Originally published as JCO Early Release 10.1200/JCO.2006.08.1935 on September 17 2007

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tang, P. A. Articles by Siu, L. L. Search for Related Content PubMed PubMed Citation Articles by Tang, P. A. Articles by Siu, L. L. Social Bookmarking                            What's this?

Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy

Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

From the Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada; and the Departments of Human Oncology and Medical Physics, University of Wisconsin Comprehensive Cancer Center, Madison, WI

Address reprint requests to Lillian L. Siu, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Suite 5-718, Toronto, Canada M5G 2M9; e-mail: lillian.siu{at}uhn.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Purpose Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS.

Methods Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points.

Results Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r_s) between differences () in surrogate end points (PFS, TTP, and RR) and OS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r_s for PFS was not significantly different from the r_s TTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 ± 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% ± 1% risk reduction for OS.

Conclusion In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
The most commonly used end point for phase III trials and for regulatory approval of new anticancer drugs is overall survival (OS), defined as the time from random assignment or first treatment to death. OS is clinically meaningful and objectively measured, but can be influenced by effective sequential therapies. Furthermore, OS requires long follow-up periods after disease progression, resulting in long and expensive phase III studies. For example, the median length of follow-up in published phase III studies of first-line chemotherapy in metastatic colorectal cancer (MCRC) from 2004 to 2006 ranged from 20.4 to 43.9 months.^1-7 The estimated average cost of a pharmaceutical industry–sponsored phase III study was more than US $10 million (in 2000 dollars), whereas that of a public-funded phase III study was more than US $1 million.⁸ A validated shorter term surrogate end point would reduce drug development costs, and allow for more rapid completion of randomized controlled trials. There is no general consensus regarding the definition of a valid surrogate end point for OS, but intuitively a useful surrogate end point would produce a reliable quantitative estimate of the expected treatment effect in OS based on the observed treatment effect in the surrogate. Potential surrogate end points for OS include progression-free survival (PFS), time to progression (TTP), and response rate (RR). PFS differs from TTP in that PFS includes death as a result of any cause in its definition in addition to progression; however, both end points are unaffected by subsequent therapies.

Despite recent advances in systemic cytotoxic and targeted therapies,^5,9-12 MCRC remains largely incurable. However, more effective therapies in the first-line setting can be expected to improve PFS, TTP, and RR. Therefore, disease progression is a logical surrogate for OS in MCRC, given that it is a common reason for stopping first-line treatment, and subsequent therapies are not curative and often much less effective. Objective response is another surrogate end point that is easily assessed during the course of treatment using standardized criteria.^13,14 RR is a good measure of efficacy and is often associated with subjective improvement in symptoms. Other end points such as toxicity and quality of life are clinically important but may be less directly related to survival.

Our aim was to perform a comprehensive literature-based analysis to determine whether PFS, TTP, or RR were correlated with OS, and whether improvements in PFS, TTP, and RR with first-line therapies were associated with improvements in OS in MCRC. The latter analysis was performed to reduce bias, given that variations in prognostic factors between trial populations among different studies could contribute to the association between a disease-related end point and OS.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Literature Search and Data Extraction
Randomized controlled trials of first-line chemotherapy in MCRC published between 1990 and 2005 were identified through a systematic search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials using the keywords "colorectal neoplasm" and "neoplasm metastasis." Results were limited to "clinical trial," "clinical trial, phase III," "controlled clinical trial," or "randomized controlled trial." A manual search was performed for abstracts presented at the annual meetings of the American Society of Clinical Oncology, European Cancer Conference, and European Society for Medical Oncology between 1995 and 2005. Bibliographies of published overviews^15-18 were checked for additional citations.

Reports of trials with a sample size of at least 100 patients per arm were included if they contained mature data on OS, RR, and either TTP or PFS. Exclusion criteria were locally advanced, unresectable disease; intermittent as opposed to continuous chemotherapy; and hepatic chemotherapy infusion. For each trial, data on sample size, RR, and chemotherapy regimens were collected. In addition, TTP or PFS and OS were determined for all treatment arms using published data or survival curves. The standard chemotherapy arm in each trial was determined by consensus of three investigators (P.A.T., E.X.C., and L.L.S.); all other arms were considered experimental. Two investigators (P.A.T. and L.L.S.) labeled an end point as TTP or PFS according to established (ie, per protocol) definitions, regardless of the terminology used by the original authors, and classified the results of each trial for TTP or PFS and OS as significant (P .05) or nonsignificant for the per-protocol analysis. The analysis was performed using the original authors' and per-protocol end point definitions. When available, hazard ratios (HRs) for PFS and OS were recorded.

