1 Jules Bordet Institute, Brussels, Belgium; 2 International Drug Development Institute, Cambridge, MA, USA
Received 6 May 2003; revised 19 August 2003; accepted 14 September 2003
ABSTRACT
Background:
The adequacy of overall survival (OS) as study end point in phase III trials for advanced solid tumors is questionable. The present review highlights the limits of OS as study end point to evaluate the efficacy of new drugs.
Methods:
Four phase III clinical trials comparing a fluorouracil-based regimen with the same regimen plus either CPT-11 or oxaliplatin in advanced colorectal cancer patients were reviewed. The primary aim of the critical assessment was to explain the lack of OS advantage observed in two of the four trials, despite the presence of increased response rate (RR) and time to progression (TTP). Four possible reasons for the lack of OS benefit (i.e. statistical power, cross-over, magnitude of the effect on RR and TTP, non-tumor-related deaths) were systematically reviewed in the trials, and the detectable 1-year OS difference, assuming a statistical power of 80%, was calculated for each.
Results:
None of these reasons for the lack of OS advantage in presence of RR and TTP benefits convincingly explained the results of the evaluated trials. Three of the four trials had roughly the same statistical power to detect 1-year OS differences, while the fourth trial was underpowered to detect realistic OS differences. The lack of OS advantage observed in the two oxaliplatin trials is therefore likely fortuitous, and due to lack of statistical power.
Conclusions:
Although increase in OS remains the ultimate goal of many clinical trials, the choice of OS benefit as a mandatory requirement to register new compounds can lead to a serious underestimation of a drugs real efficacy.
Key words: colorectal cancer, overall survival, phase III trials, study end point
Introduction
It is still a matter of debate whether overall survival (OS) represents the most practical end point for evaluating the superiority of an experimental therapy over standard treatment in patients with metastatic tumors. The undeniable advantage of OS as study end point is that it represents the ultimate clinical benefit for the patient, provided that quality of life is not compromised. Moreover, survival time is an objective end point, whereas the evaluation of tumor response and/or tumor progression may be quite dependent upon the evaluation methods and schedules used. Hence, response rate (RR) and time to progression (TTP) are less reliable end points than OS. However, potential differences in OS between the experimental and the control arms of a phase III trial could be masked by the use of active drugs delivered as salvage therapy after tumor progression to the evaluated treatments. In particular, the administration of experimental drugs to patients progressing after having received standard therapy could be a major explanation for the lack of OS advantage in clinical trials of new drugs.
In this paper, we discuss the results of four clinical trials dealing with the evaluation of CPT-11 and oxaliplatin as first-line therapies for advanced colorectal cancer patients [14]. These trials offer an interesting opportunity to evaluate the effectiveness of OS as study end point in phase III trials.
Design and main results of the trials
Figure 1 summarizes the study design and the main results of the four phase III trials analyzed [14]. Each of the trials had a control arm consisting of fluorouracil plus leucovorin and an experimental arm consisting of the same treatment combined with either oxaliplatin or CPT-11. Fluorouracil was delivered as a continuous infusion in the trials by Douillard et al. [1] and de Gramont et al. [3], as a chronotherapy in the trial by Giacchetti et al. [4], and as a bolus injection in the trial by Saltz et al. [2]. The study by Saltz et al. was the only one to include three treatment arms; patients were randomly treated either with fluorouracil plus leucovorin or with the same regimen combined with CPT-11, or with CPT-11 alone [2]. While the two CPT-11 trials showed a statistically significant benefit in favor of the experimental arm in terms of RR, TTP and OS [1, 2], in the oxaliplatin trials the advantage associated with the experimental treatment was apparently confined to RR and TTP.
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OS was not the primary study end point in any of the trials [14]. The main study end points were RR in the trials by Douillard et al. [1] and Giacchetti et al. [4], and TTP in the other two studies [2, 3]. The OS analysis was therefore a secondary objective in all cases, and in none of the trials was the sample size calculated to detect plausible OS differences. In addition, none of the published papers quantify the power of the respective trials to detect a survival advantage.
