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.

• Guaraná (Paullinia cupana) (Dietary supplement): Guaraná 50 mg capsule administered orally every 12 hours, 21 days per cycle, for up to 6 cycles (total 126 days). Manufactured by INVIMA-certified suppliers; stored under controlled conditions. Adherence monitored by capsule count plus patient diary; adverse events graded with CTCAE v5.0.

Primary outcomes

• Change in cancer-related fatigue measured by FACIT-F (Functional Assessment of Chronic Illness Therapy - Fatigue) [Baseline, week 3, and end of treatment (up to 126 days)]: Change in FACIT-F score from baseline to post-intervention. Higher scores indicate less fatigue.
• Change in fatigue measured by the Brief Fatigue Inventory (BFI) [Baseline, week 3, and end of treatment (up to 126 days)]: Brief Fatigue Inventory (BFI). Change from baseline in the BFI global fatigue score, calculated as the mean of all 9 items. Each item is rated on a 0-10 numeric scale. Severity subscale = mean of items 1-3 (range 0-10; 0 = no fatigue, 10 = as bad as you can imagine). Interference subscale = mean of items 4-9 (range 0-10; 0 = does not interfere, 10 = completely interferes). Higher scores indicate worse fatigue (worse outcome)

Secondary outcomes

• Change in quality of life measured by EORTC QLQ-C30 [Baseline, week 3, and end of treatment (up to 126 days)]: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC-30, version 3.0). Change from baseline in the global health status/QoL scale and in functional and symptom scales. All raw scores are linearly transformed to a 0-100 range. For the global health status/QoL and functional scales, higher scores indicate better outcome; for symptom scales/items, higher scores indicate worse outcome.
• Frequency and severity of adverse events (CTCAE v5.0) [Throughout treatment, up to 126 days]: Adverse events documented and graded per CTCAE v5.0, with attention to CNS stimulation (insomnia, palpitations, anxiety) and bleeding.

Other outcomes

• Change in caregiver-perceived patient quality of life measured by a caregiver proxy adaptation of the EORTC QLQ-C30 [Baseline, week 3, and end of treatment (up to 126 days)]: Change from baseline in the caregiver's perception of the patient's quality of life, assessed with a caregiver proxy adaptation of the EORTC QLQ-C30, version 3.0, in which the 30 original items are reworded so that the patient's primary caregiver rates the patient rather than the patient self-reporting. Items 1-28 are rated on a 4-point scale (1 = not at all, 4 = very much) and items 29-30 on a 7-point scale (1 = very poor, 7 = excellent). Items are grouped into one global health status/quality of life scale, five functional scales (physical, role, emotional, cognitive, social) and nine symptom scales/single items, and scored using the standard EORTC scoring procedure: the raw score for each scale is the mean of its component items, linearly transformed to a 0-100 range.Higher scores on the global health status/quality of life and functional scales indicate better perceived quality of life; higher scores on symptom scales indicate worse perceived symptom burden.
• Adherence to guaraná supplementation [Each cycle, up to 126 days]: Adherence by capsule count and patient diary (e.g., proportion of prescribed capsules taken).
• Change in serum proinflammatory cytokines (IL-1β, IL-6, TNF-α) in a subset of participants (n=30) [Baseline, weeks 6-8, and at end of treatment (up to 126 days)]: Change from baseline in serum concentrations of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), measured by \[ELISA/multiplex immunoassay\] and reported in pg/mL, in a prespecified subset of 30 participants.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologic diagnosis of breast, lung, colorectal, cervical or gastric cancer
* Receiving active cancer treatment
* Has completed at least three cycles of chemotherapy

Exclusion Criteria:

* Intolerance to the oral route
* Contraindications to guaraná intake
* Uncontrolled cardiovascular disease (uncontrolled atrial fibrillation, symptomatic tachyarrhythmias, prolonged QT)
* History of intolerance to caffeine, methylxanthines, or flavonoids
* Use of CNS stimulants
* Recent history of bleeding
* Use of warfarin or any other vitamin K antagonist
* Use of theophylline

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• Andrés F Cardona, MD, MSc, PhD, MBA, Study director, Fundación CTIC Centro de Tratamiento e Investigación sobre Cáncer Luis Carlos Sarmiento Angulo