Natural Medicine Journal Oncology Supplement: Vol 9 No 111 by Diversified Communications

NOVEMBER 2017 SUPPLEMENT

SPECIAL ISSUE

Oncology

The Microbiome in Cancer Care and Prevention

Natural Supplement for Peripheral Neuropathy

Phytotherapy for Recurrent Prostate Cancer

Intravenous Therapies for Cancer Patients

Do B Vitamins Increase Lung Cancer Risk?

Research Advances in Integrative Oncology

GET MORE OUT OF LIFE. AND YOUR SUPPLEMENTS. INTRODUCING

Liposomal Curcumin - PROVIDES SUPPORT TO THE BRAIN,

Available for Private Label

CARDIOVASCULAR, DIGESTIVE AND IMMUNE SYSTEMS.*

Turmeric (Curcuma longa): • Protects against free radical damage* • Supports brain health via Brain Derived Neurotrophic Factor (BDNF)* • Aids in digestion by soothing intestinal mucosa* • Supports the immune system through B and T cell production* for over 45 YEARS | TRUTH IN LABELING |

CLINICALLY RELEVANT FORMULAS

www.davincilabs.com

RESTORATIVE NUTRIENT LEVELS

* T HE S E S TAT E ME N T S H AV E NO T BE E N E VA L U AT E D BY T HE F OOD A ND DR UG A DMINIS T R AT ION . T HIS P R ODUC T IS NO T IN T E NDE D T O DI A GNO S E , T R E AT, C UR E OR P R E V E N T A N Y DIS E A S E .

SPECIAL ISSUE ONCOLOGY NOVEMBER 2017 VOL 9, NO. 111 (SUPPL)

Contents ABSTRACTS & COMMENTARY 6

Phytotherapy in Biochemically Recurrent Prostate Cancer

Coriolus versicolor in Advanced Hepatocellular Carcinoma

Do B Vitamins Cause Lung Cancer?

OPERA Supplementation for Chemotherapy-Induced Peripheral Neuropathy PEER-REVIEWED ARTICLE

The Human Microbiome in Cancer SPONSORED PODCAST

Intravenous Therapies in Oncology Practice: A Conversation with Paul Anderson, NMD AUDIO INTERVIEW

Major Research Projects in Naturopathic Oncology: Interview with Dugald Seely, ND, FABNO

IN YOUR INBOX EACH MONTH? http://eepurl.com/d6zXb WANT TO GET NATURAL MEDICINE JOURNAL

SUBSCRIBE FOR FREE!

http://www.natural medicinejournal.com/blog Natural Medicine Journal Blog

Contributors MEGAN CHMELIK is a third-year naturopathic medical student at National University of Natural Medicine in Portland, Oregon. Before moving to Portland, she worked for Rena Bloom, ND, and Jacob Schor, ND, FABNO, at the Denver Naturopathic Clinic. As part Megan Chmelik of a tradition of mentoring receptionists and preparing them for naturopathic school, Schor encouraged Chmelik to learn how to use PubMed and write review articles. Now years later, it is clear that this passion of his has been passed down as she continues to write for NMJ during her spare time. TINA KACZOR, ND, FABNO, is editor-in-chief of Natural Medicine Journal and a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National University of Natural Medicine and Tina Kaczor, ND, completed her residency in naturoFABNO pathic oncology at Cancer Treatment Centers of America, Tulsa, Oklahoma. Kaczor received undergraduate degrees from the State University of New York at Buffalo. She is the past president and treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peerreviewed journals. Kaczor is based in Portland. MIRANDA LABANT, ND, graduated from National University of the Health Sciences in Lombard, Illinois. She is licensed in the state of Hawaii and began her 2-year naturopathic oncology residency program at Lokahi Health Center under the direction of Miranda LaBant, Michael Traub, ND, in Kailua Kona ND this spring. She was born and raised in Northeast Ohio, where she completed her masters of health sciences from Cleveland State University before pursuing her degree in naturopathy. LaBant is passionate about endocrine and gastrointestinal health, integrative oncology, preventative health and wellness, and the use of botanical medicine and biotherapeutic drainage therapies. In her time outside of the office she can be found exploring and hiking the many landscapes of the Big Island.

ELLEN McDONELL, ND, is a naturopathic doctor and clinician scientist at the Ottawa Integrative Cancer Centre. McDonell obtained a bachelor of science in biochemistry from the University of Ottawa before completing her doctor of naturopathic medicine degree at the Canadian College of Naturopathic Medicine. After graduation, McDonell completed a research residency in integrative oncology at Ellen McDonnell, the Ottawa Integrative Cancer Centre. In addition to mainND taining a clinical practice, McDonell is involved in several research projects, including the Canadian/US Integrative Oncology Study and the Thoracic Peri-Operative Integrative Surgical Evaluation (POISE). PAUL RICHARD SAUNDERS, PhD, ND, DHANP, CCH, completed his PhD in forest ecology at Duke University, his naturopathic degree at Canadian College of Naturopathic Medicine, and his homeopathic residency at National College of Naturopathic Medicine, Portland, Oregon, where he also earned a second naturopathic degree. He is professor of materia medica and clinical medicine at the Paul Saunders, Canadian College of Naturopathic Medicine; senior natuPhD, ND, DHANP, CCH ropathic doctor, Beaumont Health System, Troy Hospital, Michigan; and adjunct professor of integrative medicine, Oakland University William Beaumont Medical School and has a private practice in Dundas, Ontario. Saunders was a member of the transition team that formed the Office of Natural Health Products, served as a natural health expert to the Directorate, and has served on several expert panels for Health Canada. He has conducted clinical research, supervised students and residents, and published widely. MICHAEL TRAUB ND, DHANP, FABNO, completed pre-med studies at the University of California at Irvine. He graduated from National University of Naturopathic Medicine in 1981 and completed a residency there in Family Practice and Homeopathy. In 2006, Traub was honored with the American Association of Naturopathic Physicians (AANP) Physician of the Year Award in recognition for his Michael Traub, ND, many years of service, which included serving as AANP DHANP, FABNO president from 2001 to 2003. His father was a dermatologist, and this inspired Traub to undertake extra study in this subject and become the leading expert in dermatology in the naturopathic profession. He has taught dermatology at 5 of the 7 accredited naturopathic medical schools in North America and is the author of Essentials of Dermatologic Diagnosis and Integrative Therapeutics. A fellow of the American Board of Naturopathic Oncology, Traub has been actively engaged in clinical research throughout most of his career and is currently a co-investigator in the Canadian/US Integrative Oncology Study. His most recent major publication, “Impact of Vitamin D3 Dietary Supplement Matrix on Clinical Response,” appears in a 2014 issue of the Journal of Clinical Endocrinology and Metabolism. Traub has served as medical director of Lokahi Health Center in Kailua Kona, Hawaii for the past 31 years.

EDITOR IN CHIEF Tina Kaczor, ND, FABNO

MESSAGE FROM THE PUBLISHER

ABSTRACTS & COMMENTARY EDITOR Jacob Schor, ND, FABNO

Broadening the Burden of Cancer Care

PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry PUBLISHED BY IMPACT Health Media, Inc. Boulder, Colorado Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2017 by IMPACT Health Media, Inc. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; IMPACT Health Media, Inc. assumes no liability for any information published herein. Advertisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this publication. IMPACT Health Media, Inc. is not liable for any injury or harm to persons or property resulting from statements made or products or services referred to in the articles or advertisements.

Whether we like it or not, caring for people diagnosed with cancer is no longer a burden that oncologists alone must carry. Because so many people are affected by cancer, their needs spill over into primary care, gynecology, urology, internal medicine and yes, integrative medicine. No matter what your specialty or practice emphasis, chances are very high that you’ve seen people diagnosed with cancer in your clinic. And that’s why, year after year, we tackle this tough topic with a special issue specifically designed with integrative medicine in mind. In this issue, our very own Editor-in-Chief, Tina Kaczor, ND, FABNO, has authored a peer-reviewed paper on the complex and fascinating topic of the microbiota and cancer. Our Abstracts & Commentary section highlights some natural substances that have been shown to reduce risk, ease treatment side effects, or complement conventional treatment. We also have two interesting audio interviews that you can listen to as you multitask. Paul Anderson, NMD, discusses IV therapies, which have become more prevalent in clinical practice; and highly respected naturopathic researcher Dugald Seely, ND, FABNO, describes the impetus and rationale behind his $3.5M Thoracic POISE study, which is the largest-ever North American grant awarded to study the effectiveness of naturopathic medicine used in combination with conventional medicine. Caring for those impacted by cancer from the point of diagnosis well into survivorship years presents an opportunity for integrative healthcare professionals. As we broaden the burden beyond conventional oncology, the hope is that we can turn the tides on an illness that has tsunamic momentum right now. We hope you find this issue interesting and informative. And if you do, please share it with your colleagues. Thanks to all those involved with creating this important special issue.

