Natural Medicine Journal Oncology Special Issue 2020

OCTOBER 2020 SUPPLEMENT

SPECIAL ISSUE

Oncology

Natural Angiogenic Agents: A Review of the Literature

Covid-19 Surfaces Cancer Care Disparities

Chemical Hair Treatments Pose Greatest Cancer Risks to Black Women

Role of IGF-1 in HER2-Positive Breast Cancer Patients

Mindfulness Approaches to Anxiety in Cancer Patients

Keto Diet During Radiotherapy

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Copyright © 2020 by the Natural Medicine Journal. All rights reserved.

SPECIAL ISSUE

ONCOLOGY OCTOBER 2020 VOL. 12, NO. 101 (SUPPL)

Contents 4 Contributors 5

Message from the Publisher

ABSTRACTS & COMMENTARY

6

Chemical Hair Treatments May Pose Highest Cancer Risk to Black Women

10

Role of Insulin-Like Growth Factor 1 in HER2-Positive Breast Cancer Patients

14

Ketogenic Diet and Breast Cancer

18

Mindfulness-Based Interventions: Do They Decrease Anxiety in Cancer Patients?

PEER-REVIEWED ARTICLE

22

Antiangiogenic Phytochemicals Best Poised for Clinical Trial Testing

EXPERT INTERVIEW

32

How is the Covid-19 Pandemic Impacting Cancer Care?

An interview with Tina Kaczor, ND, FABNO

SPONSORED INTERVIEW

33

An Innovative Approach to Integrative Oncology: A Conversation with Integrative Oncologist Isaac Eliaz, MD

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Contributors MAXWELL CRISPO, ND, attended the Canadian College of Naturopathic Medicine and graduated as valedictorian for his class in 2018. He completed a one-year primary care residency and a two-year naturopathic oncology residency at Lokahi Health Center in Kailua-Kona, Hawaii, the clinical practice of Michael Traub, ND, FABNO. Crispo has been involved in natural health research throughout his academic career, including conducting an addendum study to a clinical nutrition trial at the University of Guelph, investigating the informed-consent process in clinical nutrition research, and serving as the research site coordinator for the Canadian/United States Integrative Oncology Study (CUSIOS), a multicenter clinical research study on advanced naturopathic integrative therapies in the treatment of advanced-stage solid-tumor cancers. He was awarded the Anna MacIntosh Junior Investigator Research Fellowship in 2017 for his proposed clinical trial investigating the efficacy of n-acetyl-l-carnitine on chemotherapy-induced peripheral neuropathy in cancer patients.

Crispo looks forward to continuing a career in integrative oncology. For more information visit http://www.lokahihealth.com/maxwell-crispo/.

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.

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 is the editor of the Textbook of Naturopathic Oncology.

She has been published in several peer-reviewed journals. Kaczor is based in Portland, Oregon.

DUGALD SEELY, ND, MSC, FABNO, leads the clinical practice and cancer research program for the Ottawa Integrative Cancer Centre. In addition to his clinical role as a naturopathic doctor, he also serves as the executive director of research & clinical epidemiology at the Canadian College of Naturopathic Medicine, affiliate investigator for the Ottawa Hospital Research Institute, and vice president for the Oncology Association of Naturopathic Physicians. Seely completed his master of science in cancer research at the University of Toronto and is a fellow of the American Board of Naturopathic Oncology. As a clinician scientist, Seely has been awarded competitive grant and trainee funding from the Canadian Institutes of Health Research, the Canadian Breast Cancer Research Alliance, the SickKids Foundation, the Lotte and John Hecht Memorial Foundation, the Ottawa Regional Cancer Foundation, and the Gateway for Cancer Research Foundation.

ATHANASIOS PSIHOGIOS, ND, is the research resident at Ottowa Integrative Cancer Centre (OICC).

He’s an integrative oncology researcher dedicated to advancing this pioneer-type field in order to provide patients with safe and efficacious therapy options to support their overall care. Over the last 3 years, Psihogios has worked as a lead researcher, currently as a supervisor, with the Oncology Association of Naturopathic Physicians (OncANP) on the Knowledge in Naturopathic Oncology Website (KNOW) Database. Before starting as the OICC research resident, Psihogios was a volunteer research assistant with the clinic, with his most notable project involvement being the Integrative Pediatric Oncology Program (IPOP).

His work on this project, pertaining to practice trends in naturopathic pediatric cancer care, has been published in a peer-reviewed medical journal and presented at a conference. Psihogios graduated from the Canadian College of Naturopathic Medicine with a doctor of naturopathy degree. He received a bachelor of arts degree from the University of Ottawa, with a focus on both health science and philosophy.

4 ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12 , NO. 101 (SUPPL)

POORVI SHAH, DO, is a physician who is board-certified in family medicine and specializes in osteopathy and integrative medicine. She graduated from Michigan State University’s College of Osteopathic Medicine and completed a family medicine residency. She later completed a fellowship in integrative medicine at the Andrew Weil Center for Integrative Medicine. Shah practices integrative medicine and osteopathy in the greater Washington, DC, area.

Copyright © 2020 by the Natural Medicine Journal. All rights reserved.

EDITOR-IN-CHIEF Tina Kaczor, ND, FABNO ABSTRACTS & ­COMMENTARY EDITOR Lise Alschuler, ND, FABNO PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry ASSOCIATE EDITOR Kristin Bjornsen 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 © 2020 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.

MESSAGE FROM THE PUBLISHER

A Closer Look at Cancer Care in Clinical Practice Every year we devote an entire issue of the Natural Medicine Journal to oncology.

And we will continue to do so until the year comes when we finally turn the tides in our battle against this devastating disease. According to the American Cancer Society, this year 1.8 million new cancers will be diagnosed, resulting in the death of more than 606,000 people in the United States. Keeping this illness on the radar of all integrative practitioners remains a key goal of ours.

In this issue, the peer-reviewed paper is from our colleagues at the Ottawa Integrative Cancer Centre on the topic of antiangiogenic agents and how they may play an important role in cancer control. In addition to several Abstracts & Commentary, we have 2 audio interviews. In one, Editor-in-Chief Tina Kaczor, ND, FABNO, and I explore the issue of cancer care disparities during the present pandemic. In the other, integrative oncologist Isaac Eliaz, MD, LAc, describes the connection between galectin-3 and cancer and also updates listeners about the latest research on modified citrus pectin.

Cancer is cunning. While progress has been made regarding surgery, immunotherapy, and targeted cancer treatments, an integrative approach can help enhance outcomes and reduce mortality. Also, integrative practitioners can play a significant role in helping cancer survivors overcome issues associated with their diagnosis and treatment. We all need to work together to stop the statistics from climbing.

As with every issue of the Natural Medicine Journal, this one is the culmination of the hard work and thoughtful contributions of our authors, editorial board, and staff, and we are grateful.

In health,

Karolyn A. Gazella Publisher, Natural Medicine Journal

©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12, NO. 101 (SUPPL) 5

ABSTRACT & COMMENTARY

Chemical Hair Treatments May Pose Highest Cancer Risk to Black Women Results from an observational cohort study REFERENCE

Eberle CE, Sandler DP, Taylor KW, White AJ. Hair dye and chemical straightener use and breast cancer risk in a large US population of black and white women. Int J Cancer.

2020;147(2):383-391.

STUDY OBJECTIVE

To examine the association between use of hair dyes and chemical hair treatments and risk of breast cancer and to examine the differences in risk based on race/ethnicity DESIGN

Observational, prospective cohort study PARTICIPANTS

Participants from the Sister Study cohort, which was originally a group of 50,884 women aged 35 to 74 years from the United States who had been recruited between 2003 to 2009 and who had no personal history of breast cancer but had a sister who had been diagnosed with breast cancer. Total cohort used for analysis was 46,709, with the following subgroups: • White, non-Hispanic=39,261 • Black=4,087 • Hispanic=2,041 • Other=1,220 STUDY PARAMETERS ASSESSED

The study assessed whether individuals had been exposed to personal or nonprofessional application of permanent and semipermanent hair dye, as well as chemical relaxer/ straightener treatments, and with what frequency. Participants answered questionnaires regarding their hair product use over the past 12 months

from the time of enrollment. They were asked whether they had used dark colors (black, brown, auburn/ dark red); light colors (blonde, light red); or both. Researchers collapsed data for duration of use into categories of less than 5 years or greater than 5 years, with the latter considered long duration use.

PRIMARY OUTCOME MEASURES

The incidence of breast cancer diagnoses among the participants were reported up until 2016 and measured against their exposure to various hair treatments.

KEY FINDINGS

The majority of participants reported using hair dye at the time of enrollment (55%, or 25,887 participants).

There were 2,794 cases of breast cancer identified over a mean follow-up period of 8.3 years. Use of permanent hair dye was associated with a 45% increase in breast cancer risk in Black women (HR=1.45, 95% CI: 1.10–1.90), and a 7% increase in White women (HR=1.07, 95% CI: 0.99–1.16; heterogeneity P=0.04).

