VOL 5, NO 8
Cedars-Sinai’s Samuel Oschin Progress in Treating Prostate Comprehensive Cancer Institute Cancer CANCER CENTER PROFILE
Blood and Marrow Transplant Program
By Alice Goodman
By Alice Goodman
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 Abiraterone in Chemotherapy-Naive Metastatic CRPC1 Results of the second interim analysis Continued on page 10
Laura Snoussi, RN, BSN, OCN; Anne Rosenblatt, RN, MSN; Carolina Caso, RN, BSN, CPON; Marguerita Guerrero, RN, BSN, OCN; Seda Gharapetian, RN, MSN, FNP, OCN; and Patricia Van Strien, RN, BSN, OCN, CHTC (left to right), oncology nurses with the Blood and Marrow Transplant Program at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute. Photo courtesy of Cedars-Sinai.
he Blood and Marrow Transplant Program was established at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute in 1991 to provide stem cell transplants to patients with breast cancer. The program fell into a lull when transplant was proven ineffective for breast cancer, but about 10 years later it had a resurgence under the directorship of Michael Lill, MD, who joined the center in 1997. In 2002, the first allogeneic transplants were performed there. Now the program has grown to include 6 medical doctors and 6 nurse coordinators. An expected 140 transplants will be performed in 2012. The largest group of transplant patients is those with multiple myeloma, followed by those with lymphoma and leukemia.
Continued on page 22
THE PATIENT’S VOICE
Caring for the Caregivers By MMA
n an ideal world, all sick people would have a caregiver who could keep them company and give at least minimal medical care 24/7, or even 8/7. Unfortunately, because of the way society (at least in the United States) is organized, work demands, financial demands, geographical dispersion of family members, and the nature of medical care make that impossible for many. In my hospital, I see many solitary, lonely
patients who most probably have many loved ones who would, if they could, be with their sick relative. My luck was different. I have 2 sons older than 18. At the time I was diagnosed, one had just finished his third semester in college and the other had just found his first postcollege job. Both temporarily suspended their own lives to be with me. One took a semester off college and the other took a temporary leave
Continued on page 8
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
Side effect ManageMent
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 intermediateand high-risk localized prostate cancer, but low-risk localized prostate cancer can be safely managed with observation. Overall, absolute differences in mortality favoring surgery were less than 3
CIPN Increases Risk of Falls and Physical and Functional Problems Severe Diarrhea Associated With Molecularly Targeted Agents Can Impact Quality of Life and Healthcare Resource Utilization
Hereditary Cancer Support Organizations
the patient’S Voice
Considerations for Treatment
Continued on page 4 ©2012 Green Hill Healthcare Communications, LLC
Considerations in Lymphoma—Ask the Experts: Follicular Lymphoma .........
Popping Pills and Shooting Up
The median age of patients in the VISTAâ€Ą trial was 71 years (range: 48-91).
Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months†; 60.1-month median follow-up‡)
Approved for subcutaneous and IV administration§ VELCADE (bortezomib) Indication and Important Safety Information INDICATION
CONTRAINDICATIONS ADVERSE REACTIONS WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼
▼ ▼ ▼
News Briefs Surgery Versus Observation... Continued from cover
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 higherrisk 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 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 ng/mL. About 40% of the men had low-risk prostate cancer, 34% intermediate-risk prostate cancer, and 21% high-risk prostate cancer.
Observation vs Surgery 10-Year Follow-up Mortality Rates
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.
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
49.9% Observation Group 47.0% Surgery Group 2.9% Reduction for Surgery 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).
