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SepteMber 2012

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VOl 5, NO 6

SIDE EFFECT MANAGEMENT

CANCER CENTER PROFILE

Indiana University Health Simon Cancer Center Addressing the Needs of the Patient

Mucositis Management to Become More Personalized By Caroline Helwick

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new appreciation of the pathobiological foundation of mucositis, and the application of genomics to risk assessment, heralds an individualized and more effective approach to intervention for this costly, often disabling, toxicity, according to specialists who spoke at a session on mucosal injury during the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

By Alice Goodman

New Mechanistic Understanding Old concepts are being replaced by a

pathobiological paradigm that better captures the underlying mechanism and allows for more effective interventions. Mucositis is now “about bioinformatics, targeted treatment, risk prediction, and other exciting frontiers,” said Douglas Peterson, DMD, PhD, of the University of Connecticut Health Center in Farmington. Stephen T. Sonis, DMD, DMSc, of Biomodels in Watertown, Massachusetts, described the biological cascade leading to mucosal injury as one involving the mesContinued on page 36

THE PATIENT’S VOICE

Popping Pills and Shooting Up

The oncology pharmacy team at the Indiana University Health Simon Cancer Center. Photo courtesy of Indiana University Health.

he Indiana University Health Simon Cancer Center was established in 1992 under the leadership of Stephen D. Williams, MD, and in 1999, the center was designated by the National Cancer Institute as a clinical cancer center. The Indiana University Research Institute was opened in 1997, financed in part by federal funding. The name of the center was changed in 2006 to honor the philanthropic support of Melvin and Bren Simon. The Simon Cancer Center is a patient care, research, and educational institution within the Indiana University (IU) School of Medicine on the main campus in Indianapolis. The physicians and scientists

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Continued on page 7

By MMA

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must admit that I am not a fan of medications. I had 4 beautiful children medication-free with midwives. I drink green tea to get rid of a cold. I eat chocolate to calm a headache. I microwave rice in a sock and place it on sore muscles. Perhaps that is why I resent (yes, I said it, “resent!”) that I have been sent home with 2 medications I must in-

ject into myself twice a day for a total of 4 daily injections. When I got sent home from the hospital after my fourth chemotherapy session with both my regular white bag packed full of pills plus new injections of blood thinners and stem cell stimulators (I am preparing for a stem cell transplant), I felt nervous. Certainly, since the start of my Continued on page 16

NEWS BRIEFS

INSIDE

By Alice Goodman

Surgery Versus Observation for Localized Prostate Cancer For men with localized prostate cancer detected by prostate-specific antigen (PSA) level, treatment with radical prostatectomy did not significantly reduce mortality compared with observation, according to overall results of the large, randomized, controlled PIVOT trial (Wilt TJ, et al. N Engl J Med. 2012; 367:203-213). All-cause mortality and prostate-specific mortality were similar

The GrowTh of SpecialTy pharmacy . . . . . . . . . . . . . . . . . . . . . .

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for the surgery and observation groups over a 12-year follow-up. Results suggest that surgery may be a better option than observation for men with intermediate- and high-risk localized prostate cancer, but low-risk localized prostate cancer can be safely managed with observation. Overall, absolute differences in mor-

What Is the Impact on Patient Relationships? proSTaTe cancer

Progress in Treating Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Team Approach Enhances Choice of Observation . . . . . . . . . . . 23

Continued on page 4 ©2012 Green Hill Healthcare Communications, LLC

Side effecT manaGemenT

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Chemotherapy-Induced Peripheral Neuropathy Increases Risk of Falls and Physical and Functional Problems immune ThrombocyTopenia

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Considerations for Treatment complimenTary ce

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Considerations in Lymphoma—Ask the Experts: Follicular Lymphoma


IV R FO AND ED US ION V T O O A PR ANE ST R P A UT INI C M B SU AD

VELCADEHCP.COM


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

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

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

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

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

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

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.


News Briefs Surgery Versus Observation... Continued from cover

tality favoring surgery were less than 3 percentage points, explained lead author Timothy J. Wilt, MD, Minneapolis Veterans Affairs Health Care System, Minnesota. “Surgery might reduce mortality for men with higher PSA values and possibly among men with higher-

risk tumors, but not among men with PSA levels of ≤10 ng/mL or low-risk tumors,” Wilt wrote. He noted that PIVOT was conducted in the early era of PSA testing, and that in the current era men suspected of having prostate cancer undergo repeated PSA testing and sometimes repeat biopsies, which detect more indolent cancers. These factors increase the likelihood of overdiagnosis and overtreatment. “Our findings support observation for men

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

with localized prostate cancer, especially those who have low-risk disease,” he wrote. PIVOT randomized 364 men to radical prostatectomy and 367 to observation alone. All participants were suspected of having prostate cancer based on PSA testing and had histologically confirmed localized prostate cancer diagnosed within the previous year. Mean age was 67 years, about one-third were black, and median PSA value was 7.8

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

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

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ng/mL. About 40% of the men had lowrisk prostate cancer, 34% intermediaterisk prostate cancer, and 21% high-risk prostate cancer. At a median follow-up of 10 years, mortality was 47% in the surgery group versus 49.9% in the observation group, an absolute reduction of 2.9% for surgery. The rates of prostate-specific mortality were 5.8% for surgery versus 8.4% for observation, an absolute risk reduction of 2.6%. The effect of treatment on all-cause mortality was similar according to age, race, coexisting illness, performance status, or histologic tumor features. Radical prostatectomy was associated with reduced all-cause mortality among men with PSA >10 ng/mL and for men with intermediate- or high-risk tumors. Perioperative adverse events (occurring within 30 days of surgery) were reported in 21.4% of men. Rates of urinary incontinence and erectile dysfunction were significantly higher in the radical prostatectomy group (P <.001 for both comparisons vs observation).

Older patients With Mantle Cell lymphoma R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) induction therapy followed by maintenance therapy with rituximab was more effective than R-FC (rituximab, fludarabine, and cyclophosphamide) followed by maintenance therapy with interferon alfa in older patients with mantle cell lymphoma, according to a recently published prospective, randomized, double-blind clinical trial (Kluin-Nelemans HC, et al. N Engl J Med. 2012;367:520-531). “The excellent results with rituximab administered as maintenance therapy are important. Maintenance therapy with rituximab showed not only a progression-free survival benefit but also a significant survival advantage among patients who were successfully pretreated with R-CHOP,” wrote the authors. The long-term prognosis is poor for older patients with mantle cell lymphoma. Treatment with chemotherapy achieves low rates of complete remission (CR), the authors wrote. Most older patients with mantle cell lymphoma will relapse, and better therapy is needed for this group of patients. When the trial was first initiated, the authors hoped that the fludarabine-containing regimen would perform better than it did in this trial. However, results showed that R-FC was not more effective than R-CHOP, and the fludarabine-containing regimen was more toxic. The study enrolled 560 patients aged 60 years or older with stage II to IV mantle cell lymphoma who were ranContinued on page 21

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sEPTEmbER 2012 I VOL 5, NO 6

www.TheOncologyPharmacist.com


Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Oklahoma University College of Pharmacy Tulsa, OK

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

ASSOCIATE EDITOR-IN-CHIEF

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN

Jim Koeller, MS

Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Burt Zweigenhaft, BS

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

BioPharma Partners LLC New York, NY

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

USC/Norris Cancer Hospital Los Angeles, CA

OncologyPharmacist.net Warwick, RI

Laura Boehnke Michaud, PharmD, BCOP, FASHP

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Marlo Blazer, PharmD, BCOP

The University of Texas MD Anderson Cancer Center Houston, TX

James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

www.TheOncologyPharmacist.com

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

sEPTEmbER 2012 I VOL 5, NO 6

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From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Associate Publisher Joe Chanley joe@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

Editorial Director Kristin Siyahian kristin@greenhillhc.com

I

n this month’s issue of The Oncology Pharmacist (TOP), we explore the growth of specialty pharmacies and the implications for our relationship with patients. Author Lea Ann Hansen discusses the evolution of specialty pharmacy and the function it serves in the treatment of cancer and how this affects patients. As Hansen points out in her article, “In many cases, the complicated nature of administration or possible adverse events with specialty drugs necessitate intensive patient monitoring.” The topic of The Patient’s Voice article revolves around a patient’s complicated relationship with her oncology drugs. MMA writes about “popping pills and shooting up” at home. While not directly acknowledging adherence,

Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Jackie Luma Circulation Department circulation@greenhillhc.com

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill 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. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. BPA Worldwide membership applied for April 2011.

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sEPTEmbER 2012 I VOL 5, NO 6

MMA shows us how difficult it is to ensure that patients take medications as prescribed. In our reader survey poll, we ask how you talk to patients about adherence. Go to www.TheOncologyPharmacist.com and tell us how you try to help patients like MMA overcome their emotional reactions to taking (or not taking) their medications. We continue our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology by addressing the topic of mucositis—noting that the advent of personalized cancer medicine also means personalizing supportive care issues as well. As always, we want to hear from you about what you see in TOP. Contact us at editorial@greenhillhc.com. ●

Recent FDA News

Editorial Contact: Telephone: 732-656-7935 Fax: 732-656-7938

Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief

bosutinib for Chronic Myelogenous leukemia The US Food and Drug Administration (FDA) approved bosutinib tablets (Bosulif; Pfizer) for the treatment of adults with chronic, accelerated, or blast phase Philadelphia chromosome–positive chronic myelogenous leukemia (CML) who did not respond or were resistant to prior therapy. The September 4, 2012, approval was based on the results of a single-arm, open-label, multicenter trial in 546 adults (503 evaluable for efficacy) with chronic, accelerated, or blast phase CML. All patients had been previously treated with at least 1 tyrosine kinase inhibitor (TKI). The efficacy end points for patients with chronic phase CML were the rate of major cytogenetic response (MCyR) at week 24, and the duration of MCyR. The rate of confirmed complete hematologic response (CHR) and overall hematologic response (OHR) by week 48 were the efficacy end points for patients with accelerated or blast phase CML. For those with chronic phase CML, 33.8% of patients who had received 1 prior TKI (imatinib) achieved MCyR at week 24 while 26.9% of patients who received prior therapy with more than 1 TKI (imatinib followed by dasatinib and/or nilotinib) achieved MCyR by week 24. Among patients with accelerated or blast phase CML who had received 1 prior TKI, 30.4% and 15%, respectively, achieved CHR response by week 48, while 55.1% and 28.3%, respectively, achieved OHR by week 48. Diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue were the most common side effects in the safety population of patients. Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, noted, “With the approval of tyrosine kinase inhibitors, we are seeing improvements in the treatment of CML based on a better understanding of the molecular basis of the disease.” enzalutamide for Metastatic Castration-resistant prostate Cancer The FDA granted expedited approval for enzalutamide (Xtandi; Medivation and Astellas Pharma US) on August 31, 2012. Enzalutamide was approved for the treatment of

patients with metastatic castration-resistant prostate cancer (CRPC) who have previously received docetaxel. Approval was based on the results of a single randomized, placebo-controlled, multicenter trial of 1199 patients with metastatic CRPC. The study was designed to measure overall survival in men receiving enzalutamide compared with men receiving a placebo. The median overall survival for those patients who received enzalutamide was 18.4 months, compared with 13.6 months for those who received placebo. For more information about enzalutamide, please see page 22.

Carfilzomib for Multiple Myeloma On July 20, 2012, the FDA granted accelerated approval to carfilzomib injection (Kyprolis; Onyx Pharmaceuticals) for the treatment of patients with multiple myeloma who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of the completion of their last therapy. The safety and effectiveness of carfilzomib was evaluated in a study of 266 patients participating in a single-arm, multicenter trial. Patients received carfilzomib intravenously for a 2- to 10-minute period on 2 consecutive days weekly for 3 weeks, followed by a 12-day rest period (a 28-day treatment cycle). Treatment was continued until disease progression, unacceptable toxicity, or completion of a maximum of 12 cycles. The overall response rate was 22.9% and consisted of 1 complete response, 13 very good partial responses, and 47 partial responses. The median response duration was 7.8 months. The most common side effects observed in more than 30% of patients in the study were fatigue, low blood cell count and blood platelet levels, shortness of breath, diarrhea, and fever. Serious side effects included heart failure and shortness of breath. As a condition of having received accelerated approval for carfilzomib, Onyx Pharmaceuticals will submit a complete analysis of an ongoing randomized phase 3 trial that compares lenalidomide plus low-dose dexamethasone to lenalidomide plus low-dose dexamethasone plus carfilzomib. ●

www.TheOncologyPharmacist.com


Cancer Center Profile Indiana University Health Simon Cancer Center... Continued from cover

What is the approach to treating cancer patients at the Simon Cancer Center? Patrick Kiel (PK): We are an NCIdesignated cancer center, and we employ a multidisciplinary approach. Physicians handle diagnosis and treatment, and the oncology pharmacists monitor treatments, develop symptom reports, and participate in developing treatment algorithms and standard operating procedures. Our nursing staff includes magnet-trained nurses, and we have case managers and social workers. There is a good dynamic between case managers and pharmacists at our center to ensure that patients get their treatments covered by insurance, or if not, by assistance programs from the phar-

maceutical company or the Simon Center to offset costs so that patients can afford their treatments.

Photo courtesy of Indiana University Health.

who work at the center are mainly from the faculty of the IU School of Medicine, the IU Schools of Nursing and Dentistry, and the Purdue University School of Science. The staff works with a team of other professionals to address the full spectrum of the needs of cancer patients, including physical, emotional, psychological, and spiritual needs. Over the past decade, many milestones have been reached, including launching of the Indiana Genomics Initiative, opening of the Biotechnology Research and Training Center, expanding research space for the Walther Oncology Center, breaking ground on a new research facility, dedication of a new 405,000 square foot patient care center, and dedication of the largest research building on the campus, the Joseph E. Walther Hall, at 238,371 square feet. The mission and goals of the Simon Cancer Center drive the staff to conduct better research, provide better education, and improve patient care. The Oncology Pharmacist spoke with Patrick Kiel, PharmD, BCPS, BCOP, Cancer Pharmacy Specialist, Hematology and Stem Cell Transplant, Indiana University Health Simon Cancer Center, about the approach to managing patients at the center and his role as an oncology pharmacy specialist.

Now the emphasis is on targeted treatments for subgroups and rarer diseases. Oncology pharmacists are becoming in-

“The most important aspect of your job is to talk to patients about their experiences on therapy and get their perspective.”

cell transplant patients and how we can improve upon safety.

How has the role of the oncology pharmacist changed over the past 5 years? PK: What has changed the most is going from having oncology pharmacists at large oncology centers to now having a demand for them from smaller hospitalassociated clinics and private practices. In these smaller practice settings, pharmacy is becoming integral to the management of chemotherapy-induced toxicities and monitoring associated side effects.

—Patrick Kiel, PharmD, BCPS, BCOP

Is cost becoming more of an issue with regard to treatment? PK: Yes, there is a push nationally as well as here at our center to contain costs to help doctors and nurses be aware of the direct and associated costs of treatment; for example, considerations as to whether a treatment can be given as inpatient versus outpatient and the amount and frequency of monitoring a treatment requires. How does this approach translate to better outcomes? PK: The benefit comes from the more eyes that are on the patient, and that includes the pharmacist’s eyes. Also, patient education is a multidisciplinary effort. The pharmacist reinforces physician’s education about treatments and their side effects. I tell patients, “You are not a car getting a type of oil. You are a person, and whenever you get a medication, you should ask what this medication is for, what the side effects are, and how they can help monitor for side effects.”

volved in clinical trials and bench research. I have just been given a grant to work with a physician scientist on studying PARP inhibition in leukemias and

What advice would you give an oncology pharmacist just entering the field? PK: The most important aspect of your job is to talk to patients about their experiences on therapy and get their perspective. Always see patients first, and then go to the computer to look up laboratory reports. The computer is important, but the patient should be the top priority. Indiana University Health Simon Cancer Center. Photo courtesy of Indiana University Health.

What are you excited about now in the field of oncology? PK: I am excited about new therapies. We have already covered the low-hanging fruit, that is, treatments that affect multiple disease states and benefit large numbers of patients. Those days are over.

What inspired you to become an oncology pharmacist? PK: I was always interested in genetics as well as pharmacotherapy of disease states. At Midwestern University Chicago College of Pharmacy, I studied with David Frame and Deb Drager (both PharmDs) who taught me how to evaluate clinical trials and the rationale behind them. I gravitated toward evidence-based medicine. Oncology is a field where you can establish long-term relationships with patients that can last for many years. The best experience is a routine visit from a patient who is doing well in his or her life after being treated for cancer.

lymphomas. Pharmacists are also involved in clinical outcomes research, for example, on potential treatments to address neurotoxicity of chemotherapy, or immune suppression outcomes in stem

What work would you be doing if you weren’t an oncology pharmacist? PK: I have always been interested in chemistry and food. If I weren’t a pharmacist, I would be a brewmaster or a food critic, as long as the food was for free! One of my favorite TV shows is Alton Brown’s “Good Eats.” ●

Take action: get YOUR cancer center profiled! We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for more information. www.TheOncologyPharmacist.com

sEPTEmbER 2012 I VOL 5, NO 6

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TREANDA速 (bendamustine HCI) for Injection is his chemo.

This is his therapy.


Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). EfďŹ cacy relative to ďŹ rst-line therapies other than chlorambucil has not been established. PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Survival distribution function

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;Ą: 0.17, 0.43)

0

5

10

15

20

25

30

35

40

45

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â&#x20AC;  HR=hazard ratio. â&#x20AC;Ą CI=confidence interval.

s42%!.$!WASCOMPAREDWITHCHLORAMBUCILINARANDOMIZED OPEN LABEL PHASETRIALINTREATMENT NAĂ&#x2022;VEPATIENTSWITH"INETSTAGE"OR#2AISTAGES) )6 #,,WHOREQUIREDTREATMENT. s42%!.$!ISADMINISTEREDWITHACONVENIENTDOSINGSCHEDULE n4HE RECOMMENDED DOSE FOR 42%!.$! IS  MGM2 ADMINISTERED INTRAVENOUSLY OVER MINUTESON$AYSANDOFA DAYTREATMENTCYCLE UPTOCYCLES n)N THE PHASE  TRIAL PATIENTS RECEIVED CHLORAMBUCIL AT A DOSE OF  MGKG ORALLY ON $AYSANDN OFA DAYTREATMENTCYCLE UPTOCYCLES s)NTHEPIVOTALPHASETRIAL THEMOSTCOMMONNON HEMATOLOGICADVERSEREACTIONSFREQUENCY â&#x2030;Ľ WEREPYREXIA NAUSEA ANDVOMITING N 4HEMOSTCOMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ WERE ANEMIA  THROMBOCYTOPENIA  NEUTROPENIA LYMPHOPENIA ANDLEUKOPENIA N Important Safety Information s3ERIOUS ADVERSE REACTIONS INCLUDING MYELOSUPPRESSION INFECTIONS INFUSION REACTIONS AND ANAPHYLAXIS TUMOR LYSIS SYNDROME SKIN REACTIONS INCLUDING 3*34%. OTHER MALIGNANCIES AND EXTRAVASATION HAVE BEEN ASSOCIATED WITH 42%!.$! 3OME REACTIONS SUCH AS MYELOSUPPRESSION INFECTIONS AND3*34%.WHEN42%!.$!WASADMINISTEREDCONCOMITANTLY WITHALLOPURINOLANDOTHERMEDICATIONSKNOWNTOCAUSE3*34%. HAVEBEENFATAL0ATIENTS SHOULDBEMONITOREDCLOSELYFORTHESEREACTIONSANDTREATEDPROMPTLYIFANYOCCUR s!DVERSEREACTIONSMAYREQUIREINTERVENTIONSSUCHASDECREASINGTHEDOSEOF42%!.$! OR WITHHOLDINGORDELAYINGTREATMENT s42%!.$!ISCONTRAINDICATEDINPATIENTSWITHAKNOWNHYPERSENSITIVITYTOBENDAMUSTINEOR MANNITOL7OMENSHOULDBEADVISEDTOAVOIDBECOMINGPREGNANTWHILEUSING42%!.$! s4 HEMOSTCOMMONNON HEMATOLOGICADVERSEREACTIONSFOR#,,FREQUENCY â&#x2030;Ľ AREPYREXIA NAUSEAANDVOMITING4HEMOSTCOMMONHEMATOLOGICABNORMALITIESFREQUENCY â&#x2030;Ľ ARE ANEMIA THROMBOCYTOPENIA NEUTROPENIA LYMPHOPENIA ANDLEUKOPENIA

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Š2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510a August 2012


