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

MAY 2012 VOL 3 NO 3

www.ValueBasedCancerCare.com NCCN 2012 CONFERENCE

AVBCC Second Stakeholder Integration Conference Cancer care in 2012—strategies for optimizing value

Optimal Care for Patients with Cancer: Who Decides? Multiple stakeholders now determine matters of quality and value By Audrey Andrews Hollywood, FL—Cancer care today is influenced by an ever-broadening array of players, and what was once an intimate relationship between patient and physician now involves multiple decision makers. At the 2012 National Comprehensive Cancer Network (NCCN) meeting, a panel of various

stakeholder groups addressed the questions of what and who defines “optimal care” for today’s patient. Moderator Clifford Goodman, PhD, Senior Vice President at the Lewin Group, Falls Church, VA, summarized the panel’s observations: “The locus of Continued on page 18

ANNUAL CONFERENCE

Payer Trends in Oncology: Challenges and Solutions Putting patients first remains a key component Houston, TX—On March 29-31, 2012, approximately 200 oncologists, payers, employers, managed care executives, pharmacy benefit managers, and other stakeholders convened for the Second Annual Stakeholder Integration Conference of the Association for Value-Based Cancer Care (AVBCC). The mission of the conference was to align the various perspectives around the central needs of defining value in cancer care and developing strategies for enhancing patient outcomes.

By Caroline Helwick

Continued on page 10

ACCC ANNUAL MEETING

Ready or Not, Value-Based Purchasing Is Coming Near You CMS establishes incentives for quality, not quantity, of care By Neil Canavan Baltimore, MD—It has been said that a journey of a thousand miles begins with a single step. It is with this sensibility that Donald P. Howard of the Centers for Medicare & Medicaid Services (CMS) began his presentation at the 2012 Association of Community Cancer Centers (ACCC) meeting, detailing the current state of the hospital value-based purchasing (VBP) program. The VBP program attempts to rewrite a systemic paradigm, mov-

ing from an approach in which CMS is a passive payer based on volume to a direct involvement by CMS as a purchaser of quality care. “The VBP program is a way to incentivize hospitals to move forward in this direction,” he said. Established in the Affordable Care Act, the VBP program will financially reward hospitals by the outcomes of the service they provide. “The infrastructure is already in place to do Continued on page 26

Houston, TX—The need to optimize the treatment of patients with cancer while using healthcare resources wisely—in other words, providing “valuebased cancer care”—is not a topic of debate, but how to achieve this press-

ing goal is far from clear. In a panel discussion during the Association for Value-Based Cancer Care’s Second Annual Conference, strategists from the payer side of the issue discussed Continued on page 11

INSIDE IN THE LITERATURE

...............

Is higher cost of cancer care in US worth it? Cancer therapies’ value given preferential status VALUE PROPOSITIONS

............

Consider value in your clinical decisions CONFERENCE

Michigan oncology medical home Seeking value in oncology Aligning reimbursement with outcomes Community oncology in crisis

NCCN ANNUAL CONFERENCE . .20

Clinical practice guideline updates Updated guidelines add 3 panels

ACCC ANNUAL MEETING

.......

AACR ANNUAL MEETING

.......

Cost-containment top trend in community centers Coping with cancer drug shortages

Advances in personalized medicine Metformin protects against cancers

CONTINUING EDUCATION . . . . . . .34

Considerations in multiple myeloma

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 Votrient Receives New Indication for Advanced Soft-Tissue Sarcoma The US Food and Drug Administration (FDA) approved the oral agent pazopanib (Votrient; GlaxoSmithKline) for the treatment of patients with advanced soft-tissue sarcoma who have previously received chemotherapy. Pazopanib received orphan drug designation for this indication and is the first agent to receive approval for this indication in many years. Votrient works by interfering with the angiogenesis process (ie, the growth of new blood vessels that feed the growth/survival of solid tumors). Soft-tissue sarcoma is a rare type of cancer that begins in muscle, fat, fibrous tissue or other tissues and has many subtypes; it occurs in approximately 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to the approval of this drug. Pazopanib is not approved for patients with adipocytic soft-tissue sarcoma or gastrointestinal stromal tumors. The most common side effects in patients receiving pazopanib were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration. Votrient carries a boxed warning regarding the potential risk for hepatotoxicity, which can be fatal. Patients should be monitored for liver function, and the drug should be stopped if liver function declines. This agent is already approved for the treatment of advanced kidney cancer. (April 26, 2012)

“Today marked an important step for the TSC community, as Afinitor is now the only approved medicine to reduce kidney tumor burden in these patients,” said John Bissler, MD, Clark D. West Chair of Nephropathy, Cincinnati Children’s Hospital. The most common side effects with

Afinitor First Drug Indicated for Noncancerous Kidney Tumors The FDA accelerated the approval of the oral mTOR kinase inhibitor everolimus (Afinitor; Novartis) for the treatment of kidney tumors (ie, renal angiomyolipomas) not requiring immediate surgery in patients with tuberous sclerosis complex (TSC). This is the first drug approved specifically by the FDA for this patient population. TSC is a rare genetic disease causing noncancerous tumors in the kidney, brain, and other organs. There are approximately 40,000 patients with TSC in the United States, of whom 70% or 80% develop kidney problems. The FDA approval was based on the double-blind, randomized, placebocontrolled, international, multicenter phase 3 EXIST-2 (Examining Everolimus in a Study of TSC) trial, which showed a 42% angiomyolipoma response rate with everolimus compared with 0% response with placebo.

VALUE-BASED CANCER CARE

everolimus included inflamed/sour mouth, nausea/vomiting, skin problems, cough, headache, diarrhea, abdominal pain, joint pain/swelling, and upper respiratory infection. Everolimus is already approved as an orphan drug for advanced renalcell carcinoma after failure of treat-

ment with sunitinib (Sutent; Pfizer) or with sorafenib (Nexavar; Bayer/ Onyx), for progressive neuroendocrine tumors of pancreatic origin in unresectable, locally advanced or metastatic disease, and for subependymal giant-cell astrocytoma associated with tuberous sclerosis. (April 26, 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

MAY 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)

VOL. 3

NO. 3

In The Literature Are Higher Costs of Cancer Care in the United States versus Europe Worth It? The United States spends more on cancer care than European countries. Some people have argued that this extra expense is unwarranted, because US patients with cancer have similar

or worse outcomes despite this increased spending. However, data from a new study suggest that the higher spending for cancer in the United States than in 10 European countries may be worth the additional expense (Philipson T, et al. Health Aff [Millwood]. 2012;31:667-675).

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

VOL. 3

NO. 3

The survival differences in this study for patients who were diagnosed with cancer between 1995 and 1999 show that, on average, in the United States patients lived 11.1 years after a cancer diagnosis compared with only 9.3 years in Europe, an average increase of 1.8 years in survival. By

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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comparing these survival differences to the relative costs of cancer care, the researchers found that although US patients paid more for cancer care, they had better survival outcomes. Even after considering higher US costs for treatment, the extra survival time was worth an aggregate of $598 billion—an average of $61,000 per patient. For most solid-tumor cancers, in particular for breast and prostate cancers, even after considering the higher costs, US patients had greater survival gains than European patients. The value of additional survival gains was highest for patients with prostate cancer ($627 billion) or breast cancer ($173 billion). In addition, each $100 increase in per-capita spending on cancer— approximately $20,000 per patient with cancer—was associated with an average of another 2.3 years of life. The researchers concluded that the highercost cancer care in the US healthcare system may be “worth it,” because it delivers improved outcomes and longer survival for patients. They cautioned, however, that their findings do not prove a causal link between spending on cancer care and survival gains. The US survival gains may be a result of a more rapid uptake of new technologies, earlier access to new cancer drugs, or increased cancer screening. Furthermore, because they used databases from 1983 to 1999, these results may be outdated and skewed. Recent important changes in cancer care—including the introduction of costly new drugs and the increased use of diagnostic imaging— may lead to different results using more up-to-date data.

Cancer Therapies Given Preferential Status over Other Diseases in Assessing Value Cancer is the most dreaded of all diseases, the authors of a new study suggest, which may explain why policymakers have sometimes given cancer therapies preferential status over therapies for other conditions (Neumann PJ, et al. Health Aff [Millwood]. 2012;31:700-708). However, some oncologists and health economists believe that pharmacoeconomic evaluations and reimbursement decision makers should judge cancer interventions by the same standards as those used for all other medical conditions. This new study examined whether pharmacoeconomic analyses of therapies and biotechnologies, which help to inform payers in their coverage and reimbursement decisions, indeed give cancer interventions special treatment. Using a literature search for worldContinued on page 7

www.ValueBasedCancerCare.com

In This Issue

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

IN THE LITERATURE

NCCN ANNUAL CONFERENCE

Is higher cost of cancer care in US versus Europe worth it? Cancer therapies given preferential status when assessing value More….

Clinical practice guideline updates Updated guidelines include 3 new panels More….

VALUE PROPOSITIONS Incorporate value of cancer drugs into clinical decision-making More….

Associate Publisher Cristopher Pires cris@engagehc.com 732-992-1896 Director, Client Services Lou Lesperance, Jr. lou@engagehc.com Associate Editor Lara J. Lorton Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Director, Creative & Design Robyn Jacobs

2ND CONFERENCE The Michigan oncology medical home model Seeking value in oncology is like chasing an elephant Aligning reimbursement with outcomes Community oncology in crisis More….

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

Cost-containment top trend in community cancer centers Coping with cancer drug shortages More….

AACR ANNUAL MEETING Advances in personalized medicine Metformin protects against some cancers Role of whole-genome sequencing in cancer care More….

CONTINUING EDUCATION Considerations in multiple myeloma

Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

ACCC ANNUAL MEETING

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 Senior Vice President Medical Affairs, eviti, Inc

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

MAY 2012

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY Section Editor

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

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In The Literature Cancer Therapies Given... Continued from page 5

wide organizations that singled out cancer for special attention, Dr Neumann and colleagues found that some countries have created special assessment pathways for reviewing cancer therapies. Others have made exceptions to ease access to cancer therapies through special policies, based on disease severity or end-of-life care, or have implemented accelerated review or enhanced-access procedures for oncology products. In the United States, Medicare does not cover cancer and noncancer therapies at different rates, but cancer drugs receive special status by virtue of unique Medicare rules covering offlabel indications. Between 1999 and 2010, Medicare covered more cancerrelated diagnostic imaging and testing interventions (60%) than other interventions, such as medical devices (~19%), medications (~14%), or surgical procedures (~8%). Access to cancer drugs is greater in the United States than in other countries. For example, 100% of all cancer drugs approved by the US Food and Drug Administration between 2004 and 2008 were covered by Medicare, most of them without restrictions or additional requirements. By contrast, the UK National Institute for Health and Clinical Excellence recommended coverage for <50% of the cancer drugs licensed by the European Medicines Agency. Cancer is already the diagnosis associated with highest costs in terms of out-of-pocket medical expenses to patients, and as the costs of cancer therapies rise, policymakers wrestle with how to consider these costs. In the United Kingdom, Canada, and other countries, healthcare policymakers have sometimes made adjustments to cover cancer drugs, despite their poor cost-effectiveness. The researchers suggest that in the United States, those involved in drug assessments are unlikely to use explicit cost-effectiveness considerations to determine the clinical value of cancer therapies. Rather, they are using strategies such as (1) personalized medicine and patient-centered care as a way to limit access to therapies to patients who are most likely to benefit from those treatments, (2) tie payment more directly to patient outcomes, and (3) allow access to important advances, while trying to control costs.

mortality from prostate cancer. That controversy became more intense after a recent analysis of benefits and harms of PSA screening, conducted by the US Preventive Services Task Force, recommended against routine PSA screening in asymptomatic men. However, according to results from 2 additional years of follow-up in the European

Randomized Study of Screening for Prostate Cancer, PSA-based screening significantly reduces menâ&#x20AC;&#x2122;s long-term risk of death from prostate cancer, but not all-cause mortality (SchrĂśder FH, et al. N Engl J Med. 2012;366:981-990). The study involved 182,160 men (age, 50-74 years) in 8 European countries. The men were randomly as-

signed to the PSA-based screening group (N = 72,891) or to the control group of no screening (N = 89,352). The primary end point was mortality from prostate cancer. A total of 136,689 tests were performed, with a rate of 16.6% positive tests. At a median follow-up of 11 years, Continued on page 8

PSA Screening Reduces Prostate Cancer, but Not All-Cause, Mortality Controversy abounds regarding the question of whether routine prostatespecific antigen (PSA) testing reduces

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In The Literature PSA Screening Reduces... Continued from page 7

the 162,388 men in the core age-group (55-69 years) showed a rate ratio of 0.79 (95% confidence interval, 0.680.91; P = .001), corresponding to a 21% relative mortality risk reduction, favoring the PSA screening (the death rate

was 29% after adjusting for noncompliance). Overall, there were 9.66 prostate cancer cases per 1000 personyears in the PSA screening group versus 5.95 cases per 1000 person-years in the nonscreening group. The absolute reduction in mortality risk with PSA screening was 1.07 per

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

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1000 men at a median follow-up of 11 years. To prevent 1 death from prostate cancer in 11 years of follow-up, 1055 men would need to be screened, and 37 cancers would need to be detected. Nevertheless, despite the reduction in the mortality rate from prostate cancer, PSA screening had no effect on all-

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

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

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cause mortality in these men. The investigators suggest that more information on the balance of benefits and adverse effects, as well as the costeffectiveness of screening for prostate cancer, is needed before general recommendations can be made.

NIH: Offer Active Surveillance to Men with Localized Prostate Cancer Although most PSA-detected cancers are slow-growing and unlikely to cause death, most men opt to undergo immediate treatment in the form of surgery or radiation. The National Institutes of Health (NIH) convened a State-of-the-Science Conference to assess the evidence regarding observational strategies as an alternative to immediate treatment for localized prostate cancer (Ganz PA, et al. Ann Intern Med. 2012;156:591595). These treatments have substantial side effects, including impotence and urinary incontinence. Only a few men choose observational strategies instead of immediate treatment. Active surveillance differs from the older observational strategy of watchful waiting, which involves relatively passive patient follow-up, in which interventions occur only when symptoms appear. By contrast, active surveillance to detect disease progression involves proactive patient follow-up, with potential repeated biopsies and eventual treatment. To date, no randomized clinical trials have assessed the outcomes of patients who undergo active surveillance. However, early results of noncomparative cohort studies examining active surveillance in men with lowrisk disease show disease-free and survival rates that are similar to those reported for immediate treatment. The panel consensus was therefore that many men could benefit from active surveillance instead of immediate treatment, recommending that active surveillance is one of the options that should be offered to patients. In addition, the NIH panel noted that active surveillance is underused as a treatment strategy for many reasons. In some cases, when it is offered as a treatment option, it may be presented in a negative manner (ie, by referring to it as “doing nothing”). In other cases, “cancer” tends to set off an emotional response among patients that causes them to choose a more active treatment, regardless of potential side effects. Therefore, the panel suggests that physicians consider modifying the use of the word “cancer” when delivering a prostate cancer diagnosis, to allow for a discussion of active surveillance when appropriate. ■

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VALUE PROPOSITIONS Oncologists Should Weigh “Value” in Their Clinical Decisions A recent survey of US and Canadian oncologists explored how they perceive cost-effectiveness of the new and costly cancer treatments, and whether providers are considering value questions of quality versus cost in their clinical decisions. Ubel and colleagues asked oncologists to assess how much life expectancy would a new cancer drug have to deliver to justify its high cost and lead them to prescribe it for their patients. Overall, when asked what constituted “good value for money,” Canadian oncologists, on average, were looking for greater cost-effectiveness than US oncologists. But the majority of both groups agreed that adding 1 year of life would be worth prescribing it if the drug cost up to $100,000. However, when assessing a hypothetical example of an individual patient, the providers conceded that they might consider prescribing a drug that cost up to $250,000 for an additional 1 year of life. Overall, oncologists expected longer survival for a drug that cost $150,000 a year, but this demand did not increase in proportion to the incremental cost of the drug. This suggests a cost-effectiveness ratio that is dependent on the cost of the drug overall. The survey results show that oncologists do not agree on how to assign value to a drug when considering its cost versus the potential survival it can deliver. The investigators suggest that providers should be educated on how to incorporate cost-effectiveness information into their clinical decision-making. Ubel and colleagues suggest that clinical guidelines that consider costs within the clinical decision-making process are now needed. Ubel PA, et al. Health Aff (Millwood). 2012;31:709-715.

New Collaboration to Enhance Personalized Cancer Drug Development Genomic Health announced it has formed an alliance with OncoMed Pharmaceuticals to support the development of DNA-sequencing technologies in the search for diagnostic biomarkers that could identify patients who will best benefit from targeted drugs currently in development by OncoMed. These drugs are designed to block specific pathways believed to play a role in cancer-cell growth after chemotherapy. “Working with like-minded, innovative cancer companies, we can utilize our proven next-generation sequencing-based diagnostic research and development infrastructure to help optimize patient selection to accelerate clinical development of targeted cancer treatments,” said Steven Shak, Genomic Health’s chief medical officer. “This collaboration supports our long-term vision and belief that molecular diagnostics are inherent for bringing quality, personalized care to all cancer patients.” Paul Hastings, OncoMed’s CEO, noted, “We believe the collaboration with Genomic Health will accelerate our already existing efforts of developing predictive biomarkers alongside the development of our anticancer stem-cell therapies.” Genomic Health, May 2, 2012.

NIH Awards $10.5 Million to New Technologies for the Study of Molecular Genes The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has awarded $10.5 million to 10 researchers to develop technologies that will assist research on millions of genomic elements that play a role in determining what genes are expressed, and at what levels in different cells. This has particular implications for cancer therapies.

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These multiyear grants are part of the Encyclopedia of DNA Elements (ENCODE) project, which promotes research on the role that the human genome plays in health and disease. “The ENCODE project is providing a Rosetta Stone to understand how the sequence of the human genome forms the words that tell our bodies how to work at the molecular level,” said Eric D. Green, MD, PhD, director of NHGRI. “Researchers are beginning to use the ENCODE catalogs to understand how variation in the DNA sequence might influence diseases such as cancer and autoimmune disorders,” said Mike Pazin, PhD, program director for ENCODE in NHGRI’s Division of Extramural Research. NIH News, April 25, 2012.

Vaccine Showing Antitumor Activity: A New Paradigm in Cancer Therapy? Injecting antibodies and T cells with cancer stem cells may signal a new paradigm for anticancer immunotherapy, according to a recent study. “This is a major breakthrough in immunotherapy research, because we were able to use purified cancer stem cells to generate a vaccine, which strengthened the potency of antibodies and T cells that selectively targeted cancer stem cells,” said lead investigator Qiao Li, PhD, Research Assistant Professor, Department of Surgery, University of Michigan, Ann Arbor. Cancer stem cells, which differ from embryonic stem cells, remain present after chemotherapy or radiation treatment, and ultimately resistant to such therapy. Some scientists suggest that these cells are unique in regenerating tumors that lead to disease relapse. Destroying these cells may be a new way of preventing recurrence. Li and colleagues prepared a vaccine using cancer stem cells from 2 immunocompetent mouse models. “We found that these enriched cancer stem cells were immunogenic and far more effective as an antigen source compared with the unselected tumor cells normally used in previous immunotherapy trials,” said Dr Li. “When antibodies were primed with cancer stem cells, they were capable of targeting cancer stem cells and conferring antitumor immunity.” Enriched cancer stem cells were effective as an antigen source in inducing antitumor immunity. In addition, cytotoxic T lymphocytes harvested from vaccinated cancer stem cells were able to kill the cancer stem cells in vitro. Ning N, et al. Cancer Res. 2012;72:1853-1864.

Mevion S250 Proton Therapy System Lowers Costs, Approved in Europe The Mevion S250 Proton Therapy System has received marketing approval in Europe but is still pending clearance by the US Food and Drug Administration. Proton-beam radiation therapy is most often used for cancer therapy, but it is not widely used and is very expensive. Several studies have shown promising results for this type of therapy for the treatment of locally advanced sinonasal malignancies; it has also been used to treat patients with unresectable hepatocellular carcinoma. The primary advantage of proton therapy over other types of externalbeam radiotherapy is its ability to more precisely localize the radiation dose. Its huge cost has limited its availability and utilization. If approved in the United States, the Mevion S250 will significantly lower the cost, size, and complexity of proton therapy to levels similar to x-ray radiation therapy, according to the manufacturer. Medscape, March 15, 2012.