Low-Risk Prostate Cancer: Choosing Observation Men 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 monitoring 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 Continued on page 7
SEPTEMbER 2012 I VOL 5, NO 8 1:32 PM
Editorial Board EDITOR-IN-CHIEF
Cassandra J. Hammond, RN,
Dolores “Jeff” Nordquist, RN, MS,
Avid Education Partners, LLC Sharpsburg, MD
Mayo Clinic Rochester, MN
Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI
RN, MSN, APRN, BC, OCN
RN, BSN, OCN
Melinda Oberleitner, RN,
Karla Wilson, RN, MSN, FNP-C, CPON
DNS, APRN, CNS
City of Hope National Medical Center Duarte, CA
Beth Faiman, PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Catherine Bishop, DNP, NP, AOCNP
Novant Health Presbyterian Cancer Center Charlotte, NC
Patricia Irouer Hughes, RN, MSN,
College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA
Jayshree Shah, NP
Piedmont Healthcare Rex, GA
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Deena Damsky Dell, MSN, RN-BC,
NP, MSN, ACNP-C
University of Southern California Norris Cancer Center & Hospital Los Angeles, CA
MSN, NP, ANP-BC, AOCNP
Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC
Fox Chase Cancer Center Philadelphia, PA
PhD, RN, AOCN
Pharmacy John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
Nutrition Karen Connelly, RD, CSO
NYU Clinical Cancer Center New York, NY
Somerset Medical Center Somerville, NJ
Sandra E. Kurtin,
Lori Stover, RN,
DNP, APRN, AOCN
RN, MS, AOCN, ANP-C
Patient Advocate Peg Ford
Western Pennsylvania Cancer Institute Pittsburgh, PA
Ovarian Cancer Advocacy Alliance Coronado, CA
Joseph D. Tariman, PhD,
Social Work Carolyn Messner,
DSW, MSW, LCSW-R, BCD
Genentech New London, NH
Denice Economou, RN, MN, CNS, AOCN
Arizona Cancer Center Tucson, AZ
Ann McNeill, MSN, RN, NP-C, OCN
City of Hope National Medical Center Duarte, CA
John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ
Northwestern University Myeloma Program Chicago, IL
Constance Engelking, RN,
Kena C. Miller, RN, MSN, FNP
Jacqueline Marie Toia, RN, MS, DNP
MS, CNS, OCN
Roswell Park Cancer Institute Buffalo, NY
Northwestern University Myeloma Program Chicago, IL
The CHE Consulting Group, Inc. Mt. Kisco, NY
CancerCare New York, NY
Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY
Amy Ford, RN,
MS, RN, APN-C, AOCNS
Quintiles Dallas, TX
Pamela Hallquist Viale, RN, MS, CS, ANP, AOCN
Isabell Castellano, RN
Somerset Medical Center Somerville, NJ
Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ
Sharon S. Gentry,
Ellen A. Neylon,
Jeanne Westphal, RN
RN, MSN, AOCN
MSN, FNP-BC, CCRP, OCN
RN, PhD, APRN
Meeker County Memorial Hospital Litchfield, MN
Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC
Columbia University Medical Center Center for Lymphoid Malignancies New York, NY
University of South Florida College of Nursing Tampa, FL
september 2012 I VOL 5, NO 8
From the Editor
eptember is National Prostate Cancer Awareness Month. The August 31, 2012, presidential proclamation acknowledging this included the following statement: “we remember those we have lost to prostate cancer, and we renew our commitment to preventing, detecting, and treating this terrible illness.” In this month’s issue of The Oncology Nurse-APN/PA (TON), Beth Faiman, PhD(c), MSN, APRN-BC, AOCN we present some prostate cancer statistics in Noteworthy Numbers and Editor-in-Chief discuss some of the progress in treating this disease, including the recent approval of enzalutamide. In our cancer center profile, Anne Rosenblatt, RN, MSN, tells us about the Blood and Marrow Transplant
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SEPTEMbER 2012 I VOL 5, NO 8
Program at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute. Anne points out that this program is 1 of only 2 transplant centers in the world that provide a bloodless transfusion program for Jehovah’s Witnesses. She also tells us about some patient- and caregiver-friendly books that the staff has created for patients about to undergo transplant (see page 30 in the August issue of TON for more information about these materials). The topic of one of The Patient’s Voice articles 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, 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.TheOncologyNurse.com and tell us how you try to help patients like MMA overcome their emotional reactions to taking (or not taking) their medications. ●
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 10.
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. ●
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News Briefs Low-Risk Prostate Cancer... Continued from page 4
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 prostatectomy 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.
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 randomized 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.
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 patients 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 clinical trial evaluating OVA1 sensitivity 91% in women with early-stage ovarian cancer 94% in premenopausal women 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.
