First Quarter 2008 - Issues in Hematology - ION Solutions

C O M I N G S O O NfromCEPHALON ONCOLOGYTo register for more information, visit www.TREANDA.com©2007 Cephalon, Inc. All rights reserved.TRE004 October 2007 Printed in USA.www.CephalonOncology.com

oncologistics volume 7, issue 1 - spring 2008ONE on ONEWITH MIKE MARTINAt ION, we strive to provideinformation—both clinicaland business related—to ourmembers, that allows them tocontinue to provide the highestlevel of patient care. This issueof Oncologistics focuses onthe study of hematology. Asthe fi rst ION publication to beprinted since the recent American Society of Hematology (ASH)meeting, there are many topics that warrant discussion.In this issue, Charles Abrams, M.D., examinesthrombocytopenia, the implications of the disorder, andimproved treatment options. Also in this issue, Guido Tricot,M.D. illustrates the oncology community’s current understandingof myeloma, and what can be done to combat this disease.While patient diagnosis and treatment must always remain onthe forefront of the oncologist’s mind, a complete understandingof what is necessary for operating a successful businessmust also take priority status. ION continues to create originaltools and provide access to innovative programs that assistphysicians in managing their practices.If you haven’t done so recently, please visit www.iononline.com,where many new applications geared towards increasedpractice effi ciency have been added. Also, continue to utilizeyour ION relationship manager as your true industry consultant.As always, thank you for your continued support of our network.I look forward to another year of improving patient care together.Sincerely,editorial staff:> Ralph Boccia, M.D., F.A.C.P.Chairman, Medical Advisory Panel, ION> Jim SmithVice President, Marketing, ION> Christopher VorceSenior Manager, Marketing & Communications, ION> Danny DeAtleyDirector, Marketing, AmerisourceBergenSpecialty Group> Stacey LittleManager, Corporate Marketing, AmerisourceBergenSpecialty Grouparticle and advertising submissions:Article submissions and suggestions, as well asadvertising inquiries, may be sent to:Christopher VorceManaging Editor, Oncologisticsc/o ION3101 Gaylord ParkwayFrisco, TX 75034or by e-mail: chris.vorce@iononline.comInformation presented in Oncologistics is notintended as a substitute for the personalized advicegiven by a healthcare provider. The opinions expressedon the pages of Oncologistics magazine are those ofthe authors and do not necessarily refl ect the views ofION or AmerisourceBergen Specialty Group. AlthoughOncologistics strives to present only current and accurateinformation, readers should not consider it as professionaladvice or endorsement of any position. Although greatcare has been taken in compiling and checking theinformation given in this publication to ensure accuracy,the authors, ION, and its employees or agents shall notbe responsible or in any way liable for the continuedcurrency of the information or for any errors, omissions,or inaccuracies in this magazine, whether arising fromnegligence or otherwise or for any consequence arisingtherefrom. The staff of Oncologistics provides columnsand other editorial support. In no way are they responsiblefor the specifi c views presented in Oncologistics.Oncologistics magazine is published by ION, anAmerisourceBergen Specialty Group company.Mike MartinPresident, IONAll archived issues of Oncologistics are availableonline at www.iononline.com.oncologistics 3

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oncologistics volume 7, issue 1 - spring 2008table of contents spring 20080616202430Industry Insight: Hospira’s IncreasedRole in Oncology: An Interview withThomas G. Moore, president, GlobalPharmaceuticals, HospiraBy: Chris VorceThrombocytopenia Runs The Gamutof PossibilitiesBy: Charles S. Abrams, M.D.IV Iron Support ThroughoutChemotherapyBy: Michael Auerbach, M.D.Reimbursement Watch: The Impact ofMedicare Administrative Contractor Reformon Physician PracticesBy: Emily PhillipsDrug Update: New Studies in Vidaza®Therapy: Prolonged Survival in Higher-RiskMDS Patients, Alternate Dosing Schedules,and Use in AMLBy: Lewis R. Silverman, M.D.34 Drug Update: Nexavar® in UnresectableHCC: New Treatment Option Basedon Signifi cant Survival Benefi tBy: Ralph Boccia, M.D., F. A. C. P.424650Working Toward a Better Understandingand a Better Treatment of MyelomaBy: Guido Tricot, M.D., Ph.D.Nurse’s Forum: Outpatient Managementof Tumor Lysis Syndrome in Patientswith Diffuse Large B-Cell Lymphoma:Considerations for the Oncology NurseBy: Tamika M. Turner, M.S.N., N.P.-C.,O.C.N.Eye on IONoncologistics 5

industry insightHOSPIRA’S INCREASED ROLEIN ONCOLOGYby: Chris VorceHospira is a global specialty pharmaceutical and medication deliverycompany providing solutions to help improve the productivity, safety,and effectiveness of patient care. In early 2007, Hospira acquiredMayne Pharma to become the world leader in specialty genericinjectable pharmaceuticals. Historically, Hospira has not been known asan oncology-centric company, but with the acquisition of Mayne, andwith a variety of products and devices for both the treatment of tumorsand for use in supportive care in its pipeline, Hospira is well positionedto increase its involvement in the oncology market.ION recently had a chance to speak with Thomas G. Moore, president, Global Pharmaceuticals,Hospira, about his company’s acquisition of Mayne Pharma, as well as its strategic positioning in theoncology setting.oncologistics volume 7, issue 1 - spring 2008 6What is Hospira’s position in the genericinjectables market, and why was theacquisition of Mayne Pharma an importantstrategic step for Hospira?It’s important to note that in the United States,Hospira is just now approaching its 4-yearanniversary as an independent company, followingour 2004 spin-off from Abbott Laboratories.So, in one sense, we are relatively new to theU.S. marketplace. As part of Abbott; however,Hospira has led the U.S. market in genericinjectables for a number of years. Thisachievement is the direct result of 25 yearsof dedicated investments in generics.Outside of North America, Hospira has traditionallynot held as strong of a position with genericinjectables, offering only a select number ofpharmaceuticals in Asia, Europe and Latin America. TheMayne acquisition allowed us to quickly and dramaticallyexpand our global footprint and vaulted our company intothe leading position worldwide in the generic injectablemarket. The acquisition also allowed Hospira to changeour balance of sales by expanding our worldwidepositioning. This helps us to better serve the needs ofpatients and healthcare providers around the world.Another compelling component of the acquisition wasthe depth of Mayne’s oncology business. Prior to theacquisition, developing high-potency cytotoxic agents wasnot a fundamental part of Hospira’s business. With Mayne,we brought this capability to the forefront of our strategicplanning, allowing us to continue to grow our offering ofoncology products for clinicians and the patients theyserve. It truly jumpstarted the initiative.

oncologistics industry insightTHE MAYNE ACQUISITION ALLOWEDHOSPIRA TO QUICKLY ANDDRAMATICALLY EXPAND ITS GLOBALFOOTPRINT, AND VAULTED THECOMPANY INTO A LEADING POSITIONWORLDWIDE IN THE GENERICINJECTABLE MARKET.oncologistics 7

industry insightWhat core competencies did Hospirabring to the acquisition? How havethese competencies benefitedoncology customers?Hospira is proud of our leadership position andbroad portfolio of generic injectables and infusiontherapy products. In addition, we have specializedin the development of medication managementdevices, such as electronic infusion systems forintravenous therapies, for many years. Together,our pharmaceuticals and devices allow us toadvance wellness for patients and help addressthe healthcare industry’s key needs.want to continue our focus on genericinjectables, while moving beyond small-moleculegenerics into the development of novelpharmaceutical compounds in oncologyand acute-care therapeutics.Our strengths benefi t oncology customers byallowing us to bring more products and moresolutions to the market. As we move forward,oncology clinicians and patients will also benefi tfrom Hospira’s proprietary products and portfoliogrowth. Altogether, we continue to look for waysto be part of the solution for patients, cliniciansand the healthcare industry as a whole.When offering injectable pharmaceuticals, it isextremely important to offer a broad portfolio ofpharmaceuticals, and Hospira has demonstrateda history of consistently producing high-qualityproducts at higher volumes and at a faster ratethan other companies. In addition, Hospira’sclinical development capabilities are strong andimportant to our strategy. Looking forward, weHow has the acquisition of Mayne Pharmamade Hospira become more competitiveboth globally and in the oncology market?Traditionally, more than 90% of ourpharmaceutical sales have come from NorthAmerica, but we are now focusing on healthcareneeds worldwide. With a more balancedoncologistics volume 7, issue 1 - spring 2008 8

oncologistics industry insightglobal portfolio, Hospira currently recognizesapproximately 30% of our revenue from outsideof North America.oncologists and their patients. With our diversifi edapproach, we can offer a number of products andsolutions to oncology customers.Going forward, the largest percentage of saleswill likely continue to come from the U.S., sinceit is the largest market in the world. But, Hospirawill maintain a much broader presence outsidethe U.S., specifi cally in Europe and the Asia-Pacifi c region, where we are building on Mayne’shistoric strength. As we expand our portfolioof pharmaceutical products, we can build andsolidify our offering to oncology patients andclinicians going forward.Eventually, proprietary pharmaceuticals andbiosimilar therapies will comprise a largerpart of our oncology offering. Hospira’sinvestments in biosimilars and the launchof Retacrit (epoetin zeta), our biosimilarerythropoietin, in Europe, where there is asubstantial oncology population, are improvingpatient access to this important treatment.A number of additional oncology-focusedbiosimilar programs are currently underway.What is Hospira’s position within the genericmarket today?We currently lead the generic injectables industryglobally. (Currently, we do not compete in thebroader oral/solids generic markets.) Prior tothe Mayne acquisition, Hospira already heldthe leading position in the U.S. for genericinjectables, even without an oncology portfolio.With the acquisition, the company now hasglobal leadership in this area across all businesssegments. Moving forward, we strive to betterserve the oncologists’ needs, as well as tomaintain and grow our offering outside the U.S.Where do you see Hospira in the next 5 to 10years in the oncology market? What wouldyou like to see Hospira accomplish?Oncology is a very important therapeutic segmentwith growing patient needs, and our vision isfor Hospira to consistently bring products ofincreasing value to people worldwide who aredealing with cancer.As a diversifi ed healthcare company specializingin both drugs and devices, we will continuebringing medication management, infusiontherapy and pharmaceutical products toIn short, we are working to leverage ourdiversifi ed product development skills acrosspharmaceuticals and medication delivery devicesto bring an increased number of effectiveproducts to the oncology market.WITH THE RECENTLAUNCH OF GENERICIRINOTECAN IN THE U.S.,PATIENTS WITH COLON ORRECTAL CANCER WHOSEDISEASE HAS RECURRED ORPROGRESSED FOLLOWINGTHERAPY WITH OTHERTREATMENTS NOW HAVEANOTHER VIABLE TREATMENTOPTION, AT A DRAMATICALLYREDUCED COST.oncologistics 9

industry insightWhat differentiates Hospira from itscompetitors in the oncology market?We are a diversifi ed healthcare company,specializing in both drugs and devices. Whilemost of our competitors have a businessstrategy aligned to only one segment – eitherdrugs or devices – at Hospira, we have chosento build and invest in both. This allows us tooffer a complete and diverse suite of solutionsto oncologists.How strong is Hospira’s pipeline? Arethere any new upcoming products you candiscuss?region. We currently have a very strong presencein Australia and New Zealand, and a consistentlygrowing presence in Japan.Companies must pick and choose whichcustomer needs to serve. One company simplycannot do everything, and you must focus yourresources. At Hospira, we have chosen oncologyand acute care as primary components of ourstrategy to bring novel products to market andto address patient and clinical needs for theseimportant therapies. We are also expanding ourposition in biosimilars and proprietary drugs inboth acute care and oncology, primarily throughclinical development.Hospira’s pipeline is robust, with 43 newmolecules in development as of early 2008.This includes biogenerics and a large numberof oncology products for either direct therapyof tumors or supportive care. We expect tointroduce several of these products in theupcoming year.With our recent launch of generic irinotecan inthe U.S., patients with colon or rectal cancerwhose disease has recurred or progressedfollowing therapy with other treatments now haveanother viable treatment option, at a dramaticallyreduced cost. We also launched Retacrit, ourbiosimilar version of erythropoietin, in February inGermany and Austria, with plans to roll it out inthe major European markets throughout 2008.Whether we are expanding our product portfolioor our geographic reach, our strategy is unifi edby a common question: How can we advancewellness for clinicians and the patients theyserve? As long as we maintain that vision, I amconfi dent that we will continue to make the rightinvestments to better serve healthcare industryneeds worldwide. ❚oncologistics volume 7, issue 1 - spring 2008 10What new geographic markets or marketsegments do you see Hospira expanding inthe near and long term?Hospira will grow our presence in Europe andAsia. In some of these countries, we currentlyuse distributors. Moving forward, we will increaseour direct presence in some areas with strongand growing patient needs, such as Poland, theCzech Republic, Turkey and the Asia-Pacifi c

Thomas G. Moore is president, GlobalPharmaceuticals at Hospira, where he isresponsible for the long-term growth, globalbusiness strategy, and management ofHospira’s pharmaceutical product portfolio.Chris Vorce is senior manager of marketingand communications at ION.oncologistics 11

