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Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 183-189 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.8099 Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107
From the Mayo Clinic, Rochester, MN; Genentech Inc, South San Francisco, CA; Translational Genomics Research Institute, Scottsdale, AZ; Duke University, Durham, NC; and University of North Carolina, Chapel Hill, NC Corresponding author: Axel Grothey, MD, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905; e-mail: grothey.axel{at}mayo.edu
Purpose In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. Patients and Methods For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. Results Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. Conclusion In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.
The treatment of advanced colorectal cancer has been significantly advanced in the last 10 years, mainly through the introduction of novel, active agents into medical practice. Since the end of the 5-fluorouracil (5-FU)–alone era, conventional chemotherapy drugs, such as irinotecan and oxaliplatin, and—most recently—targeted agents, such as bevacizumab (BV), a monoclonal antibody against vascular endothelial growth factor (VEGF), and antibodies against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, have become standard components of palliative treatment in metastatic colorectal cancer (mCRC). The availability of more active agents in this setting has been associated with an increase in the median overall survival (OS) reported in clinical trials, which now routinely exceeds 20 months.1 In the sequence of clinical trials that advanced the standard of care in first-line mCRC, it first was demonstrated that oxaliplatin- or irinotecan-based combinations were superior to fluorouracil (FU)/leucovorin (LV).2-7 Subsequently in separate trials, infusional/bolus FU and LV plus oxaliplatin (FOLFOX) was superior to bolus FU/LV plus irinotecan (IFL; Intergroup trial N9741),8 and the addition of BV to IFL significantly improved efficacy compared with IFL alone (trial AVF2107g).9 The improved activity of the superior treatment arm in these two trials was demonstrated by improvements in response rates (RR) and by the time-related end points of progression-free survival (PFS) and OS. However, the effect of BV on RR was relatively modest compared with its more pronounced effect on PFS and OS, particularly compared with conventional chemotherapy.10 One explanation for this finding could relate to differences in the mechanism of action between BV and conventional chemotherapy. The full range of mechanisms of action (MOA) underlying the clinical benefit of BV is not completely understood. Preclinical experiments with the single agent A4.6.1, the murine precursor of BV, support a primarily cytostatic MOA.11 Although objective change in tumor size remains an important assessment criterion for the treatment for solid tumors, tumor regression rates or RRs may be more relevant as surrogate markers of drug efficacy for standard, cytotoxic chemotherapy than for new, targeted biologic agents, which have primarily cytostatic MOAs.12-14 Because of the possible disassociation of objective tumor response from PFS and OS in patients treated with cytostatic biologic agents, retrospective exploratory analyses were performed to compare clinical outcomes in subgroups of patients who, in the pivotal mCRC trial of BV,9 did or did not have an objective tumor response. It was unclear, however, whether the results of these analyses were specific to the primarily cytostatic agent BV or could be observed with superior cytotoxic chemotherapies as well. Therefore, we conducted a similar retrospective analysis that used the same definition of responders and nonresponders in another landmark trial in treatment of mCRC—Intergroup study N9741.8
AVF2107g Study Design The methods and treatment regimens used in the AVF2107g trial in mCRC have been reported in detail elsewhere9 and are summarized briefly here. AVF2107g was a multicenter, randomized trial; 923 patients with histologically confirmed, bidimensionally measurable, previously untreated mCRC were enrolled onto the study. Patients were randomly assigned to IFL plus BV (IFL/BV; n = 402), bolus FU/LV plus BV (FU/LV/BV; n = 110), or IFL plus placebo (IFL/placebo; n = 411). Enrollment into the FU/LV/BV group was suspended when the planned interim analysis after enrollment of approximately 100 patients into each study arm established an acceptable safety/tolerability profile for the IFL/BV combination. The retrospective analyses reported here were limited to the data from the 813 patients in the IFL/BV and IFL/placebo groups. Tumor status was assessed at baseline, every 6 weeks for the first 24 weeks on study, and then every 12 weeks, by using the Response Evaluation Criteria for Solid Tumors (RECIST; Table 1). 12 Complete response (CR) or partial response (PR) was confirmed at the next tumor assessment (at least 4 weeks later). Study treatment continued until disease progression (PD). Patients who discontinued chemotherapy early because of chemotherapy-related adverse events could continue BV or placebo until PD. Patients were followed until death, loss to follow-up, or termination of the study. PFS was defined as the time from randomization to the first occurrence of PD or death resulting from any cause during first-line therapy.
