Natural Medicine Journal Oncology Special Issue 2014 by Diversified Communications

FEBRUARY 2014 SUPPLEMENT

SPECIAL ISSUE

Oncology

TREATMENT PROTOCOL

INTERVIEW WITH HEATHER ZWICKEY, PhD

Intravenous Vitamin C in Cancer Care

Chemotherapy-Induced Immunosuppression

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SPECIAL ISSUE ONCOLOGY FEBRUARY 2014 VOL 6, NO. 2 (SUPPL)

Contents

AUDIO INTERVIEW

Advancing Integrative Oncology

An Interview with Heather Greenlee, ND, PhD

ABSTRACTS & COMMENTARY

New Evidence Suggests Chemoprevention Activity of Green Tea Supplements

American Ginseng Improves Cancer-Related Fatigue

Flaxseeds Reduce Prostate Cancer Aggressiveness

Leaky Gut and Chemo: To Treat or Not to Treat?

PEER-REVIEWED ARTICLE

Intravenous Vitamin C in Cancer: A Brief Overview of Its Use and Considerations

by Michael Traub, ND, DHANP, FABNO, Paul S. Anderson, ND

EXPERT Q&A

Chemotherapy-induced Immunosuppression

A discussion with researcher Heather Zwickey, PhD

This Issue’s Contributors LISE ALSCHULER, ND, FABNO, is a naturopathic physician with board certification in naturopathic oncology. She practices naturopathic oncology at Naturopathic Specialists LLC—New Hampshire, specializing in prevention and naturopathic care Lise Alschuler, ND, FABNO for people who have been affected by cancer. Alschuler has authored many articles in professional and popular press publications and coauthored The Definitive Guide to Cancer: An Integrative Approach to Prevention, Treatment and Healing (Celestial Arts, 2010) and The Definitive Guide to Thriving After Cancer (Random House, 2013). Alschuler is past-president of the AANP and is vice president of quality and education at Emerson Ecologics. PAUL S. ANDERSON, ND, is medical director of Anderson Medical Specialty Associates. We was formerly a professor of pharmacology and clinical medicine at Bastyr University and chief of IV services for Bastyr Oncology Research Center. Anderson Paul S. Anderson, graduated from the National College ND of Natural Medicine and began instructing classes at naturopathic medical schools in the early 1990s. He continues to hold board review classes and continuing medical education courses for most of the naturopathic programs in the United States and Canada. He also is a founding board member of the Academy of Parenteral Therapies specialty group and an instructor and author for the International IV Nutritional Therapy for Professionals IV Therapy training group. In addition to being the publisher of Natural Medicine Journal, KAROLYN A. GAZELLA has been writing and publishing wellness information since 1992. She is the author or coauthor of hundreds of articles and several books including the two books that Karolyn A. Gazella she has written with Dr. Lise Alschuler, The Definitive Guide to Cancer and The Definitive Guide to Thriving After Cancer. For more information, visit www.karolyngazella.com.

TINA KACZOR, ND, FABNO, is a naturopathic physician, board certified in naturopathic oncology. She is in private practice at the Clinic of Natural Medicine in Eugene, Ore. Kaczor received her naturopathic doctorate from National College of Natural Medicine and completed her residency in naturopathic oncology at Cancer Treatment Tina Kaczor, ND, Centers of America in Tulsa, Okla. She has been FABNO published in several peer-reviewed journals and is the senior medical editor of Natural Medicine Journal. Kaczor writes and lectures extensively on a broad range of topics in natural medicine, with specific expertise in naturopathic oncology. For more information, visit clinicofnaturalmedicine.com.

Landon Opunui, ND

LANDON OPUNUI, ND, is a naturopathic physician in his first year of residency at Lokahi Health Center. Opunui received his naturopathic doctorate from Bastyr University and his undergraduate degree from Loyola Marymount University. He currently serves as the treasurer of the Hawaii Society of Naturopathic Physicians. For more information visit DrOpunui.com.

JACOB SCHOR, ND, FABNO, is a graduate of National College of Naturopathic Medicine and now practices in Denver. He served as president to the Colorado Association of Naturopathic Physicians, and is now on the board of directors of the Oncology Association of Naturopathic Physicians and is recognized as a Fellow by the Jacob Schor, ND, American Board of Naturopathic Oncology. He FABNO is the assistant medical editor for Natural Medicine Journal and serves on the editorial board for the International Journal of Naturopathic Medicine. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears often in Naturopathy Digest and Naturopathic Doctor News and Review. MICHAEL TRAUB, ND, DHANP, FABNO, has been medical director of Lokahi Health Center in Hawaii for the past 29 years. He is past-president of the American Association of Naturopathic Physicians and was awarded the AANP’s Naturopathic Physician of the Year award in 2006. He is a member of the ExamMichael Traub, ND, ining Board of the American Board of NaturoDHANP, FABNO pathic Oncology. As past chairman of the Hawaii Board of Naturopathic Medicine, he helped develop guidelines for parenteral therapy.

SENIOR MEDICAL EDITOR Tina Kaczor, ND, FABNO

MESSAGE FROM THE PUBLISHER

ASSOCIATE MEDICAL EDITOR Jacob Schor, ND, FABNO

Time for Collaboration, Integration, and Patient-Centered Care

PUBLISHER Karolyn A. Gazella EDITOR-IN-CHIEF Deirdre Shevlin Bell COMMUNICATIONS SPECIALIST Adam Skogen DESIGN Karen Sperry PUBLISHED BY CHAT Inc. P.O. Box 17232 Boulder, CO 80308 Natural Medicine Journal (ISSN 2157-6769) is published 12 times per year by CHAT Inc. Copyright © 2014 by CHAT 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; CHAT 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. CHAT 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.

Quit the Cure

On February 3, 2014, the International Agency for Research on Cancer (an arm of the World Health Organization) announced that each of the next 22 years will bring 22 million new cancer cases worldwide. This is up considerably from about 14 million new cancer cases in 2012. Deaths from cancer are expected to rise from 8.2 million to 13 million per year. Statistics aside, you don’t need to be an oncologist to witness the toll of cancer—you need only to be alive. Everyone experiences cancer, either personally or because it strikes someone they know. This special issue of the Natural Medicine Journal is published on the heels of World Cancer Day and in conjunction with the annual conference of the Oncology Association of Naturopathic Physicians (OncANP). We are also pleased to collaborate with the Society for Integrative Oncology (SIO). Those active in the field of integrative oncology echo the sentiments expressed by Christopher Wild, director of the International Agency for Research on Cancer (IARC) who told CNN, “We cannot treat our way out of the cancer problem.” The days of desperately searching for a cure are long gone. More focus and attention need to be placed on prevention and early detection. The integrative cancer care model illustrates the direction we must take to impact this illness and stop the statistical nightmare that has unfolded before us. This model embraces collaboration, scientific evidence, and proactive prevention. Most importantly, it places the patient at the center of care. Because of the magnitude and complexity of this topic, we could do an oncology special issue several times a year and still not begin to scratch the surface. While this special issue is certainly not comprehensive, we do hope it’s a valuable contribution to a vital conversation. In this issue you will find a peer-reviewed article on intravenous vitamin C, as well as commentary about green tea, ginseng, flax, and intestinal permeability. Immunologist researcher Heather Zwickey, PhD, weighs in on chemotherapy-induced immunosuppression, and our senior medical editor, Tina Kaczor, ND, FABNO, interviews the president of SIO, Heather Greenlee, ND, PhD. To us, this issue represents more than just a few compelling articles on integrative oncology. It signifies the collaboration critical to bring about the seismic shift that must occur in cancer prevention and treatment.

AUDIO INTERVIEW

Advancing Integrative Oncology An Interview with Heather Greenlee, ND, PhD In this interview, newly elected president of the Society for Integrative Oncology (SIO), Heather Greenlee, ND, PhD, discusses the landscape of integrative oncology research, including what she envisions is needed for widespread adoption of evidence-based integrative programs.

