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The Controversy: Antioxidant Supplementation And Chemotherapy

Taking antioxidant supplements during chemotherapy is controversial. Some cancer patients may wish to take antioxidants during chemotherapy in the hope of reducing side effects or improving their prognosis. However, many physicians are hesitant to recommend antioxidants to their cancer patients during treatment. Their concern is that antioxidant supplements might interfere with chemotherapy because some chemotherapy drugs kill cancer cells by generating oxidative stress. However, this concern is largely theoretical and is not supported by the weight of evidence from human clinical trials.

The reality is that many human studies show antioxidant supplements do not reduce the efficacy of chemotherapy. On the contrary, some studies have found that antioxidants may reduce negative side effects and even improve outcomes from cancer therapies (Zhu 2004; Erhola 1996; Conklin 2004a; Conklin 2004b; Alam 2011; Victorino 2014; Nakayama 2011; Block 2004; Drisko 2003; Sak 2012; Block 2007; Seifried 2003; Lawenda 2008).

A recent large systematic review addressed the concern vigorously (Yasueda 2015). Researchers from The Osaka University School of Medicine in Japan scoured the scientific literature and identified 399 reports of antioxidant supplementation in the context of cancer therapy. After excluding all but the best-designed studies, they were left with 49 reports to include in their analysis. They evaluated the outcomes of studies that used vitamin-, mineral-, phytochemical-, or amino acid-based antioxidants alongside cancer therapy. These scientists concluded as follows:

“Although there are many opinions about the risks or benefits of antioxidant supplementation, the only supportable conclusions based on the present research are… that there is no evidence of antioxidant supplementation causing harm alongside cancer therapy, except for smokers undergoing radiotherapy.”

The caveat for smokers is based on a trial in head and neck cancer patients in which supplementing with alpha-tocopherol and beta-carotene during radiotherapy had a negative impact on rates of cancer recurrence and death in participants who smoked during the trial (Meyer 2008). Although the mechanism behind this finding is not fully understood, several theories exist, all of which involve beta-carotene. One of these theories is based on evidence that, when oxidized, high levels of beta-carotene are transformed into strong free radicals that could enhance smoke-induced oxidative stress, damaging DNA and leading to carcinogenesis (Black 2010; Palozza 2006). Also, an analysis of blood chemistries of smokers supplementing with beta-carotene revealed that the combination of beta-carotene and cigarette smoke may increase cancer cell growth by promoting certain detoxification pathways and raising the levels of specific metabolites (Mondul 2013). Overall, more research in this area is needed, and smokers interested in supplementing with beta-carotene are encouraged to consult with their healthcare provider. In non-smokers, the use of antioxidant supplements during cancer therapy appears to have neutral or beneficial effects.

The authors of a 2007 systematic review (Block 2007), which included 19 randomized controlled trials, reached a similar conclusion. They noted that, despite the consistent lack of statistical power in the body of literature on this topic, “None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls.”

Even at high doses, antioxidant supplements were shown not to interfere with cancer treatment. In one trial, 136 patients with non-small cell lung cancer were randomized to receive chemotherapy alone (paclitaxel and carboplatin) or in combination with high-dose antioxidant supplements. The daily antioxidants included 6100 mg ascorbic acid, 1050 mg dl-alpha-tocopherol (a form of vitamin E), and 60 mg beta-carotene. There were no statistically significant differences in one- and two-year overall survival between groups, suggesting the high-dose antioxidants did not reduce the efficacy of chemotherapy (Pathak 2005).

Table 3 summarizes selected studies that have evaluated antioxidant supplements in the context of chemotherapy. Many more examples of the beneficial effects of antioxidant use before, during, or after chemotherapy are described throughout this protocol.

Table 3: Clinical Trials and Meta-Analyses of Antioxidants and Chemotherapy



Type of Trial



136 patients with stage III and IV non-small cell lung cancer

Chemotherapy with paclitaxel and carboplatin alone or with a daily combination antioxidant supplement (6100 mg vitamin C; 1,050 mg vitamin E; and 60 mg beta-carotene)

Randomized controlled trial

No significant differences in treatment response rates or overall survival between groups

(Pathak 2005)

103 cervical cancer patients

Oral antioxidant supplement (10 mg vitamin C, 200 IU vitamin E, 15 mcg selenium, and 8000 IU beta-carotene) or placebo once daily during six weeks of treatment with cisplatin and radiation therapy

Randomized placebo-controlled trial

Significantly higher hemoglobin concentrations—a potential proxy for improved general status—and lower levels of oxidative stress markers in the antioxidant group

Significantly improved quality of life in those receiving antioxidants

(Fuchs-Tarlovsky 2013)

48 patients with various cancers (testicular-16; osteosarcoma-13; gastrointestinal-6; urogenital-5; head and neck-5; and melanoma-3)