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AVBCC Second Stakeholder Integration Conference...

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Co-Chairs: Al B. Benson, III, MD, FACP; Gary M. Owens, MD; Burt Zweigenhaft, BS “We have brought together viewpoints from all the stakeholders across the cancer care continuum, and it has been an interactive and productive experience,” said Gary M. Owens, MD, President of Gary Owens Associates, and conference co-chair, at the conclusion of the meeting that featured more than 20 sessions and symposia led by nearly 30 oncology leaders. Optimizing Value Discussions focused on current trends and challenges in optimizing value, cost, quality, and access issues, and the different approaches and tools that providers and payers are using to manage and deliver cancer care collaboratively.

“We have brought together viewpoints from all the stakeholders across the cancer care continuum.” —Gary M. Owens, MD

“Our goal is the same: to provide the best care possible for patients with malignancies, while utilizing healthcare resources wisely. We want to continue the dialogue among providers, payers, and all other members of the oncology team.” —Burt Zweigenhaft, BS

The conference was chaired by Dr Owens, Al B. Benson, III, MD, FACP, Professor of Medicine at Northwestern University School of Medicine, Chicago, IL, and Burt Zweigenhaft, BS, Chief Executive Officer and President of OncoMed, Great Neck, NY. Different Viewpoints, but Common Goals Commenting on the rationale for the conference, Mr Zweigenhaft noted, “This past year we witnessed a great deal of change in the field of oncology, including a movement toward personalized care, numerous challenges to healthcare providers, drug shortages, the advent of biosimilar agents, and the ever-shifting landscape of oncology drug reimbursement. Our goal is the same: to provide the best care possible for patients with malignancies while utilizing healthcare resources wisely. We want to continue the dialogue among providers, payers, and all other members of the oncology team to foster a better understanding of their points of view.”

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Dr Owens concurred: “The current system is at a crisis point, and we need concerted efforts across multiple stakeholders to resolve this crisis. Patients want the best care for a disease that is frightening to them and want to be sure they have access to care. Providers want to be sure they can provide that care in a relatively unimpeded fashion, and to continue to operate their practices. Payers want to assure access, but must be responsible to people whose dollars they manage. They want to communicate that they are ‘minding the store.’ They ultimately pay the bill and they want to know what they are getting for that.” Dr Benson agreed that unity in the effort to establish value-based cancer care is critical. “It is imperative that we have more platforms for interaction. No one group will solve our complex problems,” he pointed out. “As a clinician, I know there is concern that if we are not at that table, we will be increasingly left out of the loop. Our hope is that clinicians will

“We all have a vested interest in problem-solving, and everyone has to hear everyone else’s side of the equation. It’s the only way to make progress and to develop new models that are desperately needed for providing high-quality care for our patients.” —Al B. Benson, III, MD, FACP

provide direction for decision-making and not have decisions mandated by others who are not directly engaged at this level. We all have a vested interest in problem-solving, and everyone has to hear everyone else’s side of the equation. At this meeting, we can bring together people for these discussions. It’s the only way to make progress and to develop new models that are desperately needed for providing high-quality care for our patients.” ■

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Payer Trends in Oncology... the current trends and the challenges they are facing. Burt Zweigenhaft, BS, President and Chief Executive Officer of OncoMed, Great Neck, NY, who led the discussion, noted that the rising cost of cancer care is clearly the trigger point for change. “The cost curve is unsustainable. Who will win and who will lose? Clearly, there are realignments.” Ira M. Klein, MD, MBA, Chief of Staff to the Chief Medical Officer at Aetna Oncology Strategy, New York, added, “We get feedback from our different customers as to what they want, from the self-insured employers to the small businesses down to the individual in the market. And the unifying theme is that they cannot sustain any more cost.”

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Grand Rapids, MI, proposed 2 main reasons for this. “Number one, we do not have the wherewithal or interest in the public domain to say that society will not pay for a cancer drug because it is too expensive,” Dr Fox offered. “Number two, there are state mandates to cover expensive drugs, and the drug companies have the power to set the price of

“We get feedback from our different customers as to what they want, from the self-insured employers to the small businesses down to the individual in the market. And the unifying theme is that they cannot sustain any more cost.” —Ira M. Klein, MD, MBA

Employers Are Confused Employers may be steadily downsizing their benefits, but this does not mean they do so without pain, participants noted. “Employers are more paternalistic than one would think. They are concerned about the care their employees are getting,” said Dr Klein. “They want benefit designs that do not deny patients access to essential services, but they want these to be acquired at the most favorable unit price. Cost is a very big factor to them.” Maria Lopes, MD, MS, Chief Medical Officer for AMC Health, Cresskill, NJ, agreed. “Employers are concerned about cost and about what is happening in the marketplace, and they are looking to payers for solutions.” Employers clearly do not understand why costs are so high, added Winston Wong, PharmD, Associate Vice President of Pharmacy Management with CareFirst BlueCross BlueShield in Maryland. “The employers ask their consultants. The consultants come to us because they think pharmacy is the silver bullet. When you look at it from the employer and consultant standpoints, you see there is not much understanding about what is driving the numbers,” he said.

the drug. We cannot control these prices, yet that is where the greatest cost is.” Dr Fox contrasted the US system with that of the United Kingdom, which does consider the cost of drug when deciding its fate. “In the United Kingdom, they take the 2 independent variables, which are outcomes established through clinical trials and willingness to pay, and that defines the dependent variable, which is the cost of the drug,” he said. “In this country, the manufacturer sets the cost of the drug….The conundrum is that the pharmaceutical industry has a responsibility to its investors and the innovators have to recoup their investments, yet the people who pay for that are increasingly unable to do so.” Although discussions about reducing emergency department visits and hospitalizations as a cost-savings approach have merit, they stem merely from the fact that these are “things we can control,” Dr Fox said. “The reality is that until we find a way to provide more rationality around our drug reimbursements, I do not know that there is a solution.”

Drug Costs: The Big Bugaboo The exorbitant cost of new treatments clearly contributes to the crisis in paying for cancer care, and payers’ hands are relatively tied to do much about this, the panelists said. “We know drugs are the biggest part of the escalation,” observed Mr Zweigenhaft, and John Fox, MD, MHA, Associate Vice President of Medical Affairs for Priority Health,

Keeping Oncology Community-Based Payers indicated and studies have shown that cancer care is more affordable when delivered in the community rather than the hospital setting; however, economic factors are steadily threatening the viability of this site of care, because community practices are being sold or absorbed by hospitals, or are merely closing.

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This trend worries Jeffrey A. Scott, MD, Senior Vice President and General Manager for P4 Healthcare Cardinal Health Specialty Solutions. “What will it take for this to stop?” he questioned. “When will health plans incentivize doctors to stay out of the hospital? We know the lowest cost comes from treating patients in the community, but how do we drive this?”

Mr Zweigenhaft noted that the “shift to a hospital base” is a universal concern in the payer community, because this essentially doubles the cost of delivering cancer care, with little or no improvement in outcomes. Panelists agreed that site of service is an important issue. Part of the lure of hospital-based care, as Mr Zweigenhaft put it, is the 340B Drug Pricing Program, which limits the cost of covered outpatient drugs to certain federal grantees, federally qualified health center lookalikes, and qualified hospitals. Participation in the program results in savings estimated to be 20% to 50% of the cost of pharmaceuticals, which naturally appeals to providers. According to Mr Zweigenhaft, the pitch made by hospital representatives to physician groups is the opportunity to share in the substantial additional revenue afforded through 340B drug pricing. Dr Scott agreed that 340B pricing is “clearly a driver for getting new doctors into the hospital,” and part of the reason why struggling community practices view the hospital system as “the savior.” What it will take to strengthen community oncology practices is not completely clear, but Mona M. Chitre, PharmD, CGP, Director of Clinical Services, Strategy and Policy for Excellus BlueCross BlueShield, FLRx Pharmacy Management, Rochester, NY, said helping them maintain “cost neutrality” is important. Her company’s goals are to create innovative programs to pay for patient management, help patients avoid emergency depart-

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ment visits, and aid clinicians in reducing other unnecessary services. Guiding Physicians to Best Practices Value in cancer care, however, is not only about cost but also about quality, and the 2 components are necessary for optimizing value while maintaining good outcomes, the panel agreed. Dr Lopes suggested that the concept of value must be aligned with an appropriate outcome, and this can be difficult to determine. Dr Scott added that better measures are needed to define quality outcomes, and that there is increasing recognition that it is “total cost of care” that matters most—which includes reductions in downstream costs and returning patients to work. Dr Klein agreed that benefits programs cannot be designed simply on the basis of cost. “We want quality

“Employers are concerned about cost and about what is happening in the marketplace, and they are looking to payers for solutions.” —Maria Lopes, MD, MS

first, then we deliver on cost,” he said. Dr Scott added, “There is no question that good, quality care is already being provided, but it comes down to how to maintain that quality at a lower cost. That is the big discussion we have with providers.” Standardization is an important part of this strategy, typically via guidelines and clinical pathways. “We found that by more or less standardizing treatments in the program we have with community oncologists, we take out variability and have a gross savings of about 13%,” Dr Wong reported. Continued on page 12

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Payer Trends in Oncology... Continued from page 11 “These savings will be shared with the community oncologists as an effort to maintain their margins and to be an incentive to sustain their community practices.” Moving from branded to generic products has also been a big costsaver, and reducing emergency department visits and hospitalization rates by 4% has produced additional savings. “We know the savings are there,” he said. According to Dr Klein, this works best when providers are in the driver’s seat. “We delegate decision-making to physician groups and allow them to choose their pathways. You get higher quality and lower costs because you give control and power to the providers to use what they are comfortable with,” he said. Dr Scott suggested that pathways work best when they are “narrow,” which is what P4 attempts to do with providers. “We try to neutralize the name of the drugs so physicians are free to choose a regimen based on what is best for the patient and separate from the economics of it. We have demonstrated in 10 different markets that you can use consensus to drive a narrow set of pathways, and it works, although it may not be the long-term answer.” Dr Lopes added that there is a need to do more to aid physicians in decision-making. “We want to align incentives,” she said, emphasizing that healthy collaboration is critical to success. “We will not win without good partnerships with our treating providers.”

Need to Involve the Patient Central to any conversation about cancer care should be the patient. They should also become more active participants in the quest for value, and there is room for improvement in this area, the panel pointed out.

Dr Wong reported that CareFirst programs are beginning to integrate oncology with primary care through the patient-centered medical home model, and this is helping to steer care in the direction of value. “These 2 specialties are collaborating. Primary care

“We have demonstrated in 10 different markets that you can use consensus to drive a narrow set of pathways, and it works, although it may not be the long-term answer.” —Jeffrey A. Scott, MD

“The ‘value proposition’ has to be considered at the patient level,” said Dr Chitre. New York State now has chemotherapy parity. “Patients will not pay any differential for generic versus branded drugs, so the ‘value discussion’ with the patient is actually absent,” she noted. “If a drug is indicated or listed as 2A or 2B in the Compendia, it is covered and at a high level. There is very little patient out-ofpocket expense, and therefore very little driving our members to ask ‘value questions’ of their providers.” She observed, however, that the trend toward high-deductible premiums is beginning to alter how patients talk about value to their providers.

is directing patients to oncology practices they perceive will provide the best quality and value,” he said (see interview with Dr Wong on page 16). Ultimately, what emerges as the picture of value-based cancer care must be patient-centered, the panel agreed. A “fully engaged” patient is one who understands the treatment scenario and determines what is most important to him or her, said Dr Fox. This is only done when physicians have time for it, added Dr Klein. “If we could get physicians to spend more time talking to patients, all our costs would go down, because the patient would feel more empowered to do the right thing,” he maintained.

at a glance ➤ Employers are concerned about cost and about what is happening in the marketplace, looking to payers for solutions ➤ The exorbitant cost of new treatments clearly contributes to the crisis in paying for cancer care ➤ Standardization via guidelines and pathways, moving from branded to generic drugs, as well as reducing emergency department visits and hospitalization rates by 4% have all been cost savers ➤ Cancer care is more affordable when delivered in the community rather than the hospital setting ➤ The shift to hospital-based care is a universal concern in the payer community ➤ Controlling cost and providing quality are necessary for optimizing value while maintaining good outcomes “Comparatively speaking, physician labor time is cheap. The costover-quality balance must hierarchically satisfy all stakeholders as equitably as possible. We have to manage expectations. We cannot move cancer care forward until we change society’s perceptions,” Dr Klein said. ■

The Michigan Oncology Medical Home Model Payer–provider partnership to enhance outcomes “As a health plan, our focus is to create provider partnerships around the ‘triple aim,’ which seeks to balance the individual patient experience, population health outcomes, and per-capita cost.”

By Caroline Helwick Houston, TX—In Michigan, 7 oncology practices are now participating in Priority Health’s oncology medical home. At the Association for ValueBased Cancer Care second annual conference, John Fox, MD, MHA, Associate Vice President for Medical Affairs, Priority Health, Grand Rapids, MI, described the key components and goals of this model. The oncology medical home is an innovative care model that integrates services and streamlines care as a way to achieve better outcomes. Among its collaborators are Cancer and Hematology Centers of Western Michigan, the largest private oncology/hematol-

ogy practice in the state, and Physician Resource Management, which provides customized business solutions and services to oncology practices in Michigan. Patient Experience, Outcomes, and Cost “As a health plan, our focus is to create provider partnerships around the ‘triple aim,’ which seeks to balance the individual patient experience, population health outcomes, and per-capita cost,” Dr Fox said. The oncology medical home offers many benefits to providers, payers, patients, and even manufacturers

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—John Fox, MD, MHA (Figure, page 13), according to Dr Fox. He said that the development of this concept relied on “full transparency and development of a lot of trust between payers and providers.” A key goal of the oncology home

model is to preserve access to oncology care in the community. “If oncology care migrates toward hospital ownership or an employee situation, society, the plan, employees, and even patients Continued on page 13

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The Michigan Oncology Medical Home... Continued from page 12 incur additional cost, without improved outcomes or improved patient experience,” he said. “We wanted to build upon what’s been done by others, and thinking of our triple aim, we challenged the focus on drugs and pathways. We asked, ‘What about the patient?’ and that is how we developed our concept,” Dr Fox said. “We tried to design something that is a win-win for all parties.” The Case Management Fee Concept Most oncology payment reform models share savings when pathways

reduce drug costs, but Priority Health considered whether there might be other models. The key components of their model include payment reform, enhanced payment, and care reform (Table). Under payment reform, payers and providers agreed “that each party will get what they need out of this,” Dr Fox said. The plan pays the acquisition cost of the drugs, then takes the margin that oncologists traditionally make on drugs and turns that into a monthly case management fee for all eligible patients. Oncologists receive a standard fee, regardless of whether using

Figure Benefits of the Oncology Medical Home Provider

Patient

• Reimbursement for patient care management – Both intravenous and oral chemotherapy • More predictable reimbursement • Shared savings on performance metrics – Reductions in ED visits/hospitalizations – Reduced cost of imaging • Reduced risk for drug carrying cost • Waived prior authorizations on drugs and imaging • Enhanced readiness for accountable care organizations

• Enhanced cancer care regimens coordinated with the NCCN • Enhanced access to oncology provider – Continuity of care in the provider office – After-hours services – Medication therapy management • Improved quality of life – Reduce side effects/readmissions and improve adherence • American College of Physicians and survivorship programs

Payer

Manufacturer

• Reduced variability of cancer care – Following NCCN guidelines • Comprehensive care management programs – Reduce side effects and readmissions and improve adherence • Reduction in avoidable costs – Reductions in ED visits/ hospitalizations – Reduced cost of imaging • Enhanced independence of community practices

• Optimal treatment selection (sequencing) • Improved time on therapy – Via side effect management and patient/provider education • Data on pathway selection and compliance • Maintenance of community-based practices

ED indicates emergency department; NCCN, National Comprehensive Cancer Network.

Table

The Oncology Medical Home Model

Payment reform • Plan pays acquisition cost for drugs • Difference between fee schedule and invoice paid as a care management fee for patients on chemotherapy independent of cancer type or mode of administration Enhanced payment • Annual $1500 per-physician per-year infrastructure development fee • Share savings for reductions in emergency department visits and hospitalizations • Share savings for reduced cost of imaging (future) • Incentive payment for select quality metrics (future) Care reform • Adherence to preferred regimens, including imaging and monitoring • Advance care planning and survivorship (future) programs • Standardized care management programs Does not hold providers accountable for the cost of drugs.

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an intravenous or an oral therapy, and regardless of the tumor type. Patients who are active members of Priority Health who are receiving infused and/or oral chemotherapy, independent of when the treatment was started, or who are receiving palliative care services, are eligible to participate in this model, regardless of whether the treatment is according to pathways. Patients are not eligible if they receive selected drugs for maintenance chemotherapy; receive chemotherapy in the inpatient or outpatient hospital setting; no chemotherapy, or radiation only, during a calendar month; or if they are enrolled in a hospice. “Physicians have said for a number of years that one of the reasons they need margins on drugs is to provide high-quality cancer care, and we created the case management fee concept to cover services they have not been compensated for in the past,” Dr Fox explained. “It’s simple to do. The oncologist doesn’t bill. We pay them automatically every month.” These high-quality cancer care services include: • After-hours services • Care plan oversight services • Medication therapy management • Patient education • Team conferences • Telephone services • Financial services • Care coordination. Separately payable fees include

at a glance ➤ Preserving access to oncology care in the community is key to the oncology medical home model ➤ The Priority Health oncology medical home model created the case management fee concept to cover services that providers have not been compensated for in the past ➤ Physicians are asked to measure their performance against what they believe is the optimal pathway, based on utilization and quality performance metrics ➤ This model offers many benefits to providers, payers, patients, and even manufacturers through payment reform, enhanced payment, and care reform

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“If oncology care migrates toward hospital ownership or an employee situation, society, the plan, employees, and even patients incur additional cost, without improved outcomes or improved patient experience.” —John Fox, MD, MHA

board-certified genetic counseling, advanced care planning, and psychological counseling. Reimbursement remains unchanged for evaluation and management codes, infusion fees, and laboratory and imaging. Care Management Reform The model also pays an “infrastructure development fee,” which is intended to help defray the cost of care management changes. Care management reforms under the plan include: • Preferred regimens for 4 highvolume conditions • Care management/navigator programs • Patient engagement programs with a “call me first” policy • Advanced care planning • Survivorship programs. “We recognize the physicians for their efforts to reduce avoidable care, such as emergency room visits and hospitalizations,” Dr Fox noted. “If successful, they will share in the savings. We believe that oncologists will find that this enhances their reimbursement in the long-run.” Physicians are asked to measure their performance against what they believe is the optimal pathway, and to perform well on a number of utilization and quality performance metrics. Key domains are end-of-life care, office triage for case management, and chemotherapy compliance. ■

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Seeking Value in Oncology Is Like Chasing an Elephant Integrating providers’, payers’, and patients’ perspectives By Caroline Helwick Houston, TX—Defining value in cancer care is like a group of blind men trying to define what an elephant is, by touch: it is described according to one’s own experience and perceptions, said Mark Zitter, MBA, Founder and Chief Executive Officer, The Zitter Group, San Francisco, CA. “Overall, value depends on one’s perspective. No one person can define it,” Mr Zitter said. “The main problem is that we as a society collectively want to consume more healthcare than we collectively want to pay for. Everyone wants the innovation, but no one wants the cost. Before we can make value ‘happen,’ we have to figure out what it is.” In his presentation at the Association for Value-Based Cancer Care annual conference, he described The Zitter Group’s Managed Care Oncology Index findings, a semiannual survey of 100 payers, 100 oncologists, and 100 oncology practice managers. What Is Value in Oncology? The elimination of “waste” is thought to improve “value,” but healthcare stakeholders disagree about where to look for waste, Mr Zitter said. Findings from the Summer 2011 Index show that payers and oncologists believe that end-of-life excessive care is the greatest contributor to “excess costs” in the US healthcare system. Practice managers see administrative issues as the biggest source. Inappropriate drug use was deemed important by payers and oncologists, and excessive diagnostic testing was

Figure

deemed wasteful by oncologists and practice managers. Overall, in determining value, much attention is paid to the high cost of drugs that offer only marginal survival benefits to patients. The value of the new biologics for cancer has been debated by many. Mr Zitter noted that the drugs that were considered “least valued” or with “too much hype” by oncologists and by payers included bevacizumab (Avastin), sipuleucel-T (Provenge), erlotinib (Tarceva), and cetuximab (Erbitux); payers also listed ipilimumab (Yervoy) in that category.