Hair straightener use across the entire cohort was associated with an 18% increased risk, and the frequency of self-use of straightener correlated with increasing risk (P for trend=0.02).

For those administering dyes and straighteners to others (non-professionals), the application of semipermanent dye was associated with a 28% increased risk (HR=1.28, 95% CI: 1.05–1.56), and application of straightener was associated with a 27% increased risk (HR=1.27, 95% CI: 0.99–1.62).

6 ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12 , NO. 101 (SUPPL)

By Maxwell Crispo, ND PRACTICE IMPLICATIONS This study suggests that the use of chemical hair treatments increases cancer risk—specifically breast cancer risk—in women, regardless of ethnicity. With the number of known endocrine disruptors (along with other toxic ingredients) in both salon and at-home hair treatment products,1 environmental medicine advocates have been warning of the carcinogenicity of chemical hair treatments for many years. And while some integrative health practitioners may have been telling their patients to avoid these beauty practices or switch to more natural alternatives, the evidence in support of that claim has not necessarily “matched colors” with a number of previous studies finding no associated cancer risks from conventional hair treatments.2,3 However, the large sample size of this study, combined with the reasonable length of follow-up (7-13 years), allows for better statistical analysis than previously possible with small cohorts and case-control studies.

The results of this study suggest that women increase their risk of breast cancer when they are exposed to permanent hair dye or chemical straightener compared to women who do not use these treatments at all. These results, combined with other case-controlled studies,4,5 provide clinicians reason to counsel patients about the use of these agents and the possible increased breast cancer risk.

The results of this study suggest that women increase their risk of breast cancer when they are exposed to permanent hair dye or chemical straightener compared to women who do not use these treatments at all. (continued on page 8)

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ABSTRACT & COMMENTARY

The study also tried to address whether there was a “dose-­ response” effect with exposure—that is, whether the increased risk is greater among women who use these treatments more often (for example, more than once a month) compared to those who use them less frequently (for example, 1-2 times a year). The answer to this question does not seem to be as clear. From the study results, use of permanent hair dye is associated with an increased risk of breast cancer, but the frequency of use does not seem to impact the risk. However, for chemical straightener use, increased frequency very clearly seems to increase risk. Furthermore, counterintuitively, while personal use of semipermanent hair dye was not associated with any increased risk of breast cancer, the nonprofessional application of semipermanent hair dye was, and that risk increased with more frequent applications. A serious limitation of the study is that it only recorded chemical hair treatment usage at enrollment, but not throughout the follow-up period, so the long-term usage of chemical hair treatments may not have been accurately assessed.

The most significant finding from this study is not that these treatments increase breast cancer risk, but that the increased risk seems to be especially high for Black women. Whenever medical research reports outcomes that differ based on race or ethnicity, it is extremely important to critically evaluate the study design and context of the research. Accordingly, it is important to summarize the following: Of the almost 47,000 participants in this study, 39,261 were White and 4,087 were Black. Not only does this mean that the sample size of White participants was almost 10 times larger than the sample size of Black participants, it also means that, demographically, the total sample population did not accurately reflect the North American population (US census data reports an African-American/Black population of approximately 13%, whereas in this study Black women made up only 8% of the study population). Even with the study adjusting for many different demographic differences, one cannot ignore the fact that there was a much

“

The results of this study suggest that women increase their risk of breast cancer when they are exposed to permanent hair dye or chemical straightener compared to women who do not use these treatments at all.

”

more robust sample size from which to draw conclusions (and eliminate confounding biases) for White women than Black women. This means that in the statistical analysis of the data, there is a higher likelihood for chance to influence results in the Black cohort versus the White, simply due to the smaller sample size of the former. Since this study concluded that the overall sample (N=46,706) showed a statistically significant increase in associated breast cancer incidence with the use of dyes and straighteners, none of this negates the strong evidence of harm from these agents. However, there are clearly differences in the amount of risk for Black women (45% increase) versus White women (7% increase), and it is essential that we bring better awareness to this common issue in research of study cohorts not aligning with the ethnicities found in the overall population.

Among the study participants, White women were more likely to have been exposed to permanent hair dye than not at all (56% versus 44%) compared with Black women. Black women were more likely to never have used permanent hair dye (58%) than to have ever used it (42%). So, based on these results, it means that even though Black women, in general, are more likely to not use permanent hair dye at all compared to White women, they are at a greater increased risk of breast cancer if they do use permanent hair dye compared to White women. Conversely, Black women were much more likely to

8 ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12, NO. 101 (SUPPL)

ABSTRACT & COMMENTARY

have ever used chemical straighteners (72%) versus White women (3%). However, risk of breast cancer was not found to be different between ethnicities when it was related to chemical straightener use (increased risk of 31%). So, while Black women use chemical straighteners significantly more than White women, the increased risk of breast cancer with usage did not appear to differ between races in this study (granted, the straightener usage of 3% in the White cohort may have contributed to this finding).

Lastly, this study also accounted for personal versus the nonprofessional application of these products, which would inherently mean that women who work with these products are at increased risk of breast cancer through occupational exposure. This may imply that women who are hair treatment specialists should undergo increased breast cancer screening measures and/or should prioritize implementing preventative medicine strategies for lowering breast cancer risk.

The authors of this paper acknowledge the obvious social injustice implications of these findings, writing, “The strength of association [with increased breast cancer risk] observed for permanent dye use among black women is consistent with toxicological assessments that report higher concentrations of estrogens and endocrine-disrupting compounds in hair products that are marketed to black women”; and “previous studies on hair dye use and breast cancer risk, showing little or no association, have largely been limited to white women.” Not only are hair treatments specifically marketed toward Black women more toxic and carcinogenic,6,7 but the information and research regarding their potential risk has failed to properly represent the Black population; therefore the data misrepresents the true risk posed to Black women in particular.

Ultimately, this research helps to inform the clinical recommendation of avoidance of permanent hair dye and chemical straightening products when counseling women on the ways they can reduce their personal risk of breast cancer. It is important for this information to be made available and accessible to all women of all ethnicities and racial backgrounds, and as more attention is being brought to the systemic injustices affecting marginalized people in all aspects of life (including healthcare), the medical community must make representation of all ethnic populations in clinical research a priority to begin to create healthcare equity for all.

Black women are at an increased risk of being diagnosed with more advanced breast cancers and having poorer cancer-related outcomes,8 so potentially modifiable or preventative behaviors that can reduce risk deserve attention.

Hopefully more awareness of such data will empower more patients when it comes to making personal choices regarding their health. Of most importance is ensuring that this information is delivered in a socially conscious way and that all clinicians are sensitive to the complex history of discrimination based on hair texture that may affect their patients. For those unaware of the contextual history of the discrimination of natural hair, the NAACP has a free resource that can offer guidance before having these conversations with patients.

REFERENCES

1. Fillon M. Examining the link between hair chemicals and cancer. J Natl Cancer Inst.

2017;109:djx202.

2. Kinlen LJ, Harris R, Garrod A, et al. Use of hair dyes by patients with breast cancer: a case-control study. Br Med J. 1977;2:366-368.

3. Field NA, Metzger BB, Nasca PC, et al. An epidemiologic case-control study of breast cancer and exposure to hair dyes. Ann Epidemiol. 2010;2:577-586.

4. Heikkinen S, Pitkäniemi J, Sarkeala T, et al. Does hair dye use increase the risk of breast cancer? A population-based case-control study of Finnish women. PLoS One. 2015;10:e0135190.

5. Llanos AAM, Rabkin A, Bandera EV, et al. Hair product use and breast cancer risk among African American and White women. Carcinogenesis. 2017;38:883-892.

6. Helm JS, Nishioka M, Brody JG, et al. Measurement of endocrine disrupting and asthma associated chemicals in hair products used by Black women. Environ Res. 2018;165:448-458.

7. James-Todd TM, Chiu Y-H, Zota AR. Racial/ethnic disparities in environmental endocrine disrupting chemicals and women’s reproductive health outcomes: epidemiological examples across the life course. Curr Epidemiol Rep. 2016;3:161180 8. Warner ET, Tamimi RM, Hughes ME, et al. Racial and ethnic differences in breast cancer survival: Mediating effect of tumor characteristics and sociodemographic and treatment factors. J Clin Oncol. 2015;33:2254-2261.

©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12, NO. 101 (SUPPL) 9

ABSTRACT & COMMENTARY

Role of Insulin-Like Growth Factor 1 in HER2-Positive Breast Cancer Patients Results from a retrospective study

Jacob Schor, ND, FABNO

“

REFERENCE

Tong Y, Wu J, Huang O, et al. IGF-1 interacted with obesity in prognosis prediction in HER2-positive breast cancer patients.

Front Oncol. 2020;10:550.

For women with a history of HER2+ breast cancer who are overweight, preference is for below-average IGF-1 levels, but for those who are at a healthy weight, elevated IGF-1 levels might be preferred.