XELODAEfficacy that makes a differenceEligible for only Medicare Part B coverage in oncologyIndicationsXELODA is indicated as a single agent for adjuvant treatment in patientswith Dukes’ C colon cancer who have undergone complete resection ofthe primary tumor when treatment with fluoropyrimidine therapy alone ispreferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV)for disease-free survival (DFS). Although neither XELODA nor combinationchemotherapy prolongs overall survival (OS), combination chemotherapy has beendemonstrated to improve disease-free survival compared to 5-FU/LV. Physiciansshould consider these results when prescribing single-agent XELODA in theadjuvant treatment of Dukes’ C colon cancer.XELODA is indicated as first-line treatment of patients with metastaticcolorectal carcinoma when treatment with fluoropyrimidine therapy aloneis preferred. Combination chemotherapy has shown a survival benefit comparedto 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated withXELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has notbeen adequately studied to assure safety or preservation of the survival advantage.XELODA monotherapy is indicated for the treatment of patients with metastaticbreast cancer resistant to both paclitaxel and an anthracycline-containingchemotherapy regimen or resistant to paclitaxel and for whom furtheranthracycline therapy is not indicated, eg, patients who have received cumulativedoses of 400 mg/m 2 of doxorubicin or doxorubicin equivalents. Resistance is definedas progressive disease while on treatment, with or without an initial response, or relapsewithin 6 months of completing treatment with an anthracycline-containing adjuvant regimen.XELODA in combination with docetaxel is indicated for the treatment ofpatients with metastatic breast cancer after failure of prior anthracyclinecontainingchemotherapy.Important Safety InformationWARNINGFor patients receiving XELODA and warfarin concomitantly, frequent monitoring of INR orprothrombin time (PT) is recommended. A clinically important drug interaction betweenXELODA and warfarin has been demonstrated. Altered coagulation parameters and/orbleeding and death have been reported. Clinically significant increases in PT and INR havebeen observed within days to months after starting XELODA, and infrequently within onemonth of stopping XELODA. These events occurred in patients with and without livermetastases. Age greater than 60 and a diagnosis of cancer independently predisposepatients to an increased risk of coagulopathy.Adverse EventsIn XELODA monotherapy for colon cancer in the adjuvant setting, the most common adverseevents for all grades (≥10%) in patients receiving XELODA (%) were hand-foot syndrome (60),diarrhea (47), nausea (34), stomatitis (22), fatigue (16), lethargy (16), vomiting (15), abdominalpain (14), and asthenia (10). Grade 3/4 adverse events (≥5%) in patients receiving XELODAwere hand-foot syndrome (17) and diarrhea (12). In XELODA monotherapy for metastaticcolorectal cancer, the most common adverse events (≥10%) in patients receiving XELODA (%)were anemia (80), diarrhea (55), hand-foot syndrome (54), hyperbilirubinemia (48), nausea (43),fatigue/weakness (42), abdominal pain (35), dermatitis (27), vomiting (27), appetite decrease (26),stomatitis (25), pyrexia (18), edema (15), constipation (14), dyspnea (14), neutropenia (13), pain (12),back pain (10), headache (10), gastrointestinal motility disorder (10), oral discomfort (10),peripheral sensory neuropathy (10), and eye irritation (13). Grade 3/4 adverse events (≥5%) inpatients receiving XELODA were hyperbilirubinemia (23), hand-foot syndrome (17), diarrhea (15),

Proven efficacy in adjuvant stage III (Dukes’ C) colon cancer andmetastatic colorectal cancer 1-2Proven efficacy in metastatic breast cancer, regardless of HER2 status 3-5Dose modification does not appear to compromise efficacyacross indications 5-8Established safety profileFor more information about XELODA, contact your Roche representative or visit www.xeloda.com.abdominal pain (10), vomiting (5), and ileus (5). In XELODA monotherapy for metastatic breastcancer, the most common adverse events (≥10%) in patients receiving XELODA (%) werelymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), fatigue (41),dermatitis (37), vomiting (37), neutropenia (26), stomatitis (24), thrombocytopenia (24),anorexia (23), hyperbilirubinemia (22), paresthesia (21), abdominal pain (20), constipation (15),eye irritation (15), and pyrexia (12). Grade 3/4 adverse events (≥5%) in patients receivingXELODA were lymphopenia (59), diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia (11),fatigue (8), stomatitis (7), and dehydration (5). In XELODA combination therapy (XELODA plusdocetaxel) for breast cancer, the most common adverse events (≥10%) in patients receivingXELODA plus docetaxel (%) were lymphocytopenia (99), leukopenia (91), neutropenia/granulocytopenia (86), anemia (80), diarrhea (67), stomatitis (67), hand-foot syndrome (63),nausea (45), alopecia (41), thrombocytopenia (41), vomiting (35), edema (33), abdominal pain (30),pyrexia (28), asthenia (26), fatigue (22), constipation (20), hyperbilirubinemia (20), neutropenicfever (16), taste disturbance (16), weakness (16), arthralgia (15), headache (15), myalgia (15),dyspnea (14), dyspepsia (14), nail disorder (14), anorexia (13), cough (13), pain in limb (13),back pain (12), dizziness (12), lacrimation increase (12), paresthesia (12), sore throat (12),appetite decrease (10), and dehydration (10). Grade 3/4 adverse events (≥5%) in patients receivingXELODA plus docetaxel (%) were lymphocytopenia (89), leukopenia (61), neutropenia/granulocytopenia (69), hand-foot syndrome (24), stomatitis (18), neutropenic fever (16), diarrhea (15),anemia (10), hyperbilirubinemia (9), nausea (7), alopecia (6), vomiting (5), and asthenia (5).Contraindications and WarningsXELODA is contraindicated in patients who have a known hypersensitivity to capecitabine or toany of its components or to 5-fluorouracil. XELODA is contraindicated in patients with knowndihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is contraindicated in patients withsevere renal impairment. Patients with mild or moderate renal impairment at baseline should becarefully monitored for adverse events. Patients with moderate renal impairment at baseline requirea reduced starting dose.XELODA can induce diarrhea, sometimes severe. Patients with severe diarrheashould be carefully monitored and given fluid and electrolyte replacement ifthey become dehydrated.If an adverse event of grade 2, 3, or 4 occurs (eg, diarrhea), administration of XELODAshould be immediately interrupted until the adverse event resolves or decreases inintensity to grade 1. Subsequent doses of XELODA may need to be decreased. Pleaseconsult XELODA Prescribing Information for recommended dose modifications.Women of childbearing potential should be advised to avoid becoming pregnant whilereceiving treatment with XELODA. Men should use birth control while taking XELODA.Women should not nurse when receiving XELODA therapy.References: 1. Data on file (Ref. 111-041), Hoffmann-La Roche Inc., Nutley, NJ07110. 2. Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine vs intravenous5-fluorouracil and leucovorin: integrated efficacy data and novel analyses fromtwo large, randomised, phase III trials. Br J Cancer. 2004;90:1190-1197. 3. Tykerb[package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007. 4. Ixempra[package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.5. O’Shaughnessy JA. Superior survival with the combination of docetaxel andcapecitabine compared to docetaxel alone in anthracycline-pretreated metastatic breastcancer patients. Am J Oncol Rev. 2002;1(5):280-285. 6. Cassidy J, Twelves C,Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer:a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. AnnOncol. 2002;13:566-575. 7. Data on file (Ref. 111-036), Hoffmann-La Roche Inc.,Nutley, NJ 07110. 8. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival withcapecitabine plus docetaxel combination therapy in anthracycline-pretreated patientswith advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20(12):2812-2823.Please see summary of XELODA Prescribing Information,including boxed WARNING, on adjacent pages.Copyright © 2008 Roche Laboratories Inc. All rights reserved.

Brief summary of prescribing information.For complete prescribing information, please consult official package insert.WARNINGXELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivativeanticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequentlyin order to adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin drug interactionwas demonstrated in a clinical pharmacology trial (see CLINICAL PHARMACOLOGY and PRECAUTIONS).Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODAconcomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketingreports have shown clinically significant increases in prothrombin time (PT) and INR in patients who werestabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days andup to several months after initiating XELODA therapy and, in a few cases, within 1 month after stoppingXELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and adiagnosis of cancer independently predispose patients to an increased risk of coagulopathy.INDICATIONS AND USAGE: Adjuvant Colon Cancer:XELODA is indicated as a single agent for adjuvanttreatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumorwhen treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil andleucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapyprolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-freesurvival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent XELODAin the adjuvant treatment of Dukes’ C colon cancer. Metastatic Colorectal Cancer:XELODA is indicated asfirst-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidinetherapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LValone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODAinstead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of thesurvival advantage. Breast Cancer Combination Therapy:XELODA in combination with docetaxel is indicatedfor the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containingchemotherapy. Breast Cancer Monotherapy: XELODA monotherapy is also indicated for the treatment ofpatients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapyregimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients whohave received cumulative doses of 400 mg/m 2 of doxorubicin or doxorubicin equivalents. Resistance is definedas progressive disease while on treatment, with or without an initial response, or relapse within 6 months ofcompleting treatment with an anthracycline-containing adjuvant regimen. CONTRAINDICATIONS: XELODA iscontraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA iscontraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is contraindicated inpatients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated inpatients with severe renal impairment (creatinine clearance below 30 ml/min [Cockroft and Gault]) (seeCLINICAL PHARMACOLOGY: Special Populations). WARNINGS: Renal Insufficiency:Patients with moderaterenal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION). Patients with mild andmoderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption oftherapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event asoutlined in Table 14 in DOSAGE AND ADMINISTRATION. Coagulopathy:See Boxed WARNING. Diarrhea:XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitoredand given fluid and electrolyte replacement if they become dehydrated. In the overall clinical trial safety databaseof XELODA monotherapy (N=875), the median time to first occurrence of grade 2 to 4 diarrhea was 34 days(range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Instituteof Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as anincrease of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3, or 4diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves ordecreases in intensity to grade 1. Following a recurrence of grade 2 diarrhea or occurrence of any grade 3 or 4diarrhea, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). Standardantidiarrheal treatments (eg, loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has beenreported. Geriatric Patients:Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverseevents (see PRECAUTIONS: Geriatric Use). In the overall clinical trial safety database of XELODA monotherapy(N=875), 62% of the 21 patients ≥80 years of age treated with XELODA experienced a treatment-related grade3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), andvomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 yearsof age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome. Among the67 patients ≥60 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events,treatment discontinuations due to adverse events, and treatment discontinuations within the first two treatmentcycles was higher than in the 3 × ULN) hyperbilirubinemia occurred in 3.9% (n=34) of 875 patients with eithermetastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m 2 twice daily asmonotherapy for 2 weeks followed by a 1-week rest period. Of 566 patients who had hepatic metastases atbaseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) alsohad postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5%(n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority ofthese patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkalinephosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations inalkaline phosphatase or transaminases. In the 596 patients treated with XELODA as first-line therapy formetastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinicaltrial safety database of XELODA monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia inthe colorectal cancer population was 64 days and median total bilirubin increased from 8 µm/L at baseline to13 µm/L during treatment with XELODA. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia,49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastasesat baseline. In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel,grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemiaoccurred in 2% (n=5). If drug-related grade 2 to 4 elevations in bilirubin occur, administration of XELODA shouldbe immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. NCIC grade 2hyperbilirubinemia is defined as 1.5 × normal, grade 3 hyperbilirubinemia as 1.5 to 3 × normal and grade 4hyperbilirubinemia as >3 × normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.)Hematologic: In 875 patients with either metastatic breast or colorectal cancer who received a dose of1250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In251 patients with metastatic breast cancer who received a dose of XELODA in combination with docetaxel, 68%had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.Carcinogenesis, Mutagenesis, and Impairment of Fertility:Adequate studies investigating the carcinogenicpotential of XELODA have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test)or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitroto human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test).Fluorouracil causes mutations in bacteria and yeast. Fluourouracil also causes chromosomal abnormalities inthe mouse micronucleus test in vivo. Impairment of Fertility:In studies of fertility and general reproductiveperformance in mice, oral capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused adecrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus wasreversible. In males, this dose caused degenerative changes in the testes, including decreases in the number ofspermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUCvalues about 0.7 times the corresponding values in patients administered the recommended daily dose.Information for Patients (see Patient Package Insert):Patients and patients’ caregivers should be informed ofthe expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome,and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (seeDOSAGE AND ADMINISTRATION). Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day ornocturnal stools), grade 2 nausea (food intake significantly decreased but able to eat intermittently), grade 2vomiting (2 to 5 episodes in a 24-hour period), grade 2 hand-and-foot syndrome (painful erythema and swellingof the hands and/or feet and/or discomfort affecting the patients’ activities of daily living), or grade 2 stomatitis(painful erythema, edema or ulcers of the mouth or tongue, but able to eat) should be instructed to stop takingXELODAimmediately. Initiation of symptomatic treatment is recommended (see DOSAGE AND ADMINISTRATION).Fever and Neutropenia:Patients who develop a fever of 100.5° or greater or other evidence of potential infectionshould be instructed to call their physician. Drug-Food Interaction:In all clinical trials, patients were instructedto administer XELODA within 30 minutes after a meal. Since current safety and efficacy data are based uponadministration with food, it is recommended that XELODA be administered with food (see DOSAGE ANDADMINISTRATION). Drug-Drug Interactions: Antacid: The effect of an aluminum hydroxide- and magnesiumhydroxide-containing antacid (Maalox) on the pharmacokinetics of XELODA was investigated in 12 cancer patients.There was a small increase in plasma concentrations of XELODA and one metabolite (5'-DFCR); there was no effecton the 3 major metabolites (5'-DFUR, 5-FU and FBAL). Anticoagulants:Patients receiving concomitant capecitabineand oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombintime) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly (see BoxedWARNING and CLINICAL PHARMACOLOGY). Altered coagulation parameters and/or bleeding have been reportedin patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin andphenprocoumon. These events occurred within several days and up to several months after initiating XELODAtherapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with andwithout liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significantincrease in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction isprobably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites (see CLINICALPHARMACOLOGY). CYP2C9 substrates: Other than warfarin, no formal drug-drug interaction studies betweenXELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA iscoadministered with CYP2C9 substrates. Phenytoin: The level of phenytoin should be carefully monitored in patientstaking XELODA and phenytoin dose may need to be reduced (see DOSAGE AND ADMINISTRATION: DoseModification Guidelines). Postmarketing reports indicate that some patients receiving XELODA and phenytoin hadtoxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not beenconducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabineand/or its metabolites (see PRECAUTIONS: Drug-Drug Interactions: Anticoagulants).Leucovorin: The concentrationof 5-fluourouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis,diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.Pregnancy:Teratogenic Effects: Category D (see WARNINGS). Women of childbearing potential should beadvised to avoid becoming pregnant while receiving treatment with XELODA. Nursing Women: Lactating micegiven a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommendedthat nursing be discontinued when receiving XELODA therapy. Pediatric Use: The safety and effectiveness ofXELODA in persons