The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naĂŻve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in â&#x2030;Ľ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. t Aseptically SFDPOTUJUVUFFBDI53&"/%"WJBMBTGPMMPXTtNH53&"/%"WJBM"EEN-PGPOMZSterile Water for Injection, USPtNH53&"/%"WJBM"EEN-PGPOMZSterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be VTFEt"TFQUJDBMMZXJUIESBXUIFWPMVNFOFFEFEGPSUIFSFRVJSFEEPTF CBTFEPONHN-DPODFOUSBUJPO BOE immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2â&#x20AC;&#x201C;0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The BENJYUVSFTIPVMECFBDMFBSBOEDPMPSMFTTUPTMJHIUMZZFMMPXTPMVUJPOt6TF4UFSJMF8BUFSGPS*OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPSEJMVUJPO BTPVUMJOFEBCPWF/PPUIFSEJMVFOUTIBWFCFFOTIPXOUPCFDPNQBUJCMFt1BSFOUFSBM drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. Š2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August


the Growth of Specialty pharmacy: What Is the Impact on patient relationships? Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

T

he past decade has seen a dramatic upsurge in the utilization of specialty pharmacies for all types of therapeutic modalities, including those for cancer. The cost of cancer care may rise from about $125 billion in 2010 to $207 billion by the end of the decade. By that time, specialty drugs are predicted to account for 2 of every 5 pharmacy dollars spent.1 The purpose of this article is to explain the evolution of the specialty pharmacy and the functions it can serve in the treatment of cancer and to discuss the potential benefits and challenges of the system from the point of view of the patient.

the evolution of Specialty Drugs and Specialty pharmacy There is a lack of consensus on the definition of a specialty drug. The US Food and Drug Administration has not defined the term. Initially, the label was virtually synonymous with biotechnology products, either proteins produced by recombinant DNA techniques or monoclonal antibodies produced with cellular hybridomas, but this is no longer the case. The 2007 Medicare Modernization Act defined a specialty drug as “a part D drug with plannegotiated prices that exceed $400 per month.”2 Other health plans may define specialty drugs differently. In general, they are high cost, administered by injection or infusion, require special handling, or are used for complex diseases that require special monitoring. In oncology, however, the most common agents dispensed by a specialty pharmacy provider (SPP) are the newer targeted agents that are administered orally. After a systematic review of the literature, one academic group of authors proposed the most critical descriptors of a specialty drug to be3: • High cost (prescriptions cost more than $600 per month) • Difficult medication delivery, such as – Special handling requiring strict temperature control – Restricted location for medication preparation or distribution site – Restricted location for medication administration • Complex treatment maintenance, including – Personalized or frequent dosing, dosing adjustments, and administration protocols – Clinical management or patient support programs to monitor for serious side effects and adherence The EMD Serono Specialty Digest contains survey data from 93 health plans representing over 115 million covered in-

dividuals.4 This source lists high cost as the most common reason a plan would designate a drug as “specialty,” in that 80% of the plans ranked high cost as 4 or 5 on a 5-point impact scale. Self-administration of an injectable, office administration of an injectable, and treatment of a rare disease are other characteristics that are commonly considered when designating drugs as “specialty.” Specialty drugs have been the fastest growing segment in the pharmacy benefit sector. The number of specialty drugs on the market in the United States has grown from about 10 in 1990 to more than 250 in 2010.4 From 2008 to 2009, spending per healthcare plan member per year increased by 19.5% for specialty drugs, compared with an increase of 4.8% for traditional drugs.5 Even though less than 3% of the private healthcare population uses specialty pharmaceuticals, they account for as much as 25% of all outpatient pharmacy spending.6 With

SPPs are often able to acquire drug products with a volume discount unavailable to most pharmacies, hospitals, and physician offices. more than 600 specialty agents in the research pipeline, it is not surprising that payers have been focused on methods to manage these costs most effectively.3 SPPs are a diverse group of companies involved in overseeing distribution, management, and reimbursement of specialty pharmaceuticals.6 These companies have their origins in a number of lines of business, including community pharmacies, chain pharmacies, home infusion companies, wholesale drug distributors, and pharmacy benefit managers (PBMs). In 2006, 78% of surveyed health plans had contracted with or were in the process of contracting with an SPP for specialty drug distribution.6 As of January 2011, 88% are utilizing SPPs, 7% manage the distribution of specialty drugs in-house, and only 5% have no contractual relationship with SPPs. Forty-three percent contract with a single SPP, a proportion that has been decreasing over the past 3 years.4 Mandatory use of an SPP for dispensing is in place for at least one therapy category in 59% of commercial payers, 64% of Medicare Advantage plans, and 71% of Medicaid plans.

SPPs are often able to acquire drug products with a volume discount unavailable to most pharmacies, hospitals, and physician offices. Health plans are also able to implement formulary policies more easily with a few contracted SPPs than with hundreds of local pharmacies. Another commonly discussed strategy to manage specialty drugs is to move them to the pharmacy benefit, relying heavily Lea Ann Hansen on SPPs, rather than covering them under the medical benefit.7 This has been referred to as medical channel management.1 SPPs have the advantage to payers that claims are submitted via an electronic, real-time process, whereas medical claims are typically batched with no concurrent review. The strategy also allows plans to shift from the traditional physician reimbursement model of “buy and bill” to a more controllable system. One managed care organization with approximately 4.6 million members reported an estimated $15.5 million in savings in drug costs by converting 50 drugs to an SPP.8 The trends in this activity are shown in the Figure.4 Some health plans mandate that patients use a single, or one of a few, contracted SPPs for specialty drugs. Most in the EMD Serono survey agreed that such a mandate is an effective strategy for achieving their overall specialty drug management goals, and currently 59% use this approach for at least one therapeutic class.4 In some states, “Any Willing Provider” legislation and certificates of coverage prevent the practice in some situations. Health plans indicate that monitoring of health outcomes, such as decreases in disease progression and serious adverse event rates, for specialty drugs is of increasing interest. SPPs offer In oncology, the most outcome measurements, predictive modcommon agents eling, and comparative prescribing analysis, but health plans report the least satis- dispensed by a specialty faction with these services. Based on pharmacy provider are these findings and the overall drug development landscape, it is apparent that the newer targeted SPPs will remain in the healthcare environment for the foreseeable future. agents that are Specialty Drugs in Oncology SPPs have growing significance for persons with cancer for several reasons.9 In a number of malignancies, the treatment paradigm is shifting from a single course of chemotherapy lasting a few months to one more analogous to treatment for a chronic disease involving long-term, daily therapy with transitions from one drug to another as the disease progresses. The breakthrough medications that have achieved this possibility are expensive:

administered orally.

Continued on page 12

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the Growth of Specialty pharmacy Continued from page 11

Figure. How Health Plans Typically Cover Specialty Drugs S

Both P & M

M

P

100 90

15 80

29

29

25

7

% of Plans

70 60

13

50

71

40

62

73

30

58 20 10

1

0 SAA 2008

SAA 2012

OAA 2008

6 OAA 2010

Adapted from EMD Serono. EMD Serono Specialty Digest, 7th Edition. http://specialtydigest. emdserono.com. M indicates medical benefit; OAA, office-administered agent; P, pharmacy benefit; S, specialty benefit; SAA, self-administered agent.

Since most SPPs are in a location remote from the patient, the prescriber and/or the prescriber’s staff will usually communicate with patients electronically.

12

90% of oncology drugs approved during the last 5 years cost more than $20,000 for a 3-month course of therapy.1 Oncology is currently dominating research and development in the pharmaceutical industry, with 125 drugs in phase 3 clinical trials, 38 of which are oral medications. Additionally, cancers are increasingly being characterized by complex tumor biomarkers which will, in some cases, guide treatment. The strategies used by health plans to manage these molecular diagnostic tests, which are themselves expensive, are evolving. Many have not implemented policies as of yet, but most plan to do so within the next 12 to 24 months.4 Currently, 77% of health plans classify oral oncology agents as specialty drugs, and they represent some of the most commonly used agents in the category.4 Spending on oral cancer agents more than doubled between 2002 and 2006.9 Examples of drugs dispensed through SPPs, with their most common oncology indications, are shown in the Table.4,10-25 Some health plans include injectable chemotherapy agents in the specialty drug genre under a medical channel management strategy, even though they are not self-administered. These include paclitaxel protein-bound particles, ixabepilone, cabazitaxel, mitoxantrone, bendamustine, pralatrexate, azacitidine, decitabine, ofatumumab, bevacizumab, cetuximab, panitumumab, trastuzumab, romidepsin, leuprolide acetate, aldesleukin, temsirolimus, and bortezomib.10 Injectable agents for supportive care of cancer patients, such as epoetin alfa, darbepoetin, sargramostim, filgrastim, and pegfilgrastim, are considered specialty drugs by 78% of health plans. In addition, 59% of the survey re-

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spondents currently place some palliative care and end-of-life therapies in the specialty category or plan to increase focus on this area in the future. Currently, approximately 40% of health plans require an SPP be used for some or all specialty drugs in the oncology category.4

While there are many potential benefits to patients with cancer when they utilize an SPP, a number of concerns have been raised by other healthcare groups. benefits and Challenges of Specialty pharmacy to the patient With Cancer Learning of a cancer diagnosis and receiving treatment represent a series of stressful events for patients and their families. The entire diagnostic experience immerses them in an unfamiliar world of medical specialists, testing procedures, medical jargon, and health insurance rules. Often the cancer diagnosis was preceded by an insidious onset of vague symptoms in an otherwise healthy person, so patients may be relatively naive to navigating the healthcare system. Coexisting concerns about employment, child care, and other responsibilities add to the burden. Therefore, it is important for health professionals to be aware of benefits and challenges introduced by each type of service entity that is utilized in the care of the cancer patient, including SPPs.

Since most SPPs are in a location remote from the patient, the prescriber and/or the prescriber’s staff will usually communicate with patients electronically. The SPP would typically be more familiar with the particular specialty drug they have been contracted to provide than a general service pharmacy. Many prior authorization or reimbursement issues can be addressed by the SPP, prescriber, and health plan without direct involvement of the patient. In some cases, when high-cost specialty drugs that are administered by infusion are assigned to the pharmacy benefit, via an SPP, rather than to the medical benefit, the overall out-of-pocket expense to the patient can be reduced. Some SPPs have realized cost savings through dispensing customized quantities with close monitoring for regimen changes or discontinuation.26 However, this benefit may not be transmitted to the patient if the health plan requires a copayment each time a prescription is dispensed. The drug product will subsequently be delivered directly to the patient’s home. This represents a valuable convenience for the patient who may be fatigued by disease, travel, and medical procedures. In many cases, the complicated nature of administration or possible adverse events with specialty drugs necessitate intensive patient monitoring. Most SPPs offer patient education and 24/7 support lines staffed by a pharmacist or nurse. Some provide proactive refill programs, while others monitor for adherence based on refill patterns. Better adherence to specialty drugs with SPPs than with community pharmacies has been described in poster presentations and Internet Web sites.1,27 While there are many potential benefits to patients with cancer when they utilize an SPP, a number of concerns have been raised by other healthcare groups. The National Comprehensive Cancer Network (NCCN), a not-forprofit alliance of 21 cancer centers that are designated at the highest level by the National Cancer Institute, conducts initiatives in order to “improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives.”28 In 2010, the NCCN convened a task force on the topic of specialty pharmacy. The majority of their recommendations involve communication, coordination of care, and pharmacy practice issues as described below. When an SPP assumes the primary responsibility for delivering the anticancer medication, the potential for fragmentation of care between the SPP and the rest of the oncology care team arises. Questions regarding quantities dispensed, communication of dosage changes or modifications, and delays in treatment initiation may be difficult to resolve since

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the Growth of Specialty pharmacy

each SPP and health plan will have different procedures. Even within a health plan, logistic procedures may be different for each drug or class of drugs, and solving a problem can consume considerable provider time. Better informatics systems are needed to facilitate information flow and delineation of roles between SPPs and the healthcare team, especially since oncology patients have a frequently evolving medication regimen.28 Other specific recommendations have been made by the NCCN Specialty Pharmacy Task Force to decrease the risk of patient frustration, adverse events, and waste. These include: • SPP practitioners who care for patients with cancer should have specific expertise in oncology • Distribution models for SPPs should minimize delay in initiating therapy, and an appropriate estimate of drug delivery should be given to the provider and patient; this is important because many therapeutic regimens involve multiple drugs on a precise schedule and should not be initiated if availability of a specialty drug will be delayed • SPP should dispense small quantities on the first fill without penalties to the patient • If a self-injectable medication is sent directly to the patient, the SPP or the PBM should have the responsibility to educate the patient regarding self-administration techniques • Only agents that can be safely and appropriately self-administered should be dispensed through the SPP model • Medications requiring sterile compounding before infusion or those that a patient cannot self-administer should not be distributed through an SPP, since the process of “brown bagging,” by which patients deliver drugs to the clinical setting, creates obvious risk to product integrity and additional burden on the patient • Preparation of injectables by the SPP and dispensing directly to the hospital, clinic, or physician office (“white bagging”) does not necessarily eliminate the concerns of brown bagging and creates potential waste when dose modification or discontinuation based on patient-specific data occurs • SPPs should develop and implement procedures for proper handling and disposal of chemotherapy agents they dispense • All pharmacies, including SPPs, should participate in national incident reporting databases to include medication errors, adverse events, and near misses A roundtable convened by the American Society of Health-System Pharmacists outlined a number of additional concerns related to drug distribution and handling that impact patient welfare and the oncology workforce.29

One participant stated, “Specialty pharmacies provide a recipe for profound clinical problems for our patients as decisions are made to carve select components of the total care process out of our healthsystem setting.” A number of potential negative effects were noted:

• Supply chain control is disrupted when a patient receives a drug from an SPP and brings it to the institution for the injection, leading to the possibility of improper storage and handling and introduction of counterfeit drugs into the system

Table. Oral Anticancer Agents Often Classified as Specialty Drugs* Imatinib11

Dasatinib12

Nilotinib13 Erlotinib14

Sorafenib15 Sunitinib16

Pazopanib17 Everolimus18

Lapatinib19

Thalidomide20 Lenalidomide21

Temozolomide22

Capecitabine23

Topotecan24 Vorinostat25

• Newly diagnosed Philadelphia chromosome–positive chronic myelogenous leukemia (Ph+ CML) • Ph+ CML after failure of interferon-alpha therapy • Relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL) • Kit (CD117)+ unresectable and/or metastatic malignant gastrointestinal stromal cell tumors (GISTs) • Adjuvant treatment following resection of Kit (CD117)+ GIST • Newly diagnosed Ph+ CML • Ph+ CML when not benefitting from, or not tolerating, other treatment • Ph+ ALL when not benefitting from, or not tolerating, other treatment • Newly diagnosed Ph+ CML in chronic phase • Ph+ CML resistant or intolerant to prior therapy that included imatinib • Maintenance therapy of locally advanced or metastatic non–small cell lung cancer (NSCLC) when disease has not progressed after 4 cycles of chemotherapy • Locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen • First-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine • Unresectable hepatocellular carcinoma • Advanced renal cell carcinoma • GIST after disease progression or intolerance to imatinib • Advanced renal cell carcinoma • Progressive, well-differentiated pancreatic neuroendocrine tumors (PNETs) that are unresectable or metastatic • Advanced renal cell carcinoma • Advanced soft tissue carcinoma, after at least 1 prior chemotherapy • Advanced renal cell carcinoma after failure of sunitinib or sorafenib • Advanced hormone receptor–positive, HER2- breast cancer after failure with letrozole or anastrozole, in combination with exemestane • PNETs that are unresectable, locally advanced, or metastatic • Renal angiomyolipoma and tuberous sclerosis complex, not requiring immediate surgery • Advanced or metastatic HER2+ breast cancer after prior therapy with an anthracycline, a taxane, and trastuzumab, in combination with capecitabine • Metastatic, postmenopausal, hormone-positive HER2+ breast cancer, in combination with letrozole • Newly diagnosed multiple myeloma (MM), in combination with dexamethasone • MM, in combination with dexamethasone, after at least 1 prior therapy • Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q abnormality • Newly diagnosed glioblastoma multiforme, concomitantly with radiotherapy and then as maintenance treatment • Refractory anaplastic astrocytoma after progression on a regimen containing nitrosourea and procarbazine • Adjuvant treatment of Dukes C colon cancer • First-line treatment of metastatic colorectal cancer when a fluoropyrimidine therapy alone is preferred • Metastatic breast cancer, in combination with docetaxel after failure of prior anthracycline-containing therapy • Metastatic breast cancer resistant to both paclitaxel and an anthracyclinecontaining regimen • Relapsed small cell lung cancer • Cutaneous manifestations of cutaneous T-cell lymphoma, with progressive, persistent, or recurrent disease on or following 2 systemic therapies

Even within a health plan, logistic procedures may be different for each drug or class of drugs, and solving a problem can consume considerable provider time.

*For complete FDA-approved indications and usages, please visit the manufacturers’ Web sites.

Continued on page 14

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the Growth of Specialty pharmacy Continued from page 13

• Some drugs provided by an SPP are accompanied by an infusion device that local staff is unfamiliar with using or replenishing • These concerns lead many hospitals to adopt policies preventing such It is imperative that medications from being administered within the institution, creating professionals providing frustration for the patient who may have been required to follow this apcare are well informed proach by his or her health plan about all of the elements • Increases in bureaucracy, paperwork, and inefficiencies are created for of the healthcare system clinic nurse managers, physicians, and effectively deliver and pharmacy managers in determining where to obtain the drug for necessary information, each patient • Patients become dissatisfied because training, and services to of the disruptions and delays caused their patients. by the complicated process and difficulty obtaining accurate information about their out-of-pocket expenses When patients are treated for cancer, an entire team of professionals oversees their care. Inclusion of an additional or different entity, such as an SPP, into the system increases the potential for missed information, frustration, and even devastating consequences. In order to realize potential cost and clinical benefits while also supporting patients through a devastating cancer diagnosis, it is imperative that professionals providing care are well informed about all of the elements of the healthcare system and effectively deliver necessary information, training, and services to their patients. Conclusion At the core of the debate around specialty pharmaceuticals is the question of value and control in healthcare. Clinicians have typically been trained to

emphasize patient outcome with relatively little concern for costs. Coverage policies in health plans have not typically been designed to evaluate the therapeutic value of particular treatments relative to their direct or indirect cost. At times, patient demand for a new product that appears to be a therapeutic breakthrough swells to a level not justified by the available outcomes data. The intersection of these circumstances in the wake of hightechnology cancer innovations will require investment of all groups in order to ensure that individuals with cancer receive care that has clinical value, financial value, and above all, humanistic value. ● references 1. Medco 2011 Drug Trend Report. Drug Trend Report Web site. http://www.drugtrendreport.com/2011-report. Accessed November 29, 2011. 2. Centers for Medicare & Medicaid Services. Medicare Modernization Act: 2007 Final Guidelines—Formularies, CY07 Formulary Guidance. Washington, DC: CMS; 2006. 3. Blaser DA, Lewtas AJ, Ousterhout MM, et al. How to define specialty pharmaceuticals—a systematic review. Am J Pharm Benefits. 2010;2:371-380. 4. EMD Serono. EMD Serono Specialty Digest, 7th Edition. http://specialtydigest.emdserono.com/. Accessed November 28, 2011. 5. Miller S, Cox E, Nease B, et al. 2009 Drug Trend Report: Solving for America's $163 Billion in Pharmacy-Related Waste: A Market and Behavioral Analysis. St. Louis, MO: Express Scripts, Inc; 2010. http://www.express-scripts. com/research/research/dtr/archive/2009/dtrFinal.pdf. Accessed September 11, 2012. 6. Stern D, Reissman D. Specialty pharmacy cost management strategies of private health care payers. J Manag Care Pharm. 2006;12:736-744. 7. Robinson JC. Insurers’ strategies for managing the use and cost of bio-pharmaceuticals. Health Aff. 2006;25:1205-1207. 8. Baldini CG, Culley EJ. Estimated cost savings associated with the transfer of office-administered specialty pharmaceuticals to a specialty pharmacy provider in a medical injectable drug program. J Manag Care Pharm. 2011;17:51-59. 9. Weingart SN, Brown E, Bach PG. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008; 6(suppl):S1-S14. 10. LM Healthworks. Learn about your specialty pharmacy benefit. https://host1.medcohealth.com/art/open_ enrollment/Lockheed_SPharm_Benefit.pdf. Accessed November 27, 2011.