N9741 Study Design The methods and chemotherapy regimens used in N9741 were previously described.15 Patients with previously untreated, histologically proven, unresectable mCRC with tumors that were measurable or assessable were enrolled in two time-based cohorts and were randomly assigned to treatment. Before April 2001, the study contained three treatment arms: IFL (control), bolus/infusional FOLFOX, and oxaliplatin and irinotecan (IROX). Subsequent to April 25, 2001, because of a higher rate of toxicity in the IFL control arm relative to the other two treatment arms, the IFL dose was modified and the study's target sample size was increased, which required the enrollment of a second cohort of patients. The retrospective analyses reported here include only the 768 patients in cohorts 1 and 2 who were concurrently randomly assigned to IFL (n = 385) or to FOLFOX (n = 383). The IFL dose regimen for patients in cohort 1 (n = 245) was irinotecan 125 mg/m2 and bolus FU 500 mg/m2 plus LV 20 mg/m2 on days 1, 8, 15, and 22 every 6 weeks; for patients in cohort 2 (n = 140), the IFL dose regimen was irinotecan 100 mg/m2 and FU 400 mg/m2 FU plus LV 20 mg/m2 on the same schedule. The FOLFOX regimen was identical for both cohorts.8 Comparative analyses (not shown) showed similar results in both cohort 1 and cohort 2; thus, the two cohorts were combined for all analyses. Study treatment continued until PD, chemotherapy-related adverse events became unmanageable, or the patient withdrew consent. Tumor status was assessed every 6 weeks for the first 42 weeks or until tumor response was confirmed, then every 12 weeks, by using modified WHO criteria16 (Table 1).
Statistical Analyses Kaplan-Meier methods were used to estimate PFS and OS in the responder and nonresponder subgroups. Hazard ratios (HRs) for the treatment effect on the basis of PFS and OS were estimated by using Cox regression models. Consistent with recent Oncologic Drug Advisory Committee guidance, the primary outcome of interest for these retrospective analyses was PFS.17
In AVF2107g, the IFL/BV group included 180 responders and 222 nonresponders, compared with 143 responders and 268 nonresponders in the IFL/placebo group. Table 2 (middle column) shows the PFS and OS results by treatment arm for all patients—responders and nonresponders—by using the protocol-specified evaluation time point of 24 weeks. Statistically significant improvements were observed for both PFS and OS in BV-treated patients in both the responder and nonresponder subgroups. For the primary end point of PFS, the hazard ratio for progression that compared the IFL/BV arm to the IFL arm was 0.53 (95% CI, 0.38 to 0.74; P = .0002) for responders and 0.63 (95% CI, 0.49 to 0.80; P = .0001) for nonresponders. Similarly, for the secondary end point of OS, the hazard ratio of death comparing IFL/BV with IFL was 0.60 (95% CI, 0.40 to 0.90; P = .0136) for responders and 0.76 (95% CI, 0.60 to 0.96; P = .0188) for nonresponders. Figures 1A and 1B show the Kaplan-Meier curves for PFS for the responder and nonresponder subgroups, respectively, within the IFL/BV and IFL/placebo groups; Figures 2A and 2B show the corresponding curves for OS.
The analysis of combined data for the two period-based cohorts from N9741 is also summarized in Table 2 (left column). In N9741, both responders and nonresponders experienced statistically significant improvements from FOLFOX relative to IFL for PFS and OS. For PFS, the improvement with FOLFOX treatment compared with IFL was even slightly more pronounced in stable patients (HR, 0.78; 95% CI, 0.59 to 1.03; P = .0795) and nonresponders (HR, 0.75; 95% CI, 0.62 to 0.91; P = .0029) than in responders (HR, 0.89; 95% CI, 0.71 to 1.19; P = .3166). For OS, the benefit of FOLFOX relative to IFL was similar for responders (HR, 0.71; 95% CI, 0.56 to 0.90; P = .0047) and nonresponders (HR = 0.74; 95% CI, 0.61 to 0.91; P = .0030). Figures 3A and 3B show the Kaplan-Meier curves for PFS of the responder and nonresponder subgroups, respectively, in the IFL and FOLFOX groups; Figures 4A and 4B show the corresponding curves for OS.