CONTINUED FROM PREVIOUS PAGE Phase 3 Adjuvant ColonCancer Trial (n=995)Phase 3 MetastaticColorectal Trials (n=596)Body System/Adverse Event All Grades Grade 3/4All Grades Grade 3/4Dizziness*6

oncologistics volume 7, issue 1 - spring 2008 16THROMBOCYTOPENIA RUNS THE

oncologistics thrombocytopeniaGAMUT OF POSSIBILITIESby: Charles S. Abrams, M.D.Hemorrhage following trauma or surgery generallydoes not occur if the platelet count is morethan 50,000/µL. In an otherwise hemostaticallynormal patient, signifi cant spontaneous bleedingtypically does not occur with a platelet count ofgreater than 5,000-10,000/µL. However, there isno absolute threshold for spontaneous bleedingdue to thrombocytopenia. It may occur at highercounts when fever, sepsis, severe anemia, andother hemostatic defects are present, or whenplatelet function is impaired by medication. Notably,a prolonged cutaneous bleeding time does notaccurately predict clinical bleeding. Therefore,it is critical that the physician run the gamut ofpossibilities when diagnosing the cause of a lowplatelet count. Thrombocytopenia can be due toaccelerated platelet removal, decreased plateletproduction by bone marrow megakaryocytes, or byplatelet sequestration in an enlarged spleen. Sincethere is no easy test to differentiate among thesepossibilities, clinical evaluation is critical.The rubric of diagnosis for any condition entails the physiciantaking a detailed history. Additionally, a thorough physicalexamination, with attention to possible alternative explanationsfor thrombocytopenia must be performed. This is especiallyimportant for thrombocytopenia, because some causes suchas idiopathic thrombocytopenic purpura (ITP) remain thediagnosis of exclusion. In addition, a complete blood count witha differential is mandatory, as is the examination of the peripheralblood smear. Other tests may also be warranted based upononcologistics 17

oncologistics volume 7, issue 1 - spring 2008 18the available clinical information. For instance, patientswith appropriate risk factors should undergo testing forHuman Immunodefi ciency Virus (HIV). In older patients withunexplained thrombocytopenia, or in individuals in whomstandard therapy has not been effective, a bone marrowbiopsy may be in order. Correct diagnosis of the etiologyof thrombocytopenia is essential in order to provide thecorrect treatment, and to avoid unnecessary proceduresand treatments.MANY PATIENTS WITH THROMBOCYTOPENIAHAVE INCREASED PLATELET DESTRUCTIONNon-immune and immune processes can lead to ashortened platelet lifespan. Immune mediated plateletdestruction can occur due to medication, autoimmunity,or alloimmune antibodies following sensitization.Medications should always be scrutinized as a possiblecause of thrombocytopenia, since the pharmaceuticallist of offending agents is extensive. Drugs with strongevidence of antibody-mediated platelet destruction includequinine, quinidine, sulfonamides, and gold salts. In additionto the cessation of the offending medication, there aretreatments for severe thrombocytopenia with bleedingthat may need to be given emergently. These treatmentsmay include platelet transfusion, corticosteroids, andintravenous immunoglobulin (IVIG).A special case of drug-induced immune-mediatedthrombocytopenia that is associated with arterial andvenous thrombosis rather than bleeding is Heparin-inducedthrombocytopenia (HIT). HIT occurs in 2-5% of patientsgiven unfractionated heparin by any route for fi ve to 10days. Antibodies develop to a complex of heparin boundto PF4 (a protein secreted by activated platelets.) Whenthrombocytopenia is detected in a hospitalized patient,HIT must always be considered. If a patient has HIT, allheparin administration should be promptly stopped. Thisincludes subcutaneous injections of “minidose” heparin,heparin fl ushes of IV lines, low molecular weight heparin,and even heparin coating of intravenous catheters.Additionally, at least until the platelet count normalizes,alternative anticoagulation, such as the direct thrombininhibitors like recombinant hirudin and argatroban shouldbe administered. Warfarin should not be used in cases ofacute HIT because of its delayed therapeutic effect, and itsassociation with venous limb gangrene. Sincepatients rarely become profoundly thrombocytopenicby this disease alone, platelet transfusions are typicallynot required. In fact, the administration of platelettransfusions in this disease is controversial, and somereports suggest platelet transfusions can actuallyprecipitate thrombotic complications.Alloimmune thrombocytopenia is due to sensitization toalloantigens such as Pl A1 , and can result from transfusion(post-transfusion purpura or PTP) or maternal sensitizationduring pregnancy (neonatal alloimmune thrombocytopeniaor NAIT). PTP causes profound thrombocytopenia 7-10days after exposure to platelets that contaminate redblood cell transfusions, and can be treated withintravenous immunoglobulin or plasma exchange.NAIT can cause severe thrombocytopenia and bleedingin neonates, and is treated with transfusion of plateletsderived from the newborn’s mother, corticosteroids,and intravenous immunoglobulin.Autoimmune thrombocytopenia, also known asidiopathic thrombocytopenic purpura, is caused bycirculating anti-platelet autoantibodies. An ITP-likepicture can also occur in autoimmune diseases suchas systemic lupus erythematosis, in patients withlow-grade lymphoproliferative disorders such as chroniclymphocytic leukemia, and in patients with HIV infections.ITP can occur in patients of either sex, at any age, andmay present with either mucocutaneous bleeding orunexplained asymptomatic thrombocytopenia. Exceptfor thrombocytopenia, the CBC is completely normal.Splenomegaly is absent in this disorder, and peripheralblood smears are only remarkable for a decreased numberof platelets, some of which may be larger in size thannormal. Bone marrow examination is usually not necessaryin the absence of other fi ndings suggesting myelodysplasia.When done, the bone marrow biopsy typically showsnormal or increased numbers of megakaryocytes, but isotherwise normal.Management of ITP is guided by both symptoms andplatelet count. Asymptomatic patients with plateletcounts of greater than 30,000/µL can be followedwithout treatment. With bleeding and/or a platelet

oncologistics thrombocytopeniacount of less than 30,000/µL, treatment withprednisone is recommended. Refractory patientsmay require splenectomy (60-75% remission rate),other immunosuppressive medications, or (pendingFDA approval) new thrombopoiesis stimulatingagents. Emergent presentations of ITP with severethrombocytopenia (less than 5,000/µL) and/or internalbleeding, should be treated with high doses of pulsecorticosteroids and intravenous immunoglobulin.Platelet transfusion may be given concurrently withthe intravenous immunoglobulin for critical bleeding.In Rh+ patients, who have not undergone splenectomy,anti-D immune globulin may be substituted forintravenous immunoglobulin. However, occasionalpatients will develop severe autoimmune hemolysisfrom the administration of this treatment.THROMBOCYTOPENIA DUE TO DIC, TTP/HUS,AND HYPERSPLENISMNon-immune mediated causes of platelet destructioninclude sepsis, disseminated intravascular coagulation(DIC), thrombotic thrombocytopenic purpura/hemolyticuremic syndrome (TTP/HUS), preeclampsia/eclampsia,cardiopulmonary bypass, and giant cavernoushemangiomas. The thrombocytopenia resolveswith treatment of the underlying disorder, andplatelet transfusion is rarely necessary. In TTP/HUS,thrombocytopenia is associated with thrombosis ratherthan bleeding, and controversial reports exist of clinicaldeterioration following platelet transfusion.Approximately 20% of the circulating platelet massis normally present in the spleen. Additional plateletsmay be sequestered when the spleen enlarges dueto portal hypertension or infi ltrative diseases, and thisresults in thrombocytopenia (although the platelet countis generally are not lower than 40,000-50,000/µL.)Consequently, bleeding due to thrombocytopenia fromhypersplenism alone is unusual.marrow is replaced by metastatic carcinoma,fi brosis, or other clonal hematopoietic disorders;following chemotherapy and/or radiation therapy;with ethanol toxicity; and during infections with virusessuch as HIV, cytomegalovirus (CMV), Epstein-Barrvirus (EBV), and varicella. Thrombocytopenia alsooccurs when normal megakaryocyte proliferation isimpaired by myelodysplasia.Overt bleeding in these disorders, when clearlydue to thrombocytopenia, is treated by platelettransfusion. However, in the absence of bleeding,prophylactic platelet transfusion is an area of controversy.When making the decision whether to treat a nonbleedingpatient with thrombocytopenia, the practitionermust consider the short lifespan of platelets (10 days),the fi ve-day shelf life of stored platelets, and the potentialof a transfusion inducing platelet alloantibodies. Inpatients undergoing treatment for acute leukemia,outcome is unchanged when platelet counts as lowas 5,000-10,000/µL are used as the threshold forprophylactic transfusion. Single donor apheresis platelets,and/or platelet donors who are HLA-identical to therecipient, should be used to prevent alloimmunization.The multi-center Platelet Dose trial is currently underwayand should help to clarify the ideal parameters for platelettransfusions in patients with malignancy.FINAL THOUGHTSThrombocytopenia remains a potentially life-threateningproblem that requires careful clinical assessmentand judgment. In recent years, signifi cant advanceshave been made in elucidating the pathogenesisof thrombocytopenia and the mechanisms ofthrombopoiesis. Drawing upon decades of basic scienceand clinical research, this has led to the application ofsafer and more effi cacious therapies for this disorder. ❚DECREASED PLATELET PRODUCTION INTHROMBOCYTOPENIADecreased platelet production occurs in primarydiseases of the bone marrow such as acute leukemiaand aplastic anemia; myelophthisic processes in whichCharles S. Abrams, M.D., is associate professorin the Department of Medicine at The Universityof Pennsylvania School of Medicine.oncologistics 19

IV IRON SUPPORTTHROUGHOUT CHEMOTHERAPYby: Michael Auerbach, M.D.oncologistics volume 7, issue 1 - spring 2008 20HISTORICAL BELIEFS AND MODERN TRUTHSFor some time, there has been a common, yetmisconceived notion circulating throughout segmentsof the medical community that intravenous (IV) ironadministration is dangerous. Popular opinion states thatparenteral iron should only be used in the most extremesituations where oral iron is ineffective or not tolerated.This traditional belief has been based on poorlycharacterized and infrequent anaphylactoid reactions tothe high-molecule-weight dextran preparations (Imferon ® ,Fisons), which are no longer available, and Dexferrum ®(American Regent), which is not recommended.Nonetheless, these beliefs, born of their use, still persist.Additionally, in cases when parenteral iron use was deemednecessary, the most commonly used approach was formultiple intramuscular doses (< 100 mg), even when theIV administration of the total iron defi cit as a single doseor as repetitive boluses were shown to be just as safe andeffective. Intramuscular iron, is, in fact, painful, associatedwith gluteal sarcomas, causes permanent discoloration ofthe skin, and has never been shown to be less toxic thanIV iron. As such, many of the common negativeconnotations associated with parenteral iron treatment arethe result of less than optimal applications of the therapy.Today, low-molecule-weight iron dextran (InFeD ® , Watson),as well as two iron salt preparations—ferric gluconate(Ferrlecit ® , Watson) and iron sucrose (Venofer ® , AmericanRegent)—are available. All present fewer serious adverseevents than the previously used high-molecule-weightdextrans. There are now three published comparisontrials 1-3 of low-molecular-weight iron dextran and ironsucrose that show equal effi cacy and toxicity withconsiderable cost savings and increased conveniencewith low-molecular-weight iron dextran. The largestretrospective review of dialysis experience suggests thatmost serious adverse events have been associated withhigh-molecule-weight iron dextrans and are rare(

oncologistics IV iron support throughout chemotherapyoncologistics 21

established, and the test dose has not proved to alter thetherapeutic plan. In Europe, the test dose and black boxwarning with low-molecular-weight iron dextran have beenabandoned. With this dosage, serious adverse events areextremely rare, and any adverse event that has occurredwith iron dextran has not been related to the dose orinfusion rate. 4Regarding iron salts, when the total dose administered isless than 200 mg ferric gluconate or 300 mg iron sucrose,acute, infusion-related reactions are uncommon. No testdoses are required with these salts.IV IRON AND THE EFFICACY OF ESA THERAPYThe Centers for Medicare and Medicaid Services (CMS)has recommended that the use of erythropoiesis–stimulating agents (ESAs) begin at a hemoglobin level of