Weightlifting and Breast CancerRelated Lymphedema Although weightlifting reduced the need for lymphedema treatment by 50% compared with standard treatment in breast cancer survivors who participated in the Physical Activity Lymphedema (PAL) trial, weightlifting is not
without its own risks. A retrospective analysis of the PAL trial found that the rate of injury was higher in the weightlifting group compared with controls (Brown JC, et al. Oncologist. 2012; 17:1120-1128). Among women assigned to weightlifting, about 1 in 5 met with a healthcare provider and either stopped or modified their weightlifting program due to injury. The study included 295 breast cancer survivors with or at risk for lymphedema; 147 were randomized to a weightlifting program. The intervention was continued for 1 year. Nine women in the weightlifting group reported 10 musculoskeletal injuries that impaired activities of daily living for at least 1 week (8 injuries were in women with lymphedema and 2 in women at risk for lymphedema). The cumulative incidence of musculoskeletal injuries in the weightlifting group among women with lymphedema was 10.2 per 100 breast cancer survivors and 3.4 per 100 breast cancer survivors among women at risk for lymphedema. The results of this analysis suggest that patients need to be informed about both the risks and benefits of exercise, and in particular, weightlifting. Clinicians and staff members who suggest weightlifting to breast cancer survivors because of its established benefits need to have the resources to promote integration of this or any physical rehabilitation program into supportive care, wrote the authors. Since injury can occur during the first year of weightlifting, health fitness experts need to know the best way to modify exercise programs based on the needs of each patient. The exercises used in PAL were modified based on each individual’s needs. This type of intervention rests on interdisciplinary collaboration, the authors emphasized. The PAL weightlifting intervention was delivered after the health fitness professionals who were going to teach weightlifting to participants underwent a 3-day training course. Important aspects of the PAL weightlifting intervention that helped to ensure its successful delivery include preparticipation evaluations by physical therapists, patient education, ongoing surveillance by health fitness professionals for changes in symptoms that required intervention, staff resources for health fitness professionals, use of lymphedema compression garments, and periodic review of injury and other event rates through the clinical trial protocol. “Clinicians should refer breast cancer survivors to physical therapists with specific training in oncology or highly trained health fitness professionals (ie, certified cancer exercise specialists),” the authors wrote. ●
SEPTEMbER 2012 I VOL 5, NO 8
The Patient’s Voice
Caring for the Caregivers from, and then permanently left, his new position. Both traveled cross-country to a new city (the closest decent hospital covered by my insurance was 600 miles from our home city) to spend 8 months both in/near the hospital with me or at home with their younger sisters. Of course, my 2 younger daughters also sacrificed to take care of me: in seventh and ninth grades, they flew out as often as possible to sit by my bed and fetch me water, order food, and listen to my delirious rants when the medication took over my mind. They spent their summer vacation sitting with me every day, all day. As the patient, I recognize the sacrifices each of my children made to help me through what I hope was the worst part of my illness. I am eternally grateful for both their existence and their family commitment. Given that they are my children, their well-being is my number one priority in life. So, when not asleep or too drugged to live in my own reality, I noticed every detail of how my nurses treated my precious caregivers. I must say, the recognition and respect given to my children/caregivers ranged from a 1 (horrific, mean, disdainful treatment) to a 10 (complete respect, recognition, and gratitude), with an overall average of an 8/10, or about a B- on a traditional grading scale. Was there room for improvement? Sure! Was I happy overall with the way most nurses treated my caregivers? Without a doubt! So, for those nurses who want to improve their treatment of caregivers and those who want to know what I, as a patient, appreciate about your treatment of them, I have compiled my “Three Best Practices for Nurses in Their Treatment of Caregivers,” all requiring minimal extra effort on behalf of nurses, all of equal importance, and all incredibly important to me as the patient: 1. Greet the Caregiver Directly When a nurse first comes into my room, I notice whether she/he introduces her/himself to my caregiver (she/he always introduces her/himself to me). It does not have to be a long drawn-out greeting, just eye contact and a “Hello, my name is ________, and I am going to be the nurse for this shift.” From then on, a simple “Hi.
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How are you doing?” or something similar directed to the caregiver suffices. This greeting, or lack thereof, greatly influences my perception of how qualified my nurse is. After all, a nurse who is observant and courteous has probably been well-trained and recognizes that good medical care is holistic medical care—it includes not only scientific processes, but also the human component. 2. Make Sure the Caregiver Is Comfortable at Night This is the most oft-forgotten aspect of proper caregiver care in my experience. If the caregiver is going to spend the night in the hospital with the patient, it is imperative that he/she is comfortable. In my case, many-a-night my caregiver did not have sufficient blankets, pillows, or sheets for a comfortable stay. We constantly had to ask for them, and we often waited hours until they were brought, if they ever were. I understand the demand from patients for these necessities, but caregivers are an integral part of the care system, too (and they work for free, at least for the hospital!). If it is true that when the floor is full there are no extras to go around, then nurses need to make it known that the wash schedule or the supply quantities simply do not meet minimal needs. Please do not make us beg and constantly remind you. I, as the patient, need to get my rest (you, my trusted nurse, told me so!). I cannot do that if I perceive that my caregiver is extremely uncomfortable (have you ever tried to sleep with no pillow, sheet, or blanket on that vinyl expanding couch in the hospital room?). Please just make sure you remember to bring the bedding for my caregiver. 3. Acknowledge the Connections All the caregivers I meet in the hospital have a life outside of their caregiver role, and all give up something (free time, income, schooling, hobbies, time with other children, etc) to be there. Some are spouses who work and spend their off-hours in the hospital. Some are volunteers who spend a few hours sitting with strangers. Others are retired workers who pass
hours on end at the hospital. Still others are children of patients. Regardless of the sacrifices necessary and regardless of whether, deep down, they want to be there, fate thrust them into the caregiver role. But, like all of us (including patients and nurses), they are so much more than that role; they are caregivers and _________ (fill in the blank: runners, “Twihards,” scientists, metal workers, students, unemployed teachers, grandparents, bridge champions, “Potterheads,” krumpers, or an endless combination of an infinite number of other roles). Some of my most triumphant moments in the hospital came when a nurse would comment to one of my caregivers, “Hey, I noticed you have on a Boston Red Sox cap. How are they doing this season?” or “You look like you might be in high school. I have a daughter who looks around your age, and she loves that book you are reading, too. What do you like about it?” It can be something as simple as comparing favorite colors, exchanging a few words that show you noticed something about the caregiver, or making a comment about a view outside the window. I
Do you talk to patients about the importance of adherence to their medications? r Yes r No
Go to www.TheOncologyNurse.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.