“Value depends on one’s perspective. The main problem is that we as a society collectively want to consume more healthcare than we collectively want to pay for.” —Mark Zitter, MBA Oncologists, however, indicated that they would prescribe expensive agents even if they confer less than a 6-month extension in survival, whereas payers and practice managers expect more benefit for such an investment. “We are making these [cost] decisions daily in the healthcare system. We have to come to the conclusion that what we pay for is not completely rational in terms of value,” Mr Zitter said.

Prior Authorization Tops the List of Cancer Therapy Management Tools

Which of the following tools have been applied to manage cancer therapies? 86% 87%

Prior authorization

95%

Compendia listing guideline requirements

69% 63% 62% 27% 47% 54%

Tying drug approval to diagnostic tests/ biomarkers

47%

54%

50% 46%

Specific lab or diagnostic values

Payers (N = 101) Oncologists (N = 100) Practice Managers (N = 100)

59%

Quantity limits

70% 46% 46% 53%

Clinical treatment pathways

6 14

Significant increase from the winter 2011 report. Source: The Zitter Group. Managed Care Oncology Index, Summer 2011.

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Payers Pack a Punch “Payers believe that they are getting better at oncology management,” Mr Zitter said, based on a near-doubling of the percentage of payers (now 46%) who reported that their organization “effectively manages the oncology category” compared with 6 months earlier. They are accomplishing such effective oncology management mainly through prior authorization, which is a management tool in cancer therapy for 86% of payers (Figure). Oncologists (87%) and practice managers (95%) also perceive prior authorization as a key tool for cancer therapy. Other strategies to manage cancer therapy reported by survey payers include the use of compendia guidelines and quantity limits, tying drug approval to diagnostic tests and biomarkers, the use of specific laboratory or diagnostic values, and the incorporation of clinical pathways (Figure). Payers also seek value through the use of preferred products. “We have seen a substantial increase in the aggressive and restrictiveness of prior authorizations across health

at a glance ➤ Value in oncology depends on perspective, but no one wants to be pinned down ➤ Payers increasingly are seeking value in cancer care, using reimbursement, prior authorization, and clinical pathways ➤ Patients, too, are seeking value for the therapy they are getting; providers and payers must be cognizant of this development ➤ Cost-sharing is growing and will continue to cause patients to seek value; copay support will play a larger role in adherence ➤ Providers will be the key to driving value, but incentives are not necessarily aligned

“The elephant in the room is something very large that no one is talking about. It’s not cost. It’s the impact of cost-sharing on patient access and outcomes.” —Mark Zitter, MBA

plans and in multiple other ways in which payers are taking a much more active approach,” Mr Zitter noted. He doubts that companion diagnostics for targeted therapies will enhance value, because these tests are expensive and are not 100% accurate. When a test indicates a 5% chance of response to a given drug, the patient will still want the drug, and the health plan will pay for the drug and the test. Patients, Too, Are Rethinking Value Patients are looking more closely at value through cost-sharing and high deductibles, but this ultimately may be compromising outcomes. “The elephant in the room is something very large that no one is talking about. It’s not cost. It’s the impact of cost-sharing on patient access and outcomes,” Mr Zitter suggested. Although cost-sharing does reduce inappropriate care, it also reduces appropriate care. Patients seek treatment alternatives when monthly out-of-pocket costs are $350, or even less. “You don’t have to have a very high cost to affect patients’ choices of treatment,” Mr Zitter observed. Pharmaceutical companies’ copay support programs have become ubiquitous, because manufacturers realize that “a 20% copay may make their drugs unaffordable,” he added. Providers Feel the Pressure The Zitter Group’s surveys show that payers and providers view oncologists as “driving the decisions,” although payers are “squeezing out value” through average sale price reimbursements. This has affected incomes for more than 50% of the oncologists surveyed. Providers also feel pressure to embrace pathways, which are now being used in approximately 50% of the practices surveyed. Oncologists also feel the need to examine their patients’ benefits when selecting treatments. “A 20% copay for a drug that costs $65,000 a year is huge. Doctors have to be influenced by this in making treatment decisions,” he said. ■

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Society Must Begin to Address Value

deny healthcare. No one understands that our margins are more like grocery stores—in the 4% to 6% range—and not like technology companies or manufacturing companies, whose profits are in the 15% to 20% range. All the public sees is that a managed care Chief Executive Officer makes X millions of dollars, but that is not restricted to our industry. This perception does not help move things forward.

Interview with Ira M. Klein, MD, MBA Chief of Staff to the Chief Medical Officer at Aetna Oncology Strategy

therapy. When we can refocus around the true societal costs, then we can achieve a better dialogue about value in cancer care.

AVBCC: You mentioned that society and the individual are important components of any effort to lower cost and establish value in cancer care. How so? Dr Klein: The issues surrounding value are really societal issues as much as they are medical and insurance issues. If you raise the visibility as to the true trade-offs in healthcare, this will be more obvious. For example, we could give a particular expensive cancer drug to one person or we could vaccinate 10,000 children against a preventable communicable disease. When there is a societal conversation about these trade-offs, then the public becomes more reality based and rational about what is appropriate

AVBCC: But does the individual diagnosed with cancer, who fears for his or her life, see the situation this altruistically? Dr Klein: Not today, but perhaps in 5 to 10 years. One of the biggest ways that individuals change decisionmaking is through the signals that come to them as societal pressures in the form of norms and biases. It will be a while before we get there, but I think we will make that journey. When we talk to people from Great Britain, as much as we vilify NICE (National Institute for Clinical Excellence) in the United States, we find that most people in that country are not that unhappy with the system. What we end up doing here is exporting the horror stories about national health systems, but in Britain there is acceptance and understanding about societal trade-offs. They accept

t the Association for ValueBased Cancer Care (AVBCC) second annual meeting, Ira M. Klein, MD, MBA, maintained that establishing value in cancer care is not just up to healthcare strategists. AVBCC asked Dr Klein to elaborate on this idea in the following interview.

that it is okay to wait 6 months in the queue for a hip replacement, for example. They understand that this is what it takes to have a fair and equitable dissemination of healthcare. AVBCC: Can payers help change the perception of patients toward less self-centeredness? Dr Klein: We can, but I think we are not in the best position to do so. Payers have already been painted with the broad brush as being the ones who

AVBCC: So do we need a shift in how our own society thinks about what we, as individuals, are owed? Dr Klein: In some ways, yes. But this goes back to our roots as a culture, where we see America as a “can do” place marked by unlimited optimism and the power of the individual. But, if you base everything on optimism and the power of the individual, you will never want to restrict the patient’s decision to take that 1 in 100 chance of a cure, to have this come true even if it costs several hundreds of thousands of dollars and might hamper someone else’s ability to do something good for society. Ultimately, maybe cancer treatment will not be about doing all that the patient wants, but more about doing the right thing. ■

WellPoint: Aligning Reimbursement with Value-Based, Patient-Centered Outcomes By Caroline Helwick Houston, TX—Jennifer Malin, MD, PhD, Manager and Medical Director of Oncology at WellPoint, described new approaches that can help to align reimbursement in oncology to enhance value and patient outcomes by focusing on episode of care rather than on the drugs, by shifting physicians’ incentives to support patient-centered decision-making. Dr Malin described WellPoint’s new reimbursement programs in oncology at the 2nd Annual Conference of the Association for Value-Based Cancer Care. In colon cancer, for example, the costs of care are $80,000 with cetuximab (Erbitux) and $91,000 with bevacizumab (Avastin) for less than a 2month improvement in survival. “We are questioning whether the costs associated with this relatively modest improvement in survival is worth it,” Dr Malin said. Reimbursement Drives Overutilization Reimbursement drives overutilization of intensity-modulated radiother-

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apy (IMRT) and other high-technology therapies. For example, in prostate cancer, IMRT costs approximately $32,000, compared with 3-dimensional conformal radiotherapy at approximately $20,000. Proponents of IMRT point to a reduction in toxicity, but the evidence for this is still lacking. “Despite a lack of evidence of improved patient outcomes and a 50% higher cost, the uptake of IMRT has been very rapid,” Dr Malin noted. But urologists are investing in IMRT equipment, selectively treating patients at a higher cost, which is then reimbursed by payers. Largely because of such practices, the cost of cancer care has doubled since 1990; it now approaches $90 billion annually. Patients are bearing the brunt of this in the form of cost-sharing that many cannot afford, even with “good insurance,” Dr Malin said. These high costs, however, are not the result of “better” patient care, she said. A 2011 study suggested that only 8% of revenue in community oncology practices comes from “evaluation and

“The question is how to change the way we reimburse physicians to align reimbursement with patientcentered care.” —Jennifer Malin, MD, PhD

management,” whereas 69% of reimbursement is related to drug use, 8% to infusion, and the remainder to ancillary services. New Approaches to Reimbursement “The question is how to change the way we reimburse physicians to align reimbursement with patient-centered care,” Dr Malin said. Two models under discussion are episode-based payments and value-based benefit designs. In the latter, cost-sharing is calibrated on the value of the treatment option. Regimens that offer the most

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improvement in survival would be associated with the lowest copays. Under this model, for example, a treatment with a 2-month increase in median survival would have more out-ofpocket expense for the patient than a drug offering a 2-year improvement. A 2010 survey of patients showed that for only a 5% improvement in cure rate, 49% of patients would accept a very high copay (level 5 or higher), but for a 20% improvement in cure, 75% of patients would do so (Wong YN, et al. Oncologist. 2010; 15:566-576). WellPoint’s approach is similar and includes the following Continued on page 16

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Site of Care Influences Value in Cancer Care Interview with Winston Wong, PharmD Associate Vice President, Pharmacy Management, CareFirst BlueCross BlueShield of Maryland

t the Association for ValueBased Cancer Care (AVBCC) annual meeting, second Winston Wong, PharmD, expressed concerns that the site of delivery of cancer care affects efforts to rein in costs and provide value in cancer care. AVBCC pursued this issue with Dr Wong in the following interview.

AVBCC: Why do you believe that the site of delivery of cancer care can impact the attempt to rein in costs of cancer care and provide value? Dr Wong: Here is why. When chemotherapy is delivered to a patient in the physician’s office, there are the cost of the drug, administrative costs, and the cost of ancillary services. Let’s say the total office visit, including the cost of chemotherapy, is $4000. You can take that exact same service and drug and deliver it at a large center, such as, in our area, Johns Hopkins, and the cost could be $6000 or even up to $8000. Essentially, it may double or even triple in cost, depending on the procedure, the service, and the drug that is prescribed. AVBCC: Why is there such a large differential in cost? Dr Wong: It is basically because the healthcare system cannot function without the large hospitals. They have market power and can negotiate better deals. At the end of the day, hospital billing will be at least twice that of a community practice, across the board. AVBCC: Do large hospitals and cancer centers acknowledge this? Dr Wong: Their comment to payers would be that they are tertiary care hospitals, and that their patient population is sicker, and to some degree

that is true. Large hospitals may get more difficult cases, administer more expensive third-line therapies, and so forth. But comparing apples to apples, their costs are much higher than in community practices. AVBCC: What can be done to bring more equity? Dr Wong: On the oncology side, we have not been able to achieve more equity yet. The strategy that we at CareFirst are trying to employ initially with our pathways program is to reimburse at a higher rate to community practices. We may not necessarily be directing patients away from hospitals, but we are doing something to help maintain community oncology practices so that they are available to treat these patients. If there are fewer community practices, patients with cancer have less choices. The site of care issue will be driven by the viability of community practices. If we cannot help community oncologists stay in business, the site of care will not be an issue. AVBCC: You have talked about the need to integrate primary care and to bring more value to oncology. Could you elaborate on this? Dr Wong: Here is an example of the current state of things. My mother passed away in 2007. When she was diagnosed with cancer and was being treated with chemotherapy, she became neutropenic and ended up in the emergency department. The hospital contacted the primary care physician (PCP) on record, but he had no clue about her condition. Once an oncologist was taking care of her, there had been no communication with the PCP.

And let’s look at survivorship. She may have to go back to the oncologist for some routine tests, but she may have an annual check-up the following week with her PCP, and he may order the same laboratory tests. This kind of overlap and duplication should be eliminated from the system. AVBCC: How is CareFirst BlueCross BlueShield advancing this concept of more integrated care? Dr Wong: With the primary care patient-centered medical home, we are trying to involve the PCP as the “quarterback of care,” as we say. Currently, when an individual is diagnosed with cancer and referred by his or her PCP to a specialist, the PCP usually severs ties with the patient. We are asking our PCPs to be more accountable and to follow these patients while they are under the care of specialists—oncologists or others— and maintain primary care as the patient’s home, but within an integrated process. Maybe 5 of 10 patients with cancer will ask their PCP to refer them to an oncologist, but the other 50% will choose an oncologist on the basis of

favorable word of mouth. Or, they may want to go, for example, to M.D. Anderson, because of its reputation and not because they have seen scientific evidence that their care will be better or that community care is worse. We all pay more for that patient, with very little difference in quality of care or in outcomes compared with care in the community setting. We believe that the PCP can direct the patient more toward value-based cancer care. PCPs can help guide these referrals, and they can take care of the non–cancer-related conditions that patients with cancer will have. We want this care to be under the PCP, not the oncologist. AVBCC: How are PCPs and oncologists accepting this model? Dr Wong: We do not know yet—our program just started—but this is something we are interested in learning. We believe that it is in everyone’s best interest for patients to have a coordinator of care, and we think that the most important provider in this regard is the PCP. We think that PCPs and oncologists working together will become inevitable with the changing time. As the PCP becomes more involved, there will have to be more communication between them. AVBCC: What progress is being made to bring this concept to fruition? Dr Wong: There are many groups with their own small projects like ours, and none is known to be the best way to do this. I think that these will eventually merge into something that we will all use; however, we are still trying to get some accountability around these programs, and we are still very early in that game. ■

WellPoint: Aligning Reimbursement with Value-Based... Continued from page 15 key components: • Increase the margin on lower cost, unprofitable regimens (ie, generics) • Require preauthorization for an episode of care • Support treatment planning and disease management • Develop innovative technologies to help physicians and patients better understand the benefit of treatment and trade-offs between treatment options. WellPoint’s new web-based approach incorporates evidence-based tools for

guiding providers in precertifying episodes of treatment. “We can use this type of approach to give additional reimbursement for preferred treatment options,” Dr Malin suggested. WellPoint also has an oncology medical home pilot program. Under this program, providers document a comprehensive treatment plan and coordinate care with other specialties; oncology nurses provide proactive telephone support for patients in treatment; and acute events are evaluated in the office, not in the emer-

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gency department. In choosing treatment, the practice prespecifies the most cost-effective choice among evidence-based chemotherapy and supportive-care regimens. Metrics are reported for tracking processes and outcomes. WellPoint is also partnering with IBM Watson to develop new platforms for utilization management assistance and for oncology decision support. This decision-making platform will draw from medical research, population health informa-

tion, patient medical history, and laboratory results, and integrate these data with treatment protocols, medical policies, and guidelines. The system will analyze millions of pages per second and arrive at targeted treatment options at the point of care. “Using IBM Watson, physicians will have up-to-date, synthesized information about the patient, and clinical evidence for various treatment options. The process is automated, [in] realtime, and intelligent,” Dr Malin concluded. ■

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Community Oncology in Crisis How did we get here, and where are we going? By Caroline Helwick Houston, TX—In the past 2 decades, community oncologists have experienced an era of stability (1991-2003) and a time of adaptation (2004-2006), and are now practicing in an era that may best be described as feeling the “squeeze” (2007-present), said Thomas A. Marsland, MD, President of Cancer Specialists of North Florida, Jacksonville, who discussed the current crisis in the community oncology setting at the Association for ValueBased Cancer Care second annual conference. The current buy-and-bill outpatient practice infusion model is providing quality care, he said, “although maybe not always the best value,” because it “comes at a significant price.” A 2007 analysis of 14 million claims indicated that the average annual pharmacy cost for a patient with cancer was $110,000. Already quite high, these costs are now increasing by 20% annually, Dr Marsland emphasized. Drug and Total Costs Drug margins once subsidized oncology practices, but with the Medicare Modernization Act of 2004 came the average sales price approach; this coincided with reduced use of erythropoiesis-stimulating agents, and revenues took a hit. Over time, drug revenues increased, although the cost of cancer drugs rose faster. Oncology practices were forced to become more efficient, inventory became better managed, standardization was promoted for both billing and clinical care, clinical pathways were envisioned, and production increased. “As a result we saw a net increase in revenue,” he said. “Then the squeeze came.” Efficiencies in the practice were “maxed out,” labor costs increased, and total costs surpassed revenues, but the number of patient visits per full-time equivalent decreased, because more staff were hired to handle the additional clinical and regulatory requirements on providers. “Having a

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nurse call to see if the patient is taking his medication correctly is not a reimbursable service, but became expected as part of good quality of care delivery,” Dr Marsland said. The Shift Away from Community Care Today, direct interaction with payers takes time from administrative and nursing staff; physicians themselves spend 3 hours weekly on this, and the total national cost of this interaction is estimated at $23 billion to $31 billion annually, he said. In addition, revenue as a percentage of total revenue in oncology has decreased from 85% in 2005 to 65% in 2012. In part because of these trends, Dr Marsland and fellow medical oncologists have seen their income diminish by 30% over the past 6 years. “We are still making a comfortable living, but the point is that the income stream is on a downward trend, and practices are feeling the pinch,” he commented. “What is happening?”

“We are still making a comfortable living, but the point is that the income stream is on a downward trend, and practices are feeling the pinch.” —Thomas A. Marsland, MD A recent survey of 1000 practices from the Community Oncology Alliance found that 200 practices were closing their doors, 30 were merging, 325 reported financial distress, and 50 were sending patients to the hospital for infusion services. Another survey from the Association of Northern California Oncologists showed substantial economic stress resulting from payment delays, rejections of appeals, and so forth.

This shift away from community oncology is reducing patient access and increasing costs to the healthcare system, Dr Marsland said.

• A “silo” model of care • Fragmentation of care • Duplication of medical services. To control these trends and growing costs, a variety of strategies are being imposed on providers by payers. Cost control efforts include: • Aggressive contracting with physician/hospital • Coverage policy: tier copay, oral versus intravenous therapy • Prior authorizations • Case management • Collaborative efforts with provider: shared savings, pathways, pay for performance • New payment models: bundling, accountable care organization, medical home, episode of care, valuebased insurance design. It is expected that emerging models will be better, in that they will: • Center on systems and populations • Increase coordination of care • Promote sharing of information across all levels (including information on costs) • Encourage a team approach • Standardize care in an evidencebased way • Focus on outcomes, value, and quality. “These assumptions are intrinsic in all the new payment models,” Dr Marsland said.

Strategies to Control Costs The reasons behind the rising cost curve are numerous—not just “drugs per se,” but duplication of services and fragmentation of care, Dr Marsland told attendees. “We are daily bombarded by payers who want to reduce our payments and decrease utilization. Our collaborative efforts are still based on a fee-for-service mentality that is not sustainable in the long run, although we are beginning to talk about completely new payment models,” he added. Problems with the current system include: • Fee-for-service payment approach

The Value Proposition In closing, Dr Marsland said his definition of “value” is giving the right care to the right patient at the right time and at the right cost. With the emerging models of cancer care, “you see commonality and a vague image of what the ideal healthcare delivery system might look like,” he acknowledged. Embedded in these new models are some tough demands, including a total integration of economics, cost, clinical care, and standardization to rid the system of variance. “This will take some deep pockets,” Dr Marsland predicted. ■

“Our collaborative efforts are still based on a fee-forservice mentality that is not sustainable in the long run, although we are beginning to talk about completely new payment models.” —Thomas A. Marsland, MD

MAY 2012

www.ValueBasedCancerCare.com

NCCN 2012 Conference

Optimal Care for Patients with Cancer...

Continued from cover

decisions that we call the ‘crucible’ has changed. It’s not just the clinicians, patient, and family; it extends much further. Whether you think literally or figuratively, other actors are in that room. The content for decision-making now ranges from the small exam room all the way to Congress.”