Oral antioxidant supplement (1000 mg vitamin C, 600 IU vitamin E, and 100 mcg selenium) or placebo daily during multiple courses of cisplatin-based chemotherapy

Randomized placebo-controlled trial

Significantly reduced rates of ototoxicity in those who achieved the highest blood levels of vitamins C and E and selenium

More patients receiving antioxidants were able to receive optimal doses of cisplatin

Treatment response rates were similar between groups

(Weijl 2004)

52 individuals with advanced colorectal cancer

Intravenous glutathione, 1500 mg per square meter of body surface area, before oxaliplatin administration

Randomized, double-blind, placebo-controlled trial

Significantly lower rates of moderate-to-severe neurotoxicity in the glutathione group after 12 months

No reduction in oxaliplatin activity

(Cascinu 2002)

50 patients with advanced gastric cancer

Intravenous glutathione, 1500 mg per square meter of body surface area, immediately before cisplatin administration plus 600 mg glutathione by intramuscular injection on days 2 to 5

Randomized, double-blind, placebo-controlled trial

Significantly reduced neurotoxicity in the glutathione group

No reduction in clinical activity of the chemotherapeutic drugs

(Cascinu 1995)

151 women with stage I–IV ovarian cancer

Six courses of intravenous cisplatin, and intravenous glutathione, 3 grams per square meter of body surface area, or placebo, every three weeks

Randomized, double-blind, placebo-controlled trial

Significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath, and difficulty concentrating in the glutathione group

Trends toward better clinical outcomes and receiving (tolerating) higher doses of cisplatin in the glutathione group

More patients in the glutathione group were able to complete a higher number of cycles of chemotherapy

Rates of complete remission were 46% in cisplatin plus glutathione group and 9% in the cisplatin alone group

(Smyth 1997)

54 women with advanced ovarian cancer

Cisplatin alone or with 2.5 grams of intravenous glutathione immediately before chemotherapy

Randomized controlled trial

Significantly lower rates of neurotoxicity in the glutathione group

Glutathione did not impair cisplatin effectiveness

(Bogliun 1996)

33 women with relapsed ovarian carcinoma, after being disease free for at least one year

Cisplatin alone or with 2.5 grams of intravenous glutathione, every week for nine weeks

Randomized controlled trial

More than twice the percentage of women in the glutathione group were able to receive the full cisplatin dosage (56% vs. 27%), and the response rate was higher in the glutathione group; no reduction in antitumor response rate was noted

(Colombo 1995)

6 patients with advanced non-small cell lung cancer and 14 patients with head and neck cancer

Cisplatin along with etoposide and 5-FU every four weeks; 11 patients received 5 grams of intravenous glutathione and 9 patients received 2000 mL electrolyte infusion (placebo) immediately before cisplatin; and all patients were treated with 2000 mL normal saline and forced diuresis following cisplatin

Randomized placebo-controlled trial

Significantly less pronounced blood cell toxicity, as indicated by hemoglobin, white blood cell count, and platelet count, in those receiving glutathione

Although not statistically significant, survival time in the glutathione group was 3 months (29%) longer

(Schmidinger 2000)

100 patients with metastatic non-small cell lung cancer

Cisplatin and etoposide, with or without 20 mg oral melatonin each evening

Randomized controlled trial

Significantly higher overall tumor regression rate and 5-year survival, as well as better tolerance of chemotherapy, in those receiving melatonin

No patient treated with cisplatin/etoposide alone was alive after two years, but nearly 30% of patients who received melatonin along with treatment were alive after two years

(Lissoni 2003)

250 patients with metastatic solid tumors (lung cancer-104; breast cancer-77; gastrointestinal tract-42; head and neck cancers-27)

Chemotherapy alone or with 20 mg per day of oral melatonin

Chemotherapy consisted of cisplatin (CDDP) plus etoposide or gemcitabine alone for lung cancer; doxorubicin alone, mitoxantrone alone, or paclitaxel alone for breast cancer; 5-FU plus folinic acid for gastrointestinal tumours; and 5-FU plus CDDP for head and neck cancers

Randomized controlled trial

Significantly higher one-year survival rate and objective tumor regression rate in those who received melatonin

Significantly reduced frequency of low platelets, nerve and cardiac toxicity, oral ulcers, and fatigue in the melatonin group

(Lissoni 1999)

108 patients with various cancers

Chemotherapy using cisplatin plus 600 IU of oral vitamin E per day or placebo beginning prior to chemotherapy and continuing for three months after the end of treatment

Randomized placebo-controlled trial

Significantly lower neurotoxicity incidence and severity in the vitamin E group

Treatment response was similar in the two groups

(Pace 2010)

27 patients with solid tumors

Six cycles of cisplatin alone or with vitamin E (alpha-tocopherol, 448 IU) daily during and for three months following treatment

