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In January 2013, James D. Watson, PhD, codiscoverer of DNA's double helix, published a paper in which he called into doubt the safety of antioxidants for cancer patients. I disagree with him, but Prof. Watson is a great scientist, and anything that he says deserves the utmost attention. This is especially so when it comes to life-and-death questions affecting cancer patients.
"The time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer," Watson wrote in the online journal Open Biology. He pointed to the beneficial role of reactive oxygen species (ROS) in killing cancer cells. ROS molecules, he said, are directly involved in inducing apoptosis (a kind of programmed cell death) in malignant cells. As a result, he inferred that antioxidants are undesirable when one is trying to kill cancer cells, especially in patients with late-stage disease. The key paragraph is this:
In light of the recent data strongly hinting that much of late-stage cancer's untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer. … Future data may, in fact, show that antioxidant use, particularly that of vitamin E, leads to a small number of cancers that would not have come into existence but for antioxidant supplementation. Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.
There is much else in this wide-ranging paper, some of which I agree with. But I think that Prof. Watson should have grounded his paper in clinical reality by citing actual examples of antioxidant use in patients with cancer, especially those with advanced-stage cancers.
Block on Breast Cancer
I cannot here survey all of the relevant clinical data. But I do want to focus attention on three papers in particular. The first is from the Block Center for Integrative Cancer Treatment in Skokie, Illinois. Keith Block, MD, and his wife Penny Block, PhD, founded this clinic 32 years ago and have been instrumental in integrating complementary with conventional medicine ever since.
In a 2009 study, they analyzed outcomes in patients with metastatic (stage IV) breast cancer who were diagnosed and treated between 1984 and 1997.
The paper appeared in the Breast Journal, a peer-reviewed publication from Wiley. I want to mention the authors of the paper so that the reader understands that this comes from a group of highly respected and sophisticated researchers. Block, in addition to being the medical director of the Block Center, is affiliated with the University of Illinois, is editor-in-chief of Integrative Cancer Therapies, and was the 2011 program chairman of the Society for Integrative Oncology (SIO)'s annual meeting. Coauthor Debu Tripathy, MD, of USC Norris Comprehensive Cancer Center, Los Angeles, is the author of 73 PubMed-listed articles on breast cancer; Sally Freels, PhD, is an epidemiologist at the University of Illinois at Chicago; Robert A. Newman, PhD, was a pharmacologist at M. D. Anderson Cancer Center, Houston; and Jacob Shoham, MD, PhD, is a medical oncologist and professor emeritus at Bar-Ilan University in Israel.
In addition to administering chemotherapy, Block's program included "an antioxidant-rich low-fat diet high in whole grains, legumes, vegetables and fruits, individualized supplementation," and other CAM treatments (2009). The supplements taken by all patients included a multivitamin-mineral supplement designed for cancer patients and a phytochemically rich vegetable and fruit drink; other supplements included mixed carotenoids, melatonin, calcium-d-glucarate, reishi mushrooms, and green tea. Needless to say, most of these are either antioxidants themselves or contain antioxidant ingredients. Even more antioxidants were added.
"In addition, patients received intravenous vitamin infusions during chemotherapy to prevent treatment-related nutrient deficiencies. These infusions include vitamins A, C, D, E, K, B-vitamins ... all in doses slightly under to a few times higher than Recommended Daily Allowances" (Block 2009).
According to Watson's theory, this intensively antioxidant-rich program should have been a prescription for disaster. So let us see how these advanced cancer patients actually fared.
 Ninety consecutive patients with metastatic breast cancer received chemotherapy at this integrative cancer center. All patients had metastatic disease at baseline, 96% had already relapsed, and 52% had received prior chemotherapy for their metastatic disease. Median overall survival in this group was 38 months. Five-year survival was 27%. By comparison, the published literature on patients treated at conventional clinics during this time period showed a median survival of between 12 and 24 months.
Particularly apt was the comparison with a private oncology clinic in northeast Louisiana, whose outcomes were reported in detail in Cancer in 2000 (Anderson 2000). In this study, patients who had a somewhat better prognoses had a median survival after recurrence of 20.1 months. Their 5-year survival rate was 17% (vs. 27% at the Block Center). Thus, survival of metastatic breast cancer patients at the Block Center was approximately double that of a comparison population.
As with any nonrandomized and retrospective review, a bias that comes from self-selection cannot be ruled out. However, in this case, the self-selection process seemed to work against Block, not for him. His patients were sicker and more heavily pretreated than in the Anderson study group. Yet they survived longer.
McCulloch Papers
Another pair of papers on the clinical outcome of patients receiving antioxidants came from Northern California. These patients all had colon or lung cancer. The authors gave detailed follow-up information on patients receiving a panoply of antioxidants, vitamins, herbs, and other CAM treatments at the Pine St. Clinic in San Anselmo, California. The paper was published in a peer-reviewed, PubMed-indexed journal.