“We are seeing more narrow network types of plans, and this is shifting power to the payers and hospitals for making more granular decisions, which have an impact on treatment choices.” —Scott Gottlieb, MD

quality of life, as well as the economic bottom line. Although hospice is handling these patients well, too few patients die there. The problem, she noted, is that these conversations occur too late in the game. “We need to

Photo taken at the NCCN conference

The Need to Define and Measure Quality Quality care has yet to be fully defined, but to Sheri Ling, MD, Deputy Chief Medical Officer for the Centers for Medicare & Medicaid Services (CMS), it means care that is safe, well-coordinated, and centered around patients and their families. Evidence of good outcomes is also important, and the delivery of care should be monitored through structured systems that are beginning to emerge, Dr Ling said. The issue of quality permeates the entire cancer journey, according to Karen Alban, RN, OCN, of the Carroll Regional Cancer Center in Westminster, MD. “Cancer care decisions are not a one and done proposition,” she said. Furthermore, end-of-life care should be an important part of the care planning, because it greatly affects

at a glance

do better at moving palliative care into the continuum sooner,” Ms Alban suggested. Al B. Benson, III, MD, FACP, past president of the NCCN, and Professor of Medicine, Northwestern University, Chicago, IL, said that the “first encounter sets the tone for what happens in making decisions over time.” This is the time to “recognize who is in the decision-making arena” and to offer patients guidance, not just for their cancer treatment, but for wellness, psychological issues, financial concerns, and all the rest. David Pfister, MD, an oncologist at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical School, NY, noted that treatment options are rapidly expanding, and this increasingly requires multidisciplinary planning. He applauded the emergence of new metrics to help guide physicians and patients in making choices. However, Ray Lynch, MBA, Executive Director of Huntsman Cancer Hospital, Salt Lake City, UT, said that multiple options also enhance the complexity of care, and that “crawling through the data is a challenge.” Rural oncology practices that lack other specialists in the area may have trouble meeting the demand for comprehensive cancer care, Mr Lynch said. Cost Affecting Treatment Options: Who Pays for What? It is clear that payers have become integral to the decision-making process, and the patient’s financial reality is a component of modern cancer care, the panelists maintained. As Mr Lynch noted, “What we do in the inner circle is conditioned on who is going to pay for what.”

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MAY 2012

Nancy Davenport-Ennis, Chief Executive Officer of the National Patient Advocate Foundation, agreed. “The payer plays a role through the benefits that are offered” by the health plan, she said. “Treatment protocols

“Guidelines are advisory, with lots of value. If we start to pay more attention to standardizing and becoming closer to those guidelines, a lot of the cost discussions will go away.” —Lee N. Newcomer, MD, MHA

are often impacted by the insurance product,” especially when out-ofpocket expenses are high. Although 15 states have passed legislation that mandates parity in the payment structure between intravenous and oral agents, for states that have not, the disparity in drug costs clearly impacts decision-making, she said. “Discrete differences in reimbursement influence care.”

➤ What was once an intimate relationship between patient and physician now involves multiple decision makers ➤ Treatment options are rapidly expanding, and this increasingly requires multidisciplinary planning ➤ Payers have become integral to the decision-making process, and the patient’s financial reality is a component of modern cancer care ➤ More narrow network types of plans are emerging, which is shifting power to the payers and hospitals for making more granular decisions, thus having an impact on treatment choices Lee N. Newcomer, MD, MHA, Senior Vice President of Oncology Services at UnitedHealthcare, took some exception. Although fee-forservice still reigns, virtually any approved regimen will be reimbursed, at least by the major third-party payers, he said. When cancer is diagnosed, insurance premiums, copays, and deductibles more than pay for themselves, he maintained. “For a $3000 deductible, a person is going to get $120,000 worth of therapy for her disease. I would say that’s a pretty good deal,” Dr Newcomer commented. Discussing the impact of payers on optimal care for patients with cancer, Scott Gottlieb, MD, a physician and resident fellow at American Enterprise Institute, said we need to look separately at the public and private marketplaces. “In the private sector, we are seeing consolidation of practices, hospitals acquiring practices, 340B programs, capitated arrangements, and so on. We are seeing more narrow network types of plans, and this is shifting power to the payers and hospitals for making more granular decisions, which have an impact on treatment choices,” he said. “In the government sector, you are seeing a similar move toward centralization of decision-making, but it is driven by different needs and political realities.” “For instance, the CMS wants authority to make decisions about what should and should not be covered,” Dr Gottlieb said. Power to follow the “least costly alternative” policy, which would allow CMS to Continued on page 20

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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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NCCN 2012 Conference

NCCN Clinical Practice Guidelines Update TM

Significant changes will affect patient care By Audrey Andrews Hollywood, FL—The 2012 updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology™ have elevated several drugs to category 1 recommendation and have changed the algorithm for work-up in some tumors. A synopsis of the key updates presented at the 2012 annual conference is reported here. Breast Cancer The breast cancer panel recommended a more conservative use of imaging modalities for assessing, staging, and conservative management of the axillae in selected patients. “In the past, imaging studies in early-stage disease were listed as ‘consider the following,’ but updated guidelines have shifted toward recommendations of when clinicians should not perform certain ones,” said Benjamin O. Anderson, MD, of the University of Washington/Seattle Can-

cer Care Alliance. “We are moving away from the concept in early-stage disease that the patient should routinely get a battery of tests, which often will mislead us.”

“We are moving away from the concept in early-stage disease [in breast cancer] that the patient should routinely get a battery of tests, which often will mislead us.” —Benjamin O. Anderson, MD

Routine systemic tumor staging is not indicated for early breast cancer in the absence of signs or symptoms of possible metastatic disease. Specifically, the guidelines now recommend

the following strategies: • Bone scans if localized bone pain or elevated alkaline phosphatase are present • Abdominal ± pelvic diagnostic computed tomography (CT) or magnetic resonance imaging (MRI), but not ultrasound, in the presence of elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis • Chest diagnostic CT if pulmonary symptoms are present. For clinical stage IIIA breast cancer (T3N1), the clinician can consider chest diagnostic CT, abdominal ± pelvic CT or MRI, bone scan or fluoride positronemission tomography (PET)/CT, and 18 fluorodeoxyglucose (FDG)-PET/CT, which is considered equivalent to bone scanning. “What is new is the use of fluoride PET/CT looking for bone lesions; FDG-PET/CT is still optional,” Dr Anderson said.

Optimal Care for Patients with Cancer...

Based on the landmark American College of Surgeons Oncology Group Z0011 study (Guiliano AE, et al. JAMA. 2011;305:569-575), which showed no difference in locoregional recurrence or survival whether patients underwent complete axillary lymph node dissection (ALND) or sentinel lymph node biopsy only, the recommendations for managing the axillae have changed. The panel stated that ALND can be avoided in patients meeting the strict Z0011 criteria: T1-T2 clinically node-negative disease and 1 or 2 involved sentinel lymph nodes, and treated with breast-conserving surgery and whole-breast radiation. Patients with metastatic disease should be assessed for estrogen/progesterone receptor and HER2 status, if these are unknown or are originally negative or not overexpressed based on high rates of discordance observed in multiple studies. Continued on page 21

Continued from page 18

Predicting the Care Delivery Landscape for 2017 Dr Goodman challenged the roundtable panelists to project how healthcare delivery will be different 5 years from now. Ms Alban: “Survivorship care plans will be much better defined,” and appropriate end-of-life care will be part of the treatment continuum. Mr Lynch: “I hope that we will have seen the end of dysfunctional marketdriven ideas such as bundled payments, and we will be working on a singlepayer system.” Dr Pfister: “There will be continued focus on guidelines and pathways and increased rigor in their development. We will also start to consider issues related to value in our guidelines, although an increased number of metrics.” Dr Gottlieb: “Eighty percent of oncologists will be working for hospitals or hospital health systems, and these institutions will impose more resource utilization and control on what providers can do.” Dr Ling: “We need to see convergence and closer collaboration built on our data sources, and to use this information to drive the system toward optimal outcomes and improvements in quality.”

reimburse only for the lowest-cost interchangeable option, “may in the near future be conferred on CMS,” he observed. Adherence to Guidelines Key to Quality and Value Guidelines and pathways help providers understand the best use of diagnostic and treatment modalities in an increasingly complex era, said Dr Benson, and they should be part of

training programs and tumor boards. Mr Lynch agreed, stating, “The closer we get to conforming to the NCCN guidelines, the more quality we can deliver.” Dr Newcomer added, “Guidelines are advisory, with lots of value; they are as good for an individual as they are for a population,” and they can eliminate waste. “If we start to pay more attention to standardizing and becoming closer to those guidelines, a

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MAY 2012

Dr Newcomer: “In less than 18 years, the average household income will be exceeded by a family’s insurance premium. By 2017 or so, if we have not come to a decision about what we can prune out of this system, we are on a flight path for a crisis.” Ms Davenport-Ennis: “Comparative effectiveness research will inform more treatment decisions. I am concerned that the data may not be the most current, and therefore it will not give the best results. But there will be more informed guidelines and better national adherence to them.” She also predicted an increase in cancer survivors as a result of improved treatments, although she also predicted more delays in diagnosis and treatment as more care shifts to primary care. Dr Benson: “We will have better understanding of tumor biology, and our ability to select individual patients and treatment strategies will be more effective and provide more value to the care we deliver. By understanding these subsets, even a common disease may become a collection of rare diseases.”

lot of the cost discussions will go away,” he predicted. Inconsistent use of guidelines is the current norm. UnitedHealthcare, he said, was surprised to see a guideline adherence rate in the 60% range among 5 conscientious oncology groups. “For other oncologists not thinking about guidelines on a daily basis, the adherence rate is probably far less,” Dr Newcomer speculated. But Dr Benson added that devia-

tion from guidelines is often warranted, and that guidelines and pathways are intended to assist with decision-making. “A guideline is just that, not a prescription of care,” he stated. Dr Newcomer acknowledged that physicians in his network can deviate from the guidelines when there is a medical reason, “and it is never a deviation from a pathway to go onto a clinical trial.” ■

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NCCN 2012 Conference

NCCN Clinical Practice Guidelines ... TM

The guidelines also contain new recommendations for monitoring metastatic disease and discourage the use of PET scanning in this setting. Although not a recommendation, the panel stated that postmenopausal endocrine-sensitive patients with advanced HER2-negative disease may benefit from the combination of anastrozole (Arimidex) plus fulvestrant (Faslodex) therapy, and from the addition of everolimus (Afinitor) to exemestane (Aromasin).

“We need close collaboration among all providers, and the pathologist has a role at all levels. The more involved the pathologist, the greater the likelihood that you will come up with the right answers [in NSCLC].” —Richard T. Cheney, MD Non-Hodgkin Lymphoma Within the Non-Hodgkin Lymphoma Guidelines™, the NCCN panel introduced inaugural recommendations for the rare but aggressive disorder of mature T-cells known as T-cell prolymphocytic leukemia (T-PLL). “Most patients with T-cell prolymphocytic leukemia are symptomatic, with fairly aggressive disease and need treatment,” said Leo I. Gordon, MD, of the Robert H. Lurie Comprehensive

Cancer Center of Northwestern University, Chicago, IL. The treatment approach is based on the presence or absence of symptoms. Asymptomatic patients can be observed until disease progression, or until occurrence of symptoms. Previously untreated patients with symptomatic disease should receive intravenous (IV) alemtuzumab (Campath), based on a 2011 study in which IV alemtuzumab produced an overall response rate of 91%, an 81% complete response rate, and median survival of 15 to 19 months. In addition to the T-PLL recommendations, the panel also advised testing for MYC positivity for all diffuse large B-cell and related lymphomas because of the poor prognostic impact related to this feature. For hairy-cell leukemia, the 2012 NCCN algorithm for immunophenotyping/genetic testing in the differential diagnosis of mature B-cell and natural killer T-cell neoplasms was also revised. Malignant Melanoma Immunotherapy with the monoclonal antibody ipilimumab (Yervoy) and targeted therapy with the BRAF inhibitor vemurafenib (Zelboraf) were added to the guidelines as category 1 options for the first-line treatment of systemic melanoma. Although dacarbazine (DTIC), temozolomide (Temcad), and taxane combinations remain options, “enthusiasm for these other agents has rapidly declined,” said John A. Thompson, MD, of the Seattle

Cancer Diagnosis Increases Suicide Risk or CV Death in the First Few Weeks Patients receiving a diagnosis of cancer are at increased risk for suicide and other adverse health effects that are triggered by the trauma associated with such a diagnosis, according to results of a recent study (Fang F, et al. N Engl J Med. 2012;366:1310-1318). It has previously been shown that receiving a diagnosis of cancer is associated with a high level of psychological stress, but that has often been attributed to the stress associated with the treatment itself or to the burden of living with cancer. Now researchers in Sweden investigated the association between a cancer diagnosis and the risk for suicide or death from cardiovascular (CV) causes immediately after the cancer diagnosis. The study included >6 million persons aged ≥30 years between January 1991 and December 2006. Participants

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were followed for the entire study duration or until death, whichever came first. Compared with cancer-free persons, those who received a cancer diagnosis had a 12.6 relative risk of suicide during the first week of diagnosis and a 3.1 risk during the first year. The relative risk for CV death was 5.6 during the first week after cancer diagnosis and 3.3 during the first 4 weeks. The increase in risk of suicide in the first few weeks after diagnosis dropped significantly during the balance of the first year after diagnosis. The increase in suicide risk was most prominent for patients with a cancer associated with a poor prognosis. These findings, the investigators write, “suggest that a cancer diagnosis constitutes a major stressor, one that immediately affects the risk of critical, fatal outcomes.” ■

Continued from page 20

Cancer Care Alliance. Ipilimumab led to overall survival (OS) improvements in previously treated patients in the MDX-010-20 trial and in previously untreated patients in the CA184-024 trial.

“Based on the importance of the vascular endothelial growth factor and mTOR pathways in RCC, drugs hitting these targets have not only proved effective in this malignancy, but the results have been replicated in large phase 3 trials.” —Toni K. Choueiri, MD In patients with the BRAF V600E mutation, vemurafenib improved OS as well (Chapman PB, et al. N Engl J Med. 2011;364:2507-2516). In a more recent study (Sosman JA, et al. N Engl J Med. 2012;366:707-714), vemurafenib induced clinical responses in more than 50% of patients with the mutation. The results with vemurafenib have been “striking,” Dr Thompson noted, observing that 80% of patients experience tumor shrinkage, and median survival has reached 16 months, “much better than expected in pretreated metastatic melanoma.” The panel emphasized the need to screen patients with metastatic disease for BRAF status, which, along with degree of disease, can dictate choice of first-line treatment. In addition, the panel does not recommend routine imaging and blood work for clinical stage IIA melanoma lacking specific signs and symptoms, but does recommend that for earlystage disease, sentinel lymph node biopsy be discussed and offered to patients. Non–Small-Cell Lung Cancer The pathologist should be an integral part of the non–small-cell lung cancer (NSCLC) management team, not just for diagnosis but for treatment planning as well, said Richard T. Cheney, MD, of Roswell Park Cancer Institute, Buffalo, NY. The panel updated the section on principles of pathologic review to reflect the growing role of the pathologist in this malignancy. “We need close collaboration among all providers, and the pathologist has a role at all levels,” Dr Cheney pointed out. “The more involved the patholo-

MAY 2012

gist, the greater the likelihood that you will come up with the right answers.” The guidelines refined the use of chemotherapy in the adjuvant setting and molecularly targeted agents for metastatic NSCLC, and added crizotinib as an option for advanced disease in patients with the EML4-ALK alteration. “We see dramatic responses, and some are durable, with crizotinib,” observed Ramaswamy Govindan, MD, of Siteman Cancer Center and Washington University School of Medicine, St. Louis, MO. The NSCLC panel also emphasized the need for sufficient tissue for molecular analy-sis and revised the classifications for adenocarcinomas. Renal-Cell Carcinoma The recent US Food and Drug Administration approval of the multi– tyrosine kinase inhibitor axitinib (Inlyta) led to its inclusion as a category 1–recommended second-line option for metastatic renal-cell carcinoma (RCC) and a category 3 option in nonclear-cell RCC. The drug joins a long list of targeted agents for this disease, noted Toni K. Choueiri, MD, of DanaFarber Cancer Institute, Harvard Medical School. “Based on the importance of the vascular endothelial growth factor and mTOR pathways in RCC, drugs hitting these targets have not only proved effective in this malignancy, but the results have been replicated in large phase 3 trials,” Dr Choueiri noted. “I have yet to see, in other solid tumors, the approval of 7 drugs in just 6 or so years.” Hodgkin Lymphoma As initial treatment for favorable stage IA or IIA Hodgkin lymphoma, the panel gave category 1 recommendations to both the ABVD regimen (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) and Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, bleomycin, vincristine, and prednisone) to be administered along with involved field radiotherapy. “Stanford V is an acceptable regimen, particularly for patients who may have some underlying cardiac disease,” said Leo I. Gordon, MD, of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL. The guidelines do not recommend routine PET surveillance after treatment of early disease, unless relapse is suspected, or bone marrow biopsy for favorable disease. ■

www.ValueBasedCancerCare.com

NCCN 2012 Conference TM

Updated NCCN Practice Guidelines in Oncology Include 3 New Panels By Audrey Andrews Hollywood, FL—The National Comprehensive Cancer Network (NCCN) introduced 3 new panels to its Clinical Practice Guidelines in Oncology™ at its 2012 annual conference. The key components of these new guidelines are described below. New Panel on Lung Cancer Screening The new Lung Cancer Screening Panel recommended that persons at risk for lung cancer be screened regularly (in some cases, annually) with helical low-dose computed tomography (LDCT) in an effort to detect cancer at its earliest stage. “If you leave this meeting with just one pearl of information, it should be that screening with low-dose chest CT [computed tomography] conclusively reduces mortality from lung cancer in high-risk patients,” said Douglas E. Wood, MD, of the University of Washington/Seattle Cancer Care Alliance, who is the chair of the new panel. The NCCN guidelines (1) describe the risk factors for lung cancer, (2) recommend criteria for selecting highrisk persons for screening, (3) provide recommendations for evaluation and follow-up of nodules found during screening, (4) discuss the accuracy of LDCT screening protocols and imaging modalities, and (5) discuss the benefits and risks of screening.

“If you leave this meeting with just one pearl of information, it should be that screening with low-dose chest CT conclusively reduces mortality from lung cancer in high-risk patients.” —Douglas E. Wood, MD

Ella Kazerooni, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, noted that the panel based the results on the landmark National Lung Screening Trial (Aberle DR, et al. N Engl J Med. 2011;365:395-409), which found that LDCT, compared with chest radiography alone, reduced lung cancer mortality by 20% and all-cause mortality by almost 7% among current or former smokers aged 55 to 75 years who underwent 3 annual LDCT scans.

However, lung cancer screening also resulted in a false-positive rate exceeding 90%. “Moving forward we need a good algorithm for managing the large number of false-positives we see,” Dr Kazerooni said.