Karolyn A. Gazella Publisher, Natural Medicine Journal

ABSTRACT & COMMENTARY

Phytotherapy in Biochemically Recurrent Prostate Cancer A pilot study REFERENCE

Van Die MD, Williams SG, Emery J, et al. A placebo-controlled doubleblinded randomized pilot study of combination phytotherapy in biochemically recurrent prostate cancer. Prostate. 2017;77(7):765-775. DESIGN

Double-blind, randomized, placebo-controlled 2-cohort parallel trial; participants were assessed at baseline and at week 12. PARTICIPANTS

Twenty-two Australian men aged 56 to 84 years with biochemically recurrent prostate cancer (BCR) recruited from a cancer hospital in Melbourne, Australia. STUDY MEDICATION AND DOSAGE

Participants randomly allocated to the experimental group took 2 capsules of broccoli sprout concentrate 20:1 twice a day (each equivalent to fresh sprouts 2,000 mg [8 g/day]), and 2 capsules containing 30 mg resveratrol (from Polygonum cuspidatum extract 100:1) and 100 mg catechins (from green tea leaf extract 25:1) per capsule, twice a day. The placebo group took 2 capsules containing microcrystalline cellulose, calcium hydrogen phosphate, magnesium stearate, and hypromellose twice a day and two 100-mg capsules of powdered green oats twice a day. OUTCOME MEASURES

To estimate PSA doubling time, 3 to 6 prostate specific antigen (PSA) measurements were obtained at least 12 months before enrollment. Clinical measures collected at baseline were PSA, blood urea nitrogen (BUN), electrolytes, liver function tests, estradiol, blood pressure, BMI, and Karnofsky performance score. Quality of life was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLA-C30) and Prostate 25 (EORTC PR-25), administered at baseline and week 12, and the International Prostate Symptom Score (IPSS) and Hospital Anxiety and Depression Scale (HADS). Dietary intake of trial substances was recorded in weekly diaries, along with adverse events. KEY FINDINGS

The study was not adequately powered to detect effects of the phytotherapeutic intervention on PSA doubling times from baseline to 12 weeks. There were no statistically significant differences in prostate symptoms as measured on the IPSS, anxiety and depression as measured on the HADS, or in the EORTC QLA-C30 or EORTC PR-25. The phytotherapeutic combination was well-tolerated. Few and mild side effects were reported, and adherence to protocol was high. The width of the confidence intervals of PSA doubling times by group allowed for the possibility that the herbal group would have a better PSA outcome in a future adequately powered trial, consistent with other recent promising trials of similar herbal interventions.1-3

Michael Traub, ND, DHANP, FABNO PRACTICE IMPLICATIONS Thirty percent of patients treated for prostate cancer with prostatectomy or radiation therapy—and more than 50% in high-risk cases—eventually develop potentially life-threatening recurrences,4 which are often detected when their PSA levels start rising during post-treatment surveillance. The standard treatment for recurrent prostate cancer, whether biochemical or metastatic, is intermittent or continuous androgen deprivation therapy (ADT). Once the disease is “castration resistant,” ADT is typically continued for life. Androgens and androgen deprivation have profound effects on the immune system, a finding that has become more appreciated in an era where exploration of immune-based treatments for cancer continues to advance. Preclinical studies suggest that androgen deprivation could potentially positively or negatively affect the use of approved or investigative immunotherapies for the treatment of prostate cancer. Initially, ADT is highly effective in suppressing prostate cancer; however, the side effects are potentially significant and include fatigue; weight gain; muscle loss; hot flashes; erectile dysfunction; loss of libido; loss of strength, muscle mass, and bone density; cognitive impairment; depression; osteoporotic fractures; anemia; and increased risk of diabetes, metastatic disease, and cardiovascular events.5-7 In the context of an otherwise asymptomatic individual, such effects are especially concerning, because treatment is applied frequently for many years. Furthermore, ADT is not curative.8 Most tumors progress to metastatic castration-resistant prostate cancer after ADT in a mean interval of 38 months,4 are recalcitrant to current therapy, and progress rapidly. There is a pressing need for new, minimally toxic therapies for prostate cancer. Despite some initial encouragement from cohort and small prospective studies, lycopene, saw palmetto,

(continued on page 8)

Metatrol PRO Fermented Wheat Germ Extract – Super Concentrate ®

Mitochondrial dysregulation repaired! New Metatrol PRO helps to rescue mitochondrial function. This unique mechanism of action helps to restore normal cellular metabolism, leading to: • Enhanced energy • Better quality-of-life • Maintained healthy body weight And most importantly: • Better results!

Good news for you. Better news for your patients! For more than 50 years, the health benefits of fermented wheat germ have been studied by some of the world’s leading scientists, including two Nobel Laureates, leading to more than 40 published research articles showing benefits in various health conditions. A six year research collaboration with an NCI designated research facility has led to the identification of the most active ingredients in fermented wheat germ, providing the most advanced and concentrated version ever created -- Fermented Wheat Germ Extract SUPER CONCENTRATE. Just two capsules per day delivers the same, incredible health benefits as previous forms of fermented wheat germ and now it’s GLUTEN FREE!

For more information on Metatrol PRO, visit: abs-rx.com To see the research on fermented wheat germ extract, visit: fwgeresearch.org For FREE product samples, email: info@abs-rx.com *These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.

560 Bradley Hill Road #4, Blauvelt, NY 10913

ABSTRACT & COMMENTARY

or genistein extracts evaluated within more scientifically robust analyses did not demonstrate a benefit for prostate cancer.10 On the other hand, preliminary clinical trials have shown benefit from sulforaphane, broccoli, green tea, turmeric, pomegranate juice and extract, and white button mushroom.11-15 Although the Australian study in this review was not sufficiently powered to demonstrate efficacy, it does demonstrate the feasibility of a randomized trial of a combination of sulforaphane, green tea, turmeric, and resveratrol for treatment of men with prostate cancer, strengthening

“

There is a pressing need for new, minimally toxic therapies for prostate cancer.

”

the foundation for future investigations. Moreover, the latter 2 polyphenols have shown synergism in a preclinical bioavailability study, which supports their use in combination.16 This reviewer is currently seeking approval and funding for a clinical trial of white button mushroom in prostate cancer treatment. The main limitation of this Australian study was the slow rate of recruitment. The authors point out that accrual of participants was limited by the advent of Prostate-Specific Membrane Antigen (PSMA) PET scans at the recruitment hospital, which allowed for detection of micro-metastases in many otherwise eligible patients with BCR, who were then offered salvage treatments. A major advance in detecting metastatic prostate cancer, PSMA PET imaging uses a

radioactive peptide, Gallium-68, to mark an antigen receptor (PSMA) that sits on the surface of every prostate cancer cell, providing valuable information to help physicians make more informed treatment decisions, as well as aiding in recruitment and monitoring of research subjects. REFERENCES 1 Cipolla BG, Mandron E, Lefort JM, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev Res. 2015;8(8):712-719. 2 Thomas R, Williams M, Sharma H, et al. A double-blind, placebo-controlled randomized trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer—the UK NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014;17(2):180-186. 3 Twardowski P, Kanaya N, Frankel P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer. 2015;121(17):2942-2950. 4 Agarwal PK, Sadetsky N, Konety BR, Resnick MI, Carroll PR. Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care and outcomes. Cancer. 2007;112(2):307-314. 5 Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448-4456. 6 Chen WY, Tsai YC, Yeh HL, et al. Loss of SPDEF and gain of TGFBI activity after androgen deprivation therapy promote EMT and bone metastasis of prostate cancer. Sci Signal. 2017;10(492): eaam6826. 7 Nead KT, Sinha S, Yang DD, Nguyen PL. Association of androgen deprivation therapy and depression in the treatment of prostate cancer: a systematic review and meta-analysis. Urol Oncol. 2017;pii: S1078-1439(17)30378-2. 8 Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321(7):419-424. 9 Clark PE, Hall MC, Borden LS, et al. Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology. 2006;67(6):1257-1261. 10 Cipolla BG, Mandron E, Lefort JM, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev Res. 2015;8(8):712-719. 11 Thomas R, Williams M, Sharma H, et al. A double-blind, placebo-controlled randomized trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer—the UK NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014;17(2):180-186. 12 Dorff, TB, Grosen S, Tsao-Wei DD, et al. A phase II trial of a combination herbal supplement for men with biochemically recurrent prostate cancer. Prostate Cancer Prostatic Dis. 2014;17(4):359-365. 13 Paller CJ, Ye X, Wozniak PJ, et al. A randomised phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(1):50-55. 14 McLarty J, Bigelow RLH, Smith M, Elmajian D, Ankem M, Cardelli JA. Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res. 2009;2(7):673-682. 15 van Die MD, Bone KM, Emery J, Williams SG, Pirotta MV, Paller CJ. Phytotherapeutic interventions in the management of biochemically recurrent prostate cancer: a systematic review of randomised trials. BJU Int. 2016;117(Suppl 4):17-34. 16 Lund KC, Pantuso T. Combination effects of quercetin, resveratrol and curcumin on in vitro intestinal absorption. J Rest Med. 2014;3(1):112-120.

