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State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research—NCI Strategic Workshop Highlights of Discussion Report

State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research—NCI... Abstract In May 2016, the Office of Cancer Complementary and Alternative Medicine, Division of Cancer Diagnosis and Treatment, of the National Cancer Institute convened a special workshop focused on the State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research. The current state of the science, gaps, and future opportunities were reviewed and discussed by a distinguished panel of experts in this field of research, and the highlights of this meeting are reported herein. Over the past 10 years, there has been an increase in the use of complementary and alternative medicine modalities by cancer patients for symptom management, improving quality of life, and enhancing the outcomes of standard treatment (1–2). The National Cancer Institute (NCI) defines complementary and alternative medicine (CAM) as “any medical system, practice, or product that is not considered standard care” (3). On May 25–26, 2016, the Office of Cancer Complementary and Alternative Medicine (OCCAM), Division of Cancer Treatment and Diagnosis (DCTD), of the National Cancer Institute convened a strategic scientific workshop titled “State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research” at the National Institutes of Health. The goals of this meeting were to assess the current status of evidence-based cancer CAM therapeutics research; discuss scientific gaps, needs, hurdles, and future opportunities; and provide suggestions for NCI regarding future strategic priorities for CAM research. An NCI workshop planning committee, including NCI extramural program staff and intramural and academic research scientists, many of whom are National Institutes of Health (NIH) grantees, provided the input for developing the agenda and selection of speakers. Experts in cancer therapeutics research, bioinformatics, computation modeling and databases, clinical trial design, and CAM were invited to attend this meeting. Given limitations in time, this workshop was unable to cover the entire breadth and depth of CAM-focused research. However, we believe that this meeting included the major research areas and appropriately reflected the current major CAM cancer therapeutics research areas. This summary report reflects the participants’ personal opinions and highlights collective key aspects of the workshop discussions as well as important feedback on postworkshop communications. Session Format and Topics A range of important CAM topics were discussed in seven scientific sessions. The meeting was chaired by Dr. Dan Xi. Each session was moderated by extramural NCI program staff and/or a speaker to facilitate the panel discussion at the end of each session. Each speaker presented for five to 15 minutes on their field of science and provided their perspective on gaps, hurdles, and future opportunities. Speakers were also given a set of questions related to the goals and objectives at the meeting for discussion and feedback. On the first day, Dr. Xi gave a short overview of the “NIH Cancer CAM Portfolio Analysis,” followed by Session 1, “CAM Intervention and Immune-Modulators.” The five speakers who presented at this session were Yung-chi Cheng, “PHY906 as Adjuvant for Cancer Chemotherapy and Radiation Therapy”; Jun Yan, “Nature Compound β-Glucan-Mediated Tumor Immunotherapy”; Gregory Lesinski, “Dietary Soy as a Modulator of Anti-tumor Immunity”; Simon Yeung, “Medicinal Mushrooms Overview and Cancer Treatment (Maitake Mushroom)”; and Leanna Standish, “Polysaccharide Krestin (PSK) Medical Mushroom Clinical Trial.” Session 2 was titled “Molecular Mechanism, Drug Discovery, and Systems/Network Pharmacology” and included six speakers: Chung Yang, “Green Tea and Cancer: Can EGCG Be an Effective Cancer Therapeutic Agent?”; Peiying Yang, “Molecular Mechanisms and Clinical Evaluation of Omega-3 Fatty Acids in Cancer”; Channing J. Paller, “Mistletoe in Cancer: Promises and Challenges”; David Frank, “Targeting Oncogenic Transcription Factors for Cancer Therapy: The Potential of Natural Products”; Channing Yu, “PRISM: Discovering Targeted Therapeutics for Cancer Using Mixtures of Barcoded Cancer Cell Lines”; Sushing Chen, “Systems Pharmacology: A Computational Platform for Screening Traditional Chinese Medicine Herbals and a Personalized, OMICS-based Approach to CAM”; and Curtis Henrich, “Discovery of Natural Product Sensitizers of TRAIL-Induced Apoptosis in Renal Carcinoma Cells.” Session 3 focused on “CAM Therapeutic Intervention and Microbiome,” and the speakers included Giorgio Trinchieri, “Cancer as a Disease of the Metaorganism”; Yujui Y. Wan, “Dysbiosis-Associated Liver Tumorigenesis—A Model to Study the Effect of Synbiotics”; Stephen O’Keefe, “The Microbiome and Colon Cancer”; and Cara Fiore, “Regulatory Considerations for Early Development of Live Biotherapeutic Products.” On Day 2, Session 4, “Vitamins and Other Nutritional and Pharmacological CAM Interventions,” included George Studzinski, “Vitamin D as a Treatment Option for Cancer: The Promise and the Challenges”; Jonathan Friedberg, “Vitamin D and Follicular Lymphoma”; and Jeffrey Lee, “Association of Vitamin D Levels with Melanoma Patient Outcome.” This session continued with talks focused on vitamin C, and the speakers included Mark Levine, “Connecting Vitamin C Pharmacokinetics Discoveries to Cancer Treatment”; Joseph Cullen, “Pharmacological Ascorbate Acid Trial (Pancreas)”; Qi Chen, “High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanism and a Phase I/IIa Study”; Channing J. Paller, “A Randomized Phase 2 Trial of Ascorbic Acid in Combination with Docetaxel in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)”; Manish Shah, “Vitamin C as a Novel Targeted Therapy in KRAS/BRAF Mutant Solid Tumor Malignancies”; and Gaofeng Wang, “Epigenetic Prevention of Cancer by Vitamin C.” Session 5 focused on “International Collaboration” with a representative from the National Natural Science Foundation of China (NSFC) and Chinese medicine physician-scientists from Beijing, China. The speakers for this session included Ruijuan Sun, “NSFC Funding Profile on Cancer Research in the Field of Traditional Medicine”; Anlong Xu, “Basic Mechanisms and Clinical Outcomes of Cancer Treatments through an Integrated Approach”; Guangbiao Zhou, “Translating the Power of Traditional Chinese Medicine into Patients’ Hope: Screening for Magic Bullets from Medicinal Herbs to Tame Cancers”; Shao Li, “Network Pharmacology and Computation Modeling to Traditional Chinese Medicine Research”; and Pingping Li, “Integrative Chinese Medicine for Late Stage and Elderly Lung Cancer Patients.” Session 6 was titled “Precision Medicine, Biomarkers and Integrative Medicine Clinical Research” with Ian Kronish, “Another