“Moving forward we need a good algorithm for managing the large number of false-positives we see.” —Ella Kazerooni, MD Who Should Be Screened? The NCCN guidelines recommend that individuals without symptoms of lung cancer be assessed for risk based on the following risk factors: smoking history, radon exposure, occupational exposure, cancer history, family history of lung cancer, lung disease history, and secondhand smoke exposure. Screening is recommended for highrisk patients who are: • Aged 55 to 74 years, with a ≥30pack-year history of smoking tobacco; if a former smoker, must have quit within 15 years (category 1) • Aged ≥50 years and a ≥20-pack-year history of smoking and 1 additional risk factor (other than secondhand smoke; category 2B). Further analyses of cost-effectiveness, resource utilization, quality of life, anxiety resulting from positive screens, and impact of smoking cessation are under way. These will be important in discussions regarding public health policy and reimbursement, Dr Kazerooni said. Acute Lymphoblastic Leukemia Panel New guidelines were also devel-

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MAY 2012

oped for acute lymphoblastic leukemia (ALL) and a new ALL panel established. “On the pediatric side, there has been a significant advance in cure rates for ALL over the past decade, yet the story has not been near as rosy on the adult side,” said Patrick A. Brown, MD, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore. Half of all pediatric patients with ALL have 1 or 2 cytogenetic abnormalities that confer an excellent prognosis, approaching a curability rate of 100%, but these favorable abnormalities occur in <10% of adults with ALL. In contrast, BCL-ABL and T-cell lineage represent higher-risk subsets of ALL, and these are 3 times more common in adults. Also, the Philadelphia (Ph) chromosome, which is related to worse prognosis, is a common feature in adults with ALL but not in pediatric patients with ALL. For this reason, molecular chromosomal analysis is key to the work-up of patients suspected of ALL. “For adults, the advancements in the next 5 to 10 years will come through better identification of molecular targets and novel therapeutic agents that can be added to dose-intensified therapy,” predicted Joseph C. Alvarnas, MD, of City of Hope Comprehensive Cancer Center, Duarte, CA. An expert pathologist should also confirm the diagnosis through flow cytometry and chromosomal analysis to aid in stratifying patients by risk, which helps with treatment decisionmaking. “If patients have adverse risk factors or minimal residual disease, it is important to move to transplant earlier rather than later,” Dr Alvarnas said. The NCCN Acute Lymphoblastic Leukemia Panel encourages the use of pediatric-inspired protocols for younger adults with ALL. The guidelines also recommend the incorporation of tyrosine kinase inhibitors for patients with Ph+ ALL, because these always improve outcomes. The role of stem-cell transplantation remains unclear, although transplant is typically offered to suitable patients. Dr Brown emphasized the importance of an extended maintenance phase and the use of adequate central nervous system prophylaxis with intrathecal therapy to prevent relapse. The panel recommends that patients with ALL be referred to specialized treatment centers if possible and enrolled in clinical trials.

Adolescents and Young Adults Oncology Panel Also introduced were new supportive care guidelines that focus on the unique psychosocial issues of an underserved group—adolescents and young adults with cancer. “Compared with younger and older patients, there has been dismal progress in treating [adolescents and young adults] with cancer,” reported Peter F. Coccia, MD, of the University of Nebraska Eppley Cancer Center in Omaha. With no

“For adults [with ALL], the advancements in the next 5 to 10 years will come through better identification of molecular targets and novel therapeutic agents.” —Joseph C. Alvarnas, MD significant improvement in survival among patients aged 15 to 39 years, the need for addressing their unique needs has become clear and was the impetus for the new panel. The reasons for poor outcomes in adolescents and young adults with cancer include low participation in clinical trials, unaddressed psychosocial issues, poor treatment adherence, and lack of a consistent treatment approach. Behavioral/psychosocial issues in adolescents and young adults center on interpersonal relationships, achievement disruption, emotional concerns, and existential/spiritual matters. The NCCN’s Adolescent and Young Adult Oncology Panel’s goals for the guidelines are to: 1. Identify issues applicable to the adolescent and young adult population and recommend interventions unique to this group 2. Educate physicians about cancer in adolescents and young adults and its long-term consequences 3. Identify considerations for managing cancer in adolescents and young adults 4. Promote participation in clinical trials. The guidelines for adolescents and young adults address age-appropriate care, fertility/endocrine considerations, psychosocial/behavioral issues, and survivorship, and they include online resources. ■

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Health Information Technology

eviti: Decision Support at the Point of Care for Oncologists By Arlene A. Forastiere, MD Senior Vice President, Medical Affairs, and Chairwoman of the medical advisory board, eviti, Inc (www.eviti.com)

n independent health information technology company, eviti, Inc, provides a suite of web-based decision-support services that connects and delivers value to all parties in the care process—patients receive quality care, physicians are assured payment, insurers pay for quality care only, and pharmacy benefit managers (PBMs) or specialty pharmacy improve adherence. This decisionsupport platform is a transformative solution that reduces variability in care, improves quality, and enables realignment of provider incentives. Introduced in October 2010, the eviti platform ensures that evidence-based treatments are prescribed, followed, and appropriately reimbursed. Developed for use at the point of care, eviti supports physicians in the prescription of evidence-based treatment that is compliant with payer plan language and that automates the preauthorization process, thereby eliminating costly retrospective claims review that cannot improve patient outcomes or quality. eviti is an innovative and collaborative approach that promotes quality oncology practice to benefit all parties in the care process. As of April 1, 2012, close to 1500 oncology practices are registered users of eviti. The company has evolved its services in oncology over nearly a decade. Initially providing telephonic specialized oncology case management to covered members of client payer organizations, we saw that 32% to 41% of prescribed treatments did not meet nationally recognized evidence-based standards, which is consistent with reporting by others.1,2 As a result, we added a treatment plan review service by working with more than 4500 oncologists and a wide range of payers. Although these services delivered significant savings to clients, we recognized that much greater value could be achieved by connecting all parties at the point of care, which led to the launch of the eviti decision-support solution.

To achieve this, eviti supports physician decision-making with the most comprehensive and unbiased single information source of available cancer treatments for all cancer types (>120, including pediatric cancers); more than 1200 systemic therapy regimens plus radiation therapy treatments; and, since January 2012, more than 9000 registered clinical trials. Each evidence-based regimen entry contains granular details of the appropriate treatments (ie, surgery, radiation therapy, and systemic therapies, such as chemotherapy and hormonal therapy, and stem-cell transplant), stratified by specific pathology and by cancer stage, data on the resulting clinical outcome and toxicities, and levels of medical evidence and endorsement within the oncology community. Regimens are added or revised based on multiple data sources, including peer-reviewed journal publications of clinical trial results, government sources (ie, US Food and

eviti

Treatment Decision Support At the point of care, eviti’s decision support empowers physicians with all evidence-based treatment options and electronically connects physicians with payers in real time. Using this platform, physicians are ensured of payment, and insurers receive transparency of risk and know that they are paying for quality treatment.

VALUE-BASED CANCER CARE

Drug Administration, National Cancer Institute), oncology professional organizations (eg, American Society of Clinical Oncology, American Society of Hematology, and American Society of Therapeutic Radiology), and other recognized guideline standards groups, such as the National Comprehensive Cancer Network. A library of evidence-based medicine is kept current by a dedicated team of full-time oncologists, oncology-certified nurses, and a director of clinical informatics, along with oversight from the company’s medical advisory board composed of nationally recognized leaders in oncology. eviti identifies all clinical trials for which a patient may qualify, to facilitate physician–patient discussions of investigational treatment options and to reduce the use of ineffective therapies. How It Works Upon input of the diagnosis, clinical characteristics, relevant molecular markers, line of treatment, and treatment intent, eviti identifies and displays all evidence-based treatment options and indicates those that are compliant with a payer plan language for oncology reimbursement decisions. The regimen details of drug, dose, schedule, and appropriate supportive-care drugs are shown. For each regimen, the literature reference and endorsing entities are provided, along with the regimen cost (average sales

price plus 6%), outcomes, and toxicity. Once an evidence-based treatment that is consistent with the health plan benefits is selected, an eviti code is generated, with a simultaneous electronic notification to the physician, payer, and PBM or specialty pharmacy if approved by the payer. The eviti code assures the oncologist of payment, and confirms for the insurer that quality care is prescribed. Real-time preauthorization is transmitted to the PBM to facilitate shipment of the drug. An eviti provider dashboard allows real-time tracking of treatment plans and assigned eviti codes. At the moment of prescribing, the eviti payer dashboard enables payers to see treatment details, costs, and efficacy. However, as practicing oncologists know, all treatment authorization cannot always be automated. Approximately 10% of prescribed treatments will vary from evidence-based medicine for reasons justified by patient-specific clinical information. How eviti Delivers Value eviti is a front-end solution to ensure that the right care is prescribed before treatment begins. Its value is not dependent on retrospective review or dictating treatment to the physician. Of note, eviti is configured for integration into any electronic health record system, and as noted, it is free to physicians. Since becoming commercially available, eviti has reduced the rate of noncompliance with nationally accepted standards of care from a range of 32% to 41%, to 9%. This 72% reduction in treatment plan deviation translates into a cost avoidance of $12.4 million annually to payers (and lower copay for patients), which can be realized for every 1 million covered lives. Automated review reduces payer administrative and claims processing costs, while ensuring consistency, quality treatment, and appropriate reimbursement. Expert peer-to-peer conversations help eviti staff to advocate for reimbursement of high-quality care for medically justified variances or deviations from payer plan language. A platform for promoting variable pay-for-performance arrangements, eviti can protect and enhance physician income, while promoting high-quality, costeffective care. This approach supports practices to maintain economic viability within the framework of any of several compensation models that aim to control costs (eg, bundling, accountable care organizations, pay for performance). ■ References 1. Harlan LC, Greene AL, Clegg LX, et al. Insurance status and the use of guideline therapy in the treatment of selected cancers. J Clin Oncol. 2005;23:9079-9088. 2. Wu X-C, Lund MJ, Kimmick GG, et al. Influence of race, insurance, socioeconomic status, and hospital type on receipt of guideline-concordant adjuvant systemic therapy for locoregional breast cancers. J Clin Oncol. 2012;30:142-150.

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ACCC Annual Meeting

Ready or Not, Value-Based Purchasing Is Coming... Continued from cover this,” he said. Hospitals are already reporting to CMS through the Hospital Inpatient Quality Reporting (IQR) Program. Indeed, the quality measures established for the VBP program echo those of the IQR. “This is just the next step in promoting higher quality care for Medicare beneficiaries at a lower cost.” What distinguishes the VBP program from anything yet in practice is the funding mechanism. “VBP is funded by a 1% withhold from participating hospitals’ diagnosis-related group payments,” Mr Howard said. Hospitals that perform well get the withholding back; hospitals that excel in quality outcomes get a bit more of the payment pie in addition to the withhold, and hospitals that underperform are financially penalized (their withhold being shifted to those with superior outcomes). On VBP rollout, 1% is withheld, but proportion rises to 2% by 2017. Who Is In, Who Is Out The list of eligibility requirements is fairly straightforward. Those who are ineligible for VBP include hospitals subject to payment reductions under the IQR program and hospitals and hospital units excluded from the inpatient prospective payment system (eg, psychiatric hospitals, children’s hospitals). Eligible institutions—estimated to account for >3000 hospitals, according to Mr Howard—include hospitals that have at least 10 cases for each of at least 4 applicable measures during the VBP performance period, and hospitals with at least 100 completed Hospital Consumer Assessment Healthcare Providers and System surveys during that same period. “My guess is that most people in this room are going to be in this program,” said Mr Howard, adding that, “For the 2013 assessment, the performance period was from July 1, 2011, to March 31, 2012.”

not indicate how your hospital will actually perform in fiscal year 2013, “or whether your hospital will be eligible for the 2013 VBP program.” Specific examples of how quality-ofcare measures are derived and how total performance scores are interpreted can be found at www.cms.gov/ hospital-value-based-purchasing/ 01_ overview.asp?.

“The VBP program is a way to incentivize hospitals to move forward in this direction. This is just the next step in promoting higher quality care for Medicare beneficiaries at a lower cost.” —Donald P. Howard Keeping Score As noted, the domains measured are those of the IQR: 12 clinical processes of care (eg, prophylactic antibiotic selection for surgical points) and 8 patient experience of care dimensions (eg, discharge information). “Most of these will apply to cancer patients,” he said. Scores consist of points awarded for achievement or improvement in a given domain. Achievement is defined as having a given institution ranked in the top 50% of total percentile ratings for all participating hospitals (your accomplishments compared with those of everyone else). Improvement is gauged by a comparison of what you did during the current performance period compared with the last performance period (your accomplishments compared with you). Confused yet? That is why CMS has recently concluded a round of dry runs of the VBP program. “Our desire was

to give hospitals the opportunity to really try to understand the program and what impact it would have on them as early as possible,” Mr Howard explained. “We also wanted to provide

“We are clearly evolving from payment for volume to payment for value, and that is okay, because the incentives in the current system are perverse.” —Mark S. Soberman, MD, MBA, FACS quality improvement organizations with a better understanding of the hospital reports and the type of questions their hospitals may ask.” “Some of you have these reports in hand now,” he added. However, he warned listeners that the report does

If at First You Don’t Succeed… “This is a first step,” said Mark S. Soberman, MD, MBA, FACS, Oncology Service Line Director, Frederick Regional Health System, MD. “To their credit, the CMS folks acknowledge that.” Dr Soberman is very supportive of the overall goal. “We are clearly evolving from payment for volume to payment for value, and that is okay, because the incentives in the current system are perverse.” Like any new idea, there are adjustments to be made. However, “what CMS is looking at here are surrogates of quality,” Dr Soberman said. “These are actually process measures—did you do this, did you do that, did you report this or that. This is not yet true value-based purchasing, where you take outcomes measures and use those to determine payment, because outcomes are not the giving of antibiotics, outcomes are. Did the patient get well? Did the patient go home, return to their family, go back to work? Those are outcomes.” In addition, “everybody takes a 1% hit. If you do okay, you get the 1% back. If you just do a reasonable job, you theoretically might not get the 1% back. If you do a phenomenal job, you get the 1% plus 0.91% more. If you really bust your tail and do great, you get (a minor increase) in your Medicare payments. It is definitely a carrot and a stick,” Dr Soberman said, “but it is a pretty tiny carrot.” But, Dr Soberman acknowledged, “Again to their defense, they have to start somewhere.” ■

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MAY 2012

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ACCC Annual Meeting

Cost-Containment Efforts Top Trend in Community Cancer Centers Surprisingly, many programs report good/very good “financial health” in latest survey By Neil Canavan Baltimore, MD—Results from the latest survey of the Association of Community Cancer Centers (ACCC) membership suggest that although cancer centers have stepped up their efforts to introduce cost-reduction and revenue-enhancing initiatives, the rising tide of underinsured or uninsured patients with cancer is straining even the most optimistic of business plans. The survey, Cancer Care Trends in Community Cancer Centers, has been conducted annually for the past 3 years. A total of 59 community cancer programs participated in this survey. “As in previous years, a majority of the survey respondents are not-forprofit programs that provide both inpatient and outpatient services,” reported Rhoda Dunn of Kantar Health, “and 78% represents community hospital programs.” Ms Dunn’s presentation at the 2012 ACCC annual meeting highlighted the following key trends: • Cost-containment • Revenue enhancement • Drug acquisition • Patient affordability • Commission on cancer standards. Community Cancer Cost-Containment All survey respondents are actively engaged in controlling costs. That being said, “Cancer programs report that their financial health is ‘good’ or ‘very good,’ and this has been consistent over the past 3 years,” Ms Dunn said. “It suggests that cancer is insulated, to a certain extent, from variations in the economy.” Nevertheless, cancer programs are engaged in efforts to control costs, but these are largely not clinically focused, as can be seen by these cost-cutting initiatives indicated by respondents: • Reducing education-related travel expenses (81%) • Engaging in renegotiation of vendor contracts, “particularly around the purchase of infusion oncology drugs” (68%) • Cutting administrative costs (64%) • Delaying purchasing of equipment (58%) • Staff reductions (42%). “What is different this year…is that hiring freezes have dropped dramatically between the second and third year of the survey—32% last year as

“We are seeing a greater uptake of reimbursement specialists in community practices, where they are more subject to a variable cash flow.” —Rhoda Dunn

opposed to 57% the previous year; these are very encouraging changes,” said Ms Dunn. ACCC members also emphasized that rather than freezing hires or even reducing staff, the focus is on the “right” staff with regard to overtime, benefits, retirement programs, and call pay. Regarding cost-containment via purchasing, one survey respondent described their efforts this way: “We did Six Sigma about 18 months ago. This program helped us increase value add and remove waste. Specifically, we improved the way patients flow through the system, as well as reduced drug inventory.” Revenue Enhancement “Although [revenue enhancement] has always been important,” Ms Dunn said, “we are now seeing a lot more focus here.” Topping the list of things programs are doing is an increase in physician-to-physician liaisons (61%). “Referral patterns are very important in establishing referral networks—that came through as a major focus in the survey this year.” Other initiatives include increased coding reviews (56%), introduction of new technologies “to enhance offerings,” increased advertising (39%), and reduced rates of implementation,

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MAY 2012

including mergers and acquisitions, increased pricing, and increased screening activities, in that order. Regarding coding reviews, the use of reimbursement specialists is on the rise—29% in 2011—but this proportion does not seem to correlate with the need. “Respondents are of 2 minds here,” said Ms Dunn. One view recognizes the value of such professionals, but a different perspective suggests that the people administering the services to the patient should also possess the required expertise. “On the whole, we are seeing a greater uptake of reimbursement specialists in community practices, where they are more subject to a variable cash flow.” Survey results indicate that cancer programs can increase their revenue primarily through community physician outreach and by adding services. “Cancer programs rely on their service-line physician groups to network with local physicians who can refer oncology patients,” said Ms Dunn. Cancer programs also expect to attract referrals by expanding infrastructure, adding technology, and enhancing program offerings. Approximately 50% of the cancer programs surveyed are planning to expand their infusion center, with many (20%) anticipating the use of a satellite facility. One survey respondent noted, “To drive new volume, we are looking at adding oncology rehabilitation, outpatient palliative care, and a survivorship clinic.” Although 51% of respondents indicated a desire to add new technology, “IGRT [image-guided radiation therapy] (78%) and CyberKnife (17%) are the only areas of significant growth over the 3 years of this study,” commented Ms Dunn. The general feeling is that right now, major acquisitions are to be approached cautiously, if at all. Drug Acquisition Participation in the 340B drug-pricing program is increasing, and oncology practices are seeking out affiliations to gain access to the economic benefits. Ms Dunn believes that this rise is being spurred by loosened eligibility criteria and by increased discounts included in the Affordable Care Act. “Participation in 340B is strongly on the rise, with 26% of respondents onboard in year 1 of the

survey to almost 50% by year 3,” Ms Dunn pointed out. In addition, 6 of the 32 organizations currently not participating have indicated that they soon plan to sign up. However, “All current participants were quick to point out that the program is difficult to administer, particularly at the onset,” she noted. Acquisition of injectables through specialty pharmacy is also on the rise, from 16% last year to 32%, with payers driving the rising trend. “Payers can then reimburse at a lower rate, because specialty pharmacies have bigger volumes,” Ms Dunn noted. “However, from the hospital perspective, it is like going to a BYOB [bring your own bottle] restaurant, but in this analogy you not only bring your own bottle; [you] ask the restaurant to store it for you and then serve you, thereby making the establishment liable should you get sick from drinking too much wine.” This practice does not seem to be in the best interest of the hospital. As one respondent commented, “It is a lot of additional work to verify the source and whether the drug is legitimate. Ultimately, we may need to charge an additional fee for this.” Patient Affordability Many cancer programs (75% in this survey) continue to see an increase in the number of uninsured/underinsured patients receiving chemotherapy. At the same time, 47% reported that the number of commercially insured patients is dropping. “Roughly a quarter of patients being seen have Medicaid plus a secondary [insurance],” said Ms Dunn, “another quarter are on commercial plans, and 20% are covered by Medicaid alone.” Consequently, cancer programs are seeing more patients who need help affording their medications: 95% of respondents say that patient coverage is inadequate and that they require help with their copays; 83% report an increase in patients who must be referred to patient access programs. “This is resulting in more and more administrative time in the hospital,” said Ms Dunn, “while at the same time we are talking about cutting administration expenses. This is a bit of a conundrum.” And 80% of respondents Continued on page 29

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ACCC Annual Meeting

Cost-Containment Efforts... report that patients need help with transportation expenses—up from 69% just 1 year earlier. As one respondent stated, “Moving forward, we plan to have a dedicated person to get free and replacement drugs and copay assistance.”

“Referral patterns are very important in establishing referral networks—that came through as a major focus in the survey this year.”

Continued from page 28

and need to be done by hand,” which is very time-consuming, commented one respondent. Another survey response was,

“Evaluating patients for psychosocial distress is one thing, but we need to have the resources to help these patients when we find them.”

