NCCN Task Force Report: Oral Chemotherapy - National ...

JNCCNVolume 6 Supplement 3MastheadPublishing and DesignJones and BartlettExecutive Publisher:Christopher DavisVP, Design and Production:Anne SpencerProduction Editor:Rachel RossiEditorialNational Comprehensive CancerNetworkDirector of NCCN Publications/Managing Editor:Kimberly A. Callan, MS, ELSEditor:Kerrin Robinson, MAEditorial Assistant:Genevieve Hartzman, MANational Comprehensive Cancer NetworkChairman of the Board:Al B. Benson III, MDVice Chair of the Board:Thomas A. D'Amico, MDChief Executive Officer:William T. McGivney, PhDExecutive Vice President/Chief Operating Officer:Patricia J. GoldsmithSenior VP, Finance/Chief Financial Officer:Lisa Kimbro, CPA, MBAClinical Practice GuidelinesSenior VP, Clinical Information andPublications:Joan S. McClure, MSDirector, Clinical InformationOperations:Kristina M. Gregory, RN, MSNAssociate Director, ClinicalInformation:Dorothy A. Shead, MSGuidelines Coordinators:Nicole R. 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JNCCNVolume 6 Supplement 3Journal of the National Comprehensive Cancer NetworkNCCN Member InstitutionsCity of HopeLos Angeles, CaliforniaDana-Farber/Brigham andWomen's Cancer Center|Massachusetts General HospitalCancer CenterBoston, MassachusettsDuke Comprehensive Cancer CenterDurham, North CarolinaFox Chase Cancer CenterPhiladelphia, PennsylvaniaHuntsman Cancer Institute at theUniversity of UtahSalt Lake City, UtahFred Hutchinson CancerResearch Center/Seattle Cancer Care AllianceSeattle, WashingtonArthur G. James Cancer Hospital& Richard J. Solove ResearchInstitute at The Ohio StateUniversityColumbus, OhioThe Sidney KimmelComprehensive Cancer Centerat Johns HopkinsBaltimore, MarylandRobert H. Lurie ComprehensiveCancer Center ofNorthwestern UniversityChicago, IllinoisMemorial Sloan-KetteringCancer CenterNew York, New YorkH. Lee Moffitt Cancer Center& Research InstituteTampa, FloridaRoswell Park Cancer InstituteBuffalo, New YorkSiteman Cancer Center atBarnes-Jewish Hospital andWashington University Schoolof MedicineSt. Louis, MissouriSt. Jude Children's ResearchHospital/University ofTennessee Cancer InstituteMemphis, TennesseeStanford ComprehensiveCancer CenterStanford, CaliforniaUniversity of Alabama atBirmingham ComprehensiveCancer CenterBirmingham, AlabamaUCSF Helen Diller FamilyComprehensive Cancer CenterSan Francisco, CaliforniaUniversity of MichiganComprehensive Cancer CenterAnn Arbor, MichiganUNMC Eppley Cancer Center atThe Nebraska Medical CenterOmaha, NebraskaThe University of TexasM. D. Anderson Cancer CenterHouston, TexasVanderbilt-Ingram Cancer CenterNashville, TennesseeFor more information, visitwww.nccn.orgMission StatementJNCCN is dedicated to improving the quality of cancer care locally, nationally,and internationally while enhancing the collaboration between academic medicineand the community physician. JNCCN is further committed to disseminatinginformation across the cancer care continuum by publishing clinicalpractice guidelines and reporting rigorous outcomes data collected and analyzedby experts from the world’s leading care centers. JNCCN also provides aforum for original research and review papers focusing on clinical and translationalresearch and applications of the NCCN guidelines in everyday practice,as well as correspondence and commentary.NCCN275 Commerce DriveSuite 300Fort Washington, PA 19034215–690–0300www.nccn.orgAbout the NCCNThe National Comprehensive Cancer Network (NCCN), a not-for-profit allianceof 21 of the world's leading cancer centers, is dedicated to improving the quality andeffectiveness of care provided to patients with cancer. Through the leadership andexpertise of clinical professionals at NCCN member institutions, NCCN developsresources that present valuable information to the numerous stakeholders in the healthcare delivery system. As the arbiter of high-quality cancer care, NCCN promotes theimportance of continuous quality improvement and recognizes the significance ofcreating clinical practice guidelines appropriate for use by patients, clinicians, and otherhealth care decision-makers. The primary goal of all NCCN initiatives is to improvethe quality, effectiveness, and efficiency of oncology practice so patients can livebetter lives. For more information, visit www.nccn.org.

JNCCNVolume 6 Supplement 3Journal of the National Comprehensive Cancer NetworkAccreditationThe National Comprehensive CancerNetwork (NCCN) is accredited by theAccreditation Council for ContinuingMedical Education (ACCME) toprovide continuing medical educationfor physicians.The NCCN designates thiseducational activity for a maximum of1 AMA PRA Category 1 Credit.Physicians should only claim creditcommensurate with the extent of theirparticipation on the activity.This educational activity wasplanned and produced in accordancewith ACCME Essential Areas andPolicies.The NCCN adheres to theACCME Standards for CommercialSupport of Continuing MedicalEducation.This activity is approved for1 contact hour. NCCN is an approvedprovider of continuing nursingeducation by the PA State NursesAssociation, an accredited approverby the American Nurses CredentialingCenter’s Commission onAccreditation.Approval as a provider refers torecognition of educational activitiesonly and does not imply ANCCCommission Accreditation of PANurses approval or endorsement ofany product. Kristina M. Gregory, RN,MSN, OCN, is our nurse planner forthis educational activity.Continuing Education InformationTarget AudienceThis educational program is designed to meet the needs of advanced practicenurses, medical oncologists, radiation oncologists and pharmacists who treat andmanage patients with cancer. This program will also benefit cancer center administrators.Educational ObjectivesAfter completion of this CME activity, health care providers should be able to:• Outline how oral chemotherapy is financed and how payment issues for oralchemotherapy may differ from those of parenteral chemotherapy• Recognize the common misperceptions about oral chemotherapy and discussthese with patients• Utilize patient selection criteria for oral chemotherapy regimens• Summarize the impact that widespread use of oral chemotherapies may haveon oncology practiceThe opinions expressed in this publication are those of the participatingfaculty and not those of the National Comprehensive Cancer Network, Pfizer,or the manufacturers of any products mentioned herein.This publication may include the discussion of products for indications notapproved by the FDA.Participants are encouraged to consult the package inserts for updated informationand changes regarding indications, dosages, and contraindications.This recommendation is particularly important with new or infrequently usedproducts.Activity InstructionsParticipants will read all portions of this monograph, including all tables, figures,and references. A post-test and an evaluation form follow this activity, bothof which require completion. To receive your continuing education certificate,you will need a score of at least 70% on the post-test. The post-test and evaluationform must be completed and returned by March 31, 2009. It should takeapproximately 1 hour to complete this activity as designed. There are no registrationfees for this activity. Certificates will be mailed within 3 to 4 weeks ofreceipt of the post-test.Copyright 2008, National Comprehensive Cancer Network (NCCN). Allrights reserved. No part of this publication may be reproduced or transmittedin any other form or by any means, electronic or mechanical, without firstobtaining written permission from the NCCN.