Analysis of Trials
For each trial, the differences in overall survival (OS) and in surrogate end points (PFS, TTP, RR) were calculated as the estimate in the experimental arm(s) minus the estimate in the standard arm. For trials with multiple arms, we compared the control arm to a randomly chosen experimental arm, to avoid the analysis of correlated data in multiarm trials and to better parallel the two-arm trials. The nonparametric Spearman rank correlation coefficient (r_s) was used as a measure of correlation between the difference in each surrogate end point and the difference in OS. Correlation coefficients were compared using the normal approximation to the z-transformation of r_S and its standard deviation. Linear regression analysis through the origin of the plot evaluating OS as a function of PFS was used to obtain a conversion factor between PFS and OS, and to determine the proportion of variability explained (R²). Linear regression analysis was also performed through the origin of the plot evaluating percent risk reduction of OS as a function of percent risk reduction of PFS, calculated based on the HR of PFS and HR of OS.

Statistical analyses were performed using SPSS software release 14.0.0 (SPSS Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Trials Included in Analysis
A total of 45 trials were identified with at least 100 patients per arm. One trial only reported TTP for one study arm,¹⁹ four included patients with locally advanced disease,^20-23 and one had a secondary randomization to continuous chemotherapy until progression compared with intermittent chemotherapy.²⁴ These six trials were excluded from the analysis. Therefore, 39 trials with 87 treatment arms and 18,668 patients were included.^{2,4-7,9-12,25-54} Seven trials had multiple arms^{5,11,31,42,48,49,51}: six of these had three arms and one had five arms. Median follow-up duration ranged from 12 to 57.6 months. Trial characteristics are outlined in Table 1. Four trials included death in the definition of TTP^5,39,41,43 and were labeled as PFS in the per-protocol analysis. The results were similar for the per-protocol and the original authors' analyses; hence, only per-protocol data are included. All trials that reported a significant difference in OS also reported a significant difference in TTP or PFS.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Correlation between median progression-free survival and median overall survival. FU, fluorouracil; LV, leucovorin.

Correlation Between Differences in Surrogate End Points and OS Within Trials

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Correlation between differences in progression-free survival (PFS) and differences in overall survival (OS). The middle line is the regression line; the 95% CIs are indicated by the outside lines.

Correlation Between HR for Surrogate End Points and OS
A total of 18 pairs of HRs for PFS and OS between treatment arms were reported in 15 trials. There is a highly significant relationship between risk reductions for PFS and OS on linear regression analysis (P = 6 x 10^–5; Fig 3). Because of the potential correlation of data in trials with multiple arms, the linear regression analysis was performed by including only one randomly chosen pair comparison in each multiarm trial, resulting in 15 pairs of HRs for OS and PFS. Pairs of HRs between trial arms were analyzed by linear regression through the origin (ie, assuming that trials comparing fully equivalent treatment options would give rise to the same risk reduction estimates between trial arms for both PFS and OS). The slope of this regression line was 0.54 ± 0.10. This means that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% ± 1% risk reduction for OS. A similar analysis for TTP was not performed because only three trials reported HR for this end point.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Correlation between percent risk reductions for progression-free survival and overall survival. The linear regression line is shown.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Lead-time resulting from using progression-free survival (PFS) rather than overall survival (OS) as the primary end point. The difference between the median OS and the median PFS is plotted against the median OS.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

There is no consensus on the definition of a valid surrogate end point.^55,56 Ideally, a surrogate would correlate with the true end point, and would fully capture the net effect of treatment on the true end point.⁵⁷ Others have proposed that for a surrogate to be valid, the effect of treatment on the surrogate end point must predict the effect of treatment on the true end point, or that a test of a statistical hypothesis based on the surrogate end point should come to the same conclusion as a statistical hypothesis based on the true end point.^58-60

In our analysis, the percent risk reduction calculated from HR for OS showed a highly significant association with the percent risk reduction calculated from HR for PFS, indicating that the effect of treatment on PFS predicts the effect of treatment on OS. HRs take into account the entire pattern of events for each treatment arm, and may be more meaningful than a single time point estimate such as median PFS. Given that the present analysis focuses on surrogate end point at the level of a trial rather than at the level of an individual patient, the strongest result presented here is the demonstration of a highly significant relationship between the HRs for the two end points.