Although the standards are overall seen as a good idea, there is widespread uncertainty about how to achieve them. ■

RJ Health Systems The Creators of ReimbursementCodes.com

—Rhoda Dunn

New Commission on Cancer Standards This “was a very hot topic this year,” Ms Dunn said. “Members agree it will be good for patients, but are concerned about meeting the new requirements.” The new standards include the provision of treatment and survivorship plans, palliative care services, genetics services, navigation programs, and psychosocial distress screenings. “Most difficult is the treatment summaries and care plans. These are not in the EMR [electronic medical record]

at a glance ➤ Cancer programs surprisingly report that their financial health has been consistently good or very good over the past 3 years ➤ However, all programs are engaged in cost-containment efforts, and these are largely not clinically focused ➤ Survey respondents suggest that cancer programs can increase their revenue primarily through community physician outreach and by adding services ➤ Acquisition of injectables through specialty pharmacy is on the rise, with payers driving this trend ➤ New standards for cancer care include survivorship plans, palliative care services, genetics services, navigation programs, and psychosocial distress screenings

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29 10:36 PM

ACCC Annual Meeting

Coping with Cancer Drug Shortages: Practical Tips By Neil Canavan Baltimore, MD—According to Ernest Anderson, Jr, MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, MA, “If you’re not familiar with the drug shortage issue, you must be living under a rock.” Just before Mr Anderson’s presentation at the 2012 annual meeting of the Association of Community Cancer Centers (ACCC) as part of a panel discussion on the topic, the US Food and Drug Administration (FDA) exercised its authority to allow the immediate importation of the liposomal formulation of doxorubicin (Doxil) from a previously unauthorized international supply chain. This action and others recently taken by the FDA will not, Mr Anderson says, solve the drug shortage problem; in fact, the FDA’s reactive perspective is in itself part of the problem. “The FDA can’t just react after the problem has occurred,” he said. “That’s when it’s too late.” What we need are long-term solutions. Who Dropped the Ball? ACCC panel member Warren Dodge, Principal, Creekside Holdings, San Anselmo, CA, explained what his research has revealed. “When I first became aware of the problem, I thought…this is the result of the government mandating average wholesale pricing [AWP], and now companies can’t make any money,” Mr Dodge said. “But after I looked closer, I realized the problem is much more complex.” He identified many ways the drug supply can be negatively impacted, but AWP is indeed part of the problem. “It prevents the normal laws of supply and demand from going into effect,” he said. “Normally, if there is a shortage, the prices go up and manufacturers are incented to increase production. But that’s not happening.” There can also be problems when the FDA enforces safety regulations that, at first consideration, seem to be in the patient’s best interest. “If you shut down a manufacturer that wasn’t meeting safety requirements, the consequence may well be that there is not enough remaining capacity in the industry to fill the void,” Mr Dodge noted, “ergo, shortages occur.” Other Reasons for Shortages Mr Dodge listed other reasons for shortages: Shortages in the raw materials needed to make the drugs. “Around 5%

“This is about not wasting drugs, and often that has to do with stability testing. Yet, most would agree that current benchmarks for stability bear no resemblance to reality for many drugs.” —Warren Dodge

of shortages in 2010 were simply a result of the raw materials not being available.” Drug wholesalers negotiating singlesource multiyear contracts with generic manufacturers. “As a result, if you didn’t win that competitive bid, you were not incented to continue to manufacture that product because you don’t have enough access to the market.” Too much of the supply is coming from too few vendors. “If there’s a problem with one source, and you’ve only got 2 to begin with,” then it can lead to a shortage. Drug hoarding. “There have been occasions where hospitals and providers have been hoarding drugs,” and on behalf of your patients, it’s very tempting to do so. But that means that someone, somewhere, instead of having a small supply of a drug, has none. Buying/selling drugs on the gray market. “This is hospitals reselling drugs out of the back door, and the practice makes me a bit crazy. Everybody knows the gray market exists, but I can’t find anybody who will admit to buying or selling drugs this way.” Pricing of generics. “I mean, come on—a bottle of 5-FU is $15. How much can you possibly be making on that transaction?” New Drug Application (NDA) requirements for generics. “The FDA put these rules regarding safety and efficacy in effect fairly recently. If a drug was approved before these regulations went into effect, a generic of that drug still has to go through the new NDA process. Well, it makes no economic sense for a company to invest in clinical trials for a generic drug under current pricing arrangements.” Inventories are too tight. “This is about not wasting drugs, and often that has to do with stability testing. Yet, most would agree that current

VALUE-BASED CANCER CARE

MAY 2012

benchmarks for stability bear no resemblance to reality for many drugs.” Perfectly good drugs are being discarded or, to avoid discard, are understocked.” A change in treatment guidelines. “I’ve seen examples where the guideline switches from drug A to drug B, and overnight you have a drug shortage.”

“Cure the disease first. With methotrexate, acute leukemia patients get first dibs. For cytarabine, acute leukemia first, then mantlecell lymphoma.” —Michael A. Kolodziej, MD

One End User’s Experience “About 2 and a half years ago, a guy comes to me for a consult for his stage III colon cancer,” said ACCC panelist Michael A. Kolodziej, MD, New York Oncology Hematology, PC, Albany Cancer Center, an affiliate of US Oncology. “So, I tell him FOLFOX is my choice for treatment (FOL, folinic acid [leucovorin]; F, 5-FU; OX, oxaliplatin [Eloxatin].” The patient sought out a second opinion from an oncologist at Memorial Sloan-Kettering Cancer Center, NY. “After having my recommendation confirmed at Sloan-Kettering, the patient returned, and we sent him to the infusion room to begin treatment.” But then came a surprise. “When the patient got to the infusion room, he was told there was no leucovorin, and that he would have to wait, and boy was he mad,” Dr Kolodziej said. So mad, in fact, that the patient went back to New York for treatment, “where, much to my sur-

prise, they had leucovorin.” “I called my contacts at SloanKettering, and they said, ‘yes, we’ve got it. Then I went back to my executive team at US Oncology and said ‘there’s something up.’” There was at least 1 hospital that had figured out a way to get what it needed, and Dr Kolodziej needed to figure out how. Dr Kolodziej and his team did a very thorough analysis of the purchasing and distribution of generics at US Oncology. “We subsequently set out to develop a new methodology whereby we violated every single principle we had preached about inventory management, about how, with carboplatin at $5 a vial, it was okay to have a little more on hand.” Dr Kolodziej then had to go to US Oncology’s physicians and explain that their cooperation and input was critical to making the new inventory policies workable. “Our goals had to be both aggressive and transparent,” Dr Kolodziej insisted. “We asked them to consider what therapeutic alternatives could be used for drugs that may not be available.” For example, if there wasn’t any bleomycin, cisplatin might have to be used. “We got out information about potential shortages early and often.” Strategies to Deal with Shortages More is better. Manufacturers are engaging in de facto rationing so that most customers are at least getting some product. For those working in a network, reaching out to practices within the network may help find the needed drug. “Since US Oncology has 10 hospitals, we’re almost certain to get something, which can then be distributed to our networked centers,” Dr Kolodziej said. He encourages those not in a network to join forces with other providers within the geographic region. Institute a priority plan. “Cure the disease first,” Dr Kolodziej advised. “With methotrexate, acute leukemia patients get first dibs. For cytarabine, acute leukemia first, then mantle-cell lymphoma….You can make up a prioritization schedule, but make sure that patients receiving curative therapy get first crack.” Communicate with payers. “Let them know what’s going on,” Dr Kolodziej stressed. Even if you make a substitution for a drug, you are still going to want to get paid for it. Updates. And finally, keep on top of the news. For updates, and related information on drug shortages, visit www.ashp.org/drugshortages. ■

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Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace09 TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in DCIS patients • Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer • Describe the design and findings of the ECOG 5194 validation study • Apply the 12-gene assay for DCIS into clinical decision-making • Explain relevant information about the 12-gene DCIS assay and DCIS score to patients

Release Date: May 8, 2012 Expiration Date: May 7, 2013

FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA

E. Shelley Hwang, MD, MPH Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC

Kathy D. Miller, MD Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.

ACCREDITATION Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057.

AACR Annual Meeting

Advances in Personalized Medicine: Focus on Prostate and Brain Cancers Chicago, IL—Targeting prostate cancer with extreme accuracy, using tissue oxygen content to predict its recurrence, and using breast cancer drugs on brain tumors were a few highlights of a news conference on advances in personalized medicine at the 2012 American Association for Cancer Research meeting.

Photo by © AACR/Todd Buchanan 2012

In a trial of 247 men with prostate cancer, tumor oxygen levels were measured before treatment with highprecision radiotherapy. A follow-up 6.6 years after treatment found that patients with hypoxic tumors did worse than those with well-oxygenated tumors. Hypoxic tumors recurred earlier—usually within 3 to 4 years of completion of treatment. “Probably the most exciting thing in the context of personalized cancer medicine is the concept that…if we can identify hypoxic tumors, the next step is, can we do something about it? And there are new treatment strategies coming along all the time that specifically target aspects of hypoxia in cancer,” Dr Milosevic said. Hypoxia can predict prostate cancer recurrence after radiotherapy, and measuring it could help identify the best treatment course. New personalized treatments could then target hypoxia to improve outcomes. Michael J. Evans, PhD, Research Fellow in the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center in New York, NY, described his study of noninvasive imaging, which allows clinicians to visualize metastasized prostate cancer and monitor it quantitatively as potential markers, thus advancing the prospect of personalized therapy. “One of the major unmet clinical needs for the prostate cancer commu-

“Probably the most exciting thing in the context of personalized cancer medicine is the concept that…if we can identify hypoxic tumors, the next step is, can we do something about it?” —Michael Milosevic, MD, FRCPC

“One of the major unmet clinical needs for the prostate cancer community, as well as for other cancers, is the development of noninvasive imaging markers that can give us some sense of the pathological activation, or the inhibition, of key biologic pathways for the respective cancer.” —Michael J. Evans, PhD

nity, as well as for other cancers, is the development of noninvasive imaging markers that can give us some sense of the pathological activation, or the inhibition, of key biologic pathways for the respective cancer,” Dr Evans pointed out.

at a glance ➤ Prostate cancer is the most common cancer in men in the United States, and approximately 25% of men will develop a recurrence after treatment

Photo by © AACR/Todd Buchanan 2012

Prostate Cancer Prostate cancer is the most common cancer in men in the United States. It can be treated equally effectively with surgery or radiotherapy, but approximately 25% of men will develop a recurrence after treatment. “How can we do better? How can we actually tailor treatment more specifically to the needs of these men?” asked Michael Milosevic, MD, FRCPC, Professor of Radiation Oncology and a radiation oncologist in the Princess Margaret Hospital Cancer Program, University Health Network, University of Toronto, Canada. One answer, he said, is high-precision radiotherapy with intensity-modulated radiation, but it needs to go hand in hand with a better understanding of the biology of prostate cancer. This is where hypoxia comes in. Many tumors contain hypoxic regions that cause the cancer to behave aggressively. Hypoxia drives the spread of cancer and also reduces the effectiveness of therapy.

Photo by © AACR/Todd Buchanan 2012

By Richard Hyer

“Glioblastoma cells that harbor the extracellular domain are indeed addicted to the EGFR, so there is an opportunity to target this.”

VALUE-BASED CANCER CARE

—Ingo K. Mellinghoff, MD

MAY 2012

➤ Hypoxia drives the spread of cancer and reduces the effectiveness of therapy ➤ Hypoxia can predict prostate cancer recurrence after radiotherapy; its measurement could help identify the best treatment course ➤ 89Zr-5A10, a radiotracer that was engineered to locate free PSA, facilitates risk assessment with more accuracy than with serum PSA ➤ Lapatinib can potently inhibit EGFR in glioblastoma

A radiotracer engineered to locate free prostate-specific antigen (PSA) allows the clinician to assess risk with more accuracy than is available with serum PSA. This tracer, 89Zr-5A10, also allows the study of metastatic bone lesions, which are not yet clearly visible in bone scans. At present, bone scans cannot discriminate between malignant and nonmalignant lesions. The radiotracer is used in conjunction with positron-emission tomography scans. To date, it has only been tested in mice; investigators hope to stage a human trial by 2013. Glioblastoma Ingo K. Mellinghoff, MD, Oncologist, Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, presented his finding that lapatinib (Tykerb), which is approved by the US Food and Drug Administration for use in HER2-positive breast cancer, can potently inhibit epidermal growth factor receptors (EGFR) in glioblastoma. The problem is getting enough drug to the tumor. As many as 40% of patients with glioblastoma have EGFR mutations. “So the question we are trying to answer in this particular project is, do glioblastoma cells that harbor an extracellular domain mutation require EGFR for survival? Are they addicted to EGFR as are lung cancer and tyrosine kinase mutations? And if so, do they respond to the same type of EGFR inhibitor?” Dr Mellinghoff asked. Lapatinib and erlotinib (Tarceva; indicated for lung cancer) are both EGFR inhibitors, but only the former inhibits phosphorylation of glioblastoma multiforme cells. In a large clinical trial, patients with brain tumors received lapatinib before surgery, and tumor specimens were examined after surgery. The specimens showed lapatinib to be a potent inhibitor of EGFRs, but it was not completely effective; some phosphorylation continued. “So it’s good, but it’s not good enough,” said Dr Mellinghoff. What remains to be seen, he said, is how much drug is needed to induce complete cell death. Another trial is being planned, this one using pulsatile lapatinib at intermittenthigh doses. “Glioblastoma cells that harbor the extracellular domain are indeed addicted to the EGFR, so there is an opportunity to target this,” Dr Mellinghoff noted. ■

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Metformin Protects Against Several Cancers By Richard Hyer Chicago, IL—Metformin cannot seem to stay out of the news. This antidiabetes drug that is derived from the French lilac is now also thought to possibly protect against liver cancer, lower the risk for oral cancer, improve prognosis of pancreatic cancer in diabetic patients, and increase response to melanoma tumors with BRAF mutations when used in combination with a common cancer drug, according to several studies presented at the 2012 American Association for Cancer Research meeting. Metformin suppresses the liver’s production of glucose and may actually protect against liver cancer, according to a recent study (Bhalla K, et al. Cancer Prev Res [Phila]. 2012;5:544-552). “There has been a lot of interest in metformin in the last several years, because of its role as an anticancer agent,” said coauthor Geoffrey Girnun, PhD, Assistant Professor of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore. “We were surprised that there were no actual direct studies looking at the role of metformin in liver cancer in any preclinical models, so that is what we did.” When liver tumors were chemically induced in mice, the mice taking metformin displayed minimal tumor

activity, whereas the controls displayed significant tumor growth. Dr Girnun said that the mechanism by which metformin prevents liver cancer may be transferable to other patient populations at risk for the disease, including those with hepatitis, nonalcoholic fatty liver disease, and obese persons. In an unrelated study, the incidence of oral cancer was reduced by 70% to 90% in mice receiving metformin (Vitale-Cross L, et al. Cancer Prev Res [Phila]. 2012;5:562-573). The study showed that metformin acts against the mTOR protein to prevent lesion progression. The mTOR protein regulates cell growth, proliferation, motility, survival, protein synthesis, and transcription. Investigators induced premalignant lesions into laboratory mice and then studied metformin’s effect on the progression to oral cancer. Metformin reduced the size and number of oral tumor lesions in the mice, and reduced the development of squamous-cell carcinoma by 70% to 90%. Metformin inhibited the mTORC1 (metformin complex 1), function in the basal layer of oral premalignancies and prevented their development into head and neck squamous-cell carcinoma.

Results of yet another study suggest that patients with concomitant diabetes and pancreatic cancer who are prescribed metformin may have improved survival compared with those who are not prescribed metformin (Sadeghi N, et al. Clin Cancer Res. 2012 Mar 31).

Metformin’s protective effect was evident at all disease stages, with the exception of metastatic disease.

Patients with pancreatic cancer have a high prevalence of diabetes and impaired glucose tolerance. In this retrospective study of 302 patients with diabetes and pancreatic cancer, 117 were prescribed metformin. At 1 year, 63.9% of the patients prescribed metformin were still alive, whereas 46.3% of those who were not receiving metformin survived. By 2 years, 30.1% of the metformin group remained alive compared with 15.4% of the nonmetformin group. Patients using metformin had a 32% reduced risk of mortality. According to this study, metformin’s protective effect was evident

at all disease stages, except metastatic disease, where metformin had no measurable effect. Combining metformin with vascular endothelial growth factor-A (VEGF-A) inhibitors increased suppression of tumor growth in melanoma tumors with BRAF mutations compared with treatment with the VEGF-A inhibitors alone, according to a new study (Martin MJ, et al. Cancer Discov. 2012;2:344-355). The investigators first tested metformin on NRAS-mutated and BRAFmutated melanoma cells grown in culture, then grew BRAF-mutated melanoma tumors in mice. They found that metformin caused BRAF-mutated cells to secrete increased levels of VEGF-A, a molecule that promotes blood vessel formation and increases tumor growth. This prompted the investigators to use an animal model in combination with often used VEGF-A inhibitors. Tumor growth increased 2-fold with metformin alone, but when combined with the tyrosine kinase inhibitor axitinib (Inlyta), tumor growth was suppressed by 45%. When metformin was combined with bevacizumab (Avastin), tumor growth was suppressed by 64% compared with 34% with bevacizumab alone. ■

Chicago, IL—For the individual at average risk for disease, wholegenome sequencing (WGS)—mapping the sequence of one’s full set of genetic material—is not a crystal ball to reliably predict future health, according to a study presented at the 2012 American Association for Cancer Research meeting. WGS “cannot substitute for conventional risk management strategies, including routine checkups and lifestyle optimization,” said coinvestigator Bert Vogelstein, MD, Clayton Professor of Oncology and Pathology, Johns Hopkins Kimmel Cancer Center. WGS, however, may be extremely valuable for individuals with a strong family history of disease, Dr Vogelstein said. The researchers estimated the maximum capacity of WGS to identify individuals at significant risk for 24 different diseases, including cancer, Alzheimer’s disease, heart disease, and stroke, based on 53,666 monozygotic twin pairs worldwide (Roberts

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NJ, et al. Sci Transl Med. 2012 Apr 2). Monozygotic twins share the same genome and therefore have identical genetic risk factors. The potential scope of data is overwhelming. Every individual has 4.5 million variants in DNA sequence, and the significance of almost any given variant is yet unknown. Furthermore, the number of potential interactions between variants, which may cause, enhance, or even reduce disease risk, is “astronomical,” he said. Within the more narrow confines of the study, for each disease in twin 1, the prevalence of that disease in twin 2 was assumed to yield the genetic risk for the twins’ genome. The investigators used a model to predict minimum and maximum risk distributions and used these to estimate the capacity of WGS to provide useful clinical information. A positive test result was defined as an actionable (at least a 10% disease risk), meaning that 1 in 10 would develop the disease from all factors

Photo by © AACR/Scott Morgan 2012

Can Whole-Genome Sequencing Predict Future Cancer? WGS “cannot substitute for conventional risk management strategies, including routine checkups and lifestyle optimization.” —Bert Vogelstein, MD

combined. Getting a positive test result would therefore make someone a candidate for intense surveillance. A negative, by contrast, result on the other hand would suggest that the individual had a slightly lower risk than the general population. Why does WGS have such limited predictive power in cancer? “Because cancer is a mixture of genetic and nongenetic effects….Cancers are caused by the sequential accumulation of

MAY 2012

mutations, almost all occurring after birth. These things occur by chance; as cells divide, they make mistakes. If they occur in a cancer gene, that represents one step toward cancer. Cancer is a bad side effect of evolution,” Dr Vogelstein said. WGS could, however, be extremely valuable for identifying the genetic basis of monogenic diseases. “If the consumer is purchasing the test because he or she hopes it will alert them to a risk that they don’t necessarily know about, then they will likely be satisfied, because these are risks for which these tests can in fact alert them. We estimate that at least one half of individuals, once all the research is done, will get such a result. However, if the individual wants to get tested because he or she thinks that this will be able to be a crystal ball, so to speak, to tell them what their medical history will be, they will be disappointed. It will not do that,” Dr Vogelstein said.—RH ■

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CONTINUING EDUCATION APRIL 2012 • VOLUME 5 • NUMBER 1

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Newly Diagnosed Patients LETTER PUBLISHING STAFF

FROM THE

EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). This is due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinical investigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria for diagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management of comorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regarding the application and interpretation of recent clinical advances. In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questions are answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowledge, and professional experience regarding evidence-based care. In this first issue, experts from Winship Cancer Institute of Emory University answer questions pertaining to the management of newly diagnosed patients.

