Natural Medicine Journal Oncology Special Issue 2021 by Diversified Communications

OCTOBER 2021 SUPPLEMENT

SPECIAL ISSUE

Oncology

Racial Disparities in Breast Cancer

Vitamin D In Gastrointestinal Cancers

Zinc Chloride for Mucositis During Chemotherapy

Could Bright Light Therapy Reduce Chemo-Related Sleep Disturbances?

Antibiotics May Help in Pancreatic Cancer

Caffeine’s Effects on Breast Cancer

POWERFUL

CELLULAR PROTECTION

*^^

Clinically Studied Ingredients for Cellular Support*

Driven by

SCIENCE

Focused on

NATURE

Rich in

HISTORY

Available At: emersonecologics.com | fullscript.com | meyerdc.com Learn more at euromedicausa.com ^^Protection from oxidative stress and damage. †Occasional infl ammation due to exercise or overuse. ^Based on enhanced absorption of CuraPro ® curcumin versus equivalent weight capsule of unstandardized turmeric containing 2% curcumin. ††Compared to the rare, noble ginsenoside content of conventional ginseng. *THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THESE PRODUCTS ARE NOT INTENDED TO DIAGNOSE, TREAT, CURE OR PREVENT ANY DISEASE.

SPECIAL ISSUE

ONCOLOGY OCTOBER 2021 VOL. 13, NO. 101 (SUPPL)

Contents 4 Contributors 5

A Message From the New Publisher

ABSTRACTS & COMMENTARY

Antibiotics Show Benefit in Pancreatic Cancer

Coffee and Tea Consumption and the Risk of Invasive Breast Cancer in Postmenopausal Women

Can Supplementation With Vitamin D Affect PD-L1 Expression in Gastrointestinal Cancers?

Precisely Timed Light May Reduce Chemotherapy-Related Sleep Disruption and Fatigue

Zinc Chloride Mouthwash Limits Chemotherapy-Induced Oral Mucositis and Weight Loss

SPONSORED PODCAST

Integrative Interventions That Inhibit Cancer Stem Cell Activity: A Conversation with Holly Lucille, ND, RN

EXPERT INTERVIEW

Racial Disparities in Breast Cancer An interview with Aminah Keats, ND, FABNO

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

SUBSCRIBE FOR FREE!

Contributors LINDSAY ADRIAN, ND, FABNO, graduated from the naturopathic program at the Boucher Institute of Naturopathic Medicine in Vancouver, Canada. She has been driven to learn and grow and practice in the field of integrative oncology from the beginning and was very proud to be awarded the FABNO designation last year. She is an active member of the Oncology Association of Naturopathic Physicians, as a member of both the Conference Content Committee and the Specialization Committee for the association. She is also a member of the College of Naturopathic Physicians of BC Examination Committee, which is responsible for conducting provincial board exams for naturopathic physicians wanting to practice in British Columbia. SHAUNA BIRDSALL, ND, FABNO, graduated from National University of Natural Medicine in 2000 and completed a 2-year residency at Cancer Treatment Centers of America (CTCA) in Illinois in 2002. She provided patient care and supervised naturopathic medical residents at CTCA in Illinois until 2008, when she transferred to CTCA in Phoenix, Arizona, as director of naturopathic medicine. Birdsall was elected as vice chief of the CTCA Phoenix Medical Staff in 2011 and served in that elected role until 2018. She also chaired the Medical Executive Committee, Credentials Committee, and Peer Review Committee and served as the medical director of Integrative Oncology at CTCA until 2018. She joined Avante Medical Center in Anchorage, Alaska, in 2019, as well as Advanced Oncology Associates at Anchorage Radiation Oncology Center and Peninsula Radiation Oncology Center in Soldotna, Alaska. Birdsall and her husband, Tim Birdsall, ND, FABNO, started a virtual practice in 2020, Resilience Health, providing telemedicine consultations to oncology and general medicine patients.

CATHERINE DARLEY, ND, is the director of The Institute of Naturopathic Sleep Medicine in Seattle. Her clinical work focuses on the treatment of sleep disorders in adults and children using behavioral and naturopathic medicine. Additionally she regularly trains corporate employees and first responders on a variety of sleep, performance, and safety issues. Darley is adjunct faculty at Bastyr University and National University of Natural Medicine in Portland, Oregon, and has served on the Board of the Washington Association of Naturopathic Physicians. You can learn more about her work at www.naturalsleepmedicine.net. In her personal time she likes to be outside in nature with her loved ones. JACOB SCHOR, ND, FABNO, is a graduate of National University of Naturopathic Medicine, Portland, Oregon, and recently retired from his practice in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is a past member of the board of directors of the Oncology Association of Naturopathic Physicians and American Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician’s Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the past Abstracts & Commentary editor.

MICHAEL WALKER, ND, FABNO, practices naturopathic oncology in metro Detroit, at Emcura Integrative, and through the Beaumont Health Integrative Medicine Department. Walker completed undergraduate studies at Yale University, naturopathic medical school at the Southwest College of Naturopathic Medicine, and a naturopathic oncology residency at Cancer Treatment Centers of America in Illinois. He is a fellow of the American Board of Naturopathic Oncology (FABNO) and a past board member of the Oncology Association of Naturopathic Physicians.

EDITOR-IN-CHIEF Tina Kaczor, ND, FABNO ABSTRACTS & COMMENTARY EDITOR Lise Alschuler, ND, FABNO GROUP VICE PRESIDENT Liz Plizga ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry ASSOCIATE EDITOR Kristin Bjornsen PUBLISHED BY Diversified Communications 121 Free St Portland, ME 04101 Natural Medicine Journal (ISSN 2157-6769) is published 13 times per year by Diversified Communications. Copyright © 2021 by Diversified Communications. 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; Diversified Communications 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. Diversified Communications 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.

MESSAGE FROM THE PUBLISHER

A Message from the New Publisher As the new publisher of Natural Medicine Journal, we are pleased to present this special issue on the important topic of oncology. In the following pages, you will find a range of content by leading integrative healthcare practitioners including results from a prospective, observational study evaluating coffee and tea consumption and the risk of invasive breast cancer in postmenopausal women, the supplementation of vitamin D and its impacts on gastrointestinal cancers, and the benefits of antibiotics in pancreatic cancer. We also invite you to listen to the podcast interview with Aminah Keats, ND, FABNO, featuring a discussion on racial disparities in breast cancer care. This is the first special issue under Diversified Communications, and we would like to take the opportunity to express our sincere appreciation of the authors, editorial board, and staff for their valuable time and insights to make these publications possible. We also thank our sponsors and advertisers for their ongoing support. As an addition to our integrative healthcare portfolio, including the digital online resource Integrative Practitioner and the annual in-person conference the Integrative Healthcare Symposium, Natural Medicine Journal will remain a standalone entity and continue to produce the high-value, informative content that you’ve come to rely on. As we get to know the NMJ community, we invite you to share your feedback concerning content, including proposed topics and preferred formats. We would love to hear from you at editor@naturalmedicinejournal.com. Lastly, please share this special issue with other colleagues who may find this material of interest to meet the evolving needs of their patients. We thank you for your continued support of Natural Medicine Journal and to integrative, whole-patient care. Kind regards,

Liz Plizga Group Vice President Diversified Communications

ABSTRACT & COMMENTARY

Antibiotics Show Benefit in Pancreatic Cancer Examining the link between antibiotics and survival REFERENCE

Weniger M, Hank T, Qadan M, et al. Influence of Klebsiella pneumoniae and quinolone treatment on prognosis in patients with pancreatic cancer. Br J Surg. 2021;108(6):709-716.

Jacob Schor, ND, FABNO

OUTCOME MEASURES

A retrospective study of patients from the Massachusetts General Hospital (USA) and Ludwig-Maximilians-University (Germany)

The primary outcomes examined were overall survival (OS) and progression-free survival (PFS). These measures were examined in light of the patients’ demographic data and preoperative treatments, plus additional adjuvant treatments. Bile microbiota were assessed using intraoperative cultures, and corresponding resistance patterns were analyzed. These outcomes were compared between those who had received quinolone antibiotics and those who had not.

PARTICIPANTS

KEY FINDINGS

DESIGN

Data were obtained for 211 patients who underwent preoperative treatment for borderline resectable pancreatic cancer (BRPC) or locally advanced (LAPC) pancreatic cancer followed by pancreatoduodenectomy with curative intent between January 2007 and December 2017, and for whom intraoperative bile cultures were available. Median age of patients was 65.9 years with a median follow up time of 18 months; 108 of these patients were women (51.2%) and mean BMI was 24.8. STUDY MEDICATION AND DOSAGE

Patients were treated with a range of different protocols during the decade these data were collected, including FOLFIRINOX alone and with radiation, proton-beam therapy and capecitabine, and gemcitabine in combination with various other chemotherapy drugs. Patient records were screened for postoperative treatment with quinolone antibiotics, either intravenous or oral. Patients who received any dose for any duration at any time between surgery and death were considered to have had quinolone treatment. About half of the patients (n=104) had been treated with quinolones. Associations between tumor characteristics, survival data, antibiotic use, and results of intraoperative bile cultures were investigated. Survival was analyzed using Kaplan-Meier curves and Cox regression analysis.

An increasing number of pathogen species found in intraoperative bile cultures was associated with a decrease in PFS (-1.9 months per species found; P=0.009). Overall, 48 different pathogens were cultured and identified from the bile samples obtained during surgery. Of these, only Klebsiella pneumoniae, which was cultured in 73 patients, was associated with reduced PFS (16.5 vs 20.7 months in patients who tested positive and negative for K. pneumoniae respectively; P=0.032). Patients with K. pneumoniae had larger tumors than patients without (mean 29.9 mm vs 23.7 mm; P=0.003). Adjuvant treatment with gemcitabine improved PFS in patients who were negative for K. pneumoniae (26.2 vs 15.3 months; P=0.039), but not in those who tested positive (19.5 vs 13.2 months; P=0.137). Quinolone treatment was associated with improved median overall survival (OS) independent of K. pneumoniae status (48.8 vs 26.2 months; P=0.006) and among those who tested positive for K. pneumoniae (median not reached versus 18.8 months; P=0.028). Patients with quinolone-resistant K. pneumoniae had shorter PFS than those with quinolone-sensitive K. pneumoniae (9.1 vs 18.8 months; P=0.001). K. pneumoniae appears to promote chemoresistance to adjuvant gemcitabine, and quinolone treatment is associated with improved survival.

