The Role of Fucoidan in Locally Advanced Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy
The landscape of cancer therapy has witnessed a steady increase in the use of complementary and alternative medicine (CAM), with dietary supplements like fucoidan gaining considerable popularity, especially in the Asia-Pacific region. Fucoidan, a general term for sulfated and fucosylated polysaccharides found in brown seaweed, was first described in 1913. Over 1400 studies have since explored its diverse biological activities, which include antitumor activity, immunomodulation, anticoagulation, anti-inflammation, and enhancement of chemotherapy efficacy.
Fucoidan products vary in molecular weight depending on extraction methods, ranging from 20,000 to 200,000 Da or 400 to 5000 Da. Fucoidan in the lower molecular weight range is known as low-molecular-weight fucoidan (LMF). The biological activities of fucoidan are reportedly linked to its structure and molecular weight, with LMF demonstrating potentially greater biological activity compared to high-molecular-weight fucoidan (HMF). The anticancer activities of fucoidan have been demonstrated in various cancers, including colorectal cancer (CRC), hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, prostate cancer, and melanoma.
For locally advanced rectal cancer (LARC), neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection is the gold standard treatment. However, CCRT can increase the risk of adverse events (AEs) and may diminish patients' quality of life (QoL). Given the reported benefits of LMF, including its potential to improve disease control rates in metastatic CRC and its potent bioactivities, a double-blind, randomized, placebo-controlled study was conducted to investigate the auxiliary effects of LMF as a supplemental therapy for LARC patients undergoing neoadjuvant CCRT.
Study Design and Methodology
This prospective, randomized, double-blind, placebo-controlled study enrolled 107 patients with LARC between November 2018 and December 2021. After exclusions, 87 patients were unblinded for analysis: 44 in the fucoidan group and 43 in the placebo group. The demographic and clinical characteristics of both groups were similar at baseline.
Participants were aged 20-80 years, had LARC confirmed by pathology or radiology, an ECOG score between 0 and 2, and a life expectancy of at least 4 months, among other criteria. Patients receiving LMF orally took 4g twice daily (BID), while the placebo group received 4g of cellulose powder BID for a 3-month intervention period. The LMF powder used was prepared by Hi-Q Marine Biotech.
All enrolled patients received neoadjuvant CCRT. The chemotherapy regimen involved a modified FOLFOX6 (mFOLFOX6) regimen, with oxaliplatin and 5-fluorouracil administered every two weeks. Radiotherapy delivered a total dose of 45-50.4 Gy with daily fractions of 1.8-2.0 Gy.
The primary endpoint of the study was Quality of Life (QoL), assessed using the Functional Assessment of Cancer Therapy for Patients with Colorectal Cancer (FACT-C). This scale includes physical, social, emotional, and functional well-being domains, along with a colorectal cancer subscale. Secondary endpoints included disease-free survival (DFS), overall survival (OS), adverse events (AEs), and changes in gut microbiota composition. Gut microbiota were compared from stool samples collected before and after treatment, with metagenomics DNA extraction and taxonomic classification performed.
Key Findings
The study's database was locked on June 30, 2022, with a median follow-up time of 25.0 months.
- Quality of Life (QoL):
While the overall FACT-C scores did not show significant differences between the groups, the mean scores in the fucoidan group were consistently higher post-treatment.
- Physical Well-Being (PWB):
A domain of QoL related to physical activities, social roles, bodily pain, and biological health, was significantly enhanced in the fucoidan group at both 2 months (P=.007) and 3 months (P=.006) post-treatment compared to the placebo group.
- Adverse Events (AEs)
The rates of two specific AEs were significantly lower in the fucoidan group:
Skin rash and itching (0% in fucoidan vs. 9.3% in placebo, P=.038).
Fatigue (75.0% in fucoidan vs. 95.3% in placebo, P=.008).
- Gut Microbiota Changes:
Post-treatment, the genus Parabacteroides was significantly more common in the gut microbiota of the fucoidan group compared to the placebo group (P=.015). This genus has been associated with both beneficial and pathogenic effects, Parabacteroides distasonis specifically has been reported to have beneficial effects on CRC, with levels inversely correlated with intestinal tumors.
- Clinical Outcomes (DFS, OS):
Median disease-free survival (DFS) and overall survival (OS) were not reached and showed no statistically significant differences between the groups (P=.582 for DFS; P=.071 for OS), a trend toward better outcomes in the fucoidan group was observed.
- The 24-month DFS rates were 86% for the fucoidan group versus 76% for the placebo group, and 36-month DFS rates were 80% versus 76% respectively.
- The 24-month OS rates were 100% for the fucoidan group versus 91% for the placebo group, and 36-month OS rates were 96% versus 83% respectively.
- The study indicates that a longer follow-up time is necessary to definitively determine if superior DFS and OS are associated with fucoidan administration.
Discussion and Conclusion
This study, a pioneering prospective, randomized, double-blind, placebo-controlled trial on LMF as a supplemental therapy in LARC patients, demonstrates several advantages of LMF administration during neoadjuvant CCRT. The findings suggest that LMF can help reduce the deterioration of QoL, particularly Physical Well-Being, induced by CCRT. The significant reduction in the frequency of fatigue and skin rash/itching in the fucoidan group further highlights its potential in mitigating common and distressing side effects of chemotherapy. This improvement in PWB and reduction in AEs like fatigue may allow patients to maintain a healthier QoL and better tolerate their daily activities.
Furthermore, the observed increase in the Parabacteroides genus in the gut microbiota of the fucoidan group post-treatment is an intriguing finding. Given the reported beneficial effects of certain species within this genus on colorectal cancer, this alteration in gut microbiota composition may contribute to the overall auxiliary benefits of LMF.
In conclusion, this study provides strong evidence that LMF administration can significantly improve the QoL, specifically physical well-being, reduce the incidence of skin rash/itching and fatigue, and beneficially alter gut microbiota composition in LARC patients undergoing neoadjuvant CCRT. These findings are crucial for informing the implementation of cancer therapies, particularly those involving the combination of chemotherapy and radiotherapy, and suggest LMF as a valuable supplementary intervention to enhance patient experience during treatment.
Full Article:
Tsai H-L, Yeh Y-S, Chen P-J, et al. The Auxiliary Effects of Low-Molecular-Weight Fucoidan in Locally Advanced Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy Before Surgery: A Double-Blind, Randomized, Placebo-Controlled Study. Integrative Cancer Therapies. 2023;22. doi:10.1177/15347354231187153
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