ABSTRACT & COMMENTARY

Coriolus versicolor in Advanced Hepatocellular Carcinoma Further research warranted

Ellen McDonnell, ND

REFERENCE

KEY FINDINGS

Chay WY, Tham CK, Toh HC, et al. Coriolus versicolor (Yunzhi) use as therapy in advanced hepatocellular carcinoma patients with poor liver function or who are unfit for standard therapy. J Altern Complement Med. 2017;23(8):648-652.

Median treatment duration was 12.1 weeks for CV group and 5.9 weeks for placebo group. Seventy percent of participants terminated treatment due to progressive disease or death, and no difference in treatment tolerability between groups was found.

OBJECTIVE

Disease-related outcomes There were no statistically significant differences in median TTP, PFS, or OS when treatment was compared to placebo: • Median TTP (months): 2.5 (95% confidence interval [CI]: 1.4-5.3) vs 4.2 (95% CI: 0.4-4.2), with an HR of 0.7 (95% CI: 0.16-3.05, P=0.63). • Median PFS (months): 2.5 (95% CI: 1.4-5.3) vs 1.1 (95% CI: 0.4-4.2), with an HR of 0.42 (95% CI: 0.13-1.34, P=0.144) • Median OS (months): 6.5 (95% CI: 3.3-24.1) vs 2.2 (95% CI: 0.8-23.3) with an HR of 0.35 (95% CI: 0.10-1.25, P=0.105) • Overall response rates: 11.1% (95% CI: 0.3-48.2) vs 16.7% (95% CI: 0.4-64.1%)

To evaluate the impact of Coriolus versicolor (CV) on disease progression, survival, quality of life, and blood markers in individuals with advanced hepatocellular carcinoma. DESIGN

Randomized controlled trial PARTICIPANTS

Fifteen individuals (14 men, 1 woman) of Asian ethnicity aged 48 to 74 with advanced hepatocellular carcinoma (HCC) were randomized 2:1 to receive CV (n=9) or placebo (n=6). Participants were eligible if they had inoperable HCC and liver cirrhosis (Child-Pugh class C) or HCC with liver cirrhosis (Child-Pugh class A or B) and had failed or were unfit for standard chemotherapy or radiotherapy. STUDY PARAMETERS ASSESSED

Median time to progression (TTP), response rates, toxicity, quality of life (QoL), progression-free survival (PFS), overall survival (OS), correlative analysis of blood markers PRIMARY OUTCOME MEASURES

Median TTP, PFS, and OS, and QoL; TTP, PFS, and OS were analyzed by KaplanMeier, and hazard ratio (HR) was determined by Cox regression analysis. QoL was measured using the Functional Assessment of Cancer Treatment questionnaire for individuals with hepatobiliary cancer (FACT-Hep) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). INTERVENTION

Oral administration of 2.4 g CV daily until disease progression or unacceptable toxicity

Quality of life On the EORTC QLQ-30, the CV group reported significantly lower pain and appetite loss scores compared to placebo, differences of −38.6 (95% CI: −65.5 to −11.8), and −39.7 (95% CI: −64.5 to −15.0), respectively.

No other scores on the EORTC or FACTHep were statistically significantly different. Blood analyses iInterleukin (IL)-17F and monocyte chemoattractant protein (MCP)-1 were reduced, and prolactin and tumor necrosis factor (TNF)related apoptosis-inducing ligand (TRAIL) R1 levels were increased in the CV group compared to placebo at the end of treatment. However, no statistical comparisons were reported.

Alpha-fetoprotein (AFP) levels were not different between groups.

PRACTICE IMPLICATIONS Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver tumors. Worldwide, liver cancer is the sixth most common malignancy and second largest cause of cancer-related mortality.1 Although the incidence of HCC is highest in Asia and Africa, rates in North America and Europe have risen in the past 3 decades.1 Over 50% of patients are considered advanced at time of diagnosis,2 and in the United States the 5-year relative survival of liver cancer is only 17%.3 In addition to survival, QoL is an important consideration for individuals with HCC as sleep disturbances, depression, fatigue, malnutrition, anorexia, and pain are commonly reported symptoms.3 Given the high mortality rate associated with HCC and poor quality of life, research into adjunctive treatments is warranted. Mushroom extracts including Cori olus versicolor are commonly used in integrative oncology as adjuncts to conventional treatment.4 Coriolus versicolor (also known as Turkey tail, Trametes versicolor, and Yun-Zhi) contains polysaccharides, specifically polysaccharopeptide Krestin (PSK) and polysaccharopeptide (PSP), which are largely responsible for its medicinal benefit.5 As a source of fungal polysaccharides, supplemental Coriolus versicolor extracts are used primarily for their immunomodulating properties.6 Coriolus (continued on page 12)

^ Based on enhanced absorption of BCM-95 curcumin versus equivalent weight capsule of unstandardized turmeric containing 2% curcumin *THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THESE PRODUCTS ARE NOT INTENDED TO DIAGNOSE, TREAT, CURE OR PREVENT DISEASE.

ABSTRACT & COMMENTARY

versicolor is most commonly administered as an extract standardized to PSK and has been studied for effect in various cancers including lung, gastric, breast, and colorectal cancers, showing benefit for various outcomes including OS, immune function, performance status, and tumor-related symptoms.6,7

Given current evidence, AHCC is likely the better mushroom extract to consider for individuals with HCC. The present paper on Coriolus versicolor is hypothesis-generating, and larger trials are warranted to determine if Coriolus may improve QoL and survival in individuals with HCC.

This current paper is the first to evaluate the impact of Coriolus versicolor on individuals with advanced HCC. However, little conclusive information can be gathered from this paper due to its small sample size and overall lack of statistically significant findings. The study did provide evidence that CV may improve appetite and pain scores, and this should be further evaluated in a larger population. The paper generates hypotheses for future research given the non-statistically significant improvements in OS, PFS, and QoL outcomes. A larger trial that is adequately powered to detect clinically meaningful changes is warranted.

LIMITATIONS The biggest limitation of the study is its small sample size; the study was not sufficiently powered to detect significant changes between groups.

Given the evidence supporting Coriolus versicolor in other cancer types and the demonstrated safety profile of this mushroom, it is not unreasonable for clinicians to consider it for patients with HCC. However, there is another mushroom extract that has demonstrated superior results specifically for HCC.

Finally, the methodology of the paper was incomplete in some areas, making it difficult to recreate the study and jeopardizing the external and internal validity of the results. For example, trial setting and selection of patients was not well described, details of the treatment, including standardization and extraction method, were not mentioned, and there was no description of the placebo or blinding, which could introduce bias.

Baseline characteristics were different between CV and placebo arms; however, statistical comparisons were not presented, so the significance is unclear. The treatment arm had greater numbers of participants with prior liver resection, chemotherapy, and radiotherapy. This may impact the differences observed between study arms.

Active hexose correlated compound (AHCC) is a mushroom extract from the Basidiomycota division of fungi that has been studied in HCC with promising results. A prospective REFERENCES cohort study in 269 patients evaluated time to disease recur- 1 McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19(2):223rence and OS in individuals with advanced HCC post-liver 238. resection. One-hundred and thirteen patients received 3 g 2 Colagrande S, Inghilesi AL, Aburas S, Taliani GG, Nardi C, Marra F. Challenges of hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645-7659. AHCC each day; compared to controls, the AHCC group 3 advanced National Cancer Institute. Survival Epidemiology and End Results (SEER) Program. Cancer Stat Facts: Cancer of the Liver and Intrahepatic Bile Duct. https://seer.cancer. had longer recurrence-free survival (HR: 0.639, P=0.0277), gov/statfacts/html/livibd.html. Published 2017. Accessed September 27, 2017. 8 and improved OS (HR: 0.42, P=0.0009). 4 PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. Medicinal A second, smaller prospective cohort study gave 6 g of AHCC daily to 34 patients with unresectable advanced HCC receiving supportive care only, and compared them to 10 placebo controls.9 Median survival was 3.5 months in the AHCC group vs 1.5 months in the control group (P=0.000). Furthermore, albumin and lymphocyte counts were statistically significantly improved in the AHCC group compared to controls.

