In an analysis that evaluated the outcomes of anticancer drug studies in the advanced disease setting with regard to patient quality of life (QOL), improved QOL outcomes were associated with improved overall survival but not with improved progression-free survival. Almost half of the studies that demonstrated improved progression-free survival showed no improvements in overall survival or QOL. Some publications summarized QOL findings with statements that were not directly supported by the study data, and contrary to common perception, inferior QOL outcomes were more common with targeted drugs than with cytotoxic drugs. Findings from this retrospective cohort study of 45 randomized clinical trials were published by Samuel et al in JAMA Oncology.

Study Background

The authors explained that overall survival and QOL are the most important markers of therapeutic benefit of anticancer drugs in clinical studies. However, several studies have shown that many anticancer drugs receive regulatory approval without any evidence of improvement in either of these endpoints, based only on improvement of putative surrogates of efficacy. In particular, QOL is less frequently evaluated in randomized clinical studies of anticancer drugs and, even when tested, is underreported. Studies have shown that progression-free survival—a commonly used intermediate primary endpoint—is poorly correlated with QOL and overall survival. Some physicians and patients also believe that targeted drugs are associated with better QOL than cytotoxic chemotherapy, thus promoting chemotherapy-free regimens.

Furthermore, the authors wrote that although worsening QOL is clearly an adverse outcome, failure to improve QOL demands special consideration in making risk-benefit decisions. However, study publications often report an observed lack of improvement in QOL in a positive way, such as QOL being maintained rather than not improved, which may be misinterpreted as a beneficial effect on QOL. To best inform discussions with patients about proposed treatments, the authors emphasized that it is important to clearly understand and communicate the effects of anticancer drugs on QOL alongside the effects on overall survival and intermediate endpoints such as progression-free survival.

Methodology

This retrospective cohort study included all patients with advanced cancer who were enrolled into phase III randomized clinical studies of anticancer drugs reporting QOL data and published in English in PubMed-indexed journals in 2019. The systematic search of PubMed was conducted in July 2020. Main outcomes and measures were the association of QOL outcomes with overall and progression-free survival, framing of unchanged QOL outcomes in study publications, and the association of favorable framing with study funding by industry.

A total of 45 phase III randomized clinical studies enrolling 24,806 patients (with 13,368 in the experimental arm and 11,438 patients in the control arm) met the inclusion criteria.

Improvements in QOL

Improvement in global QOL with the experimental drug being tested was reported in 11 randomized clinical studies (24%). Randomized clinical studies with improved QOL were more likely to show improved overall survival compared to studies with unimproved QOL (7 of 11 studies [64%] vs 10 of 34 studies [29%] P = .04). No such association was observed for progression-free survival (6 of 11 studies [55%] vs 17 of 34 studies [50%], P = .87). Furthermore, 6 studies reported QOL worsening, of which 3 studies (50%) were with targeted drugs, and 11 studies reported improvement in QOL, of which 6 (55%) were studies of immunotherapy drugs.

Of the 34 studies in which QOL was not improved compared with controls, 16 studies (47%) reported these results in a positive light—an observation statistically significantly associated with study funding by industry (P = .01).

Conclusions

The authors commented that numerous studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues they have raised. Although they focused on global QOL, some patients may find specific subdomains of QOL meaningful in some clinical settings. But they explained that focusing on noncurative settings only is a strength rather than a limitation of the analysis, because the risk-benefit thresholds are different in curative settings, where patients may be willing to accept QOL worsening to a certain degree in exchange for improved odds of cure.

Findings from this analysis have important implications for physicians, patients, regulators, and payers, who must be aware of these issues to interpret QOL data from anticancer drug studies accurately and meaningfully.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.