__MAIN_TEXT__

Page 1

OCTOBER 2018 SUPPLEMENT

SPECIAL ISSUE

Oncology

Sexuality After Diagnosis

Probiotics in Cancer Care

Does Complementary Medicine Really Hinder Cancer Survival?

The Effects of Fish Oil on Inflammation and Survival

Green Tea Extract in the Prevention of Breast Cancer

Mistletoe Extract in Patients with Advanced Cancer


Simply The Best

Online Dispensary for You and Your Patients Meet Wellevate, the industry’s fastest growing and highly trusted online dispensary.

Reliable

Unmatched Brand Selection

Activate your account now at wellevate.me or call 855-WELLEVATE

Free


Copyright © 2018 by the Natural Medicine Journal. All rights reserved.

SPECIAL ISSUE

ONCOLOGY OCTOBER 2018 VOL. 10, NO. 101 (SUPPL)

Contents

ABSTRACTS & COMMENTARY

  6 Green Tea (Camellia sinensis) and Breast Density in At-Risk Postmenopausal Women 10

A Role for Protein Intake Before Allogeneic Stem Cell Transplantation

14

Fish Oil Supplementation in Adults With Hematological Malignancies

18

Intravenous Application of Mistletoe Extract

21

Does Complementary Medicine Increase Risk of Death for Cancer Patients?

PEER-REVIEWED ARTICLE

24

Let’s Talk About Sex: Sexuality During and After Cancer Treatment

SPONSORED PODCAST

39

Probiotics and Cancer Prevention: A Conversation with Ross Pelton, RRh, CCN

Sponsored by Essential Formulas Inc.

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

SUBSCRIBE FOR FREE!

http://www.naturalmedicinejournal.com/blog Natural Medicine Journal Blog


Contributors JUDITH BOICE, ND, LAC, FABNO, is a naturopathic physician, acupuncturist, best-selling and award-winning author, and international teacher. Her mission is to treat the whole person, not just the symptoms. Boice consults with private Judith Boice, ND, LAc, FABNO patients, writes books, and offers trainings that teach people with chronic illness how to increase their energy, reduce symptoms, and reverse disease by restoring their health with natural medicines. ZACH KADRO, ND, is naturopathic doctor at the Goshen Center for Cancer Care, where he is a secondyear resident specializing in naturopathic integrative oncology. Kadro obtained a bachelor of general studies degree from the UniverZach Kadro, ND sity of Michigan (Ann Arbor) prior to completing his doctor of naturopathic medicine degree at Bastyr University. In addition to seeing patients at the cancer center, Kadro is also involved in developing a comparative effectiveness research project examining the effect of naturopathic care in conjunction with standard of care on the incidence and severity of chemotherapy-induced peripheral neuropathy compared with standard of care alone. MIRANDA LABANT, ND, graduated from National University of Health Sciences in Illinois. She completed a 1-year Council on Naturopathic Medical Education– accredited residency in integrative oncology under the direction of Miranda LaBant, Michael Traub, ND. LaBant earned ND her master of health sciences degree from Cleveland State University. She is an active member of the Oncology Association of Naturopathic Physicians and New Hampshire Association of Naturopathic Doctors. LaBant is currently practicing at North Coast Family Health in Portsmouth, NH, where she focuses on integrative oncology, Lyme disease, endocrine health, gastrointestinal health, and preventative care.

ELLEN MCDONELL, ND, is a clinician scientist at the Ottawa Integrative Cancer Centre. McDonell earned a bachelor of science in biochemistry from the University of Ottawa before completing her doctor of naturopathic medicine degree at the Canadian College of Naturopathic Medicine. Elen McDonell, ND After graduation, McDonell completed a research residency in integrative oncology at the Ottawa Integrative Cancer Centre. In addition to maintaining a clinical practice with a focus in adjunctive cancer care, McDonell is involved in several research projects, including the Canadian US Integrative Oncology Study and the Thoracic Peri-Operative Integrative Surgical Care Evaluation (POISE). JACOB SCHOR, ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology Association Jacob Schor, of Naturopathic Physicians. He is recogND, FABNO nized 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. MARIE WINTERS, ND, FABNO, is a 2006 graduate of Bastyr University. She was the first naturopathic doctor to establish a free-standing practice in Philadelphia. In addition to serving patients in her private practice, Winters is committed to the growth and development of the field Marie Winters, of naturopathic medicine. She serves as ND, FABNO adjunct faculty at Bridgeport University College of Naturopathic Medicine, where she supervises integrative oncology shifts in their teaching clinic, and as president of the Pennsylvania Association of Naturopathic Physicians. She was instrumental in the successful legislative effort to regulate naturopathic medicine in Pennsylvania.

4 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


Copyright © 2017 by the Natural Medicine Journal. All rights reserved.

EDITOR IN CHIEF Tina Kaczor, ND, FABNO

MESSAGE FROM THE PUBLISHER

ABSTRACTS & ­COMMENTARY EDITOR Jacob Schor, ND, FABNO

Addressing the Special Needs of People Diagnosed with Cancer

PUBLISHER Karolyn A. Gazella ASSOCIATE PUBLISHER Kathi Magee VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell DESIGN Karen Sperry PUBLISHED BY IMPACT Health Media, Inc. 1610 Pace St. Unit 900 #305 Longmont, CO 80504 Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc. Copyright © 2018 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.

As a cancer survivor, the topic of oncology is near and dear to me. The fact is, it’s near and dear for many people. The American Cancer Society estimates that 1 in 2 men and 1 in 3 women will be diagnosed with cancer in their lifetime. That staggering statistic makes it highly likely that you are seeing patients who have had a diagnosis or may be presently battling cancer in your practice. Whether your focus is on general practice, women’s health, internal medicine, or any other discipline, it’s important to understand oncology. And we want to help. Every year we publish an oncology special issue to help you stay abreast of what’s happening with integrative oncology. In this issue, our peer-review paper by Judith Boice, ND, LAc, FABNO, addresses a very important topic that affects many cancer survivors: sexuality during and after cancer treatment. We also have several Abstracts & Commentary highlighting new research on varied topics, including IV mistletoe, fish oil, and green tea. Our very own Jacob Schor, ND, FABNO, tackles the headline-grabbing recent paper regarding refusal of conventional cancer therapy among patients diagnosed with curable cancers. In addition, I have the pleasure of interviewing integrative pharmacist and nutritionist Ross Pelton, RPh, CCN, about probiotics and cancer. Cancer care in integrative medicine is an important topic. We hope you find the quality content from our talented group of writers and editors helpful. And we hope you share this with your colleagues who are seeing cancer survivors in their practice. Let’s work together to change the course of cancer in this country! In health,

Karolyn A. Gazella Publisher, Natural Medicine Journal

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  5


ABSTRACT & COMMENTARY

Green Tea (Camellia sinensis) and Breast Density in At-Risk Postmenopausal Women An ounce of prevention? REFERENCE

Samavat H, Ursin G, Emory TH, et al. A randomized controlled trial of green tea extract supplementation and mammographic density in postmenopausal women at increased risk of breast cancer. Cancer Prev Res (Phila). 2017;10(12):710-718. OBJECTIVE

To determine the effect of 12 months of daily green tea extract (GTE) consumption on mammographic density (MD) DESIGN

Phase II, randomized, double-blind, placebo-controlled trial PARTICIPANTS

Healthy postmenopausal women (N=1,075) between the ages of 50 and 70 at high risk of breast cancer due to having “heterogeneously dense” or “extremely dense” breast tissues (>50% fibroglandular tissue) as defined by the American College of Radiology’s Breast Imaging Reporting and Data System (BI-RADS) density assessment criteria. The women were randomized to receive either the GTE intervention (n=538) or placebo (n=537). Of those allocated to receive the GTE intervention, 463 completed the trial following Intention to Treat (ITT) guidelines. Ultimately 462 participants in the GTE group were analyzed (1 was excluded from analysis because no mammogram was available at month 12). Of the 537 participants allocated to receive the placebo intervention, 474 completed the trial following ITT guidelines and 470 were analyzed (4 were excluded from analysis because no mammogram was available at month 12). Study participants’ (n=932) baseline characteristics were equally distributed between the GTE and placebo groups. Mean (SD) baseline age was 59.8 (±5.0) years. Mean (SD) BMI was 25.1 (±3.7). The majority of participants had some level of college education, were never-smokers, and were parous; the vast majority (97%) were non-Hispanic white women. Baseline energy, food, and nutrient levels were similar between treatment groups, although a higher intake of vitamin supplements was found among GTE participants compared to the placebo participants (P=0.038). INTERVENTION

Green tea extract (decaffeinated) in capsule form, with each capsule containing 328.8 mg total catechins, 210.7 mg epigallocatechin-3-gallate (EGCG), and less than 4 mg caffeine; participants consumed 4 capsules a day, for a total of approximately 1,315 mg total catechins, 843 mg EGCG, and less than 16 mg total caffeine (equivalent to 5 brewed 8-ounce cups of decaffeinated green tea) per day, for 12 months.

Zach Kadro, ND STUDY PARAMETERS ASSESSED

Each participant had a mammogram at baseline (month 0) and month 12, to assess MD pre- and postintervention. Comprehensive health history questionnaires, which included questions about lifestyle, demographics, medication and supplement use, and medical and reproductive history, were completed at baseline. Dietary history questionnaires were completed at baseline and end of intervention. Hepatic function and potential adverse events were closely monitored throughout the intervention. During the pre-intervention screening visit, COMT genotyping was conducted, along with nonfasting blood tests, vital signs, and anthropometric measurements. Other breast cancer biomarkers, including plasma insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), estrone, estradiol, androstenedione, sex hormone–binding globulin (SHBG), urinary estrogen metabolites, and plasma F2-isoprostanes were also assessed. Mammographic density is calculated by dividing the dense area of the breast, called the absolute density, by the total breast area. It is reported as a percentage and may be referred to as percent MD (PMD). PRIMARY OUTCOME MEASURES

Change in PMD from baseline at the end of the 12-month ­intervention. This study was part of a larger study that, in addition to MD, also assessed as primary outcomes circulating concentrations of IGF-1, IGFBP-3, reproductive hormones (estrone, estradiol, androstenedione) and SHBG; and the effects of COMT genotype on GTE effects.1 KEY FINDINGS

Overall, 12 months of daily GTE consumption did not significantly reduce PMD or absolute mammographic density compared to placebo after adjustment for age (at baseline) and BMI (at baseline and at month 12). However, for women aged 50 to 55 at enrollment, 12 months of daily GTE supplementation significantly reduced PMD, resulting in a 4.40% decrease in PMD compared to those receiving placebo, who experienced a 1.02% increase in MD (P for difference=0.05). A statistically borderline significant result (P interaction=0.07) was observed in the interaction between age and GTE supplementation on PMD change. Other factors, including BMI, years since menopause, alcohol, parity, and tea-drinking status showed no modifying effect on PMD with GTE intake. Those in the placebo group experienced a significant reduction in vitamin C intake compared to the GTE group (P=0.045), but weight, BMI, and energy/diet intake remained stable in both groups over the course of the 12-month trial.

6 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)

(continued on page 8)


ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS In 2018 an estimated 266,120 new cases of breast cancer will be diagnosed in the United States, making it the most commonly diagnosed cancer across genders and accounting for 15.3% of all new cancer cases.2 While almost 90% of those diagnosed with breast cancer are still alive 5 years after diagnosis, an estimated 40,920 people in the United States will die of the disease in 2018. It is estimated that 12.4% of US women will be diagnosed with breast cancer at some time in their lives, based on 2013-2015 data.2 Mammographic density reflects the relative proportion of fibroglandular tissue to fat tissue in the breast and serves as an established predictor of breast cancer risk.3,4 Boyd, et al reported that a 2% higher risk of breast cancer is associated with every 1% increase in MD.3 In one interventional study, postmenopausal hormone use was shown to increase MD by 4.7% after 12 months of use, which could potentially translate to a 9.4% increase in breast cancer risk.5 In contrast, the 4.4% decrease in MD in women aged 50 to 55 who consumed GTE for 1 year, observed in the present study, could potentially translate to an 8.8% reduction in breast cancer risk. Interestingly, Cuzick et al reported tamoxifen (an estrogen receptor antagonist in breast tissue and first-line antiestrogen drug) demonstrated a similar effect, reducing breast density by 4.4% over 18 months compared to placebo (P<0.001).6 In the same study, Cuzick et al reported that after 54 months of treatment, tamoxifen reduced MD by 13.4% (95% confidence interval [CI]: 8.6-18.1) in women age 45 or younger; those older than 55 had only a 1.1% decrease in MD with the same intervention and time frame. Whether or not GTE supplementation in women 45 years or younger for 54 months would result in similar reductions in MD compared to tamoxifen has yet to be studied, but it is certainly of interest. Similarly, would GTE supplementation beyond 1 year in women age 55 or younger result in additional reductions in MD? We do not

know yet, but the intriguing findings of the GTE study warrant additional investigations into these questions. A 2007 study published in the New England Journal of Medicine found that women with greater than 75% MD had an increased risk of breast cancer compared to women with less than 10% MD (odds ratio [OR]: 4.7; 95% CI: 3.0-7.4), and the risk was particularly greater for women younger than 56 years.4 In this group, 26% of all breast cancer cases and 50% of cancers detected within 12 months of a negative screening were attributable to an MD of 50% or more. Given the value of PMD in predicting a woman’s risk of developing breast cancer, healthcare providers should consider interventions to reduce breast density when they are developing strategies to reduce breast cancer risk. The study examined in this review has particular relevance for women ages 50 to 55 who are at increased risk of breast cancer due to increased breast density. Green tea has a good safety profile, a long historical use, a growing number of favorable clinical studies, and is generally well-tolerated; it may well continue to emerge as a promising adjunct in breast cancer prevention. It would be great to see if additional studies could replicate the findings of this study. It would also be helpful to have a more ethnically and racially diverse population in future studies so results can be more generalizable to, and reflective of, our diverse population. REFERENCES

1 National Institutes of Health, US National Library of Medicine. Green tea and reduction of breast cancer risk. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00917735. Updated February 22, 2016. Accessed September 13, 2018. 2 National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: female breast cancer. https://seer.cancer.gov/statfacts/html/breast.html. Last modified July 24, 2018. Accessed September 13, 2018. 3 Boyd NF, Lockwood GA, Martin LJ, et al. Mammographic densities and breast cancer risk. Breast Dis. 1998;10:113-126. 4 Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356:227-236. 5 Greendale GA, Reboussin BA, Slone S, Wasilauskas C, Pike MC, Ursin G. Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst. 2003;95:30-37. 6 Cuzick J, Warwick J, Pinney E, Warren RM, Duffy WW. Tamoxifen and breast density in women at increased risk of breast cancer. J Natl Cancer Inst. 2004;96;621-628.

