MelanomaRecent Advances in the Treatment of Metastatic MelanomaMegan Hagerty, PharmD, BCOP
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7% 8%CR
43% 42%
ORRPrimary Endpoint
11% 12%
CR
53% 51%
ORR
SC (n=148)IV (n=74)
Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint
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RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV
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! The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE
SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety.
* INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
†Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1
VELCADE IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.
WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ! Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients
with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ! Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope,
and those who are dehydrated! Closely monitor patients with risk factors for, or existing heart disease ! Acute diffuse infiltrative pulmonary disease has been reported! Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal
medications or fluid replacement! Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment! Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported
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a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification g
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AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone
AT 12 WEEKS (AFTER 4 CYCLES)Single-agent VELCADE® (bortezomib)
NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION IN ALL INDICATIONS*
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6%16%
GRADE !3
38%53%
SC (n=147)IV (n=74)
ALL GRADES
Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE
PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IVR
Please see Brief Summary for VELCADE on next page.
For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.comReference: 1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.
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! Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment
! Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness
! Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN
WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED! Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the
potential harm to the fetus
! Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended
ADVERSE REACTIONS Most commonly reported adverse reactions (incidence !30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported
INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
CONTRAINDICATIONS:VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.
WARNINGS AND PRECAUTIONS:VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.
Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ! Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ! 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ! 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ! Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ! Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.
Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been 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). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.
ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of !Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).
In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).
In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.
DRUG INTERACTIONS:Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.
USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.
Geriatric Use: No overall differences in safety or effectiveness were observed between patients ! age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.
Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.
Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.
Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Please see full Prescribing Information for VELCADE at VELCADEHCP.com.
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EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK
ASSOCIATEEDITOR-IN-CHIEFSteve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL
John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT
David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA
Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA
Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME
Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY
EDITORIAL CORRESPONDENCE should beaddressed to EDITORIAL DIRECTOR, The OncologyPharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp,NJ 08831. E-mail: [email protected]. YEARLYSUBSCRIPTION RATES: United States and posses-sions: individuals, $105.00; institutions, $135.00; singleissues, $17.00. Orders will be billed at individual rate untilproof of status is confirmed. Prices are subject to changewithout notice. Correspondence regarding permission toreprint all or part of any article published in this journalshould be addressed to REPRINT PERMISSIONSDEPARTMENT, Green Hill Healthcare Commun i -cations, LLC, 241 Forsgate Drive, Suite 205C, MonroeTwp, NJ 08831. The ideas and opinions expressed in TheOncology Pharmacist® do not necessarily reflect those of theEditorial Board, the Editorial Director, or the Publisher.Publication of an advertisement or other product mentionin The Oncology Pharmacist® should not be construed as anendorsement of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damage topersons or property arising out of or related to any use ofthe material contained in this periodical. The reader isadvised to check the appropriate medical literature and theproduct information currently provided by the manufac-turer of each drug to be administered to verify the dosage,the method and duration of administration, or contraindi-cations. It is the responsibility of the treating physician orother healthcare professional, relying on independent expe-rience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every efforthas been made to check generic and trade names, and toverify dosages. The ultimate responsibility, however, lieswith the prescribing physician. Please convey any errors tothe Editorial Director. BPA Worldwide membershipapplied for April 2011.
Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™
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241 Forsgate Drive, Suite 205CMonroe Twp, NJ 08831
6 MAY 2012 I VOL 5, NO 3 www.TheOncologyPharmacist.com
This month’s Fourth Annual Review Issue of TheOncology Pharmacist (TOP) highlights some of theadvances in cancer care over the past year. While
this issue presents several of the most noteworthy devel-opments, we could only scratch the surface of all that hashappened in the world of oncology. One needs only tolook at the total number of abstracts presented at theAmerican Society of Hematology and the AmericanSociety of Clinical Oncology annual meetings to knowhow much potentially practice-changing research is in thepipeline. Some of these developments have been present-ed in previous issues, while others will be featured inupcoming issues as researchers release updated data fromongoing studies.
Although each issue of TOP features articles that illustrate
how rapidly practices are changing—everything from theexpanding use of oral oncolytics to the increasing role of per-sonalized medicine in oncology—this issue in particularpoints out how important it is for oncology pharmacists to beaware of all these advances both for themselves and for theirpatients. Newer therapies bring about changes to daily prac-tice, and informed pharmacists can better help their patientsunderstand these treatments.
Visit our Web site, www.TheOncologyPharmacist.com, and tell us how you feel about what you see inTOP—in print and online. We want to know the positiveand the negative. Let us know what topics you want us tocover. Is there a specific issue you would like us to exam-ine? We want to hear from you and we appreciate yourfeedback. !
From the Editors
Patrick Medina, PharmD, BCOPEditor-in-Chief
Steve Stricker, PharmD, MS, BCOPAssociate Editor-in-Chief
Noteworthy Numbers
Lung cancer (both smallcell and non–small cell) is the second most com-mon cancer in both men(after prostate cancer) and women (after breastcancer).
Approximately 14% of all new cancers are lungcancers.
The ACS’s most recentestimates for lung cancerin the United States for2012 include:
• New diagnoses totaling226,160
" 116,470 in men" 109,690 in women
• An estimated 160,340deaths
" 87,750 in men" 72,590 in women
• Deaths will account forapproximately 27% ofall cancer deaths
Lung cancer occurs moreoften in older people.
From 2004-2008, the aver-age age at the time of lungcancer diagnosis wasapproximately 71 years; thepercentage of patients diag-nosed according to age wasapproximately:
• 0.2% between 20 and 34• 1.6% between 35 and 44• 8.8% between 45 and 54• 20.9% between 55 and 64• 31.1% between 65 and 74• 29.0% between 75 and 84 • 8.3% for 85+ years of age
Since 1994, death rates havedeclined consistently for
men at a rate of about 3%each year. Currently, therisk of developing lungcancer during a man’s life-time is about 1 in 13.
After increasing for severaldecades, the death rates forwomen with lung cancerhave stabilized since 2003.
Currently, the possibility ofdeveloping lung cancer islower for women thanmen—about 1 in 16.
The 1-year survival ratefor all people diagnosedwith lung cancer is 43%.
The leading cause of cancer death among men and women is lung cancer. According to the AmericanCancer Society (ACS), more people die of lung cancer than of breast, colon, and prostate cancers com-bined. Because this deadly disease affects so many Americans, lets delve into these lung cancer–relat-ed statistics.
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 6
The link between cancer andthrombosis has been known formany years. Recently this con-
nection has come to the forefront withincreased recognition by healthcareproviders and mandates by governingbodies. The results of a thromboembolicevent can be catastrophic in a patientwith cancer. Malignant neoplasms aloneare associated with a 4-fold increased riskof a venous thromboembolic event(VTE), and cytotoxic or immunosup-pressive chemo therapy in creases themalignant neoplasm–associated risk tomore than 6-fold.1,2 VTE leads to a sig-nificant reduction in survival3-5 and isthe second-leading cause of death inpatients with cancer.6 Patients withcancer who have a VTE are also atincreased risk of recurrence, bleedingcomplications, and morbidity.7
Patients with cancer have multiplefactors that increase their risk of VTE.First, the cancer itself produces a hyper -coaguable state for these patients.Certain cancers appear to carry a high-er risk than others (malignant braintumors; adenocarcinoma of the lung,ovary, pancreas, colon, stomach,prostate, and kidney; and hematologicmalignancies),8 but all cancers willincrease the patient’s overall VTE risk.
The patient’s therapy also plays amajor role in the risk of VTE. Manynewer chemotherapeutic agents, suchas bevacizumab, carry an increased riskof thromboembolism.9 VTE riskincreases 2- to 5-fold when womenwith breast cancer are treated withtamoxifen.10,11 Aromatase inhibitorsalso increase this risk, but at about halfthe rate of tamoxifen.12 Thalidomideor lenalidomide increases throm boem-bolic risk, especially when used in com-bination with chemotherapy or high-dose dexamethasone.13 All of these areadditive to the other general risk fac-tors that these patients may already beexposed to, such as decreased mobility,surgeries or procedures, age, indwellingcatheters, and other comorbidities.
Due to the high risk faced by cancerpatients, many guidelines have beendeveloped to help assist in the preven-tion and treatment of thromboembolicevents in these patients. The NationalComprehensive Cancer Network(NCCN), American Society of ClinicalOncology (ASCO), and the AmericanCollege of Chest Physicians (CHEST)
have issued guidelines to help practi-tioners prevent and treat thrombosis inpatients with cancer. These guidelineshave much overlap in their recommen-dations, and rightfully so. I will attemptto give a brief summary of some of theseguidelines specific to patients with can-cer (Table).
For prevention of VTE, all 3 societiesagree that pharmacologic prophylaxisshould be initiated in hospitalized cancer patients in the absence of con-traindications.14-16 Low-dose unfrac-tionated heparin (LDUH), low-molecular-weight heparin (LMWH),or fondaparinux should be utilized.Pharmacologic prophylaxis would becontraindicated in patients who arebleeding or have a high risk for majorbleeding. In these patients, considermechanical prophylaxis with graduatedcompression stockings or intermittentpneumatic compression. If the throm-botic risk persists once the bleeding riskhas subsided, the use of pharmacologicprophylaxis should be reassessed and sub-stituted for mechanical prophylaxis.
For prevention of VTE in the surgicalpatient with cancer, again all 3 societiesagree. The guidelines recommendextended prophylaxis for surgical cancerpatients for up to 4 weeks, particularly inhigh-risk abdominal or pelvic sur-gery.14,15,17 All 3 recommend LMWH.NCCN and ASCO also support unfrac-tionated heparin as an alternative, andNCCN supports fondaparinux as well.Mechanical methods can be added topharmacologic prophylaxis in patients athighest risk.
For patients in the ambulatory setting,the societies previously agreed that rou-tine prophylactic anticoagulation wasnot recommended except in patientswith multiple myeloma who werereceiving thalidomide- or lenalidomide-based combination regimens and inwhom the risk of VTE warranted pro-phylaxis.14,15 The latest additions to theCHEST guidelines have extended thisrecommendation. These guidelines sug-gest that outpatients with solid tumorswho have additional risk factors for VTEbut who have a low risk for bleeding use
prophylactic doses of LMWH or LDUHover no prophylaxis.16 The additionalrisk factors include previous thrombosis,immobilization, hormonal therapy,angiogenesis in hibitors, and againthalidomide or lenalidomide therapy.This recommendation is based on mod-erate-quality evidence of reduction inmortality and high-quality evidence ofreduction in VTE. These effects werelarger than any plausible increase inbleeding risk.
For patients with cancer who haveindwelling central venous catheters(CVCs), routine prophylactic anticoagu-lation is not recommended.14-16 Over thenext few years, more evidence maybecome available on the efficacy andcost-effectiveness, and specific groups ofpatients with CVCs that may benefitfrom prophylaxis, taking into considera-tion VTE risk versus bleeding risk.
Prevention and Treatment ofThromboembolism in Patients WithCancerBy Aaron D. Dush, PharmD, CACPThe Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University
Aaron D. Dush, PharmD, CACP
Table Recommendations for Prevention and Treatment of VTE in Patients With Cancer
ASCO CHEST NCCN
Prevention of VTE in thehospitalized patient withcancer
Prophylactic anticoagulationconsidered for all in theabsence of contraindications
Prophylactic anticoagulationconsidered for all in theabsence of contraindications
Prophylactic anticoagulationconsidered for all in the absence of contraindications
Prevention of VTE in thesurgical patient with cancer
Extended prophylaxis up to 4 weeks postprocedure high-risk surgery
Extended prophylaxis up to 4 weeks postprocedure high-risk surgery
Extended prophylaxis up to 4 weeks postprocedure high-risk surgery
Prevention of VTE in theambulatory patient withcancer
Not recommended exceptwith thalidomide/lenalidomide-based regimens
Prophylactic anticoagulationsuggested in patients withsolid tumors who have addi-tional risk factors for VTEand who are at low risk ofbleeding
Not recommended except withthalidomide/lenalidomide-based regimens
Prevention of VTE inpatients with CVC andcancer
Not recommended Not recommended Not recommended
Treatment of VTE inpatients with cancer
LMWH preferred and treatedindefinitely as long as cancerpersists
LMWH preferred and treatedindefinitely as long as cancerpersists
LMWH preferred and treatedindefinitely as long as cancerpersists
Treatment of catheter-related thrombosis inpatients with cancer
Anticoagulation as long ascatheter is in place or at least3 months after removal
Anticoagulation as long ascatheter is in place or at least 3 months after removal
Abbreviations: ASCO, American Society of Clinical Oncology; CHEST, American College of Chest Physicians; CVC,central venous catheter; LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network;VTE, venous thromboembolic event.
Continued on page 8
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Prevention and Treatment of Thromboembolism... Continued from page 7
For treatment of VTE in cancerpatients, therapy is driven by the find-ings of the CLOT trial.18 This trial wasconducted over a 6-month period. Itcompared the efficacy of LMWH (dal-teparin) to oral anticoagulation in the
prevention of recurrent thrombosis inpatients with cancer. The trial showedno significant difference in bleedingrisk or 6-month mortality but did showa statistically significant difference in recurrent thromboembolism at 6
months favoring the LMWH group.When treating cancer patients who
have a pulmonary embolism (PE) ordeep vein thrombosis (DVT), LMWHis the preferred agent. These patientsshould be treated indefinitely as long
as they have active cancer or risk fac-tors persist.14,15,19 Well-managed vita-min K antagonists, such as warfarin,may be an acceptable alternative whenLMWH is not advisable. This may betrue in patients who cannot affordLMWH, patients who are opposed todaily injections, or those who haverenal insufficiency.
As for the dose of LMWH, in theCLOT trial dalteparin was given at200 IU/kg once daily for the firstmonth then 150 IU/kg once daily forthe remaining 5 months.18 Enoxaparincarries an indication for inpatienttreatment of DVT with or without PEat a dose of 1 mg/kg every 12 hours or1.5 mg/kg every 24 hours. For outpa-tient DVT without PE, the indicateddose is 1 mg/kg every 12 hours.20 Bothindications are in conjuction with theinitiation/administration of warfarin.The quality of evidence comparingonce-daily versus twice-daily LMWHis low because of impression andinconsistency in studies comparing the2 types of administration. A meta-analysis of studies showed similar ratesof mortality, recurrent DVT, and majorbleeding.21 Keep in mind, these studieswere not for long-term treatment withLMWH. LMWH was administered fora period of 5 to 10 days in conjunctionwith a vitamin K antagonist. The studyby Merli and colleagues, published inAnnals of Internal Medicine in 2001,suggested that outcomes may be inferi-or with once-daily versus twice-dailyregimens.22 In the subset of patientswith malignancy, the study showed a12.2% rate of recurrence with theonce-daily dose and only a 6.4% rate ofrecurrence with the twice-daily group;however, statistical significance wasnot achieved. This study also did notinclude long-term use of LMWH.