Again, I think it necessary to mention the authors by name, to emphasize that these were not inexperienced or naïve observers. The lead author was Michael McCulloch, LAc, MPH, PhD, and the second author was Michael Broffman, LAc, both of the Pine St. Clinic. The other authors included Mark van der Laan, PhD; Alan Hubbard, PhD; and John M. Colford Jr., MD, all of the University of California, Berkeley; the epidemiologist Lawrence Kushi, DSc, of Kaiser Permanente North California, Oakland; the oncologist Donald I. Abrams, MD, of the University of California, San Francisco; and Jin Gao, MD, PhD, of the Chinese Academy of Sciences, Beijing.
Colon Cancer Study
This study, which appeared in Integrative Cancer Therapies in 2011, involved 193 patients, with a minimum of 10 years of follow-up at the Pine St. Clinic. The authors compared survival at various points in patients using what they call Pan-Asian medicine plus vitamins (PAM+V) vs. concurrent external controls from two databases. The two control groups came from Kaiser Permanente of Northern California and the California Cancer Registries.
According to the paper:
"PAM+V reduced the risk of death in stage I by 95%, stage II by 64%, stage III by 29 percent, and stage IV by 75%. Combining PAM+V with conventional therapy improved survival. …" (2011a).
Lung Cancer Study
In a similarly designed study of 239 patients who had non-small cell lung cancer (NSCLC), the authors found the following:
Long-term PAM+V combined with conventional therapy reduced stage IIIA deaths by 46%, stage IIIB by 62%, and stage IV by 69% compared with conventional therapy alone. Survival rates for stage IV patients treated with PAM+V were 82% at 1 year, 68% at 2 years, and 14% at 5 years. PAM+V combined with conventional therapy improved survival in stages IIIA, IIIB, and IV, compared with conventional therapy alone. (2011b)
Unlike in colon cancer, in NSCLC the use of long-term PAM+V resulted in a better outcome than short-term use:
"Long-term use of PAM+V beyond completion of chemotherapy reduced stage IIIB deaths by 83% and stage IV by 72% compared with short-term use only for the duration of chemotherapy" (2011b).
In lung cancer, patients who received radiotherapy minimized their use of "antioxidants during the radiation phase," but then resumed antioxidants after radiation was completed. Antioxidants in use included N-acetylcysteine (600–1800 mg per day), curcumin (500–1000 mg per day), coenzyme Q10 (90–150 mg), and melatonin (3–20 mg per day), as well as an antioxidant-containing combination pill, including vitamins A, B complex, B12, C, D, E, folic acid, selenium, and zinc. Other herbs and supplements included antioxidants as well.
If a single antioxidant, such as N-acetylcysteine or vitamin E, could diminish survival, as Watson suggests, then what would be the expected impact of a panoply of vitamins and antioxidants, such as is used at the Block Center, the Pine St. Clinic, or many other CAM clinics around the world? It should be catastrophic, especially in stage IV disease!
Instead, in these studies, we find exactly the opposite. Patients in every stage of the disease did better, sometimes much better, but never worse, as Watson suggests should happen.
These are lengthy papers that give very detailed comparative survival data, and I cannot do them justice in this short space. However, I will look in greater detail at one parameter of benefit, which was overall 5-year survival in stage IV colon and lung cancer. Needless to say, this a difficult treatment situation.
In the standard-treatment Kaiser Permanente data, 5-year survival in stage IV colon cancer was just 7%, while in the California Cancer Registry it was 8%. But in patients who received long-term PAM+V, 5-year survival was an extraordinary 60% and in those receiving short-term PAM+V it was 82%.
In lung cancer, the survival advantage of PAM+V was not as great, but was certainly better than receiving just conventional care. Thus, 5-year survival in stage IV was 1% in the standard-treatment Kaiser Permanente database and 2% in the California Cancer Registry. But it was 14% with long term PAM+V and 5% with short-term PAM+V.
Admittedly, there are limitations to these otherwise excellent studies. (The authors themselves point out some of the limitations.) For example, these are not randomized trials. They report observational data, which were retrospectively gathered from medical records and cancer registries. So there is a possible selection bias that might contribute to the better survival of patients in the antioxidant-rich (PAM+V) treatment groups. There may also be survival advantages associated with the patients' favorable socioeconomic advantages or better access to conventional cancer therapy.
But, that said, if Watson's hypothesis were correct, one would expect to see a pattern (or at least an inkling) of diminished survival in patients using so many powerful antioxidants as part of their cancer treatment. Instead, one sees exactly the opposite: a strongly positive association of antioxidant use with increased survival.