Approach to Personalized Medicine: N-of-1 Trials”; Kelly Kim, “NCI-MATCH Trial”; Alice Chen, “Master Protocol Design”; Larry Rubinstein, “The Statistics of Phase 0 Trials Application to Cancer CAM Therapeutics”; Edward Chu, “Early-Phase Clinical Trials with PHY906”; Jun Mao, “The Promise of Precision CAM Intervention Trials”; Ting Bao, “Integrative Approach during Cancer Treatment and Neuropathy Management”; and Weidong Lu, “Strategies on Clinical Research of Chinese Herbal Medicine on Cancer.” The speakers for Session 7, “Material Standardization and Drug-Herb Interaction,” were Simon Yeung, “Drug and Herb Interactions”; Craig Hopp, “Standardizing Snowflakes: How Do We Normalize Nature”; and Sau Lee, “Botanical Drug Development and Quality Standards.” Gaps, Challenges, and Future Opportunities 1. Natural Products (Including Pure Compounds, Fraction/Mixture of Medicinal Natural Products, Diet, Nutrient, Probiotics, and Other Biological CAM Interventions) (1,) Productresources/suppliers: Given the low interest level of for-profit companies in nonpatentable natural products, it has been challenging to obtain natural product material manufactured in the United States (4). This situation has the potential to create problems for research reproducibility and sustainability. There is a clear need to explore the appropriate avenues of US funding and manufacturing sources for natural products. (2,) Product standardization: To ensure reproducibility of research and safety of participants enrolled in clinical trials, standardization and quality control for CAM and other natural products are essential (5). Product purity and bioactive component(s) identification are important issues for research. The consistent production of key compositions of multicomponent compounds and the development of biological and analytical assays are critical and challenging needs. If the bioactive compound(s) and their mechanisms of actions are not fully understood, standardization can be especially difficult, for example, mistletoe. Medicinal natural products need to be manufactured according to the US Food and Drug Administration’s (FDA’s) guidelines of Current Good Manufacturing Practices (CGMP) for clinical studies. It is also important to use high-quality CGMP material pre–clinical research (6). Seasonal and location variability and batch-to-batch consistency need to be considered (5). The presence of microbial organisms, pesticides, herbicides, and heavy metal contamination must be considered as potential contaminants of herbal products (7). Botanical verification methods, plant parts used, and compound/fraction preparation methods should always be documented to increase reproducibility (5–6). (3,) Mechanism(s) and translational research: Natural products, even the most “pure” single compounds, often have multitargeted effects (8). This can be an advantage for developing natural product-based therapeutic drugs, but it is a challenge for identifying specific molecular targets and understanding biological mechanisms of action. Innovative development of properly controlled experimental designs suitable for natural products and proper interpretation of results are important. Investigating the complex mechanisms of action can be greatly aided by applying modern computation and bioinformatics methodologies, including databases of preclinical and clinical studies, data mining for bioactive compounds, computational network pharmacology and modeling for pathway(s) identifications, and artificial intelligence for high-throughput drug discovery (9–12). Pharmacokinetics (PK), pharmacodynamics (PD), and biomarker discovery are also critical for future design of hypothesis-driven, mechanistic-based clinical trials. More research is needed to study the effect of nutritional intervention (eg, nutrients/diet) on cancer progression and cancer treatment outcome, especially clinical trials. Nutritional status and associated biomarkers, as well as nutritional needs for different ages, different types, and different stages of cancers during treatment have not been well investigated. Future prioritizing of medicinal natural product drug discovery can include developing new therapeutic compounds and new usage or formulas based on their molecular mechanisms of action to target currently undruggable targets and novel network pathway(s), modulate immune cell function and tumor immune microenviroments modify epigenetic pattern, and overcome drug resistance. (4,) Microbiome: The microbiota plays an important role in metabolism, immunity, inflammation, and response to cancer therapeutics (13). Most herbal medicines and nutritional interventions are taken orally, and their potential interactions with and effects on microbiota are just now being investigated (14). There is also emerging evidence that certain gut microbiota may enhance the antitumor effects of immune checkpoint inhibitors for cancer therapy and/or reduce the side effects of treatment. Additional research and innovative approaches (eg, biosynthetic engineering or synthetic biology) are needed to develop pre/probiotics and microbiome-based cancer therapy and better understand the potential impact of the microbiome on novel immunotherapy agents and/or TCM in early-phase clinical trials. (5,) Immune-modulators: Several CAM modalities, including medicinal natural products, diet/nutrient, and mind-body techniques, have immunomodulatory activities (15–17). The major gap in this area is the lack of detailed mechanistic studies and clinical trials on their immune modulatory effects on standard cancer therapeutics and emerging immunotherapy. Some challenges include material standardization, proper preclinical models, rigors of clinical trial design, and incorporation of proper immune biomarkers to assess end points and stratify appropriate patient populations. Studies to investigate microbiome biomarkers of metabolism and individual variations of responses are also needed. Future opportunities should also include the interaction of diet and the microbiome on the immune system and detailed mechanistic studies of their effects on immune cell function and on immunotherapy. 