11. Gleevec Prescribing Information. Novartis Pharmaceuticals Corporation Web site. http://www.pharma.us. novartis.com/product/pi/pdf/gleevec_tabs.pdf. Accessed November 29, 2011. 12. Sprycel Prescribing Information. Bristol-Myers Squibb Web site. http://packageinserts.bms.com/pi/pi_sprycel.pdf. Accessed November 29, 2011. 13. Tasigna Prescribing Information. Novartis Pharmaceuticals Corporation Web site. http://www.pharma. us.novartis.com/product/pi/pdf/tasigna.pdf. Accessed November 29, 2011. 14. Tarceva Prescribing Information. Genentech Web site. http://www.gene.com/gene/products/information/pdf/ tarceva-prescribing.pdf. Accessed November 29, 2011. 15. Nexavar Prescribing Information. http://www.univ graph.com/bayer/inserts/nexavar.pdf. Accessed November 29, 2011. 16. Sutent Prescribing Information. Pfizer Web site. http://labeling.pfizer.com/ShowLabeling.aspx?id=607. Accessed November 29, 2011. 17. Votrient Prescribing Information. GSK Source Web site. https://www.gsksource.com/gskprm/htdocs/documents/ VOTRIENT-PI-MG.PDF. Accessed September 11, 2012. 18. Afinitor Prescribing Information. Novartis Pharmaceuticals Corporation Web site. http://www.pharma.us. novartis.com/product/pi/pdf/afinitor.pdf. Accessed September 11, 2012. 19. Tykerb Prescribing Information. GlaxoSmithKline USA Web site. http://us.gsk.com/products/assets/us_ tykerb.pdf. Accessed November 29, 2011. 20. Thalomid Prescribing Information. http://www. thalomid.com/pdf/Thalomid%20PI%2072991-10.pdf. Accessed November 29, 2011. 21. Revlimid Prescribing Information. http://www.revlimid. com/pdf/REVLIMID_ PI.pdf. Accessed November 29, 2011. 22. Temodar Prescribing Information. http://www.spfiles. com/pitemodar.pdf. Accessed November 29, 2011. 23. Xeloda Prescribing Information. Genentech Web site. http://www.gene.com/gene/products/information/xeloda/ pdf/pi.pdf. Accessed November 29, 2011. 24. Hycamtin Prescribing Information. GlaxoSmithKline USA Web site. http://us.gsk.com/products/assets/us_ hycamtin_capsules.pdf. Accessed November 29, 2011. 25. Zolinza Prescribing Information. Merck Web site. http://www.merck.com/product/usa/pi_circulars/z/zolinza/ zolinza_pi.pdf. Accessed November 29, 2011. 26. Frederick J. Walgreens promotes big savings via monitored oncology Rx therapy. Drug Store News Web site. http://www.drugstorenews.com/article/walgreens-promotesbig-savings-monitored-oncology-rx-therapy. Accessed November 30, 2011. 27. Allen JD, Zabriski S, Brown J. Effectiveness of a direct-to-patient specialty pharmacy compliance program. J Manag Care Pharm. 2005;11:602. Abstract. 28. Schwartz RN, Eng KJ, Frieze DA, et al. NCCN Task Force Report: specialty pharmacy. J Natl Compr Canc Netw. 2010;8(suppl 4):S1-S12. 29. Armistead J, Lloyd L, Pane F, et al. Implications of the specialty drug marketplace for health-system pharmacy: a roundtable discussion. Am J Health Syst Pharm. 2007;64: 2364-2372.

A pharmacist’s perspective Steve Stricker, PharmD, MS, BCOP

T Steve Stricker

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he evolution of drug research and development toward oral therapies for cancer over the past decade has created a number of questions for the oncology healthcare provider. Will insurance companies pay for these exceptionally expensive medications? How and when will patients receive their medication? Who will be responsible for ensuring patient education and monitoring to maximize safe drug administration and patient compliance? In the accompanying article, Dr Hansen builds a case for specialty pharmacy providers (SPPs) to assume these responsibilities in a marketplace increas-

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ingly focused on reducing drug costs while also remaining committed to pharmacovigilance. When appropriately uti-

Many SPPs have pharmacists available 24 hours a day to be responsive to the needs of their customers and patients. lized, the SPP can become a benefit to the healthcare team and an additional

resource at the disposal of the oncology pharmacist. When a patient is initially introduced to the concept of oral chemotherapy, it often becomes the duty of the oncology pharmacist to ensure that the patient and family are well educated with regard to the dosage, schedule, and side effects related to the new medication. As these drugs are often used in the second-line (or beyond) setting, frequently counseling sessions are undertaken while patients are still processing the news that their cancer has returned or worsened. Thus, it becomes important that patients are provided with written education ma-

www.TheOncologyPharmacist.com


the Growth of Specialty pharmacy terials and have an available “life line” when questions arise regarding these oral drugs. While a provider from our practice is always available to the patient and family around the clock, the availability of additional highly reliable patient resources can play a significant role in ensuring that patients receive timely advice or an appropriate answer to a question or

concern in the event that they feel uncomfortable asking us directly. The SPP may then provide education as an extension of the oncology team rather than having the patient seek out information or anecdotes from the Internet or other such unreliable references. As Dr Hansen notes, “The SPP would typically be more familiar with the partic-

ular specialty drug they have been contracted to provide than a general service pharmacy.” In addition to enhanced knowledge of these drugs, many, if not all, SPPs have pharmacists available 24 hours a day to be responsive to the needs of their customers and patients. This is a significant advantage in contrast to the Continued on page 16

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sEPTEmbER 2012 I VOL 5, NO 6

15


the Growth of Specialty pharmacy Continued from page 15

pharmacist in a traditional community pharmacy where patients may, otherwise, feel inclined to seek additional drug information. In an article in the Journal of the American Pharmacists Association in 2008, O’Bryant and Crandell surveyed community pharmacists’ knowledge and attitudes toward oral chemotherapy and concluded that only 45% of community pharmacists were knowledgeable regarding adverse events of these drugs. They also reported a low level of comfort in dispensing these highly specialized oral medications (mean 2.4; Likert scale 1 [low] to 5 [high]).1 Thus, an insurance company that contracts an SPP to provide dispensing services for these drugs also is more likely to ensure that patients

will be the beneficiaries of competent drug information. While the SPP may play a favorable role in patient education, there are obvious concerns related to the possibility of fragmentation of care ultimately related to communication issues. In my opinion, it is important for the oncology pharmacist in the ambulatory care setting to be aware of the SPPs used by insurance plans commonly encountered in a community. Oncology pharmacists would be well served to communicate directly with the SPPs, become knowledgeable in the drugs and services offered by specific SPPs, and maintain open channels of communication to ensure that when questions arise related to quantities dispensed, dosage

changes, or delays in treatment, this information may be exchanged in a cordial and professional manner, no differently than communicating with a community pharmacy down the street. We must, as a profession, recognize that SPPs will remain a significant factor in the dispensing of expensive, highly specialized oral oncology drugs for the foreseeable future. Thus, our responsibility should be to utilize the SPP as a resource to enhance care for the patient with cancer rather than view the SPP as an insurmountable barrier to patient care. ● reference 1. O’Bryant CL, Crandell BC. Community pharmacists’

knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc. 2008;48:632-639.

The Patient’s Voice

Popping Pills and Shooting Up... Continued from cover illness I have been charged with taking pills at home. If I had to rank myself on a scale of 1 to 10, with 1 being a patient who constantly forgets to take his/her medicine and 10 being the highly conscientious patient who never misses medicine time while following all the directions about eating, drinking, and driving exactly, I would place myself around a 7 or 8. Honestly, I don’t forget to take the medicine; sometimes, probably for some psychological reason, I resist taking it. That means, if the pharmacist or nurse wrote on my medicine sheet to take a pill (or series of them) every day at 9:00 in the morning, some days I may take it at 11:00, even if the bottle is sitting right in front of me for those extra 2 hours. Furthermore, if the bottle says not to eat for a half hour after taking the pill, I often wait only 20 minutes. I cannot explain my behavior. I know I am only hurting myself. Nonetheless, I just do it that way, sometimes. The injections, which I had been taught to give myself in the hospital, presented an entirely new challenge. First of all, I have a deep-seated fear of needles. When the nurse first told me I would need to inject myself, I started to cry and sweat. She tried to calm me by telling me the needle was very small. That did nothing. She brought me the fake skin to place on my belly to practice injecting myself without actually doing it. The doctor even came in to tell me that because of the size of the needle, even if I jammed the injec-

16

sEPTEmbER 2012 I VOL 5, NO 6

tion into myself, I would not hit a vital organ. Then, after about a hundred practice runs, the nurse watched as I cleaned off my own skin with an alcohol wipe, pinched the skin 2 inches from my belly button, counted “1-2-3” and stuck the needle into my virgin belly skin. Yet, this self-injection bothers me not only because of my fear of needles, but also because I honestly think I should not have to do it. I think the hospital should either do the injections so as not to force me into this masochistic routine morning and afternoon, or give me another pill that I can take relatively on time every day. Perhaps some people prefer to be able to self-inject at home instead of having to go back to the hospital, but I do not fall into that category. I find it very hard to understand how— with all the advances in medicine, with all the brilliant minds working on hardcore issues such as finding cures for cancer, with all the nurses who spend years in school, and with all the specialized fields within pharmacology—I am still required to “shoot up” in my own bathroom as part of my treatment. Perhaps I should feel lucky that I have access to medical care (and I do). Perhaps I should stop whining and think of all the millions of people with diabetes who have to inject themselves every day for the rest of their lives (and I do). Perhaps I should think of all those who have passed away from my illness and be thankful I have the opportunity

to receive medications that may save me (and I do/am). Perhaps I should somehow look on the bright side and breathe a sigh of relief that at least the injections are not another pill I need to remember to take (unfortunately, I cannot). The truth of the matter is, that while I am pretty comfortable with popping pills, I am not at all comfortable

with shooting up in my bathroom even after a month of doing so. Can someone please invent something that makes it unnecessary while still maintaining the same level of care? ● MMA is undergoing treatment for cancer. She wishes to use her initials.

Reader Poll Do you talk to patients about the importance of adherence to their medications? r Yes r No

Go to www.TheOncologyPharmacist.com to cast your vote and add your comments. Please tell us what your patients are telling you, directly or indirectly, about how they take their medications.

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

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

THE AFINITOR DUAL BENEFIT CO-PAY CARD

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

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

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

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2012 Novartis

9/12

AFB-1046627


AFINITOR速 (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve. For grade 3 cases, interrupt AFINITOR until resolution to ) grade 1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment. Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR. Geriatric Patients: In the randomized advanced hormone receptorpositive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients * 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent discontinuation occurred in 33% of patients * 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended. Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids,

and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Drug-Drug Interactions: Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments. Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment. Adverse Reactions: The most common adverse reactions (incidence * 30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%) and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence * 2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%) and diarrhea (2%). Laboratory Abnormalities: The most common laboratory abnormalities (incidence * 50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%). The most common grade 3/4 laboratory abnormalities (incidence * 3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%). Please see accompanying Brief Summary of Prescribing Information for AFINITOR on the following pages.


AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] . Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo


Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in â&#x2030;Ľ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: O >8GB6BA4MB?84FGEBA:0)<A;<5<GBE4A74):)<A;<5<GBE max 4A7-<A6E84F875L  4A7 

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Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers "A;84?G;LFH5=86GF6B 47@<A<FGE4G<BAB9"'",(*J<G;E<94@C<A4FGEBA:<A7H68EB9CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared GB 8I8EB?<@HFGE84G@8AG4?BA8 BA F<78E47BF8<A6E84F8B9"'",(*J;8A6B 47@<A<FG8E87J<G;FGEBA:0)<A7H68EF<94?G8EA4G<I8 treatment cannot be administered. St. Johnâ&#x20AC;&#x2122;s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions 58GJ88A"'",(*4A7G;8!& BE87H6G4F8<A;<5<GBEF4GBEI4FG4G<A40)FH5FGE4G84A7CE4I4 FG4G<A4ABA 0)FH5FGE4G84A7CBCH?4G<BAC;4E@46Bkinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. FGH7L<A;84?G;LFH5=86GF78@BAFGE4G87G;4G6B 47@<A<FGE4G<BAB94ABE4?7BF8B9@<74MB?4@F8AF<G<I8 0)FH5FGE4G8J<G;8I8EB?<@HFE8FH?G87<A4<A6E84F8<A@<74MB?4@max and a 30% increase in @<74MB?4@- <A9. Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse 8I8AGFE8?4G87GB8K8@8FG4A8J4FB5F8EI87<AC4G<8AGFJ<G;;BE @BA8E868CGBE CBF<G<I8!* A8:4G<I847I4A6875E84FG64A68EE868<I<A:G;86B@5<A4G<BA  Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. ,;8E84E8AB478DH4G84A7J8?? 6BAGEB??87FGH7<8FB9"'",(*<ACE8:A4AGJB@8A;BJ8I8E54F87BA the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. I8EB?<@HF64HF878@5ELB 98G4?GBK<6<G<8F<A4A<@4?F4G@4G8EA4?8KCBFHE8FG;4GJ8E8?BJ8EG;4A;H@4A exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the 7EH:G;8C4G<8AGF;BH?7584CCE<F87B9G;8CBG8AG<4?;4M4E7GB498GHF /B@8AB96;<?7584E<A:CBG8AG<4? should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and G;EBH:;BE:4AB:8A8F<F<A7H6878@5ELB 98G4?GBK<6<G<8F<A6?H7<A:<A6E84F87E8FBECG<BACE8 <@C?4AG4G<BA 4A7CBFG <@C?4AG4G<BA?BFF786E84F87AH@58EFB9?<I898GHF8F@4?9BE@4G<BA8 : FG8EA4?6?89G4A7 retarded skeletal development. These eff86GFB66HEE87<AG;845F8A68B9@4G8EA4?GBK<6<G<8F @5ELB 98G4? toxicities in rats occurred at doses â&#x2030;Ľ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC ;) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

"A4CE8 4A7CBFG A4G4?78I8?BC@8AGFGH7L<AE4GF4A<@4?FJ8E87BF879EB@<@C?4AG4G<BAG;EBH:;?46G4 tion. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or F<:AFB9@4G8EA4?GBK<6<GL;BJ8I8EG;8E8J8E8E87H6G<BAF<A5B7LJ8<:;GHCGBE87H6G<BA9EB@G;8 6BAGEB?4A7<AFHEI<I4?B9B99FCE<A:N7<87BE@<FF<A: ,;8E8J8E8AB7EH: E8?4G8789986GFBAG;8 developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use AFINITOR is recommended for use only in patients with SEGA who are aged â&#x2030;Ľ 3 years. CEBFC86G<I8BC8A ?458?F<A:?8 4E@GE<4?J4F6BA7H6G87GB8I4?H4G8G;8F498GL4A7899<646LB9"'",(* <AC4G<8AGFJ<G;+ 4FFB6<4G87J<G;,+ "AGBG4?C4G<8AGFE868<I87GE84G@8AGJ<G;"'",(*@87<4A 4:8J4F L84EFE4A:8  "'",(*;4FABG588AFGH7<87<AC4G<8AGFJ<G;+ L84EFB94:8

Geriatric Use "AG;8E4A7B@<M8747I4A687;BE@BA8E868CGBECBF<G<I8!* A8:4G<I85E84FG64A68EFGH7L B9 "'",(* GE84G87C4G<8AGFJ8E8â&#x2030;Ľ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients â&#x2030;Ľ 65 years of age compared to 2% in C4G<8AGFL84EFB94:8 7I8EF8E846G<BAF?847<A:GBC8E@4A8AGGE84G@8AG7<F6BAG<AH4G<BAB66HEE87<A 33% of patients â&#x2030;Ľ L84EFB94:86B@C4E87GB <AC4G<8AGFL84EFB94:8[see Warnings and Precautions]. "AGJBBG;8EE4A7B@<M87GE<4?F47I4A687E8A4?68??64E6<AB@44A747I4A687A8HEB8A7B6E<A8GH@BEFB9 pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and LBHA:8EFH5=86GF "AG;8E4A7B@<M8747I4A687*FGH7L B9"'",(*GE84G87C4G<8AGFJ8E8â&#x2030;Ľ 65 L84EFB94:8J;<?8J8E84A7BI8E "AG;8E4A7B@<M8747I4A687)',FGH7L B9"'",(* treated patients were â&#x2030;Ľ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out 1F88?<A<64?);4E macology (12.3) in the full prescribing information]. 'B7BF4:847=HFG@8AG<A<A<G<4?7BF<A:<FE8DH<E87<A8?78E?LC4G<8AGF5HG6?BF8@BA<GBE<A:4A74CCEBCE< ate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal <@C4<E@8AG<FABG8KC86G87GB<A9?H8A687EH:8KCBFHE84A7AB7BF4:847=HFG@8AGB98I8EB?<@HF<FE86 ommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose FGH7LB98I8EB?<@HF<AFH5=86GFJ<G;<@C4<E87;8C4G<69HA6G<BAE8?4G<I8GBFH5=86GFJ<G;ABE@4?;8C4G<69HA6 tion. KCBFHE8J4F<A6E84F87<AC4G<8AGFJ<G;@<?7;<?7 )H:;6?4FF@B78E4G8;<?7 )H:;6?4FF 4A7F8I8E8;<?7 )H:;6?4FF;8C4G<6<@C4<E@8AG1F88?<A<64?);4E@46B?B:L  <AG;89H??CE8 scribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the E<F> BEC4G<8AGFJ<G;@<?7;<?7 )H:;6?4FFBE@B78E4G8;<?7 )H:;6?4FF;8C4G<6<@C4<E@8AG4 dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. BE+ C4G<8AGFJ<G;F8I8E8;8C4G<6<@C4<E@8AG;<?7 )H:;6?4FF"'",(*<FABGE86B@@8A787

BE+ C4G<8AGFJ<G;@<?7;<?7 )H:;6?4FFBE@B78E4G8;<?7 )H:;6?4FF;8C4G<6<@C4<E@8AG 47=HFG@8AGGBG;8FG4EG<A:7BF8@4LABG58A88787;BJ8I8EFH5F8DH8AG7BF<A:F;BH?758<A7<I<7H4? <M8754F87BAG;8E4C8HG<67EH:@BA<GBE<A:[see Dosage and Administration (2.4  <AG;89H??CE8F6E<5 ing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG +G8<A+J<GM8E?4A7 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis ,   July 2012


News Briefs Older patients With Mantle Cell... Continued from page 4

domized to receive either 6 cycles of RFC every 28 days or to 8 cycles of RCHOP every 21 days. Responders (n = 316) were randomized to maintenance therapy with rituximab or interferon alfa, and treatment was continued until disease progression. Median age was 70 years, about 70% were male, and about 80% were stage IV at baseline. An intent-to-treat analysis for response was based on 532 patients. Rates of CR were similar for the regimens: 40% for R-FC and 34% for R-CHOP. However, more patients progressed on R-FC (14% vs 5% with R-CHOP). Four-year survival rates were significantly lower on R-FC: 47% versus 62%, respectively (P = .10). Also, more patients treated with R-FC died during first remission (10% vs 4%, respectively). Hematologic adverse events were reported more frequently in the R-FC group than in the R-CHOP group, but the rates of infection were similar (17% for R-FC and 14% for R-CHOP). In the analysis of responders, maintenance therapy with rituximab reduced the risk of progression or death by 45%: progression or death occurred in 58% of those on maintenance with interferon alfa versus 29% of those on maintenance rituximab (P = .01). Among responders to R-CHOP, maintenance therapy with rituximab significantly improved overall survival at 4 years from 63% with interferon alfa maintenance to 87% (P = .005). Toxic effects during the maintenance phase were more pronounced in the interferon alfa group, with more patients having leukocytopenia, thrombocytopenia, and fatigue, whereas rituximab was associated with more infections. These observed differences led to differences in adherence, with an overall median treatment duration of 25 months with rituximab versus 7 months with interferon alfa.

tients have a normal CA125 level, and premenopausal women, who typically have a high incidence of benign cysts and a low incidence of ovarian cancer. OVA1 is the first US Food and Drug Administration–approved blood test for ovarian cancer; the test has a high sensitivity to determine if cancer is present in women with an ovarian mass prior to surgery. OVA1 is an in vitro diagnostic

test that combines results of 5 immunoassays using a proprietary algorithm to come up with a single numerical score indicating a woman’s likelihood of having ovarian cancer. Vermillion, Inc, the diagnostic company that is marketing OVA1, released preliminary results of OVA500 and said that further details of the study have been submitted to a peer-review publication.