Clinical Approaches to Targeted Technologies REGISTER TODAY AT www.globalbiomarkersconsortium.com SEPTEMbER 2012 I VOL 5, NO 8
MMA is undergoing treatment for cancer. She wishes to use her initials.
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know nurses are busy and often do not have time for small talk. Yet, when possible, such comments can be essential to lifting the morale of both the patient and the caregiver (and maybe even nurses) by creating a community of humans who get recognized for who they are outside the confines of the hospital. No matter how small the connection, there is one. Please just look for it. I know that most nurses recognize that caregivers deserve undying respect. Apart from their function for the patient, let’s face it: they cover some of the duties that otherwise would have to be assumed by the nurse (do I hear helping the patient to the restroom, cleaning up minor accidents, getting ice, and filling water cups?). For those of you who treat my caregivers with humanity and care (even when you only get monosyllabic answers), thank you! For those of you who are really not too sure how to treat them, please try to implement a few of the practices mentioned above. We will all be better for it. ●
October 4-6, 2013 The Seaport Boston Hotel 1 Seaport Lane Boston, MA 02210
MULTIPLE MYELOMA NEVER GIVES UP.
BUT NEITHER DO WE.
For 15 years, Celgene has been working to develop innovative therapies and has partnered with the multiple myeloma community to advance patient care. We’re relentless. We’re persistent. We’re progressive. And we’re not done yet.
© 2012 Celgene Corporation
Progress in Treating Prostate Cancer Continued from cover
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 combina-
tion therapy could improve outcomes for a substantial number of men with early high-risk prostate cancer,” stated
CRPC. Primary end point results for OS reported earlier showed that enzalutamide significantly improved OS by
“These results…suggest that this combination therapy could improve outcomes for a substantial number of men with early high-risk prostate cancer.” —Mary-Ellen Taplin, MD
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. 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 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
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.
Photo © ASCO/Silas Crews 2012.
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.
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. 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
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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SEPTEMbER 2012 I VOL 5, NO 8
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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.
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
• 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®
0 SOC Nplate®
Incidence of Treatment Failure at 1 Year
60 Patients (%)
Mean (SE) platelet count (109/L)
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
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
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• 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.
11% 18/157 Nplate®
!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%
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.
Including betamethasone, dexamethasone, methylprednisolone, prednisolone, and prednisone.
2% 7% 6%
Including anti-D immunoglobulin and intravenous immunoglobulin.
Rituximab is not FDA approved for treatment of ITP.
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
less P = 0.02
8 events 10 events 21 events 34 events in 7294 in 3050 in 3050 in 7294 patient-weeks patient-weeks patient-weeks patient-weeks
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 0AIN IN %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 NplateÂŽ have been performed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of NplateÂŽ 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. NplateÂŽ 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 NplateÂŽ use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the NplateÂŽ 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 NplateÂŽ 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 NplateÂŽ, a decision should be made whether to discontinue nursing or to discontinue NplateÂŽ, taking into account the importance of NplateÂŽ 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 NplateÂŽ 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 NplateÂŽ with caution in this population. Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment. Use NplateÂŽ 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 NplateÂŽ and monitor platelet counts. Reinitiate treatment with NplateÂŽ 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. ÂŠ 2008-2012 Amgen Inc. All rights reserved. www.nplate.com v5 64256-R2-V1
Side Effect Management
Chemotherapy-Induced Peripheral Neuropathy Increases Risk of Falls and Physical and Functional Problems, Especially in Older Patients By Alice Goodman
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
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. ● 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.
