Natural Medicine Journal Oncology Special Issue 2019 by Diversified Communications

OCTOBER 2019 SUPPLEMENT

SPECIAL ISSUE

Oncology

Soyâ&#x20AC;&#x2122;s Effect on Bone Fracture Risk in Women with Breast Cancer History Is Open-Label Placebo a Smart Treatment for Cancer-Related Fatigue?

Omega-3 Supplementation & Breast Cancer The Cardiovascular Implications of Cancer Treatments Cancer-Related Dermatology: What Clinicians Need to Know

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SPECIAL ISSUE

ONCOLOGY OCTOBER 2019 VOL. 11, NO. 101 (SUPPL)

Contents

ABSTRACTS & COMMENTARY

Omega-3 Fatty Acid Supplementation and Breast Cancer

Honest Placebo: Good Medicine for Cancer-Related Fatigue?

Soy Intake and Osteoporotic Fracture Risk in Women with a History of Breast Cancer

Doxycycline Treatment in Early Breast Cancer

Esophageal Cancer: Treatment with Radiation, Oral Vitamin C, Chemotherapy and the Effects on Inflammatory Markers

HEALTHCARE PERSPECTIVES

Cancer Therapy and Cardiotoxicity

EXPERT INTERVIEW

What Every Clinician Needs to Know About Cancer-Related Dermatology

SPONSORED INTERVIEW

Three Botanicals in Cancer Care: An interview with researcher Ajay Goel, PhD

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Contributors DANIEL CHONG, ND, is a licensed naturopathic physician, practicing in Portland, OR, since 2000. Chong’s focus is on healthy aging of the brain and body, as well as risk assessment, prevention, and drug-free treatment strategies for cardiovascular disease and diabetes. He also maintains a virtual practice for group and individual coaching in cardiovascular disease prevention. Chong has completed certificate training in cardio-metabolic medicine with Drs. Mark Houston and Joel Kahn at The Academy of Anti-Aging Medicine. He is also a contributing editor in cardiology for the Natural Medicine Journal and a clinical consultant for Cleveland Heart Lab. You can learn more about him at DrDanielChong.com. TINA KACZOR, ND, FABNO, is editor-in-chief of Natural Medicine Journal and a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National University of Natural Medicine, and completed her residency in naturopathic oncology at Cancer Treatment Centers of America, Tulsa, Oklahoma. Kaczor received undergraduate degrees from the State University of New York at Buffalo. She is the past president and treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peer-reviewed journals. Kaczor is based in Portland, OR. MIRANDA LABANT, ND, graduated from National University of Health Sciences in Illinois. She completed a 1-year Council on Naturopathic Medical Education (CNME) accredited residency in integrative oncology under the direction of Michael Traub, ND. Labant earned her master of health sciences degree from Cleveland State University. She is an active member of Oncology Association of Naturopathic Physicians and New Hampshire Association of Naturopathic Doctors. LaBant is currently practicing at The Sante Center in Hampton, NH, where her clinical focus includes integrative oncology, Lyme disease, endocrine health, gastrointestinal health, and preventative care.

TODD ROBINSON, ND, is a graduate of Bastyr University. His private practice in Jacksonville Beach, FL, focuses on the integration of evidence-based natural medicine into cancer treatment. He is the Immediate past president of the Florida Naturopathic Physicians Association. His website is www.WellnessWorkingGroup.com. PAUL RICHARD SAUNDERS, PhD, ND, DHANP, CCH, completed his PhD in forest ecology at Duke University, his naturopathic degree at Canadian College of Naturopathic Medicine, and his homeopathic residency at National University of Naturopathic Medicine, where he also earned a second naturopathic degree. He is professor of materia medica and clinical medicine at the Canadian College of Naturopathic Medicine; senior naturopathic doctor, Beaumont Health System, Troy Hospital, Michigan; and adjunct professor of integrative medicine, Oakland University William Beaumont Medical School and has a private practice in Dundas, Ontario. Saunders was a member of the transition team that formed the Office of Natural Health Products, served as a natural health expert to the Directorate, and has served on several expert panels for Health Canada. He has conducted clinical research, supervised students and residents, and published widely. JACOB SCHOR ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now lives in Denver. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology 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 Abstracts & Commentary editor.

EDITOR-IN-CHIEF Tina Kaczor, ND, FABNO

MESSAGE FROM THE PUBLISHER

ABSTRACTS & COMMENTARY EDITOR Jacob Schor, ND, FABNO

Integrative Oncology Update

PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry PUBLISHED BY IMPACT Health Media, Inc. 223 N. Guadalupe #718 Santa Fe, NM 87501 Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2019 by IMPACT Health Media, Inc. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; IMPACT Health Media, Inc. assumes no liability for any information published herein. Advertisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this publication. IMPACT Health Media, Inc. is not liable for any injury or harm to persons or property resulting from statements made or products or services referred to in the articles or advertisements.

Every year we produce a special issue on Oncology. We realize that many of our Natural Medicine Journal readers do not specialize in oncology; however, we also realize that the prevalence of cancer makes it highly likely that you are seeing cancer survivors in your clinical practice, no matter what your area of expertise. It could be a patient who is actively going through treatment, has had a cancer diagnosis in the past, or is at higher risk of developing cancer. Cancer is in your practice whether it’s your specialty or not. And the fact remains, there is a lot going on in the field of integrative oncology. That’s why we like to shine a light on this subject each year. In this issue, we’ve chosen to look at some specific natural substances that can impact cancer treatment. For example, our sponsored podcast with leading oncology researcher Ajay Goel, PhD, discusses curcumin, boswellia, and French grape seed extract. We also look at studies involving vitamin C, glutamine, soy, and omega-3 fatty acids. In addition, our Editor-in-Chief, Tina Kaczor, ND, FABNO, interviews oncology expert Shauna Birdsall, ND, FABNO, about skin cancer prevention. We think you will really appreciate this in-depth audio conversation between 2 leading integrative oncology experts. This issue also features a paper by integrative cardiologist Daniel Chong, ND, who discusses the important and underrecognized topic of cardio-oncology. We hope you appreciate this issue enough to pass it on to a colleague who may not have received it. Let’s spread the word about the value of integrative oncology. As always, we’d like to thank our dedicated contributors and reviewers for making this special issue possible. In health,

Karolyn A. Gazella Publisher, Natural Medicine Journal

ABSTRACT & COMMENTARY

Omega-3 Fatty Acid Supplementation and Breast Cancer Insights on VEGF and Ki-67 expression in patients treated with chemotherapy REFERENCE

Darwito D, Dharmana E, Riwanto I, et al. Effects of omega-3 supplementation on Ki-67 and VEGF expression levels on clinical outcomes of locally advanced breast cancer patients treated with neoadjuvant CAF chemotherapy: a randomized controlled trial report. Asian Pac J Cancer Prev. 2019;20(3):911-916. STUDY OBJECTIVE

To determine effects of omega-3 supplementation on Ki-67 and vascular endothelial growth factor (VEGF) expression levels at the time of surgery in women with locally advanced, invasive carcinoma. Overall survival and progression-free survival were also tracked. DESIGN

Randomized double-blind placebo-controlled trial PARTICIPANTS AND STUDY INTERVENTION

Participants were women with locally advanced stage IIIB invasive ductal breast cancer (n=48) between the ages of 25 and 60. All participants received 3 cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil, or CAF). Study participants were assigned to receive 1 g/day of omega-3 fatty acids from fish oil (n=24) or placebo (n=24) alongside their chemotherapy (51 days total). The contents of the placebo were not disclosed. OUTCOME MEASURES

• Expression of Ki-67 and VEGF were semi-quantified using immunohistochemistry from paraffin blocks of tumor materials obtained from mastectomy after neoadjuvant chemotherapy. • Overall survival and disease-free survival were assessed via Kaplan-Meier curve and Cox-regression tests.