OVA500 follows a previous study published online in Obstetrics & Gynecology in March 2011 showing that use of OVA1 in place of the CA125 test correctly identified ovarian cancer 94% of the time versus 77% for CA125 in 516 women having surgery. The company hopes that results of OVA500 will support adoption and reimbursement for this blood test. ●

NOW AVAILABLE

blood test for Ovarian Cancer The OVA1 blood test had a high chance of correctly identifying whether an ovarian mass was malignant prior to surgery, according to results of the OVA500 clinical trial. In a study of 494 patients, the test had 94% sensitivity in premenopausal women and 91% sensitivity in the early-stage ovarian cancer group, for an overall sensitivity of 96%. The OVA1 blood test had a negative predictive value of 98%. OVA500 was designed to evaluate the test in 2 subgroups: those with early-stage ovarian cancer, where about 50% of pa-

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

KYPROLIS.com sEPTEmbER 2012 I VOL 5, NO 6

21


Prostate Cancer

progress in treating prostate Cancer By Alice Goodman

22

sEPTEmbER 2012 I VOL 5, NO 6

At 3 months, 10% of the men who were treated with LHRHa/AA/prednisone had pathologic complete response (pCR), compared with 4% of those treated with LHRHa alone; near

“These results…suggest that this combination therapy could improve outcomes for a substantial number of men with early high-risk prostate cancer.”

Neoadjuvant Abiraterone Acetate2 Another study of even earlier use of AA suggests that the drug will find a role prior to the development of metastatic prostate cancer. Preadjuvant treatment with 6 months of AA given concurrently with leuprolide acetate (LHRHa), a hormonal therapy, and prednisone prior to radical prostatectomy successfully eradicated prostate cancer cells in about 30% of men with high-risk early prostate cancer in a randomized phase 2 trial. “These results are particularly amazing in this incredibly high-risk group of patients, and suggest that this combination therapy could improve outcomes for a substantial number of men with early high-risk prostate cancer,” stated lead author Mary-Ellen Taplin, MD, of Harvard Medical School and the DanaFarber Cancer Institute in Boston, Massachusetts. This is a preliminary study, and larger, longer trials will be needed to establish a role for AA plus hormone therapy in the neoadjuvant setting. The phase 2 trial included 58 men who were defined as high risk because they had at least 1 of the following features: ≥3 positive biopsies; Gleason score ≥7 (71% of men had scores of 8-10); prostate-specific antigen (PSA) >20 ng/mL (19%); T3, T4 bulky disease (24%); or PSA velocity >2 ng/mL/year (16%). Men with extranodal disease were allowed to enroll. The men were randomized to receive 3 months of treatment with LHRHa alone or 3 months of LHRHa plus AA plus low-dose prednisone. Prednisone 5 mg/day was given with AA to prevent side effects associated with this drug. After 3 months, a prostate biopsy was performed to measure serum testosterone and dihydrotestosterone levels, after which the men received 12 more weeks of LHRHa/AA/prednisone.

—Mary-Ellen Taplin, MD

pCR was observed in 24% and 11%, respectively. enzalutamide in Metastatic CrpC3 Enzalutamide, an androgen receptor signaling inhibitor, was superior to placebo for both the primary and secondary end points in the phase 3 AFFIRM trial in men with progressive CRPC. Primary end point results for OS reported earlier showed that enzalutamide significantly improved OS by 4.8 months compared with the placebo group; the risk of death was reduced by 37% in men randomized to enzalutamide (P <.0001).4,5

Photo © ASCO/Silas Crews 2012.

Abiraterone in ChemotherapyNaive Metastatic CrpC1 Results of the second interim analysis of COU-AA-302 showed that AA plus prednisone significantly improved radiographic progression-free survival (rPFS), with a strong trend toward increased overall survival (OS) compared with placebo plus prednisone in men with metastatic CRPC who had not received chemotherapy. This study evaluated earlier use of AA than the current FDA indication for use following failure of chemotherapy in CRPC. “This is the first randomized trial to demonstrate both an overall survival and progression-free survival benefit in chemotherapy-naive patients with metastatic CRPC and show that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemotherapy,” stated lead author Charles J. Ryan, MD, of the University of California San Francisco. The study enrolled 1088 patients at 151 centers in 12 countries. Patients were randomized 1:1 to AA (1 g) plus prednisone (5 mg BID) versus placebo plus prednisone. The Independent Data Monitoring Committee unblinded the study early, when all primary and secondary outcomes were seen to favor AA, and patients were allowed to cross over from placebo to the AA arm. At a median follow-up of 22.3 months, median rPFS was not yet reached in the AA arm versus 8.3 months in the placebo arm (P <.0001). Median OS was not yet reached in the

AA arm and was 27.2 months in the placebo arm (P = .0097). The interim analysis also confirmed the acceptable tolerability and safety profile of AA in this setting.

Photo © ASCO/Silas Crews 2012.

T

wo studies presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting suggested that abiraterone acetate (AA; Zytiga), an androgen biosynthesis inhibitor,1 has the potential to be used earlier in the course of prostate cancer than its current US Food and Drug Administration (FDA) indication (ie, after failure of chemotherapy in men with metastatic castration-resistant prostate cancer [CRPC]). A second interim analysis of a phase 3 trial had positive outcomes with AA in men with metastatic CRPC who had not yet received chemotherapy,1 and a preliminary phase 2 study suggested AA may have a role in the neoadjuvant setting before radical prostatectomy is performed in men with early-stage localized high-risk prostate cancer.2 In addition, secondary results from the AFFIRM trial confirmed the superiority of enzalutamide to placebo in men with CRPC following treatment with docetaxel.3

At the ASCO Annual Meeting, de Bono presented new data on secondary outcomes in AFFIRM. Enzalutamide was superior to placebo for the following measures: PSA response, soft tissue objective response, and quality-of-life response as assessed by FACT-P, as well as such indicators of disease progression as rPFS and time to first skeletal-related event. AFFIRM randomized 800 patients to enzalutamide and 399 to placebo. Median age was 69 years. At baseline, both groups were well matched for demographic and disease characteristics. Almost 50% of the group assigned to enzalutamide had received prior hormone therapy compared with 53% of placebo patients; median number of prior chemotherapy regimens was similar between groups. PSA response to enzalutamide was high; 54% of patients in the enzalutamide group had >50% declines in PSA level. Following a prespecified interim analysis, the Independent Data Monitoring Committee recommended that the AFFIRM trial be halted and unblinded, and eligible patients in the placebo arm were allowed to cross over to enzalutamide. Enzalutamide was well tolerated. A greater percentage of patients in the treated group reported fatigue, and 5 patients had seizures versus none with placebo. On August 31, 2012, enzalutamide (Xtandi; Medivation) was approved by the FDA for the treatment of patients with metastatic CRPC who have previously received docetaxel. ● references

“These are the best survival rates we have seen in the postchemotherapy setting.” —Johann S. de Bono, MD, ChB

“These are the best survival rates we have seen in the post-chemotherapy setting,” said Johann S. de Bono, MD, ChB, of the Institute for Cancer Research and the Royal Marsden NHS Foundation Trust, United Kingdom.

1. Ryan CJ, Smith MR, de Bono JS, et al; on behalf of the COU-AA-302 Investigators. Interim analysis (IA) results of COU-AA-302, a randomized, phase 3 study of abiraterone acetate (AA) in chemotherapy-naïve patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract LBA4518. 2. Taplin M-E, Montgomery RB, Logothetis C, et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized highrisk prostate cancer (LHRPC): results of a randomized phase II study. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 4521. 3. de Bono JS, Fizazi K, Saad F, et al; for the AFFIRM Investigators. Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 4519. 4. Scher HI, Fizazi K, Saad F, et al; for the AFFIRM Investigators. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: results from the phase III AFFIRM study. J Clin Oncol. 2012;30 (suppl 5):Abstract LBA1. 5. Scher HI, Fizazi K, Saad F, et al; the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy [published online ahead of print August 15, 2012]. N Engl J Med.

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Evidence-based Results From a 1-Year Trial Evaluating Nplate® (romiplostim) or Medical Standard of Care in Nonsplenectomized Patients With Immune Thrombocytopenia (ITP) A summary of the Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia article previously published.3

mmune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production.1 Many therapies are aimed at reducing platelet destruction.2 Treatments aimed at increasing platelet production, alone or in combination with existing therapies, provide an opportunity to improve outcomes in patients with ITP.2 The thrombopoietin mimetic Nplate® (romiplostim) is an Fc-peptide fusion protein that stimulates platelet production by binding the thrombopoietin receptor, thereby increasing the body’s natural production of platelets.3 Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase their risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts. A summary of the trial that compares Nplate® to medical standard of care (SOC) in patients with ITP published in the New England Journal of Medicine is presented. The design of the trial does not allow for the comparison of Nplate® to the individual treatments received in the SOC arm.

Thrombopoietin Mimetics

Two 6-month, Phase 3 Pivotal Trials 2,5

Thrombopoietin mimetics increase platelet count in patients with chronic ITP and reduce the risk of bleeding.2,4 Nplate®, a thrombopoietin mimetic, increases platelet production by binding to and activating the thrombopoietin receptor, a mechanism analogous to endogenous thrombopoietin.5 In patients who have had an insufficient response to corticosteroids or immunoglobulins, Nplate® may offer the potential for effective maintenance treatment in patients who wish to avoid or defer splenectomy or in whom splenectomy is contraindicated.5,7 Continuous weekly treatment with Nplate® increases platelet counts in many patients who have chronic ITP with an acceptable safety profile.4

The results from the SOC study should be viewed in context with the prior pivotal, prospective, multicenter, randomized, placebo-controlled, international, double-blind phase 3 studies that evaluated Nplate® and placebo, one in splenectomized and one in nonsplenectomized patients. The primary end point was durable platelet response (weekly platelet responses of ≥ 50 × 109/L during 6 or more weeks of the last 8 weeks of treatment; no rescue therapy at any time during study). The secondary end point was overall platelet response (durable plus transient* rates of platelet response). In nonsplenectomized patients: • Durable platelet response was 61% (25/41) of patients on Nplate® versus 5% (1/21) of the control group (P < 0.0001). • Overall platelet response was 88% (36/41) of patients on Nplate® versus 14% (3/21) of the control group (P < 0.0001).

Please see additional Important Safety Information on pages 3 and 4.

Study Design 3 • This was a multicenter, randomized, controlled, 52-week, open-label study designed to assess the efficacy and safety of Nplate® or SOC in adult patients with ITP. • Patients were randomized, in a 2:1 ratio, to receive Nplate® (n=157) or SOC (n=77).

Medical SOC (n=77) Prescribed by investigator according to standard institutional practices or therapeutic guidelines 1-year treatment period

6-month post-treatment safety monitoring period

Nplate® (n=157) Weekly SC injections starting at 3 µg/kg; dose adjustments based on platelet count

End of trial

Nplate or SOC Study Design

Randomization 2:1

• In Nplate® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression from MDS to acute myelogenous leukemia (AML) has been observed. Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. • Additional serious adverse reactions associated with Nplate® are Thrombotic/Thromboembolic Complications, Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis, Worsened Thrombocytopenia after Cessation of Nplate®, and Lack or Loss of Response to Nplate®. • In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction.

ITP diagnosis based on ASH guidelines Platelet count < 50 x 109/L and ≥ 1 prior ITP treatment

Important Safety Information

In splenectomized patients: • Durable platelet response was 38% (16/42) of patients on Nplate® versus 0% (0/21) of the control group (P = 0.0013).2 • Overall platelet response was 79% (33/42) of patients on Nplate® versus 0% (0/21) of the control group (P < 0.0001). In the pivotal trials for Nplate®, prior ITP treatments in the Nplate® and control groups included corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine. Patients receiving corticosteroids, azathioprine or danazol at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies. The recommended starting dose for Nplate® is 1 µg/kg. See the Nplate® prescribing information for complete dosing instructions, including guidelines for dose adjustments. In the pivotal trials, the median dose of Nplate® was 2 µg/kg (25th–75th percentile: 1–3 µg/kg) in the study of nonsplenectomized patients and 3 µg/kg (25th–75th percentile: 2–7 µg/kg) in the study of splenectomized patients.

The recommended starting dose for Nplate® is 1 µg/kg based on actual body weight. Use the actual body weight at initiation of therapy, then adjust the weekly dose of Nplate® by increments of 1 µg/kg until the patient achieves a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 µg/kg. In clinical studies, most patients who responded to Nplate® achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 µg/kg.5 Patients already receiving ITP therapies at baseline (21/157 in Nplate® group; 5/77 in SOC group) could continue receiving these treatments throughout the trial. ASH, American Society of Hematology SC, subcutaneous

© 2012 Amgen, Inc. • © 2012 Green Hill Healthcare Communications, LLC


Platelet Count Over 1 Year 80

200 150 100 50 Nplate®

SOC

0 SOC Nplate®

Incidence of Treatment Failure at 1 Year

60 Patients (%)

Mean (SE) platelet count (109/L)

250

69% 40 20

4 8 12 16 20 24 28 32 36 40 44 48 52 1 n = 72 68 62 59 57 54 53 54 51 51 49 51 48 38 n = 153 150 148 148 141 137 137 135 132 135 126 127 130 122

0

I bars indicate standard errors.

Patient Population 3 • The clinical diagnosis of ITP was based on a platelet count < 150 × 109/L without any other clearly associated cause. • Patients must not have undergone splenectomy. • Patients with a history of ≥ 1 type of therapy for ITP and a pretreatment platelet count of < 50 × 109/L. • A bone marrow–biopsy specimen was required to confirm the diagnosis of ITP in patients > 60 years of age. • Key exclusion criteria were previous splenectomy, active cancer or stem cell disorder, history of cancer, previous exposure to a thrombopoietin mimetic, pregnancy, and lactation. • At the time of enrollment, patients could have been receiving any therapy for ITP, except experimental treatments. • Median duration of treatment for ITP at the time of study entry was approximately 2 years, but 36% of patients (85/234) entered the study after having ITP for a year or less (median duration in this subgroup, 0.25 years). • Treatment groups did not differ significantly

%!0 !-$.,)7%$ .-20.++%$ /%- !"%+ 0)!+ 2. 4!+3!2% /+!2%8 .0 %$)#!+ )- .-1/+%-%#2.,)7%$ $3+2 !2)%-21 )!'-.1%$ )2(

• Incidence of splenectomy. • A patient who had received any study treatment and had then discontinued the study was counted as having had both treatment failure and splenectomy. • Secondary efficacy end points included: • Time to splenectomy • Platelet count • Platelet response (platelet count > 50 × 109/L at any scheduled visit, excluding counts obtained after discontinuation of the randomized treatment or within 8 weeks after receipt of rescue medications) • Safety end points: bleeding events, bloodproduct transfusions, and laboratory results

Study Results 3: Platelet Count Over 1 Year The mean platelet count was higher in the romiplostim group than in the SOC group throughout the treatment period. • Platelet response from week 2 through the end of the 1-year treatment period ranged from 71% (108/152 patients) to 92% (127/138 patients) in the romiplostim group and 26% (16/62 patients) to 51% (26/51 patients) in the SOC group. • Median platelet count was 108 × 109/L to 176 × 109/L in the romiplostim group and 35 × 109/L to 52 × 109/L in the SOC group. • The mean (± standard error) weekly dose was 3.9 ± 2.1 µg/kg.

30% 23/77

11% 18/157 Nplate®

SOC

!2)%-21 )- 2(% /+!2%8 0.3/ %0% ),%1 !1 )*%+6 2. !4% ! +!2%+%2 %1/.-1% !1 (.1% )- 2(% 0.3/ #.-&)$%-#% )-2%04!+ 9

Treatment Failure and Splenectomy The incidence of treatment failure was significantly lower among patients receiving romiplostim (18/157 [11%]) than among those receiving SOC (23/77 [30%], P < 0.001). The time to treatment failure was significantly longer in the Nplate® group than in the SOC group (P = 0.02). Incidence of splenectomy was significantly lower among patients receiving romiplostim (14/157 [9%]) than among those receiving SOC (28/77 [36%], P < 0.001). Time to splenectomy was also significantly longer in the romiplostim group than in the SOC group (P < 0.001). Throughout the study, all patients could receive additional therapies for ITP (including short-term rescue therapies, such as intravenous immune globulin, but excluding other thrombopoietin mimetics and investigational products) if they were deemed medically necessary by the investigator.

Analysis of Additional Treatments During the Study (percentage of patients) 63%

SOC

7%

Immunoglobulins§ Rituximab¶

Nplate®

37%

Corticosteriods‡ with respect to any baseline characteristics. • Median age across the 2 groups was 57 years (with 36% of patients > 65 years of age and 18% > 75 years).

relative risk reduction Odds ratio: 0.31 (95% Cl: 0.15–0.61) P < 0.001

33% 1% 20%

The trial design did not allow for comparison of Nplate® with individual treatments received in the SOC arm. ‡

Primary and Secondary End Points 3 • There were 2 coprimary end points: • Incidence of treatment failure was defined as a platelet count of ≤ 20 × 109/L for 4 consecutive weeks at the highest recommended dose, a major bleeding event, or requirement for a change in therapy (including splenectomy) because of an adverse event (AE) or bleeding symptom.

Azathioprine

Including betamethasone, dexamethasone, methylprednisolone, prednisolone, and prednisone.

1% 9%

Other agentsll

2% 7% 6%

Platelet transfusions#

6%

Danazol

§

Including anti-D immunoglobulin and intravenous immunoglobulin.

Rituximab is not FDA approved for treatment of ITP.

ll

19%

Including vincristine, cyclosporine, tranexamic acid, ascorbic acid, calcium, ethamsylate, pantoprazole, and Expasyl®. (Expasyl® is a registered trademark and entire property of Pierre Rolland.)

#

Including therapeutic and prophylactic transfusions.

16% Patients could receive ≥1 types of SOC therapies, including watchful waiting.

This article was written by Amgen and is a promotional advertisement.


Safety 3 • Headache and fatigue were the most common AEs reported during treatment. • SAEs occurred in 23% of patients (35/154) receiving Nplate® and in 37% of patients (28/75) receiving SOC. • Treatment-related SAEs occurred in 5% of patients (7/154) receiving Nplate® and 8% of patients (6/75) receiving SOC. • Treatment-related SAEs reported in > 1 subject in the Nplate® group included pulmonary embolism (3 subjects) and deep vein thrombosis (2 subjects).3 • Thrombocytopenia was the most common SAE, occurring in 3% of patients (5/154) receiving Nplate® and in 12% of patients (9/75) receiving SOC. • The Nplate® group had significantly lower adjusted incidences of overall bleeding events (P = 0.001) and bleeding events of grade 3 or higher (P = 0.02) as compared with the SOC group. • There were no significant differences between the treatment groups regarding less severe bleeding (P = 0.17). • A total of 41 blood transfusions were administered to 12/154 patients (8%) receiving Nplate®, and 76 blood transfusions were administered to 13/75 patients (17%) receiving SOC. • There were 3 deaths, not considered to be related to treatment, which occurred during the treatment period: 1 in the Nplate® group and 2 in the SOC group.

Rate of bleeding events per 100 patient-weeks

Bleeding Events 1.0 0.8 0.6 0.4 0.2 0

≥ Grade 2 bleeding events

≥ Grade 3 bleeding events

0.69 P = 0.17

67%

0.47

less P = 0.02

0.33

0.11

8 events 10 events 21 events 34 events in 7294 in 3050 in 3050 in 7294 patient-weeks patient-weeks patient-weeks patient-weeks

Nplate® (n=154)

SOC (n=75)

Grade 2 = moderate; grade 3 = severe grade; grade 4 = life-threatening; grade 5 = fatal Rate = Adverse event rate per 100 patient-weeks on study medication. Rate was calculated by dividing the total number of reported events by the total number of patient-weeks and then multiplying by 100.

Indication Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts.

Important Safety Information Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia • In Nplate® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression from MDS to acute myelogenous leukemia (AML) has been observed. • Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.

Thrombotic/Thromboembolic Complications • Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate®. Nplate® should be used with caution in patients with ITP and chronic liver disease. • To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 × 109/L.

Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis • Nplate® administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate®. • In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias. • If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis.

Worsened Thrombocytopenia after Cessation of Nplate ® • In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days. • Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines.

Lack or Loss of Response to Nplate® • Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neu-

tralizing antibodies to Nplate®. • To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO). • Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.

Laboratory Monitoring • Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose. • Obtain CBCs, including platelet counts, weekly for at least two weeks following discontinuation of Nplate®.

Adverse Reactions • In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. • Most common adverse reactions (≥ 5% higher patient incidence in Nplate® versus placebo) were arthralgia (26%, 20%), dizziness (17%, 0%), insomnia (16%, 7%), myalgia (14%, 2%), pain in extremity (13%, 5%) , abdominal pain (11%, 0%), shoulder pain (8%, 0%), dyspepsia (7%, 0%), and paresthesia (6%, 0%). Please see Brief Summary of the Prescribing Information on the next page.