oncologistics IV iron support throughout chemotherapypatients and to predict erythropoietic responseimprovement to intravenous iron in the cancer setting.If intravenous iron is thought to improve the effi cacyof ESAs, can the same be said for orally administerediron? Two randomized trials have compared the effi cacyof oral and intravenous iron in anemic patients withcancer who are receiving recombinant erythropoietin.In both studies, oral iron with recombinanterythropoietin was not signifi cantly better thanrecombinant erythropoietin alone, but intravenousiron with recombinant erythropoietin resulted in asignifi cantly better erythropoietic response. 14-15 Inorder to avoid the CMS recommendations that willeffectively remove ESA therapy from the oncologyarmamentarium, IV iron should be incorporated intothe treatment paradigm to maximize effi cacy.CONCLUSIONThe role of intravenous iron in oncology is poorlyunderstood and is currently a vastly underusedtherapy in the treatment of a host of disordersassociated with absolute or functional iron defi ciencyand anemia. The reliance upon outdated informationinvolving high-molecule-weight iron dextran is partlyresponsible for the underuse of IV iron in the clinicalsetting today. By demonstrating advantageous effectswhen used in conjunction with ESA therapy, and byserving as an option with little to no serious adverseevents, the continued and increased use of IV ironas maintenance therapy for chemotherapy patientsshould be considered. ❚Michael Auerbach, M.D., is in private practice inBaltimore, MD, and is a clinical professor of medicineat Georgetown University. Dr. Auerbach has publishedextensively on the use of IV iron alone and asadjunctive therapy with ESAs. His study in the Journalof Clinical Oncologyin 2004 was the fi rst paperdemonstrating the synergy of IV iron in optimizingESA responsiveness in oncology patients.References:1. Moniem KA, Bhandari S. Tolerability and effi cacy of parenteral irontherapy in haemodialysis patients, a comparison of preparations.Trans Alt Trans Med2007; 1-7.2. Critchley J, Dundar Y. Adverse events associated with intravenousiron infusion (low-molecular-weight iron dextran and iron sucrose):a systematic review. Trans Alt Trans Med2007; 8-36.3. Sav T, Tokgoz B, Sipahioglu MH. Is there a difference betweenallergic potencies of the iron sucrose and low molecular weightiron dextran? Renal Failure 2007; 29: 423-426.4. Auerbach M, Witt D, Toler W, Fierstein M, Lerner RG, Ballard H,Clinical use of the total dose intravenous infusion of iron dextran.J Lab Clin Med1988; 111: 566-70.5. Barton JC, Barton EH, Bertoli LF, et al. Intravenous iron dextrantherapy in patients with iron defi ciency and normal renalfunction who failed to respond to or did not tolerate oral ironsupplementation. Am J Med2000; 109: 27-32.6. Auerbach M, Chaudhry M, Goldman H, Ballard H. Value ofmethylprednisolone in prevention of the arthralgia-myalgiasyndrome associated with the total dose infusion of iron dextran:a double blind randomized trial. J Lab Clin Med1998; 131:257-260.7. MacDougall IC, Roche A. Administration of intravenous ironsucrose as a 2-minute push to CKD patients: a prospectiveevaluation of 2297 injections. Am J Kidney Dis 2005; 46: 283-89.8. Fishbane Sm Frei GL, Maesaka J. Reduction in recombinanthuman erythropoietin doses by the use of chronic intravenous ironsupplementation. Am J Kidney Dis 1995; 26: 41-46.9. Fishbane S, Ungureanu VD, Maesaka JK, Kaupke CJ, Lim V, WishJ. The safety of intravenous iron dextran in hemodialysis patients.AM J Kidney Dis 1996; 28: 529-34.10. Fishbane S, Mittal SK, Maesaka JK. Benefi cial effects of irontherapy in renal failure patients on hemodialysis. Kidney Int1999;55: 567-70.11. Adamson JW, Eshbach JW. Erythropoietin for end-stage renaldisease. N Engl J Med1998; 339: 625-27.12. Ganz T. Hepcidin, a key regulator of iron metabolism andmediator of anemia of infl ammation. Blood 2003; 102: 783-88.13. Andrews NC. Anemia of infl ammation: the cytokine-hepcidin link.J Clin Invest2004; 113: 1251-53.14. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizesthe response to recombinant human erythropoietin in cancerpatients with chemotherapy-related anemia: a multicenter, openlabel, randomized trial. J Clin Oncol2004; 22: 1301-07.15. Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR.Intravenous ferric gluconate signifi cantly improves response toepoetin alfa versus oral iron or no iron in anemic patients withcancer receiving chemotherapy. Oncologist2007; 12: 231-42.16. Hedenus M, Birgegard G, Nasman P, et al. Addition ofintravenous iron to epoetin beta increases hemoglobin responseand decreases epoetin dose requirement in anemic patientswith lymphoproliferative malignancies: a randomized multicenterstudy. Leukemia 2007; published online Jan 25. DOI:10.1038/sj.leu.2404562.oncologistics 23

eimbursement watchoncologistics volume 7, issue 1 - spring 2008 24STAYING ON TOP OF MAC-RELATED DEVELOPMENTS WILL BE IMPORTANTAS EACH JURISDICTION STARTS TRANSITION ACTIVITIES. BEING AWAREOF JURISDICTION-SPECIFIC TIMELINES RELATED TO LOCAL CONTRACTORTRANSITION DATES AND POLICY CHANGES WILL HELP TO ENSUREAPPROPRIATE AND TIMELY CLAIMS PAYMENT.

oncologistics reimbursement watchTHE IMPACT OFMEDICARE ADMINISTRATIVECONTRACTOR REFORM ONPHYSICIAN PRACTICESby: Emily PhillipsIn the next 2 years, oncology and hematology practices across the United Stateswill experience dramatic changes in their regional Medicare contractors’ operationalrequirements, claims processing, and coverage policies. Yet with this rapidtransformation already starting, few healthcare providers have given much thoughtto the impact Medicare Administrative Contractor (MAC) reform will have on theirpractices. Providers who fail to take notice of these important changes could see claimdenials, payment delays, or missed opportunities to weigh in on proposals for newcoverage policies that could impact patient care.BACKGROUNDMAC reform is part of the Medicare ModernizationAct (MMA) of 2003, which was passed byCongress in an effort to stem rising Medicarecosts. Under MAC reform, Medicare carriers andfi scal intermediaries will be replaced by 15 PartA/B MACs divided into multi-state jurisdictions.Prior to MAC reform, there were nearly 50operational Medicare fi scal intermediaries andcarriers operating across the United States. Theend result of MAC reform will be one contractorper jurisdiction. The goal is to simplify the numberof Medicare processes and requirements onthe local level through consolidation of multipleMedicare administrators. The transitions, whichstarted in 2006 with the award for J3 to Noridian,and most recently, in J4 and J5, are intendedto improve the consistency of coverage andclaims processing requirements. Previously,CMS contracted with nearly 50 private insurersto process Medicare claims and administerMedicare benefi ts. That ultimately hamperedMedicare’s ability to meet healthcare deliverychallenges. Some issues with the formerMedicare contracting structure included a lack ofcompetition, specialization restrictions, separateprocessing for Part A and B claims, and anabsence of performance-based incentives.oncologistics 25

eimbursement watch1423613215815124101171Figure1. Medicare Part A/B MAC Jurisdictions9oncologistics volume 7, issue 1 - spring 2008 26LEGACY CONTRACTORS, FISCAL INTERMEDIARIES,AND CARRIERSPart A/B MACs will now be the sole claims processorsfor services rendered in both physician offi ces andhospitals, duties previously processed separately bycarriers and fi scal intermediaries. The impact of MACreform on Medicare providers and benefi ciaries maydepend on whether or not their new MAC is alreadyan existing Medicare legacy contractor in their region.For example, providers in the J4 region, which includesthe states of Colorado, New Mexico, Oklahoma, andTexas, are transitioning to TrailBlazer Health Enterprises,LLC (TrailBlazer), and may experience fewer changessince TrailBlazer was a legacy contractor for these J4states. The company previously operated as a Part Bcarrier for Delaware, the District of Columbia, Maryland,Texas, and Virginia, and as a fi scal intermediary inColorado, New Mexico, and Texas. Outgoing legacycontractors transitioning their current responsibilitiesto TrailBlazer include:> Group Health Service of Oklahoma> Part A Fiscal Intermediary (OK)> Noridian Administrative Services> Part B Carrier (CO)> Pinnacle Business Solutions> Part B Carrier (NM, OK)Conversely, Wisconsin Physician Service (WPS) did notoperate as a Medicare contractor in the J5 states of Iowa,Nebraska, Kansas, and Missouri prior to its award onSeptember 5, 2007, as a MAC in that jurisdiction. Itsnew status as a MAC creates an opportunity for WPS toeducate providers on unfamiliar processes related toclaims submission, redeterminations or appeals, as wellas the applicability of new local coverage determinations(LCDs). Still, regardless of whether a region’s MAC isa legacy Medicare contractor or not, providers will haveto juggle potential changes in coverage policies andoperational requirements.WHAT TO WATCH FORStaying on top of MAC-related developments will beimportant as each jurisdiction starts transition activities.Being aware of jurisdiction-specifi c timelines related tolocal contractor transition dates and policy changes willhelp ensure appropriate and timely claims payment. Eachstate within a specifi c jurisdiction may have a differenttransition date (also referred to as a “cutover date”), which

oncologistics reimbursement watchcan include separate transition timelines for the Part Aand Part B workload (claims processing responsibilitiestransferred from a legacy carrier or fi scal intermediary to aMAC). Providers will want to track the transition from theircurrent, legacy contractor to a new MAC for importantinformation such as:> Deadlines to submit electronic fi le transferagreements to the new MAC> Cutoff dates for the submission of electronic andpaper claims, redetermination requests, and auditsto the outgoing contractor> Reviewing resources, such as transition checklistsand communiqués available on the new MAC’s Website section designated for new MAC providers> Watching for signifi cant education andoutreach initiatives> Researching Frequently Asked Questions (FAQs)as they are posted by other providers> Obtaining and saving claims addresses, phoneand fax numbers, and interactive voice responsesystem processes> Last date the outgoing contractor will make claimspayments and keep their interactive voice responsesystem open> Last date for cost reports and cost report appeals> System Dark Day (cut off date for all services fromthe outgoing contractor)> First day the MAC will accept electronic orpaper claims> Date when the MAC will begin the claimspayment cycle> Date when the MAC will start offering customerservice for providersPhysician practices can stay involved with and aware ofupcoming details that may affect claim processing by:> Visiting their MAC’s Web site and bookmarkingimportant information> Joining listservs and trainings to stay up-to-date onimportant cutover dates and details> Dialing into MAC teleconferences to ask questionsand to voice concerns> Staying abreast of dates for MAC teleconferences aspublicized through listservs, provider education, andevent calendars, or on the MAC’s Web site> Reviewing and submitting comments on newjurisdiction-specifi c LCDs to have a voice in thepolicy revision processREMAKING LOCAL COVERAGE POLICIESThe consolidation of local policies, also known as LCDs,by newly awarded MACs is among the most prominentand important changes associated with MAC reform.Different MACs may take different approaches inconsolidating policies. In most cases, CMS instructsMACs to select the “least restrictive” LCD on a singletopic. However, in practice, contractors have exercisedsignifi cant latitude when consolidating existingcoverage policies within a jurisdiction. Contractorsmay vary in their interpretation of what is considereda “least restrictive policy.” MACs may differ in howto treat legacy contractors that have not published apolicy on a particular topic, how to apply standards of“clinical appropriateness,” and whether to implement ajurisdiction-wide policy or restrict a policy toa certain workload (i.e., Part A or Part B).The recent policy consolidation activities in J4 andJ5 give some insight into how this process may playout in other parts of the country. Both the J4 and J5MACs have chosen different approaches to their policyconsolidation process. WPS and TrailBlazer offereddetailed explanations as to how they consolidated LCDsin their jurisdictions. Based on our experience examiningsome of the new MAC LCDs, we have noted:> Depending upon the product or drug class, WPScollected sections from several LCDs on a topicarea from the legacy contractors and pieced themtogether to create a “clinically appropriate” LCD.WPS has decided not to always implement an LCDoncologistics 27

eimbursement watchon a coverage topic for both Part A or for Part B,even if there were legacy LCDs for consolidation.WPS has also created separate LCDs for PartA services.> In several instances, TrailBlazer selected its ownexisting LCD as the new MAC jurisdiction-widepolicy. TrailBlazer has created one policy that isapplicable for both Part A and Part B services.As CMS awards additional MAC contracts, newapproaches to LCD consolidation could emerge.Understanding your MAC’s rationale behind thedevelopment of a new jurisdiction-wide LCD can helpyour practice determine whether to ask for additionalclarifi cation or to submit comments.EXPRESS YOURSELFComment and notice periods allow providers a chanceto voice their opinions on newly created LCDs. Aminimum comment period of 45 days on any proposedrevision that restricts an existing LCD is required.In addition, a minimum notice period of 30 days isrequired before the policy takes effect. This time periodis very important for providers to be aware of, ascoverage changes could impact the delivery of care aswell as reimbursement for certain treatment regimens ortherapies. MACs are instructed to notify providers aboutpertinent information and to solicit feedback on LCDsthrough bulletins and listservs, meetings, and trainingseminars. MACs in both J4 and J5 have recentlyprovided a 45-day comment period for providers tosubmit comments electronically via email on any of thenew MAC LCDs. These comments have been reviewedby each of the MACs and the MACs have postedseveral revisions to the originally posted LCDs.IT IS IMPERATIVE FORPROVIDERS TO REVIEWNEW LCDS FOR COVERAGECHANGES AND PROVIDEAPPROPRIATE COMMENTSTO THE CONTRACTORWHEN NEEDED.oncologistics volume 7, issue 1 - spring 2008 28As transition activities start taking place in otherjurisdictions, it will be important for providers to:> Monitor the postings of new LCDs for theirrespective region> Review the new LCDs> Provide comment on LCDs if appropriate> Be prepared to submit clinical documentationalong with comments if changes to coverageare requested