Volume 6 Supplement 3JNCCNJournal of the National Comprehensive Cancer NetworkNCCN Oral Chemotherapy Task Force Panel Members*Saul N. Weingart, MD, PhDDana-Farber Cancer Institute*Elizabeth Brown, MDNational Comprehensive CancerNetworkPeter B. Bach, MD, MAPPΞ€Memorial Sloan-KetteringCancer CenterKirby Eng, RPh∑CVS CaremarkShirley A. Johnson, RN, MS, MBAλSiteman Cancer Center atBarnes-Jewish Hospital andWashington University School ofMedicineTimothy M. Kuzel, MD‡Robert H. Lurie Comprehensive CancerCenter at Northwestern UniversityTerry S. Langbaum, MASλThe Sidney Kimmel ComprehensiveCancer Center at Johns HopkinsR. Donald Leedy, MBA, CPAλFox Chase Cancer CenterRaymond J. Muller, MS, RPh∑Memorial Sloan-KetteringCancer CenterLee N. Newcomer, MD, MHA†UnitedHealthcareSusan O’Brien, MD‡The University of TexasM. D. Anderson Cancer CenterDenise Reinke, MS, NP, AOCN#University of MichiganComprehensive Cancer CenterMark Rubino, RPh, MHA∑AetnaLeonard Saltz, MD†Memorial Sloan-KetteringCancer CenterRonald S. Walters, MD, MBA†The University of TexasM. D. Anderson Cancer CenterKEY:*Writing Committee MemberSpecialties: ΞPulmonary Medicine;€Critical Care; ∑Pharmacology;λPolicy, Program Administration, andHealthcare Financing;‡Hematology/Hematology Oncology;†Medical Oncology; InternalMedicineDisclosures of Affiliations and Significant RelationshipsDr. Bach has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this reportor who may financially support the educational activity. He has received honoraria for speaking from Genentech, Inc., Biogen Idec, and Johnson &Johnson. He is also a consultant for Abraxis BioScience, Inc.Dr. Brown has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in thisreport or who may financially support the educational activity. She is an employee of the National Comprehensive Cancer Network.Mr. Eng has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this reportor who may financially support the educational activity. He has participated on the advisory boards for Amgen Inc., Novartis AG, and AstraZeneca.Ms. Johnson has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed inthis report or who may financially support the educational activity.Dr. Kuzel has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this reportor who may financially support the educational activity. He is on the speakers’ bureau for and has received grant or research support from NovartisAG and Bayer HealthCare Pharmaceuticals. He is also on the advisory board and a speaker for Pfizer Inc.Ms. Langbaum has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussedin this report or who may financially support the educational activity.Mr. Leedy has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in thisreport or who may financially support the educational activity.Mr. Muller has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this reportor who may financially support the educational activity. He is a speaker and consultant for Amgen Inc., and is on the advisory board for sanofiaventis.Dr. Newcomer has disclosed that he has accepted financial support in the form of travel expenses from Genentech.Dr. O’Brien has disclosed that she has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in thisreport or who may financially support the educational activity. She has received grant or research support from Genentech, Berlex Laboratories, BiogenIdec, Eli Lilly and Company, Novartis AG, Bristol-Myers Squibb Company, Gemin X Biotechnologies Inc.; she is also a consultant for Genta Incorporated.Ms. Reinke has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed inthis report or who may financially support the educational activity.Mr. Rubino has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in thisreport or who may financially support the educational activity.Dr. Saltz has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this reportor who may financially support the educational activity. He has received grant or research support from Pfizer Inc., Roche, Genentech, Bristol-Myers SquibbCompany, ImClone Systems Incorporated, Amgen Inc., Merck & Co., Inc., Bayer HealthCare Pharmaceuticals, and Taiho Pharmaceutical Co., Ltd. He is alsoa consultant for Merck & Co., Inc. and YM BioSciences Inc.Dr. Walters has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in thisreport or who may financially support the educational activity.Dr. Weingart has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in thisreport or who may financially support the educational activity. He has received grant or research support from Physicians’ Foundation for Health SystemsExcellence, Risk Management Foundation of the Harvard Medical Institutions, Agency for Healthcare Research and Quality, and Blue Cross and Blue Shieldof Massachusetts, Inc,; is a consultant for Advanced Practice Strategies, Inc.,; and is a board for governors member for the National Patient SafetyFoundation.

S-1SupplementNCCN Task Force ReportNCCN Task Force Report: Oral ChemotherapySaul N. Weingart, MD, PhD; Elizabeth Brown, MD; Peter B. Bach, MD, MAPP; Kirby Eng, RPh; Shirley A. Johnson, RN, MS, MBA;Timothy M. Kuzel, MD; Terry S. Langbaum, MAS; R. Donald Leedy, MBA, CPA; Raymond J. Muller, MS, RPh;Lee N. Newcomer, MD, MHA; Susan O’Brien, MD; Denise Reinke, MS, NP, AOCN; Mark Rubino, RPh, MHA;Leonard Saltz, MD; and Ronald S. Walters, MD, MBAKey WordsNCCN Task Force Report, oral chemotherapy, parenteral chemotherapy,chemotherapy administration, cancer care, coverage andreimbursement, patient adherenceAbstractOral chemotherapy is emerging as a new option for well-selectedpatients who can manage potentially complex oral regimens andself-monitor for potential complications. If a choice between oraland parenteral therapy is available, patients may opt for oralchemotherapy because it is more convenient to administer, allowsthem to avoid multiple office visits, and gives them a sense of controlover their own cancer care. Whether these potential advantagesare maintained in regimens that combine oral and parenteral drugsis less clear. The use of oral chemotherapeutic agents profoundly affectsall aspects of oncology, including creating significant safety andadherence issues, shifting some traditional roles and responsibilitiesof oncologists, nurses, and pharmacists to patients and caregivers. Thefinancing of chemotherapy is also affected. To address these issues,the NCCN convened a multidisciplinary task force consisting of oncologists,nurses, pharmacists, and payor representatives to discussthe impact of the increasing use of oral chemotherapy. (JNCCN2008;6[Suppl 3]:S1–S14)Oral chemotherapeutic drugs have been available fordecades and include the familiar agents chlorambucil,cyclophosphamide, methotrexate, and 6-mercaptopurine(6-MP). However, the past 4 years has seen anaccelerating expansion of the development of oralanticancer drugs, including oral cytotoxic agents, smallmolecule inhibitors directed at cell surface receptorsand other proteins, and other agents targeted at thetumor microenvironment.Capecitabine received FDA approval in April 1998,ushering in a new era of oral chemotherapy. Capecitabineapproval was followed by FDA approval of a number oforal small molecule inhibitors of a variety of defined targets,including imatinib in 2001, gefitinib in 2003, anderlotinib in 2004. Five more new oral agents were thenapproved in the 7 months between December 2005 andJuly 2006. Lapitinib and nilotinib were approved in 2007.Experts anticipate that this trend will continue in thecoming years. They further estimate that more than onequarter of the 400 antineoplastic agents now in thepipeline are planned as oral drugs.Compared with the oral chemotherapy drugs availablebefore 1996, these newer drugs, consistent with theirparenteral contemporaries, are considered costly. For example,the estimated yearly cost of lenalidomide for a patientwith multiple myeloma is $74,000, and, dependingon dosage, the yearly cost of imatinib for patients withchronic myelogenous leukemia (CML) ranges from$29,000 to $57,000. Imatinib accounts for the largest percentageof spending on oral chemotherapy, ranging from29% to 39%, depending on whether pharmacy benefitsare provided by an insured health plan or self-insured employer.The availability of these new drugs has had animmediate impact on pharmacy budgets. Spending onoral chemotherapy drugs, while still a small proportion oftotal pharmacy benefit costs, has more than doubledbetween 2002 and 2006, from 0.3% to 0.7%. 1Anticancer agents, including oral drugs, can bebroadly categorized as chemotherapy, which in the pastgenerally referred to cytotoxic agents, and biologictherapy, which generally referred to therapy targetedspecifically at cell surface proteins or pathways that arerelatively specific to cancer biologic pathways. Biologictherapy is also often referred to as targeted therapy.However, chemotherapy has also been used as an inclusiveterm encompassing all antineoplastic therapies, andthe distinctions between targeted and non-targeted andbiologic therapy versus chemotherapy would, at this time,appear to be somewhat artificial. In this discussion, theterm chemotherapy is used generally to describe bothcytotoxic and biologic therapy.© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-2 SupplementNCCN Task Force ReportDrivers of Oral ChemotherapyIn the past, developers of new anti-cancer therapiesfocused primarily on parenteral drug delivery, in partbecause this route bypassed the variable absorptionpatterns of the gastrointestinal tract. For example, oraldrugs must be stable in the low pH environment ofthe stomach but also must dissolve in the small intestinewhere the drug is absorbed. Additionally interactionwith other substances in the gastrointestinal tract,such as food or other drugs, must be considered, asmust the first pass effect on the liver.In contrast, parenteral administration was consideredrelatively straightforward and compatiblewith the cytotoxic action of most chemotherapies.Cytotoxic chemotherapy regimens are designed todeliver the maximal tolerated dose of chemotherapyto optimize cell kill in a single episode, followed by aseveral week period to allow bone marrow recovery.This episodic administration lends itself to the parenteralroute. In fact, the operational and financialinfrastructure of oncology practice has been based onthe parenteral administration of chemotherapy.Oncology office visits and the configuration of officespace have been centered on chemotherapy infusion,and oncologists derive a substantial portion of their incomefrom supplying and administering parenteralchemotherapy.Oral chemotherapy is changing this model. Manycurrent anti-cancer therapies are primarily cytostaticin nature and thus are optimally effective when givenchronically, so both tumor cells and the tumor microenvironmentare continually exposed. This mechanismof action virtually requires oral daily therapy.Furthermore, the daily low-dose schedules often donot have the same dose-limiting side effects as highdoseintermittent schedules, making the cycling ofregimens to allow for marrow recovery unnecessary.Older paradigms