PRACTICE IMPLICATIONS Before we consider this current research by Weniger et al, we should step back and review an earlier study for context—a paper by Leore Geller and colleagues from the Weizmann Institute, which was published in Science in September 2017.1 Geller et al reported that certain bacteria make an enzyme that inactivates the chemotherapy drug gemcitabine (Gemzar™). Gemcitabine is used to treat patients with pancreatic, lung, breast, and bladder cancers. It seems bacteria, particularly gammaproteobacteria, may produce an enzyme called cytidine deaminase (CDD) that inactivates gemcitabine. Tumor cells normally sensitive to gemcitabine are resistant to treatment when grown with bacteria that produce this enzyme. Geller demonstrated this both in vitro and ex vivo. In mice infected with CDD-producing bacteria, the quinolone antibiotic ciprofloxacin both eliminated the bacteria and ensured a marked antitumor effect from gemcitabine. Tumors in control-mice untreated with antibiotics continued to grow, unhindered by gemcitabine. Geller turned from mice to humans and questioned how often similar bacteria might pose a problem in cancer treatment. Samples from 113 patients with pancreatic ductal adenocarcinoma (PDAC) were tested using bacterial DNA to see how many tumors contained CDD-producing bacteria. Of the 113 samples, 86 (76%) did. Of 20 samples taken from healthy patients, only 3 (15%) produced CDD. This new study by Wenger advances our knowledge a few steps. Protocols for treating pancreatic cancer have shifted in recent years with the publication of 2 studies, a 2020 Dutch study by Versteijne et al and a 2018 Korean study by Jang et al.2,3 It is now standard for chemotherapy and radiation to precede surgery. Such presurgical treatment often shifts disease status to allow potentially curative surgery afterwards. It does often require biliary drainage and stenting, and the combination of stenting and chemotherapy alters the bile microbiome, increasing likelihood of bacterial growth.4

“

Gut microbiota play a role in the antitumor response and influence long-term survival.

”

Goel reported in 2019 that when comparing 83 patients who received neoadjuvant treatment with 89 patients who only underwent surgery, the neoadjuvant group were almost twice as likely to have Enterococci and Klebsiella growth in their bile (Enterococci 45 vs 22%, P<0.01; Klebsiella 37 vs 19%, P<0.01).5 Gut microbiota play a role in the antitumor response and influence long-term survival. Fecal transplants from humans into mice have shown that modulation of the tumor biome affects tumor growth and the natural history of this disease.6 There are 3 take homes from this study that add to our understanding: 1. Increasing biodiversity of bile pathogens correlates with reduced PFS. 2. K. pneumoniae decreases the benefit gained from gemcitabine treatment. 3. Pre-gemcitabine quinolone therapy may restore benefit from gemcitabine and prolong survival. BILE BACTERIAL DIVERSITY The bile culture findings were surprising. Only 10% of the patients (n=21) had sterile bile. The remaining patients had positive bile cultures and the median number of bacteria found was 3. For each additional species found, there was nearly a 2-month decrease in PFS (-1.9% months per species; P=0.009). The more biodiversity found in the bile, the worse the outcome. This is different than we might have guessed,

ABSTRACT & COMMENTARY

as greater diversity within most systems, including tumors of the pancreas, is considered desirable.

did not improve PFS in patients who tested positive for K. pneumoniae.

Overall, 48 different pathogens were identified in the bile, but only K. pneumoniae, which was found in 73 patients, was associated with reduced PFS. Patients with K. pneumoniae had larger tumors than patients without. No differences were found in nodal (N) status, perineural invasion, vascular invasion, ratio of patients with borderline resectable and locally advanced disease, tumor stage, or margin status. There were also no differences in morbidity or mortality.

However, in the K. pneumoniae–negative patients, treatment with gemcitabine improved PFS. No effect was seen for OS.

While K. pneumonia status did not predict OS or PFS in patients treated with FOLFIRINOX or proton beam therapy and capecitabine, it did make a significant difference in those treated with gemcitabine. Gemcitabine treatment

Bottom line: Postoperative quinolone is associated with improved postoperative survival in both the overall population and patients positive for Klebsiella pneumoniae. Of the patients in this study, 104 received quinolones and 106 did not. Treatment with quinolones was associated with improved OS and PFS. In patients who were positive for K. pneumoniae, quinolone therapy was associated with improved OS but not PFS. In the K. pneumoniae-negative group, mean survival was nearly twice as long in the patients who received

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 N atural Medicine Journal means you’ll always stay on top of the latest d evelopments in the field of natural medicine.

JOIN US ON FACEBOOK AND TWITTER AND JOIN OUR C ONVERSATIONS ABOUT ALL THINGS NATURAL MEDICINE–RELATED.

quinolones, but this fell short of statistical significance. This might hint that the antibiotics provided benefits in addition to blocking K. pneumoniae interference with gemcitabine’s efficacy. Previous evidence suggests that quinolones may have an independent anticancer effect.7-9 While gemcitabine has in recent years been a mainstay in the treatment of pancreatic cancer, it is also used to treat non-small cell lung, bladder, sarcoma, breast, and ovarian cancers. There is little reason to think that this same relationship between K. pneumoniae and the drug’s efficacy will not also hold true for these cancers. Many of us have seen K. pneumoniae reported present on stool microbiology test results. These bacteria vary widely in virulence and antibiotic sensitivity.10 It is unclear how predictive stool cultures are of bile infection with K. pneumoniae, although the idea of substituting stool testing is tempting. Although Weniger et al used bile samples obtained during surgery, identifying K. pneumoniae in the stool may be equally predictive or it may have little correlation. The risk of false negatives might also suggest that it is more efficacious to assume all patients are positive for K. pneumoniae and treat them with quinolones prior to gemcitabine. Time might also favor such an approach as gemcitabine treatment might be initiated quickly after diagnosis—sooner than a stool test result could be obtained. It may well be that in the near future it will become common practice for at least some medical oncologists to prescribe a course of antibiotics prior to a treatment course of gemcitabine based on these findings. In such a situation we might consider the addition of the botanical extract berberine into the treatment plan. Berberine has been reported to have a synergistic effect with quinolone antibiotics against drug-resistant K. pneumoniae.11 The knowledge that berberine may also act against pancreatic cancer cells12,13 and may sensitize these cells to gemcitabine14 only adds encouragement to incorporate it into the protocols for these patients. Although some patients may want to use berberine in place of quinolones, it is important that they understand berberine acts as an adjuvant, not as a substitute.

This discussion has focused on one specific aspect of how the microbiome impacts treatment of pancreatic cancer. Evidence continues to accumulate that pancreatic cancer is greatly impacted by microbiota far more than was once assumed. There are multiple other interactions documented between gut microbiota and adjuvant effectiveness in treating PDAC.15 Further developments in understanding about these interactions should be expected in the future.16 REFERENCES

1 Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357(6356):1156-1160. 2 Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020;38(16):1763-1773. 3 Jang JY, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg. 2018;268(2):215-222. 4 Scheufele F, Aichinger L, Jäger C, et al. Effect of preoperative biliary drainage on bacterial flora in bile of patients with periampullary cancer. Br J Surg. 2017;104(2):e182-e188. 5 Goel N, Nadler A, Reddy S, Hoffman JP, Pitt HA. Biliary microbiome in pancreatic cancer: alterations with neoadjuvant therapy. HPB (Oxford). 2019;21(12):17531760. 6 Riquelme E, Zhang Y, Zhang L, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 2019;178(4):795-806.e12.

7 Aranha O, Wood DP Jr, Sarkar FH. Ciprofloxacin mediated cell growth inhibition, S/ G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clin Cancer Res. 2000;6(3):891-900. 8 Herold C, Ocker M, Ganslmayer M, Gerauer H, Hahn EG, Schuppan D. Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. Br J Cancer. 2002;86(3):443-448.

9 El-Rayes BF, Grignon R, Aslam N, Aranha O, Sarkar FH. Ciprofloxacin inhibits cell growth and synergises the effect of etoposide in hormone resistant prostate cancer cells. Int J Oncol. 2002;21(1):207-211. 10 El Fertas-Aissani R, Messai Y, Alouache S, Bakour R. Virulence profiles and antibiotic susceptibility patterns of Klebsiella pneumoniae strains isolated from different clinical specimens. Pathol Biol (Paris). 2013;61(5):209-216. 11 Zhou XY, Ye XG, He LT, et al. In vitro characterization and inhibition of the interaction between ciprofloxacin and berberine against multidrug-resistant Klebsiella pneumoniae. J Antibiot (Tokyo). 2016;69(10):741-746.

12 Park SH, Sung JH, Kim EJ, Chung N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz J Med Biol Res. 2015;48(2):111-119. 13 Pinto-Garcia L, Efferth T, Torres A, Hoheisel JD, Youns M. Berberine inhibits cell growth and mediates caspase-independent cell death in human pancreatic cancer cells. Planta Med. 2010;76(11):1155-1161. 14 Abrams SL, Lertpiriyapong K, Yang LV, et al. Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals. Adv Biol Regul. 2018;69:16-34.

15 Zhang X, Liu Q, Liao Q, Zhao Y. Pancreatic cancer, gut microbiota, and therapeutic efficacy. J Cancer. 2020;11(10):2749-2758. 16 Wei MY, Shi S, Liang C, et al. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer. 2019;18(1):97.