8 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


Want Brains and Brawn? Contact the Experts

Balchem’s got you covered VitaCholine®

Albion®—Magnesium chelate

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

• Supports brain health

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

Changing the Way you see Nutrition


ABSTRACT & COMMENTARY

A Role for Protein Intake Before Allogeneic Stem Cell Transplantation A randomized controlled trial REFERENCE

Ren G, Zhang J, Li M, et al. Protein blend ingestion before allogeneic stem cell transplantation improves protein-­ energy malnutrition in patients with leukemia. Nutr Res. 2017;46:68-77. STUDY OBJECTIVE

To determine whether the addition of supplemental whey and soy protein could mitigate muscle wasting and loss of muscle strength typically seen following allogeneic stem cell transplantation for acute lymphoblastic and acute myelogenous leukemia STUDY DESIGN

Double-blind, randomized, controlled clinical trial PARTICIPANTS

Participants were recruited from the Bone Marrow Transplantation Center at Hebei Yanda Lu Daopei Hospital in Hebei, China. Participants included both males and females and ranged in age from 9 to 50; all were diagnosed with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). All participants underwent an allogeneic stem cell transplant during the study period utilizing the same protocol: busulfan, total body irradiation, and cyclophosphamide. Eighty patients were enrolled; 77 had complete information. Of these, 27 were excluded due to other hematopoietic disease or infections. Out of the remaining 50, 26 were not included in the final study results due to either a change in their protocol or missing specimen(s). Thus, 24 participants completed the study. INTERVENTION

The control group (n=12) consumed a “natural foods” diet that consisted of standard nutritionist-designed daily meals. The intervention group (n=12) was provided the same natural foods diet in addition to 1.5 g/kg per day of a whey and soy protein blend. Actual dietary intake was monitored daily. Participants in the intervention group were instructed to drink 0.5 g/kg protein powder (50% protein from whey protein isolate and 50% protein from soy isolate) 30 minutes after each of the 3 main meals of the day, for a total of 1.5 g/kg/ day. The study was conducted from patient enrollment (0-30 days prior to transplant) through 30 days after transplant. STUDY PARAMETERS ASSESSED

Routine monitoring of dietary intake, anthropomorphic variables, and biochemical indicators was performed on a daily

Marie Winters, ND, FABNO and weekly basis from enrollment (0-30 days prior to transplant) through the conclusion of the study (30 days posttransplant). Time to engraftment, a measure of transplant success, was also tracked for all participants. Dietary intake was assessed with a 24-hour dietary recall questionnaire, a food nutrition composition table, and nutritionist software. Blood samples were collected to assess biochemical indicators: serum albumin, globulin, and total protein levels. Muscle strength was tested at 3 points during the study: at baseline (time of enrollment into study), pretransplantation, and posttransplantation. Anthropomorphic measures were taken by the same clinical nutritionist at each weekly interval and included the following: • Height in centimeters using a wall-mounted stadiometer • Weight in kilograms using an electronic scale • BMI • Triceps skinfold thickness (TSF) with a dial calibrated to 0.2 mm at the halfway point between the acromion and the olecranon process of the right upper arm • Upper arm circumference (AC) using flexible tape at the nearest 0.1 cm halfway between the right acromion and olecranon process • Muscle mass, measured as upper arm muscle circumference (AMC) • Calf girth and thickness of the thenar eminence PRIMARY OUTCOME MEASURES

Changes in anthropometric measurements, changes in muscle strength, and changes in serum protein composition from enrollment through the conclusion of the study at 30 days posttransplantation. Three time points were used for the final analysis: baseline (time of enrollment; varied from 0-30 days before transplant); pretransplant; and posttransplant. Time to engraftment was a secondary outcome measure. KEY FINDINGS

Pretransplant and posttransplant energy (caloric) intake and protein intake from natural food diets was similar between the control and intervention groups. Energy intake decreased dramatically and proportionally in both groups in the posttransplant period. The majority of patients in control and intervention groups showed no statistically significant weight change in the posttransplant period. However, the majority of patients in the

10 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


ABSTRACT & COMMENTARY

intervention group (n=9, or 75%) had improved muscle mass in the posttransplant period as measured by upper arm circumference (AC), while the majority of patients in the control group (75%) had a loss in muscle mass/AC. Similarly, 100% of the participants in the treatment group who consumed additional protein during the period from baseline to pretransplant (n=6) showed an increase in muscle strength. Measures of albumin, globulin, and total protein assessed in both the pretransplant and posttransplant periods were consistently higher in a majority of the intervention group participants compared to the control group. From baseline to pretreatment, albumin levels increased in 75% of the intervention group and only 25% of the control group; globulin levels increased in 75% of the intervention group and 41% of the control group; and total protein levels increased in 75% of the intervention group and only 25% in the control group. From pretreatment to posttreatment, globulin levels increased in 66% of the intervention group and 41% of the control group; total proteins increased in 58% of the intervention group and 33% of the control group. Secondary outcome measures also showed notable differences between control and intervention groups. Engraftment is a reliable measure of transplant success, marking the end of the most critical portion of the transplant period and the beginning of a return to immune competence. There was a statistically significant difference in time to engraftment between the 2 arms of this study. Time to engraftment was 12.2±2.0 days in the intervention group and 15.1±2.9 days for the control group (P<0.05). Time to engraftment for 2 patients in the intervention group was as short as 10 days. As one might expect with a shortened time to engraftment, the incidence of pulmonary infections was lower in the intervention group (41%) than the control group (66%). Baseline incidence of infection was 0 in both groups.

PRACTICE IMPLICATIONS According to the Center for International Blood and Marrow Transplant Research, there were almost 9,000 allogeneic stem cell transplants performed in the United States in 2016, the most recent data available.1 Allogeneic stem cell transplantation involves the ablation of a patient’s immune system to rid the body of leukemia, lymphoma, or myeloma cell lines, followed by the infusion of hematopoietic stem cells from other related or unrelated donors with an acceptable human leukocyte antigen (HLA) match.2 Weight loss and malnutrition are common following allogeneic stem cell transplantation. In one study of almost 200 people who received an allogenic transplant, 55.6% of patients lost over 5% of their body weight, and there was a 1.6% rise in malnutrition.3 Longitudinal studies have demonstrated that loss of muscle mass associated with allogeneic transplants is extremely common and can last for as long as 6 years posttransplant.4,5 This loss in muscle mass has been positively correlated with graft-versus-host disease and decreased performance status.4

Even with declining caloric intake in the posttransplant period, the additional protein may have an impact on maintaining and gaining muscle mass, and supporting serum markers of protein status.

Serum measures of protein also tend to decline after bone marrow transplant. The decline in albumin, globulin, and total protein has been positively correlated with severe acute graft-versus host-disease and posttransplant mortality.6,7 Immunodeficiency is universal in patients who have received an allogeneic stem cell transplant, often persisting for months after the procedure. As a result, infectious complications are common in this posttransplant patient population, leading to significant morbidity and mortality.8

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  11


ABSTRACT & COMMENTARY

In the present clinical trial, the addition of 1.5 g/kg of a 1:1 combination of soy and whey protein powder was added to the recommended diet of patients undergoing allogeneic stem cell transplantation. The whey-soy combination was chosen based on the results of a prior study demonstrating its ability to augment the grasping force in a rat exercise model.9 An earlier human trial conducted by Reidy et al on the same whey-soy combination found that it promoted muscle protein synthesis in healthy individuals.10 Whey is unique in that it is rapidly degraded into branched-chain amino acids on ingestion. These branched chain amino acids, leucine in particular, have the ability to stimulate muscle protein synthesis through activation of the mammalian target of rapamycin (mTOR)-P70s6K pathway.11,12 Both whey and soy protein can also enhance the gastrointestinal microbiome. Soy protein has been documented to increase gastrointestinal microdiversity in a rat model, while soy has been shown to increase Lactobacillus species, while decreasing Clostridium in a mouse model.13,14 The present study demonstrates the feasibility of adding whey-soy protein to a recommended diet during the transplant period. Even with declining caloric intake in the posttransplant period, the additional protein may have an impact on maintaining and gaining muscle mass, and supporting serum markers of protein status. Evidence that this may positively impact morbidity associated with transplant comes in the form of secondary outcomes, with decreased time to engraftment and a decreased incidence of posttransplant infections in the experimental group. Notably, the experimental and control groups were otherwise comparable with respect to age, gender, leukemia type, and stem cell source.

While the results of this trial are encouraging, additional research is warranted. The patient population was relatively small (N=24), and patients were enrolled in the study anywhere between 0 to 30 days prior to transplant, adding inconsistency to the timing of the study. REFERENCES

1 US Department of Health and Human Services. How many bone marrow or umbilical cord blood transplants are performed in the United States? Health Resources and Services Administration. Center for International Bone and Marrow Research. https://bloodcell.transplant.hrsa.gov/about/general_faqs/index.html#1990%20 number%20tx%20inUS. Accessed September 14, 2018. 2 Singh AK, McGuirk JP. Allogeneic stem cell transplantation: a historical and scientific overview. Cancer Res. 2016;76(22):6445-6451. 3 Rieger CT, Wischumerski I, Rust C, et al. Weight loss and decrease of body mass index during allogeneic stem cell transplantation are common events with limited clinical impact. PLoS One. 2015;10(12):e0145445. 4 Kyle UG, Chalandon Y, Mirabell R, et al. Longitudinal follow up of body composition in hematopoietic stem cell transplant patients. Bone Marrow Transplant. 2005;35(12):1171-1177. 5 Iestra JA, Fibbe WE, Zwinderman AH, et al. Body weight recovery, eating difficulties and compliance with dietary advice in the first year after stem cell transplantation: a prospective study. Bone Marrow Transplant. 2002;29(5):417-424. 6 Ferriera EE, Guerra DC, Baluz, K, et al. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study. Rev Bras Hematol Hemoter. 2014;36(6):414-419. 7 Resvani AR, Storer BE, Storb RF, et al. Decreased serum albumin as a biomarker for severe acute graft-versus-host disease after reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17(11):1594-1601. 8 Center for International Blood and Marrow Transplant Research. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Bone Marrow Transplant. 2009;44(8):453-558. 9 Ren G, Yi S, Zhang H, et al. Ingestion of soy-whey blended protein augments sports performance and ameliorates exercise-induced fatigue in a rat exercise model. Food Funct. 2017;8(2):670-679. 10 Reidy PT, Walker DK, Dickinson JM, et al. Protein blend ingestion following resistance exercise promotes human muscle protein synthesis. J Nutr. 2013;143(4):410416. 11 Anthony JC, Yoshizowa F, Anthony TG, et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via rapamycin-sensitive pathway. J Nutr. 2000;130(10):2413-2419. 12 Crozier SJ, Kimball SR, Emmert SW, et al. Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J Nutr. 2005;135(3):376-382. 13 Butteiger DN, Hibberd AA, McGraw NJ, et al. Soy protein compared with milk protein in a western diet increase gut microbial diversity and reduces serum lipids in golden Syrian hamsters. J Nutr. 2016;146(4):697-705. 14 McAllan L, Skuse P, Cotter PD, et al. Protein quality and the protein to carbohydrate ratio within a high fat diet influences energy balance and the gut microbiota in c57BL/6J mice. PLoS One. 2014;9(2):e88904.

12 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


THE GLOBAL STANDARD IN BREATH TESTING

QuinTronâ&#x20AC;&#x2122;s patented non-invasive breath tests for Small Intestinal Bacterial Overgrowth (SIBO) and various carbohydrate malabsorptions have been featured on numerous television series and networks such as The Doctors on CBS, Discovery Health, Lifetime and CNBC. QuinTron accurately measures Hydrogen, Methane and Carbon Dioxide in each sample using state-of-the-art sensing technology unmatched by other analyzers on the market.

SIMPLE

ACCURATE

&

BEST MEDICAL DEVICE MANUFACTURER-MIDWEST USA, 2017

RELIABLE

BEST IN HYDROGEN & METHANE BREATH TESTING SOLUTIONS, 2017

W W W. B R E AT H T E S T S . C O M W W W . Q U I N T R O N - U S A . C O M | 1 - 8 0 0 - 5 4 2 - 4 4 4 8 | M I L WA U K E E , W I

Breath Test Kits For: Small Intestinal Bacterial Overgrowth (SIBO) Lactose Intolerance Fructose Intolerance Sucrose Intolerance


ABSTRACT & COMMENTARY

Fish Oil Supplementation in Adults With Hematological Malignancies Inflammatory prognostic scores and cancer outcomes REFERENCE

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 longterm survival: a randomised clinical trial. J Hum Nutr Diet. 2017;30(6):681-692. STUDY OBJECTIVES

The primary objective was to evaluate the effect of fish oil supplementation on nutritional parameters and inflammatory status in individuals newly diagnosed with a hematological cancer initiating chemotherapy. A secondary objective was to assess survival at 465 days from the start of supplementation. DESIGN

Randomized controlled trial, no placebo PARTICIPANTS

Participants were adults with newly diagnosed leukemia or lymphoma who were about to initiate first-line treatment with chemotherapy. The total population analyzed was 22 individuals (10 women, 12 men). There were no statistically significant differences in characteristics of the participants at baseline, including age, which averaged 53.8 years in the control group and 43.8 years in the fish oil group. Diagnoses included acute leukemia (n=9), non-Hodgkin lymphoma (n=8), Hodgkin lymphoma (n=4), and chronic leukemia (n=1). INTERVENTION

Participants were randomized to receive oral fish oil at a dose of 2 g per day (containing 367 mg eicosapentaenoic acid [EPA] and 243 mg docosahexaenoic acid [DHA]) for 9 weeks, starting on the first day of chemotherapy, or no fish oil (control group). The intervention group was instructed to consume the fish oil 20 to 30 minutes before lunch or dinner.

STUDY PARAMETERS ASSESSED

Assessment measures included anthropometric data, blood work (complete blood count, albumin, C-reactive protein [CRP], plasma free fatty acids), survival at 465 days, number of hospital readmissions, and number of chemotherapy sessions. Blood samples and anthropometric measurements were taken at baseline (1 day before initiation of fish oil), and at 9 weeks. Nutritional status was determined by anthropometric data and the Nutritional Risk Index (NRI), which is calculated by the following equation: 1.519 x serum albumin (g/dL) + 41.7 x current weight (kg)/usual weight (kg). A score >100 means no nutrition risk; 99.9-97.5 means borderline nutrition risk; 83.5-97.5 means mild nutrition risk; and <83.5 means severe nutritional risk. Anthropometric measurements included BMI, arm circumference, mid-upper arm circumference (MUAC), triceps skin fold (TS), and mid-upper arm muscle circumference (MUAMC). Inflammatory status was determined by the inflammatory nutrition prognosis index, which is calculated as the CRP/albumin ratio (CAR). The interpretation was defined as no risk <0.4; low risk 0.4-1.2; moderate risk 1.2-2.0; and high risk >2.0. Overall survival at 465 days from study initiation was calculated using the KaplanMeier method and compared using log-rank tests. Date of death, hospital admissions, and number of chemo-

Ellen McDonell, ND therapy sessions were recorded from medical records. PRIMARY OUTCOME MEASURES

The effects of fish oil on nutritional and inflammatory status was determined by changes in the NRI, CAR, and anthropometric measures from baseline to the end of the 9-week study. Secondary outcomes were determined by overall survival, number of chemotherapy sessions, and change in plasma fatty acids. KEY FINDINGS

Two models were used for statistical analysis. Model 1 included all study participants who finished the 9 weeks of follow up (n=22). Model 2 included only individuals in the control group whose plasma EPA and DHA remained stable at 9 weeks (defined as <50% increase; n=8), and only participants in the fish oil group who had a 100% or greater increase in plasma EPA and DHA (n=6). Plasma EPA and DHA did not change in the control group in either model of analysis. Plasma EPA and DHA significantly increased in the fish oil group in both models, except for DHA in model 1 where the increase was not statistically significant (P=0.07). There were no statistically significant  between group changes  for any outcome other than CAR, survival, and number of chemotherapy sessions.  The CAR was significantly reduced (indicating improvement) in both groups in

Although useful as predictive tools, these inflammatory prognostic indices lead a practicing clinician to ask 2 important questions: Are they modifiable, and does modifying the prognostic index change long-term outcomes?