oncologistics reimbursement watchAnticipated MAC Award and Transition Schedule*Jurisdictions34, 5, 121, 2, 7, 136, 11, 14, 158, 9, 107/2006 3/20077/2007 6/20089/2007 6/20087/31/2008 6/20099/2008 5/2009* There has been a delay in awarding J2, J7, andJ13 (Cycle 1B anticipated award for September2007). This will likely cause the date of completeimplementation (cutover) for these jurisdictions tobe later than anticipated.1/2007 1/2008 1/2009 1/2010Anticipated MAC AwardsRange of Earliest Completed TransitionsAs new policies are posted, providers may want toconsider examining them and asking the followingquestions as they evaluate the policies:> Are the covered indications for a particular productor treatment regimen inappropriately restrictingcoverage or are particular indications of interest notlisted as covered?> Are the previously available ICD-9-CM codes stillincluded within the LCD (primary and secondaryICD-9-CM codes)?> Do the coverage limitations or utilizationrestrictions hamper services or therapies that werepreviously covered?Emily Phillips, analyst, is a member of theReimbursement Strategy & Solutions consultinggroup within Xcenda’s national consulting practice,where she works on reimbursement projects forclients across the product commercializationspectrum. She assists with research for strategicconsulting projects, new business development,and client strategies and tactical plans.It is imperative for providers to review new LCDs forcoverage changes and provide appropriate commentsto the contractor when needed.It is CMS’ mission to ensure healthcare security forbenefi ciaries by establishing a premier health plan thatallows for comprehensive, quality care and worldclassbenefi ciary and provider service. 4 Through theimplementation of MAC reform, CMS hopes to realizethis mission. Awareness and communication betweenthe provider community and each MAC is critical fora smooth transition. This will also help to incorporateprovider input as part of the policy revision process. ❚References:1. Pub. L. 108-173, 117 Stat 2066, “Medicare Prescription Drug,Improvement, and Modernization Act of 2003,” (MMA 2003)(December 8, 2003).2. Report to Congress, Medicare Contracting Reform,“A Blueprint for a Better Medicare.” February 7, 2005, pp. 9.http://www.cms.hhs.gov/MedicareContractingReform/Downloads/report_to_congress.pdf3. Centers for Medicare & Medicaid Services, MedicareAdministrative Contractor, Workload Implementation Handbook,March 1, 2007, 4.10.1 Local Coverage Determinations, pp. 4-7.4. Medicare Contracting Reform Overview. http://www.cms.hhs.gov/MedicareContractingReform/oncologistics 29

drug updateTHESE STUDIESDEMONSTRATE THATVIDAZA MONOTHERAPYALTERS THE NATURALHISTORY OF MDS ANDRESULTS IN SIGNIFICANTIMPROVEMENT OFOVERALL SURVIVALFOR PATIENTS WITHHIGHER-RISK MDS.oncologistics volume 7, issue 1 - spring 2008 30

oncologistics drug updateNEW STUDIES IN VIDAZA ®THERAPY: PROLONGED SURVIVALIN HIGHER-RISK MDS PATIENTS,ALTERNATE DOSING SCHEDULES,AND USE IN AMLby: Lewis R. Silverman, M.D.The U.S. Food and Drug Administration (FDA) approvedVidaza (azacitidine) as the fi rst treatment for themyelodysplastic syndrome (MDS) for all FAB subtypesincluding both low-risk and high-risk patients. These FABsubtypes include: refractory anemia (RA) or refractoryanemia with ringed sideroblasts (RARS) if accompaniedby severe neutropenia (< 1 x 10 9 /L) or thrombocytopenia(< 0.5 x 10 9 /L) or anemia requiring RBC transfusions;refractory anemia with excess blasts (RAEB), refractoryanemia with excess blasts in transformation (RAEB-T),and chronic myelomonocytic leukemia (CMMoL).Vidaza is a substituted cytidine nucleoside analog andis believed to exert its antineoplastic effects by causinghypomethylation of DNA and direct cytotoxicity onabnormal hematopoietic cells in the bone marrow.Vidaza is a hypomethylating agent and belongs toa new class of anti-cancer compounds known asepigenetic therapies. Epigenetics refers to normalcontrol mechanisms in the genome that regulate geneexpression, mediated in part by changes in DNAmethylation and histone acetylation, two of the morestudied epigenetic regulatory mechanisms. Epigeneticchanges in cancer cells and other states can aberrantlysilence gene expression and, unlike DNA mutations,may be reversed by targeting the mechanisms involved.Thus, an epigenetic approach to cancer therapy isdesigned to reactivate silenced genes through targetedtherapy, re-establishing the cancer cells’ naturalmechanisms to control abnormal growth resulting in areversal of the malignant phenotype. By inhibiting DNAmethyltransferase and thus reversing hypermethylation,Vidaza may restore normal expression of silenced genescritical to cell differentiation and proliferation. The drugalso appears to exhibit its effects, through directtoxicity, when cells are undergoing DNA synthesis inS phase. Because all cells are not in the same phasesimultaneously, longer treatment time will expose morerapidly dividing cells to Vidaza. Vidaza therapy alsocauses the death of rapidly dividing cancer cells nolonger responsive to normal growth control mechanisms.The benefi ts of Vidaza therapy in MDS have long beenknown, however, recent studies have shown new resultsnot previously recognized. Trials demonstrating increasedsurvival in higher-risk MDS patients as comparedto conventional regimens, effective alternate dosingschedules in MDS patients with lower risk disease, andeffectiveness in acute myeloid leukemia (AML) patientshave generated additional and increased interest inVidaza therapy throughout the oncology community.oncologistics 31

drug updateoncologistics volume 7, issue 1 - spring 2008 32PROLONGED SURVIVAL IN HIGHER-RISK MDSFrom Abstract #817 in Blood, Volume 110, Issue 11,November 16, 2007A previous Cancer and Leukemia Group B (CALGB) trial,CALGB 9221, showed a positive overall survival (OS)trend with Vidaza versus best supportive care (BSC)in MDS patients. With this in mind, a new Phase III,international, multicenter, randomized, prospective trialwas initiated to demonstrate the superiority of Vidazaplus BSC over conventional care regimens (CCR) plusBSC for prolonging OS. In this study, only higher-riskMDS patients—those presenting with a FAB defi ned asRAEB, RAEB-T, or CMML (10-29% marrow blasts) withan IPSS of Int-2 or High by central pathology/cytogeneticreview—were eligible.Before randomization, trial participants chose amongone of three conventional care regimens: BSC only,low-dose ara-C (LDAC, 20 mg/m 2 /d x 14d, q 28d), orstandard chemotherapy. Patients were then stratifi ed byFAB/IPSS and randomized to Vidaza (75 mg/m 2 /d x 7d,q 28d) or CCR. During the trial, Vidaza was administeredfor a median of nine cycles and the median follow-upfor OS analysis was 21.1 months. Results showed thatVidaza demonstrated statistically superior OS versusCCR, with a median OS (Kaplan-Meier ) of 24.4 monthsversus 15 months, respectively (p=0.0001). The hazardratio was 0.58 for a 74% OS improvement. There wasa two-fold increase in the percent surviving at 2 yearsfor the Vidaza group, 50.8% compared to 26% for thosein the CCR group.In the trial, Vidaza was well tolerated, and the safety datawas consistent with previous reports. This trial involvingVidaza was the fi rst MDS clinical study demonstratinga signifi cant OS advantage that altered natural diseasecourse, and supports the notion that Vidaza should beconsidered fi rst-line therapy for higher-risk MDS patients.ALTERNATE DOSING IN MDSFrom Abstract #819 in Blood, Volume 110, Issue 11,November 16, 2007At a dosing schedule of 75 mg/m 2 /day subcutaneousfor 7 days every 4 weeks, Vidaza has proven to be aneffective treatment for patients with MDS. However, manypatients, as well as clinicians, would benefi t from theconvenience of a dosing schedule that does not includeweekend administration. The initial phase of an ongoingstudy evaluating three alternative dosing schedules wasrecently completed.In this Phase II multicenter, open-label trial, MDS patientswere randomized to one of three regimens administeredevery 4 weeks for 6 cycles: Vidaza 5-2-2 (75 mg/m 2 /dayx 5 days, followed by 2 days without treatment, followedby 75 mg/m 2 /day x 2 days); Vidaza 5-2-5 (50 mg/m 2 /dayx 5 days, followed by 2 days no treatment, followed by50 mg/m 2 /day x 5 days); or Vidaza 5 (75 mg/m 2 /dayx 5 days). Hematologic improvements were assessedby International Working Group (IWG) criteria andparticipants with >56 treatment days were evaluablefor response. To determine whether or not the desiredresponse was maintained after 6 cycles of therapy,a 12-month maintenance phase using the Vidaza5 regimen administered every 4 or 6 weeks wassubsequently added. Patients who presented with atleast stable disease were eligible to participate in thisphase of the study.A total of 151 patients were randomized to treatmentwith Vidaza 5-2-2 (n=50), Vidaza 5-2-5 (n=51), or Vidaza5 (n=50). Of the 139 patients (92%) who received>56 days of treatment and were evaluable for response:74 (49%) completed >6 treatment cycles. Of IWGevaluablepatients, 71 (51%) experienced hematologicimprovements. The proportions of red blood cell (RBC)transfusion-dependent patients who achieved transfusionindependence were Vidaza 5-2-2: 55%, Vidaza 5-2-5:60%, and Vidaza 5: 67%. In FAB low-risk (RA/RARS)transfusion-dependent patients at baseline, RBCtransfusion independence was reached by 60%, 56%,and 61%, respectively. No treatment-related mortalityhad been reported at the time of the study’s release.Most grades 3 and 4 treatment-related adverse eventswere hematological.Independent of the alternative dosing regimen, theresults of the initial 6-cycle treatment phase demonstratea consistent response for hematologic improvements,

oncologistics drug updateRBC transfusion independence, and safety profi le acrossa broad range of MDS patients, including FAB low-riskpatients. The majority of patients treated in this studyto date are lower-risk patients (RA and RARS) and thusthe alternative dosing schedules produce hematologicimprovements and transfusion independence. The impactof these alternative regimens on survival of higher-riskpatients is unknown and thus these alternative doseregimens cannot be recommended as equivalentsubstitutes for the standard 7 consecutive day regimen.AZACITIDINE (VIDAZA) AND AMLFrom Abstract #1849 in Blood, Volume 110, Issue 11,November 16, 2007Approved for MDS by the FDA, Vidaza is also currentlybeing investigated in AML. ATUs are patient-namedprograms launched by French health authorities forpromising drugs that have yet to be approved. A programis currently ongoing for Vidaza in MDS and AML. FromSeptember 2004 through June 2007, 108 AML patientswho had completed one or more courses of Vidazaparticipated in the program. The participants receivedVidaza 75 mg/m 2 /d (d 1-7) subcutaneous every 4 weeksfor a minimum of 4 courses.Median age in the study was 75 years, with a male tofemale ratio of 66/42. Fifty-one patients had AML withoutand 57 patients with preceding MDS, p-AML and s-AML,respectively. Patients received a median of 4 cyclesof therapy [range 2-16], and response was assessedonly after these 4 cycles, with patients who progressedbefore the exception. As such, 15 patients were not yetevaluable, and of the remaining 93 patients, 12 achievedcomplete response, 34 achieved partial response (PR)(OR=49%) and 43 (46%) were considered failure.Four patients died before end of cycle 2, withoutevidence of progression. Thirty-fi ve of the 46 respondersreceived maintenance therapy after response wasachieved. Myelosuppression led to dose reductionin 16% of patients and the hospitalization of 17% ofpatients, but no toxic deaths were seen. Other sideeffects included local reactions (reversible with localNSAID) (19%), and grade I-II gastrointestinal disorders(52%). OR was 34% (11% CR+23% PR) in p-AML and60% in s-AML patients (12% CR+48% PR) (p1 relapse/refractory (p

POWER ANDPERFORMANCEVIDAZA hits MDS with the strengthof transfusion independence. 1,2• 44% of red blood cell (RBC) transfusion-dependentpatients achieved RBC transfusion independence. 1 *• Median time to RBC transfusion independencewas about 2.5 months. 1• In responding patients, † transfusion independence wasdurable, lasting a median of 330 days. 2Important Safety Information• VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine ormannitol and in patients with advanced malignant hepatic tumors.• In clinical studies, the most commonly occurring adverse reactions by SCroute were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%),vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%),fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%),neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions includeddizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%),injection site reaction (13.6%), aggravated fatigue (12.7%), and malaise (10.9%).The most common adverse reactions by IV route also included petechiae (45.8%),weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%).• Because treatment with VIDAZA is associated with neutropenia and thrombocytopenia,complete blood counts should be performed as needed to monitor response andtoxicity, but at a minimum, prior to each dosing cycle.• Because azacitidine is potentially hepatotoxic in patients with severe preexistinghepatic impairment, caution is needed in patients with liver disease. In addition,azacitidine and its metabolites are substantially excreted by the kidneys and therisk of toxic reactions to this drug may be greater in patients with impaired renalfunction. Because elderly patients are more likely to have decreased renal function,it may be useful to monitor renal function.• VIDAZA may cause fetal harm. While receiving treatment with VIDAZA, women ofchildbearing potential should avoid becoming pregnant, and men should avoidfathering a child. In addition, women treated with VIDAZA should not nurse.Please see the brief summary of prescribing information on the adjacent page.VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation.All rights reserved. 2007288 May 2007 Printed in the USA.VIDAZA is FDA-approved for the treatment of all myelodysplastic syndrome(MDS) subtypes 2‡ : RA or RARS (if accompanied by neutropenia orthrombocytopenia or requiring transfusions), RAEB, RAEB-T, or CMMoL.9221 Study Design: A randomized, open-label, phase III study comparing the efficacy and safetyof VIDAZA plus supportive care vs supportive care alone. 191 patients (132 male, 59 female,age 31–92) with all 5 subtypes of MDS classified according to the French, American, British (FAB)classification system were studied. VIDAZA was administered to patients subcutaneously at adose of 75 mg/m 2 daily for 7 days every 4 weeks. Dosage adjustments were allowed based onresponse or adverse events. The primary study endpoint was response rate.Response Criteria: Complete response was defined as

