of making sure that if patients take the time to tell us what is happening and what has happened, we will then spend the office visit focusing on improving their health rather than collecting data. All of this reengineering forced us to ask, what is it we do? What is it that doctors do? A physician’s ultimate training is to analyze data and make decisions based on evidence to achieve the best outcomes and then communicate to the patient. Many people can help in that communication and reinforce it, and other clinicians can actually oversee the treatment plan, symptom management, and follow-up care. We train our mid-level providers one on one with us to work as clinicians at the fellow level of medical training. We have advanced oncology nurses who are highly skilled in symptom management, chemotherapy infusion, and oral chemotherapy management. Our medical assistants are brilliant at collecting and entering data and tracking down things, so when we see the patient, we are ready to help improve their health. We really try and make it as seamless as possible for the patient to get care. Active patient engagement is a key component in our care model. The reengineering process makes us think what is it we need to do for patients? What is it we have to do for our payers? VBCC: Can you elaborate on your work with payers? Dr Bosserman: When we stepped back and looked at how we were being paid for care, traditionally medical oncologists grew their practices, and all the extensive support services patients need, based on the margin of the drugs. From the 1980s through the 2000s, drugs became more expensive; there were larger margins, groups grew beautiful offices, we brought in a psychologist, and we developed extensive emotional, psychosocial, financial, and medical support. As the costs became greater and greater, Medicare, and then the private payers, cut the drug margin without raising the fees for the cognitive and support services that we provide to patients. It is the cognitive and support services that help patients get through, and manage their symptoms, and then at the end of life, help them understand when a treatment Continued on page 11

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Wilshire Oncology Medical Home Pilot... may not benefit them. When we put all of that together, we had managed care contracts where we learned to comprehensively manage costs in and outside of the office as well as our experiences with our team work in our county contracts. Approximately 4 or 5 years ago, we said, “We need to take this comprehensive care approach to the private payers, because our patients are being priced out of private insurance. Patient copays are going up, and it is becoming very unaffordable for our patients.” In response to growing cancer costs, private payers had implanted many work-arounds via third parties: specialty pharmacy delivery and oversight of drugs, care managers calling clinicians and patients from afar and trying to direct care they were uninvolved in at the community or practice level, and growing authorization programs with continuously expanding dataset requirements for every aspect of our cancer care. These health plan programs added costs and inefficiencies to our integrated team approach as well as frustrating delays for patients at a time they are already overwhelmed by their cancer diagnosis and intensive therapies. These programs were not working for the health plans nor for the clinicians and became a driver for physicians joining larger hospital systems to have more favorable relationships with payers and more administrators to deal with the crushing administrative burdens. We felt that community oncology was the best option for long-term price controls to manage patient copay and payer costs, but a new payment model was needed. We contacted the largest payer in our practice, which is Anthem Blue Cross WellPoint of California, and brought them to a meeting in our office. They came to our practice, and they thought our ideas were very interesting, but health plans have huge responsibilities to actuarially validate things. The first thing that most doctors do not understand is that health plans are organized into silos. There are medical directors whose responsibility is to ensure that medical policies are followed consistently and appropriately, and that medical policies are up to date. Then there is the contracting team that negotiates the contract. Their incentives are about keeping the contract rates under control with whatever the guidelines are. Then we have the pharmacy team trying to manage pharmacy. In my observation, no one is connected. Approximately 10 years ago, when

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the health plans began to see costs soar, we all realized that almost 80% of the costs are associated with approximately 10% to 20% of the patients, particularly those with the 5 top chronic illnesses—cancer, heart disease, diabetes, obesity, and hypertension—and in the younger populations, asthma and respiratory diseases. We then saw the rise of disease management companies. Some nurses would call patients, or they would send programs out. They had many people coming to the health plans with their solutions, which were not about improving their health but about saving money.

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More decisions on treatment are based on what I call “tumor features.” In breast cancer, it is whether the patient is hormone-sensitive, whether she is HER2-positive. In lung cancer, it depends whether the patient has squamous-cell carcinoma or adenocarcinoma. In the explosion that is personalized medicine, the features of the tumor will determine which targeted therapies, and in what combination and order, will give the patient the best outcome. We convinced our payer that we had those kinds of data at the practice, and health plans are beginning to ask clinicians to enter this information online to get treatment authorizations.

We launched our pilot in August 2011; it was to be a 1-year pilot, but we are already extending it. We are showing very substantial savings. There are 6 points that evolved and developed into our medical home.

One of the things we emphasized when we brought the health plan to our office was that we actually manage these patients. We have been doing it in managed care. We work closely with our hospitalists, our primary care doctors, and our surgeons, and we have many examples of how much money we were able to save. Our nurses know when our patients cannot open their pill bottles or if they need things written down. We will then put the pills in a pill dispenser for them, or we call their kids and say, “Mom needs some help here.” We really know our patients, and you cannot get that from case management from afar. VBCC: What is your oncology medical home pilot? Dr Bosserman: We launched our pilot in August 2011; it was to be a 1year pilot, but we are already extending it. We are showing very substantial savings. There are 6 points that evolved and developed into our medical home:

Patient-focused approach. The health plan does not have a description of its full population. Who is it that the oncologists are seeing? What is their age, performance status, comorbidities, actual diagnosis, and disease stage?

Health plans need it to understand their population, but we have that data and can report it along with the therapies and outcomes.

Guideline-based therapy and supportive care. All people receiving therapy can receive the most costeffective therapy. We know that many drug regimens have the same outcome, and a study from US Oncology showed that you can save 35% of the costs, with the same outcome in lung cancer. We know that this is true for a lot of different cancers. These drugs tend to be the generic, the inexpensive or lessexpensive regimens. If these drugs have the same outcome, we wanted to make sure doctors were paid to give the right treatment, and not the one that has the largest margin to pay the rent and pay the staff. We showed these models to the health plan. All patients will get cost-effective therapy following evidence-based guidelines, for the treatment and supportive care. Supportive care is getting to be just as expensive. Nausea therapies, therapies for bone metastasis, and red or white cells, all have to be used appropriately.

Interval care management. We see a lot of the small doctor groups that do not have many support staff or

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nursing because of cutbacks. If the patient gets a treatment, and gets incredibly sick, he/she comes into the hospital for 10 days. The doctor then bills for 10 days of hospital care. But this pattern is truly not good for anyone. For instance, a patient with head and neck cancer who receives combined chemotherapy/radiation needs an early feeding tube, education, home care from day 1, extra care for hydration and nutrition, and management of their electrolytes. This type of care avoids all avoidable hospitalizations and emergency department visits. The impact of that is the patient gets much better care. The patient is kept healthier and feeling better. This centers everything we are doing on helping the patient minimize suffering and stay as healthy as possible during therapy, and it takes an experienced and coordinated oncology staff to do this. Interval care management is the nursing, the physician, the staff management, phone calls, and coordinated care. If someone is not well on Tuesday, we bring them in for a visit. We do not wait until Friday when the patient is so dehydrated that he has to be admitted. If the patient is getting anemic or needs a transfusion, we can manage it right away in the outpatient setting. We stay late in the office. If someone calls with a problem, we ask them to come to the office. We are staffed, and we are spending the time in our office managing and saving everyone the cost. Also, we know the patients. These are our patients, and we take responsibility to keep them as healthy as possible, relieve suffering, and improve their outcomes.

End-of-life care. We have always had the sense that no one wants to give chemotherapy to dying patients. Even before we have reached the end of our options, and another treatment is only going to bring suffering, it is time to have tough conversations about the limits of medicine. There is a time and a place where we can keep people feeling much better and improve the end of their life by being honest with them and offering palliative and hospice care. When you talk to patients, this is what they want. But there has never been the funding to spend multiple visits with these patients and their families, to have tough conversations about when the disease is not responding to therapy and share the information that the patient will do much better on palliative care only and hospice. Continued on page 12

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Wilshire Oncology Medical Home Pilot... With end-of-life support, we now get the same funding for care management as we would if they were getting active treatment. It means that the care and the time are valued by the health plan. It gives us time to talk about advanced-care directives before a medical crisis occurs. Patients can have their wishes respected and communicate with their families. They can initiate hospice with our coordination so they can be with their family and have dignity at the end of life.

Transparent data reporting. We now meet every 3 months with the health plan team to discuss all the data and the treatments as well as benchmarks. This has been illuminating. We have so little hospitalization and emergency department visits that it was eye-opening. We have been able to talk to the health plan about how we might even optimize that further. Depending on when patients go for transfusions, for example, if the hospital is full, they may have to wait, and they may end up staying overnight or have a full hospitalization for an outpatient procedure. We are able to transfuse in our office, so it gives us a way to look at how they could cover the blood expenses. Intravenous immunoglobulin (IVIG) has not had a stable price in the market. We never know if the codes will cover the costs of IVIG. Most doctors admit for IVIG, usually as an outpatient, but occasionally if the hospital is busy, the person can end up with an inpatient stay. The health plan can stabilize the price of this so we can move it back to the office. We can also track other cancerrelated care: we have tracked ommaya reservoir, thoracentesis, surgical procedures, and radiation. We can give a complete picture of care, unlike health plans claims data that may take 3 to 9 months. Then it depends on the accuracy of the codes people used for the hospital care. Our process is a very transparent way of saying, “Here is the population you are asking us to manage. Here is what they have. Here is what we did. Here is how we did it. Here are the complications. Here is how they were managed. Here are our costs. Let’s benchmark these and continuously work to provide cost-effective, high-quality care to your patients.” As a team, we are focused on keeping patients healthier and lowering their costs by minimizing things that are avoidable.

Quality measure validation. Although these ideas seemed great to

the health plan, they wanted to be sure that the quality we were providing was reportable against nationally validated quality measures. We are participating in meaningful use and PQRI (Physician Quality Reporting Initiative), as well as being active American Society of Clinical Oncology (ASCO) members. As part of our pilot, we are providing the health plan reports of our results against relevant, nationally validated quality measures. VBCC: Do you follow your own pathway, or the National Comprehensive Cancer Network (NCCN) or the ASCO guidelines? Dr Bosserman: Everything we do is consistent within NCCN and ASCO, but we delve deeper to make sure it is also the cost-effective regimen. Our pathways include US Oncology’s Level 1 Pathways and are consistent with the health plan’s medical policies. But within those ranges, there are vast differences in cost. In fact, we were just reviewing treatments for multiple myeloma. They go from a $25,000 regimen to a $120,000 regimen with the same outcomes.

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gency department and hospital care by taking better care of people. Now with our pilot, we have a system that supports that. We developed a payment system for care planning, so that the care plan, coordination with the surgeon, radiation, and evaluation for clinical trials, rehabilitation, or physical therapy—all that planning that is so important—is paid for, as well as the ongoing active care management for people receiving therapy and endof-life care. VBCC: Did you develop the payment method together with the payer? Dr Bosserman: We did an analysis of what the work components were. Then we showed Anthem Blue Cross WellPoint of California how much savings we thought there would be, by using more cost-effective regimens and preventing avoidable emergency department and hospital care. We agreed on a pilot study fee structure that, once we get all the data, we believe will have a much greater savings. This started 4 or 5 years ago. It was not a priority for the payers then, but they came and they listened. They then

We did an analysis of what the work components were. Then we showed Anthem Blue Cross WellPoint of California how much savings we thought there would be, by using more cost-effective regimens and preventing avoidable emergency department and hospital care. Often doctors never knew all the different costs that went together, especially as oral cancer drugs have become more prevalent in regimens. They can be $6000 to $10,000 per month for an oral drug. Before, the doctor drove the choice; now, we like to reflect value. If 2 or 3 treatments have the same outcome and similar toxicities, we give the one that is the least costly so the patient has the lowest copay, unless there is a reason for a warranted variation. But the lowest-cost regimens do not have enough margins in them to support the work of the practice. So, the second point at the medical home was to develop a payment plan that supported our delivery of the most costeffective, evidence-based therapy and supportive care regimens. When we look at the major savings in patient care going forward, we need to figure out how to avoid what is avoidable, especially avoidable emer-

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engaged their actuaries, who have to analyze the numbers and make sure that this is correct. They would poll our patients, look at regimens, and then compare us to other groups. All of this took months of validation, because health plans have very complex computer systems. We could provide data pretty quickly from our EMR and billing records. The medical directors have worked diligently with us. They have a lot of responsibilities, and we would have meetings every few months. The pilot took on various priorities at different times. Approximately 2 years ago, the medical director and the actuary came to our office and saw our nurses, and our mid-level providers and talked to patients. That was an important step. When you talk to a medical director who is not trained in oncology, details are overwhelming. Once we agreed on everything and the initial finances, what we are going to track and how

we were going to do this, it took a while to get all the legal issues in order. Because health plans have many requirements both to the state and to their parent organizations, it took another year to get all the processes in place to launch the pilot this past August. VBCC: Is this a model that other practices could follow? Dr Bosserman: It is completely scalable, teachable, and implementable. But one thing that all of us have to recognize is that the most important healthcare reform we need is to put the patient at the center of care, not the doctor. Now we are moving to models which can be just as financially rewarding to physicians, but it is going to be as leaders in groups and teams where everything is about the patient. That can be very scary for doctors who are rugged individualists who were trained to make their independent analysis, stand on their own, and defend their decisions. It is a huge challenge, but we are encouraged by younger doctors who are facile with data entry and EMR use as well as trained in more cooperative team care approaches. Our payer found out that our approach can work. Everybody has talked about accountable care organizations and the primary care model. Primary care can manage chronic diseases such as hypertension and diabetes, but cancer has to be managed by the oncologist. We have to manage with our primary care partners and in the medical home neighborhood, but our work can serve as a model for the kind of reengineering needed at the practice with standardization, staffing, electronics, data, and analytics. VBCC: How do you manage your data analysis? Dr Bosserman: Now that we are working with McKesson Specialty Health, we have their national actuaries and analytic team crunching all the data for us. They have taken our pilot work to a whole other level with their ability to bring in all the national benchmarking data and additional practice support for all the analytic reporting. For other health plans that want to do this, we have the tools, administrative, and analytic expertise to put these programs in place in partnership with practices. VBCC: What do you see as your main challenges and rewards? Dr Bosserman: The real challenge I Continued on page 39

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Personalized Vaccine Promising When Added to Sunitinib in Patients with Metastatic Renal-Cell Carcinoma By Wayne Kuznar San Francisco, CA—A personalized form of immunotherapy added to sunitinib (Sutent) treatment prolonged survival to beyond 30 months in almost half of patients with newly diagnosed, unfavorable-risk metastatic renal-cell carcinoma (mRCC), according to the results of an open-label phase 2 study presented at the 2012 Genitourinary Cancer Symposium. Only approximately 1 in 10 patients with unfavorable-risk mRCC treated with sunitinib, the standard first-line treatment for clear-cell mRCC, survive past 30 months. This new therapy, AGS-003, uses the patients’ own dendritic cells, loads them with mRNA amplified from a specimen of their tumor, and then reintroduces the cells into the body to stimulate the proliferation of cytotoxic T-lymphocytes targeted to each patient’s tumor, explained Robert A. Figlin, MD, Samuel Oschin Comprehensive Cancer Institute, CedarsSinai Medical Center, Los Angeles, CA. The amount of AGS-003 produced generates up to 5 years of treatment for each patient.

