Introduction

Carolyn M. Matthews, MD
Texas Tech Health Sciences Centerand Baylor University Medical Center

As you can surmise from the articles by Dr. Mark Moyad and Dr. L. Michael Glodé, one thing we can say with certainty is that dietary supplements are mired in controversy. Dogmatic statements for and against supplements abound in the medical literature; however, the evidence to support or discourage their use is not as clean as we would like.

Dietary supplements, according to the Dietary Supplement Health and Education Act of 1994 (DSHEA) are products intended to support the diet and may contain one or more o fvitamins, minerals, botanicals, amino acids, or a combination thereof. Thi sis a huge “mixed bag” of compounds, and optimally each supplement would be assessed on a patient-by patient basis, with potential benefits measured against potential harms. Itis not appropriate to lump all dietary supplements together because it is such a broad group of compounds.

Even the research on multivitamins is limited as there is not a universally accepted “best practice” multivitamin, but innumerable formulations on the market.

We do know that dietary supplements are commonly used—by some estimates in 50% of the population.^1,2 We also know that population intake of many nutrients declined in the last half of the 20th century, suggesting there might be somebenefit to taking multivitamins to address individual health needs. Wedo know that some, but not most, common dietary supplements go through the same stringent quality testing as pharmaceuticals, resulting in varying levels of quality. We know that many botanicals have been safely used for centuries, without evidence of harm. At the same time, we also know that many products marketed as “natural” and “botanical” do not meet safety requirements.For example, a 2004 study showed that as many as one out of five Ayurvedic products purchased on the Internet is contaminated with heavy metals.^3,4

My takeaway from this discussion is the following: It is difficult, given the broad variety of products and limitations of our current research, to make thoughtful, evidence-based recommendations to patients with cancer for the entire category of dietary supplements. Therefore, each supplement must be considered on an individual patient basis, with potential benefits measured against potential harms, and with an eye as well towards the quality testing for each product considered.

Dr. Matthews is a Clinical Professor of Obstetrics and Gynecology at the Texas Tech Health Sciences Center and the Director of Integrative Medicine at Baylor University Medical Center. She has been an ASCO member since 1992.

References

1. Luc L, Baumgart C, Weiss E, et al. Public Health Nutr. 2014;27:1-11
2. Wallace TC, McBurney M, Fulqoni VL. J Am Coll Nutr. 2014;33:94-102
3. Saper RB, Kales SN, Paquin J, et al. JAMA. 2004;292:2868-73.
4. Levine M, Mihalic J, Ruha AM, et al. J Med Toxicol. 2013;9:21-4.

Significant Evidence Exists for Use of Certain Individual Vitamins or Analogs in Cancer Care

By L. Michael Glodé, MD, FACP, FASCO
University of Colorado Cancer Center

I have been fortunate to participate as a research subject in the Physician’sHealth Study II. I mention this because, while I am not an expert in the research on vitamins and cancer, it seems to me that a careful reading of this landmark is a good place to start a pro-vitamin discussion.

The Physician’s Health Study II randomly assigned 14,681 U.S.–based male physicians over the age of 50 to take a placebo or a standard multivitamin preparation with the same composition as the widely advertised and widely utilized Centrum Silver supplement. Although there was no statistically significant reduction in any single nonskin epithelial cancer, after more than a decade of follow-up the overall hazard ratio (HR) for taking the multivitamin was 0.92 (0.86-0.998; p = 0.04). Removal of prostate cancer diagnoses from the analysis made the reduction in these types of cancers slightly more apparent (HR 0.88; p = 0.02). An even stronger effect was seen among the 1,312 patients who had entered the study with a previous cancer diagnosis (HR 0.73; p = 0.02), although this subgroup was not statistically different from the noncancer group.¹

The discussion section of the Physician’s Health Study reviews many of the large, prospective trials on vitamins as preventives for cancer. My impression from the trials reviewed (including the Nurses’ Health Study, the Cancer Prevention Study II, the Women’s Health Initiative, and others) is that multivitamin supplementation for prolonged periods (more than 10 years) usually shows a small, statistically significant benefit in cancer mortality, but of a magnitude only interesting to statisticians and perhaps manufacturers of products tested.^2-4

An exception to this impression is the probable protective role of multivitamin supplementation in nutritionallydeficient populations. For example,a study of the nutrition intervention trials in Linxian, China, “targeting 29,584 adults with low baseline nutrient status, tested a combination of beta carotene, vitamin E, and selenium for six years and found significant reductions of 9% in total mortality,13% in cancer mortality, and 21% in gastric cancer mortality.”⁵ These results are certainly noteworthy inview of our increasing understanding of the global burden of cancer within developing countries.

