OS is traditionally used to evaluate treatment efficacy in phase II clinical trials for newly diagnosed malignant glioma patients. Unquestionably, the ultimate goal of a treatment is to improve patient survival. As such, a treatment regimen that demonstrates the property of prolonging survival is more likely to lead to regulatory approval. However, the use of survival as the primary endpoint is limited by the need for a longer trial period, often measured in years before the final results are known and published. Beyond this, the potential for the dilution of treatment effect due to second- or third-line salvage treatments patients receive after going off study adds another layer of challenge. Alternative endpoints in oncology clinical trials have been evaluated in several disease areas in the literature including colorectal cancer and breast cancer.9–11
In brain cancer specifically, Ballman et al.12
assessed the relationship between PFS-6 and OS-12 by pooling data from a total of 27 phase II North Central Cancer Treatment Group (NCCTG) trials. In that study, the analysis of association between the two endpoints was done separately for newly diagnosed and recurrent GBM patients via a variety of approaches. The authors documented that progression status at the 6th month is highly predictive of survival in both patient cohorts, indicating that PFS-6 may be a useful alternative endpoint to survival. However, their analysis only included older trials (trial start years ranged from 1980 to 2001), and none of the upfront trials included TMZ as part of their protocol treatments. Therefore, their investigation does not address the question of whether PFS is a suitably reliable endpoint for upfront studies in place of OS in the framework of the current standard of care. Lamborn et al.13
analyzed data from 596 patients with high-grade gliomas treated in phase II North American Brain Tumor Consortium (NABTC) protocols. They reported that, in addition to progression status at 6 months, progressions at earlier time points (2 and 4 months) were also strong predictors of survivorship and hence may provide further insight into the evaluation of treatment success in the design of future clinical trials in neuro-oncology. However, their evaluation focused on endpoints for trials at recurrence and may not apply to upfront trials.
This study was conducted to answer a simple question: in the TMZ era, can a nonsurvival primary endpoint help us make decisions about the efficacy of a new treatment regimen more rapidly in first-line GBM trials? In this report, we present results from an analysis of 3 phase II trials conducted at our institution in newly diagnosed GBM patients: our primary objective was to examine whether progression status at an early time point may be predictive of survival. All trials included in this study reflect the current standard of care for newly diagnosed GBM patients, which comprises surgical resection followed by RT with concurrent TMZ, followed by adjuvant TMZ. Our analyses indicate that, in this setting, progression status at 2, 4, and 6 months are each highly predictive of subsequent survival on the patient level. This pattern of association was consistently found in all three trials. In addition, although our analysis only included 3 trials, our results seemed to provide encouraging insights into the correlation between the endpoints of early progression and survival on a study level. Specifically, Table shows that a treatment regimen (OTRT) that demonstrates increased PFS-2, PFS-4, and PFS-6 is also likely to be associated with the higher likelihood of survival at later time points.
Although the use of progression status at a time point even earlier than 6 months may provide an additional reduction in the time required to complete a trial and to interpret its results, some questions remain as to whether these endpoints will prove to be reliable substitutes for survival. Clearly, there are potential problems that may limit the use of these early time points. First, many studies have suggested that patients with malignant gliomas who have undergone concurrent chemotherapy and RT are likely to manifest worrisome findings on their first post-RT MRI scan. Originally thought to universally indicate early tumor progression, this phenomenon has often been found to be due to a transient effect on imaging characteristics induced by chemoradiotherapy, referred to as “pseudoprogression” within the neuro-oncology community.14–17
In any treatment regimen modeled after the Stupp protocol, patients would receive RT 5 days per week for a total of 6 weeks in conjunction with daily TMZ, followed by a 1–2-week break before starting adjuvant TMZ. On the basis of this schedule, the evaluation of progression at 2 months would be 1–2 weeks after the completion of RT. Consequently, the reliability of evaluation of progression at 2 months may be confounded by pseudoprogression. In our analysis, the accrual period of the trials spanned from 2000 to 2007. During that time, increasing attention has been paid to the phenomenon of pseudoprogression, which may explain the decreasing incidence of early progression over time seen in our data. Specifically, by the chronological order with which these trials were conducted, the respective percentages of patients evaluated as having progressed at the first MRI scan (after completion of RT) were 28%, 26%, and 15%. It is difficult to determine whether the marked decrease in early progression at the 2-month time point in the most recent trial (OTRT) was influenced by the investigators' increased awareness of pseudoprogression, or if it was the actual result of treatment success. Regardless, we were able to establish a strong relationship between progression status at 2 months and survival not only in this trial, but in the other two trials as well.
Second, the trade-off in using an earlier time point to evaluate efficacy is a corresponding increase in sample size required. To illustrate, suppose in designing a new phase II single-arm upfront GBM trial, the criteria for a successful/unsuccessful trial is 75% vs 54% (consistent with Stupp et al.1
) PFS-6. If we assume an exponential distribution, then a 54% vs 75% difference at 6 months would correspond to 82% vs 90% at 2 months and 66% vs 83% at 4 months. Whereas 33 patients are sufficient to have 90% power (with 1-sided α = 0.1) for the PFS-6 endpoint, 121 and 42 patients would be required to have similar power for the earlier PFS-2 and PFS-4 endpoints, respectively. For these reasons, there does not appear to be sufficiently compelling rationale to recommend the use of PFS at a very early time points such as 2 months as primary efficacy endpoints for the phase II upfront GBM trials. However, with increasing understanding of pseudoprogression, it may be appropriate to consider using these very early endpoints to devise early stopping rules for lack of efficacy in upfront trials, as a way to limit the investment of patients, time, and money in an ineffective trial.
A major appeal of using PFS-6 as the primary endpoint for upfront GBM trials is its potential to substantially shorten the time required to move forward an effective treatment regimen. In the example described in the previous paragraph, a trial using PFS-6 as the primary endpoint would need 33 patients to detect an improvement of PFS-6 from 54% to 75%. In addition to the accrual period, the trial would require a maximum 6 months of follow-up after the last subject has been enrolled. In contrast, assuming exponential distribution and 61% survival at 1 year under the null (consistent with Stupp et al.1
), a trial that uses survival as the primary endpoint with the same effect size (54% vs 75%) would require a maximum 15 months of follow-up. Nevertheless, it should also be emphasized that our analysis does not represent a formal assessment of surrogacy of PFS for OS. Formal validation of surrogacy would call for analysis of patient data from large comparative phase III trials. In addition, the ability to generalize our results may be somewhat limited by the fact that all trials included in this analysis were based on a single-institutional experience.
In summary, in this analysis of 183 patients from 3 trials in the setting of a newly diagnosed GBM, we demonstrated that progression status at 2, 4, and 6 months were significant predictors of OS. Patients who showed the signs of early progression were at significantly higher risk of earlier death. Our analysis suggested that PFS at 6 months may be an appropriate primary endpoint in the context of phase II trials evaluating treatment regimen in newly diagnosed GBM patients based on the Stupp protocol. Future research is needed to validate our findings in a larger population, both to confirm our results and to ensure their generalizability.