Photo Courtesy © ASCO/Todd Buchanan 2012

Overall survival extended by >30 months “The addition of AGS-003 to sunitinib is associated with encouraging long-term OS beyond 30 months.” —Robert A. Figlin, MD “AGS-003 combined with sunitinib is designed to overcome the inherent immune suppression in the tumor microenvironment and stimulate a durable clinical and immunologic response to the patient’s tumor,” said Dr Figlin. To this end, AGS-003 with sunitinib was tested in 21 adults with newly diagnosed mRCC who received no previous systemic therapy. All patients had intermediate- or poor-risk disease according to various criteria. Patients received sunitinib (4 weeks on, 2 weeks off) combined with AGS-003 (5 doses, used 3 weeks apart, and then every 12

weeks) until disease progression. Among this group, 38% of patients demonstrated an objective (partial) response, and 73% of evaluable patients showed an immunologic response (ie, increases in the numbers of CD28positive, CD45RA-negative T-cells). The estimated median overall survival (OS) was 29.3 months, and progression-free survival (PFS) was 11.2 months. By comparison, the PFS for sunitinib alone in similar patients is approximately 6 months, Dr Figlin noted. “The addition of AGS-003 to sunitinib is associated with encouraging long-term OS beyond 30 months,” he said. Some 43% of the patients receiving the dual agents achieved an OS beyond 30 months. Recent data indicate that approximately 13% of patients with nonfavorable-risk mRCC treated with sunitinib survive beyond 30 months. To date, the 21 patients have received more than 150 doses of AGS003. The observed adverse events were consistent with the experience with single-agent sunitinib in this disease. The only adverse event attributable to AGS-003 was grade 1 injection-site reactions. No patients showed evidence

at a glance ➤ An investigational vaccine, AGS-003, shows promise at increasing survival in patients with unfavorable-risk mRCC when combined with sunitinib ➤ AGS-003 plus sunitinib is designed to overcome the inherent immune suppression in the tumor microenvironment and stimulate a durable response ➤ In this phase 2 open-label study, the estimated median OS was 29.3 months, and PFS was 11.2 months compared with 6-months PFS with sunitinib alone in similar patients

of emergent autoimmune disease. These results support a planned international randomized phase 3 study that will compare AGS-003 plus standard therapy to standard therapy alone in 450 planned patients with newly diagnosed mRCC, Dr Figlin stated. ■

months, and some patients were followed up for as long as 16 years. The researchers combed the SEERMedicare database collected between 1991 and 2007 for patients with prostate cancer treated with EBRT, prostatectomy, or brachytherapy. “Using this database linkage that exists, we were able to associate billing codes with diagnoses. For example, we could associate billing codes not only with the treatmentrelated toxicity that patients experienced after therapy but also the billing code associated with the initial therapy cost,” said Dr Ciezki. “Using that information, we could compute a cost per patient-year with each treatment modality over time.” The stage of prostate cancer in individual patients was not available in the SEER database. The database uncovered 137,427 patients aged ≥65 years at the time of their prostate cancer diagnosis. Among this group, 43% received prostatectomy, 44.2% EBRT, and 12.4% brachytherapy. None of the patients received combined therapy.

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Photo Courtesy © ASCO/Todd Buchanan 2012

External Beam Radiation More Toxic, Costlier... “Using that information, we could compute a cost per patient-year with each treatment modality over time.” —Jay P. Ciezki, MD

Overall, 7.3% of patients required an intervention for a therapy-related adverse event. The cost per patientyear for the 3 procedures was: • $2557.36 for brachytherapy • $3205.71 for prostatectomy • $6412.29 for EBRT. In addition, treatment-related toxicities were most frequent with EBRT. Genitourinary (GU) toxicity occurred in:

• 3.4% who received brachytherapy • 6.7% who received prostatectomy • 7.1% of patients receiving EBRT. The most frequent GU toxicity was urethral stricture (3.6% of all patients). At 15 years, the rate of GU toxicity was 5% to 6% with prostatectomy and 12% to 13% with EBRT. Cauterization of rectal bleeding was the most common gastrointestinal (GI) adverse effect (0.8% of all patients). “Well over 50% of the patients who had any GI toxicity expressed that with GI bleeding, usually rectal bleeding,” said Dr Ciezki. GI adverse effects were also most frequent with EBRT (1.7%) compared with prostatectomy (0.1%) and brachytherapy (0.3%). “This is a fascinating piece of work,” commented Nicholas J. Vogelzang, MD, Chair and Medical Director, Developmental Therapeutics Committee, US Oncology. “It begs the question as to why brachytherapy, which won the trifecta [least toxic in 2 areas, and most effective], if you will, is less used, at 12%. The lower cost is

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impressive, and I’m surprised that we don’t see more use of that modality.”

“It begs the question as to why brachytherapy…is less used. The lower cost is impressive, and I’m surprised that we don’t see more use of that modality.” —Nicholas J. Vogelzang, MD

Dr Ciezki said that at the inception of brachytherapy in the 1990s, “the target population that was promoted as being appropriate for this was the low-risk group, and people with small prostates. This limited the population to whom you would be applying brachytherapy. With more experience, people have gotten to the point where they’re more comfortable offering it to more people.”—WK ■

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Dose Escalation of Axitinib as Second-Line Treatment of mRCC May Be Needed to Optimize Outcome By Wayne Kuznar despite previous therapy with either sunitinib, cytokines, bevacizumab, or temsirolimus-based regimens. Patients were randomized to axitinib at a starting dosage of 5 mg twice daily or to sorafenib 400 mg twice

dosage to >5 mg twice daily. Of the 37%, approximately half titrated their dosage to 7 mg twice daily and half to 10 mg twice daily; 20% of those who titrated their dosage had to reduce it subsequently.

“Due to interpatient variability in pharmacokinetics, a dose increase [of axitinib] to >5 mg twice daily may be required to optimize exposures and efficacy.”

Photo Courtesy © ASCO/Todd Buchanan 2012

San Francisco, CA—The dosage of axitinib, the standard second-line treatment for metastatic renal-cell carcinoma (mRCC), should be uptitrated in those patients who fail to achieve therapeutic blood levels on the standard 5-mg daily dosage, according to a new analysis of an international randomized trial presented at the 2012 Genitourinary Cancers Symposium. The primary results of the phase 3 AXIS study were reported previously and revealed a significantly longer progression-free survival (PFS) with axitinib versus sorafenib (mean PFS, 6.7 months vs 4.7 months, respectively) in patients with previously treated mRCC. In a secondary analysis of AXIS presented here, the clinical effect of dose titration on axitinib efficacy was evaluated. The results were presented by Brian I. Rini, MD, Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland. He also reported on the effect of the duration of prior first-line treatment and response on axitinib efficacy. AXIS included 723 patients with clear-cell mRCC who had measurable disease and who had progressed

—Brian I. Rini, MD

daily. The axitinib dosage could be increased to 7 mg twice daily and then to 10 mg twice daily in patients who met the criteria for dose titration (no toxicity grade >2 for at least 2 weeks and a blood pressure <150/90 mm Hg without antihypertensive medication). Patients receiving titrated doses were allowed to reduce the dosage of axitinib if toxicity occurred. Among patients assigned to axitinib, 37% met the criteria for dose escalation and were able to titrate their

Subtherapeutic exposure of axitinib was defined as an area under the curve at 12 hours <150 ng × hr/mL. With an increase in the dosage, axitinib drug levels increased to above the therapeutic threshold “not in all patients, but for many patients who were originally subtherapeutic at 5 mg twice daily,” said Dr Rini. “Dose titration with axitinib serves to normalize plasma exposure,” he explained. “We’re not increasing their drug levels above what patients at 5

mg get, but, rather, the drug levels are catching up to what some patients are able to achieve without titration.” The PFS was approximately the same in those who did or did not have dose escalation of axitinib, and it was superior to that in patients who received sorafenib in the second-line setting, said Dr Rini. “Due to interpatient variability in pharmacokinetics, a dose increase [of axitinib] to >5 mg twice daily may be required to optimize exposures and efficacy,” he said. Another finding from the secondary analysis was that PFS with previous sunitinib therapy appears to influence PFS with second-line vascular endothelial growth factor receptor tyrosine kinase inhibitors (ie, axitinib, sorafenib). Patients who received axitinib and had previously received sunitinib for ≥9 months had a median PFS of 6.3 months, whereas patients who received axitinib and had previously taken sunitinib for <9 months had a median PFS of 4.5 months. The trend toward superior PFS in patients who received sunitinib for >9 months was evident for both axitinib and sorafenib. ■

A Large Subset of Patients with Metastatic Prostate Cancer Go Untreated Racial and income disparities play a role in access to treatment San Francisco, CA—More than 1 in 10 patients with metastatic prostate cancer never receive anticancer treatment for their disease, according to an examination of the National Cancer Database. Lack of private health insurance and lower income play a role in the lack of anticancer treatment, based on a new analysis.

Alexander C. Small, a fourth-year medical student at Mount Sinai School of Medicine, New York City, sought to characterize the population of patients with advanced prostate cancer who did not receive treatment. He presented his findings at the 2012 Genitourinary Cancers Symposium. From the National Cancer Database,

at a glance ➤ More than 1 in 10 patients with metastatic prostate cancer never receive treatment for their disease

➤ In one study, with every $10,000 increase in income, the prevalence of untreated metastatic prostate cancer decreased by 7%

➤ Lack of health insurance, lower income play a role in the lack of anticancer treatment

➤ Blacks were 32% more likely and Hispanics were 41% more likely than whites to receive no treatment

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“While tumor biology likely plays a role with regard to rapid disease onset and progression, these data suggest that age, racial, and socioeconomic disparities exist in the treatment of metastatic prostate cancer.” —Alexander C. Small

he identified 59,074 patients diagnosed with stage IV prostate cancer between 2000 and 2008. Of these, 6582 (11.1%) received no anticancer therapy (including chemotherapy, hormonal therapy, radiation, or surgery).

With every 10-year increase in age, the prevalence of untreated metastatic prostate cancer increased 43%. Blacks were 32% more likely and Hispanics were 41% more likely than whites to receive no treatment. With every $10,000 increase in income, the prevalence of untreated metastatic prostate cancer decreased by 7%. Patients with Medicaid were 57% more likely to be untreated, patients with Medicare were 82% more likely to be untreated, and uninsured patients were 96% more likely to be untreated than patients with private insurance. “While tumor biology likely plays a role with regard to rapid disease onset and progression, these data suggest that age, racial, and socioeconomic disparities exist in the treatment of metastatic prostate cancer,” Mr Small concluded.—WK ■

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GU CANCERS SYMPOSIUM

Many Patients with mRCC Ineligible for Clinical Trials Outcomes are worse than for trial-eligible patients By Wayne Kuznar Patients received antivascular endothelial growth factor–targeted therapy for mRCC, which included sunitinib, sorafenib, bevacizumab, pazopanib, and axitinib. Patients were retrospectively deemed ineligible for clinical trials based on frequently used inclusion/exclusion criteria. All other patients were assumed to be potentially eligible for clinical trials. Photo Courtesy © ASCO/Todd Buchanan 2012

San Francisco, CA—A large number of patients with metastatic renal-cell carcinoma (mRCC) are ineligible for clinical trials and their clinical outcomes are inferior to those of patients who are trial eligible, according to a study presented at the 2012 Genitourinary Cancers Symposium. The data were presented by the International mRCC Database Consortium, a group that analyzed data from 17 international cancer centers on consecutive series of patients with mRCC. Clinical trials have strict eligibility criteria to maintain internal validity. “Many patients in everyday practice may not meet these criteria, yet in clinical practice, the results of these trials are being extrapolated to all patients with mRCC being treated with targeted therapy,” said Daniel Heng, MD, MPH, Medical Oncologist, Tom Baker Cancer Center, University of Calgary, Alberta, and lead investigator of the study. The consortium estimated the number of trial-ineligible patients who received targeted therapy and compared their outcomes with those of trial-eligible patients from the 17 cancer centers.

count <1500/mm3, and corrected calcium ≤12 mg/dL. Of 2076 patients with mRCC who received targeted therapy, 894 (43%) were deemed ineligible. The most frequent (13%) reason for exclusion was a KPS score <70%. More than twice as many patients deemed ineligible for clinical trials as those who were potentially eligible had a

“The discrepancies in clinical outcome should be taken into account when applying protocol therapies to protocol-ineligible patients. These patients should still be treated with targeted therapy, but when it comes to patient counseling and prognostication, we should temper those discussions with these data.” —Daniel Heng, MD, MPH The frequently used exclusion criteria were a Karnofsky Performance Status (KPS) score <70%, brain metastases, non–clear-cell histology, hemoglobin ≤9 g/dL, creatinine >2 times the upper limit of normal, platelet count <100 × 103/µL, a neutrophil

poor prognosis (43% vs 16%, respectively), said Dr Heng; 25% of eligible patients had favorable-risk disease compared with only 9% of ineligible patients. The response rate to therapy was significantly worse in ineligible versus eligible patients (21% vs 29%, respectively).