2. Clinical Research Focused on Cancer Complementary and Integrative Medicine in the Era of Precision Medicine Several challenges exist in conducting clinical trials on natural products and nonpharmacological CAM interventions, including standardization of CAM interventions; patient population selection; proper dosage, timing, and duration of interventions; identification of well-defined end points to determine effect and proper placebo control; and incorporation of translational PD biomarkers. Strong preclinical scientific rationale and proper well-controlled in vivo animal studies are needed. CAM clinical trial investigators must be acutely aware of the possibility that clinical practice standard treatments may change during the course of study. The workshop participants suggested that researchers conduct small pilot trials for proof of principle before considering larger and more expensive randomized phase II trials. One such pilot design is a single-arm trial to assess feasibility and efficacy, including comparison with historical controls. Phase 0 and window-of-opportunity trials were proposed to expedite CAM intervention development, improve our understanding of mechanism of actions and clinical efficacy, and explore the potential biomarkers to guide improved design of hypothesis-driven phase I/II trials. Phase 0 trials with small numbers (3–5) of patients for each dose enable evaluation of PD end points, comparing before and after intervention periods using known biological target(s) and available biological assays (tumor tissue or blood) (18–19). Window-of-opportunity trials are usually conducted in the context of locally advanced cancer, and they can be especially helpful to identify key biomarkers that predict response to therapy (20). One important area to focus on relates to phase II efficacy clinical trials. It is also important to conduct well-designed, appropriately powered, randomized, biomarker-driven, mechanistic-based phase II and III clinical trials. Further clinical and translational studies are also needed to understand differences and mechanisms among exceptional responders, responders, and nonresponders to CAM interventions. Another gap is the lack of funding for clinical trials of evidence-based, real-world, integrative-multimodality CAM interventions (eg, common practices at integrative oncology clinical programs in cancer centers and hospitals; the combinations of acupuncture, lifestyle modifications, nutrition/diet/herbs and exercise, mind-body and spiritual practices, and art/music therapies) during cancer treatment to reduce side effects and toxicity, improve quality of life, and improve adherence to and tolerance of conventional cancer treatments (eg, chemotherapy, hormonal treatment, targeted or immunotherapy), and ultimately enhance therapeutic outcome (eg, progression-free survival [PFS] and overall survival [OS]). Further research is needed to transform integrative medicine into a possible standard care treatment option for cancer patients. We discussed N-of-1 trials (ie, one-person trials) as one type of trial design that can be used in clinical practice to evaluate the effects of CAM in cancer survivors (21). N-of-1 trials are multiple crossover design experiments in which individual patients can compare CAM with placebo or two or more CAM treatments with one another. This study design may lead researchers to identify which CAM modality is best for an individual patient. Data from a series of N-of-1 trials can then be pooled to efficiently gain population-level estimates of CAM treatment effects. 3. Computation, Bioinformatics, Systems Medicine, and Data Sharing Computational network pharmacology and systems modeling, bioinformatics, data mining, artificial intelligence, and statistical analysis methodology development are critically important for understanding the underlying mechanisms of action and to aid in the design of effective integrative clinical trials involving multiple targets, multiple systems, and multiple interventions with holistic systems medicine thinking (9–12,22). Databases and improved methodologies are needed to increase the accuracy of therapeutic effect predictions and adverse events related to CAM modalities and their interactions with standard care. Important future tasks also include incorporating comprehensive CAM information into electronic health records, patient-reported outcomes, and NCI’s Surveillance, Epidemiology, and End Results (SEER) Program and enhancing data dissemination to the public (23). 4. Adverse Effect of Drug-CAM Interactions Potential drug/natural product (or drug/CAM modality) interaction during cancer treatment is an important area that has not yet been extensively studied. Chemical and biological genotyping can be incorporated into these analyses. Gender and ethnicity also need to be considered (24). Clinical research data, along with biomarkers and other correlates, are central to understanding the mechanisms of action and assessing adverse events and other drug-CAM interactions. There is a need to foster more research, especially clinical research, to develop centralized publicly accessible databases and validated methodologies to accurately predict drug/natural product or drug/CAM intervention interactions in humans. Support for relevant animal model development is also important. Future studies should also focus on prioritizing potential candidates for clinical evaluation and providing education to physicians unfamiliar with CAM. 5. Vitamins C and D Several challenges relating to vitamin D studies were identified, including methodology standardization for the measurement of vitamin D metabolites in blood plasma, identification of the optimal dose of vitamin D replacement/supplementation, ideal duration of vitamin D supplementation, elucidation of the optimal biomarkers to use as surrogate end points, and inclusion of proper primary end points (25,26). Given the low profitability of vitamin D supplements, vitamin D research funding from industry remains challenging. There is a need to support randomized, blinded, placebo-controlled, appropriately powered, biomarker-driven, mechanism-based phase II and III vitamin D intervention trials during cancer treatment in this area. Studies have shown that when used in combination with standard cancer treatment for some cancer types, intravenous (IV) pharmacologic ascorbate can improve therapeutic outcomes and enhance quality of life while being safe and well-tolerated (27–29). A challenge with the current formulation of ascorbate is its short half-life and volume load of delivery, requiring multiple repeated weekly administrations (30). The newly discovered role of vitamin C in epigenetic regulation provides some evidence for its potential role in cancer prevention and treatment (31). Another recent preclinical data in an experimental model system suggests further exploring high-dose vitamin C as a targeted therapy for KRAS- or BRAF-mutant tumors (32). IV ascorbate, directly and indirectly, may have multiple mechanisms of effect with varying efficacy on heterogeneous tumor cells, and its therapeutic outcome can depend on spatial and temporal dynamics of specific tumor cells’ overall genetic and molecular pathways, tumor cell physiology and metabolism status, and tumor microenvironment. The next important step is to research the mechanism of IV ascorbate that selectively kills some types of cancer cells and conduct a randomized, double-blind, placebo-controlled trial with surrogate biomarker end points that includes clinically relevant end points of OS and/or PFS. Such a study should also evaluate ascorbate’s impact on quality of life and its effect on adverse events related to standard cancer therapy. Novel imaging modalities to investigate ascorbate delivery to the tumor may have additive value (33). Potential priority can be given to IV ascorbate in combination with standard treatments in metastatic pancreatic, ovarian, glioblastoma, and renal clear cell cancer, or in non–small cell lung cancer and lymphomas that are not responsive to initial therapies. A greater level of funding support would be essential for these clinical studies, given the lack of pharmaceutical company support for pharmacologic ascorbate testing. 