ABSTRACT & COMMENTARY

Coffee and Tea Consumption and the Risk of Invasive Breast Cancer in Postmenopausal Women Results from a prospective, observational study

By Lindsay Adrian, ND, FABNO

REFERENCE

Zheng KH, Zhu K, Wactawski-Wende J, et al. Caffeine intake from coffee and tea and invasive breast cancer incidence among postmenopausal women in the Women’s Health Initiative [published online ahead of print, 2021 Aug 21]. Int J Cancer. 2021;10.1002/ ijc.33771. doi:10.1002/ijc.33771 STUDY OBJECTIVE

To determine if there is an association between caffeine intake from coffee or tea and the formation of invasive breast cancer in postmenopausal women

“

The positive or negative connections between coffee and tea consumption and cancer risk in general

DESIGN

Prospective, observational study PARTICIPANTS

The Women’s Health Initiative (WHI) recruited close to 100,000 women from 1993 to 1998 to participate in their observational study. Of these, 79,871 racially and ethnically diverse women from 40 centers across the United States were included in the present study. They were postmenopausal at recruitment and ranged in age from 50 to 79 years. Investigators excluded women from the present analysis if they had a history of cancer or had cancer at the onset of the study. STUDY PARAMETERS ASSESSED

In an annual survey, the study participants were asked questions about their intake of caffeinated and decaffeinated coffee and tea, with participants noting either none, 1 cup, 2 to 3 cups, 4 to 5 cups, or 6 or more cups. Caffeine intake from other sources was not included and is not part of this study. The original study was conducted with the annual survey over a 10-year period; however, there were 2 additional 5-year extension studies

”

have long been debated.

encompassing up to September 2015. Data were also collected on age, race, ethnicity, education, smoking status and intensity, alcohol consumption and frequency, sleep duration, exercise, caloric intake, hormone therapy history, age at menarche, age at menopause, age at first full-term birth, parity, and family history of breast cancer. Further, a healthy eating questionnaire was used, and body mass index (BMI) was calculated from the height and weight collected by investigators. PRIMARY OUTCOME MEASURES

The incidence of invasive breast cancer, with data collected including hormone receptor status, HER2 (human epidermal growth factor receptor 2) receptor status, stage, grade, size, tumor type, nodal status, and histology. Investigators put these outcomes through multivariable analysis using covariates in groups of demographic variables (age, race, ethnicity, and education), lifestyle variables (smoking, alcohol, caloric intake, exercise, healthy eating scores, BMI, and sleep

duration), and reproductive variables (hormone therapy use, menarche, menopause, age at first birth, parity, and family history of breast cancer). KEY FINDINGS

When investigators accounted for all of the variables, they observed no significant associations between risk of invasive breast cancer and consumption of various amounts of caffeine through coffee or tea consumption. The lack of association was maintained when data were isolated for receptor subtypes, grade, stage, and histology. In subgroup analysis, participants who drank 2 to 3 cups per day of decaffeinated coffee had an increased risk of hormone receptor–positive cancer; however, this was no longer statistically significant after accounting for multiple comparisons. There was a statistical significance in the heterogeneity of tea intake between hormone receptor status (ER positive vs negative) and histological subtype (ductal vs lobular). (continued on page 12)

ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS The positive or negative connections between coffee and tea consumption and cancer risk in general have long been debated. What we have found through numerous studies is that there are many variables to consider. Coffee and tea contain many phytochemicals in addition to caffeine; thus the studies to date should not be interpreted as a surrogate for caffeine intake. In addition, there are changes that occur in the processing of the coffee berries and tea leaves— roasting or fermenting, as well as the natural variations in phytochemicals that would be found in different growing regions—and this adds to the complexity of precisely what is being studied. The study currently under review sought to determine if caffeine intake from coffee or tea was associated with breast cancer incidence in postmenopausal women. The results imply that there is no difference in breast cancer incidence regardless of intake of regular or decaffeinated coffee or tea. That said, one of the study’s limitations was the lack of inclusion of other sources of caffeine, such as energy drinks, soft drinks, or chocolate. The lack of inclusion of these negates the validity of this being a study on caffeine effects and points more to it being a study of the associations of coffee or tea consumption and breast cancer incidence.

LISTEN TO NATURAL MEDICINE JOURNAL ON THE GO.

These findings are similar to those of the Black Women’s Health Study,1 the Swedish Women’s Lifestyle and Health Study,2 and other cohort studies. However, it contrasts with the beneficial effects of regular coffee intake on incidence of breast cancer found in the Nurses’ Health Study. In the August 2021 edition of NMJ, there is an excellent overview by Jacob Schor, ND, FABNO, of the analysis of the latter study. This study was more specific to the risk of primary diagnosis of invasive breast cancer with coffee or tea consumption, as opposed to the effects of said consumption after breast cancer diagnosis. A recent analysis of Nurses’ Health Study data by Farvid, et al found there was a statistically significant reduction in death from breast cancer with the consumption of more than 3 cups per day of coffee.3 What do these studies mean for clinical practice? According to this study, there seems to be no reason to alter coffee or tea consumption in primary prevention of invasive breast cancer. However, after the diagnosis of invasive breast cancer, coffee consumption of more than 3 cups per day may be added to the treatment protocol as a tasty tool to reduce the breast cancer specific mortality in our patients, at least in those patients who are able and willing to do so. The possible caveat to altering coffee or tea consumption in primary prevention remains the recommendation of green tea high in catechins. In a meta-analysis published in 2020, Wang et al found that there is reduced incidence of breast cancer with long-term, high intake of green tea.4 This may be different from the findings of the Women’s Health Initiative Study due to the specific type of tea intake they analyzed. REFERENCES

1 Boggs DA, Palmer JR, Stampfer MJ, et al. Tea and coffee intake in relation to risk of breast cancer in the Black Women’s Health Study. Cancer Causes Control. 2010;21:1941-1948.

PODCAST SERIES SUBSCRIBE TO OUR PODCAST

2 Oh JK, Sandin S, Ström P, Löf M, Adami HO, Weiderpass E. Prospective study of breast cancer in relation to coffee, tea and caffeine in Sweden. Int J Cancer. 2015;137(8):1979-1989. 3 Farvid MS, Spence ND, Rosner BA, et al. Post-diagnostic coffee and tea consumption and breast cancer survival. Br J Cancer. 2021;124:1873-1881. 4 Wang Y, Zhao Y, Chong F, et al. A dose-response meta-analysis of green tea consumption and breast cancer risk. Int J Food Sci Nutr. 2020;71:6:656-667.

The only HIPAA-compliant virtual dispensary and patient engagement platform.

Exclusive and FREE for Health Care Practitioners and Patients Request Your Invitation: bit.ly/well-world Why Should You Consider Well World? Earn up to 30% more revenue You e-script, we ship™ — eliminate inventory headaches Fast, free, and easy to set up Turnkey protocols and lifestyle plans available at the click of a button Video chat support for virtual visits Access to over 300+ evidence-based Designs For Health formulas

What other customers are saying … “Well World gave me the complete package for growing my practice.” — Dr. Laurianne, D.O.

“Clients get interested in the app, and I can send them automated emails to keep in touch about upcoming programs.” — Dr. Kat, PhD Biochemistry, Functional Medicine Practitioner “I wanted a way to give people meal plans, have some coaching and accountability, order supplements, and be able to offer a discount if I wanted to. Well World met all those needs. It was one of the first things we implemented.” — Dr. Brandy, Chiropractor

ABSTRACT & COMMENTARY

Can Supplementation With Vitamin D Affect PD-L1 Expression in Gastrointestinal Cancers? Results from a post hoc analysis of the AMATERASU trial in Japan REFERENCE

Morita M, Okuyama M, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Vitamin D supplementation regulates postoperative serum levels of PD-L1 in patients with digestive tract cancer and improves survivals in the highest quintile of PD-L1: a post hoc analysis of the AMATERASU randomized controlled trial. Nutrients. 2021;13(6):1987. STUDY OBJECTIVE

To examine whether vitamin D supplementation regulates serum programmed cell death ligand 1 (PD-L1) and, thus, could alter survival time of gastrointestinal (GI) cancer patients DESIGN

A post hoc analysis of the AMATERASU trial in Japan, which was a randomized, double-blind, placebo-controlled trial conducted at a single university hospital PARTICIPANTS

The study recruited patients aged 30 to 90 years with stage I to III cancers of the digestive tract from the esophagus to the rectum, who were surgical candidates. Of the 439 eligible patients, 15 declined and 7 were excluded after surgery. The investigators included all 417 randomized patients (mean age 66 years; male 66%; esophageal cancer 10%; gastric cancer 42%; colorectal cancer 48%) in the analysis to compare the effects of vitamin D3 supplements (2,000 IU/day) and placebo on relapse and/or death, at an allocation ratio of 3:2, between January 2010 and February 2018. The trial included patients with stage I (44% of participants), II (26%), or III (30%) digestive tract cancers who underwent

curative surgery with complete tumor resection. Only those not taking vitamin D supplements already were included. INTERVENTION

Investigators randomized patients to receive oral supplemental capsules of vitamin D (2,000 IU/d; n=251) or placebo (n=166) from the first postoperative outpatient visit to until the end of the trial. Placebo contained sesame oil, gelatin (swine-derived), and glycerin, and the active supplement contained the same constituents plus vitamin D3 as 25-hydroxycholecalciferol, 25(OH)D. STUDY PARAMETERS ASSESSED

Investigators measured postoperative serum PD-L1 levels using ELISA and divided them into quintiles (Q1– Q5). Serum samples were available for 396 (95.0%) of the original trial participants. Investigators collected serum samples for PD-L1 measurements after the surgery (23 days, interquartile range (IQR): 13–43.5 days) and just before the start of vitamin D/placebo supplementation. They also measured serum PD-L1 levels 1 year after starting vitamin D/ placebo supplements. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/ mL, and greater than 40 ng/mL. Because of small sample size for the highest-baseline-level group, investigators tested interactions between only the low- and middle-baselinelevel serum 25(OH)D groups.