Response rates were worse in ineligible patients for all prognostic categories defined by Dr Heng and colleagues. The median progression-free survival (PFS) with first-line targeted therapy was 5.2 months for ineligible patients versus 8.8 months for eligible patients, and the median overall survival (OS) was 14.5 months versus 28.8 months, respectively (all P <.001). Of the 896 patients who continued to second-line therapy, PFS was 3.2 months in the trial-ineligible patients versus 4.4 months in the trial-eligible patients. When adjusted by prognostic categories, the hazard ratio for death between the trial-ineligible and trialeligible patients was 1.511. “The discrepancies in clinical outcome should be taken into account when applying protocol therapies to protocol-ineligible patients,” said Dr Heng. “These patients should still be treated with targeted therapy, but when it comes to patient counseling and prognostication, we should temper those discussions with these data.” Specific trials addressing the needs of protocol-ineligible patients and assessing OS are required, he said. ■

Nonpharmacologic Strategies Have Mixed Results in Prostate Cancer Prevention By Phoebe Starr San Francisco, CA—Nonpharmacologic strategies for prevention of cancer are potentially attractive and costeffective, but success stories are few. According to 2 separate studies presented at the recent Genitourinary Cancers Symposium, vigorous exercise prevented recurrence of prostate cancer and reduced mortality, whereas long-term vitamin E supplementation at commonly used doses actually increased the risk of prostate cancer in otherwise healthy men. Value of Vigorous Exercise Men who exercised vigorously at least 3 hours per week had favorable changes in gene expression patterns in normal prostate tissue, according to June M. Chan, MD, University of California at San Francisco, and colleagues. This study builds on a previous study showing that vigorous exercise slowed the progression of prostate cancer and reduced the number of prostate cancer deaths. “The favorable effects on gene expression may explain

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the protective effects of vigorous exercise,” Dr Chan said. Vigorous exercise was defined as jogging, playing singles tennis, brisk walking, or any sustained exercise that accelerates the heart rate. The study included 70 men diagnosed with low-risk prostate cancer who were treated with watchful waiting. Prostate biopsies were obtained at baseline. Men who reported vigorous exercise at least 3 times per week (N = 23) showed different expression in 184 genes in normal prostate tissue compared with men who did not do vigorous exercise (N = 47). Upregulated genes included the known tumor-suppressor genes BRCA1 and BRCA2. Gene-set analysis demonstrated that cell cycle and DNA repair pathways related to cancer were positively modulated in the men who reported vigorous exercise at least 3 times per week versus those who exercised less. These favorable effects on genes and pathways were not found in men who reported engaging in any

type of physical activity—but not vigorous exercise—3 times per week, or those who did not exercise. The findings suggest that a certain threshold of intensity or duration of exercise may be important in reducing the risk of prostate recurrence. Larger studies are needed to replicate its findings.

Long-Term Vitamin E May Increased Risk for Prostate Cancer The large, National Cancer Institute– sponsored Selenium and Vitamin E Cancer Prevention Trial (SELECT) suggests that healthy people should exercise caution in taking supplements without firm evidence. Long-term follow-up of the SELECT trial showed that vitamin E 400 IU/ day was associated with a 17% increased risk of developing prostate cancer when taken for 5.5 years by healthy men. The study also looked at the effect of selenium 200 mg/day alone or in combination with vitamin E, and found no increased risk of prostate cancer, as well as no benefit. SELECT enrolled 35,434 men aged ≥55 years (aged >50 years if they were

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black) at more than 400 study sites across the United States, Puerto Rico, and Canada. At an interim analysis in 2008, selenium 200 mg/day and vitamin E 400 IU/day alone or in combination had no effect on preventing prostate cancer in otherwise healthy men. The trial was halted early, and subjects stopped taking both supplements, but follow-up continued to determine long-term effects. Longer-term follow-up found that for every 1000 men who took placebo, 65 cases of prostate cancer developed over 7 years. For every 1000 men who took vitamin E, 76 cases of prostate cancer developed. Updated results were presented by Eric J. Klein, MD, of the Cleveland Clinic Foundation, OH (Klein EJ, et al. JAMA. 2011;306:1549-1556). Dr Klein said that the supplement industry accounts for approximately $23 billion annually; approximately 50% of men aged >60 years take vitamin E, and approximately 23% take selenium for putative prevention of prostate cancer. SELECT suggests that taking vitamin E is in fact harmful, whereas taking selenium has no positive effect. ■

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BREAST CANCER

For Metastatic Breast Cancer, Nab-Paclitaxel Requires Less Growth Factor Support Total cost of care is less than with other taxanes By Caroline Helwick San Antonio, TX—In a retrospective utilization and cost analysis, nab-paclitaxel (Abraxane) therapy was associated with substantially lower total use of prophylactic colony-stimulating factor (CSF) than docetaxel (Taxotere) and paclitaxel (Taxol) in the treatment of breast cancer. The study was reported at the 2011 San Antonio Breast Cancer Symposium by Rex W. Force, PharmD, Professor and Director of Research, Family Medicine and Pharmacy Practice, Idaho State University, and Partner, ImproveRX, LLC, and colleagues.

“Although the other taxanes are less expensive than nab-paclitaxel, the difference is almost made up for when considering the total cost of care with CSF support.” —Rex W. Force, PharmD

“Although the other taxanes are less expensive than nab-paclitaxel, the difference is almost made up for when considering the total cost of care with CSF support,” Dr Force told ValueBased Cancer Care. It is estimated that $15 billion in total healthcare costs are spent annually on the treatment of breast cancer in the United States, and much of this cost stems from the use of taxanes. Clinically meaningful differences in adverse effects, including rates of neutropenia, may be present among the different drugs. Comparative trials have shown lower rates of grade 3 or 4 neutropenia with nab-paclitaxel compared with docetaxel or paclitaxel. “Docetaxel tends to be much more toxic to the bone marrow, and comparative trials have shown more grade 3 and 4 neutropenia with both docetaxel and paclitaxel than with nab-paclitaxel,” Dr Force said. “The costs of managing adverse effects related to neutropenia are likely to be significant,” the investigators stated in their poster. The study was conducted to deter-

mine if differences exist in the rates of CSF use for prophylaxis and treatment in women receiving taxane-based chemotherapy for metastatic breast cancer and to compare the costs of this use. study Details Investigators used actual paid medical claims from a national commercial payer (Ingenix Consulting). The dataset included more than 56 million procedure claims from more than 350,000 unique patients with cancer treated between 2006 and 2009. CSF use was defined as prophylactic (days 0-5 posttaxane administration), treatmentrelated (days 6-21 posttaxane administration), or nontaxane-associated (all other CSF administration). In calculating daily CSF costs, investigators controlled for age, comorbidity score, prior chemotherapy use, and concurrent chemotherapy use. The primary outputs of the analyses were CSF use and daily per-patient CSF costs adjusted for those variables. The study included 2599 patients receiving docetaxel, 1643 receiving paclitaxel, and 261 receiving nab-paclitaxel. The average number of days receiving a taxane were 91, 88, and 156, respectively. Dr Force suggested that patients may be receiving more nabpaclitaxel because of its better tolerability. “We have shown in previous studies that patients with nab-paclitaxel actually have less neutropenia, and neutropenia is one of the main reasons for discontinuing the taxanes,” he pointed out. Less CsF Use, Lower Treatment Costs with Nab-Paclitaxel Overall, more women receiving docetaxel and paclitaxel received CSF support compared with women treated with nab-paclitaxel. Most of this was in the form of prophylaxis; the use of treatment-related CSF was not different between the taxane groups, Dr Force reported. Any use of CSF was documented for 76% of the docetaxel cohort, 50% of the paclitaxel cohort, and 37% of the nabpaclitaxel cohort (P <.05 for all comparisons). Prophylactic use was recorded for 73%, 47%, and 33% of patients, respectively. Treatment-related CSF was administered to 16% of patients receiving docetaxel, 11% receiving paclitaxel, and 15% receiving nab-paclitaxel (P <.05 for docetaxel vs paclitaxel). Non-

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Table

Mean Per-Patient Unadjusted CSF Costs

Taxane Docetaxel (N = 2599) Paclitaxel (N = 1643) Nab-paclitaxel (N = 261)

Total use, $

Prophylaxis, $

Treatment, $

Nontaxaneassociated cost, $

15,504

11,440

625

3438

7742

5444

437

1860

6265

4384

520

1361

CSF indicates colony-stimulating factor.

taxane-associated CSF was used by 26%, 31%, and 10% of patients, respectively (P <.05 for all comparisons). Prophylactic CSF administration represented approximately 70% of overall CSF expenditures. The mean per-patient unadjusted CSF costs are shown in the Table. Median daily CSF expenditures were lower for nab-paclitaxel ($46.24) compared with docetaxel ($176.81), which was 3.8-fold higher, and paclitaxel ($127.71), which was 2.8-fold higher than for nab-paclitaxel, he said. “The manufacturer of nab-paclitaxel

asserts that the formulation of this product has a different pharmacokinetic and pharmacodynamic profile that translates into less neutropenia. What we have seen, in this claims dataset, is that there is, in fact, far less spent in terms of CSF support for patients getting nab-paclitaxel,” Dr Force said in the interview. “Nab-paclitaxel is more expensive in drug acquisition costs, but the total cost of care in terms of managing a sick patient is small,” he said. “The cost of CSF support is a good chunk of this.” ■

Oncotype DX Assay CostEffective for Patients with ER-Positive Breast Cancer But some experts question the economics of universal testing San Antonio, TX—Assessing all eligible patients with breast cancer for recurrence risk with the 21-gene Oncotype DX assay at diagnosis could save $330.8 million annually by avoiding ineffective chemotherapy, according to data presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. This analysis involved nearly 200,000 estrogen receptor (ER)-positive tumor samples. The Oncotype DX assay, which is approved in this subgroup of patients with breast cancer, yields a risk score for disease recurrence. “We believe that a low risk score on the assay is presently the most reliable biomarker for a chemotherapy-resistant phenotype, and we believe that

the excess harm of chemotherapy outweighs the potential benefit of chemotherapy for those patients,” said lead investigator Joseph Ragaz, MD, FRCP, University of British Columbia, Vancouver. The analysis of tumor samples from 196,967 ER-positive patients in the Genomic Health Database showed that a low 10-year recurrence risk score (<18) was more common among patients with axillary node-positive tumor than those with node-negative tumor. Of the nearly 14,000 patients with node-positive disease, 59% have a low risk score compared with 54% of those with node-negative disease. Major studies have shown no significant benContinued on page 17

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New Data Suggest Oncotype DX Unnecessary in Some Cases of Low-Grade Cancer Cost of testing may not always be justified By Rosemary Frei, MSc Grapevine, TX—A New Jersey research team is making the case for relying less on the Oncotype DX test for breast-cancer prognosis and instead focusing on conventional pathological analyses. Pathologists at Saint Barnabas Medical Center, Livingston, NJ, and Monmouth Medical Center, Long Branch, NJ, found that in a retrospective review of 90 cases, 88% of those who had the following 3 characteristics were in the Oncotype DX low-risk category: • Scarff-Bloom-Richardson (SBR) grade 1 tumor • Progesterone-receptor (PR) positivity • HER2 negativity. Oncotype DX costs a little more than $2900, and not using it in these cases would have resulted in a total savings of $70,000, the investigators reported in a poster presentation of their results at the College of American Pathologists’ 2011 annual meeting. “Clinicians are reluctant to change their practice simply because Oncotype DX has become an important component of their clinical algorithms,” investigator Ashhad Mahmood, MD, told Value-Based Cancer Care (VBCC) after the meeting. “Further evidence delineating a subset of patients who may not require [Oncotype DX] testing may act as the impetus required to change clinical practice.” Amelia Zelnak, MD, MSc, Assistant Professor of Hematology and Oncology, Winship Cancer Center, Emory

University School of Medicine, Atlanta, GA, was contacted by VBCC to discuss the study.

“Oncotype DX is expensive, but studies have shown that 5% of patients with lowgrade tumors have high Oncotype DX scores.” —Amelia Zelnak, MD, MSc She takes the view that Oncotype DX is useful in many breast cancer cases because SBR grading is “subjective and can miss cases with a high risk of recurrence.” “Oncotype DX is expensive,” said Dr Zelnak, “but studies have shown that 5% of patients with low-grade tumors have high Oncotype DX scores. So, Oncotype DX really helps differentiate who should get chemotherapy and who shouldn’t.” Dr Zelnak is referring to a 651patient study that showed 5% of patients with an SBR grade 1 tumor had a high recurrence score (Paik S, et al. J Clin Oncol. 2006;24:3726-3734). The study by Dr Mahmood, Wendy Shertz, MD, and Byung-Kyu Kim, MD, involved cases submitted for Oncotype DX testing at Monmouth Medical Center between 2004 and 2010. Of the cases, 84 had final Oncotype DX results. The median age of the patients

whose tumors underwent Oncotype DX testing was 57 years, and their median tumor size was 2.4 cm. Thirty (35.7%) cases were SBR grade 1; 24 of these were in the low-risk Oncotype DX category. Twenty-two of the 44 SBR grade 2 cases had a low-risk Oncotype DX score, 18 had an intermediate-risk score, and 4 had a high-risk score. Furthermore, 1 of the 6 SBR grade 3 cases had a low-risk score, 3 had an intermediate-risk score, and the remaining 2 cases had a high-risk score. Furthermore, 24 (80%) of the 30 SBR grade 1 cases also had a low-risk recurrence score. The remaining 6 had intermediate recurrence scores, with 5 of the 6 having scores in the lowest range of the intermediate category. The other case was PR-negative, with an elevated antigen Ki-67 proliferation index; these latter 2 measures are proved negative prognostic indicators, the investigators point out. Overall, the team found that estrogen receptor (ER), PR, Ki-67, and HER2 status correlate highly with Oncotype DX categories. In addition, they uncovered a significant correlation between Oncotype DX categories and PR and HER2 status. Twenty-seven cases were SBR grade 1, PR-positive, and HER2-negative, and 24 (88%) of these had low-risk recurrence scores. If Oncotype DX testing had not been used in these 24 cases, the total savings would have been $70,000, the team calculated. Other research groups arrived at similar conclusions. For example, pathologists at the University of Pittsburgh Medical Center found that the

Oncotype DX Assay Cost-Effective... efit of adjuvant chemotherapy in ERpositive breast cancer in patients with a low risk score. Among the estimated 225,000 new cases of breast cancer diagnosed annually in the United States, 94,500 are ERpositive and are candidates for the Oncotype DX to assess their need for chemotherapy. At an estimated cost for chemotherapy of $15,000 per patient and $4000 per Oncotype DX assay, avoiding chemotherapy in patients with a low risk score would save $330.8 million annually, according to Dr Ragaz. Dr Ragaz advocated universal testing for all ER-positive patients, regardless of their axillary nodal status, sug-