Finally, the right column in Table 2 lists the results of the AVF2107g analysis by using a revised evaluation time point of 12 weeks, to be consistent with the analysis in N9741. The PFS and OS results for responders and nonresponders did not change with this revised definition. However, the benefit of BV with respect to PFS in stable patients became statistically significant (HR, 0.55; 95% CI, 0.4 to 0.74; P < .001).
The efficacy of a new oncology drug or regimen traditionally has been assessed by its potency to shrink existing tumors and, ideally, to prolong OS. Although the effect on OS can only be routinely assessed in larger randomized trials, tumor shrinkage can be readily evaluated in smaller trials, thus providing early evidence that an investigational agent warrants further testing. In clinical practice, the observation of a tumor response reassures the patient and the oncologist that the selected therapy is active in the malignant disease. To characterize and quantify the cytotoxic, response-inducing effect of conventional chemotherapy, different evaluation systems have been developed, such as the WHO criteria or, more recently, RECIST. The common use of tumor response as a measure of efficacy in colorectal cancer has persisted despite multiple analyses demonstrating a weak relationship between tumor response and OS.18 The introduction of novel drugs without intrinsic direct cytotoxic activity, such as antiangiogenic agents, into oncology further challenges the concept of tumor response as a key indicator of efficacy. Here, we presented a side-by-side analysis of two large, recent trials in mCRC. Each of these trials changed the standard of care in this disease. Intergroup trial N9741 established the superiority of FOLFOX compared with the previous standard, IFL; AVF2107g demonstrated the efficacy of BV as a component of first-line treatment. These trials led to the US Food and Drug Administration approvals of oxaliplatin and BV, respectively, for the first-line treatment of mCRC. The specific MOA of BV is not completely understood, but its targeting of VEGF, a key factor in angiogenesis, implies a cytostatic rather than a direct cytotoxic effect. Conceivably, this should lead to a more pronounced effect on the time to tumor progression than tumor shrinkage in the clinical setting. Substantial increases in PFS and OS relative to a modest increase in the RR have been a consistent finding in the pivotal BV phase III trials in CRC,9 non–small-cell lung cancer, and breast cancer. FOLFOX, on the other hand, is thought to improve patient outcome by exerting direct cytotoxic/proapoptotic effects on tumor cells and thereby inducing tumor shrinkage. Prolonged PFS obtained with superior conventional chemotherapy conceivably is due to a reduced percentage of tumor cells that able to proliferate over time. On the basis of these considerations, we sought to test whether the effect observed with superior therapy on PFS and OS was linked to the induction of tumor response, both for a superior cytotoxic regimen, FOLFOX, and for a regimen that tested an antiangiogenic agent. Our results clearly indicate that patients classified as nonresponders (ie, patients without confirmed CR or PR of their tumors) had a similar reduction of risk of tumor progression and death compared with patients classified as responders for both superior treatments. In the AVF2107g trial, patients who achieved stable disease (confirmed at 12 weeks) as the best response on IFL plus BV experienced significant benefit in terms of PFS compared with patients on IFL alone, and results were similar to the observation in patients with CR or PR. The effect on PFS observed for nonresponders also translated into significant gains in OS. No benefit with respect to PFS was observed in patients with primary progressive disease, although even in this group a trend toward increased OS favored BV. Remarkably similar results were found in N9741, in which nonresponders experienced a significant benefit from FOLFOX in terms of PFS and OS, which again was consistent with the benefits observed in patients with a CR or PR. These findings could be explained in various ways. First, regardless of the subgroup of patients analyzed, patients in general simply benefit from a superior regimen in terms of efficacy and tolerability. N9741 demonstrated that FOLFOX was superior to IFL in terms of efficacy and safety profile. Consequently, the ability of patients to stay on FOLFOX longer than on IFL could have accounted for some of the incremental gain in PFS and OS in the FOLFOX arm. However, the time to treatment failure in N9741 was identical with IFL and FOLFOX. Likewise, in AVG2107g, differences in toxicity and tolerability cannot explain the observed effect, because the same cytotoxic chemotherapy regimen was used in both treatment arms and because the percentage