Table 1 shows the detectable 1-year OS difference for each study, which is defined as the smallest difference in the 1-year OS rate between the control and the experimental arms that could have been detected with a statistical power of 80%. To perform this calculation, survival was assumed to be exponentially distributed, as is approximately the case in advanced colorectal cancer. Thus, the 1-year OS differences could easily be transformed into overall hazard ratios. The study sample size, as well as the 1-year OS rate of the control arm, were taken into account in the calculations as well.
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At least three reasons could explain the lack of a survival benefit in the presence of an improved RR or TTP: (i) an imbalance between the control and the experimental arms in the proportion of patients receiving active second-line therapies (including cross-overs to the experimental therapy for patients progressing to control therapy); (ii) the fact that the benefit in terms of RR and TTP was modest and not large enough to lead to OS benefit; and (iii) a higher risk of non-tumor-related deaths in one of the two study arms, which would counterbalance a benefit in terms of tumor-related survival. We will examine each of these possible explanations in turn.
(i) Imbalance in use of active second-line therapies
Table 2 shows, for each arm of the four trials, the proportion of patients receiving CPT-11, oxaliplatin or second surgery (mainly liver metastasectomy after tumor response to first-line chemotherapy) as second-line therapies. In all of the trials, a significant proportion of patients in the control arm received the experimental drug after progression. The percentage of cross-over was 28% and 57% in the oxaliplatin trials [3, 4] and 31% and 56% in the CPT-11 trials [1, 2]. The proportion of patients receiving CPT-11 as second-line therapy in the oxaliplatin trials, or the proportion of patients treated with second-line oxaliplatin in the CPT-11 trials, was well balanced between the two study arms. In the trial by Giacchetti et al. [4], no data regarding the use of second-line CPT-11 were reported. All in all, similar proportions of patients in the control arms were crossed-over in the oxaliplatin trials and in the CPT-11 trials, and therefore the impact of second-line therapies on OS should be similar.
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(ii) Benefit in RR and TTP not large enough to lead to OS benefit
Table 3 shows, for each trial, the percentage of RR according to an intention-to-treat analysis, the percentage of complete responses, as well as the median response duration and the median TTP (in months).
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(iii) Increased risk of non-tumor-related deaths
Non-tumor-related deaths may be due to treatment toxicity or to accidental causes. The percentage of accidental deaths is unknown in the four trials, but there is no reason to assume that it was substantially different between the study arms of each trial, and across the four trials. The percentage of toxic deaths was <1% in each arm. It therefore seems unlikely that the lack of OS benefit in the oxaliplatin trials was related to an increased risk of non-tumor-related deaths.
Conclusion: are we seeing chance at play?
None of the above reasons seems sufficient to explain a difference in survival outcome between the CPT-11 and the oxaliplatin studies. It may well be fortuitous that the advantage reached statistical significance in only two of the four trials; the apparently different conclusions about the impact of CPT-11 and oxaliplatin on OS could largely be due to chance as well.
Notably, the Food and Drug Administration (FDA) recently approved CPT-11 as first-line therapy for advanced colorectal cancer, but not oxaliplatin. Based on the same evidence, the European Agency for the Evaluation of Medicinal Products (EMEA) has approved both of them in this indication. There are therefore differences in the criteria used for drug approval in the USA and in Europe.
Differences in guidelines for approval of a new anticancer treatment in the USA and Europe
The FDA and the EMEA accept clinical trials, wherever they are conducted, as critical data for marketing authorization, assuming the trials characterize drug activity and safety in a clinically relevant and statistically valid manner. This means that studies must be conducted ethically, at least to the level delineated in the Declaration of Helsinki; adequate assessment of the drug profile and protection of the subjects involved in the study must be ensured by having trials conducted by competent investigators who follow internationally accepted Good Clinical Practice standards; the data need to be validated; and both the FDA and the EMEA insist upon the right to verify the data at the investigational site at the source document level.