14 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


ABSTRACT & COMMENTARY

model 1; changes were not statistically significant in model 2. Median scores from baseline to week 9 showed statistically significantly greater improvement in the fish oil compared to control group (5.1 to 1.4 in the control group and 12.6 to 1.1 in the fish oil group, P<0.05). There were no deaths in the 14-month follow up in the fish oil group. There were 8 deaths in the control group in model 1 and 6 deaths in model 2; these differences were statistically significant compared to the fish oil group (P=0.005 and P=0.008, respectively). The number of chemotherapy sessions was significantly higher in the fish oil group in both models compared to the control group. There was no difference in hospital readmissions. There were no significant changes in weight, MUAC, MUAMC, or TS with either model. The NRI was higher (which indicates lower risk) in the fish oil than the control group in model 2 at 9 weeks (P<0.05); however, there were no statistically significant changes from baseline between groups. C-reactive protein was significantly reduced in the fish oil group in model 1 (P<0.05), but there was no change in the control group and no statistically significant change between groups.  In summary, fish oil supplementation increased plasma EPA and DHA.  Survival was significantly better in the fish oil vs control group at 14 months, and the fish oil group received more chemotherapy sessions than the control group. Improvement in CAR was greater in the fish oil group compared to the control group at 9 weeks.

PRACTICE IMPLICATIONS The present study is the first to look at changes in CAR associated with fish oil use in hematological malignancies. It confirms previous findings that CAR is elevated in people with hematological cancers pretreatment, demonstrates that cancer treatment improves this ratio, and suggests that the addition of fish oil may result in greater improvement in this index. The present study also found improved survival at 14 months, providing some preliminary evidence that fish oil may improve survival in hematological malignancy, and that this improvement may be at least partially mediated by changes in systemic inflammation.

The present study defined no risk as <0.4 and low risk as 0.4 to 1.1. Although CAR has relatively few studies compared to some of the other inflammatory prognostic scores, a study in colorectal cancer found CAR to be positively correlated with other known inflammation-based prognostic indices such as neutrophil-to-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS).5 Less is known about the prognostic value of CAR in hematological malignancies. Only 1 study has previously looked at CAR in hematological cancers and found it to be elevated prior to chemotherapy initiation. However, the study did not look at future risk associated with these scores.10

Prognostic inflammatory indices, which include the GPS, Prognostic Nutritional Index (PNI), platelet-to-lymphocyte ratio (PLR), and NLR are well-validated prognostic tools for solid cancers.11-13 These indices are markers of the systemic inflammatory response, which plays an important role in cancer physiology, An inflammatory prognostic score, including carcinogenesis, dedifferentiaCAR was initially demonstrated to tion, and tumor cell proliferation.6 They predict mortality in septic patients2,3 but are usually measured preoperatively, and has more recently been associated with predict risk of postoperative complicaoverall survival in patients with a variety tions and overall survival in a variety of of solid tumors, including pancreatic,4 malignancies.7,8 colorectal,5,6 gastric,7 small cell lung,8 and hepatocellular9 cancers. Similarly to other Although useful as predictive tools, these inflammatory prognostic scores, this index inflammatory prognostic indices lead a is utilized as pretreatment in solid tumors practicing clinician to ask 2 important as a method to predict posttreatment questions: Are they modifiable, and does survival. Higher CAR indicates a greater modifying the prognostic index change level of systemic inflammation and greater long-term outcomes? risk of mortality. The threshold for low or optimal CAR varies depending on the Inflammatory prognostic tools such study, but ranges from 0.038 to 0.441.5,6,8,9 as CAR, NLR, and GPS are useful for The ability of fish oil to improve CAR has been previously demonstrated in colorectal cancer. Patients undergoing chemotherapy for colorectal cancer who were supplemented with 2 g fish oil (600 mg combined EPA/DHA) had significantly reduced CAR status after 9 weeks.1

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  15


ABSTRACT & COMMENTARY

clinicians. They are strong predictors of long-term outcomes and they are usually readily available because their components are often ordered in standard blood work. While research on the ability of natural therapies such as fish oil to modify these indices, including the implications for overall survival, is still limited, this study provides some preliminary indication that systemic inflammation can be modified with natural therapies, and this may confer a survival advantage. Given other known benefits of fish oil, it is certainly warranted to consider its use for patients with hematological cancers initiating treatment. Very few prior prospective clinical trials have evaluated fish oil supplementation for people with hematological malignancies. One study in children with leukemia found that fish oil supplementation improved appetite, caloric intake, and

MUAMC after 8 weeks compared to control.14 Another study in children with acute lymphoblastic leukemia found that the addition of fish oil alongside maintenance treatment with methotrexate reduced hepatotoxicity compared to placebo.15 Fish oil is unlikely to be effective for reducing risk of severe neutropenic enterocolitis in patients with AML.16 There may be benefit to fish oil supplementation around bone marrow transplant (BMT) and hematopoietic stem cell transplant (HSCT). One small study in 16 people found that EPA supplementation before and for 180 days after BMT reduced complications and improved survival, and the authors hypothesize the effect was mediated through EPA lowering the systemic inflammatory response.17,18 Pretreatment with EPA in one study of BMT reduced risk of acute colonic graft-versus-host disease. However, short-term use of omega-3 fats after stem

16 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


ABSTRACT & COMMENTARY

cell transplants may not be sufficient to modify inflammatory markers,19 but it may improve antioxidant status.20 There are several limitations to the present study. The study had a very small sample size, which limits the generalizability of the findings and resulted in large confidence intervals giving an imprecise estimate of effect. The study was not placebo-­ controlled, potentially inflating results due to the placebo effect. The population may have had slightly different baseline characteristics in terms of disease aggressiveness; the control group had 5 individuals with acute leukemia, 6 with non-Hodgkin lymphoma (NHL), and 1 with Hodgkin disease (HD), while the fish oil group had 4 with acute leukemia, 2 with NHL, and 3 with HD. Recognizing that HD has a high cure rate and acute leukemias are typically more aggressive, with the small sample size it is possible that small differences between cancer type could alter the findings. The heterogeneity in the study population (type of hematological malignancy, staging, and chemotherapy regimens) makes it difficult to interpret outcomes and may play a role in differences seen, especially given the small sample size. Lastly, the dose of EPA/DHA used in this study is quite low—only 610 mg combined. In practice, it is likely that most naturopathic doctors are using a higher dose, and although more is not always better, it would be interesting to look at the impact of a higher and possibly more therapeutic dose of fish oil on the outcomes evaluated in this study. Further research with larger sample sizes is warranted. CONCLUSION Preliminary evidence from this study suggests that fish oil supplementation may improve the CAR inflammatory index and improve survival at 14 months for individuals with lymphoma and leukemia initiating chemotherapy. Therapies that can modify systemic inflammation may be able to improve survival, and more research should investigate anti-­ inflammatory agents and their impact on inflammatory-based prognostic scores and overall survival. Due to methodological limitations, the results should be interpreted cautiously, and future studies should further evaluate the impact of fish oil supplementation on inflammation and survival for people with hematological cancers.

REFERENCES

1 Mocellin MC, Pastore e Silva J de A, Camargo C de Q, et al. Fish oil decreases C-reactive protein/albumin ratio improving nutritional prognosis and plasma fatty acid profile in colorectal cancer patients. Lipids. 2013;48(9):879-888. 2 Ranzani OT, Zampieri FG, Forte DN, Azevedo LCP, Park M. C-reactive protein/albumin ratio predicts 90-day mortality of septic patients. PLoS One. 2013;8(3):e59321. 3 Kim MH, Ahn JY, Song JE, et al. The C-reactive protein/albumin ratio as an independent predictor of mortality in patients with severe sepsis or septic shock treated with early goal-directed therapy. PLoS One. 2015;10(7):e0132109. 4 Haruki K, Shiba H, Shirai Y, et al. The C-reactive protein to albumin ratio predicts long-term outcomes in patients with pancreatic cancer after pancreatic resection. World J Surg. 2016;40(9):2254-2260. 5 Ishizuka M, Nagata H, Takagi K, Iwasaki Y, Shibuya N, Kubota K. Clinical significance of the C-reactive protein to albumin ratio for survival after surgery for colorectal cancer. Ann Surg Oncol. 2016;23(3):900-907. 6 Shibutani M, Maeda K, Nagahara H, Iseki Y, Hirakawa K, Ohira M. The significance of the C-reactive protein to albumin ratio as a marker for predicting survival and monitoring chemotherapeutic effectiveness in patients with unresectable metastatic colorectal cancer. SpringerPlus. 2016;5(1):1798. 7 Toiyama Y, Shimura T, Yasuda H, et al. Clinical burden of C-reactive protein/ albumin ratio before curative surgery for patients with gastric cancer. Anticancer Res. 2016;36(12):6491-6498. 8 Zhou T, Zhan J, Hong S, et al. Ratio of C-reactive protein/albumin is an inflammatory prognostic score for predicting overall survival of patients with small-cell lung cancer. Sci Rep. 2015;5(1):10481. 9 Kinoshita A, Onoda H, Imai N, et al. The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma. Ann Surg Oncol. 2015;22(3):803-810. 10 Camargo C de Q, Borges D da S, Oliveira PF de, et al. Individuals with hematological malignancies before undergoing chemotherapy present oxidative stress parameters and acute phase proteins correlated with nutritional status. Nutr Cancer. 2015;67(3):463-471. 11 Bugada D, Allegri M, Lavand’homme P, De Kock M, Fanelli G. Inflammation-based scores: a new method for patient-targeted strategies and improved perioperative outcome in cancer patients. Biomed Res Int. 2014;2014:1-11. 12 Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Futur Oncol. 2010;6(1):149-163. 13 Proctor MJ, Morrison DS, Talwar D, et al. A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur J Cancer. 2011;47(17):2633-2641. 14 Abu Zaid Z, Shahar S, Jamal ARA, Mohd Yusof NA. Fish oil supplementation is beneficial on caloric intake, appetite and mid upper arm muscle circumference in children with leukaemia. Asia Pac J Clin Nutr. 2012;21(4):502-510. 15 Elbarbary NS, Ismail EAR, Farahat RK, El-Hamamsy M. ω-3 fatty acids as an adjuvant therapy ameliorates methotrexate-induced hepatotoxicity in children and adolescents with acute lymphoblastic leukemia: a randomized placebo-controlled study. Nutrition. 2016;32(1):41-47. 16 Bükki J, Stanga Z, Tellez FB, et al. Omega-3 poly-unsaturated fatty acids for the prevention of severe neutropenic enterocolitis in patients with acute myeloid leukemia. Nutr Cancer. 2013;65(6):834-842. 17 Takatsuka H, Takemoto Y, Iwata N, et al. Oral eicosapentaenoic acid for complications of bone marrow transplantation. Bone Marrow Transplant. 2001;28(8):769-774. 18 Takatsuka H, Takemoto Y, Yamada S, et al. Oral eicosapentaenoic acid for acute colonic graft-versus-host disease after bone marrow transplantation. Drugs Exp Clin Res. 2002;28(4):121-125.. 19 Baena-Gómez MA, de la Torre-Aguilar MJ, Aguilera-García CM, Olza J, PérezNavero JL, Gil-Campos M. Inflammatory response using different lipid parenteral nutrition formulas in children after hematopoietic stem cell transplantation. Nutr Cancer. 2016;68(5):804-810. 20 Baena-Gómez M, Aguilar M, Mesa M, Navero J, Gil-Campos M. Changes in antioxidant defense system using different lipid emulsions in parenteral nutrition in children after hematopoietic stem cell transplantation. Nutrients. 2015;7(9):7242-7255.

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  17


ABSTRACT & COMMENTARY

Intravenous Application of Mistletoe Extract Insights into safety and tolerability REFERENCE

Huber R, Schlodder D, Effertz C, Rieger S, Tröger W. Safety of intravenously applied mistletoe extract - results from a phase I dose escalation study in patients with advanced cancer. BMC Complement Altern Med. 2017;17(1):465. STUDY OBJECTIVE

The primary objective was to determine the maximum tolerated dose (MTD) of intravenous Helixor P. The MTD is determined by the incidence of dose-limiting toxicities (DLTs). A secondary objective was to investigate the safety and tolerability of the different doses and patients’ clinical course. DESIGN

Prospective, dose-escalating phase I good clinical practice (GCP) study without a control group PARTICIPANTS

Female and male patients ≥18 years of age (N=21) with a histologically or cytologically confirmed diagnosis of an advanced malignant disease in an interval without antineoplastic therapies, with an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and sufficient bone marrow function STUDY MEDICATION AND DOSAGE

Helixor P (Helixor Heilmittle GmbH, Rosenfeld: Germany) was used in a classical phase I 3 + 3 dose escalation scheme (200 mg, 400 mg, 700 mg, 1,200 mg, and 2,000 mg). If 3 patients tolerated 3 infusions of the first dose (200 mg) in weekly intervals for 3 weeks, the next 3 patients received 3 infusions of the next dose (400 mg), and so forth. Maximum planned dose was 2,000 mg. OUTCOME MEASURES

Adverse events (AEs) were assessed based on grade of severity, causality to the study medication, clinical consequences, and

PRACTICE IMPLICATIONS For several decades, extract preparations from natural mistletoe (Viscum album) have been widely used as an alternative therapy in the management of patients with malignant disease, based on presumed immunostimulatory and antineoplastic effects. As a natural cancer therapy, mistletoe has one of the most extensive research bases. To date, there are more than 2,600 published scientific papers, over 250 of which reflect inclusion of modern North American scientific thought.1

Miranda LaBant, ND outcome classified as serious (SAE) or suspected unexpected serious (SUSAR), if applicable. Dose-limiting toxicity (DLT) was defined as a specific AE ≥ grade 2. Grading was defined as follows: • Grade 1: Transient rash, drug fever ≤39.8°C for less than 24 hours • Grade 2: Urticaria, and/or asymptomatic bronchospasm, drug fever >39.8°C or drug fever >39.5°C continuing more than 24 hours • Grade 3: Symptomatic bronchospasm, requiring parenteral medication(s), with or without urticaria; allergy-related edema/angioedema • Grade 4: Anaphylaxis Dose-limiting toxicity was also defined as an unexpected increase of aminotransferase levels to >3 times baseline levels KEY FINDINGS

• MTD was not reached. • 1 DLT was reported during a 2,000 mg infusion; 3 patients were added to the study, at this same dose, and tolerated it well. • Weekly infusions of 2,000 mg of pine-mistletoe extract were well-tolerated and can be used in further studies. • Use of intravenous viscum can cause allergic reactions or fever. • 155 AEs during the trial. At least 20 of 155 AEs were mostly linked to the 2,000 mg (40,000 ng natural ML III) dose group. These were apart from an allergic reaction in 1 patient; grade 1 fever in 4 patients; weakness the day after infusion (3 patients); eosinophilia (2 patients); and slight temporary elevation of alanine aminotransferase (ALT) in 2 patients. • Mean levels of ALT, aspartate aminotransferase (AST), and alkaline phosphatase (ALP), neutrophils, and lymphocytes were unchanged.