Introducing an informational podcast series about integrative oncology sponsored by Cancer Treatment Centers of America beginning February 2014. For more information visit NaturalMedicineJournal.com.

ABOUT THE EXPERT

Heather Greenlee is a naturopathic doctor and epidemiologist at the Mailman Center for Public Health at Columbia University. Her research focuses on the use of complementary and integrative medicine and lifestyle modifications for breast cancer prevention and control. Through funding from the National Cancer Institute (NCI), Greenlee is developing strategies for increasing fruit and vegetable intake and reducing fat intake among Latina breast cancer survivors. Greenlee has served on NCI and NCCAM grant review committees and currently serves as the President of the Society for Integrative Oncology.

Meet the Naturopathic Physicians at Cancer Treatment Centers of America in Phoenix, Arizona Adam Kerievsky, ND, LAc, FABNO

Lucas Tims, ND, FABNO

Leah Sherman, ND

Shauna Birdsall, ND, FABNO

Laura Martell, ND, LAc, FABNO

Tim Birdsall, ND, FABNO

Jeffrey Sager, ND, FABNO

Amy Loschert, ND

Casey Martell, ND

Southwest College of Naturopathic Medicine Practicing Since 1998

National College of Naturopathic Medicine Practicing Since 2000

Southwest College of Naturopathic Medicine and Health Sciences Practicing Since 2000

Southwest College of Naturopathic Medicine Practicing Since 2010

National College of Naturopathic Medicine Practicing Since 1999

Southwest College of Naturopathic Medicine and Health Sciences Practicing Since 2003

National College of Natural Medicine Practicing Since 2007

Bastyr University Practicing Since 1986

National College of Naturopathic Medicine Practicing Since 1999

ABSTRACT & COMMENTARY

New Evidence Suggests Chemoprevention Activity of Green Tea Supplements REFERENCE

Yu SS, Spicer DV, Hawes D, et al. Biological effects of green tea capsule supplementation in pre-surgery postmenopausal breast cancer patients. Front Oncol. 2013;3:298. DESIGN

A presurgical trial comparing green tea capsule supplementation to no green tea supplementation PARTICIPANTS

All of the study participants were postmenopausal female breast cancer patients who were at the Los Angeles County-University of Southern California Medical Center between 2008 and 2009. The green tea intervention group (n=13) included 12 patients with primary invasive stage I or II breast cancer and 1 with ductal carcinoma in situ (DCIS). The control group (n=15) included 10 patients with primary invasive stage I or II breast cancer and 5 with DCIS. All of the participants in the study were non–tea drinkers. ER/PR status was similar in both groups, with 4 in the treatment group who were ER-/PR- and 5 in the control group who were ER-/PR-. INTERVENTION

The green tea capsule contained 725 mg of total green tea with 314 mg of epigallocatechin-3-gallate (EGCG). The daily dose was 3 capsules, so each participant received 940 mg of EGCG daily—the equivalent to about 8–10 cups of green tea. The intervention took place between breast cancer diagnosis and initial surgery date with an average duration of 35 days. This was not a placebo-controlled trial; the women in the control group did not take any capsules. OUTCOMES MEASURES

Urine samples measured tea catechin levels. Three key markers were measured in the diagnostic core biopsy tissue and surgical specimens: 1. Ki-67 = proliferation 2. Casp-3 = apoptosis 3. CD34 = angiogenesis Benign and malignant cells were separated. Samples were available from 13 breast cancer patients in the green tea intervention group and 15 controls. KEY FINDINGS

In the green tea group, patients experienced a decrease in Ki-67 activity in benign cells (-3.14%; P=0.007), as well as malignant cells (-4.29%; P=0.10) compared to patients in the control group who experienced a statistically insignificant change in Ki-67 in the benign cell components (0.75%; P=0.22) and an increase in malignant cells (0.68%; P=0.91). The decrease in Ki-67 in benign cells in the green tea group reached statistical significance when compared to benign cells from the control group (P=0.033); however, changes in malignant cell components between the 2 groups did not reach statistical significance (P=0.45). The decrease in Ki-67 in the green tea group was found regardless of ER/PR status or tumor stage at diagnosis. There were no significant changes in casp-3 or CD-34.

Lise Alschuler, ND, FABNO, and Karolyn A. Gazella PRACTICE IMPLICATIONS The chemopreventive effects of green tea have been the subject of hundreds of studies. A 2008 review based upon 43 epidemiological studies, 4 randomized clinical trials, and one meta-analysis found that 58% of the included studies demonstrated a cancer prevention effect from long-term consumption of green tea.1 A 2012 review of 8 cohort studies and 3 case-control studies by Sasazuki et al found a consistent small risk reduction of gastrointestinal cancers, especially in women who drank or took green tea.2 In 2006, Bettuzzi et al studied men with high-grade prostatic intraepithelial neoplasia, a precancerous state, and found that men who took 200 mg green tea extract supplements for 1 year developed fewer cancers than men taking placebo.3 Of note, other studies have not shown benefit in prostate cancer prevention, including a small 2005 study involving men with hormone refractory prostate cancer.4 The anticancer effects of green tea in chronic lymphocytic leukemia were demonstrated in a 6-month phase 2 trial using 2,000 mg of a green tea extract.5 In a pilot study of 136 patients, green tea supplementation equivalent to 10 cups of green tea daily (2.5 g green tea extract) reduced the incidence of colonic adenomas by 51% and was determined to be an effective chemopreventive agent for this precancerous condition of the colon.6 The chemopreventive properties of green tea specific to breast cancer have

Continued on page 10

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ABSTRACT & COMMENTARY

been demonstrated in at least 2 prospective clinical studies. The subjects in both studies were premenopausal women with diagnosed breast cancer who were followed after surgery for recurrence. In both studies green tea consumption greater than 5 cups per day was associated with a reduced risk of recurrence in women with stages I and II breast cancer. One study found a recurrence rate of 16.7% in women with stage I and II breast cancer who drank an average of 8 cups of green tea per day, compared to a recurrence rate of 24.3% in women drinking an average of 2 cups per day.7 The other study found a 57% decreased risk of recurrence in women diagnosed with stage I breast cancer who drank an average of 5 cups of green tea daily over 4.5 years.8 Prior studies have demonstrated a multifaceted impact of green tea on breast carcinogenesis. In 2012, data from Crew et al demonstrated that green tea supplementation prevented tumor cell growth, migration, and invasion in 34 women following breast cancer treatment.9 Because green tea extract has been shown to prevent or slow the growth of breast cancer cells, the National Cancer Institute is presently engaged in clinical trials to determine safety and dosage. One of the secondary outcomes measures of the phase I trials presently underway is to evaluate green tea’s ability to modulate immunohistochemical Ki-67 expression.10 This appears to be a key area of emphasis and potential. The preventive effects of green tea have been related to its antiproliferative effects when studied in other cancer types. In 2009, Tsao et al saw partial regression (50%) in oral lesions compared to placebo, and the treatment group also experienced fewer increases in lesion size.11 The dose used in that study was 3 grams of mixed tea given orally and used topically. Tsao and colleagues noted that Ki-67 increased in the patients with oral cancer as the tissue went from normal to hyperplasia to dysplasia to cancer. While regression did not achieve statistical significance in this study, Tsao concluded that increased Ki-67 was associated with a higher risk of developing oral cancer and that impacting Ki-67 could decrease proliferation. Proliferative potential is highly relevant with regards to breast carcinogenesis. High Ki-67 in residual disease after neoadjuvant therapy for breast cancer is associated with higher recurrence rates and worse disease-free survival.12

“

The findings of this clinical study indicated that green tea reduced cell proliferation in breast tissue.

