Current trends of clinical trials for older patients with cancer: A systematic review.
Authors: Fazio Roberta , Audisio Alessandro , Saad Everardo D. , Bregni Giacomo , Sur Daniel Genel , Daprà Valentina , Conti Chiara , Abbassi Fatima-Zahra , Benhima Nada , Assaf Irene Georges , Hendlisz Alain , Van Laethem Jean-Luc , Buyse Marc E. , Sclafani Francesco 
Published: May 2024

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Background: While accounting for 40% of the cancer population, older adults are underrepresented in clinical trials. Older-age-selected studies are desirable, but their characteristics and overall performance are unknown. This systematic review assessed design and outcomes of trials focused on this patient population. Methods: We searched Embase and PubMed with the keywords “older adults”, “cancer” and “clinical trials”, from inception to March 1, 2023. We included phase (Ph) I, II and III trials testing systemic therapies in solid cancer patients (pts) aged ≥70 yrs. For each of the selected trials, we carried out an ad-hoc search for age-unselected trials testing the same interventions in the same setting. We followed the PRISMA guidelines for systematic reviews and registered the study on the PROSPERO database (CRD42023465089). Results: We screened 25,868 records and included 313 studies. 48 (15.4%) were Ph I-I/II, 232 (74.1%) Ph II, and 33 (10.5%) Ph III. The minimum-age threshold used to define ‘old’ was 70-74 yrs in 79.9%, 75-79 in 19.8%, and 80 in 0.3% of cases. Most trials (76.7%) were run in the palliative setting. Common tumors included lung (60.4%) and colorectal cancer (15%), while chemotherapy (88.5%) and targeted therapy (23.6%) were the most frequently tested treatments. Non-conventional primary endpoints (e.g., toxicity, feasibility, functional status, quality of life [QoL]) were used in 8.3% of Ph II-III trials. 24 studies were published in 1990-2000, 126 in 2001-2011, and 163 in 2012-2023. The median accrual time was 32 (IQR 21.5-44.5), 30 (IQR 20-43) and 43 months (IQR 36-65) for Ph I, I/II-II, and III, respectively. Of 234 trials reporting the pre-planned target accrual, 77.8% enrolled ≥90% of the required pts. Premature study discontinuation occurred in 50 studies (5.9% of Ph I, 14.2% of Ph II and 39.4% of Ph III), the major reason being slow accrual, while only 9 and 6 closed due to futility and overt efficacy, respectively. Among the 233 trials with a pre-defined statistical hypothesis, 60% met the primary endpoint, including 63.7% Ph I/II-II and 35.5% Ph III trials. Geriatric assessments (GA) and QoL analyses were carried out in 88 (28.1%) and 72 (23%) trials, respectively. Only 18 (5.8%) studies were dedicated to frail pts. Corresponding age-unselected trials were available for 154 older-patient studies. Compared with those, a higher proportion of age-unselected studies enrolled ≥90% of the required pts (95% vs 83.5%, p=0.03) and met the primary endpoint (80.3% vs 63.9%, p=0.03). Conclusions: The interest in clinical trials of solid tumors in older patients has increased over time. While Ph I and II trials are feasible, still a substantial proportion of Ph III trials suffer from slow accrual and premature discontinuation. Interventions to tackle barriers to recruitment should be implemented. Efforts should be made to systematically include GA and QoL analyses, which are key for this patient population.