Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Scott Ramsey and Veena Shankaran J Natl Compr Canc Netw 2012;10:1037-1042 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Print ISSN: 1540-1405. Online ISSN: 1540-1413. JNCCN – The Journal of the National Comprehensive Cancer Network is published by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724 Online article Subscriptions Permissions NCCN.org http://www.jnccn.org/content/10/8/1037.full Information about subscribing to JNCCN – The Journal of the National Comprehensive Cancer Network is online at http://www.jnccn.org/site/subscriptions/ For information about photocopying, republishing, reprinting, or adapting material, please go online to http://www.NCCN.org/permissions Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Managing the Financial Impact of Cancer Treatment: The Role of Clinical Practice Guidelines 1037 Journal of the National Comprehensive Cancer Network The Last Word Managing the Financial Impact of Cancer Treatment: The Role of Clinical Practice Guidelines The rising cost of cancer treatment in the United States poses a significant challenge to health systems, government and private insurers, and individual patients. To some degree, cancer treatment costs are rising due to inappropriate, non–evidence-based use of expensive new technologies and drugs. However, adherence to evidence-based clinical practice guidelines does not necessarily guarantee that cancer treatment will be less costly or optimally cost-effective. Although clinical practice guidelines may endorse many acceptable evidence-based treatment options, the financial implications of different treatment decisions within these guidelines can vary significantly. In the case of first-line treatment for metastatic colorectal cancer (CRC) and gastric cancer, for example, the cost of 6 months’ treatment varies widely while the clinical effectiveness of these regimens is comparable. Patients’ out-of-pocket payments for various treatment regimens may also vary significantly. In the setting of rapidly rising cancer treatment costs, it is essential that clinical practice guidelines begin to incorporate economic information from the patient and health system perspectives to minimize the financial impact of cancer care on patients and society. The Influence of Clinical Practice Guidelines Clinical practice guidelines play a vital role in providing oncologists and patients with evidence-based cancer treatment algorithms. Clinical practice guidelines also broadly influence what patients, health delivery systems, and health insurers pay for cancer care. The economic impact of treatment decision-making on these stakeholders has been of great interest recently. Patients are increasingly faced with high copayments and other treatment-related expenses, which may not only cause significant anxiety but also may limit their ability to pay for basic necessities such as food and housing.1 In a recent population-based survey of patients with CRC receiving adjuvant chemotherapy, 38% experienced severe financial hardship (defined as accruing debt, borrowing money from friends or family, selling/refinancing their primary home, or ≥ 20% decline in income).2 From a societal standpoint, cancer treatment costs in the United States are projected to increase by as much as 39% by 2020.3 Although efforts to discourage the use of non– evidence-based procedures, tests, and treatments may help curb these rising costs to some degree, the high variability in the costs of evidence-based treatments remains an economic challenge for patients and other key stakeholders.4–6 Reducing the financial burden of cancer treatment while maintaining high-quality care will require a coordinated national strategy. In this commentary, we argue that oncology clinical practice guidelines have a key role in this national effort. Scott Ramsey, MD, PhD Scott Ramsey, MD, PhD, is a full member in the Cancer Prevention Program at Fred Hutchinson Cancer Research Center, where he directs the Research and Economic Assessment in Cancer and Healthcare (REACH) group, a multidisciplinary team devoted to clinical and economic evaluations of new and existing cancer prevention, screening, and treatment technologies. He is also a Professor in the School of Medicine, School of Pharmacy, at the University of Washington. Trained in medicine and economics, his primary research interest is in studying the economic aspects of new medical technologies. Dr. Ramsey is a leader in the field of comparative effectiveness research, past President of the International Society of Pharmacoeconomics and Outcomes Research, and has served on the Institute of Medicine’s National Cancer Policy Forum. Current Role of Clinical Practice Guidelines Clinical practice guidelines are intended primarily to