This clinical study investigates the anti-inflammatory and anti-cancer properties of a high-bioavailability formulation of curcumin (BCM-95) in patients with mid-to-low rectal cancer receiving neoadjuvant chemoradiotherapy (nCRT). Curcumin, a polyphenolic compound derived from Curcuma longa, has demonstrated potent anti-inflammatory and anti-neoplastic activities through the modulation of multiple molecular signaling pathways. It has been recognized by the U.S. Food and Drug Administration (FDA) as "Generally Recognized as Safe" (GRAS; GRN No. 686), with an excellent safety profile when administered orally. Reported adverse effects are rare and primarily related to interference with bile secretion or iron metabolism.
Despite its biological potential, conventional curcumin exhibits extremely low oral bioavailability due to its lipophilic nature, rapid metabolism, and systemic elimination. Clinical studies have reported that even at an oral dose of 12 grams per day, the maximum plasma concentration reaches only about 0.051 mg/mL, with up to 75% of the administered dose excreted in feces. To overcome this limitation, the current trial utilizes a curcumin formulation with enhanced absorption (BCM-95), which combines curcumin with essential oils of turmeric to improve systemic bioavailability.
The primary objective of this single-arm, phase II trial is to evaluate whether oral curcumin supplementation can mitigate radiation-induced gastrointestinal toxicity-particularly radiation enteritis-during neoadjuvant chemoradiotherapy for rectal cancer. The secondary objectives include assessing its effect on treatment response, such as the pathological complete response (pCR) rate, tumor regression grade, and patient-reported outcomes related to bowel function and quality of life.
In addition, a translational research component is embedded within this study. Serial tumor tissue and blood samples will be collected at predefined time points to explore the molecular and immunological mechanisms underlying curcumin's therapeutic effects. Analyses will include assessments of inflammatory cytokines, oxidative stress markers, and tumor microenvironmental changes using molecular and histopathologic methods.
Overall, this study aims to provide both clinical and mechanistic evidence supporting the potential of high-bioavailability curcumin as a safe, adjunctive therapeutic strategy to improve treatment tolerance and oncologic outcomes in rectal cancer patients undergoing chemoradiotherapy.
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Single group
Curcumin (BCM-95®)
Dietary supplementParticipants will receive oral high-bioavailability curcumin (BCM-95®) 3 g per day, divided into two doses, during the full course of standard neoadjuvant chemoradiotherapy (nCRT) for mid-to-low rectal adenocarcinoma. Treatment starts on day one of nCRT and continues until its completion. The curcumin formulation (BCM-95®) combines curcuminoids with turmeric essential oils to improve systemic absorption and bioavailability. All participants receive institutional standard nCRT, including: Radiotherapy: either long-course (50.4 Gy/28 fractions) or short-course (25 Gy/5 fractions). Chemotherapy: fluoropyrimidine-based regimens such as TEGAFOX, FOLFOX, or UFUR. Curcumin capsules are taken orally after meals. The study evaluates whether curcumin can reduce radiation-induced gastrointestinal toxicity and enhance tumor response. Translational analyses of tumor and blood samples will further investigate its anti-inflammatory and anti-cancer mechanisms.
Incidence of Grade ≥3 Gastrointestinal Toxicity (Enteritis or Proctitis) During Neoadjuvant Chemoradiotherapy
The primary endpoint is the incidence of grade ≥3 gastrointestinal adverse events, including enteritis or proctitis, occurring during neoadjuvant chemoradiotherapy (nCRT). Toxicities will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and validated by Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Clinical symptoms (abdominal pain, diarrhea, bloody stool, tenesmus, nausea) will be documented by investigators and research nurses. Colonoscopic assessment using the Vienna Rectoscopy Score will be performed 2-3 weeks after radiotherapy completion to evaluate acute radiation proctitis.
Vienna Rectoscopy Score for Radiation-Induced Proctitis
Endoscopic evaluation of rectal mucosa using the Vienna Rectoscopy Score (VRS) to assess the severity of radiation-induced proctitis. Colonoscopy will be performed before treatment, and again 2 ± 1 weeks and 12 ± 1 weeks after completion of radiotherapy. Scores will be compared across time points to determine curcumin's protective effect against radiation injury.
Three-Year Disease-Related Treatment Failure Rate
Disease-related treatment failure is defined as the occurrence of any locoregional recurrence, distant metastasis, or cancer-related death from the completion of neoadjuvant chemoradiotherapy to three years after curative surgery. Disease status will be assessed through regular clinical visits, imaging studies (CT or MRI), and colonoscopic surveillance.
Five-Year Overall Survival
Overall survival (OS) is defined as the time from the initiation of chemoradiotherapy to death from any cause. Patients will be followed through outpatient visits, hospital records, and national death registry data to determine long-term survival outcomes associated with curcumin treatment.
Molecular and Immune Marker Changes in Tumor and Adjacent Tissues
Tumor and adjacent mucosal biopsies collected at baseline, after radiotherapy, and at surgery will be analyzed by multiplex immunohistochemistry to assess immune-cell infiltration (CD4⁺, CD8⁺ T cells, macrophages, dendritic cells) and expression of immune checkpoint molecules (PD-1, PD-L1, CTLA-4, CD47). Comparisons will determine how curcumin modulates the tumor microenvironment and inflammatory response.
Cytokine Profile and Circulating Tumor DNA (ctDNA) Dynamics
Peripheral blood samples will be analyzed for serum cytokines (Milliplex Human Cytokine/Chemokine Magnetic Bead Panel) and circulating tumor DNA (ctDNA) levels before and after neoadjuvant treatment. Changes in inflammatory cytokines and ctDNA concentration will be correlated with clinical and pathological response to curcumin-based therapy.
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