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Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3392-3394 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9503
A Renewed Call for EquipoiseFox Chase Cancer Center, Philadelphia, PA
Oft expectation fails, and most oft there In this issue of the Journal of Clinical Oncology, Saltz et al1 report the results of Cancer and Leukemia Group B (CALGB) 89803, a prospective randomized phase III trial of adjuvant therapy for patients with stage III colon cancer. In this study, patients with resected stage III adenocarcinoma of the colon were assigned to treatment with fluorouracil (FU) plus leucovorin (LV; weekly x 6, every 8 weeks for four cycles) or FU plus LV plus irinotecan (CPT-11; weekly x 4, every 6 weeks for five cycles). This well-designed and well-conducted clinical trial by the publicly funded National Cancer Institute (Bethesda, MD) cooperative group system clearly demonstrated that CPT-11 plus FU plus LV failed to improve disease-free, recurrence-free, or overall survival compared with FU plus LV. These results were unexpected. After all, CPT-11 had previously shown clear activity in patients with metastatic cancer—the accepted proving ground for subsequent adjuvant therapies. In 1996, CPT-11 was granted accelerated US Food and Drug Administration approval based on phase II single-agent activity in patients with metastatic colorectal cancer refractory to FU. Full approval was granted approximately 2 years later based on randomized phase III trials that demonstrated a modest (2 to 3 months) survival benefit from CPT-11 compared with best supportive care,2 or to infusional FU3 in patients who had previously received bolus FU. Subsequent phase III studies showed that CPT-11 improved survival when added to FU plus LV compared with FU plus LV in the initial management of patients with metastatic colorectal cancer.4-6 One of these CPT-11 regimens, CPT-11 plus FU plus LV,5 was selected as the experimental arm of CALGB 89803. We may consider several potential explanations for the negative results of CALGB 89803. One might initially question whether the weekly bolus CPT-11 plus FU plus LV regimen was an optimal choice for the experimental arm. At the time that CALGB 89803 was designed, the CPT-11 plus FU plus LV regimen was the standard in North America FU plus LV plus CPT-11 regimen in North America. During the study, toxicity concerns surfaced, including an excess of toxic deaths on the experimental arm.7 It would be useful to know whether there was a substantial imbalance in scheduled therapy delivered between the study conditions that might help explain the outcomes. In fact, Saltz et al1 note that nearly twice as many patients withdrew consent or discontinued treatment on the CPT-11 plus FU plus LV arm than in the control group. Subsequent to this trial, data emerged to suggest that infusional FU delivery has a superior therapeutic index in combination with CPT-11.8-10 However, preliminary results of two additional adjuvant studies comparing infusional FU plus LV to infusional FU plus LV plus CPT-11 also failed to demonstrate superiority of the CPT-11–containing arms.11,12 Therefore, a demonstrable lack of activity for CPT-11 in the adjuvant setting has been consistently observed. These data must be interpreted in the context of other studies that demonstrated improved recurrence-free survival when oxaliplatin is added to a FU plus LV backbone as adjuvant therapy.13,14 The benefit of CPT-11 in patients with metastatic disease in terms of response rate and progression is similar to that observed with oxaliplatin.15,16 In addition, two studies comparing infusional FU plus oxaliplatin to infusional FU plus CPT-11 as initial therapy in patients with metastatic colorectal cancer showed equivalent response rates, time to progression, and overall survival between the study arms.17,18 Thus, one may have reasonably expected similar results in the adjuvant setting. However, these advanced disease studies comparing oxaliplatin and CPT-11 were of moderate size and were not powered to demonstrate equivalency. The trial reported by Tournigand et al18 included 220 patients and was designed to have 80% power to detect a 20% difference in the proportion of patients without progression at 15 months. Similarly, Colucci et al17 enrolled 336 patients with response rate as the primary objective, with statistical power to demonstrate a 15% difference between the arms. Thus, it is plausible that there are subtle differences in the clinical activity of CPT-11 and oxaliplatin that were not observed in underpowered trials in patients with metastatic disease, but became manifest in much larger trials in the adjuvant setting. Furthermore, patient preferences and tolerance of specific toxicities that differ between regimens (such as alopecia or hospitalization rate) might