Mistletoe preparations/extracts are most commonly administered as subcutaneous injections starting at a low dose, which is gradually increased over time based on individual responses.2 Increasingly, mistletoe preparations are also administered at high initial doses as subcutaneous injections, intravenous infusions, or intratumorally, depending on the location of the tumor, disease stage, and the experience of the physician.3 There appears to be accumulating evidence that traditional subcutaneous mistletoe therapy is safe, improves quality of life, and reduces adverse drug reactions to conventional

18 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


ABSTRACT & COMMENTARY

therapies. However, the evidence regarding intravenous and intratumoral use is limited or inconclusive. The major active constituents of natural mistletoe extracts are mistletoe lectins (MLs), which have been reported to induce apoptosis in various cancer cell lines4,5 and elicit immunomodulatory properties.6 Absorption of MLs from the gastrointestinal tract has been shown to be poor because they interact with carbohydrate residues on epithelial cells.7 Therefore, a parenteral route is of interest. Regarding administration and dosing, the MTD of mistletoe is unknown. The authors of this study investigated the safety and tolerability of intravenous mistletoe extract. Several studies have shown that applications of 1-5 mg were safe and tolerable when given intravenously.6

In general, the investigators of the current study report mistletoe (Helixor P) was well-tolerated, with minimal AEs at a dose of 2,000 mg per week for 9 weeks. A review of literature supports the use of mistletoe having minimal AEs when given subcutaneously or orally.8-11 Some side effects are common, but most are minor, dose-dependent, and subside on their own within a few days after treatment. Common side effects for subcutaneous administration include local reactions at the injection site (eg, swelling, redness, local pain, itchiness, rash, warmth), fatigue, mild flu-like symptoms, anemia, fever, and diarrhea.12-14 Six serious AEs occurred during the study, and none of the 6 were attributed to the study medication. Reasons included progression of disease or other events (eg, hospital admission

Are you ready to advance your clinic and become a

certified mistletoe practitioner? PRESENTED BY NORTH AMERICA'S LEADING EXPERT DR. ERIC MARSDEN ND. JOIN OUR MISTLETOE IN ONCOLOGY CERTIFICATION COURSE Our course offers • Online CE accredited training •  Lifetime access to course materials •  One Year access to instructor •  Content at your fingertips

Our course allows you to

• Learn at your own pace •  Stop and rewatch over again •  Access course materials through smartphones,     tablets,  laptops or desktops

Visit us at integrativemedicinecme.com/mistletoe to get started today!

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  19


ABSTRACT & COMMENTARY

because of dyspnea due to pulmonary metastasis) that were not drug-related. Adverse events from intravenous mistletoe administration have been documented through case reports, case series, and other clinical studies, but serious AEs are rare. Reported AEs include urticaria and angioedema,15 hypotension and loss of consciousness,16 anaphylaxis,17 fever,18 hyper-eosinophilia,19 severe delayed type hypersensitivity reaction,20 and liver toxicity. The authors were unable to define an MTD, due to European Pharmacopeia regulations, but they were able to ascertain that a predefined maximum dose of 2,000 mg has a certain risk of allergic reactions, provokes short-term (<12 h) elevated body temperature and does not seem to have bone marrow or other organ toxicity. While this study does address some of the questions around intravenous administration of mistletoe extracts, a concern that is often raised is the potential for interactions with conventional chemotherapy drugs and/or radiation. As part of the exclusion criteria of this study, none of the participants were undergoing chemotherapy or radiation therapy. There is evidence that the risk of chemotherapy-associated AEs might be reduced if patients are treated with subcutaneous mistletoe alongside chemotherapy.21,22 Furthermore, there is a small evidence base that suggests intravenous application of Viscum album has significant beneficial effects with respect to chemotherapy-related side effects (ie, nausea, constipation, pain, stomatitis, appetite),23 and improved quality of life.8 Given the promising safety profile, possible clinical anticancer effects, and extensive research base supporting the use of mistletoe, the parenteral application of mistletoe deserves future investigation. REFERENCES

1 Stengler M, Anderson P. Outside the Box Cancer Therapies: Alternative Therapies That Treat and Prevent Cancer. Carlsbad, CA: Hay House; 2018: 179-180. 2 Steele ML, Axtner J, Happe A, Kroz M, Matthes H, Schad F. Evid Based Complement Alternat Med. 2014;2014:236310. 3 Kroz M, Kienle G, Feder G, Kaveri S, Rosenzweig S. Mistletoe: from basic research to clinical outcomes in cancer and other indications. Evid Based Complement Alternat Med. 2014;2014:987527.

4 Huber R, Rostock M, Goedl R, et al. Mistletoe treatment induces GM-CSF and IL-5 production by PBMC and increases blood granulocyte and eosinophil counts: a placebo controlled randomized study in healthy subjects. Eur J Med Res. 2005;10(10);411-418. 5 Huber R, Ludtke H, Wieber J, Beckmann C. Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters- a placebo controlled clinical trial in healthy subjects. BMC Complement Altern Med. 2011;11 (1): 116. 6 Elluru S, Duong van Huyen J, Delignat S, et al. Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer. 2008;8:161. 7 Bussing A. Biological and pharmacological properties of Viscum album L. In: Mistletoe: The Genus Viscum. London, England: CRC Press; 2000:123-182. 8 Horneber M, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Databas Syst Rev. 2008;2:CD003297. 9 Kienle GS, Kiene H. Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res. 2007;12(3):103-119. 10 Kienle G, Kiene H. Review article: influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies. Integr Cancer Ther. 2010;9(2):142-157. 11 Kienle G, Grugel R, Kiene H. Safety of higher dosages of Viscum album L. in animals and humans--systematic review of immune changes and safety parameters. BMC Complement Altern Med. 2011;11(1):72. 12 Schöffski P, Riggert, S, Fumoleau P, et al. Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Ann Oncol. 2004;15(12):1816-1824. 13 Eisenbraun J, Scheer R, Kröz M, Schad F, Huber R. Quality of life in breast cancer patients during chemotherapy and concurrent therapy with a mistletoe extract. Phytomedicine. 2011;18 (2):151-172. 14 Hutt N, Kopferschmitt-Kubler M, Cabalion J, Purohit A, Alt M, Pauli G. Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergol Immunopathol (Madr). 2001;29(5);201-203. 15 Kienle G, Glockmann A, Schink M, Kiene H. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. J Exp Clin Cancer Res. 2009;28:79. 16 Hutt N, Kopferschmitt-Kubler M, Cabalion J, Purohit A, Alt M, Pauli G. Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergol et Immunopathol. 2001;29(5) 201-203. 17 Bauer C, Oppel T, Rueff F, Przybilla B. Anaphylaxis to viscotoxins of mistletoe (Viscum album) extracts. Ann Allergy Asthma Immunol. 2005;94(1):86-89. 18 Schlappi M, Ewald C, Kuehn J, Weinert T, Huber R. Fever therapy with intravenously applied mistletoe extract for cancer patients: a retrospective study. Integr Cancer Ther. 2017;16(4):479-484. 19 Huber R, Barth H, Schmitt-Graff A, Klein R. Hypereosinophilia induced by high-dose intratumoral and peritumoral mistletoe application to a patient with pancreatic carcinoma. J Altern Complement Med. 2000;6(4):305-310. 20 Shaw H, Hobbs K, Seewaldt V, Kroll D. Delayed-type hypersensitivity reaction with iscador m given in combination with cytotoxic chemotherapy. J Clin Oncol. 2004;22(21): 4432-4433. 21 Bock P, Friedel W, Hanisch J, Karasmann M, Schneider B. Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma [in German]. Arzneimittelforschung. 2004;54(8):456-466. 22 Piao B, Wang Y, Xie G, et. al. Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial. Anticancer Res. 2004;24(1):303-309. 23 Bussing A, Bischof M, Hatzmann W, et al. Prevention of surgery-induced suppression of granulocyte function by intravenous application of a fermented extract from Viscum album L. in breast cancer patients. Anticancer Res. 2005; 25(6C):4753-4758.

20 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


ABSTRACT & COMMENTARY

Does Complementary Medicine Increase Risk of Death for Cancer Patients? Evaluating the headline-grabbing JAMA study REFERENCE

Johnson SB, Park HS, Gross CP, Yu JB. Complementary medicine, refusal of conventional cancer therapy, and survival among patients with curable cancers. JAMA Oncol. 2018;4(10):1375-1381. DESIGN

A retrospective observational analysis of data obtained from the National Cancer Database (NCDB) PARTICIPANTS

The initial cohort included 1,901,815 patients who were diagnosed with non-metastatic breast, prostate, lung, or colorectal cancer between 2004 and 2013. The NCDB is a clinical database that captures approximately 70% of all newly diagnosed cancers from more than 1,500 Commission on Cancer accredited centers in the United States and is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. Patients were selected from this cohort based on their use of complementary medicine during cancer treatment. From the initial group of 1,901,815 patients with cancer, 258 people met the study’s definition of using complementary medicine (the CM group). Of the remaining patients, 1,032 served as the control group. The CM group consisted of 199 women and 59 men, with a mean age of 56 years. Patients were matched on age, clinical group stage, comorbidity score, insurance type, race/ethnicity, year of diagnosis, and cancer type to other patients in the database. STUDY MEDICATION AND DOSAGE

Patients were defined as undergoing complementary medicine if they received “Other-Unproven: Cancer treatments administered by nonmedical personnel” in addition to any conventional cancer treatment (CCT) as noted in the patient record. Treatment refusal was defined as any NCDB-documented refusal of chemotherapy, radiotherapy, surgery, and/or hormonal therapy in the patient record. OUTCOME MEASURES

Overall survival, adherence to treatment, and patient characteristics KEY FINDINGS

Patients who chose CM did not have a longer delay to initiation of CCT but had higher refusal rates of surgery (7.0% vs 0.1%; P<0.001), chemotherapy (34.1% vs 3.2%; P<0.001), radiotherapy (53.0% vs 2.3%; P<0.001), and hormone therapy (33.7% vs 2.8%; P<0.001). Use of CM was associated with poorer 5-year overall survival compared with no CM (82.2% [95% CI: 76.0%-87.0%] vs 86.6% [95% CI: 84.0%-88.9%]; P=0.001) and was independently associated with greater risk of death (hazard ratio: 2.08; 95% CI: 1.50-2.90) in a multivariate model that did not include treatment delay or refusal. However, there was no significant association between CM and survival once treatment delay or refusal was included in the model (hazard ratio: 1.39; 95% CI: 0.83-2.33). In this study, patients who received CM were more likely to refuse additional CCT, and those who did had a higher risk of death.

Jacob Schor, ND, FABNO PRACTICE IMPLICATIONS This could be an important study for our practices. It could inform how we counsel patients who are contemplating not following the standard of care and ignoring the advice of their medical oncologists. If the authors’ conclusions were correct we would be strongly lobbying in favor of conventional cancer therapy. I write ‘could be’ because many of us remain skeptical about this study’s methodology. Put simply, the numbers do not add up. Before considering the math though, we need to look at definitions. In this research Johnson et al chose to use a definition of complementary medicine that differs from the way it has been defined in the medical literature to date. In Johnson’s view, “Complementary medicine (CM) is used in addition to conventional cancer therapy (CCT) and may be used as a substitute for adjuvant therapies.” Past researchers have made a significant distinction between complementary medicine, which is used in addition to standard of care therapies, and alternative medicine, which is used instead of conventional therapies. The National Institutes of Health (NIH) also officially defines “complementary” and “alternative” medicines as separate entities.1 Johnson et al chose to consider use of “complementary therapies” as falling on a continuous spectrum, grouping together all practices whether they are used along with or instead of conventional cancer care. Johnson et al also defined CM as “unproven cancer treatments administered by nonmedical personnel in addition to at least

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  21


ABSTRACT & COMMENTARY

1 conventional cancer treatment such as surgery, radiotherapy, chemotherapy and/or hormone therapy.” They go on to write, “Our work demonstrates that CM and alternative medicine likely represent entities along a continuum, rather than being distinct entities.” Now, let us consider the numbers. Our professional experience is that a high percentage of cancer patients choose to include complementary therapies in their cancer treatment. This experience is borne out by published research that confirms our observations in practice. A 1998 review by Cassilith reported complementary and alternative medicine (CAM) usage at a high of 64% and a low of 7%.2,3 The NIH suggest that 30% of adults and 12% of kids with cancer are engaged in nonconventional cancer therapies.1 More recent estimates suggest use of CAM therapies is anywhere between 25% and 84%, and that this varies by part of the country, type of cancer, and criteria for defining CAM.4-12

One has to wonder just how peculiar a patient had to be to be selected into the CM group. We do know that they were unusually noncompliant, based on these data: • 7 % of them refused recommended surgery compared to 0.1% of the control group • 34% of them refused chemotherapy compared to 3.2% of the control group • 53% refused radiotherapy compared to 2.3% of the control group • 33.7% refused hormone therapy compared to 2.8% of the control group In our practice we see an occasional patient who refuses standard conventional treatment, but not many. These percentages stand out as unusually high. Again, this comes back to the initial definition of “complementary” medicine the authors used.

Yet in Johnson et al’s data, only 258 cases out of nearly 2 million patients met the study’s criteria as using either complementary or alternative medicine. This calculates to less than 0.01% of the initial cohort. Even if we take the NIH’s conservative estimate that only 30% of adults with cancer engage in CAM practices, there should be half a million or more patients in the CM group; the incredibly low number of people meeting the study criteria is highly suspect for a flawed study design. Clearly, something is wrong early on in the process with how study participants were selected. Something about the selection process used by Johnson et al is far askew from all previous accounts of CAM usage. Of course, once we acknowledge this, we have to question all the study’s conclusions.

If we were to take the authors and their data at face value, we might conclude that of patients who chose complementary medicine, a high percentage will use it as an alternative treatment instead of conventional care and will experience greater chance of a poor outcome. CM was associated with increased risk of death when the data were analyzed, but if the data were categorized by which patients refused conventional treatment, the associations disappeared: “CM (vs no CM) no longer had a statistically significant association with the risk of death (HR, 1.39; 95% CI, 0.83-2.33).”

A clue that something may be amiss is mentioned in the study’s text: “The American College of Surgeons and the Commission on Cancer have not verified and are neither responsible for the analytic or statistical methods used herein, nor for the conclusions drawn from these data by investigators.” This is an odd sort of caveat to include.

The authors’ analysis of the data does not inform us whether those who use complementary medicine in an adjunctive and integrative manner with conventional care fare better or not.

In other words what Johnson et al really measured is the effect of using CCT. Not using CCT was associated with a worse prognosis.

