Rethinking Overall Survival: Still an Acceptable Sole Primary Endpoint in Cancer Clinical Trials?

Maurie Markman, MD
Published: Friday, Mar 29, 2013
Maurie Markman, MD

Maurie Markman, MD

So that there is no confusion on this point: A major goal of all antineoplastic therapies and trials designed to evaluate them should be to improve survival—period. However, the question that this clinical commentary will address is not whether improved overall survival is a valid aim of such trials, but whether overall survival can still be considered the sole acceptable primary endpoint in studies of novel anticancer therapeutic strategies.

This question is critical to the development of effective strategies in nonresearch-based cancer management, and can be illustrated by the following phase III trial results involving entirely different cancers (ovarian vs lung cancer) and types of antineoplastic strategies (standard cytotoxic chemotherapy vs molecularly targeted drugs), and conducted more than a decade apart.1,2

Consider, first, a trial by Muggia et al, reported in 2000, in which patients with ovarian cancer were randomized to single-agent cisplatin, single-agent paclitaxel, or the combination of cisplatin and paclitaxel (Table 1).1 The study found a substantially higher objective response rate and superior time to disease progression in favor of the platinum-containing regimens (both the single-agent and combination regimens) compared with single-agent paclitaxel. However, there was no difference in overall survival between the study arms, and specifically between the platinum-containing and non-platinum-containing primary chemotherapy strategies.

This outcome almost certainly occurred because patients in both of the single-agent treatment arms crossed over to the alternative single agent or had the second drug added to their treatment, in some cases prior to the time of documented disease progression. As a result, by the time the study was completed and analyzed, the majority of patients had actually received both cisplatin and paclitaxel.

Table 1. Single Agent Cisplatin Versus Single Agent Paclitaxel Versus Cisplatin Plus Paclitaxel as Primary Chemotherapy in Advanced Ovarian Cancer1

  Response Rate Progression-Free Survival (median) Overall Survival (median)
Cisplatin 67% 16.4 months 30.2 months
Paclitaxel 42% 11.2 months 26 months
Cisplatin + Paclitaxel 66% 14.0 months 26.6 months
  P <.001, 2 cisplatin-containing regimens compared with paclitaxel P <.001, 2 cisplatin-containing regimens compared with paclitaxel P =.31, between the 3 treatment groups


Since there was no overall survival advantage observed in this trial, does this outcome indicate there was no advantage associated with employing both cisplatin and paclitaxel in ovarian cancer management, and that single-agent treatment with either of these therapies is of equivalent clinical utility? The answer to this question is unequivocally no.

In fact, a previous study by the same research group clearly demonstrated superior overall survival results in advanced ovarian cancer for cisplatin/paclitaxel versus cisplatin/cyclophosphamide.3 However, in that study, few patients randomized to the non-taxane-containing regimen (cisplatin/cyclophosphamide) ever subsequently received paclitaxel prior to their death from progressive cancer.

Thus, in the study by Muggia et al, the absence of an overall survival benefit within the trial population does not indicate a lack of benefit associated with the use of the two novel drugs.1 Rather, the data demonstrate that delivering a second clinically effective agent at some later point in the course of the illness may be as useful (in a statistical sense within a given patient population) as administering the drug as a component of the primary treatment regimen.

The bottom line is that all patients who participated in the study by Muggia et al were given the opportunity to potentially benefit from the delivery of the second active agent.1,4-6 Under such circumstances, there may be no difference in the measurement of survival between the study arms.


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