”

The findings of this clinical study indicated that green tea reduced cell proliferation in breast tissue. This has significant cancer prevention implications and underscores the importance of green tea in cancer prevention. The ability of green tea to effectively reverse established breast cancer has not been confirmed in published human clinical trials. Thus, its benefit appears to be most evident in women at risk for breast cancer or its recurrence. On that note, in women receiving chemotherapy as a recurrence prevention strategy, there is question whether green tea will interfere with chemotherapy. Although a 2012 review by Sak concluded that catechins from green tea did actually increase the efficacy of some chemotherapeutic agents, such as doxorubicin, in drug-resistant tumors, the conclusion is based primarily on in vitro and in vivo data.13 Green tea has been shown to work synergistically with the taxanes (paclitaxel, docetaxel), as well as fluorouracil, floxuridine, and capcetibine.14 A 2007 animal study also showed that green tea polyphenols were protective against lipid peroxidation and inflammation induced by the chemotherapeutic drug irinotecan.15

The discussion of chemotherapy is beyond the scope of this commentary. The present study enhances our understanding of one of the mechanisms by which green tea can help prevent breast cancer development and its recurrence. The use of green tea as a key component of an integrative breast cancer prevention strategy makes clinical sense. This study suggests that for patients who are not consuming the recommended amount of green tea, taking a green tea supplement at a dosage of 940 mg EGCG daily is a viable alternative.

REFERENCES 1 Liu J, Xing J, Fei Y. Green tea (Camellia sinensis) and cancer prevention: a systematic review of randomized trials and epidemiological studies. Chin Med. 2008;3:12.

10 National Institutes of Health. Defined green tea catechin extract in treating women with hormone receptor negative state I-III breast cancer. National Cancer Institute. http:// www.cancer.gov/clinicaltrials/search/view?cdrid=653465& version=HealthProfessional. Accessed January 17, 2014.

2 Sasazuki S, Tamakoshi A, Matsuo K, et al. Green tea consumption and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol. 2012;42(4):335-346.

11 Tsao AS, Liu D, Martin J, et al. Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila). 2009;2(11):931-941.

3 Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a oneyear proof-of-principle study. Cancer Res. 2006;66(2):1234-1240.

12 de Azambuja E, Cardoso F, de Castro G, et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007;96(10):1504-1513.

4 Choan E, Segal R, Jonker D, et al. A prospective clinical trial of green tea for hormone refractory prostate cancer: an evaluation of the complementary/alternative therapy approach. Urol Oncol. 2005;23(2):108-13. 5 Shanafelt TD, Call TG, Zent CS, et al. Phase 2 trial of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2013;119(2):363-370. 6 Shimizu M, Fukutomi Y, Ninomiya M, et al. Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomarkers Prev. 2008;17(11):3020-3025.

13 Sak K. Chemotherapy and dietary phytochemical agents. Chemother Res Pract. 2012;2012:282570. 14 Stearns ME, Wang M. Synergistic Effects of the Green Tea Extract Epigallocatechin3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors. Transl Oncol. 2011;4(3):147-156. 15 Wessner B, Strasser EM, Koitz N, Schmuckenschlager C, Unger-manhart N, Roth E. Green tea polyphenol administration partly ameliorates chemotherapy-induced side effects in the small intestine of mice. J Nutr. 2007;137(3):634-640.

7 Nakachi K, Suemasu K, Suga K, Takeo T, Imai K, Higashi Y. Influence of drinking green tea on breast cancer malignancy among Japanese patients. Jpn J Cancer Res. 1998;89(3):254-261. 8 Inoue M, Tajima K, Mizutani M, et al. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett. 2001;167(2):175-82. 9 Crew KD, Brown P, Greenlee H, et al. Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer. Cancer Prev Res. 2012;5(9):11441154.

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ABSTRACT & COMMENTARY

American Ginseng Improves Cancer-Related Fatigue REFERENCE

Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230-1238. DESIGN

An 8-week multisite, randomized, double-blind, placebocontrolled study using 1,000 mg twice daily of Panax quinquefolius (American ginseng) versus placebo in cancer patients with cancer-related fatigue (CRF). Assessment of fatigue symptoms, secondary outcomes, and toxicities were assessed. PARTICIPANTS

This study evaluated 364 non-brain or CNS lymphoma cancer patients at 40 sites suffering from CRF (qualified as a score of 4 or more on an 11-point scale) with a mean age of 55. In both arms, greater than 75% of patients were female, greater than 90% were Caucasian, roughly 50% of subjects were currently undergoing cancer treatment, a little more than 50% were regular exercisers, and the distributions of cancer types ranged from breast (60%), colon (11%), prostate (4%), hematologic (5%), gynecologic (4%), and combined/other (16%). There was no statistical significance in fatigue scores between groups. OUTCOME MEASURES

The primary outcome measure was fatigue assessed by the Multidimensional Fatigue Symptoms Inventory-Short Form (MFSI-SF). Secondary outcomes included the Profile of Mood States fatigue-inertia and vigor-activity subscales, the Brief Fatigue Inventory, and self-reported side effects. KEY FINDINGS

Comparing placebo versus the P. guinquefolius intervention, the group receiving ginseng demonstrated significant improvement in fatigue at 8 weeks, with greater benefit reported in patients receiving active treatment than those who had completed treatment. Side effects of moderate agitation, anxiety, insomnia, nausea, and vomiting were reported in both treatment and placebo groups. The most common side effect was moderate nausea in 5% of subjects in the treatment group with no statistical difference of all side effects between groups, suggesting that P. quinquefolius is a safe and tolerable intervention for the treatment of CRF.

Michael Traub, ND, DHANP, FABNO, and Landon Opunui, ND CLINICAL IMPLICATIONS In a systematic review using control group comparisons, Prue and colleagues found the prevalence of fatigue to be between 39% and 90% in cancer patients undergoing anticancer therapy, with fatigue occurring up to 5 years after completion of adjuvant treatment in some studies. In advanced stages of cancer, 78% of palliative care patients report having severe fatigue.1 To date, few randomized controlled trials of nonpharmacologic or pharmacologic interventions for improving fatigue in cancer patients have been performed. The most well-researched interventions for CRF are outlined in the National Comprehensive Cancer Network (NCCN) guidelines (updated in 2013), which includes exercise; psychosocial interventions (stress management, relaxation, and support groups); sleep restoration interventions; treatment of potential contributing factors (anemia, pain, malnutrition); or a therapeutic trial of methylphenidate.2 A 2012 Cochrane Review concluded there is no convincing evidence for a clear improvement in subjective fatigue with exercise used as an intervention.3 However, with the potential for fewer safety concerns compared to pharmacotherapy and the multitude of other health parameter benefits, regular aerobic exercise should be included in every treatment plan. Pharmacological intervention for CRF often includes 6 different classes of medication, including hematopoietic growth factors, psychostimulants, bisphosphonates, anti-TNF-α antibodies, antidepressants, and steroids. Little to no benefit has been found with many of these drugs, with the exception of erythropoietin and darbepoetin, which are most likely playing more of an important corrective role in the management of cancer-related anemia.4,5 Due to the ineffectiveness of many of these medications at managing CRF, there is room for effective natural agents with better safety profiles to be used therapeutically. Though much of the clinical research looking at the fatigue response with ginseng administration has been with Panax ginseng (Asian ginseng),6 P. quinquefolius was chosen for this investigation due to its similar ginsenosides (Rb1 and Rg1), which have been found to enhance activity performance in mice, have favorable

toxicity reports in the literature, and have respectable quality assurance and available sourcing opportunities.7

REFERENCES

In the management of patients with cancer, fatigue is a common symptom requiring appropriate assessment and intervention to help relieve its impact on quality of life.8 There is now emerging evidence for effective CRF treatment options with acceptable safety profiles, such as with this recently published article on P. quinquefolius.

2 Cancer-related fatigue. National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/pdf/fatigue. Published January 2013. Accessed December 30, 2013.