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Director, Medical & Scientific Services Linda M. Ritter, PhD linda@coexm.com

Editorial Director Susan Berry susan@coexm.com

Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Project Manager Elizabeth S. Cohen liz@coexm.com

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Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

FACULTY Leonard T. Heffner, Jr., MD Associate Professor of Hematology and Oncology and Internal Medicine Emory University Clinical Director of the Myeloma Program at Winship Cancer Institute of Emory University, Atlanta, GA

Quality Control Director Barbara Marino

Web Coordinator Jose Valentin

Business Manager Blanche Marchitto

Melanie Watson, RN, OCN Oncology Certified Registered Nurse Myeloma Team/BMT Winship Cancer Institute Emory University Atlanta, GA

Minal Surati, PharmD Clinical Pharmacy Specialist Department of Hematology and Medical Oncology Emory University Hospital/ Winship Cancer Institute Atlanta, GA

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Supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company.

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 241 Forsgate Drive Suite 205B Monroe Township, NJ 08831

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

MAY 2012

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsor This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Educational Objectives Upon completion of this activity, the participant will be able to: • Use diagnostic and staging criteria to distinguish active multiple myeloma (MM) from smoldering MM and monoclonal gammopathy of undetermined significance • Determine appropriate treatment for newly diagnosed MM based on patient- and disease-related characteristics and the riskbenefit profile of available agents and combinations • Apply evidence-based strategies to prevent and/or manage common comorbidities in patients with MM Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12025.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or cgusack@mlicme.org. Physician Credit Designation The Medical Learning Institute, Inc. (MLI) designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas

and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Center of Excellence Media, LLC. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute, Inc. (MLI). Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours. Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 04689999-12-012-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by MLI for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. Leonard T. Heffner, Jr., MD, has nothing to disclose. Melanie Watson, RN, OCN, has nothing to disclose. *Minal Surati, PharmD, has nothing to disclose. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Agenda: 1.25 hours Articles/Commentaries: 60 minutes Evaluation/Posttest: 15 minutes Date of original release: April 16, 2012 Valid for CME/CE credit through: April 16, 2013

Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose. Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosed that her spouse is investigator on a study for Agenix and Lilly; on the data monitoring committee for Infinity; and on the data monitoring committee and PI on a study for Pfizer.

SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

Evolving Concepts in the Management of Newly Diagnosed Multiple Myeloma Leonard T. Heffner, Jr., MD Associate Professor of Hematology and Oncology and Internal Medicine, Emory University Clinical Director of the Myeloma Program at Winship Cancer Institute of Emory University, Atlanta, GA

Introduction The management of multiple myeloma (MM) is rapidly changing. New prognostic systems based on clinical and biologic features, such as cytogenetic abnormalities, continue to be developed and refined. Novel agents designed to interrupt myeloma growth and survival pathways have also entered the clinical arena, leading to improved response rates, survival, and quality of life. A major challenge is to define the optimal use of these new tools and therapies in order to significantly impact the natural history of disease. In this article, Leonard T. Heffner, Jr., MD, answers questions related to the diagnosis, staging, and initial management of patients with MM, and offers insights on his institution’s approach to aligning patient- and disease-characteristics with the most appropriate treatments to optimize care.

monoclonal (M) protein in serum and <10% of bone marrow plasma cells (BMPCs), but they do not have end-organ damage. In SMM, the clinical and laboratory findings are the same as MGUS except that the serum Mprotein is 3 g/dL and/or the BMPCs are 10%. Symptomatic MM is determined by the presence of 10% BMPCs, serum or urinary M-protein, and evidence of end-organ damage; specifically, hypercalcemia, renal insufficiency, anemia, or bone lesions (Table 1).1-4 Overall, the risk of MGUS progressing to MM is about 1% per year.2 However, the risk of progression for SMM is considerably higher; approximately 10% per year in the first 5 years.2 Risk factors for progression in SMM include: plasma cell mass including M-protein size and the percentage of BMPCs, abnormal free light chain (FLC) ratio, proportion of phenotypically abnormal BMPC, and presence of magnetic resonance imaging (MRI) abnormalities2 (Table 2). Patients with SMM who have an FLC ratio of either <0.125 or >8 have an increased risk for progression to symptomatic myeloma, and this risk is independent of the risk defined by the percentage of BMPCs or size of the M-protein spike.2,5 Should patients with high-risk SMM be observed or treated?

What criteria are used to distinguish smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) from active myeloma?

MGUS and SMM are asymptomatic, and each carries a considerably different potential for progression to MM. Patients with MGUS have <3 g/dL

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The current standard of care for asymptomatic SMM is observation.6 However, we do know that a large majority of high-risk patients will evolve into symptomatic myeloma that requires treatment. Clinical trials are ongoing to assess whether the progression of SMM can be delayed or halted with early treatment. One such study is the Eastern Cooperative Oncology Group

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CONTINUING EDUCATION

Table 1. Diagnostic Criteria for Specific Plasma Cell Disorders1-4

Table 2. Risk Factors for Progression in Smoldering Multiple Myeloma5

Monoclonal gammopathy of undetermined significance (MGUS) All 3 criteria must be met: • Serum monoclonal protein <3 g/dL • Clonal bone marrow plasma cells <10% • Absence of end-organ damage (such as CRAB criteria) that can be attributed to the plasma cell proliferative disorder

Higher plasma cell mass (including monoclonal-protein size and percentage of BMPCs) Abnormal free light chain ratio Abnormal immunophenotype and immunoparesis (95% of BMPCs with abnormal phenotype; decrease in 1-2 uninvolved immunoglobulins)

Smoldering multiple myeloma (SMM) (also referred to as asymptomatic multiple myeloma)

Evolving pattern (progressive increase in the serum monoclonal-protein value, eg, increase in monclonal-protein level in each of the first 2 follow-up visits)

Both criteria must be met: • Serum monoclonal protein (IgG or IgA) 3 g/dL and/or clonal bone marrow plasma cells 10% • Absence of end-organ damage (such as CRAB criteria) that can be attributed to the plasma cell proliferative disorder

Presence of MRI abnormalities (especially a focal pattern on spinal MRI) BMPCs indicates bone marrow plasma cells; MRI, magnetic resonance imaging.

Multiple myeloma (MM) All 3 criteria must be met, except as noted: • Clonal bone marrow plasma cells 10% • Presence of serum and/or urinary monoclonal protein (except in patients with true nonsecretory MM) • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (specifically CRAB): Calcium elevation: serum calcium 11.5 mg/dL or Renal insufficiency: serum creatinine >2 mg/dL Anemia: hemoglobin >2 g/dL below lower limit of normal or value <10 g/dL Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

(ECOG) E3A06 phase 2/3 trial, which is comparing the progression-free survival of patients with high-risk SMM treated with lenalidomide or observation.7 Lenalidomide was chosen because of its clinical activity in MM, as well as the fact that it can be administered orally and is generally well tolerated. Thirty-four patients were enrolled in the phase 2 portion of the trial and were treated with lenalidomide 25 mg/day on days 1 to 21 of a 28-day cycle for 6 cycles in the absence of disease progression or unacceptable toxicity. Following a 6-month hold for safety analysis of the phase 2 data, the phase 3 portion of the trial, in which 370 patients will be randomized to either lenalidomide or observation, will begin enrollment. I think this is an exciting trial because we are trying to move back the clock a little rather than wait until a patient with SMM has become symptomatic. It will be interesting to see whether the natural history of the disease can be influenced with early treatment, especially in a population that has a fairly high risk of eventually requiring therapy. How have staging criteria for MM evolved over time?

First published in 1975, the Durie-Salmon (DS) staging system was the method clinicians commonly relied on for staging MM for more than 25 years. This system assessed myeloma tumor burden, and based stages I, II, and III on serum M-spike, hemoglobin, calcium level, and number of bone lesions. Subclassifications A and B reflected the degree of kidney involvement, as measured by creatinine level.8 The DS staging system provided a framework by which clinicians could communicate clearly with each other regarding the extent of the disease. Unfortunately, there were drawbacks to this system. Many found it to be too complex, and there were problems in terms of evaluating lytic bone lesions accurately. To address these issues, investigators proposed a new method of staging called the International Staging System (ISS). This system includes an assessment of beta-2-microglobulin (ß2M) and serum

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albumin levels, which were shown in a multi-variant analysis to be the 2 important prognostic factors in myeloma.9 Patients with stage I disease have a ß2M level <3.5 mg/L and albumin level 3.5 g/dL (median survival 62 months) compared with stage III with ß2M 5.5 mg/L (median survival 29 months) and stage II (not meeting criteria for either stage I or III) (median survival 44 months).9 Because ß2M and serum albumin are easily obtainable parameters, the ISS has superseded the DS staging system and is now widely accepted as the standard of care for staging MM. What role does cytogenetic testing play in the prognosis and treatment of newly diagnosed patients with MM?

The use of cytogenetic testing to help identify myeloma patients with highrisk disease continues to evolve as we learn more about the biology of the disease. Conventional metaphase karyotyping is one modality for assessing risk, but it is not as informative as we would like because myeloma cells proliferate poorly in vitro.10 This method of analysis is useful, however, for the screening of hyper- and hypodiploidy and cytogenetic abnormalities such as deletion of chromosome 13 [del(13q)].4,11 Fluorescence in situ hybridization (FISH), on the other hand, analyzes cells in mitotic interphase, which allows better identification of certain chromosomal abnormalities.11 In particular, it is instrumental in screening for del(13q), deletion of the short arm of chromosome 17 [del(17p)], translocations involving chromosomes 4, 11, 14, and 16 [t(4;14), t(11;14), and t(14;16)], and 1q21 amplification.4,11 Abnormalities indicative of poorer prognosis in myeloma include del(17p), t(4;14), and t(14;16).10,12,13 Interestingly, del(13q), once considered a high-risk characteristic, is no longer thought to indicate a poor prognosis if it occurs independently of other cytogenetic abnormalities.10,14 At diagnosis, metaphase karyotyping and FISH results are certainly very important to obtain and use in treatment planning, but they must be considered in the context of other features of a patient’s condition, such as age, stage of disease, extent of bone disease and renal function, and comorbidities. In addition, there is still a question as to how best to incorporate results into a patient’s course of therapy because cytogenetic abnormalities continue to evolve over time.14,15 At our institution, we retest cytogenetics prior to transplantation to determine whether a patient’s risk status has changed in any way. Clinical evidence suggests that bortezomib and lenalidomide may have particular value in the context of certain high-risk cytogenetics.13,16-19 Whenever possible, we treat newly diagnosed myeloma patients with regimens that contain one or both of these agents. In addition to cytogenetic abnormalities, gene expression profiling (GEP) signatures are now being identified, including a 70-gene profile from the

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University of Arkansas20 and a 15-gene profile by the Intergroupe Francophone du Myélome.21 Although these 2 profiles do not share any common genes, GEP has the potential to be a useful tool for risk-stratifying patients and determining optimal therapy, and investigation in this area continues. For example, GEP signatures are being utilized in the ECOG E3A06 trial for SMM,7 to help identify patients who are going to have higher or lower risk of progression.

Figure. Best responses to RVD for the treated population and the phase 2 population.19

100

100%

How do you determine the appropriate treatment for newly diagnosed MM?

What advances have been made to help clinicians assess bone disease in MM?

74% 67%

Patients (%)

For transplant-eligible patients, the approach we typically use is frontline treatment with a combination of lenalidomide, bortezomib, and dexamethasone (RVD). In a phase 1/2 study in newly diagnosed patients, this combination was shown to have favorable tolerability, and resulted in a partial response or better rate of 100%, with a 74% rate of very good partial response or better in the phase 2 population (Figure).19 The study included subgroup analyses of patients with high-risk cytogenetics, which showed that response to RVD was unaffected by cytogenetic abnormalities. This finding suggested that RVD may overcome high-risk cytogenetics, but was not definitive because of the small sample size of patients with these abnormalities. We almost always use this combination, whether the risk is standard or high, unless the patient has plasma cell leukemia or another medical condition that would require a different approach to treatment. RVD is also being used more frequently in the nontransplant setting, as long as patients can tolerate these agents. If RVD is too aggressive, we consider regimens using melphalan and prednisone combined one of the novel agents bortezomib, lenalidomide, or thalidomide. If we can find a clinical trial that would suit the needs of transplant-ineligible patients better, we may offer that to them.

PR VGPR CR/nCR

57%

39%

Best Responses in All Patients (n=66)

Best Responses in Phase 2 Patients (n=35)

CR/nCR indicates complete response/near-complete response; PR, partial response; VGPR, very good partial response; RVD, lenalidomide/bortezomib/dexamethasone.

sion. We also repeat bone assessments by PET or MRI after a course of therapy. For transplant-eligible patients, this is done prior to transplant to document the degree of response to treatment. For transplant-ineligible patients, this practice helps us to determine whether we should continue with the current approach to therapy. Conclusion

In the most recent consensus guidelines from the International Myeloma Working Group, the bone survey is still the gold standard for assessing myeloma bone disease.22 However, there is a movement among many cancer centers to make more frequent use of MRI and positron emission tomography/computed tomography (PET/CT) scans.4,23 Fortunately, Medicare now allows coverage of PET/CT scans for myeloma. At our institution, we consider each patient’s case on an individual basis. In general, we still conduct a bone survey. If results are negative, we will typically do an MRI of the spine and pelvis, as this procedure can pick up abnormalities even if a plain film is negative in symptomatic patients.22 The use of PET scans is clearly important, because they can detect not only bone-based disease, but also extramedullary disease.22,24

The use of PET scans is clearly important, because they can detect not only bone-based disease, but also extramedullary disease.

For patients with oligosecretory or nonsecretory disease who do not have laboratory parameters to monitor outside of a bone marrow examination, and particularly for patients with extramedullary plasmacytomas, we use PET scans to monitor them and to document whether they are in remis-

Progress in the diagnosis and treatment of MM has been tremendous over the past 10 to 15 years and continues to move forward. We are going to continue to see new drugs come along that will no doubt result in even more progress. In this last decade alone, we have been able to take the novel agents thalidomide, lenalidomide, and bortezomib, and utilize them in numerous combinations and schedules. In addition to the continued research to find an approach to cure, I think the future of myeloma may be in going back to the precursor diseases. I believe MGUS and SMM are where we are ultimately going to learn why these plasma cell dyscrasias progress to myeloma. ◆ References 1. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9. 2. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010:24:11211127. 3. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haem. 2003;121:749-757. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple myeloma. Version 1.2012. www.nccn.org/professionals/physician_gls/pdf/ myeloma.pdf. Accessed March 18, 2012. 5. Blade J, Dimopoulos M, Rosinol L, et al. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010;28:690-697. 6. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111:785-789. 7. Lenalidomide or observation in treating patients with asymptomatic high-risk smoldering multiple

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Improving Patient Outcomes in Newly Diagnosed Multiple Myeloma Oncology Certified Registered Nurse/Myeloma Team/BMT Winship Cancer Institute, Emory University Atlanta, GA

Introduction At the time of diagnosis, patients with multiple myeloma (MM) may present with numerous disease-related symptoms. Each of these complications requires supportive care, and providing that care demands a high degree of individualization. In many cases, one symptom can influence the management of another. For example, renal insufficiency may impact the administration of bisphosphonates used to protect bone health. In addition, specific agents used to treat myeloma may produce confounding symptoms, such as neurotoxicity in a patient already experiencing disease-related bone pain. In this article, Melanie Watson, RN, OCN, discusses her center’s evidence-based approach to providing symptom relief for patients with newly diagnosed myeloma.

What is the nurse’s role in the assessment and management of patients with MM who present with hypercalcemia?

Elevated calcium is a relatively common laboratory finding in patients newly diagnosed with MM (Figure).1 The incidence of hypercalcemia— defined as a very high serum calcium ( 11 mg/dL)—is approximately 13%; however, an additional 15% of patients present with calcium levels of 10.2 mg/dL to 10.9 mg/dL.1 When we conduct an initial work-up on a patient, a finding of hypercalcemia prompts us to take necessary steps to minimize this complication. Intervention becomes especially urgent if the patient reports potential symptoms of hypercalcemia, such as emesis, weakness, and confusion. Immediate hydration is essential, and many patients will also require bisphosphonate therapy. In some instances, it is necessary to prescribe antiemetic agents for patients who are experiencing hypercalcemia-related nausea and vomiting. At our center, we treat hypercalcemia if the serum calcium level is 10.5 mg/dL. We also initiate treatment if serum calcium is only borderline high, but serum albumin is low, as the serum calcium should be corrected based on the serum albumin. Some patients present with very mild hypercalcemia (10.5 mg/dL with a low albumin); our approach with these patients is to treat with intravenous (IV) hydration only, and then routinely check their calcium levels. For all other patients, we control hypercalcemia with hydration plus bisphosphonate therapy (zoledronic acid or pamidronate). If zoledronic acid is used, it is given as a single IV dose of 4 mg infused over 15 to 30 minutes. This is followed by a second 4-mg dose given at a minimum of 7 days, if necessary.2 Pamidronate dosing of 60 mg to 90 mg, infused over 2 to 4 hours, is dependent on the level of albumin-corrected serum calcium as well as a patient’s renal function.3 Treatment with bisphosphonate therapy generally results in rapid resolution of hypercalcemia.

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Renal insufficiency is also prevalent in newly diagnosed patients with MM. What role do nurses play in the evaluation, monitoring, and supportive care of this complication?

Approximately 19% of patients with MM present with a serum creatinine 2 mg/dL at the time of diagnosis (Figure). Renal dysfunction may be exacerbated by hypercalcemia, but even after serum calcium levels have stabilized, we still have to contend with myeloma-related renal tubular pathology.4 The presence of renal insufficiency sometimes signals that the patient has light-chain myeloma, which has been correlated with elevated creatinine.1 Circulating monoclonal immunoglobulin free light chains can clog up renal tubules; myeloma kidney is characterized by light-chain cast nephropathy.4 Laboratory testing for serum creatinine, creatinine clearance, and serum and urine protein electrophoresis are critical in the initial work-up of patients with MM. Nurses are primarily responsible for the evaluation of any symptom patterns related to impaired renal function, such as elevated blood pressure, changes in urination, and fatigue. It is important to remember, however, that a patient may have renal insufficiency in the absence of any physical signs or symptoms. Following initial assessment, we keep a close watch on renal function and check laboratory results at every visit, which during frontline treatment may be several times a week. We also encourage patients to drink between 2 and 3 L of fluid a day to stay hydrated. It is imperative to obtain a list of every drug the patient is taking, to ensure that none of them are renally toxic—this includes over-the-counter (OTC) medications. We strongly advise patients to avoid the use of OTC or prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), which can have adverse renal effects. We also remind them to report any changes in their urine (eg, output, frequency, appearance, presence of blood).

Figure. Incidence of anemia, renal dysfunction, and hypercalcemia in newly diagnosed patients with MM (N=1027).1

50 40

Patients (%)

Melanie Watson, RN, OCN

35%

30 19%

13% 10 0 Hemoglobin 10 g/dL

Creatinine 2 mg/dL

Calcium 11 mg/dL

MM indicates multiple myeloma.

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Table 1. Suggested Lenalidomide Dose Reductions for Renal Impairment7 Degree of Renal Dysfunction Moderate

Renal Function (Cockcroft-Gault CrCl) 30-60 mL/min

Dose for MM 10 mg orally every 24 hours

Severe (not requiring dialysis)

<30 mL/min

15 mg orally every 48 hours

End-stage renal disease (requiring dialysis)

<30 mL/min

5 mg orally once dailya

CrCl indicates creatinine clearance; MM, multiple myeloma. a Doses that fall on dialysis days should be given after dialysis.

Table 2. Bortezomib Dose Modifications Based on Severity of Peripheral Neuropathy10 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

Grade 1 (paresthesia or loss of reflex) without pain or loss of function

No action

Grade 1 with pain or grade 2 (interferes with function but not with activities of daily living)

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

Grade 2 with pain or grade 3 (interferes with activities of daily living)

Withhold bortezomib until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

Grading based on NCI Common Toxicity Criteria CTCAE V 3.0.

A small subset of patients with myeloma-related renal insufficiency will require dialysis. In many cases, this need for dialysis is reversible with effective antimyeloma treatment. Reducing the myeloma burden as quickly as possible is the key to getting patients off dialysis. Our induction therapy for newly diagnosed patients with significant renal dysfunction—certainly in the transplant-eligible group but also in many nontransplant candidates— is the combination of bortezomib, thalidomide, and dexamethasone (VTD).5 The inclusion of novel agents in this regimen offers a benefit to patients with renal insufficiency.6 Current consensus suggests that treatment with bortezomib plus dexamethasone provides optimal therapy to reverse renal dysfunction in myeloma. Lenalidomide is also effective in reversing renal insufficiency if given at doses appropriately reduced on the basis of renal function (Table 1).6,7

The severity of renal impairment affects our selection of bisphosphonate therapy to protect against skeletal-related events.