become more apparent in the adjuvant setting where premature treatment discontinuation could affect long-term outcomes. Underlying successful application of adjuvant therapy is the hypothesis that microscopic metastatic disease exists and can be eradicated with systemic treatment. Another possible explanation for the findings of CALGB 89803, and other adjuvant studies of CPT-11 in combination with FU plus LV, is that mechanisms of CPT-11 resistance might be expressed in micrometastases to a greater extent than in macrometastatic colon cancer. The primary mechanism of action for CPT-11 is interference with topoisomerase I function. CPT-11 is activated to SN38 by carboxylesterase, which is subsequently inactivated predominantly through glucuronidation by uridine diphosphate glucuronosyltransferase (UGT)–family glucuronosyltrasferases. Preclinical studies explored a variety of potential mechanisms of resistance, including carboxylesterase or UGT activity, multidrug resistance transport protein activity, expression or activity of topoisomerase I, and the cellular response to the topoisomerase I-camptothecin-DNA complex.19 The responsibility of these mechanisms for disappointing results with CPT-11 in the adjuvant setting is purely speculative. However, there is clear evidence that the gene expression profiles of colon cancers evolve during tumor progression,20,21 and hence, it is conceivable that drug sensitivity may vary during the natural history of this malignancy. The sobering results of CALGB 89803 illustrate the importance of conducting prospective randomized clinical trials of new treatments, even when the preponderance of evidence suggests that the therapy should be superior to standard approaches. A modest survival benefit of 2 to 3 months in patients with metastatic colorectal cancer does not guarantee success in the adjuvant setting. This mandate for phase III trial can create an awkward and ethically difficult scenario in which physicians are forced to balance the roles of caregiver and investigator.22 Typically, the physician with primary medical responsibility recruits patients from her practice to take part in a clinical trial in which she is an investigator. As investigators, our duty is to the protocol and the promise of knowledge gained. As physicians, our ethical duty lies with individual patients. Thus, the importance of supporting a phase III study can be obscured when an investigator is faced with an individual patient who asks whether the investigator believes that the new therapy is likely to be superior to the standard approach. Equipoise has been proposed as the conceptual basis for the ethical conduct of randomized phase III clinical trials. This principle holds that a phase III trial is acceptable only insofar as there is reasonable uncertainty regarding the outcome of the study.23,24 In oncology clinical research, the stakes are high as patients are facing a tangible threat to their lives, and equipoise is not to be taken for granted. An argument in the ethics literature concerns the issue of whether a clinician-investigator needs to maintain equipoise regarding enrollment of an individual patient, or rather whether the existence of disagreement among experts (so-called "clinical," "community," or "collective" equipoise)23,25,26 permits ethical cover for enrollment of a patient in a phase III trial for which the clinician-investigator has a personal preference for the experimental condition. Philosophical controversies notwithstanding, several current conditions are likely to put new strains on the clinician-investigator who seeks to maintain equipoise and, by extension, further impede phase III clinical trial recruitment. First, targeted agents with improved therapeutic indices may hold less potential for unexpected acute and late toxicities (ie, equipoise becomes less multidimensional), and therefore, the weighing of risks and benefits in considering off-study treatment with the "investigational" arm of a phase III trial may increasingly favor the investigational approach. Furthermore, studies designed to prospectively validate prognostic and predictive markers may present new obstacles for equipoise in randomized trials. For example, if a putative molecular prognostic marker assigns a patient to less-aggressive therapy, but established clinical features suggest a more aggressive phenotype, patients and their physicians may feel uncomfortable with molecularly directed treatment assignment. Similarly, patients may request the use of a putative predictive marker to select their therapy outside of a clinical trial, concluding that if it's worth testing in a phase III trial, the investigator must be pretty confident that it's a good marker. The promise of cost-effective personalized oncology treatment is within reach, but only if the necessary commitment to clinically validate new