Though the results in this study are favorable for the treatment of CRF, it would have been even more interesting if interventions were administered for longer periods, as some CRF studies have reported fatigue occurring up to 5 years after completion of cancer therapy.

1 Prue G, Rankin J, Allen J, Gracey J, Cramp F. Cancer-related fatigue: A critical appraisal. Eur J Cancer. 2006;42(7):846-863.

3 Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2012;11:CD006145. 4 Minton O, Stone P, Richardson A, Sharpe M, Hotopf M. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev. 2010;(7):CD006704. 5 Minton O, Richardson A, Sharpe M, Hotopf M, Stone PC. Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. J Pain Symptom Manage. 2011;41(4):761-767. 6 Lü JM, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol. 2009;7(3):293-302. 7 Barton DL, Soori GS, Bauer BA, et al. Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dosefinding evaluation: NCCTG trial N03CA. Support Care Cancer. 2010;18(2):179187. 8 Minton O, Berger A, Barsevick A, et al. Cancer-related fatigue and its impact on functioning. Cancer. 2013;119 Suppl 11:2124-2130.

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ABSTRACT & COMMENTARY

Flaxseeds Reduce Prostate Cancer Aggressiveness REFERENCE

Azrad M, Vollmer RT, Madden J, et al. Flaxseedderived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer. J Med Food. 2013;16(4):357-360. DESIGN

Data extraction from previous phase II randomized controlled trial PARTICIPANTS

The study included 161 men with prostate cancer who underwent prostatectomy, 147 of whom had sufficient information for analysis. STUDY MEDICATION AND DOSAGE

Data for this study was procured from a previous study in which men were randomized by race (Black vs non-Black) and Gleason score (Gleason ≥7 vs ≤6) into 4 groups: control (n=41), flaxseed (FS; n=40), low-fat diet (LF; n=40), or flaxseed and low-fat diet (FS & LF; n=40). Flaxseed groups consumed 30 g/day and “low fat” diet groups consumed <20% of calories per day from fat. For purposes of the current study both flaxseed groups were combined for the flaxseed group (n=73) and the control and LF groups combined to make the no flaxseed group (n=74). Dietary and flaxseed intervention began approximately 30 days prior to prostatectomy. OUTCOME MEASURES

Urinary enterolactone, enterodiol, and total lignans (µg/day) at baseline and at time of surgery. Correlations between urinary enterolignans and prostate tumor expression of Ki-67, vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NFkB) were assessed. KEY FINDINGS

There were significant correlations between plant lignan intake and urinary concentrations of total enterolignans (P<0.0001), enterolactone (P<0.0001) and enterodiol (P<0.0001 ). Total urinary enterolignans and enterolactone were inversely correlated with tumor tissue levels of Ki-67 (P=0.011 and P=0.007, respectively). Although not statistically significant, an inverse association was also observed with enterolactone and VEGF (P=0.141). There was no association with urinary lignan levels and NFkB expression in the tumor tissue.

Tina Kaczor, ND, FABNO

COMMENTARY Lignans are a type of phytoestrogen found in a variety of foods, including brassica vegetables, legumes, seeds, and whole grains. Flaxseed has exceptionally high content, with the lignan secoisolariciresinoldiglycoside (SDG) comprising approximately 0.05–0.2% by weight.1 Epidemiological studies suggest diets high in lignans have a protective effect against many cancers, including breast, colon, and prostate.2–4 The current study demonstrates this “protection” may go one step further—reducing the aggressiveness of an already existing tumor. This publication is a follow-up to the authors’ previous publication, “Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates.”5 Using the same group of participants, the authors established that both groups consuming flaxseed supplement had a lower proliferative index (Ki-67) compared to the control and low-fat groups. In the current abstract the authors analyzed the same prostatic tissues to assess the molecular changes in VEGF and NFkB. For statistical analysis, the 4 groups were divided into just 2—flaxseed and no flaxseed. VEGF and NFkB were assessed in addition to Ki-67. Once again, Ki-67 was significantly lower in the flaxseed group. While the VEGF expression trended lower in the flaxseed group, the NFkB had no associated changes. This implies the lower proliferation of cells may be due to factors other than VEGF and NFkB. Precisely how enterolignans such as enterolactone may lessen prostate cancer development and growth is not well known. One in vitro study suggests enterolactone can increase apoptosis in prostate cancer through mitochondrial effects.6 Another in vitro study suggests it is able to block 5 alpha reductase enzyme.7 Yet another possible mechanism is downregulation of insulin-like growth receptors, an antiproliferative effect demonstrated in androgen-sensitive and androgen-independent prostate cell lines.8 While the mechanism will continue to be elucidated in time, the reduction of proliferation through the down-regulation of the cell cycle appears to be one net effect of enterolactone on prostate cancer.9 Of course, flaxseed was given as a whole food in this study (just under ¼ cup daily), and reducing it down to merely a source of enterolignans is an oversimplification. Another component, alpha linolenic acid (ALA), is also high in flaxseeds. Epidemiological data on the effects of linolenic acid on prostate cancer risk and aggressiveness are conflicting,

so it is not clear whether dietary ALA gives some protection or whether the trend toward an increased risk of prostate cancer risk is real.10–12 The authors of the current study have shed some light on this inconsistency. Using the same study participants and flaxseed intervention as the current abstract, they assessed levels of ALA, Ki-67 and prostate specific antigen (PSA) in prostate cancer tissue.13 In addition, they tracked 6 different single nucleotide polymorphisms (SNPs) of the enzyme used to metabolize ALA, delta 6 desaturase. They found 2 surprising results: First, levels of ALA in prostatic tissue were not higher in those consuming flaxseed, despite the fact that they were ingesting 7 times the levels of ALA compared with the no flaxseed group. Second, the higher the ALA level in the prostate itself, the more aggressive the cancer as measured by Ki-67 (P=0.058) and the higher the PSA (P=0.004). Variants of SNPs in the delta 6 desaturase gene were correlated with higher or lower levels of Ki-67, suggesting there is genetic influence on ALA’s role in prostatic tissue. Such variability may explain the disparate results in epidemiological studies of ALA consumption and prostate cancer. Prostate cancer takes years, even decades to develop. What is striking is that a disease process that takes many years to develop is affected at all by a dietary change lasting only 30 days. It is a reminder that cancerous growth, no matter what the stage, is dynamic and may be influenced by lifestyle choices.

5 Demark-Wahnefried W, Polascik TJ, George SL, et al. Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3577-3587. 6 Chen LH, Fang J, Li H, Demark-Wahnefried W, Lin X. Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway. Mol Cancer Ther. 2007;6(9):2581-2590. 7 Evans BA, Griffiths K, Morton MS. Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol. 1995;147(2):295-302. 8 Chen LH, Fang J, Sun Z, et al. Enterolactone inhibits insulin-like growth factor-1 receptor signaling in human prostatic carcinoma PC-3 cells. J Nutr. 2009;139(4):653659. 9 McCann MJ, Gill CI, Linton T, Berrar D, McGlynn H, Rowland IR. Enterolactone restricts the proliferation of the LNCaP human prostate cancer cell line in vitro. Mol Nutr Food Res. 2008;52(5):567-580. 10 Brouwer IA, Katan MB, Zock PL. Dietary alpha-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr. 2004;134(4):919-922. 11 Simon JA, Chen YH, Bent S. The relation of alpha-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis. Am J Clin Nutr. 2009;89(5):1558S1564S. 12 Carleton AJ, Sievenpiper JL, de Souza R, McKeown-Eyssen G, Jenkins DJ. Casecontrol and prospective studies of dietary α-linolenic acid intake and prostate cancer risk: a meta-analysis. BMJ Open. 2013;3(5). 13 Azrad M, Zhang K, Vollmer RT, et al. Prostatic alpha-linolenic acid (ALA) is positively associated with aggressive prostate cancer: a relationship which may depend on genetic variation in ALA metabolism. PLoS One. 2012;7(12):e53104.