Watson's paper contains no clinical data, only theoretical speculation along with select laboratory findings (that, in my opinion, are not representative of the in vitro data as a whole). I think that his paper could have been greatly strengthened had he considered actual clinical data such as those discussed above. But, then, he might have had to alter his warnings about the alleged danger of antioxidants to cancer patients.
Warnings Over the Years
Over the years, I have heard many admonitions about the alleged danger of antioxidants to cancer patients, especially when taken in conjunction with chemotherapy or radiation therapy. Some of these caveats were based on the interaction of various agents in the test tube; at other times they were based on a more generalized fear of the unknown nature of complementary medical practices. Rarely were they based on clinical results.
A dozen or so years ago Rudolph I. Salganik, MD, created a sensation at an American Society for Cell Biology (ASCB) meeting when he claimed that depleting certain mice of dietary antioxidants increased the reactive oxygen species (ROS) activity in their tumors (1999).
Dr. Salganik's findings were then amplified by the ASCB and his university. A press release claimed that the "antioxidant-free diet had obvious health benefits for the mice. Their brain tumors measured about half the size of tumors in mice eating normal amounts of the vitamins. Their tumors also looked better, with large areas free of malignant cells."
In the UNC press release, Salganik himself drew broad inferences from his work. For instance, he claimed that "giving patients vitamins may prevent cancer cells from self-destructing and work against cancer therapy."
Oncologist Charles B. Simone, MD, and I had the pleasure of debating Prof. Salganik at the June 2000 Comprehensive Cancer Care meeting in Arlington, Virginia. Salganik's idea was to put cancer patients on a diet that was almost entirely depleted of antioxidants. He thought that the build-up of ROS would be great enough, in this way, to cause a therapeutic effect. How he would avoid vitamin deficiency diseases was never made clear. Prof. Salganik retired soon afterwards, and I do not believe that his ideas were ever put into clinical trials, much less general practice.
Now we are told, on no less an authority than Prof. Watson, that eating blueberries could be harmful and should be avoided by cancer patients.
The problem is that these fear statements do not flow from, or accord with, the clinical facts. In fact, a careful review of studies performed over many decades shows that antioxidants do not harm cancer patients, even when given in conjunction with chemotherapy.
Almost invariably, such studies show that antioxidants are beneficial to cancer patients and enhance the effectiveness of conventional treatments. In addition, some of the serious side effects of radiation and chemotherapy can be decreased with antioxidants. Danger may arise in particular situations, however, such as when patients attempt to receive radiotherapy, take one or two synthetic vitamins, and continue smoking at the same time (Bairati 2006, Meyer 2008).
The bottom line will always be what happens to patients in the clinic. To date, no one has shown that harm ensues to nonsmoking patients whose physicians utilize a combination of conventional and complementary treatment methods, including antioxidants. Rather, such patients seem able to experience the "best of both worlds." They look and feel healthier and, according to these retrospective studies, they also live longer. And that is the most important thing.
References
• Anderson WF, Reeves JE, Elias A, Berkel H. Outcome of patients with metastatic breast carcinoma treated at a private medical oncology clinic. Cancer. 2000;88(1):95–107.
• Bairati I, Meyer F, Jobin E, et al. Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer. 2006;119(9):2221–2224.
• Meyer F, Bairati I, Fortin A, et al. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int J Cancer. 2008;122(7):1679–1683.
• Block KI, Gyllenhaal C, Tripathy D, et al. Survival impact of integrative cancer care in advanced metastatic breast cancer. Breast J. 2009;15(4):357–366.
• McCulloch M, Broffman M, Van der Laan M, et al. Colon cancer survival with herbal medicine and vitamins combined with standard therapy in a whole-systems approach: ten-year follow-up data analyzed with marginal structural models and propensity score methods. Integr Cancer Ther. 2011;10(3):240–259. [McCulloch 2011a]
• McCulloch M, Broffman M, Van der Laan M, et al. Lung cancer survival with herbal medicine and vitamins in a whole-systems approach: ten-year follow-up data analyzed with marginal structural models and propensity score methods. Integr Cancer Ther. 2011;10(3):260–279. [McCulloch 2011b]
• Salganik RI, Albright CD, Rodgers J, et al. Enhancement of apoptosis and inhibition of brain tumor growth in transgenic mice by depletion of antioxidants. Annual Meeting of American Society for Cell Biology; 1999.
• Watson J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol. 2013;3(1). Available at: http://rsob.royalsocietypublishing.org/content/3/1/120144. Accessed January 22, 2013.
Acknowledgements
I want to thank the following individuals for their input on this issue: Donald Abrams, MD; Keith Block, MD; Penny Block, PhD; Isaac Eliaz, MD; and David Wales. (Any remaining errors are my own.)
Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.
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