But all of that is only relevant if we trust the findings of the study, and many do not. In fact, some are suggesting that JAMA Oncology should retract the study.13

22 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


ABSTRACT & COMMENTARY

This is all unfortunate, because it would be valuable to have accurate data on the outcomes of CM in cancer care. Lately it seems that more and more patients come into our office having, as they claim, “done research on the internet.” They come in with the belief that a long list of natural medicines will effectively cure their cancer. Sadly, they are often mistaken in their conclusions and the faith they place in online information. Do these patients who choose not to undergo standard of care treatments or conventional cancer care have a worse outcome than those patients who do as their oncologist suggests, though? It would be nice for us to know a definitive answer. According to Johnson et al, that answer is yes.

are hardwired to want to say, “I told you so.” Or to gloat at someone else’s mistake or misfortune. The New York Times chose an exaggerated headline to write about this study: “Alternative Cancer Treatments May Be Bad for Your Health: People who used herbs, acupuncture and other complementary treatments tended to die earlier than those who didn’t.” The author did point out in the course of the story that, “The complementary treatments did no harm when conventional treatment was carried out simultaneously.”14 But with that headline few readers will notice such a qualification. REFERENCES

Yet common sense and simple math tell us that there is something fundamentally wrong with how Johnson et al selected their study participants—wrong enough that we need more than a grain of salt to swallow their findings.

1 National Center for Complementary and Integrative Health. Complementary, alternative, or integrative health: what’s in a name? https://nccih.nih.gov/health/integrative-health. Updated July 2018. Accessed October 11, 2018.

Negative studies about alternative medicine get attention in the news media. There is something that draws us in; we

4 Maskarinec G, Shumay DM, Kakai H, Gotay CC. Ethnic differences in complementary and alternative medicine use among cancer patients. J Altern Complement Med. 2000;6(6):531-538.

IT’S GOOD TO SHARE

6 Lee MM, Chang JS, Jacobs B, Wrensch MR. Complementary and alternative medicine use among men with prostate cancer in 4 ethnic populations. Am J Public Health. 2002;92(10):1606-1609.

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

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

2 Adams M, Jewell AP. The use of Complementary and Alternative Medicine by cancer patients. Int Semin Surg Oncol. 2007;4:10.

3 Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in cancer: a systematic review. Cancer. 1998;83(4):777-782.

5 Morris KT, Johnson N, Homer L, Walts D. A comparison of complementary therapy use between breast cancer patients and patients with other primary tumor sites. Am J Surg. 2000;179(5):407-411.

7 Burstein HJ, Gelber S, Guadagnoli E, Weeks JC. Use of alternative medicine by women with early-stage breast cancer. N Engl J Med. 1999;340(22):1733-1739. 8 Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE. Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol. 2000;18(13):2505-2514.

9 Patterson RE, Neuhouser ML, Hedderson MM, et al. Types of alternative medicine used by patients with breast, colon, or prostate cancer: predictors, motives, and costs. J Altern Complement Med. 2002;8(4):477-485. 10 VandeCreek L, Rogers E, Lester J. Use of alternative therapies among breast cancer outpatients compared with the general population. Altern Ther Health Med. 1999;5(1):71-76.

11 Adler SR, Fosket JR. Disclosing complementary and alternative medicine use in the medical encounter: a qualitative study in women with breast cancer. J Fam Pract. 1999;48(6):453-458. 12 Vapiwala N, Mick R, DeNittis A, et al. Initiation of complementary and alternative medical therapies (CAM) by cancer patients (pts) during radiation therapy (RT). Proc Am Soc Ther Radiat Oncol. 2005;63(suppl 1):S451. 13 Weeks J. Follow-up: Action on erroneous JAMA Oncology “Complementary Medicine Kills” article. The Integrator Blog. http://www.johnweeks-integrator. com/uncategorized/follow-up-action-on-erroneous-jama-oncology-complementary-medicine-article/. Published August 24, 2018. Accessed October 11, 2018.

14 Bakalar N. Alternative cancer treatments may be bad for your health. New York Times. https://www.nytimes.com/2018/07/23/well/alternative-cancer-­treatments-therapiesharm-health-death.html. Published July 23, 2018. Accessed October 11, 2018.

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  23


PEER-REVIEWED ARTICLE

Let’s Talk About Sex: Sexuality During and After Cancer Treatment Attention to sexuality can profoundly enhance well-being ABSTRACT Cancer alters almost every aspect of patients’ and caregivers’ lives, including their sexuality. Many factors during cancer treatment can impact sexual desire, including sequelae of treatments, fatigue, hormonal changes, and pain. Patients look to their healthcare providers to start the conversation about sexuality, and many never receive information about how cancer treatments may alter their sexuality. Sexual intimacy includes much more than intercourse. Providers can help patients and their partners expand their understanding of intimacy and sexuality to include all aspects of sensuality. Lesbian, gay, bisexual, transgender, and queer (LGBTQ) patients and their partners require appropriate support, both during and after cancer treatment. Sexuality has a place in end-of-life care and can profoundly enhance a patient and their partner’s last phase of their life together. Vaginal dryness, one of the most commonly reported sexual concerns for women, can be addressed with nonhormonal treatments. For men, difficulty achieving and maintaining an erection is one of the most widely reported sexual concerns. Conventional treatments for erectile dysfunction (ED) include phosphodiesterase type 5 (PDE5) inhibitor therapy; constriction devices, intraurethral prostaglandins, and penile injection therapy; and penile prosthesis implantation. Combining these therapies often yields better outcomes for cancer patients. Naturopathic and other vitalistic medicines offer tools to restore core energy, which in turn can enhance libido, intimacy, and sexuality.

Judith Boice, ND, LAc, FABNO

INTRODUCTION Over 15.5 million people in the United States have a history of cancer,1 and an estimated 60% of these cancer survivors report having sexual difficulties. Despite these astonishing figures, less than 20% of survivors seek a healthcare provider’s help for intimacy problems that result from their cancer treatment.2 Many cancer patients are unaware of how cancer treatments will impact their sexuality, and a minority of oncologists are willing to broach the subject. An Italian study of breast cancer survivors, for example, reported that 60% of postmenopausal and 39.4% of premenopausal breast cancer survivors developed vulvovaginal atrophy (VVA) as a result of cancer treatment. Despite this high rate of VVA, only 48% of breast cancer oncologists surveyed discussed the potential for vulvovaginal changes with their patients before the onset of treatment.3 Forty-one percent of the oncologists referred patients to a gynecologist for VVA treatment and 35.1% managed VVA on their own; 25% of the patients were unaccounted for. Context for sexuality: the life cycle of a relationship

Dr Patricia Love, in her book Hot Monogamy, clarifies why libido usually changes dramatically over the course of a relationship by identifying 3 distinct stages: 4 • S tage 1: During the first 6 months after falling in love, the body produces prodigious amounts of energizing, pleasure-­ producing hormones, including phenylethylamine, dopamine, and norepinephrine. Every thought about a partner, every touch, every interaction triggers a “dump” of these bliss-producing hormones. During this early stage, people will do all kinds of things they normally would not do in order to be with their new partner and experience this hormonal rush. • Stage 2: The production of the bliss-producing hormones declines over the next 18 to 24 months. • Stage 3: By 24 to 30 months, hormone levels return to normal range. At that point you hope you like your partner because the hormonal ride is over. According to the American Cancer Society, 9 out of 10 cancer patients are diagnosed after age 50; 5 therefore, many cancer

24 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

patients are in already established, long-term relationships, often well beyond the initial high-libido period. Why does libido decline?

difficulties included vaginal dryness, fatigue, and feeling unattractive. Men cited ED, the effects of surgery, and aging as most problematic. Conversely, several participants reported experiencing increased intimacy and closeness after cancer treatment.6

Any individual may experience decline of libido, for one or more of the following reasons:

Sexuality: beyond intercourse

• • • • •

 ecline of initial hormonal surge, as previously mentioned D Menopause Andropause Emotional distress Changes in cardiovascular function (affects the entire vascular system, including the genital region) • Fatigue Cancer patients face particular challenges that may lead to loss of libido: • C  ancer-related fatigue • Changes after surgery (eg, scar tissue formation, loss of tissue elasticity, pain) • Vaginal changes due to chemotherapy and/or radiation • Erectile dysfunction (ED) • Painful bone metastases • Loss of tissue elasticity from radiation • Changes in body image Although patients with pelvic tumors and reproductive cancers (cancers of the cervix, ovaries, uterus, vagina, vulva, breast, prostate, testicles, and epididymis) are at highest risk of developing sexual dysfunction, all cancer patients have increased tendency for issues with intimacy. Research in Britain revealed both men and women have reduced sexual frequency, sexual satisfaction, and engagement for both penetrative and nonpenetrative sexual activities after cancer treatment. These changes were true for reproductive and nonreproductive cancer types. Cancer survivors’ primary concerns included the physical consequences of cancer treatment; psychological factors; body image; and relationship factors. For women, the most commonly reported sexual

Male sexuality in our culture often is narrowed, even telescoped, to encompass only “erection” and “performance,” that is, the ability to sustain an erection and ejaculate. Survivors of prostate cancer often struggle with this limited understanding of sexuality, particularly if their cancer treatment alters or eliminates their ability to have an erection. Cancer impacts multiple physical and psychosocial domains, and ideally these patients would be viewed as a whole person within the context of a “biopsychosocial model” that includes their partner as a complex whole.7 One of the primary ways clinicians can support cancer survivors is to help them expand their understanding of sexuality to include sensuality. As a sexual signature, sensuality is the ability to fully experience one’s senses. Smelling, tasting, seeing, hearing, touching, and feeling combine to awaken the body and can strongly contribute to a sexual connection. Masters and Johnson’s book Heterosexuality includes a chapter, “Sex and Sensuality,” that outlines progressive exercises to cultivate sensuality in a sexual relationship. These exercises can easily be adapted to LGBTQ relationships as well. Cultivating sensuality in a relationship requires communication as each partner has his or her own particular comfort level for sensory stimulation.8 The impact of cancer treatment on caregivers

Many caregivers struggle with the impact of cancer treatments on their partners.9 Of 156 caregivers responding to a survey, 76% of partners with nonreproductive cancer types and 84% of those with reproductive cancers reported changes in their sexual relationship. Seventy-nine percent of male and 59% of female caregivers reported reduction or cessation of sexual activity. Despite these changes, only 14% of men and 19% of women discussed and renegotiated these changes with their partners.

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  25


PEER-REVIEWED ARTICLE

Caregivers offered several reasons for these adjustments including the impact of cancer treatments; exhaustion from their caregiving role; and redefining their mate as a patient, not a sexual partner. Caregivers associated sexual changes with self-blame, rejection, sadness, anger, and lack of sexual fulfillment. Ideally, all healthcare providers would acknowledge the sexual needs of people with cancer as well as their partners during cancer treatment and palliative care. SEXUALITY AND CANCER AMONG THE LGBTQ COMMUNITY The current medical system primarily is oriented to serve heterosexual patients. In the United States, however, a significant portion of the population identifies as lesbian, gay, bisexual, transgender, or queer. Because this group has been closeted, or, in truth, “hidden in plain sight,” for generations, the special needs and concerns of this population have been largely overlooked. Approximately 3% to 12% of adults in the United States identify as LGBTQ,10 and 0.6% of the US population identify as transgender.11 Definitions

Lesbian, gay, and bisexual are defined by sexual orientation or sexual attraction. Those who identify as transgender relate to a gender that does not align with their sex assigned at birth.12 Queer or “questioning” identify as sexual and/or gender minorities but do not specifically identify as lesbian, gay, bisexual, or transgender. Queer also refers to people who are currently exploring their sexual orientation or gender identity.13,14 Special concerns and healthcare needs of the LGBTQ community

The LGBTQ community, also referred to as sexual and gender minorities (SGMs), is a medically underserved and understudied population in the United States.10 This population faces several barriers to healthcare, such as difficulty obtaining and/ or affording health insurance coverage, fear of judgment and/or stigmatization by healthcare providers, and healthcare providers’ lack of knowledge about LGBTQ-specific health issues.15

One in 5 transgender patients seeking healthcare is turned away by providers,16-18 and LGBTQ people are at increased risk for depression, anxiety, suicide, and substance abuse. Lesbian and bisexual women are more likely to be obese than straight women,19-22 which in turn increases their risk for developing cancer. Sexual minorities overall have increased incidences and mortality rates for several types of cancer, including the following: • Lung • Colorectal • Anal • Prostate • Cervical • Breast14-22 Many physicians incorrectly assume that because lesbian women do not have intercourse with men, they are at lower risk for contracting human papilloma virus (HPV) and therefore at lower risk of developing cervical and other reproductive cancers. Data demonstrates just the opposite: bisexual women have the highest rates of any type of cancer (17.6%), followed by lesbian women (14%) and heterosexual women (11.9%). Researchers suggest many possible contributing factors, including bisexual women passing HPV exposures from male to female partners; increased obesity rates in lesbian and bisexual women; and greater prevalence of high-risk health behaviors in the LGBTQ community, such as alcohol abuse and cigarette smoking.23 SEXUALITY DURING END-OF-LIFE CARE For each patient, dying “is a process of personal trial and error.”24 Each patient must discover through his or her own experience what matters most during this final stage of life. Sexuality may or may not play an important role in a patient’s end-of-life journey.

26 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

For many older patients, sexuality may have shifted to nongenital sensuality. These patients and their partners tend to fit more easily into social and institutional norms, such as inpatient hospital and hospice environments.25

Benefits of sexuality in end-of-life care:

Younger patients may struggle with grief and anger over the loss of their sexual relationship. Patients both young and old may desire intimate connection in the most life-affirming way possible during this vulnerable time. They may want to touch and be touched, and they may require more privacy.26,27

• T  riggers oxytocin release in men and women,32 which acts on the emotional centers of the brain, generally leading to comforting feelings of warmth and relaxation33

Physician and medical sex therapist Dr Margaret Redelman notes, “It is the health professional’s responsibility to raise this issue.”28 Ideally healthcare providers would advocate for patients to have the privacy and support they need for intimacy during end-of-life care.

• Improves self-concept and sense of personal integrity29 • D  ecreases hypothalamic-pituitary-adrenal axis activity, which in turn modulates the autonomic nervous system30,31

• I ncreases oxytocin, which acts as a natural antistress neurotransmitter34 • Improves sleep quality35 and may have a sedative effect36 • I ncreases pain thresholds, specifically via vaginal self-­ stimulation that can produce analgesia rather than anesthesia37-40

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  27


PEER-REVIEWED ARTICLE

SEXUAL CHALLENGES FOR WOMEN AFTER CANCER TREATMENT Talking about sexuality with women

In a cross-sectional survey of 218 women with a history of breast or gynecological cancer, 70% (n=152) reported they preferred that the medical team raise the topic of sexual health needs; 48% (n=105) raised the topic themselves. Most (66%; n=144) preferred written educational material followed by discussion with their healthcare provider. Younger women preferred to discuss their concerns face-to-face. Older women were less interested in online interventions, despite 94% having computer access.41

burning sensation, severe dyspareunia, dysuria, and stress urinary incontinence.46,47 Many women face this problem for more than one-third of their adult life,45 making it an important issue to address.

Healthcare providers can support women by broaching the topic, offering written information, and scheduling time to discuss concerns and review treatment suggestions.

According to research conducted in 2012 as part of the National Survey of Sexual Health Behavior, 30% of women over age 18 report pain during vaginal sex, 72% report pain during anal sex, and “large proportions” don’t tell their partners when sex is painful.48 Debra Herbenick, PhD, a professor at the Indiana University School of Public Health and one of the researchers behind the National Survey of Sexual Health and Behavior notes, “when it comes to ‘good sex,’ women often mean without pain, men often mean they had orgasms.”49

Breast cancer treatment and sexuality

Addressing vulvovaginal atrophy

Recent research demonstrates that the more invasive a woman’s breast cancer surgery, the more likely she is to have sexual dysfunction after treatment. In one study, 34% of 74 breast surgery patients reported having sexual dysfunction after surgery.¹ Of the women who had conservative mastectomy, however, only 14% reported having sexual dysfunction. Of women who had a radical mastectomy plus reconstruction, 29% reported having sexual difficulties, while 63% of those who had radical mastectomy without reconstruction reported having sexual dysfunction. The women who had mastectomy without reconstruction tended to be older. Age and changes in self-image in addition to the invasiveness of their surgery may have contributed to the significantly higher rate of sexual dysfunction among this group of patients.