Table 1 demonstrates some discordance between PFS and OS based on historical trials. Twenty-one trials did not show a significant difference in TTP/PFS or OS. For the remaining trials, there were six in which there was a significant difference in OS and a corresponding significant difference in TTP or PFS.^{5,10-12,28,38} There were two trials in which there was a significant difference in TTP, but no significant difference in OS.^31,46 There were 10 trials that demonstrated a significant difference in PFS, but no significant difference in OS.^{4,9,33,39,40,47,49-51,54} However, only four of these studies were powered to show a difference in OS.^33,50,51,54 The observed percent risk reduction for PFS was nearly twice that of the percent risk reduction for OS, indicating that this is a more sensitive end point for treatment effect. Given that we have also demonstrated a significant lead time using PFS rather than OS as the end point, there typically will be more events at the time of analysis for PFS compared with OS. This will result in a higher statistical power when using the surrogate end point.

The proportion of variability in OS explained by PFS was moderate (R² = 0.65), but some of the unexplained variation simply reflects random sampling error associated with the final sample size of each trial. The inadequacy of R² as a measure of surrogacy can be illustrated by the fact that even for a perfect surrogate end point, R² is likely to be smaller in a set of trials with smaller sample sizes.

PFS is appealing as a surrogate end point for several reasons. From a patient's point of view, prolongation of PFS is clearly desirable regardless whether OS is improved or not. Using PFS instead of OS would accelerate the drug development process by allowing for earlier reporting of results, thereby bringing new treatments to patients more rapidly. However, there are a few important considerations if PFS is used as a primary end point. A standard definition of progression (eg, WHO, Response Evaluation Criteria in Solid Tumors Group) should be used.^13,14 The time interval between clinical and radiologic assessments should be the same across study arms, and at sufficiently frequent intervals to maximize the lead time gained. The magnitude of improvements in PFS will always have to be balanced by toxicity, both acute and chronic, and quality of life.

Our literature-based analysis encompassed the largest number of randomized controlled trials of first-line chemotherapy for MCRC to date, and included recent trials that evaluated combination regimens containing irinotecan, oxaliplatin, or bevacizumab. Other groups have also examined the relationship between surrogate end points and OS in MCRC. Louvet et al⁶¹ performed a literature-based analysis of 29 phase III trials of first-line chemotherapy published between 1990 and 2000. There was a moderate correlation between RR and OS, with an r_s of 0.408 (P = .0009). PFS and TTP were used as a combined end point, and the correlation between PFS/TTP and OS was moderate (0.481; P < .0001). Buyse et al⁶² examined the relationship between RR and OS in an individual patient data meta-analysis of 25 randomized trials of first-line treatment comparing standard bolus fluoropyrimidines versus experimental treatments (fluorouracil and leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). The coefficient of determination of the regression line between the treatment effects on RR and OS was 0.38, indicating that less than half of the variability of the survival benefits in the trials could be explained by the variability of the response benefits.

In another study, Buyse et al⁶³ performed an individual patient data meta-analysis of 11 historical randomized trials of first-line therapy comparing fluorouracil and leucovorin versus either fluorouracil alone or raltitrexed, and found strong correlations between PFS and OS, and their HRs, using bivariate distribution over the entire time range ( = 0.82 and = 0.986, respectively). The historical trials were used to create a model that accurately predicted the treatment effect of OS, based on the effect on PFS, for two recent trials^10,11 in which there was no effective second-line therapy. The model was not as accurate for trials in which there were effective second-line therapies.^5,9 Thus, sequential lines of treatment disconnect early effects on tumor control from OS, making PFS an ideal surrogate. The different composition of trials and statistical methods may account for the varying strengths of association between PFS and OS reported in the literature. However, all of the analyses have shown a consistent relationship between PFS and OS, similar to our results.

There are a few limitations to our analysis because it was based on literature, rather than based on individual patient data. PFS andthe associated HRs were only reported in 55 of 87 treatment arms and in 15 of 39 trials, respectively. The definitions of progression varied among the trials we analyzed, and it was impossible to ascertain whether disease progression was assessed at comparable time points between treatment arms within the same trial. Most trials did not report on the details of subsequent treatments after progression on first-line regimens; therefore, the potential confounding effects of subsequent treatments on OS could not be evaluated.