Brief Summary of Prescribing InformationVIDAZA ® (azacitidine for injection)onlyFor subcutaneous and intravenous use onlyINDICATIONS AND USAGEVIDAZA is indicated for treatment of patients withthe following myelodysplastic syndrome subtypes: refractoryanemia or refractory anemia with ringed sideroblasts(if accompanied by neutropenia or thrombocytopeniaor requiring transfusions), refractory anemia withexcess blasts, refractory anemia with excess blasts intransformation, and chronic myelomonocytic leukemia.CONTRAINDICATIONSVIDAZA is contraindicated in patients with a knownhypersensitivity to azacitidine or mannitol. VIDAZAis also contraindicated in patients with advancedmalignant hepatic tumors. (See PRECAUTIONS).WARNINGSPregnancy - Teratogenic Effects: Pregnancy Category DVIDAZA may cause fetal harm when administeredto a pregnant woman. Early embryotoxicity studiesin mice revealed a 44% frequency of intrauterineembryonal death (increased resorption) after a singleIP (intraperitoneal) injection of 6 mg/m 2(approximately8% of the recommended human daily dose on a mg/m 2basis) azacitidine on gestation day 10. Developmentalabnormalities in the brain have been detected in micegiven azacitidine on or before gestation day 15 atdoses of ~3–12 mg/m 2 (approximately 4%–16% therecommended human daily dose on a mg/m 2 basis).In rats, azacitidine was clearly embryotoxic when given IPon gestation days 4–8 (postimplantation) at a dose of6 mg/m 2 (approximately 8% of the recommended humandaily dose on a mg/m 2 basis), although treatment in thepreimplantation period (on gestation days 1–3) had noadverse effect on the embryos. Azacitidine caused multiplefetal abnormalities in rats after a single IP dose of3–12 mg/m 2 (approximately 8% the recommended humandaily dose on a mg/m 2 basis) given on gestation day 9,10, 11 or 12. In this study azacitidine caused fetal deathwhen administered at 3-12 mg/m 2 on gestation days 9and 10; average live animals per litter was reduced to9% of control at the highest dose on gestation day 9.Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, clubfoot,syndactyly, oligodactyly), and others (micrognathia,gastroschisis, edema, and rib abnormalities).There are no adequate and well-controlled studies inpregnant women using VIDAZA. If this drug is usedduring pregnancy, or if the patient becomes pregnantwhile taking this drug, the patient should be apprisedof the potential hazard to the fetus.Women of childbearing potential should be advised to avoidbecoming pregnant while receiving treatment with VIDAZA.Use in MalesMen should be advised to not father a child whilereceiving treatment with VIDAZA. (See PRECAUTIONS:Carcinogenesis, Mutagenesis, Impairment of Fertilityfor discussion of premating effects of azacitidineexposure on male fertility and embryonic viability.)PRECAUTIONSGeneralTreatment with VIDAZA is associated with neutropeniaand thrombocytopenia. Complete blood counts should beperformed as needed to monitor response and toxicity, but ata minimum, prior to each dosing cycle. After administrationof the recommended dosage for the first cycle, dosage forsubsequent cycles should be reduced or delayed based onnadir counts and hematologic response as described inDOSAGE AND ADMINISTRATION.Safety and effectiveness of VIDAZA in patients with MDSand hepatic or renal impairment have not been studiedas these patients were excluded from the clinical trials.Because azacitidine is potentially hepatotoxic in patientswith severe preexisting hepatic impairment, cautionis needed in patients with liver disease. Patients withextensive tumor burden due to metastatic disease havebeen rarely reported to experience progressive hepaticcoma and death during azacitidine treatment, especiallyin such patients with baseline albumin

drug updateBased on recent findingswith Nexavar in patientswith HCC, the NCCN hasupdated the clinicalpractice guideline forhepatobiliary cancersto include Nexavar asa treatment option forselected patients withboth Child-Pugh A and Bliver function status. 4oncologistics volume 7, issue 1 - spring 2008 1

oncologistics drug updateNexavar ® in Unresectable HCC:New Treatment Option Basedon Significant Survival Benefitby: Ralph Boccia, M.D., F. A. C. P.Nexavar (sorafenib) is an oral multiple kinase inhibitorthat, as of November 2007, became the first systemictherapy approved by the U.S. Food and DrugAdministration (FDA) for patients with unresectablehepatocellular carcinoma (HCC), the most common formof liver cancer. As the only agent that has demonstrateda significant survival advantage in patients withunresectable HCC, Nexavar offers new hope for thisdifficult-to-treat disease. The HCC indication came within2 years of Nexavar’s approval for advanced renal cellcarcinoma (RCC)–for which the agent is now approved inmore than 60 countries.The incidence of HCC has been rising in the UnitedStates and globally. Current estimates are thatapproximately 19,000 new HCC cases are diagnosedannually in the United States. 1 The classic late diseasestage at diagnosis and the lack of effective systemictherapies have contributed to the dismal 8% 3-yearsurvival rate among patients with advanced disease. 2SHARP Results Move HCC to the Era ofTargeted TherapyFinal results of the international, double-blind, PhaseIII Sorafenib HCC Assessment Randomized Protocol(SHARP) trial, 3 which provided the basis for the FDA’sapproval of Nexavar in HCC, marked the first time anyagent has shown a survival advantage with predictableside effects in patients with unresectable HCC, and hasmoved HCC to the era of targeted therapy.The SHARP trial, reported at the 2007 annual meetingof the American Society of Clinical Oncology, enrolled602 patients recruited from centers in North and SouthAmerica, Europe, Australia, and New Zealand. 3Patients had histologically proven unresectable ormetastatic HCC, had not received previous systemictherapy, Eastern Cooperative Oncology Group(ECOG) performance status of 0-2, and lifeexpectancy of > 12 weeks. Patients could have receivedlocal therapy, including surgery, radiotherapy, hepaticarterial embolization, chemoembolization radiofrequencyablation, percutaneous ethanol injection, or cryoablation,as long as one target lesion had not been subjected tolocal therapy or a treated target lesion had increased insize by 25%. Patients were randomly assigned to receiveoral Nexavar tablets 400 mg twice daily (n=299) orplacebo tablets twice daily (n=303) dosed continuously.Primary study end points were overall survival (OS) andtime to symptom progression. Secondary end pointswere time to disease progression and disease controlrate, defined as complete or partial response or stabledisease for at least two treatment cycles.Baseline patient characteristics were similar in thetwo treatment groups. The median patient age wasapproximately 67 years, 87% were men, and 54% hadECOG performance status of 0. The majority of studyparticipants (> 95%) had Child-Pugh A liver functionstatus, approximately 82% had Barcelona Clinic LiverCancer (BCLC) stage C disease, and 70% had portalvein thrombosis.In February 2007, when 321 deaths had occurred(143 in the Nexavar arm, 178 in the placebo arm), thestudy was terminated early, after a prescheduled interimanalysis showed that the primary OS end pointoncologistics 2

drug updatehad been met. Median OS was 10.7 months and 7.9months for the Nexavar and placebo groups, respectively,representing a significant 44% improvement in OS inthe Nexavar-treated patients (hazard ratio [HR], 0.69;95% confidence interval [CI]: 0.55 - 0.88; P=.0006)(See Figure 1). Furthermore, subgroup analysis showedthat Nexavar’s survival benefit was maintained in patientswith HCC representing a range of potential clinicalpresentations, i.e., those with ECOG performancestatus of 0, ECOG performance status of 1 and 2, andin patients both with and without macroscopic vascularinvasion and/or extrahepatic spread of disease.Therapy with Nexavar also resulted in a 73%improvement in time to cancer progression relative toplacebo treatment (median time to progression, 5.5months versus 2.8; HR, 0.58; 95% CI: 0.44, 0.74;P=.000007), and an improved disease control rate(43% versus 32%). Side effects in the Nexavar andplacebo groups (52% and 54%) were predictable, withsimilar adverse event rates. The most common grade 3/4effects were diarrhea (11% versus 2%), hand-foot skinreaction (8% versus 1%), fatigue (10% versus 15%), andbleeding (6% versus 9%), respectively.Revised National ComprehensiveCancer Network (NCCN) GuidelinesInclude Nexavar as Treatment Optionfor Child-Pugh A and B Patients with HCCBased on recent findings with Nexavar in patientswith HCC, the NCCN has updated the clinical practiceguideline for hepatobiliary cancers to include Nexavaras a treatment option for selected patients with bothChild-Pugh A and B liver function status. 4 This includespatients with unresectable tumors, those with localdisease who are deemed inoperable based on poorperformance status or comorbidities, and those withmetastatic disease. The guidelines caution that there islimited safety data available for Child-Pugh B patients. 4Figure 1oncologistics volume 7, issue 1 - spring 2008 3Survival Probability1.000.750.50NEXAVARMedian: 46.3 wk (10.7 mo)(95% CI: 40.9, 57.9)PlaceboMedian: 34.4 wk (7.9 mo)(95% CI: 29.4, 39.4)0.25 Hazard ratio(NEXAVAR/placebo): 0.69(95% CI: 0.55, 0.87)P=.00058*00 8 16 24 32 40 48 56 64 72 80Time (Weeks)Patients at riskNEXAVAR: 299 274 241 205 161 108 67 38 12 0 0placebo: 303 276 224 179 126 78 47 25 7 2 0Overall survival curve from the international Phase III SHARP trial of sorafenib vs. placebo in patients with inoperable HCC (N=602).Results show a statistically significant benefit of sorafenib (n=299) vs. placebo (n=303) (intention-to-treat population). *O’Brien-Flemingthreshold for statistical significance was P=.0077. 3

oncologistics drug updateIn the placebo-controlled Phase III SHARP trial,therapy with Nexavar resulted in a significant 44%survival improvement in HCC patients, and is thus theonly agent that has demonstrated a survival benefitin this malignancy.Nexavar Inhibits Both Tumor CellProliferation and AngiogenesisTwo processes that are important for HCC tumor growthare angiogenesis and signaling through the Raf/mitogenactivatedprotein (MAP)/extracellular signal-regulatedkinase (ERK) kinase (MEK)/ERK (Raf/MEK/ERK) cascade.Nexavar exerts its antitumor effects by targeting multiplekinases involved in both of these processes (SeeFigure 2). 5,6 The Raf/MEK/ERK pathway, which relayssignals from cell surface receptors to the nucleus, playskey roles in governing cell proliferation, differentiation, andsurvival, and has been shown to be activated in HCC and5, 7-10other solid tumors.Nexavar targets the Raf/MEK/ERK pathway at thelevel of the serine-threonine kinase Raf, resulting inreduced tumor cell proliferation. 5,6 Furthermore, HCCtumors are highly angiogenic, 11 and in-vitro modelsshow that Nexavar reduces HCC tumor angiogenesisby targeting multiple receptor tyrosine kinases, includingvascular endothelial growth factor receptor (VEGFR)-2,VEGFR-3, platelet-derived growth factor-betaFigure 2Tumor CellEndothelial Cell or PericyteEGF/HGFAutocrine LoopParacrineStimulationPDGF-ßVEGFPDGFR-ßRAFMEKERKRASNexavarHIF-2NucleusApoptosisMitochondriaEGF/HGFPDGFVEGF }ProliferationSurvivalMitochondriaApoptosisRAFMEKERKNucleusRASNexavarVEGFR-2Angiogenesis:DifferentationProliferationMigrationTubule FormationMechanism of action of Nexavar in preventing tumor growth. Nexavar targets multiple tyrosine kinases in tumor cells,endothelial cells, and pericytes, resulting in reduced tumor cell proliferation and angiogenesis. 5oncologistics 4

drug update(PDGF-ß), FLT-3, RET, and C-KIT, which have beenshown to be important proangiogenic factors for tumorgrowth and metastasis. 5,12ConclusionNexavar is an oral multiple kinase inhibitor that preventstumor growth by blocking tumor cell proliferation andangiogenesis, two critical processes in the developmentof HCC. In the placebo-controlled Phase III SHARPtrial, therapy with Nexavar resulted in a significant 44%survival improvement in HCC patients, and is thus theonly agent that has demonstrated a survival benefit inthis malignancy. Therapy with Nexavar also resulted ina doubling of the time to cancer progression. Based onits efficacy and predictable side-effect profile, Nexavarmay be considered a standard of care for patients withunresectable HCC. Further trials are assessing theoptimal use of Nexavar in patients with HCC and othertumor types.Patient Support Programs to Begin andMaintain Nexavar TherapyPrescriptions for Nexavar tablets are not filled throughretail pharmacies but rather through specialty pharmacyproviders that are experienced with oncology products.To help patients begin and maintain Nexavar therapy,two support programs are available.oncologistics volume 7, issue 1 - spring 2008 5

oncologistics drug updateREACH ® (Resources for Expert Assistanceand Care Helpline)The REACH program provides reimbursement informationas well as support for clinical questions. By calling1.87.REACH.4.IT (1.877.322.4448) Monday through Fridayfrom 9:00 a.m. to 8:00 p.m. (Eastern), a REACH programcounselor can provide reimbursement support and patientservices, including processing insurance information, findingfinancial assistance, and matching patient needs withspecialty pharmacies.NexConnect This program provides patients with further support bymaking additional information available to complement theirNexavar treatment, as follows:> Access to a nurse-counselor who can provideinformation about Nexavar therapy>Patient education materials that clearly explainthe importance of adherence and effective tipsfor incorporating Nexavar treatment intopatients’ lives zRalph Boccia, M.D., F. A. C. P., is president andmedical director of The Centers for Cancer andBlood Disorders in Bethesda, MD. He also servesas chair of the ION Medical Advisory Panel.References:1. Jemal A, Siegel R, Ward E, et al: Cancer Statistics 2007.CA Cancer J Clin 57:43-66, 20072. Llovet JM: Updated treatment approach to hepatocellularcarcinoma. J Gastroenterol 40:225-235, 20053. Llovet J, Ricci S, Mazzaferro V, et al: Sorafenib improvessurvival in advanced hepatocellular carcinoma (HCC):results of a phase III randomized placebo-controlled trial(SHARP trial). 2007 ASCO Annual Meeting Proceedings.J Clin Oncol 25:18S, 2007 (abstr LBA1)4. NCCN Version 2.2008, 10/31/07. NationalComprehensive Cancer Network, Inc. Available at:www.nccn.org. Accessed on January 3, 20085. Wilhelm SM, Carter C, Tang L, et al: BAY 43-9006 exhibitsbroad spectrum oral antitumor activity and targets theRAF/MEK/ERK pathway and receptor tyrosine kinasesinvolved in tumor progression and angiogenesis. CancerRes 64:7099-7109, 20046. Liu L, Cao Y, Chen C, et al: Sorafenib blocks the RAF/MEK/ERK pathway inhibits tumor angiogenesis, andinduces tumor cell apoptosis in hepatocellular carcinomamodel PLC/PRF/5. Cancer Res 66:11851-11858, 20067. Ito Y, Sasaki Y, Horimoto M, et al: Activation of mitogenactivatedprotein kinases/extracellular signal-regulatedkinases in human hepatocellular carcinoma. Hepatology27:951-958, 19988. Hwang YH, Choi JY, Kim S, et al: Over-expressionof c-raf-1 proto-oncogene in liver cirrhosis andhepatocellular carcinoma. Hepatol Res 29:113-121, 20049. Calvisi DF, Ladu S, Gorden A, et al: Ubiquitousactivation of Ras and Jak/Stat pathways in human HCC.Gastroenterology 130:1117-1128, 200610. Villanueva A, Newell P, Chiang DY, et al: Genomics andsignaling pathways in hepatocellular carcinoma. SeminLiver Dis 27:55-76, 200711. Semela D, Dufour JF: Angiogenesis and hepatocellularcarcinoma. J Hepatol 41:864-880, 200412. Carlomagno F, Anaganti S, Guida T, et al. BAY 43-9006inhibition of oncogenic RET mutants. J Natl Cancer Inst98(5):326-334, 200613. Abou-Alfa G, Johnson P, Knox J, et al. Preliminaryresults from a phase II, randomized, double-blind studyof sorafenib plus doxorubicin versus placebo plusdoxorubicin in patients with advanced hepatocellularcarcinoma. Proceedings of the 2007 meeting of theEuropean CanCer Organization. European Journal ofCancer Supplements 5:259, 2007 (abstr 3500)oncologistics 6