5 6 7 8 9

Mushrooms (PDQ®): Health Professional Version; 2002. http://www.ncbi.nlm.nih.gov/ pubmed/27929633. Accessed September 27, 2017. Cui J, Chisti Y. Polysaccharopeptides of Coriolus versicolor: physiological activity, uses, and production. Biotechnol Adv. 2003;21(2):109-122. Fritz H, Kennedy DA, Ishii M, et al. Polysaccharide K and Coriolus versicolor extracts for lung cancer. Integr Cancer Ther. 2015;14(3):201-211. Eliza WLY, Fai CK, Chung LP. Efficacy of Yun Zhi (Coriolus versicolor) on survival in cancer patients: systematic review and meta-analysis. Recent Pat Inflamm Allergy Drug Discov. 2012;6(1):78-87. Matsui Y, Uhara J, Satoi S, et al. Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: a prospective cohort study. J Hepatol. 2002;37(1):78-86. Cowawintaweewat S, Manoromana S, Sriplung H, et al. Prognostic improvement of patients with advanced liver cancer after active hexose correlated compound (AHCC) treatment. Asian Pacific J Allergy Immunol. 2006;24(1):33-45.

IBS may be treatable. This test helps you know. Irritable bowel syndrome (IBS) has traditionally been a diagnosis of exclusion. Now there is an inclusionary tool to include in your IBS diagnostic workup. The IBSDetex™ test from Quest Diagnostics is for post-infectious IBS-D and IBS-M. It’s a quick, simple, first-line diagnostic test. For more information, contact your Quest Diagnostics sales representative or visit QuestDiagnostics.com/CD or QuestDiagnostics.com/IBS.

When the result is clear, you can be, too. Test Name: IBSDetex

Test Code: 94445

ABSTRACT & COMMENTARY

Do B Vitamins Cause Lung Cancer? The answer is sex-, supplement-, and smoking-dependent REFERENCE

Brasky TM, White E, Chen CL. Long-term, supplemental, one-carbon metabolismrelated vitamin B use in relation to lung cancer risk in the vitamins and lifestyle (VITAL) cohort. J Clin Oncol. 2017;35(30):3440-3448. STUDY OBJECTIVE

To examine the relationship between longterm supplemental B vitamin intake and lung cancer risk DESIGN

Prospective cohort study in 13 counties around the Puget Sound in northwest Washington state (VITAL cohort) PARTICIPANTS

Men and women, aged 50 to 76 at baseline and covered by the Surveillance, Epidemiology, and End Results (SEER) program cancer registry, were recruited from 364,418 baseline questionnaires from October 2000 to December 2002. Individuals with a history of lung cancer at baseline, lung cancer diagnosis on death certificate with no date of diagnosis, lung lymphoma and in situ lung cancer were excluded; after exclusions, 77,118 were available for study. Cohort members were followed from baseline to December 31, 2007, a mean follow-up of 6 years. STUDY PARAMETERS ASSESSED

Diet was assessed by food frequency questionnaire of 120 foods and beverages adapted from the Women’s Health Initiative, and the following demographic and health-related characteristics were collected: height, weight, computed BMI, education, family history of lung cancer, medical history, and cigarette smoking history, including age of onset of daily smoking, current smoking habits, cumulative years of smoking, number of years since quitting, and categorization as never smoked, former smoker (quit ≥10 years ago), recent smoker (quit <10 years ago), or current smoker. Cohort members reported their regular intake (≥1 per week for ≥1 year) of multivitamin, individual vitamin supplements, and

mixtures in a closed-ended format including usual daily dose of B6, B9, and B12, use of a multivitamin formulation, and brand name. KEY FINDINGS

Participants who developed lung cancer tended to be older, male, and less educated at baseline. They also had a lower BMI, consumed less alcohol, were more likely to be current smokers at baseline, had greater pack years, and were more likely to have a positive history of chronic obstructive pulmonary disease (COPD) and cancer. Comparing men and women, women consumed more B vitamins from supplements (P<0.001), men tended to consume more B vitamins from diet (P<0.001), and women had lower overall B vitamin intake (food and supplements; P<0.001). Both groups exceeded the US recommended daily allowance (RDA) for each B vitamin. There was no correlation of lung cancer risk with B vitamins in women. In men, compared to nonusers, intake of individual B vitamin supplements was associated with increased lung cancer risk for B6 (hazard ratio [HR]: 1.84; 95% confidence interval [CI]: 1.01-3.36) and B12 (HR: 2.42; 95% CI: 1.49-3.95). The 10-year average daily dose for men in the highest to lowest categories of B6 intake (>20 mg/d; HR: 1.82; 95% CI: 1.25-2.65) and B12 (>0.55 mcg/d; HR: 1.98; 95% CI: 1.32-2.97) was greater for current smokers compared to recent smokers or former smokers. Among current male smokers, only B6 above 20 mg per day (HR: 2.93; 95% CI: 1.5 -5.72, P=0.04) and B12 above 55 mcg per day (HR: 3.71; 95% CI: 1.77 -7.74, P<0.01) were significant for lung cancer risk. There was no risk for lung cancer in former smokers who quit more than 10 years ago or less than 10 years ago. There were too few participants who had never smoked to evaluate associations. The association with increased use of B vitamins was similar across all histological subtypes of lung cancer except adenocarcinoma.

Paul Richard Saunders, PhD, ND, DHANP PRACTICE IMPLICATIONS The relationship between B vitamins and cancer has been examined in a few prior studies. A randomized intervention study by Ebbing et al provided B vitamins to 6,837 patients with ischemic heart disease for 38 months, with another 39 months of follow-up. The study, which was conducted from 1998 to 2007, had 4 arms: 0.4 mg/d B12 plus 0.8 mg/d folic acid; 0.8 mg/d folic acid plus 40 mg/d B6; 40 mg/d B6 only; and placebo.1 Investigators found no effect of B6 on lung cancer. In the B12 plus folic acid arm, 10% developed cancer, while 8.4% of participants who did not receive that combination developed cancer (HR: 1.21; 95% CI: 1.03 -1.41, P=0.02). In this study, 40% were current smokers and 72% were current or former smokers. All-cause mortality was higher in the B12 with folic acid vs other treatments (16.1% vs 13.8%; HR: 1.18, P=0.01) and was mainly due to lung cancer. The cause of the increased cancer was unknown. The Hordaland Health Studies were surveys performed in Hordaland County, Norway during the 1990s. The surveys were used to explore homocysteine in about 7,000 residents.2 An analysis of B6 metabolism found that the 4-pridoxic acid/ pyridoxal + pyridoxal-5-phosphate ratio was a marker of B6 catabolism during inflammation and may be a marker of carcinogenesis. Smoking creates inflammation that can take

ABSTRACT & COMMENTARY

years for the body to quell. Perhaps B6 during smoking and quelling of its inflammation will in some people lead to lung cancer. To date no prospective studies have found an association between B12 and lung cancer risk. However, 2 prospective biomarker studies reported an elevated lung cancer risk in the highest versus the lowest categories of serum B12 in both sexes; methionine and B6 were associated with a lower risk.3,4 Hartman et al reported no association in men with high serum B6 levels; in this study, the highest serum levels had half the lung cancer risk (odds ratio [OR]: 0.51; 95% CI: 0.23-0.93, P=0.02).4 In the present study by Brasky et al, men who took individual B6 and B12 were at increased risk of lung cancer, and this association was almost two-fold among current smokers at baseline. No association was found in women who took multivitamins or individual vitamins, and no association was found with folate/B9 in men or women. The amount of B6 posing a hazard was >20 mg/d; the daily US RDA is 1.7 mg for men and 1.5 mg for women.5 The amount of B12 posing a hazard was 55 mcg/d; the daily US RDA is 2.4 mcg for men and women 14 years and older.6 However, this value is easily exceeded in the normal nonvegetarian standard North American diet; for example, a single double-cheeseburger or tuna sandwich at home, at a fast food establishment, or an upscale restaurant provides the RDA for B12. So, depending on the study, B6 can increase or decrease the risk for lung cancer. Vitamin B12 has been reported to elevate the risk, but the mechanism is not reported. Cyanocobalamin, ubiquitous in the over-the-counter marketplace, is a suspect. Cyanocobalamin provides 20 mcg of cyanide per 1,000 mcg of cobalmin. The structure of B12 contains a corrin ring, similar to the porphyrin ring of hemoglobin, chlorophyll, and cytochrome.7 Cyanocobalamin is easily synthesized in the laboratory and used in food and supplements because it is not oxidized air.5 Once ingested, cyanide is rapidly

“

…smokers may not be good candidates for vitamin A/beta-carotene and B6 or B12 supplementation until biochemical mechanisms are better understood.

