Taiwanese Green Propolis for Lipid Profiles, Fatigue, and Quality of Life in Oral Cavity Cancer Survivors (TGP-OCS)

Background:

Oral cavity squamous cell carcinoma (OSCC) survivors frequently experience persistent metabolic complications after treatment, including dyslipidemia, chronic low-grade inflammation, cancer-related fatigue (CRF), muscle weakness, and impaired quality of life. The prevalence of metabolic syndrome in this population substantially exceeds that of the general Taiwanese adult population.

Taiwanese green propolis (TGP), derived from Macaranga tanarius (L.) Müll.Arg. (Euphorbiaceae), has a phytochemical profile distinct from Brazilian or Mediterranean propolis, comprising prenylated flavanones-principally propolin C, D, F, G, and H. These compounds have demonstrated hepatoprotective effects (TGF-β/Smad2/3 pathway), anti-inflammatory activity (NLRP3 inflammasome suppression), and lipid-metabolic regulatory properties in preclinical studies. No prior clinical trial has evaluated TGP in OSCC survivors.

Study Design:

Pilot double-blind, placebo-controlled, parallel-group randomized controlled trial (RCT). Intervention period: 12 weeks. Post-intervention follow-up: 12 weeks (total 24 weeks). Assessment timepoints: Week 0 (T0/baseline), Week 4 (T4), Week 8 (T8), Week 12 (T12), Week 24 (T24).

Intervention:

• Experimental: TGP capsules (500 mg/capsule), 4 capsules/day (2 capsules BID), providing 2,000 mg TGP/day containing approximately 200 mg propolin compounds/day; 12 weeks.
• Control: Identical-appearing placebo capsules, 4 capsules/day, 12 weeks. Both capsules were identical in appearance, size, color, and smell.

Randomization and Blinding:

Computer-generated random number sequence with allocation concealment. Participants, care providers, investigators, and outcome assessors were blinded throughout the 24-week study period (quadruple blinding).

Primary Outcomes (T0, T8, T12, T24):

Total cholesterol (TC, mg/dL); Triglycerides (TG, mg/dL); High-density lipoprotein cholesterol (HDL-C, mg/dL); Low-density lipoprotein cholesterol (LDL-C, mg/dL).

Secondary Outcomes:

• Cancer-related fatigue: BFI-T mean score (0-10); T0,T8,T12,T24
• Symptom distress: ESAS-r total score (0-90); T0,T4,T8,T12,T24
• Quality of life: FACT-H&N total score; T0,T8,T12,T24
• Grip strength (kg), dominant hand, mean of 3 trials; T0,T4,T8,T12,T24
• 30-second sit-to-stand test (repetitions); T0,T4,T8,T12,T24
• C-reactive protein (CRP, mg/dL); T0,T8,T12,T24
• Alanine aminotransferase (ALT/GPT, U/L); T0,T8,T12,T24
• Aspartate aminotransferase (AST/GOT, U/L); T0,T8,T12,T24
• Gamma-glutamyl transferase (γ-GT, U/L); T0,T8,T12,T24

Exploratory Outcomes:

Body weight, BMI, waist circumference, hip circumference, body fat %, hemoglobin, albumin, fasting glucose, HbA1c, BUN, creatinine, uric acid, WBC count, TSH, T3, T4. Serum interleukin-6 (IL-6, pg/mL); T0,T8,T12,T24. Gut microbiota alpha diversity (Shannon index) and beta diversity (Bray-Curtis dissimilarity) via stool 16S rRNA amplicon sequencing; T0,T8,T12,T24. Gut microbiota relative abundance of key bacterial taxa; T0,T8,T12,T24. Oral microbiota composition via saliva 16S rRNA amplicon sequencing; T0,T8,T12,T24. Salivary inflammatory markers including IL-6 (pg/mL); T0,T8,T12,T24. Heart rate variability: RMSSD and SDNN via smart wristband (minimum 24 hours per timepoint); T0,T4,T8,T12,T24.

Statistical Analysis:

Generalized Estimating Equations (GEE) with exchangeable working correlation structure; independent variables: group, time, and group × time interaction; adjusted for baseline values. Cohen's d calculated for significant interaction terms. Intent-to-treat (ITT) principle; N=25.

Sample Size:

Target: 62 participants (G*Power v3.1; repeated-measures ANOVA; f²=0.30; α=0.05; power=0.80; 10% dropout). Actual enrollment (pilot phase): 25.

Ethics:

Enrolment commenced in April 2024 under the original approved protocol N202305017 (approved 2023-05-22, Taipei Medical University Joint Institutional Review Board). A protocol amendment (N202407011, approved 2024-08-15) refined the inclusion criteria to focus on post-treatment oral cavity cancer survivors, designated lipid profiles as the primary outcome, and repositioned fatigue and quality of life as secondary outcomes. The amendment applied prospectively to all subsequently enrolled participants. Written informed consent was obtained from all participants prior to enrolment.