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“We believe that a low risk score on the assay is presently the most reliable biomarker for a chemotherapy-resistant phenotype.” —Joseph Ragaz, MD, FRCP

gesting that guidelines should be revised to avoid chemotherapy in all patients with a low risk score, regardless of nodal status as well. “Until prospective randomized trials

at a glance ➤ This study suggests that the Oncotype DX assay is not necessary for some low-grade cancers ➤ Almost all reviewed cases demonstrating PR-positive and HER2-negative status and SBR grade 1 tumors had a low-risk Oncotype DX score ➤ A significant correlation was found between Oncotype DX– measured risk and PR and HER2 status

Oncotype DX score is significantly correlated with tubule formation, nuclear grade, mitotic count, ER immunohistochemical score, PR immunohistochemical score, and HER2/neu status (Flanagan MB, et al. Mod Pathol. 2008;21:1255-1261). Furthermore, a team from the Montefiore Medical Center and the Albert Einstein College of Medicine in New York City determined that a mitotic-count score of >1 combined with a negative PR result as determined by pathologic assessment correlates significantly with an intermediate or high Oncotype DX score (Auerbach J, et al. Arch Pathol Lab Med. 2010;134:1697-1701). The Saint Barnabas Medical CenterMonmouth Medical Center team is expanding their study by continuing to collect and review cases submitted for Oncotype DX. ■

Continued from page 16

confirm chemotherapy benefit among low risk score patients, its use among these chemotherapy-resistant cases should be considered investigational,” he said. “This is pretty strong stuff,” said Thomas J. Smith, MD, Harry J. Duffey Family Professor of Palliative Care, Johns Hopkins University, Baltimore, MD. Dr Smith agreed that this approach has economic appeal to avoid wasteful spending and spare many women the unnecessary toxicity of chemotherapy. But he also pointed out that a much less-expensive alternative to the Oncotype DX assay can accomplish the same thing, including standard

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immunohistochemical (IHC) tests for estrogen, progesterone, and HER2 status, and tumor-cell proliferation marker Ki67. Emerging data suggest IHC4 can similarly predict recurrence risk in this patient population. Simon D.H. Holt, MD, Prince Philip Hospital, Llanelli, Wales, presented a favorable cost-effectiveness analysis of the Oncotype DX assay in UK oncology practices. He noted that the Ki-67 assay must be validated, because results can vary considerably among laboratories. He added that Oncotype DX has very tight quality assurance and is “certainly the best thing on the market.”—CH ■

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Everolimus Has Minimal Economic Impact... For patients with advanced pNETs, the median overall survival is typically approximately 2 years. Everolimus was recently approved for the treatment of advanced, progressive pNET based on a significant 65% reduction in risk of disease progression. It is expected, therefore, that oncologists will be incorporating this mTOR inhibitor into their treatment plans for this patient population. Roman Casciano, MS, of Analytica International, New York, and colleagues developed a budget impact model from a US payer’s perspective to simulate a typical health plan with 1 million covered lives. study Details The eligible patient population was derived using the incidence of ad-

Table

vanced pNETs of 0.001%. Patients with advanced, nonprogressive pNETs accounted for 60% of the population, and patients with advanced, progressive tumors accounted for 40%. Treatments included chemotherapy (capecitabine, doxorubicin, streptozocin, temozolomide), the new targeted agents everolimus and sunitinib (Sutent), and best supportive care. Treatment utilization was based on a previous study of resource utilization in the treatment of pNETs. Drug costs were derived from the 2011 Micromedex RED BOOK, and medical resource utilization costs were taken from the 2011 MAG Mutual Physicians’ Fee and Coding Guide. Treatment-related grade 3/4 adverse event rates were obtained from clinical trials, whereas the cost

Economic Impact of Various Therapies for pNETs

Drug

Current practice cost, $

Future practice cost, $

Capecitabine

19,021

6087

Doxorubicin

34,249

10,960

Everolimus

53,927

Streptozocin

35,107

11,234

Temozolomide

63,731

20,394

72,164

185,124

Sunitinib Best supportive care

NA indicates not available; pNETs, pancreatic neuroendocrine tumors.

of management was based on secondary literature.

“The antitumor treatment costs composed the largest percent increase, 601%, in cost among all healthcare resource costs. Conversely, infusion costs decreased by 68% and surgical procedure costs decreased by about 35%.” —Roman Casciano, MS

Limited Budget Impact When Everolimus Is Added Before the approval of sunitinib and everolimus, 43% of patients with pNETs received chemotherapy and 57% received best supportive care alone, Mr Casciano and colleagues determined. After the approval of these 2 new therapies, the prediction model assumed that 14% of patients would receive chemotherapy, 13% would receive everolimus, and 16% would receive sunitinib. The researchers constructed a scenario to evaluate the economic impact of increasing and decreasing the market share of everolimus relative to sunitinib. The model estimated the annual aggregate budget impact, strat-

Continued from cover ified by resource, and budget impact per member per month. Prevalence estimates applied to the hypothetical population yielded 12 patients with advanced pNETs. Stratifying the annual cost by treatment comparators, the investigators determined that the use of targeted therapies was associated with a budget increase of $53,927 in a hypothetical healthcare plan of 1 million subscribers; however, reductions in cost from other comparators produced the net increase of $22,657 (Table), according to Mr Casciano. In the base-case analysis, this amounted to an increase of only $0.0019 per member per month, or $0.0227 per member per year, he said. “The antitumor treatment costs composed the largest percent increase, 601%, in cost among all healthcare resource costs. Conversely, infusion costs decreased by 68% and surgical procedure costs decreased by about 35%,” he noted. Scenario analyses showed that increases in the share of everolimus relative to sunitinib (29% everolimus vs 2% sunitinib) resulted in a lower aggregate economic impact, or an additional cost to the plan of $18,000. Increasing the market share of sunitinib relative to everolimus (0% everolimus vs 29% sunitinib) yielded a higher aggregate economic impact compared with the base-case analysis, which assumed 13% of patients received everolimus and 16% received sunitinib. ■

BREAST CANCER

Dose-Dense Chemotherapy plus Growth Factors in Elderly ER-Positive Patients Unnecessary, Costly By Caroline Helwick San Antonio, TX—Women with estrogen receptor (ER)-positive breast cancer are unlikely to benefit from dosedense chemotherapy, but many are receiving this type of treatment, which involves the use of colonystimulating factors (CSFs), that is, growth factors. Limiting the use of these therapies in a population that is unlikely to benefit from it, would save nearly $40 million annually, suggests a study presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. Dawn L. Hershman, MD, Columbia University, New York, reported an analysis of Medicare data showing that the use of CSFs in the first cycle of dose-dense chemotherapy (ie, chemotherapy given every 2 weeks, not every

“If we have to make decisions in terms of controlling costs, we should not be giving drugs that are costly and have no benefit for specific subpopulations of patients.” —Dawn L. Hershman, MD 3 weeks) skyrocketed in response to published reports of its benefit. The use of CSFs among patients with stage I to III breast cancer increased accordingly, from 13% before 2002 to 68% between 2002 and 2005; the use of pegfilgrastim, in particular, jumped from 4% to 85%, she noted. “We are very quick in oncol-

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ogy to adopt, and we never pull back,” Dr Hershman said. “If we have to make decisions in terms of controlling costs, we should not be giving drugs that are costly and have no benefit” for specific subpopulations of patients. Her study identified 10,773 patients in the SEER-Medicare database aged ≥65 years who were diagnosed with early breast cancer between 1998 and 2005 and had at least 1 chemotherapy claim. Of these, 5266 patients had a claim for CSF use during therapy, and such claims increased substantially over time. For patients with ER-negative breast cancer, the dose-dense approach plus CSF was estimated to cost $19.5 million annually but was cost-saving in terms of event-free survival (ie, recurrences,

deaths). For ER-positive patients, however, there was no savings in life-years, and annual costs rose to nearly $40 million for patients aged >65 years. Incorporating patients of all ages, the annual costs for the ER-positive population was estimated to exceed $86 million, Dr Hershman reported. Thomas J. Smith, MD, of Johns Hopkins University, Baltimore, who chaired the session where the study was presented, commented that the only thing the $40 million was buying in the ER-positive Medicare group was toxicity. “You are not buying any disease benefit,” he agreed, suggesting further that dose-dense chemotherapy in elderly patients with ER-positive tumors should be put on the “do not use” list. ■

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GI CANCERS SYMPOSIUM

For Pancreatic Cancer, Neoadjuvant Chemoradiation Cost-Effective Compared with Surgery First By Caroline Helwick San Francisco, CA—For resectable pancreatic cancer, administering chemotherapy and radiation before surgery results in better outcomes and lower costs than performing surgery first, reported researchers from M.D. Anderson Cancer Center, Houston. “Compared with a surgery-first approach, the neoadjuvant approach eliminates an ineffectual, costly, and potentially morbid treatment in patients with early metastases or a prohibitive function status. It is associated with improved survival, and it costs less per patient,” said lead investigator Daniel Erik Abbott, MD. “So, as a rule we generally recommend neoadjuvant treatment now.” Multimodality therapy for resect-

Table

able pancreatic head adenocarcinoma provides the best chance for prolonged survival, but because of a lack of randomized data, the optimal sequence of surgery, chemotherapy, and radiation therapy has not been clear. “With fiscal realities increasingly impacting healthcare, cost should be considered when making treatment decisions,” he said. Dr Abbott and colleagues, therefore, conducted this study to compare the cost and outcomes of a surgery-first approach versus chemoradiation first followed by surgery. They constructed a decision model to contrast the 2 strategies, using literature and databases to estimate outcomes in the surgery-first arm,

Cost Comparisons: One-Way Sensitivity Analysis Neoadjuvant chemoradiation– first cohort, $

Cost component

Cost range, $

Surgery-first cohort, $

Hospital reimbursement for major complication

31,302-54,460

44,373-46,830

34,901-36,583

Hospital reimbursement for minor complication

23,430-31,302

44,453-46,830

35,100-36,583

Cost of adjuvant chemotherapy

19,511-34,571

47,017-53,382

36,583

Use of adjuvant radiation therapy

0-11,875

42,186-46,830

36,583

including operative outcomes, complications rates, pathologic stage, adjuvant therapy, and stage-specific survival. The outcomes of “highperforming centers” populated the surgery-first model.

“With fiscal realities increasingly impacting healthcare, cost should be considered when making treatment decisions.” —Daniel Erik Abbott, MD

Data from a prospectively maintained pancreatic cancer database populated the neoadjuvant arm, who received gemcitabine- or capecitabinebased regimens. Based on Medicare reimbursement, cost (in 2011 dollars) included technical or professional fees and hospital reimbursements. It did not include preoperative work-up procedures, because these were assumed to have been completed for the diagnosis to be made. Survival, discounted when appropriate, was reported in quality-adjusted life-months (QALMs). A 1-way sensitivity analysis was based on the rates of perioperative mortality, complications, and unresectability; costs of

adjuvant chemotherapy; radiation therapy practices; and reimbursement for complications (Table). Clinical outcomes, CostEffectiveness A total of 164 patients completed neoadjuvant chemoradiation. Of these, 22% did not proceed to surgery because of metastasis, poor performance status, or patient choice, or because unresectability was determined at laparotomy. Definitive surgical resection was possible for 116 patients (77%). The surgery-first approach cost $95,781 to yield a survival of 8.7 QALMs, whereas the neoadjuvant strategy cost $71,416 to achieve 18.8 QALMs. In the intent-to-treat neoadjuvant population, which included patients not undergoing surgery, those with unresectable cancer at laparotomy, and those completing surgery, the respective costs were $12,401 to yield 7.7 QALMs, $39,112 to yield 7.1 QALMs, and $92,887 to yield 23.4 QALMs, respectively. “Under no circumstances does cost or effectiveness for surgery first even approximate that achieved with neoadjuvant CRT,” he said. “Neoadjuvant chemoradiation should be more widely used as a cost-effective treatment strategy for resectable pancreatic head adenocarcinoma.” ■

Oncotype DX Assay Changes 29% of Treatment Decisions in Patients with Stage II Colon Cancer San Francisco, CA—Results obtained on the Oncotype DX Colon Cancer Assay led to changes in treatment decisions 29% of the time for patients with stage II colon cancer, according to a survey of community oncologists reported at the 2012 Gastrointestinal Cancers Symposium. “One of the more difficult decisions is what stage II patients to treat,” said lead investigator Thomas H. Cartwright, MD, Ocala Oncology, FL. “In stage II patients, we typically rely on more subjective factors, number of lymph nodes, tumor grade, and so forth. This test helps us determine recurrence risk.” The difference between this assay and the Oncotype DX assay for breast cancer (see page 16) is that the breast cancer test is not only prognostic but also predictive, whereas the test in colorectal can-

cer (CRC) is prognostic only. Some physicians, therefore, have wondered about the utility of the test in CRC. That treatment for more than 25% of patients was clearly determined by test results confirms the assay’s utility in the management of CRC, Dr Cartwright maintained. Oncotype DX, which produces a 12gene recurrence score, has been commercially available since January 2010. This study was the first evaluation of its impact on treatment recommendations in CRC in a survey of medical oncologists. Similar surveys in breast cancer have shown that treatment decisions are altered approximately 30% of the time based on test results. The web-based survey involved 116 US oncologists who had ordered Oncotype DX testing for ≥3 patients

VALUE-BASED CANCER CARE

MARCH 2012

with stage II CRC. Most came from a community practice setting and had an average of 16 years of oncology practice. Half of the oncologists saw >40 patients with newly diagnosed CRC in a typical year. The 34-item survey recorded patient characteristics, preassay and postassay treatment recommendations, and the oncologist’s general practice patterns. Impact of Test on Treatment Recommendations Of the 116 respondents, 92 (79%) had a treatment recommendation before ordering the assay. Of these recommendations, 57% included chemotherapy. After the 12-gene recurrence score was obtained, 29% of the recommendations changed. For 67%, the treatment intensity decreased; for 33%,

the treatment intensity increased, said Dr Cartwright. Decreased treatment intensity was defined as a change from chemotherapy to observation or a change from oxaliplatin-containing to non–oxaliplatin-containing chemotherapy. Increased intensity was defined as a change from observation to any chemotherapy or from non–oxaliplatin-containing to oxaliplatin-containing chemotherapy. “These results suggest that the use of the recurrence score may be associated with a meaningful change in treatment recommendations for stage II CRC patients,” Dr Cartwright concluded, “and may lead physicians to reduce the treatment intensity, which contributes to the assay’s cost-effectiveness.”—CH ■