KEY FINDINGS

• Decreased Ki-67 expression was evident in the intervention group compared to the control group (P=0.032)

• Decreased VEGF expression was also observed in the intervention group versus the control group (P=0.041) • VEGF was positively correlated with Ki-67 expression (P<0.001) • Overall survival in the intervention group was significantly longer compared to the control (mean survival: 30.9 vs 25.9 weeks; P=0.048). • Disease-free survival in the intervention group compared to the control group was also reported to be significantly longer (mean survival: 28.5 vs 23.7 weeks; P=0.044).

Miranda LaBant, ND PRACTICE IMPLICATIONS Overview of Omega 3s and Breast Cancer

Before discussing this study on the use of omega-3 fatty acids on the expression of Ki-67 and VEGF in locally advanced breast cancer patients undergoing neoadjuvant CAF, it is useful to consider the evidence to date supporting the use of omega 3s in breast cancer. Women who consumed high intake ratios of marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to omega-6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case-control and cohort studies.1 If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, mechanisms may include reduction in pro-inflammatory lipid derivatives, inhibition of nuclear factor-kappa B–induced cytokine production, and altered cell signaling. More interventional trials designed to assess biomarkers or cancer incidence as endpoints need to be done to definitively determine if omega-3 fatty acids may be lowering risk.

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Evidence from several observational studies suggests that higher intakes of omega 3s are associated with a lower risk of breast cancer.

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ABSTRACT & COMMENTARY

Evidence from several observational studies suggests that higher intakes of omega 3s are associated with a lower risk of breast cancer. In the prospective Singapore Chinese Health Study of 35,298 women aged 45–74 years, those in the top 3 quartiles of dietary omega 3 intake had a 26% lower risk of breast cancer after an average of 5.3 years of follow-up than those in the lowest quartile.2

to cancer and DNA repair.1 Studies have also demonstrated the influence of omega-3 fatty acids and their ability to decrease the potent inflammatory markers interleukin-6 (IL-6),8 tumor necrosis factor (TNF)-alpha,9 and C-reactive protein.10

Similarly, among 35,016 female participants aged 50–76 years in the Vitamins and Lifestyle cohort, those who reported current use of fish-oil supplements had a 32% lower risk of breast cancer after a mean of 6 years than those who did not take fish oil.3

VEGF has been recognized as playing a role in breast cancer progression.11 VEGF expression in breast cancer is well documented and is produced by both macrophages and cancer cells in breast carcinoma.12 VEGF receptor expression has also been observed on breast cancer cells.13

According to a systematic review of 3 case-control studies and 5 prospective studies published between 2007 and 2011, evidence increasingly suggests that higher intakes of dietary and supplemental omega 3s are associated with a lower risk of breast cancer. Similarly, the authors of a meta-analysis of data from 21 prospective cohort studies concluded that women with the highest dietary intakes and/or tissue levels of omega 3s had a 14% lower risk of breast cancer than those with the lowest intakes and tissue levels.4 These authors also found a dose-response relationship between higher intakes of combined omega 3s and reduced breast cancer risk.

Ki-67 is present in all proliferating cells, and its role as a proliferation marker attracts considerable interest as a biomarker of cancer growth and treatment.14 Ki-67 is a nuclear nonhistone protein present in all active phases of cell cycle, except the resting phase (G0).15 Potential uses of Ki-67 in breast cancer include prognosis of relative responsiveness, resistance to chemotherapy or endocrine therapy, or as a dynamic biomarker of treatment efficacy in neoadjuvant therapy.16

While these studies don’t speak to the effect of omega 3s on VEGF and Ki-67 expression, they suggest that omega-3 fatty acid ingestion is associated with less incident breast cancer. Role of Omega 3s in Cancer

Omega-3 fatty acids are used in a variety of conditions for their role as a systemic anti-inflammatory.5 Chronic inflammation is a known risk factor for cancer growth and progression.6 Research has shown that omega-3 fatty acids DHA and EPA influence cancer cell proliferation, differentiation, and apoptosis while also inhibiting angiogenesis, tumor cell invasion, and metastasis.7 Omega 3s can positively influence the genetic expression related

Expression Levels of Ki-67 and VEGF in Breast Cancer

Influence of Omega 3s on Ki-67 and VEGF

An extensive amount of evidence has shown that the omega-3 fatty acids EPA and DHA play an essential role in the regulation of inflammatory responses.17 In the current study under review, immune staining of Ki-67 and VEGF in the intervention and control groups was performed at baseline and after neoadjuvant chemotherapy plus supplementation of omega 3 or placebo. The authors reported an expression of Ki-67 that was positively correlated with VEGF expression (P<0.001). The results of this study imply that omega-3 supplementation may be a consideration to lower VEGF and Ki-67 expression in locally advanced breast cancer. Although the mechanism of action for the omega-3 fatty acids was not investigated, local anti-inflammatory effects may have influenced expression of VEGF and Ki-67.

(continued on page 10)

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ABSTRACT & COMMENTARY

Effects of Omega 3s in Chemotherapy

Omega-3 fatty acids have the ability to modulate inflammatory responses and intracellular signaling; thus incorporation of omega-3 fatty acids to improve clinical outcomes during standard chemotherapy may benefit patients through regulation of cytokines and immune cell signaling.18 The authors of this study suggest the results of this trial contribute to the evidential use of omega-3 supplementation in conjunction with chemotherapy. This conclusion may carry some bias based on the failure to reach statistical significance. However, this conclusion does not seem to be an entirely false claim based on the previous body of evidence. There is a significant evidence base for the use of dietary intake of omega-3 fatty acids to improve the efficacy of chemotherapeutic agents, in vivo and in vitro and in animal and clinical studies.19,20 In a previous study, fish oil was shown to improve the effectiveness of chemotherapy agents, including 5-fluorouracil (5-FU), paclitaxel, doxorubicin, and oxoplatin.21 While the overall survival was short for both cohorts in this current study, intervention with omega-3 fatty acids was associated with both significantly longer overall survival and longer disease-free progression. Based on this and previous evidence, one could argue that there is significant benefit for the utilization of omega-3 fish oil in conjunction with chemotherapy.10,21,22 Omega 3 Dosing, Bioavailability, Quality

Standard doses of omega-3 fatty acids range from 300 mg to 2,000 mg (EPA/DHA).23 All participants in this study received standard neoadjuvant CAF chemotherapy as well as 1 g/day omega-3 fatty acids or placebo. The study intervention was observing the effects of fish oil on VEGF and Ki-67 expression. The authors fail to mention the ratio of EPA/DHA, which could alter the effects on VEGF and Ki-67 expression. They also omit the sourcing of the fish oil, which could also impair the effectiveness of this intervention.

“

Intervention with omega-3 fatty acids was associated with both significantly longer overall survival and longer disease-free progression.

”

Dietary supplements can contain several different forms of omega 3s, including natural triglycerides, free fatty acids, ethyl esters, reesterified triglycerides, and phospholipids.24 Triglycerides are the form that occurs naturally in fish oil, whereas ethyl esters are synthesized by removing the natural glycerol backbone of the triglycerides and replacing it with ethyl ester end caps on each fatty acid. Re-esterified triglycerides are formed by the conversion of ethyl esters back to triglycerides. Omega 3s as reesterified triglycerides, natural triglycerides, and free fatty acids have somewhat higher bioavailability than ethyl esters, but consumption of all forms significantly increases plasma EPA and DHA levels.25

Since the authors of this study did not assess bioavailability, it might be beneficial to look at the absorption via erythrocyte levels in the blood of patients to evaluate their nutrient status prior to treatment; this would also help to define a more appropriate/optimal dose for patients. Adverse Effects

During treatment, 3 patients in the study suffered from diarrhea, and their omega-3 supplementation was discontinued for 5-7 days. The authors did not mention whether these adverse events were from treatment intervention or neoadjuvant therapy. Safety was not assessed in this study. Overall Survival and Progression-Free Survival

The authors of this study claim that “omega-3 fatty acid supplementation improved overall survival and progression-free