Beyond the multivitamin trials, one can find significant support for certain individual vitamins or analogs. All-transretinoic acid, a vitamin A derivative, has revolutionized the care of acute promyelocytic leukemia.⁶ Vitamin D plus calcium supplementation can almost certainly reduce overall mortalityin the elderly.^7,8 And, in large cohort studies, higher levels of 25-hydroxy vitamin D (25(OH)D) are associated with a lower risk for pancreatic cancer.⁹

These data are of increasing concern considering the high frequency of vitamin D deficiency in patients with advanced cancer and suggest that we should be more vigilant in testing for 25(OH)D deficiency in our patients.¹⁰

Folate, a water-soluble B vitamin, plays a critical role in maintaining genomic stability through one-carbon metabolism, and most studies suggest that folate deficiency increases the risk of colon cancer. This folate paradigm, however, is more complex in that excessive folate supplementation may actually accelerate the adenoma-carcinoma sequence.¹¹

In summary, although there can be little doubt that the massive vitamin and supplement industry in the developed world preys on the naive view that our immune systems need help and that we can prevent or delay some of the ravages of aging by simply popping a pill, there is evidence for the role of vitamins in cancer prevention and care.

As oncologists, we all encounter patients who have the inappropriate belief that synthetic supplements and vitamin preparations of all sorts will aid them in fighting cancer. We need to support these individuals by telling them that the best way to obtain the vitamins (perhaps with the exception of vitamin D in the era of greater sunscreen utilization) is by eating a balanced diet of colorful vegetables and following your mother’s advice to “eat your broccoli!”

Dr. Glodé is a Professor in the Division of Medical Oncology at the School of Medicine at the University of Colorado Denver. An ASCO member since 1980, he previously served as Chair of the Integrated Media &Technology Committee and the Cancer Education Committee.

References

1. Gaziano JM, Sesso HD, Christen WG, et al. JAMA. 2012;308:1871-80.
2. Giovannucci E, Stampfer MJ, Colditz GA, et al. Ann Intern Med. 1998;129:517-24.
3. Jacobs EJ, Connell CJ, Chao A, et al. Am J Epidemiol. 2003;158:621-8.
4. Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al. Arch Intern Med.2009;169:294-304.
5. Blot WJ, Li JY, Taylor PR, et al. J Natl Cancer Inst. 1993;85:1483-92.
6. Lo-Coco F, Avvisati G, Vignetti M, et al. N Engl J Med. 2013;369:111-21.
7. Rejnmark L, Avenell A, Masud T, et al. J Clin Endocrinol Metab. 2012;97:2670-81.
8. Bjelakovic G, Gluud LL, Nikolova D,et al. Cochrane Database Syst Rev.2011;(6):CD007469.
9. Wolpin BM, Ng K, Bao Y, et al. Cancer Epidemiol Biomarkers Prev. 2012;21:82-91.
10. Churilla TM, Brereton HD, Klem M, et al.Nutr Cancer. 2012;64:521-5.
11. Duthie, SJ. J Inherit Metab Dis. 2011;34:101-9.

Eliminate the Antiquated Perceptions and Embrace the Reality

By Mark A. Moyad, MD, MPH
University of Michigan

“Vitamin E is dangerous.” “Herbal products have no evidence.” “Supplements don’t do anything but feed cancer, so don’t waste your money.”

For almost 30 years I have watched not just patients, but especially some influential clinicians generalize, embellish, and misconstrue data on dietarysupplements. This type of commentary just mirrors the lack of objective education in this area, does nothing to improve the clinician and patient relationship, and arguably sends countless individuals to seek out information from less credible sources and misguided sales pitches (as it did through the years for many of my own family members). The perception of vitamin samong medical providers is skewed,but fortunately, I can inform you about several basic but critical realities since, arguably, I have worked in this area full time, longer than many people—a fact I mention not to impress you, but to increase the odds you will continue reading this article.¹

Reality #1 (establishing the validity of vitamin use): Even though some vitamins are not indicated for use in an oncology setting, they can nevertheless be effectively used for other specific conditions and are, in fact, considered drugs in many countries. In other words, supplements, when used for specific indications, can be as effective as good drugs.

Prolonged-released melatonin is indicated in Europe for insomnia, and oral and IV alpha-lipoic acid is indicated for diabetic peripheral neuropathy in some Asian and European countries.^2,3 Recently, a U.S. trial showed that patients with Alzheimer’s disease who took 2,000 IU of vitamin E per day experienced a clinically and statistically significant benefit in terms of functional decline.^4,5 That trial was one of the most rigorous ever published in this specialty; so why, may I ask, is vitamin E considered dangerous or worthless? Perhaps, one could argue—and I would agree—that based on the SELECT trial, vitamin E is dangerous in an oncology setting.⁶ However, that doesn’t negate the fact that when used for mild to moderate Alzheimer’s disease, in addition to conventional treatment, it has the potential to provide a desperately needed improvement in patient care.^4,5,7 Thus, at established dosages, vitamin E can serve in the United States essentially as a drug for this specific indication.