VOL. 3

NO. 2

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HEALTH POLICY

AMA Delegates and Oncologists Balk... mitment to improve the regulatory climate for physicians.” Dr Madara said that ICD-10 is something that will impact essentially all business processes within a physician’s practice and will be a “massive administrative and financial undertaking for physicians.” The timing, he said, “could not be worse,” because physicians are in the midst of implementing electronic health records (EHRs) to avoid penalties. Should ICD-10 coincide with these efforts, Dr Madara predicted “physicians will be forced to close their Medicare patient panel or limit the number of Medicare patients they treat in order to minimize the aggregate financial and administrative blows to their practice due to unfunded regulatory mandates and the unfair penalty programs.” The AMA’s efforts were successful in at least delaying the start date, which was previously set for October 2013. “We have heard from many in the provider community who have concerns about the administrative burdens” of ICD-10, Ms Sebelius wrote in her statement. She said the HHS will announce a new compliance deadline after reexamining the pace of implementing ICD-10. The HHS press release stated that, “ICD-10 codes provide more robust and specific data that will help improve patient care and enable the exchange of our healthcare data with that of the rest of the world that has long been using ICD-10.”

at a glance ➤ The ICD-10 is expected to be a needless and expensive burden to oncology practices, without enhancing patient care ➤ ICD-10 contains approximately 68,000 codes compared with only 14,000 in the ICD-9; the new codes also contain 7 characters compared with a maximum of 5 in ICD-9 ➤ Implementing ICD-10 is projected to cost $83,000 for a 3-physician office and $285,000 for a 10-person group, costs that could mean the end of some practices ➤ ICD-10 lumps things together that were more finely divided in ICD-9; this is important because hematologic diseases are getting more specific, especially with regard to drug therapy

Expensive Move from ICD-9 to ICD-10 Delegates at the AMA interim meeting called the ICD-10 overly complex, burdensome to medical practices, expensive to implement, an obstacle to implementation of EHRs (with a more pressing deadline), and worthless in terms of patient care. The new version contains approximately 68,000 codes compared with only 14,000 codes in the ICD-9. But the complexity of ICD-10 coding extends beyond sheer volume. The new codes contain as many as 7 characters compared with a maximum of 5 in ICD-9. Mike Green, MD, a family physician in Macon, GA, said, “It doesn’t take an expert in coding to review this and ask, ‘Do we really need to know what kind of dog bit you to be able to code a dog bite?’”

“It costs us time, effort, and money to comply with such nonsense.” —Steven Vogl, MD Implemention of ICD-10 is projected to cost $83,000 for a 3-physician office and $285,000 for a 10-person group. Several physicians predicted that this additional cost, and other financial fall out, could sink some marginal practices. “This will be used by every insurer in the country to deny payment, because with so many codes it’s simple to say ‘You coded this wrong.’ At best, it will significantly delay payment,” Dr Green predicted. “There are many practices in my area that run month to month. You interrupt the cash flow and the physician is either taking out a loan or closing his doors.” oncologists Weigh In Steven Vogl, MD, an oncologist who practices in Bronx, NY, was vehement in his disdain for the whole package. “I consider this more of the excrement heaped upon doctors, and it only makes it harder for us to take care of patients,” he told Value-Based Cancer Care. “It costs us time, effort, and money to comply with such nonsense.” The payers “keep cutting what they pay us, and then expect us to document more and spend more of our money doing so,” he said.

VALUE-BASED CANCER CARE

MARCH 2012

Continued from cover

“ASH has done ‘crosswalk’ studies between ICD-9 and ICD-10 and has found that for a number of our diseases, ICD-10...lumps things together that were more finely divided in ICD-9. This is important because hematologic diseases are getting more and more specific, especially with regard to therapeutics.” —Samuel M. Silver, MD, PhD, FACP Regarding the “granularity” of ICD-10, which proponents say will foster quality care, Dr Vogl commented, “It will be absurdly detailed in ways that make no medical sense. And do I care if Egypt has the same coding system we have? No. But I do care that I will spend more time coding office visits. If my patient with bone cancer is limping, will it matter which corner of the bone is involved, or which corner of the breast the cancer started in?” Dr Vogl predicted that the additional complexity of coding will hinder oncologists’ willingness to provide second opinions, which will cost more to document than will be reimbursed. Like Dr Green, he also feared there will be more claims denials and delays from insurance companies and CMS. “This is bad for doctors, bad for patients, and good for the insurance companies,” Dr Vogl concluded. Samuel M. Silver, MD, PhD, FACP, Director, Cancer Center Network Division of Hematology/Oncology, University of Michigan Health System, Ann Arbor, and Chair of the Subcommittee on Reimbursement for the American Society of Hematology (ASH), said that the delay in implementation was necessary. He also said that there was work to be done on improving the upcoming version of the coding system. “ASH has been concerned about ICD-10,” said Dr Silver. Although the greater “granularity” of the codes may be reasonable for conditions that are managed surgically, such changes are not necessary in oncology. “We don’t care if it’s Hodgkin lymphoma of the left great toe. That kind of anatomic localization does not help us,” Dr Silver pointed out. “But even more so, ASH has done ‘crosswalk’ studies between ICD-9 and ICD-10 and has found that for a number of our diseases, ICD-10 actually becomes less granular. It lumps things together that were more finely divided in ICD-9.” “This is important because hemato-

logic diseases are getting more and more specific, especially with regard to therapeutics,” he continued. “If CMS or any agency needs to determine that there has been a high quality of care and that therapy was appropriately delivered, having an understanding of this is an important part of advanced coding. If we are lumping rather than dividing, we lose granularity, and we may not know if the right drugs— which are very expensive—are being delivered.” Dr Silver agreed that physicians simply have too much on their plates right now. “We are dealing with huge electronic health record conversions and various quality initiatives. This onslaught of new codes will be another huge burden.” Jeff Ward, MD, Chair-Elect of the American Society of Clinical Oncology’s Clinical Practice Committee and part of a 9-person practice in Edmonds, WA, admitted to having “mixed feelings” about ICD-10. “As oncologists, we are looking forward to having a coding system that reflects modern medicine and terminology,” he said. “On the other hand, we recognize that converting to a new system at the same time our whole practice system is rapidly changing is just one more thing that will be onerous and time-consuming for our practice staff and management.” Dr Ward said that the terminology in the current coding system is woefully out of date. “The lymphoma nomenclature has changed 3 times since ICD-9 was started,” he said. For example, “lymphosarcoma,” a term that is no longer used, has a code; “mantle-cell lymphoma” and even “follicular lymphoma” do not. “We look forward to the day the changes are in place,” Dr Ward said, “but we don’t look forward to having to put the changes in place without a major increase in reimbursement for the cost this will entail, especially in a situation that is increasingly difficult from a financial standpoint.” ■

VOL. 3

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NOW APPROVED!

Indication Erivedgeâ&#x201E;˘ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.1

Boxed Warning and Additional Important Safety Information Embryo-Fetal Death and Severe Birth Defects s

Erivedge capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Erivedge is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations

Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen

Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant

Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation s

Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers s

Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

Adverse Reactions s

The most common adverse reactions (*10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia

In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge

Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%)

Please see adjacent page for brief summary of important safety information Reference: 1. Erivedgeâ&#x201E;˘ (vismodegib) capsule full prescribing information; Genentech, Inc., January 2012.

ÂŠ2012 Genentech, Inc., So. San Francisco, CA HED0000885000 2/12

A Member of the Roche Group

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials 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 clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). D Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. D Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. D Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. D Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. D Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. D Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. D Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. D Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

ASH ANNUAL MEETING

Economic Burden of Febrile Neutropenia in NHL Exceeds $11,000 per Episode By Caroline Helwick San Diego, CA—Among patients with non-Hodgkin lymphoma (NHL), costs related to febrile neutropenia (FN) treated with hospitalization exceed $11,000 per episode, researchers reported at ASH 2011. Although the research was conducted on patients in the United Kingdom, the investigators converted costs to US dollars and noted that their findings were in keeping with previous published US studies. “Our key point is that a high level of resource utilization is required in managing FN when it occurs in NHL patients,” Derek Weycker, PhD, Policy Analysis, Brookline, MA, told ValueBased Cancer Care. “There are significant costs associated with the development of FN; therefore, it’s a good idea to prevent it.” Data were obtained from an observational study of supportive care in patients with NHL receiving standard chemotherapy (with or without rituximab) for NHL. Patients developing

FN in a given cycle were matched to control patients not developing FN; matched pairs were stratified on the basis of the initial setting of care for

“Our key point is that a high level of resource utilization is required in managing FN when it occurs in NHL patients. There are significant costs associated with the development of FN; therefore, it’s a good idea to prevent it.” —Derek Weycker, PhD FN (ie, inpatient, outpatient, home, and other/unknown). FN-related healthcare use and costs, estimated from the UK National Health Service perspective (2010), were tallied for

patients through the last chemotherapy cycle. The study included 221 patients with FN and 221 comparison patients with NHL. Inpatient care for the initial FN event involved 76% of patients; outpatient care was provided to 6% of patients, and home care was delivered to 12%. Among patients with FN requiring inpatient care, the mean number of FN events was 1.44 versus 0.13 for comparison patients; the mean number of days in the hospital was 8.0 versus 0.7, respectively. Inpatient Costs for FN Among patients with FN requiring hospitalization, FN costs totaled $14,538 (£9476), which were divided almost equally between the index cycle in which FN first occurred and the period of postindex cycle care. In contrast, healthcare costs among non-FN controls was $3510 (£2288), for a difference of $11,028 (£7188), Dr

Weycker reported. “Cost of care subsequent to initial hospitalization accounted for 27% of the difference in FN-related healthcare costs,” Dr Weycker noted. The difference in costs between patients with FN requiring outpatient or home care and their matched controls was $2415 (£1574). The cost of care subsequent to initial hospitalization (the difference in postindex cycle cost between patients with FN and controls) accounted for 79% of the difference in FN-related healthcare costs. “Follow-up care is an important component of the economic burden, particularly in the outpatient/home care settings, where costs in the index cycle account for only about 10% of the total FN cost,” he said. “We need additional research to ascertain whether some patients treated on an inpatient basis may be candidates for outpatient or home care, where the cost of services may be lower,” he added. ■

Long-Term Survivors of Hematopoietic Stem-Cell Transplant Pose Significant Burden to Healthcare System By Phoebe Starr San Diego, CA—Survivors of hematopoietic cell transplant (HCT) have substantial medical illnesses and psychological symptoms ≥10 years after the procedure, representing a substantial burden to our healthcare system. Long-term HCT survivors have nearly a 6-fold greater risk than their siblings of life-threatening or severe illness or death, according to a study presented at ASH 2011. “Patients, families, and healthcare providers need to be aware of the high burden [of HCT] so they can plan for post-HCT care, even many years after HCT,” said lead author Can-Lan Sun, MD, PhD, Associate Research Professor, City of Hope National Medical Center, Duarte, CA. HCT is often the only curative option for patients with hematologic malignancies, but not much is known about the long-term burden of HCT. This study showed that compared with age- and sex-matched siblings, survivors of ≥10 years had a higher risk of somatic illness (generalized pain) as well as chronic illness that includes cardiovascular disease, dia-

betes, and second cancers. The investigators analyzed late medical effects and quality of life in 366 HCT survivors of ≥10 years and 309 matched siblings enrolled in the Bone Marrow Transplant Survivor Study. The survivors had a variety of primary diagnoses, including acute myelogenous leukemia (28%), chronic myelogenous leukemia (17%), acute lymphoblastic leukemia (17%), aplastic anemia (11%), Hodgkin lymphoma (7%), and other diagnoses (10%).

“Patients, families, and healthcare providers need to be aware of the high burden so they can plan for post-HCT care, even many years after HCT.”

VALUE-BASED CANCER CARE

—Can-Lan Sun, MD, PhD

During a 15-year follow-up period, nearly 75% of survivors reported at least 1 chronic health condition versus

MARCH 2012

29% of siblings. Approximately 25% of survivors reported severe or lifethreatening conditions versus only 6% of siblings. Common illnesses among survivors included myocardial infarction, stroke, diabetes, subsequent cancers, and long-term somatic distress. For survivors, the 15-year cumulative incidence of any chronic health condition was 71%, and the incidence of severe or life-threatening illnesses and death was 40%. After adjusting for age, sex, marital status, race/ethnicity, education, income, insurance status, health status, and chronic health conditions, the prevalence of anxiety and depression was similar for HCT survivors and their siblings, but survivors were >3 times as likely to report somatic distress. “This is very important research,” said Stephanie J. Lee, MD, Professor of Medicine, University of Washington Fred Hutchinson Cancer Center, Seattle, WA, who was not involved in the study. “With improvements in transplant, the numbers of survivors are growing and they are living longer. It is great that we now

at a glance ➤ HCT is often the only curative option for patients with hematologic malignancies ➤ Patients who undergo HCT are at higher risk for subsequent morbidity and require preventive and survivorship care ➤ HCT survivors of ≥10 years have a higher risk of somatic illness and chronic illness, including cardiovascular disease, diabetes, and second cancers have many more survivors, but this study shows us that when it is over, it is not really over.” Dr Lee, a transplant expert herself, said that people who undergo HCT should be aware that they are at higher risk for subsequent morbidity and seek preventive care and survivorship care. “As a society, we need to realize that HCT patients need long-term monitoring and care,” she stated. ■

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ASH ANNUAL MEETING

Novel Oral B-Cell Receptor Inhibitor Very Effective in Chronic Lymphocytic Leukemia Response rates increasing over time, with low toxicities By Caroline Helwick San Diego, CA—A novel inhibitor of B-cell receptor signaling, PCI-32765, produced high rates of remission and was well tolerated in patients with chronic lymphocytic leukemia (CLL) whose disease was refractory to at least 2 previous treatments, reported Susan O’Brien, MD, of the University of Texas M.D. Anderson Cancer Center, Houston. “To have agents that are this effective and that are not myelosuppressive is very exciting,” Dr O’Brien said. “These agents will change the paradigm for the treatment of CLL.” PCI-32765 is the first drug designed to target Bruton’s tyrosine kinase, a protein that is essential for CLL cell survival and proliferation. A total of 61 patients with relapsed or refractory CLL received oral PCI-32765 daily (420 mg in previously untreated and 840 mg in previously treated patients) for 28-day cycles or until disease progression. At least 1 poor-risk