ABSTRACT & COMMENTARY

survival of locally advanced breast cancer treated with CAF neoadjuvant chemotherapy and mastectomy.” The study was conducted in Indonesia, where women are often diagnosed in late stages, the staging itself is prone to missing stage IV disease due to limitations of diagnostic equipment, and there are much higher mortality rates and shorter disease-free progression in that geographic region.26 STUDY LIMITATIONS Limitations of this study include: • Small sample size (n=48) • Recruitment of locally advanced stage IIIB breast cancer only • Failure to reach statistical significance • No stated reasons for choosing this dose of fish oil • Source of the fish oil capsules in the intervention group is not divulged • Single dosage (1 g of fish oil) In future studies, we should consider a trial that includes intervention groups at incremental doses of omega 3s. Expanding a trial with multiple dose levels would likely provide a clearer evidence base as well as optimal dosing. CONCLUSION It is clear there is a significant evidence base for the use of omega-3 fatty acids in breast cancer. This study, while not statistically significant, supports the extensive positive data for the use of omega-3 supplementation during standard chemotherapy and clinical outcomes. Future studies should include the assessment of optimal dosing, quality of supplementation, safety, and bioavailability assessments. REFERENCES

1 Fabian CJ, Kimler BF, Hursting SD. Omega-3 fatty acids for breast cancer prevention and survivorship. Breast Cancer Res. 2015;17:62. 2 Gago-Dominguez M, Yuan JM, Sun CL, Lee HP, Yu MC. Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study. Br J Cancer. 2003;89(9):1686-1692. 3 Brasky TM, Lampe JW, Potter JD, Patterson RE, White E. Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1696-1708.

4 Zheng JS, Hu XJ, Zhao YM, Yang J, Li D. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ. 2013;346:f3706. 5 Ellulu MS, Khaza’ai H, Abed Y, Rahmat A, Ismail P, Ranneh Y. Role of fish oil in human health and possible mechanism to reduce the inflammation. Inflammopharmacology. 2015;23(2-3):79-89. 6 Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493-e503. 7 Merendino N, Costantini L, Manzi L, Molinari R, D’Eliseo D, Velotti F. Dietary ω-3 polyunsaturated fatty acid DHA: a potential adjuvant in the treatment of cancer. Biomed Res Int. 2013;2013:310186. 8 Weiss G, Meyer F, Matthies B, Pross M, Koenig W, Lippert H. Immunomodulation by perioperative administration of n-3 fatty acids. Br J Nutr. 2002;87(Suppl 1):S89S94. 9 Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr. 2004;23(1):71-88. 10 Chagas TR, Borges DS, de Oliveira PF, et al. Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial. J Hum Nutr Diet. 2017;30(6):681-692. 11 Duffy AM, Bouchier-Hayes DJ, Harmey JH. Vascular Endothelial Growth Factor (VEGF) and Its Role in Non-Endothelial Cells: Autocrine Signalling by VEGF. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6482/ 12 Lewis JS, Landers RJ, Underwood JC, Harris AL, Lewis CE. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol. 2000;192(2):150-158. 13 Speirs V, Atkin SL. Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours. Br J Cancer. 1999;80(5-6):898-903. 14 Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med. 2016;13(4):496-504. 15 Nishimura R, Osako T, Okumura Y, Hayashi M, Toyozumi Y, Arima N. Ki-67 as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer. Exp Ther Med. 2010;1(5):747-754. 16 Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656-1664. 17 Mori TA, Beilin LJ. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep. 2004;6(6):461-467. 18 McKinney N. Naturopathic Oncology: An Encyclopedic Guide for Patients and Physicians. 3rd ed. Vancouver, Canada: Creative Guy Publishing; 2016:80. 19 Corsetto PA, Colombo I, Kopecka J, Rizzo AM, Riganti C. ω-3 long chain polyunsaturated fatty acids as sensitizing agents and multidrug resistance revertants in cancer therapy. Int J Mol Sci. 2017;18(12):E2770. 20 Lee JY, Sim TB, Lee JE, Na HK. Chemopreventive and chemotherapeutic effects of fish oil derived omega-3 polyunsaturated fatty acids on colon carcinogenesis. Clin Nutr Res. 2017;6(3):147-160. 21 Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer. 2011;117(16):3774-3780. 22 Shirai Y, Okugawa Y, Hishida A, et al. Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia. Sci Rep. 2017;7(1):4826. 23 Stengler M, Anderson P. Outside the Box Cancer Therapies. Carlsbad, CA: Hay House Inc; 2018:144-145. 24 Dyerberg J, Madsen P, Møller JM, Aardestrup I, Schmidt EB. Bioavailability of marine n-3 fatty acid formulations. Prostaglandins Leukot Essent Fatty Acids. 2010;83(3):137-141. 25 Davidson MH, Kling D, Maki KC. Novel developments in omega-3 fatty acid-based strategies. Curr Opin Lipidol. 2011;22(6):437-444. 26 Anwar SL, Adistyawan G, Wulaningsih W, Gutenbrunner C, Nugraha B. Rehabilitation for cancer survivors: how we can reduce the healthcare service inequality in low- and middle-income countries. Am J Phys Med Rehabil. 2018;97(10):764-771.

ABSTRACT & COMMENTARY

Honest Placebo: Good Medicine for Cancer-Related Fatigue?

A novel approach to one of cancer’s most debilitating effects REFERENCE

Zhou ES, Hall KT, Michaud AL, et al. Open-label placebo reduces fatigue in cancer survivors: a randomized trial. Support Care Cancer. 2019;27(6):2179-2187. STUDY OBJECTIVE

To evaluate the effect of an open-label placebo on cancer- related fatigue (CRF) in cancer survivors and to assess whether personality characteristics or a genetic variation in dopamine catabolism (catechol-O-methyltransferase) affect the placebo response

Todd Robinson, ND

tive Significance Questionnaire). No data were collected after day 22. STUDY PARAMETERS ASSESSED

• Fatigue: Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) • Physical and mental health status: Short Form-12 (SF-12) • Mood disturbance: Profile of Mood States-Short Form (POMS-SF)

DESIGN

• Exercise participation: Godin Leisure Time Exercise Questionnaire (GLTEQ)

PARTICIPANTS

• Generalized optimism: Life Orientation Test-Revised (LOT-R)

Randomized trial with participants allocated to either an openlabel placebo group (ie, participants were aware they were receiving a placebo) or a non-treatment control group Forty cancer survivors, all of whom had no evidence of active disease, were at least 6 months post-treatment, scored <43 on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale, and were not being treated or evaluated for any other medical cause of fatigue. The average age of participants was 47.3 years (range 22-74) and most were married (62.5%), non-Hispanic white (87.5%) females (92.5%) who had been diagnosed with breast cancer (55%) an average of 9.3 years previously. INTERVENTION

On day 1 of the study, all participants completed 7 questionnaires (FACIT-F, SF-12, POMS-SF, GLTEQ, BIDR-7, LOT-R, and the Subjective Significance Questionnaire) and provided a saliva sample for genetic testing. Participants then met with an investigator for a scripted 15-minute study initiation discussion during which the investigator outlined both the rationale of the study and prior evidence indicating that placebo can improve fatigue. At the end of this discussion, participants opened a sealed envelope indicating their study allocation (either openlabel placebo [OLP] or non-treatment control). OLP participants received 120 placebo pills with instructions to take 2 pills twice a day for 22 days. On day 8 of the study, all participants repeated 3 questionnaires (FACIT-F, GLTEQ, and the Subjective Significance Questionnaire). OLP participants were reminded and encouraged to continue taking their placebo pills. On day 22 of the study, all participants repeated 5 questionnaires (FACIT-F, SF-12, POMS-SF, GLTEQ, and the Subjec-

• Tendency toward socially desirable responding: Balanced Inventory of Desirable Responding-Version 7 (BIDR-7)

• Subjective fatigue and overall quality of life: Subjective Significance Questionnaire • Catechol-O-methyltransferase (COMT) SNPs rs4680 and rs4818: genetic testing PRIMARY OUTCOME MEASURES

Differences in the questionnaire scores from those in the control group were considered to reflect the influence of placebo. KEY FINDINGS

OLP significantly improved CRF as reflected by changes in the FACIT-F score between days 1 and 8 and days 1 and 22. Changes in FACIT-F scores were not significantly correlated with measures of socially desirable responding (BIDR-7) or generalized optimism (LOT-R), suggesting that a general tendency to expect the best or to present oneself in the best light are not personality variables associated with OLP responsiveness. OLP responsiveness did differ significantly based on the COMT rs4818 genotype, suggesting that the dopamine system may play a role. The SF-12, POMS-SF, and GLTEQ questionnaires found no significant difference between OLP and control. The Subjective Significance Questionnaire found significant subjective improvement in fatigue and overall quality of life in response to OLP at day 8, but not day 22.