6. Workforce Development and Research Funding Participants highlighted the lack of scientist, physician-scientist, and clinical investigator appreciation of CAM and their relatively low levels of experience in conducting CAM-focused clinical trials. Integrative medicine practitioners face great challenges in developing collaborations with medical oncologists and other cancer investigators. There is a need to foster stronger collaborations between integrative medicine practitioners and oncologists by encouraging interdisciplinary training and research. The relative lack of funding to support CAM research was viewed as one of the major barriers and challenges to moving this area of research forward. The development of integrative oncology centers and/or a network of such centers could significantly enhance research collaboration, quality, reproducibility, and data sharing. 7. International Collaboration In the era of precision medicine, it is a challenge and an opportunity for CAM to contribute to personalized integrative medicine during cancer treatment for improving quality of life and enhancing overall survival. It may be beneficial for institutions in the United States and other countries to leverage and share funding resources and integrative oncology research expertise in common interest areas, such as clinical trials, the microbiome, bioinformatics computational modeling, nutrition research, and data sharing. Outline of Scientific Discussions and Feedback Summary The impact and quality of evidence-based cancer research using CAM modalities and integrative approaches—including medicinal natural products, lifestyle modifications (eg, diet/nutritional intervention, physical exercise, and sleep), mind-body techniques, art and music therapy, manual therapy (eg, massage), traditional medicines (eg, acupuncture and herbal medicine), and other modalities (eg, intravenous ascorbate acid and chronotherapy)—may be substantially enhanced through well-designed preclinical mechanistic studies, translational research, and appropriately powered clinical trials that are biomarker-driven and mechanism-based. In order for CAM-cancer therapeutics research to flourish, several key priorities should be to: conduct translational research and biomarker-driven, mechanistic-based clinical trials to focus on improving overall survival, reducing side effects, improving quality of life, and/or adherening to cancer treatment; enhance development of computation bioinformatic tools, databases, methodologies, and experimental research that will improve the accuracy of predictions related to therapeutics effects as well as adverse effects of interactions of CAM modalities with standard care, immunotherapy, and investigational drug/treatment; address health disparities by focusing research on improved overall survival and enhanced quality of life for late-stage, elderly, and pediatric cancer patients, as well as disadvantaged populations; develop innovative clinical trial designs for real-world multimodality integrative medicine interventions; develop pre/probiotics, microbiome-based cancer therapies, or combination therapies to enhance the outcome of cancer treatments, reduce side effects, and improve quality of life; support international collaborations; support workforce development and improve collaboration between oncologists and integrative medicine practitioners; and enhance research data dissemination, reproducibility, standardization, and sharing. Notes Authors: Dan Xi, Ting Bao, Qi Chen, Sushing Chen, Yung-chi Cheng, Joseph Cullen, David A. Frank, Jonathan W. Friedberg, Ian Kronish, Jeffrey E. Lee, Mark Levine, Pingping Li, Shao Li, Weidong Lu, Jun J. Mao, Stephen O’Keefe, Larry Rubinstein, Manish A. Shah, Leanna Standish, Ruijuan Sun, YuJui Y. Wan, Gaofeng Wang, Anlong Xu, Jun Yan, Chung Yang, Peiying Yang, Simon Yeung, Guangbiao Zhou, Channing J. Paller*, Edward Chu* *Authors contributed equally to this work. Affiliations of authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD (DX, LR); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (ML); Memorial Sloan Kettering Cancer Center, New York, NY (TB, JM, SY); University of Kansas, Lawrence, KS (QC); University of Florida, Gainsville, FL (SC); Yale University, New Haven, CT (YCC); University of Iowa, Iowa City, IA (JC); Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (DF, WL); University of Rochester Medical Center, Rochester, NY (JWF); Columbia University Medical Center, New York, NY (IK); The University of Texas MD Anderson Cancer Center, Houston, TX (JEL, PY); Peking University Cancer Hospital, Beijing, China (PPL); University of Pittsburgh, Pittsburgh, PA (EC, SOK); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD (CJP); Weill Cornell Medicine at Cornell University, New York, NY (MAS); Bastyr University, Kenmore, WA (LS); National Natural Science Foundation of China, Beijing, China (RJS); University of California, Davis, Health Systems, Sacramento, CA (YYW); Beijing University of Chinese Medicine, Beijing, China (ALX); University of Miami Miller School of Medicine, Miami, FL (GW); University of Louisville, Louisville, KY (JY); Rutgers, The State University of New Jersey, Camden, NJ (CY); Tsinghua University, Beijing, China (SL); Chinese Academy of Sciences, Beijing, China (GBZ). The workshop organizers and authors would like to thank the Workshop Planning Committee; Office of Cancer Complementary and Alternative Medicine, Division of Cancer Treatment and Diagnosis, National Cancer Institute leadership; session moderators; and all of the invited speakers for their valuable contributions in helping to organize and make this meeting such a success. We would like to thank the National Cancer Institute’s funding support for the workshop and for this manuscript. Finally, we appreciate editorial assistance from Christina Seluzicki at the Memorial Sloan Kettering Cancer Center (in part supported by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748). References 1 Ndao DH , Ladas EJ, Bao Y, et al. Use of complementary and alternative medicine among children, adolescent, and young adult cancer survivors: A survey study . J Pediatr Hematol Oncol. 2013 ; 35 4 : 281 – 288 . 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Int J Funct Inform Pers Med. 2009 ; 2 3 : 244 – 247 . Google Scholar OpenURL Placeholder Text WorldCat 23 Ryerson AB , Eheman CR, Altekruse SF, et al. Annual Report to the Nation on the Status of Cancer, 1975–2012, featuring the increasing incidence of liver cancer . Cancer. 