hypotheses is strong. The report by Saltz et al1 sends a strong message: Randomized trials are necessary to prove the obvious, as history tells us that the obvious is often disproved. In fact, a recent review of 444 phase III trials conducted by the National Cancer Institute–sponsored cooperative groups found that the experimental arms were not more likely to be superior, and equipoise was vindicated.27 In a survey of pharmaceutical drug development, DiMasi and Grabowski28 found that only 57% of oncology drugs examined in phase III trials ultimately succeeded in gaining US Food and Drug Administration regulatory approval. Thus, drugs deemed most promising and worthy of the expense of phase III investigation commonly fail to demonstrate benefit compared with standard therapy. The value of conducting phase III oncology trials is clear, and the importance of timely reporting of both positive and negative clinical trial results cannot be overstated. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Neal J. Meropol, Amgen (C), Bristol-Myers Squibb (C), Pfizer (C), Genentech (C), ImClone Systems Inc (C), AstraZeneca (C), Genomic Health (C) Stock Ownership: None Honoraria: None Research Funding: Neal J. Meropol, Genentech Expert Testimony: None Other Remuneration: None ACKNOWLEDGMENTS I thank Steven Cohen, MD, and Louis Weiner, MD, for helpful comments on an earlier draft of this manuscript. REFERENCES
1. Saltz LB, Niedzwiecki D, Hollis D, et al: Irinotecan fluorouracil and leucovorin is not superior to fluorouracil and leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803. J Clin Oncol 25:3456-3461, 2007 2. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline] 3. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline] 4. Kohne CH, van Cutsem E, Wils J, et al: Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 23:4856-4865, 2005 5. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000 6. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline] 7. Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001 8. Goldberg RM, Sargent DJ, Morton RF, et al: Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: A North American Intergroup Trial. J Clin Oncol 24:3347-3353, 2006 9. Meropol NJ: Turning point for colorectal cancer clinical trials. J Clin Oncol 24:3322-3324, 2006 10. Fuchs CS, Marshall J, Mitchell EP, et al: Updated results of BICC-C study comparing first-line irinotecan/fluoropymidine combinations ± celecoxib in mCRC: Clinical data cut-off September 1, 2006. 2007 Gastrointestinal Cancers Symposium. Orlando, FL, January 19-21, 2007 (abstr 276) 11. Van Cutsem E, Labianca R, Hossfeld D, et al: Randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3). J Clin Oncol 23:16S, 2005 (abstr 8) 12. Ychou M, Raoul J, Douillard J, et al: A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). J Clin Oncol 23:16S, 2005 (abstr 3502) 13. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 14. Wolmark N, Wieand HS, Kuebler JP, et al: A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol 23:16S, 2005 (abst 3500) 15. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000 16. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 17. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866-4875, 2005 18. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 19. Rasheed ZA, Rubin EH: Mechanisms of resistance to topoisomerase I-targeting drugs. Oncogene 22:7296-7304, 2003[CrossRef][Medline] 20. Friederichs J, Rosenberg R, Mages J, et al: Gene expression profiles of difficult clinical stages of colorectal carcinoma: Toward a molecular genetic understanding of tumor progression. Int J Colorectal Dis 20:391-402, 2005[CrossRef][Medline] 21. Habermann JK, Paulsen U, Roblick UJ, et al: Stage-specific alterations of the genome, transcriptome, and proteome during colorectal carcinogenesis. Genes Chromosomes Cancer 46:10-26, 2007[CrossRef][Medline] 22. Veatch RM: The patient as partner: Ethics in clinical oncology research. Johns Hopkins Med J 151:155-161, 1982[Medline] 23. Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 317:141-145, 1987[Abstract] 24. Fried C: Medical Experimentation: Personal Integrity and Social Policy. Amsterdam, the Netherlands, North-Holland Publishing Co, 1974 25. Gifford F: Freedman's clinical equipoise and sliding-scale all-dimensions-considered equipoise. J Med Philos 25:399-426, 2000[CrossRef][Medline] 26. Lilford RJ, Jackson J: Equipoise and the ethics of randomization. J R Soc Med 88:552-559, 1995[Medline] 27. Djulbegovic B, Kumar A, Soares HP: What is the probability that new cancer treatments are better than standard treatments? J Clin Oncol 24:18S, 2006 (abstr 6120)[CrossRef] 28. DiMasi JA, Grabowski HG: Economics of new oncology drug development. J Clin Oncol 25:209-216, 2007 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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