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ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS CRF is defined as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer and/or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”1 This academic definition, though descriptive in a technical sense, fails to convey a real sense of the human impact of CRF. Nothing compares to the words of actual patients sharing their own experiences: “It is not exhaustion. I’ve been exhausted. I’ve never had fatigue like this. It’s not work fatigue or emotional fatigue. It’s very different. It’s incredible.”2 CRF is inherently different from the fatigue experienced as a part of everyday life. It’s not clearly connected to physical exertion, it’s not relieved by rest or sleep, and it includes additional manifestations such as apathy, cognitive dysfunction, emotional lability, and generalized weakness.2 Formal estimates of the prevalence of CRF have ranged from 4% to 91%, depending on the type of cancer studied and the assessment methods used.3 A more recent estimate suggests that non-trivial CRF is experienced by 45% of cancer patients undergoing treatment and 29% of cancer survivors (ie, CRF persists for years as a long-term problem).4 CRF ranks among the top self-reported concerns of cancer patients and can be so severely disruptive to activities of daily living and quality of life that it consistently ranks as being more troublesome than other cancer-related symptoms like depression, nausea, and pain.5,6 CRF may also predict shorter survival for cancer patients.7,8 As such, the successful treatment of CRF can be expected to improve quality of life for patients and may also improve their survival. Current treatment options for CRF include exercise, mindbody approaches, psychosocial interventions, and pharmaceutical therapy.9 A strong case can be made that exercise is the most effective of these treatment options.10-12 However, it can be very challenging to get fatigued patients to exercise.

“

The successful treatment of cancer-related fatigue can be expected to improve quality of life for patients and may also improve their survival.

”

The present results reported by Zhou et al may be helpful in this respect. They independently confirm results from a similar study in 2018 and thus position OLP as an intriguing treatment option for CRF.13 They also suggest that OLP can be leveraged to help patients implement a program of therapeutic exercise. While Zhou et al did not find statistically significant evidence that OLP helped patients to increase their physical activity, it is not unreasonable to suspect that a longer time period would increase this likelihood. Placebo effects have been documented to last as long as 12 months and represent a valid option for patients.14 Finally, when seeking to implement OLP in clinical practice, the clinician’s approach probably matters. Zhou et al were very deliberate in their approach to participants and the way in which they presented information, encouragement, and support. “Belief activation” may be an important element for the success of placebo in clinical practice.15 LIMITATIONS This study is limited by the preponderance of female participants (92.5%) and the short study period (22 days). Further studies in a more diverse group of subjects with a longer intervention will be needed. CONCLUSION Even when administered open-label, placebo improved subjective cancer-related fatigue compared to no treatment in cancer survivors.

ABSTRACT & COMMENTARY

REFERENCES

1 Bower JE, Bak K, Berger A, et al. Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology Clinical Practice Guideline Adaptation. J Clin Oncol. 2014;32(17):1840-1850. 2 Scott JA, Lasch KE, Barsevick AM, Piault-Louis E. Patients’ experiences with cancer-related fatigue: a review and synthesis of qualitative research. Oncol Nurs Forum. 2011;38(3). 3 Lawrence DP, Kupelnick B, Miller K, Devine D, Lau J. Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients. J Natl Cancer Inst Monogr. 2004;(32):40-50. 4 Wang XS, Zhao F, Fisch MJ, et al. Prevalence and characteristics of moderate to severe fatigue: A multicenter study in cancer patients and survivors. Cancer. 2014;120(3):425-432. 5 Yanez B, Pearman T, Lis CG, Beaumont JL, Cella D. The FACT-G7: a rapid version of the functional assessment of cancer therapy-general (FACT-G) for monitoring symptoms and concerns in oncology practice and research. Ann Oncol. sy of 2012;24(4):1073-1078. Courte 6 Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. Oncologist. 2007;12(suppl_1):4-10. 7 Groenvold M, Petersen MA, Idler E, Bjorner JB, Fayers PM, ZMouridsen HT. PsychoT. by R orted logical distress and fatigue predicted recurrence re rep and survival in primary breast a s te taboli 2007;105(2):209-219. cancer patients. Breast CancerdRes meTreat.

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8 Quinten C, Maringwa J, Gotay CC, et al. Patient self-reports of symptoms and clinician ratings as predictors of overall cancer survival. J Natl Cancer Inst. 2011;103(24):1851-1858. 9 Bower JE. Cancer-related fatigue—mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 2014;11(10):597-609. 10 Tomlinson D, Diorio C, Beyene J, Sung L. Effect of exercise on cancer-related fatigue: a meta-analysis. Am J Phys Med Rehabil. 2014;93(8):675-686. 11 Hilfiker R, Meichtry A, Eicher M, et al. Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med. 2017;52(10):651-658. 12 Kessels E, Husson O, van der Feltz-Cornelis CM. The effect of exercise on cancer-related fatigue in cancer survivors: a systematic review and meta-analysis. Neuropsychiatr Dis Treat. 2018;14:479-494. 13 Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Open-label placebo treatment for cancer-related fatigue: a randomized-controlled clinical trial. Sci Rep. 2018;8(1). 14 Hansen BJ, Meyhoff HH, Nordling J, Mensink HJ, Mogensen P, Larsen EH. Placebo effects in the pharmacological treatment of uncomplicated benign prostatic hyperplasia. The ALFECH Study Group. Scand J Urol Nephrol. 1996;30(5):373-377. 15 Green J, Wright H. From bench to bedside: converting placebo research into belief activation. J Altern Complement Med. 2017;23(8):575-580.

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ABSTRACT & COMMENTARY

Soy Intake and Osteoporotic Fracture Risk in Women with a History of Breast Cancer Results of the Shanghai Breast Cancer Survival Study REFERENCE

Zheng N, Hsieh E, Cai H, et al. Soy food consumption, exercise, and body mass index and osteoporotic fracture risk among breast cancer survivors: the Shanghai Breast Cancer Survival Study. JNCI Cancer Spectr. 2019;3(2):1-8. STUDY OBJECTIVE

To assess associations between soy food intake, exercise, and BMI and osteoporosis-related bone fractures in women with a history of breast cancer (stages 0-III) DESIGN

Population-based, longitudinal study (Shanghai Breast Cancer Survival Study) PARTICIPANTS

Participants are part of the ongoing Shanghai Breast Cancer Survival Study. A total of 4,139 women, all with a diagnosis of breast cancer (stages 0-III), were evaluated (1,987 were pre/perimenopausal, 2,152 women were postmenopausal). STUDY PARAMETERS ASSESSED

Osteoporosis-related bone fractures were evaluated at 18 months and 3, 5, and 10 years post-diagnosis. Exercise and soy isoflavone intake was assessed at 6 and 18 months post-diagnosis. Weight and height were taken at baseline PRIMARY OUTCOME MEASURES

Outcome measures were the number of osteoporotic fractures, defined as “fractures caused by falls from standing height and at sites associated with osteoporosis” relative to menopausal status, soy intake and BMI. KEY FINDINGS

The overall risk for osteoporotic fracture was 2.9% and 4.4% for pre/perimenopausal women and postmenopausal women, respectively. High soy isoflavone intake was associated with less risk of fracture for pre/perimenopausal women but not postmenopausal women. Specifically, pre/perimenopausal women who consumed >56.06 mg/d of isoflavones had significantly lower risk of fracture (hazard ratio [HR]: 0.22, 95% confidence interval [CI]: 0.09-0.53) compared to pre/perimenopausal women who consumed <31.31 mg/d (P<0.001). Being overweight (BMI >25 kg/m2) was associated with a higher risk for fracture (HR: 1.81, 95% CI: 1.04-3.14) for pre/perimenopausal women, but being overweight/obese was not an associated risk for the postmenopausal cohort. Exercise was inversely associated with osteoporotic fractures in postmenopausal women (HR: 0.56, 95% CI: 0.33-0.97 for metabolic equivalent hours >12.6 vs <4.5), and exercise followed a dose- response pattern (Ptrend=0.035).