summarize scientific evidence, formulate best practice recommendations, and reduce variations in care. Practice guidelines in oncology reflect the opinion of expert clinicians regarding single or multiple evidence-based approaches to treating an individual with cancer. Selecting among the range of acceptable treatment options depends on clinical assessment of characteristics, such as performance status, medical comorbidity, and prior treatment. The ideas and viewpoints expressed in this editorial are those of the author and do not necessarily represent any policy, position, or program of NCCN. © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012 Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Scott Ramsey, MD, PhD, and Veena Shankaran, MD 1038 The Last Word Ramsey and Shankaran Choosing Between Multiple Guideline-Supported Treatment Options Veena Shankaran, MD Veena Shankaran, MD, is an Assistant Professor of Medical Oncology at The University of Washington. Her clinical focus is in gastrointestinal cancers. She is also an Assistant Member in the Clinical Research Division at Fred Hutchinson Cancer Research Center and recently completed a Masters degree in the Pharmaceutical Outcomes, Research, and Policy Program at the University of Washington School of Pharmacy. Her research focuses on the impact of cancer treatment costs on individual patients and decision-making about high-cost oncology drugs in advanced cancers. In addition to clinical factors such as performance status and medical comorbidity, other patient characteristics may influence selection of a particular treatment regimen from a range of acceptable options. Characteristics such as distance to infusion center and convenience (eg, pills vs. infusion) may also influence decisions. These factors are not routinely addressed in clinical practice guidelines, but patients and physicians can usually sort out how these issues might factor into the treatment plan. However, the potential financial impact of treatment choices on patients, health systems, and health insurers can be difficult to predict. Patients and physicians often have very little advance knowledge about copayments for chemotherapeutics or supportive medications. Further, many oncologists in the United States do not know the differential total costs associated with one chemotherapy regimen versus another.8 Clinical guidelines list a number of “acceptable” treatment options, but rarely address the financial variability of those options. Given the rising cost of cancer care, we believe that physicians and patients need to understand the financial implications of their treatment decisions. The next question, however, is whether guidelines can—and should—report expected financial outcomes for regimens considered to be therapeutically acceptable based on clinical evidence. Examples: Variability in CRC and Gastric Cancer Treatment Recommendations Clinical practice guidelines that support several evidence-based treatment options without reference to cost may result in very different financial outcomes for insurers, health systems, and patients. We present 2 examples of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for first-line therapy in metastatic cancer to illustrate this issue. Metastatic CRC Several first-line treatment options exist for patients with good performance status who can tolerate intensive therapy. Some of these options depend on KRAS mutational status, which has been shown to predict responsiveness to the anti–epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab.9,10 Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has also been shown to improve survival in the first-line treatment setting.11 Many of the first-line CRC regimens endorsed in the NCCN Guidelines are outlined in Table 1.12 Although median survival is relatively comparable between regimens (range, 21.3– 28.0 months), Medicare reimbursement rates vary significantly from one regimen to the next (range, $2200–$10,000 per treatment cycle). Patients with metastatic CRC may receive multiple regimens over time (Table 1), potentially minimizing cost savings seen with the first regimen; however, the treatment duration may also be © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012 Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Most oncology guidelines do not explicitly incorporate nonclinical factors, such as treatment cost, expected patient out-of-pocket financial burden, or cost-effectiveness, into the guideline development process. Public and private health insurers commonly use guidelines and compendia to support reimbursement decisions. The NCCN Drugs & Biologics Compendium, for example, is recognized by the Centers for Medicare and Medicaid Services (CMS) and UnitedHealthcare as a standard reference for oncology coverage