By Shauna Birdsall, ND, FABNO PRIMARY OUTCOME MEASURES

The primary outcome was relapse-free survival, time to relapse, or death. The outcome of relapse or death was confirmed by regular outpatient follow-up. The elapsed time to relapse or death was calculated from the time of randomization (ie, time from starting the study supplements). KEY FINDINGS

Vitamin D supplementation significantly (P=0.0008) increased serum PD-L1 levels in the lowest quintile of PD-L1 (Q1; ie, those patients who started out with the lowest levels of PD-L1), whereas it significantly (P=0.0001) decreased PD-L1 levels in the highest quintile of serum PD-L1 levels (Q5), and it neither increased nor decreased PD-L1 levels in the middle quintiles of PD-L1 (Q2–Q4). Significant effects of vitamin D supplementation compared with placebo on death (HR, 0.34; 95% CI, 0.12–0.92) and relapse/death (HR, 0.37; 95% CI, 0.15–0.89) were observed in the highest quintile (Q5) of serum PD-L1, whereas significant effects were not observed in other quintiles (Pinteraction=0.02 for death, Pinteraction=0.04 for relapse/death). Vitamin D supplementation significantly reduced the risk of relapse and/or death by approximately two-thirds in the highest quintile of serum PD-L1.

PRACTICE IMPLICATIONS Cancer immunotherapy has been a rapidly progressing field of research over the last decade, with the first checkpoint inhibitor, ipilimumab, approved by the Food and Drug Administration (FDA) for the treatment of melanoma in 2011.1 Meanwhile, researchers were investigating the first PD-1 inhibitor, pembrolizumab, which was approved in 2014 for patients with advanced or unresectable melanoma.2 As of 2021, checkpoint inhibitors are likely the most well-known, and perhaps the most successful, immunomodulators developed so far, and have revolutionized oncology by improving outcomes and survival for many cancer patients.3 The mechanism of action and wide applicability of the checkpoint inhibitors have broadened our understanding of the complexity of immune function, particularly in relationship to cancer cells. Our immune system’s inhibitory checkpoint pathways are critical for ensuring we maintain self-tolerance (and prevent autoimmunity). However, we now know that tumors utilize immune checkpoint pathways to evade immune detection.4 During a healthy immune response, programmed cell death protein 1 (PD-1) serves to inhibit immune responses and promote self-tolerance via regulating the activity of T-cells. Likewise, programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is a coinhibitory factor of the immune response and responsible for reducing the activity of PD-1 positive cells and inducing apoptosis. We now know that the PD-1/PD-L1 pathway controls the initiation and maintenance of immune tolerance within the tumor microenvironment.5 In addition to activated immune cells, PD-1 is also highly expressed on tumor-specific T cells.6 PD-L1 is usually expressed by macrophages, some activated T cells and B cells, dendritic cells, and some epithelial cells, particularly under inflammatory conditions.7 In addition, PD-L1 is expressed by tumor cells as an “adaptive immune mechanism” to escape antitumor responses as well as activating proliferative and survival signaling pathways.8 PD-L1 is also implicated in subsequent tumor progression.9

“

It seems prudent in the interim to continue to test 25(OH)D serum levels in all cancer patients and replete those who are deficient into a healthy range.

”

A recent meta-analysis, including a total of 21 studies, demonstrated that elevated serum PD-L1 levels were associated with worse survival of patients with cancer.10 In particular, higher postoperative, but not preoperative, plasma total PD-L1, in addition to exosomal PD-L1, was shown to be associated with poor survival in patients with gastric cancer.11 It is theorized that in addition to checkpoint inhibitors, reducing serum PD-L1 levels after surgery may be a strategy to improve survival in patients with cancer. Vitamin D signaling has been increasingly investigated for its role in stimulation of innate immunity and suppression of inflammatory responses. Hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcriptional inducer of the human genes encoding PD-L1 and PD-L2 through the vitamin D receptor (VDR).12 In this clinical study, vitamin D supplementation increased serum PD-L1 levels in the lowest quintile (Q1; those patients with lowest baseline PD-L1 levels). In contrast, vitamin D supplementation decreased serum PD-L1 levels in the highest quintile (Q5). Thus, vitamin D appears to be serving as a biological response modifier, functioning to increase serum PD-L1 when the serum PD-L1 levels are low and to decrease serum PD-L1 when the serum PD-L1 levels are high.13 In this study, vitamin D supplementation, compared with placebo, significantly reduced the risk of all-cause death, as well as relapse or death, to approximately one-third in the highest quintile (Q5) of serum PD-L1, but not in other quintiles (ie,

ABSTRACT & COMMENTARY

Q1–Q4 of PD-L1 levels). The authors noted that vitamin D supplementation mainly reduces the risk of total death and hypothesized that this was at least in part by enhancing anticancer immunity and perhaps keeping cancer tissue dormant by downregulating serum PD-L1 levels.13

REFERENCES

The association of vitamin D and cancer has been studied for many years, and the data have at times been positive, at times conflicting, and at times have shown no association.14 From the results of this study and others, it is apparent that a significant amount of interplay exists between vitamin D and genetic expression of PD-L1, and that further research is needed to explore the exact parameters of this relationship before specific clinical strategies can be created. However, it seems prudent in the interim to continue to test 25(OH)D serum levels in all cancer patients and replete those who are deficient into a healthy range.

4 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.

As a note of caution, the results of this study may or may not be applicable to other patient populations. There are several limitations of this study: The study was conducted in Japan, and all the patients were of Asian descent; the esophageal carcinomas were squamous cell in origin; and the incidence of gastric cancer is relatively high, as compared to other patient populations.

1 Cameron F, Whiteside G, Perry C. Ipilimumab: first global approval. Drugs. 2011;71(8):1093-1104. 2 Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018;6(1):8. 3 Marin-Acevedo JA, Kimbrough EO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol. 2021;14:45.

5 Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.

6 Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-1544. 7 Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239-245. 8 Dong P, Xiong Y, Yue J, Hanley SJB, Watari H. Tumor-intrinsic PD-l1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front Oncol. 2018;8:386. 9 Akinleye, A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol. 2019;12:92.

10 Li X, Zheng Y, Yue F. Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in various cancers: a meta-analysis. Target Oncol. 2021;16(1):13-26.

11 Li G, Wang G, Chi F, et al. Higher postoperative plasma EV PD-L1 predicts poor survival in patients with gastric cancer. J Immunother Cancer. 2021;9(3):e002218. 12 Dimitrov V, Bouttier M, Boukhaled G, et al. Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice. J Biol Chem. 2017;292(50):20657-20668. 13 Morita M, Okuyama M, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Vitamin D supplementation regulates postoperative serum levels of PD-L1 in patients with digestive tract cancer and improves survivals in the highest quintile of PD-L1: a post hoc analysis of the AMATERASU randomized controlled trial. Nutrients. 2021;13(6):1987. 14 Young MRI, Xiong Y. Influence of vitamin D on cancer risk and treatment: why the variability? Trends Cancer Res. 2018;13:43-53.

DON’T MISS OUT

Click here to sign up for free and be sure you receive every issue of the Natural Medicine Journal.

http://eepurl.com/d6zXb

INNOVATIVE ANTIOXIDANTS 42 YEARS AND COUNTING

Melatonin 20 mg

Molecular H2

High Potency Melatonin

Effervescent Hydrogen Tablets

Allergy Research Group® introduced melatonin to the U.S. market in 1995.

Readily passes through cellular membranes and the blood-brain barrier, supporting DNA repair and delivering neuroprotective benefits.*

Melatonin promotes sleep, scavenges hydroxyl radicals, and activates the Nrf2-pathway.* Clinical research shows significant evidence for numerous benefits of melatonin supplementation, with high safety.*

Learn More About Melatonin 20 mg

Balances the immune and stress response in human studies, neutralizes damaging hydroxyl and peroxynitrite radicals, and activates endogenous antioxidant pathways.* Also available for a limited time in natural raspberry flavored tablets!

Learn More About Molecular H2

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.

INNOVATIVE, LEADING-EDGE SUPPLEMENTS SOURCED FROM THE PUREST RAW MATERIALS SINCE 1979

www.allergyresearchgroup.com | 800.545.9960

ABSTRACT & COMMENTARY

Precisely Timed Light May Reduce ChemotherapyRelated Sleep Disruption and Fatigue Results from a controlled pilot study REFERENCE

Wu H-S, Davis JE, Chen L. Bright light shows promise in improving sleep, depression, and quality of life in women with breast cancer during chemotherapy: findings of a pilot study. Chronobiol Int. 2021;38(5):694-704. STUDY OBJECTIVE

To learn if home-based bright-light treatment customized to participants’ circadian phase preference would impact their sleep, fatigue, daytime sleepiness, depression, and quality-of-life measures while undergoing chemotherapy DESIGN

Controlled pilot study PARTICIPANTS

A total of 18 women newly diagnosed with breast cancer stages I to III participated in this study, with 16 completing it in entirety. Their ages ranged from 29 to 68 years, with the majority being white/Caucasian and college-educated. Most were being treated for stage II breast cancer. People were excluded if they had a history of seasonal affective or psychiatric disorders, were on photosensitizing or sleep medications, or had other malignancies or cancer treatments, along with other exclusions. INTERVENTION

Investigators assigned participants to the experimental condition (bright blue-green light of 12,000 lux) or the control condition (dim red light of 5 lux). Participants received the light therapy for 30 minutes via a light visor each day at customized times depending on their circadian chronotype. Evening types began the light within 30 minutes of waking, and morning types had the light exposure between 7 to 8 pm. The light therapy was delivered for 21 consecutive days after the second cycle of chemotherapy. STUDY PARAMETERS ASSESSED

Investigators collected a variety of both subjective and objective measures. They collected baseline data prior to participants’ initiating their second cycle of chemotherapy, and they performed final data collection on the day of the third chemotherapy treatment.