”

absorbed by the liver, lungs, blood, and brain in humans and rodents. Cyanide from tobacco has been implicated in tobacco-alcohol amblyopia, cyanide can prevent uptake of iodine into the thyroid, and long-term low-level exposure can produce neuropsychiatric symptoms and Parkinson-like motor symptoms.8 To date cyanocobalamin has been considered safe given that foods such as apricots, cherries, and cassava contain over 100 times more cyanide. This study may prompt a re-examination given its tendency to accumulate in the lungs, among other tissues. Smoking is an inflammatory habit, with 85% of smokers developing COPD by ages 40 to 50.9 Perhaps this or related processes also alter the metabolism of B12 and B6 in some individuals. Vitamin A and beta-carotene pose risk in smokers as well.10 In summary, smokers may not be good candidates for vitamin A/beta-carotene and B6 or B12 supplementation until biochemical mechanisms are better understood.

LIMITATIONS A cohort self-reporting study encompassing 6 or more years carries accuracy risks associated with self-reporting regarding actual frequency of use, dose of the B vitamin used, and consistent use of the same brand manufactured with the same dose. Also, in the United States no agency regulates the manufacturing of B vitamins or certifies that the label and the contents are in agreement, which further muddies the waters. Companies often produce proprietary formulas that list ingredients but not the actual amounts of each ingredient. Consumer Labs is an independent company that

ABSTRACT & COMMENTARY

tests many nutritional supplements and has reported label diverse genetic polymorphisms may have difficulty converting discrepancies in the past; actual amounts are generally less to the active pyridoxal-5-phosphate or absorbing folic acid not than the label claim.11,12 in the methyl form, or utilizing cyanocobalamin, the most common form in over-the-counter supplements. In clinical practice it is not unusual for patients to purchase supplements and use them at less than the suggested rate, or An unanswered question is why members of this cohort were take a break on the weekend. Thus the doses claimed in the taking individual B6, B9, B12, or a multivitamin. If they study by self-reporting may well be under or over the dose are smokers one might argue they were taking B vitamins actually consumed. In this study, supplement consumption to treat fatigue or to prevent cancer. With a quick search of was counted if the participants took it one or more days per the internet, patients may learn that B6 will benefit fatigue, week for one or more years. mood, and depression. Folic acid is advertised for anemia, to build new cells, and to prevent cancer, and B12 is adverAccuracy of dietary recall is also unreliable, particularly when tised for anemia, weakness and tiredness, and building nerve a study spans several years. Most of us realize that unless cells. It takes much further internet searching and nutritional patients complete a diet diary each day, their recall of what biochemistry to determine which form of each vitamin is best they ate yesterday is poor and often selective. absorbed or most bioavailable. The authors do not speculate An additional weakness of the study is that the form of the B or provide data on why the individuals in the SEER catchvitamins is unknown. The authors cite Centrum Silver Adults ment took supplements. as an example of a good multivitamin-mineral supplement but the label does not state the chemical form of B6 (3 mg) REFERENCES 1 Ebbing M, Bonaa KH, Nygard, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302:2119-2126. of which there are 6, of folic acid (400 mcg) of which there 2 Zuo H, Ueland PM, Eussen SJ, et al. Markers of B6 status and metabolism as predictors are 3 main forms encompassing 18 chemical structures, or of of cancer: the Hordaland health study. Int J Cancer. 2015; 136(12):2932-2939. M, Relton C, Ueland PM, et al. Serum B vitamin levels and risk of lung B12 (25 mcg) of which there are 4 forms.13 Individuals with 3 Johansson cancer. JAMA. 2010. 303(23):2377-2385. 4

LISTEN TO NATURAL MEDICINE JOURNAL ON THE GO.

5 6 7

8 9 10 11 https://itunes.apple.com/us/podcast/natural-medicine-journal-podcast/id1112377770?mt=2

PODCAST SERIES

12 13

Hartman TJ, Woodson K, Stolzenber-Solomon R, et al. Association of the B-vitamins pyridodoxal 5’-phosphate B6, B12 and folate with lung cancer risk in older men. Am J Epidemiol. 2001;153(7):688-694. National Institutes of Health. Office of Dietary Supplements. Vitamin B6 Dietary Supplement Fact Sheet. https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/ . Updated February 11, 2016. Accessed September 8, 2017. National Institutes of Health. Office of Dietary Supplements. Vitamin B12 Dietary Supplement Fact Sheet. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/. Updated February 11, 2016. Accessed September 8, 2017. Scientific Panel on Food Additives and Nutrient Sources Added to Food. The metabolic fate and biological distribution of methylcobalamin and 5’-deoxyadenosylcobalamin are expected to be similar to that of other sources of vitamin B12 in the diet. EFSA Journal. 2008(815):1-21. World Health Organization. Hydrogen Cyanide and Cyanides: Human Health Aspects. Concise International Chemical Assessment Document 61. Geneva: World Health Organization; 2004. World Health Organization. Chronic Obstructive Pulmonary Disease Fact Sheet. http:// www.who.int/mediacentre/factsheets/fs315/en/. Published November 2016. Accessed September 11, 2017. Sommer A, Vvas KS. A global clinical view on vitamin A and carotenoids. Am J Clin Nutr. 2012;96(5):1204. Glassman NR. ConsumerLabs.com, electronic resources review. J Med Library Assoc. 2004.92(4):509-510. ConsumerLabs. https://www.consumerlab.com/. Accessed September 8, 2017. Centrum Silver Adults Product Label. http://labeling.pfizer.com/ShowLabeling. aspx?id=3770. Accessed October 25, 2017.

Zen Suite

Relaxation without sedation.*

200 mg of Zen contains gamma-aminobutyric acid (GABA) and theanine, an amino acid derivative found naturally in green tea (Camellia sinensis). Together they help support healthy mood and a feeling of calm relaxation, whether during the day or the night.*

Key Features • Supports a feeling of general relaxation and enhanced calmness* • GABA and pure Suntheanine® L-theanine • May promote a normal, healthy attitude and normal symptoms during PMS*

200 mg of Zen #74700 • 60 vegetarian capsules #76650 • 120 vegetarian capsules

• Liposomal Zen provides enhanced liposomal delivery.*

Liposomal Zen #76810 • 50 mL (1.7 fl. oz.)

Contains Suntheanine®, pure L-theanine from Taiyo International, Inc.

This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

800.545.9960 • info@allergyresearchgroup.com • www.allergyresearchgroup.com

ABSTRACT & COMMENTARY

OPERA Supplementation for Chemotherapy-Induced Peripheral Neuropathy Positive results, but how significant? REFERENCE

Desideri I, Francolini G, Becherini C, et al. Use of alpha lipoic, methylsulfonylmethane and bromelain dietary supplement (OPERA) for chemotherapy-induced peripheral neuropathy management, a prospective study. Med Oncol. 2017;34(3):46. OBJECTIVE

To determine the efficacy and safety of OPERA supplementation (240 mg alpha lipoic acid, 40 mg Boswellia serrata, 20 mg bromelain, and 200 mg methylsulfonylmethane [MSM]) in a series of patients with chemotherapyinduced peripheral neuropathy (CIPN). DESIGN

Prospective intervention study PARTICIPANTS

Twenty-five Caucasian adults with CIPN during or after chemotherapy with potentially neurotoxic agents; patients were enrolled in the study at the first clinical manifestation of neuropathy. The diagnosis of CIPN was based on the National Cancer Institute-Common Toxicity Criteria for Adverse Event (NCICTCAE) v4.0 grade of ≥1 for sensory neuropathy, with at least a report of paresthesia of fingers or toes (a criterion for grade 1). Inclusion criteria were as follows: 18 years or older; Karnofsky performance score >70; treatment with one of the following agents: paclitaxel, docetaxel, nab-paclitaxel, oxaplatin, cisplatin, carboplatin, vinorelbine, vincristine, etoposide, eribulin mesylate; CIPN that evolved after or during standard chemotherapy. Twenty-three patients (92%) received chemotherapy with a neurotoxic agent at

enrollment, while 2 patients (8%) had completed chemotherapy with a neurotoxic drug. INTERVENTION

All patients were required to take an OPERA capsule once a day, without regard to administration of food. STUDY PARAMETERS ASSESSED

Chemotherapy-induced peripheral neuropathy was assessed at the enrollment visit and repeated every 3 weeks until 12 weeks, using the following: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) v3.0, sensory and motor neuropathy score; the Total Neuropathy Score clinical version (TNSc); and the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory summary score (mISS). The Visual Analog Scale (VAS) for pain was used to assess pain intensity. PRIMARY OUTCOME MEASURES

Primary endpoint was the evaluation of changes of measured scores after 12 weeks of therapy compared to baseline evaluation. Secondary endpoints were the evaluation of neuropathy reduction at 12 weeks after beginning of therapy with OPERA. KEY FINDINGS

OPERA dietary supplement was able to improve CIPN symptoms in a prospective case series of patients treated with neurotoxic chemotherapy, with no significant toxicity or interaction. In addition, no worsening of pain or CIPN symptoms was reported with use of OPERA. There was no statistical analysis performed for this study.