References: 1. Nugent D, McMillan R, Nichol JL, Slichter SJ. Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production. Br J Haematol 2009;146:585-96. 2. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371:395-403. 3. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:1889-99. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:188999. http://www.nejm.org/doi/full/10.1056/NEJMoa1002625. Accessed July 31, 2012. 4. Kuter DJ, Bussel JB, Newland A, et al. Long-term efficacy and safety of romiplostim treatment of adult patients with chronic immune thrombocytopenia (ITP): a final report from an open-label extension study. Blood. 2010;116: Abstract 68. [Presented at 52nd American Society of Hematology Annual Meeting and Exposition; Orlando, FL; December 4-7, 2010.] 5. Nplate® (romiplostim) [prescribing information]. Thousand Oaks, CA: Amgen. 6. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009;113:2161-71. [Erratum, Blood 2009b;113:4822.] 7. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-186.

This article was written by Amgen and is a promotional advertisement.


BRIEF SUMMARY OF PRESCRIBING INFORMATION NplateÂŽ (romiplostim), for subcutaneous injection WARNINGS AND PRECAUTIONS Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical studies with NplateÂŽ. A randomized, doubleblind, placebo-controlled study enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the NplateÂŽ treatment arm. At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with NplateÂŽ or placebo (147 NplateÂŽ: 72 placebo), 11 patients showed progression to AML, including nine on the NplateÂŽ arm versus two on the placebo arm. In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were in the romiplostim treatment arm. Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML, and 20 patients had not progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of NplateÂŽ. In a single-arm study of NplateÂŽ given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up. In addition, in three patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of NplateÂŽ. NplateÂŽ is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from increases in platelet counts with NplateÂŽ use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving NplateÂŽ. NplateÂŽ should be used with caution in patients with ITP and chronic liver disease. To minimize the risk for thrombotic/thromboembolic complications, do not use NplateÂŽ in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of * 50 x 109/L [see Dosage and Administration]. Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis NplateÂŽ administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of NplateÂŽ. In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during NplateÂŽ therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias. If new or worsening morphological abnormalities or cytopenia(s) occurs, consider a bone marrow biopsy to include staining for fibrosis [see Adverse Reactions]. Worsened Thrombocytopenia after Cessation of NplateÂŽ In clinical studies of patients with chronic ITP who had NplateÂŽ discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to NplateÂŽ therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of NplateÂŽ, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions]. Lack or Loss of Response to NplateÂŽ Hyporesponsiveness or failure to maintain a platelet response with NplateÂŽ should prompt a search for causative factors, including neutralizing antibodies to NplateÂŽ [see Adverse Reactions]. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to NplateÂŽ and thrombopoietin (TPO). Discontinue NplateÂŽ if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg. Laboratory Monitoring Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of NplateÂŽ therapy and then monthly following establishment of a stable NplateÂŽ dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of NplateÂŽ [see Dosage and Administration and Warnings and Precautions].

ADVERSE REACTIONS Clinical Studies Experience Serious adverse reactions associated with NplateÂŽ in ITP clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after NplateÂŽ discontinuation [see Warnings and Precautions]. The data described below reflect NplateÂŽ exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. NplateÂŽ was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received NplateÂŽ over an extended period of time. Overall, NplateÂŽ was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving NplateÂŽ and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a * 5% higher patient incidence in NplateÂŽ versus placebo. The majority of these adverse drug reactions were mild to moderate in severity. Table 2. Adverse Drug Reactions Identified in Two Placebo-Controlled Studies Preferred Term Arthralgia Dizziness Insomnia Myalgia 0AININ%XTREMITY Abdominal Pain Shoulder Pain Dyspepsia Paresthesia

NplateÂŽ (n = 84) 26% 17% 16% 14% 13% 11% 8% 7% 6%

Placebo (n = 41) 20% 0% 7% 2% 5% 0% 0% 0% 0%

Among 142 patients with chronic ITP who received NplateÂŽ in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies. Postmarketing Experience The following adverse reactions have been identified during post approval use of NplateÂŽ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. s%RYTHROMELALGIA s(YPERSENSITIVITY s!NGIOEDEMA Immunogenicity As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay. In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (43/537) and the incidence of binding antibody development during NplateÂŽ treatment was 6% (31/537). The incidence of preexisting antibodies to endogenous TPO was 5% (29/537) and the incidence of binding antibody development to endogenous TPO during NplateÂŽ treatment was 4% (21/537). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, two (0.4%) patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug interaction studies of NplateŽ have been performed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of NplateŽ use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. NplateŽ should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Pregnancy Registry : A pregnancy registry has been established to collect information about the effects of NplateŽ use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the NplateŽ pregnancy registry by calling    !-'%.     In rat and rabbit developmental toxicity studies no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred. In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses. Nursing Mothers It is not known whether NplateŽ is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NplateŽ, a decision should be made whether to discontinue nursing or to discontinue NplateŽ, taking into account the importance of NplateŽ to the mother and the known benefits of nursing. Pediatric Use The safety and effectiveness in pediatric patients (< 18 years) have not been established. Geriatric Use Of the 271 patients who received NplateŽ in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment No clinical studies were conducted in patients with renal impairment. Use NplateŽ with caution in this population. Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment. Use NplateŽ with caution in this population. OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue NplateŽ and monitor platelet counts. Reinitiate treatment with NplateŽ in accordance with dosing and administration recommendations [see Dosage and Administration]. Rx Only. Consult package insert for complete Prescribing Information. Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,835,809, 7,189,827, 7,994,117 and 8,044,174, as well as other patents or patents pending. Š 2008-2012 Amgen Inc. All rights reserved. www.nplate.com v5 64256-R2-V1


Prostate Cancer

team Approach enhances Choice of Observation in Men With low-risk prostate Cancer By Alice Goodman

M

en diagnosed with low-risk prostate cancer are more likely to choose active surveillance as their primary treatment if their care is managed by a multidisciplinary team, according to a recent study (Aizer AA, et al. J Clin Oncol. 2012;30:3071-3076). In 2012, about 240,000 men in the United States will be diagnosed with prostate cancer. About 70% will be low risk, but more than 90% of these men will opt for definitive treatment with radiation or radical prostatectomy. Neither of these treatments is superior to active surveillance in reducing prostate cancer–specific mortality. Active surveillance entails observation with moni-

toring for disease progression and initiating curative therapy at the earliest sign of progression. “Efforts to prevent unnecessary treatment are crucial from medical, social, and economic standpoints,” wrote the authors. Multidisciplinary teams provide a balanced view of the risks and benefits of various treatment options, while a single specialist tends to recommend the treatment he or she is trained to deliver, the investigators wrote. Author Jason Efstathiou, MD, Massachusetts General Hospital, Boston, and colleagues analyzed choices made by 701 men with low-risk prostate cancer who were treated at 3 different Boston

area hospitals. Low risk was defined as Gleason score of 6 or less, prostate-specific antigen level of 10 ng/mL or less, and clinical stage T1c or T2a. At baseline, the groups were similar for age, comorbidity score, family history of prostate cancer, race, marital status, and annual income. One-third were managed by a multidisciplinary team of doctors (urologic, radiologic, and medical oncologists), and 43% of this group opted for active surveillance rather than surgery or radiation. By contrast, only 22% of men seen by individual practitioners opted for active surveillance. The proportion of men treated with radiation or prosta-

tectomy declined by about 30% in the active surveillance group. In a multivariate analysis, older age, being unmarried, increased comorbidities, fewer positive cores on biopsy, and consultation with a multidisciplinary team were significantly associated with choice of active surveillance. Efstathiou commented that a visit to a multidisciplinary clinic allowed the patient to hear multiple views about appropriate management choices and for improved informed decision making. He said this was the first study to show that multidisciplinary care may reduce bias of specialists toward the type of care they deliver. ●

Side Effect Management

Chemotherapy-Induced peripheral Neuropathy Increases risk of Falls and physical and Functional problems, especially in Older patients

M

otor toxicities of chemotherapy-induced peripheral neuropathy (CIPN) are likely to lead to falls, deficits in physical performance (PP), and functional losses, according to a substudy of a phase 3 clinical trial in patients with CIPN reported at the 2012 Annual Meeting of the American Society of Clinical Oncology.1 “This study suggests that cancer survivors who have received chemotherapy should be evaluated over time not only for CIPN toxicities, but also for physical functioning and falls,” cited Supriya Gupta Mohile, MD, of the University of Rochester Medical School in Rochester, New York. Mohile suggested that balance and mobility training should be considered during chemotherapy to reduce the risk of falls. Falls and PP problems are common in cancer patients, and older patients are more likely to fall than age-matched peers without cancer. Falls are a significant cause of morbidity. Prior to this study, data were limited on the relationships between CIPN and falls, PP deficits, and functional problems. The study enrolled 461 patients who participated in a randomized, doubleblind, placebo-controlled clinical trial

www.TheOncologyPharmacist.com

to evaluate a topical cream in cancer survivors with CIPN. All participants had completed chemotherapy, were not on medications for pain or neuropathy, and had self-reported painful CIPN at baseline, as reflected by daily pain scores of >4 on an 11-point scale from 0

Falls and physical performance problems are common in cancer patients, and older patients are more likely to fall than age-matched peers without cancer.

to 10 for severity. Patients also completed sensory and motor subscales of the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for neuropathy toxicities and self-reported falls. A primary outcome measure was selfreported falls in the previous 3 months. A PP deficit was defined as finding it difficult or being unable to perform any

of 6 physical tasks, including lifting objects, walking a quarter of a mile, reaching arms above shoulder level, and stooping, crouching, or kneeling. Functional losses were defined as having difficulty or being unable to perform any of 5 functional tasks: managing money, bathing, light housework, walking across the room, and shopping. Patients who reported falls and/or PP deficits were compared with those who did not. A logistic regression analysis was performed to examine the association of baseline characteristics and CIPN toxicities with falls, PP deficits, and functional losses. Among the study population, 11.9% experienced recent falls, 58.6% reported a PP deficit, and 26.6% reported a functional loss. Patients who reported falls and/or PP deficits were significantly more likely to be older (P = .02), female (P = .03), have less education (P <.01), and to have higher severity of CIPN toxicities: pain (P <.001), sensory (P <.001), and motor (P <.001) neuropathy (in an unadjusted analysis). Groups with falls and/or PP deficits and without these factors did not differ according to cancer and chemotherapy history. An analysis adjusted for age, gender, race, ethnicity, marital status, educa-

tion, history of taxane therapy, previous radiation therapy, cancer diagnosis, pain, and sensory neuropathy found factors independently and significantly associated with falls were a history of breast cancer (P = .045) and motor neuropathy (P = .006). Factors independently associated with having a PP deficit were previous surgery (P = .013) and motor neuropathy (P <.001). Factors that were significantly associated with functional losses included nonwhite race (P = .01), Hispanic ethnicity (P = .048), PP deficit (P <.0001), and motor neuropathy (P = .0001). The study was limited by its heterogeneous cancer sample; its cross-sectional nature, which did not allow for assessment of causality and temporal relationships; and the self-reporting of CIPN toxicities. Nevertheless, the study confirmed that CIPN toxicities, primarily motor related, are significantly associated with falls, PP deficits, and functional losses.—AG ● reference 1. Mohile SG, Fan L, Gewandter JS, et al. Falls, physical performance deficits, and functional losses in cancer survivors with chemotherapy-induced neuropathy (CIPN): a University of Rochester CCOP study. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 9014.

sEPTEmbER 2012 I VOL 5, NO 6

23


Immune Thrombocytopenia

Considerations for treatment of Immune thrombocytopenia By Kathy Hogan Edwards, PharmD, BCPS Clinical Pharmacy Specialist Hollings Cancer Center Medical University of South Carolina Charleston, South Carolina

SG is a 29-year-old female, recently married, who was referred to the hematology clinic due to a platelet count of 11 × 109/L. Additionally, she recently had 3 nosebleeds and heavy menstrual bleeding. She had dismissed them as another sign of stress from her hectic schedule, including her recent wedding, teaching full-time, and evening graduate school. A detailed and extensive review of her history and physical, serum chemistries, CBC, and peripheral smear does not reveal any potential underlying causes for her thrombocytopenia. She is negative for HCV and HIV, and her blood type is AB negative. Because her platelet count is <100 × 109/L without an identifiable cause, she is diagnosed with primary immune thrombocytopenia. What are considerations for appropriate first-line therapy? Regardless of the stage of immune thrombocytopenia (ITP), previously referred to as idiopathic thrombocytopenic purpura, treatment decisions must take into account an individual’s preferences as well as comorbidities, bleeding, the urgency to increase the platelet count, and potential advantages and adverse effects of each treatment. The goal of therapy is to prevent major bleeding, and because most major bleeds are associated with platelet counts <20-30 × 109/L, treatment is generally instituted at a platelet level <30 × 109/L. In this patient with newly diagnosed (within 3 months of diagnosis) ITP requiring initial therapy, evidence-based practice guidelines suggest prednisone 1 mg/kg daily for 21 days with a subsequent taper.1 Other acceptable options include dexamethasone 40 mg PO daily for 4 days, or intravenous immunoglobulin (IVIg) 1 g/kg × 1; however, the longer course of corticosteroids is preferable due to longer response. Though anti-D Ig has demonstrated efficacy, SG would not be a candidate because she is Rh-negative. Anti-D therapy also carries a risk of severe hemolysis and should be used only in carefully selected patients.1

As SG did not have any contraindications to steroid therapy (eg, uncontrolled diabetes mellitus, active infection), she received a 21-day course of prednisone, which was quickly tapered over the subse-

24

sEPTEmbER 2012 I VOL 5, NO 6

quent week. One month after starting therapy, her platelet count increased to >100 × 109/L, with no further bleeding episodes for the next 2 months. At that time, her platelet count had dropped to 9 × 109/L. She received IVIg 1 g/kg × 1, which increased her platelet count to 35 × 109/L one week later. Does she need further therapy, and if so, what options does she have at this time?

strength of these recommendations is lower (grade 2C).1 For several decades, splenectomy has been considered the gold standard for second-line treatment of ITP. The major advantage of a splenectomy is that approximately two-thirds of patients achieve a long-term response of at least 5 to 10 years.3 Laparoscopic splenectomy is associated with fewer

Treatment decisions must take into account an individual’s preferences as well as comorbidities, bleeding, the urgency to increase the platelet count, and potential advantages and adverse effects of each treatment.

Because of her young age, lack of recent bleeding episodes, and platelet count >30 × 109/L, SG does not receive further treatment, but again receives extensive counseling regarding monitoring for signs and symptoms of bleeding and use of bleeding precautions. Though IVIg rapidly increases the platelet count, response is not durable, typically lasting only 2 to 4 weeks.2 SG begins wearing a stylish medical alert bracelet, a present from her husband. Four months later she reports mucosal bleeding (nosebleed and gum bleeding), and her platelet count has dropped to 7 × 109/L. She and her husband are very anxious and would like to know her options for treatment at this time. The 2011 American Society of Hematology evidence-based guidelines recommend either a splenectomy for patients failing corticosteroid therapy (grade 1B) or a thrombopoietin receptor agonist (romiplostim or eltrombopag) if the patient has relapsed after splenectomy or has a contraindication to splenectomy and has failed ≥1 other therapy (1B). Other options include romiplostim or eltrombopag in a patient who has failed ≥1 other therapy and has not undergone splenectomy, or rituximab in a patient who has failed ≥1 other therapy such as corticosteroids, IVIg, or splenectomy, though the

complications than open splenectomy and is often the preferred approach in appropriate patients. The major risks associated with splenectomy include bleeding and infections. Additional complications include transfusion-related adverse events, thrombosis requiring anticoagulant therapy, adhesions/obstruction, hernia formation, and nerve palsies. To minimize risk of infection, all patients should receive recommended immunizations preoperatively (at least pneumococcal, meningococcal, and Haemophilus influenzae) as well as extensive counseling regarding the need for early detection and treatment for infections.4 Because patients may spontaneously go into remission, splenectomy may be deferred until 1 to 2 years after diagnosis, but there are no specific recommendations for optimal timing. This patient is young and without comorbidities, and she would likely tolerate a splenectomy.

Though splenectomy is not a contraindication, SG does not want to undergo surgery at this time, due to her busy work and school schedules. She and her husband have done much research on the Internet and have many questions about the potential benefits and risks associated with the thrombopoietin receptor agonists. She is 7 months postdiagnosis and is considered to have persistent ITP, as she has not had a spontaneous remission or a

complete response to therapy. What are considerations before initiating romiplostim or eltrombopag therapy? Both romiplostim and eltrombopag have demonstrated efficacy in both splenectomized and nonsplenectomized patients.5,6 In a prospective, randomized, open-label study of 234 patients with ITP without splenectomy, Kuter and colleagues assigned 157 patients to weekly romiplostim and 77 patients to standard of care for 52 weeks.6 The treatment in the standard-of-care arm was left to the investigator’s decision. The group receiving romiplostim exhibited a significantly lower incidence of treatment failure than those receiving standard of care (11% vs 30%, respectively; P <.001), and they were less likely to require a splenectomy (9% vs 36%, respectively; P <.001). The rate of platelet response (to a level >50 × 109/L) was 2.3 times that in the standard-of-care arm, and fewer patients required blood transfusions (8% vs 17%). At any given time between weeks 2 and 52, 71% to 92% of patients had an adequate platelet response. This study did allow short-term treatment with other therapies (most commonly glucocorticoids), which was required in 44% of the romiplostim group versus 79% of those receiving standard of care.

Both romiplostim and eltrombopag have demonstrated efficacy in both splenectomized and nonsplenectomized patients. Despite the evidence that romiplostim is effective, there are important considerations before initiating therapy. Romiplostim is given as a subcutaneous injection and requires weekly platelet counts until dosage is stabilized. For some, this may be an inconvenience or burden that would rule out this therapy. Compliance is particularly important, because upon discontinuation of romiplostim, the platelet count will likely drop, in some cases to levels lower than when initiated. Cost is usu-

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Immune Thrombocytopenia ally an additional factor, and depending on the insurance coverage and copays, the patient may be responsible for extraordinary out-of-pocket copays. There are excellent patient assistance programs to help qualified patients with expenses, and these should be fully investigated before ruling out this therapy based on cost alone. For most people receiving romiplostim, the dose usually stabilizes after the first 12 weeks or so, and frequency of platelet counts may be extended to once every 4 weeks. In an open-label extension study, 63% of patients were stabilized on a dosage and were able to self-administer romiplostim at home.7 Although this would provide a convenient option for appropriate patients, self-administration of romiplostim is not approved by the US Food and Drug Administration at this time.8 From 2008 to 2011, romiplostim was available only through the restrictive Nplate NEXUS (REMS) Program, which required enrollment of the patient, prescriber, and pharmacy. Since termination of the program in 2011, however, any prescriber or institution can now order romiplostim, allowing for greater flexibility for patients to obtain treatment.9 In the short term, romiplostim is well tolerated, with primary side effects being headache, fatigue, arthralgia, insomnia, myalgia, and dyspepsia.8 A significant concern is formation of reticulin and development of fibrosis in the bone marrow; the long-term incidence and significance of this is unknown at this time.8 Other serious, yet rare, potential risks include development of thrombosis from elevated counts. For these reasons, romiplostim should be used only at the lowest dosage necessary to minimize bleeding by maintaining the platelet count >50,000 × 109; it is not the goal of romiplostim therapy to normalize the platelet count.8 Another concern for this patient is that romiplostim is not indicated during pregnancy and should be discontinued beforehand. Romiplostim crosses the placenta, though the effects on the fetus are unknown at this time.8 Current evidence-based guidelines suggest treatment with corticosteroids or IVIg during pregnancy and lactation.1 There are a multitude of additional considerations regarding ITP and pregnancy and delivery, and these should be discussed and planned for with experienced physicians. In addition to romiplostim, several other second-line treatment options are available to treat ITP, including eltrombopag, rituximab, azathioprine, cyclosporine A, cyclophosphamide, mycophenolate mofetil, danazol, dapsone, vinblastine, and vincristine.1,2 Eltrombopag, an oral agent taken once daily, also demonstrates efficacy and

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toxicities similar to romiplostim, with the exception of an increased incidence of elevated liver function tests, requiring close monitoring.1,3 Rituximab, a CD20 monoclonal antibody typically

When deciding on a course of therapy, the pros and cons of each option should be discussed with the patient, and a realistic plan should be formulated. administered once weekly for 4 weeks, also has demonstrated efficacy, with reports of long-term response. Concerns with rituximab include infusion reactions and increased infections.3 Many of the studies for the additional agents are small and nonrandomized, using many different inclusion, exclusion, and assessment criteria. Thus, the heterogeneity of the data makes it difficult to con-

fidently predict outcomes with many of these treatment options. Fortunately for patients with ITP, there are more options than ever for treatment. When deciding on a course of therapy, the pros and cons of each option should be discussed with the patient, and a realistic plan should be formulated. Treatment decisions may be heavily influenced by patient preferences, as well as lifestyle, socioeconomic, and other practical considerations, in addition to existing comorbidities. As we do not have a means to predict who will have the best responses with the least toxicity, the approach to ITP treatment remains individualized.3

SG and her husband elect to begin therapy with romiplostim. She works near the clinic, and brief weekly visits will not be a burden, particularly if she has her platelet count drawn the day before her injection, omitting the need to wait for results. Her insurance covers the costs with minimal copay. The couple are diligent about using effective contraception and do not plan to have children for a few years. They continue to hope she will achieve a remission and that the romi-

plostim will buy them this time to perhaps avoid splenectomy, to plan for splenectomy at a better time, or to await for additional treatment options. ● references 1. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011; 117(16):4190-4207. 2. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115 (2):168-186. 3. Ghanima W, Godeau B, Cines DB, et al. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120(5):960-969. 4. Stasi R, Newland A, Thornton P, et al. Should medical treatment options be exhausted before splenectomy is performed in adult ITP patients?: a debate. Ann Hematol. 2010;89(12):1185-1195. 5. Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365(8):734-741. 6. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363(20):1889-1899. 7. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161-2171. 8. Nplate [package insert]. Thousand Oaks, CA: Amgen Inc; December 2011. 9. Amgen Inc. Important prescribing information: Nplate® (romiplostim) REMS Program (Nplate® NEXUS Program): elimination of prescriber, institution, and patient enrollment requirements to prescribe and receive Nplate; serious risks associated with Nplate [letter]. http://www.amgen.com/pdfs/products/Nplate_ REMS_DHCP_12-06-2011.pdf. Published December 6, 2011. Accessed September 4, 2012.