Randomized controlled trial

Significant reductions in incidence and severity of neurotoxicity in those receiving vitamin E

Vitamin E did not interfere with response to cisplatin treatment

(Pace 2003)

22 women with newly diagnosed stage III or IV ovarian cancer

High-dose intravenous vitamin C at up to 100 grams per infusion (12 months) added to paclitaxel /carboplatin therapy (6 months)

Randomized controlled trial

Significantly decreased rates of mild-to-moderate toxicities, with reduced toxicity to nervous system, pancreas/gallbladder/liver, gastrointestinal tract, bone marrow, kidney and urinary tract, lungs, and skin in the vitamin C group

A trend toward improved overall survival in the vitamin C group

(Ma 2014)

48 men with hormone-refractory prostate cancer who had not yet undergone chemotherapy

Weekly chemotherapy with vinorelbine and estramustine for six weeks, with or without 180 mg per day of ellagic acid (in the form of ellagic tannins) from pomegranate seeds

Randomized controlled trial

Reduced systemic toxicity, with statistical significance in reduction of neutropenia, in the ellagic acid group

Higher average number of rounds of chemotherapy in the ellagic acid group (6.5 vs. 4.0)

Better objective and biochemical response to treatment with ellagic acid

Complete response in 25% of those receiving chemotherapy plus ellagic acid and none of those receiving chemotherapy alone; partial response in 33% and 25%, respectively

A trend toward improved overall survival in the ellagic acid group

(Falsaperla 2005)

32 stage I and II melanoma patients who had surgical removal of primary lesions

Low-dose recombinant interferon (IFN) alpha-2b administered twice daily plus 400 mg per day of coenzyme Q10 (CoQ10), or interferon only, for three years

Controlled trial

Approximately 10-fold lower risk of metastases in those receiving IFN plus CoQ10

Lower rate of recurrence in patients with stage II disease receiving CoQ10

(Rusciani 2007)

153 chronic myelogenous leukemia patients

Oral busulfan for four days every four weeks, with or without high-dose vitamin A (50 000 IU/day)

Randomized controlled trial

Trend toward increased progression-free and overall survival times in those receiving vitamin A

(Meyskens 1995)

100 patients with metastatic breast cancer

Various doses and schedules of chemotherapy, alone or with oral vitamin A, 350,000–500,000 IU per day based on body weight

Randomized controlled trial

Significantly increased treatment response rate, duration of response, and projected survival in those receiving vitamin A who were also post-menopausal

(Israel 1985)

353 participants from six randomized controlled trials

Vitamin E in combination with chemotherapy


Significantly reduced neurotoxicity from cisplatin when combined with vitamin E

Four of six studies included safety assessment, and no adverse events were reported

(Huang 2016)

768 participants from eight randomized controlled trials

Melatonin in combination with chemotherapy or radiation therapy


Significantly increased complete or partial tumor remission and one-year survival in patients receiving concurrent melatonin

Significantly lower occurrences of thrombocytopenia, neurotoxicity, and fatigue in those receiving melatonin

(Wang 2012)

Participants in 21 trials, all of whom had solid tumors

Melatonin in cancer therapy, including in combination with chemotherapy


Significant 40% decreased 1-year mortality in those receiving melatonin along with chemotherapy

2.5-fold increased rate of complete response with the addition of melatonin to chemotherapy

Significant reductions in chemotherapy-related weakness, neutropenia, nausea and vomiting, low blood pressure, and thrombocytopenia in those receiving concurrent melatonin

(Seely 2012)

Antioxidant Drugs Used With Chemotherapy

Aside from the controversy surrounding antioxidant supplements in chemotherapy, readers may be unaware that several FDA-approved antioxidant drugs are regularly used to reduce chemotherapy-associated side effects (Moss 2006). These prescription antioxidant drugs have been investigated in many clinical cancer studies (Antman 1993; Komaki 2002).


Dexrazoxane, a powerful antioxidant drug (Junjing 2010), was approved by the FDA in 2002 and is recommended by the American Society of Clinical Oncology for preventing doxorubicin-associated cardiotoxicity (Steiner 2013; Ichikawa 2014; Hensley 2009). Dexrazoxane is used in people with metastatic breast cancer, as well as other malignancies, who have received more than 300 mg of doxorubicin per square meter of body surface area and for whom continued doxorubicin therapy may be indicated (Hensley 2009). In early trials of dexrazoxane, myelosuppression was a dose-limiting toxicity (Wang, Zhang 2013; Jones 2008). Dexrazoxane may be used when the risk of chemotherapy-associated cardiac damage is expected to be high, but its benefits need to be weighed against the possible risk of bone marrow suppression (Jones 2008; van Dalen, van den Berg 2011).

