The Role of End-of-Life Issues in the Design and Reporting of Cancer Clinical Trials: A Structured Literature Review.

Background: Randomized controlled trials (RCTs) are important sources of information on the benefits and harms patients may expect from treatment options. The aim of this structured literature review by the German Institute for Quality and Efficiency in Health Care was to explore whether and how the end-of-life (EoL) situation of patients with advanced cancer is considered in RCTs investigating anti-cancer treatments.

Methods: Our journal pool comprised 19 medical journals, namely five preselected key general medical journals as well as 14 specialist journals (mainly cancer) identified via a scoping search. We systematically searched these journals in MEDLINE to identify RCTs investigating anti-cancer treatments for the following four cancer types: glioblastoma, lung cancer (stage IIIb-IV), malignant melanoma (stage IV), and pancreatic cancer (search via OVID; November 2012). We selected a representative sample of 100 publications, that is, the 25 most recent publications for each cancer type. EoL was defined as a life expectancy of ≤ two years. We assessed the information provided on (1) the descriptions of the terminal stage of the disease, (2) the therapeutic goal (i.e. the intended therapeutic benefit of the intervention studied), (3) the study endpoints assessed, (4) the authors' concluding appraisal of the intervention's effects, and (5) the terminology referring to the patients' EoL situation.

Results: Median survival was ≤ one year for each of the four cancer types. Descriptions of the terminal stage of the disease were ambiguous or lacking in 29/100 publications. One or more therapeutic goals were mentioned in 51/100 publications; these goals were patient-relevant in 38 publications (survival alone: 30/38; health-related quality of life (HRQoL) or HRQoL and survival: 6/38; symptom control or symptom control and survival: 2/38). Primary endpoints included survival (50%), surrogates (44%), and safety (3%). Patient-reported outcomes (PROs) were assessed in 36/100 RCTs. The implications of treatment-related harms for the patients were discussed in 22/100 appraisals. Terminology referring to the patients' EoL situation (e.g. "terminal") was scarce, whereas terms suggesting control of the disease (e.g. "cancer control") were common.

Conclusions: The EoL situation of patients with advanced cancer should be more carefully considered in clinical trials. Although the investigation and robust reporting of PROs is a prerequisite for informed decision-making in healthcare, they are rarely defined as endpoints and HRQoL is rarely mentioned as a therapeutic goal. Suggestions for improving standards for study design and reporting are presented.