In summary, we found a strong association between improvements in PFS and improvements in OS. The usage of PFS as a surrogate end point in randomized controlled trials in first-line chemotherapy for MCRC may be appropriate.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Patricia A. Tang, Søren M. Bentzen, Lillian L. Siu

Collection and assembly of data: Patricia A. Tang

Data analysis and interpretation: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

Manuscript writing: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

Final approval of manuscript: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

	NOTES

 
published online ahead of print at www.jco.org on September 17, 2007.

Presented in part at the 2006 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 26-28, 2006, San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. 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[Abstract/Free Full Text]

2. 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[Abstract/Free Full Text]

3. Souglakos J, Androulakis N, Syrigos K, et al: FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): A multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 94:798-805, 2006[CrossRef][Medline]

4. Köhne 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[Abstract/Free Full Text]

5. 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[Abstract/Free Full Text]

6. Giacchetti S, Bjarnson G, Garufi C, et al: First line infusion of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer: 4-day chronomodulated (FFL4-10) versus 2-day FOLFOX2—A multicenter randomized phase III trial of the Chronotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC 05963). J Clin Oncol 22:251s, 2004 (suppl; abstr 3526)

7. 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[Abstract/Free Full Text]

8. Roberts TG Jr, Lynch TJ Jr, Chabner BA: The phase III trial in the era of targeted therapy: Unraveling the "go or no go" decision. J Clin Oncol 21:3683-3695, 2003[Abstract/Free Full Text]

9. 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[Abstract/Free Full Text]

10. 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]

11. 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[Abstract/Free Full Text]

12. 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[Abstract/Free Full Text]

13. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

14. 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[Abstract/Free Full Text]

15. Kelly H, Goldberg RM: Systemic therapy for metastatic colorectal cancer: Current options, current evidence. J Clin Oncol 23:4553-4560, 2005[Abstract/Free Full Text]

16. Folprecht G, Cunningham D, Ross P, et al: Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: A pooled analysis of clinical trials. Ann Oncol 15:1330-1338, 2004[Abstract/Free Full Text]

17. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer: Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 12:960-969, 1994[Abstract/Free Full Text]

18. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate—Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 10:896-903, 1992[Abstract]

19. Pazdur R, Vincent M: Raltitrexed (Tomudex) versus 5-fluorouracil and leucovorin (5FU + LV) in patients with advanced colorectal cancer (ACC): Results of randomized, multicenter, North American trial. Proc Am Soc Clin Oncol 16:228a, 1997 (abstr 801)

20. Bajetta E, Colleoni M, Rosso R, et al: Prospective randomised trial comparing fluorouracil versus doxifluridine for the treatment of advanced colorectal cancer. Eur J Cancer 29A:1658-1663, 1993[CrossRef]

21. Blijham G, Wagener T, Wils J, et al: Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: Final results of a randomized European Organization for Research and Treatment of Cancer Study. J Clin Oncol 14:2266-2273, 1996[Abstract]

22. Price TJ, Ross PJ, Hickish T, et al: Phase III study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil in advanced colorectal carcinoma. Clin Colorectal Cancer 3:235-242, 2004[Medline]

23. Seymour MT, Slevin ML, Kerr DJ, et al: Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer: Colorectal Cancer Working Party of the United Kingdom Medical Research Council. J Clin Oncol 14:2280-2288, 1996[Abstract]

24. Maughan TS, James RD, Kerr DJ, et al: Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: A multicentre randomised trial. Lancet 361:457-464, 2003[CrossRef][Medline]

25. Laufman LR, Bukowski RM, Collier MA, et al: A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 11:1888-1893, 1993[Abstract/Free Full Text]

26. Buroker TR, O'Connell MJ, Wieand HS, et al: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12:14-20, 1994[Abstract]

27. Mustacchi G, Pavesi L, Milani S, et al: High-dose folinic acid (FA) and fluorouracil (FU) plus or minus thymostimulin (TS) for treatment of metastatic colorectal cancer: Results of a randomized multicenter clinical trial. Anticancer Res 14:617-619, 1994[Medline]