DESIGN

Retrospective study OBJECTIVE

To evaluate the prognostic value (recurrence and mortality) of insulin-like growth factor 1 (IGF-1) and metabolic abnormalities in women with a history of HER2+ breast cancer PARTICIPANTS

Researchers analyzed data from 679 Chinese breast cancer patients, all of whom were positive for human epidermal growth factor receptor 2 (HER2+) and who had been treated at Ruijin Hospital in Shanghai, China, between November 2012 and June 2017. There were 299 women whose tumors were estrogen receptor (ER) positive and 380 who had ER-­­negative tumors. There were 244 women under 50 years of age and 435 women 50 years of age or more. There were 394 postmenopausal participants and 285 peri/premenopausal participants. Nearly all of the women had received prior chemotherapy (n=606). Of the 679 women, 209 had metabolic syndrome (MetS) as defined by the criteria of the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI). Being overweight was defined by body mass index (BMI) ≥ 24.0 kg/m2, which is 1 BMI point lower than is customary in most studies in the United States.

OUTCOME MEASURES

Researchers calculated recurrence-free survival (RFS) from the date of surgery to the first recurrent event or death from any cause. Parameters measured included BMI, fasting glucose, IGF-1, IGF binding protein 3 (IGFBP-3), insulin, C-peptide, triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Researchers divided the participants into 2 cohorts based on high or low IGF-1 levels.

As tumor size, node involvement, histological grade, hormone receptor status, proliferation index, HER2-enrichment intrinsic subtype, and anti-HER2 therapy application are known prognostic factors for HER2+ cancers, the researchers tracked these parameters as well.

KEY FINDINGS

”

The median IGF-1 of the participants was 160.00 ng/mL, and the researchers used this midpoint as the dividing line between low or high IGF-1. High IGF-1 (P<0.001) and high IGFBP-3 (P<0.001) were both more common in pre- and perimenopausal women. After a median of 3 years follow-up, 52 women had disease recurrence. IGF-1 levels were not associated with recurrence-free survival (RFS, P=0.620) overall (N=679).

However, when BMI was taken into account, RFS analysis revealed a clear association between IGF-1 and RFS; BMI and IGF-1 interacted in predicting RFS (P=0.009). For non-overweight patients, high IGF-1 levels were associated with a superior 4-year RFS (91.1% vs 85.0%; HR 0.53, 95% CI 0.27–1.00, P=0.049) compared with non-overweight patients with low IGF-1 levels. In contrast, for overweight patients, high IGF-1 was associated with an impaired 4-years RFS (88.3% vs 95.7%; HR 3.20, 95% CI 1.00–10.21, P=0.038) versus overweight women with low IGF. Overall, the IGF-1/IGFBP-3 ratio was much higher in the recurrent patients compared to those without recurrence (45.14 vs 40.53, P=0.030) regardless of BMI. Overall, recurrent patients also had higher C-peptide levels (2.24 vs 2.04, P=0.045).

Again, the only metabolic variables that differed between those with recurrence and those disease-free were the IGF-1/IGFBP-3 ratio and circulating C-peptide level unless the groups were

10 ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12 , NO. 101 (SUPPL)

ABSTRACT & COMMENTARY

divided by BMI. Blood pressure (P<0.001), IGFBP-3 (P<0.001), insulin (P<0.001), C-peptide (P=0.001), and the number of MetS components (P=0.033) significantly differed

by IGF-1 expression, but not when comparing recurrent and nonrecurrent groups.

The results for overall survival and IGF levels were also stratified by BMI. High IGF-1 was protective in non-overweight patients but appeared to be a risk factor for those who were overweight. High IGF-1 levels were independently associated with better overall survival (OS) in the whole cohort (HR 0.26, 95% CI 0.08–0.82, P=0.044) as well as in the non-overweight population (n=433; HR 0.15, 95% CI 0.03–0.68, P=0.005).

For women with a history of HER2+ breast cancer who are overweight, preference is for below-average IGF-1 levels, but for those who are at a healthy weight, elevated IGF-1 levels might be preferred.

Treatment with “targeted therapy” (trastuzumab [Herceptin]) non-significantly improved OS from 96.7% to 97.7% (P=0.149). Better 4-year OS was observed in the high IGF-1 group compared to the low IGF-1 group (99.2% vs 95.8%, P=0.044). Subgroup analysis showed a modest but insignificant interaction of IGF-1 and BMI in predicting OS (P for interaction=0.054). High IGF-1 levels were associated with improved OS in non-overweight women (4-years OS 99.4% vs 93.7%, P=0.005; HR 0.15, 95% CI 0.03–0.68), but not in overweight women (4-years OS 98.7% vs 98.9%, P=0.438; HR 2.51, 95% CI 0.23–27.63, P for interaction=0.054).

For lean patients with HER2+ disease, high IGF-1 was significantly associated with better OS (P=0.020). For patients who received HER2 targeted therapy (trastuzumab), IGF-1 levels interacted with obesity; in patients with BMI < 24.0 kg/m2 who received adjuvant therapy, those with higher IGF-1 had significantly superior OS than those with lower IGF-1 (P<0.001).

PRACTICE IMPLICATIONS This is the largest study to date that looks at the relationship between IGF-1 and HER2+ breast cancer, and the first to report a significant interaction between IGF-1, BMI, and outcomes.

The reported conclusions stand in contrast to what many of us would have predicted and require our careful attention as these findings may influence the interventions that we suggest to some breast cancer patients who are HER2+.

Our basic understanding of insulin-like growth factor is that it is critical to the growth, development, and maintenance of many tissues in the human body.1 IGF-1 is especially important during neonatal and pubertal growth and acts by stimulating cell proliferation and interrupting programmed cell death.2 IGF-1 is of particular importance in breast tissue development. Binding of IGF-1 to its receptor (IGF-1R) stimulates activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways that cause cell proliferation. There are a half dozen IGF binding proteins that moderate IGF bioavailability and half-life, although in vivo the majority of IGF binds to IGFBP-3.

IGF-1 signaling is involved in 87% of invasive breast cancers.4 For several years we have relied on a hypothesis that cross-talk exists between the IGF-1 pathway, insulin, and the epidermal growth factor receptor family. Given our current understanding and hypothesis, increased IGF signaling should lead to progression of breast cancer and metastatic invasion, and promote resistance to therapies such as chemotherapy and radiotherapy.4,5 Elevated insulin levels bind to certain IGF-1 receptors on breast cancer cells and stimulate proliferation.6 This has been our rationale for encouraging women with a history of breast cancer to reduce excess carbohydrate consumption, as this might lower insulin production. In keeping with this line of thought, an increase in IGF is expected to lead to a decrease in breast cancer survival7 and an increased all-cause mortality in HER2+ patients.8 Or at least this has been our rationale and approach to date.

This study amends this thinking and suggests that a benefit from lowering IGF-1 only occurs in women who are overweight. In healthy weight women, it appears higher levels of IGF-1 are associated with ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12, NO. 101 (SUPPL) 11

ABSTRACT & COMMENTARY

possible benefit against recurrence and that strategies for lowering IGF-1 might be counterproductive, at least in those who had HER2+ tumors.

Fasting and fasting-mimicking diets reliably lower IGF-1 levels, and this effect has been used to explain the benefits of these diets on limiting cancer growth and improving survival. Stefanie de Groot et al reported in Nature Communications earlier this year that in a randomized trial of 131 HER2-negative breast cancer patients who either followed a fasting-mimicking diet or their regular diet for 3 days prior to and during chemotherapy, that a complete or partial response to treatment occurred more often in those following the fasting-mimicking diet, presumably because they had lowered their IGF-1 levels.9 Thus, we are left with seemingly conflicting data. Fasting, which lowers IGF-1, seems helpful for breast cancer patients in general, but lower IGF-1 levels are associated with a worse prognosis in women with HER2+ breast cancer—unless the patients are overweight, with a BMI ≥ 24.0 kg/m2, and then lower IGF levels are a possible advantage. We must remember that this was a retrospective study, and the associations reported should not be interpreted as causative. We should note that this isn’t the first report that differentiates the effect of IGF-1 in women with a history of breast cancer based on BMI. In 2013, Catherine Duggan et al reported that increased IGF-1 levels were associated with an approximately 2-fold greater risk of breast cancer-specific mortality in participants with a BMI > 25 kg/m2, but not in lean women. On the other hand, they also found that high serum levels of IGF-1 and the IGF-1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer.8 Duggan’s study participants were not limited

by HER2 status, and their findings suggest that a similar division by BMI might apply to a broader range of breast cancer patients.

Clearly something else is at play in the high BMI subgroup of women with HER2+ breast cancer and also possibly with

other breast cancer subtypes. The authors have not offered a theory to explain their results.