2016 ; 122 : 1312 – 1337 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Choi JG , Eom SM, Kim J, et al. A comprehensive review of recent studies on herb-drug interaction: A focus on pharmacodynamic interaction . J Altern Complement Med. 2016 ; 22 4 : 262 – 279 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Yuan C , Qian ZR, Babic A, et al. Prediagnostic plasma 25-hydroxyvitamin D and pancreatic cancer survival . J Clin Oncol. 2016 ; 34 : 2899 – 2905 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Yao S , Kwan ML, Isaac JE, et al. Association of serum level of vitamin D at diagnosis with breast cancer survival in a case-cohort analysis in the Pathways Study . 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Cancer Chemother Pharmacol. 2013 ; 72 : 139 – 146 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Camarena V , Wang G. The epigenetic role of vitamin C in health and disease . Cell Mol Life Sci. 2016 ; 73 8 : 1645 – 1658 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Yun J , Mullarky E, Lu C, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH . Science. 2015 ; 350 6266 : 1391 – 1396 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Keshari KR , Sai V, Wang ZJ, et al. Hyperpolarized [1-13C]dehydroascorbate MR spectroscopy in a murine model of prostate cancer: Comparison with 18F-FDG PET . J Nucl Med. 2013 ; 54 : 922 – 928 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes See the Notes section for the full list of authors and affiliations. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research—NCI Strategic Workshop Highlights of Discussion Report

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Abstract

Abstract In May 2016, the Office of Cancer Complementary and Alternative Medicine, Division of Cancer Diagnosis and Treatment, of the National Cancer Institute convened a special workshop focused on the State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research. The current state of the science, gaps, and future opportunities were reviewed and discussed by a distinguished panel of experts in this field of research, and the highlights of this meeting are reported herein. Over the past 10 years, there has been an increase in the use of complementary and alternative medicine modalities by cancer patients for symptom management, improving quality of life, and enhancing the outcomes of standard treatment (1–2). The National Cancer Institute (NCI) defines complementary and alternative medicine (CAM) as “any medical system, practice, or product that is not considered standard care” (3). On May 25–26, 2016, the Office of Cancer Complementary and Alternative Medicine (OCCAM), Division of Cancer Treatment and Diagnosis (DCTD), of the National Cancer Institute convened a strategic scientific workshop titled “State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research” at the National Institutes of Health. The goals of this meeting were to assess the current status of evidence-based cancer CAM therapeutics research; discuss scientific gaps, needs, hurdles, and future opportunities; and provide suggestions for NCI regarding future strategic priorities for CAM research. An NCI workshop planning committee, including NCI extramural program staff and intramural and academic research scientists, many of whom are National Institutes of Health (NIH) grantees, provided the input for developing the agenda and selection of speakers. Experts in cancer therapeutics research, bioinformatics, computation modeling and databases, clinical trial design, and CAM were invited to attend this meeting. Given limitations in time, this workshop was unable to cover the entire breadth and depth of CAM-focused research. However, we believe that this meeting included the major research areas and appropriately reflected the current major CAM cancer therapeutics research areas. This summary report reflects the participants’ personal opinions and highlights collective key aspects of the workshop discussions as well as important feedback on postworkshop communications. Session Format and Topics A range of important CAM topics were discussed in seven scientific sessions. The meeting was chaired by Dr. Dan Xi. Each session was moderated by extramural NCI program staff and/or a speaker to facilitate the panel discussion at the end of each session. Each speaker presented for five to 15 minutes on their field of science and provided their perspective on gaps, hurdles, and future opportunities. Speakers were also given a set of questions related to the goals and objectives at the meeting for discussion and feedback. On the first day, Dr. Xi gave a short overview of the “NIH Cancer CAM Portfolio Analysis,” followed by Session 1, “CAM Intervention and Immune-Modulators.” The five speakers who presented at this session were Yung-chi Cheng, “PHY906 as Adjuvant for Cancer Chemotherapy and Radiation Therapy”; Jun Yan, “Nature Compound β-Glucan-Mediated Tumor Immunotherapy”; Gregory Lesinski, “Dietary Soy as a Modulator of Anti-tumor Immunity”; Simon Yeung, “Medicinal Mushrooms Overview and Cancer Treatment (Maitake Mushroom)”; and Leanna Standish, “Polysaccharide Krestin (PSK) Medical Mushroom Clinical Trial.” Session 2 was titled “Molecular Mechanism, Drug Discovery, and Systems/Network Pharmacology” and included six speakers: Chung Yang, “Green Tea and Cancer: Can EGCG Be an Effective Cancer Therapeutic Agent?”; Peiying Yang, “Molecular Mechanisms and Clinical Evaluation of Omega-3 Fatty Acids in Cancer”; Channing J. Paller, “Mistletoe in Cancer: Promises and Challenges”; David Frank, “Targeting Oncogenic Transcription Factors for Cancer Therapy: The Potential of Natural Products”; Channing Yu, “PRISM: Discovering Targeted Therapeutics for Cancer Using Mixtures of Barcoded Cancer Cell Lines”; Sushing Chen, “Systems Pharmacology: A Computational Platform for Screening Traditional Chinese Medicine Herbals and a Personalized, OMICS-based Approach to CAM”; and Curtis Henrich, “Discovery of Natural Product Sensitizers of TRAIL-Induced Apoptosis in Renal Carcinoma Cells.” Session 3 focused on “CAM Therapeutic Intervention and Microbiome,” and the speakers included Giorgio Trinchieri, “Cancer as a Disease of the Metaorganism”; Yujui Y. Wan, “Dysbiosis-Associated Liver Tumorigenesis—A Model to Study the Effect of Synbiotics”; Stephen O’Keefe, “The Microbiome and Colon Cancer”; and Cara Fiore, “Regulatory Considerations for Early Development of Live Biotherapeutic Products.” On Day 2, Session 4, “Vitamins and Other Nutritional and Pharmacological CAM Interventions,” included George Studzinski, “Vitamin D as a Treatment Option for Cancer: The Promise and the Challenges”; Jonathan Friedberg, “Vitamin D and Follicular Lymphoma”; and Jeffrey Lee, “Association of Vitamin D Levels with