Vaginal dryness is the most commonly reported symptom women experience after gynecological cancer treatment. Most oncologists (71%) prefer nonhormonal treatments because of the fear of increased cancer recurrence, possible interference with tamoxifen or aromatase inhibitors, and fear of litigation.3 The following are the primary nonsurgical means of rejuvenating vulvovaginal tissue:

Genitourinary syndrome of menopause (GSM)

Lubricants

Genitourinary syndrome of menopause (GSM) affects approximately 50% of postmenopausal women.42-44 Genitourinary syndrome of menopause is characterized by the involution of genitourinary mucosa and the adjacent vulvo-vaginal tissues, and a reduction in both the quantity of elastic fibers and the vascularization of genitourinary tissue.45 As a result, the vaginal diameter contracts and the vaginal epithelium becomes susceptible to infection. The clinical presentation may include dryness,

• Lubricants • Hormones • Carbon dioxide (CO2) laser • Radiofrequency devices For cancer patients, the first-line therapy for vaginal dryness is regular applications of water-based gels and vaginal moisturizers to hydrate the vaginal wall.50,51 Vaginal moisturizers are similar to vaginal lubricants but stay in contact longer with the vaginal wall, thereby heightening their lubricating effects. Vaginal moisturizers may have similar efficacy to topical vaginal estrogen and ideally would be offered to women who choose to avoid hormone therapy.52

28 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

One research study compared the efficacy of vitamin E suppositories to 0.625 mg of conjugated estrogen cream applied nightly for 2 weeks, then twice a week for another 10 weeks. The study measured “success” as an increase in the vaginal maturation value of at least 10 units. Seventy-six percent of the vitamin E group and 100% of the conjugated estrogen group successfully reached this benchmark.53 Another study compared hyaluronic acid gel with estriol cream for vaginal dryness. Both groups reported a similar improvement in vaginal lubrication; however, the estriol group had a decrease in vaginal pH and the hyaluronic acid group did not.54 The OVERcome trial (n=25) incorporated olive oil, vaginal exercise and moisturizer to address vaginal dryness. The women performed pelvic floor muscle relaxation exercises twice a day to manage pelvic floor muscle tension. They also applied a polycarbophil-based vaginal moisturizer 3 times a week to alleviate vaginal dryness, used olive oil as a lubricant during intercourse, and completed a weekly compliance diary. The women rated pelvic floor muscle relaxation exercises (92%), vaginal moisturizer (88%), and olive oil (73%) as helpful. Researchers also reported an unexpected finding—6 of the women (11%) had vaginal stenosis.55 Many patients who are diagnosed with vaginal stenosis are incorrectly told they can never regain normal vaginal elasticity. With patience and gradual stretching, women can restore normal vaginal elasticity. Vaginal dilators can be used for this purpose, as can a finger gently inserted into the vagina. Over time the woman uses a larger diameter dilator or inserts a larger finger, or more than 1 finger. Gentle, gradual stretching over time is the key to success. Choosing an appropriate vaginal lubricant

Vaginal lubricants vary widely in osmolality and pH. Normal vaginal pH ranges from 3.8 to 4.5. Vaginal pH commonly becomes more alkaline after menopause, which can increase the tendency for vaginal and urinary tract infections. Ideally, a vaginal lubricant for a menopausal woman would be slightly acidic and have an appropriate osmolality. Some water-based

lubricants are hyperosmolar, which dehydrates the vaginal cells and increases susceptibility to sexually transmitted infections. This is most commonly caused by glycerin, so women should avoid water-based lubricants that list glycerin among the top 3 ingredients. Edwards and Panay compiled an excellent international review of lubricant and moisturizer products that summarizes ingredients, pH, and osmolality. This is a valuable guide to choosing the correct products for a particular patient (eg, “sperm friendly,” anal, vaginal lubricants).56 The author’s clinical experience is that calendula suppositories improve vaginal dryness, but there is no data to support this in clinical practice. Coconut or olive oil on a nightly basis may also be helpful. The key to success is using a lubricant nightly, regardless of whether the patient engages in penetrative sexual activity or not. Topical vaginal hormones for cancer survivors

While the majority of oncologists avoid prescribing hormones for survivors of reproductive cancer, recent research suggests that certain hormones in extremely low doses may be viable for addressing VVA. While I personally am uncomfortable with this option, I offer this information as a foundation for discussion and consideration for patients with VVA. The most recent meta-analysis involving 3,898,376 participants and 87,845 cases of breast cancer demonstrated increased risk of developing breast cancer for women currently using estrogen replacement therapy and estrogen plus progestin therapy (EPT).57 Overweight and obese women who took hormone replacement therapy (HRT) were at lower risk of developing breast cancer than slim HRT users and nonusers; hence, weight may be an important factor in deciding whether or not to offer HRT after breast cancer treatment. The vaginal wall is extremely absorptive. A vaginal application of estradiol can increase blood levels 10 times higher than an equivalent oral dose.58 New research suggests that ultra-low doses of estriol (0.005%) may be effective for vaginal atrophy. In one study, women applied 1 g of either vaginal gel

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  29


PEER-REVIEWED ARTICLE

containing 50 mcg (0.05 mg) of estriol or placebo gel daily for 3 weeks and then 2 times a week for up to 12 weeks.59 Women using the estriol vaginal gel had a significant improvement in the vaginal maturation index and vaginal pH, while those using the placebo gel had no improvement compared with baseline.

estradiol. Maturation of vaginal cells was 100% (DHEA 3.25 mg/d), 86% (DHEA 6.5 mg/d), and 64% (plain moisturizer), suggesting that DHEA 3.25 mg is the more appropriate dose; pH decreased more in DHEA arms than with plain moisturizer.

Another study demonstrated a 7.5 mcg dose of estradiol delivered via vaginal ring was effective, as was a 10 mcg estradiol tablet inserted vaginally. These low doses did increase serum estrogen levels, but not above menopausal range of ≤20 pg/ mL.60 The question is whether any increase in estrogen levels is safe, particularly for women with estrogen receptor–positive breast cancer.

Hormone replacement therapy vs nonhormonal lubricants and vaginal pH

Vaginal dehydroepiandrosterone (DHEA) also has been investigated as a possible treatment for VVA. One study divided 464 postmenopausal women with a history of breast or gynecological cancer into 3 randomized arms for a 12-week controlled trial. One arm was given vaginal applications of DHEA 3.25 mg; a second arm DHEA 6.5 mg; and the control group plain moisturizer. All 3 arms reported improvement in either vaginal dryness or dyspareunia. Neither DHEA group was statistically different from the control group at 12 weeks, but the 6.5 mg DHEA group reported significantly improved sexual health at 6 weeks.61

Nonsurgical vulvovaginal rejuvenation is defined as “the application of thermal or nonthermal energy to vaginal tissue, stimulating collagen regeneration, contracture of elastin fibers, neovascularization, and improved vaginal lubrication.”63 Both aestheticians and gynecologists offer 2 types of nonsurgical, nonhormonal treatment for VVA: the Erbium:YAG (Er:YAG) laser and a variety of radiofrequency devices.

Of the women in this trial, 345 contributed evaluable blood, and 46 contributed evaluable cytology and pH values that facilitated further analysis.62 Circulating DHEA-S and testosterone levels increased significantly for those on vaginal DHEA in a dose-dependent manner compared to plain moisturizer. Estradiol was significantly increased in those on 6.5 mg per day DHEA but not in those on 3.25 mg per day DHEA (P<0.05 and P=0.05, respectively). Estradiol also did not increase in participants who were on aromatase inhibitors (AIs), which makes sense when considering the steroidogenesis pathway: DHEA → androstenedione ↔ testosterone → estradiol. “Excess” DHEA can convert to testosterone, which the aromatase enzyme can then catalyze to estradiol production. If that pathway is blocked, however, as in AI therapy, testosterone cannot convert testosterone to

Key point: both hormonal and nonhormonal lubricants will improve vaginal lubrication and maturation, but only hormonal supports will change (acidify) vaginal pH. Nonsurgical vulvovaginal rejuvenation

Carbon dioxide and Erbium:YAG laser treatments for vulvovaginal atrophy

Both carbon dioxide (CO2) and Er:YAG lasers have been evaluated for their ability to rejuvenate vaginal tissue. The Er:YAG is considered the “second generation” of thermotherapy for VVA.64 The Er:YAG laser emits light at a wavelength of 2.94 µm and is 16 times more highly absorbed by water than the CO2 laser light.65-67 Because of this higher water absorption rate, the Er:YAG causes much more superficial penetration and ablation of tissue. Most importantly, the Er:YAG laser does not increase the zone of thermal damage with each subsequent laser impact, as the CO2 laser does. Currently, the Er:YAG is the most commonly used laser treatment for VVA. With the Er:YAG laser patients usually are treated once a month for 3 months. Women are instructed to refrain from intercourse for at least 2 weeks after treatment. Laser treatments address the vagina only, not the perineum. Published data suggests the treatments need to be repeated annually.68,69

30 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

The Er:YAG laser has demonstrated promising results for breast cancer survivors. In one study 43 postmenopausal breast cancer survivors were treated with 3 laser applications every 30 days. Their symptoms were assessed before treatment and after 1, 3, 6, 12, and 18 months, using 2 methods: subjective visual analog scale (VAS) and objective Vaginal Health Index Score (VHIS). For all of the women in the study, vaginal dryness, VAS, dyspareunia, and VHIS scores significantly improved after the third treatment. The scores declined at 12 and 18 months but were still significantly improved compared with baseline. The study suggests “vaginal erbium laser is effective and safe for the treatment of genitourinary syndrome of menopause in breast cancer survivors.”68 Using laser devices for VVA truly is a formative science, and we do not have definitive answers about the optimal number and frequency of treatments. Athanasiou and Pitsouni aimed to address this question in a recently published study.69 In their study, 55 women received 3 sessions of CO2 laser therapy, 53 had an additional fourth session, and 22 had an additional fifth session. Results of their study are summarized in Figure 1. The authors concluded that laser therapy may contribute to complete regression of dyspareunia and dryness in a dose-­ response manner. An additional fourth or fifth session may further increase the GSM symptom-free rate. Radiofrequency devices for vulvovaginal rejuvenation

Radiofrequency devices are the newest options for treatment of VVA. The radiofrequency treatments include monopolar, bipolar, and multipolar devices. We have far fewer studies to corroborate their safety and effectiveness compared with laser treatments. Radiofrequency treatments are repeated weekly to monthly, usually for a total of 3 treatments. While the CO2 and Er:YAG lasers treat only the vagina, the radiofrequency devices rejuvenate the perineum as well. Women can have intercourse the same day. Like the laser treatments, the effects of radiofrequency treatments diminish over time and likely need to be repeated annually.70

Dyspareunia resolution

Vaginal dryness resolved

Normal sexual function

Vaginal maturation value

Vaginal health index score

n 3 treatments   n 4 treatments   n 5 treatments Figure 1. Improvement in sexuality-related parameters among women treated with carbon dioxide laser therapy for vulvovaginal atrophy after 3, 4, and 5 treatments.

Summary of nonsurgical treatment for vulvovaginal atrophy

Both the laser and radiofrequency treatments offer viable options for nonhormonal treatment of VVA. The CO2 and Er:YAG lasers have been used clinically for a couple of decades, while the radiofrequency devices offer promising new treatment options. The Er:YAG laser has been shown to benefit both VVA and mild to moderate stress urinary incontinence (SUI).71 Less is known about the effectiveness of the radiofrequency devices for treating SUI, but they have the added benefit of treating the perineum as well as vaginal tissue. Insurance companies do not currently cover either laser or radiofrequency treatments for VVA or SUI, and the out-of-pocket expenses are customarily $1,000 per treatment. SEXUAL CHANGES FOR MEN AFTER CANCER The primary sexual concerns men report after cancer treatments are ED, surgical sequelae, and age-related changes.6 Prostate cancer is the most commonly diagnosed non–skin cancer for men, and treatments can have a devastating effect on sexuality. The Fourth International Consultation for

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  31


PEER-REVIEWED ARTICLE

Sexual Medicine (ICSM 2015) made the following recommendations for healthcare practitioners working with prostate cancer patients: • H  ealthcare providers should discuss the potential for postsurgical ED, temporary or permanent, with every candidate for radical prostatectomy (RP). • M  en undergoing RP are at risk of sexual  changes other than ED, including the following:

n

Decreased libido

n

n

n

n

Changes in orgasm Anejaculation Peyronie-like disease Changes in penile size

• N  o conclusive evidence supports any specific surgical technique (eg, open vs laparoscopic vs robot-assisted RP) as promoting better postoperative erectile function (EF) recovery results. • D  ata are inadequate to support any specific regimen as optimal for penile rehabilitation. • Recovery of postoperative EF can take several years. • R  ecognized predictors of EF recovery include but are not limited to younger age, preoperative EF, and bilateral nerve-sparing surgery. Impacts of prostatectomy and radiotherapy treatments

Prostate cancer patients often undergo either RP or radiotherapy but may not be given information about the possible outcomes of these treatments. At 2 and 5 years posttreatment, patients who have RP are more likely to have urinary incontinence and ED and less likely to have bowel urgency than those who have radiotherapy. At 15 years, however, there is no significant difference in sequelae between the 2 treatment groups.72 In the short term (2-5 years), patients are choosing between urinary incontinence and ED or bowel urgency. While both treatments involve challenging side effects, having this

information allows a patient to make informed choices that can significantly impact his lifestyle. A late-stage prostate cancer patient with a poor prognosis for whom sexual life is very important, for example, may choose treatment that preserves his EF. For an earlier stage prostate cancer patient who has a good long-term prognosis and wishes to continue traveling, choosing RP may be more appropriate so that he can avoid bowel urgency. Another major decision facing RP patients is whether and when to have salvage radiation therapy (SRP). Erectile recovery after nerve-sparing surgery takes 18 to 24 months.73 However, 3 recent studies (Southwest Oncology Group [SWOG], European Organization for Research and Treatment of Cancer [EROTC], and a German study), all suggest the optimal time for radiation salvage treatment is within a month of RP surgery.74-76 This creates a very difficult balance between protecting healing time after RP to optimize sexual function and initiating radiation therapy for maximum benefit. Factors that predict greater success with salvage radiation include the following: 77 • Gleason’s score of >8 • P  re-radiation therapy prostate-specific antigen (PSA) of >2.0 ng/mL • Positive surgical margins • W  hen treatment was given for early recurrence (PSA level ≥2.0 ng/mL), patients with Gleason scores of 4 to 7 and a rapid PSA doubling time (PSADT) had a 4-year ­progression-free probability (PFP) of 64% (95% confidence interval [CI]: 51%-76%) and 22% (95% CI: 6%-38%) when the surgical margins were positive and negative, respectively. Note that the patients with positive surgical margins had a better PFP (64%) than those with negative margins (22%). • Pretreatment PSADT of >10 months • No seminal vesicle invasion

