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Originally published as JCO Early Release 10.1200/JCO.2009.23.3114 on August 31 2009 © 2009 American Society of Clinical Oncology.
Reply to F. Montagnani et alMayo Clinic, Rochester, MN In their commentary, Montagnani et al1a raise an important question regarding the most appropriate end point for clinical trials in colorectal cancer, an issue which has been discussed repeatedly by various contributions to this journal. The authors question the validity of progression-free survival (PFS) as primary end point of first-line trials in advanced colorectal cancer by presenting a preliminary pooled analysis of various clinical trials involving bevacizumab, an anti–vascular endothelial growth factor (VEGF) antibody. In these trials, based only on published summaries and not individual patient data, it did not appear that improvements in first-line PFS in these trials were accompanied by a consistent improvement in overall survival (OS), in contrast to prior trials with conventional chemotherapy alone. The authors suggest a possible biologic explanation for this perceived phenomenon by stating that bevacizumab—and presumably other targeted agents—could alter the biologic behavior of colorectal cancer and thereby affect the correlation between surrogate end points and survival. Finally, they propose that for future trials using bevacizumab as component of first-line medical therapy, OS should remain the primary end point. While we acknowledge the Montagnani et al’s1a quest for an unbiased, reliable, and clinically meaningful end point which can be consistently used in clinical trials in colorectal cancer, their analysis unfortunately ignores several issues intrinsically embedded in the complexity of modern medical approaches to this disease. From a methodologic perspective, some of the trials cited by Montagnani et al1a to substantiate their hypothesis and conclusions represent nonrandomized comparisons of chemotherapy with or without bevacizumab. Specifically both the TREE (Three Regimens of Eloxatin Evaluation) and BICC-C (Bolus, Infusion, or Capecitabine With Camptosar ± Celecoxib) trials did not concurrently randomly assign patients to a nonbevacizumab and bevacizumab-containing treatment arm, but conducted to phases of their trials consecutively.1,2 These trials should have been eliminated from the analysis the authors propose. In addition, a very small number of trials are available, which greatly limits the power of the correlation analysis, and the lack of the use of individual patient data severely limits strength of conclusions that may be drawn from the presented analysis. Setting aside methodology, the question of whether PFS should be regarded as an adequate end point for first-line trials in advanced colorectal cancer remains relevant. The key issue raised by Montagnani et al1a specifically refers to the correlation between PFS and OS in advanced colorectal cancer. Over the past several years, the benefit of second and later lines of therapy on OS has become readily apparent with the increased availability of active drugs in this disease.3-6 In fact, since the introduction of irinotecan and oxaliplatin into the treatment algorithms of colorectal cancer (before the era of bevacizumab), the only phase III trials which were able to demonstrate a significant effect on PFS and OS were trials in which either cross-over to the (effective) experimental agent or the overall availability of salvage therapy options were limited.7–9 In contrast, in trials with significant cross-over and/or effective second- and third-line treatment options even impressive gains in PFS did not translate into significant increases in OS.10–13 The emergence of biologic agents has not changed this consistent finding. The single randomized first-line phase III trial which demonstrated a PFS and OS benefit for bevacizumab did not allow cross-over from the placebo arm to bevacizumab on tumor progression, but actually allowed patients to stay on bevacizumab beyond first progression.14 In addition, the availability of active second-line therapies at the time when the Hurwitz et al14 study was conducted was limited. All of these factors combined conceivably contributed to the fact that in that trial the difference observed in PFS translated almost into the exact differential gain in OS. When the second large randomized phase III trial investigating bevacizumab in first-line therapy added to an oxaliplatin-based backbone was conducted, second- and even third-line options were readily available, likely obscuring the effect on first-line PFS on OS.15 Beyond bevacizumab, the results of recent trials on cetuximab and panitumumab as single agent last-line therapy highlight the fact that substantial cross-over in a clinical trial setting abrogates a potential significant effect on OS. While the cetuximab versus best supportive care (BSC) trial did not allow cross-over from the BSC arm to the active agent, the panitumumab versus BSC trial saw substantial cross-over from BSC to panitumumab with 75% of patients in the BSC arm eventually gaining access to the active agents.5,6 Consequently, while both trials showed a highly statistically significant increase in PFS, only the cetuximab trial demonstrated a significant effect on OS. Thus, in the era of complex therapeutic strategies in colorectal cancer with several salvage treatment options available for patients after first progression, OS can no longer be considered a realistic end point for first-line trials in this disease. In fact, if only OS and not PFS was considered an appropriate end point for first-line trials in colorectal cancer (and other diseases in which multiple salvage treatment options are available), it would make the development and subsequent approval of novel agents almost impossible. We and others have discussed these issues in detail elsewhere.16,17 Unfortunately, PFS itself has several well-known limitations as end point for phase III clinical trials, in particular, in a disease with complex medical treatment algorithms. For example, the results of trials investigating strategic treatment sequences with intermittent use of chemotherapy agents, such as induction therapy followed by maintenance treatment and reintroduction of more active therapy, is not adequately captured by the traditional definition of PFS. Other end points to address this issue have been proposed in colorectal cancer (including duration of disease control18,19 and time to failure of strategy20), but so far none of these novel end points have been validated in prospective trials. The use of PFS as a primary end point requires additional care in many aspects including the treatment of missing scans, therapy discontinuation before progression, the need for blinding, and multiple other issues that also have been extensively discussed21,22 and also captured in guidelines issued by the US Food and Drug Administration.23 Despite all limitations, at this point in time, we feel that PFS should be regarded as the most appropriate end point for first-line trials of new agents in colorectal cancer. It is best suited to capture the antitumor effect of a novel agent or treatment modality and thus has the potential to facilitate drug development in this disease. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a"U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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: Axel Grothey, Genentech (U), Pfizer (U), sanofi-aventis (U); Daniel J. Sargent, Genentech (C), sanofi-aventis (C) Stock Ownership: None Honoraria: None Research Funding: Axel Grothey, Genentech, sanofi-aventis; Daniel J. Sargent, Bristol Myers-Squibb, sanofi-aventis Expert Testimony: None Other Remuneration: None REFERENCES
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J Clin Oncol 25:5218–5224, 2007. 18. Maindrault-Goebel F, Lledo G, Chibaudel B, et al: Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study. J Clin Oncol 25:166s; 2007 abstr 4013. 19. Tournigand C, Cervantes A, Figer A, et al: OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—A GERCOR study. J Clin Oncol 24:394–400, 2006. 20. Allegra C, Blanke C, Buyse M, et al: End points in advanced colon cancer clinical trials: A review and proposal. J Clin Oncol 25:3572–3575, 2007. 21. Dodd LE, Korn EL, Freidlin B, et al: Blinded independent central review of progression-free survival in phase III clinical trials: Important design element or unnecessary expense? J Clin Oncol 26:3791–3796, 2008. 22. Panageas KS, Ben-Porat L, Dickler MN, et al: When you look matters: The effect of assessment schedule on progression-free survival. J Natl Cancer Inst 99:428–432, 2007. 23. Johnson JR, Williams G, Pazdur R: United States Food and Drug Administration Approval of Oncology Drugs. J Clin Oncol 21:1404–1411, 2003.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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