Success, significance, and social responsibility
Authors: Jan C. Buckner
Journal: Neuro-Oncology (2015)

At the 2014 Annual Meeting of the Society for Neuro-Oncology, Dr. Michael Prados, in his Victor Levin Award presentation, poignantly reminded us that personal or group successes such as obtaining a degree, completing a clinical trial, or publishing a paper do not necessarily translate into clinically significant advances that improve survival or quality of life for our patients. At the same meeting, investigators presented results of 3 randomized clinical trials suggesting early success. The first, BELOB, was a randomized, noncomparative, phase 2 trial in patients with recurrent glioblastoma who received either lomustine alone, bevacizumab alone, or the combination of lomustine and bevacizumab.1 The study was a success in that it met its primary, prespecified endpoint of 9-month survival in favor of the combination of lomustine and bevacizumab (59% of patients) versus bevacizumab alone (38%) or lomustine alone (43%). Median survival in the combination arm was approximately 3 months longer than that for either single-agent arm. The second trial, ReACT, involved patients with recurrent glioblastoma who received either bevacizumab alone or in combination with rindopepimut, a vaccine to the EGFRvIII mutant receptor.2 Again, median survival in the arm containing rindopepimut was approximately 3 months longer than that of the control arm with bevacizumab alone. In the third trial, the investigators presented the results of a planned interim analysis of an initial cohort of patients with newly diagnosed glioblastoma who all received standard radiation therapy plus concurrent temozolomide. Those who had not progressed following radiation received either temozolomide alone or a combination of temozolomide and tumor-treating fields (TTF). TTF consists of continuous application of electrical impulses generated through electrodes placed on the scalp.3 In the initial cohort of patients analyzed per protocol (315 of more than 700 enrolled), this trial also met a prespecified endpoint, with increased median survival in the TTF arm being 3 months longer than that in the radiation and TMZ alone arm (19.6 vs 16.6 months).

All of the investigators are to be congratulated for their success in identifying potential benefit for those patients in the experimental arms of the trials. Of note, the results of each study are preliminary. The BELOB and REACT trials were randomized phase 2 trials that were not designed to demonstrate conclusively the superiority of the experimental arm compared with the control arm. Consequently, we do not yet know if this apparent success is a true success. Similarly, analysis of the TTF trial, while clearly promising, is preliminary. The investigators reported a planned interim analysis of the first 315 patients out of a total of more than 700 patients in the study. In addition, the results of quality control measures are not yet available. For example, we do not know the concordance between local pathology and central pathology review to confirm the diagnosis of glioblastoma in all patients in both the treatment and experimental arms. We also do not know if postprogression treatment is similar in the experimental and control arms. Moreover, as with randomized phase 2 trials, the results of interim analyses do not always reflect the final results. Until the data from the entire randomized population are available, we will not know if the TTF trial is a true success.

On the issue of significance, it is important to note that results from each of the 3 trials indicate an approximately 3-month improvement in overall survival for patients with either recurrent or newly diagnosed glioblastoma. Are these results truly significant (if verified to be true)? None of the trials indicates a significant increase in long-term survival, and none purports to offer curative therapy. Toxicity, inconvenience, and expenses are increased with each new promising treatment in comparison with control arms. Only a portion of patients benefit at all. Consequently, it is imperative that additional investigations attempt to identify those patients who benefit and those who do not. While a 3-month improvement in overall survival is promising, the clinical significance is modest at best.

On the other hand, the principles established in each trial may be more important for future advances in the field than the clinical significance observed in these trials. Concurrent bevacizumab with lomustine was more beneficial than treatment with either agent alone, demonstrating the beneficial effect of combining an alkylating agent with a VEGF-binding agent. Can this approach be exploited to achieve greater benefit in other settings or with related agents? Rindopepimut is the first vaccine to demonstrate a potential increase in survival for glioblastoma patients. It was delivered in combination with bevacizumab. Does this represent clinical evidence for interaction between immunostimulatory agents and VEGF-binding agents? TTF is a novel, nonpharmaceutical approach that induces tumor cell mitotic arrest. This novel approach could be exploited in other tumor types and in combination with other therapeutic interventions. For all 3 trials, their greater significance may be in providing insights into subsequent therapeutic approaches rather than in the treatment effect observed in these trials.

Finally, for each of the 3 promising studies, the cost for the incremental benefit (possibly 3 more months of life) is accompanied by significant cost. As practicing clinicians, we have responsibilities to individual patients as well as to society as a whole: our social responsibility. For each of the 3 studies, the new technology is estimated to cost about $20 000 per month of treatment delivered, whether or not individual patients are achieving significant benefit. Does society as a whole agree that expensive, noncurative therapies that delay end of life by 3 months should be widely deployed? Furthermore, we are morally and socially obligated to seek the means of predicting the patients who will derive benefit from therapy and those who will not.

In summary, Dr. Prados reminded us to reconsider the distinction between success and significance. The results of the 3 studies cited may well represent successes for the investigators. The significance of those successes remains unclear. Outcomes reported in the BELOB and REACT trials should be verified in appropriately powered phase 3 trials. Analysis of the entire cohort of patients treated with TTF needs to occur. Further trials confirming the principles of treatment suggested by these trials may also verify their significance over time. Finally, their significance must be weighed in the context of the substantial societal costs associated with delivery of those therapies. Can we find ways to reduce per-patient costs and maintain therapeutic benefits? Do we need to establish a threshold of benefit for admittedly palliative therapies in order to remain socially responsible? If we ourselves do not determine ways to address concerns of social responsibility, others will certainly do so for us, and we may not like the results.