These studies did lead to the latestCHEST recommendation for patientswith acute DVT of the leg treated withLMWH. They suggest once-daily overtwice-daily administration, but thisrecommendation applies only if theapproved once-daily regimen uses thesame total daily dose as the twice-dailyregimen.19 This would be true for dal-teparin using 200 IU/kg once daily butnot for enoxaparin that uses 1.5 mg/kgonce daily (twice-daily dose is 1 mg/ kgevery 12 hours). This recommendationcould then be interpreted as indicatingthat the preferred treatments are dal-teparin 200 IU/kg every 24 hours orenoxaparin 1 mg/kg every 12 hours.The recommendation carries a 2Cgrade from CHEST, which is a weakrecommendation with low- or verylow-quality evidence. In patients withcancer, again based on the CLOT trialthat did study long-term LMWH ther-
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apy, clinicians should utilize LMWHdosing where the full total daily dose isutilized. Dalteparin is the only LMWHto carry a treatment indication forpatients with cancer at 200 IU/kg dailyfor the first month, then 150 IU/kgdaily. If we carry this to a class indica-tion, enoxaparin should be dosed at 1mg/kg every 12 hours initially for treat-ment of VTE in patients with cancer.Also, one must remember that LMWHis eliminated renally, so dose adjust-ments may be necessary based on thepatient’s renal function.
For the treatment of catheter-relatedthrombosis, it is suggested that thecatheter not be removed if it is still func-tioning. The treatment for this thrombo-sis is based on whether the catheter is oris not removed. If the catheter isremoved, the patient should be treatedfor 3 months after the catheter isremoved. If the catheter is not removed,the patient should be treated with anti-coagulation therapy as long as thecatheter remains in place.15,19
Two new oral anticoagulants haverecently joined the market, and moreare in the pipeline. These will mostlikely be approved in the next fewyears, as will additional indications forthe oral anticoagulants already avail-able. Two agents that have recentlybeen approved are dabigatran(Pradaxa) and rivaroxaban (Xarelto).Dabigatran is a direct thrombininhibitor, and rivaroxaban is a selec-tive inhibitor of factor Xa. Currentlyboth are approved for nonvalvular atri-al fibrillation, and rivaroxaban is alsoapproved for DVT prophylaxis postknee and hip replacement.23,24 Neitheris currently approved for the treatmentof VTE. The goal for any of the newanticoagulants is to develop an agentthat is oral, requires minimal monitor-ing, has a predictable and rapid effect,has a large therapeutic index, and hasminimal drug interactions.
Dabigatran is a twice-daily medica-tion, whereas rivaroxaban is given oncedaily. Both are eliminated by the kid-neys, so are contraindicated in patientswith renal impairment. They do have arapid onset and a larger therapeuticindex. There are no regular monitoringrecommendations with these agents.
Although these medications seem tomake anticoagulation therapy simpler,there are a few things to consider inpatients with cancer. There is currentlyno reversal agent available to complete-ly reverse the anticoagulation effect ofthese agents. This plays a major role inanticoagulation therapy in patientswith cancer who are already at a higherrisk of bleeding. With the rapid onsetand rapid clearance of these agents, ashort half-life syndrome can result. Ifcompliance is an issue, patients on thesemedications can return to baseline after
missing only 1 or 2 doses, which canrapidly increase their risk of a throm-boembolic event.
An interesting phase 2 trial by Levineand colleagues that was recently pub-lished in the Journal of Thrombosis andHaemostasis initiated patients receivingchemotherapy on apixaban for 12weeks.25 Apixaban is a factor Xainhibitor that is not yet approved by theFDA. These were patients without aprior history of VTE. The outcomeswere to determine major or clinicallyrelevant nonmajor bleeding, VTE, andadverse events related to the drug. Thetrial did show a low bleeding risk forthese patients and a decrease in VTE.The study protocol did potentially selectfor patients with a lower bleeding risk bynot including patients with a prolongedbleeding time or patients receiving mod-erate to high doses of aspirin or otherantiplatelet agents, and caution shouldbe used when extrapolating these resultsto a less selective population. This doesintroduce what may be on the horizonfor anticoagulation and cancer and theuse of the newer agents. Further studieswill need to be completed to supportthese findings.
In cancer patients in whombleeding risk is already elevated, aclear picture of the real-life bleed-ing risk associated with theseagents is still not available. Lack ofmonitoring may actually be a neg-ative in these patients. With theother agents, we have a standardlaboratory value that can measurethe extent of the patient’s antico-agulation. There is no standardlaboratory value to measure thenewer agents. Certain anticoagu-lation markers may be elevatedwith therapy, but there is no directcorrelation to the actual level ofanticoagulation. With cancerpatients receiving chemotherapyand having frequent procedures orsurgeries, we cannot assess theirtrue bleeding risk. In patients withcancer, these medications shouldbe used with extreme cautionuntil more postmarketing data areavailable and analyzed. !
References1. Heit JA, Silverstein MD, Mohr DN, et al.Risk factors for deep vein thrombosis and pul-monary embolism: a population-based case-con-trol study. Arch Intern Med. 2000;160:809-815.2. Blom JW, Doggen CJ, Osanto S, et al.Malignancies, prothrombotic mutations, andthe risk of venous thrombosis. JAMA.2005;293:715-722.3. Alcalay A, Wun T, Khatri V, et al. Venousthromboembolism in patients with colorectalcancer: incidence and effect on survival. J ClinOncol. 2006;24:1112-1118.4. Chew HK, Wun T, Harvey D, et al.Incidence of venous thromboembolism and itseffect on survival among patients with commoncancers. Arch Intern Med. 2006;166:458-464.5. Sørensen HT, Mellemkjaer L, Olsen JH, etal. Prognosis of cancers associated with venousthromboembolism. N Engl J Med. 2000;343:1846-1850.
6. Khorana AA, Francis CW, Culakova E, et al.Thromboembolism is a leading cause of death in cancerpatients receiving outpatient chemotherapy. J ThrombHaemost. 2007;5:632-634.7. Prandoni P, Lensing AW, Piccioli A, et al. Recurrentvenous thromboembolism and bleeding complicationsduring anticoagulant treatment in patients with cancerand venous thrombosis. Blood. 2002;100:3484-3488.8. Falanga A, Donati MB. Pathogenesis of thrombosis inpatients with malignancy. Int J Hematol. 2001;73:137-144.9. Nalluri SR, Chu D, Keresztes R, et al. Risk of venousthromboembolism with the angiogenesis inhibitor beva-cizumab in cancer patients: a meta-analysis. JAMA.2008;300:2277-2285.10. Lee AY, Levine MN. Venous thromboembolism andcancer: risks and outcomes. Circulation. 2003;107(23suppl 1):I17-I21.11. Fisher B, Costantino JP, Wickerham DL, et al.Tamoxifen for the prevention of breast cancer: currentstatus of the National Surgical Adjuvant Breast andBowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-1662.12. Thürlimann B, Keshaviah A, Coates AS, et al.Breast International Group (BIG)1-98. CollaborativeGroup. A comparison of letrozole and tamoxifen inpostmenopausal women with early breast cancer. N EnglJ Med. 2005;353:2747-2757.13. El Accaoui RN, Shamseddeen WA, Taher AT.Thalidomide and thrombosis. A meta-analysis. ThrombHaemost. 2007;97:1031-1036.14. Lyman GH, Khorana AA, Falanga A, et al.American Society of Clinical Oncology Guideline:Recommendations for venous thromboembolism pro-phylaxis and treatment in patients with cancer. J ClinOncol. 2007;25:5490-5505.15. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology: VenousThromboembolic Disease. Version 1.2009. http://www.oncologycast.net/guidelinecasts/NCCN_Guidelines.pdf.Accessed April 26, 2012.
16. Kahn SR, Lim W, Dunn AS, et al. Prevention ofVTE in nonsurgical patients: Antithrombotic Therapyand Prevention of Thrombosis, 9th ed: American Collegeof Chest Physicians Evidence-Based Clinical PracticeGuidelines. Chest. 2012;141(suppl 2):e195S-e226S.17. Gould MK, Garcia DA, Wren SM, et al. Preventionof VTE in nonorthopedic surgical patients:Antithrombotic Therapy and Prevention ofThrombosis, 9th ed: American College of ChestPhysicians Evidence-Based Clinical PracticeGuidelines. Chest. 2012;141(suppl 2):e227S-e277S.18. Lee AY, Levine MN, Baker RI, et al. Low-molecu-lar-weight heparin versus a coumarin for the preventionof recurrent venous thromboembolism in patients withcancer. N Engl J Med. 2003;349:146-153.19. Kearon C, Akl EA, Comerota AJ, et al.Antithrombotic therapy for VTE disease: Anti -thrombotic Therapy and Prevention of Thrombosis, 9thed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.2012;141(suppl 2):e419S-e494S.20. Lovenox [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; 2011.21. Couturaud F, Julian JA, Kearon C. Low molecularweight heparin administered once versus twice daily inpatients with venous thromboembolism: a meta-analysis.Thromb Haemost. 2001;86:980-984.22. Merli G, Spiro TE, Olsson CG, et al. Subcutaneousenoxaparin once or twice daily compared with intra-venous unfractionated heparin for treatment of venousthromboembolic disease. Ann Intern Med. 2001;134:191-202.23. Pradaxa [package insert]. Ridgefield, CT: BoehringerIngelheim; 2012.24. Xarelto [package insert]. Leverkusen, Germany:Bayer HealthCare; 2011.25. Levine MN, Gu C, Liebman HA, et al. A ran-domized phase II trial of apixaban for the prevention ofthromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10:807-814.
Our new comprehensive Cancer Care Center located at 620 Washington Street in Winchester, MA incorporates a coordinated team approach including radiation oncologists, medical oncologists, surgeons, pharmacists, nurses and support sta!. We o!er advanced radiation therapy treatment, Holistic treatment as well as integrative therapies. Our Cancer Care Center o!ers a comforting, healing environment for every patient’s cancer care journey — comprehensive cancer care in one place, close to home.
The Oncology Pharmacist compounds and dispenses medications and other pharmaceutical supplies according to established operational procedures as prescribed by physicians and other quali"ed hospital personnel. This position reviews medication orders, obtains clari"cations when necessary in addition to regularly consulting with Medical Sta!, Nursing personnel and others to coordinate delivery of high quality pharmaceutical services to patients.
Massachusetts Licensed Pharmacist required. At least 1 year of experience in#an Oncology practice setting preferred. Doctor#of Pharmacy
or residency training# in Oncology area is a plus.# Candidate must be able to e!ectively create, manipulate and employ common microcomputer applications including word processing, spreadsheets, pharmaceutical informational databases, and Pharmacy computerized purchasing systems. Position requires the ability to input data and maintain an# Oncology EMR system (Mosaiq) and Pharmacy Meditech module.
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Winchester Hospital o!ers a full comprehensive bene"ts package that includes 403(b) plan, choice of medical and dental plans, short- and long-term disability insurance, life insurance and more!
Oncology PharmacistWinchester Hospital Reno Oncology Center Winchester MA
Full-time, Monday–Friday 8:30am–5pm, Day shift
For inquiries, please contact: Deb Coen-Coder, Senior HR Business PartnerWinchester Hospital, 41 Highland Ave.Winchester, MA 01890Email: [email protected]
Winchester Hospital is an Equal Opportunity Employer.