Miranda LaBant, ND PRACTICE IMPLICATIONS Chemotherapy-induced peripheral neuropathy describes damage to the peripheral nervous system incurred by a patient who has received a neurotoxic chemotherapeutic agent. It is a frequent dose-limiting side effect for cancer patients treated with platinumderived compounds, vinca alkaloids, taxanes, and the proteasome inhibitors.1 Neurotoxicity incidence varies depending on the agent used and cumulative dose, with rates ranging from 19% to more than 85% in patients treated with multiple agents.2 A recent metaanalysis showed a CIPN prevalence of 68.1% (95% CI: 57.7-78.4) within the first month post-chemotherapy, 60.0% at 3 months, and 30.0% at 6 months or later.3 No reliably effective treatment has been established to prevent or treat CIPN symptoms. Duloxetine has provided only modest benefit and has associated side effects and a high dropout rate. The 2014 American Society of Clinical Oncology CIPN guideline gives a moderate recommendation for treatment with duloxetine, and recommends further research in this area.4 New safe and effective treatments are needed. Increased interest in CIPN has included the investigation of several nonpharmaceutical interventions. This study evaluates the dietary supplement OPERA to treat CIPN. While the authors established the efficacy and safety of OPERA for CIPN, there are several restrictive variables. There is limited and conflicting evidence for the components of OPERA. Alpha-lipoic acid has been shown to boost levels of glutathione and support healthy nerve tissue and blood sugar levels.5 Boswellia serrata is a potent anti-inflammatory herb and helps to balance the activity of 5-lipoxygenase (LOX) and support a healthy inflammatory response.6 Methylsulfonylmethane has been shown to reduce C-fiber nerve conduction,7 which is essential for effective pain control. It also has chemopreventive properties and anti-inflammatory activities.8,9 The components of OPERA may work synergistically to improve the symptoms of CIPN because they

ABSTRACT & COMMENTARY

collectively have anti-inflammatory effects, potent antioxidant properties, and potential benefit for diabetic neuropathy (nerve health and blood sugar control); however, evidence is lacking for the effectiveness of these constituents individually for the use of CIPN. A clear limitation of this study is its small sample size and nonhomogeneous patient population. Despite these limitations, the authors claim that OPERA reduced patients’ perception of pain, improved motor and sensory impairments, and was well-tolerated, with no treatment-related toxicities. Unfortunately, the authors failed to statistically analyze their results. Lack of statistical significance makes these seemingly positive outcomes impossible to interpret. While the authors of this study report that OPERA was safe and effective, these results are not significant given the lack of statistical analysis. The activity of this dietary supplement may benefit patients with CIPN, but future well-designed,

prospective, randomized controlled trials are warranted to support its use in these patients. REFERENCES 1 2 3

5 6 7 8 9

Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249(1):9-17. Fallon MT. 2013. Neuropathic pain in cancer. Br J Anaesth. 2013;111(1):105-111. Seretny M, Currie G, Sena E, et al. 2014. Incidence, prevalence, and predictors, of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain. 2014;155(12):2461-2470. Hershman D, Lachetti C, Dworkin R, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941-1967. Vallianou N, Evangelopoulous A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230-236. Ammon HP. Boswellic acids in chronic inflammatory diseases. Planta Med. 2006;72(12):1100-1116. Jimenez R, Wilkens R. Dimethylsulfoxide: a perspective of its use in rheumatic diseases. J Lab Clin Med. 1982:100(4):489-500. Ebisuzaki K. Aspirin and methylsulfonylmethane (MSM): a search for common mechanisms, with implications for cancer prevention. Anticancer Res. 2003;23(1A):453-458. Debbi EM, Agar G, Fichman G, et al. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complement Altern Med. 2011;11:50.

PEER-REVIEWED ARTICLE

The Human Microbiome in Cancer A mini-review of microbiome optimization in oncology ABSTRACT The gut microbiome is fast becoming a central focus in understanding the effectiveness of chemotherapies and immunotherapies in cancer care. In addition, various other organs have their own distinct microbiomes. These microbiomes—and imbalances in them—are associated with cancers of the head and neck, larynx, lung, breast, pancreas, esophagus, gallbladder, and colon/rectum. It is incumbent on integrative practitioners to maintain an evidence-based approach to optimizing health through microbiome optimization. Human microbiomes can be considered micro-ecosystems, and their benefit to the host may be best reflected in their complexity. We now understand the human microbiome to be intimately linked to both cancer causation and outcomes of cancer treatment. Recent advances in technology and bioinformatics are allowing for elucidation of the microbiome established in various tissues. These microbiomes are being better appreciated as microecosystems whose relationship with the human host can dictate health or disease.

INTRODUCTION According to the World Health Organization, singular organisms are directly responsible for causing up to 15% of cancers worldwide.1 Now microbiota imbalances—from species-specific to phylum-wide—are also implicated in cancer etiology. Cancers of the colon, breast, larynx, esophagus, pancreas, head and neck, lung, and gallbladder have been associated with imbalances of their resident microbiota.2-7 These relationships are slowly being unraveled as the complex, entwined biology of the host-biota symbiosis is better understood as a micro-ecosystem in which the health or disease state of its host is wholly dependent.8 There is also a growing appreciation for the role of the microbiota in general, and the gut flora specifically, in cancer treatment outcome.9 The idea that chemotherapy works by directly assaulting cancer cells has been an

Tina Kaczor, ND, FABNO

oversimplification. We now know that chemotherapies depend on the immune system to home in on tumors, and immune stimulation may account for much of chemotherapy’s “tumor kill.”10 This immune response is intimately dependent on the gut microbiome.11 The microbiota of the body comprise bacteria, fungi, archaea, and viruses, with bacterial organisms dominating the populations in healthy people. The taxonomy (identification of organisms by phyla, family, species, etc.) of organisms between organs is called spatial diversity or beta variation. For example, the colon is generally dominated by 2 phyla: Firmicutes and Bacteroidetes. From the mouth to the stomach, however, Firmicutes and Actinobacteria are the dominant phyla. Thus, each organ can be considered as having its own unique micro-ecology. In addition to spatial diversity, these micro-ecologies also undergo temporal changes, varying over the lifespan and shifting according to lifestyle habits and seasons of the year.12-14 Taxonomy can help us understand human microbiota. However, we cannot fully understand the complexity of interactions between the microbiota and its human host by merely identifying the organisms. It is the net functions of the microbiota that the human body relies on. For example, in one study the taxonomy of the mouth and gut varied dramatically by phylum, but the functional aspects, such as carbohydrate metabolism, purine metabolism, and cofactor/ vitamin biosynthesis (measured through metagenomics) were remarkably similar.15 Again, the idea of the microbiome as a micro-ecosystem is apt. Comparing function over phylum is analogous to comparing the complex ecology of a healthy rainforest to a healthy deciduous forest. They may have little in common taxonomically, but the net effect of their functions, such as oxygen production, water filtration, and organic matter decay, is very similar. Much like the human microbiome, forest ecosystems rely on high levels of diversity for their health, and it is only after perturbations in this diversity (eg, invasive species, clear cutting) that we begin to discover the consequences.

(continued on page 22)

W nt Brains and Brawn? Wa Contact the Experts

Balchem’s got you covered VitaCholine®

Albion®—Magnesium chelate

• Supports mental focus • Aids in fat metabolism • Optimizes nitric oxide for a better pump www.VitaCholine.com

• Supports brain health



• Improves muscle recovery • Delivers more energy www.AlbionMinerals.com

Changing the Way you see Nutrition

PEER-REVIEWED ARTICLE

A systems biology approach, together with the ability to discern form and function of the microbiome with technology only recently available, has led to a renaissance of sorts in medicine, and oncology is no exception. Practitioners of integrative oncology should be ready to incorporate the support with the most evidence to maximize outcomes of conventional treatments for our patients. For example, proper sleep hygiene, plant-based diets, and exercise all optimize the health of the human microbiota.16-18 This review describes some of the most recent data furthering our understanding of the microbiota in cancer care. HUMAN MICROBIOTA AND CANCER THERAPIES In 2013 the journal Science published 2 seminal studies on the gut microbiota and conventional cancer therapies. In the first experiment, by Viaud and colleagues, cyclophosphamide (a chemotherapy drug) was given to tumor-bearing mice.19,20 Cyclophosphamide is a known cytotoxic agent and an immune-modulating drug that can affect T lymphocytes (T cells).21 The administration of cyclophosphamide caused a translocation of gram-positive commensal bacteria from the gut to secondary lymph tissues (mesenteric nodes and spleen). This stimulated a measurable anticancer immune response, specifically through engaging T helper 17 (Th17) cells and memory T cells. When mice were treated with antibiotics, the tumor response to cyclophosphamide was greatly reduced. To be clear, chemotherapy’s ability to affect immune function through antigen stimulation and T cell activation has been known for some time.22 That commensal organisms translo cated intact to stimulate this response is paradigm-shifting. This concept should give us pause when we contemplate the long-held assumptions of separation between our body’s internal organs and our microbiota and make us reconsider the indiscriminant use of antibiotics during chemotherapy or radiation treatment.22 In 2016, Pflug et al conducted a retrospective analysis of 800 cyclophosphamide-treated chronic lymphocytic leukemia (CLL) patients and 122 cisplatin-treated lymphoma patients