SAVE THE DATE SECOND ANNUAL CONFERENCE

July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

sEPTEmbER 2012 I VOL 5, NO 6

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Noteworthy Numbers Although the 10-year survival rate for prostate cancer is 98%, the disease is still the second leading cause of cancer death for men in the United States. With each new treatment developed, vaccine examined, and screening test created, scientists draw closer to the day when the survival rate for all patients with prostate cancer will be 100%. The following numbers reflect today’s prostate cancer statistics.

The ratio is 1:6 that a man will be diagnosed with prostate cancer in his lifetime.

More than 80% of those prostate cancer diagnoses are made in patients aged 65 years or older.

Overall, approximately 241,740 men in the US will be diagnosed with prostate cancer in 2012.

Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

Topics include: • Newly Diagnosed Patients • Maintenance Settings • Transplant-Eligible and -Ineligible Patients • Retreatment Settings • Bone Health

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.

Accreditation These activities will be accredited for physicians, nurses, and pharmacists. For complete accreditation information, please refer to each activity. This activity is jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC.

COEAsize71912AskExperts

sEPTEmbER 2012 I VOL 5, NO 6

Thus, the number of deaths from prostate cancer in 2012 in the US is estimated to be 28,170. Compared with white men, African American men are more likely to be diagnosed with prostate cancer and have a mortality rate 2 times higher. As researchers strive for a cure, prostate cancer treatments—including new drugs, surgical approaches, and improved radiotherapy—continue to expand. Due to these medical advances and others, there are more than 2.5 million men diagnosed with prostate cancer in the US who are still alive today. However, estimates show that about 20% to 30% of men will relapse 5 years after initial treatment and begin to show signs of disease recurrence. Therefore, most doctors recommend prostate-specific antigen tests about every 6 months for the first 5 years after treatment, and at least yearly after that.

ALL NEW CONTENT FOR 2012

26

The ratio of men who will die of prostate cancer is 1:36.

Sources http://www.cancer.net/cancer-types/ prostate-cancer/statistics; http://www. cancer.org/Cancer/ProstateCancer/Detailed Guide/prostate-cancer-key-statistics; http:// www.cancer.net/cancer-types/prostatecancer/risk-factors-and-prevention; http:// seer.cancer.gov/statfacts/html/prost.html; http://www.pcf.org/site/c.leJRIROrEpH/b.582 2791/k.1DC2/Recurrence.htm; http://www. cancer.org/Cancer/ProstateCancer/Detailed Guide/prostate-cancer-after-follow-up.

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w www.BMSAccessSupport.com ww.BMSAccess Support.com Bristol-Myers Squibb Oncology is committed to helping appropriate patients get access to our medications by providing reimbursement support services for healthcare professionals. The ac accurate curate ccompletion of reimbursement or coverage-related documentation is the responsibility of the healthcare provider and patient. Bris Bristol-Myers tol-Myers Squibb and its agents make mak ma no guarantee regarding reimbursement for any service or item. Bris Bristol-Myers tol-Myers Squibb | © 2012 Bristol-Myers Bristol-Myers Squibb; All rights reserved. reserved. | ONUS12UBPI09702 03/12


CONTINUING EDUCATION SEPTEMBER 2012 • VOLUME 4 • NUMBER 2

4th Annual

CONSIDERATIONS

Lymphoma

IN

ASK THE EXPERTS: Follicular Lymphoma LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

According to recent estimates from the American Cancer Society, approximately 70,130 individuals will be diagnosed with non-Hodgkin lymphoma (NHL) in 2012 and about 18,940 deaths will be attributed to the disease. There has been significant progress in the treatment of these hematologic malignancies, including the development and approval of new, highly effective therapies. However, more progress is needed and numerous questions remain unanswered regarding the application and interpretation of recent clinical advances. The goal of our 4th annual “Considerations in Lymphoma” newsletter series is to provide clinicians with the latest evidence-based strategies for managing NHL in the era of novel agents. To address the needs of key members of the interdisciplinary team, frequently asked questions have been posed to physicians, midlevel providers, and pharmacists from leading cancer centers specializing in the treatment of lymphoma. In this second issue, experts from Winship Cancer Institute at Emory University discuss the effective management of follicular lymphoma. It is our hope that the insight, knowledge, and professional experience offered by these professionals will facilitate the optimal care of your patients with NHL.

Sincerely, Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

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

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

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

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

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

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

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

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CONSIDERATIONS IN LYMPHOMA Sponsor This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with follicular lymphoma. Educational Objectives Upon completion of this activity, the participant will be able to: • Review current and novel treatment approaches for optimizing clinical outcomes in patients with follicular lymphoma (FL) • Summarize expert guideline recommendations and clinical trial data to determine appropriate treatment plans for patients with newly diagnosed and relapsed/refractory FL • Formulate strategies for incorporating consolidation and maintenance therapy in appropriate patients with FL • Discuss clinical issues of importance in the treatment paradigm for FL, including the timing of initial therapy, the role of transplantation, and the management of adverse events Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12031.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or cgusack@mlicme.org. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accor-

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

and has received research support from Celgene, Gilead Sciences, Janssen Biotech, and Millennium: The Takeda Oncology Company. Loretta Nastoupil, MD, is a consultant for Genentech/Roche. Lisa Anderson, RN, BSN, OCN, has nothing to disclose.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-12-027-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Ryan Sims, CRNA, MS, MLI Reviewer, has nothing to disclose. Shelley Chun, PharmD, MLI Reviewer, has nothing to disclose.

Nassoma King, PA-C, has nothing to disclose. *Content will include non–FDA-approved uses. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred. Agenda: 1 hour Articles/Commentaries: 45 minutes Evaluation/Posttest: 15 minutes Date of original release: September 14, 2012 Valid for CME/CE credit through: September 14, 2013

SCAN HERE to Download the PDF or Apply for Credit.

Faculty Disclosures Stephanie A. Gregory, MD, is on the advisory board for Genentech/ Roche, and Spectrum Pharmaceuticals, and on the data safety monitoring board for Genentech/Roche. *Christopher R. Flowers, MD, MS, is a consultant for Celgene, Genentech/Roche, and Millennium: The Takeda Oncology Company,

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New Treatment Paradigms in Follicular Lymphoma Christopher R. Flowers, MD, MS 1 and Loretta Nastoupil, MD 2 1 Associate Professor of Hematology and Medical Oncology, Emory School of Medicine, Winship Cancer Institute, Atlanta, GA; 2 Hematology/Oncology Fellow, Emory University, Winship Cancer Institute, Atlanta, GA

Introduction Over the past several years, the treatment paradigm for patients with follicular lymphoma (FL) has undergone significant changes, with the development of effective new agents that are now being used in the frontline, maintenance, and relapsed settings. Although these new therapies have led to improvements in patient outcomes, numerous questions remain regarding their optimal use. In this article, Christopher Flowers, MD, MS and Loretta Nastoupil, MD, discuss results from recent clinical trials evaluating novel agents and combination regimens for FL and provide their professional insights on future directions related to the management of this disease.

Is there a standard approach to the initial treatment of patients with FL?

The American Cancer Society estimates that 70,130 new cases of nonHodgkin lymphoma (NHL) and 18,940 NHL-related deaths will occur in 2012 in the United States.1 FL is the second most frequently occurring NHL subtype worldwide, with an increasing incidence in Western nations over the

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last 2 decades.2 It accounts for approximately 22% of all NHLs.2 Most patients with FL have stage III or IV disease at the time of diagnosis.3,4 Depending on stage and presenting characteristics, there are numerous available options for the initial management of FL. These include observation (ie, watchful waiting), radiation alone, single-agent chemotherapy, singleagent rituximab, and rituximab-chemotherapy combinations (ie, immunochemotherapy).5 According to data from the National LymphoCare Study (NLCS), there is no single standard of care for frontline management of FL in the United States.6 Stage I/II FL is often managed with radiation therapy, based on observational studies indicating long-term disease-free survival for select patients.5 For example, a British National Lymphoma Investigation study reported that, following radiation therapy for stage I FL, relapse was rare after 10 years of follow-up.7 However, emerging data on practice patterns from the NLCS suggest that other management strategies for patients with localized disease may produce outcomes similar to those achieved with radiation.8 Regarding stage III/IV disease, preliminary NLCS data also indicate that outcomes for patients with high-risk scores on the Follicular Lymphoma International Prognostic Index (FLIPI) differ depending on the type of immunochemotherapy selected.9,10 For high-risk FLIPI patients, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves progression-free survival (PFS) and overall survival (OS) compared with rituximab plus cyclophosphamide, vincristine, and prednisone (RCVP).9,10 A third combination, rituximab plus fludarabine, produces a significantly longer PFS and time to next treatment compared with R-CVP; however, it is also associated with more frequent treatment discontinuation.10 The

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CONTINUING EDUCATION

Figure. Comparison of immunochemotherapy regimens for frontline therapy of advanced FL: results of FOLL05.12

100

P=0.021

P=0.007

P=0.969

98% 95% 93%

Patients (%)

80 60 40

64%

R-CVP R-CHOP R-FM

61%

46%

20 0

3-Year TTF

3-Year OS

FL indicates follicular lymphoma; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, prednisone; R-FM, rituximab, fludarabine, mitoxantrone; TTF, time to treatment failure.

above findings have been corroborated by a secondary analysis of the Primary Rituximab and Maintenance (PRIMA) trial, which reported that R-CHOP produces both higher response rates and longer PFS than does R-CVP, with comparable tolerability.11 Recent findings from the FOLL05 study, a clinical trial evaluating frontline immunochemotherapy regimens, provided a definitive comparison.12 In this study, previously untreated patients with advanced-stage FL (N=534; 178/arm), the majority of whom had high-risk FLIPI scores, were randomly assigned to receive R-CVP, R-CHOP, or rituximab plus fludarabine and mitoxantrone (R-FM), with no maintenance therapy. Significant differences between regimensâ&#x20AC;&#x201D;favoring R-CHOP and R-FMâ&#x20AC;&#x201D;were observed in terms of 3-year time to treatment failure (TTF), the primary endpoint (Figure). The trial also showed superior 3-year PFS with R-CHOP and R-FM compared with R-CVP; 3-year OS rates, on the other hand, were comparable among groups. Unfortunately, R-FM was associated with a higher rate of grade 4 neutropenia than R-CVP or R-CHOP (64%, 28%, and 50%, respectively). Rummel and colleagues investigated a regimen of bendamustine plus rituximab (BR) versus R-CHOP for indolent lymphomas (FL and other subtypes, N=549), with favorable outcomes.13,14 At a median follow-up of 45 months, median PFS was 69.5 in the BR group versus 31.2 months in the R-CHOP group, representing a significant prolongation of PFS with BR (P<.001).14 In the FL subgroup, PFS benefit was independent of FLIPI risk.14 In comparison to R-CHOP, BR was associated with less hematologic toxicity and no alopecia greater than grade 1.13 No significant difference in OS was reported between groups, although the authors suggest that interpretation of OS may be confounded by the fact that 21% of patients treated with R-CHOP also received BR as a salvage treatment.14 Although the FL cohort undergoing collection in this trial was small, results showed that stem cells could be harvested adequately from patients treated with either regimen. In addition, the occurrence of second malignancies, including myelodysplastic syndromes and acute myeloid leukemia, were similar in both groups. What are the latest data on maintenance and consolidation strategies in FL?

Results from the PRIMA trial showed significant improvements in PFS with rituximab maintenance versus observation following first-line induction with a

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sEPTEmbER 2012 I VOL 5, NO 6

variety of immunochemotherapy regimens.15 Although BR was not one of the induction regimens offered in PRIMA, an ongoing trial by the Eastern Cooperative Oncology Group (ECOG) is evaluating the safety and efficacy of this combination, followed by maintenance rituximab with or without lenalidomide.16 This randomized phase 2 trial (ECOG E2408) is enrolling high-risk patients with FL who will be randomized to either BR followed by rituximab maintenance; bortezomib, bendamustine, and rituximab (VBR) followed by rituximab maintenance; or BR followed by maintenance with lenalidomide plus rituximab (RR).16 Study results should be available for analysis by August 2016. The phase 3 ECOG 4402 RESORT trial was designed to determine whether a maintenance rituximab strategy following induction rituximab could improve TTF compared with a rituximab retreatment strategy in patients with low tumor burden FL.17 At 3 years of follow-up, 95% of patients receiving maintenance rituximab and 86% of patients randomized to rituximab retreatment remained free of cytotoxic chemotherapy. However, the authors reported that rituximab retreatment was as effective as maintenance rituximab in terms of TTF, which was the primary endpoint of this study, and was the preferred strategy for this patient population. Radioimmunotherapy (RIT), which combines a radiation-emitting radionuclide with an antibody, continues to be evaluated as consolidation in FL. In the FIT trial, 414 patients with advanced-stage FL, who had achieved a complete response (CR)/unconfirmed complete response (CRu) or partial response (PR) to frontline chemotherapy (with or without rituximab), were randomized to either 90Y-ibritumomab tiuxetan (90Y-IT) or observation. In this trial, only 31 patients received rituximab-based frontline therapy.

Despite the substantial improvements in PFS with frontline immunochemotherapy and maintenance regimens, nearly all patients with FL eventually relapse.

Patients in the 90Y-IT consolidation arm had a high conversion rate from PR to CR/CRu (77%) and a high overall CR rate (89%). RIT consolidation also significantly prolonged median PFS compared with no further treatment in patients who were responsive to frontline therapy.18 For all patients, at 8 years of follow-up, 41% who received consolidation were still free of relapse compared with 22% in the control group. There was no statistically significant difference between groups regarding the occurrence of secondary malignancies. There was also no difference in OS. What treatment options are available for patients in the relapsed setting?

Despite the substantial improvements in PFS with frontline immunochemotherapy and maintenance regimens, nearly all patients with FL eventually relapse. Therefore, strategies aimed at treating relapsed disease are the focus of numerous investigations. Allogeneic stem cell transplantation (alloSCT) is the only approach that is demonstrably curative.5 However, it carries significant morbidity and mortality risks and is therefore reserved for young, highly motivated patients with relapsed or resistant FL. Alternatively, reduced intensity conditioning (RIC) regimens are associated with lower transplantrelated mortality. For example, single-center studies and registry analyses indicate that long standing disease control can be achieved in 40% to 75% of patients with FL following RIC and allo-SCT.19 Therefore, this appears to be a promising approach for select populations of patients.19,20

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CONSIDERATIONS IN LYMPHOMA

Regimens using molecularly targeted agents, such as bortezomib and lenalidomide, have also emerged as useful options in the management of relapsed FL. For example, in the phase 2 VERTICAL trial, treatment with VBR was shown to be active in previously treated patients, producing an 88% overall response rate (ORR), a 53% CR rate, and a median PFS of 14.9 months.21 A randomized trial in recurrent FL from the Cancer and Leukemia Group B (CALGB 50401) reported that RR yielded a greater response rate and a longer event-free survival than single-agent rituximab (Table).22 In addition, several novel antibody therapies are being studied in FL. Recent trials include a phase 1/2 study of veltuzumab in relapsed/refractory B-cell NHL, including 55 FL patients, showing good response with no adverse events grade 3 or higher, despite short infusion times.23 Subcutaneous dosing of this agent is also being explored.24 Ofatumumab has shown activity in patients with rituximab-refractory FL25 and has also yielded promising results in frontline use with CHOP.26 It is still uncertain as to whether the efficacy of adding an antibody to chemotherapy is a class effect common to all B-cell–targeted antibodies. This question will remain unanswered pending randomized trials comparing the monoclonal antibody rituximab to other antibodies plus chemotherapy. In addition, defining the mechanisms of action and resistance for emerging antibodies across lymphoma subtypes will become increasingly important. Another intriguing approach to the treatment of FL is the use of drugs that target B-cell receptor signaling. CAL-101 (GS-1101) is an orally bioavailable, small-molecule inhibitor that selectively targets phosphatidylinositol 3kinase-delta, which regulates survival and proliferation of normal and malignant B cells.27 An early phase 1 study of this inhibitor demonstrated substantial clinical activity in patients with hematologic malignancies.27 In a subsequent phase 1 study that evaluated CAL-101 in combination with rituximab, bendamustine, or both drugs in patients with extensively pretreated indolent NHL, all evaluable patients had reductions in lymphadenopathy, resulting in an ORR of >65% for all regimens.7 CAL-101 is thus an attractive agent, given its reported favorable safety profile28 and lack of overlapping toxicity, allowing delivery at a full single-agent dose even when coadministered with immunochemotherapy in heavily pretreated patients. PCI-32765 is an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase, a downstream mediator of B-cell receptor signaling.29 A phase 1 study of PCI-32765 in patients with relapsed/refractory B-cell malignancies reported a 43% ORR.29 Durable responses occurred at all dose levels and across various histologic subtypes, irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase levels, or disease burden. With its good safety profile and lack of cumulative hematologic toxicities, PCI-32765 warrants further studies in patients with FL. It is hoped that these studies, along with those of other novel agents, will reveal new strategies that continue to enhance outcomes in FL. ◆ References 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. 2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma: The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909-3918. 3. Smith SM. What is the best strategy for incorporating new agents into the current treatment of follicular lymphoma? ASCO Educational Book. 2012:481-487. 4. Solal-Céligny P, Roy P, Colombat P, et al. Follicular Lymphoma International Prognostic Index. Blood. 2004;104:1258-1265. 5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-Hodgkin’s Lymphoma. Version 3.2012. www.nccn.org. Accessed May 14, 2012. 6. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the National LymphoCare Study. J Clin Oncol. 2009;27:1202-1208. 7. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, Anderson L, Linch DC. Clinical stage 1 non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer. 1994;69:1088-1093. 8. Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study [published online ahead of print August 20, 2012). J Clin Oncol. doi:10.1200/JCO.2011.40.6546. 9. Nastoupil L, Sinha R, Byrtek M, et al. A comparison of the effectiveness of first-line chemoim-

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Table. Efficacy and Tolerability of Lenalidomide Alone or With Rituximab in Recurrent FL: Results of CALGB 5040122 Regimens

Lenalidomide

Lenalidomide + Rituximab

P Value

OR rate

49%

75%

NR

CR rate

13%

32%

NR

1.2 years

2.0 years

.0063

49% 16% 9% 16%

52% 19% 14% 4%

Median EFS Grade 3/4 AEs • Overall • Neutropenia • Fatigue • Thrombosis

NS

AEs indicates adverse events; CALGB, Cancer and Leukemia Group B; CR, complete response; EFS, event-free survival; FL, follicular lymphoma; NR, not reported; NS, not significant; OR, objective response.

munotherapy regimens for follicular lymphoma (FL) used in the United States. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 97. 10. Nastoupil L, Sinha R, Byrtek M, et al. Effectiveness of first-line chemoimmunotherapy regimens for patients diagnosed with follicular lymphoma (FL) in the US: data from the National LymphoCare Study (NLCS). Haematologica (EHA Annual Meeting Abstracts). 2012;97:Abstract 0800. 11. Morschhauser F, Seymour J, Feugier P, et al. Impact of induction chemotherapy regimen on response, safety and outcome in the PRIMA Study. Ann Oncol (ICML Annual Meeting Abstracts). 2011; 22(suppl 4):Abstract 022. 12. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8006. 13. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405. 14. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 3. 15. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42-51. 16. National Cancer Institute. Bendamustine hydrochloride and rituximab with or without bortezomib followed by rituximab with or without lenalidomide in treating patients with high-risk stage II, stage III, or stage IV follicular lymphoma (E2408). www.clinicaltrials.gov. Accessed August 10, 2012. 17. Kahl BS, Hong F, Williams ME, et al. Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): a randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Blood (ASH Annual Meeting Abstracts). 2011;118:LBA 6. 18. Morschhauser F. Y-90 Ibritumomab tiuxetan consolidation in follicular lymphoma: the 7-year update of the FIT trial. Oral presentation at: 17th Congress of the European Hematology Association (EHA); June 14-17, 2012; Amsterdam, the Netherlands. 19. Dreger P. Role of allotransplantation for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Ann Oncol. 2011;22(suppl 4):iv36-iv39. 20. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008;111;5530-5536. 21. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389-3395. 22. Leonard J, Jung S-H, Johnson JL, et al; Alliance for Clinical Trials in Oncology. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8000. 23. Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol. 2009;27:3346-3353. 24. Negrea GO, Elstrom R, Allen SL, et al. Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin’s lymphoma. Haematologica. 2011;96:567-573. 25. Czuczman M, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119:3698-3704. 26. Czuczman MS, Hess G, Gadeberg OV, et al. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157:438-445. 27. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 , in patients with relapsed or refractory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 1777. 28. de Vos S, Schreeder MT, Flinn IW, et al. A phase 1 study of the selective phosphatidylinositol 3kinase-delta (PI3K ) inhibitor, CAL-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 2699. 29. Fowler N, Porte Sharman J, Smith SM, et al. The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity in patients with relapsed/refractory B-cell malignancies: results from a phase I study. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 964.