With advances in the diagnosisand treatment of cancer, theestimated 5-year survival
rate for cancer patients has significant-ly improved to approximately 67%.1The most common malignancies inmen and women in the UnitedStates—breast and prostate cancers—have 2 of the highest 5-year survivalrates reported, at 90% and 99%,respectively.1 As oncology patients areliving longer, bone health has becomea pertinent issue in the treatment ofboth metastatic and nonmetastaticoncology patients.2
Bone metastases have been identifiedin approximately 68% of patients withmetastatic prostate cancer and 73% ofpatients with metastatic breast cancer.2Even though bone metastases are nottypically life threatening, their compli-cations, including severe pain, bonefractures, and spinal cord compression,can cause significant morbidity.3
Pharmacologic therapies utilized inthe treatment of metastatic and non-metastatic cancer, including hormonedeprivation and corticosteroids, canstimulate osteoclast activity and resultin bone demineralization. Prolongedtherapy may result in significant boneloss leading to osteoporosis and bonefractures in both the metastatic andnonmetastatic populations.2
Bone Health in Metastatic CancerIn 2011, the American Society ofClinical Oncology (ASCO) publishedupdated guidelines on the role of bone-modifying therapies in the managementof metastatic breast cancer. While priorguidelines did include management oftreatment-associated bone loss, ASCOlimited this publication update tometastatic disease.4 Key changes in rec-ommendations from this ASCO guide-line update include4:
• Bone-modifying agents are recom-mended for patients with metastat-ic disease and evidence of bonedestruction; the following agentsare recommended (none is recom-mended over another):
– Denosumab 120 mg subcuta-neously (SC) every 4 weeks
– Zoledronic acid 4 mg intra-venously (IV) over at least15 minutes every 3 to 4weeks
– Pamidronate 90 mg IV overat least 2 hours every 3 to 4weeks
• Bone-modifying agents should beutilized as an adjunctive therapy,not as first-line treatment, for can-cer-related bone pain, in additionto standard-of-care pain-manage-ment strategies (eg, nonsteroidalanti-inflammatory agents, opioidand nonopioid analgesics)
This published guideline limits dis-cussion to metastatic breast cancer withbone metastases.4 Since other solidtumors, including prostate cancer, fre-quently metastasize to the bone, clini-cians should similarly support theimplementation of bone-modifyingtherapies to promote bone health anddecrease skeletal-related events inpatients with bone metastases due tosolid tumors.3
Bone Health in NonmetastaticCancerSome anticancer treatments commonlyseen in breast and prostate cancer,including hormone deprivation andcorticosteroids, increase osteoclastactivity and result in loss of bone mass.2Bone-modifying therapy should be con-sidered for cancer patients with 1 of thefollowing2:
Tool (FRAX) score:– 3% for hip fractures– >20% for all major fractures
In 2011, the US Food and DrugAdministration (FDA) completed theevaluation of the two phase 3 clinicaltrials of denosumab 60 mg SC every 6months to prevent bone loss. These trialsincluded patients with prostate cancerreceiving androgen-deprivation therapyand breast cancer receiving aromataseinhibitors.5,6 As a result of these studies,the FDA expanded the approved indica-tions for denosumab 60 mg SC every 6
months to include the following7:• Treatment to increase bone mass in
men at high risk for fracture receiv-ing androgen-deprivation therapyfor nonmetastatic prostate cancer
• Treatment to increase bone mass inwomen at high risk for fracturereceiving adjuvant aromataseinhibitor therapy for breast cancer
• Treatment of postmenopausalwomen with osteoporosis at highrisk for fracture
Also in 2011, the European Societyfor Clinical and Economic Aspectsof Osteoporosis and Osteoarthritis(ESCEO) submitted a position paper onpreventing bone loss and fractures inpostmenopausal women receiving aro-matase inhibitors for breast cancer.8
At a minimum, the final publicationrecommends measuring serum concen-trations of parathyroid hormone, calci-um, and 25-OH vitamin D prior to ini-tiation of an aromatase inhibitor toestablish the risk for osteoporosis.Pharmacologic interventions, includingvitamin D and calcium supplementa-tion, should be considered for all
patients receiving aromatase inhibitorsto promote bone health.8 Bone-modify-ing therapy with either zoledronic acid4 mg IV over at least 15 minutes every6 months or denosumab 60 mg SCevery 6 months should be considered inpatients with osteoporosis or osteopeniawith risk factors for fractures and con-tinue as long as aromatase inhibitortherapy is maintained.8
There is no clear recommendationfor bisphosphonate therapy in non-metastatic prostate cancer for patientsreceiving androgen-deprivation thera-py. Recent evaluations have studiedzoledronic acid 4 mg IV every 3 monthsfor 1 year and found that therapyimproved bone mineral density. TheFDA has approved the use of alen-dronate, risedronate, and zoledronicacid in men to decrease fractures andincrease bone density.9
Oral bisphosphonate therapy can beconsidered as an alternative to IV ther-apy, but these agents may be associatedwith additional adverse effects and vari-
able compliance. In an evaluation onmedication adherence, preference, andsatisfaction in 250 postmenopausalwomen with low bone-mineral density,investigators determined that patientswere significantly more compliant withdenosumab 60 mg SC every 6 monthscompared with alendronate 70 mg bymouth once weekly.10 Additionally, at12 months’ follow-up, those receivingdenosumab were more likely to reportbeing very satisfied or quite satisfiedwith the dosing frequency, route ofadministration, convenience, and over-all satisfaction with treatment.10
Nonpharmacologic interventionsshould also be considered to further pro-mote bone health. Additional supportivecare measures include smoking cessation,minimizing alcohol consumption, anddietary supplementation with calcium(1000-1200 mg by mouth daily) andvitamin D (approximately 10,000 IU bymouth daily).8,9
Drug Safety MonitoringSafety concerns with bone-modifyingtherapies include, but are not limited to,renal toxicity, hypocalcemia, osteo -necrosis of the jaw, and atypical femurfractures.4,11,12 Appropriate monitoringshould occur at initiation of treatmentand with each dose to minimize severetoxicities.4 The ASCO guidelines rec-ommend the following for patientsreceiving bone-modifying therapies4:
• Serum creatinine should be moni-tored prior to each dose of bisphos-phonates
• Serum calcium, electrolytes, phos-phate, magnesium, and hemoglo-bin/hematocrit should be monitoredregularly [no specific recommenda-tion provided on the interval]
• Calcium should be followed closelyduring denosumab therapy if thecalculated creatinine clearance isless than 30 mL/min [no specificrecommendation provided on theinterval]
• Prior to initiation of bone-modify-ing therapies, all patients shouldundergo a dental examination andpreventive dentistry to minimizeosteonecrosis of the jaw
Although bisphosphonates areknown to strengthen bone and preventfractures, there have been reports thatlong-term therapy can lead to fragilebones and atypical fractures of the sub-trochanteric or diaphyseal femur afterminimal or no trauma; these atypicalfractures account for less than 1% of hip
Use of Bone-Modifying Agents inOncology PatientsBy Raj Duggal, PharmDIndiana University Simon Cancer Center, Indianapolis
Raj Duggal, PharmD
Bone health has become a pertinent issue in the
treatment of both metastatic and nonmetastatic
oncology patients.
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and femur fractures overall.11-13 A safetyannouncement published by the FDAas an update to the bisphosphonate drugsafety review in 2010 indicated that it isyet unclear whether these atypical frac-tures are related to bisphosphonatetherapy; this safety evaluation is ongo-ing.13
Since this FDA update, 2 studiesevaluating the rates of atypical fracturesin nononcology patients with osteo-porosis have been published. Asdescribed below, the studies do not ruleout a correlation between bisphospho-nate therapy and atypical fractures, butthey do confirm that the rates of atypi-cal femur fractures are very low withconcurrent bisphosphonate therapy.11,12
In the first study, an evaluation of12,777 Swedish women with femurfractures identified atypical fractures in59 patients.11 The investigators con-cluded that, because 46 of the 59patients with atypical fractures were onbisphosphonate therapy, there was a 47-fold increased risk compared tononusers. Based on these results, theyestimated that it would take 2000 bis-phosphonate users per year to have 1case of atypical fracture to occur.11
In the second study, investigatorscompared the incidence of atypical frac-tures between patients receiving eitherbisphosphonate therapy or nonbisphos-phonate therapy (raloxifene or calci-tonin) in 33,815 patients.12 Over themedian follow-up of 2.13 years, 104 sub-trochanteric or diaphyseal femur frac-tures occurred. There was no significantdifference in the incidence of atypicalfemur fractures between bisphospho-nate users and nonusers, however.12
Nevertheless, the authors could noteliminate the possibility that bisphos-phonate therapy could increase the riskof atypical fractures with prolonged use.12
Ongoing Clinical Evaluations Many studies investigating novel thera-pies in the management of bone healthare currently ongoing. New promisingapproaches to the management of bonehealth include tyrosine kinase inhibitors(dasatinib, cabozantinib, and saraca-tinib), endothelin-A receptor antago-nists (atrasentan and zibotentan), andbisphosphonates tagged with radiophar-maceuticals.4,14,15 It is to be hoped thatthese novel therapies will provide moreoptions for clinicians to manage thebone health of oncology patients. !
References1. Siegel R, Naishadham D, Jemal A. Cancer statistics,2012. CA Cancer J Clin. 2012;62:10-29.2. Gralow JR, Biermann JS, Farooki A, et al. NCCNtask force report: bone health in cancer care. J NatlCompr Netw. 2009;7(suppl 3):S1-S32.3. Coleman RE, Guise TA, Lipton A, et al. Advancingtreatment for metastatic bone cancer: consensus recom-mendations from the Second Cambridge Conference.Clin Cancer Res. 2008;14:6387-6395.4. Van Poznak CH, Temin S, Yee GC, et al. AmericanSociety of Clinical Oncology executive summary of theclinical practice guideline update on the role of bone-
modifying agents in metastatic breast cancer. J ClinOncol. 2011;29:1221-1227.5. Smith, MR, Egerdie B, Hernández Toriz N, et al.Denosumab in men receiving androgen-deprivationtherapy for prostate cancer. N Engl J Med.2009;361:745-755.6. Ellis GK, Bone HG, Chlebowski R, et al.Randomized trial of denosumab in patients receivingadjuvant aromatase inhibitors for nonmetastatic breastcancer. J Clin Oncol. 2008;26:4875-4882.7. Prolia [package insert]. Thousand Oaks, CA: AmgenInc; September 2011.8. Rizzoli R, Body JJ, De Censi A, et al; on behalf of theEuropean Society for Clinical and Economical Aspectsof Osteoporosis and Osteoarthritis (ESCEO). Guidancefor the prevention of bone loss and fractures in post-
menopausal women treated with aromatase inhibitorsfor breast cancer: an ESCEO position paper [publishedonline ahead of print January 24, 2012]. Osteoporos Int.doi:10.1007/s00198-011-1870-0, http://www.springerlink.com/content/0754828832806p24/fulltext.pdf.Accessed April 16, 2012.9. Adler RA. Management of osteoporosis in men onandrogen deprivation therapy. Maturitas. 2011;68:143-147.10. Kendler DL, McClung MR, Freemantle N, et al.Adherence, preference, and satisfaction of post-menopausal women taking denosumab or alendronate.Osteoporosis Int. 2011;22:1725-1735.11. Schilcher J, Michaëlsson K, Aspenberg P.Bisphosphonate use and atypical fractures of the femoralshaft. N Engl J Med. 2011;364:1728-1737.
12. Kim SY, Schneeweiss S, Katz JN, et al. Oral bis- phosphonates and risk of subtrochanteric or diaphysealfemur fractures in a population-based cohort. J BoneMiner Res. 2011;26:993-1001.13. US Food and Drug Administration. FDA drug safe-ty communication: safety update for osteoporosis drugs,bisphosphonates, and atypical fractures. http://www.fda.gov/drugs/drugsafety/ucm229009.htm. PublishedOctober 13, 2012. Accessed April 18, 2012.14. Hannon RA, Finkelman RD, Clack G, et al. Effectsof Src kinase inhibition by saracatinib (AZD0530) onbone turnover in advanced malignancy in a phase Istudy. Bone. 2012;50:885-892.15. Saylor PJ, Lee RJ, Smith MR. Emerging therapies toprevent skeletal morbidity in men with prostate cancer.J Clin Oncol. 2011;29:3705-3714.
“Managing patients with myeloma means staying current.”
Value-Based Care in Myeloma !"#$%"&'(")*#+'$%"($,-"&%$".'(/,!(0"&'0"*-$%"'(&"#/-"!(-1(*1'-2(3+/#$-42(/,!(/**"''($''+"'5(60"*$/#('"*-$1,'(71&(89:;/'"!(*#$,$*$/,'2(/!%/,*"!(0&/*-$*"(,+&'"'2(/,!(0</&=/*$'-'(.$##(/#'1(71*+'(1,(-<"(+,$3+"(*</##",>"'($,(-<"(=/,/>"=",-(17(=+#-$0#"(=4"#1=/5
Ira Klein, MD, MBA, FACPChief of Staff to the Chief Medical OfficerAetnaHartford, CT
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Supportive Care
www.TheOncologyPharmacist.com MAY 2012 I VOL 5, NO 3 11
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 11
Myeloproliferative neoplasms(MPNs) are somewhat rarechronic hematologic malig-
nancies. There are no known cures, butthe disease itself is treatable. Accordingto the World Health Organization’srevised WHO Classification of Tumors ofthe Hematopoietic and Lymphoid Tissues,MPNs include essential thrombo-cythemia (ET), polycythemia vera(PV), and idiopathic myelofibrosis(IMF), also referred to as primarymyelofibrosis (Table 1).1 IMF, ET, andPV are considered Philadelphia chro-mosome (Ph) negative. Chronic myel-ogenous leukemia (CML) is consideredPh positive. This review article willfocus on IMF, and the new treatmentapproved by the US Food and DrugAdministration (FDA).
In 1951, William Dameshek, a pre-eminent American hematologist,described the concept of myeloprolifer-
ative disorders by grouping togetherCML, ET, PV, IMF, and erythro -leukemia. He articulated that a self-per-petuating trilineage myeloproliferationunderlined their pathogenesis.2
EtiologyIMF is a disorder of the blood cellswherein the bone marrow revealsfibrous tissue, and lab values demon-strate varying degrees and combinationsof leukopenia, anemia, and thrombocy-topenia. The disease is thought to origi-nate from the neoplastic transformationof a single hematopoietic stem cell. Thedisease presents either de novo or in thesetting of PV or ET.3 Bone marrow mor-phology is critical to the diagnosis andwill generally show a dramatic increasein reticulin fibers and collagen togetherwith a loss of normal hematopoieticcells. Additionally, normocytic anemiawith nucleated red blood cells and anincrease in megakaryocytes is seen onhistologic examination.4 The diseaseaffects both men and women equallyand is usually diagnosed in the fifth toseventh decade of life. There are noknown risk factors, but there have beenreports that myelofibrosis may be linkedto immunologic-mediated hyperplasiaof marrow suggestive of lupus erythe-matosus, and other connective tissuediseases.4 Additionally, exposure to ben-zenes or high-dose ionizing radiationhas preceded the diagnosis of primarymyelofibrosis.5 Prognosis varies accord-
ing to a set of clinical factors, includinghemoglobin level, constitutional symp-toms, circulating blasts, leukocytecount, and cytogenetics.6 Morbidity andmortality are commonly associated withleukemic transformation, infection, por-tal hypertension, and thrombohemor-rhagic events.7
Clinical Presentation and DiagnosisApproximately one-quarter of patientswith IMF are asymptomatic at the timeof diagnosis.8 Patients who are sympto-matic may present to the primary careprovider with complaints of fatigue,weakness, shortness of breath, andweight loss. Some patients may alsocomplain of left upper quadrant pain ordiscomfort due to splenomegaly.8 Labvalues can be very broad. Normocytic-
normochromic anemia is present inalmost all patients. In 1 study the hemo-globin concentration in patients atdiagnosis was 9.5 to 11.6 g/dL, with arange of 4 to 20 g/dL among a total of539 patients in 4 studies.8 Anisocytosis(variation in size) and poikilocytosis(variation in shape) are constant find-ings, as are teardrop-shaped red cells.7Prognosis worsens with increased pres-ence of the clinical manifestations list-ed above and shown in the Figure.9 In2008, WHO recommended 2 sets ofspecific criteria (major and minor) tohelp clinicians make an accurate diag-nosis (Table 2).10
Role of the Janus-AssociatedKinase (JAK) PathwayAdvances in the understanding of thepathogenesis of Ph-negative MPNssuch as IMF have led to the discovery ofthe JAK2V617F mutation as a prospec-tive therapeutic target.11 The JAK path-way plays a major role in blood cell pro-duction and immune and inflammatoryresponses.12 Overactivity or imperfec-tions in this pathway are thought to beresponsible, in part, for many diseasestates, including IMF. The JAK pathwaysends out signals from blood cell growthfactors, cytokines, or hormones outsidethe bone marrow stem cell to its nucle-us. Under normal functioning of thebone marrow, suitable blood cell devel-opment and utility are ensured.12 Thereis a strong association between abnor-
Essential Thrombocythemia (ET)1. Chronic-phase ET2. Post-ET myelofibrosis3. Blast-phase ET
Primary Myelofibrosis1. Chronic-phase primary
myelofibrosis2. Blast-phase primary
myelofibrosis
Abbreviations: CML, chronic myelogenous leukemia; MPNs, myeloproliferative neoplasms. Adapted from Vardiman JW, Thiele J,Arber DA, et al. The 2008 revision ofthe World Health Organization (WHO)classification of myeloid neoplasms andacute leukemia: rationale and importantchanges. Blood. 2009;114:937-951.