policy.7 1039 The Last Word Financial Impact of Clinical Practice Guidelines Table 1 First-Line Combination Regimens in the NCCN Guidelines for Metastatic Colorectal Cancer Medicare Reimbursement Regimen and Dosing Schedule Median OS 1 Cyclea 6 moa mFOLFOX6 + bevacizumab13,14 Every 14 days: Oxaliplatin, 85 mg/m2 IV, day 1 Leucovorin, 400 mg/m2 IV, day 1 5-FU, 400 mg/m2 IV bolus, day 1 5-FU, 1200 mg/m2/day CIV, days 1 and 2 Bevacizumab, 5 mg/kg, day 1 21.3 mo $5005.42 $60,065.04 CapeOx + bevacizumab15–17 Every 21 days: Oxaliplatin, 130 mg/m2 IV, day 1 Capecitabine, 850–1000 mg/m2 PO bid, days 1–14 Bevacizumab, 7.5 mg/kg, day 1 21.3 mo $10,077.15 $80,617.16 FOLFIRI + bevacizumab17,18 Every 14 days: Irinotecan, 180 mg/m2 IV, day 1 Leucovorin, 400 mg/m2 IV, day 1 5-FU, 400 mg/m2 IV bolus, day 1 5-FU, 1200 mg/m2/day CIV, days 1 and 2 Bevacizumab, 5 mg/kg IV, day 1 28.0 mo $2247.60 $26,971.08 mFOLFOX6 + panitumumab10,b,c Every 14 days: Oxaliplatin, 85 mg/m2 IV, day 1 Leucovorin, 400 mg/m2 IV, day 1 5-FU, 400 mg/m2 IV bolus, day 1 5-FU, 1200 mg/m2/day CIV, days 1 and 2 Panitumumab, 6 mg/kg, day 1 23.9 mo $6534.97 $78,419.6 FOLFIRI + cetuximab9,19,b Every 14 days (cetuximab either every 7 or 14 days): Irinotecan, 180 mg/m2 IV, day 1 Leucovorin, 400 mg/m2 IV, day 1 5-FU, 400 mg/m2 IV bolus, day 1 5-FU, 1200 mg/m2/day CIV, days 1 and 2 Cetuximab, 400 mg/m2 IV first infusion, then 250 mg/m2 IV weekly OR Cetuximab 500 mg/m2 IV, day 1 every 2 weeks 23.5 mo $4399.62 $52,795.44 FOLFIRI + panitumumabb Every 14 days: Irinotecan, 180 mg/m2 IV, day 1 Leucovorin, 400 mg/m2 IV, day 1 5-FU, 400 mg/m2 IV bolus, day 1 5-FU, 1200 mg/m2/day CIV, days 1 and 2 Panitumumab, 6 mg/kg, day 1 NA $3777.11 $45,325.37 FOLFOXIRI20 Every 14 days: Irinotecan, 165 mg/m2 IV, day 1 Oxaliplatin, 85 mg/m2 IV, day 1 Leucovorin, 400 mg/m2 IV, day 1 5-FU, 1600 mg/m2/day CIV, days 1 and 2 22.6 mo $2910.77 $34,929.20 Abbreviations: BSA, body surface area; CIV, continuous intravenous infusion; IV, intravenous; OS, overall survival; PO, orally. a Medicare reimbursement rate based on 2012 average sale price; dosing calculations based on weight 70 kg and BSA 1.7 m2 b For patients with KRAS wild-type only. c In the cited clinical trials, panitumumab was combined with FOLFOX4; however, NCCN Guidelines list mFOLFOX6 + panitumumab as a first-line treatment option. longest with the first regimen. Thus, the financial impact of this initial decision is significant. Metastatic Gastric Cancer For patients with metastatic gastric cancer, several firstline treatment options supported by the NCCN Guidelines are available, ranging from single drugs to 3-drug combinations. For patients with excellent performance status, the NCCN Guidelines endorse multiple 3-drug combinations. In a first-line gastric cancer clinical trial that used a 2 x 2 factorial design to compare 4 different triple-drug regimens, all regimens were associated with comparable response and median survival rates, but toxicity profiles varied. As in the previous example for © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012 Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Initial Regimen and Study 1040 The Last Word Ramsey and Shankaran Table 2 Triple-Drug First-Line Systemic Chemotherapy Options for Metastatic Gastric Cancer in the NCCN Guidelines Regimen and Dosing Schedulea Median OS, (m) DCF21 Every 28 days: Docetaxel, 75 mg/m2 IV, day 1 Cisplatin, 75 mg/m2 IV, day 1 5-FU, 1000 mg/m2/day CIV, days 1–5 ECF22 Medicare Reimbursement 1 Cycleb 6 mob 9.2 $1534.43 $9206.56 Every 21 days: Epirubicin, 50 mg/m2 IV, day 1 Cisplatin, 60 mg/m2 IV, day 1 5-FU, 200 mg/m2/day CIV, days 1–21 9.9 $104.98 $839.84 ECX22 Every 21 days: Epirubicin, 50 mg/m2 IV, day 1 Cisplatin, 60 mg/m2 IV, day 1 Capecitabine, 625 mg/m2 PO bid, days 1–21 9.9 $2269.06 $18,152.51 EOF22 Every 21 days: Epirubicin, 50 mg/m2 IV, day 1 Oxaliplatin, 130 mg/m2 IV, day 1 5-FU, 200 mg/m2 CIV, days 1–21 9.3 $4420.67 $35,365.32 EOX22 Every 21 days: Epirubicin, 50 mg/m2 IV, day 1 Oxaliplatin, 130 mg/m2 IV, day 1 Capecitabine, 625 mg/m2 PO bid, days 1–21 11.2 $7184.75 $57,478.03 Abbreviations: BSA, body surface area; CIV, continuous intravenous infusion; IV, intravenous; OS, overall survival; PO, orally. Dosing calculations based on weight of 70 kg and BSA of 1.7 m2. b Medicare reimbursement rate based on 2012 average sale price; dosing calculations based on weight of 70 kg and BSA of 1.7m2. a metastatic CRC, the cost associated with one treatment cycle varies widely among regimens (range $100–$7000; Table 2). Because many patients with gastric cancer do not reach second- or third-line therapy, choice of first-line treatment can have a dramatic impact on overall costs associated with treatment. Out-of-Pocket Expenses Importantly, the out-of-pocket expenses associated with particular