The severity of renal impairment affects our selection of bisphosphonate therapy to protect against skeletal-related events (SREs), since this class of drugs is excreted via the kidney and can therefore produce renal toxicity. At our institution, we use zoledronic acid for patients with a baseline crea-

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Table 3. Selected Outcomes in Cancer Patientsa with Vertebral Compression Fractures Treated with Balloon Kyphoplasty vs Nonsurgical Management12 Outcome Variable at 1 Month of Follow-Up

Kyphoplasty (n=70)

Nonsurgical Management (n=64)b

P Value

Mean change from baseline in RDQc score (primary endpoint; improvement = decline in score)

-8.3 points

+0.1 points

<.0001

Change in medication utilization (% change in the incidence of use)

-44.7

-2.3

<.001

Overall incidence of adverse events (% of patients)

37.1

29.7

Not reported

a 32% of patients in the kyphoplasty group and 44% of patients in the nonsurgical management group had a diagnosis of MM. b Analgesics, bed rest, bracing, physiotherapy, rehabilitation programs, walking aids, radiation treatment, and other antitumor therapy at the discretion of treating physicians. Patients receiving kyphoplasty were allowed to receive these treatments as well, in addition to their surgery, if needed. c RDQ indicates back-specific functional status measured by the Roland-Morris disability questionnaire.

tinine clearance of 30 mL/min, dose-adjusted as creatinine clearances from >60 mL/min to 30 mL/min.2 This is given as a 30-minute infusion, which, in our experience, tends to be gentler on the kidney than the standard 15-minute infusion. If creatinine clearance is below 30 mL/min we use pamidronate, although the pharmacokinetic data on its use in such instances is limited.3 In addition to initiating bisphosphonate therapy, what other supportive care strategies are necessary for patients with myelomarelated bone disease?

Approximately 80% of patients with MM present with SREs, which typically manifest as osteolytic lesions or fractures.1 Therefore, bisphosphonate therapy is a mainstay of bone support in MM. From a nursing perspective, ongoing patient education about bisphosphonate use is critical to help patients remain on this effective therapy. The most important educational intervention is in the area of dental hygiene, since osteonecrosis of the jaw (ONJ) is a rare but very serious adverse effect of bisphosphonate therapy, for which there is no satisfactory intervention.8 For example, zoledronic acid was shown in the Medical Research Council Myeloma IX study to reduce SREs and improve overall survival compared with clodronic acid, but it also produced a higher rate of ONJ than clodronic acid.9 We require a dental exam before we start a bisphosphonate for SRE prevention. We repeatedly inform patients that they should have no invasive dental procedures that disturb the bone while being treated with bisphosphonates. We tell patients, “If it’s above the gum line, it’s fine. If it’s below the gum line, it’s not.” If an invasive procedure becomes necessary, we need to know in advance. We hold the bisphosphonate therapy for 2 months before and 2 months after any invasive dental procedure. Treatment of bone pain is another critical aspect of supportive care. Nurses have always held a leadership role in the management of pain, and it takes all of our skill and insight to effectively treat the complexities of

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pain associated with MM. The first step is always an assessment based on the patient’s self-reported level of pain, using both qualitative inventories and a quantitative scale such as the 1-10 visual analog scale. Pain assessment should be frequent and routine, not only to determine severity, but also to help distinguish between bone pain and neurotoxicity that may be associated with the use of specific novel agents.7,10 We recently switched from IV to subcutaneous (SC) bortezomib in certain regimens, because SC dosing appears to significantly reduce the risk of bortezomib-induced peripheral neuropathy (BIPN).11 For patients who receive bortezomib as an IV infusion, dose reductions can be implemented to prevent irreversible nerve damage and ensure optimal benefits of treatment (Table 2).10 BIPN typically improves following implementation of these recommendations or resolves following treatment discontinuation.

As a nurse, I feel I have done my job well when a patient demonstrates an understanding of their disease and feels comfortable calling me to report a new symptom or potential complication.

Opioid treatment is often necessary for myeloma-associated bone pain, which was reported by 58% of patients at the time of diagnosis in one study.1 Since we cannot prescribe NSAIDs to myeloma patients, we rely on opioid analgesics to control pain. When we give these medications, we always put patients on a bowel regimen that includes dietary and hydration support and a stool softener, as opioids can cause significant constipation. We try not to use radiation therapy for pain; we only radiate for severe pain that has not responded to other interventions, including analgesic medication, physical therapy (PT), and surgery. Patients sometimes do not understand why PT can help with bone pain, so we explain that improving muscle strength around a bone may improve pain control and function. Compression fracture of the spine is one of the more common SREs in myeloma patients.1 In our weekly clinic, a spine specialist is available to evaluate individuals with back pain. If necessary, patients may undergo kyphoplasty, which has been shown to be effective in treating vertebral compression fractures in patients with MM or bone metastasis from solid tumors (Table 3).12 The specialist may also recommend a steroid injection into the back to relieve the pain. Finally, we advise patients to take the necessary steps to protect themselves from trauma. The last thing they need is an injury to bone. We urge them to avoid risky sports and counsel them to evaluate their homes for hazards such as slippery rugs and broken steps. What supportive care strategies are necessary for managing anemia in patients with MM?

Anemia is a common finding among newly diagnosed MM patients (Figure).1 This condition may also occur at later points in the clinical course of the disease and can be an adverse effect of specific agents. We take a dual approach to combat anemia, using effective antimyeloma therapy and transfusions. Controlling a patient’s disease is the best way to manage anemia over the long term. We order blood transfusions whenever a patient’s hematocrit drops to about 25% to 27%. Hematocrit 25% signals that a transfusion is appropriate; 26% to 27%, in the presence of anemia symptoms, also indicates a need for transfusion.6

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We rarely use erythropoietins to treat anemia, as most of our patients are receiving therapies that may elevate risk of thrombosis, such as thalidomide or lenalidomide, combined with dexamethasone.13 In addition, erythropoietins can increase thromboembolic risk.13,14 We therefore do not want to augment risk of thrombosis by adding an erythropoietin to the mix. In rare instances, we may opt for erythropoietin support of anemia in heavily treated patients who are far into the clinical course and have already received multiple transfusions and anticoagulant therapy. It is important to provide ongoing education to patients regarding the signs and symptoms of anemia, which can include shortness of breath or extreme fatigue. We describe how hemoglobin in red blood cells carries oxygen throughout the body, so that they understand why we must frequently check their counts and recommend transfusions. Patients often call us and say, “I’ve been extremely tired over the past couple of days. I wonder if I need a transfusion.” When this occurs, we have them come in to the clinic so that we can assess their blood cell counts, and we often find that these patients are correct and do need to be transfused. To be effective in providing prompt and appropriate supportive care, nurses must listen attentively to their patients’ concerns. Most patients can sense subtle changes in their bodies, and our education is designed to contribute to that knowledge. As a nurse, I feel I have done my job well when a patient demonstrates an understanding of their disease and feels comfortable calling me to report a new symptom or potential complication. Good communication between nurses and patients is the cornerstone for providing the best possible supportive care. Conclusion

MM is an incurable hematologic malignancy that attacks the body in many ways, resulting in renal dysfunction, hypercalcemia, SREs, and anemia. It is imperative that patients are carefully screened for these complications at the time of diagnosis and throughout the course of the disease. Proactive nursing measures are the key to reducing the impact and severity of these symptoms, which in turn will help patients remain on therapy and achieve the best possible outcomes. ◆ References 1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33. 2. Zometa® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. February 2011. 3. Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008. 4. Hutchison CA, Batuman V, Behrens J, et al. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2011;8:43-51. 5. Kaufman JL, Nooka A, Vrana M, et al. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010;116:3143-3151. 6. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984. 7. Revlimid® [package insert]. Summit, NJ: Celegene Corporation. October 2010. 8. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945-952. 9. Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376:1989-1999. 10. Velcade® [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. December 2010. 11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 12. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12:225-235. 13. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 14. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25-41.

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Pharmacologic Considerations in Newly Diagnosed Multiple Myeloma Minal Surati, PharmD Clinical Pharmacy Specialist Department of Hematology and Medical Oncology Emory University Hospital/Winship Cancer Institute Atlanta, GA

Introduction Symptom patterns in patients with newly diagnosed multiple myeloma (MM) can influence the approach to both antimyeloma therapy and supportive care. The core “CRAB” symptoms (hypercalcemia, renal insufficiency, anemia, or bone lesions) may require interventions, such as transfusions for anemia or bisphosphonates for hypercalcemia; renal dysfunction may influence drug selection and dosing. Complicating the clinical picture are several additional factors: drug-drug interactions; medical comorbidities; the adverse events associated with treatments for MM; and the inherent, myeloma-related risks of fracture and venous thromboembolism (VTE). In this article, Minal Surati, PharmD, describes the key role of pharmacy in identifying and clarifying the needs of each patient, to personalize drug choices and dosing strategies.

Symptomatic MM is defined by the presence of CRAB symptoms, which identify end-organ involvement. As a pharmacy professional, what is your role in minimizing these symptoms in newly diagnosed patients?

Our priority as pharmacists is to counsel patients regarding their treatment regimen and assess the interaction of agents, whether it be with other drugs or with a patient’s comorbid conditions.1 When a patient newly diagnosed with MM presents with CRAB symptoms, we evaluate the drugs he or she takes for preexisting conditions in the context of the proposed treatment regimen, in an effort to discover and manage any problematic interactions. For example, a newly diagnosed, elderly woman may present with renal insufficiency and bone lesions attributable to MM, but may also have a history of diabetes, controlled with oral metformin, and osteoporosis treated with the oral bisphosphonate, ibandronate. Oral ibandronate and metformin do not interact.2 However, the risk of lactic acidosis, a rare but serious complication of metformin, is elevated in patients with renal insufficiency and older age.3 Antimyeloma regimens that include steroids such as dexamethasone or prednisone may interfere with glycemic control.3 Intravenous (IV) bisphosphonate therapy for MM should replace oral ibandronate; if the patient’s creatinine clearance is <30 mL/min, IV pamidronate rather than IV zoledronic acid would be the recommended agent.4,5 It is important to stress that medication therapy management provided by a pharmacist is not a one-time event. Patients are assessed prior to each cycle of chemotherapy or IV bisphosphonate treatment, to ensure medications are adjusted appropriately based on changes in renal function, anemia, calcium levels, etc, that may have occurred since their last visit.

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We have found that patients often research their disease state and therapies through various means such as the internet or discussions with other patients, family, and friends. This is encouraged to promote knowledge and support throughout their treatment. However, with the increasing trend of holistic and alternative health movements, patients may begin taking overthe-counter (OTC) supplements or herbal medications without discussing it with their providers. For example, I recently consulted with a myeloma patient who was taking 21 different supplements. Pharmacists must check for herbal and synthetic supplements—especially high-dose vitamins, which can affect the efficacy of chemotherapy treatment or exacerbate a patient’s disease. For example, if a newly diagnosed patient with hypercalcemia is taking excess calcium OTC, we need to address this issue. After discussing the situation with the team, we inform the patient of the appropriate calcium supplementation strategy. This may include discontinuation of the supplement, decreasing the dose, or replacing it with a simple multivitamin. Our fundamental approach to the symptom of anemia in MM is to provide effective antimyeloma treatment, which should elevate and stabilize red blood cell counts.6 We do provide transfusions if necessary,6 when the hemoglobin is <10 g/dL or hematocrit is <25%. Given the fact that many of our patients’ treatments include thalidomide or lenalidomide, we seldom use erythropoietins to treat chronic anemia. Both thalidomide and lenalidomide can put patients at an increased risk of developing a VTE. The addition of erythropoietins would further increase this risk,7,8 therefore, we do not use these agents concurrently. This is a cautious interpretation of guidance from the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO), which also warns against the use of an erythropoietin in combination with lenalidomide or thalidomide plus corticosteroids.7

It is important to stress that medication therapy management provided by a pharmacist is not a one-time event.

Myeloma-related bone disease tends to be very painful, as is peripheral neuropathy (PN) that may result from bortezomib or immunomodulators used in the treatment of MM.9-11 Since we increasingly use the RVD regimen (lenalidomide, bortezomib, and dexamethasone) in newly diagnosed patients (Figure),12 we monitor closely for PN. Working with pain assessments provided by the nursing staff, the pharmacist plays a key role in developing a rational plan for pharmacologic management of nociceptive and neuropathic pain in the myeloma patient. We rely on opioid medication, typically oxycodone or morphine, for bone pain, which requires us to be very cautious about opioid adverse effects. One must distinguish between opioid tolerance, a natural physiological response to these drugs, and opioid addiction, which has psychological ramifications.13 In our practice, we avoid the use of both acetaminophen and nonsteroidal antiinflammatory drugs since these agents may affect liver and/or kidney func-

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Figure. Common adverse events with RVD in newly diagnosed patients with MM (N=66).12

Table. Disease-Related and Comorbid Thromboembolic Risk Factors in Patients with Myeloma8 Risk Factors

Specific Examples

Related to the disease and treatment

Myeloma itself Hyperviscosity Therapies: erythropoietins, immunomodulators, high-dose dexamethasone, doxorubicin, multiagent chemotherapy

Related to comorbidities

History of venous thromboembolism Obesity Heart disease/atrial fibrillation Chronic renal disease Diabetes Infection Immobilization Surgery/anesthesia Trauma Central venous catheter or pacemaker Clotting disorders

100

Overall Grade 3

90 80

80%

Patients (%)

64% 61%

60 50

45%

44%

36%

35% 32%

32%

30 20 10 2%

0 y sor Sen

thy pa uro ne

3% 0%

e n n ain ma tio tio igu de ep ipa ma Fat scl be ua nst m i o Mu L C esq d / sh Ra

r Dia

a rhe

a use Na N

y ath rop eu

MM indicates multiple myeloma; RVD, lenalidomide, bortezomib, and dexamethasone.

tion, as well as mask fevers, which can deprive us of a warning sign for infection in our frequently neutropenic patients. To a large extent, opioid therapy is very helpful with neuropathic pain.14 However, additional agents such as gabapentin or pregabalin can be useful as well. Other therapies that may also be used are alpha lipoic acid, L-carnitine, folic acid, and B complex vitamins. What strategies can be used for the prevention of infection in patients with MM?

Many newly diagnosed MM patients experience a disease-related increase in infection risk; extensive disease, poor renal function, and compromise to plasma cells can produce poor health status. Add to that the risks of therapy, such as viral reactivation and neutropenia, and the result is a significant potential for infection. At our center, we ensure that every individual receives basic preventive care. Patients receive vaccines, including seasonal flu vaccine and, if not up-to-date, pneumococcal vaccine. Bortezomib use can increase the risk of herpes zoster reactivation,15 therefore, if a patient receives this agent as part of the treatment regimen, we always include antiviral prophylaxis with acyclovir or another drug in its class. Pneumocystis carinii pneumonia (PCP) is always a concern in patients receiving high-dose steroids. If a steroid is part of the patientâ&#x20AC;&#x2122;s treatment regimen, we will begin prophylaxis for PCP. With regard to the use of prophylactic antibiotics and antifungals, we are selective and commensurate with recommendations from the National Comprehensive Cancer Network.16 We simply do not want to add the adverse events of antimicrobial agents if not necessary. From my perspective, education is an extremely important aspect regarding infection control. When counseling patients for the first time, I typically ask if they have a history of herpes viral infections, cold sores, or zoster. If they report recurrent zoster infections, this would prompt me to consider the use of valacyclovir, if acyclovir has previously not been effective. Bisphosphonates are a mainstay of therapy for myeloma-related bone disease, but their use can be complicated by certain CRAB symptoms. What is your approach to bisphosphonate use in patients with renal dysfunction or hypercalcemia?

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The bisphosphonate we use the majority of the time is IV zoledronic acid, administered monthly for 2 years, then every 2 to 6 months, depending on the patientâ&#x20AC;&#x2122;s status at that time. An advantage of zoledronic acid is a relatively short IV infusion time of at least 15 minutes.4,17 Zoledronic acid also produced favorable outcomes in the recent Medical Research Council Myeloma IX study.18 However, this bisphosphonate must be dose-adjusted downward in increments, ranging from 4 mg to 3 mg, as patientsâ&#x20AC;&#x2122; baseline creatinine clearance falls from a normal value (>60 mL/min) to 30 mL/min; zoledronic acid is not recommended in patients with severe renal insufficiency (creatinine clearance <30 mL/min).4,17 Although the prescribing information for zoledronic acid suggests that the criterion for dose adjustment is the baseline creatinine clearance, we assess serum creatinine and calculate clearance at each visit and adjust the dose accordingly. We will also infuse zoledronic acid over 30 minutes rather than 15 minutes. For patients with significant renal impairment, we often elect to use pamidronate infused over 2 to 4 hours.5,17

When counseling patients for the first time, I typically ask if they have a history of herpes viral infections, cold sores, or zoster. The approach is different, however, when hypercalcemia complicates the clinical picture. A newly diagnosed MM patient presenting with hypercalcemia will receive aggressive, acute treatment with zoledronic acid, which is the preferred bisphosphonate for this condition.19 Per our institutional guidelines, zoledronic acid dosing for hypercalcemia is 4 mg as a single-dose IV infusion over 30 minutes, followed by close monitoring to assess if further treatment is needed. No specific dose adjustment is suggested for patients with renal impairment. Similarly, if a patient with renal impairment is receiving zoledronic acid monthly, and we detect the emergence of hypercalcemia, we will administer a 1-time, full 4-mg dose, rather than adjusting the dose for renal dysfunction. There are situations in which a switch from zoledronic acid to pamidronate may be necessary. We look for trends in serum creatinine and

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creatinine clearance with our patients, and if we notice a trend toward worsening renal insufficiency, with serum creatinine rising, we may discontinue the zoledronic acid and begin pamidronate, with the infusion rate at the slower end of the recommended time.17 How do you reduce the risk of disease- or treatment-related VTE in newly diagnosed patients?

We ensure that all patients with thromboembolic risk factors, specifically those receiving thalidomide- or lenalidomide-containing regimens, receive VTE prophylaxis.8 Clinicians should be aware of the increased risk of VTE in the MM population—typically older patients with a disease that exacerbates thrombosis8—regardless of therapy (Table). Many patients present with a history of VTE, or with comorbidities that can increase the risk of thrombus formation. Numerous patients may already be taking warfarin or low-molecularweight heparin, which we continue as their VTE prophylaxis. Conclusion

It is vitally important for all members of the interdisciplinary cancer care team to understand the complexity of MM. Symptoms of the disease, including hypercalcemia, renal insufficiency, anemia, and bone disease, will influence not only which therapies can be used, but the dose and duration of treatment. Myeloma-related complications may change over time, as the disease responds to treatment or progresses. In addition, drug-drug interactions have the potential to cause clinical emergencies, which require immediate interventions. The pharmacist plays a key role in identifying these complex relationships, counseling patients, and monitoring responses to various therapies to ensure optimal clinical outcomes. ◆

References 1. Tam-McDevitt J. Polypharmacy, aging, and cancer. Oncology (Williston Park). 2008;22:10521055. 2. Boniva® [package insert]. South San Francisco, CA: Genentech USA, Inc. January 2011. 3. Glucophage® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. January 2009. 4. Zometa® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. February 2011. 5. Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cancer- and chemotherapy-induced anemia. Version 2.2012. www.nccn.org/professionals/physician_gls/pdf/anemia.pdf. Accessed March 26, 2012. 7. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25-41. 8. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 9. Velcade® [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. December 2010. 10. Thalomid® [package insert]. Summit, NJ: Celegene Corporation. August 2010. 11. Revlimid® [package insert]. Summit, NJ: Celegene Corporation. October 2010. 12. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679686. 13. Jan SA. Introduction: landscape of opioid dependence. J Manag Care Pharm. 2010;16(suppl 1b):S4-S8. 14. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237-251. 15. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prevention and treatment of cancer-related infections. Version 2.2011. www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed March 26, 2012. 17. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. 18. Morgan GJ, Child JA, Gregory WM, et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 2011;12:743-752. 19. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple myeloma. Version 1.2012. www.nccn.org/professionals/physician_ gls/pdf/myeloma.pdf. Accessed March 15, 2012.

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