Figure. Clinical Manifestations of Idiopathic Myelofibrosis Indicated in Worsening Prognosis9
Adapted from “Development of New Therapies for Myelofibrosis” presentation by Srdan Verstovsek, MD, PhD, Associate Professor,Department of Leukemia, University of Texas, MD Anderson Cancer Center.
Cytopenias
Low or high white cell count Transformation to acute leukemia•Blast percent
Increasing bone marrow fibrosis
Low total cholesterol Progressive splenomegaly/hepatomegaly
Weight loss Constitutional symptoms
Prognostic Factors
Approximately
one-quarter of patients
with idiopathic
myelofibrosis are
asymptomatic at the
time of diagnosis.
Myelofibrosis
12 MAY 2012 I VOL 5, NO 3 www.TheOncologyPharmacist.com
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mal cell signaling in the JAK pathwayand the development of MPNs.12,13
TreatmentAllogeneic stem cell transplantation(SCT) offers the possibility of cure forsome patients with IMF.14 However, therisk of graft-vs-host disease, transplant-related death, and relapse of themyelofibrosis requires careful selectionof appropriate candidates. Until recent-ly there were few, if any, treatments thatprovided hope for patients ineligible fortransplant. Most of the treatmentoptions were palliative in nature,intended to minimize anemia, neu-tropenia, or thrombocytopenia, as wellas the many constitutional symptomsexperienced by the majority of IMFpatients. Given the essential role of theJAK pathway in blood cell productionand immune function, scientists beganresearching the potential of JAK inhibi-tion for treating patients with IMF.
Approval of a New DrugOn November 16, 2011, the FDAapproved ruxolitinib (Jakafi) for thetreatment of intermediate- and high-risk myelofibrosis.15,16 The oral drug isthe first in a new class of drugs knownas JAK inhibitors. The drug inhibitsJAK1 and JAK2 pathways. Theapproval was based on results from 2randomized phase 3 trials—COM-FORT-I and COMFORT-II—whichtested the drug in patients with post-PV myelofibrosis and post-ET myelofi-brosis. Patients in both trials wereresistant or refractory to available ther-apy. Additionally, they were ineligiblefor SCT. The COMFORT trials estab-lished that patients treated with rux-olitinib experienced significant reduc-tions in splenomegaly. COMFORT-Ialso demonstrated improvements insymptoms as measured by the modifiedMyelofibrosis Symptom AssessmentForm (MFSAF) and the MFSAF TotalSymptom Score to include abdominaldiscomfort, pain under left ribs, satiety,night sweats, bone and muscle pain,and itching. Most patients on placebohad worsening of these symptoms.15
At the time of approval, 75% of thepatients on study 1 and 67% on study 2who achieved at least a 35% reductionin spleen volume maintained this
reduction. The most common adverseevents in both studies were thrombo-cytopenia and anemia. These weremanageable and rarely led to discon-tinuation of the drug.16 The recom-
mended starting dose of ruxolitinib is20 mg orally twice daily for patientswith a platelet count above 200 x109/L, and 15 mg twice daily for thosewith a platelet count between 100 and200 x 109/L.16
ConclusionPatients diagnosed with IMF do notcomprise a great proportion of patientsin the oncology setting. However, theiruncommon, mostly incurable diseasemakes them at least as vulnerable asthose with the most commonly diag-nosed cancers. Science has been focus-ing on personalized medicine, and forthe few diagnosed with IMF, the JAKinhibitors represent a new option forIMF management. Based on the datafrom the COMFORT studies, ruxoli-tinib has been approved for use inpatients with intermediate/high-riskmyelofibrosis, offering patients somehope now, and for the future develop-ment of other targeted therapies. !
References1. Vardiman JW, Thiele J, Arber DA, et al. The 2008revision of the World Health Organization (WHO)classification of myeloid neoplasms and acuteleukemia: rationale and important changes. Blood.2009;114:937-951.2. Tefferi A. The history of myeloproliferative disorders:
before and after Dameshek. Leukemia. 2008;22:3-13.3. Passamonti F, Malabarba L, Orlandi E, et al.Polycythemia vera in young patients: a study on thelong-term risk of thrombosis, myelofibrosis andleukemia. Haematologica. 2003;88:13-18.4. el Mouzan MI, Ahmad MA, al Fadel Saleh M, alSohaibani MO, al Gindan YM. Myelofibrosis and pan-cytopenia in systemic lupus erythematosus. ActaHaematol. 1988;80:219-221.5. Tondel M, Persson B, Carstensen J. Myelofibrosis andbenzene exposure. Occup Med (Lond). 1995;45:51-52.6. Arana-Yi C, Quintás-Cardama A, Giles F, et al.Advances in the therapy of chronic idiopathic myelofi-brosis. Oncologist. 2006;11:929-943.7. Thiele J, Kvasnicka HM, Steinberg T, et al. Survivalin primary (idiopathic) osteomyelofibrosis, so calledagnogenic myeloid metaplasia. Leuk Lymphoma.1992;6:389.8. Lichtman MA. Idiopathic myelofibrosis (agnogenicmyeloid metaplasia). In: Beutler E, Lichtman MA,Coller BS, et al, eds. Williams Hematology. 6th ed. NewYork, NY: McGraw-Hill; 2001:chap 95. http://medtextfree.wordpress.com/2012/01/23/chapter-95.Accessed April 18, 2012.9. Verstovsek S. Development of new therapies formyelofibrosis. Presented at Mayo Clinic, Scottsdale,Arizona, February 2009.10. Swerdlow SH, Campo E, Harris NL, et al, eds. WHOClassification of Tumours of Haemopoietic and LymphoidTissues. 4th ed. Lyon, France: IARC Press; 2008.11. Quintás-Cardama A, Kantarjian H, Cortes J,Verstovsek S. Janus kinase inhibitors for the treatmentof myeloproliferative neoplasias and beyond. Nat RevDrug Discov. 2011;10:127-140.12. The JAK/STAT pathway: fact sheet. NovartisOncology Web site. http://www.novartisoncology.com/files/media/research/JAK-STAT%20Pathway%20Fact%20Sheet_FINAL.pdf. Accessed April 1, 2012.13. Tefferi A. Essential thrombocythemia, poly-cythemia vera, and myelofibrosis: current managementand the prospect of targeted therapy. Am J Hematol.2008;83:491-497.14. Bacigalupo A, Soraru M, Dominietto A, et al.Allogeneic hemopoietic SCT for patients with primarymyelofibrosis: a predictive transplant score based ontransfusion requirement, spleen size and donor type.Bone Marrow Transplant. 2010;45:458-463.15. FDA approves Incyte’s Jakafi(TM) (ruxolitinib) forpatients with myelofibrosis [press release]. Wilmington,DE: Incyte Corporation; November 16, 2011.http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=1631201&highlight=. AccessedApril 18, 2012. 16. Pazdur R. FDA approval for ruxolitinib phosphate.National Cancer Institute Web site. http://www.cancer.gov/cancertopics/druginfo/fda-ruxolitinibphosphate.Accessed April 4, 2012.
Table 2 Diagnostic Criteria for Primary Myelofibrosis (WHO 2008)10
3 major criteria + 2 minor criteria must be met to confirm diagnosis.
Major diagnostic criteria1. Megakaryocyte proliferation and atypia*2. Not meeting WHO criteria for PV, BCR-ABL1!positive CML, MDS, or
other myeloid neoplasm3. Presence of JAK2V617F or other clonal marker or no evidence of secondary
bone marrow fibrosis in absence of clonal markerMinor diagnostic criteria1. Leukoerythroblastosis2. Increase in serum lactate dehydrogenase3. Anemia4. Splenomegaly
*Accompanied by either reticulin and/or collagen fibrosis, or in the absence of significant reticulin fibrosis, a prefibrotic cellular-phase disease.Abbreviations: CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome;PV, polycythemia vera; WHO, World Health Organization.
Given the essential role of the JAK pathway in
blood cell production and immune function, scientists
began researching the potential of JAK inhibition
for treating patients with IMF.
Prospective data from a recentstudy links the long-term use ofnonsteroidal anti-inflammatory
drugs (NSAIDs) with the increasedrisk for renal cell carcinoma. The
use of acetaminophen and aspirinwas not associated with the risk for
renal cell carcinoma.
—Arch Intern Med. 2011;171:1487-1493.
Did You Know?The oral drug is the first
in a new class of
drugs known as
JAK inhibitors.
Visit our user-friendly Web sitewww.TheOncologyPharmacist.com
In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, you’ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!
Myelofibrosis
www.TheOncologyPharmacist.com MAY 2012 I VOL 5, NO 3 13
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 13
www.TheOncologyPharmacist.com14 MAY 2012 I VOL 5, NO 3
Melanoma
In 2010, there were an estimated68,130 new melanoma cases in the United States,1 of which
approximately 2% to 5% presentedwith metastatic disease.2 Advancedmelanoma remains an incurable andhighly treatment-refractory tumor,with treatment response rates of only10% to 25% and a median survival of 2to 8 months (Table 1).3-8 According tothe National Comprehensive CancerNetwork (NCCN), consensus is mini-mal regarding first- and second-linechemotherapy for patients withmetastatic melanoma.2 Until the USFood and Drug Administration (FDA)approved ipilimumab and vemurafenibin 2011, dacarbazine and interleukin-2
(IL-2) were the only drugs indicated forfrontline therapy.
Chemotherapy can be used for thepalliative treatment of metastaticmelanoma. Single-agent dacarbazine isstill the “gold standard” treatmentagainst which many newer regimenshave been compared. An optimal dosingschedule has yet to be determined, how-ever, with doses ranging from 250mg/m2/day on days 1-5 every 21 days to1200 mg/m2 only on day 1 of the 21-daycycle.4,9 Response rates to dacarbazinerange from 5% to 15%, with an overallsurvival (OS) of about 7 months.4,9
Temozolomide is an oral prodrug ofdacarbazine that can cross the blood-brain barrier. Similar to dacarbazine,temozolomide provides an objectiveresponse rate of 13.5%, with an OS of7.7 months.4 Several other chemothera-py drugs have been used as single agentsfor the treatment of metastaticmelanoma with similarly disappointingresults, including carmustine, cisplatin,carboplatin, vinblastine, and paclitaxel.3
The disappointing response rates
with single-agent chemotherapy haveled to the evaluation of combinationchemotherapy as well as biochemothera-py regimens.3 Combination chemothera-py such as the Dartmouth regimen(tamoxifen, carmustine, cisplatin, and
dacarbazine) and CVD (cisplatin, vin-blastine, and dacarbazine) were createdto improve outcomes and enhanceresponse rates. Biochemotherapy addedimmunologic manipulation with IL-2
and/or interferon alfa to chemotherapyto try to improve response rates with syn-ergistic mechanisms of action. However,a 2001 meta-analysis comparing single-agent dacarbazine with combinationchemotherapy and biochemotherapyregimens failed to provide evidence thatcombination treatments are superior tosingle-agent dacarbazine.10 Althoughcombination regimens provide anincrease in response rates over single-agent dacarbazine, their use is associatedwith significant increases in toxicitiesand no increase in OS.
Immunotherapy with high-dose IL-2has shown promise in the treatment ofthis disease, with a small percentage ofpatients achieving a durable remission.5IL-2 is secreted by CD4+ T lymphocytesand modulates immunologic effects byactivating natural killer cells, B lym-phocytes, and macrophages.11 Althoughoverall response rates (ORRs) havebeen low at 16%, patients who were ableto achieve a response did not progressfor more than 30 months. However, therisk of severe life-threatening toxicities(eg, capillary leak syndrome) associatedwith high-dose IL-2 therapy requirescareful patient selection and inpatientadministration of the drug.
In March 2011, ipilimumab receivedFDA approval for the treatment ofmetastatic melanoma. Ipilimumab is amonoclonal antibody targeted againstthe immune checkpoint receptor cyto-toxic T lymphocyte antigen-4 (CTLA-4).2,12 By blocking CTLA-4, ipilimumabaugments T-cell activation and prolifer-ation, thus enhancing the patient’s ownimmune response against the tumor.
A phase 3 clinical trial evaluatedipi lim umab alone or in combinationwith the cancer vaccine gp100 versusgp100 alone.13 In this study, previouslytreated patients with unresectable stageIII or IV melanoma were randomized3:1:1 to receive either ipilimumab 3 mg/kg plus gp100 peptide vaccine (n = 403), ipilimumab plus placebo (n = 137), or gp100 plus placebo (n = 136) every 3 weeks for 4 cycles.Pertinent exclusion criteria includedautoimmune disease, untreated cen-tral nervous system metastases, orongoing treatment with long-termsystemic corticosteroids. The primaryend point, best ORR, was amended toOS to align with results from multipleipilimumab trials.
The study found that the median OSsignificantly increased in patients
Recent Advances in the Treatment ofMetastatic MelanomaBy Megan Hagerty, PharmD, BCOPOncology Clinical Pharmacist, IU Simon Cancer Center, Indiana University Health
Affiliate Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, Purdue University
Megan Hagerty, PharmD, BCOP
In March 2011, ipilimumab
received FDA approval
for the treatment of
metastatic melanoma.
Table 1 Selected Treatments for Metastatic Melanoma4-8
Regimen Dose(s) Response Rate, n (%) Overall Survival
Abbreviations: AUC, area under the curve; BID, twice a day; d, day; IV, intravenous; mo, month; PO, orally; q, every; wk, week.