By Catherine Darley, ND Subjective measures included the Patient-Reported Outcomes Measurement Information System (PROMIS), which measures fatigue. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). The Patient Health Questionnaire (PHQ-9) measured depression. Quality of life was measured using the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30). Sleep was assessed objectively using ambulatory polysomnography (PSG). PRIMARY OUTCOME MEASURES

Investigators computed the relative change from baseline data to post-test data for both groups. Also a between-group analysis was done using 2 sample t-tests. KEY FINDINGS

The experimental group had meaningful improvements in their sleep, both subjectively and objectively. Subjectively, falling asleep took less time—only 10 minutes in the experimental group versus 20 minutes in controls (P=0.045). This was corroborated by the PSG data (14 vs 63 min) from the 7 participants who used the PSG at home. Polysomnography showed a longer sleep time of 467 minutes and greater sleep efficiency at 74% in those who received bright light, versus 315 minutes total sleep and only 58% sleep efficiency in the control group. While these differences did not reach statistical significance, the trends in the short time period of the study warrant mention here. There was a 30% relative decrease in depression for those in the bright light group, and a 24% relative increase in the controls, but again these did not reach statistical significance. Quality of life was less negatively impacted by chemotherapy for those in the intervention group, with symptom intensity (as reported in the EORTC questionnaire scores) increasing 33% versus 166% in the control group. Fatigue levels did not change with bright-light therapy, despite apparently better sleep.

PRACTICE IMPLICATIONS Given that fatigue and sleep disruption affect a large proportion of breast cancer patients, if validated, this approach could have a significant impact on a large population of women. Light therapy is relatively low-cost and easy to implement and has few, if any, negative side effects. Light therapy is currently used to treat circadian rhythm sleep-wake disorders and seasonal affective disorder. Maybe we can add adjunct to chemotherapy to that list? The sleep improvements seen with light therapy in this study were quite amazing, with greater than 2 hours more sleep each night and 16% greater sleep efficiency in the experimental group. For the individual cancer patient (and other patients), improved sleep can translate into better daytime function. Adults are recommended to get between 7 to 9 hours of sleep nightly.1 The light therapy group achieves this goal after 21 days of treatment. Poor sleep quality or duration will translate into multiple impairments from performance to mood to health measures. Notably, sleep-stage percentages remained abnormal in both the control and experimental groups, with 78% Stage 2 sleep (increased from normal of about 50%) and reduced REM and Stage 3 sleep percentages. It may be that fatigue levels did not change in part because REM and Stage 3 sleep were reduced from normal. This study was unique in using the participants’ chronotype to determine the time of day for the intervention. Our chronotype is an inherent characteristic, set by the suprachiasmatic nucleus in the hypothalamus, and reinforced by the clock genes within each cell.2 With light therapy (and slightly by melatonin supplementation), the circadian phase can be manipulated. However, once the light therapy is discontinued, the person will return to their natural phase preference. Therefore, a third evaluation of cancer patients after the treatment period would be useful to see if any changes recorded when doing active light therapy are maintained (and if so, for how long), or if light therapy needs to be ongoing.

“

This study was unique in using the participants’ chronotype to determine the time of day for the intervention.

”

It is interesting that the treatment group was not separated into the 2 treatment conditions: light in the morning versus light at night. Light at these different times of day has significantly different impacts on our circadian system.3 Light in the evening will suppress evening melatonin production and shift the circadian rhythm later, while light in the morning will have the opposite effect, shifting the circadian rhythm earlier, and boosting the next night’s nocturnal melatonin peak. The researchers intentionally customized the light-therapy timing so as to shift participants to a more neutral circadian phase. This furthers the earlier work by Dr. Sonia Ancoli-Israel,4 which demonstrated that morning bright light worked to prevent both quality of life and fatigue from declining during chemotherapy. Additionally, humans have historically been exposed to bright light in the morning, but not in the evening. Our circadian system evolved in accordance with this pattern in the color and brightness of light in the natural environment. It is known that artificial light at night can have negative effects on human health, including cancer risk. The International Agency for Research on Cancer came to the conclusion that night shift is a probable carcinogen (Group 2A carcinogen).5 Other research reviews have found that women who work night shift are at increased risk of breast cancer.6 For these reasons we are cautious in the clinic about giving light therapy during a patient’s circadian night. In future studies with more participants, it would be interesting to see the morning and evening treatment groups

ABSTRACT & COMMENTARY

reported separately. Also, there was no mention of the ambient light conditions of the control group in their homes and lifestyles, so it is unknown how much light they were getting at the intervention times. The control group may have been in bright-light (or blue-light) conditions in their home environment. This pilot study gives hope that light therapy, a relatively easy and low-cost treatment, can improve the sleep and quality of life of women receiving chemotherapy for breast cancer. Stay tuned as this approach develops.

REFERENCES

1 Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: consensus statement of the American Academy of Sleep and Sleep Research Society. Sleep. 2015;38(6):843-844. 2 Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;94(4);747-765. 3 Emens JS, Burgess HJ. Effect of light and melatonin and other melatonin receptor agonists on human circadian physiology. Sleep Med Clin. 2015;10(4):435-453.

4 Ancoli-Israel S, Rissling M, Neikrug A, et al. Light treatment prevents fatigue in women undergoing chemotherapy for breast cancer. Support Care Cancer. 2012;20(6):1211-1219. 5 Erren TC, Morfeld P, Groß JV, et al. IARC 2019: “Night shift work” is probably carcinogenic: what about disturbed chronobiology in all walks of life? J Occup Med Toxicol. 2019;14:29. 6 Gehlert S, Clanton M. Shift work and breast cancer. Int J Environ Res Public Health. 2020;17(24):9544.

LISTEN TO

NATURAL MEDICINE JOURNAL ON THE GO.

PODCAST SERIES CLICK HERE TO SUBSCRIBE TO OUR PODCAST

ABSTRACT & COMMENTARY

Zinc Chloride Mouthwash Limits Chemotherapy-Induced Oral Mucositis and Weight Loss A placebo-controlled trial investigates a promising preventive treatment REFERENCE

Oshvandi K, Vafaei SY, Kamallan SR, Khazaei S, Ranjbar H, Mohammadi F. Effectiveness of zinc chloride mouthwashes on oral mucositis and weight of patients with cancer undergoing chemotherapy. BMC Oral Health. 2021;21(1):364. STUDY OBJECTIVE

To assess whether zinc chloride mouth rinses during chemotherapy impact the severity of oral mucositis and change in body weight DESIGN

Double-blind, randomized, placebocontrolled trial at a single institution PARTICIPANTS

In the study, 96 participants enrolled (male=51, female=45). They were aged 23 to 66 years. Average age was 46.21 years in the zinc group and 46.22 years in the placebo group. The study was done on various cancer types, stage I or II: liver (n=7), stomach (6), uterus (5), breast (4), kidney (7), bladder (5), and lung (7). Chemotherapy involved fluorouracil (n=28) and mitoxantrone (n=20). INTERVENTION

The intervention contained zinc chloride 0.2% mouthwash, and the placebo was a matching mouthwash without the added zinc chloride. Procedure: Mouth rinse with 7.5 mL mouthwash for 2 minutes, every 8 hours, 2 times.

By Michael Walker, ND, FABNO

STUDY PARAMETERS ASSESSED

Investigators graded oral mucositis severity weekly for 3 weeks, according to World Health Organization (WHO) criteria, on a scale from 0 to 4, using a combination of objective measures and subjective symptoms. They measured weight at baseline and at 3 weeks following the intervention. PRIMARY OUTCOME MEASURES

Severity of oral mucositis per the WHO criteria KEY FINDINGS

There were significant betweengroup differences in mucositis grade at week 1 (P=0.046), week 2 (P=0.01), and week 3 (P=0.01). There was also a difference in severity of oral mucositis between groups at week 1 (P=0.026), week 2 (P=0.002) and week 3 (P=0.001) While there was no change in mucositis from baseline in the zinc chloride group, there was an increase in mucositis in the placebo group (P=0.027). Incidence of mucositis in the zinc chloride group was 3 out of 48 patients who initially enrolled, compared to 23 of 48 in the placebo group. Paired t test showed a significant increase in weight at 3 weeks in the zinc chloride group compared to baseline (71.61 kg [SD 1.21] vs 67.89 kg [SD 1.17]), respectively. There was no significant change in weight in the placebo group.

PRACTICE IMPLICATIONS Oral mucositis (OM) is a common side effect of cancer therapies including chemotherapy, targeted systemic therapy, radiation therapy, and concurrent treatment regimens. The discomfort and pain directly impact quality of life and threaten oral nutritional intake. OM compounds the impact of multiple risks related to cancer treatment: risk of dehydration and weight loss, particularly in association with treatment-induced nausea, vomiting, and alterations to sense of taste and smell; as well as risk of infection and sepsis secondary to bacterial colonization of mucosal ulceration.1 Moreover, compromised efficacy of cancer treatment may result from dose delay and discontinuation when OM is severe. The current study from Oshvandi et al comes at a time when we are fortunate, if not slightly overwhelmed, to see an expanding and diverse list of preventive treatments achieving positive results in clinical trials for OM. Furthermore, the zinc chloride is a new addition to the multiple other zinc forms and administration options (mouth rinse, enteral, rinse-and-swallow) that have been investigated and that, ultimately, will be compared for clinical use and further study. Does the trial in question change how naturopathic doctors address this important toxicity? The findings from Oshvandi et al are notable and encouraging primarily for the proportionately dramatic improvement in incidence and severity with use of the zinc chloride mouth rinse. Twenty-three of 48 initial participants in the placebo group developed mucositis (all grade 2 or 3), compared to 3