For HER2+ patients, if this study is to be relied upon, assessment of both IGF-1 levels and BMI become crucial in making our therapeutic suggestions. For women with a history of HER2+ breast cancer who are overweight, preference is for below-average IGF-1 levels, but for those who are at a healthy weight, elevated IGF-1 levels might be preferred.

These findings may influence our general recommendations regarding fasting. We may reconsider the general dietary suggestions we have made aimed at impacting IGF-1 levels.

High animal-protein diets raise IGF-1 levels while low animal-protein diets are associated with decreased IGF-1.

Thus, in HER2+ breast cancer, we may even want to fine-tune diet recommendations based on BMI and IGF-1 levels. For normal-weight women, a diet high in animal protein, associated with elevated IGF, might be advantageous compared to a vegan diet that will lower IGF. For overweight women, the opposite recommendation might be appropriate.

REFERENCES

1 LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer.

Cancer Lett. 2003;195:127-137.

2 Vincent AM, Feldman EL. Control of cell survival by IGF signaling pathways.

Growth Horm IGF Res. 2002;12:193-197.

3 Christopoulos PF, Msaouel P, Koutsilieris M. The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer. 2015;14:43.

4 Denduluri SK, Idowu O, Wang Z, et al. Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis. 2015;2:13-25.

5 Nahta R. Pharmacological strategies to overcome HER2 cross-talk and trastuzumab resistance. Curr Med Chem. 2012;19:1065-1075.

6 Lanzino M, Morelli C, Garofalo C, et al. Interaction between estrogen receptor alpha and insulin/IGF signaling in breast cancer. Curr Cancer Drug Targets.

2008;8(7):597-610.

7 Yerushalmi R, Gelmon KA, Leung S, et al. Insulin-like growth factor receptor (IGF1R) in breast cancer subtypes. Breast Cancer Res Treat. 2012;132:131-142.

8 Duggan C, Wang CY, Neuhouser ML, et al. Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer. Int J Cancer. 2013;132:1191-1200.

9 de Groot S, Lugtenberg RT, Cohen D, et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun. 2020;11(1):3083.

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ABSTRACT & COMMENTARY

Ketogenic Diet and Breast Cancer

Feasibility and effects during adjuvant radiotherapy REFERENCE

Klement RJ, Champ CE, Kämmerer U, et al. Impact of a ketogenic diet intervention during radiotherapy on body composition: III—final results of the KETOCOMP study for breast cancer patients. Breast Cancer Res. 2020;22:94.

DESIGN

A prospective comparison study, nonblinded, at a single outpatient clinic in Germany OBJECTIVE

To assess the feasibility and effects on body composition of a ketogenic diet versus a standard “prudent” diet during adjuvant radiotherapy for breast cancer PARTICIPANTS

All participants were women with nonmetastatic breast cancer (aged 25-78 years) who were scheduled to receive adjunctive radiotherapy (from 16-35 days). Allocation of participants was done consecutively at a single clinic (Leopoldina Hospital Schweinfurt, Germany) in 3 batches: For Batch 1, 5 consecutive participants were placed into the ketogenic diet (KD) group to assess whether compliance was likely; for Batch 2, the standard diet (SD) group was recruited (38 women were asked, 30 enrolled, and 1 dropped out before analysis); and for batch 3, the rest of the KD group was filled (total of 52 women were asked, 19 declined, 32 enrolled, and 3 dropped out). Participants were given the opportunity to self-select KD or SD group if they felt strongly, and this resulted in 1 woman electing to participate in the SD group. Total participants in each group at the study’s end point were KD=29 and SD=30.

Despite nonrandomization, there were no significant differences in baseline characteristics between participants, except the average phase angle per bioimpedance analysis (BIA) was slightly higher in the KD group (4.98 vs 4.65, P=0.05) at baseline.

EXCLUSION CRITERIA

Karnofsky Performance Scale Index <70, body mass index (BMI) <18 kg/m2, metallic implants (due to interference with BIA measurements), pregnancy, inability to understand German, any condition that made the KD a contraindication INTERVENTION

The SD group received no specific dietary recommendations or advice. However, 4 patients in the SD group requested dietary guidance and received standard guidelines of the

Tina Kaczor, ND, FABNO

“

Many patients who believe they are eating a ketogenic diet are not doing so in the strict sense of producing ketones.

”

German Nutrition Society. This included consuming mostly “unrefined foods of plant origin (in particular whole grains, vegetables, and fruits), and limiting fats to 30-35% daily energy intake, with an emphasis on reducing fat from animal origin.”

Participants in the KD group were briefly counseled by their medical oncologist (5 minutes). The day of their baseline metabolic measurements, they also received instructions from a registered dietician experienced in KD implementation. This included handouts with food choices and cooking recipes. KD participants were instructed to replace carbohydrates with fat, specifically consuming 75% to 80% of calories from fat and limiting carbohydrates to 50 grams daily or 10 grams per meal.

There was no caloric restriction. High-quality animal protein and nutrient-dense foods were emphasized along with avoidance of grains, legumes, processed foods, and vegetable oils (except olive and coconut). Dairy was allowed in moderation, with instructions to favor butter, cheese, and fermented dairy products.

Medium-chain triglyceride (MCT) oil was provided for free. Lastly, they were instructed to begin the KD at least 2 days prior to initiating radiotherapy.

Note: Of the 29 participants in the KD group, 15 were given a 10-gram amino acid supplement on the days of radiotherapy (Master Amino Acid Pattern, or MAP), which they consumed right after receiving radiation. (Contrary to what may be expected, this did not modify body composition trends, likely due to adequate high-quality protein in the KD group as a whole.)

PARAMETERS ASSESSED

Baseline measurements, which were taken at the time of radiotherapy planning (about 1 week before radiotherapy) and included weight, BIA, a validated quality-of-life (QOL) questionnaire (EORTC QLC-C30), and a blood draw for baseline measurements of complete blood count CBC, metabolic parameters, liver enzymes, insulin, insulin-like growth factor 1 (IGF-1), and free T3 and T4. BIA and weight measurements were repeated weekly throughout the

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ABSTRACT & COMMENTARY

study. The QOL questionnaire and blood analysis were repeated once during therapy and during the final week of radiotherapy.

In the KD group, compliance measures included: a food diary for 2 days, measures of acetoacetate in urine daily (using ketone strips at home), blood ketones and glucose weekly using finger stick testing after BIA measurement.

OUTCOMES

The primary outcome measures included: 1) dropout rate in the ketogenic diet group, 2) changes in body composition parameters from baseline to final week of radiation: body weight (BW), fat-free mass (FFM), skeletal muscle mass (SMM), extracellular water (ECW), total body water (TBW), and intracellular water (ICW=TBW – ECW), and 3) changes in bioimpedance phase angle (PA) at 50 kHz. KEY OUTCOMES

The implementation of the KD was feasible, with only 3 women dropping out of the KD group (3/32), while 1 woman dropped out of the SD group (1/31).

As expected, the KD group reached ketosis, with mean and median beta hydroxybutyrate (BHB) concentrations of 0.72 and 0.49 mmol/L (range 0.06–4.9). This was significantly higher than the SD group (P<2.2x10-16). In the SD group there was a small increase in total body weight and fat mass and a decrease in fat-free mass, none of which reached statistical significance.

In the KD group, there was a rapid loss of body weight and fat-free and skeletal muscle mass, which was attributed mostly to rapid water loss. After this rapid loss, there was no further loss of fat-free mass or skeletal mass, but there was a slow decrease of 0.4 kg (0.9 lb) of body weight and fat mass per week (P<0.0001). In addition, the KD group had decreased free T3 levels (0.06 pg/mL/week) (P=6.3x10-5).

PRACTICE IMPLICATIONS In integrative oncology there are 2 diets that are sweeping both professional conferences and popular online searches: the ketogenic diet and fasting diets of various forms. The earliest studies on ketogenic diets that showed therapeutic promise were specifically for primary brain tumors, and these were calorically restricted ketogenic diets, making them difficult to maintain long term.1,2 In addition, a study on 16 people with metastatic cancers found that many were unable to reach ketosis, and 14 of the participants progressed while the 2 who achieved stability did not have high ketones in circulation.3 Add to this that while “ketogenic” diets in medicine are well-­established therapeutic diets that reliably induce ketosis, much of what is dubbed “ketogenic” in nonmedical sources fails to adhere to the strict guidelines that a therapeutic ketogenic diet requires. Many patients who believe they are eating a ketogenic diet are not doing so in the strict sense of producing ketones. This is all to say that the term “ketogenic diet” must be looked at closely when considering its effect on the patient, their treatment, and their outcome over time.

Therapeutic ketogenic diets, while promising in conjunction with other treatments, are not a stand-alone means of controlling cancer growth. In the current study under review, a medically prescribed ketogenic diet was studied for its feasibility and metabolic effects. This study was not designed to assess outcomes, although the authors indicate that this will be reported in time. Rather, this study is instructive of the short-term metabolic effects of a non-calorie-restricted KD in a real-world clinical setting.