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Managing Treatment-Related Adverse Events in Follicular Lymphoma Lisa Anderson, RN, BSN, OCN Clinic Nurse Emory Bone Marrow and Stem Cell Transplant Center Winship Cancer Institute, Atlanta, GA

Introduction Follicular lymphoma (FL), one of the most common forms of nonHodgkin lymphoma (NHL), comprises approximately 1 in 5 of all cases of the disease.1 FL is slow growing and incurable, and it typically must be treated over a period of several years. As a result, effective management of patients requires that nurses be aware of the latest treatment approaches as well as effective strategies for the prevention and management of adverse events (AEs). In this article, Lisa Anderson, RN, BSN, OCN, discusses these key issues related to the administration of newer therapies for FL.

What are some of the toxicities and risks related to the use of bendamustine?

Hematologic toxicities are common AEs associated with the alkylating agent bendamustine. In a recent multicenter study by Kahl and colleagues, the efficacy and toxicity of this agent as monotherapy was evaluated in patients with rituximab-refractory indolent B-cell lymphoma.2 Among 100 patients aged 31 to 84 years who received bendamustine 120 mg/m2 (days 1 and 2 every 21 days for 6-8 cycles), 61% experienced grade 3/4 neutropenia, resulting in filgrastim or pegfilgrastim administration in 38% of cases; grade 3/4 thrombocytopenia occurred in 25% of patients (Figure).2 Combination therapy with bendamustine plus rituximab (BR) is associated with less hematologic and nonhematologic toxicity than is a regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). In the phase 3 study by Rummel and colleagues, which included patients with FL and other indolent lymphomas, serious AEs were less frequent with BR than with R-CHOP. The rate of grade 3/4 neutropenia was 10.7% with BR versus 46.5% with R-CHOP (P<.0001).3 Incidence rates of alopecia, infectious complications, peripheral neuropathy (PN), and stomatitis were also lower with BR, although this regimen produced more skin reactions. Bendamustine has been associated with tumor lysis syndrome (TLS) in both clinical trials and postmarketing reports.3,4 If TLS occurs, it generally appears within the first treatment cycle and may be life-threatening if clinicians do not intervene.3 To prevent TLS, it is crucial to maintain adequate volume status and closely monitor blood potassium, uric acid, and other chemistries.3,5 In addition, allopurinol or rasburicase can be used prophylactically at the start of bendamustine therapy to help prevent TLS.5 If a TLS event should occur, management requires aggressive hydration, diuresis, and treatment with allopurinol or rasburicase.5,6 Caution must be used, however, as there may be an elevated risk of potentially fatal skin toxicity when bendamustine and allopurinol are coadministered; toxicity syndromes include Stevens-Johnson syndrome and toxic epidermal necrolysis.3

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How do you monitor and manage AEs related to the use of bor tezomib and lenalidomide?

Hematologic toxicities, including neutropenia, thrombocytopenia, and anemia, may occur with other agents being used to treat FL, including bortezomib and lenalidomide.7,8 Management of these AEs may require dose interruption and/or dose reduction.7,8 At our center, we ensure that patients have complete blood counts weekly for the first 8 weeks of treatment, and then monthly thereafter. Since neutropenia increases infection risk, patients receiving lenalidomide or bortezomib are given sulfamethoxazole/trimethoprim (for pneumonia prophylaxis) on Monday, Wednesday, and Friday of the treatment week. We also reinforce bleeding precautions at each patient visit, and thrombocytopenic patients receive transfusions when their platelet count falls to 20,000 cells/mm3. For anemia, we transfuse patients at hematocrit 26% to 27%. Neuropathy is a common AE among patients receiving bortezomib-based therapy.7 Preexisting neuropathic symptoms are a potential but unconfirmed risk factor for treatment-induced PN,9,10 with a recent animal model demonstrating a more marked effect of bortezomib on peripheral nerves when baseline neuropathy is moderate or severe.10 Following a baseline neuropathy assessment, we monitor all of our bortezomib-treated patients for symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, neuropathic pain, or weakness. If we identify PN, we follow recommendations for reducing, interrupting, or discontinuing the dose, depending on the severity. Our goal is amelioration of bortezomib-induced PN, which can be reversible when promptly managed.7,11

Caution must be used, however, as there may be an elevated risk of potentially fatal skin toxicity when bendamustine and allopurinol are coadministered. Herpes zoster reactivation has been documented in patients receiving bortezomib, but the occurence of this AE can be reduced with antiviral prophylaxis.7,12,13 For example, in a trial of bortezomib in combination therapy for multiple myeloma, incidence of zoster reactivation was 13% before but 7% after the introduction of antiviral prophylaxis into the protocol.13 At our institution, patients are given acyclovir 400 mg BID while receiving bortezomib treatment, with dose adjusted for renal insufficiency. Risk of venous thromboembolic events (VTEs)â&#x20AC;&#x201D;deep vein thromboses and pulmonary emboliâ&#x20AC;&#x201D;may be elevated in patients treated with lenalidomide, and the drug carries a boxed warning for this AE.8,14 Therefore, we administer prophylactic aspirin at either 81 mg or 325 mg daily for patients receiving this agent.14,15 Hormone-containing medications, such as oral contraceptives, should be avoided in female patients to minimize the risk of VTE.16 Lenalidomide also has a boxed warning for human birth defects risk.8 Specific risk evaluation and mitigation strategies for nurse/pharmacist counseling, pregnancy prevention, and avoidance of sperm donation are offered via the manufacturerâ&#x20AC;&#x2122;s RevAssist program.8

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Figure. Incidence of Grade 3/4 Hematologic Adverse Events in a Multicenter Study of Single-Agent Bendamustine (N=100)2 38%

40

Grade 3 Grade 4

Patients (%)

30 23%

Reactions Lichenoid dermatitis Paraneoplastic pemphigus Stevens-Johnson syndrome Toxic epidermal necrolysis Vesiculobullous dermatitis

Symptom patterns that raise suspicion Blistering Painful sores/ulcers on skin, lips, mouth Peeling skin Pustules Rashes

19%

20

10

Table. Serious Mucocutaneous Reactions Associated with Rituximab Use18

7%

tologic toxicities, notably skin reactions, TLS, PN, and VTEs. Best nursing practices include frequent counseling, preventive strategies, and prompt intervention to minimize AEs, maintain quality of life, and allow for continuation of therapy. ◆

6% 3%

0 Anemia

Thrombocytopenia

Neutropenia

References

What are necessary precautions that need to be discussed with patients receiving rituximab maintenance therapy?

There is concern that maintenance rituximab therapy has the potential for causing additional hematologic and nonhematologic toxicities.17 At our center, each patient who starts or resumes rituximab therapy receives written and verbal education from the nurse and outpatient pharmacist at the time of the first clinic visit, followed by reinforcement education on the day of the first treatment in the infusion center. Potential AEs related to the use of rituximab are reviewed with the patient at each additional clinic visit. Mucocutaneous reactions, some with fatal outcome, may occur with rituximab (Table).18 We are vigilant in monitoring for these reactions because of their potential severity. Serious reactions of this kind require discontinuation of rituximab.18 We also carefully observe rituximab-treated patients for blood-count changes and other signs of infection. Serious infections may occur during and after rituximab-based therapy18; postmarketing reports have documented infections in some patients, with prolonged hypogammaglobulinemia >11 months after exposure to rituximab.19 The 5 most frequent infections reported in the rituximab maintenance arm of the PRIMA trial were bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, and nasopharyngitis.20 Vaccination with live-virus vaccines is not recommended in patients receiving rituximab.18 For example, in a study of NHL patients in remission who had been treated with rituximab-containing immunochemotherapy, humoral response to influenza vaccine was significantly reduced for a prolonged period versus healthy controls.21 Conclusion

Novel and targeted therapies have enhanced outcomes in FL, but they present unique challenges in the occurrence and management of AEs. Newer therapies are associated with myelosuppression and potentially elevated infection risks. Patients may also be at risk for potentially serious nonhema-

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1. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89: 3909-3918. 2. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010;116:106-114. 3. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405. 4. Treanda [package insert]. Frazer, PA: Cephalon Inc; July 2010. 5. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26: 2767-2778. 6. Hummel M, Buchheidt D, Reiter S, Bergmann J, Adam K, Hehlmann R. Recurrent chemotherapy-induced tumor lysis syndrome (TLS) with renal failure in a patient with chronic lymphocytic leukemia—successful treatment and prevention of TLS with low-dose rasburicase. Eur J Haematol. 2005;75:518-521. 7. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals Inc; June 2012. 8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012. 9. Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593-1599. 10. Bruna J, Alé A, Velasco R, Jaramillo J, Navarro X, Udina E. Evaluation of pre-existing neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model. J Periph Nerv Syst. 2011;16:199-212. 11. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120. 12. Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy. Cancer. 2009; 115:229-232. 13. Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006;108:2165-2172. 14. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008; 22:414-423. 15. Niesvizky R, Martínez-Baños D, Jalbrzikowski J, et al. Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide of lenalidomide in myeloma. Leuk Lymphoma. 2007;48:2330-2337. 16. Koopman K, Uyttenboogaart M, Vroomen PC, van der Meer J, De Keyser J, Luijckx GJ. Risk factors for cerebral venous thrombosis and deep venous thrombosis in patients aged between 15 and 50 years. Thromb Haemost. 2009;102:620-622. 17. Fowler NH. Role of maintenance rituximab (Rituxan) therapy in the treatment of follicular lymphoma. P T. 2011;36:590-598. 18. Rituxan [package insert]. South San Francisco, CA: Genentech Inc; July 2012. 19. US Food and Drug Administration. Rituxan (rituximab) intravenous injection: detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER). FDA Web site. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm296234.htm. Updated March 28, 2012. Accessed August 29, 2012. 20. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42-51. 21. Bedognetti D, Zoppoli G, Massucco C, et al. Impaired response to influenza vaccine associated with persistent memory B cell depletion in non-Hodgkin’s lymphoma patients treated with rituximab-containing regimens. J Immunol. 2011;186:6044-6055.

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Improving Patient Outcomes in Follicular Lymphoma Nassoma King, PA-C Physician Assistant,Winship Cancer Institute Emory University, Atlanta, GA

Introduction Despite recent advancements, the management of follicular lymphoma (FL) remains challenging for many reasons. Physician assistants (PAs) play an essential role in improving patient outcomes by provid-

From Cancer Patient to Cancer Survivor: Lost in Transition,1 cancer patients who have finished primary therapy should be given a summary of their treatments and a comprehensive plan for follow-up.2 To achieve this goal at our center, we have instituted survivorship clinics, where we provide patients with treatment summaries detailing their chemotherapy and/or radiation schedules (including specific doses), as well as any complications that may have occurred and information regarding short- and long-term AEs. We also give these summaries to the patient’s PCP and referring oncologist, which helps to close the communication gap posttreatment.

ing continuity of care before, during, and after treatment. In this article, Nassoma King, PA-C, responds to questions pertaining to the care

What are the greatest challenges patients face during therapy?

of patients with FL, including the need for pretreatment assessments, education and counseling, follow-up care, and the prevention and management of treatment- and disease-related complications.

What is the role of the PA in the management of patients with FL?

As members of the interdisciplinary care team, PAs can be involved in all aspects of care for patients with FL. Working collaboratively with the supervising physicians, we order and review tests, set up treatment schedules and follow-up visits, and arrange appropriate restaging studies. PAs also enhance care by performing health assessments and physical examinations, ordering chemotherapy and other medications, and helping patients cope with the numerous challenges related to their diagnosis and treatment. At our institution, we provide individuals with counseling and education and work with them to set realistic expectations both during and after therapy. Our center also offers patients and their families a “pretreatment” visit, which gives us the opportunity to discuss treatment-related adverse events (AEs), nutrition and exercise, potential drug–drug interactions, and sexuality/fertility issues. During this meeting, a social worker, a nutritionist, and a pharmacist are also available to provide more in-depth evaluation if necessary. These visits are instrumental in identifying additional needs as well as any possible barriers to successful outcomes. PAs also assume the role of “coordinator of care.” Frequently, after their initial visit with the oncologist, patients may feel overwhelmed by a diagnosis of lymphoma. As a result, it may be difficult for them to process all of the information they have received. Regardless of whether the oncologist prescribes a “watch and wait” approach or active treatment, the PA will review the established plan of care and schedule necessary visits and studies. For patients who are scheduled to undergo active therapy, all required testing must be ordered and evaluated prior to the first treatment cycle. During follow-up visits, PAs will address treatment-related AEs and other concerns and arrange appropriate referrals. We encourage our patients’ caregivers to attend clinic visits to help reiterate instructions and information. Our institution also provides additional assistance in the way of caregiver support groups, massage therapy sessions, and social worker services. After a patient has completed therapy, PAs continue to manage several aspects of care. In particular, they are an important bridge between the primary care physician (PCP) and the oncology team. As recommended in

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With FL, the goal of therapy is to maintain optimal quality of life and to treat only when patients develop symptoms. Any alteration to this approach requires demonstration of improved survival with early institution of therapy, or identification of criteria that define patients at a sufficiently high risk to merit early intervention.3 Numerous therapeutic options for FL are now available, ranging from radiotherapy to single-agent chemotherapy to combination regimens.3 For patients who undergo active treatment, the greatest challenges are often related to physical and psychosocial changes. It is well known that certain chemotherapeutic agents destroy normal cells as well as malignant cells, resulting in numerous AEs, including nausea and vomiting, reduced appetite, hair loss, and mouth sores.4 Damage to healthy immune cells may also place patients at greater risk for infection.4 Single-agent rituximab is generally well tolerated but may cause infusion-related complications and myelosuppression.5,6 Radioimmunotherapy may also result in the development of AEs such as transient bone marrow depression, fatigue, fever, chills, sweating, rash, arthralgias, erythema, and edema.7 It is therefore critical for PAs and other members of the oncology care team to be familiar with the toxicity profiles associated with these therapies so they can initiate appropriate interventions, including growth factor support to manage infection, erythropoietin to treat anemia, and antiemetics to relieve nausea and vomiting. Psychosocial changes, which are often triggered by the AEs described above, may cause patients to feel emotionally distraught.8 Interpersonal relationships may become strained due to disruptions in everyday life, job loss, decreased finances, and changes in family dynamics. Depression, fatigue, and changes in physical appearance often lead to sexual dysfunction and poor body image. Chemotherapy is often associated with loss of libido and decreased physical intimacy for both men and women. Combining psychosocial therapy with treatment for the disease itself can help to alleviate emotional distress. Our team, which includes a social worker and a psychiatrist, provides individual and family counseling, as well as support groups geared toward addressing many of the psychosocial issues related to chemotherapy. We offer an in-house boutique that provides hair and make-up classes, as well as hair prostheses and accessories. Elderly patients may be more difficult to treat due to preexisting comorbidities, diminished organ function, altered drug metabolism, and irregular drug clearance rates.9 They may often present with poor performance status and underlying cardiac or renal dysfunction. In addition, the risk of developing treatment-related AEs and the inability to tolerate full doses of therapeutic

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CONSIDERATIONS IN LYMPHOMA

agents generally increases with age, and cure and remission rates usually decrease.9 The key to maintaining quality of life and helping patients reap the optimal benefits of therapy involves good communication between members of the oncology team and their patients regarding AEs and other complications. What special considerations are necessary for patients who undergo transplantation?

Although patients with FL typically demonstrate good response to induction therapy, most will eventually relapse. When this occurs, cure is very unlikely; the median survival after disease recurrence is approximately 4.5 years.10 There are several options available to patients who relapse, including chemotherapy, radioimmunotherapy, and stem cell transplant. Investigators addressed the role of autologous stem cell transplantation (ASCT) in the European CUP trial, which randomized patients with relapsed FL to undergo chemotherapy alone (C), ASCT with an unpurged autograft (U), or ASCT with a purged autograft (P).11 The 2-year progression-free survival (PFS) rates were 26% (C), 58% (U), and 55% (P), whereas 4-year overall survival (OS) rates were 46% (C), 71% (U), and 77% (P). No difference in PFS or OS was seen between the transplant groups. However, a significant reduction in hazard ratios for both PFS and OS was observed in the combined groups of patients undergoing ASCT compared with the chemotherapy group. Allogeneic stem cell transplantation (allo-SCT) may be a viable option for patients whose lymphoma is behaving in an aggressive fashion (ie, early recurrence after intensive frontline or salvage therapy). However, due to relatively high treatment-related mortality, patients must have an excellent performance status, minimal comorbidities, and an human leukocyte antigen–identical donor (related or unrelated) to be considered for this procedure.12 For transplant-eligible patients, it is important to consider factors such as nutritional status prior to transplant, neutropenic precautions during transplant, and posttransplant changes. Patients must undergo a rigorous pretransplant evaluation, which includes testing to assess organ function and disease status. It is also necessary to arrange a meeting with a social worker to address psychosocial needs. At our institution, patients typically meet with a nutritionist to help improve their performance status prior to transplant, because disease status, the amount of time since the last cycle of chemotherapy, infection, and anorexia can all significantly impact nutritional status.13 Malnutrition prior to transplantation has been reported to increase the length of hospital stay and can be a negative prognostic factor for survival.13 Opportunistic infections remain a significant cause of morbidity and mortality related to transplant.14 The conditioning regimen causes pancytopenia, impaired phagocytosis, and damaged mucocutaneous barriers.15 Venous access devices may also place patients at an increased risk for infection, as they serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (eg, coagulase-negative staphylococci, Staphylococcus aureus, Candida species, and enterococci).15 At our center, we start patients on prophylactic antibiotics on day 1, continuing until engraftment of white blood cells. If patients develop fever, we order a culture and initiate broad spectrum antibiotics until the pathogen is identified. Upon discharge from the hospital, patients who have undergone ASCT will usually continue acyclovir for herpes simplex virus prophylaxis; whereas patients who have undergone alloSCT will continue with both acyclovir and fluconazole. The Centers for Disease Control and Prevention has established extensive guidelines for the prevention of opportunistic infections following transplantation, including hospital infection control, food safety, pet and travel safety, vaccinations, and general infection precautions.15