ABSTRACT & COMMENTARY

of 48 in the zinc chloride group. Twenty of these patients developed grade 3 oral mucositis, for a rate of 41.7%, which is uncommonly high in chemotherapy-only treatment of solid tumors.2-4 Interpretation is somewhat limited by heterogeneity of tumor type and lack of subgroup analysis by specific chemotherapy agent, as 5-fluorouracil (5-FU) is encountered far more often in practice for treatment of solid tumors compared to mitoxantrone. Nevertheless, zinc chloride merits further study in commonly used regimens posing high mucositis risk comparable with that seen in the trial, particularly concurrent chemoradiation and hematopoietic stem cell transplantation (HSCT) conditioning regimens. What might limit incorporation of zinc chloride mouth rinse into regular practice? The zinc chloride was studied in patients with solid tumors receiving chemotherapy only. As noted, a range of therapies have been investigated for OM prevention and treatment in the setting of chemotherapy, concurrent chemoradiation, and HSCT conditioning chemotherapies. Many are common to integrative-medicine supportive-care regimens, including L-glutamine, probiotics, curcumin, propolis, honey, and omega-3 fatty acids, though an exhaustive list is beyond the scope of this commentary. The MASCC/ISOO Mucositis Clinical Practice Guidelines, updated 2019/2020, do include a number of “natural and miscellaneous” agents for their analysis.5 In most cases such natural therapies are ingested and, therefore, systemic. Among these are several that we might consider multidimensional in the sense that clinical research finds therapeutic effect for 1 or multiple endpoints other than oral mucositis, and zinc itself is arguably included in that list. For clinicians selectively discussing therapeutic options for OM, the examples of omega-3 fatty acids and curcumin provide comparators in considering a place for zinc chloride. With regard to omega-3 fatty acid interventions, in a randomized, controlled trial of “ω-3-rich” compared to “ω-3-poor” enteral nutrition, patients on chemotherapy with docetaxel, cisplatin, and 5-FU for esophageal cancer receiving the “ω-3-rich” supplementation had lower

“

Incidence of mucositis in the zinc chloride group was 3 out of 48 patients who initially enrolled, compared to 23 of 48 in the placebo group.

”

frequency of stomatitis as well as hepatic enzyme elevations.6 Additional clinical trials with omega-3 suggest improved management of several chemotherapy-induced toxicities, including peripheral neuropathy; 7,8 xerostomia in patients on the frequently encountered neoadjuvant breast cancer regimen of doxorubicin/cyclophosphamide, followed by paclitaxel (+/- trastuzumab); 9 maintained or increased weight during chemotherapy, specifically from muscle mass.10,11 Investigations of curcumin in various applications have demonstrated a reduction in chemoradiation-induced mucositis, including with a mouth rinse12 and nanomicelle preparations.13,14 While the anticipated selective radiosensitizing effects of curcumin have not translated clearly to clinical impact, the 2019 open-label phase IIa from Howells et al suggests there is a chemosensitization effect of curcumin in the 5-FU-containing regimen, FOLFOX.15 Does zinc chloride mouth rinse provide a unique or added benefit in the chemotherapy-treated population? The large magnitude of effect, if confirmed, might vault zinc chloride into wider use. In further research, an active control would be preferred, and even expected, in a study group at high risk of developing severe OM. Anticipating this need, a 2019 study from Hussain et al found that in patients undergoing “7+3” induction chemotherapy with cytarabine and doxorubicin for acute myeloid leukemia, those randomized to use Nigella sativa mouth rinse had

ABSTRACT & COMMENTARY

reduction in OM severity and pain when compared to a “magic mouthwash” containing nystatin, tetracycline, lidocaine, and dexamethasone.16 An additional possible advantage of zinc chloride to which the authors allude may be cost-effectiveness. This consideration was not explored in depth but may offer an avenue to demonstrate value separating this from other therapies. In the settings of chemoradiation and HSCT conditioning chemotherapy, a nontoxic mouth rinse with exceptional preventive effect for OM and weight loss would be a welcome therapy. In the case of concurrent chemoradiation, MASCC/ ISOO guidelines currently suggest (level of evidence, II) oral glutamine for prevention during chemoradiation of patients with head and neck cancer,17 and suggest honey for prevention during either radiation or chemoradiation. Supporting this is a 2021 meta-analysis of randomized, controlled trials, including 998 participants, finding that L-glutamine reduced severity of OM and incidence of severe OM.18 Moreover, a reduction in hospital stay and cost can be achieved in

select clinical settings.19 The zinc chloride mouth rinse may find a niche for use in patients who decline or discontinue L-glutamine. Several other forms of zinc have been investigated for activity over the past 2 decades, including zinc sulfate, zinc L-carnosine, and zinc magnesium aspartate, and the majority of clinical studies assessing OM have been positive. However the updated MASCC/ISOO guidelines notably removed the suggestion for zinc supplementation in the 2014 iteration,20,21 citing the conflicting data seen specifically in the zinc sulfate research.22 To naturopathic doctors accustomed to splitting hairs over the form of nutrients, this bundling of zinc-based therapies may seem a minimization of potentially substantial differences. Conversely, the impulse to compare zinc-based therapies to one another is understandable and reasonable. Any rigorous comparison is limited by the absence of head-tohead trials, in which several questions may be addressed in the future. First, is there a difference in efficacy between mouth rinse applications such as zinc chloride, encapsulated zinc

LISTEN TO

NATURAL MEDICINE JOURNAL PODCAST SERIES

ON THE GO.

CLICK HERE TO SUBSCRIBE TO OUR PODCAST

(sulfate, magnesium aspartate), and forms such as lozenge or rinse-and-swallow, the latter being functionally both topical and systemic (zinc L-carnosine and possibly other forms)? For patients undergoing chemotherapy prior to HSCT, zinc carnosine is the most documented of the zinc-based therapies, and though individual studies are limited by size, variations in compounding, and lack of randomization, effectiveness in reducing OM severity is consistently found, in both adult and pediatric populations.23-25 Second, do baseline and serial measures of zinc such as serum or red blood cell zinc correlate with any protective effect of treatment? Do ingested forms of zinc confer additional protective effect during cancer treatment? Given some literature finding zinc deficiency to be not uncommon at least in head and neck cancer,26,27 laboratory informed approaches may have a future role in practice. For now, though zinc chloride may be temporarily overshadowed in terms of research volume for OM, and in clinical use by more common formulations, its potential as a widely available and even cost-effective therapy for OM prevention may have been previewed in this trial. REFERENCES

1 Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004;4(4):277-284.

2 Hansen RM, Ryan L, Anderson T, et al. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst. 1996;88(10):668-674. 3 Jones JA, Avritscher EB, Cooksley CD, Michelet M, Bekele BN, Elting LS. Epidemiology of treatment-associated mucosal injury after treatment with newer regimens for lymphoma, breast, lung, or colorectal cancer. Support Care Cancer. 2006;14(6):505-515. 4 Negrin RS. Oral toxicity associated with chemotherapy. Up To Date. https://www. uptodate.com/contents/oral-toxicity-associated-with-chemotherapy?source=history_widget. Accessed September 24, 2021. 5 Elad S, Cheng KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy [published correction appears in Cancer. 2021 Oct 1;127(19):3700]. Cancer. 2020;126(19):4423-4431. 6 Miyata H, Yano M, Yasuda T, et al. Randomized study of the clinical effects of ω-3 fatty acid-containing enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer. Nutrition. 2017;33:204-210. 7 Anoushirvani AA, Poorsaadat L, Aghabozorgi R, Kasravi M. Comparison of the effects of omega 3 and vitamin E on palcitaxel-induced peripheral neuropathy. Open Access Maced J Med Sci. 2018;6(10):1857-1861.

8 Esfahani A, Somi MH, Ayromlou H, et al. The effect of n-3 polyunsaturated fatty acids on incidence and severity of oxaliplatin induced peripheral neuropathy: a randomized controlled trial. Biomark Res. 2016;4:13. 9 de la Rosa Oliva F, Meneses García A, Ruiz Calzada H, et al. Effects of omega-3 fatty acids supplementation on neoadjuvant chemotherapy-induced toxicity in patients with locally advanced breast cancer: a randomized, controlled, double-

blinded clinical trial. Efecto de la suplementación con ácidos grasos omega -3 sobre la toxicidad secundaria a quimioterapia neoadyuvante en pacientes con cáncer de mama localmente avanzado: ensayo clínico aleatorizado. Nutr Hosp. 2019;36(4):769-776. 10 Abe K, Uwagawa T, Haruki K, et al. Effects of ω-3 fatty acid supplementation in patients with bile duct or pancreatic cancer undergoing chemotherapy. Anticancer Res. 2018;38(4):2369-2375.

11 Aredes MA, da Camara AO, de Paula NS, Fraga KYD, do Carmo MDGT, Chaves GV. Efficacy of ω-3 supplementation on nutritional status, skeletal muscle, and chemoradiotherapy toxicity in cervical cancer patients: a randomized, triple-blind, clinical trial conducted in a middle-income country. Nutrition. 2019;67-68:110528. 12 Patil K, Guledgud MV, Kulkarni PK, Keshari D, Tayal S. Use of curcumin mouthrinse in radio-chemotherapy induced oral mucositis patients: a pilot study. J Clin Diagn Res. 2015;9(8):ZC59-ZC62.

13 Delavarian Z, Pakfetrat A, Ghazi A, et al. Oral administration of nanomicelle curcumin in the prevention of radiotherapy-induced mucositis in head and neck cancers. Spec Care Dentist. 2019;39(2):166-172. 14 Kia SJ, Basirat M, Saedi HS, Arab SA. Effects of nanomicelle curcumin capsules on prevention and treatment of oral mucosits in patients under chemotherapy with or without head and neck radiotherapy: a randomized clinical trial. BMC Complement Med Ther. 2021;21(1):232.

15 Howells LM, Iwuji COO, Irving GRB, et al. Curcumin combined with FOLFOX chemotherapy is safe and tolerable in patients with metastatic colorectal cancer in a randomized phase IIa trial. J Nutr. 2019;149(7):1133-1139. 16 Hussain SA, Mohammed Ameen HA, Mohammed MO, et al. Nigella sativa oil mouth rinse improves chemotherapy-induced oral mucositis in patients with acute myeloid leukemia. Biomed Res Int. 2019;2019:3619357.