Tina Kaczor, ND, FABNO PRACTICE IMPLICATIONS Risk for osteoporosis and bone fracture increases in women who have been diagnosed with estrogen-receptor-positive breast cancer.1 Selective estrogen receptor modulators (SERMs, such as tamoxifen) for pre/perimenopausal women and aromatase inhibitors in postmenopausal women result in lowering the estrogenic milieu within bone.2–7 The publication currently under review is the first to suggest that higher isoflavone intake is associated with fewer osteoporotic fractures in pre/perimenopausal women. This study also confirms that exercise is inversely associated with fracture risk in a dosedependent manner. Osteoporosis, and the risk of fracture that comes with lowered bone mineral density (BMD), are a consequence of several other types of cancer therapies. Androgen deprivation, stem cell transplantation, and ovarian failure secondary to treatment with chemotherapy are all associated with treatment-induced bone loss.8 Primary care providers are often tasked with monitoring bone health in many of these patient populations since standards of care within oncology often do not provide such guidance. In bone, estrogen has a protective effect from the loss of BMD. When estrogen binds to its receptor, there is a reduction in the activity of osteoclasts; thus anything that limits estrogenic effects in bone results in greater osteoclastic activity and reduction of BMD. Antiestrogenic drugs that universally lower estrogen, such as aromatase inhibitors, reliably lead to bone loss through this mechanism. Similarly, premenopausal women who undergo ovarian ablation due to drugs or surgery lose the bone-protective effect of their endogenous estrogens.

ABSTRACT & COMMENTARY

Unlike aromatase inhibitors, which universally lower estrogen by >95%,9 SERMs have a differential effect on estrogen receptors, either as an antagonist or an agonist, depending on the tissue/organ. Tamoxifen, the most widely used SERM, is an antagonist when bound to estrogen receptors in breast tissue, while having a slight agonist effect when binding to receptors in bone.10 This slight agonist effect leads to increased BMD in postmenopausal women who take tamoxifen.11 Premenopausal women who take tamoxifen, however, will not derive this benefit. Premenopausally, endogenous estrogens are still circulating at relatively high levels, making the weak agonist effect of tamoxifen a net reduction in estrogenic effects on bone.12 While isoflavones are commonly referred to as phytoestrogens, they are more akin to “phyto-SERMs,” with effects that are dependent on the estrogen receptors expressed (alpha/ beta) as well as the tissue type.13 Previous studies on isoflavone intake from soy foods in women with a history of breast cancer have suggested an inverse relationship with recurrence as well as overall mortality.14–19 We know less about highdose, isolated soy isoflavones; experimental studies suggest that isoflavones as isolates in high doses have unique risks and lack proof of safety.20

“

The publication currently under review is the first to suggest that higher isoflavone intake is associated with fewer osteoporotic fractures in pre/perimenopausal women.

”

Intake of isoflavones per day in the Shanghai Breast Cancer Survival Study had a mean [SD] value of 45.9 [38.3]. In comparison, in the Women’s Healthy Eating and Living (WHEL) study, a US-based cohort that assessed soy intake in women with a history of breast cancer, the mean [SD] intake was 2.6 [7.9] mg. In the Life After Cancer Epidemiological (LACE) study, women consumed a mean [SD] 4.1 [11.9] mg per day.16 While these studies did show associations for benefit of soy consumption on mortality and recurrence of breast cancer at these low levels, it is unclear if the effects translate to bone health at all.

Given that this study tracked the consumption of isoflavones from whole foods, it is possible that other constituents in soy are responsible for the reduced risk of osteoporotic fracture observed in premenopausal women. In the current study, there was a lack of any associated decrease in osteoporotic fractures in the postmenopausal cohort, further implying the presence of non-estrogen-mediated mechanism(s). Like any plant, soy has a complex array of thousands of phytochemicals. For example, soy-derived flavonoids have dozens of known physiological effects, although none of them alone can account for the observation on bone health observed in the current study.20

There are several limitations of this study, as outlined by the authors: The data collection was dependent on self-reporting of osteoporotic fractures, which has been suggested to be reliable but inherently has risks of misclassification. Also, there was no information collected on osteoporosis screening, bisphosphonate use, or compliance with guidelines for osteoporosis prevention. This study used data prior to the widespread adoption of monitoring bone health in those with a history of breast cancer in China. Similarly, bisphosphonate use was unlikely, although possible, given the years of enrollment into this study were 2002-2006.

This study took place in China where consumption of soy foods is dramatically higher than in Western populations.

There is no doubt that bone health is a top priority in women with a history of breast cancer and that active surveillance

ABSTRACT & COMMENTARY

should be done with sequential bone density scans over time. Given the preponderance of evidence that whole soy food can benefit these women, we now have yet another reason to assure them that a serving or 2 daily of soy is not only okay, it is encouraged. While studies on soy do not delineate between conventional and organic sources, it goes without saying that organic sourcing is advisable. REFERENCES

1 Body J-J. Increased fracture rate in women with breast cancer: a review of the hidden risk. BMC Cancer. 2011;11(1):384. 2 Reid DM, Doughty J, Eastell R, et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK expert group. Cancer Treat Rev. 2008;34(Suppl 1):S3-S18. 3 Rabaglio M, Sun Z, Price KN, et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. 2009;20(9):1489-1498. 4 Bruning P, Pit M, de Jong-Bakker M, van den Ende A, Hart A, van Enk A. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer. 1990;61(2):308-310. 5 Delmas P, Fontana A. Bone loss induced by cancer treatment and its management. Eur J Cancer. 1998;34(2):260-262. 6 Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE. Effect of an aromatase inhibitor on BMD and bone turnover markers: two-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) Trial (18233230). J Bone Miner Res. 2006;21(8):1215-1223. 7 JM Lappe ST. Prevention of osteoporosis in women treated for hereditary breast and ovarian carcinoma: a need that is overlooked. Cancer. 1998;83:830-834. 8 Guise TA. Bone loss and fracture risk associated with cancer therapy. Oncologist. 2006;11(10):1121-1131.

9 Brueggemeier RW, Hackett JC, Diaz-Cruz ES. Aromatase inhibitors in the treatment of breast cancer. Endocr Rev. 2005;26(3):331-345. 10 Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol. 1998;54(1):105-112. 11 Clines GA, Choksi P, Van Poznak C. Adjuvant endocrine therapy and bone health in breast cancer. Curr Osteoporos Rep. 2015;13(5):263-273. 12 Vehmanen L, Elomaa I, Blomqvist C, Saarto T. Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol. 2006;24(4):675-680. 13 Mangalath DL, Sadasivan C. Selective estrogen receptor modulators (SERMs) from plants. In: Brahmahari G, ed. Bioactive Natural Products: Chemistry and Biology. Weinheim, Germany: 2015 Wiley‐VCH; 2014. Published online 2015 https://onlinelibrary.wiley.com/doi/abs/10.1002/9783527684403.ch13. Accessed September 25, 2019. 14 Messina M. Impact of soy foods on the development of breast cancer and the prognosis of breast cancer patients. Complement Med Res. 2016;23(2):75-80. http:// www.karger.com/DOI/10.1159/000444735. Accessed September 25, 2019. 15 Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302(22):2437. 16 Nechuta SJ, Caan BJ, Chen WY, et al. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr. 2012;96(1):123-132. 17 Chi F, Wu R, Zeng Y-C, Xing R, Liu Y, Xu Z-G. Post-diagnosis soy food intake and breast cancer survival: a meta-analysis of cohort studies. Asian Pac J Cancer Prev. 2013;14(4):2407-2412. 18 Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009;118(2):395405. 19 Caan BJ, Natarajan L, Parker B, et al. Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev. 2011;20(5):854-858. 20 Uifălean A, Schneider S, Ionescu C, Lalk M, Iuga CA. Soy isoflavones and breast cancer cell lines: molecular mechanisms and future perspectives. Molecules. 2015;21(1):E13.