used anticancer therapy for a limitednumber of cycles and then stopped. In contrast,many current therapies require prolonged treatment.For example, life-long imatinib therapy has revolutionizedthe treatment of CML and is an alternativeto allogeneic stem cell transplantation.New monitoring techniques for residual diseasehave also prolonged the duration of therapy. Before theavailability of molecular monitoring of disease recurrence,the duration of treatment of some leukemiaswas based on the normalization of the peripheral bloodor marrow. Now therapy may be continued if sensitivemonitoring techniques detect minimal residual disease.These factors have prompted oncologists toreframe some cancers as chronic diseases requiringchronic therapy.Imatinib therapy for CML is perhaps the bestexample yet of the promise of targeted therapies; thetarget is well defined and exquisitely sensitive toimatinib monotherapy. However, it is becomingapparent that this elegant simplicity is not typicalof the more common epithelial malignancies. Thecomplexity of the underlying pathobiology in coloncancer, for example, suggests that multiple differenttargeted therapies will be needed, both directed at thetumor cells themselves and the underlying tumormicroenvironment. This suggests that there will be agrowing market for the simultaneous use of multipledifferent targeted therapies.The very terms targeted and biologic therapy suggestthat toxicity will be less than that encountered usingtraditional cytotoxic therapies (although to whatdegree toxicities are lower, versus different, is debatable).This perception and the perceived ease of oraladministration may lead clinicians to add targetedtherapies to other cytotoxic regimens or to use themas monotherapies in situations in which minimalvalidated treatment options are available.The perception also exists that the standards forefficacy may be lower for targeted therapies. In fact,the standards for efficacy have been progressively loweringover the past several decades, but this process hasmore to do with the date of application than the mechanismof action of the agent involved. This differencein acceptable outcomes may also be related to the factthat targeted therapies are assumed to be less toxic,although the side effects of some biologic therapiescan be quite significant.For a number of reasons, pharmaceutical companieshave invested heavily in the development of oralcancer drugs. One strong incentive is the introductionof Medicare Part D, which provides coverage formany oral chemotherapies for the first time. Researchhas been invested in both novel oral agents and alsooral counterparts to existing cytotoxic therapies. Forexample, oral versions of docetaxel and topotecan areunder development. 2 Experts suggest a market will existfor both oral and intravenous versions of manydrugs. For example, in the new histone deacetylaseinhibitors class of drugs (e.g., the recently approvedvorinostat), both oral and intravenous agents are© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

Supplement S-3Oral Chemotherapyunder development. For agents such as these, thechoice between oral and intravenous administrationmay depend on physician and patient preferences andtype of insurance coverage.Common Misconceptions About OralChemotherapyAs the previous discussion shows, oral chemotherapysuggests a number of benefits. However, growing experiencein administering these therapies suggests thata cautious approach is warranted. Clinicians shouldalso understand the common misconceptions that maybe contributing inappropriately to the enthusiasm fororal chemotherapy.Patient PreferencePatient preference for oral chemotherapy has beenone of the main drivers for its current popularity. Oraladministration would seem to avoid many of the moreobjectionable aspects of parenteral therapy: the officevisit and associated inconvenience of transportationand parking, time spent waiting in the office, and timelost during intravenous set up and infusion.In 1997 Liu et al. 4 reported on the results of a questionnaireaddressing patient preference for oral versusintravenous palliative chemotherapy. Preference forroute of administration was evaluated against diminishingtreatment response. Of 102 assessable patients,92 preferred oral chemotherapy and 10 preferredintravenous therapy. Not unexpectedly, the majorreason given for preferring oral chemotherapy wasconvenience. However, although patients expresseda clear preference for oral chemotherapy, they wereunwilling to sacrifice efficacy for this preference.Although these results seem to support convenienceas a driving factor for patient preference, atleast in the palliative setting, this survey may havepresented oral chemotherapy in an overly simplisticfashion. For example, the convenience of oralchemotherapy will only be realized if the patient is onan exclusively oral regimen. Patients on combinationregimens will need to make office infusion visits anyway;for these patients, it may actually be more convenientto receive the entire regimen parenterally.Capecitabine, for example, is an oral alternative to5-fluorouracil (5FU) that is often administered withother parenteral agents.Additionally, patients may not realize that choosingan oral therapy over an intravenous equivalentwill shift many of the responsibilities of managing theregimen and monitoring for doses and toxicity from theoncology team more directly to the patient. Although,some patients may appreciate a sense of empowermentfrom oral chemotherapy and get a sense of satisfactionfrom having direct responsibility for managingtheir chemotherapy, this same responsibility couldbecome overwhelming, particularly for sick patientssimultaneous dealing with complicated dosingregimens and schedules or for patients without reliableassistance from family or friends. The reliable administrationof oral chemotherapy in the pediatric populationis also challenging, even among well-intentionedfamilies. 5These advantages and disadvantages of oralchemotherapy must be carefully discussed with thepatient. Only well-motivated and health-literatepatients and families may be able to manage complexoral chemotherapy regimens, and only patientswith good oral food intake, good gut function, andminimal nausea and vomiting will be good potentialcandidates.Fewer Side Effects and Easier AdministrationPatient preference for oral chemotherapy may be basedon the incorrect assumption that oral therapy is associatedwith minimal side effects; some patients mayincorrectly assume that oral chemotherapy is not “real”chemotherapy and is more akin to taking a vitamin orantibiotic. This dangerous misconception may also bethe rationale for the preference of oral chemotherapyin frail elderly patients.Patients must understand that oral equivalentsof cytotoxic therapies, such as capecitabine, have sideeffects that are similar to their parenteral counterparts(in this case, fluorouracil). The need to monitorfor side effects and titrate dosages increases thecomplexity of oral chemotherapy regimens. For example,many oncologists can relate examples of patientswho began to experience toxicity from capecitabineon a Friday but who did not consult a physician overthe weekend. If these patients continue on the samedosage, either because they do not recognize the incipientside effects or because they do not want tocompromise the effectiveness of their chemotherapy,they may have a life-threatening level of toxicity byMonday.Furthermore, from the patient’s perspective, anoral regimen may not be simple to administer.Instructions for capecitabine may include:© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-4 SupplementNCCN Task Force Report• Take with water within 30 minutes of a meal.• If a dose is missed, do not take the drug when rememberedand do not take a double dose.• Stop taking capecitabine and contact the doctor ifexperiencing 4 or more bowel movements thanusual per day, diarrhea at night, loss of appetite orlarge reduction in fluid intake, more than 1 vomitingepisode in 24 hours, mouth sores, temperaturegreater than 100.5 o F, or pain, redness, orswelling of hands or feet that prevents normal activity.6Oral regimens must also be integrated with noncancerdrug therapies taken for comorbidities. Oralchemotherapy regimens may be particularly difficultto manage in assisted living situations where drugs aredispensed by staff with limited experience in monitoringthe side effects of chemotherapy.Furthermore, supportive care agents such as the5-hydroxytyptamine3 (5-HT3) antagonist antiemeticdrugs are best used parenterally and intermittently.Reimbursement for these agents on a daily oral basisis often limited when pharmacy benefit managementprograms base reimbursement on the FDA-labeled indications.When all these requirements are considered,a periodic office visit to receive chemotherapymay be more attractive to patients.Another common perception is that oral drugshave a broader therapeutic index and thus are saferthan parenteral drugs. The therapeutic index is basedon the class of drug and its mechanism of action, notthe route of administration. Thus, the therapeutic indexof oral agents versus intravenous counterparts isgenerally the same. Nevertheless, clinicians shouldnote that although biologic agents are not cytotoxicin nature, the adverse effects associated with themcan still be significant. For example, the skin rash anddiarrhea associated with epidermal growth factor inhibitorscan be debilitating.In summary, the assumption that all patients willprefer oral agents or that all patients are appropriatecandidates for oral therapies is overly simplistic.Furthermore, that oral chemotherapy is routinelypreferable for frail, elderly, and less motivated patientsis also a commonly held misconception. Generally,highly motivated, capable patients who want and canactively participate in their care are better suited toassume the increased responsibility that comes withchronic home oral administration of chemotherapy.Certainly, for some regimens, oral chemotherapy isthe only alternative. However, the example of imatinibmonotherapy, a simple regimen with minimal sideeffects, may be the exception rather than the rule. Anentirely oral chemotherapy regimen may offer significantadvantages over traditional infusion therapy incarefully selected patients, but patients must understandthat the decision to use oral chemotherapyrequires detailed consultation with the oncologist andoncology team, as well as ongoing support over thecourse of therapy.Cost of Oral Chemotherapy: Offset by DecreasedNeed for Support Staff or Infusion Centers?Some have argued that the high cost of oralchemotherapy drugs may be offset by the decreasedneed for ancillary services, particularly oncology nursingstaff and infusion centers. Experience, however,has not uniformly borne this out. Oral chemotherapyrequires a significant amount of nursing time forpatient education when starting an oral chemotherapyregimen and extensive telephone consultationthereafter. Furthermore, in most practices, no time isbuilt in for counseling patients on oral chemotherapy,and most offices do not have any dedicated space orpersonnel for this counseling. Thurs, education andcounseling have been improvised in hallways andother less private settings. Some oncologists offerwritten material, video material, or group educationalsessions, but the bottom line is that the extensive andongoing patient education required to ensure safe andeffective oral chemotherapy is uncompensated andperhaps underappreciated. In contrast, prolonged infusionsessions provide many built-in opportunitiesfor education.Patient Selection Criteria for OralChemotherapyAdherenceAlthough many patients may be eligible for oralchemotherapy, only a subset will both want to takeoral agents and be considered appropriate candidatesbased on their ability to adhere to the regimen. Oneof the key factors in assessing candidacy for oralchemotherapy is adherence. Adherence can be a challengingcommitment for many patients, and the decisionto take oral chemotherapy must be based on acollaborative discussion between the patient and physician,with appropriate support from oncology staff.© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