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MAY 2012 I VOL 5, NO 3 15www.TheOncologyPharmacist.com
Melanoma
receiving ipilimumab, either alone or incombination, compared with the pep-tide vaccine gp100 alone: ORR was 10months for ipilimumab/gp100, 6.4months for gp100/placebo (hazard ratio[HR] for death, 0.68; P <.001), and 10.1months for ipilimumab/placebo (HR fordeath vs gp100/placebo, 0.66; P = .003).There was no difference in OS detectedbetween the 2 ipilimumab groups. The12-month OS rates in the ipilimu -mab/gp100 group, ipilimumab/placebogroup, and gp100/placebo group were43.6%, 45.6%, and 25.3%, respectively.The 18- and 24-month OS rates fol-lowed a similar trend (Table 2).13
Adverse events were primarilyimmune related and occurred in 60% ofpatients receiving ipilimumab and 32%of those receiving gp100 alone.Immune-related events included diar-rhea, rash, and endocrine effects.Diarrhea was the most common adverseevent, present in 27% to 31% ofpatients in the ipilimumab groups.Administration of corticosteroidsresolved the symptoms in about 2weeks. Death attributed to study drugoccurred in 14 patients (2.1%), ofwhich 7 were attributed to immune-related events.13
In a subsequent study, Robert andcolleagues evaluated ipilimumab plusdacarbazine in previously untreatedpatients with metastatic melanoma.14
This phase 3 clinical trial randomizedpatients to receive ipilimumab 10 mg/kgplus dacarbazine 850 mg/m2 (n = 250)or dacarbazine plus placebo (n = 252) atweeks 1, 4, 7, and 10, both regimens fol-lowed by dacarbazine alone every 3weeks until week 22 for the inductionphase. Patients with stable disease or anobjective response rate without dose-limiting toxicities at week 24 were eligi-ble to enter a maintenance phase, dur-ing which they received ipilimumab orplacebo every 12 weeks until progres-sion, toxicity, or end of the study period.The primary end point was againchanged from progression-free survival(PFS) to OS.
Treatment with ipilimumab plusdacarbazine resulted in significantlylonger OS compared with dacarbazineplus placebo (11.2 months vs 9.1months, P value not provided).Ipilimumab/dacarbazine therapy reducedthe risk of progression by 24% comparedwith dacarbazine/placebo (HR for pro-gression, 0.76; P = .006). Interestingly,after 6 months, some patients who werereceiving ipilimumab had an improve-ment from partial to complete response.Immune-related adverse events occurredin 77.7% of ipilimumab/dacarbazine-treated patients and 38.2% of dacar-bazine/placebo patients. Adverse eventrates were similar to those seen in priortrials and included diarrhea, pruritus,and rash; however, the rates of grade 3
or 4 hepatic events (ie, AST/ALT ele-vations) were higher than in previoustrials.14
BRAF is a serine/threonine kinasethat is frequently activated by muta-tions in cancer.15 It is estimated thatabout 40% to 60% of cutaneousmelanomas carry mutations in BRAFthat lead to constitutive activation ofdownstream signaling through theMAPK pathway.15,16 Vemurafenib is aBRAF kinase inhibitor that specificallytargets the BRAFV600E mutation, a muta-tion harbored by approximately 45% ofpatients with metastatic melanoma.2,17
In August 2011, vemurafenib wasapproved for the treatment ofBRAFV600E-mutated unresectable ormetastatic melanoma. The FDA simul-taneously approved the Cobas 4800BRAF V600 Mutation Test to deter-mine eligibility for treatment withvemurafenib.16
FDA approval of vemurafenib wasbased, in part, on a pivotal phase 3 clin-ical trial by Chapman and colleaguesthat evaluated OS and PFS in previous-ly untreated melanoma patients ran-domized to vemurafenib or dacar-bazine.16 Patients were required to havestage IIIC or IV melanoma that testedpositive for the BRAFV600E mutation.Pertinent exclusion criteria includeduntreated central nervous system metas-tases and the need for continued gluco-corticoid therapy. Patients were ran-domized to receive vemurafenib 960 mg
At the time of interim analysis, thedata and safety monitoring board deter-mined that prespecified OS end pointshad been met for statistical significancefavoring vemurafenib, and dacarbazinepatients were then allowed to cross overto vemurafenib. The response rate was48% for vemurafenib and 5% for dacar-
bazine (P <.001). OS was 84% (95%confidence interval [CI], 78%-89%) forthe vemurafenib group and 64% (95%CI, 56%-73%) for the dacarbazinegroup. Vemurafenib resulted in a signif-
icant reduction in the risk of death (HRfor death, 0.37 [95% CI, 0.26-0.55]; P <.001).16
Vemurafenib was associated withincreased cutaneous events, arthralgia,fatigue, and photosensitivity skin reac-tions compared to dacarbazine. Amongthe cutaneous events, 61 patients (18%)developed cutaneous squamous cell car-cinoma, keratoacanthoma, or both. Theskin lesions were successfully treated by
surgical excision. Of the patients receiv-ing vemurafenib, 38% required dosereductions due to toxicity.16
These recently approved treatmentsfor metastatic melanoma come withadvantages but also significant limita-tions.2 Ipilimumab is associated withserious, potentially fatal immuneadverse events (Table 3), includingdiarrhea. Responses to ipilimumab maytake months to develop and occur inless than 20% of patients; however, sim-ilar to immunotherapy with IL-2,responses are quite durable.2 In contrast,vemurafenib demonstrates high re -sponse rates that occur quickly.However, to be considered for vemu-rafenib therapy, a patient must test pos-itive for the BRAFV600E mutation, andthe median response duration is onlyabout 5 to 6 weeks.2
Historically, treatment of metastaticmelanoma has yielded low responserates and limited OS. The year 2011brought about 2 advances in the treat-ment of metastatic melanoma—ipilim -umab and vemurafenib—and theirapproval has altered the landscape of
Table 2 OS Rates in Patients Treated With Ipilimumab/gp100, Ipilimumab/Placebo, and gp100/Placebo13
OS Rate Ipilimumab/gp100 Ipilimumab/Placebo gp100/Placebo
12 mo 43.6% 45.6% 25.3%18 mo 30.0% 33.2% 16.3%24 mo 21.6% 23.5% 13.7%Abbreviations: mo, month; OS, overall survival.
Table 3 Immune-Mediated Adverse Reactions to Ipilimumab12
System Organ Class Signs and Symptoms
Gastrointestinal DiarrheaAbdominal painBlood or mucus in the stoolBowel perforationPeritoneal signsIleus
www.TheOncologyPharmacist.com16 MAY 2012 I VOL 5, NO 3
Melanoma
Recent Advances in the Treatment of Metastatic Melanoma Continued from page 15
melanoma treatment. Despite theseexciting advances, however, metastaticmelanoma remains a universally fataldisease. Therefore, the NCCN recom-mends a clinical trial be considered asthe first line of therapy for any patientwith metastatic melanoma.2 If a patientis ineligible or unwilling to participate ina clinical trial, choice of therapy dependson patient characteristics. A BRAFV600E–positive patient who is symptomaticfrom his or her disease may benefit fromup-front therapy with vemurafenib.Conversely, a clinician may chooseipilim umab for the patient who has low-volume disease, a good performance sta-tus, and tests positive for the BRAF–wildtype mutation.
While questions remain regarding
optimal dosing of ipilimumab (3 mg/kgvs 10 mg/kg), the role of maintenancetherapy, and the efficacy of combinationregimens, as well as the fact that thesedrugs also have a significant financialimpact both on the individual patientand the healthcare system as a whole,this is still an exciting new era in thetreatment of metastatic melanoma. !
References1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010.CA Cancer J Clin. 2010;60:277-300.2. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology (NCCNGuidelines®): Melanoma. Version.3.2012. http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.Accessed May 1, 2012.3. Mouawad R, Sebert M, Michels J, et al. Treatment formetastatic malignant melanoma: old drugs and newstrategies. Crit Rev Oncol Hematol. 2010;74:27-39.4. Middleton MR, Grob JJ, Aaronson N, et al.
Randomized phase III study of temozolomide versusdacarbazine in the treatment of patients with advancedmetastatic malignant melanoma. J Clin Oncol. 2000;18:158-166.5. Atkins MB, Lutze MT, Dutcher JP, et al. High-doserecombinant interleukin 2 therapy for patients withmetastatic melanoma: analysis of 270 patients treatedbetween 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.6. Chapman PB, Einhorn LH, Meyers ML, et al. PhaseIII multicenter randomized trial of the Dartmouth regi-men versus dacarbazine in patients with metastaticmelanoma. J Clin Oncol. 1999;17:2745-2751.7. Eton O, Legha SS, Bedikian AY, et al. Sequentialbiochemotherapy versus chemotherapy for metastaticmelanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20:2045-2052.8. Hodi FS, Soiffer RJ, Clark J, et al. Phase II study ofpaclitaxel and carboplatin for malignant melanoma. AmJ Clin Oncol. 2002;25:283-286.9. Chiarion Sileni V, Nortilli R, Aversa SM, et al. PhaseII randomized study of dacarbazine, carmustine, cis-platin and tamoxifen versus dacarbazine alone inadvanced melanoma patients. Melanoma Res. 2001;11:189-196.10. Huncharek M, Caubet JR, McGarry R, et al. Single-
agent DTIC versus combination chemotherapy with orwithout immunotherapy in metastatic melanoma: ameta-analysis of 3273 patients from 20 randomized tri-als. Melanoma Res. 2001;11:75-81.11. Feldmann M. Cell cooperation in the antibodyresponse. In: Roitt I, Brostoff J, Male D, eds.Immunology. 5th ed. London: Mosby; 1998:147-155.12. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011.13. Hodi FS, O’Day SJ, McDermott DF, et al. Improvedsurvival with ipilimumab in patients with metastaticmelanoma. N Engl J Med. 2010;363:711-723.14. Robert C, Thomas L, Bondarenko I, et al.Ipilimumab plus dacarbazine for previously untreatedmetastatic melanoma. N Engl J Med. 2011;364:2517-2526.15. Davies H, Bignell GR, Cox C, et al. Mutations ofthe BRAF gene in human cancer. Nature. 2002;417:949-954.16. Chapman PB, Hauschild A, Robert C, et al; for theBRM-3 Study Group. Improved survival with vemu-rafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.17. Zelboraf [package insert]. South San Francisco, CA:Genentech USA, Inc; August 2011.
The best strategy for managementof low-tumor-burden follicularlymphoma (FL) following re -
sponse to induction therapy is controver-sial. The phase 3 RESORT study com-pared maintenance rituximab therapyversus rituximab retreatment at diseaseprogression, and results suggest thatretreatment is the preferred approach.The study was presented at the 53rdAnnual Meeting of the AmericanSociety of Hematology.
The strategies achieved a similartime to treatment failure (TTTF) inthis FL patient population, with no dif-ference in quality of life or anxiety at12 months. Both strategies appear todelay time to chemotherapy comparedwith historical controls. Althoughmaintenance therapy prolonged thetime until cytotoxic therapy was need-ed, almost 4 times more rituximab wasused, making maintenance therapy by
far the more costly approach.“Given the excellent outcome with
retreatment, the toxicity profile, the lackof quality of life difference [between the2 approaches], and the required doses of
rituximab, retreatment is our recom-mended strategy if electing to use ritux-imab,” stated lead investigator BradKahl, MD, University of Wisconsin,
Madison. “The retreatment strategy isless costly, and we believe it is the pre-ferred option to help patients with low-tumor-burden FL manage their disease.”
Kahl said that the study did not deter-mine which strategy is best for improvingoverall survival. Such a study would haveto compare watch and wait versusretreatment versus maintenance therapy.
RESORT enrolled 384 patients withFL histology; of these, 274 (71%)responded to induction therapy with rit-uximab and were randomized to retreat-ment (n = 134) or maintenance ritux-imab (n = 140).
Median TTTF (primary end point)was 3.6 years with retreatment versus 3.9years with maintenance rituximab. At 3years of follow-up, only 5% of patients inthe maintenance arm required cytotoxicchemotherapy versus 14% of patients inthe retreatment arm. However, patientsassigned to retreatment used a mean of
4.5 doses of rituximab over that time,while those assigned to maintenance rit-uximab used a mean of about 16 doses.
Fewer than 5% of patients in the trialexperienced severe hematologic or non-hematologic toxicities. No differencebetween the arms was observed in deathsand second cancers. There was 1 adverseevent leading to discontinuation in theretreatment arm and 7 in the mainte-nance arm.
At 12 months’ follow-up after ran-domization, no difference was found inhealth-related quality of life or burden ofstress.
Kahl said that the investigators wereconcerned that patients assigned toretreatment might experience more anx-iety than those in the maintenance armbecause they knew they had cancer andweren’t being treated, but this concernwas not borne out.
Commenting on this study, JaneWinter, MD, moderator of the press con-ference where RESORT was discussed,and Professor at Northwestern Uni -versity Feinberg School of Medicine,Chicago, said: “If we can limit the fre-quency of treatment, or reduce the needfor chemotherapy and still maintaingood outcomes, we can reduce some ofthe burdens on both the patients and thehealthcare community.” !
Retreatment With Rituximab as Effectiveas Maintenance Rituximab but LessCostly in Indolent Follicular LymphomaBy Alice Goodman
Lymphomas
Visit our user-friendly Web sitewww.TheOncologyPharmacist.com
In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, you’ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!
“The retreatment strategy
is less costly, and we
believe it is the preferred
option to help patients
with low-tumor-burden FL
manage their disease.”
—Brad Kahl, MD
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 16
Oral nutritional interventions doincrease nutritional intake andresult in weight gain in some
malnourished patients with cancer aswell as improve some aspects of qualityof life (QOL), but do not seem toincrease survival, according to a system-atic review and meta-analysis of the lit-erature (Baldwin C, et al. J Natl CancerInst. 2012;104:371-385).
Lead author Christine Baldwin, PhD,RD, School of Medicine, King’sCollege, London, United Kingdom, saidthat current international guidelinesrecommend oral interventions in thisgroup of patients, assuming they areable to swallow, but this recommenda-tion is not based on level A evidencefrom well-designed randomized trials.Since several studies have attempted toevaluate the effect of oral interventionsin cancer patients but have reachedvariable conclusions, she and her col-leagues wanted to revisit the questionby reviewing the literature.
The systematic review and meta-analysis included 13 studies with a totalof 1414 adult cancer patients with can-cer of all sites and stages who wereeither malnourished or at risk of malnu-trition and compared oral nutritionalinterventions versus usual care. Thepatient population, quality, and designof these studies were quite heteroge-neous, which is a limitation of thereview, Baldwin said.