Severe Diarrhea Associated With Molecularly Targeted Agents Can Impact Quality of Life and Healthcare Resource Utilization
preliminary report of a metaanalysis of clinical trials of molecularly targeted therapies shows that they are not benign and can add to the toxicity of standard chemotherapy. In particular, increased rates of oral mucositis and diarrhea are reported with several US Food and Drug Administration (FDA)-approved agents. Increased mucositis seen with bevacizumab and erlotinib does not appear to be clinically significant, but severe diarrhea occurs with a number of targeted agents and has a potential impact on quality of life (QOL) and healthcare resource utilization. The meta-analysis provides some perspective on toxicities associated with molecularly targeted agents, and preliminary findings were presented at the 2012 Multinational Association of Supportive Care in Cancer (MASCC) International Symposium, held in New York City.
“We know oral and gastrointestinal mucositis reduce quality of life, increase healthcare resource utilization and costs, and can lead to treatment delays and dose reductions, which interfere with treatment efficacy. There are no systematic reviews of toxicities of targeted agents, and trials are inadequately powered to look at toxicity. We get around this with meta-analysis to come up with more precise estimates of toxicities,” explained Linda Elting, DrPH, of the M.D. Anderson Cancer Center in Houston, Texas. Elting and colleagues searched the literature for molecularly targeted therapies, limiting the search to randomized, controlled phase 2 or 3 clinical trials of FDA-approved targeted drugs and approved indications for those drugs. The 78 studies they included compared current standard of care with standard of care plus a molecularly targeted drug. The studies had different
designs, treatment regimens, and dose differences. All studies listed all-grade toxicity as well as grade 3, 4, and 5 separately. “We included only drugs for which at least 3 papers were published,” she explained. Bevacizumab was associated with an increase in all-grade oral mucositis, and the risk of grades 3 and 4 was increased 5-fold compared with standard therapy alone. The risk increases with higher doses. Elting remarked that the absolute risk of grades 3 and 4 mucositis was low, only around 3%, with the addition of bevacizumab-targeted therapy. “The risk of [severe] mucositis with bevacizumab is very low and does not appear to be a clinically significant finding,” she stated. A 5-fold increase in all-grade oral mucositis was found with erlotinib, but no increase in grades 3 and 4 was observed compared with standard ther-
apy alone. “As with bevacizumab, this is not clinically significant and is limited to low-grade oral mucositis,” she said. “Diarrhea is a hallmark of targeted therapy, so don’t be surprised by high rates,” she told listeners. With both trastuzumab and lapatinib, all grades of diarrhea are increased when added to standard therapy. A 10fold increase in grades 3 and 4 diarrhea is reported with trastuzumab, with an absolute increased risk of 12%. “This could be important for clinical care and resource utilization,” Elting commented. “Lapatinib, erlotinib, cetuximab, gefitinib, and sorafenib are also associated with increased risk of diarrhea, including a 2- to 5-fold increase in grades 3 and 4 diarrhea, which is clinically significant and has a clear impact on quality of life and resource utilization,” she stated.—AG ●
SEPTEMbER 2012 I VOL 5, NO 8
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-
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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 transfusionrelated 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 sponta-
neous 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 shortterm treatment with other therapies (most commonly glucocorticoids), which was required in 44% of the romiplostim group versus 79% of those receiving standard of care. 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 usually 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 romi-
Immune Thrombocytopenia plostim, 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 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 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 hetero-
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
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.
geneity of the data makes it difficult to confidently 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
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 romiplostim will buy them this time to perhaps avoid splenectomy, to plan for splenecto-
my 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.
Online Exclusive To read a nursing perspective about treating patients with immune thrombocytopenia, visit
www.TheOncologyNurse.com/ITP Laura Milligan, MSN, FNP, BC, AOCN, focuses on presentation, diagnosis, and nursing management in ITP.