28. Smyth JF, Hardcastle JD, Denton G, et al: Two phase III trials of tauromustine (TCNU) in advanced colorectal cancer. Ann Oncol 6:948-949, 1995[Free Full Text]

29. Cunningham D, Zalcberg JR, Rath U, et al: Final results of a randomised trial comparing ‘Tomudex’ (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer: "Tomudex" Colorectal Cancer Study Group. Ann Oncol 7:961-965, 1996[Free Full Text]

30. Greco FA, Figlin R, York M, et al: Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol 14:2674-2681, 1996[Abstract/Free Full Text]

31. Hansen RM, Ryan L, Anderson T, et al: Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst 88:668-674, 1996[Abstract/Free Full Text]

32. Jäger E, Heike M, Bernhard H, et al: Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: Results of a randomized multicenter trial—Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol 14:2274-2279, 1996[Abstract]

33. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997[Abstract/Free Full Text]

34. Goldberg RM, Hatfield AK, Kahn M, et al: Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol 15:3320-3329, 1997[Abstract/Free Full Text]

35. Labianca R, Cascinu S, Frontini L, et al: High-versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: A ‘GISCAD’ phase III study—Italian Group for the Study of Digestive Tract Cancer. Ann Oncol 8:169-174, 1997[Abstract/Free Full Text]

36. Scheithauer W, Kornek G, Marczell A, et al: Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: A randomized phase III study. J Clin Oncol 15:908-914, 1997[Abstract/Free Full Text]

37. Aranda E, Diaz-Rubio E, Cervantes A, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol 9:727-731, 1998[Abstract/Free Full Text]

38. Borner MM, Castiglione M, Bacchi M, et al: The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of a phase III trial—Swiss Group for Clinical Cancer Res (SAKK). Ann Oncol 9:535-541, 1998[Abstract/Free Full Text]

39. Cocconi G, Cunningham D, Van Cutsem E, et al: Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer: Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943-2952, 1998[Abstract/Free Full Text]

40. 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[Abstract/Free Full Text]

41. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001[Abstract/Free Full Text]

42. O'Dwyer PJ, Manola J, Valone FH, et al: Fluorouracil modulation in colorectal cancer: Lack of improvement with N-phosphonoacetyl-l-aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule—An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study. J Clin Oncol 19:2413-2421, 2001[Abstract/Free Full Text]

43. 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 19:4097-4106, 2001[Abstract/Free Full Text]

44. Blanke CD, Shultz J, Cox J, et al: A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol 13:87-91, 2002[Abstract/Free Full Text]

45. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617-3627, 2002[Abstract/Free Full Text]

46. Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605-3616, 2002[Abstract/Free Full Text]

47. 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) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 20:129a, 2002 (abstr 512)

48. Maughan TS, James RD, Kerr DJ, et al: Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: A multicentre randomised trial. Lancet 359:1555-1563, 2002[CrossRef][Medline]

49. Punt CJ, Keizer HJ, Douma J, et al: Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer: Final results of a randomised European study. Ann Oncol 13:81-86, 2002[Abstract/Free Full Text]

50. Schilsky RL, Levin J, West WH, et al: Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol 20:1519-1526, 2002[Abstract/Free Full Text]

51. Köhne CH, Wils J, Lorenz M, et al: Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol 21:3721-3728, 2003[Abstract/Free Full Text]

52. Fischer von Weikersthal L, Schalhorn A, Quietzsch D, et al: Randomised comparison of 5-FU/folinic acid plus irinotecan (FOLFIRI) and irinotecan plus oxaliplatin (IROX) in first-line therapy of metastatic colorectal cancer (CRC): The fire-trial. Eur J Cancer 3:167, 2005 (suppl 2; abstr 598)

53. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al: Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502-3508, 2005[Abstract/Free Full Text]

54. Pluzanska A, Mainwaring P, Cassidy J, et al: Final results of a randomized phase III study evaluating the addition of oxaliplatin first line to 5-FU followed by irinotecan at progression in advanced colorectal cancer (LIFE study). J Clin Oncol 23:250s, 2005 (suppl; abstr 3517)

55. Sargent DJ, Wieand HS, Haller DG, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005[Abstract/Free Full Text]

56. Baker SG: Surrogate endpoints: Wishful thinking or reality? J Natl Cancer Inst 98:502-503, 2006[Free Full Text]

57. Prentice RL: Surrogate endpoints in clinical trials: Definition and operational criteria. Stat Med 8:431-440, 1989[Medline]