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ABSTRACT & COMMENTARY

Doxycycline Treatment in Early Breast Cancer

Commonly prescribed doses show anticancer effects REFERENCE

Scatena C, Roncella M, Di Paolo A, et al. Doxycycline, an inhibitor of mitochondrial biogenesis, effectively reduces cancer stem cells (CSCs) in early breast cancer patients: a clinical pilot study. Front Oncol. 2018;8:452. OBJECTIVE

This clinical pilot study tested whether short-term preoperative treatment with doxycycline reduced cancer stem cell (CSC) activity in breast cancer patients. PARTICIPANTS

A total of 15 women with early breast cancer participated. Nine patients received doxycycline for a 14-day period between breast biopsy and lumpectomy. Six post-lumpectomy specimens were used as controls (no treatment). Controls were chosen from women who were well-matched for age and clinical characteristics. In the doxycycline treatment group, patient ages at diagnosis ranged from 42 to 65, tumor size varied between 10 and 30 mm, and 7 out of 9 patients were estrogen receptor (ER)–positive (ER+), with 6 being of the luminal A subtype and one of the luminal B subtype. Six out of 9 patients were grade 2, or intermediate in Ki-67. In addition, 2 patients were of the HER2(+) subtype. INTERVENTION

The women were given 200 mg per day of doxycycline orally for 14 days before surgery, with breast biopsy serving as the baseline. OUTCOME MEASURES

Testing was performed on the biopsy and post-resection specimen of each participant, and comparisons were made between measures for each sample. All samples were tested for known biomarkers of “stemness” (CD44, ALDH1); mitochondria (TOMM20); cell proliferation (Ki-67, p27); apoptosis (cleaved caspase-3); and neo-angiogenesis (CD31). Changes from baseline to posttreatment were assessed with MedCalc 12 (unpaired t-test) and ANOVA. KEY FINDINGS

Post-doxycycline tumor samples demonstrated a statistically significant decrease in the stemness marker CD44 (P<0.005) when compared to pre-doxycycline tumor samples. Levels of CD44 were reduced between 17.65% and 66.67% in 8 out of 9 patients treated with doxycycline. One patient showed a 15% increase in CD44. Overall, this represents a nearly 90% positive response rate. Similar results were obtained for ALDH1, another marker of stemness. There were no changes in any of the biomarkers measured in the control group specimens from time of biopsy to resection, thus the biopsy itself is not likely to have affected measures of stemness. 20 ©2019 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2019 SUPPLEMENT—VOL. 11, NO. 101 (SUPPL)

Jacob Schor, ND, FABNO PRACTICE IMPLICATIONS Cancer stem cells are well-recognized to confer treatment resistance and perhaps give rise to the tumor itself. As Dawood and colleagues summarized in a review of the subject in 2014: “Cancer stem cells have been identified in a number of solid tumors, including breast cancer, brain tumors, lung cancer, colon cancer, and melanoma. Cancer stem cells have the capacity to self-renew, to give rise to progeny that are different from them, and to utilize common signaling pathways. Cancer stem cells may be the source of all the tumor cells present in a malignant tumor, the reason for the resistance to the chemotherapeutic agent used to treat the malignant tumor, and the source of cells that give rise to distant metastases.” 1 To understand the implications of these results, we should review some of the earlier work these researchers published prior to this study. In 2015, Michael Lisanti reported that antibiotics, which target mitochondria, can eradicate cancer stem cells in multiple types of cancer. In other words, it is possible “to treat cancer like an infectious disease.”2 They had first assessed cancer stem cells from multiple tumor types and “identified a conserved phenotypic weak point—a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells.” Their analysis revealed that mitochondria of stem cells might be the Achilles heel of stem cells. Aware that several classes of antibiotics inhibit mitochondrial biogenesis, they next identified a list of drugs that could eradicate cancer stem cells in 12 different cancer cell lines and across 8 different tumor types (ie, breast, ductal carcinoma in situ, ovarian,

ABSTRACT & COMMENTARY

prostate, lung, pancreatic, melanoma, glioblastoma).2 That same year these researchers identified doxycycline as the preferred drug to use in targeting cancer stem cell mitochondria.3 The US Food and Drug Administration first approved doxycycline as a broad-spectrum antibiotic in 1967. The standard dose is 200 mg/day. Recall that in an evolutionary sense, mitochondria are descendants of bacteria and remain sensitive to the antibiotics more often employed to inhibit bacterial growth.4 Doxycycline is already used to treat infections in cancer patients and there have been case reports of unexpected remissions, particularly in lymphoma.5,6 In April 2017 Zhang et al delineated doxycycline’s action inhibiting the transitional steps of stem cell phenotypes into breast cancer.7 In June 2017 this research took a turn that many of us will find fascinating: Lisanti’s group reported that the effect of doxycycline is optimized when combined with vitamin C and berberine in vitro. (The breast cancer patients in the trial being reviewed here only received doxycycline. Vitamin C and berberine were not included in the study protocol.) Doxycycline is so effective at suppressing cancer stem cell populations that it creates high selection pressure that synchronizes the surviving cancer cell population to a predominantly glycolytic phenotype, which results in metabolic inflexibility. They identified 2 natural products (ie, vitamin C, berberine) and 6 clinically approved drugs (ie, atovaquone, irinotecan, sorafenib, niclosamide, chloroquine, stiripentol) that target the doxycycline-resistant CSC population. This combination strategy eliminates surviving cancer stem cells, which the researchers say provides “a simple pragmatic solution to the possible development of doxycycline-resistance in cancer cells.”8 This earlier in vitro work suggested that doxycycline not only inhibits CSCs but may work best when combined with agents that exploit the metabolic inflexibility, such as vitamin C and berberine.8

“

Simply adding vitamin C and berberine during their doxycycline course of treatment might enhance any anticancer effects.

”

It was in light of these earlier publications that the small clinical trial discussed in this review was published. This pilot study suggests that doxycycline at commonly prescribed doses may lessen the “stemness” of tumors in women with breast cancer. These results suggest, but do not prove, efficacy. The significant decrease in “stemness” observed is not proof that doxycycline will reduce risk of recurrence or slow progression of advanced cancer in the real world. Yet given the safety profile of doxycycline, it is tempting to employ this treatment strategy before definitive evidence is published. Of note, an April 2019 publication suggested that adding azithromycin might further enhance the effectiveness of a doxycycline and vitamin C combination.9 These publications suggest some obvious implications. Patients will, on occasion, take a course of doxycycline to treat infection. This might be a useful opportunity. Simply adding vitamin C and berberine during their doxycycline course of treatment might enhance any anticancer effects. There is no published evidence that doing so will lower risk of cancer or its recurrence, but could it hurt? Such prophylaxis might be particularly useful in patients previously treated for cancers whose recurrences we suspect are driven by cancer stem cells. Glioblastoma and ovarian cancer come to mind.