FURTHER PROGRESS IN THE TREATMENT OF MYELOMAWILL ONLY BE MADE IF WE HAVE A BETTER UNDERSTANDINGOF THE MYELOMA POPULATION THAT SURVIVES EVEN THEMOST INTENSIVE TREATMENT STRATEGIES.oncologistics volume 7, issue 1 - spring 2008 42

oncologistics a better treatment of myelomaAutologous stem cell transplantation representsa major step forward in the treatment of myeloma.While most transplant protocols in myeloma call forone round of high-dose chemotherapy and no furthertreatment thereafter, we now know that a more intensiveapproach including induction therapy, two cycles of highdose chemotherapy coupled with an autologous stemcell transplant, consolidation therapy, and two yearsof maintenance therapy is more effective. This is thelesson we have learned as a result of our Total Therapystudies, which consistently have delivered the besttreatment results for newly diagnosed myeloma patients.Further improvements will come, for the most part, froma better understanding of myeloma biology and also,to a lesser extent, from some tweaking of the TotalTherapy approach to decrease toxicity and furtherincrease survival.Multiple myeloma (MM) is a differentiated clonal B-celltumor, consisting in the early stages of the disease ofslowly proliferating malignant plasma cells (myelomacells). It is the second most common hematologicmalignancy after non-Hodgkin lymphoma. Normalplasma cells are very hardy cells and usually the onlytype of cell to survive the effects of myelosuppressivechemotherapy and radiation. The clonal plasma cellshave abnormal cytogenetics even at the stage ofmonoclonal gammopathy of undetermined signifi cance.Before it transforms to an aggressive disease—whichis typically associated with extramedullary disease,immature morphology of the myeloma cells, rapidproliferation, and increase in LDH—the disease isentirely bone marrow stroma-dependent and, therefore,contained within the active hematopoietic bone marrow,although breakout lesions from the bone can be seen.The myeloma cell displays on its membrane a multitudeof receptors, the ligands of which are present in themicro-environment. Binding of these receptors by theirligands promotes growth and survival of the myelomacells and also results in the secretion by the plasma cellsof angiogenic factors. In addition to supporting growthand survival, the micro-environment also places most ofmyeloma cells in a deep G1 phase by up-regulation ofp21 and p27. Cells in the G1 phase of the cell cycle arevery poor targets for conventional dose chemotherapy.It is very likely that in myeloma, just as many othercancers, a cancer stem cell population exists. It isestimated that one in 10,000 to one in 20,000 malignantcells is a cancer stem cell. Based on the extensivesomatic mutations in the complementarity regions ofthe gene coding for the heavy chain, it is very likely thatthis cancer stem cell arises from a B-cell that has hadextensive exposure to antigen in the germinal centerand therefore most likely is either a memory B-cell ora plasmablast. If there is indeed a myeloma stem cell,such a cell will have many characteristics in commonwith a hematopoietic stem cell in that it is resistant toconventional doses of chemotherapy and that highdoses of chemotherapy will be necessary, which can atleast eradicate hematopoietic stem cells and thereforesuch therapy will require stem cell support. The agentsmost toxic to hematopoietic stem cells are alkylators,such as melphalan, busulfan, and BCNU, agents foundto be very effective in myeloma, while other alkylators,such as cyclophosphamide and platinum compoundsWORKING TOWARD A BETTERUNDERSTANDING AND A BETTERTREATMENT OF MYELOMAby: Guido Tricot, M.D., Ph.D.oncologistics 43

oncologistics volume 7, issue 1 - spring 2008 44that spare hematopoietic stem cells, are much lesseffective in myeloma even at higher doses. The diffi cultyin myeloma is not to eradicate the more differentiatedmyeloma compartment, which comprises more than99.9% of the tumor mass, but also to kill the myelomastem cells. Consequently, achieving a hematologicremission, as currently defi ned, will have a poor correlationwith long-term outcome and should not be used as anearly substitute for survival estimates.It has been more than 25 years since the late TimMcElwain and colleagues introduced high dose melphalanfor the treatment of MM. Administration of melphalan100-140 mg/m2 without stem cell support inducedbiochemical and bone marrow remissions in three (allpreviously untreated) of the nine myeloma patients, whichwas much higher than the 3-5% complete responsetypically seen with conventional therapy. However, highdose melphalan induced prolonged aplasia of fi ve to eightweeks and was therefore associated with high morbidityand mortality rates in a disease with a median age of 67years. This led other investigators to the concept of stemcell rescue, which allowed further dose escalation ofmelphalan to 200 mg/m2. Stem cell support was initiallyprovided with autologous bone marrow and subsequentlywith peripheral blood stem cells, containing more CD34cells/kg and therefore resulting in more prompt bonemarrow recovery and less morbidity and mortality. Thismade application of autologous transplantation feasiblein patients 60 to 75 years old, who were in otherwisegood clinical condition, and it reduced procedure-relatedmortality to 2-5%, which is not higher than that seenwith six months of conventional chemotherapy and/orthe novel agents, such as bortezomib, thalidomide,and lenalidomide.In an attempt to minimize toxicity and to maximizemyeloma cell kill, the concept of tandem autologoustransplantation was introduced in Total Therapy I. Theunderlying hypothesis was that rather than giving asingle very intensive preparative regimen prior to stemcell rescue, providing effective but less toxic high dosechemotherapy twice would be better tolerated in olderpatients and equally effective. A total of 231 patientswere enrolled from 1990 to 1994. With a median followupof 12 years, 62 patients are still alive and 31 have notprogressed. The 10 year event-free and overall survivalswere 15% and 33%, respectively. In its evidence-basedreview, the American Society for Blood and MarrowTransplantation concluded that autotransplantation is thepreferred treatment modality for myeloma and that itsapplication is recommended as de novo rather than assalvage therapy. Yet, less than half of the patients aged 65or less with myeloma actually proceeds to transplantation.In Total Therapy II, 668 newly diagnosed myelomapatients were randomized upfront to intensive therapyincluding tandem autologous transplants with or withoutthalidomide during the whole treatment. The completeremission rate and the 5-year event-free survival weresuperior in the thalidomide arm. However, the 5-yearoverall survival was similar, approximately 65% in botharms (p = 0.9), but this may be due to the limitedfollow-up. The 5-year event-free survival was better onTotal Therapy II (43% versus 28%; p < 0.001) with alsoa trend for better overall survival (62% versus 57%;p = 0.11). Superior event-free and overall survivals wereseen in the two-thirds of patients with normal metaphasecytogenetics. In Total Therapy III, which enrolled 303patients, not only the myeloma cells were targeted butalso the micro-environment to prevent rescue of myelomacells after transplantation. The latter was achieved byadding thalidomide and bortezomib to the intensivetreatment regimen. Approximately 80% of patientsachieved a complete remission and with a limited followupof 20 months, the two-year event-free and overallsurvivals were 84% and 86%, respectively. Based onthese data, it is reasonable to expect that the 10-yearsurvival of newly diagnosed myeloma patients on TotalTherapy II and III will be more than 50%, compared witha median survival of 4 years with the best non-transplantbased therapies (See Figure 1).Although we have made major strides in the treatmentof myeloma in the last 15 years, most myeloma patientswill still relapse, although much later than it used to be.Further progress in the treatment of myeloma will only bemade if we have a better understanding of the myeloma

oncologistics a better treatment of myelomaFigure 110 Year Survival is a Reasonable Expectation in MyelomaTandem Transplants IFM and Total Therapy100%80%60%40%IFM99-04TT2TT1Deaths/N79/32676/1221064Median MonthsNR80NR@ 66 mos20%Age < 60yr0%0 2 4 6 8 10Years from EnrollmentOverall survival of three different tandem autologous transplantation studies are depicted. Total Therapy I, Total Therapy II, andthe French IFM study. It should be noted that the French IFM study replicated Total Therapy I and shows exactly the same results.Therefore, it proved possible to independently confi rm the results of Total Therapy I.population that survives even the most intensive treatmentstrategies. We are now focusing on obtaining gene expressionprofi les of such cells to see if we can fi nd targets to eliminatethose cells. We are also interested in investigating if those cellshave the same gene expression profi le as the myeloma stem cell.Another area of our research is to fi nd treatment modalities thatare non-cross resistant with high dose chemotherapy, and weare especially interested in immunotherapy with natural killer cells(NK cells) to mop up residual myeloma cells.More than 30 new anti-myeloma drugs are now in earlydevelopment. Some of those will be winners, but it probablywill take another 3 to 4 years before we have identifi ed those.Although the hope is that one day we will be able to treatmyeloma without high-dose chemotherapy and transplantation,it appears much more likely that these new drugs will have theirbest application if used after transplantation when the tumor loadis low and the risk of developing resistance has been drasticallyreduced. The outlook for patients with myeloma will continue toimprove, but it will require patients to participate in cutting edgeclinical trials to see myeloma becoming a curable disease in asubstantial proportion of patients. ❚Guido Tricot, M.D., Ph.D., is the director ofthe Utah Blood and Marrow Transplant andMyeloma Program at Huntsman CancerInstitute at the University of Utah. He has beenresearching and treating multiple myeloma forover 20 years. He is working to further refi netreatment for recently diagnosed myelomapatients and is studying gene expression profi lesof myeloma cells surviving transplantation toinvestigate how to target these resistant cellswith specifi c therapies.oncologistics 45

nurse’s forumOUTPATIENT MANAGEMENT OF TUMORLYSIS SYNDROME IN PATIENTS WITHDIFFUSE LARGE B-CELL LYMPHOMA:CONSIDERATIONS FOR THEONCOLOGY NURSEby: Tamika M. Turner, M.S.N., N.P.-C., O.C.N.oncologistics volume 7, issue 1 - spring 2008 46Approximately 80-90% of chemotherapy is given inthe outpatient setting. 1 Oncology nurses who work inoutpatient chemotherapy infusion clinics are the keyplayers in fi rst recognizing adverse side effects fromchemotherapy. These nurses spend time with patientsfrom the initiation of chemotherapy to the completion ofeach infusion. Oncology nurses must be knowledgeableregarding the possible adverse reactions of eachchemotherapy medication infused to appropriatelycare for patients in this setting.The purpose of this article is to review tumor lysissyndrome as it relates to patients with non-Hodgkinlymphoma (NHL). This article will review one type ofNHL commonly treated in the outpatient infusion clinic,commonly used chemotherapy regimens to treat this typeof lymphoma, adverse reactions to these chemotherapymedications to include tumor lysis syndrome, and oncologynursing considerations.NHL is the fi fth most common cancer in men and womenin the United States: approximately 64,000 people inthe United States were diagnosed with non-Hodgkinlymphoma in 2007. 2 Lymphomas occur when lymphocytesundergo a malignant change. This change causes thecell to multiply out of control and crowd out healthy cells,thus causing tumors in the lymphatic system. The mostcommon places for lymphomas to start are in the lymphnodes or in organs like the stomach or intestines. Theseorgans have collections of lymphatic tissue that make themprone for lymphomas to originate. 2The oncology nurse may be asked what it is that increasesa patient’s risk for lymphoma. The incidence of NHL hasalmost doubled over the last century, and there are anumber of possible factors that may increase the risk forNHL. Immunosuppression is one of those risk factors.Patients with HIV have approximately 50 to 100 times theincidence of NHL than those without HIV. The Epstein-Barr virus has been found to increase the risk for Burkettlymphoma and Helicobacter pylori has been found toincrease the risk for MALT or gastric lymphoma. Farmershave also been found to have an increased risk for NHL.It is thought that this is from the pesticides and herbicidesused to maintain farms and/or crops. 2Diffuse large B-cell lymphoma is the most aggressive formof NHL and the most common form in the Western world.These lymphomas are aggressive but can be curable.Diffuse large B-cell lymphomas have large B lymphocytesmaking up the tumors, and there is usually extranodaland widespread involvement. Patients may present witha variety of symptoms, such as enlarged lymph nodes inthe neck, axillary area, or groin. Occasional symptoms willoccur in other areas of the body, such as bone, lung, orgastrointestinal tract. These patients may experience bonepain, cough, or gastrointestinal distress. Other symptomsmay include unexplained weight loss,