chemotherapy regimens can vary widely depending on the patient’s insurance plan and state of residence. A Medicare patient without a supplemental insurance plan, for example, may be responsible for 20% of the costs of all chemotherapeutics (infusional and capecitabine), whereas a patient with a supplemental plan may have complete coverage for these drugs. Although capecitabine is covered under Medicare Part B, many other oral chemotherapeutics used in other diseases (eg, sunitinib and erlotinib) are covered under Medicare Part D, which means that patients receiving these drugs often reach the $4700 out-of-pocket “donut hole” in coverage very early on in their treatment course. Except in certain states that have legislation requiring that oral chemotherapeutics be covered as a medical benefit rather than an outpatient prescription, many patients with commercial insurance might experience very high copayments for oral chemotherapeutics, including capecitabine. Under some insurance plans with tiered formularies, these copayments may be as high as 50% of the total monthly cost for the drug. The variability in patient prescription plans and drug coverage policies for oral chemotherapeutics can profoundly impact a patient’s treatment-related financial experience. Further, the out-of-pocket expenses associated with a new regimen are difficult to predict, making preemptive conversations about anticipated costs difficult. Ignoring Nonclinical Issues Reduces the Potential Impact of Practice Guidelines The costs of chemotherapy regimens commonly used in metastatic CRC and gastric cancer vary greatly. Practice guidelines that give equal weight to these regimens create a situation in which accepted variations may produce vastly different economic outcomes for patients and society while producing potentially equivalent clinical outcomes. In particular, high out-of-pocket expenses associated with oral chemotherapeutics can result in nonadherence and, in turn, poorer response © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012 Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Initial Regimen and Study The Last Word 1041 Financial Impact of Clinical Practice Guidelines A Way Forward: Acknowledging Economic Issues in Practice Guidelines We believe it is crucial that the oncology community take the lead in encouraging cost-effective prescribing practices and developing supplementary information that allows clinicians and patients to understand the personal financial consequences of specific therapeutic options. Below, we describe 4 items that could be incorporated into clinical practice guidelines today to move toward this goal: • Identify a minimal clinical difference among therapeutic choices and group therapies that are equivalent within that range. • Identify the lowest cost option to patients within a group of acceptable alternatives, based on minimal clinical differences. • Provide information to oncologists and patients on the expected total costs and personal financial costs of recommended regimens. • Develop practice guidelines language that allows health insurers to promote care that minimizes financial burden to patients and health systems. We acknowledge that these recommendations create additional burdens for organizations that produce clinical practice guidelines. Obtaining information on expected patient out-of-pocket and total costs requires surveying health insurers and tracking current drug prices. These tasks are not impossible, however. With the possible exception of drugs included in Part D, Medicare coverage policies are fairly uniform nationally, making it a relatively straightforward task to estimate patient copayments and deductibles for common regimens. Medicare’s Web site also provides some information to help patients understand their potential outof-pocket expenses (www.medicare.gov). Coverage policies among commercial insurance plans contain more variability, but regular surveys of the most common oncology drug policies in the largest plans could provide valuable data. In addition, many drug manufacturers now produce budget impact analyses of their products and share these with insurance plans that request them. Guidelines groups could similarly request these analyses to inform the guideline development process. Conclusions Any treatment decision in oncology, even those based on strong clinical evidence, can have major financial impacts on patients, insurers, and society. Particularly in situations where many evidence-based treatment options exist, clinicians have tremendous influence over the cost of cancer treatment. Moving forward, incorporation of cost information into guidelines development will help increase awareness of the economic implications of routine clinical decision-making and reduce the financial burden of cancer treatment on patients and society. References 1. Kaiser Family Foundation. Employer Health Benefits 2008 Annual Survey. Available at http://ehbs.kff.org/pdf/7790.pdf. 2. Shankaran V, Jolly S, Blough D, Ramsey SD. Risk factors for financial hardship in patients receiving adjuvant chemotherapy for colon cancer: a population-based exploratory analysis. J Clin Oncol 2012;30:1608–1614. 