Supplement S-5Oral ChemotherapyIn clinical trials of oral agents, adherence has generallybeen excellent 7 except for selected populations(e.g., adolescents). However, in contrast with the clinicaltrial experience, adherence to chronic medicationtherapy in adult ambulatory care is generally fairto poor. Unfortunately, there is currently no well establishedmechanism to prospectively assess adherence.For example, approximately 50% of patientstaking statin drugs will discontinue taking the medicationwithin 6 months. 8Patients with cancer are believed to be particularlymotivated to adhere to chemotherapy regimens. Infact, occasional overadherence can pose health risks.Nevertheless, studies have shown that nonadherenceto oral chemotherapy is still an issue.For example, imatinib is a very effective oral agent;it has an uncomplicated daily regimen and few majorside effects. The drug is considered life-saving for patientswith CML, converting a universally fatal diseaseinto a manageable chronic one. Given these factors,one might expect a near 100% adherence rate.However, studies have not borne this out. Tsanget al. 9 analyzed pharmacy claims data to determineprescription adherence and persistency of 4043patients receiving imatinib over 24 months. Overallcompliance (defined as apparent mg taken/mg prescribed)was 75%, and only 50% of patients were 100%compliant. Persistency (time on therapy without significantgaps in refills) averaged 255 days over 24months. Although adherence and persistency in thisstudy may be superior to those seen with nononcologymedications, suboptimal adherence with daily imatinibmay compromise treatment effectiveness.Partridge et al. 7 reviewed the literature regardingadherence to oral chemotherapy. Most studies examinedadherence in the context of a clinical trial, whichprobably represents the optimal situation of highlymotivated and supervised patients. However, even inthis setting, adherence was variable, ranging from lessthan 20% to almost 100%.Assessing adherence to parenteral therapy isstraightforward; physicians know exactly how muchchemotherapy was given over what period of time andon which day. This level of control is not possible withoral chemotherapy, where there is shared responsibilityfor ensuring that prescriptions will be filled, thatthe patient will promptly initiate the drug therapy atthe correct time of day at the correct dosage, or thatthe patient will alert the clinician of adverse symptomsin a timely way. Payor information systems can capturewhether or not the prescription is filled, but anecdotesabound of patients who have shoeboxes fullof unused prescriptions. In addition, few innovationshave been developed in oncology care to help supportsafe and reliable administration of oral chemotherapy.Lessons for disease management programs inasthma and depression management may offer helpfullessons for oncology.Studies have shown that adherence is related tosociodemographic characteristics, type of regimen (i.e.,side effects and duration), and characteristics of the illness(i.e., symptoms and seriousness). However, predictinghow these parameters interact with each otherand determining how they can be used to predict adherenceis difficult. 7Table 1 summarizes factors often associated withnonadherence to oral regimens and lists factors thatmay help oncologists identify patients who need specializedor targeted interventions to support the reliableuse of oral chemotherapies.Monitoring AdherencePredicting adherence is an issue in selecting appropriatepatients for oral chemotherapy. However, after therapyis started, techniques to monitor adherence areimportant to determine treatment effectiveness, assesstoxicity, and assure safety. Adherence-monitoringtechniques can be broadly categorized into direct andindirect methods. The simplest direct method is todirectly observe therapy, which is, of course, possiblewith parenteral therapy. Pharmacokinetic measurementTable 1 Factors Associated WithNonadherence to Oral RegimensComplex treatment regimensSubstantial behavior change requiredInconvenient or inefficient clinicsInadequate supervisionPoor communication with health care providersPatient dissatisfaction with carePatient health beliefs in favor of nonadherenceInadequate social supportHistory of nonadherenceHistory of mental illnessFrom Partridge AH, Avorn J, Wong PS, Winer EP. Adherenceto therapy with oral antineoplastic agents. J Natl Cancer Inst2002;94:652–661; with permission.© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-6 SupplementNCCN Task Force Reportis another, more-cumbersome example of a directmethod. However, this measurememt can also be manipulatedby the patient who becomes adherent justbefore an office visit. Additionally, requiring a bloodsample to monitor oral therapy shows a certain irony.A wide variety of indirect methods have been investigated,including, most obviously, questioning thepatient about adherence. However, patient self-reportmay sometimes be unreliable because of either inaccuraterecall or shame in admitting nonadherence. Otherindirect methods include patient diaries, pill counts,rates of prescription refills, and electronic medicationmonitors. 10 Of course, relatively simple methods as pillcounts and prescription refills do not confirm adherenceto the dosing schedule. A microelectronic monitoringsystem consisting of an “intelligent” tablet bottlecan record the date and time of bottle openings. Thisapproach has been used primarily in clinical trials, inwhich measuring adherence is critical. The expense ofthis approach limits its applicability to large scale use.Regardless of the technique used to assess adherence,clinicians must realize that lack of adherence typicallyreflects the complexity of the regimen rather than willfulor manipulative behavior from the patient.Uncertainty about patients’ ability to adhere torecommended treatments can create a therapeuticdilemma for the physician who is faced with a patientwho appears to be nonresponsive to an oral drug. Thephysician cannot be certain if the lack of response representstrue chemotherapy resistance or nonadherence.Similar to oral therapy in general, the inability to accuratelyconfirm adherence has significant implicationsfor investigating effectiveness and adverse events.Oncologists may need to contract explicitly withpatients about oral chemotherapy adherence and tocreate a more elaborate infrastructure to support safeand reliable administration of oral chemotherapy.Safety IssuesMedication ErrorsMedication errors are a significant source of concernregarding the administration of chemotherapy. Inrecent years, a robust infrastructure of checks andbalances has been implemented for the administrationof parenteral chemotherapy, including templatedorders, electronic order-entry systems with decisionsupport, and clinician double-checks, In manyacademic institutions, every dose of chemotherapy isreviewed by at least 3 or 4 licensed health careproviders. Key safety measures include checking calculationsof such common parameters as dose per metersquared and estimate of body surface area. Writtenconsent forms are used in some organizations for parenteralchemotherapy. Many comprehensive cancercenters have also developed standard order forms fora variety of chemotherapy regimens.To date, however, fewer controls are built in fororal chemotherapy, so any presumed safety can onlybe characterized as hypothetical at present. For example,standard order forms generally do not exist fororal chemotherapy. Weingart et al. 11 reported the resultsof a survey of 42 cancer centers in the UnitedStates regarding current safety practices for oralchemotherapy. The information required on a prescription,such as diagnosis, cycle number, any prescriptiondouble check by other clinicians, calculationof body surface area or dose per meter squared per bodysurface area, was variable. Ten of 42 responding cancercenters had no formal process for monitoring adherence,and 10 centers reported at least 1 seriousadverse event in the prior year. The authors concludedthat few of the safeguards routinely used for infusionchemotherapy had been adopted for oral chemotherapyat U.S. cancer centers.Given these gaps in safeguards, the potentialexists for a physician to write a prescription for an oralantineoplastic agent that is then filled at a localcommunity pharmacy unfamiliar with oral chemotherapyor dosing schedules. In this possible scenario, thepatient may not be given adequate instructions or understandthe instructions for taking the chemotherapy,which may involve complicated cycles. Theconsequences of this scenario are potentially seriousif, for example, a patient takes a drug that is intendedto be taken weekly on a daily basis instead.Drug interactions are another issue for all oraldrugs. Pharmacy systems have built-in alerts to detectpotential drug interactions, but the alerts are oftenperceived to be too sensitive and are overridden. Somesystems may allow some alerts to be overridden, butin cases of serious potential risk, insist that theorder/prescription be stopped until the pharmacistconsults with the physician.Specialty pharmacies (discussed further in a latersection) may provide an additional level of safetychecks, but the number of pills that a patient mayreceive with 1 prescription is still an issue. Capecitabine© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