32 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

Patients with all 5 features had a greater than 70% chance of biochemical control 4 years after SRP.78 Researchers have relied primarily on retrospective studies to determine the efficacy of adjuvant radiation therapy (ART) and SRT. Three prospective studies currently are underway, comparing ART vs early salvage: RADICALS (NCT00541047), RAVES (NCT00860652), and GETUG 17 (NCT00667069). These trials have comparable designs and recruited men with high-risk disease at RP with a postoperative PSA<0.2 ng/mL. Men in the control arm all receive prompt SRT in the event of rising PSA, which was a weakness in the 3 retrospective studies. Researchers plan to pool analyses of these 3 trials for a total of more than 1,200 patients to help determine the role of ART.79 Three lines of therapy for erectile dysfunction

Conventional medicine offers 3 lines of therapy to address EF for noncancer patients: • First line: phosphodiesterase-5 inhibitor (PDE5) therapy • S econd line: vacuum constriction devices, intraurethral prostaglandins, and penile injection therapy • Third line: penile prosthesis implantation Combining these therapies often yields better outcomes for cancer patients. First line: phosphodiesterase-5 inhibitor therapy

Originally developed by Peter Dunn and Albert Wood for angina and hypertension, PDE5 drugs had the unexpected, and extremely lucrative, side effect of changing EF. The PDE5 drug class now includes 5 drugs that vary primarily in the speed and duration of their effect. Although PDE5 drugs are a first-line therapy, some cancer patients, particularly latestage patients, are not good candidates for this treatment. The PDE5 drugs are strong cytochrome P-450(CYP)3A4 pathway metabolizers and have a more minor impact on CYP2C and CYP3A5 pathways, all of which can interfere with chemotherapy and immune therapy drugs. In addition, these drugs are not recommended for patients with renal

and/or hepatic impairment, fairly common conditions with late-stage cancer patients. Insurance companies may not cover the cost of PDE5 drugs for ED, and a single pill can cost up to $22.49, making this therapy cost-prohibitive. L-arginine, saw palmetto and Pycnogenol for erectile dysfunction

Supplementing L-arginine and Pycnogenol may offer support for ED.80 In one study, 40 men ages 25 to 45 with mild ED were given 1.7 g L-arginine per day for 1 month. At the end the month, 5% of the men experienced normal erections. During the second month, study participants added 80 mg Pycnogenol to the L-arginine. At the end of the second month, 80% achieved normal EF. During the third month, study participants continued L-arginine and increased Pycnogenol to 120 mg, and 92.5% achieved normal EF. Participants in this study were relatively young in comparison with the average age of 66 for prostate cancer diagnoses.81 The improvements during the second and third months may have been a result of prolonged L-arginine therapy rather than the addition of Pycnogenol. Another study compared the effects of taking 320 mg of saw palmetto (n=19) with supplementing a combination of 368 mg aspartate, 460 mg L-arginine, and 80 mg Pycnogenol (n=20). Both groups showed improvement in International Prostate Symptom Score (IPSS) and IPSS-QOL. The Pycnogenol, arginine, and aspartate group also showed improvements in Overactive Bladder Symptom Score (OABSS) and International Index of Erectile Function 5 (IIEF-5). Neither group showed changes in incontinence or uroflowmetry.82 A study comparing L-arginine and L-citrulline levels in controls and patients with ED found a significant proportion of ED patients had low L-arginine or L-citrulline levels, particularly patients with arteriogenic etiology of ED.83 The study demonstrated that oral L-citrulline supplementation increases serum L-arginine levels more efficiently than L-arginine by itself, which in turn increases nitric oxide (NO) production.84

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  33


PEER-REVIEWED ARTICLE

Contraindications for L-arginine supplementation

Despite the benefits of L-arginine therapy for ED, recent research suggests cancer therapies that reduce arginine levels promote prostate cancer autophagy and cell death.85,86 Because L-arginine increases NO and therefore blood flow, albeit for a very short duration, L-arginine may potentiate prostate cancer growth. The bottom line: use L-arginine and other NO-promoting amino acids with caution for prostate cancer patients. Second-line therapies: vacuum erectile devices and penile injection therapy

Fibrotic changes following RP can be prevented by increasing oxygenation of the corpora. Vacuum erectile devices (VEDs) can be used daily for 5 to 10 minutes without the constriction ring to maximize venous flow and oxygenation. The constriction ring

prevents venous outflow, thereby reducing the percentage of oxygenated blood and resulting in ischemia after 30 minutes. Vacuum erectile devices are an excellent treatment option after RP surgery because they can stimulate oxygenation of the corpora without the need for an intact nerve supply. Increasing oxygenated blood flow may reduce or even reverse fibrotic changes after RP.87 Studies demonstrate that a VED used for 5 to 10 minutes per day in combination with the PDE5 drug tadalafil taken 3 times a week has a success rate of 90% as measured by the IIEF-5 at 1 year. In comparison, RP patients taking tadalafil alone, without using the VED, had a 60% success rate.88 The combination of VEDs with the PDE5 drug sildenafil after RP surgery resulted in 30% of the men

Discover TAP Integrative Integrative Clinical Protocols Full-text Articles Research Summaries

JOIN NOW Case Studies CEU and CME Free article retrieval Your trusted resource for clinician-tested, evidence-based clinical information. Practitioners, join now for only $99 (30% discount!) using the promo code: NMJ-TAP 34 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

reporting a return of spontaneous erections.89 In summary, VEDs can enhance the effectiveness of other ED therapies. Penile injection therapy

In France, the primary sexual rehabilitation treatment is intracavernous alprostadil injections (IAI). The French healthcare system, financed by government national health insurance, will pay for IAI therapy but not for PDE5 drugs. Several studies demonstrate EF improves with early and regular IAI alone and/or in combination with other therapies. A French study examined the effectiveness of IAI injections beginning 1 month after surgery.90 Patients learned how to administer their own twice-weekly injections and continued the treatment for a year. They were encouraged to have intercourse as often as possible. One segment of the study group continued injections for another year, but they experienced no more improvement after the first year. Study participants who continued treatment beyond 12 months reported an increase in penile pain, and 30.6% of the patients reported worsened erection at 24 months compared with 12 months. In the United Kingdom, the annual cost for VED plus PDE5 therapy is approximately US $349, with an 80% compliance rate. In contrast, the annual cost of penile injection therapy is approximately US $1,533 per year, with only a 40% compliance rate. Third-line therapy: 3-piece inflatable devices

Penile implants offer flaccidity and erection that approach natural function. Design improvements in the last 5 years have reduced mechanical failures, resulting in a 92% to 94% success rate. These newer implants have antibiotic and hydrophilic coatings that have significantly reduced infection rates. The primary risks with penile implants are infection and penis shortening.91 Men can enhance recovery from implant surgery by inflating the penile implant daily for the first 6 months. After that time, 6 to 12 months post-surgery, patients ideally would inflate to maximum for 60 to 120 minutes each day. Following

One of the primary ways clinicians can support cancer survivors is to help them expand their understanding of sexuality to include sensuality.

this protocol, some men have an increase in penile size at 6 months and 12 months.98 REVITALIZING SEXUAL HEALTH When patients request help with increasing libido, restoring their core vitality is helpful so that they have enough energy to “over-spill” into their genital organs. Although reproduction is essential for our survival as a species, the genital organs are not essential for our personal survival. For example, 91% of 738 young females studying health sciences reported menstrual problems including irregular menstruation (27%), abnormal vaginal bleeding (9.3%), amenorrhea (9.2%), menorrhagia (3.4%), dysmenorrhea (89.7%), and premenstrual symptoms (46.7%). Researchers found a significant positive correlation between high perceived stress and menstrual problems,92 suggesting that the body places its attention first on the vital organs, that is, the heart, lungs, intestines, and liver, before sharing vitality with the reproductive organs. Frequency of intercourse

Personal and cultural expectations about sexuality can strongly impact a patient’s distress about libido. Classical medical systems, including Chinese medicine, aim for a balance between too little and too much sexual activity. The table on page 36 represents a summary from the classic Chinese text, the Su Nei Jing (Table).

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  35


PEER-REVIEWED ARTICLE

Table. Chinese Medicine Guidelines for Frequency of Intercoursea Age (y)

Minimum

Average Health

Good Health

20+

Every 4 days

Once a day

Twice a day

30+

Every 8 days

Every other day

Once a day

40+

Every 16 days

Every 4 days

Every 3 days

50+

Every 21 days

Every 10 days

Every 5 days

60+

Every 30 days

Every 20 days

Every 10 days

Adapted from Wood E, 2015.93

a

Integrative practitioners have a wide variety of therapies that can enhance core vitality. Improving nutrition, for example, can profoundly increase a patient’s vitality. The Mediterranean diet in particular has been shown to improve ED.94 Late-stage cancer patients may not be able to engage in strenuous physical activity, but restorative exercise such as yoga, qigong, and tai chi could be very beneficial. Improving the quality and length of sleep reduces risk of several types of cancer95-97 and increases energy reserves for fueling libido. Intercourse and chronic illness: Traditional Chinese Medicine perspective

Much of the discussion to this point has supported intercourse and intimacy during cancer treatment and survivorship. While Traditional Chinese Medicine (TCM) supports physical intimacy with a partner, intercourse is discouraged. From a TCM perspective, ejaculation for men and vaginal lubrication for women expend “jing,” the vitality inherited from our ancestors, as well as qi. During late-stage disease, these energy sources ideally are reserved for healing and restoration. The Japanese practice of “Karezza”98 encourages sexual penetration followed by relaxation and intimate touching, without progressing to orgasm. Taoist sexual practices focus on raising sexual energy and then directing it into the internal organs for rejuvenation.

Both practices focus sexual energy inward for revitalization, rather than “spending” the energy through orgasm.99,100 Enhancing intimacy for cancer patients

Cancer patients and others with late-stage, chronic diseases can enhance intimacy by planning ahead. Encourage patients to set dates and start “making love” 3 days beforehand; for example, leaving notes for each other, spending more time talking intimately, and cuddling. The dates might be scheduled early in the day, when a patient’s energy level is higher. Patients may clear out other appointments and even nap to save energy for that special time with their partner. Holding hands increases intimacy, as does emotionally vulnerable conversation. During the date, let go of the expectation that intimacy will lead to intercourse. Aim to be in the moment as much as possible, enjoying each other’s company. Sex therapist Jane Guyn, PhD, RN, recommends the 5 most erotic things you can do with your mouth: kissing, licking, biting, sucking, and talking. “The fifth one is actually the most important,” says Guyn. “When you talk to your partner about what is true for you, you can create something that is absolutely fantastic.”101 SUMMARY Cancer alters almost every aspect of patients’ and caregivers’ lives, including their sexuality. Patients look to their healthcare providers to start the conversation about sexuality. Many patients never receive information about how cancer treatments may affect their sexuality. You can be a vital resource for filling those information gaps. Sexuality is much more than intercourse. You can help patients and their partners expand their understanding of intimacy and sexuality to include all aspects of sensuality. Remember that LGBTQ patients and their partners require appropriate support, both during and after cancer treatment. Sexuality has a place in end-of-life care and can profoundly enhance a patient and their partner’s last phase of life together. Naturopathic and other vitalistic medicines offer tools to restore core energy, which in turn can enhance libido and sexuality.

36 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


PEER-REVIEWED ARTICLE

REFERENCES

1 National Cancer Institute. Cancer Statistics. https://www.cancer.gov/about-cancer/ understanding/statistics. Updated April 27, 2018. Accessed September 14, 2018. 2 Goodman, Alice. Improving Management of Sexual Problems for Cancer Survivors. The Asco Post. http://www.ascopost.com/issues/september-25-2016/improving-management-of-sexual-problems-for-cancer-survivors/. Published September 25, 2016. Accessed September 14, 2018. 3 Biglia N, Bounous VE, D’Alonzo M, et al. Vaginal atrophy in breast cancer survivors: attitude and approaches among oncologists. Clin Breast Cancer. 2017;17(8):611617. 4 Love P, Robinson J. Hot Monogamy: Essential Steps for More Passionate, Intimate Lovemaking. CreateSpace Independent Publishing Platform; 2012. 5 American Cancer Society. Who gets cancer? https://www.cancer.org/treatment/understanding-your-diagnosis/after-diagnosis/who-gets-cancer.html. Revised January 24, 2018. Accessed September 14, 2018. 6 Ussher JM, Perz J, Gilbert E; Australian Cancer and Sexuality Study Team. Perceived causes and consequences of sexual changes after cancer for women and men: a mixed method study. BMC Cancer. 2015;15:268. 7 Katz A, Dizon DS. Sexuality after cancer: a model for male survivors. J Sex Med. 2016;13(1):70-78. 8 Masters W, Johnson V, Kolodny R. Sex and sensuality. In: Heterosexuality. New York, NY: HarperCollins; 1994:25-41. 9 Hawkins Y, Ussher J, Gilbert E, Perz J, Sandoval M, Sundquist K. Changes in sexuality and intimacy after the diagnosis and treatment of cancer: the experience of partners in a sexual relationship with a person with cancer. Cancer Nurs. 2009;32(4):271-280. 10 Quinn GP, Sanchez J, Sutton S, et al. Cancer and lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations. CA Cancer J Clin. 2015;65(5):384-400. 11 Flores AR, Herman J, Gates GJ, Brown T. How Many Adults Identify as Transgender in the United States? Los Angeles, CA: The Williams Institute; 2016:3. 12 Johnson CV, Mimiaga MJ, Bradford J. Healthcare issues among lesbian, gay, bisexual, transgender and intersex (LGBTI) populations in the United States: introduction. J Homosex. 2008;54:213-224. 13 Institute of Medicine (US) Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities. The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding. Washington, DC: National Academies Press; 2011. 14 Institute of Medicine (US) Board on the Health of Select Populations. Collecting Sexual Orientation and Gender Identity Data in Electronic Health Records: Workshop Summary. Washington, DC: National Academies Press; 2013. 15 Conron KJ, Scott G, Stowell GS, Landers SJ. Transgender health in Massachusetts: results from a household probability sample of adults. Am J Public Health. 2012;102(1):118-122. 16 Baig AA, Lopez FY, DeMeester RH, Jia JL, Peek ME, Vela MB. Addressing barriers to shared decision making among Latino LGBTQ patients and healthcare providers in clinical settings. LGBT Health. 2016;3(5):335-341. 17 Burkhalter JE, Margolies L, Sigurdsson HO, et al. The National LGBT Cancer Action Plan: a white paper of the 2014 National Summit on Cancer in the LGBT Communities. LGBT Health. 2016;3(1):19-31. 18 Boehmer U, Ozonoff AI, Miao X. An ecological analysis of colorectal cancer incidence and mortality: differences by sexual orientation. BMC Cancer. 2011;11(1):400. 19 Boehmer U, Ozonoff AI, Miao X. An ecological approach to examine lung cancer disparities due to sexual orientation. Public Health. 2012;126(7):605-612. 20 Boehmer U, Ozonoff AI, Timm A. County-level association of sexual minority density with breast cancer incidence: results from an ecological study. Sex Res Soc Policy. 2010;8(2):139-145. 21 Valanis BG, Bowen DJ, Bassford T, Whitlock E, Charney P, Carter RA. Sexual orientation and health: comparisons in the women’s health initiative sample. Arch Fam Med. 2000;9(9):843-853. 22 Cochran SD, Mays VM. Risk of breast cancer mortality among women cohabitating with same sex partners: findings from the National Health Interview Survey, 1997– 2003. J Womens Health (Larchmt). 2012;21(5):528-533. 23 Kerr DL, Ding K, Thompson AJ. A comparison of lesbian, bisexual, and heterosexual female college undergraduate students on selected reproductive health screenings and sexual behaviors. Womens Health Issues. 2013;23(6):347-355.

