CONTROVERSYImpact of antioxidant supplementation on chemotherapeutic efficacy: A systematic review of the evidence from randomized controlled trials
Introduction
The use of antioxidant supplements by patients with cancer is estimated between 13% and 87%.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 This wide range of percentages might be attributed to the variability of definitions of complementary and alternative (CAM) medicine used in the different studies, and to differences in the cancer types, age, education, economic status, and ethnicity of the groups assessed.11 Patients may take antioxidant supplements while undergoing chemotherapy to help alleviate side effects from toxic chemotherapies and to increase the efficacy of chemotherapy. However, the use of antioxidant supplements by patients undergoing chemotherapy has been criticized due to concerns that the antioxidants may interfere with the mechanism of action of the chemotherapy and subsequently decrease its efficacy.12 Others argue that antioxidant supplements are useful in conjunction with chemotherapy because they enhance the efficacy of the chemotherapy, as well as alleviate toxic side effects, allowing patients to tolerate chemotherapy for the full course of treatment and possibly at higher doses.13 As a result, patients may have better tumor response rates and increased chances of survival.
One of the main mechanisms of chemotherapy drugs against cancer cells is the formation of reactive oxygen species (ROS), or free radicals. Drugs with free radical mechanisms include but are not limited to alkylating agents (e.g., melphalan, cyclophosphamide), anthracyclines (e.g., doxorubicin, epirubicin), podophyllin derivatives (e.g., etoposide), platinum coordination complexes (e.g., cisplatin, carboplatin) and camptothecins (e.g. topotecan, irinotecan). Unfortunately, these ROS often are the source of serious side effects, as well. For example, cisplatin and other platinum-induced toxicities include nephrotoxicity, ototoxicity, and peripheral neuropathy.14, 15 Doxorubicin and other anthracyclines often cause cardiotoxicity.16 Other chemotherapy drugs generate lower levels of oxidative stress, and free radical damage is thought to be of less importance in their mechanisms of action. These drugs include the taxanes (e.g. paclitaxel, docetaxel), vinca alkaloids (e.g. vincristine, vinblastine), antimetabolites (e.g. methotrexate, fluorouracil, cytarabine).13, 17 Examples of chemotherapy drugs that are not believed to depend on oxidative mechanisms for their anticancer effects include asparaginase and dactinomycin. While attempting to characterize chemotherapeutic compounds in this manner facilitates any attempt to understand the complexity of interactions between therapy and antioxidant use, the fact remains that most effective chemotherapeutic agents are multi-mechanistic and their relative ability to generate free radicals is not only dose-dependent but also dependent on the localization and metabolism of the drug within specific tissues. In addition, antioxidants have multiple mechanisms of action, and depending on their use, have been noted to have the potential to serve as oxidant molecules themselves. The supplements included in this review range in their antioxidant mechanisms from free radical scavengers that act as reducers or that break lipid chains (melatonin, NAC, Vitamin E, GSH, beta carotene and vitamin C) to antioxidant enzymes formed by combining with a protein to form selenoproteins (selenium, GSH). Other antioxidants act as metal chelators (Vitamin C, EGCG) or cellular protectors from free radical attack (vitamins A, C, E and melatonin) and some target and repair DNA aberrations (EGCG). Thus, understanding the interactions of selected antioxidants with selected chemotherapeutic agents is difficult enough when using simple in vitro cell systems but exceedingly more difficult to interpret in a simple manner when using more complex animal tumor models. Further, aside from their antioxidant activities, these agents may affect the pharmacokinetics or pharmacodynamics of chemotherapy agents. This makes an examination of the role of antioxidants in well-designed randomized clinical trials of clinical importance.
Cancer patients often have low-antioxidant levels before initiating treatment,18 therefore, administration of the aforementioned drugs exacerbates oxidative stress in cancer patients, as shown by DNA oxidation and lipid peroxidation levels during and after cancer therapy.19, 20 In theory, antioxidant supplementation during the administration of these chemotherapies would either hinder the cytotoxic mechanism(s) of chemotherapy by quenching reactive oxygen species produced by the drug, or help protect healthy cells from additional oxidative stress and toxicity from treatment. This then represents the heart of the dilemma for patients with cancer in trying to understand whether antioxidant therapy will increase their quality of life through protection of normal tissues or interfere with the eventual clinical outcome of their disease. Alternatively, antioxidants might improve outcomes through increasing the ability of patients to tolerate full doses of antineoplastics with uninterrupted treatment schedules. This review evaluates randomized, controlled trials in which studies measured survival and/or treatment response levels of patients given antioxidants concurrently with chemotherapy in order to determine if the antioxidants enhanced or interfered with the efficacy of the chemotherapy.
Section snippets
Methods
Electronic databases searched included MEDLINE, CENTRAL (The Cochrane Library), CinAhl, AMED/AltHealthWatch (combined) and EMBASE (all from inception to the last week of December, 2006).21 Databases were chosen for their inclusion of alternative and complementary medicine articles. All the databases were searched using the same search string, with the exception of Medline, where the string had to be altered to fit the database’s particular terminology. Terms were joined between three categories
Results
Of 845 references screened, 19 met the inclusion criteria, with a total of 1554 patients evaluated. A flow chart shows the exclusion factors and numbers of articles for each factor (Fig. 1). Nearly, half of the articles were excluded because they were not randomized, controlled trials (400). In other studies, although antioxidants were administered, they were not administered concurrently with chemotherapy (245), or the antioxidant administered was synthetic (43). Synthetic antioxidants were
Overview of outcomes
From the 19 studies included in this review, no evidence was found that supported concerns that antioxidant supplementation given concurrently with ROS-generating chemotherapy diminished the efficacy of the chemotherapy in study populations comprising mostly advanced or relapsed patients. In contrast, 17 of the 19 RCTs included in this review showed either a statistically significant advantage or non-significantly higher survival and/or treatment response in those patients given antioxidants.
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