Latitude, Seasonality, and Circadian Determinants of Outcomes of Systemic Cancer Therapy: Evidence from Chemotherapy, Immunotherapy, and Chemo-Immunotherapy Combinations. A Systematic Review.
TL;DR
Time-of-day of treatment, seasonality, latitude-related sunlight exposure, vitamin D status, and circadian rhythm integrity are potentially relevant determinants of systemic therapy outcomes.
Abstract
Objectives
To evaluate whether treatment timing (chronotherapy/time-of-day infusion), seasonality, geographic latitude, and related vitamin D status are associated with efficacy and toxicity outcomes of systemic therapy for solid tumors. STUDY
Design
PRISMA 2020-guided systematic review with qualitative synthesis.
Methods
PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched from inception to January 20, 2026, with additional screening of oncology conference proceedings and trial registries. Eligible studies included randomized trials, observational cohorts, and meta-analyses assessing treatment timing, season/latitude proxies (including serum 25-hydroxyvitamin D), and/or objective circadian disruption, with outcomes including overall survival (OS), progression-free survival (PFS), response, and treatment-related toxicity. Two reviewers independently screened and extracted data using a predefined form. Risk of bias was assessed using Cochrane RoB 2.0 and the Newcastle-Ottawa Scale. Because of substantial clinical and methodological heterogeneity, findings were synthesized qualitatively and stratified by exposure domain and study design.
Results
Thirty-five studies were included (6 randomized trials, 2 patient-level meta-analyses, 5 prospective cohorts, 22 retrospective cohorts). Chronomodulated chemotherapy consistently reduced toxicity and sometimes improved response/time-to-progression, but survival effects were heterogeneous and appeared sex-dependent. Earlier immune checkpoint inhibitor administration (morning/early daytime) was associated with longer OS/PFS in mostly retrospective cohorts; these findings should therefore be considered hypothesis-generating pending prospective confirmation. Seasonal and latitude analyses generally showed worse outcomes in winter and at higher latitudes, although ecological and observational designs limited causal inference. Higher vitamin D levels and supplementation during immunotherapy were associated with improved survival but may partly reflect baseline health status and other prognostic factors. Objective circadian disruption was repeatedly associated with poorer prognosis.
Conclusions
Time-of-day of treatment, seasonality, latitude-related sunlight exposure, vitamin D status, and circadian rhythm integrity are potentially relevant determinants of systemic therapy outcomes. Evidence is strongest for chemotherapy chronomodulation in selected historical randomized trials, whereas immunotherapy timing, seasonal/latitude effects, and vitamin D associations remain less causally established. Prospective randomized studies should test pragmatic interventions such as structured ICI scheduling and vitamin D assessment/correction before routine implementation.