Supplement S-7Oral Chemotherapyis one of the most common oral antineoplastic agents,and the policy in some academic centers is to limit aprescription to a maximum of 4 to 6 weeks of therapy.However, this safeguard is unlikely for drugs suppliedby a mail order pharmacy. In addition, prescribingphysicians may also lose patient contact if an extendedsupply of medication is given with a single prescription.This issue may be further aggravated if the patientis from out of town and does not routinely seethe prescribing physician. Large employers have financialincentives to provide pharmacy benefits throughmail-order pharmacies. The growing numbers of oralchemotherapeutics with potential serious side effectsmay prompt employers to rethink the balance betweencosts and potential safety issues when mail order pharmaciesare used across the board.Communication IssuesTo prescribe oral chemotherapy safely, the clinicianmust take a comprehensive medication history. Thiscan be challenging if clinicians do not elicit this informationreliably or keep the medication list up todate by reconciling information about medicationsfrom various sources. The situation is improving underthe Joint Commission requirement for “medicationreconciliation” and with the use of electronicmedical records and computerized order entry systems.In some organizations, clinicians can accessinformation on drugs dispensed by pharmacies. Somepayers can provide up-to-date dispensing histories,but these systems are not widely available or accessible.Other institutions’ dispensing information systemscapture prescriptions filled within the particularhospital network, but do not provide information ondrugs received through mail order or communitypharmacies.Adequate communication of side effects and toxicitiesis another key factor that may affect patientsafety. Parenteral therapy provides opportunities forcommunication, particularly with nursing staff duringtherapy. Patients may be more comfortable detailingside effects and other concerns to support staff,but this kind of key interaction with nurses and otherclinicians may not be available for patients receivingan entirely oral regimen. Therefore, additional communicationchannels and mechanisms may be necessary.These communication issues are similar to thoseassociated with other complicated oral regimens forsuch common medical conditions as diabetes orasthma, although the potential for adverse events maybe higher with oral chemotherapies.The ability to monitor symptoms in real-timewould help identify toxicities that may resolve by thenext physician visit and consequently not be adequatelyrecalled by the patient. Internet systems mayimprove communication for all patients. For example,patient-friendly web-based programs have beendeveloped that allow patients to communicatechemotherapy toxicities in real-time either from homeor in the oncologist’s office.One such program is called the STAR program,which has been investigated in patients with lung cancerand gynecologic malignancies. 12,13 Patients wereencouraged to log in and report symptoms at eachfollow up or to access the system from home. In onestudy involving 80 patients with gynecologic cancer,42 severe toxicities (grade 3–4) entered from homeprompted 7 clinician interventions. Additionally, onlineself reporting of toxicity symptoms was shown tobe feasible in 107 patients with lung cancer. Patientsreported high satisfaction with the program, and thenurses who received the symptom reports felt that theinformation was useful for clinical decisions, documentation,and discussions.BiohazardSome 20 to 30 years ago, biohazards of chemotherapywere not appropriately recognized. Residents andinterns could be found mixing doxorubicin solutionsin a back office sink. Since that time, various workplaceregulations have addressed the issue of occupationalbiohazards of parenteral chemotherapy;however, no such systems are in place for oralchemotherapy. Issues include whether or not oralchemotherapy should be placed in automatic pillcounting machines and, if they are manually countedby the pharmacists, whether a dedicated countingtray should be used. Tablets will leave residue in thebottle and on the patient’s hand, an issue which maybe most relevant for parents treating their children athome. These issues have not been well investigatedfor oral chemotherapy.Oral Chemotherapy: Factors Affectingthe Practice of OncologyThe large number of oral chemotherapies in the pharmaceuticalpipeline prompts consideration of how thepractice of oncology could change in the future.© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-8 SupplementNCCN Task Force ReportProcess of CareThe transition to oral chemotherapy may lead to adiffusion of direct patient care from the oncologist toa variety of individuals that the oncologist has no personalor financial relationship with or no direct supervisoryrole for. For example, specialty pharmaciesparticipate in safety monitoring and some monitoringof chemotherapy side effects. Free-standing outpatientclinics, some run by pharmacists, may evolve to providemonitoring services for oncology patients. However,the oncologist still retains the ultimate responsibilityfor the patient’s care, and the expanding number of entitiesinvolved in cancer care management can makecoordinating this care more challenging.Oncology Offices and Infusion CentersAs noted, many oncology offices are set up to deliverparenteral chemotherapy, and the growing number oforal alternatives raises the potential problem of overcapacity.For the foreseeable future, however, this doesnot seem to be an issue. Cancer is primarily a diseaseof an older population, and given the aging of the U.S.population, the incidence of cancer is likely to grow.Although many novel cancer therapies provide onlyan incremental survival benefit, these new drug therapiesmay cumulatively result in a greater number ofpatients living for a longer period of time.Even if the percentage of chemotherapy given asoral chemotherapy grows to 20% to 25% over the nextdecade, the most likely scenario is that oral chemotherapywill primarily be complementary to parenteraltherapy. Whether oral therapy precedes, follows, or isused in combination with parenteral therapy, mostpatients will probably be treated parenterally at somepoint in their care. Thus, the bottom line is that oralchemotherapy is unlikely to substantially replace parenteraltherapy at least for the next decade.Oral chemotherapy may present a particular problemif a patient receiving oral therapy is admitted.The hospital must determine how to continue the oralchemotherapy while the patient is hospitalized: shouldpatients bring the drugs to the hospital or should thehospital bear the uncompensated cost of providingthe drugs? Continuing oral chemotherapy during anacute inpatient hospitalization has emerged as a complicatedfinancial, ethical, and emotional issue.Financial ImpactOncology revenues in private practice have beenlargely based on the delivery of parenteral agents. Incontrast, oncologists do not derive any revenue fromoral chemotherapy independent of the fees receivedfrom office visits needed to monitor care. In addition,although oncologists generally receive payment foradministering parenteral chemotherapy, no similarreimbursement is provided for administering oralchemotherapy.Not surprisingly, research has suggested thatfinancial constraints may play a role when a choicebetween oral and parenteral drugs is possible. Forexample, Jacobsen et al. 14 analyzed the prescribingpractices for chemotherapy according to type of physicianreimbursement for treatment of Medicare beneficiarieswith metastatic lung, breast, or colorectalcancers treated between 1995 and 1998. The studyfocused on the treatment of metastatic disease becausea wide variety of chemotherapies are available in thissetting without definitive evidence of one regimen’ssuperiority.The authors found that providers who were moregenerously reimbursed prescribed more costlychemotherapy regimens. Frequently, the financial incentivesof providers align with those of patients, whoare trying to cope with a burdensome co-pay for oraltherapy.Other specialties face these same choices betweenoral and parenteral drugs. Rheumatologists and theirpatients, for example, must choose between 2 tumornecrosis factor inhibitors for the treatment of rheumatoidarthritis; infliximab (Remicade), which requiresan IV infusion, and etanercept (Enbrel), which is selfadministered subcutaneously.Distribution of Oral ChemotherapyPrescriptions for oral chemotherapy can be filled in severalways: community pharmacies, mail order pharmacies,specialty pharmacies, hospital pharmacies,through the physician’s office as part of competitiveacquisition programs (CAP), or through an officebasedpharmacy that is legal in a number of states.Each of these distribution channels has different implicationsfor the patient and physician.Mail Order PharmaciesMail order pharmacies typically provide a minimum90 day drug supply, which may represent thousands ofdollars for oral cancer chemotherapeutics. The rationalebehind a 90 day supply is that cost savings are availablerelated to volume discounts and to eliminating© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

Supplement S-9Oral Chemotherapymultiple dispensing fees. However, oral chemotherapydoes not easily fit into the model of mail orderpharmacy. For example, for safety reasons, hospitalpharmacies frequently limit oral chemotherapies to a30 day supply. Additionally, some oral chemotherapiesrequire dose alterations, but these cannot be easily accommodatedbecause mail orders typically includeonly 1 dosage. Additionally, patients do not have anyopportunity to interact with a pharmacist, and thislost educational opportunity could impact the safetyof oral chemotherapy.Specialty PharmaciesSpecialty pharmacies were specifically designed toaddress the limitations of mail order pharmacies byfocusing on a specific class of therapeutic drug thatinvolved more complex management issues, a greaterpotential for harm, and more significant expense. Mostoften, patients take their prescriptions to their regularpharmacy, where the prescription is routed to asingle vendor staffed by oncology pharmacists. Thespecialty pharmacist then calls the patient and discussesthe therapy before shipping the drug.In some programs, the specialty pharmacist willhave access to the patients’ prescription medicationrecords through payor information systems so thatpotential drug interactions can be anticipated. Theoncology pharmacist can then call the physician forfurther discussion. Each drug may also have its ownmonitoring program, which notifies the pharmacistto call the patient within the time frame when commontoxicities are expected. For example, the side effectsof capecitabine therapy may be most severe in thefirst 4 days of therapy. Although these side effects willbe identified by the specialty pharmacist, oncologistsmay not be informed by the monitoring program.Specialty pharmacies are also more flexible in boththe number and dosages of pills provided. Unlike mailorder pharmacies, many impose 30 day limits on oralchemotherapies for safety reasons, but also to ensurethat a subsequent refill is needed, thus avoiding waste.In addition, many can also provide a variety of dosagesto accommodate needed dose alterations.One potential source of confusion for patients isthat they may receive drugs and information about appropriateuse of those drugs from multiple sources. Forexample, drugs for hypertension may come from a mailorder pharmacy, drugs for treatment of acute illnessmay come from a community pharmacy, and the oralchemotherapy may come from the specialty pharmacy.Another challenge of specialty pharmacies is theinsertion of an