of patients who discontinued therapy because of toxicity was identical in both arms. Second, these findings also might be explained by the binary all-or-nothing response definitions that are specified in the WHO criteria and RECIST. In clinical practice, attainment of a best response of SD—or a minor response that does not meet conventional response criteria—can represent clinical benefit in a palliative setting. Unless systemic chemotherapy for mCRC is being used as a neoadjuvant strategy with curative intent or is meant to palliate tumor-related symptoms, tumor shrinkage is less important than tumor control. It is conceivable that the nature of the definition of response is the primary factor that leads to the findings of our analysis, and this applies equally to both clinical trials. Because clinical trial metrics currently focus on RR, PFS, time to progression, and OS, a clear definition of confirmed SD has not been established. Neither RECIST nor the WHO criteria defines SD positively, but rather defines it as a failure to meet the criterion for either an objective response or PD. We propose that confirmed SD should be defined as SD that is confirmed by appropriate imaging techniques after 12 or more weeks. This is the definition used in N9741 and in the secondary analysis of AVF2107g reported here, and it reflects a clinically meaningful and realistic time interval for the definition of SD. It is striking, however, that our retrospective analyses of data from both the AVF2017g and N9741 trials yielded the same indication of a response-independent survival benefit even when the definitions, timetables, and conventions for disease assessment from the original study protocols were used. Because of the limitations of standard response assessment, the technique of waterfall plot analyses recently was developed to indicate benefit that does not reach the conventional criteria for response as another methodology to indicate and quantify the effect of medical therapy on the malignant disease.19,20 Tthe analyses presented here are not standard subgroup analyses of treatment effect on the basis of pretreatment patient characteristics; a patient's ultimate response status is unknown at the initiation of treatment. Our goal was not to compare the outcomes of responders versus nonresponders (an analysis known to be biased); rather, it was to investigate the impact of tumor response on treatment benefit. Responding patients have consistently and clearly enjoyed a better outcome compared with nonresponders. This was true in N9741 and in AVF2107g as well. The data presented here do not address the relationship between various levels of response to therapy and outcome. They do, however, confirm that a treatment benefit on OS related to superior therapy is independent of the tumor response status. Our results suggest that, even if a patient's ultimate response status was known before treatment, this knowledge should not impact the decision to treat or not treat, as both responders and nonresponders received a PFS and OS benefit from both of the superior regimens. The within-trial comparisons of FOLFOX or IFL/BV with IFL alone in the subgroups of responders and nonresponders clearly are not protected by random assignment, as responder status is a post–random assignment factor; also, there was an improvement in RR from the superior therapy in both trials. In conclusion, analysis of two recent, large trials in mCRC clearly demonstrates that even patients who did not achieve a response according to traditional criteria significantly benefited from being treated with the superior regimen and had the same magnitude of benefit as responders, regardless of whether this regimen was chemotherapy alone or included the antiangiogenic agent BV. Although achieving a response was associated with a better prognosis, it was not predictive of the benefit derived from the superior treatment in either trial. These findings have a clear implication for the choice of end points in future clinical trials. Consistent with previous analyses18 that demonstrated a lack of trial-level surrogacy, results demonstrate the lack of an individual-level surrogacy for the relationship between tumor response and survival.21 On the basis of these data and on other pooled analyses,22 PFS and the percentage of patients experiencing tumor control appear to be the most appropriate end points for future trial designs in mCRC. These considerations likely extend to other malignant tumors, in which other agents have demonstrated improvements in OS or PFS despite the limited impact on tumor response rates.23-25 Our analysis suggests that the emphasis on response assessment in clinical trials in mCRC should be reduced, as it is subjective, is expensive, is difficult to confirm, and—most importantly—is not reflective of treatment benefit in many patients.