ABSTRACT & COMMENTARY

In recent years some practitioners have promoted treatment strategies that are the direct opposite of Lisanti’s approach. The thinking is that mitochondrial injury is responsible for cancer progression and so supplements selected to repair mitochondrial injury should be of benefit.10 These 2 approaches are in such direct opposition to one another that one might be justified in thinking that both ideas cannot be true. It is possible that prevention of cancers involves preservation of mitochondria while the existence of established cancer should be considered as a distinctly different state for the cells and their mitochondria.11 In an August 2019 paper, oxidative phosphorylation itself is identified as a potential therapeutic target for cancer therapy.12 Based on published evidence available at this point, once cancer stem cells are present, Lisanti’s argument to target mitochondrial biogenesis is persuasive. It is certainly more well-evidenced than any suggestions that nourishing and promoting mitochondrial biogenesis is useful, even if the latter appears more philosophically congruent with vis medicatrix naturae.

REFERENCES

1 Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology (Williston Park). 2014;28(12):1101-1107, 1110. 2 Lamb R, Ozsvari B, Lisanti CL, et al. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease. Oncotarget. 2015;6(7):4569-4584. 3 Peiris-Pagès M, Sotgia F, Lisanti MP. Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose. Oncoscience. 2015;2:696-699. 4 Ozsvari B, Sotgia F, Lisanti MP. A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis. Aging. 2017;9:2098-2116. 5 Abramson DH, Rollins I, Coleman M. Periocular mucosa-associated lymphoid/low grade lymphomas: treatment with antibiotics. Am J Ophthalmol. 2005;140(4):729730. 6 Kiesewetter B, Raderer M. Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature. Blood. 2013;122(8):1350-1357. 7 Zhang L, Xu L, Zhang F, Vlashi E. Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle. 2017;16(8):737-745. 8 De Francesco EM, Bonuccelli G, Maggiolini M, Sotgia F, Lisanti MP. Vitamin C and doxycycline: a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs). Oncotarget. 2017;8(40):67269-67286. 9 Fiorillo M, Tóth F, Sotgia F, Lisanti MP. Doxycycline, azithromycin and vitamin C (DAV): a potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs). Aging (Albany NY). 2019;11(8):2202-2216. 10 Hill S. Repairing mitochondrial DNA for cancer and age-related diseases. https://www.leafscience.org/mitochondria/. Published May 2, 2017. Accessed September 21, 2019. 11 Ahn CS, Metallo CM. Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. 2015;3(1):1. 12 Sica V, Bravo-San Pedro JM, Stoll G, Kroemer G. Oxidative phosphorylation as a potential therapeutic target for cancer therapy [published online ahead of print August 9, 2019]. Int J Cancer. 2019.

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ABSTRACT & COMMENTARY

Esophageal Cancer: Treatment with Radiation, Oral Vitamin C, Chemotherapy and the Effects on Inflammatory Markers Results of a pilot study REFERENCE

Abdel-Latif MMM, Babar M, Kelleher D, Reynolds JV. A pilot study of the impact of Vitamin C supplementation with neoadjuvant chemoradiation on regulators of inflammation and carcinogenesis in esophageal cancer patients. J Cancer Res Ther. 2019;15(1):185-191. STUDY OBJECTIVE

To assess the effects of oral vitamin C supplementation with neoadjuvant chemoradiation in esophageal adenocarcinoma on the nuclear factor-kappa B (NF-ΚB) and associated cytokines DESIGN

Randomized 4-week trial of vitamin C, but the entire treatment protocol was 8 weeks until surgery PARTICIPANTS

Twenty patients diagnosed with esophageal carcinoma who were undergoing multimodal treatment INCLUSION CRITERIA

Patients with adenocarcinoma of the esophagus who had samples collected from both the tumor and their normal esophageal tissue and received external beam radiotherapy (40 Gy in 15 fractions over 3 weeks), as well as chemotherapy in weeks 1 and 6 (5-FU 50 mg/kg for 5 days and then cisplatin 75 mg/m2 on day 7) and surgery during week 8 EXCLUSION CRITERIA

Taking other nutritional supplements

Paul Richard Saunders, PhD, ND, DHANP, CCH

TREATMENT

Oral vitamin C (1,000 mg/day) for 4 weeks KEY FINDINGS

All 20 patients completed the trial; 9 received the oral vitamin C and 11 did not. Of the 20 patients, 4 were female, median age was 64.5 years old, 6 were smokers, 17 drank alcohol, 12 had a family history of cancer, and 13 had Barrett adenocarcinoma. NF-ΚB was activated in the cancer tissue of all patients before treatment. Down-regulation of NF-ΚB >10% was noted in 5 patients (25%), including 2 from the vitamin C group, post- treatment. NF-ΚB binds to the inhibitory IχBα and is degraded. In the 5 patients with >10% change, their tumor tissue had lower IχBα compared to normal esophageal tissue. The trend was for greater NF-ΚB reduction in the vitamin C group, but it was not significant. Both treatment arms had a significant reduction in their cytokine profiles, with the effect more pronounced in the vitamin C treatment arm (P<0.05). NF-ΚBp50 and NF-ΚBp65 levels were elevated in the cancer tissue of all patients before treatment. Nine had lower levels post treatment, but vitamin C had no effect on these levels. Cytokines vascular endothelial growth factor (VEGF), interleukin (IL) 8, IL1α, and IL1β were significantly elevated in the tumor compared to normal tissue. Cytokine levels were significantly reduced after treatment and this effect was greater in the vitamin C arm (P<0.05).

INSTRUMENTS

Colorimetric NF-ΚB assay, cell extracts and Western blot analysis, and cytokine analysis

ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS The authors chose a dose of 1,000 mg because they felt it would provide an adequate dose. However, those who use intravenous vitamin C (IVC) know that high serum levels cannot be achieved or maintained from oral treatment compared to IV treatment. The dose used in this study was based first on the 1999 paper by Levine et al that calculated 200 mg would maintain an adequate level of vitamin C in the body, and second on their prior pilot study in which 1,000 mg/d of vitamin C for 4 weeks in 25 Barrett esophagus patients yielded 8 (35%) patients with down-regulation of activated NF-KB and cytokines.1,2

“

The administration of IVC to oncology patients does not initially raise serum levels to those of healthy patients receiving IVC, which is why repeated dosing is needed.

”

In their 2018 review paper, Carr and Cook provided a comprehensive summary of the literature on IVC, including both knowledge and gaps.3 They note that a large proportion of cancer patients present with hypovitaminosis C (<23 umol/L) or frank vitamin C deficiency (<11 umol/L).3 The administration of IVC to oncology patients does not initially raise serum levels to those of healthy patients receiving IVC, which is why repeated dosing is needed.4 Work by Cieslak and Cullen showed that radiation plus IVC decreased tumor growth.5 Schoenfeld et al found that the addition of chemotherapy increased survival rates.6 In the Schoenfeld et al trial involving patients with glioblastoma multiforma and non-small cell lung carcinoma (N=11), there was longer progression-free survival and longer average overall survival, 4 (36%) subjects remained alive, and 1 (9%) of the 4 showed no evidence of cancer on MRI when the paper was published.6

patients with cancer are generally low in ascorbate at the time of diagnosis. The source of oral vitamin C and its verification were not stated in this paper or their previous paper.2 A trial using IVC may have had a better outcome and given us additional information on the effects of IVC on the various inflammatory cytokines in Barrett esophageal adenocarcinoma.

The authors of the current study noted in their discussion and conclusions that they did not achieve the success they had hoped for and that future studies should evaluate patient molecular profiles and involve parenteral administration of vitamin C.