SECOND ANNUAL CONFERENCE
• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma
July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive • San Diego, California
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Hereditary Cancer Support Organizations By Cristi Radford, MS, CGC
hat do you get when you combine the terms predisposition and survivor? The term previvor. A previvor is an individual who has not had cancer but is at increased risk due to a gene mutation or family history. He or she is a survivor of a predisposition to cancer. According to Sue Friedman, the founder of Facing Our Risk of Cancer Empowered (FORCE), the term originated in 2000 as a result of a challenge on its message board with a poster stating “I need a label!” “As a result, FORCE developed and promoted the term ‘cancer previvor’ for ‘survivor of a predisposition to cancer.’ ”1 The use of the term has continued to grow. In 2007, Time magazine listed it as the number 3 buzzword of the year, and in 2010 the US House of Representatives declared the last Wednesday of September National Previvor Day. This year, that date is September 26. Be sure to check in your community for planned events. The coining and evolution of the term previvor is one example of the importance of patient support organizations focused on hereditary cancer. Not only do these organizations raise awareness, they also fulfill patient needs that are not met by traditional cancer support organizations. As a genetic counselor, I have lost count of the number of times I have been asked “Where are the people like me?” Previvors often express that they do not fit in at cancer support organizations because they are not survivors, while survivors of hereditary
Cristi Radford, MS, CGC
cancer often express frustration because traditional organizations do not have the specific resources they seek. However, for patients to benefit from hereditary cancer organizations, they must first be made aware of them. Below is a list of some of the organizations with a focus on hereditary cancer. Cowden Syndrome Online support groups: http://health.groups.yahoo.com/ group/cowdensyndrome/ http://www.ptenworld.com/ Hereditary Breast and Ovarian Cancer Bright Pink http://www.brightpink.org/ “Bright Pink is a national non-profit organization that provides education and support to young women who are at
high risk for breast and ovarian cancer. We arm young women with knowledge, options and a great attitude, and offer companionship and empathy during their journey. We empower them to take control of their breast and ovarian health and in turn, grant them the freedom and peace of mind to live a beautiful and fulfilling life.” Facing Our Risk of Cancer Empowered (FORCE) http://www.facingourrisk.org/ “FORCE is the only national nonprofit organization devoted to hereditary breast and ovarian cancer. Our mission includes support, education, advocacy, awareness, and research specific to hereditary breast and ovarian cancer. Our programs serve anyone with a BRCA mutation or a family history of cancer.” Sharsheret http://www.sharsheret.org/ “Sharsheret, Hebrew for ‘chain,’ is a national not-for-profit organization supporting young women and their families, of all Jewish backgrounds, facing breast cancer. Our mission is to offer a community of support to women diagnosed with breast cancer or at increased genetic risk, by fostering culturally-relevant individualized connections with networks of peers, health professionals, and related resources.” Familial Adenomatous Polyposis (FAP) FAP Gene Support Group http://www.fapgene.com/
Have you treated adult patients who are survivors of childhood cancer? In the August issue, we published an article about the growing number of adults worldwide who are childhood cancer survivors. The article explored the challenges that face these survivors, including the likelihood that two-thirds of survivors will have at least 1 chronic condition as a consequence of their childhood treatment. We asked our online reading community if they had treated any adults who were survivors of childhood cancer. • 39% said they had treated adults who survived childhood cancer • 61% indicated they had not treated such patients Several of our online readers described the circumstances of their treatment of adult survivors of childhood cancer, including one reader treating a 19-year-old patient with breast cancer who survived acute myelogenous leukemia as a child.
Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 8 for details.
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Hereditary Diffuse Gastric Cancer No Stomach for Cancer http://www.nostomachforcancer.org/ “We advance awareness and education about stomach cancer, including Hereditary Diffuse Gastric Cancer (HDGC), provide a support network for affected families, and support research efforts for screening, early detection, treatment, and prevention of stomach cancer.” Li-Fraumeni Syndrome (LFS) Li-Fraumeni Syndrome Association http://www.lfsassociation.org/ “LFS Association provides a wide range of information, advocacy, and support services for individuals and families with Li-Fraumeni Syndrome. We support a consortium of researchers, medical providers and caregivers to further research and promote optimal care for the LFS community.” Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer Colon Cancer Alliance for Research and Education for Lynch Syndrome http://www.fightlynch.org/ “Our mission is to educate the public and health care professionals about Lynch syndrome and to help fund research for a cure for this disease.” Lynch Syndrome International http://www.lynchcancers.org/ “The primary mission of Lynch Syndrome International (LSI) is to serve our global communities by focusing on providing support for individuals afflicted with Lynch syndrome, creating public awareness of the syndrome, educating members of the general public and health care professionals and providing support for Lynch syndrome research endeavors.” Multiple Endocrine Neoplasia Association for Multiple Endocrine Neoplasia Disorders http://www.amend.org.uk/ “The Association for Multiple Endocrine Neoplasia Disorders (AMEND) is an international patient group set up in 2002 to support and inform anyone affected by or interested in multiple endocrine neoplasia disorders and their associated endocrine tumours.” Peutz-Jeghers Syndrome and Juvenile Polyposis Syndrome Online support group: http://listserv.acor.org/scripts/ wa-ACOR.exe?A0=PJS ● Reference 1. Friedman S. Previvor: past, present & future. FORCE Web site. http://facingourrisk.wordpress.com/2008/07/22/ previvor-past-present-future/. Posted July 22, 2008. Accessed August 16, 2012.