To further my point about specific indications for vitamins, let me provide an example: A clinician would never give docetaxel to treat dyslipidemia o rhypertension, but of course the evidence shows that docetaxel can be utilized for indications such as castrate resistant prostate cancer.⁸ Likewise, there are many vitamins that have no standard role in oncology, but are indicated for other conditions. There is the example of vitamin E that I stated above. Vitamin E has a clear indication in Alzheimer’s disease and is also shown to be effective in nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and as part of a combination supplement to prevent vision loss in patients with intermediate to advanced stages of age-related macular degeneration (indeed, taking vitamin E is the standard of care in ophthalmology).^4,5,9-12 So, too, butterbur extract, categorized as an herbal supplement in the United States, would never be used to treat any cancer but is part of the American Academyof Neurology’s clinical guidelines to prevent migraines.¹³ Also, the dietary supplement inosine continues to garner positive interest as data builds for its possible use as a treatment for Parkinson’s disease, albeit with the potential for serious toxicity if not monitored by a clinician.¹⁴ And, I could go on and on...

Reality #2: The real current and future promise of dietary supplements in oncology is for the reduction of common and not-so-common side effects of conventional cancer treatments and not in treating or curing advanced cancer.

Over the decades, I have been surprised whenever supplements have been studied in clinical trials in the hope that they will provide some substantial benefit in advanced disease.^15-18 There is no indication that supplements can provide this kind of efficacyand benefit. However, as more rigorous trials are completed, oncology is becoming replete with examples where supplements—when used in specific circumstances with standardized ingredients and meticulous quality control—are shown to, at the least, improve quality of life or reduce side effects of proven cancer treatments (assuming,of course, that in all of these situations, lifestyle changes were not effective enough).

For example, the potential for low-dose melatonin to improve sleep in some patients with cancer is now an interesting option.¹⁹ Also, how about reducing cancer-related fatigue with American ginseng, which demonstrated similar side effects to a placebo over an eight week period?²⁰ And what about using ginger to reduce the nausea from chemotherapy when used in addition to conventional anti-emetic agents?^21,22 The list goes on: A variety of phase III trials studied the potential of calciumand vitamin D supplements in combination with denosumab or bisphosphonates to prevent skeletal-related events.^23-25 These supplements may even play a future role in preventing hypocalcemia.²⁶ Calcium supplementation (for example, carbonate) is being studied for its ability to reduce citrate toxicity that can occur from apheresis procedures.^27,28 In all of the above cases, I believe the benefit outweighs the risk, especially in light of all other available options. Which brings me to...

Reality #3: There are numerous supplements that could also exacerbate side effects, when used with certain cancer treatments. These should also be discussed with patients to reinforce overall objectivity.²⁹

Reality #4: The number of corrections I would like to make regarding misperceptions about dietary supplements in medicine far outweighs the space allowed in this column. So, I will be brief with “reality #4,” which is this:In the supplements world, some of the lowest-priced supplements have some of the best clinical evidence compared to the higher-priced options.¹

Reality #5: “Natural” usually means nothing more than an easy way to get the patient/consumer to pay a higher price.

In conclusion, dietary supplements are now studied in thousands of clinical studies every year, which means that the study of this discipline now requires a full-time commitment. Dabbling part-time (as many do) can be dangerous because it often leads to sweeping, unfounded generalizations about supplements—which to me are no different than ridiculous generalizations about drugs. These generalizations, in turn, fuel patients’ perceptions that doctors do not know about supplements and are biased against them.

Coincidentally, I finished writing this argument on the same day that I had to give a lecture to health care professionals on metformin research in cancer prevention and treatment. During this lecture, I had to also explain that significant reductions in vitamin B12 (and perhaps magnesium) with potential clinical implications have occurred in past noncancer trials on metformin and that this potential for vitamin B12 reduction needs to be addressed in oncologic trials (clinicaltrials.gov lists over 100 trials studying metformin and cancer). Past trials have also found that some carefully monitored patients may need to utilize a vitamin B12 and/or magnesium supplement to prevent toxicity.^30-32 These nutritional issues are somewhat similar to those that can occur with treatment for chronic acid reflux medications; per the U.S. Food and Drug Administration (FDA), “Treatment. . . generally requires supplements.”^33,34