CELEBRATING EXCELLENCE IN CANCER CARE Special thanks to:

While this study is small and further prospective studies are needed to guide clinical decision-making, flaxseed is also a food and there is little to no down side risk in encouraging our patients with prostate cancer to indulge in a liberal amount of flaxseed in their diets. REFERENCES 1 Setchell KD, Brown NM, Zimmer-Nechemias L, Wolfe B, Jha P, Heubi JE. Metabolism of secoisolariciresinol-diglycoside the dietary precursor to the intestinally derived lignan enterolactone in humans. Food Funct. 2014 Jan 16. [Epub ahead of print] 2 Hedelin M, Klint A, Chang ET, et al. Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden). Cancer Causes Control. 2006;17(2):169-180. 3 Zamora-Ros R, Not C, Guinó E, et al. Association between habitual dietary flavonoid and lignan intake and colorectal cancer in a Spanish case-control study (the Bellvitge Colorectal Cancer Study). Cancer Causes Control. 2013;24(3):549-557.

TOGETHER WE CAN MAKE A DIFFERENCE.

4 Suzuki R, Rylander-Rudqvist T, Saji S, Bergkvist L, Adlercreutz H, Wolk A. Dietary lignans and postmenopausal breast cancer risk by oestrogen receptor status: a prospective cohort study of Swedish women. Br J Cancer. 2008;98(3):636-640.

ABSTRACT & COMMENTARY

Leaky Gut and Chemo: To Treat or Not to Treat? REFERENCE

Russo F, Linsalata M, Clemente C, et al. The effects of fluorouracil, epirubicin, and cyclophosphamide (FEC60) on the intestinal barrier function and gut peptides in breast cancer patients: an observational study. BMC Cancer. 2013;13(1):56. DESIGN

Prospective observational study of consecutive patients PARTICIPANTS

The study enrolled 60 breast cancer patients who had undergone surgical resection of the tumor and lymph nodes and received adjuvant chemotherapy. Thirtyseven patients completed the study. A questionnaire was used to determine which patients developed diarrhea. STUDY MEDICATION AND DOSAGE

All participants received the same chemotherapy FEC-60 (fluorouracil 600 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days for 6 cycles). OUTCOME MEASURES

During chemotherapy, intestinal permeability was assessed by lactulose/mannitol (La/Ma) urinary test on days 0 and 14. Levels of several GI peptides, specifically zonulin, glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF), and ghrelin were measured by ELISA tests at 5 time-points (days 0, 3, 10, 14, and 21). As the authors explain, zonulin modulates the mucosal barrier by breaking down the tight junctions during inflammation and plays a “role in the pathogenesis of autoimmune diseases such as celiac disease and type-1 diabetes.” The authors note that GLP-2 is an “intestinotrophic growth hormone that promotes many aspects of intestinal function, including rapid enhancements of mucosal growth and the intestinal barrier function.” It is thought that EGF and GLP-2 protect against chemotherapy-induced damage to the intestinal mucosa. Ghrelin, which is produced by GI enteroendocrine cells, is “involved in the control of the mucosal barrier and is considered a potential protective agent against chemotherapy complications. In mice, ghrelin administration has been demonstrated to prevent the doxorubicin-induced GI mucosal damage.” KEY FINDINGS

During chemotherapy, the lactulose-mannitol ratio increased significantly by day 14 from baseline. Zonulin levels were unaffected. GLP-2 and EGF levels decreased significantly. GLP-2 levels on day 14 were significantly lower than on day 0 and day 3, while EGF values were significantly lower on day 10 than at the baseline. Ghrelin increased significantly at day 3 compared to days 0 and 21. Ten patients (27%) suffered from diarrhea. On day 14 of chemotherapy, a significant increase of the La/Ma ratio occurred in patients with diarrhea compared to patients without it. Patients with diarrhea had significantly lower GLP-2 and higher ghrelin levels. In the patients with diarrhea, an inverse correlation between BLP-2 and the La/ Ma ratio was seen at day 14. All patients showed significantly increased intestinal permeability and shifts in GLP-2, ghrelin, and EGF. Those who developed diarrhea during treatment had a different GI peptide profile.1

Jacob Schor, ND, FABNO PRACTICE IMPLICATIONS These results should not surprise any clinician. Cancer patients undergoing treatment frequently develop diarrhea and it is fair to assume this is linked to increased intestinal permeability. The question is what, if anything, we do about it. This FEC-60 drug cocktail is not alone in causing gut damage. Other cancer treatments are associated with increased gut permeability. For example, bevacizumab, oxaliplatin, 5-fluorouracil, and leucovorin,2 abdominal radiation, which causes its own special form of gastritis, is also associated with increased permeability.3 What may surprise many people is that this increase in permeability may be a good thing. Several recent papers suggest that with several chemotherapy drugs—the platinum drugs and cyclophosphamide in particular—this increase in permeability and resultant bacterial translocation is important, if not necessary, for the drugs’ anticancer action. In an article published in the November 2013 issue of Science, Viaud et al suggested that certain chemotherapy drugs act only indirectly against cancer; their primary mechanism of action is to trigger intestinal permeability that in turns leads to the translocation of bacteria from the intestine into the body, where their presence triggers an immune response.4 In experiments on mice, Viaud et al found that cyclophosphamide wreaked havoc on the gut lining; the villi shrank, and the small intestine’s permeability increased. Several species of bacteria, in particular Gram-positive bacteria, emigrated

into the body. Two Lactobacillus species and Enterococcus hirae bacteria found their way into the lymph nodes and spleen. This migration may be key to the drugs’ action. In vitro work suggests these Gram-positive bacteria cause immature T cells to transform first into Th17 cells, and later some of them convert into memory cells allowing a prolonged immune response to the tumor. Mice with cancer who were bred to be germ-free or treated with antibiotics that kill these Gram-positive bacteria did not increase Th17 cells when treated with cyclophosphamide. More importantly, the drug no longer shrank their tumors. In a parallel paper, Iida et al suggest that gut bacteria are necessary for platinum drugs to work.5 Pretreatment of mice with antibiotics lessens the drugs’ action against implanted tumors. Oxaliplatin typically works at least in part by increasing reactive oxygen species (ROS) in cancer cells, and this leads to cancer cell apoptosis. In a study of mice implanted with various cancers, Iida’s group treated half with antibiotics before administering oxaliplatin. The mice lacking bacteria did not increase ROS. Within 3 weeks, 80% of the antibiotic-treated mice had died. The mice not given antibiotics still had normal intestinal flora and fared far better; they increased ROS production and 80% were still alive. In mice at least, intestinal bacteria are necessary for certain types of chemotherapy to work. Domino Trincheiri, one of the lead authors, is quoted in Science as saying, “We suspected that platinum therapy may involve some immune pathway on which the gut microbiota could have a modulating effect, but we were surprised by the extent to which inflammatory cell reactive oxygen species production was strictly dependent on the presence of gut microbiota.”6 This is a new viewpoint. Up until the publication of these studies in Science, we considered bacterial translocation part of the problem. These wandering bacteria are blamed for cancer cachexia and considered a “therapeutic target” and the cause of many adverse reactions.7,8 Our treatment goal has been to prevent diarrhea and leaky gut.9 We have actively employed treatments to prevent or counter intestinal permeability including probiotics, l-glutamine, AND melatonin, thinking we are doing the right thing.10–13