oncologistics nurse’s forumoncologistics 47

nurse’s forumoncologistics volume 7, issue 1 - spring 2008 48excessive sweating or night sweats, anorexia, fever,or unexplained fatigue. 2 Enlarged lymph nodes can befound upon physical examination or on radiology fi lms,such as chest x-rays or CT scans. Diagnosis is made byobtaining a tissue biopsy of an involved organ or lymphnode. A complete blood count, lactic dehydrogenase level,electrolytes, liver function tests, and renal function tests arealso done as part of the routine workup for Diffuse largeB-cell lymphoma. Further workup may include a positronemission tomography test to evaluate if metastatic diseaseis present. 3Diffuse large B-cell lymphoma is staged by utilizingCotswold’s classifi cation system. Stage one diseaseinvolves a single lymph node or structure; stage twodisease involves two or more lymph nodes on the sameside of the diaphragm; stage three disease involves two ormore lymph nodes on both sides of the diaphragm; andstage four disease involves one or more extranodal sites. 4Treatment options are based on staging of the disease,and for all intensive purposes, the goal of inductionchemotherapy for Diffuse large B-cell lymphoma iscurative. Treatment for localized (stage I or II) diseaseis based on the size or bulkiness of the tumor. Tumorsthat are “non-bulky” and less than 10 cm can be treatedwith three cycles of Rituxan ® (rituximab), Cytoxan ®(cyclophosphamide), Oncovin ® (vincristine), Adriamycin ®(doxorubicin), prednisone, and radiation therapy. Tumorsthat are greater than or equal to 10 cm or “bulky”should be treated with six to eight cycles of rituximab,cyclophosphamide, vincristine, doxorubicin, prednisone,and radiation therapy. Tumors that are “advanced” (stage IIIor IV) should be treated the same as bulky tumors. Clinicaltrials are also an option for those with advanced disease aswell as autologous stem cell transplants. 5Adverse effects from the chemotherapy agents usedto treat Diffuse large B-cell lymphoma include: nausea,vomiting, diarrhea, constipation, oral mucositis, anorexia,cytopenias, oral candidiasis, cystitis, pain, peripheralneuropathy, alopecia, depression, and tumor lysis syndrome.Of the adverse effects, tumor lysis syndrome is knownas one of the “oncologic emergencies” as it can be lifethreatening. It is a complication that follows chemotherapyfor lympho-proliferative disorders. There is a spontaneousor chemotherapy-induced mass destruction of tumorcells. Cell lysis releases intracellular contents into thebloodstream and can cause fatal arrhythmias if notcorrected. Nucleic acids are also released into thebloodstream and further broken down into uric acid.Renal insuffi ciency can result in the inability of the kidneysto excrete uric acid, which can lead to acute renal failure. 6Tumor lysis syndrome is characterized by hyperuricemia,hyperkalemia, hypocalcemia, hyperphosphatemia, lacticacidosis, and renal failure. 7What role do oncology nurses, who work in outpatientinfusion clinics, play in patients receiving chemotherapyfor Diffuse large B-cell lymphoma? Oncology nurses haveto fi rst be aware of those patients at risk for tumor lysis.Tumor lysis syndrome commonly occurs in tumors that arehighly responsive to chemotherapy such as lymphomas.The risk for tumor lysis is also greater in those patientswith extreme leukocytosis, bulky tumors, elevated LDH,pre-existing renal insuffi ciency, and hyperuricemia priorto initiation of chemotherapy. 8 The oncology nurseshould be assessing all patients with risk factors prior tothem receiving chemotherapy. The patient’s laboratorydata should be reviewed and renal function should beassessed. Any abnormal laboratory results, as well asabnormal fi ndings on a physical exam, should be reportedimmediately to the physician or mid-level provider (NP orCNS). Management of tumor lysis syndrome involves goodhydration with diuresis, alkalinization of urine with sodiumbicarbonate, use of Allopurinol or Rasburicase for reductionof uric acid, dietary restriction of phosphorus or phosphatebinders, and Kaexylate for hyperkalemia. Allopurinolshould be given at a dose of 300 mg by mouth twicedaily and should begin at least two days prior to startingchemotherapy. Rasburicase is given intravenously, its effectpeaks within hours of infusing and it removes existing uricacid from the body. It is given at 0.05mg/kg up to 0.2mg/kg. The disadvantage of Rasburicase is that it should begiven for three to fi ve days in order to control tumor lysis.Table 1 by Cairo and Bishop shows laboratory valuesconsistent with tumor lysis syndrome. They also gradedtumor lysis syndrome on a scale of one to fi ve. Grade I

oncologistics nurse’s forumTable 1Parameters:1234Cairo and Bishop reported a classification for grading the acute tumor lysis syndrome (TLS).This was based on the model of Hande and Garrow.laboratory evidence of TLSserum creatininecardiac arrhythmiasseizuresLaboratory evidence of TLS:1234elevation serum uric acid (≥ 8 mg/dL OR 25% increase from baseline)elevation of serum potassium (≥ 6 mmol/L OR 25% increase from baseline)elevation of serum phosphorus (≥ 6.5 mg/dL OR 25% increase from baseline)decrease in serum calcium (≤ 7 mg/dL OR 25% decrease from baseline)criteria are: laboratory values consistent with tumor lysis,creatinine 1.5 x the upper limit of normal, minimal cardiacarrhythmias, and no seizure activity. Grade II has laboratoryevidence of tumor lysis, creatinine 1.5 to 3.0 x the upperlimit of normal, mild cardiac arrhythmias, and one seizureor seizures controlled by medications. Grade III haslaboratory evidence of tumor lysis, creatinine 3.0 to 6.0 xthe upper limits of normal, symptomatic cardiac arrhythmias,and seizures with impaired consciousness. Grade IV haslaboratory evidence of tumor lysis, creatinine greater thansix times the upper limit of normal, life threatening cardiacarrhythmias, and status epilepticus. Grade V has laboratoryevidence of tumor lysis followed by death from tumorlysis syndrome. 9Tumor lysis syndrome is an oncologic emergencythat can be fatal. Management of tumor lysis syndromestarts with assessment of those patients at risk prior toinitiating chemotherapy. Oncology nurses are the vital linkbetween the patient and the physician. Appropriate patientassessment can catch signs of tumor lysis syndrome inthe outpatient clinic and hopefully prevent the patient fromhaving to be hospitalized for more aggressive managementof symptoms. ❚Tamika M. Turner M.S.N., N.P.-C., O.C.N.,is an oncology nurse practitioner at American HealthNetwork Hematology Oncology in Indianapolis, IN.References:1. Roemer, J. (1999). An end to outpatient chemotherapy?Medicare takes aim at reimbursement. Journal of theNational Cancer Institute, 91(17), 1444-1445.2. Howard, S.C. and Pui, C. (2006). Commentary on matoet al.: A predictive model for the detection of tumor lysissyndrome during AML induction therapy. Leukemia andLymphoma, 47, 877-883.3. Long, J.M. (2007). Treatment approaches and nursingapplications for Non-Hodgkin lymphoma. Clinical Journalof Oncology Nursing, supplement to 11(1), 13-21.4. Casciato, D.A. (2004). Manual of clinical oncology. 5th ed.,Philadelphia: Lippincott Williams and Wilkins.5. www.nccn.org6. Cope, D. (2004). Tumor lysis syndrome. Clinical Journal ofOncology Nursing, 8(4), 415-416.7. Mourad, Y.A., Shamseddine, A., and Taher, A. (2003). Acutetumor lysis syndrome in large B-cell Non-Hodgkin lymphomainduced by steroids and anti-CD20. The HematologyJournal, 4, 222-224.8. Abubakar, S., Khan, A., and Malik, I. (1994).Dexamethasone-induced tumor lysis syndrome in high gradeNon-Hodgkin lymphoma. Southern Medical Journal, 87(3),409-411.9. Cairo, M.S. and Bishop, M. (2004). Tumor lysis syndrome:New therapeutic strategies and classifi cation. British Journalof Haematology, 127, 3-11.oncologistics 49

oncologistics eye on ionEYE on IONGABRAIL CANCER CENTER RECOGNIZEDoncologistics volume 7, issue 1 - spring 2008 50Gabrail Cancer Center (GCC) in Canton, OH, with a satelliteoffi ce in Dover, OH, is a two-physician practice founded byNash Gabrail, M.D., in 1990. Multiple organizations haverecently recognized the center for demonstrating excellentpatient care.First, the practice has been nominated for the AmericanSociety of Clinical Oncology (ASCO) Foundation’sCommunity Oncology Research Award. GCC received theonly nomination from the Ohio/West Virginia Hematology/Oncology Society for the national award. This recognitionis based on the practice’s commitment to clinical research,and its contribution to the development, approval, andmarketing of several oncology drugs and supportivecare medications over the last 10 years. The winner ofthis award will be announced at this year’s annual ASCOmeeting in Chicago, IL.Also, Hematology & Oncology News & Issues (HONI)has recognized GCC with its Hematology and OncologyPractice Excellence (HOPE) award in the Clinical BestPractices category. Award panelists cited GCC’sinvolvement in clinical trials, development of FDA-basedSOPs, and utilization of EMR technology as some of thefactors contributing to its recognition.As the center continues to excel in the community,practice leaders consistently look for ways to improvecare. Over the past 18 months, the facility’s square footagehas increased by more than 400%, a second physicianwas added to the staff, a CT scanner was installed in theCanton facility, and the practice converted to an entirelypaperless model.GCC is a comprehensive cancer treatment facility wherepatients receive chemotherapy, obtain results quickly fromin-house lab and CT scanner, participate in clinical trials,and undergo procedures performed by the physicians allwithin the facility. GCC takes pride in the fact that all newpatients are seen within 48 hours, regardless of insurancestatus, and established patients are seen the same day.Through the use of cutting-edge technology, with a desireto stay on the forefront of clinical research, and withextreme dedication to their community, GCC continuesto provide the best treatments available for its patientsin a serene, home-like atmosphere. ❚

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oncologistics eye on ionEYE on IONION ENHANCES WEB: NEW TOOLS FORPHYSICIANS AND ADMINISTRATORSIf you have logged onto ION’s Web site, www.iononline.com,recently, you may have noticed some important updatesand improvements to the layout and functionality ofthe site. These updates were made in an in an effort toadd greater value to the site and improve ease of usefor all ION members, but particularly for physicians andpractice administrators. ION has allocated signifi cantresources to this cause so that iononline.com truly servesas an essential, interactive hub, with easy-to-accessinformation and tools built specifi cally for enhancingpractice effi ciencies.The ION Practice Analyzer subheading containsinformation, including an FAQ and an interactive tutorial onION’s latest data collection and aggregation tool, as well asinformation about enrolling in the program.The Clinical Applications subheading currently links to theION-approved clinical guidelines that have been completedto date. This area will house the new clinical forum forphysicians, which is coming soon. Look for the forum, aswell as additional ION guidelines to be loaded here as theyare fi nalized.Of the updates made, several are of important note, andare detailed as follows:REIMBURSEMENT CENTERUnder the Reimbursement Center tab on the main page ofthe site, logged-on ION members can access numerousprograms and documents pertaining to physicianreimbursement, many of which currently focus on the useof ESA therapies. Also under the Reimbursement Centertab, are the tools that reimbursement expert Bobbi Buellnow provides to ION members. Included here are archivesof past reimbursement Web events and a link to Bobbi’snew “Ask the Consultant” blog, where you can posereimbursement and coding specifi c questions about issuescurrently affecting your practice.PRACTICE MANAGEMENTThis portion of the site is divided into three primarysegments that help practices achieve maximum effi ciency:ION Practice AnalyzerClinical ApplicationsPractice ResourcesThe Practice Resources subheading includes informationabout the various tools, services, and programs thatION currently offers. This is the segment of the Web sitewhere members can fi nd information about ProtocolAnalyzer, ION’s Pharmacy Program, and the multitude ofION service partners.ION understands that with the demands of treating yourpatients, managing a busy practice, and maintaining asuccessful business, you have little time to spend onlinesearching for the information you need. At iononline.com,you can now exchange therapeutic ideas with clinicalexperts, research the latest reimbursement changes,and begin to build a best practice model.If you have any questions about what ION can do for yourpractice, please contact your ION relationship manager.For Web site login assistance, emailmemberid@iononline.com. ❚oncologistics 53

“ ION provides me with a better viewof my practice so I don’t lose sightof what’s best for my patients.”ION’s Web site offers key insight into three areas that are notonly beneficial to me as a physician, but also greatly assist myadministrator, nursing staff, and billing department:Practice Management> How Do You Compare Tools> ION Pathways Practice Analyzer> Ask the Consultant Practice Management AdviceReimbursement Support> Reimbursement/Coding Consultations> ION’s ESA Tool Kit> ION Protocol AnalyzerClinical Support and Educational Initiatives> ION Clinical Guidelines> Clinical and Coding Web Casts> Live Clinical MeetingsWith all of the issues affecting private practice oncology today, fromreimbursement cuts to CMS regulations, it’s imperative that we, as acommunity, utilize all of the resources made available to us, so thatwe can continue to provide the highest possible level of patient care.To access the features mentioned above, as well as other toolsand applications, please visit www.ionyourpractice.com today.www.ionyourpractice.comInformatics EMR/Practice Management Payor/Reimbursement Strategies Market-leading GPO/Clinical Education

emendforinjection.comFor reimbursement support, please contactthe ACT (Accessing Coverage Today) programat 866-363-6379.EMEND is a registered trademark of Merck & Co., Inc.Copyright © 2008 Merck & Co., Inc. All rights reserved. 20801630(1)-02/08-EME