24 Taylor PB. Understanding sexuality in the dying patient. Nursing. 1983;13:54-55. 25 Lemieux L, Kaiser S, Pereira J, Meadows LM. Sexuality in palliative care: patient perspectives. Palliat Med. 2004;18:630-637. 26 Hordern A. Sexuality in palliative care: addressing the taboo subject. In: Aranda S, O’Connor M, eds. Palliative Care Nursing: A Guide to Practice. Melbourne, Australia: Ausmed; 1999:197-211. 27 Hordern A. Intimacy and sexuality for the woman with breast cancer. Cancer Nurs. 2000;23:230-236. 28 Redelman MJ. Is there a place for sexuality in the holistic care of patients in the palliative care phase of life? Am J Hosp Palliat Care. 2008;25(5):366-371. 29 Loehr J, Verma A, Sequin R. Issues of sexuality in older women. J Womens Health. 1997;6:451-457. 30 Carter CS. Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology. 1998;23:779-818. 31 Insel TR. A neuro-biological basis of social attachment. Am J Psychiatry. 1997;154:726-735. 32 Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf W, Davidson JM. Plasma oxytocin increases in the human sexual response. J Clin Endocrinol Metab. 1987;64:27-31. 33 Weeks DJ. Sex for the mature adult: health, self-esteem and countering ageist stereotypes. Sex Relation Ther. 2002;17:231-240. 34 Charnetski CJ, Brennan FX. Feeling Good Is Good for You: How Pleasure Can Boost Your Immune System and Lengthen Your Life. Emmaus, PA: Rodale Press; 2001 35 Weeks D, James J. Secrets of the Superyoung. New York, NY: Villard; 1998. 36 Odent M. The Scientification of Love. London, UK: Free Association Books; 1999. 37 Komisaruk BR, Whipple B. Evidence that vaginal self stimulation in women suppresses experimentally-induced finger pain. Soc Neurosci Abstr. 1984;10:675. 38 Komisaruk BR, Whipple B. The suppression of pain by genital stimulation in females. Annu Rev Sex Res. 1995;6:151-186. 39 Whipple B, Komisaruk BR. Elevation of pain threshold by vaginal stimulation in women. Pain. 1985;21:357-367. 40 Whipple B, Komisaruk BR. Analgesia produced in women by genital self-stimulation. J Sex Res. 1988;24:130-140. 41 Stabile C, Goldfarb S, Baser RE, et al. Sexual health needs and educational intervention preferences for women with cancer. Breast Cancer Res Treat. 2017;165(1):7784. 42 The North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013;20:888-902. 43 Portman DJ, Gass ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and The North American Menopause Society. Climacteric. 2014;17:557563. 44 Sturdee DW, Panay N. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric. 2010;13:509-522. 45 Fadare O. Vaginal stromal sclerosis: a distinctive stromal change associated with vaginal atrophy. Int J Gynecol Pathol. 2011;30:295-300. 46 Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: results from an international survey on vaginal atrophy. Maturitas. 2010;67:233-238. 47 Nappi RE, Kokot-Kierepa M. Vaginal health: insights, views & attitudes (viva)— results from an international survey. Climacteric. 2012;15:36-44. 48 Herbenick D, Schick V, Sanders SA, Reece M, Fortenberry JD. Pain experienced during vaginal and anal intercourse with other-sex partners: findings from a nationally representative probability study in the United States. J Sex Med. 2015;12(4):10401051. 49 Loofbourow L. The female price of male pleasure. The Week. http://theweek. com/articles/749978/female-price-male-pleasure. Published January 25, 2018. Accessed September 13, 2018. 50 Derzko C, Elliott S, Lam W. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy. Curr Oncol. 2007;14(Suppl 1):S20-S40. 51 Pruthi S, Simon JA, Early AP. Current overview of the management of urogenital atrophy in women with breast cancer. Breast J. 2011;17:403-408 52 Sinha A, Ewies AA. Non-hormonal topical treatment of vulvovaginal atrophy: an up-to-date overview. Climacteric. 2013;16(3):305-312.

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  37


PEER-REVIEWED ARTICLE

53 Parnan Emamverdikhan A, Golmakani N, Tabassi SA, Hassanzadeh M, Sharifi N, Shakeri MT. A survey of the therapeutic effects of vitamin E suppositories on vaginal atrophy in postmenopausal women. Iran J Nurs Midwifery Res. 2016;21(5):475-481. 54 Stute P. Is vaginal hyaluronic acid as effective as vaginal estriol for vaginal dryness relief? Arch Gynecol Obstet. 2013;288(6):1199-1201. 55 Juraskova I, Jarvis S. The acceptability, feasibility, and efficacy (phase I/II study) of the OVERcome (Olive Oil, Vaginal Exercise, and MoisturizeR) intervention to improve dyspareunia and alleviate sexual problems in women with breast cancer. J Sex Med. 2013;10(10):2549-2558. 56 Edwards D, Panay N. Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition? Climacteric. 2016;19(2):151-161. 57 Wang K, Li F, Chen L, Lai YM, Zhang X, Li HY. Change in risk of breast cancer after receiving  hormone  replacement  therapy  by considering effect-modifiers: a  systematic review and dose-response meta-analysis of prospective studies. Oncotarget. 2017;8(46):81109-81124. 58 Tourgeman DE, Gentzchein E, Stanczyk FZ, Paulson RJ. Serum and tissue hormone levels of vaginally and orally administered estradiol. Am J Obstet Gynecol. 1999;180(6):1480-1483. 59 Cano A, Estévez J, Usandizaga R, et al. The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. Menopause. 2012;19(10):1130-1139. 60 Santen RJ. Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels. Climacteric. 2015;18(2):121-134. 61 Barton DL,  Sloan JA, Shuster LT, et al. Evaluating the efficacy of vaginal dehydroepiandrosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance). Support Care Cancer. 2017;26(2):643-650. 62 Barton DL, Shuster LT, Dockter T, et al. Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance). Support Care Cancer. 2018;26(4):1335-1343. 63 Karcher C, Sadick N. Vaginal rejuvenation using energy-based devices. Int J Womens Dermatol. 2016;2(3):85-88. 64 Gambacciani M, Levancini M, Cervigni M. Vaginal erbium laser: the second-generation thermotherapy for the genitourinary syndrome of menopause. Climacteric. 2015;18(5):757-763. 65 Walsh JT, Flotte TJ, Deutsch TF. Er:YAG laser ablation of tissue: pulse duration, tissue type and thermal damage. Lasers Surg Med. 1989;9(4):12319- 12327. 66 Walsh JT, Deutsch TF. Er:YAG laser ablation: measurement of ablation rates. Lasers Surg Med. 1989;9(4):327-337. 67 Dickinson MR, Charlton A, King TA, Freemont J, Bramley R. Studies of Er:YAG laser interactions with soft tissue. Laser Med Sci. 1991;6(2):125-131. 68 Gambacciani M, Levancini M. Vaginal erbium laser as second-generation thermotherapy for the genitourinary syndrome of menopause: a pilot study in breast cancer survivors. Menopause. 2017;24(3):316-319. 69 Athanasiou S, Pitsouni E, Falagas ME, Salvatore S, Grigoriadis T. CO2-laser for the genitourinary syndrome of menopause. How many laser sessions? Maturitas. 2017;104:2428. 70 Qureshi AA, Tenenbaum MM, Myckatyn TM. Nonsurgical vulvovaginal rejuvenation with radiofrequency and laser devices: a literature review and comprehensive update for aesthetic surgeons. Aesthet Surg J. 2018;38(3):302-311. 71 Gambacciani M, Levancini M, Russo E, Vacca L, Simoncini T, Cervigni M. Long-term effects of vaginal erbium laser in the treatment of genitourinary syndrome of menopause. Climacteric. 2018;21(2):148-152. 72 Resnick MJ, Koyama T. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013;368:436-445. 73 Miller DC, Sanda MG, Dunn RL, et al. Long-term outcomes among localized prostate cancer survivors: health-related quality-of-life changes after radical prostatectomy, external radiation, and brachytherapy. J Clin Oncol. 2005;23(12):2772-2780. 74 Thompson IM, Tangen CM, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term follow-up of a randomized clinical trial. J Urol. 2009;181(3):956-962. 75 Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. 2005;66(9485):572578. 76 Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate

cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/ AUO AP 09/95. J Clin Oncol 2009;27(18):2924-2930. 77 Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291(11):13251332. 78 Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035-2041. 79 Pra AD, Abramowitz MC, Stoyanova R, Pollack A. Contemporary role of postoperative radiotherapy for prostate cancer. Transl Androl Urol. 2018;7(3):399-413. 80 Stanislavov R, Nikolova V. Treatment of erectile dysfunction with pycnogenol and L-arginine. J Sex Marital Ther. 2003;29(3):207-213. 81 American Cancer Society. Key statistics for prostate cancer. https://www. cancer.org/cancer/prostate-cancer/about/key-statistics.html. Revised January 4, 2018. Accessed September 14, 2018. 82 Yagi H, Sato R, Nishio K, Arai G, Soh S, Okada H. Effects of a supplement combining Pycnogenol (registered TM) and L-arginine aspartate on lower urinary dysfunction compared with saw palmetto extract. J Tradit Complement Med. 2017;7(1):117-120. 83 Barassi A, Corsi Romanelli MM, et al. Levels of L-arginine and L-citrulline in patients with erectile dysfunction of different etiology. Andrology. 2017;5(2):256261. 84 Shiota A, Hotta Y, Kataoka T, Morita M, Maeda Y, Kimura K. Oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction. J Sex Med. 2013;10(10):2423-2429. 85 Szlosarek PW. Arginine deprivation and autophagic cell death in cancer. Proc Natl Acad Sci U S A. 2014;111(39):14015-14016. 86 Hsueh EC, Knebel SM, Lo WH, Leung YC, Cheng PN, Hsueh CT. Deprivation of arginine by recombinant human arginase in prostate cancer cells. J Hematol Oncol. 2012;5:17. 87 Yuan J, Hoang AN, Romero CA, Lin H, Dai Y, Wang R. Vacuum therapy in erectile dysfunction—science and clinical evidence. Int J Impot Res. 2010;22(4):211219. 88 Engel JD. Effect on sexual function of a vacuum erection device post-prostatectomy. Can J Urol. 2011;18(3):5721-5725. 89 Albaugh JA. Addressing and managing erectile dysfunction after prostatectomy for prostate cancer. Urol Nurs. 2010;30(3):167-177, 166. 90 Yiou R, Bütow Z, Parisot J, et al. Is it worth continuing sexual rehabilitation after radical prostatectomy with intracavernous injection of alprostadil for more than 1 year? Sex Med. 2015;3(1):42-48. 91 Montague DK. Penile Prosthesis implantation for end-stage erectile dysfunction after radical prostatectomy. Rev Urol. 2005;7(Suppl 2):S51-S57. 92 Rafique N,  Al-Sheikh MH. Prevalence of menstrual problems and their association with psychological stress in young female students studying health sciences. Saudi Med J. 2018;39(1):67-73. 93 Wood E. The connection between sexual frequency and good health. http://www.bensprostate.com/the-connection-between-sexual-frequency-and-good-health/Published September 17, 2015. Accessed September 15, 2018. 94 Di Francesco S, Tenaglia RL. Mediterranean diet and erectile dysfunction: a current perspective. Cent European J Urol. 2017;70(2):185-187. 95 Thompson CL, Parker EK, Patel S, Berger NA, Redline A, Li L. Short duration of sleep increases risk of colorectal adenoma. Cancer. 2011;117(4):841-847. 96 Thompson Cl, Li L. Association of sleep duration and breast cancer OncotypeDX recurrence score. Breast Cancer Res Treat. 2012;134(3):1291-1295. 97 Hu ML, Yeh KT, Lin PM. Deregulated expression of circadian clock genes in gastric cancer. BMC Gastroenterol. 2014;14:67. 98 Lloyd JW. The Karezza Method: Magnetation, the Art of Connubial Love. London, United Kingdom: Forgotten Books; 2008. 99 Chia M, Chia M. Healing Love Through the Tao: Cultivating Female Sexual Energy. Merrimac, MA: Destiny Books; 2005 100 Chia M, Winn M. Taoist Secrets of Love: Cultivating Male Sexual Energy. Santa Fe, NM: Aurora Press; 1984. 101 From an interview for “Healing Body and Soul Summit: The Power of Earth and Spirit in Healing the Body” September 15, 2018.

38 ©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)


SPONSORED PODCAST

Probiotics and Cancer Prevention: A Conversation with Ross Pelton, RRh, CCN Sponsored by Essential Formulas Incorporated Play Now

Approximate listening time: 32 minutes

In this podast episode, we speak with Ross Pelton, RRh, CCN, about the variety of mechanisms of action that probiotics have when it comes to reducing cancer risk. Pelton also talks about colon cancer, H. pylori, and probiotic safety and dosage. Finally, he describes how to support a healthy microbiome with a healthy lifestyle.

ABOUT THE EXPERT

ABOUT THE SPONSOR

Ross Pelton, RPh, CCN, is Essential Formula’s director of science, in addition to being a practicing pharmacist, clinical nutritionist, and health educator in Southern Oregon. Pelton earned his bachelor of science in pharmacy from the University of Wisconsin. A certified clinical nutritionist, Pelton was named as one of the Top 50 Most Influential Pharmacists in the United States by American Druggist magazine for his work in natural medicine. Pelton teaches continuing education programs for healthcare professionals to use natural medicine and integrate it into their practices. He also has authored numerous books, including The Drug-Induced Nutrient Depletion Handbook, which is a gold-standard reference book for health practitioners.

Essential Formulas Incorporated (EFI) was established in 2000 as the sole US distributor of world-renowned microbiologist Dr. Iichiroh Ohhira’s award-winning probiotic dietary supplements and skin care products. Always an innovator, EFI introduced REG’ACTIV in 2015, containing ME-3, a probiotic catalyst that produces the “master’” oxidant glutathione inside the body’s cells. A family-owned and operated business, EFI was founded on the philosophy of providing high-quality preventative, supportive, and comprehensive pro-health products for the entire family. EFI continues to flourish and grow through a strong company and product integrity and the knowledge that they’re providing scientifically proven products that positively impact the health and well-being of their customers.

SUBSCRIBE TO THE NMJ

PODCAST IN iTunes

©2018 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2018 SUPPLEMENT—VOL. 10, NO. 101 (SUPPL)  39

Profile for Impact Health Media

Natural Medicine Journal Oncology Special Issue 2018  

Our annual update on integrative oncology includes papers on sexuality after diagnosis, the recent headline-grabbing JAMA study, and more.

Natural Medicine Journal Oncology Special Issue 2018  

Our annual update on integrative oncology includes papers on sexuality after diagnosis, the recent headline-grabbing JAMA study, and more.