At least with cyclophosphamide and platinum drugs, perhaps we should choose therapies that increase intestinal permeability, such as piperine or fasting, in the hope of gaining more cytotoxic action from chemotherapy.14,15 This is heretical thinking—the opposite of what we have thought or done for years. Of course, these ideas only come from mouse studies; these findings may not be confirmed in people. If they are though, some serious reorganization of our treatment strategies will be in order. REFERENCES 1 Russo F, Linsalata M, Clemente C, et al. The effects of fluorouracil, epirubicin, and cyclophosphamide (FEC60) on the intestinal barrier function and gut peptides in breast cancer patients: an observational study. BMC Cancer. 2013;13:56. 2 Melichar B, Hyspler R, Kalábová H, Dvorák J, Tichá A, Zadák Z. Gastroduodenal, intestinal and colonic permeability during anticancer therapy. Hepatogastroenterology. 2011;58(109):1193-1199. 3 Mihaescu A, Santén S, Jeppsson B, Thorlacius H. Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction. Br J Surg. 2011;98(1):124-131. 4 Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971-976. 5 Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967970. 6 Pennisi E. Biomedicine: cancer therapies use a little help from microbial friends. Science. 2013;342(6161):921. 7 Klein GL, Petschow BW, Shaw AL, Weaver E. Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target. Curr Opin Support Palliat Care. 2013;7(4):361-367. 8 Wardill HR, Bowen JM, Gibson RJ. Chemotherapy-induced gut toxicity: are alterations to intestinal tight junctions pivotal? Cancer Chemother Pharmacol. 2012;70(5):627-635. 9 Yang J, Liu KX, Qu JM, Wang XD. The changes induced by cyclophosphamide in intestinal barrier and microflora in mice. Eur J Pharmacol. 2013;714(1-3):120-124. 10 Sözen S, Topuz O, Uzun AS, Cetinkünar S, Das K. Prevention of bacterial translocation using glutamine and melatonin in small bowel ischemia and reperfusion in rats. Ann Ital Chir. 2012;83(2):143-148. 11 Zhang G, Ducatelle R, Pasmans F, et al. Correction: effects of helicobacter suis γ-glutamyl transpeptidase on lymphocytes: modulation by glutamine and glutathione supplementation and outer membrane vesicles as a putative delivery route of the enzyme. PLoS ONE. 2014;9(1). 12 Benjamin J, Makharia G, Ahuja V, et al. Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn’s disease: a randomized controlled trial. Dig Dis Sci. 2012;57(4):1000-1012. 13 Sözen S, Topuz O, Uzun AS, Cetinkünar S, Das K. Prevention of bacterial translocation using glutamine and melatonin in small bowel ischemia and reperfusion in rats. Ann Ital Chir. 2012;83(2):143-148. 14 Khajuria A, Thusu N, Zutshi U. Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine. 2002;9(3):224-231. 15 Bark T, Katouli M, Svenberg T, Ljungqvist O. Food deprivation increases bacterial translocation after non-lethal haemorrhage in rats. Eur J Surg. 1995;161(2):67-71.

PEER-REVIEWED ARTICLE

Intravenous Vitamin C in Cancer: A Brief Overview of Its Use and Considerations By Michael Traub, ND, DHANP, FABNO, Paul S. Anderson, ND ABSTRACT New information has become available about the clinical use of intravenous vitamin C in recent years, particularly in its application in cancer. However, great variability in practice persists, reflecting a lack of knowledge of how this treatment should be most safely and effectively employed. This article reviews the forms of nutrients that best balance changes in blood chemistry inherent in this therapy and the appropriate use of B vitamins and glutathione.

INTRODUCTION Intravenous vitamin C (IVC) is quite different physiologically than the oral form of the vitamin. Plasma values of intravenous vitamin C can reach more than 25 mmol/L versus the plasma limit of 250 µmol/L for orally ingested vitamin C.1 Therefore, IVC infusions have unique clinical applications, including the use of high doses as a therapeutic tool in cancer care.2 Many clinical trials have been done or are currently being done assessing the use of IVC in cancer care. 3–7 Such research into the biochemistry and application of this clinical tool is leading to a better understanding of best practices in implementing IVC in cancer care. IVC has at least 2 diverse therapeutic applications, one derived from high doses of vitamin C, the other from lower doses. Both uses may be clinically helpful over a wide range of applications. This apparent therapeutic dichotomy exists because at lower doses, IVC acts as a cell-support and antioxidant supplement, whereas at higher doses it acts as an oxidative pro-drug.8 While there is no concrete definition of high-dose versus low-dose vitamin C, the general consensus among practitioners is that high-dose intravenous vitamin C (HDIVC) is greater than 10 g/infusion and low-dose intravenous vitamin C (LDIVC) is less than 10 g/infusion. HDIVC is being researched as a possible adjunct in cancer care and anti-infective protocols.9 HDIVC protocols are purely oxidative and contain only minerals needed to specifically balance electrolytes. Because HDIVC is meant to be oxidative, glutathione and supplements that increase

glutathione (eg, n-acetyl cysteine) should not be given on the same day, lest the oxidative capacity be lowered.10 There is also in vitro research suggesting that other antioxidants, such as quercetin, curcumin, and melatonin, may interfere with the oxidative capacity of vitamin C, although this has not been demonstrated in animal models or humans.11 LOW-DOSE INTRAVENOUS VITAMIN C Many protocols exist for the use of LDIVC. This is commonly referred to as a Myers’ cocktail, and the ordering physician can create a combination of nutrients specific to the patient’s condition and needs. While it can be used in the context of complementing conventional cancer treatment, LDIVC is also used for other conditions such as headaches, muscle spasms, arrhythmia, and anxiety, to name a few. A thorough review of LDIVC is beyond the scope of this article, but it should be noted that the use of LDIVC is generally considered safe. When IVC is given at low doses, there is little risk to the patient other than the risks inherent in the delivery of any IV solution. Namely, there is some risk of infection at the access site as well as risk of fluid overload if too much volume is delivered too quickly or if the kidneys are impaired. LDIVC can be delivered in iso-osmolar concentrations, creating little disturbance in fluid or electrolyte balance. Some LDIVC is given in hyperosmolar concentrations and as such can have a dehydrating effect in the patient largely due to the shortterm sodium load that has to be excreted following the IV. If employing HDIVC, there are a few compounding and administration points to consider that are not an issue with a lower-dose IVC. These include optimum electrolyte additions and separation of B vitamins and glutathione from the oxidative HDIVC treatment. BALANCING BLOOD CHEMISTRY Data from the Bastyr Integrative Oncology Research Center (BIORC) led to the use of chloride salts of potas-

sium, magnesium, and calcium in HDIVC formulas (P. Anderson, ND, unpublished data, February 2012). The additional minerals have been calculated and adjusted to decrease any blood chemistry changes inherent in HDIVC infusions for cancer and were derived through pre- and postIVC blood chemistry analysis at BIORC (P. Anderson, ND, and L. Standish, ND, unpublished data, 2012). The chloride form of the mineral additive is critical to this balance to compensate for electrolyte shift concerns with HDIVC. These concerns are hypocalcemia (ascorbate is a weak calcium chelator), hypokalemia, hypernatremia (IVC carries sodium hydroxide as a buffer: 25 g of IVC contains 2,750 mg of sodium—in our research at BIORC, this included all preparations of 500 mg/mL ascorbic acid from any source) and hypochloremia (high sodium causes a downward shift in chloride). Most of the published trials on HDIVC and cancer come from the work of Jeanne Drisko at the University of Kansas Medical Center. Drisko’s group used vitamin C with magnesium sulfate and now uses magnesium chloride. The BIORC data led to replacing sulfate with chloride and also adding calcium chloride and potassium chloride. Of note is the fact that the BIORC data were derived from the first trial using pre- and post-HDIVC blood chemistry analysis to set the baseline chemistry shifts with the IVC-mg formula, and then the same chemistry analysis was used to derive the new formulas in human subjects. The BIORC formula for an infusion of 25 g of IVC is displayed in Table 1, and the BIORC formula for an infusion of 50 g of IVC is displayed in Table 2. Table 1 BIORC Formula for an Infusion of 25 g of Intravenous Vitamin C Nutrient

Concentration

Amount added

Vitamin C

500 mg/mL

50 mL

Calcium chloride

100 mg/mL

1 mL

Magnesium chloride

200 mg/mL

2 mL

Potassium chloride

2 mEq

1 mL

Sterile water

500 mL

For a total volume of 554 mL and an osmolarity of 558 mOsm/L.