REFERENCES

LIMITATIONS It was not clear in which 4 weeks (5 weeks in another part of the paper) of their 8-week protocol the oral vitamin C was given. The oral dose may have been too low, especially since

SUMMARY In this small trial of patients with Barrett esophageal adenocarcinoma, an oral daily dose of 1 g vitamin C for 4 weeks, along with radiotherapy and chemotherapy prior to surgery, there was a down-regulation of NF-KB in 25% of patients, but not all were in the vitamin C group, and there was a significant reduction in cytokines that was more pronounced in the vitamin C group. 1 Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281(15):1415-1423. 2 Babar M, Abdel-Latif MM, Ravi N, et al. Pilot translational study of dietary vitamin C supplementation in Barrett’s esophagus. Dis Esophagus. 2010;23(3):271-276. 3 Carr AC, Cook J. Intravenous vitamin C for cancer therapy - identifying the current gaps in our knowledge. Front Physiol. 2018;9:1182. 4 Mikirova N, Casciari J, Riordan N, Hunninghake R. Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients. J Transl Med. 2013;11:191. 5 Cieslak JA, Cullen JJ. Treatment of pancreatic cancer with pharmacological ascorbate. Curr Pharm Biotechnol. 2015;16(9):759-770. 6 Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al. O2- and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell. 2017;31(4):487-500.

HEALTHCARE PERSPECTIVES

Cancer Therapy and Cardiotoxicity Practical considerations in post-treatment care

By Daniel Chong, ND

ver half of people treated for cancer can now expect to live 10 years or more after diagnosis.1 And while longevity is obviously important, optimizing wellness throughout survival may be of equal or greater importance. Unfortunately, an under-recognized detractor— cardiovascular damage—may get in the way of living to one’s fullest after a cancer diagnosis. Indeed, many commonly used conventional cancer therapies can have potent cardiotoxic effects and impart significant, long-term risk on the cardiovascular system.2 Awareness of this issue, along with implementation of thorough risk assessment and appropriate, evidence-based preventive care in cancer survivors is essential to help ensure longterm wellness in this patient population. RISK REDUCTION IN A VULNERABLE POPULATION Figure: Cardiovascular toxicities associated with antineoplastic drugs Cancer is the number one cause of death in in patients with cancer higher socioeconomic populations within the Originally published in Frontiers in Psychology. Copyright © 2018 Varricchi, Ameri, Cadeddu, Ghigo, Madonna, Marone, Mercurio, Monte, Novo, Parrella, Pirozzi, Pecoraro, United States, but cardiovascular disease is still Spallarossa, Zito, Mercuro, Pagliaro and Tocchetti. the primary killer of men and women overall, accounting for approximately 1 in every 3-4 deaths.3,4 Traditional risk factors like family cardiovascular disease.8 In fact, surviving childhood cancer history, obesity, diabetes, high cholesterol, smoking, and in general imparts a nearly 2-fold increased risk of multiple high blood pressure make thorough risk assessment for most cardiovascular diseases on its own, including congestive heart aging adults a necessity. When you also consider the prevafailure and venous thromboembolism. Patients who survived lence of less recognized—but important—risk factors such as childhood cancers are also at increased risk of having high inflammation, nutritional deficiency, and mental/emotional blood pressure and dyslipidemia.9 stress, it’s clear that screening for the presence of cardiovascular diseases in just about everyone is warranted.5–7 MULTIPLE TOXIC EFFECTS LEAD TO Diseases of the cardiovascular system are already highly MULTIPLE PATHOGENIC SEQUELAE prevalent, and standard cancer therapies increase the risk. While previously noted circumstances may impart the most This issue is of particular concern in older cancer survisignificant risk, review of the wide scope of negative effects vors, who may already have one or more cardiovascular that can be anticipated, depending on therapies applied, comorbidities. It’s also relevant for younger adults who went should spark concern for ruling out heart disease presence in through cancer treatment during childhood, as adverse treatanyone previously treated for cancer (Figure). ment effects during that time can lead to an earlier onset of (continued on page 28)

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ABSTRACT & COMMENTARY

Table: Cardiotoxic Side Effects of Commonly Used Cancer Therapies10,11 Anthracyclines • Loss of myocardium/cardiomyopathy Cyclophosphamide • Myocarditis Cisplatin • Thromboembolism from endothelial damage Anti-HER2 therapies (most likely when combined with anthracycline) • Mitochondrial dysfunction Pyrimidine analogues • Myocardial ischemia from coronary vasospasm Anti-VEGF therapies • Myocardial ischemia from arterial thrombosis • Thromboembolism from endothelial damage • Arterial hypertension Arsenic trioxide • Myocardial ischemia Some tyrosine kinase inhibitors • Myocardial ischemia • Thromboembolism from endothelial damage • Peripheral arterial occlusive disease • Pleural effusion Radiation • Damage to small and large vessels, valves, and pericardium damage

Commonly used individual therapies have the potential to cause a wide range of health effects (Table). It is abundantly clear that heart disease following radiotherapy, chemotherapy, or hormone therapy may be due to direct cardiovascular damage caused by the treatment itself, or to the development and augmentation of cardiovascular risk factors related to those treatments.2 PRACTICAL STEPS FOR RISK ASSESSMENT AND REDUCTION Typical follow-up care after cancer therapy consists mostly of monitoring for recurrence. But as life expectancy after cancer treatment continues to increase, this follow-up care is becoming inadequate.12 Cardiovascular screening is clearly necessary. However, the potential complexities involved from case to case, lack of universally accepted guidelines, and lack of sufficient long-term data to help predict cardiovascular outcomes in this patient population creates a situation that is still somewhat fluid and does not allow for a definitive, one-size-fits-all cardiovascular work up. Nonetheless, after a patient has been treated for cancer, assessment of cardiovascular risk factors and symptom history is still advisable in the primary care setting. Some simple additions such as advanced cardiovascular biomarkers and imaging studies like coronary calcium scoring, carotid intima-media thickness, and echocardiography can help further ensure a more thorough approach to long-term cardiovascular health promotion in cancer survivors. REFERENCES

1 Quaresma M, Coleman MP, Rachet B. 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: a population-based study. Lancet. 2015;385(9974):1206-1218. 2 Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102(1):14-25. 3 Hastings KG, Boothroyd DB, Kapphahn K, et al. Socioeconomic differences in the epidemiologic transition from heart disease to cancer as the leading cause of death in the United States, 2003 to 2015. Ann Intern Med. 2018;169(12):836. 4 Centers for Disease Control and Prevention. Underlying Cause of Death 1999-2017. CDC Wonder website. https://wonder.cdc.gov/wonder/help/ucd.html. Updated December 6, 2018. Accessed October 9, 2019. 5 Packard RR, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008;54(1):24-38. 6 Ginter E. Chronic vitamin C deficiency increases the risk of cardiovascular diseases. Bratisl Lek Listy. 2007;108(9):417-421. 7 Brotman DJ, Golden SH, Wittstein IS. The cardiovascular toll of stress. Lancet. 2007;370(9592):1089-1100. 8 Armenian SH, Armstrong GT, Aune G, et al. Cardiovascular disease in survivors of childhood cancer: insights into epidemiology, pathophysiology, and prevention. J Clin Oncol. 2018;36(21):2135-2144. 9 Faber J, Wingerter A, Neu MA, et al. Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study. Eur Heart J. 2018;39(17):1555-1562. 10 Kirby M. Adding life to years: heart health and cancer. Prim Care Cardiovasc J. 2016. https://www.issuesandanswers.org/wp-content/uploads/MacMillanHeartHealthCancer.pdf. Accessed October 9, 2019. 11 Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015;12(9):547-558. 12 Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.

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SHAUNA M. BIRDSALL, ND, FABNO, is a naturopathic physi-

cian and fellow of the American Board of Naturopathic Oncology. Birdsall graduated from National University of Natural Medicine in 2000. After completing a residency at Cancer Treatment Centers of America (CTCA) at Midwestern Regional Medical Center in 2002, she provided patient care and supervised naturopathic medical students there until 2008. She took on a leadership role at Western Regional Medical Center at CTCA in Goodyear, AZ, in 2008 and was later elected vice chief of the medical staff there. She also chaired the Medical Executive Committee, Credentials Committee, and Peer Review Committee and served as the Medical Director of Integrative Oncology until 2018. Birdsall recently joined Avante Medical Center in Anchorage, AK. One of Phoenix Magazine’s Top Doctors 2014-2018, Birdsall is strongly committed to providing individualized, compassionate, evidence-based care to empower and provide hope to cancer patients.

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