Later on that same day, I was informed of a clinician who could not convince her longtime patient to try conventional medicine despite a biopsy-proven, aggressive prostate cancer with a PSA approaching 250 ng/ml (the patient was diagnosed with a PSA of 10 and had, at the time I wrote this article, at least T3N1M0 disease). The patient was taking over 20 different supplements to treat his disease and was quoting a variety of nefarious alternative medicin e“experts.” I was called to talk to him and all I did was provide a similar argument to the one in this column. I also informed him that if he had sleep issues, fatigue, and other fairly common and not-so-common side effects of treatment, and if lifestyle changes were not effective, I would recommend to his oncologist a variety of low-cost, generic supplements that have undergone quality-control testing (and with which I have no affiliation) and that he could purchase those supplements at the grocery store or pharmacy down the street. He quickly informed the oncologist that he would be moving forward with conventional treatment. Perceptions changed that day and new realities set in—it was a beautiful day!

Dr. Moyad is the Jenkins/Pokempner Director of Complementary and Alternative Medicine in the Department of Urology at the University of Michigan Medical Center.

References

1. Moyad MA. The Supplement Handbook: A trusted expert’s guide to what works & what’s worthless for more than 100 conditions. New York, NY: Rodale; 2014.
2. Wade AG, Crawford G, Ford I, et al. Curr Med Res Opin. 2011;27:87-98.
3. Tesfaye S, Boulton AJ, Dickenson AH. Diabetes Care. 2013;36:2456-65.
4. Dysken MW, Sano M, Asthana S, et al.JAMA. 2014;311:33-44.
5. Evans DA, Morris MC, Rajan KB. JAMA. 2014;311:29-30.
6. Klein EA, Thompson IM Jr, Tangen CM, etal. JAMA. 2011;306:1549-56.
7. Cummings JL, Morstorf T, Zhong K. Alzheimers Res Ther. 2014;6:37.
8. Basch E, Loblaw DA, Oliver TK, et al. J Clin Oncol. 2014;32:3436-48.
9. Ji HF, Sun Y, Shen L. Nutrition. 2014;30:986-91.
10. Pearlman M, Loomba R. Curr Opin Gastroenterol. 2014;30:223-37.
11. Arch Ophthalmol. 2001;119:1417-36.
12. Chew EY, Clemons TE, Agrón E, et al. Ophthalmology. 2013;120:1604-11.
13. Holland S, Silberstein SD, Freitag F, et al. Neurology. 2012;78:1346-53.
14. JAMA Neurol. 2014;71:141-50.
15. Miller DR, Anderson GT, Stark JJ, et al. JClin Oncol. 1998;16:3649-55.
16. Jatoi A, Ellison N, Burch PA, et al. Cancer. 2003;97:1442-46.
17. Stephenson CM, Levin RD, Spector T, et al. Cancer Chemother Pharmacol. 2013;72:139-46.
18. Moertel CG, Fleming TR, Creagan ET, et al.N Engl J Med. 1985;312:137-41.
19. Chen WY, Giobbie-Hurder A, Gantman K, et al. Breast Cancer Res Treat. 2014;145:381-8.
20. Barton DL, Liu H, Dakhil SR, et al. J Natl Cancer Inst. 2013;105:1230–8.
21. Panahi Y, Saadat A, Sahebkar A, et al. Integr Cancer Ther. 2012;11:204-11.
22. Ryan JL, Heckler CE, Roscoe JA, et al. Support Care Cancer. 2012;20:1479-89.
23. Stopeck AT, Lipton A, Body JJ, et al. J ClinOncol. 2010;28:5132-9.
24. Henry DH, Costa L, Goldwasser F, et al. J Clin Oncol. 2011;29:1125-32.
25. Fizazi K, Carducci M, Smith M, et al. Lancet. 2011;377:813-22.
26. Segal E, Felder S, Haim N, et al. Isr Med Assoc J. 2012;14:607-12.
27. Sassi M, Dell’Anna P, Bernuzzi G, et al. Blood Tranfus. 2012;10:108-9.
28. Kishimoto M, Ohto H, Shikama Y, et al. Tranfusion. 2002;42:1340-7.
29. Hershman DL, Unger JM, Crew KD, et al. J Clin Oncol. 2013;31:2627-33.
30. Liu Q, Li S, Quan H, Li J, et al. PLoS One. Epub 2014 June 24.
31. Peters KE, Chubb SA, Davis WA. PLoS One.Epub 2013 Sep 3.
32. Liebman MF, Brien W, Parulekar WR, et al. J Clin Oncol. 2014;32:(suppl; abstr 542).
33. Lam JR, Schneider JL, Zhao W, et al. JAMA. 2013;310:2435-42.
34. US Food and Drug Administration. www.fda.gov/Drugs/DrugSafety/ucm245011.htm.Published March 2, 2011.