“To have agents that are this effective and that are not myelosuppressive is very exciting. These agents will change the paradigm for the treatment of chronic lymphocytic leukemia.” —Susan O’Brien, MD

molecular feature was present in 72% of patients. Median follow-up was 10.2 months for the 420-mg cohort and 6.5 months for the 840-mg cohort. Response rates were 70% in the 420mg cohort and 44% in the 840-mg group. Nodal partial responses (PRs) were reported in 35% of patients (>50% reduction in aggregate lymph node size) with residual lymphocytosis. Responses appear to be independ-

Lymphoma Treatment in Pregnancy Does Not Compromise Fetal/Maternal Outcomes San Diego, CA—The treatment of lymphoma during pregnancy does not compromise fetal outcomes or maternal health and cancer-specific survival, according to a study presented at ASH 2011 from the University of Massachusetts Medical School in Worcester. Cancer diagnosed during pregnancy is rare—20% are hematologic malignancies—and data on outcomes are scarce, said Andrew Evens, DO, who presented the findings. Dr Evens and his colleagues therefore conducted a retrospective analysis of patients treated at 9 medical centers between 1998 and 2011. They found 82 cases of lymphoma diagnosed during pregnancy, of which 43 were nonHodgkin lymphoma and 39 were Hodgkin lymphoma. Six women, including 5 in the first trimester and 1 in the second, elected to terminate their pregnancies. Another 28 women, most of whom were in their third

trimester, deferred treatment until after delivery. The remaining 48 patients began treatment at a median of 25 weeks gestation; 79% were in the second trimester. Treatment was usually with a standard regimen, modified to avoid antimetabolites. Of these 48 patients, full-term deliveries occurred for 73%, compared with 86% who deferred therapy. The most common complication was the need to induce labor, which was observed in 45%. Complications were similar between women who were treated during pregnancy and those who postponed treatment, Dr Evens reported. Fetal outcomes were good and comparable to those in the general population of women without lymphoma. The 3-year overall survival rate was 92% for the patients who underwent treatment, 83% for those who deferred treatment, and 100% for those who terminated their pregnancies.—CH ■

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ent of molecular risk features. Dr O’Brien noted that response rates have steadily increased over the duration of the study. “At ASCO, we reported a PR rate of 48%. Now we report a response rate of about 70%. The responses have evolved over time,” she said. Some 82% of the original patients are still using this treatment; only 8% of patients have progressed so far. The 6-month progression-free survival was 92% in the 420-mg cohort and 90% in the 840-mg cohort. PCI-32765 is well tolerated, with

most adverse events reported being grade 1 or 2. Myelosuppression has not been a problem with this agent, Dr O’Brien said. Phase 3 clinical trials with PCI-32765 are planned. Jane Winter, MD, Professor of Medicine at Northwestern University Feinberg School of Medicine, Chicago, who moderated the press briefing, commented, “This appears to be a highly effective new agent, with a new strategy that targets the B-cell receptor. It has a very low toxicity profile and high efficacy, and it is just the beginning of many new agents in CLL.” ■

Chemotherapy Superior to Radiation for Nonbulky Hodgkin Lymphoma, but Older Radiotherapy Method Was Evaluated In patients with early-stage, nonbulky Hodgkin lymphoma (HL), overall survival (OS) was superior at 12 years in patients who received standard chemotherapy compared with radiotherapy in a study conducted by the National Cancer Institute of Canada’s Clinical Trials Group and the Eastern Cooperative Oncology Group. The HD.6 trial enrolled 405 patients, who were followed for a median of 11.3 years. At 12 years, 94% of patients receiving ABVD (Adriamycin [doxorubicin/hydroxydaunorubicin]/bleomycin/vinblastine/dacarbazine) chemotherapy were alive compared with 87% receiving subtotal nodal radiation with or without chemotherapy. Deaths were reduced by 50% (P = .04) among the chemotherapy group. However, the study found that disease control was superior with radiation, with a rate of 92% versus 87% with chemotherapy, and a 91% risk of progression with chemotherapy (P = .05). “The reason for the difference in OS is the greater number of deaths from other causes in the radiation group,” said Ralph Meyer, MD, of Queen’s University in Kingston, Ontario. “The long-term outcomes in patients with Hodgkin lymphoma depend on the

“The long-term outcomes in patients with Hodgkin lymphoma depend on the ability to control cancer itself, but, in addition, the nature of the treatment has its own long-term effects, including the risks of developing other cancers and cardiovascular problems.” —Ralph Meyer, MD ability to control cancer itself, but, in addition, the nature of the treatment has its own long-term effects, including the risks of developing other cancers and cardiovascular problems.” Of 12 deaths in the chemotherapy arm, 6 were the result of HL or early complications, whereas 6 were related to other causes. Of the 24 deaths in the radiation arm, 4 were the result of HL or toxicity and 20 were related to other causes, including 10 second cancers. Cardiac events were also much higher in the radiation arm. Continued on page 29

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Confusion Still Surrounds Prophylaxis for Venous Thromboembolism Risk assessment model could help identify candidates Table 1 Hierarchy of Successful VTE Prevention Programs

By Caroline Helwick San Diego, CA—Venous thromboembolism (VTE) occurs in 1% of hematologic malignancies and can lead to fatal pulmonary emboli, postthrombotic syndromes, bleeding as a result of anticoagulant treatment, and recurrent VTE. VTEs are potentially preventable with appropriate thromboprophylaxis, and numerous quality measures have been developed to enhance this practice. The “curve ball” is that there is “much confusion” regarding VTE prophylaxis, said Richard H. White, MD, of the University of California Davis School of Medicine, who spoke at a special symposium on quality indicators in hematology.

“VTE quality and safety measures are here to stay, and preventing VTE in hospitalized patients is a major goal.” —Richard H. White, MD

In its most recent assessment (Ann Intern Med. 2011;155:625-632), the American College of Physicians (ACP) issued guidelines for VTE prophylaxis in hospitalized patients, noting that risk of VTE should be carefully assessed because there is no net benefit in lowrisk patients. The group also advised using pharmacologic prophylaxis rather than mechanical means. The ACP does not support universal VTE prophylaxis, stating the lack of

evidence that it reduces deep-vein thrombosis (although it does protect against pulmonary embolism) and the lack of an accurate means of assessing risks versus benefits. “But VTE quality and safety measures are here to stay, and preventing VTE in hospitalized patients is a major goal,” Dr White said. “The Centers for Medicare & Medicaid Services, The Joint Commission, and nongovernmental agencies all endorse prevention. Quality-of-care measures for VTE will evolve.” Prevention Measures “Will Take Work” “Setting up a VTE prevention program will take a lot of work and effort,” added Dr White. To institute optimal prophylaxis, there needs to be a hospital-wide policy to provide VTE prophylaxis to all appropriate patients. This requires “buy in” from all departments and the education of all caregivers. Simple order sets need to be created on paper or in the electronic health record. All must include VTE prophylaxis orders coupled with a risk assessment tool, or an “opt out” tool stating which patients can be appropriately excluded. A designated thrombosis expert (eg, hematologist) must “monitor the process,” he said. There are many barriers to useful protocols, for example, the risk tool is overly complicated; practical guidance is lacking (ie, a prompt does not link to a protocol); there is failure to update and streamline old order sets; there are too many risk categories; mechanical prophylaxis is allowed over medical

Chemotherapy Superior to... Continued from page 28 Today’s Radiotherapy, However, May Be safer Dr Meyer acknowledged that subtotal nodal irradiation is no longer standard practice. “The control arm would, today, be considered excessive and likely contributed to second cancers and cardiovascular events….but the use of radiation in this population would still include fields that would encompass the coronary arteries and potentially involve the heart and, depending on the extent of disease, substantial areas of the superdiaphragmatic

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structures. While the risk we saw would likely be reduced with modern strategies, we don’t know the magnitude of this.” Jane Winter, MD, of Northwestern University Feinberg School of Medicine, Chicago, who moderated a press briefing, commented, “Treatment of Hodgkin lymphoma is a real balance between achieving control and cure, while limiting long-term side effects. This presentation speaks to that balance and the importance of long-term follow-up in evaluating our new therapies.”—CH ■

Prevention program

Success rate

No policy of protocol

40%

Decision support without order sets

50%

Order sets but no decision support

50%

Decision support integrated into order sets at point of care

65%-85%

Protocol enhanced by other quality indicator efforts or other reliable strategies

90%

Oversight and feedback in real time

>95%

VTE indicates venous thromboembolism.

Table 2 VTE Risk Assessment Model Odds ratio for VTE

Points

History of congestive heart failure

8.6

History of rheumatologic or inflammatory disease

7.7

Fracture in past 3 mo

3.8

History of VTE

2.7

Heart rate ≥100 bpm on admission

2.5

History of cancer in past 12 mo

1.6

Oxygen saturation <90% or intubated on admission

1.9

White blood cell count ≥11 × 109/L on admission

1.9

Platelet count ≥350 × 109/L on admission

1.9

Risk factor

bpm indicates beats per minute; VTE, venous thromboembolism.

prophylaxis; there is failure to pilot, revise, and monitor; and there is too much separation (in time or space) between risk assessment and prophylaxis choices. Not all programs are successful, he noted, citing the ways to “get to 95%” (Table 1). Dr White said that patients lacking anticoagulation should be readily identified, nurses should be empowered to place pneumatic compression, physicians should be contacted if no anticoagulant is in place and there is no obvious contraindication, and program directors should have the “political will” to back up these interventions after risk assessment. simple Risk Assessment Model Investigators from the University of Vermont in Burlington described a simple risk assessment model for use with hospitalized patients. “The score is simple, relies only on information easily known at the time of admission, and could be incorporated into an

MARCH 2012

electronic medical record,” said Neil Zakai, MD, MSc. “It will allow clinicians to assess VTE risk at admission for medical inpatients and weight the risks and benefits of pharmacologic prophylaxis.” Dr Zakai and colleagues evaluated 299 cases of VTE and 601 matched controls, and found the rate of VTE per 1000 admissions to be 4.6. They identified factors that placed patients at greatest risk (Table 2) and generated a Medical Inpatients and Thrombosis Study Score. Using a cutoff of ≥2 as indicative of high risk, they determined that the probability of VTE in the absence of prophylaxis for a score <2 was only 1.5 per 1000 admissions but was 8.8 for a score ≥2; in their population, 74% of cases and 39% of controls were considered at high risk. Dr Zakai suggested that this model could be applied to studies to determine the optimal VTE prevention strategies in medical inpatients, including patients with cancer. ■

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ASH ANNUAL MEETING

High-Risk Myelodysplastic Syndrome: First-Line Treatment Choices Often Not Supported by Evidence Many opt for a drug without demonstrated survival advantage By Caroline Helwick

review of treatment patterns for higher-risk myelodysplastic syndrome (MDS) shows growing use of lenalidomide, despite the lack of phase 3 survival data supporting this approach, according to research conducted at the Mayo Clinic Florida, Jacksonville, in collaboration with Xcenda, a research and consulting firm. Since 2006, lenalidomide has been approved for the treatment of anemia in lower-risk patients with MDS and deletion of chromosome 5q (del[5q]). However, no phase 3 survival data have been presented with lenalidomide in patients with higher-risk MDS, nor is it an expert consensus first-line treatment recommendation in the higher-risk setting, James M. Foran, MD, of the Mayo Clinic Florida, pointed out. The hypomethylating agents azacitidine and decitabine are both approved for higher-risk MDS. Azacitidine has shown a survival advantage compared with conventional-care regimens whereas decitabine, versus best supportive care, has not.

“In view of the availability of these 3 FDA [US Food and Drug Administration]-approved agents, we sought to evaluate the change in first-line treatment preference for higher-risk MDS among American hematologyoncology providers from 2006 to 2010 in relation to pertinent survival data as they became available,” Dr Foran said.

treatment from up to 10 relevant available or emerging first-line options. In the non-del(5q) scenario (20062010), a clear and significant shift toward greater azacitidine preference was apparent, from 40% in 2007 to 78% in 2010. There were declines in the use of both decitabine and lenalidomide over time.

“These findings suggest there are important educational gaps concerning the available phase 3 survival data supporting first-line prescribing preferences for patients with higher-risk MDS, and efforts to address this gap via evidencebased approaches are warranted.” —James M. Foran, MD

The analysis included 1960 providers who took part in a prospective annual research series. The physicians were presented with a scenario of an older patient with higher-risk MDS and specific cytogenetic abnormalities; they then indicated their preferred

For the same scenario with del(5q), treatment preferences also changed significantly over time (2008-2010), with decitabine use declining and azacitidine and lenalidomide use increasing. In 2010, decitabine was preferred by 11% of physicians; 42%

preferred azacitidine and 42% preferred lenalidomide. “Significant changes in first-line treatment preferences among providers for patients with higher-risk MDS are demonstrated in this prospectively acquired 5-year database. Between 2008 and 2010, an increasing divergence in preferences for azacitidine rather than decitabine as first-line therapy in patients with non-del(5q) higher-risk MDS is evident. When the presence of a abnormality is added to the same higher-risk scenario, treatment preferences during the same 3-year interval are markedly different, with a significantly increased preference for lenalidomide, despite no available phase 3 survival data supporting this approach,” Dr Foran said. “These findings suggest there are important educational gaps concerning the available phase 3 survival data supporting first-line prescribing preferences for patients with higher-risk MDS, and efforts to address this gap via evidence-based approaches are warranted.” ■

Cryoprecipate Is Overused, an Unnecessary Expense Inappropriate use as high as 70% among surgeons San Diego, CA—Only 30% of cryoprecipitate was used in accordance with established guidelines in a tertiary care center, in a study presented at ASH 2011 by researchers from Beth Israel Medical Center, Newark, NJ. “Hence, it seems that opportunities may exist for lower cryo usage,” said Manpreet K. Sandhu, MD, of the hematology/ oncology department at Beth Israel. The literature has suggested that blood products, including cryoprecipitate, are overused. Their appropriate indications, and cryo constituent, according to the American Association of Blood Banks, are: • Hypofibrinogenemia or dysfibrinogenemia: fibrinogen • Factor XIII deficiency: factor XIII • Bleeding associated with hemophilia A, or von Willebrand disease: factor VIII or von Willebrand factor • Uremic bleeding: factor VIII and von Willebrand factor. Dr Sandhu and colleagues conducted a retrospective audit from January to May 2011, examining medical

records and laboratory data of all patients who received cryo. The number of units transfused per patient, as well as the hospital service requesting the transfusion, were noted. The indication for cryo in each case was evaluated as appropriate or inappropriate, according to the guidelines.

