Table 2.
Summary of Clinical Trials Using Antioxidants in Patients Diagnosed With CRC
| Trial characteristic | Population | Subjects | Intervention; duration | Outcome summary | Conclusion | Reference, year |
|---|---|---|---|---|---|---|
| Randomized, double-blind, placebo controlled (ATBC study) | Male smokers of southwestern Finland; age: 50–69 y | n=29,133 | Oral alpha-tocopherol (50 mg/day) or beta-carotene (20 mg/day) or combination of both; 5–8 y | CRC incidence was modestly lower but not significant in alpha-tocopherol group (RR = 0.78; 95% CI, 0.55–1.09); beta-carotene had no effect on CRC incidence (RR = 1.05; 95% CI, 0.75–1.47) | No response on CRC incidence in older male smokers | 138, 2000 |
| Randomized, double-blind, placebo controlled (ATBC study) | Male smokers of southwestern Finland; age: 50–69 y | N=15,538 | Oral alpha-tocopherol (50 mg/day) or beta-carotene (20 mg/day) or combination of both; 6.3 y | Alpha-tocopherol increased the risk of adenoma (RR = 1.66; 95% CI, 1.19–2.32); beta-carotene had no effect on adenoma risk (RR = 0.98; 95% CI, 1.71–1.35) | Negative response; alpha-tocopherol increased the risk of adenoma; however, beta-carotene had no effect on adenoma in older male smokers | 139, 1999 |
| Randomized, controlled clinical trial | Patients post-removal of at least 1 colonic adenoma | n=864 | Oral beta carotene (25 mg/day) or vitC (1 g/day) and vitE (400 mg/day); 4 y | RR for beta carotene was 1.01 (95% CI, 0.85–1.20) and for vitC and E was 1.08 (95% CI, 0.91–1.29) | No response; neither treatment was effective in prevention of any subtype of polyp irrespective of size and location | 114, 1994 |
| Prospective interventional study | Patients previously diagnosed with colorectal adenomas; age: 50–76 y | n= 116 | Oral antioxidants and calcium tablet once daily that contains beta-carotene (15 mg), vitC (150 mg), vitE (75 mg), selenium (101 μg), and calcium (1.6 g); 3 y | No difference was detected in growth of adenomas between treated and placebo groups; significantly lower number of patients free of new adenomas in placebo group compared with treated group | No response on polyp growth; positive response on protection from developing new adenoma | 140, 1998 |
| Randomized, double-blind, placebo-controlled | Patients with history of sporadic colorectal adenoma; age: 30–74 y | n=47 | Oral antioxidant micronutrient cocktail delivering vitE (800 mg), beta-carotene (24 mg), vitC (1 g), selenium (200 μg), riboflavin (7.2 mg), niacin (80 mg), zinc (60 mg), and manganese (5 mg) per day; 4 mo | TNF-α decreased by 37% and cystine decreased by 19% in antioxidants treatment group relative to placebo; interleukin 6 and F2-isoprostane levels decreased in antioxidant-treated nonsmokers but increased in smokers | Positive response only in nonsmoker subjects; an antioxidant micronutrient cocktail decreased the level of oxidants and inflammation only in nonsmokers | 141, 2010 |
| Randomized, controlled study | Patients with colonic polypectomy; mean age: 59.2 y | n=255 | Oral vitamins tablet containing vitC (1 g/day), vitA (30,000 IU/day), and vitE (70 mg/day); ∼5 y | Percentage of recurrence of adenomas was 5.7% in vitamins group compared with 35.9% in untreated group | Positive response; vitamins treatment lowered recurrence rate of colonic adenomas | 142, 1993 |
| Randomized, double-blind trial | Patients post-removal of at least 1 colonic adenoma | n=200 | Oral vitC (400 mg/day) and vitE (400 mg/day); 2 y | Difference in incidence of polyp recurrence was small in treated group compared with placebo (RR = 0.86; 95% CI) | Positive response (small effect); small reduction in rate of polyp recurrence with vitamin supplement | 143, 1988 |
| Randomized, double-blind, placebo-controlled | Patients with advanced colonic adenocarcinoma | n=100 | Oral vitC (10 g/day) as capsule; 2 y | No benefit with high-dose vitC either as disease progression or survival compared with placebo | No response on either overall survival or progression of advanced CRC | 144, 1985 |
| Pilot study | Patients with terminal cancer including colon cancer; age: 32–93 y | n=100 vitC treated and 1000 control subjects | VitC; 10 g/day IV for 10 days followed by 10 g/day oral; ∼ 210 days | Survival was about 4.2 times greater in treated group (∼210 days) compared with control group (∼50 days) | Positive response on overall survival; treatment with vitC increased survival time by about 3 times in terminal cancer patients | 145, 1976 |
| Randomized, double-blind, placebo-controlled | Patients with large bowel adenoma/polyposis coli; age: 20–63 y | n=36 | Oral vitC (3 g/day); ∼2 y | Reduction in both number and area of rectal polyps in vitC group at 9 months of follow-up | Positive response (temporary, only at 9 months of follow-up) on reduction of polyp growth and turnover | 112, 1982 |
| Phase 1 open-label, single-center, dose escalation, and speed-expansion study | Metastatic colorectal cancer (mCRC) or gastric cancer (mGC); age: 18–75 y | n=36 | VitC infusion in dose escalation (0.2–1.5 g/kg) and in speed expansion study (1.5 g/kg) once daily for 3 days in 14-day cycle in combination with mFOLFOX6 or FOLFIRI; 12 cycles | Maximum tolerated dose of vitC not achieved; recommended phase 2 dose of vitC at 1.5 g/kg/day was established; response rate was 58.3%, and disease control rate was 95.8% in treated group | Positive response as combination therapy; favorable safety profile and potential clinical efficacy were observed with combined treatment of vitC and mFOLFOX6/FOLFIRI | 146, 2019 |