to see if outcomes were affected by antibiotics specific for gram-positive bacteria.23 Consistent with Viaud’s observations in mice, the patients with CLL who received antibiotics (n=45) had significantly worse outcomes. Progressionfree survival (PFS) was 14.1 months, and median overall survival (OS) was 56.1 months for patients who received antibiotics, compared to 44.1 months (P<0.001) and 91.7 months (P<0.001) for those who did not. Outcomes were similar for lymphoma patients treated with cisplatin. Patients who received antibiotics (n=21) had a PFS of 2.3 months, compared to 11.5 months for those who did not (P=0.001). The authors concluded, “Our data supports a potential negative impact of anti-Gram-positive antibiotics on the anticancer activity of cyclophosphamide and cisplatin in a clinical setting.”23 This clinical outcome data certainly informs us on the use of antibiotics with cyclophosphamide and platinum drugs. However, we are still left wondering if a damaged mucosal lining may augment immune stimulation, or even facilitate translocation of gram-positive bacteria. Jacob Schor, ND, FABNO, posed this conundrum in this journal shortly after Viaud’s research in 2013: Should a patient’s increased gut permeability during chemotherapy be treated or not?24 There is no doubt that chemotherapeutics damage the epithelial layer of the gut, with those inducing mucositis the worst culprits.25,26 Does this damage somehow optimize the interface of the microbiota with the underlying immune reaction at the epithelial interface? Do those with “leaky gut” have better response to therapies? Or, is there an amount of intestinal permeability that is optimal, and a point at which it is so severe it poses more threat than possible benefit? Another 2013 study published in Science was aptly titled “Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment.”27 This study, by Iida and colleagues, was actually 2 experiments. Mice with transplanted tumors were treated either with chemotherapy (oxaliplatin) or with an immune treatment (CpG-oligonucleotide immunotherapy). In each case tumor response to the anticancer treatment required the presence

(continued on page 24)

PEER-REVIEWED ARTICLE

of commensal bacteria in the gut. Mechanistically, Iida and colleagues demonstrated that commensal flora is requisite to obtain the oxidative burst or the inflammatory necrosis induced by oxaliplatin or the immune therapy, respectively. How does the gut microflora manage to affect distant tumors? Just below the intestinal epithelial layer dendritic cells sample antigens or whole organisms and present these to secondary lymph tissue.28 At the tumor itself, tumorassociated myeloid (TAM) cells communicate with nearby T cells, largely through Toll-like receptors.29 These myeloid cells are highly plastic cells that can differentiate into various phenotypes involved in tumor progression or regression, depending on the molecular signals received.30,31 Experiments have shown that many of the signals that myeloid cells use to elicit immune response/recognition of the tumor require the presence of intact gut microbiota.10,32 In the experiments already mentioned, Iida and colleagues showed TAMs were not capable of producing the requisite oxidation for oxaliplatin cytotoxicity when the gut was sterilized. In Viaud’s cyclophosphamide experiment, myeloid cells gave rise to increased effector T cells and memory cells, and this reaction did not take place when the gut was sterile. In addition, experiments with whole body irradiation plus adoptive T cell transfer demonstrate that TAMs lead to cytotoxic lymphocytes expansion and ensuing cytotoxicity, but only in the presence of normal gut microbiota.33 CHECKPOINT BLOCKADE AGENTS AND MICROBIOTA Immunotherapies have been in the news due to the emergence of checkpoint inhibitors approved for several toughto-treat cancers. Programmed death-1 (PD-1) receptor, programmed death ligand-1 (PD-L1), and cytotoxic T lymphocyte–associated protein-4 (CTLA-4) are checkpoint blockade proteins expressed by cancer cells and cells in tumor stroma. Monoclonal antibodies that target these checkpoint blockade proteins include pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), and ipilimumab (Yervoy).

“

While we cannot recommend specific probiotics or prebiotics, we are in a position to optimize microbiota diversity in an effort to create the healthiest micro-ecosystem possible.

”

Normally, once engaged, PD-1, PDL-1, or CTLA-4 act as brakes to halt the immune attack of cancer cells. When one of the monoclonal antibodies binds to the checkpoint protein, the brake is rendered ineffective, which allows the immune response to proceed. Several studies in mice have assessed the effect of various gut flora on checkpoint inhibitor antibody efficacy. In one study, Bacteroides fragilis reduced CTLA-4 blockade– induced colitis and promoted the maturation of intratumoral dendritic cells.34 These effects would seem to be beneficial to a patient, making the treatment more tolerable and perhaps more effective. However, this mouse study should be interpreted with caution. Colitis severity may be associated with treatment efficacy. In a small study of metastatic melanoma patients (n=26), fecal microbiota composition was assessed at baseline and before each infusion of ipilumimab.35 Patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A; n=12) had longer PFS (P=0.0039) and OS (P=0.051) than patients whose baseline microbiota was driven by Bacteroides (cluster B; n=10). Those with Firmicutesdominant flora also had fewer immunosuppressive regulatory T cells (Tregs), less colitis, and overall better benefit of treatment.35 In another study of tumors in mice, Bifidobacterium spp (breve, longum, and adolescentis) enhanced dendritic cell activation

PEER-REVIEWED ARTICLE

and improved response to PD-1 inhibitor treatment.36 In Iida’s experiment mentioned above, commensals that augmented immunotherapy included Ruminococcus and Alistipes shahii, while Lactobacillus fermentum dampened immunotherapy. While we continue to sort out what bacterial composition is optimal with checkpoint inhibition, recent human data suggests that a diversity of flora may be of particular benefit. In a large cohort (n=221) of metastatic melanoma patients, most of whom had received PD-1 inhibitors (n=105), there was higher microbiota diversity in treatment responders vs nonresponders (P=0.03).37 There was also a higher abundance of the class Clostridiales in responders but higher Bacteroidales in nonresponders. The authors concluded that diversity (P= 0.009; hazard ratio [HR]=7.67) and abundance of specific bacteria (P=0.007; HR=3.88) was associated with improved PFS to anti-PD-1 therapy.

The first clinical study to specifically look at the gut flora and checkpoint inhibitor outcomes was published in 2015. Dubin and colleagues found that metastatic melanoma patients with Bacteroidetes-dominant gut flora undergoing treatment with a CTLA-4 inhibitor had less colitis than those without Bacteroidetes dominance.38 Colitis was also more prevalent in those whose biome had fewer genes involved in polyamine transport and B-vitamin synthesis. Bacteroidetes are bile acid– resistant bacteria that are found more often in those consuming diets higher in animal proteins and fats. Theoretically, suggesting patients consume more animal-based products may lead to less colitis with treatment. But at what cost? CLINICAL CONSIDERATIONS For now, precise recommendations regarding what species of probiotics, which prebiotics, and what type of diet optimize JOIN US AT

THE 2018

INTEGRATIVE

SIBO

CONFERENCE

April 7-8

Le Meridien New Orleans Hotel | New Orleans, Louisiana

BROUGHT TO YOU BY

synergycmegroup.com

PEER-REVIEWED ARTICLE

gut flora during checkpoint blockade treatment is not clear. While side effect reduction—such as lessening colitis by enhancing Bacteroidetes—is often the goal, data suggests this could undermine the treatment response itself.

must help our patients maintain a strong defensive immune system, through reminders about hygiene, sleep, exercise, laughter, nutrient repletion, and a healthy diet, as the foundation of care to avoid any need for antibiotics.

One consistent finding in both rodents and humans is that antibiotics blunt the immune response induced by the checkpoint blockade agents.19,27,39 A recent study by Derosa and colleagues found that antibiotic use during treatment with PD-1 inhibitors can affect outcomes adversely. In a retrospective analysis of 175 patients receiving PD-1 inhibitor therapy for a variety of cancers, almost a third received an antibiotic (mostly beta lactamases or fluoroquinolones) within 1 month before or 2 months after starting treatment with a PD-1 inhibitor. Overall, those who took an antibiotic had lower PFS and lower OS (3.4 months vs 5.2 months, P<0.013, and 12.2 months vs 20.8 months, P<0.001). This held true when patients were stratified by cancer type as well.