Seven of the studies included assess-ment of QOL, 5 of them using theEORTC cancer-specific questionnaire.There was a great deal of variability inthe findings, but after adjusting for het-erogeneity, oral nutritional interventionswere associated with statistically signif-icant improvement in “emotionalfunctioning,” “global QOL,” and “dysp -nea” and “loss of appetite” symptomscales. Changes in other QOL scalesdid not reach statistical significance.No effect on mortality was observed inpatients who received oral nutritionalintervention.
“The findings suggest that oral nutri-tional interventions have no effect onsurvival and that the effect on body
weight and energy intake is inconsistent,but that statistically significant improve-ments in some aspects of QOL may beachieved,” wrote Baldwin. She pointed
out that several of the studies included inthe review were of poor quality, empha-sizing the need for more in-depthresearch to characterize the benefits of
oral nutritional support in cancerpatients and to strengthen the evidencebase for nutritional management in thisgroup of patients. !
Oral Supplement in Malnourished Cancer PatientsDoes Not Improve Survival By Alice Goodman
MAY 2012 I VOL 5, NO 3 17www.TheOncologyPharmacist.com
News Briefs
Pub:
IndicationYERVOY (ipilimumab) is indicated for the treatmentof unresectable or metastatic melanoma.1
REFERENCES 1. YERVOY (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011.2. Alpha-numeric HCPCS. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/HCPCSReleaseCodeSets/Downloads/12anweb.zip. Accessed November 1, 2011.
Please see Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions, continued on the following pages.
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.
Important Safety Information
Announcing: J-code for YERVOY™ (ipilimumab) J9228
The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agentsmake no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide speci! c directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the speci! c insurer requirements.
aReplaces J9999, J3490, J3590, and C9284.
www.destinationaccess.com1-800-861-0048 (phone) Monday through Friday, 8:00 A M to 8:00 P M ET1-888-776-2370 (fax)
ProductDescription
50-mg/10 mL (5 mg/mL),single-use vial of YERVOY
200-mg/40 mL (5 mg/mL),single-use vial of YERVOY
NDC Number
10-digit 0003-2327-11 0003-2328-22
11-digit 00003-2327-11 00003-2328-22
50-mg/10 mL (5 mg/mL),single-use vial of YERVOY
Replaces J9999, J3490, J3590, and C9284.
4:23 PM
No effect on mortality
was observed in patients
who received oral
nutritional intervention.
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 17
Pub:
Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.
Recommended Dose Modifi cationsWithhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following:
Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
Failure to complete full treatment course within 16 weeks from administration of ! rst dose
Severe or life-threatening adverse reactions, including any of the following– Colitis with abdominal pain, fever, ileus, or peritoneal
signs; increase in stool frequency ("7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation
– AST or ALT >5 # the upper limit of normal (ULN) or total bilirubin >3 # the ULN
– Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations
– Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis
– Severe immune-mediated reactions involving any organ system
– Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy
Immune-mediated Enterocolitis: In the pivotal Phase 3 study in YERVOY-treated patients,
severe, life-threatening or fatal (diarrhea of "7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients
Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis
In$ iximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms
Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to %Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid
tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients
Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)
Immune-mediated Hepatitis: In the pivotal Phase 3 study in YERVOY-treated patients,
severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%
13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but %5x the ULN or total bilirubin elevation >1.5x but %3x the ULN; Grade 2)
Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution
Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids
Withhold YERVOY in patients with Grade 2 hepatotoxicityImmune-mediated Dermatitis: In the pivotal Phase 3 study in YERVOY-treated patients,
severe, life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients
– 1 (0.2%) patient died as a result of toxic epidermal necrolysis
– 1 additional patient required hospitalization for severe dermatitis
There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identi! ed, signs or symptoms of dermatitis should be considered immune-mediated
Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms
Important Safety Information (cont)
4:23 PM
Pazopanib, an angiogenesis in -hibitor, achieved meaningful re -sponses in about three-quarters of
patients with refractory urothelial cancerin preliminary clinical trial results pre-sented at a press briefing during the 2012Annual Meeting of the American
Association for Cancer Research(AACR) in Chicago, Illinois.
According to lead author of thestudy, Andrea Necchi, MD, InstitutoNazionale dei Tumori, Milan, Italy,this is the first targeted therapy todemonstrate meaningful clinical activ-
ity in patients with refractory urothe-lial cancer. He called the 76% rate ofdisease stabilization “remarkable,” not-ing that data on other efficacy out-comes are needed in the future.
The study also provided some newinformation on interleukin-8 (IL-8) lev-
els as a potential biomarker for response.Elevated levels of IL-8, as well as risingIL-8 levels during the first 4 weeks ofpazopanib treatment, were associatedwith tumor progression and shorter over-all survival. These data need to be con-firmed in further trials.
Pazopanib Potential Treatment for Refractory Urothelial Cancer
News Briefs
18 MAY 2012 I VOL 5, NO 3 www.TheOncologyPharmacist.com
Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.
Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week
Immune-mediated Neuropathies: In the pivotal Phase 3 study in YERVOY-treated patients, 1
case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported
Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes
Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities)
Immune-mediated Endocrinopathies: In the pivotal Phase 3 study in YERVOY-treated
patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients
– All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insuf! ciency, hypogonadism, and hypothyroidism
– 6 of the 9 patients were hospitalized for severe endocrinopathies
Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insuf! ciency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome
Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insuf! ciency (including adrenal crisis), and hyper- or hypothyroidism
– Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspeci! c symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identi! ed, signs or symptoms should be considered immune-mediated
– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland
Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:
In the pivotal Phase 3 study in YERVOY-treated patients, clinically signi! cant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis
Permanently discontinue YERVOY for clinically signi! cant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions
Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy
Pregnancy & Nursing: YERVOY is classi! ed as pregnancy category C. There are
no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential bene! t justi! es the potential risk to the fetus
Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus
It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY
Common Adverse Reactions: The most common adverse reactions ("5%) in patients
who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%)
Important Safety Information (cont)
“Our data indicate that pazopanibseems to be a legitimate drug in this dis-ease. Most interestingly, our biomarkeranalysis clearly pointed out the role ofrising levels of circulating interleukin-8as an early and potentially practice-changing indicator of tumor resistanceand poor survival,” he said, as reported ina news release from AACR.
Second-line therapies thus far have
been disappointing in advancedurothelial cancer, which has a poorprognosis. Median overall survival isabout 4 to 5 months. Five-year overallsurvival of metastatic urothelial canceris about 10% to 15%. Although target-ed therapies are theoretically attractivein bladder cancers, thus far no benefi-cial strategies have been identifieduntil this trial.
The phase 2, open-label, proof-of-concept study enrolled 41 patients withadvanced or metastatic urothelial can-cer. Fifty percent progressed on second-line therapy. Patients received dailypazopanib 800 mg once a day untildevelopment of disease progression orunacceptable toxicity, or withdrawal.
According to RECIST criteria (fortumor shrinkage), objective responses
were seen in 7 patients and stable dis-ease in 24 patients (total disease stabi-lization, 31 out of 41 patients: 76%).Median progression-free survival(PFS) was 2.6 months and medianoverall survival was 4.7 months. At 2months, 61% of patients were free ofprogression, and durable PFS was seenin 10% of patients at a median follow-up of 19 months. ! —AG
News Briefs
www.TheOncologyPharmacist.com MAY 2012 I VOL 5, NO 3 19
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 19
www.TheOncologyPharmacist.com20 MAY 2012 I VOL 5, NO 3
News Briefs
YERVOY™ (ipilimumab) Injection, for intravenous infusion
Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information]
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions]
INDICATIONS AND USAGE
YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning]
Immune-mediated Enterocolitis
In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.
The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.
Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (!40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.
Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.
Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information]
Immune-mediated Hepatitis
In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]
Immune-mediated Dermatitis
In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.
The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).
Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.
Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information]
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
Immune-mediated Neuropathies
In Study 1, one case of fatal Guillain-Barré syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information]
Immune-mediated Endocrinopathies
In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations
The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.
Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
[see Warnings and Precautions].
[see Warnings and Precautions].
[see Warnings and Precautions].
[see Warnings and Precautions].
[see Warnings and Precautions].
[see Warnings and Precautions].
A
Pub: 4:23 PM
Aspecific subgroup of womenwith early-stage breast cancermay be able to avoid adjuvant
radiation, according to a presentationat the 2012 Annual Meeting of the
American Association for CancerResearch (AACR) held in Chicago,Illinois. Women with the luminal Asubtype of breast cancer, particularlythose older than age 60, had fewer local
recurrences at 10 years when treatedwith tamoxifen alone versus tamoxifenplus radiation therapy in a post hocanalysis of a randomized trial that com-pared these 2 forms of treatment.
Senior author of this paper, Fei-FeiLiu, MD, radiologist at Princess MargaretHospital, senior scientist at the OntarioCancer Institute, and professor at theUniversity of Toronto, Canada, cau-
Women With Luminal A Subtype Breast Cancer May Be Ableto Forgo Radiation
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 20
tioned that local radiation therapy is stillthe standard of care for all other breastcancer subtypes.
Liu commented that avoiding radia-tion therapy in these patients, whoaccount for about 25% of all newlydiagnosed breast cancer cases in NorthAmerica, could achieve an estimated$400 million in savings for the health-care system in the United States.
The luminal A subtype of breastcancer is defined as estrogen receptor–positive, progesterone receptor–posi-tive, HER2-negative, and low Ki-67(<14%), a proliferation marker. Thestudy was based on molecular subtyp-ing analysis of 304 tumor blocks from769 women with early T1 or T2, node-negative breast cancer who participat-ed in a randomized controlled trial
comparing tamoxifen plus whole-breast radiation therapy versus tamox-ifen alone. Using immunohistochem-istry, the researchers classified tumorsinto 6 categories: luminal A, luminalB, luminal-HER2, HER2-enriched,basal-like, or triple-negative pheno-type nonbasal.
Overall, breast cancer recurrence at10 years was 13.8% with tamoxifen
alone compared with 5% for tamox-ifen plus breast radiation. The luminalA subtype had the best outcome ofany subgroup, with a 10-year risk oflocal relapse of 8% with tamoxifenalone versus 4.6% with tamoxifen andradiation. Luminal A patients olderthan age 60 had a 10-year local recur-rence rate of 4.3% on tamoxifen aloneversus 6% for combined modalitytherapy. Grade 1/2 luminal A tumorshad a similar rate of recurrenceregardless of treatment; 4.9% withtamoxifen versus 5.5% with tamox-ifen plus radiation.
The researchers said that thesefindings suggest that local breastradiation therapy did not affect theoutcome of older patients with theluminal A subtype.
By contrast, radiation therapy had apositive impact on other breast cancersubtypes. For example, women withluminal B tumors had a 10-year recur-rence rate of 16.1% with tamoxifenalone versus 3.9% with tamoxifenplus radiation therapy. A similar trendwas seen for HER2, HER2-enriched,and basal-like tumors, but the num-bers in each group were small.
These findings have implications forpersonalized cancer medicine, suggest-ing that Ki-67 be added to the currentstandard testing for hormone receptorand HER2 status in newly diagnosedpatients with breast cancer. If thesedata on the luminal subtype A tumorsare validated, that would pave the wayfor discussions with patients with thissubtype about the need to undergoradiation therapy in addition totamoxifen or other adjuvant therapy.
In a news release from AACR, Liuwas quoted as saying: “This is yetanother powerful of example of ‘per-sonalized cancer medicine.’ When thisinformation is combined with well-conducted randomized clinical trials,significant advances can be madewhereby we can truly start to tailortherapies, based on new molecularmarkers, which can be introduced intoroutine clinical practice.” ! —AG
MAY 2012 I VOL 5, NO 3 21www.TheOncologyPharmacist.com
News Briefs
[
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.
The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.
The most common adverse reactions (!5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.
Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.
Table 1: Selected Adverse Reactions in Study 1
Percentage (%) of Patientsa
YERVOY 3 mg/kg n=131
YERVOY 3 mg/kg+gp100
n=380
gp100 n=132
System Organ Class/ Preferred Term
Any Grade
Grade3–5
Any Grade
Grade3–5
Any Grade
Grade 3–5
Gastrointestinal Disorders Diarrhea ColitisSkin and Subcutaneous Tissue Disorders Pruritus RashGeneral Disorders and Administration Site Conditions Fatigue
328
3129
41
55
02
7
375
2125
34
43
<12
5
202
118
31
10
00
3
a Incidences presented in this table are based on reports of adverse events regardless of causality.
Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.
Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1
Percentage (%) of Patients
YERVOY3 mg/kgn=131
YERVOY3 mg/kg+gp100
n=380
Any Immune-mediated Adverse ReactionEnterocolitisa,b
a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established.
Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.
Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.
Immunogenicity
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.
DRUG INTERACTIONS
No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab).
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information]
In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes.
Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.
Nursing Mothers
It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.
Pediatric Use
Safety and effectiveness of YERVOY have not been established in pediatric patients.
Geriatric Use
Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
Renal Impairment
No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]
Hepatic Impairment
No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]
OVERDOSAGE
There is no information on overdosage with YERVOY.
PATIENT COUNSELING INFORMATION
See MEDICATION GUIDE in Full Prescribing Information.
Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA
1281558A2 IP-B0001A-03-11 Issued: March 2011
7 Pub:
The luminal A subtype
of breast cancer is
defined as estrogen
receptor–positive,
progesterone receptor–
positive, HER2-negative,
and low Ki-67 (<14%).
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 21
Alarge, population-based studyfound that a significant propor-tion of female cancer survivors
had poor health behaviors comparedwith women who have not had cancer(Rausch SM, et al. Am J Clin Oncol.2012;35:22-31).
Several differences in engaging inhealth behaviors emerged among pri-mary cancer types, with more cervicalcancer survivors reporting being currentsmokers and regular alcohol users com-pared with other cancer types. Ovarianand uterine cancer survivors reportedbeing obese more often than other can-cer types, and the largest weight gain wasobserved among cervical cancer sur-vivors. By contrast, leukemia survivorsreported engaging in regular mammogra-phy more often, had a higher percentageof “never” smokers, and a higher per-centage of normal-weight individualscompared with individuals with otherprimary cancers.
Even though more than half of allcancer deaths in the United States canbe attributed to health behaviors suchas smoking (30%), poor dietary choic-es and obesity (25%-30%), and physi-cal inactivity, very little is knownabout these behaviors in cancer sur-
vivors, wrote the authors of this study.“There is considerable need for addi-tional studies to document the preva-lence of cancer-related risk factors in adiverse sample of cancer survivors,”they added.