In this study, all of the participants were receiving radiotherapy 5 out of 7 days per week, and the median duration was 35 days. The women were able to ask questions and get clarifications regarding the KD protocol at will. Daily oversight may improve compliance with any program, but this likely affected the compliance with the KD given its rigorous standards to achieve ketosis. Daily measurement of urinary ketones at home also apprised the women of their status, perhaps prompting them to improve compliance when needed. In addition, participants were under close oversight, including weekly glucose and ketone measurements along with weekly BIA assessment.

All of this resulted in a very low dropout rate, which was 1 of the primary outcome measures of this study.

Klement and colleagues included the use of bioimpedance analysis to track precisely what type of weight is being lost. The KD often leads to rapid ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12, NO. 101 (SUPPL) 15

ABSTRACT & COMMENTARY

weight loss in the first weeks of institution, and that held true in this study. They noted that most of the changes occurred by the second measurement in the KD group. The rapid loss of weight was attributed mostly to water loss, per the BIA data.

The authors contend this is expected due to rapid depletion of glycogen stores, which require water for glycogen storage at a 3:1 ratio (every gram of glycogen holds 3 grams of water in the liver or muscle). Ketogenic diets also lead to lower insulin levels, as was demonstrated in this study. Insulin increases the reabsorption of sodium in the kidneys, and the authors speculate that this diuretic effect may also have led to a more rapid water loss at the start of the KD. The KD not only led to rapid weight loss at the start of the study, but it also led to a more gradual decrease of fat mass with preservation of muscle mass. This is in keeping with prior data that suggested a KD can help preserve muscle mass.4 In comparison, while not statistically significant, the SD group had small gains in total body weight and fat mass (0.04 and 0.08 kg/wk) along with small decreases in fat-free mass/muscle (–0.05 kg/wk). This was highly variable between participants, but prior studies have suggested women undergoing radiotherapy for breast cancer often gain fat, lose muscle, or both.5 The authors predicted that a KD would influence free T3, insulin, and IGF-1 levels. While there was a decrease in insulin and IGF-1 in the KD group versus the SD group, this was a small difference. The authors postulated that if the trends continued over a longer time horizon, there may be a significant difference eventually. Overall, higher BMI was significantly associated with higher insulin levels, and higher age was significantly associated with lower IGF-1 levels. There was a highly significant average drop in free T3 (0.06 pg/mL/ week) in the KD group, which was present whether the analysis was total KD group versus SD group or limited to only those not taking thyroid medication (KD=22 and SD=21 participants). The authors did not speculate on the meaning of this finding.

There are several limitations of this study. It is limited to a single institution with highly trained dieticians and staff

familiar with the KD. There is no standardization of the KD apart from generalized guidelines. The study design was dramatically altered from the original. The original study was a larger study that included several types of cancers, including breast, head and neck, and rectal cancers, and had a prepackaged ketogenic drink and amino-acid supplements versus a whole-food KD with MAP. However, before any breast cancer patients enrolled into that study, over half of the participants undergoing radiotherapy for head and neck or rectal cancers dropped out due to inability to tolerate the maximum target doses of the keto drink and amino-acid supplements. This clearly indicated that a program with large doses of MCT and amino acids was not feasible for those with rectal or head and neck cancers. This study essentially took arm 2 (the whole-food KD ) of the original study, limited recruitment to women with breast cancer only, and created a SD group for comparison.

We eagerly await future results of this study, since there are theoretical reasons for a therapeutic benefit of combining KD and radiation.6 The close oversight and high compliance, along with documentation of ketosis throughout this study for the KD group, should provide some insight into whether the KD affects outcomes of recurrence or breast cancer–related mortality. For now, we know that the KD is feasible and may be useful for those women who have excess adipose, which is considered a risk factor in itself for recurrence of breast cancer.

REFERENCES

1 Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond). 2007;4:5.

2 Schwartz K, Chang HT, Nikolai M, et al. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab. 2015;3:3.

3 Schmidt M, Pfetzer N, Schwab M, Strauss I, Kämmerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr {&} Metab. 2011;8(1):54.

4 Paoli A, Cancellara P, Pompei P, Moro T. Ketogenic diet and skeletal muscle hypertrophy: a frenemy relationship? J Hum Kinet. 2019;68:233-247.

5 Genton L, Kyle UG, Balmer Majno S, Pichard C. Body composition changes in breast cancer patients during curative radiation therapy. e-SPEN. 2006;1(1):2-8.

6 Klement RJ. Fasting, fats, and physics: combining ketogenic and radiation therapy against cancer. Complement Med Res. 2018;25(2):102-113.

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ABSTRACT & COMMENTARY

Mindfulness-Based Interventions: Do They Decrease Anxiety in Cancer Patients?

A systematic review and meta-analysis

Poorvi Shah, DO

REFERENCE

PRIMARY OUTCOME MEASURES

STUDY OBJECTIVE

KEY FINDINGS

Oberoi S, Yang J, Woodgate RL, et al. Association of mindfulness-based interventions with anxiety severity in adults with cancer: a systematic review and meta-analysis.

JAMA Netw Open. 2020;3(8):e2012598.

The aim of this review was to determine whether mindfulness-based interventions (MBIs) improve anxiety in cancer patients.

STUDY DESIGN

The researchers conducted a systematic review and meta-analysis of clinical trials “extracted from MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and SCOPUS from database inception to May 2019.”

All trials were randomized to MBI versus a control group, which could be a sham treatment, no intervention, waitlisted participants, or usual care. Inclusion criteria included adults and children with cancer or who were receiving stem cell treatment for cancer.

Exclusion criteria included “observational, quasi-­randomized, crossover, or cluster-randomized trial designs and trials that did not report any outcomes of interest to this review.” There were no languages excluded from the data extraction. Interventions that included physical movement, such as yoga, qigong, and tai chi, were excluded.

PARTICIPANTS

The 28 studies included in the meta-analysis involved a total of 3,053 individuals. All participants were adults, since none of the trials with subjects aged less than 18 years met review criteria. Participants could be in active treatment or posttreatment, with some receiving MBIs both during and after their treatments.

STUDY PARAMETERS

An initial search found 5,686 citations. After blinded screening and independent review by 2 of this publication’s authors, 27 trials ultimately met the review criteria.

The researchers added another study, which they found by hand, for a total of 28 trials.

The primary outcome measure was the severity of short-term anxiety up to 1 month post MBI. Secondary outcome measures included anxiety, depression, and quality of life in the medium term (1–6 months) and long term (6–12 months) after MBI. The most common MBI used in the trials included mindfulness-based stress reduction (MBSR; 13 trials, 46.4%) and mindfulness-based cognitive therapy (MBCT; 6 trials, 21.4%).

The median duration of MBIs was 8 weeks. There were 12 different anxiety scales used in the trials, with Hospital Anxiety and Depression Scale A (HADS-A; 5 trials) and State-Trait Anxiety Inventory (STAI; 5 trials) being the most common. Breast cancer was by far the most well-represented cancer type in this review.

Twelve trials (42.8%) looked at MBIs and breast cancer exclusively. Eleven recruited participants with various cancer types, and of these, breast cancer was still the most prevalent cancer in 10 of the studies.

MBIs significantly reduced short-term (0–1 month) anxiety (23 trials; 2,339 participants; SMD, −0.51; 95% CI, −0.70 to −0.33; I 2=76%). Reduction in short-term anxiety was evident when HADS-A or the STAI scale was used in independent statistical analysis of each.

MBIs also reduced the severity of medium-term (>1–6 months) anxiety (9 trials; 965 participants; SMD, −0.43; 95% CI, −0.68 to −0.18; I 2=66%).

MBIs were not associated with long-term (>6 months–1 year) reduction in anxiety (2 trials; 403 participants; SMD, −0.02; 95% CI, −0.38 to 0.34; I 2= 68%).

Additional findings demonstrated a reduction in depression in the short term (19 trials; 1,874 participants; SMD, −0.73; 95% CI, −1.00 to −0.46; I 2=86%) and medium term (8 trials; 891 participants; SMD, −0.85; 95% CI, −1.35 to −0.35; I 2= 91%), but not in the long term (2 trials; 349 participants; SMD, −0.96; 95% CI, −2.38 to 0.46; I 2= 97%).

MBIs were also associated with improvement in overall health-related quality-of-life (HRQOL) scores in both the short term (9 trials; 1,108 participants; SMD, 0.51; 95% CI, 0.20 to 0.82; I 2=82%) and medium term (5 trials; 771 participants; SMD, 0.29; 95% CI, 0.06 to 0.52; I 2=57%) The single trial that tracked HRQOL long term did not show any benefit (1 trial; 153 participants; WMD, 0.78; 95% CI, −5.98 to 7.54).