additional health care professional intothe medical care of the patient, creating the need forfurther coordination. For example, patients can beconfused if the information provided by the pharmacistis not consistent with that from the oncologist.Additionally, if the patient tells the pharmacist aboutadverse reactions, the pharmacist must then ensurethat the information is relayed correctly to the oncologistand placed in the patient’s medical record. Fewprograms have robust mechanisms in place to ensurethat information is communicated to (and receivedby) the appropriate parties. This can be a particularvexing challenge.From the oncologist’s perspective, adding the pharmacistis an asset to the patient’s overall care as longas the pharmacy team is well integrated into overallcare. Specialty pharmacies may be superfluous in adedicated cancer center with large and active clinicalpharmacy departments that already have sophisticatedsupport strategies in place. In contrast, a specialtypharmacy system may be particularly helpful to smallercommunity practices with no other access to an oncologypharmacist.Hospital PharmaciesHospital pharmacies associated with comprehensivecancer centers most often have similar capabilities tospecialty pharmacies. For example, oncology pharmacistsand nurses are often part of the health careteam that reviews all medications and interacts withthe patients. The comprehensive cancer center alsointeracts with satellite community pharmacies toprovide the same services. In addition, an informationsystem that records all the medications the patientreceives through the parent hospital pharmacy istypically in place. However, the sophistication of theinformation systems is variable. Furthermore, informationmay be incomplete if some prescriptions arefilled through specialty pharmacies or pharmaciesoutside the center network. In some institutions,almost half of the oral prescriptions are filled outsidethe network.One exception is investigational therapies thatare only provided through a hospital pharmacy. Theseoral drugs have a higher risk of adverse events andtypically have a prescribing and tracking system thatis independent of other routine oral agents.© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-10 SupplementNCCN Task Force ReportCommunity PharmaciesDepending on insurance coverage and set-up of the localhospital-based pharmacy, patients may access oralchemotherapy through a community pharmacy. Forexample, some hospitals may limit the availabilityof oral chemotherapy to investigational agents orpatients with inadequate coverage, and mail order orspecialty pharmacies may not be an option in someinsurance plans. In this situation, the communitypharmacy may order the drug for the patient, but thepharmacy staff may not have adequate experience toprovide appropriate counseling. Some pharmacychains may require counseling for some oral chemotherapyagents, but the quality and value of theseconsultations may be variable.CAPCAPs are a component of the Medicare ModernizationAct (MMA) in which physician-owned clinics wereoffered the opportunity to acquire drugs for theirMedicare patients from a CAP vendor. The CAP vendorassumes the risk of purchasing the drug, includingthe 20% co-pay from the beneficiary. The limitationof the CAP program is that the physician must acquireall drugs from the single vendor. Because of problemsin administering the program and aligningeconomic incentives, very few physicians signed up,and CAP has not emerged as a major supplier of oralchemotherapy.Financing Oral ChemotherapyMedicare Part DMedicare Part D, part of the MMA, profoundlychanged the landscape of reimbursement for oralchemotherapy. Before Part D, the only oral chemotherapiescovered by Medicare were a limited number oforal drugs with injectable counterparts covered underMedicare Part B, such as capecitabine. With Part D,cancer chemotherapy is now covered by 2 differentcomponents of Medicare: Part B for parenteral therapiesand Part D for oral chemotherapies. This dual systemcan be very confusing to both patients andphysicians.In Medicare Part D, oral drugs are providedthrough either a prescription drug plan offering drugonlycoverage or a Medicare Advantage PrescriptionDrug Plan (MA-PD), which offers both medicaland drug coverage. Most patients have opted for aprescription drug plan, since it does not require themto change their existing medical coverage.Both of these programs may use formulary andother management tools. The Centers for Medicareand Medicaid Services (CMS) review Part D plans’ formulariesto ensure that they do not discriminate againstbeneficiaries with certain health conditions. One stipulationwas the requirement that any Part D formularyinclude “substantially all members” of certaintherapeutic classes of drugs, including anti-neoplasticdrugs. The rationale for this policy was that a choiceof therapies was more important in cancer treatmentthan in other illnesses; therefore virtually all oral cancerchemotherapies are included on formularies.As originally set up, Part D has a $250 deductibleand a 25% co-pay for the next $2000 in oral drug costs.Unfortunately, Part D also has a gap in coverage,referred to as the “donut hole,” and the patient isresponsible for the next $2850 in drug costs. The particularlevels that establish the 25% co-pay and thedonut hole are indexed to inflation and adjusted onan annual basis. After the $2850 has been fully paid,the beneficiary is responsible for 5% of the remainingcosts. This cycle starts again at the beginning of everycalendar year.Hundreds of different private insurance companiesoffer Part D plans with different co-pay rates anddifferent deductibles. For example, some plans offer aversion of the standard benefit that features a reduceddeductible or flat co-payments instead of co-insurance.A 2006 analysis of Part D formularies found that bothprescription drug plans and local MA-PDs cover 75%of cancer drugs, whereas regional MA-PDs cover 85%.No plans applied step therapy restrictions to cancerdrugs. 3Although Medicare Part D does provide relieffrom catastrophic drug costs, the co-pays can still beburdensome, particularly given the high cost of oralchemotherapy. Medicare beneficiaries may qualify fora low income subsidy that reduces the cost-sharingburden, but this program is underused, perhaps becauseit adds one more form to an already complexprocess. Patients who cannot afford either the donuthole or co-pays may take their drugs intermittently ornot at all.These factors may affect the choice of oral versusparenteral chemotherapy. For example, patients startingchemotherapy toward the end of the year willpromptly experience the large “donut hole” expense,© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

Supplement S-11Oral Chemotherapyonly to be faced with the same expense during thenext year. Therefore, one could envision some patientschoosing to start parenteral therapy and transitionto oral therapy at the beginning of the next year.Co-pays and co-insurance, although familiar aspectsof medical care, are relatively new concepts forcancer chemotherapy. The idea of cost sharing is to exposethe patient to the cost of therapy so that he orshe can judge whether a treatment is worth the cost.Traditionally, patients with cancer have been shieldedfrom this type of decision-making, and pharmacy benefits,at least for large employers, have not yet requiredhigh co-pays or co-insurance for cancer care. However,smaller employers may be considering these strategiesas one way to make health insurance affordable fortheir employees.Additionally, consumer-directed health plans andhealth savings accounts are other strategies to offeraffordable insurance. Consumer-directed health planstypically combine a health plan with a high deductibleand a health reimbursement arrangement (HRA) orhealth savings account (HSA). HRAs and HSAs aretax-advantaged accounts used to pay health care expenses.Balances can be used for future health use, potentiallycreating the incentive for enrollees to controltheir medical expenses.High co-pays, co-insurance, or deductibles havean uncertain impact on chemotherapy use. Whetherpatients would choose to undergo additionalchemotherapy for metastatic disease if the drug offeredis associated with only an incremental benefit buta very high cost is unknown. This is a frequent situationin the use of biologic therapies to treat metastaticepithelial tumors.Studies in non-oncology settings suggest that outof-pocketexpenses will affect therapy decisions. Forexample, Schneeweiss et al. 15 studied adherence tostatin therapy after myocardial infarction during 3 differenttime periods: when the statins were fully covered,with a co-pay, and with co-insurance. Although initiatingtherapy was not affected by coverage, the authorsfound that adherence was greatest with full coveragepolicies and that sudden changes to full out-of-pocketspending, similar to Medicare’s Part D donut hole,almost doubled the risk of patients stopping. Similarstudies have not been done in the oncology setting,for either primary or adjuvant therapy. However, giventhe gravity of a cancer diagnosis, many oncologistsreport that patients are unlikely to interrupt primarytherapy if at all possible, and seek other funding, suchas second mortgages on their homes.Avoiding co-pays can affect prescribing practicesin other ways. For example, sunitinib comes in 3strengths, 12.5, 25, and 50 mg tablets. The startingdose is typically 50 mg, and dose reductions are notunusual. Therefore, physicians may prescribe the12.5 mg tablets so that if dose adjustments are required,patients can avoid a separate prescription with a newco-pay. In this scenario, the patient must take 4 tabletsinstead of one to reach the starting dose of 50 mg.This type of maneuvering adds to the complexity oforal chemotherapy.The array of Part D plans is confusing to patientsand physicians alike, and physicians typically do notknow what type of coverage patients have when planningtreatment. Thus, they cannot anticipate theeconomic consequences. The assumption that mostpatients over age 65 have some sort of Medicare coverageis tempting, but many patients in that age rangeare covered by commercial plans based on prior employment.Conversely, patients under age 65 may haveMedicare coverage based on other disabilities.No easy mechanism is currently in place in thephysician’s office to determine what type of coveragea patient has for oral chemotherapy. Making this determinationcan be time consuming, and further costis added to the health care system when staff mustmake sure that the correct payment and co-paymenthave been received.The Medicare donut hole also affects the revenuestreams at hospital pharmacies. At the beginning of theyear, hospitals may accumulate bad debt as patientsare working their way through the donut hole. In contrast,revenue is more secure in subsequent months asMedicare Part D assumes coverage for most of thecosts. To compensate for this shortfall, hospital pharmaciesmust increase their charges in subsequent years,thus creating a vicious cycle. Some hospitals haveadopted the policy of