Melanoma Patient Outcome.” This session continued with talks focused on vitamin C, and the speakers included Mark Levine, “Connecting Vitamin C Pharmacokinetics Discoveries to Cancer Treatment”; Joseph Cullen, “Pharmacological Ascorbate Acid Trial (Pancreas)”; Qi Chen, “High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanism and a Phase I/IIa Study”; Channing J. Paller, “A Randomized Phase 2 Trial of Ascorbic Acid in Combination with Docetaxel in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)”; Manish Shah, “Vitamin C as a Novel Targeted Therapy in KRAS/BRAF Mutant Solid Tumor Malignancies”; and Gaofeng Wang, “Epigenetic Prevention of Cancer by Vitamin C.” Session 5 focused on “International Collaboration” with a representative from the National Natural Science Foundation of China (NSFC) and Chinese medicine physician-scientists from Beijing, China. The speakers for this session included Ruijuan Sun, “NSFC Funding Profile on Cancer Research in the Field of Traditional Medicine”; Anlong Xu, “Basic Mechanisms and Clinical Outcomes of Cancer Treatments through an Integrated Approach”; Guangbiao Zhou, “Translating the Power of Traditional Chinese Medicine into Patients’ Hope: Screening for Magic Bullets from Medicinal Herbs to Tame Cancers”; Shao Li, “Network Pharmacology and Computation Modeling to Traditional Chinese Medicine Research”; and Pingping Li, “Integrative Chinese Medicine for Late Stage and Elderly Lung Cancer Patients.” Session 6 was titled “Precision Medicine, Biomarkers and Integrative Medicine Clinical Research” with Ian Kronish, “Another Approach to Personalized Medicine: N-of-1 Trials”; Kelly Kim, “NCI-MATCH Trial”; Alice Chen, “Master Protocol Design”; Larry Rubinstein, “The Statistics of Phase 0 Trials Application to Cancer CAM Therapeutics”; Edward Chu, “Early-Phase Clinical Trials with PHY906”; Jun Mao, “The Promise of Precision CAM Intervention Trials”; Ting Bao, “Integrative Approach during Cancer Treatment and Neuropathy Management”; and Weidong Lu, “Strategies on Clinical Research of Chinese Herbal Medicine on Cancer.” The speakers for Session 7, “Material Standardization and Drug-Herb Interaction,” were Simon Yeung, “Drug and Herb Interactions”; Craig Hopp, “Standardizing Snowflakes: How Do We Normalize Nature”; and Sau Lee, “Botanical Drug Development and Quality Standards.” Gaps, Challenges, and Future Opportunities 1. Natural Products (Including Pure Compounds, Fraction/Mixture of Medicinal Natural Products, Diet, Nutrient, Probiotics, and Other Biological CAM Interventions) (1,) Productresources/suppliers: Given the low interest level of for-profit companies in nonpatentable natural products, it has been challenging to obtain natural product material manufactured in the United States (4). This situation has the potential to create problems for research reproducibility and sustainability. There is a clear need to explore the appropriate avenues of US funding and manufacturing sources for natural products. (2,) Product standardization: To ensure reproducibility of research and safety of participants enrolled in clinical trials, standardization and quality control for CAM and other natural products are essential (5). Product purity and bioactive component(s) identification are important issues for research. The consistent production of key compositions of multicomponent compounds and the development of biological and analytical assays are critical and challenging needs. If the bioactive compound(s) and their mechanisms of actions are not fully understood, standardization can be especially difficult, for example, mistletoe. Medicinal natural products need to be manufactured according to the US Food and Drug Administration’s (FDA’s) guidelines of Current Good Manufacturing Practices (CGMP) for clinical studies. It is also important to use high-quality CGMP material pre–clinical research (6). Seasonal and location variability and batch-to-batch consistency need to be considered (5). The presence of microbial organisms, pesticides, herbicides, and heavy metal contamination must be considered as potential contaminants of herbal products (7). Botanical verification methods, plant parts used, and compound/fraction preparation methods should always be documented to increase reproducibility (5–6). (3,) Mechanism(s) and translational research: Natural products, even the most “pure” single compounds, often have multitargeted effects (8). This can be an advantage for developing natural product-based therapeutic drugs, but it is a challenge for identifying specific molecular targets and understanding biological mechanisms of action. Innovative development of properly controlled experimental designs suitable for natural products and proper interpretation of results are important. Investigating the complex mechanisms of action can be greatly aided by applying modern computation and bioinformatics methodologies, including databases of preclinical and clinical studies, data mining for bioactive compounds, computational network pharmacology and modeling for pathway(s) identifications, and artificial intelligence for high-throughput drug discovery (9–12). Pharmacokinetics (PK), pharmacodynamics (PD), and biomarker discovery are also critical for future design of hypothesis-driven, mechanistic-based clinical trials. More research is needed to study the effect of nutritional intervention (eg, nutrients/diet) on cancer progression and cancer treatment outcome, especially clinical trials. Nutritional status and associated biomarkers, as well as nutritional needs for different ages, different types, and different stages of cancers during treatment have not been well investigated. Future prioritizing of medicinal natural product drug discovery can include developing new therapeutic compounds and new usage or formulas based on their molecular mechanisms of action to target currently undruggable targets and novel network pathway(s), modulate immune cell function and tumor immune microenviroments modify epigenetic pattern, and overcome drug resistance. (4,) Microbiome: The microbiota plays an important role in metabolism, immunity, inflammation, and response to cancer therapeutics (13). Most herbal medicines and nutritional interventions are taken orally, and their potential interactions with and effects on microbiota are just now being investigated (14). There is also emerging evidence that certain gut microbiota may enhance the antitumor effects of immune checkpoint inhibitors for cancer therapy and/or reduce the side effects of treatment. Additional research and innovative approaches (eg, biosynthetic engineering or synthetic biology) are needed to develop pre/probiotics and microbiome-based cancer therapy and better understand the potential impact of the microbiome on novel immunotherapy agents and/or TCM in early-phase clinical trials. (5,) Immune-modulators: Several CAM modalities, including medicinal natural products, diet/nutrient, and mind-body techniques, have immunomodulatory activities (15–17). The major gap in this area is the lack of detailed mechanistic studies and clinical trials on their immune modulatory effects on standard cancer therapeutics and emerging immunotherapy. Some challenges include material standardization, proper preclinical models, rigors of clinical trial design, and incorporation of proper immune biomarkers to assess end points and stratify appropriate patient populations. Studies to investigate microbiome biomarkers of metabolism and individual variations of responses are also needed. Future opportunities should also include the interaction of diet and the microbiome on the immune system and detailed mechanistic studies of their effects on immune cell function and on immunotherapy. 