17 Elad S, Cheng KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy [published correction appears in Cancer. 2021 Oct 1;127(19):3700]. Cancer. 2020;126(19):4423-4431.

18 Tang G, Huang W, Zhang L, Wei Z. Role of glutamine in the management of oral mucositis in patients with cancer: a meta-analysis of randomized controlled trials [published online ahead of print, 2021 Feb 19]. Nutr Cancer. 2021;1-14. 19 Hayashi H, Kobayashi R, Suzuki A, et al. Polaprezinc prevents oral mucositis in patients treated with high-dose chemotherapy followed by hematopoietic stem cell transplantation. Anticancer Res. 2014;34(12):7271-7277. 20 Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy [published correction appears in Cancer. 2015 Apr 15;121(8):1339]. Cancer. 2014;120(10):1453-1461.

21 Yarom N, Hovan A, Bossi P, et al. Systematic review of natural and miscellaneous agents for the management of oral mucositis in cancer patients and clinical practice guidelines-part 1: vitamins, minerals, and nutritional supplements [published correction appears in Support Care Cancer. 2021 Jul;29(7):4175-4176]. Support Care Cancer. 2019;27(10):3997-4010. 22 Sangthawan D, Phungrassami T, Sinkitjarurnchai W. A randomized double-blind, placebo-controlled trial of zinc sulfate supplementation for alleviation of radiation-induced oral mucositis and pharyngitis in head and neck cancer patients. J Med Assoc Thai. 2013;96(1):69-76.

23 Kitagawa J, Kobayashi R, Nagata Y, et al. Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: a multi-institutional randomized controlled trial. Int J Cancer. 2021;148(6):1462-1469. 24 Funato M, Ozeki M, Suzuki A, et al. Prophylactic effect of polaprezinc, a zinc-l- carnosine, against chemotherapy-induced oral mucositis in pediatric patients undergoing autologous stem cell transplantation. Anticancer Res. 2018;38(8):46914697. 25 Hayashi H, Kobayashi R, Suzuki A, et al. Polaprezinc prevents oral mucositis in patients treated with high-dose chemotherapy followed by hematopoietic stem cell transplantation. Anticancer Res. 2014;34(12):7271-7277. 26 Prasad AS, Beck FW, Doerr TD, et al. Nutritional and zinc status of head and neck cancer patients: an interpretive review. J Am Coll Nutr. 1998;17(5):409-418.

27 Büntzel J, Bruns F, Glatzel M, et al. Zinc concentrations in serum during head and neck cancer progression. Anticancer Res. 2007;27(4A):1941-1943.

SPONSORED PODCAST

Integrative Interventions that Inhibit Cancer Stem Cell Activity: A Conversation with Holly Lucille, ND, RN Sponsored by EuroMedica

Play Now In this interview, integrative medical expert Holly Lucille, ND, RN, describes why it’s important to look at cancer stem cell activity when creating an integrative cancer treatment plan. She discusses scientific literature that looks at whether natural interventions can help stop cancer formation and growth and inhibit cancer stem cell activity.

Approximate playing time: 32 minutes

ABOUT THE EXPERT

ABOUT THE SPONSOR

HOLLY LUCILLE, ND, RN, is a nationally recognized and licensed naturopathic doctor, educator, natural products consultant, and television and radio host. She is the author of several books, including Creating and Maintaining Balance: A Women’s Guide to Safe, Natural, Hormone Health and The Healing Power of Trauma Comfrey. Lucille is on the editorial advisory board of Alternative Medicine, Alternative Therapies in Health and Medicine, Advances in Mind-Body Medicine, and Natural Practitioner, is the medical advisor for Natural Partners Inc., and is the vice-chair of the Institute for Natural Medicine. A past president of the California Naturopathic Doctors Association, Lucille has also worked to ensure the availability of safe naturopathic healthcare by spearheading a lobbying effort to have naturopathic doctors licensed in the state of California. A graduate of the Southwest College of Naturopathic Medicine in Tempe, Arizona, Lucille believes in the science, art, and mystery of healing. Through this belief, she uses the magnificence of media to truly make a difference and empower people to heal. Her private practice in Los Angeles, Healing from Within Healthcare, focuses on comprehensive naturopathic medicine and individualized care.

EuroMedica® specializes in bringing proven natural medicines to the United States and in developing unique formulas containing clinically tested, safe, and effective ingredients. EuroMedica’s founder and president, Terry Lemerond, has more than 45 years’ experience in the nutritional supplement industry, beginning with the founding of his first companies, Enzymatic Therapy and PhytoPharmica, and culminating in his current company, EuroMedica. Terry Lemerond is credited as the first to introduce standardized ginkgo, glucosamine sulfate, and IP-6 to the United States. Several of EuroMedica’s products have been featured in published scientific papers. New clinical trials, some including the well known BCM-95®/Curcugreen™ Curcumin, are now underway at prestigious research centers. EuroMedica is perhaps best known for Curaphen® Professional Pain Formula and CuraPro® products, both containing BCM-95®/Curcugreen™ Curcumin. Additionally, EuroMedica pro vides unique and proprietary products including EurOmega-3®, Traumaplant® Comfrey Cream from Germany, Bladder Manager® featuring the clinically studied SagaPro®, ProHydra-7™ with SB-150™ Seabuckthorn Oil, and Clinical Glutathione™ with Sublinthion®.

subscribe to the NMJ

PODCAST in iTunes

JOIN THE INTEGRATIVE HEALTHCARE COMMUNITY – ONLINE AND IN-PERSON! FEBRUARY 17-19, 2022

KEYNOTE SPEAKER

New York Hilton Midtown, New York

Andrew Weil, MD

The Integrative Healthcare Symposium – a multidisciplinary conference – educates, inspires and connects like-minded integrative practitioners through globally-relevant sessions about alternative and complementary approaches to healthcare. The education sessions offer Q&A opportunities and deliver takeaways that can be implemented into your practice immediately. LIMITED TIME OFFER!

KEYNOTE SPEAKER

Jeffrey Bland PhD, FACN, CNS

Members of the Natural Medicine Journal can SAVE 25% on the purchase of a Standard Conference Pass.

Learn more and register with code: SAVE25NMJ at ihsymposium.com

NOVEMBER 2, 2021 Online

IntegrativePractitioner.com, the official media of the Integrative Healthcare Symposium, is your 24/7/365 resource for industry news and valuable resources. Explore the latest integrative advancements through news articles, whitepapers, podcasts and more before expanding your knowledge base in immersive Digital Summits. Subscribe to the Integrative Practitioner newsletter for FREE! Don’t miss the next FREE Digital Summit, Immune Health & Detoxification, a day packed with valuable content, activity-focused breaks and opportunities for networking via an online forum.

Learn more and register at: integrativepractitioner.com/digital-summit

EXPERT INTERVIEW

Racial Disparities in Breast Cancer An interview with Aminah Keats, ND, FABNO

In this interview, our editor-in-chief, Tina Kaczor, ND, FABNO, speaks with Aminah Keats, ND, FABNO, about breast cancer disparities in African American women. Keats is a practicing naturopathic physician at Capital Integrative Health in Bethesda, Maryland, and is also vice president on the board of directors for the Oncology Association of Naturopathic Physicians (OncANP). You can find Keats on Facebook and on Instagram @draminahkeats or at her website: drkeats.com.

Play Now Approximate listening time: 37 minutes

Tina Kaczor, ND, FABNO: Let’s start by talking about incidence and mortality from breast cancer. What is the latest data telling us? Aminah Keats, ND, FABNO: This topic is something that is just so near and dear to my heart. I’m so happy to be here and to participate in this discussion. When it comes to breast cancer incidence, the percentages of White women compared to Black women are pretty close. White women have the highest incidence of breast cancer, and Black women closely trail behind. Now, when you look at that same data from 10 or 20 years ago, that gap was wider, but that percentage has increased for Black women. But when you look at the mortality rates, numbers differ pretty significantly. The death rate from breast cancer is about 40% higher in Black women compared to White women. So that gap is pretty significant, and that has actually been pretty consistent over the last several decades.

“

When you look through

the literature, the socioeconomic piece is probably the most commonly named factor that we see. But what’s interesting is when we look at some of the data, even when that is accounted for, there’s still a racial difference.

”

is most commonly diagnosed in women across the board of all races and ethnicities. That subtype has the best kind of prognosis. However, that particular subtype is lowest in Black women, which is very interesting. It’s definitely something to pay attention to. We know that the most aggressive subtype is triple-negative: ER-negative, PR-negative, and HER2-negative. That is the most aggressive, with the poorest prognosis, and that is actually highest in Black women.

For women who are aged 40 years of age and younger, the incidence rate actually flips—the percentage of breast cancer in Black women is higher compared to White women. However, that mortality gap across the board is consistent.

So out of the breast cancers diagnosed in Black women in this country, triple-negative disease actually accounts for about 20% to 21%, and that is probably about double compared to other populations in this country. Obviously that plays a role in the disparity.

Kaczor: We know there are certain things that are predictive or at least a prognostic indicator for women. There are higher rates of death with certain subtypes. Can you talk a little bit more about cancer subtypes and the direction that the data goes?

Kaczor: It’s poignant to hear Black women under the age of 40 have a very high rate of death from breast cancer compared to their White counterparts. Is there any advice you would give clinicians for their young Black patients? Should we be screening earlier?

Keats: When it comes to that tumor and biology piece, when we look at the subtypes, ER-/PR-positive and HER2-negative

Keats: That’s a really great question. There are no definitive guidelines for that, but there’s definitely a need for more

SECTION

According to the National Cancer Institute, as many as 50% of cancer patients have problems sleeping.