The study included almost 20,000women aged 35 and older with no priorbreast cancer who presented for screen-
ing mammography. Participants weregiven a self-assessment questionnaireabout their health behaviors and previ-ous cancer history.
The questionnaire was completed by18,510 women—15,797 with no cancerhistory and 2713 cancer survivors.Health behaviors assessed includedsmoking, alcohol consumption, physicalactivity, weight, use of complementaryand alternative medicine (CAM), mam-mography screening, and overall self-
rating of health during the past year.Mean age was 58 years, mean body
mass index (BMI) was 26 kg/m2, and74% had education beyond high school.Compared with women who did nothave cancer, cancer survivors were about5 years older on average, had a similarBMI, and 4% more had educationbeyond high school.
Cancer survivors were less likely thanwomen with no cancer history to reportthat they had “excellent” health: 13.6%versus 21.5%, respectively; that theyengaged in moderate or strenuous exer-cise: 56.5% versus 63.3%, respectively,and to use CAM: 57.4% versus 60.2%,respectively. Cancer survivors were morelikely to be current smokers (6.3% vs5.5%) and to rate their overall health as“poor” (15.9% vs 9.1%, respectively),and to gain more weight over time.
Cancer survivors reported more regu-lar participation in mammographyscreening than women with no cancer:91.1% versus 86.3%, respectively; thedifference was more marked in patientsyounger than age 40: 80.2% versus74.3%, respectively.
Cancer survivors were more likely tohave had a smoking history; 59% versus63.7%, respectively, reported being“never” smokers; 34.6% versus 30%,respectively, reported being “former”smokers; and 6.3% versus 5.9% said theywere current smokers. The smoking rateswere similar between cancer survivorsand those without cancer for womenolder than age 65, whereas cancer sur-vivors aged 30 to 49 years were morelikely to be current smokers thanwomen of the same age group whowere not cancer survivors: 13% versus8.5%, respectively.
The authors state that presenting forscreening mammography is “a teachablemoment” when healthcare providers caneducate cancer survivors and discussrisky behaviors. Studies such as this onesuggest that there is much room forimprovement in areas such as smoking,alcohol consumption, exercise, andweight gain. ! —AG
Health Behaviors Worse Among Cancer SurvivorsThan Patients With No History of Cancer
Ovarian and uterine cancer survivors reported being
obese more often than other cancer types, and the
largest weight gain was observed among
cervical cancer survivors.
Failure of remission-induction thera-py in pediatric acute lymphoblasticleukemia (ALL), although rare,
can lead to highly adverse outcomes, butoutcomes differ according to type ofALL: B-cell or T-cell, as well as othercharacteristics (Schrapps M, et al. N EnglJ Med. 2012;366:1371-1381).
The study showed that patientswith childhood ALL who fail oninduction therapy are highly hetero-geneous. T-cell leukemia appears to beassociated with improved outcomes iftreated with allogeneic stem-celltransplant, while precursor B-cell
leukemia with no adverse featuresappears to be better treated withchemotherapy.
According to the authors, “Thesefindings have considerable implica-tions, since transplantation is general-ly considered to be standard of carefor such patients.”
The study was based on 1041 chil-dren and adolescents (aged 0-18years) with newly diagnosed ALL whoexperienced failure after 4 to 6 weeksof remission-induction therapy; thesechildren were culled from 44,017patients with childhood ALL treated
by 14 cooperative study groupsbetween 1985 and 2000.
Patients with induction failuretended to have high-risk features thatincluded older age, high leukocytecount, T-cell leukemia phenotype, thePhiladelphia chromosome, and 11q23rearrangement. With a median fol-low-up of 8.3 years, the 10-year sur-vival rate was 32%.
Characteristics associated with aparticularly poor outcome includedage of 10 years or more, T-cellleukemia, the presence of an 11q23rearrangement, and 25% or more
blasts in the bone marrow at the endof induction therapy. Improved out-comes in precursor B-cell ALL wereassociated with high hyperdiploidy (amodal chromosome number >50) andage of 1 to 5 years; these patients com-posed about 25% of the sample.
Improved outcomes in T-cell ALLwere seen with allogeneic stem-celltransplant from matched, relateddonors. Children younger than 6 yearswith precursor B-cell ALL and noadverse genetic features had a 10-yearsurvival rate of 72% when treated withchemo therapy only. ! —AG
Acute Lymphoblastic Leukemia: Remission-Induction Failure Can Be Treated
Visit our user-friendly Web sitewww.TheOncologyPharmacist.com
In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, you’ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!
News Briefs
22 MAY 2012 I VOL 5, NO 3 www.TheOncologyPharmacist.com
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 22
The inaugural annual conferenceof the Global BiomarkersConsortium brought together an
international panel of oncology expertsto explore the rapidly evolving field ofbiomarker research. Cochairs of theevent were Hope S. Rugo, MD, directorof Breast Oncology and Clinical TrialsEducation at the University of CaliforniaSan Francisco, and Rüdiger Hehlmann,MD, PhD, professor of medicine at theUniversity of Heidelberg. MichaelKattan, PhD, Vincent Miller, MD, EdithPerez, MD, and Charles Bennett, MD,PhD, served as session chairs.
At the conference, held March 9-11,2012, in Orlando, Florida, a diverse fieldof experts addressed oncologists, hema-tologists, oncology nurses, pharmacists,and other healthcare professionals on awide range of topics related to the clini-cal application of biomarkers in thetreatment of solid tumors and hemato-logic malignancies. Conference attend -ees had numerous opportunities to askquestions. In addition, an audienceresponse system provided opportunitiesfor interactive learning experiences.
Hehlmann opened the conferencewith a valuable historical overview ofgenetic profiling and oncologic biomark-ers. In discussing development of newtechnologies, Miller reported, “There arean unprecedented number of targetedtherapies in clinical trials—about 500targeted therapies looking at about 140genomic alterations.” In looking forwardto next-generation sequencing, Millerconcluded, “So I’m really excited aboutthese broader technologies that mayallow us to help more patients and morerationally approach treating patients inthe near future.”
Case studies of several types of cancerwere presented by panel members. Perezpresented “Evidence-Based Medicine toTranslational Medicine to PersonalizedMedicine: A Natural Evolution,” andBeth Faiman, PhD(c), MSN, APRN-
BC, AOCN, discussed “Roles andResponsibilities of the InterprofessionalTeam.” Perez and Faiman led a groupcomposed of several doctors who hadpresented case studies in a panel ques-
tion-and-answer session on “In -corporating Personalized Medicine IntoPractice.”
Personalized medicine based on anunderstanding of predictive molecular
biomarkers holds great promise.Conferences such as this one help clini-cians and other healthcare professionalskeep up to date on developments in thischallenging field. !
Global Biomarkers Consortium—Implementing thePromise of Personalized Cancer Care
Personalized medicine
based on an
understanding of
predictive molecular
biomarkers holds
great promise.
PERSONALIZEDMEDICINE INONCOLOGY
The Next Generation in Oncologic Care
Join us on our journey to realizethe tremendous possibilities ofimproving cancer prevention,diagnosis, and treatment througha new medical model of personalized care.
Where are you on the path?
MOP
Conference News:
www.TheOncologyPharmacist.com MAY 2012 I VOL 5, NO 3 23
TOP_May 2012_v4_TOP 5/22/12 12:50 PM Page 23
Conference News:
The need to optimize the treat-ment of patients with cancerwhile using healthcare resources
wisely—in other words, providing“value-based cancer care”—is not atopic of debate, but how to achieve thispressing goal is far from clear. In a paneldiscussion during the Association forValue-Based Cancer Care’s SecondAnnual Conference, held in Houston,Texas, strategists from the payer side ofthe issue discussed the current trendsand the challenges they are facing.
Burt Zweigenhaft, BS, President andChief Executive Officer of OncoMed,Great Neck, New York, who led the dis-cussion, noted that the rising cost ofcancer care is clearly the trigger pointfor change. “The cost curve is unsus-tainable. Who will win and who willlose? Clearly, there are realignments.”
Ira M. Klein, MD, MBA, Chief ofStaff to the Chief Medical Officer atAetna Oncology Strategy, New York,added, “We get feedback from our dif-ferent customers as to what they want,from the self-insured employers to thesmall businesses down to the individ-ual in the market. And the unifyingtheme is that they cannot sustain anymore cost.”
Employers Are ConfusedEmployers may be steadily downsizingtheir benefits, but this does not meanthey do so without pain, participantsnoted. “Employers are more paternalis-tic than one would think. They areconcerned about the care theiremployees are getting,” said Klein.“They want benefit designs that do notdeny patients access to essential servic-es, but they want these to be acquiredat the most favorable unit price. Cost isa very big factor to them.”
Maria Lopes, MD, MS, Chief Med -ical Officer for AMC Health, Cresskill,New Jersey, agreed. “Employers are con-cerned about cost and about what ishappening in the marketplace, and theyare looking to payers for solutions.”
Employers clearly do not understandwhy costs are so high, added WinstonWong, PharmD, Associate VicePresident of Pharmacy Managementwith CareFirst BlueCross BlueShieldin Maryland. “The employers ask theirconsultants. The consultants come tous because they think pharmacy is thesilver bullet. When you look at it fromthe employer and consultant stand-points, you see there is not much
understanding about what is driving thenumbers,” he said.
Drug Costs: The Big BugabooThe exorbitant cost of new treatmentsclearly contributes to the crisis in pay-ing for cancer care, and payers’ handsare relatively tied to do much aboutthis, the panelists said.
“We know drugs are the biggest part of the escalation,” observedZweigenhaft, and John Fox, MD,MHA, Associate Vice President ofMedical Affairs for Priority Health,Grand Rapids, Michigan, proposed 2main reasons for this.
“Number one, we do not have thewherewithal or interest in the publicdomain to say that society will not payfor a cancer drug because it is too expen-sive,” Fox offered. “Number two, thereare state mandates to cover expensivedrugs, and the drug companies have thepower to set the price of the drug. Wecannot control these prices, yet that iswhere the greatest cost is.”
Fox contrasted the system in theUnited States with that of the UnitedKingdom, which does consider the costof a drug when deciding its fate. “In theUnited Kingdom, they take the 2 inde-pendent variables, which are outcomesestablished through clinical trials andwillingness to pay, and that defines thedependent variable, which is the cost ofthe drug,” he said. “In this country, themanufacturer sets the cost of thedrug…. The conundrum is that thepharmaceutical industry has a responsi-bility to its investors and the innovatorshave to recoup their investments, yetthe people who pay for that are increas-ingly unable to do so.”
Although discussions about reducingemergency department visits and hospi-
talizations as a cost-savings approachhave merit, they stem merely from thefact that these are “things we can con-trol,” Fox said. “The reality is that untilwe find a way to provide more rational-ity around our drug reimbursements, Ido not know that there is a solution.”
Keeping Oncology Community-BasedPayers indicated and studies haveshown that cancer care is more afford-able when delivered in the communityrather than the hospital setting; howev-er, economic factors are steadily threat-ening the viability of this site of care,because community practices are beingsold or absorbed by hospitals, or aremerely closing.
This trend worries Jeffrey A. Scott,MD, Senior Vice President and GeneralManager for P4 Healthcare CardinalHealth Specialty Solutions. “What willit take for this to stop?” he questioned.“When will health plans incentivizedoctors to stay out of the hospital? Weknow the lowest cost comes from treat-ing patients in the community, but howdo we drive this?”
Zweigenhaft noted that the “shift to ahospital base” is a universal concern inthe payer community, because thisessentially doubles the cost of deliveringcancer care, with little or no improve-ment in outcomes. Panelists agreed thatsite of service is an important issue.
Part of the lure of hospital-based care,as Zweigenhaft put it, is the 340B DrugPricing Program, which limits the cost ofcovered outpatient drugs to certain fed-eral grantees, federally qualified healthcenter look-alikes, and qualified hospi-tals. Participation in the program resultsin savings estimated to be 20% to 50% ofthe cost of pharmaceuticals, which natu-rally appeals to providers. According toZweigenhaft, the pitch made by hospitalrepresentatives to physician groups is theopportunity to share in the substantialadditional revenue afforded through340B drug pricing.
Scott agreed that 340B pricing is“clearly a driver for getting new doctorsinto the hospital,” and part of the rea-son why struggling community practicesview the hospital system as “the savior.”
What it will take to strengthen com-munity oncology practices is not com-pletely clear, but Mona M. Chitre,PharmD, CGP, Director of ClinicalServices, Strategy and Policy forExcellus BlueCross Blue Shield, FLRx
Pharmacy Management, Rochester,New York, said helping them maintain“cost neutrality” is important. Her com-pany’s goals are to create innovativeprograms to pay for patient manage-ment, help patients avoid emergencydepartment visits, and aid clinicians inreducing other unnecessary services.
Guiding Physicians to BestPracticesValue in cancer care, however, is notonly about cost but also about quality,and the 2 components are necessary foroptimizing value while maintaininggood outcomes, the panel agreed. Lopessuggested that the concept of valuemust be aligned with an appropriateoutcome, and this can be difficult todetermine.
Scott added that better measures areneeded to define quality outcomes, andthat there is increasing recognition thatit is “total cost of care” that mattersmost—which includes reductions indownstream costs and returningpatients to work.
Klein agreed that benefits programscannot be designed simply on the basisof cost. “We want quality first, then wedeliver on cost,” he said. Scott added,“There is no question that good, qualitycare is already being provided, but itcomes down to how to maintain thatquality at a lower cost. That is the bigdiscussion we have with providers.”
Standardization is an important partof this strategy, typically via guidelinesand clinical pathways. “We found thatby more or less standardizing treatmentsin the program we have with communi-ty oncologists, we take out variabilityand have a gross savings of about 13%,”Wong reported. “These savings will beshared with the community oncologistsas an effort to maintain their marginsand to be an incentive to sustain theircommunity practices.”
Moving from branded to genericproducts has also been a big cost-saver,and reducing emergency departmentvisits and hospitalization rates by 4%has produced additional savings. “Weknow the savings are there,” he said.
According to Klein, this works bestwhen providers are in the driver’s seat.“We delegate decision-making to physi-cian groups and allow them to choosetheir pathways. You get higher qualityand lower costs because you give controland power to the providers to use whatthey are comfortable with,” he said.
