Guaraná Supplementation for Cancer-Related Fatigue

Background and rationale: Cancer-related fatigue affects 50-90% of patients across the disease trajectory and may persist for years after treatment. Its pathophysiology involves systemic inflammation, mitochondrial and skeletal-muscle dysfunction, oxidative stress, immune activation, and central-nervous-system involvement, with proinflammatory cytokines (IL-1, IL-6, TNF-α) contributing to symptom perpetuation. Available pharmacologic options (methylphenidate, modafinil, megestrol acetate) carry meaningful toxicity. Guaraná seeds contain 6-8% caffeine plus theophylline, theobromine, tannins, flavonoids and saponins, conferring stimulant, antioxidant and anti-inflammatory activity; prior trials and meta-analyses suggest benefit on fatigue with minimal toxicity, but results are inconsistent and ASCO/SIO have called for more rigorous trials. Design: Pragmatic, prospective, single-arm study conducted in real-world clinical practice at a single center. Intervention: guaraná 50 mg capsule orally every 12 hours, 21 days per cycle, up to 6 cycles (total 126 days). Assessments at baseline, week 3, and end of treatment. Primary outcome: change in fatigue (FACIT-F and BFI). Secondary outcomes: quality of life (EORTC QLQ-C30), adverse events (CTCAE v5.0), and caregiver-perceived quality of life (proxy survey). Exploratory: adherence (capsule count, diary) and change in serum proinflammatory cytokines (IL-1, IL-6, TNF-α by ELISA) in a randomly selected subset of 30 participants (5 mL fasting venous blood at baseline, after 6-8 weeks, and at end of treatment; serum stored at -80 °C). Statistics: paired t-test or Wilcoxon for the pre-post change; multivariable regression adjusting for prespecified covariates; ITT with multiple imputation and per-protocol sensitivity analyses; α = 0.05 (two-sided), 80% power. Data captured in REDCap.