2. Clinical Research Focused on Cancer Complementary and Integrative Medicine in the Era of Precision Medicine Several challenges exist in conducting clinical trials on natural products and nonpharmacological CAM interventions, including standardization of CAM interventions; patient population selection; proper dosage, timing, and duration of interventions; identification of well-defined end points to determine effect and proper placebo control; and incorporation of translational PD biomarkers. Strong preclinical scientific rationale and proper well-controlled in vivo animal studies are needed. CAM clinical trial investigators must be acutely aware of the possibility that clinical practice standard treatments may change during the course of study. The workshop participants suggested that researchers conduct small pilot trials for proof of principle before considering larger and more expensive randomized phase II trials. One such pilot design is a single-arm trial to assess feasibility and efficacy, including comparison with historical controls. Phase 0 and window-of-opportunity trials were proposed to expedite CAM intervention development, improve our understanding of mechanism of actions and clinical efficacy, and explore the potential biomarkers to guide improved design of hypothesis-driven phase I/II trials. Phase 0 trials with small numbers (3–5) of patients for each dose enable evaluation of PD end points, comparing before and after intervention periods using known biological target(s) and available biological assays (tumor tissue or blood) (18–19). Window-of-opportunity trials are usually conducted in the context of locally advanced cancer, and they can be especially helpful to identify key biomarkers that predict response to therapy (20). One important area to focus on relates to phase II efficacy clinical trials. It is also important to conduct well-designed, appropriately powered, randomized, biomarker-driven, mechanistic-based phase II and III clinical trials. Further clinical and translational studies are also needed to understand differences and mechanisms among exceptional responders, responders, and nonresponders to CAM interventions. Another gap is the lack of funding for clinical trials of evidence-based, real-world, integrative-multimodality CAM interventions (eg, common practices at integrative oncology clinical programs in cancer centers and hospitals; the combinations of acupuncture, lifestyle modifications, nutrition/diet/herbs and exercise, mind-body and spiritual practices, and art/music therapies) during cancer treatment to reduce side effects and toxicity, improve quality of life, and improve adherence to and tolerance of conventional cancer treatments (eg, chemotherapy, hormonal treatment, targeted or immunotherapy), and ultimately enhance therapeutic outcome (eg, progression-free survival [PFS] and overall survival [OS]). Further research is needed to transform integrative medicine into a possible standard care treatment option for cancer patients. We discussed N-of-1 trials (ie, one-person trials) as one type of trial design that can be used in clinical practice to evaluate the effects of CAM in cancer survivors (21). N-of-1 trials are multiple crossover design experiments in which individual patients can compare CAM with placebo or two or more CAM treatments with one another. This study design may lead researchers to identify which CAM modality is best for an individual patient. Data from a series of N-of-1 trials can then be pooled to efficiently gain population-level estimates of CAM treatment effects. 3. Computation, Bioinformatics, Systems Medicine, and Data Sharing Computational network pharmacology and systems modeling, bioinformatics, data mining, artificial intelligence, and statistical analysis methodology development are critically important for understanding the underlying mechanisms of action and to aid in the design of effective integrative clinical trials involving multiple targets, multiple systems, and multiple interventions with holistic systems medicine thinking (9–12,22). Databases and improved methodologies are needed to increase the accuracy of therapeutic effect predictions and adverse events related to CAM modalities and their interactions with standard care. Important future tasks also include incorporating comprehensive CAM information into electronic health records, patient-reported outcomes, and NCI’s Surveillance, Epidemiology, and End Results (SEER) Program and enhancing data dissemination to the public (23). 4. Adverse Effect of Drug-CAM Interactions Potential drug/natural product (or drug/CAM modality) interaction during cancer treatment is an important area that has not yet been extensively studied. Chemical and biological genotyping can be incorporated into these analyses. Gender and ethnicity also need to be considered (24). Clinical research data, along with biomarkers and other correlates, are central to understanding the mechanisms of action and assessing adverse events and other drug-CAM interactions. There is a need to foster more research, especially clinical research, to develop centralized publicly accessible databases and validated methodologies to accurately predict drug/natural product or drug/CAM intervention interactions in humans. Support for relevant animal model development is also important. Future studies should also focus on prioritizing potential candidates for clinical evaluation and providing education to physicians unfamiliar with CAM. 5. Vitamins C and D Several challenges relating to vitamin D studies were identified, including methodology standardization for the measurement of vitamin D metabolites in blood plasma, identification of the optimal dose of vitamin D replacement/supplementation, ideal duration of vitamin D supplementation, elucidation of the optimal biomarkers to use as surrogate end points, and inclusion of proper primary end points (25,26). Given the low profitability of vitamin D supplements, vitamin D research funding from industry remains challenging. There is a need to support randomized, blinded, placebo-controlled, appropriately