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It is important to be cognizant of the fact that patients and families may have unrealistic expectations after transplant. For example, they may be under the impression that life will return to normal as soon as the procedure is complete. Some of the common difficulties that patients face posttransplant include the inability to resume social roles, concerns about the future, work-related problems, infertility, fear of relapse, and anxiety and depression.16 In addition, fatigue may last anywhere from 3 to 6 months posttransplant for recipients of ASCT and up to 2 years or more for recipients of alloSCT. For patients who develop graft-versus-host disease, fatigue may last even longer. As a result, they may be unable to return to their jobs or may need to perform their responsibilities in a limited capacity, causing additional financial stress. At our center, an oncology supportive care team consisting of social workers and psychiatrists works collaboratively with the medical team to help patients and caregivers address physical, emotional, and financial stressors. Conclusion

Because many patients with FL face physical, financial, and emotional challenges before, during, and after treatment, it is essential that they feel comfortable contacting the nurse practitioner or PA regarding any and all concerns. In addition to providing information on external support groups, we employ an interdisciplinary approach to tackle issues preemptively. It is critical to recognize that each patient has specific needs and that each should be cared for in a way that addresses those needs appropriately. ◆ References 1. Hewitt M, Greenfield S, Stovall E, eds. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC: The National Academies Press; 2005. www.nap.edu/catalog.php?record_id= 11468. Accessed August 29, 2012. 2. Bhatia S, Landier W; on behalf of the Children’s Oncology Group (COG) Nursing Discipline and Late Effects Committees. Appendix F: treatment summary forms developed by the Children’s Oncology Group (COG). In: A National Coalition for Cancer Survivorship and Institute of Medicine National Cancer Policy Forum Workshop, The Lance Armstrong Foundation and The National Cancer Institute, Hewitt M, Ganz PA, eds. Implementing Cancer Survivorship Care Planning. Washington, DC: The National Academies Press; 2007. www.nap.edu/openbook.php?record_id=11739&page=288. Accessed August 29, 2012. 3. Gribben JG. How I treat indolent lymphoma. Blood. 2007;109:4617-4626. 4. American Cancer Society. Chemotherapy principles: an in-depth discussion. American Cancer Society Web site. www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/ Chemotherapy/ChemotherapyPrinciplesAnIn-depthDiscussionoftheTechniquesanditsRolein Treatment/chemotherapy-principles-indepth-toc. Accessed August 29, 2012. 5. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomized controlled trial. Lancet. 2011;377:42-51. 6. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28:4480-4484. 7. Buchegger F, Antonescu C, Helg C, et al. Six of 12 relapsed or refractory indolent lymphoma patients treated 10 years ago with 131I-tositumomab remain in complete remission. J Nucl Med. 2011;52:896-900. 8. Bergeson B. Emotional effects of chemotherapy. Livestrong.com Web site. www.livestrong. com/article/143086-emotional-effects-chemotherapy/#ixzz23NwEZ4LT. Updated June 8, 2010. Accessed August 29, 2012. 9. Cabanillas ME, Lu H, Fang S, Du XL. Elderly patients with non-Hodgkin lymphoma who receive chemotherapy are at higher risk for osteoporosis and fractures. Leuk Lymphoma. 2007;48:1514-1521. 10. Thieblemont C, Coiffier B. Lymphoma in older patients. J Clin Oncol. 2007;25:1916-1923. 11. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol. 2003;21:3918-3927. 12. van Besien K. Allogeneic stem cell transplantation in follicular lymphoma: recent progress and controversy. Hematology Am Soc Hematol Educ Program. 2009:610-618. 13. Horsley P, Bauer J, Gallagher B. Poor nutritional status prior to peripheral blood stem cell transplantation is associated with increased length of hospital stay. Bone Marrow Transplant. 2005;35:1113-1116. 14. Nevill TJ, Shepherd JD, Nantel SH, et al. Stem cell transplant-related mortality (TRM) 19851996: the Vancouver experience. Blood. 1997;90(10)(suppl 1 [part 2 of 2]):4426. 15. Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49:1-125. 16. Hjermstad MJ, Evensen SA, Kvaløy SO, Fayers PM, Kaasa S. Health-related quality of life 1 year after allogeneic or autologous stem-cell transplantation: a prospective study. J Clin Oncol. 1999;17:706-718.

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Side Effect Management Mucositis Management to Become More Personalized... Continued from cover enchyme, extracellular matrix, and epithelium; the local environment; and the microflora. Once thought of as a direct epithelial process in which chemotherapy or radiotherapy killed cells, the development of mucositis is actually a multifactorial process within the diverse tissues of the submucosa, he said.

“The cascade of events starts with oxidative stress, followed by an innate immune response, leading to a primary damage response, initiation of signaling pathways, amplification and feedback, then ulceration, surface colonization, and healing,” Sonis said. The involvement of so many process-

es means, he said, “that in developing drug targets and in looking for risk predictors, we have a bigger palette to go after, versus just focusing on epithelial cells, as in the historical paradigm.” Emerging areas of research are the local environment of the gastrointestinal tract and mouth, especially salivary

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

and intestinal proteins secreted in response to mucosal injury, as well as changes in bacterial flora, Sonis said. targeted Agents May Not be Much better Dorothy Keefe, MD, MBBS, of Royal Adelaide Hospital in Australia, cautioned against thinking that new targeted agents will carry less risk of mucositis. The mTOR inhibitors, for example, produce a unique mucositis pattern. “Every new drug class brings new toxicities, despite the temptation to think that ‘targeted’ equals ‘nontoxic,’ ” she said. The toxicities of targeted therapies are often clinically significant, longlasting, and not reversible, she added. Keefe pointed out that signaling pathways may be related to both the toxicity and oncogenesis, and interfering with pathways is “tricky territory.” Understanding of mechanisms, she said, is key to optimal management. “Time-tested empiric foundational approaches” that have been used for decades will continue to be important in the new frontier of targeted cancer therapies and their toxicities, Peterson said. These include patient education and compliance, simple wound care approaches, structured approaches to pain control, adequate hydration and nutritional support, surveillance, and treatment of infectious complications. “The problem is that these approaches are not fundamentally targeting the pathobiology,” he said. “The new world order, where we are headed, will include individualized risk profiles and customized therapies.”

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.

risk prediction “Personalized cancer medicine involves both tumor and toxicity. It is not good enough to personalize the cancer treatment. We have to personalize the supportive care as well, and risk prediction for toxicity is becoming a reality,” Keefe said. “We are at a very serendipitous time,” Sonis agreed. “Risk prediction has become possible through the evolution of genomics.” Single-nucleotide polymorphisms (SNPs) are the most common form of variation in the genome. SNPs can reside intracellularly (and affect transcription) or extracellularly (and be an indicator of toxicity risk). Advances in bioinformatics are making it possible to select clusters of SNPs, out of millions, that can predict for toxicity. This is already possible for patients undergoing conditioning regimens for autologous stem cell transplant, 40% of whom will develop severe mucositis and 60% of whom will therefore be treated unnecessarily, he said. Continued on page 38

36

sEPTEmbER 2012 I VOL 5, NO 6

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Whoâ&#x20AC;&#x2122;s Your

TOP Pharmacist Nominee? The Oncology Pharmacist is pleased to announce the 2013 T.O.P. Pharmacist Award, sponsored by Teva Oncology. This annual award recognizes an oncology pharmacist for outstanding contributions to oncology pharmacy practice, research, or education in 2012. Nominate a pharmacist before December 31, 2012. The 6 leading nominees will be profiled online and in the February issue of The Oncology Pharmacist. Vote for the winner at TheOncologyPharmacist.com/award. The winner will be announced at the 2013 Hematology/Oncology Pharmacy Association (HOPA) meeting, March 20â&#x20AC;&#x201C;23, 2013 in Los Angeles, CA, and profiled in the April 2013 issue of The Oncology Pharmacist.

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Side Effect Management Mucositis Management to Become More Personalized... Continued from page 36 In a retrospective analysis of myeloma and lymphoma patients undergoing transplant at a single center, Sonis and his team identified 51 patients who developed oral mucositis and 102 who did not. They looked for SNPs in the DNA of patients’ saliva and found that a cluster of 82 SNPs that predicted for mucositis with 99.3% accuracy.

The area under the ROC (receiver operating characteristic) curve was 0.997 (0.9-1.0 is considered an excellent predictor). The ROC for mammography is 0.74, he noted for comparison. A multicenter study of the model is planned, and this model is being further developed for commercialization. “We were thrilled,” Sonis comment-

ed. “This approach should be a game changer in terms of our ability to predict mucositis and other biologically based toxicities. This means we can be much more precise in developing risk assessments, understanding the patient’s response to risk, and being able to favorably impact toxicity with targeted interventions for the patient at risk.” ●

www.avbcconline.org

MAY 2-5, 2013

THIRD ANNUAL CONFERENCE

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

!

Novel Mouth rinse reduces Course and Severity of Oral Mucositis Topical administration of a novel mouth rinse, AG013, appears safe, well tolerated, and effective in reducing the severity and course of oral mucositis (OM) in patients receiving induction chemotherapy in a study presented at the 2012 ASCO Annual Meeting (Abstract 9024). AG013 is a mouth rinse composed of a recombinant Lactococcus lactis engineered to secrete human trefoil factor 1 (hTFF1) and deficient in the gene encoding thymidylate synthase. TFFs have wound-healing properties and are protective of mucosal tissues. The compound was evaluated in 25 patients who developed symptomatic oral mucositis after induction chemotherapy for head and neck cancer in a phase 1B, multicenter, single-blind, placebo-controlled study reported by Sewanti Atul Limaye, MD, of the DanaFarber Cancer Institute in Boston, Massachusetts.

Three dosing cohorts were evaluated and compared with placebo recipients.

For more information please visit

www.AVBCConline.org 38

sEPTEmbER 2012 I VOL 5, NO 6

Three dosing cohorts were evaluated and compared with placebo recipients. Patients receiving AG013 on any dosing schedule had a lower percentage of days with OM and fewer unplanned office and emergency room visits compared with patients who received placebo. Responses (≤1 day of ulcerative OM) were observed in 29% of AG013 patients but in none of the placebo patients. Ulcerative OM was observed during 35% to 40% of study days for patients receiving the mouth rinse, compared with 60% of study days in the placebo group. The absolute reduction in the percentage of days with ulcerative OM, with the use of the novel mouth rinse, was 35%. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement.

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection, USP safely and effectively. See full prescribing information for Docetaxel.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Oxaliplatin safely and effectively. See full prescribing information for Oxaliplatin.

Docetaxel Injection, USP

Gemcitabine Injection

Oxaliplatin for Injection,

For intravenous infusion only. Initial U.S. Approval: 1996

For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996

Oxaliplatin Injection,

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning F &  >1-@91:@>18-@109;>@-85@E5:/>1-?1?C5@4-.:;>9-8 85B1>2A:/@5;:-@45341>0;?1?-:05:<-@51:@?C5@4 !%-:0<>5;><8-@5:A9.-?10@41>-<E>1/15B5:3 docetaxel at 100 mg/m2 (5.1) F % 4;A80:;@.135B1:52.585>A.5:'!;>52%&-:0;> &  D'!/;:/;95@-:@C5@4-87-85:1<4;?<4-@-?1   D'!&181B-@5;:?5:/>1-?1>5?7;2?1B1>1;> 8521@4>1-@1:5:3/;9<85/-@5;:?".@-5:&?.12;>11-/4 treatment cycle (8.6) F % 4;A80:;@.135B1:52:1A@>;<458/;A:@?->1 < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) F % 1B1>14E<1>?1:?5@5B5@E5:/8A05:3B1>E>->12-@-8 -:-<4E8-D5?4-?.11:>1<;>@105:<-@51:@?C4;>1/15B10 dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4) F   ;:@>-5:05/-@105245?@;>E;2?1B1>14E<1>?1:?5@5B5@E >1-/@5;:?@;0;/1@-D18;>@;0>A3?2;>9A8-@10C5@4 polysorbate 80 (4) F % 1B1>128A50>1@1:@5;:9-E;//A>01?<5@101D-91@4-?;:1 (5.5) CONTRAINDICATIONS H G>3@A3<A7B7D7BGB=2=13B/F3:=@>=:GA=@0/B3   H $3CB@=>67:1=C<BA=4  13::A;;3  WARNINGS AND PRECAUTIONS H   1CB3;G3:=72:3C93;7/<>/B73<BAE6=@3137D322=13B/F3: 2=F=@C0717</<21G1:=>6=A>6/;723;=<7B=@4=@23:/G32 ;G3:=2GA>:/A7/=@;G3:=72:3C93;7/ H CB/<3=CA@3/1B7=<A'3/1B7=<A7<1:C27<53@GB63;/=4B63 3FB@3;7B73AE7B6323;/4=::=E320G23A?C/;/B7=<;/G=11C@ (3D3@3A97<B=F717BG;/G@3?C7@32=A3/28CAB;3<B H $3C@=:=571@3/1B7=<A'3/1B7=<A7<1:C27<5>/@3AB63A7/ 2GA3AB63A7//<2>/7<;/G=11C@(3D3@3<3C@=A3<A=@G AG;>B=;A@3?C7@32=A3/28CAB;3<B=@27A1=<B7<C/B7=<74 >3@A7AB3<B H AB63<7/(3D3@3/AB63<7/;/G=11C@/<2;/G@3?C7@3B@3/B;3<B 27A1=<B7<C/B7=< H &@35</<1G3B/:6/@;1/<=11C@E63</2;7<7AB3@32B=/ >@35</<BE=;/<,=;3<=4167:203/@7<5>=B3<B7/:A6=C:203 /2D7A32<=BB=031=;3>@35</<BE63<@3137D7<5=13B/F3: <831B7=<*(&   ADVERSE REACTIONS #=AB1=;;=</2D3@A3@3/1B7=<A/1@=AA/::2=13B/F3:7<271/B7=<A /@37<431B7=<A<3CB@=>3<7//<3;7/430@7:3<3CB@=>3<7/ 6G>3@A3<A7B7D7BGB6@=;0=1GB=>3<7/<3C@=>/B6G2GA53CA7/ 2GA><3/1=<AB7>/B7=</<=@3F7/</7:27A=@23@A4:C72@3B3<B7=< /AB63<7/>/7<</CA3/27/@@63/D=;7B7<5;C1=A7B7A/:=>317/A97< @3/1B7=<A;G/:57/ To report SUSPECTED ADVERSE REACTIONS, contact Hospira, :/-@ 

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INDICATIONS AND USAGE 3;17B/07<37A/<C1:3=A723;3B/0=:717<6707B=@7<271/B324=@ H %D/@7/<1/<13@7<1=;07</B7=<E7B61/@0=>:/B7<   H @3/AB1/<13@7<1=;07</B7=<E7B6>/1:7B/F3:   H $=<A;/::13:::C<51/<13@7<1=;07</B7=<E7B617A>:/B7<   H &/<1@3/B711/<13@/A/A7<5:3/53<B   DOSAGE AND ADMINISTRATION 3;17B/07<3<831B7=<7A4=@7<B@/D3<=CACA3=<:G H %D/@7/<1/<13@ ;5; =D3@ ;7<CB3A=</GA /<2=4 3/16 2/G1G1:3   H @3/AB1/<13@  ;5; =D3@ ;7<CB3A=</GA /<2=4 3/16 2/G1G1:3   H $=<A;/::13:::C<51/<13@ E339A1632C:3 ;5; =D3@

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<;C01>2;>?;8A@5;:2;>5:@>-B1:;A?A?1 solution for intravenous use Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning. Anaphylactic reactions to Oxaliplatin have been >1<;>@10-:09-E;//A>C5@45:95:A@1?;2"D-85<8-@5: administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1) INDICATIONS AND USAGE %F/:7>:/B7<7A/>:/B7<C;0/A322@C5CA327<1=;07</B7=<E7B6 7<4CA7=</:4:C=@=C@/17::3C1=D=@7<E67167A7<271/B324=@ H  /28CD/<BB@3/B;3<B=4AB/531=:=<1/<13@7<>/B73<BAE6= 6/D3C<23@5=<31=;>:3B3@3A31B7=<=4B63>@7;/@GBC;=@ H  B@3/B;3<B=4/2D/<1321=:=@31B/:1/<13@  H 

H  H  H  H  H 

CONTRAINDICATIONS  <=E</::3@5GB=%F/:7>:/B7<=@=B63@>:/B7<C;1=;>=C<2A !    WARNINGS AND PRECAUTIONS  ::3@571'3/1B7=<A#=<7B=@4=@23D3:=>;3<B=4@/A6  C@B71/@7/3@GB63;/>@C@7B7A0@=<16=A>/A;/<2 6G>=B3<A7=<  $3C@=>/B6G'32C13B632=A3=@27A1=<B7<C3%F/:7>:/B7<74 <313AA/@G  &C:;=</@G)=F717BG#/G<332B=27A1=<B7<C3%F/:7>:/B7< C<B7:7<B3@AB7B7/::C<527A3/A3=@>C:;=</@G470@=A7A/@3 3F1:C232  3>/B=B=F717BG#=<7B=@:7D3@4C<1B7=<B3ABA  &@35</<1G3B/:6/@;1/<=11C@E63</2;7<7AB3@32B= />@35</<BE=;/<,=;3<A6=C:203/>>@7A32=4B63 >=B3<B7/:6/@;B=B6343BCA 

ADVERSE REACTIONS #=AB1=;;=</2D3@A3@3/1B7=<A7<1723<13I E3@3 >3@7>63@/:A3<A=@G<3C@=>/B6G<3CB@=>3<7/B6@=;0=1GB=>3<7/ /<3;7/</CA3/7<1@3/A37<B@/<A/;7</A3A/<2/:9/:7<3 >6=A>6/B/A327/@@63/3;3A7A4/B75C3/<2AB=;/B7B7A%B63@ /2D3@A3@3/1B7=<A7<1:C27<5A3@7=CA/2D3@A3@3/1B7=<A6/D3033< @3>=@B32  To report SUSPECTED ADVERSE REACTIONS, contact Hospira :/-@ 

 ;>-@  ;> CCC20-3;B910C-@/4 See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling. Revised: 04/2011

ADVERSE REACTIONS )63;=AB1=;;=</2D3@A3@3/1B7=<A4=@B63A7<5:3/53<B I /@3</CA3//<2D=;7B7<5/<3;7/")()<3CB@=>3<7/ :3C9=>3<7//:9/:7<3>6=A>6/B/A3>@=B37<C@7/43D3@63;/BC@7/ @/A6B6@=;0=1GB=>3<7/2GA><3/  To report SUSPECTED ADVERSE REACTIONS, contact ;?<5>-:/-@ 

 ;>181/@>;:5/-88E at ProductComplaintsPP@hospira.com, or FDA at  ;>www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 09/2011

#/<C4/1BC@320G=A>7@/CAB@/:7/&BG"B2#C:5@/D3CAB@/:7/ #/<C4/1BC@320G.G2CA=A>7@/%<1=:=5G&@7D/B3"B2C8/@/B<27/ 7AB@70CB320G=A>7@/<1"/93=@3AB" *( * '*(  

#/<C4/1BC@320G Zydus Hospira %<1=:=5G&@7D/B3"B2 6;32/0/2  

C8/@/B<27/ 4=@Hospira, Inc. "/93=@3AB" *( &@=2C1B=4<27/

#/<C4/1BC@320G =A>7@/CAB@/:7/"B2 #C:5@/D3+

 CAB@/:7/ Manufactured for: Hospira, Inc. "/93=@3AB" *(


AVAILABLE FROM HOSPIRA

OXA L I PL ATI N I N JE C TI ON ( 5 mg /mL )

50 mg/10 mL single-dose vial 100 mg/20 mL single-dose vial

As the complexity of healthcare evolves,

See Black Box Warning Below

we’re doing our part to improve cost savings, optimize workflow and enhance patient care. With our generic oncology portfolio we provide

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR CLINICIANS—UNIQUE ONCO-TAIN ™ VIALS REINFORCE SAFETY 1

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST D OC E TA XE L I N JE C TI ON ( 1 0 mg /mL )

U N I Q U E O N C O - TA I N S A F E T Y F E AT U R E S 1

PVC BOTTOM offers shatter resistance.

2

SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3

GLASS CLARITY allows for easy inspection of the vial as a final safety check before administration.

4

PREWASHED VIALS reduce cytotoxic residue.

160 mg/16 mL multiple-dose vial 80 mg/8 mL multiple-dose vial 20 mg/2 mL single-dose vial See Black Box Warning Below

For more information, contact your

Hospira representative or call 1-877-946-7747. Or visit us at products.hospira.com. Docetaxel: WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION Oxaliplatin: WARNING: ANAPHYLACTIC REACTIONS

GE MC I TA B I N E I N JE C TI ON ( 3 8 mg /mL )

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

2 g/52.6 mL single-dose vial Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

1 g/26.3 mL single-dose vial P12-3707-11.125x14.125-Jul., 12

200 mg/5.26 mL single-dose vial


September 2012, Vol 5, No 6