3. Yabroff KR, Lund J, Kepka D, Mariotto A. Economic burden of cancer in the United States: estimates, projections, and future research. Cancer Epidemiol Biomarkers Prev 2011;20:2006–2014. 4. Brody H. Medicine’s ethical responsibility for health care reform— the Top Five list. N Engl J Med 2010;362:283–285. 5. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical Oncology identifies five key oppotunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol 2012;30:1715–1724. 6. Burstein HJ. If all treatments cost the same, why not choose the least expensve option? JNCCN 2012;10:425–426. 7. National Comprehensive Cancer Network. National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN Compendium). Available at: http://www.nccn.org/ professionals/drug_compendium/content/contents.asp. 8. Meropol NJ, Schrag D, Smith TJ, et al. American Society of Clinical Oncology guidance statement: the cost of cancer care. J Clin Oncol 2009;27:3868–874. 9. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29:2011–2019. 10. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as firstline treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697– 4705. 11. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342. 12. Centers for Medicare & Medicaid Services. 2012 ASP Drug Pricing Files. Available at: http://www.cms.gov/Medicare/Medicare-Feefor-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2012ASPF iles.html. 13. Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer 2007;7:91. 14. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012 Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. rates or survival. Providers must be aware of the impact that high out-of-pocket costs have on their patients.23,24 1042 The Last Word Ramsey and Shankaran 16. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097–4106. 17. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in firstline treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol 2008;26:689–690. 18. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007;25:4779–4786. 19. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–1417. 20. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;25:1670– 1676. 21. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24:4991–4997. 22. Cunningham D, Okines AF, Ashley S. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36– 46. 23. Sedjo RL, Devine S. Predictors of non-adherence to aromatase inhibitors among commercially insured women with breast cancer. Breast Cancer Res Treat 2011;125:191–200. 24. Kelley RK, Venook AP. Nonadherence to imatinib during an economic downturn. N Engl J Med 2010;363:596–598. To access www.JNCCN.org, you must first activate your FREE subscription. Before you activate, make sure you have your subscriber number available. This number is printed on your journal’s mailing label. See the example below—the subscriber number is in red. If you no longer have your mailing label, please e-mail your request for your subscriber number to [email protected]. In your e-mail, please provide your name and the address to which your copy of JNCCN was mailed. To activate your subscription: 12345-6789 #BXBBRZD AUTO**SCH 3-DIGIT 123 #C12345678912# JOHN SMITH MD 123 ANY STREET BROOKLYN NY 1. Go to the journal home page: http://www.JNCCN.org/ 2. Click on the button marked SUBSCRIPTIONS, located near the top of this page. 3. Click on the link: ACTIVATE Your Individual Subscription. 4. Please review the Terms and Conditions of the online subscription. 5. In the box marked “Enter your Customer Number,” enter your Subscriber Number (from your mailing label). 6. Click the SUBMIT button. 45678 912345 7. Fill out all the information on the following screen and press the “Send Form” button at the bottom on the right. DO NOT CLICK THE “Clear Form” button. You will receive an email confirmation that your subscription has been activated. 8. Once your subscription is activated, you will need only your user name and password to access www.JNCCN.org. 9. If you have any questions, please contact Harborside Press at 631-692-0800 or [email protected]. © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 8 | August 2012 Downloaded from jnccn.org by guest on August 30, 2012from 00.000.000.0 Copyright © 2012 by the National Comprehensive Cancer Network. All rights reserved. Oncol 2008;26:2013–2019. 15. Cassidy J, Clarke S, Díaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006–2012.