Payer Trends in Oncology: Challenges andSolutionsPutting Patients First Remains a Key ComponentBy Caroline Helwick
“Employers are
concerned about cost
and about what is
happening in the
marketplace, and they
are looking to payers
for solutions.”
—Maria Lopes, MD, MS
24 MAY 2012 I VOL 5, NO 3 www.TheOncologyPharmacist.com
TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 24
Conference News:
Scott suggested that pathways work bestwhen they are “narrow,” which is whatP4 attempts to do with providers. “Wetry to neutralize the name of the drugsso physicians are free to choose a regi-men based on what is best for thepatient and separate from the econom-ics of it. We have demonstrated in 10different markets that you can use con-sensus to drive a narrow set of pathways,and it works, although it may not be thelong-term answer.”
Lopes added that there is a need to domore to aid physicians in decision-mak-ing. “We want to align incentives,” shesaid, emphasizing that healthy collabo-ration is critical to success. “We will notwin without good partnerships with ourtreating providers.”
Need to Involve the PatientCentral to any conversation about can-cer care should be the patient. Theyshould also become more active partici-pants in the quest for value, and there isroom for improvement in this area, thepanel pointed out.
“The ‘value proposition’ has to beconsidered at the patient level,” saidChitre. New York State now haschemotherapy parity. “Patients will notpay any differential for generic versusbranded drugs, so the ‘value discussion’with the patient is actually absent,” shenoted. “If a drug is indicated or listed as2A or 2B in the Compendia, it is cov-ered and at a high level. There is verylittle patient out-of-pocket expense,and therefore very little driving our
members to ask ‘value questions’ of theirproviders.”
She observed, however, that thetrend toward high-deductible premiumsis beginning to alter how patients talkabout value to their providers.
Wong reported that CareFirst pro-grams are beginning to integrate oncol-ogy with primary care through thepatient-centered medical home model,and this is helping to steer care in thedirection of value. “These 2 specialtiesare collaborating. Primary care is direct-ing patients to oncology practices theyperceive will provide the best qualityand value,” he said (see an interviewwith Wong below).
Ultimately, what emerges as the pic-ture of value-based cancer care must be
patient-centered, the panel agreed. A“fully engaged” patient is one whounderstands the treatment scenario anddetermines what is most important tohim or her, said Fox.
This is only done when physicianshave time for it, added Klein. “If wecould get physicians to spend more timetalking to patients, all our costs wouldgo down, because the patient would feelmore empowered to do the right thing,”he maintained. “Comparatively speak-ing, physician labor time is cheap. Thecost-over-quality balance must hierar-chically satisfy all stakeholders as equi-tably as possible. We have to manageexpectations. We cannot move cancercare forward until we change society’sperceptions.” !
At the Association for Value-Based Cancer Care (AVBCC)second annual meeting,
Winston Wong, PharmD, expressed con-cerns that the site of delivery of cancercare affects efforts to rein in costs andprovide value in cancer care. Wongexpanded on this issue in the followinginterview.
Why do you believe that the site ofdelivery of cancer care can impactthe attempt to rein in costs of cancer care and provide value?Wong: Here is why. When chemother-apy is delivered to a patient in thephysician’s office, there are the cost ofthe drug, administrative costs, and thecost of ancillary services. Let’s say thetotal office visit, including the cost ofchemotherapy, is $4000. You can takethat exact same service and drug anddeliver it at a large center, such as, in ourarea, Johns Hopkins, and the cost couldbe $6000 or even up to $8000.Essentially, it may double or even triplein cost, depending on the procedure, theservice, and the drug that is prescribed.
Why is there such a large differential in cost?Wong: It is basically because thehealthcare system cannot functionwithout the large hospitals. They havemarket power and can negotiate betterdeals. At the end of the day, hospitalbilling will be at least twice that of acommunity practice, across the board.
Do large hospitals and cancer centers acknowledge this?Wong: Their comment to payers wouldbe that they are tertiary care hospitals,
and that their patient population is sick-er, and to some degree that is true. Largehospitals may get more difficult cases,administer more expensive third-linetherapies, and so forth. But comparingapples to apples, their costs are muchhigher than in community practices.
What can be done to bring moreequity?Wong: On the oncology side, we havenot been able to achieve more equity yet.The strategy that we at CareFirst are try-ing to employ initially with our PathwaysProgram is to reimburse at a higher rateto community practices. We may notnecessarily be directing patients awayfrom hospitals, but we are doing some-thing to help maintain communityoncology practices so that they are avail-able to treat these patients. If there arefewer community practices, patients withcancer have less choices.
The site-of-care issue will be driven bythe viability of community practices. Ifwe cannot help community oncologistsstay in business, the site of care will notbe an issue.
You have talked about the need tointegrate primary care and to bringmore value to oncology. Could youelaborate on this?Wong: Here is an example of the cur-rent state of things. My mother passedaway in 2007. When she was diagnosedwith cancer and was being treated withchemotherapy, she became neutropenicand ended up in the emergency depart-ment. The hospital contacted the pri-mary care physician (PCP) on record,but he had no clue about her condition.Once an oncologist was taking care of
her, there had been no communicationwith the PCP. And let’s look at sur-vivorship. She may have to go back tothe oncologist for some routine tests,but she may have an annual check-upthe following week with her PCP, andhe may order the same laboratory tests.This kind of overlap and duplicationshould be eliminated from the system.
How is CareFirst BlueCrossBlueShield advancing this conceptof more integrated care?Wong: With the primary care patient-centered medical home, we are trying toinvolve the PCP as the “quarterback ofcare,” as we say. Currently, when anindividual is diagnosed with cancer andreferred by his or her PCP to a special-ist, the PCP usually severs ties with thepatient. We are asking our PCPs to bemore accountable and to follow thesepatients while they are under the care ofspecialists—oncologists or others—andmaintain primary care as the patient’shome, but within an integrated process.
Maybe 5 of 10 patients with cancerwill ask their PCP to refer them to anoncologist, but the other 50% willchoose an oncologist on the basis offavorable word of mouth. Or, they maywant to go, for example, to MDAnderson, because of its reputation andnot because they have seen scientificevidence that their care will be better orthat community care is worse. We allpay more for that patient, with very littledifference in quality of care or in out-comes compared with care in the com-munity setting. We believe that the PCPcan direct the patient more towardvalue-based cancer care. PCPs can helpguide these referrals, and they can take
care of the non–cancer-related condi-tions that patients with cancer will have.We want this care to be under the PCP,not the oncologist.
How are PCPs and oncologistsaccepting this model?Wong: We do not know yet—our pro-gram just started—but this is somethingwe are interested in learning. Webelieve that it is in everyone’s bestinterest for patients to have a coordina-tor of care, and we think that the mostimportant provider in this regard is thePCP. We think that PCPs and oncolo-gists working together will becomeinevitable with the changing time. Asthe PCP becomes more involved, therewill have to be more communicationbetween them.
What progress is being made tobring this concept to fruition?Wong: There are many groups withtheir own small projects like ours, andnone is known to be the best way to dothis. I think that these will eventuallymerge into something that we will alluse; however, we are still trying to getsome accountability around these pro-grams, and we are still very early inthat game. !
Site of Care Influences Value in Cancer CareInterview With Winston Wong, PharmDAssociate Vice President, Pharmacy Management, CareFirst BlueCross BlueShield of Maryland
Winston Wong, PharmD
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Emerging Agents
Oncology pharmacists shouldunderstand the characteristics of7 emerging drugs and biologics.
At the 2012 Pharmacy Program heldduring the 17th Annual Conference ofthe National Comprehensive CancerNetwork (NCCN) in Hollywood,Florida, Van Anh Trinh, PharmD, of theUniversity of Texas MD AndersonCancer Center, Houston, and RobertIgnoffo, PharmD, of the University ofCalifornia San Francisco and the TouroUniversity College of Pharmacy inVallejo, described the appropriate use ofaxitinib, crizotinib, ipilimumab, andvemurafenib, and previewed carfilzomib,regorafenib, and vosaroxin.
New Tyrosine Kinase InhibitorsAxitinib was recently approved for, andcarries an NCCN category 1 recommen-dation for, advanced renal cell carcino-ma after failure of 1 prior systemic thera-py, joining everolimus and sorafenib inthis setting. “It’s hard to say which to usefirst. Selection can be guided by the tox-icity profile,” Trinh suggested. In the piv-otal phase 3 trial comparing axitinibwith sorafenib, the most potency wasseen in cytokine-refractory patients,while in patients with prior sunitinibtreatment the delay in progression was amodest 1.4 months, she noted. Theapproved dosing schedule is 5 mg orallytwice a day (PO BID), with titration(after 2 weeks) to 7 mg BID, then (after2 more weeks) to 10 mg BID. Axitinibshould not be used concurrently withCYP3A4/5 inducers.
Crizotinib is indicated for, and car-ries an NCCN category 1 recommen-dation for, locally advanced ormetastatic non–small cell lung cancerwith the ALK translocation. Off-labeluse is anticipated for anaplastic largecell lymphoma, Trinh said.
The approved dose is 250 mg PO BID,with adjustments recommended forpatients with hepatic impairment or
severe renal insufficiency but not for cre-atinine clearance 30 mL/min. Druginteractions can occur with potentCYP3A inducers or CYP3A substrateswith a narrow therapeutic index.Complete blood count, liver functiontests, and EKG are recommended formonitoring.
Novel Melanoma Agents“Ipilimumab and vemurafenib are long-awaited treatments for melanoma,”Trinh said. “Ipilimumab was the first drugto provide a survival improvement in arandomized phase 3 trial in melanoma.”
The approved dosing schedule foripilim umab is 3 mg/kg intravenouslyevery 3 weeks for 4 doses, by 90-minuteinfusion. Premedication and prophylac-tic anti emetics are not needed, nor areadjustments necessary for patients withhepatic or renal dysfunction. It is unclearwhether “reinduction” is effective uponprogression, but ipilimumab has beenshown to restore disease control in two-thirds of patients and is an option in theNCCN Guidelines, although whether itwill be reimbursed beyond 4 doses is anopen question, according to Trinh.
Since the drug works via the immunesystem, the unique clinical features ofipilimumab are a delayed onset ofresponse and immune-related adverseeffects. Inflammatory T-cell infiltratescan produce tissue necrosis within 12weeks, which is mostly mild to moder-ate and reversible but can be life-threat-ening. The skin, gastrointestinal tract,liver, and endocrine system can beaffected (Table).
Patients should be instructed to reportside effects promptly; clinicians shouldmonitor for these closely and treat themimmediately with steroids (1-2 mg/kgprednisone or equivalent, then tapered).Ipilimumab can be restarted when grade1 or 2 toxicity resolves but should bestopped in the case of grade 3+ toxicity.
Vemurafenib is a kinase inhibitor of
mutant BRAF (with activity against sev-eral other mutations) and is approved,with an NCCN category 1 recommen-dation, for unresectable or metastaticmelanoma with the BRAFV600E muta-tion. Vemurafenib led to a 67% reduc-tion in risk of death in the phase 3 trial.
The approved dosing schedule is 960mg PO BID; adjustments are not neededfor patients with mild to moderate liveror kidney dysfunction, although vemu-rafenib should be used with caution inpatients with severe impairment. Druginteractions are possible when used alongwith CYP3A4 inducers and withCYP1A2, CYP2D6, and CYP3A4 sub-strates with a narrow therapeutic index.
Adverse events are largely dermato-logic, and more than one-third ofpatients may need dose modificationsbecause of them. Clinicians should alsowatch for changes in liver function testsand for QT prolongation.
“There is no consensus yet about howto integrate these agents into the treat-ment schema for advanced melanoma,”Trinh said. A reasonable approach is touse vemurafenib first in patients withmutant BRAF and rapidly growing dis-ease or a need for immediate relief ofsymptoms, since patients respond rapidly,although drug resistance also emergessoon. Ipilimumab may be a good firstchoice for patients with limited tumorburden who “can afford to wait 3 or 4months for clinical benefit.”
Emerging Drugs Ignoffo described 3 agents on the horizonthat could also be game-changers.
Carfilzomib is a novel irreversible pro-teasome inhibitor that is mechanisticallydistinct from, more potent than, and amore selective inhibitor of the protea-some and immunoproteasome thanbortezomib. In the PX-171-004 study, inbortezomib-naïve patients with relapsed/refractory disease, median progression-free survival (PFS) was 8 months and
median overall survival (OS) was notreached in myeloma patients receivingcarfilzomib. (Vij R et al. Blood. Publishedonline ahead of print May 3, 2012).
Carfilzomib is dosed on 2 consecutivedays, 1 week apart, in 28-day cycles. Itsrapid plasma clearance is not affected byrenal dysfunction. Proteosome inhibi-tion occurs after 1 dose and is pro-longed, due to inhibition of proteasomerecovery between doses. In striking con-trast to bortezomib, peripheral neuropa-thy grade 2-3 occurs in <1% of patients.Fatigue is the dose-limiting toxicity.Approval from the FDA is “highly prob-able,” he predicted.
Regorafenib is an oral multikinaseinhibitor against several endothelialreceptor tyrosine kinases that is active incolorectal cancer. In the phase 3 COR-RECT trial, median OS was significantlyimproved, although the difference wasonly 1.4 months (P = .005) (Grothey Aet al. J Clin Oncol. 2012;30[suppl 4].Abstract LBA385). Median PFS wasimproved by 1.2 months, a 51% reduc-tion in risk (P <.000001).
“Clinically, it’s an exciting drug basedon the PFS curve,” Ignoffo said. “It seemsregorafenib does not so much producetumor shrinkage as prevent progression,leading to a high disease control rate.”
Vosaroxin is a first-in-class anti-cancer quinolone derivative thatinduces site-selective DNA damage byintercalating DNA and inhibitingtopoisomerase II, leading to apoptosis.Vosaroxin combined with cytarabineshowed favorable clinical activity andtolerability in patients with relapsed orrefractory acute myeloid leukemia, witha median OS of 7.1 months, a 29%complete remission rate, and a medianleukemia-free survival of 14.4 months.(Stuart RK. Presented at: Chemo -therapy Foundation Symposium XXVII,New York, November 10, 2012).
Pharmacist’s RoleTrinh concluded the session, “These arenew and exciting drugs with efficaciousand unique safety profiles. Pharmacistsneed to ensure their appropriate use, edu-cate patients, monitor for and manageadverse events, guide patients to drugassistance programs, and stay updatedwith emerging information.” !
What Pharmacists Need to KnowAbout 7 New AgentsBy Caroline Helwick
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