While we cannot recommend specific probiotics or prebiotics, we are in a position to optimize microbiota diversity in an effort to create the healthiest micro-ecosystem possible. As reviewed above, evidence implies that diversity may be one of the keys to immune recognition of cancer cells and efficacy of anticancer treatments.41

Antibiotics are sometimes a necessary component of care, but they should be reserved as a last resort in those undergoing cancer treatment.40 As integrative practitioners we

IT’S GOOD TO SHARE Do you like what you’re reading? Your friends and colleagues probably would, too. Be sure to share Natural Medicine Journal with them. A free subscription to Natural Medicine Journal means you’ll always stay on top of the latest developments in the field of natural medicine.

JOIN US ON FACEBOOK, TWITTER, AND GOOGLE+ AND JOIN OUR CONVERSATIONS ABOUT ALL THINGS NATURAL MEDICINE–RELATED.

Perhaps one of the most profound studies suggesting that gut flora diversity affects cancer outcomes was published in 2014 by Taur and colleagues.42 Stool samples were obtained from 80 stem cell transplant recipients at the time of stem cell engraftment, and patients were followed over the course of the next few years. At 3 years post-transplant, survival was 36%, 60%, and 67% for the low, intermediate, and high diversity groups, respectively (P=0.019). In this study bacterial diversity was an independent risk factor for mortality. In the end, microbiota diversity, like ecological diversity, may be the ultimate measure of a healthy micro-ecosystem. If this is true, then a highly varied diet may be the dietary recommendation. CONCLUSION Currently, dysbiosis of the human microbiome in many organs is associated with variety of cancers. It is only a matter of time before microbiome profiles are used as clinical tools that will stratify cancer risk or assist early detection.43 Of course, association of organ dysbiosis with cancer is not synonymous with causation. However, corroborative evidence, such as the increased incidence of breast cancer in women with high antibiotic use, certainly strengthens the case.44-47 We are just beginning to define an optimal microbiome that will positively affect outcomes of chemotherapy or immunotherapies. Given the early data, it appears likely that commensal organisms are integrally involved in a tumor’s response to many cancer treatments. In addition,

PEER-REVIEWED ARTICLE

bacterial diversity appears to be associated with better treatment response. One piece of evidence-based medicine that may affect outcomes is the use of antibiotics as a last resort during treatment. Evidence to date does not support use of high-dose, specific probiotic strains to improve cancer treatment outcomes. A healthy omnivorous diet, such as the Mediterranean diet, along with exercise and proper sleep, may be the best, though less-than-precise, prescription to complement conventional therapies. REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22

World Health Organization. Cancer prevention. http://www.who.int/cancer/prevention/en/. Accessed August 31, 2017. Gao Z, Guo B, Gao R, Zhu Q, Qin H. Microbiota disbiosis is associated with colorectal cancer. Front Microbiol. 2015;6:20. Sinha R, Ahn J, Sampson JN, et al. Fecal microbiota, fecal metabolome, and colorectal cancer interrelations. PLoS One. 2016;11(3):e0152126. Xuan C, Shamonki JM, Chung A, et al. Microbial dysbiosis is associated with human breast cancer. PLoS One. 2014;9(1):e837. Sheflin AM, Whitney AK, Weir TL. Cancer-promoting effects of microbial dysbiosis. Curr Oncol Rep. 2014;16(10):406. Kantono M, Guo B. Inflammasomes and cancer: the dynamic role of the inflammasome in tumor development. Front Immunol. 2017;8:1132. Wang H, Altemus J, Niazi F, et al. Breast tissue, oral and urinary microbiomes in breast cancer. Oncotarget. 2017;8:88122-88138. Raes J, Bork P. Molecular eco-systems biology: towards an understanding of community function. Nat Rev Microbiol. 2008;6(9):693-699. Viaud S, Daillère R, Boneca IG, et al. Harnessing the intestinal microbiome for optimal therapeutic immunomodulation. Cancer Res. 2014;74(16):4217-4221. Karin M, Jobin C, Balkwill F. Chemotherapy, immunity and microbiota--a new triumvirate? Nat Med. 2014;20(2):126-127. Bordon Y. Tumour immunology: anticancer drugs need bugs. Nat Rev Immunol. 2014;14(1):1. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015;21(29):87878803. Hisada T, Endoh K, Kuriki K. Inter- and intra-individual variations in seasonal and daily stabilities of the human gut microbiota in Japanese. Arch Microbiol. 2015;197(7):919934. Davenport ER, Mizrahi-Man O, Michelini K, Barreiro LB, Ober C, Gilad Y. Seasonal variation in human gut microbiome composition. PLoS One. 2014;9(3):e90731. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489(7415):220-230. Sheflin AM, Melby CL, Carbonero F, Weir TL. Linking dietary patterns with gut microbial composition and function. Gut Microbes. 2017;8(2):113-129. Chandrakumaran H, Safdar A, Sager M, Nazli A, Akhtar M. Regular exercise shapes healthy gut microbiome. J Bacteriol Mycol Open Access. 2016;3(3):63. Zhang SL, Bai L, Goel N, et al. Human and rat gut microbiome composition is maintained following sleep restriction. Proc Natl Acad Sci. 2017;114(8):E1564-E1571. Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971-976. Madondo MT, Quinn M, Plebanski M. Low dose cyclophosphamide: mechanisms of T cell modulation. Cancer Treat Rev. 2016;42:3-9. Scurr MJ, Pembroke T, Bloom A, et al. Low-dose cyclophosphamide induces antitumor T-cell responses which associate with survival in metastatic colorectal cancer. Clin Cancer Res. 2017:clincanres.0895. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050-1059.

23 Pflug N, Kluth S, Vehreschild JJ, et al. Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota. Oncoimmunology. 2016;5(6):e1150399. 24 Schor J. Leaky gut and chemo: to treat or not to treat? Nat Med J. 2014;6(21). 25 Melichar B, Hyšpler R, Dragounová E, Dvořák J, Kalábová H, Tichá A. Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum. 2007;7:155. 26 van Vliet MJ, Harmsen HJM, de Bont ESJM, Tissing WJE. The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog. 2010;6(5):e1000879. 27 Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967970. 28 Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268-1273. 29 Goldszmid RS, Dzutsev A, Viaud S, Zitvogel L, Restifo NP, Trinchieri G. Microbiota modulation of myeloid cells in cancer therapy. Cancer Immunol Res. 2015;3(2):103109. 30 Schouppe E, De Baetselier P, Van Ginderachter JA, Sarukhan A. Instruction of myeloid cells by the tumor microenvironment: open questions on the dynamics and plasticity of different tumor-associated myeloid cell populations. Oncoimmunology. 2012;1(7):1135-1145. 31 Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumor-infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol. 2017;8:86. 32 Gorjifard S, Goldszmid RS. Beating cancer with a gut feeling. Cell Host Microbe. 2015;18(6):646-648. 33 Paulos CM, Wrzesinski C, Kaiser A, et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest. 2007;117(8):2197-2204. 34 Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. 2015;350(6264):1079-1084. 35 Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368-1379. 36 Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science. 2015;350(6264):1084-1089. 37 Wargo JA, Gopalakrishnan V, Spencer C, et al. Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy. J Clin Oncol. 2017;35(15):3008 38 Dubin K, Callahan MK, Ren B, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391. 39 Saleh K, Khalife-saleh N, Kourie HR. Is gut microbiome a predictive marker to response to immune checkpoint inhibitors? Immunotherapy. 2017;9(11):865-866. 40 Derosa L, Routy B, Mezquita L, et al. Antibiotics prescription to decrease progressionfree survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors. J Clin Oncol. 2017;35(15_suppl):3015. 41 Helwick C. Gut bacteria may enhance, or hamper, response to anti–PD-1 agents. The ASCO Post. http://www.ascopost.com/issues/april-10-2017/gut-bacteriamay-enhance-or-hamper-response-to-anti-pd-1-agents/. Published April 10, 2017. Accessed September 4, 2017. 42 Taur Y, Jenq RR, Perales M-A, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174-1182. 43 Zeller G, Tap J, Voigt AY, et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol. 2014;10(11):766. 44 Knekt P, Adlercreutz H, Rissanen H, Aromaa A, Teppo L, Heliövaara M. Does antibacterial treatment for urinary tract infection contribute to the risk of breast cancer? Br J Cancer. 2000;82(5):1107. 45 Garcia Rodriguez LA, Gonzalez-Perez A. Use of antibiotics and risk of breast cancer. Am J Epidemiol. 2005;161(7):616-619. 46 Deming-Halverson SL, Hodgson ME, D’Aloisio A, Shore D, Sandler D. Antibiotic use and breast cancer risk: results from the Sister Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res. 2017;77(13). 47 Sørensen HT, Skriver MV, Friis S, McLaughlin JK, Blot WJ, Baron JA. Use of antibiotics and risk of breast cancer: a population-based case–control study. Br J Cancer. 2005;92(3):594.