“It is important to use cryo judiciously, to decrease the risks associated with transfusions, such as transmission of infectious agents, as well as save the cost of unnecessarily transfused blood products.” —Manpreet K. Sandhu, MD Sixty-two patients received 71 pooled cryo transfusions, for a total of 691 units. Of the 71 transfusions, 61 in 52 patients (585 units) were evaluable.

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The mean number of units per transfusion was 9.7. The hematology/oncology department was the second-highest user of cryo (30%), whereas cardiothoracic surgery was used the most (62%); the remainder was used by pediatrics (4%) and obstetrics/gynecology (4%). All transfusions were given in the setting of bleeding, the most common reason being postoperative bleeding (34%), without a clear indication and predominantly ordered by cardiothoracic surgery (82%). In 8 patients, 81 units (14%) were transfused to correct uremic bleeding, all ordered by hematology/oncology. “Most use was by surgeons. They had a patient on the table, bleeding, and they should have determined whether the patient truly needed this. Cryo is indicated only if the patient has low fibrinogen. Surgical hemostatis and reversal of anticoagulation (65% and 4%, respectively, of the use of cryo) are not indications,” Dr Sandhu said. Overall, only 30% of cryo units were

transfused appropriately as per guidelines, 53% for hypofibrinogenemia and 47% for uremic bleeding.

The total cost of inappropriate transfusions was $28,838 (calculated at $58 per unit).

“The highest incidence of cryo transfusions for appropriate indications was in the hem/onc department (75%),” he said. The total cost of inappropriate transfusions was $28,838 (calculated at $58 per unit), the investigators determined. “It is important to use cryo judiciously, in order to decrease the risks associated with transfusions, such as transmission of infectious agents, as well as save the cost of unnecessarily transfused blood products,” Dr Sandhu concluded.—CH ■

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VBCC PERSPECTIVE

Can Value-Based Cancer Care Address the Challenges Faced by Specialty Pharmacies in Oncology? By Atheer A. Kaddis, PharmD Vice President, Managed Markets, Diplomat Specialty Pharmacy, Flint, MI

pecialty pharmacies are facing specific challenges in the ways they interact with payers, providers, and even with the pharmaceutical industry in relation to access and delivery of cancer drugs.

Limited-Distribution Drugs Although not limited to oncolytics, a major challenge specialty pharmacies face in relation to cancer drugs is with limited-distribution drugs. This especially relates to oral oncolytics, which are the primary type of cancer drugs that specialty pharmacies manage. The main challenge a specialty pharmacy faces in trying to provide quality care to patients, and in having a partnership with oncologists, is the issue of limited-distribution processes. If a specialty pharmacy has access to 80% of the oral oncolytics in the market, and another oral oncolytic is introduced to the market where the specialty pharmacy is not included in that limited-distribution network, this directly interferes with the pharmacy’s ability to provide a continuum of care for patients it serves. It also is a challenge for the relationship with the oncologist’s practice, where the specialty pharmacy is trying to support the practice for all of its oral oncolytic needs. Therefore, the oncology practice now has to send the prescription to a different specialty pharmacy to fulfill that prescription. This also causes a challenge for payers. If a new drug is approved and the preferred specialty pharmacy for a payer does not have access to that drug, the payer then has to send that prescription to a competitor specialty pharmacy with contracted discounts that may vary significantly from the discounts that could have been offered by the preferred specialty pharmacy as a result of contractual agreements. This challenge is not only specific to cancer drugs, but because oncology is such a “high-touch” category, it highlights the challenges this puts on the ability of the specialty pharmacy to provide all the patients’, payers’, and providers’ needs. Buy and Bill Another challenge involves infused chemotherapy drugs, which fall under the “buy-and-bill” process today. Oncologists buy these drugs from wholesalers or directly from the drug

manufacturers. They administer infusions in the oncology practice, bill the payer, and are reimbursed from the payer. Therefore, the specialty pharmacy today has a very limited role in the care of a patient who is receiving an infused chemotherapy drug. That presents an issue when a patient receives both an infused chemotherapy drug and an oral oncolytic, because for that patient, the specialty pharmacy is dispensing the oral drug and the oncology practice is administering the infused drug. This situation creates a break in the continuity of care for that patient, because the specialty pharmacy has little or no information on the infused drug and cannot provide complete services to that patient, as in the case of the oral oncolytics. However, it is very likely that in the near future, as reimbursement is gradually being reduced for infused chemotherapies, and as the drug shortages that we are experiencing today become even more of a problem, oncologists will likely try to reach out to the specialty pharmacy to order their infused chemotherapies. Class of Trade This, in turn, will become a challenge of the class-of-trade issue. Some manufacturers sell an infused chemotherapy drug to an oncologist, or to a wholesaler to sell to an oncologist, at a much deeper discount than the price available to a specialty pharmacy for these medications. This is the result of what is known as “class of trade.” There is a physician class of trade, a hospital class of trade, and even retail pharmacy and mail order classes of trade, but there is no specialty pharmacy class of trade today. The special-

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MARCH 2012

ty pharmacy is usually buying the drugs at the same discount level as retail pharmacies, so specialty pharmacies are not getting much of a discount on these agents. This becomes a problem when an oncologist decides to order the drug from a specialty pharmacy and let it bill the health plan for that drug. The amount that the pharmacy will be reimbursed from the health plan is likely much lower than the cost of the drug for the pharmacy. That puts any potential profit on the drug at risk for the specialty pharmacy. Therefore, as reimbursement is reduced for oncologists, it will create a new problem, because oncologists may not be able to turn to specialty pharmacies to order these drugs.

There is considerable advantage to specialty pharmacy being more involved on the whole with oncolytics, and not just with oral oncolytics. They can run the prescription through the prior authorization process; they can make sure that genomic testing is done for appropriate patients, and that the results are back before a patient receives the medication. This challenge was highlighted by the Centers for Medicare & Medicaid Services Competitive Acquisition Program that aimed to reimburse specialty pharmacies at average sales price plus 6%. Most specialty pharmacies could not afford to participate in this program, and the program has not been continued. Value-Based Reimbursement There is considerable advantage to specialty pharmacy being more involved on the whole with oncolytics, and not just with oral oncolytics. I would argue that the advantage is for all stakeholders, including oncologists, if the specialty pharmacy is dispensing all of the drugs, which allows the phar-

macy to provide other services to patients. Specialty pharmacies can manage the prescription through the prior authorization process; they can make sure that genomic testing is done for appropriate patients, and that the results are back before a patient receives the medication, to ensure that the drug is being administered according to nationally accepted guidelines or the payer’s established criteria. Specialty pharmacies can also provide educational materials, so a patient receiving a chemotherapy drug will know what to do if side effects occur. This type of support is now provided by the specialty pharmacy. In addition, especially for oral oncolytics, before a drug is dispensed to patients who have a high out-of-pocket cost, the specialty pharmacy can work with various organizations to help with financial assistance for the patient and ensure appropriate adherence. This can dramatically improve adherence to therapy, especially for self-administered oncolytics. Specialty pharmacies can also help patients and manufacturers with Risk Evaluation and Mitigation Strategies (REMS) to ensure that patients are receiving medications in accordance with prescribing requirements and to provide data to manufacturers to ensure that their medications are being used according to US Food and Drug Administration requirements. The big challenge for oncologists is that the reimbursement structure for cancer care is often skewed toward drug reimbursement rather than accurate reimbursement for all of the services being provided by oncologists. However, if oncologists are reimbursed for the value of cancer care that they are providing, using measurable metrics, that takes the burden of reimbursement away from the drug itself to focus on the value of care delivery. From the payers’ standpoint, if they are able to reduce the reimbursement on the drug and pay doctors for the value of care that is being provided, the payers can focus on paying for better-quality care, improved metrics, and more appropriate use of drug therapy, rather than for the use of higher-cost drugs. From the manufacturers’ standpoint, this can also be a benefit, because now their products will be Continued on page 33

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CHEMOTHERAPY 2.0

Chemotherapy Administration Sequencing Chart By Robert Mancini, PharmD, and Jessie Modlin, PharmD Dr Mancini and Dr Modlin are oncology pharmacists, St. Luke’s Mountain States Tumor Institute, Boise, ID

ncology pharmacists receive numerous questions regarding the sequence of chemotherapy administration. Several chemotherapy agents (eg, doxorubicin, docetaxel, paclitaxel) are extensively metabolized through the cytochrome P450 pathway, and many chemotherapy agents (eg, taxanes, platinum agents) have high degrees of protein binding. In addition, many chemotherapy agents have cell cycle–specific mechanisms of action that may

Adapted with permission from Mancini R, Modlin J. Chemotherapy administration sequence: a review of the literature and creation of a sequencing chart. J Hematol Oncol Pharm. 2011;1(1):17-25.

Robert Mancini, PharmD increase the cytotoxicity or antagonize the mechanism of the second agent. We conducted a literature

search for data supporting sameday chemotherapy administration sequences. This was achieved by searching PubMed using keywords and any combination of the drug name with “administration,” “sequencing,” or “interactions.” The literature search yielded 110 articles for evaluation. The original 110 articles provided evidence for 62 potential chemotherapy combination sequences. Based on the types of studies examined, 27 potential sequences remained clinically undefined because of a lack of clinical relevance of the studies that supported them, 21 combinations were justified with a particular sequence, and 14 combinations had evidence that

sequence was irrelevant to outcomes. From these data, a chemotherapy administration sequence chart was created as a reference for nurses and pharmacists. From this literature search, we produced a chemotherapy sequencing chart (see pages 34, 35) that helps define recommended sequences of administration based on available published data. The sequence, if not clearly defined in the literature, should follow the sequence of administration published in that regimen’s original study. ■

See chart on pages 34 & 35

VBCC PERSPECTIVE

Can Value-Based Cancer Care... used appropriately. Medications will be used based on national guidelines and diagnostic testing, thereby improving overall outcomes for patients, providers, payers, and drug manufacturers. We have started down the road of paying for services and pay for performance for cancer care; however, the road is long, and there is much more work to be done to achieve the goals of value-based cancer care. Much hope is being placed in the development of accountable care organizations and in the patient-centered medical home, but it remains to be determined if these programs will be the solution long-term. Biosimilars Specialty pharmacies are going to play a major role in the introduction of biosimilars. They will be collaborating with payers to ensure that policies are followed regarding biosimilars. Some difficult decisions will have to be made by payers as to whether they consider biosimilars alternatives to existing branded drugs. We can expect to see a 15% or 20% discount on the branded agent with biosimilars, and some manufacturers may then offer more rebates on their

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branded drugs to compete with the biosimilar agents. Some payers will prefer biosimilars in certain situations and brand-name drugs in others, but this will be largely driven by financial issues and contracts, as long as there is comfort in the ability to interchange the drugs clinically.

If oncologists are reimbursed for the value of cancer care that they are providing, using measurable metrics, that takes the burden of reimbursement away from the drug itself to focus on the value of care delivery. Specialty pharmacies are going to have an increased role in the dispensing of biosimilars, such as monoclonal antibodies, in cancer care. Today, these are primarily buy-and-bill agents. In the future, specialty pharmacy will likely have more of a role in dispensing and supporting these medications. Drug shortages, which are related mainly to generic drugs today, may also drive the uptake of biosimilars.

Continued from page 32

Evolving Role of specialty Pharmacy: From Dispensing of Drugs to Patient services and Cost Management Specialty pharmacy is evolving and is no longer focused only on the dispensing of drugs, as was the case 5 or 10 years ago. Some pharmacies are now working with payers on medical management services, providing all the back-end clinical, financial, and educational support around the dispensing of a specific drug, especially in relation to cancer drugs. Specialty pharmacies have specific strategies in terms of cost management of extremely expensive cancer drugs, and this does not necessarily mean discounts on drugs. The pricing and distribution of drugs are commodities today. Cost management, and significant savings, for a payer can come from utilization management, patient adherence, and clinical programs and pathways in oncology, making sure that the appropriate drugs are being used for the appropriate patients. Specialty pharmacies are therefore heading toward support of these services, including managing adherence, partial-fill programs, and clinical programs that relate to cancer drugs.