The FDA requirements for the approval of new drugs for the treatment of colon and rectal cancer were discussed at the Oncologic Drugs Advisory Committee (ODAC) meeting of 19 April 1988. As far as advanced metastatic disease is concerned, the FDA and ODAC stated that a favorable effect on survival and quality of life in well-controlled studies was an appropriate basis for approval of a new cancer drug. Improvement in performance status and weight gain without edema were easily assessable measurements of quality of life, and would be convincing end points in randomized controlled studies. A trial with a highly significant improvement in quality of life and immature survival data could be considered as a basis for approval. Objective RRs were not deemed to be satisfactory surrogates for quality of life or survival, nor were response duration or TTP [5].
The EMEA guidelines for the evaluation of anticancer products in human beings, which came into operation in March 1997, and were modified in November 2001, stated that to study the effect of a new agent, the appropriate end points of assessment were, in order of importance: progression-free survival, OS, RR, symptom control; and quality of life. In addition, the results must be shown to be unequivocally due to the new agent, and the selected primary end point used for assessment should be justified based on solid preclinical and clinical phase I/II data, with the study designed accordingly [6].
Should we reassess our efficacy end points for trials in advanced disease?
The trials discussed above illustrate some of the difficulties of using OS as an end point in advanced colorectal cancer, although the limit of the present work is that our analysis refers exclusively to four well-defined clinical trials run in the field of first-line treatment for advanced colorectal cancer. Nevertheless, difficulties that exist in considering OS as a main study end point have also been highlighted in the field of breast cancer [7]. In this setting, seven randomized trials have recently attempted to demonstrate OS benefits owing to the use of taxanes in the first-line treatment of advanced breast cancer. However, the reported trials were all lacking appropriate statistical power to demonstrate realistic OS differences between the study arms. Moreover, the frequent use of taxanes as a salvage treatment in the control arm contributed to further decrease the sensitivity of these trials to detect plausible OS benefits associated with the use of taxanes [7]. Of note, only one of the seven trials showed a statistically significant OS benefit in favor of the taxane arm, although the low rate of patients from the control arm who received taxanes as salvage therapy might explain, at least in part, the results of this trial [8]. As shown previously, improvements in OS thus remain the cornerstone for approval of new anticancer drugs in the USA, even though benefits to other end points are often chosen as the primary objectives of trials in advanced disease. Table 4 summarizes the pros and cons of the main end points that can be chosen in advanced disease (RR, TTP and OS).
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Accordingly, pragmatic trials that mimic clinical practice may become more common, i.e. those in which all patients receive the experimental agent, but in a different sequence with standard therapy. These trials would provide data on the efficacy of the evaluated drug as well as on the most appropriate treatment sequence. These considerations have already profoundly modified clinical research in other diseases, such as AIDS, and we believe that a similar evolution is desirable in the field of clinical oncology. If survival remains the end point of interest, trials will have to be much larger, and consequently more expensive, than the trials performed so far in advanced disease. Alternatively, a meta-analysis of those trials exploring the same research question should be performed to demonstrate realistic OS differences. However, the most serious drawback of using survival as the end point in advanced colorectal cancer is the prolonged period of observation required before the analysis is possible. With the number of promising new drugs that are now reaching the clinic, more sensitive end points that are observed earlier than death will have to replace survival in the evaluation process sooner or later.
Acknowledgements
The authors wish to thank Carolyn Straehle Ph D, for her help with the linguistic revision of the manuscript.
FOOTNOTES
* Correspondence to: Dr A. Di Leo, Sandro Pitigliani Medical Oncology Unit, Department of Oncology, Hospital of Prato, Piazza dellOspedale, 59100 Prato, Italy. Tel/Fax: +39-0574-29798; E-mail: adileo{at}us14.toscana.it
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