| Randomized, placebo-controlled trial, Selenium and vitE Cancer Prevention Trial (SELECT) | SELECT participants who underwent lower endoscopy; age: ≥50 y (African American), ≥55 y (all other men) | N=8094 | Oral selenium (200 μg/day) and vitE (400 IU/day); 7–12 y | RR for adenoma occurrence in selenium group was 0.96 (95% CI, 0.90–1.02) and in vitE group was 1.03 (95% CI, 0.96–1.10) compared with placebo | No response on colorectal adenoma occurrence | 147, 2017 |
| Randomized, placebo-controlled trial | Patients post-removal of at least 1 colorectal adenoma; age: 40–80 y | n=1621 | Selenium (200 μg/day) as selenized yeast in combination with celecoxib (400 mg daily); ∼33 mo | RR of adenoma in selenium group was 1.03 (95% CI, 0.91–1.16) compared with placebo; adenoma recurrence in patients with baseline advanced adenomas was reduced by 18% with selenium | No response on colorectal adenoma formation but showed only modest benefit on adenoma recurrence | 148, 2016 |
| Randomized, placebo-controlled trial | Patients with confirmed recent histories of nonmelanoma skin cancer; age: <80 y | n=1312 | Selenium (200 μg/day) as selenized yeast; 7.9 y | Suggestive but nonsignificant decrease in risk associated with selenium on prevalent adenomas (odds ratio = 0.67; 95% CI, 0.43–1.05); significant reduced risk was observed in subjects with lowest baseline selenium and current smokers | Positive response only in subjects with low baseline selenium or smoking habit | 149, 2006 |
| Randomized double-blind placebo-controlled | Post-polypectomy (colonic) patients; age: 29–83 y | n=411 | One tablet daily composed of 200 μg selenium, 30 mg zinc, 2 mg vitA, 180 mg vitC, and 30 mg vitE; 5 y | A 39% reduction in risk of adenoma recurrence with intervention compared with placebo; similar risk reduction was also observed in small tubular and advanced recurrent adenomas | Positive response on adenoma recurrence | 150, 2013 |
| Randomized, placebo-controlled, prospective trial | Patients post-surgical resection of colon or rectal adenocarcinoma; age: 50–75 y | n=24 | Oral zinc capsules (70 mg/day) in combination with capecitabine or capecitabine with oxaliplatin/5-fluorouracil; 16 weeks | No change in plasma level of vitC, vitE, MDA, or 8-isoprostane but increased SOD activity in zinc-treated group compared with placebo | No response on lipid peroxidation markers but improved SOD activity in zinc-treated group | 151, 2016 |
| Randomized, double-blind, placebo-controlled | Patients with familial adenomatous polyposis; age: 18–85 y | n=44 | Oral curcumin (3000 mg/day); 12 mo | No significant difference in mean polyp number or size was observed between curcumin and placebo-treated groups | No response on polyp number and size in FAP patients | 152, 2018 |
| Randomized, open-labelled, controlled trial | Patients with metastatic colorectal cancer; age: >18 y | n=28 | Oral curcumin C3 complex/d (2 g/day) in combination with FOLFOX; ∼24 weeks | Daily oral supplementation of curcumin to FOLFOX chemotherapy was safe and tolerable; no significant difference between arms for quality of life or neurotoxicity | No response on quality of life, but curcumin could be safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic CRC | 153, 2019 |
| Single-center prospective randomized open-labelled | Patients with colonic polypectomy; age: 19–85 y | n=176 | Oral GTE as tablet (0.9 g/day) equivalent to 0.6 g/day of catechin or 0.2 g/day of EGCG; 12 mo | Decreased incidence of metachronous adenoma and number of relapsed adenomas in GTE group | Positive response on metachronous colorectal adenomas | 154, 2018 |
| Pilot study | Patients with colonic polypectomy; age: 20–80 y | n=136 | Oral GTE as tablet (1.5 g/day); 12 mo | Decreased incidence of metachronous adenoma and smaller size of relapsed adenomas in GTE group | Positive response on metachronous colorectal adenoma | 155, 2008 |
| Prospective cohort study | Patients with resected colon cancer or polypectomy; age: median age 74 and 77 for treated and control groups, respectively | n=87 | Oral flavonoid mixture consists of apigenin (20 mg) and epigallocathechin-gallat (20 mg) daily; 4 y | Recurrence rate for neoplasia was 7% in treated group compared with 47% in control group | Positive response with long-term treatment on recurrence rate of colon neoplasia | 156, 2008 |
| Randomized, placebo-controlled trial | Patients with previous adenomatous colonic polyps | n=64 | Oral NAC (800 mg/day) as capsule; 12 weeks | Proliferative index of colonic epithelial cells was reduced in NAC group in comparison with placebo group | Positive response on reducing colonic epithelium hyperproliferation; could be a chemopreventive agent in human colon cancer | 157, 1999 |
| Randomized and controlled | Patients with gastrointestinal cancer undergoing major abdominal surgery | n=33 | NAC (1200 mg/day) through parenteral nutrition starting from 2 days before surgery until fifth post-surgery day; 7 days | Reduced plasma MDA but higher ratio of reduced to oxidized glutathione in NAC group; no change in plasma level of vitA, vitC, or vitE but reduction in urinary nitrate level with NAC treatment | Positive response on reducing oxidant and improving antioxidant parameters in cancer patients undergoing major abdominal surgery | 158, 2015 |
ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CI, confidence interval; EGCG, (-)-epigallocatechin gallate; GTE, green tea extract; MDA, malondialdehyde; RR, relative risk.