MARCH 2012

These services are going to drive the role of specialty pharmacies going forward rather than dispensing drugs and trying to get a deeper discount from manufacturers. Instead, specialty pharmacies are going to differentiate themselves around the services and value they provide, by helping payers manage costs related to appropriateness of therapy, comparative effectiveness, and patient adherence. That is expected to be the future for specialty pharmacy, and it is an exciting prospect. ■ Advances in Childhood Leukemia Advances in drug therapies have turned childhood leukemia, once considered a death sentence, to a curable disease in the majority of patients. The 5-year survival rates for acute lymphoblastic leukemia (ALL) among children rose from 84% between 1990 and 1994 to 90% between 2000 and 2005 for all agegroups, except for those aged ≤1 years. ALL is the most common type of leukemia in children. Read the complete details in the May issue of Value-Based Cancer Care.

www.ValueBasedCancerCare.com

CHEMOTHERAPY 2.0 Continued from page 33

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www.ValueBasedCancerCare.com

CANCER DRUGS

Vismodegib: A New Treatment Option for Basal-Cell Carcinoma By Rhonda Williams

asal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC), commonly referred to as nonmelanoma skin cancers (NMSCs), are the most common types of cancers in the United States. These 2 cancers account for approximately 2 million cases of skin cancer annually.1 BCC is approximately 4 to 5 times more common than SCC.2 Although rarely metastatic, BCC and SCC can cause substantial local destruction involving extensive areas of soft tissue, cartilage, and bone, as well as disfigurement. It is estimated that the cost of treating these NMSCs in the Medicare population exceeds $400 million annually.3 The Management of BCC The goal of primary treatment for BCC of the skin is curing the tumor. Surgical approaches are the most common treatment and offer the most effective method for achieving cure for this condition; however, considerations related to preserving function; preservation, restoration, or physical appearance; and patient preference all may lead to the choice of radiation therapy as the primary treatment to achieve optimal overall results.4 For patients who have low-risk, superficial BCC, or for those in whom surgery or radiation is contraindicated or unfeasible, topical therapies or vigorous cryotherapy may be considered, although the cure rate with these options may be lower. In addition, for patients at high risk for multiple primary skin tumors, increased surveillance and prophylactic measures may be indicated.4 Postoperative radiation has been widely accepted as a valuable approach for high-risk patients to reduce the rate of recurrence. Adjuvant radio-

therapy is recommended by the National Comprehensive Cancer Network panel for any NMSC that shows evidence of substantial perineural involvement, that is, involvement of more than a few small or large nerves.4 All patients with BCC of the trunk and extremities who have undergone lymph node dissection should be considered for adjuvant radiation therapy; despite resection followed by radiation therapy, patients at high risk often experience locoregional recurrence and distant metastasis. The behavior of cutaneous BCC is characteristically indolent, but it rarely metastasizes to distant areas. When the disease does metastasize to distant sites, systemic therapy is indicated.4 A New Treatment option for Advanced Disease Extensive research has led to advances in the understanding of the genetics of NMSCs.5 Among these advances, an understanding of the role of the sonic hedgehog pathway has played a pivotal role in the pathogenesis of BCCs. We now know that mutations in the PTCH, the patched gene located on chromosome 9q, and codes for the sonic hedgehog receptor, are the underlying causes of nevoid BCC syndrome. These mutations are also common in sporadic BCCs. In addition, specific mutations in the tumor suppressor gene p53 appear to be involved in the development of NMSCs.5 On January 30, 2012, the US Food and Drug Administration (FDA) approved vismodegib (Erivedge), a hedgehog pathway inhibitor, for the treatment of BCC in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. The FDA used its priori-

Table 1 Objective Response Rate with Vismodegib: Efficacy in Evaluable Patients Response Overall response rate, N (%)a 95% CI Complete response Partial response

Metastatic BCC (N = 33)

Locally advanced BCC (N = 63)

10 (30.3)

27 (42.9)

15.6-48.2

30.5-56.0

0 (0)

13 (20.6)

10 (30.3)

14 (22.2)

7.6

5.6-nonestimable

5.7-9.7

Median response duration, months 95% CI

a Confirmed by independent review facility. BCC indicates basal-cell carcinoma; CI, confidence interval. Source: Reference 6.

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ty review process for the approval of vismodegib; this approval was based on the results of an international, open-label, single-arm trial that evaluated the efficacy and safety of vismodegib in 104 patients with locally advanced or metastatic BCC. The approval of vismodegib represents the first approved therapy for patients with locally advanced or metastatic BCC whose disease was not amenable to surgery or radiation therapy, which are the standard treatments for this serious condition. In addition, vismodegib’s oral formulation may be viewed as more convenient for patients and may increase patient adherence to therapy. Similarly, having this oral formulation may affect patients’ ability to pay for their prescription, and some type of patient assistance program may be indicated to increase their ability to obtain the drug.

Clinical Pharmacology and Pharmacokinetics Vismodegib binds to and inhibits smoothened, a transmembrane protein involved in hedgehog signal transduction.6 Vismodegib is eliminated via multiple pathways, but it is predominantly excreted unchanged. Inhibition of the cytochrome (CY) P450 is not predicted to alter vismodegib’s systemic exposure, because steady-state plasma concentrations of vismodegib were observed in patients enrolled in vismodegib’s clinical trials who were being treated concomitantly with CYP3A4 inducers or CYP3A4 inhibitors.6 The results of in vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein; therefore, when vismodegib is coadministered with drugs that inhibit Pglycoprotein, such as clarithromycin, erythromycin, and azithromycin, systemic exposure to vismodegib and the incidence of adverse events may be increased.6 Drugs that alter the pH of the upper gastrointestinal tract may alter the solubility of vismodegib and reduce its bioavailability, but no formal studies have been conducted to evaluate the effect of gastric pH–altering drugs on the systemic exposure of vismodegib. Therefore, if vismodegib is coadministered with proton pump inhibitors, H2-receptor antagonists, or antacids, the systemic exposure of vismodegib may be decreased, and the effect of vismodegib on efficacy is unknown.6 The single-dose bioavailability of vismodegib is 31.8%. The systemic exposure of vismodegib is not affected by food; therefore, vismodegib may be

taken with or without food. The volume of distribution of vismodegib ranges from 16.4 L to 26.6 L. The plasma protein binding of the drug in patients is >99%. The primary route of elimination of vismodegib and its metabolites is hepatic, with 82% of the dose administered recovered in the feces and 4.4% recovered in urine. The dosing of vismodegib estimated elimination half-life is 4 days after continuous once-daily dosing and 12 days after administration of a single dose.6 Clinical Trial Evidence and Efficacy The efficacy and safety of vismodegib was evaluated in an international, single-arm, open-label trial of 104 patients with metastatic BCC (n = 33) or with locally advanced BCC (n = 71). Enrolled patients with locally advanced BCC had to have lesions that recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (ie, Gorlin syndrome, limitations because of the location of the tumor, or in cases where the lesion was unresectable or when surgical resection would result in substantial deformity). Patients received vismodegib 150 mg/day orally until disease progression or unacceptable toxicity occurred. The primary efficacy outcome of this study was determination of objective response rate (ORR), which was assessed by an independent review facility. In the cohort of patients with metastatic BCC, tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. In the cohort of patients with locally advanced BCC, evaluation of tumor response included measurement of externally assessable tumor (including scarring) and assessment for ulceration in photographs, radiographic assessment of target lesions when appropriate, and tumor biopsy.6 Table 1 outlines the response rates in both cohorts. Of the 104 patients enrolled in this study, 96 patients were evaluable for ORR: 33 patients in the metastatic cohort and 63 patients in the locally advanced BCC cohort. The median age of all patients evaluable for efficacy was 62 years; 46% of patients were aged ≥65 years. Of the patients in the metastatic BCC cohort, 97% of patients had received previous therapies, including surgery (97%), radiotherapy (58%), and systemic therapies (30%). Among the patients with locally advanced BCC, 94% had previous therapies, including surgery (89%), Continued on page 38

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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

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Vismodegib: A New Treatment Option... radiotherapy (27%), and systemic/ topical therapies (11%).6 The ORR was 30.3% in patients with metastatic BCC and 42.9% in patients with locally advanced BCC. There were no complete responses in the metastatic cohort compared with 20.6% of patients in the locally advanced BCC cohort who had a complete response. The median duration of response in the metastatic and the locally advanced BCC cohorts was 7.6 months.6 safety Profile When vismodegib monotherapy was administered at daily oral doses of ≥150 mg in 4 open-label, uncontrolled, doseranging or fixed single-dose clinical trials enrolling a total of 138 patients with advanced BCC, the most common adverse reactions (≥10% of patients) were muscle spasms, alopecia, dysgeusia, and others, as shown in Table 2. Furthermore, 3 of 10 premenopausal women developed amenorrhea while being treated with vismodegib. In addition, treatment-emergent grade 3 laboratory abnormalities were observed in 11 patients in clinical trials; 6 (4%) patients experienced hyponatremia, 2 (1%) patients experienced hypokalemia, and azotemia was reported in 3 (2%) patients.6 The safety and effectiveness of vismodegib has not been established in patients with renal or hepatic impairment. In addition, clinical trials of vismodegib did not include sufficient numbers of patients aged ≥65 years to establish whether this patient population responded different to vismodegib than younger patients. The safety and effectiveness of vismodegib have not been established in pediatric patients.6 Warnings and Precautions Associated with Vismodegib Black Box Warning: Embryo-Fetal Death and Severe Birth Defects Vismodegib can result in severe birth defects or embryo-fetal death. Vismodegib is embryotoxic and teratogenic in animals. Teratogenic effects with this medication included severe midline defects, missing digits, and other irreversible malformation. In rats at maternal exposures lower than human exposures of the recommended dose (150 mg/day), vismodegib was teratogenic, embryotoxic, and fetotoxic. Malformations in rats included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardation and variations were also observed. Pregnancy status should be verified

Continued from page 36

Table 2 Adverse Reactions Occuring in ≥10% of Patients with Advanced BCC MedDRA preferred term

All patients with advanced BCC (N = 138) a

All grades, N (%)

Grade 3, N (%)

Grade 4, N (%)

Nausea

42 (30.4)

1 (0.7)

–

Diarrhea

40 (29)

1 (0.7)

–

Constipation

29 (21)

–

19 (13.8)

–

55 (39.9)

7 (5.1)

1 (0.7)

62 (44.9)

10 (7.2)

–

35 (25.4)

3 (2.2)

–

Gastrointestinal disorders

Vomiting

General disorders and administration site conditions Fatigue Investigations Weight loss Metabolism and nutrition disorders Decreased appetite

Musculoskeletal and connective tissue disorders Muscle spasms

99 (71.7)

5 (3.6)

–

Arthralgias

22 (15.9)

1 (0.7)

–

Dysgeusia

76 (55.1)

–

Ageusia

15 (10.9)

–

88 (63.8)

–

Nervous system disorders

Skin and subcutaneous disorders Alopecia a

Grading according to NCI-CTCAE v3.0. BCC indicates basal-cell carcinoma; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE v3.0, National Cancer Institute Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0. Source: Reference 6.

before initiation of treatment with vismodegib. Both male and female patients should be made aware of these risks. Female patients should be advised of the need for contraception, and male patients should be advised of the potential risk to the fetus of vismodegib exposure through semen. Patients should be advised to notify their healthcare provider immediately if they suspect that they or their female partner may be pregnant. Patients exposed to vismodegib during pregnancy, either directly or through seminal fluid, should be encouraged to participate in the vismodegib pregnancy pharmacovigilance program.6 Blood Donation Patients should be advised not to donate blood or blood products while receiving vismodegib and for at least 7 months after the last dose of vismodegib is received.6 Dosing The recommended dose of vismodegib is 150 mg orally, once daily until evidence of disease progression exists

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or until unacceptable toxicity is noted. If a dose of vismodegib is missed, the dose should not be made up. Dosing should resume with the next scheduled dose.6 Vismodegib may be taken with or without food. The capsule should be taken whole and should not be opened or crushed. Vismodegib is not available at local drugstores and is only distributed through specialty pharmacies. Conclusion Vismodegib, a hedgehog pathway inhibitor, was approved by the FDA early this year for the treatment of BCC in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. This approval, which was done under the FDA’s priority review process, was based on the results of an international, open-label, single-arm trial that evaluated the efficacy and safety of vismodegib in 104 patients with locally advanced or metastatic BCC. Vismodegib is the first FDAapproved agent for the treatment of this serious condition. Although BCC

is usually curable if lesions are contained to a small area of skin, in rare cases the lesions can become disfiguring, invade surrounding tissue, and/or metastasize. In these instances of advanced BCC, the disease cannot be effectively managed with surgery or radiation, the standard treatments for this common skin cancer. This recent approval of vismodegib fills a gap and an unmet need in the treatment paradigm of this serious condition. ■ References 1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. www.cancer.org/acs/groups/content/@epidemiol ogysurveillance/documents/document/acspc029771.pdf. Accessed February 17, 2012. 2. Miller SJ, Alam M, Andersen J, et al. Basal cell and squamous cell skin cancers. J Natl Compr Cancer Netw. 2010;8:836-864. 3. Mudigonda T, Pearce DJ, Yentzer BA, et al. The economic impact of non-melanoma skin cancer: a review. J Natl Compr Canc Netw. 2010;8:888-896. 4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Basal Cell and Squamous Cell Skin Cancers. Version 1.2012. www.nccn.org/professionals/physician_gls/pdf/ns. pdf. Accessed February 3, 2012. 5. Benjamin CL, Melnikova VO, Ananthaswamy HN. P53 protein and pathogenesis of melanoma and nonmelanoma skin cancer. Adv Exp Med Biol. 2008;624:265-282. 6. Erivedge [vismodegib; prescribing information]. South San Francisco, CA: Genentech, Inc; 2012.

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Wilshire Oncology Medical Home Pilot... see is to stabilize the profession and the reimbursement for the profession. So doctors know, “My job is to go and practice medicine, and I will be rewarded appropriately.” You have all these companies and people taking money, changing rules and contracts, and there has been no stability. In my career, it has been a constant change. Every day that I am not seeing a patient is a tragedy. I have become a business and a health plan expert. I evolved my career this way to answer the question, “What is inhibiting me from taking better care of my patients?”

working together. Our doctors have all developed expertise in different tumors. We listen to each other and work together. Our mid-level providers, our nurses, and our staff are our

Continued from page 12

partners. I am proud of what every member of our team contributes. They all know what it is we are doing and why. We show data at our monthly meetings,

and we get ideas and constant improvements from the health plan, as well as from our staff and patients. We are fully engaged in healthcare reform though our medical home pilot. ■

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If we can share that—have doctors and nurses taking care of people and sharing their years of expertise, but knowing the system is working to let them do that—then everyone wins. The challenge is trust. Doctors are sure that if they are transparent about what they are doing they will not get paid. So our pilot work has just taken a position of validating information and being transparent, because the health plans will tell you over and over that they want the doctors to stay in business and they want their patients to get appropriate cancer care. Our biggest challenge right now is that doctor groups have been too small, and it has taken too much time for each group to negotiate with their many payers. Doctors do not want third parties in the middle taking money when they are doing the work. This is an opportunity to have a plan in place where doctor groups can stay in private practice and avoid working for hospitals, where patients are charged 3 to 5 times more. It is also a way to stay cost-effective for patients and healthcare premiums. If we are going to have people in private practice, it has to go a lot smoother; it has to be more efficient and standardized, so doctors can go back to practicing medicine. So again, in oncology, our group is unique to have 10 doctors and an extensive staff who actually have fun

RJ Health Systems has established and continuously maintains a Library of Drug Intelligence that provides the most comprehensive, trusted, and up-to-date coding and reimbursement information in the industry. ReimbursementCodes.com incorporates the CMS HCPCS and AMA CPT Drug codes into a system that crosswalks each drug code with the drug’s NDC and brand/generic name. Please visit www.rjhealthsystems.com to learn more about our products and services listed below:

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