Maurie Markman, MD
Although publication of clinical trial findings in a peer-reviewed journal is a vital step in disseminating emerging research developments, there is a critical need for all readers of oncology literature to approach these reports with a healthy degree of skepticism. Among the important questions that readers should ask are whether the conclusions are truly meaningful to patients and why the study was initiated in the first place.
This commentary offers examples of clinical trials where the interpretation of study results is worthy of considerable additional discussion or where justification for the actual conduct of the study can be called into question. In fact, it is not hard to find studies in the peer-reviewed oncology literature where an objective observer could lodge a serious challenge against the conclusions reached by the study investigators. The examples discussed here include a colorectal cancer study and, due to the research interests of this commentator, several studies focused on the gynecologic cancer area. However, it is virtually certain that similar arguments could be advanced in regard to multiple other areas within oncology.Debatable Conclusions in Colorectal StudyFOLFOXIRI Versus FOLFIRI
The recent publication of the results of a phase III trial that compared two multiagent combination chemotherapy regimens (FOLFOXIRI vs FOLFIRI) plus bevacizumab as first-line treatment of metastatic colorectal cancer serves as the starting point for this commentary.1
The issue here is whether the statistically significant improvement in progression-free survival (PFS) of a median 2.4 months (P
= .003) and a 12% increase the objective response rate (65% vs 53%), but nonstatistically significant superior overall survival (OS) of a median 5.2 month difference (P
= .054) associated with the delivery of the FOLFOXIRI program justify its use when the regimen is also associated with a rather impressive increased risk of certain highly clinically relevant grade 3-4 toxicities (peripheral neuropathy [5.2% vs 0%]; diarrhea [18.8% vs 10.6%]; stomatitis [8.8% vs 4.3%]).
How should the study be interpreted? Should the statistically significant improvement in PFS and objective response rate in this difficult clinical setting trump the associated increased risk of distressing side effects and permit the study to be labeled as a “positive” trial? Or should the toxicity profile in the absence of a statistically significant impact on OS result in the conclusion that this regimen is not a favored alternative in this clinical setting? This is especially relevant when another approach might be the sequential delivery of agents rather than a single combination program, resulting in equivalent survival, less treatment-related toxicity, and an overall superior quality of life.
Unfortunately, and perhaps surprisingly considering the risk of serious side effects, a formal quality-of-life assessment was not performed as a component of this study. The authors of this trial appear to conclude the added toxicity is justified based on the previously stated clinical endpoints. But considering the modest documented improvements noted in the presence of a substantial increased risk of clinically relevant side effects, it would not be difficult to challenge the interpretation of these investigators.Questionable Findings in Ovarian TrialPegylated Liposomal Doxorubicin Versus Topotecan
This study compared single-agent pegylated liposomal doxorubicin with single-agent topotecan as a treatment for platinum-resistant or recurrent potentially platinum-sensitive ovarian cancer.2
There was no observed difference in outcome (response rate, PFS, or OS) between the drugs in the platinum-resistant patient population. However, in the potentially platinum-sensitive group, the administration of pegylated liposomal doxorubicin was associated with a very modest improvement in PFS (median 28.9 weeks vs 23.3 weeks; P
= .037) but a substantially greater difference in OS (median 108 weeks vs 71.1 weeks; P
Somehow, a median difference of less than 2 months in PFS was translated into a median 9.2 month improvement in OS.
The investigators concluded that the administration of pegylated liposomal doxorubicin improved OS in recurrent platinum-sensitive ovarian cancer. But is this the only—or even the most likely—explanation for these unexpected and realistically unexplained findings?