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ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS Mindfulness is a concept dating back thousands of years to ancient Eastern philosophy and is commonly linked to the Buddhist tradition. Jon Kabat-Zinn, PhD, one of the pioneers of the modern mindfulness movement, describes mindfulness as “the awareness that emerges through paying attention on purpose, in the present moment, and nonjudgmentally to the unfolding of experience moment by moment.”1 Kabat-Zinn was one of the first individuals to study mindfulness in the context of health and well-being.

After graduating from the Massachusetts Institute of Technology (MIT), he started a stress-reduction clinic at the University of Massachusetts Medical School. In 1979, he created Mindfulness-Based Stress Reduction (MBSR), an 8-week group course. The program teaches mindfulness as a meditation practice, but also as a way of life.2 He then began researching the role of mindfulness in chronic pain and immunity. Kabat-Zinn studied the MBSR program’s effects in breast and prostate cancer patients, the first research of its kind.

While thousands of studies on mindfulness in cancer patients have been performed, most demonstrate only moderate improvement. For example, when compared to exercise, mindfulness was no more capable of producing the desired result.

DON’T MISS OUT

“

While thousands of studies on mindfulness in cancer patients have been performed, most demonstrate only

moderate improvement. For example, when compared to exercise, mindfulness was no more capable of producing the desired result.

”

Several studies have found mindfulness to benefit cancer patients. A systematic review conducted in 2019 by Ngamkham, Holden, and Smith found mindfulness interventions may decrease cancer-related pain and improve quality of life.3 A 2014 Canadian study confirmed the findings of the Nobel laureate and discoverer of the enzyme telomerase, Elizabeth Blackburn, namely that mindfulness interventions indeed affect telomere length.4 In the Canadian study, breast cancer survivors who participated in a mindfulness-based cancer recovery (MBCR) program or group therapy maintained telomere length, whereas

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ABSTRACT & COMMENTARY

those who did not participate in any program had telomere shortening, a sign of cellular aging.5 The study currently under review is a meta-analysis providing some evidence that MBIs reduce anxiety in cancer patients and is a valuable contribution due to the larger number of subjects (N=3,053), as well as the inclusion of any type cancer. Other reviews have been done. A 2017 meta-analysis of 1,709 breast cancer patients looked at how MBSR/MBCT had significant effects on quality of life, fatigue, sleep, stress, anxiety, and depression.6 Another meta-analysis from 2015 confirmed the effectiveness of MBIs on reducing anxiety and depression.7 Despite the amount of evidence we now have regarding the therapeutic effects of mindfulness, critics of mindfulness still exist. While thousands of studies on mindfulness in cancer patients have been performed, most demonstrate only moderate improvement. For example, when compared to

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exercise, mindfulness was no more capable of producing the desired result.8 The research on mindfulness has been criticized for many reasons. Some include studies having small sample sizes, lack of diversity in patients, and lack of diversity in types of cancers. Many of the study designs also lack randomized controls, as well as long-term follow-up.9 Nevertheless, a great number of oncology centers offer mindfulness, most commonly in the form of MBSR or MBCT. The programs are usually 8 weeks long, with a weekly group session covering different aspects of mindfulness and daily individual exercises to be performed at home. Common techniques include non-judging, patience, kindness, and acceptance.10 Decades of research provide an argument for the use of mindfulness in patients with cancer, but more research is needed for broad adoption of its use. While the academic debate over the efficacy of MBIs goes on, few will disagree that decreasing anxiety and depression and improving quality of life can alter a patient’s life for the better.

REFERENCES

1 Kabat-Zinn J. Mindfulness-based interventions in context: past, present and future.

Clin Psychol Sci Pract. 2003;10(2):144-156.

2 Jannsen M, Heerkins Y, Kuijer W, van der Heijden B, Engels J. Effects of Mindfulness-Based Stress Reduction on employees’ mental health: a systematic review.

PLoS One. 2018;13(1):e0191332.

3 Ngamkham S, Holden JE, Smith EL. A systematic review: mindfulness intervention for cancer-related pain. Asia Pac J Oncol Nurs. 2019;6(2):161-169.

4 Jacobs TL, Epel ES, Lin J, et al. Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology. 2011;36(5):664681.

5 Carlson LE, Beattie TL, Giese-Davis J, et al. Mindfulness-based cancer recovery and supportive-expressive therapy maintain telomere length relative to controls in distressed breast cancer survivors. Cancer. 2015;121(3):476-484.

6 Haller H, Winkler M, Klose P, Dobos G, Kummel S, Cramer H. Mindfulness-based interventions for women with breast cancer: an updated systematic review and meta-analysis. Acta Oncol. 2017;56(12):1665-1676.

7 Zhang MF, Wen YS, Liu WY, Peng LF, Wu XD, Liu QW. Effectiveness of mindfulness-based therapy for reducing anxiety and depression in patients with cancer: a meta-analysis. Medicine (Baltimore). 2015;95(45):e0897.

8 Farias M, Wikholm C. Has the science of mindfulness lost its mind?. BJPsych Bull.

2016;40(6):329-332.

9 Rouleau CR, Garland SN, Carlson LE. The impact of mindfulness-based interventions on symptom burden, positive psychological outcomes, and biomarkers in cancer patients. Cancer Manag Res. 2015;7:121-131.

10 Mehta R, Sharma K, Potters L, Wernicke AG, Parashar B. Evidence for the role of mindfulness in cancer: benefits and techniques. Cureus. 2019;11(5):e4629.

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PEER-REVIEWED ARTICLE

Antiangiogenic Phytochemicals Best Poised for Clinical Trial Testing A literature review of the most promising natural agents for treating cancer ABSTRACT

Angiogenesis is a normal physiological process involving the production and organization of blood vessels, a process required for wound healing and general health maintenance. In the case of cancer, however, the angiogenic process becomes an enabling characteristic that allows tumors to grow and metastasize more effectively. As 1 of the hallmarks of cancer, angiogenesis is also a vulnerable point for malignancy that is susceptible to influence by external modulators. Conventional treatments have the capacity to help hinder cancer growth and spread through antiangiogenic agents; however, they also have associated toxicity that can create side effects that limit their application. A number of natural health products have shown promise in clinical application against cancer through antiangiogenic mechanisms. In this paper we explore a few of these agents that have some of the strongest related research for application. We discuss some of the clinical evidence that currently exists and, importantly, how to enable effective research to further explore this topic.

INTRODUCTION & BACKGROUND Angiogenesis Process

Similar to normal tissue, malignant tumors require a sustained delivery of nutrients and removal of waste to subsist.

Delivery and removal are primarily achieved through tumor neovascularization via a process called angiogenesis, which involves the formation of new blood vessels from existing vasculature. Unlike normal tissue, malignancies circumvent the ordinarily quiescent and well-organized nature of angiogenesis and exploit the process to facilitate unimpeded malignant growth.1,2 The process of cancer-related angiogenesis is heavily influenced by mediators in the tumor environment and is accelerated by localized tissue breakdown. Amongst other angiogenic

Athanasios Psihogios, ND, and Dugald Seely, ND, MSc, FABNO mediators, vascular endothelial growth factor (VEGF) is the primary signal protein implicated in the process of angiogenesis.1,3 As a ligand, it stimulates VEGF receptor 2 (VEGFR-2), which is highly expressed by endothelial cells engaging in angiogenesis.3 Binding results in up-regulation of genes that mediate proliferation and migration of endothelial cells, while promoting survival and permeability of the vasculature.3 Angiogenesis in Modern Cancer Care

In the early 1970s, Dr Judah Folkman theorized that angiogenesis could serve as a potential therapeutic target,4 with the first approved pharmaceutical agents coming out in the early 2000s.3-6 Bevacizumab, a monoclonal antibody that binds circulating VEGF, was the first FDA-approved angiogenesis inhibitor, which when combined with standard chemotherapy, improved survival for patients with metastatic colorectal cancer.7 Similarly, patients with advanced non-small-cell lung cancer (NSCLC) experienced a survival benefit with bevacizumab in combination with standard chemotherapy.8 Overall, pharmaceutical VEGF inhibitors have shown modest benefit when added to standard care and have proven to be a valuable addition to standard care in certain circumstances.3 Based on 33 randomized controlled clinical trials (RCTs) (N= 17,396 NSCLC participants), the addition of approved angiogenesis inhibitors significantly improved progression-free survival (PFS; HR: 0.81, 95% CI 0.76–0.85, P<0.001), overall survival (OS; HR: 0.95, 95% CI 0.92–0.98, P= 0.004), objective response rate (ORR; RR: 1.54, 95% CI 1.37–1.73 P<0.001), and disease control rate (DCR; RR: 1.18, 95% CI 1.10–1.27, P<0.001) compared to non-angiogenesis inhibitor treatments.9 Approved angiogenesis inhibitors have also demonstrated improved survival outcomes for patients with ovarian10 and gastric11 cancers. In contrast, a meta-analysis of 7 RCTs (N=1,322 participants) exploring use of angiogenesis inhibitors in small-cell lung cancer (SCLC) found angiogenesis inhibitors did not significantly improve prognosis,12 indicating the potential for cancer-type specificity related to clinical impact.