58. Rustin GJ, Nelstrop AE, Bentzen SM, et al: Selection of active drugs for ovarian cancer based on CA-125 and standard response rates in phase II trials. J Clin Oncol 18:1733-1739, 2000[Abstract/Free Full Text]

59. Buyse M, Molenberghs G, Burzykowski T, et al: The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics 1:49-67, 2000[Medline]

60. Begg CB, Leung DHY: On the use of surrogate endpoints in randomized trials. J R Stat Soc (Ser A) 163:15-28, 2000[CrossRef]

61. Louvet C, de Gramont A, Tournigand C, et al: Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma. Cancer 91:2033-2038, 2001[CrossRef][Medline]

62. Buyse M, Thirion P, Carlson RW, et al: Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: A meta-analysis—Meta-Analysis Group in Cancer. Lancet 356:373-378, 2000[CrossRef][Medline]

63. 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 23:249s, 2005 (suppl; abstr 3513)[CrossRef]

Submitted July 6, 2006; accepted April 17, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				K. R. Broglio and D. A. Berry Detecting an Overall Survival Benefit that Is Derived From Progression-Free Survival J Natl Cancer Inst, November 9, 2009; (2009) djp369v1. [Abstract] [Full Text] [PDF]

				E. D. Saad, A. Katz, P. M. Hoff, and M. Buyse Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature Ann. Onc., November 9, 2009; (2009) mdp523v1. [Abstract] [Full Text] [PDF]

				P. A. Tang, G. R. Pond, and E. X. Chen Influence of an independent review committee on assessment of response rate and progression-free survival in phase III clinical trials Ann. Onc., October 29, 2009; (2009) mdp478v1. [Abstract] [Full Text] [PDF]

				F. Montagnani, C. Migali, and G. Fiorentini Progression-Free Survival in Bevacizumab-Based First-Line Treatment for Patients With Metastatic Colorectal Cancer: Is It a Really Good End Point? J. Clin. Oncol., October 1, 2009; 27(28): e132 - e133. [Full Text] [PDF]

				E. D. Saad and A. Katz Progression-free survival and time to progression as primary end points in advanced breast cancer: often used, sometimes loosely defined Ann. Onc., March 1, 2009; 20(3): 460 - 464. [Abstract] [Full Text] [PDF]

				R. M. Giusti, M. H. Cohen, P. Keegan, and R. Pazdur FDA Review of a Panitumumab (VectibixTM) Clinical Trial for First-Line Treatment of Metastatic Colorectal Cancer Oncologist, March 1, 2009; 14(3): 284 - 290. [Abstract] [Full Text] [PDF]

				F. G Miller and S. Joffe Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option? Clinical Trials, December 1, 2008; 5(6): 617 - 623. [Abstract] [PDF]

				I. Iwanicki-Caron, F. Di Fiore, I. Roque, E. Astruc, M. Stetiu, A. Duclos, D. Tougeron, S. Saillard, S. Thureau, J. Benichou, et al. Usefulness of the Serum Carcinoembryonic Antigen Kinetic for Chemotherapy Monitoring in Patients With Unresectable Metastasis of Colorectal Cancer J. Clin. Oncol., August 1, 2008; 26(22): 3681 - 3686. [Abstract] [Full Text] [PDF]

				C. Pozzo and C. Barone Is There an Optimal Chemotherapy Regimen for the Treatment of Advanced Gastric Cancer That Will Provide a Platform for the Introduction of New Biological Agents? Oncologist, July 1, 2008; 13(7): 794 - 806. [Abstract] [Full Text] [PDF]

				P. A. Gimotty, D. Guerry, and K. Flaherty Using Benchmarks Based on Historical Survival Rates for Screening New Therapies for Stage IV Melanoma Patients J. Clin. Oncol., February 1, 2008; 26(4): 517 - 518. [Full Text] [PDF]

				W. M. Stadler Tumor Burden Endpoints and Phase II Clinical Trial Design ASCO Educational Book, January 1, 2008; 2008(1): 89 - 93. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tang, P. A. Articles by Siu, L. L. Search for Related Content PubMed PubMed Citation Articles by Tang, P. A. Articles by Siu, L. L. Social Bookmarking                            What's this?