Overcome occasional sleeplessness and get relaxation and reduced tension support from ZenBiome Sleep™ microbiomelabs.com ©2021 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2021 SUPPLEMENT—VOL. 13, NO. 101 (SUPPL) 29

EXPERT INTERVIEW

individualized research. In terms of screening, we need to be careful about increased radiation exposure, etc. But if there is a strong family history and other kinds of things that we might be concerned about, we should definitely be an advocate for our patients for early screenings if they’re warranted based on the current guidelines. I would also pay closer attention to the laboratory evaluation, like looking at estrogen profiles, insulin resistance versus insulin sensitivity, inflammatory markers. Then looking at things like stress management and cortisol levels. So really taking all of those things into account, because in terms of the contributing factors, those are the kinds of things that could potentially manifest and have an impact on that disparity. Kaczor: Can you talk about socioeconomic barriers to care? Keats: When you look through the literature, the socioeconomic piece is probably the most commonly named factor that we see. But what’s interesting is when we look at some of the data, even when that is accounted for, there’s still a racial difference. When it comes to lack of resources, the obvious question is, are you able to afford insurance? And if so, what is the quality of that insurance, or is the insurance through the state perhaps? How does that compare to private insurance? That can definitely have an impact there.

A lack of resources can also affect transportation. Suppose the medical facility is far from home—how do you afford to travel there? And if you have children, you’re having to be concerned about childcare. For women working hourly jobs, can they afford to have their hours cut for testing, screening, or treatment? When you’re thinking about needing money for food, bills, etc., sometimes that can be a challenge. The other thing is the lack of trust in the healthcare system that has been present within the African-American community for centuries. That plays a factor as well, just as far as trusting your medical providers. All these things combined, I think definitely drop into that larger bucket.

Kaczor: You talk about tumor biology in a way that’s enlightening and clinically relevant. Could you give us a little overview of that aspect? Keats: Absolutely. As I mentioned, that big, important factor that stands out is the prevalence of triple-negative disease. What’s really interesting is that when you look at women in West African countries, which is the origin of most African Americans in this country, that triple-negative prevalence is very similar. Even though their incidence of breast cancer is not as high, their percentages of triple-negative disease, just like African American women, are very high. Also there’s a higher rate of early diagnosis before that 35 to 40 year age range.

Another interesting thing is that with HER2-positive versus -negative, there’s no difference between the races; it’s more with that ER/PR. Other molecular characteristics would include things like increases in p53 expression, greater mitotic indexes (which have been associated with poor prognosis), more aggressive disease, and greater potential for a metastatic spread. It’s really interesting because even when you think about, let’s say the socioeconomic factors, that tumor biology is something that you can’t shift. So even if you are able to provide all the resources in the world, the tumor biology is a constant. Kaczor: One of the biological aspects of a tumor with breast cancer that we talk a lot about is the ER/PR status. You say that in the biology of the individual person with the diagnosis, there’s differing estrogen profiles. Can you talk about that a little bit? Keats: Some of the data does reveal that estradiol levels may be higher in African American women. In a study involving teenage girls whose menstrual cycle started earlier, estradiol levels were higher, and weight gain was more advanced. In a couple of other studies involving adults, Black women had higher levels of estradiol across the board.

Other conditions, like osteoporosis, are less prevalent in Black women. But uterine fibroids are very common in Black women compared to other groups. We may want to think about focusing more on hormonal metabolism and elimination in this patient population. I know that we do that quite a bit across the board

in breast cancer, but maybe really prioritizing that more a bit in Black women.

Kaczor: Can you talk more about stress as a possible contributor to the higher rates?

Kaczor: What is popularly called estrogen dominance.

Keats: Stress contributes to everything for everyone. When we think about the impact of stress on the Black community, we have to think about the larger historical view around that. There are different layers. That could be around structural racism and the role that that plays psychologically. That could be around political stressors. That can be around neighborhood discrimination. That can be around environmental stressors, whether that be just actual physical stress within your environment or even pollutants within your environment. So just putting all these things together and the impact that it has mentally, when you think about that connection on a molecular level, when we think about epigenetics and the role that that plays, I think that’s definitely something to take into account.

Keats: Yes. Kaczor: It is interesting on the heels of another risk factor— obesity and insulin resistance. Keats: What’s really interesting about the insulin resistance piece is that when you look at the literature, it’s not necessarily tied to obesity and Black women. Black women have a higher risk of insulin resistance regardless of the BMI. Matched with White women with same age, same BMI, Black women have a higher risk of insulin resistance. That is something to pay attention to and perhaps evaluate, even in our patients who don’t present with obesity. Kaczor: So clinically, that would be a tool that could be used throughout one’s life—just check the glycohemoglobin as a routine lab? Keats: Exactly. I always check for fasting insulin as well. Kaczor: Do you do C-reactive protein routinely? Keats: Absolutely: CRP, ESR, IL-6 often, reviewing N/L ratio. Even with the obesity picture, what’s interesting about that is BMI is the standard measurement used to evaluate for obesity, but that is not necessarily the most accurate source to evaluate obesity in each group. For example, in Black people in general, Black people tend to have larger bones, denser muscles, different fat distribution. The percentage of Black women who are categorized as obese may not be 100% accurate, or maybe that needs to be adjusted.

Going back to the insulin resistance piece, there could be a connection with that and fat distribution specific to Black people versus White people. For example, subcutaneous adipose tissue versus visceral adipose tissue and the percentages between those 2—there’s a connection there. Also distribution of gluteal-femoral distribution is different in African-American women compared to other groups. And insulin resistance is one hypothesis to explain that.

I definitely found that in the literature. Even when you date back to studies during the Jim Crow time, which was a time with very repressive laws that significantly impacted the lives and the livelihood of Black people in this country, I actually found studies looking at breast cancer specifically, showing that women who were exposed to this environment had a higher risk of developing ER-negative or triple-negative breast cancer. So definitely again, something to pay attention to. I mentioned before in terms of evaluation, some of us will do cortisol testing, some of us will just do our own evaluation, counseling, but definitely taking that into account when it comes to creating a whole integrative complete treatment plan for our patients. Kaczor: If you’re seeing someone with an established diagnosis and you’re looking to prevent recurrence, what labs would you run? Keats: Outside of the foundational labs that we all know, I would run CBC with differentials, comprehensive vitamin D, and inflammatory markers (CRP, ESR, LDH). I’d look at glucose regulation, so along with fasting glucose, also hemoglobin A1c and insulin levels. I would probably look at leptin as well. As I mentioned, the hormonal aspect of things is important, so I’d look at the metabolism of estrogens, and

EXPERT INTERVIEW

I’d look at cortisol, too. I’m thinking of the DUTCH test specifically and that layout. Naturopathic and integrative care is all about individualized care, so as other things pop up in the interview, whether it be comorbidities or symptoms that a patient presents with, of course we add on to that. Kaczor: If you did see a high CRP or ESR, what are some things you might do? Keats: We’re so lucky because there’s so much creativity within the naturopathic field. I like to start with just the foundational things. That stress piece is definitely important, so really focusing on that. Focusing on sleep hygiene and nutrition, and then building from there. We know that food timing is important as far as intermittent fasting, if we think that that’s appropriate, that can definitely support a time inflammatory pathway. Of course, supplementation. So all the heavy hitters like curcumin and fish oil and grapeseed extract. Those are the main things that I would go to. And then again, just building all of that based on the specific patient presentation. Kaczor: Is there anything really specific that we need to drill down to look at in Black women specifically when it comes to their tumor biology? Keats: I do think it’s important to be more aggressive with Black women with breast cancer. As I mentioned, even for Black women who present with ER-positive, PR-positive, HER2-negative (the better prognostic subtype) their risk of death is still higher, even though it’s not an aggressive subtype compared to the others. Also, even when you look at the Oncotype DX to determine the risk of occurrence and aggressiveness of early stage breast cancer, even for Black women who have matching scores, their risk of death is still higher.

I think that it’s important for us to be an advocate for our patients, because sometimes they may not recognize red flags that we’re able to catch quickly. And we can inform them about clinical trials. When you look at clinical trials

ABOUT THE EXPERT

Aminah Keats, ND, FABNO, received her undergraduate degree in psychology from Spelman College and completed premedical coursework at Rutgers University. After completing her naturopathic medical training at the University of Bridgeport College of Naturopathic Medicine, Keats completed a 2-year, hospital-based residency in naturopathic oncology at Cancer Treatment Centers of America (CTCA). She then continued her work at CTCA as a naturopathic oncology consultant and director of naturopathic medicine. She currently practices naturopathic medicine and specializes in naturopathic oncology at Capital Integrative Health in Bethesda, Maryland. Keats also serves as a faculty member at Maryland University of Integrative Health. She is a member of the American Association of Naturopathic Physicians, the Oncology Association of Naturopathic Physicians, and member on the OncANP Board of Directors.

throughout the world, the people of the African diaspora are not well represented. Encouraging them to participate if we think it’s appropriate may be beneficial to their survival. Kaczor: Great point. Is there anything else you’d like to share with our listeners? Keats: One thing that I didn’t mention about tumor biology was around PTEN and mTOR. I was so desperate to find something specific, concrete in the literature. I did find a couple of studies looking at PTEN, the tumor suppressor gene, showing that it’s expressed less in Black women compared to White women. Some treatment strategies we may want to implement include encouraging the expression of that particular tumor suppressor gene. The data shows things like curcumin and certain dietary habits, things like DEM and some other nutrients, may help to support that. In addition, the mTOR pathway tends to be more activated in Black women compared to White women. So thinking about natural things that may potentially inhibit mTOR expression is important from the tumor biology aspect.

Natural Medicine Journal Oncology Special Issue 2021

Articles inside

Antibiotics Show Benefit in Pancreatic Cancer

Coffee and Tea Consumption and the Risk of Invasive Breast Cancer in Postmenopausal Women

Precisely Timed Light May Reduce Chemotherapy-Related Sleep Disruption and Fatigue

Racial Disparities in Breast Cancer

Can Supplementation With Vitamin D Affect PD-L1 Expression in Gastrointestinal Cancers?

Contributors