Table 2 BIORC Formula for an Infusion of 50 g of Intravenous Vitamin C Nutrient

Concentration

Amount Added

C-500

500 mg/mL

100 mL

Calcium chloride

100 mg/mL

3 mL

Potassium chloride

2 mEq

4 mL

Magnesium chloride

200 mg/mL

5 mL

Sterile Water

500 mL

For a total volume of 612 mL and an osmolarity of 1,001 mOsm/L. SEPARATION OF B VITAMINS AND GLUTATHIONE FROM THE OXIDATIVE IVC THERAPY Pharmacologic ascorbic acid concentrations in tissue creates oxidation through the production of extracellular H2O2, which can diffuse into cells, deplete ATP in sensitive cells, and possibly cause cell death.12 While B vitamins and other antioxidants may be needed during cancer therapy to simply maintain repletion in a patient, they may decrease the oxidative effect of HDIVC if concurrently administered.13 Assuming it is the oxidative effects of IVC that lead to cell death of cancerous cells, it stands to reason that the powerful antioxidative system that centers on glutathione may impair this effect as well. Indeed, one study in rodents confirms that HDIVC and glutathione (GSH) should not be administered on the same day. In that study, mice with pancreatic cancer xenografts were given intraperitoneal ascorbic acid (AA) at 4g/kg daily, which reduced tumor volume by 42%. However, addition of intraperitoneal GSH inhibited the AA-induced tumor volume reduction.14 As mentioned, patients receiving HDIVC may need nutrient repletion with B vitamins, other nutrients and possibly even GSH for normal cells to remain replete. The reason for this assumption is that during the biochemical processing of high doses of intravenous ascorbate, the cycling of glutathione peroxidase and glutathione reductase (GSH-GSSG redox cycle) is increased. This increase in GSH-GSSG cycling utilizes NAD, FAD, selenium,

magnesium, and other nutrients.15 If repletion of these nutrients is to be done in intravenous form, the infusion should be separated from HDIVC by at least 24 hours to ensure that oxidative effects of the HDIVC are maximized. As an example, a patient at BIORC assessed through clinical and laboratory metrics who may require both IV strategies will often receive HDIVC on Monday and Wednesday and then a vitamin-mineral support IV on Thursday or Friday. Assessment of what is needed for each patient is being tracked in conjunction with an ongoing research protocol of IVC at BIORC, the details of which will be published at study end. CONSIDERATIONS OF IVC USAGE In a yet unpublished review of safety and adverse events from the BIORC study, it is clear that most side effects or adverse events associated with HDIVC really relate to 2 basic physiologic changes during IVC administration: dehydration and, less commonly, blood sugar changes. HDIVC causes dehydration (the only hydrating solutions given via IV route are isotonic or mildly hypotonic— HDIVC is generally hypertonic, and all hypertonic solutions dehydrate the patient), which can lead to bounding pulse, increased blood pressure, and headache. The reason for dehydration in hypertonic IV solutions is the transient increase in plasma osmolarity resulting in cellular dehydration. As the patient hydrates, the osmolarity shift between plasma and extracellular fluid equalizes and the cellular dehydration resolves. Clinicians should encourage patients to stay well hydrated before, during, and after the HDIVC and expect to urinate frequently during and after the course of each treatment. In patients with poor oral intake and preexisting nausea, we typically infuse 250 mL to 500 mL 0.45 or 0.9% saline before or after the HDIVC. Such preemptive hydration is gauged by standard safety precautions to avoid fluid overload in susceptible patients. HDIVC also has been reported to have the potential to induce pancreatic insulin release, which in some patients can cause hypoglycemic symptoms during the IV.16 In yet unpublished data from the BIORC blood chemistry study, a nonlinear and patientdependent response of blood sugar to HDIVC has been noted. This means that in some patients, the hypoglycemic reaction is nonexistent, and in some it can be profound. For this reason, it is suggested (and borne out

by better comfort and outcome in the BIORC trial) that patients should eat before the HDIVC and have protein snacks during infusion. It is also important to remember that a finger stick glucometer will not be accurate during or for up to 8 hours following HDIVC (it will read factitiously high because the glucometer will read the ascorbate as glucose), but serum or plasma drawn in the same time period and processed by common commercial lab methodology will have reliable glucose readings. CONTRAINDICATIONS TO IVC As oxidation is possible when using moderate to high doses of IVC pre-testing for patient glucose-6-phosphate dehydrogenase enzyme (G6PD), deficiency is recommended for all patients receiving IVC at either oxidative doses or repeated lower-dose IVC given frequently. While rare, deficiency of G6PD can lead to hemolytic anemia, which presents many hours after the infusion and can be fatal. Since IVC is given in volumes over 250 cc and often contains significant amounts of sodium due to sodium hydroxide buffer in solution, caution should be taken in patients who may be adversely affected by volume expansion such as those with congestive heart failure and edema/ ascites. In a voluntary survey of practicing clinicians first published in 2006 and updated in 2008 by Padayatty and et al, adverse events included 59 patients reporting fatigue/ lethargy and 21 patients with mental status changes in the 9,328 patients for whom data were available.17 There were also 2 fatalities in the survey; in one case, the patient had a G6PD enzyme deficiency and the other was receiving renal dialysis. Caution should be used in those with impaired kidney clearance as well as those with a history of calcium oxalate stones, as stone formation was also reported as a rare adverse event in the survey, and previous case reports of such reactions can be found in published literature.18–20 Lastly, IVC acidifies urine so caution should be taken in cases where more acidic urine may lead to bladder damage (ie, chronic hemorrhagic cystitis) or increased toxicity of chemotherapeutics (ie, methotrexate). CONCLUSION While there is much still to be learned about the optimal use of HDIVC in cancer therapy, ongoing research continues to elucidate its role in cancer care. Only prospective, randomized trials will give us the definitive informa-

tion needed to create practice guidelines. Until then, we must REFERENCES use the “best evidence” guidelines that are available to date. 1 Levine M, Padayatty SJ, Espey MG. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr. 2011;2(2):78-88. Ongoing research at BIORC (unpublished) suggests that the 2 Riordan NH, Riordan HD, Meng X, Li Y, Jackson JA. Intravenous ascorbate as a tumor use of chloride salts of magnesium, calcium, and potassium cytotoxic chemotherapeutic agent. Med Hypotheses. 1995;44(3):207-213. is prudent to balance electrolytes in those receiving HDIVC. 3 Stephenson C. Study of high-dose intravenous (IV) vitamin C treatment in patients with solid tumors. Clinical Trials. http://clinicaltrials.gov/ct2/show/NCT00441207. The research project is ongoing, and outcome data will be Accessed January 24, 2014. published at a later date. Until then, it is advisable to include 4 Copenhagen University Hospital at Herlev. Vitamin C as an anti-cancer drug. Clinical Trials. http://clinicaltrials.gov/ct2/show/NCT01080352. Accessed January 24, 2014. the chloride forms of added minerals and to avoid glutathione 5 Thomas Jefferson University. Pilot trial of intravenous vitamin C in refractory and B vitamins on the day of HDIVC infusion. non-Hodgkin lymphoma (NHL). Clinical Trials. http://clinicaltrials.gov/ct2/show/ NCT00626444. Accessed January 24, 2014.

APPENDIX 1

References for IVC oxidative levels.21 A definitive level for the threshold of oxidation in intravenously (IV) administered ascorbate is unclear. Some research suggests lower levels than previously considered (5–10 g IVC) may cause oxidation and another disagrees.22–24

6 Situs Cancer Research Center. Study of high dose intravenous (IV) ascorbic acid in measurable solid tumor disease. Clinical Trials. http://clinicaltrials.gov/ct2/show/ NCT01125449. Accessed January 24, 2014. 7 Hoffer J. Trial of chemotherapy plus intravenous vitamin C in patients with advanced cancer for whom chemotherapy alone is only marginally effective. Clinical Trials. http:// clinicaltrials.gov/ct2/show/NCT01050621. Accessed January 24, 2014. 8 Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA. 2005;102(38):13604-13609.