continuing treatment forpatients even if insurance coverage runs out. In thissituation, the hospital could end up buying oralchemotherapy for some patients.Trends in Financing and Managing OralChemotherapyFormulary Management: The high cost of many neworal chemotherapies has set the stage for new managementcost control strategies. Payers have limited waysof monitoring parenteral therapy; frequently the© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-12 SupplementNCCN Task Force Reporttherapy has already been administered when the payorreceives an initial claim. However, oral therapy can bemore tightly monitored and controlled throughpharmacy benefits because the patient will present aprescription to a community or cancer center pharmacyor have the drug provided by specialty pharmaciescontracted for by insurance companies.One common strategy for pharmacy benefit managementis the tiered drug formulary. Whether thisstrategy could be applied to oral chemotherapies isunclear, however, at least for the foreseeable future. Forexample, states have variable regulations regardingwhat drugs must be included in a formulary. Oncologydrugs often must be included despite minimal data inthe published literature, making it difficult to excludeeven a few drugs.Furthermore, formulary management is based onthe preferential selection of one member from a classof drugs. Currently, no oral chemotherapy drug classesincluding multiple agents, making it impossible toapply formulary management. Additionally, head-toheadtrials investigating the equivalence or potentialsuperiority of 2 related drugs have not been done andare unlikely, because manufacturers have no financialincentive to do such studies. Sunitinib and sorafenibor cetuximab and panitumumab are examples of relatedagents; however, the differences among the multipletargets of these agents prevent them from being consideredbioequivalent. The class of multikinase inhibitorsthat includes imatinib, nilotinib, sunitinib,dasatinib, sorafenib, and lapatinib is an example ofa pharmacologic class that might lend itself to formularymanagement. In addition, gaps in the clinical datalimit the ability to create a formulary system, be it simpleor tiered.Finally, the business premise of formularies is thatthe manufacturer will provide a pricing discount if theirdrug is favorably listed on the formulary. This may notapply to biologic therapies, however, because negotiatingdiscounts are only possible when a different manufacturermakes 2 similar compounds for the sameindication. Dasatinib and nilotinib are both tyrosinekinase inhibitors used to treat CML, and they are madeby different manufacturers. However, a manufacturerwill only be receptive to providing a discount if thepayor can prove that usage of the drug will increase ifit is preferentially placed on the formulary. This can bemore difficult to prove for oral chemotherapy than fordrugs in non-cancer therapeutic classes. In summary,the lack of a cogent argument for a managed care companyto favor a particular agent or agents impairs theavailability of market forces (e.g. discounts) to limitthe costs of these compounds via the implementationof formularies for oral chemotherapy.Preference for generic drugs is another basic formularymanagement strategy, but creating generic versionsof bioengineered therapies will be very difficult.For example, for a pharmaceutical drug, generic manufacturersneed only demonstrate that the generic hasthe same chemical formula and bioavailability. Thiscannot be done with bioengineered drugs, however,and regulators are considering whether generic versionsof bioengineered therapies must reach the samestandards of research and testing as their predecessor.16 The issue of FDA regulation of generic versionsor “biosimilars” of bioengineered drugs has been ahotly debated issue for years.Value-Based Co-Insurance: Value based co-insuranceis essentially a form of health care rationing controlledby the patient in which incentives are put intoplace to promote the use of high-value interventions.17,18 This concept is similar to current pharmacyformularies, but applied on a broader scale to the comparativeeffectiveness of procedures, diagnostic services,and medical devices. In the context of oralchemotherapy, a drug that has been shown to have avery minimal incremental benefit on progression-freesurvival would have a high rate of co-insurance.In contrast, a drug such as imatinib, which may beconsidered curative or at least associated with a longprogression-free survival, would have minimalco-insurance.Objections to value-based plans include the inequityof a tiered benefit. However, other experts pointout the inequity of the current situation of millions ofuninsured Americans who lack access to essentialhealth benefits. The values applied to differentchemotherapy scenarios will obviously be controversialand will require additional data on clinical andcomparative effectiveness.Annual and Life Time Maximums for Cancer Care:Annual and lifetime maximum covered amounts areanother strategy used by employers, particularly smallerones, to limit their financial exposure with beneficiarieswith serious or life-threatening illnesses. However,this type of coverage often creates an underinsuredpopulation of patients, especially in cancer care.Although coverage amounts may seem adequate to© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

Supplement S-13Oral Chemotherapyaverage consumers, patient undergoing extensive treatmentsmay find the inadequacy of these coverage maximumsreadily and tragically apparent.ConclusionsOral chemotherapy is emerging as an alternative forappropriately selected patients who, with support fromTable 2 Advantages and Disadvantages of Oral Compared With Parenteral ChemotherapiesSafety/AdherencePatient Physician/Health Care Team Health Care SystemOralParenteralConvenienceOralParenteralPatients assume greater responsibilityand controlAdherence based on controlledadministration in clinic or officeConvenience gain only if oralchemotherapy is NOT given withparenteral therapyOften has shorter duration oftherapy than oralDifficult for clinicians to monitoradherence and toxicityLack of safety checks may lead tomedication errorsTight control of adherence; robustsystem of checks and balances toreduce medication errorsBusy cancer centers may havehazards related to high-volume,high-intensity settingPoor adherence or overadherence canlead to acute inpatient admissions anddiminished effectivenessConvenience of oral therapy is over simplified for some regimens; patientappropriateness must be carefully consideredDrug Supply and DistributionOral Can receive from hospital pharmacy,mail order, or specialtypharmacySpecialty pharmacy may berequiredOral drugs can be tightly controlledthrough pharmacy benefitMay be cost savings with 90 day supplyDrug waste may be an issueParenteral Requires office visit Direct control by oncologist Payors have limited ability to directlymanage parenteral therapyCommunication IssuesOral Requires new patient education Expanding role for mid-levelproviders in patient educationParenteral Infusion sessions allow for prolonged contact of the patient with thehealth care team.Oncology InfrastructurePatient education time notcompensatedOralParenteralPotentially fewer office visits;follow up may occur at specialtymonitoring clinicsOffice set up specifically forparenteral therapyAdequate space for patientcounseling not always availableInfusion centers must bemaintained; most patients receiveparenteral therapy at some pointImproved information systems andintegrated electronic medical recordmay improve safetyFinancingOralParenteralMay face significant cost sharing,including Medicare Part D “donuthole”May have better coveragecompared with oralNo revenue for dispensing/administering oral therapyApproximately 80% of communityoncologists’ revenue is fromdispensing/administeringparenteral chemotherapyBoth oral and parenteral biologic ortargeted therapies are consideredcostly; consideration of new benefitdesigns may be needed© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-14 SupplementNCCN Task Force Reporttheir clinicians, can adequately manage the challenges.Some patients may respond to an increased sense ofcontrol associated with the self-management of someof their care, others may prefer to avoid the multipleoffice visits and intravenous infusions required inparenteral chemotherapy. Additionally, some oralchemotherapies may be associated with fewer sideeffects than parenteral alternatives. However, thepromise of oral chemotherapies will only be realizedwith careful attention to the safety and monitoringrequirements.The growing number of oral chemotherapies,either currently marketed or in the developmentpipeline, will significantly impact all aspects of oncologycare. From the oncologist’s perspective, oralchemotherapies may have a major impact on officepractice, reducing the traditional revenues derivedfrom the administration of parenteral therapy andrequiring heightened attention to the selection ofpatients who are appropriate candidates for oralchemotherapy, with subsequent monitoring and supportfor adherence. The patient–physician relationshipmay be altered, with fewer oncology office visits andan increased need to coordinate cancer care with otherentities, such as specialty pharmacies or clinics.For older patients, the advent of Medicare Part Densures that they will not be subject to catastrophicmedical costs related to oral chemotherapy, but significantgaps in drug reimbursement still exist. Inaddition, in response to the growing cost of pharmaceuticals,employers are contemplating other benefitdesigns, such as lifetime caps on cancer care coverage,higher deductibles, co-pays, or co-insurance.Oral chemotherapy has been conceptualized as aconvenient, less toxic form of therapy that will bedriven by patient preference. However, many of thesafety issues related to oral chemotherapy are underappreciated,and many patients will not be appropriatecandidates. Safety issues include the lack of checksand balances to avoid medication errors, possible lackof patient adherence, and a shift in the responsibilityfor managing a potentially complicated oral regimento the patient. The risks and benefits of oralchemotherapy from the patient, physician and healthcare system perspective shown in Table 2. Cliniciansshould note that many of the disadvantages listed arenot inherent to oral chemotherapy, but reflect the factthat adequate safety and support systems have notevolved as quickly as oral chemotherapy agents.References1. Curtiss FR. Pharmacy benefit spending on oral chemotherapy drugs.J Managed Care Pharm 2006;12:57–77.2. Schellens JHM. Challenges of oral chemotherapy. Clin Adv HematolOncol 2005;3:99–100.3. Bowman J, Rousseau A, Silk D, Harrison D. Access to cancer drugsin Medicare Part D. Formulary placement and beneficiary cost sharingin 2006. Health Aff 2006;25:1240.4. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oralversus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110–115.5. Taylor JA, Winter L, Geyer LJ, Hawkins DS. Oral outpatientchemotherapy medication errors in children with acute lymphoblasticleukemia. Cancer 2006;107:1400–1406.6. Viele CS. Managing oral chemotherapy: The health practitioner’srole. Am J Health Syst Pharm 2007;64(Suppl 5):S25–32.7. Partridge AH, Avorn J, Wong PS, Winer EP. Adherence to therapywith oral antineoplastic agents. J Natl Cancer Inst 2002;94:652–661.8. Benner JS, Glynn RJ, Mogun H, et al. Long-term persistence in useof statin therapy in elderly patients. JAMA 2002;288:455–461.9. Tsang J, Rudychev I, Pescatore SL. Prescription compliance andpersistency in chronic myelogenous leukemia and gastrointestinalstromal tumor patients on imatinib [abstract]. J Clin Oncol2006;24(Suppl 1):330s. Abstract 6119.10. Osterberg L, Blaschke T. Adherence to medication. N Eng J Med2005;353:487–497.11. Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safetypractices at US cancer centres: questionnaire survey. BMJ 2007;334:407.12. Basch B, Artz D, Dulko D, et al. Patient online self-reporting oftoxicity symptoms during chemotherapy. J Clin Oncol 2005;23:3552–3561.13. Basch E, Iasonos A, Barz A, et al. Long-term toxicity monitoring viaelectronic patient-reported outcomes in patients receiving chemotherapy.J Clin Oncol 2007;25:5374–5380.14. Jacobson M, O’Malley AJ, Earle CC, et al. Does reimbursement influencechemotherapy treatment for cancer patients? Health Aff(Millwood) 2006;25:437–443.15. Schneeweiss S, Patrick AR, Maclure M, et al. Adherence to statintherapy under drug cost sharing in patients with and without acutemyocardial infarction: a population-based natural experiment.Circulation 2007;115:2128–2135.16. Mannheim BS, Granahan P, Dow KJ. Follow-on biologics: ensuringcontinued innovation in the biotechnology industry. Health Affairs2006;25:394–404.17. Fendrick AM, Chernew ME. Value-based insurance design; a “clinicallysensitive” approach to preserve quality and contain costs. AmJ Manag Care 2006;12:18–20.18. Denny CC, Emmanuel EJ, Pearson SD. Why well-insured patientsshould demand value-based insurance benefits. JAMA 2007;297:2515–2518.© Journal of the National Comprehensive Cancer Network Volume 6 Supplement 3 March 2008

S-15Post-testPlease circle the correct answer on the enclosed answer sheet.1. Which of the following drugs is/are available in an oralformulation?a. Imatinibb. Laptinibc. Capecitabined. Lenalidomidee. All of the above2. Which of the following is/are considered drivers of oralchemotherapy?a. New oral biologic therapies are primarily cytostaticin nature and require daily therapy.b. Molecular monitoring of disease has prolongedduration of treatment, favoring oral therapy.c. The perception exists that patients clearly preferoral therapy.d. Biologic agents have predictable absorption.e. Only a and c abovef. Only a, b, and c above3. Which of the following is/are TRUE about patientpreference for oral therapy?a. Although oral monotherapy may avoid the inconvenienceof an office visit, many combinationtherapies include parenteral therapy, andtherefore require an office visit anyway.b. Most oral chemotherapy regimens are simple forthe patient to manage.c. Oral chemotherapy will shift some aspects of managingchemotherapy to the patient; not all patientsrespond positively to this empowerment.d. Only a and c abovee. a, b, and c above4. Which of the following is/are common misperceptionsabout oral chemotherapy?a. Oral chemotherapy has fewer side effects thanparenteral chemotherapy.b. Oral chemotherapy is particularly appropriate forfrail elderly patients.c. Monitoring the side effects of oral chemotherapyis easier than monitoring the side effects of parenteraltherapy.d. Only a and b abovee. a, b, and c above5. Which of the following is/are TRUE about adherenceto oral chemotherapy?a. Adherence is an important factor that can NOTbe easily assessed with a questionnaire.b. Adherence to oral chemotherapy in general isvery good, as is illustrated by the excellent longtermadherence to imatinib therapy.c. Payor information systems that can capturewhether or not the prescription is filled are in placeand provide additional evidence of assurance.d. All of the abovee. None of the above6. Which of the following is/are accepted as reliable techniquesfor monitoring adherence?a. Directly ask the patientb. No completely reliable method of monitoring adherenceis currently available.c. Patient diaries, pill countsd. Rates of prescription refillse. Only a and c above7. Which of the following is/are TRUE about the stepsthat have been taken to ensure the safety of oralchemotherapy?a. The same level of checks and balances that areused for parenteral chemotherapy have been developedfor oral chemotherapy, thus reducing therisk of medication errors.b. Standard order forms have been developed fororal chemotherapy.c. Oral chemotherapy prescriptions are routinelyreviewed by 3 or 4 licensed health care staff.d. All of the abovee. None of the above8. What are the key communications issues regarding oralchemotherapy?a. Making every effort to obtain an accurate medicationhistory from the patient, electronic medicalrecord, payer information systems, or pharmacyrecordsb. Ensuring adequate time to counsel patientsc. Widespread use of online reporting systems fortoxicitiesd. Only a and b abovee. None of the above9. Which of the following is/are FALSE about the impactof oral chemotherapy on oncology practice?a. The transition to oral chemotherapy will resultin an overcapacity of infusion centers.b. The oncologist’s revenue and office structure isgeared around the delivery of parenteral therapyand thus may decline.c. Financial incentives favoring parenteral therapyfor both patients and physicians may influencetreatment decisions.d. All of the above are false.e. None of the above are false.10. What are the potential advantages of specialty pharmacies?a. The specialty pharmacist interacts directly withthe patient, providing additional education andcounseling.

S-16b. Specialty pharmacies are more flexible in thenumber and dosages of pills provided with a singleprescription.c. Dedicated hot lines allow the specialty pharmaciststo easily communicate with the prescribingphysician.d. Only a and b abovee. None of the above11. What are the implications of the “donut hole” inMedicare Part D coverage?a. The high cost of many oral chemotherapies ensuresthat many patients will experience a “donuthole” in Medicare coverage.b. Patient assistant programs adequately address the“donut hole” for many patients.c. When possible, patients may opt for parenteraltherapy to avoid the “donut hole.”d. Only a and c abovee. All of the above12. Which of the following statement(s) about formularymanagement strategies for oral chemotherapy is/areTRUE?a. State mandates have facilitated formularies fororal chemotherapy.b. Several chemotherapy drug classes have multipleagents, thus limiting formulary management.c. Head to head trials of oral chemotherapies canserve as the basis of formulary management.d. Only a and c abovee. None of the abovePost-Test Answer SheetPlease circle one answer per question. A score of at least 70% on the post-test is required.1. a b c d e7. a b c d e2. a b c d e f 8. a b c d e3. a b c d e9. a b c d e4. a b c d e10. a b c d e5. a b c d e11. a b c d e6. a b c d e12. a b c d ePlease evaluate the achievement of the learning objectivesusing a scale of 1 to 5.(1 = Not met; 3 = Partially met; 5 = Completely met)Outline how oral chemotherapy is financed and how payment issuesfor oral chemotherapy may differ from those of parenteralchemotherapy1 2 3 4 5Recognize the common misperceptions about oral chemotherapyand discuss these with patients1 2 3 4 5Utilize patient selection criteria for oral chemotherapy regimens1 2 3 4 5Summarize the impact that widespread use of oral chemotherapiesmay have on oncology practice1 2 3 4 5Please indicate the extent to which you agree or disagreewith the following statements:(1 = Strongly disagree; 3 = Not sure; 5 = Strongly agree)The material was presented in a fair and balanced manner.1 2 3 4 5The information presented in this monograph was pertinent to myeducational needs.1 2 3 4 5The information presented was scientifically rigorous andup-to-date.1 2 3 4 5The information presented in this monograph has motivated meto modify my practice.1 2 3 4 5I would recommend this monograph to my colleagues.1 2 3 4 5

NCCN Task Force Report:Oral ChemotherapyRelease Date: March 31, 2008Expiration Date: March 31, 2009Registration for CreditTo receive credit, please complete this page, the post-test, andthe evaluation, and mail to the following address:Continuing Education DepartmentNCCN275 Commerce Drive, Ste. 300Fort Washington, PA 19034There is no fee for participating in this activity.Comments and suggestions:___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Please print clearly.Name_____________________________________________ Degree ______________________________________Title/Position____________________________________________________________________________________Affiliation (University or Hospital)___________________________________________________________________Business Address_________________________________________________________________________________City______________________________________________ State_________ Zip ____________________________Business Telephone__________________________________ Business Fax ___________________________________E-mail Address__________________________________________________________________________________I am claiming _________ credits (maximum 1)I certify that I have participated in this activity as designed.Signature__________________________________________ Date________________________________________TO RECEIVE CREDIT, YOU MUST SUBMIT THIS FORM BY MARCH 31, 2009.

NCCN Task Force Report:Oral ChemotherapyRelease Date: March 31, 2008Expiration Date: March 31, 2009Registration for CreditTo receive credit, please complete this page, the post-test, andthe evaluation, and mail to the following address:Continuing Education DepartmentNCCN275 Commerce Drive, Ste. 300Fort Washington, PA 19034There is no fee for participating in this activity.Comments and suggestions:___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Please print clearly.Name_____________________________________________ Degree ______________________________________Title/Position____________________________________________________________________________________Affiliation (University or Hospital)___________________________________________________________________Business Address_________________________________________________________________________________City______________________________________________ State_________ Zip ____________________________Business Telephone__________________________________ Business Fax ___________________________________E-mail Address__________________________________________________________________________________I am claiming _________ credits (maximum 1)I certify that I have participated in this activity as designed.Signature__________________________________________ Date________________________________________TO RECEIVE CREDIT, YOU MUST SUBMIT THIS FORM BY MARCH 31, 2009.