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PEER-REVIEWED ARTICLE

The clinical value of pharmaceutical angiogenesis inhibitors is tempered by notable side effects. Possible serious adverse events include hemorrhage, hypertension, neutropenia, thromboembolic events, and impaired wound healing.13 Balancing positive effects on prognosis against patients’ quality of life and side-effect burden is an essential part of the evidence-based medicine model and needs to be factored into clinical decision making.

Natural Health Products & Angiogenesis

Compounds found in nature exist that possess antiangiogenic properties when ingested.14 An effort to both research and develop agents from phytochemical sources to address a hallmark1 of cancer progression—angiogenesis—could yield additional options to accompany conventional cancer care. Scrutiny of available evidence to select promising phytochemicals for further investigation would foster efficient and collective efforts that could support the identification of new therapeutic options for patients with cancer.

This review presents certain phytochemicals with some of the most robust current evidence for clinically meaningful angiogenic-inhibitory effects. We suggest that if natural health products are to be used for this objective (antiangiogenic effects), these agents deserve priority consideration and future investigations through more rigorous clinical research.

ANGIOGENESIS-INHIBITING COMPOUNDS FOUND IN NATURE Notable phytochemicals with evidence for antiangiogenic effects through different pathways include resveratrol, green tea catechins, curcumin, silymarin/silibinin, castanospermine, sanguinarine, brucine, tylophorine, colchicine, vinblastine, ginsenosides, taxol, and triphala churna.14 These compounds have been found to act on different angiogenesis targets and are classified into 3 major families: polyphenols, alkaloids, and terpenoids/tannins.14 Of these, certain compounds have more extensive research, making them better poised for immediate clinical investigation and judicious clinical consideration on a case-by-case basis. For each

“

Unlike normal tissue, malignancies circumvent the ordinarily quiescent and well-organized nature of angiogenesis and exploit the process to facilitate unimpeded malignant growth.

”

of the compounds below, the curated preclinical evidence, bioavailability, and clinical trial data provide a comprehensive review of each phytochemical, which may also be utilized for future investigation.

Green Tea

Produced from the common tea plant (Camellia sinensis), green tea has been extensively studied for its effects on health and human physiology, which are thought to be largely due to its catechin content, specifically (-)-epigallocatechin-3-gallate (EGCG). Epidemiological studies have found that green tea consumption is associated with a reduced risk of prostate cancer,15 liver cancer,16 breast cancer,17 and cardiovascular disease.18 At the cellular level, EGCG has been observed to inhibit VEGF expression and activity in certain cancer cell lines including gastric cancer,19 head and neck squamous cell carcinoma, and breast20 cancer, among others.

Preclinical Evidence of Antiangiogenic Activity

Green tea catechins have been extensively researched in preclinical models to identify and understand their antiangiogenic properties. A green tea extract product containing 65% EGCG inhibited invasion of MDA-MB231 breast cancer cells by up to 40% compared to controls in a concentration-dependent manner, and inhibited neovascularization in vivo in C57BL/6

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mice.21 Intraperitoneal injection of EGCG inhibited gastric cancer growth in nude mice by 60.4%, with reduced tumor micro-vessel density, VEGF-induced endothelial cell proliferation, tube formation, and migration.22 EGCG treatment of human cervical carcinoma and hepatoma cells inhibited hypoxia and serum-induced hypoxia-inducible factor (HIF) 1-alpha accumulation, resulting in significant VEGF-expression reduction.23 Treatment with EGCG dose-dependently inhibited VEGF expression and platelet-derived growth factor in human vascular smooth muscle cells.24 Bioavailability

While in vitro studies show antiangiogenic activity, achievable EGCG serum concentrations in humans are hindered by poor bioavailability, likely explaining inconsistencies in epidemiological research.25 Following oral administration in humans and animals, peak catechin plasma levels are often in the sub- or very low micromolar range, falling short of the effective concentration range of 1 to 100 μmol/L.25 Human oral bioavailability studies have yielded plasma levels that are 5 to 50 times less than those in preclinical models.26 Rat studies have shown that <5% of orally administered tea catechins present in systemic circulation, and in humans about 0.16% present in plasma.25 A small portion of ingested tea catechins undergo extensive phase II enzyme metabolism in the small intestine (primarily absorbed through passive diffusion), with the remainder passing to the colon where microorganism degradation likely occurs.25 Several approaches have been tested to increase the systemic absorption of oral EGCG. One randomized, controlled crossover trial26 assessed the effect of fasting states with differing catechin dosing in healthy volunteers. A 3.5-fold increase was observed for the average maximum plasma concentration (free EGCG) during a fasting state compared to a fed state, but no significant differences for total plasma levels.26 Other areas of active research to improve bioavailability include the formation of nanostructure carriers, molecular modification, and coadministration with bioactive components.25

Clinical Research of Antiangiogenic Effects

An open-label, single-arm phase 1 clinical trial of 26 males with prostate cancer awaiting radical prostatectomy found that 800 mg of EGCG for 6 weeks resulted in a significant reduction in plasma serum levels of VEGF compared to baseline (P<0.03), with 6 out of 25 participants experiencing ≥25% reduction.27 A double-blind, placebo-controlled, multicentered study of 33 participants with bladder cancer, split into 3 arms (800 mg EGCG, 1,200 mg EGCG, or placebo), found no significant differences between groups for VEGF tissue levels.28 A randomized, placebo-controlled, double-blind “split-face” dermatological study of 4 volunteers with significant facial erythema and telangiectasia found that an EGCG cream (2.5% weight for weight) significantly reduced VEGF levels in biopsy samples compared to control (P<0.005).29 Curcumin

Isolated from the common spice turmeric (Curcuma longa), curcumin is estimated to have been used in traditional medicine for thousands of years.30 Contemporary research has shown that curcumin is tolerated in high doses (up to 12 grams), and exerts antioxidant and anti-inflammatory effects.30 Further research has yielded evidence of VEGF-pathway alteration in models of breast cancer,31 human intestinal microvascular endothelial cells,32 and hepatocellular carcinoma.33 While traditionally turmeric as a whole has been implemented therapeutically, recent investigations have focused primarily on curcumin itself at levels beyond what would be typically consumed, in hopes of achieving drug-like actions.

Preclinical Evidence of Antiangiogenic Activity

A gastric cancer cell line study (AGS and SGC-7901 cell lines) showed that curcumin exerts antilymphangiogenic activity via inhibition of HMGB1/VEGF-D signalling.34 In a hepatocellular cancer model, curcumin significantly induced H22 cell apoptosis at the 40 µM and 80 µM concentrations compared to untreated controls (P<0.05 and P<0.01,

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respectively),35 and in mice treated with 50 mg/kg curcumin, it significantly reduced H22 tumor growth (P<0.05).35 The mechanism of observed effects in both the cell line and mouse model was the significant inhibition of VEGF expression and PI3K/AKT signalling.35 A colorectal cancer model study found that in vitro, curcumin inhibited CT26 cell proliferation and migration and exerted apoptotic activity, while inhibiting tumor growth in vivo through VEGF signalling modulation.36 Nude mice injected with A549 lung cancer cells and given 100 mg/kg curcumin intraperitoneally experienced reduced tumor weight and size, with suppression of VEGF expression.37 Bioavailability

Pure curcumin absorbs poorly in humans, resulting in low achievable serum concentrations.38 Pharmacokinetic studies have shown that curcumin undergoes both extensive phase I and II liver metabolism, and is further metabolized by microbiota.38 In 25 participants with high-risk/premalignant lesions, oral daily doses of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/ day curcumin were found to cause serum curcumin peaks at 1 to 2 hours, with the average concentrations ranging from 0.51 +/- 0.11 µM to 1.77 +/- 1.8 µM (dose-dependently).38,39 These concentrations are notably lower than the controlled environments created in experimental preclinical models. A turmeric extract dose of 0.4 to 2.2 g (containing 36-180 mg of curcumin) given to 15 patients with chemotherapy-refractory colorectal cancer yielded metabolites that were undetectable in both blood and urine.38,40 These studies, among others, present a notable bioavailability issue with unaltered oral curcumin, resulting in novel approaches to circumvent this problem.

Unlike normal tissue, malignancies circumvent the ordinarily quiescent and well-organized nature of angiogenesis and exploit the process to facilitate unimpeded malignant growth.