APPENDIX 2

A “safe” recommendation for G6PD testing.22 Run G6PD/ hemoglobinopathy screening on any person getting any single IVC over 10–15 g.

ANOTHER SPECIAL ISSUE PUBLISHED BY

9 Ichim TE, Minev B, Braciak T, et al. Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?. J Transl Med. 2011;9:25. 10 Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med. 2011;51(3):681-687. 11 Lamson DW, Gu YH, Plaza SM, Brignall MS, Brinton CA, Sadlon AE. The vitamin C:vitamin K3 system - enhancers and inhibitors of the anticancer effect. Altern Med Rev. 2010;15(4):345-351. 12 Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA. 2007;104(21):8749-8754. 13 Ochi M, Lamson D. The concern about B-vitamins affecting the oxidant effect of intravenous ascorbate for malignancy. Altern Med Rev. 2011;16(Supp):1S-5S. 14 Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med. 2011 May 30. 15 Nelson DL, Lehninger AL, Cox MM. Lehninger Principles of Biochemistry. Macmillan; 2008. 16 Cunningham JJ. The glucose/insulin system and vitamin C: implications in insulindependent diabetes mellitus. J Am Coll Nutr. 1998;17(2):105-108. 17 Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS ONE. 2010;5(7):e11414. 18 Lawton JM, Conway LT, Crosson JT, Smith CL, Abraham PA. Acute oxalate nephropathy after massive ascorbic acid administration. Arch Intern Med. 1985;145(5):950951. 19 Wong K, Thomson C, Bailey RR, Mcdiarmid S, Gardner J. Acute oxalate nephropathy after a massive intravenous dose of vitamin C. Aust N Z J Med. 1994;24(4):410-411. 20 Mcallister CJ, Scowden EB, Dewberry FL, Richman A. Renal failure secondary to massive infusion of vitamin C. JAMA. 1984;252(13):1684. 21 Anderson P. Intravenous vitamin C in naturopathic oncology. Paper presented at: Oncology Association of Naturopathic Physicians; 2012; Scottsdale, Arizona. 22 Hininger I, Waters R, Osman M, et al. Acute prooxidant effects of vitamin C in EDTA chelation therapy and long-term antioxidant benefits of therapy. Free Radic Biol Med. 2005;38(12):1565-1570. 23 Roussel AM, Hininger-favier I, Waters RS, Osman M, Fernholz K, Anderson RA. EDTA chelation therapy, without added vitamin C, decreases oxidative DNA damage and lipid peroxidation. Altern Med Rev. 2009;14(1):56-61. 24 Mühlhöfer A, Mrosek S, Schlegel B, et al. High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers. Eur J Clin Nutr. 2004;58(8):1151-1158.

EXPERT Q & A

Chemotherapy-induced Immunosuppression A discussion with researcher Heather Zwickey, PhD Nearly all patients receiving broad-based chemotherapy will experience immunosuppression. Chemotherapy, by design, targets rapidly dividing cells. It does not discriminate between cancer cells and other rapidly dividing cells. Since immune system cells divide quickly—especially during an immune response—they are among the many targets of chemotherapy. This is the reason that patients receiving chemotherapy are more prone to infections. The biggest clinical outcomes of immunosuppression are bacterial, viral, or fungal infections. Another side effect can be chemotherapy-induced long-term fatigue, which may have a cytokine etiology. Heather Zwickey, PhD, recently presented at the Oncology Association of Naturopathic Physicians (OncANP) annual conference on the topic of immunosuppression in patients undergoing chemotherapy. Natural Medicine Journal talked to Zwickey about this important oncology topic. Q. Has immunosuppression improved since the introduction of new chemotherapy drugs or the use of combination chemotherapy drugs?

A. The use of new chemotherapy drugs, specifically the monoclonal antibodies, has reduced but not eliminated chemotherapy-induced immunosuppression. And unfortunately, drug-resistant variants of the cancer commonly develop after treatment with some of the so-called “targeted therapies.” So, while these drugs elicit surprisingly fast cancer regression, long-term success with them can be less than ideal. There are very new drugs, some of which are still in clinical trials or have just been released on the market, that stimulate the immune system, specifically, sipuleucel-T and ipilimumab. However, even with these drugs we see some immunosuppression. This reinforces what we’ve known for decades—namely that the tumor itself can be immunosuppressive. Thus, only a subset of patients responds to these drugs.

ABOUT THE EXPERT

Heather Zwickey, PhD, is dean of research at the National College of Natural Medicine, director of Helfgott Research Institute, and associate professor of immunology. Currently, she heads several pilot studies looking at the effects of botanicals, hydrotherapy, energy medicine, and diet on immunological parameters. Zwickey trained at the National Jewish Medical and Research Center in Denver. She received a PhD in Immunology and Microbiology from the University of Colorado Health Sciences Center and completed a postdoctoral fellowship at Yale University. Q. What can patients and practitioners do to help reduce the chance of immunosuppression?

A. Unfortunately, nothing can be done in this regard. In fact, if you tried to stimulate the immune system during chemotherapy, you would likely make the immunosuppression worse. As the immune system is stimulated, the cells divide more quickly, and this makes them more likely to be killed by the chemotherapeutic agent. If a patient is on one of the immunostimulatory drugs, further stimulating the immune system could be favorable— although this hasn’t been studied yet. Cancer immunologists are currently writing theory papers about it. For example, sipuleucel-T is a dendritic cell (DC)–based vaccine. Further stimulating DC activation, which happens with herbs like Oregon grape root (Mahonia aquifolium), could enhance the vaccine’s effects; however, no evidence has yet confirmed this. Q. Once the patient’s immune system is compromised, are there things that can be done to rebuild the immune system? If so, what would be a few key strategies?

Naturopathic medicine is ripe with ways to bring back the immune system, especially when you recall that 70-80% of

the immune system is in the gut. There’s not a lot of literature on rebuilding the immune system post chemotherapy, specifically. However, we know from the malnutrition literature that a balanced diet is very important to bringing back immunity. Considering protein, vitamins, minerals, and trace elements is essential when trying to rebuild cell populations. Promoting a healthy gut with probiotics, glutathione, and healthy fats (polyunsaturated) is also going to be important. There’s a lot of research suggesting that acupuncture could be beneficial for reducing immunosuppression. In fact, there are now funded clinical trials studying this therapy. Q. Where would you like future research to focus on in this area?

A. I’m not a fan of chemotherapy because chemotherapy shuts down the very system that I study. Focus should be placed on validating some of the promising treatment approaches that do not include chemotherapy. My first priority with respect to cancer research is to find funding for a non-chemotherapeutic novel treatment for breast

cancer. There’s a surgeon in La Quinta, Calif., who uses a modified military digital infrared system to detect breast cancer, and then applies cold needle ablation to destroy the tumor. The whole visit can be completed in the office with local anesthesia. The physician has completed a case series of more than 500 patients, and it’s time to do a clinical trial. If the clinical trial shows the same results as the case series, it will revolutionize how breast cancer is treated. However, the clinical trial would be large and complex. And finding funding for research that doesn’t support mainstream treatment is difficult. I’m also interested in applying the “positive deviant” strategy to cancer. Positive deviants are the people who have the best results—often orders of magnitudes above others with the same diagnosis. The strategy is to determine what the positive deviants do, and then study that. We see many cases of positive deviants in cancer—those with so-called “spontaneous remission” for example. Spontaneous means that we just don’t understand it yet. If we did understand it, could we replicate it? There is really so much that needs to be done in this area.

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