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Through the Eyes of an Advocate: The American Association for Cancer Research Conference By Peg Ford
arrived in Chicago the day before the start of the 103rd Annual Meeting of the American Association for Cancer Research (AACR), filled with anticipation. I was feeling very lucky to be selected again to participate in AACR’s Scientist Survivor Program, whose goal is to build bridges and unity among the leaders of the scientific and cancer survivor and patient advocacy communities worldwide. After considerable prior communications, I was looking forward to finally meeting the advocates in my working group, as well as those in the other groups, as 27 advocates representing all different cancer disease tracks gathered at the first luncheon to prepare for the meeting. Waiting for us was the esteemed faculty of scientific researchers and mentors, ready to give of their time, energy, and experience to educate, assist, and guide us, as well as answer as many questions as we could fire at them. The credentials and influence of our group’s scientific advisors was beyond amazing: Jimmie C. Holland, MD (http://www. ipos-aspboa.org/bios/holland_ ipos.asp): Chairperson, Department of Psychiatry & Behavioral Sciences, Memorial Sloan-Kettering Cancer Center; Cofounder, International Psycho-Oncology Society and Psycho-Oncology. Dr Holland is thought of as the “mother of psychooncology.” Alex Adjei, MD, PhD, FACP (http:// www.roswellpark.org/alex-adjei): Senior Vice President of Clinical Research, Professor and Chair, Department of Medicine, the Katherine Anne Gioia Chair in Cancer Medicine, Roswell Park Cancer Institute; Academic Scholar in Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo. Barton A. Kamen, MD, PhD (http:// www.youtube.com/watch?v=fwimWE jr6Y0 and http://www.youtube.com/ watch?v=H2QiYrOvgRM): American Cancer Society Clinical Research Professor, Professor of Pediatrics and Pharmacology, Robert Wood Johnson Medical School. Patricia S. Steege, PhD (http://ccr. cancer.gov/staff/staff.asp?profileid= 5851): Head, Women’s Cancers Section, Senior Investigator, Laboratory of Molecular Pharmacology, National Cancer Institute. The meeting offered a range of special interest sessions covering a wide scope of important topics from which to choose, including Physical & Biological Sciences; Metastasis—Nature & Nur➤
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Peg Ford in front of her poster presented at the AACR conference.
ture; Patient-Scientist Partnerships in Personalized Medicine; Update—The Genome Atlas; and Tumor Microenvironment, all providing unequaled access to the impressive list of scientific researchers. From day 1, I was enthralled with the educational sessions, plenary sessions, meet-the-expert sessions, and poster sessions I was able to squeeze into my schedule, having to make hard decisions about which ones to attend as the meeting lived up to its theme: “Forging Partnerships to Accelerate Progress Against Cancer.” It was particularly gratifying to participate with my fellow advocates in a poster session
Peg Ford at the AACR conference with Lee M. Ellis, MD, of the University of Texas M.D. Anderson Cancer Center.
where we proudly displayed our posters describing our advocacy efforts right alongside those of the researchers in the main poster section. One of the high-
lights for me was communicating with the crowd when I had the honor of having my poster viewed by some of the esteemed faculty, including Lee M. Ellis,
mass production of sequencing will be available to all patients, who will then be able to present their USB flash drive to their physician; however, the key
The cutting-edge information presented at the conference boggled the mind with possibilities.