The problem of absorption has been addressed extensively, with patented formulations being produced. The contrast of 2 similar controlled studies describes the progress of altered forms of curcumin influencing bioavailability and achievable serum concentrations.41,42 A 2008 study that used 8 grams (8,000 mg) of curcumin orally (simple plant extract with no composition alteration) in patients with pancreatic cancer reported low peak levels of 22 to 41 ng/mL, which remained relatively constant over 4 weeks.41 A 2013 study assessed a novel curcumin formulation (Theracurmin®) in a similar population in order to investigate bioavailability changes.42 This formulation is composed of microscopic particles contained in a colloidal agent. In 10 participants with either pancreatic or biliary tract cancer resistant to chemotherapy, an escalating dose of 200 to 400 mg of Theracurmin resulted in a median peak plasma level of 342 ng/mL (range 47-1,029 ng/mL) at the 200-mg dose, and 440 ng/mL (range 179-1,380 ng/mL) at the 400-mg dose.42 Authors report that no unexpected adverse events occurred, and it was safely continued in 3 surviving patients for over 9 months.42 In addition to Theracurmin, other patented formulations such as Meriva®43 and BCM-95®,44 along with additive approaches such as piperine45 products combined with curcumin, are an active field of study pertaining to optimizing absorption.

Clinical Research of Antiangiogenic Effects

One randomized, controlled, double-blind, crossover study involving 30 obese participants found that 1 gram of a curcumin-complex product for 4 weeks significantly reduced VEGF (P=0.01) compared to control.46 Resveratrol

A unique type of polyphenol called a stilbene, resveratrol is primarily found in the skins of berries and grapes. At therapeutic doses, it exerts antiangiogenic effects in experimental tumor models.14 In comparison to other natural health products, resveratrol has had extensive human clinical investigation via supplementation trials for a number of non-cancer-related

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conditions, including dyslipidemia,47 metabolic syndrome,48 and hypertension,49 with overall mixed results. Preclinical angiogenesis resveratrol studies primarily focused on ovarian cancer models.

Preclinical Evidence of Antiangiogenic Activity

A 3D ovarian cancer cell aggregate model (ie, an organoid) treated with increasing doses (10, 20, or 30 μM) of resveratrol or a derivative (acetyl-resveratrol) reduced cell growth and suppressed VEGF secretion.50 An earlier, similar ovarian organoid model study found that resveratrol or acetyl-resveratrol suppressed VEGF secretion in a dose-dependent fashion.51 A lung cancer model (A549 cells) found that treatment with resveratrol reduced both interleukin (IL-6) and VEGF secretion.52 Hepatocarcinoma cells (HepG2) treated with escalating concentrations of resveratrol (ranging from 0-40 μM) experienced inhibition of VEGF gene expression, resulting in inhibited proliferation.53 Bioavailability

While resveratrol has low water solubility and absorbs primarily via passive diffusion, hindering absorption, its capacity to form a wide range of complexes increases intestinal permeability.54 While it is fairly well established that distribution of resveratrol in tissues is very low and overall it has low bioavailability, resveratrol appears to show efficacy in vivo; this is thought to be due to metabolic conversion and recirculation of metabolites that may have biological activity.54 Multiple approaches are being investigated to improve the bioavailability of resveratrol, including lipid nanocarriers, liposomes, nanoemulsions, micelle solutions, polymeric nanoparticles, solid dispersions, and nanocrystals.55 It should be noted that while resveratrol absorption is a concern for clinical efficacy, there is risk of toxicity with higher dosing, indicating a possibly narrow therapeutic window.56 The dosing approach is not linear, in the sense that higher doses don’t necessarily equate to more favorable outcomes, and future investigations should not only focus

on increasing absorption but also, more importantly, regulating the dosing to offset toxicity.

Clinical Research of Antiangiogenic Effects

A triple-blind, placebo-controlled, randomized study of 61 polycystic ovary syndrome participants receiving 800 mg/ day resveratrol for 40 days reported significant reduction in VEGF expression in recovered granulosa cells (P<0.0001).57 A randomized, double-blind placebo-controlled study of 72 participants undergoing peritoneal dialysis found that those receiving high-dose trans-resveratrol (450 mg/day) had significantly lower rates of VEGF in retrieved effluent compared to the low-dose and placebo groups.58 Ginsenosides

Triterpene saponins concentrated in the roots of red ginseng (Panax ginseng), ginsenosides have been found to exert antiangiogenic effects.14 Ginsenosides are classified using an “Rx” system, with the “R” representing the root and the “x” describing the chromatographic polarity (alphabetical order).59 Over 30 ginsenosides have been identified, with researchers adopting standardized products via specific extraction processes to improve consistency.59 A vast amount of research exists for ginsenosides’ antiangiogenic activity in multiple cancer models and using many different forms, of which Rg3 is the most rigorously studied.

Preclinical Evidence of Antiangiogenic Activity

In a dual in vitro and in vivo study, Rg3 inhibited migration and invasion in 4 thyroid cancer cell models and suppressed pulmonary metastasis in nude mice, with inhibition of VEGF expression observed.60 In a gastric cancer cell model study, where hypoxia was induced to stimulate vascular growth factors, levels of VEGF were significantly lower in the Rg3-treated group (P<0.05).61 Under induced hypoxic conditions, an esophageal cancer cell model study found that Rg3 significantly inhibited proliferation and reduced VEGF messenger RNA (mRNA).62 In an endometriosis model utilizing allotransplantation in rats, Rg3 was found to

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inhibit growth of ectopic endometrium in a dose-dependent fashion via downregulation of VEGF, p-Akt, and p-mTOR pathways.63 Bioavailability

Ginsenoside absorption across intestinal mucosa has not been clearly described; however, it appears to cross via energy-dependent transport and appears nonsaturable.59 One in vivo study using A/J mouse intestinal models determined that certain bacterial families are involved in the conversion of ginsenosides into active secondary metabolites.64 A comparative mouse study (Walker 256 tumor-bearing mice vs normal mice) using 50 mg/kg of oral Rg3 discovered that Rh2 ginsenosides were found in plasma, likely due to glycosylation hydrolysis.65 One diabetes clinical trial using ginsenoside Re found that oral administration resulted in no detectable plasma amounts at the 30-minute and 6-hour point.66 The absorption, biotransformation, and overall bioavailability of ginsenosides appear complex and variable between different forms, requiring further exploration.

Clinical Research of Antiangiogenic Effects

A randomized, placebo-controlled study of Rg3 supplementation in 20 patients with acute leukemia for 2 months in conjunction with chemotherapy significantly reduced serum VEGF levels.67 A randomized controlled trial of 71 postoperative participants with advanced gastric cancer found that those who received Rg3 + mitomycin C/tegafur, compared to chemotherapy alone, after 14 weeks experienced VEGF levels within normal range, with the median survival being 40 and 25 months, respectively (P=0.047).68 A 3-armed, randomized, controlled study (Rg3 vs Rg3 + chemotherapy vs chemotherapy alone) of postoperative patients with NSCLC found no significant survival differences over 3 years between groups (P>0.05), with VEGF levels not associated with outcomes.69 A study of 60 patients with advanced esophageal cancer receiving either Rg3 + gemcitabine/cisplatin or chemotherapy found that

the intervention group had significantly lower posttreatment VEGF levels (P=0.002).70 CLINICAL IMPLICATIONS & CLOSING REMARKS Green tea catechins (especially EGCG), curcumin, resveratrol, and ginsenosides are phytochemicals that currently hold extensive foundational antiangiogenesis research. These 4 compounds possess preclinical, bioavailability, and preliminary clinical research, poising them for rigorous clinical investigation, compared to other phytochemicals that still require further preliminary investigation prior to being considered candidates for extensive clinical investigation. The next step would be to select 1 or a combination of phytochemicals and perform a formal systematic search to identify all relevant research, including on safety, clinical data, and pharmacokinetics/dynamics. In addition, an accompanying review of the literature should be performed in order to determine the most accurate and feasible ways to assess the effects of an intervention on angiogenesis in homine.

It is notable that while the identified compounds possess an ample amount of preclinical evidence to indicate antiangiogenic effects, data of this sort cannot be relied on alone to predict effects in patients, especially in highly vulnerable patient populations, such as those with cancer. The shortcomings of preclinical data translating to human effects are twofold, with consistent evidence showing that often: 1) preclinical data are a poor predictor of effect (often no significant benefit/effect is found);71 and 2) human subjects often experience unanticipated harms even when the intervention appears safe in preclinical models, as they are also poor predictors of toxicity.72,73 Collectively, while reviewed information provides a strong rationale for subsequent clinical trial investigation, caution is warranted for extrapolating data further directly to clinical care.

Based on available evidence, a future well-designed clinical trial, with the objective of addressing malignant angiogenesis

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in cancer patients via phytochemical supplementation, would do best by using an agent with human-level and preclinical data showing VEGF effects, and by choosing a highly bioavailable form of that agent. By fast-tracking a select few phytochemicals that already have essential pieces of evidence into a rigorous clinical trial, rather than investigating a number of agents lacking foundational research, we can execute more efficient trials and hopefully identify meaningful associations.

18 Zhang C, Qin YY, Wei X, Yu FF, Zhou YH, He J. Tea consumption and risk of cardiovascular outcomes and total mortality: a systematic review and meta-analysis of prospective observational studies. Eur J Epidemiol. 2015;30(2):103-113.

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