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: Eric E. Hedrick, Genentech Inc (C); Robert D. Mass, Genentech, Inc (C); Somnath Sarkar, Genentech Inc (C); Sam Suzuki, Genentech Inc (C) Consultant or Advisory Role: Axel Grothey, Sanofi-Aventis (C), Genentech Inc (C), Roche (C); Ramesh K. Ramanathan, Genentech Inc (C), Sanofi-Aventis (C); Herbert I. Hurwitz, Genentech Inc (C); Richard M. Goldberg, Genentech Inc (C), Sanofi-Aventis (C), Pfizer (C); Daniel J. Sargent, Genentech Inc (C), Sanofi-Aventis (C) Stock Ownership: None Honoraria: Axel Grothey, Sanofi-Aventis, Genentech Inc, Roche; Ramesh K. Ramanathan, Genentech Inc, Sanofi-Aventis; Herbert I. Hurwitz, Genentech Inc; Richard M. Goldberg, Genentech Inc, Sanofi-Aventis, Pfizer; Daniel J. Sargent, Genentech Inc, Sanofi-Aventis Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Axel Grothey, Eric E. Hedrick, Robert D. Mass, Ramesh K. Ramanathan, Herbert I. Hurwitz, Richard M. Goldberg, Daniel J. Sargent Provision of study materials or patients: Axel Grothey, Eric E. Hedrick, Robert D. Mass, Herbert I. Hurwitz, Richard M. Goldberg, Daniel J. Sargent Collection and assembly of data: Axel Grothey, Eric E. Hedrick, Robert D. Mass, Somnath Sarkar, Sam Suzuki, Richard M. Goldberg, Daniel J. Sargent Data analysis and interpretation: Axel Grothey, Eric E. Hedrick, Robert D. Mass, Somnath Sarkar, Sam Suzuki, Herbert I. Hurwitz, Richard M. Goldberg, Daniel J. Sargent Manuscript writing: Axel Grothey, Eric E. Hedrick, Robert D. Mass, Somnath Sarkar, Ramesh K. Ramanathan, Herbert I. Hurwitz, Richard M. Goldberg, Daniel J. Sargent Final approval of manuscript: Axel Grothey, Eric E. Hedrick, Robert D. Mass, Somnath Sarkar, Ramesh K. Ramanathan, Herbert I. Hurwitz, Richard M. Goldberg, Daniel J. Sargent
Supported by National Cancer Institute Grant No. CA25224, by Sanofi Synthelabo (now Sanofi-Aventis), and by Pharmacia (now Pfizer). Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004 2. 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 3. 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] 4. 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 5. Grothey A, Deschler B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5-FU)/ folinic acid (FA) (Mayo) vs. weekly high-dose 24h 5-FU infusion/ FA + oxaliplatin (OXA) in advanced colorectal cancer (ACRC). J Clin Oncol 21:129s, 2002 (suppl; abstr 512)[CrossRef] 6. 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 7. 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 8. Goldberg RM, Sargent D, Morton RF, et al: N9741: FOLFOX (oxaliplatin(Oxal)/ 5-fluorouracil (5-FU)/ leucovorin (LV) or reduced dose R-IFL (CPT-11 + 5-FU/LV) in advanced colorectal cancer (CRC): Final efficacy data from an intergroup study. J Clin Oncol 23:275s, 2004 (suppl; abstr 3621) 9. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 10. Grothey A: Integrating biologics and chemotherapy in the systemic treatment of advanced colorectal cancer. Presented at Gastrointestinal Cancers Symposium, San Francisco, CA, January 26-28, 2006 11. Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841-844, 1993[CrossRef][Medline] 12. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 13. Kerbel RS: Clinical trials of antiangiogenic drugs: Opportunities, problems, and assessment of initial results. J Clin Oncol 19:45S–51S, 2001[Medline] 14. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: Are new approaches needed? J Clin Oncol 19:265-272, 2001 15. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 16. WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, Offset publication 48, 1979 17. ODAC: Colorectal Cancer Endpoints Meeting on May 4, 2004. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4037T2.htm 18. Buyse M, Thirion P, Carlson RW, et al: Re: A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer. J Natl Cancer Inst 93:399-401, 2001 19. Campbell M, Grothey A, Sargent D, et al: Waterfall plots provide detailed information on magnitude of response to conventional chemotherapy in advanced colorectal cancer (ACRC): Lessons learned from N9741. J Clin Oncol 25:4080, 2007 20. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006 21. Buyse M, Molenberghs G: Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics 54:1014-1029, 1998[CrossRef][Medline] 22. Buyse M, Burzykowski T, Carroll K, et al: Progression-free survival (PFS) as a surrogate for overall survival (OS) in patients with advanced colorectal cancer: An analysis of 3159 patients randomized in 11 trials. J Clin Oncol 23s:3513, 2005 (suppl; abstr XX) 23. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007 24. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007 25. Cassidy J, Clarke S, Diaz Rubio E, et al: First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs. FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer (MCRC). Ann Oncol 17:LBA3, 2006 (suppl 9) Submitted August 22, 2007; accepted October 5, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
