The article by Drs. Dan Labriola and Robert Livingston on possible interactions between dietary antioxidants and chemotherapy, published in the July issue of Oncology (13,1999), is based on a theoretical concern that has proven to be unfounded when actually tested in clinical trials. Contrary to the authors assertions, numerous studies, including in vitro experiments, animal trials, and small human trials, have consistently shown an enhancement of tumor kill and patient survival when antioxidants are combined with conventional cancer therapies.
A 1997 article reviewing all of the research on this issue over the past 20 years stated that there is no evidence that a mixture of vitamins ever stimulates anti-apoptotic events in cancer cells. A more recent review, published in 1999, also concluded that supplemental antioxidants: (1) potentiate the action of chemotherapy; (2) augment the efficacy of radiation therapy and hyperthermia; (3) induce normal cell growth in cancer cells; and (4) regulate gene expression in cancer cells.
Many of the references cited by Labriola and Livingston are not relevant to the issue of combining chemotherapy and antioxidants, but rather, are review articles on the favorable use of antioxidants in the prevention of cancer or general articles on complementary therapy. The one cited reference that does specifically examine possible interactions showed an enhancement of the in vitro and in vivo antitumor actions of fluorouracil(Drug information on fluorouracil) and doxorubicin(Drug information on doxorubicin) when combined with antioxidants. This article concludes that chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.
In essence, the article by Labriola and Livingston is a pharmacology essay that discusses the proposed mechanisms of action of chemotherapeutic agents, the theories behind the activity of antioxidants, and the predictable mechanisms of interaction between the two. Its conclusion, therefore, is basically a biochemical theory based on other biochemical theories. Frankly, we are surprised that the authors seem to believe their own conclusion, despite the large body of actual clinical research that contradicts it.
The authors themselves point out that mesna(Drug information on mesna), an antioxidant, is used to prevent the side effects of the chemotherapeutic agents ifosfamide(Drug information on ifosfamide) (Ifex) and cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) without affecting the efficacy of these drugs. Amifostine(Drug information on amifostine) (Ethyol), another antioxidant, has been used to prevent cisplatin(Drug information on cisplatin) (Platinol)-induced renal damage, again without reducing its efficacy. In addition, amifostine was recently approved for the prevention of xerostomia secondary to irradiation of head and neck tumors.
Findings of Recent Articles
Several recent articles published in the peer-reviewed literature support the contention that antioxidants not only reduce the side effects of cancer treatments but also enhance tumor kill:
A 1994 study published in Nutrition and Cancer showed that a mixture of vitamins enhances the growth-inhibitory effect of the chemotherapy commonly used for melanoma.
A 1991 study demonstrated that vitamin C reduces the toxicity of doxorubicin without reducing its antitumor activity. Another, more recent study, published in 1996, found that vitamin C actually improves the tumor kill of chemotherapeutic agents commonly used for breast cancer.
Green tea, a potent antioxidant, was noted to enhance the effect of doxorubicin by 2.5-fold. Even more interesting, in a 1998 research study, green tea appeared to increase the effectiveness of doxorubicin even in tumors that do not normally respond to this drug.
A large body of work has compared cisplatin alone with cisplatin combined with the antioxidant glutathione in ovarian cancer. The studies repeatedly showed better outcomes with less toxicity when glutathione was used adjunctively. One of the most recent studies found that treatment with glutathione raised the response rate from 62% to 73%.
In 1996, Scientific American published an entire issue devoted to cancer. The matter of antioxidants and chemotherapy was addressed with the following statements: for many years it was assumed that radiation therapy and many chemotherapeutic drugs killed malignant cells directly by wreaking widespread havoc in their DNA. We now know that the treatments often harm DNA to a relatively minor extent. Nevertheless, the affected cells perceive that the inflicted damage cannot be easily repaired and they actively kill themselves. An article in Cell states that cancer cells often fail to undergo apoptosis in response to treatment and that agents that stimulate apoptosis would be beneficial. This is precisely how antioxidants work.
Medicine is an evidence-based science. The history of medicine and pharmacology is replete with treatments that were discarded because they did not live up to theoretical predictions. Theory is a starting point for research, but when the evidence contradicts the theory, we must recognize the primacy of the evidence. To date, the evidence on antioxidants strongly favors their use to improve the efficacy of cancer treatments, reduce short-term side effects, and, hopefully, decrease the incidence of secondary cancers caused by these treatments.
The primary rule of medicine is, first, do no harm. We must consider the harm caused by ignoring data that do not fit our expectations and, thereby, denying patients access to protective factors. We agree with Labriola and Livingston that the fields of nutrition and oncology are complex, and that patients should consult with those experienced in the integration of the two disciplines as they undergo treatment. This would allow patients who decide to take a holistic approach to their cancer care to optimize that care.
Paul Reilly ND, Lac
Mark Gignac, ND
Ben Chue, MD
Manouchehr Sardo, MD
Cancer Treatment Centers of America