“Start low, go slow,” a strategy to tailor treatment dosing in older or vulnerable adults with advanced solid cancer: A systematic review and meta-analysis

INTRODUCTION: The use of standard-dose cancer treatment can result in a decline in the functional abilities of older adults with cancer. The "start-low, go-slow" (SLGS) strategy involves initiating cancer treatment at lower-than-standard doses in selected patients who are vulnerable to excess toxicity and escalating based on tolerance. We performed a systematic review and meta-analysis to assess the available data and the effectiveness of the SLGS strategy in the treatment of cancer in older adults with incurable solid cancer.

MATERIALS AND METHODS: The review was registered with PROSPERO. Two independent reviewers (GA and TP) conducted a comprehensive search across multiple databases (PubMed/Medline, Journal of Geriatric Oncology, American Society of Clinical Oncology abstracts, and EMBASE) of prospective studies involving patients with solid tumors who received SLGS. SLGS was defined as starting cancer therapy with a lower than standard dose and dose-escalating, if possible. The main objective of this study was to evaluate overall survival (OS) in patients treated with the SLGS strategy. Secondary objectives were to analyze treatment discontinuation and toxicity in patients treated with the SLGS strategy. Additionally, we aimed to compile a comprehensive report on studies employing the SLGS strategy in solid oncology. We utilized a random-effects meta-analysis model to consider the diversity among patient populations with different cancer stages, types, and treatments. Two researchers independently employed the Newcastle-Ottawa Quality (NOQ) assessment for cohort analysis to evaluate the methodological quality and standard of outcomes reporting in the included studies. The quality of evidence was appraised using the Grading recommendations assessment, development and evaluation GRADE summary of findings tool.

RESULTS: The systematic search identified a total of 12,690 articles. Thirteen studies met criteria for inclusion in the systematic review, totaling 8546 patients. Twelve studies evaluated OS. However, only five studies focused solely on older adults, and the studies involved different types of cancer without following a specific pattern. In meta-analysis of survival among three studies, patients who underwent the SLGS approach had lower mortality (hazar ratio 0.91, 95 % confidence interval [CI] 0.85-0.98, p = 0.01, i2 = 0 %). Toxicity ranged from 5 % to 89 % across studies; SLGS had lower grade 3 and 4 toxicity compared to the standard dose (six studies, meta-analysis relative risk 0.86, 95 % CI 0.75-0.98, p < 0.02, i2 = 30 %). Treatment discontinuation was not different for SLGS vs. standard dose (seven studies, meta-analysis RR 0.96, 95 % CI 0.87-1.05, p = 0.37 i2 = 50 %).

DISCUSSION: This systematic review and meta-analysis suggests that a SLGS approach to systemic therapy dosing may reduce toxicity without affecting survival among older patients with solid tumors, although results are limited by a limited number of prospective studies. Additional research is needed to understand better the effects of SLGS in older adults receiving palliative chemotherapy.