Intravenous dexrazoxane (Totect) is approved for treatment of accidental anthracycline extravasations (Muthuramalingam 2013; Kissei Pharmaceuticals 2014). Extravasation, which is the leaking of chemotherapy drugs from blood vessels into surrounding tissues, is a medical emergency; patients undergoing intravenous chemotherapy must be closely monitored to prevent extravasation, and immediate attention is required if it occurs (Vidall 2013; Perez Fidalgo 2012).


The antioxidant agent mesna (Mesnex) was developed to mitigate the urinary tract toxicity of some chemotherapy drugs, such as cyclophosphamide and ifosfamide, without reducing their antitumor effects (Brock 1980). Mesna tablets were approved by the FDA in 2002 as a preventive agent to reduce the occurrence of a complication called ifosfamide-induced hemorrhagic cystitis, in which the bladder becomes inflamed and bleeds (Cohen 2002; Mashiach 2001; Yeh 2008; Manikandan 2010). Intravenous mesna has been approved for this indication since 1988. The FDA also acknowledged that mesna does not appear to protect tumor cells against chemotherapy-induced cytotoxicity (Cohen 2002).

Based on findings from animal research, the bladder-protective effect of mesna may be enhanced by the addition of antioxidants such as alpha-tocopherol, melatonin, quercetin, and EGCG (Yildirim 2004; Ozcan 2005).

Several studies have reported on the use of mesna concurrently with chemotherapy. In two case reports in women with recurrent uterine leiomyosarcoma being treated with mesna along with the chemotherapy agents doxorubicin, ifosfamide, and dacarbazine (a regimen known as “MAID”), one achieved partial remission and the other complete remission (Minobe 2011). A trial in 38 patients treated for aggressive non-Hodgkin lymphoma evaluated the long-term efficacy and toxicity of a regimen that includes mesna, ifosfamide, mitoxantrone (Novantrone), and etoposide (known as “MINE”) as a post-remission treatment. These patients already achieved complete remission, or presumed complete remission, after six cycles of first-line standard therapy. After a median follow-up time of approximately 118 months, side effects of the “MINE” protocol were found to be mild and infrequent, and 5- and 10-year disease-free survival rates were both 65%. The authors concluded this regimen may be an effective consolidation strategy in such patients (Dincol 2010).


Amifostine is another antioxidant drug shown in laboratory studies to neutralize several types of free radicals (Taylor 1997; Mehta 1998; Spencer 2005; Marzatico 2000; Beijers 2012). Amifostine is FDA approved for the reduction of cumulative kidney toxicity from repeated cisplatin administration in patients with advanced ovarian cancer and non-small cell lung cancer (Ethyol 1999). However, the major side effects of amifostine, which include nausea, vomiting, and transient low blood pressure, often result in treatment discontinuation, limiting its wide acceptance (Schuchter 1996; Soref 2012).

In patients with advanced non-small cell lung cancer, subcutaneous amifostine (1000 mg), together with hematopoietic growth factors, may have contributed to a decrease in observed toxicity of combination therapy with docetaxel, gemcitabine, and liposomal doxorubicin (Patlakas 2005). In a study on 25 patients with metastatic non-small cell lung cancer, the addition of amifostine to a chemotherapy regimen of cisplatin and vinblastine (Velban) resulted in high response rates and a 64% one-year survival rate. In this trial, amifostine may have protected against long-term kidney insufficiency from cumulative doses of cisplatin, and the combination treatment appeared highly active against the cancer (Schiller 1996). A 2013 trial in which amifostine was added to carboplatin- and paclitaxel-based chemoradiation therapy in patients with locally advanced non-small cell lung cancer produced results comparable to other treatment regimens without compromising survival (Lawrence 2013).

A review concluded that patients with cervical cancer may benefit from receiving subcutaneous amifostine before chemotherapy (De Los Santos 2004). In a randomized controlled trial, 71 patients were pretreated with intravenous amifostine before platinum/taxane-based chemotherapy for ovarian cancer in order to determine whether such premedication changed the incidence of neurotoxic side effects. While nausea and vomiting were significantly more common in the amifostine group, sensory neuropathy was significantly less common (Hilpert 2005). A randomized trial in 242 patients with advanced ovarian cancer used six cycles of cyclophosphamide and cisplatin, with or without amifostine pretreatment before each cycle. Amifostine significantly reduced multiple types of chemotherapy toxicity without reducing the anticancer effects of cyclophosphamide and cisplatin (Kemp 1996).

A meta-analysis found a trend toward decreased ototoxicity (ear toxicity or hearing impairment) in patients receiving amifostine infusion prior to cisplatin chemotherapy (Duval 2012). A non-randomized trial found that amifostine protected against cisplatin-induced serious hearing loss in average-risk but not high-risk patients with medulloblastoma (a type of brain tumor) (Gurney 2014).