MD, of the University of Texas M.D. Anderson Cancer Center; Laura Shawver, PhD, of the Clearity Foundation; Zhong-Qian Li, PhD, Principal Development Scientist at Fujirebio Diagnostics; and Lauren Pecorino, PhD, Principal Lecturer and Bioscience Programme Leader of the University of Greenwich School of Science in the United Kingdom, just to name a few. Because I am in training to participate in the FDA Patient Representative Program, I was drawn to hear updates on concepts in clinical trials. For example, I attended the meet-the-expert session presented by George W. Sledge, Jr, MD, entitled “Lessons From Clinical Trials of Targeted Therapy in Cancer,”1 where I was inspired by his analysis of the next generation of clinical trials based on personal genome sequencing, real-time bioinformatics, increased collaboration, trial design focused around multitargeting, redesigned informed consent process (more user friendly), and different regulatory apparatuses. It is clear that we have entered the “Genomic Era,” where, very shortly,
question, especially initially, will be whether the physician will be able to do something about the information. The cutting-edge information presented at the conference boggled the mind with possibilities. For example, will it be possible to normalize tumor vessels for better reception of chemotherapy via the use of angiogenesis therapy to reach and open closed-off blood vessels and nonfunctional lymphatic vessels, thereby normalizing the tumor environment to improve therapeutic outcomes? As cancer can be a genetic disease, will genetic analysis covering all cancer disease tracks continue to affect how we study and treat cancer, moving us more toward personalized treatment for each patient? I was able to view Zhong-Qian Li and colleagues’ poster “Detection of Serum CYFRA 21-1 as a Biomarker for Stratification of Ovarian Cancer Risk of a Pelvic Mass,” a nonprofit preliminary study by an industry company for the scientific community.2 CYFRA 21-1 is a known lung cancer biomarker. This pilot study was designed to evaluate
Patient Advocacy create a system to identify markers and molecular signatures and utilize clinical characteristics and molecular profiling to match the right person to the right drug. With the privilege of attending and participating in AACR’s Scientist Survivor Program this year, I felt an upsurge of excitement at the conference. One thing is certain: We advocates must continue to share with our ‰
serum CYFRA 21-1 as a biomarker for stratification of ovarian cancer risk in women with a pelvic mass. The subject demographics covered premenopausal women (median age, 43.3 years) and postmenopausal women (median age, 64.2 years). Results were encouraging, with serum ARCHITECT CYFRA 211 demonstrating a sensitivity of 76%, a specificity of 95%, a positive predictive value of 82%, a negative predictive value of 92%, and a likelihood ratio (+) of 14, with a cutpoint at 1.8 ng/mL. The authors concluded that serum CYFRA 21-1 appears to be a useful biomarker for stratification of ovarian cancer risk in women with a pelvic mass.2
I have the sense that we
legislative representatives and patient communities how important it is to continue funding research to support these efforts, as I have the sense that we are getting close to revolutionizing cancer treatment and research. l References 1. Sledge GW Jr. Lessons from clinical trials of targeted therapy in cancer. Presented at: American Association
for Cancer Research Annual Meeting; March 31-April 4, 2012; Chicago, IL. 2. Li Z-Q, Smalley RJ, Glover CL, et al. Detection of serum CYFRA 21-1 as a biomarker for stratification of ovarian cancer risk in women with a pelvic mass. Presented at: American Association for Cancer Research Annual Meeting; March 31-April 4, 2012; Chicago, IL; Abstract 3574. 3. Kamen B. What is wrong with the way we deliver chemotherapy—metronomic therapy: is it really a new paradigm for chemotherapy, or simply rediscovering the wheel? Presented at: American Association for Cancer Research Annual Meeting; March 31-April 4, 2012; Chicago, IL.
Pushing Your Limits
are getting close to revolutionizing cancer treatment and research.
In addition, I was delighted to attend a special session by Barton Kamen, MD, PhD, entitled “What Is Wrong With the Way We Deliver Chemotherapy?”3 The opening remarks of his lecture “Metronomic Therapy: Is It Really a New Paradigm for Chemotherapy, or Simply Rediscovering the Wheel?” had me sitting straight up in my chair: “At some EFFECTIVE DOSE, TIME is the more significant variable in cell kill! Metronomic dosing schedule Rx involves dosing at constant intervals. It is an implied use of lower doses to minimize toxic side effects and eliminate the obligatory rest periods.”2 A move toward dosing at constant intervals (ie, metronomic therapy, or maintenance dosing) may be the new norm in chemotherapy treatment, rather than the optimal dose-schedule involving the maximally tolerated dose and doselimiting toxicities. From my own personal severe adverse reaction to just 4 days of treatments on cycle 1 of chemotherapy, and from the unsettling experiences of other cancer survivors, is metronomic therapy indeed rediscovering a more gentle yet more effective approach to chemotherapy treatment? Finally, can we reach the goal stated by the US Department of Health and Human Services Secretary, Kathleen Sebelius, to “…prescribe the right treatment, to the right person, at the right time…”? I wondered if we were closer to a breakthrough toward this goal when William Dalton, MD, PhD, of the H. Lee Moffitt Cancer Center & Research Institute, mentioned in his session the term precision medicine, where we can
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sepTember 2012 I VOL 5, NO 8
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
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P<.0001 HRâ€ =0.27 (95% CIâ€Ą: 0.17, 0.43)
Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â€ HR=hazard ratio. â€Ą CI=confidence interval.
s 42%!.$! WAS COMPARED WITH CHLORAMBUCIL IN A RANDOMIZED OPEN LABEL PHASE TRIAL IN TREATMENT NAĂ•VE PATIENTS WITH "INET STAGE "