powered, biomarker-driven, mechanism-based phase II and III vitamin D intervention trials during cancer treatment in this area. Studies have shown that when used in combination with standard cancer treatment for some cancer types, intravenous (IV) pharmacologic ascorbate can improve therapeutic outcomes and enhance quality of life while being safe and well-tolerated (27–29). A challenge with the current formulation of ascorbate is its short half-life and volume load of delivery, requiring multiple repeated weekly administrations (30). The newly discovered role of vitamin C in epigenetic regulation provides some evidence for its potential role in cancer prevention and treatment (31). Another recent preclinical data in an experimental model system suggests further exploring high-dose vitamin C as a targeted therapy for KRAS- or BRAF-mutant tumors (32). IV ascorbate, directly and indirectly, may have multiple mechanisms of effect with varying efficacy on heterogeneous tumor cells, and its therapeutic outcome can depend on spatial and temporal dynamics of specific tumor cells’ overall genetic and molecular pathways, tumor cell physiology and metabolism status, and tumor microenvironment. The next important step is to research the mechanism of IV ascorbate that selectively kills some types of cancer cells and conduct a randomized, double-blind, placebo-controlled trial with surrogate biomarker end points that includes clinically relevant end points of OS and/or PFS. Such a study should also evaluate ascorbate’s impact on quality of life and its effect on adverse events related to standard cancer therapy. Novel imaging modalities to investigate ascorbate delivery to the tumor may have additive value (33). Potential priority can be given to IV ascorbate in combination with standard treatments in metastatic pancreatic, ovarian, glioblastoma, and renal clear cell cancer, or in non–small cell lung cancer and lymphomas that are not responsive to initial therapies. A greater level of funding support would be essential for these clinical studies, given the lack of pharmaceutical company support for pharmacologic ascorbate testing. 6. Workforce Development and Research Funding Participants highlighted the lack of scientist, physician-scientist, and clinical investigator appreciation of CAM and their relatively low levels of experience in conducting CAM-focused clinical trials. Integrative medicine practitioners face great challenges in developing collaborations with medical oncologists and other cancer investigators. There is a need to foster stronger collaborations between integrative medicine practitioners and oncologists by encouraging interdisciplinary training and research. The relative lack of funding to support CAM research was viewed as one of the major barriers and challenges to moving this area of research forward. The development of integrative oncology centers and/or a network of such centers could significantly enhance research collaboration, quality, reproducibility, and data sharing. 7. International Collaboration In the era of precision medicine, it is a challenge and an opportunity for CAM to contribute to personalized integrative medicine during cancer treatment for improving quality of life and enhancing overall survival. It may be beneficial for institutions in the United States and other countries to leverage and share funding resources and integrative oncology research expertise in common interest areas, such as clinical trials, the microbiome, bioinformatics computational modeling, nutrition research, and data sharing. Outline of Scientific Discussions and Feedback Summary The impact and quality of evidence-based cancer research using CAM modalities and integrative approaches—including medicinal natural products, lifestyle modifications (eg, diet/nutritional intervention, physical exercise, and sleep), mind-body techniques, art and music therapy, manual therapy (eg, massage), traditional medicines (eg, acupuncture and herbal medicine), and other modalities (eg, intravenous ascorbate acid and chronotherapy)—may be substantially enhanced through well-designed preclinical mechanistic studies, translational research, and appropriately powered clinical trials that are biomarker-driven and mechanism-based. In order for CAM-cancer therapeutics research to flourish, several key priorities should be to: conduct translational research and biomarker-driven, mechanistic-based clinical trials to focus on improving overall survival, reducing side effects, improving quality of life, and/or adherening to cancer treatment; enhance development of computation bioinformatic tools, databases, methodologies, and experimental research that will improve the accuracy of predictions related to therapeutics effects as well as adverse effects of interactions of CAM modalities with standard care, immunotherapy, and investigational drug/treatment; address health disparities by focusing research on improved overall survival and enhanced quality of life for late-stage, elderly, and pediatric cancer patients, as well as disadvantaged populations; develop innovative clinical trial designs for real-world multimodality integrative medicine interventions; develop pre/probiotics, microbiome-based cancer therapies, or combination therapies to enhance the outcome of cancer treatments, reduce side effects, and improve quality of life; support international collaborations; support workforce development and improve collaboration between oncologists and integrative medicine practitioners; and enhance research data dissemination, reproducibility, standardization, and sharing. Notes Authors: Dan Xi, Ting Bao, Qi Chen, Sushing Chen, Yung-chi Cheng, Joseph Cullen, David A. Frank, Jonathan W. Friedberg, Ian Kronish, Jeffrey E. Lee, Mark Levine, Pingping Li, Shao Li, Weidong Lu, Jun J. Mao, Stephen O’Keefe, Larry Rubinstein, Manish A. Shah, Leanna Standish, Ruijuan Sun, YuJui Y. Wan, Gaofeng Wang, Anlong Xu, Jun Yan, Chung Yang, Peiying Yang, Simon Yeung, Guangbiao Zhou, Channing J. Paller*, Edward Chu* *Authors contributed equally to this work. Affiliations of authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD (DX, LR); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (ML); Memorial Sloan Kettering Cancer Center, New York, NY (TB, JM, SY); University of Kansas, Lawrence, KS (QC); University of Florida, Gainsville, FL (SC); Yale University, New Haven, CT (YCC); University of Iowa, Iowa City, IA (JC); Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (DF, WL); University of Rochester Medical Center, Rochester, NY (JWF); Columbia University Medical Center, New York, NY (IK); The University of Texas MD Anderson Cancer Center, Houston, TX (JEL, PY); Peking University Cancer Hospital, Beijing, China (PPL); University of Pittsburgh, Pittsburgh, PA (EC, SOK); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD (CJP); Weill Cornell Medicine at Cornell University, New York, NY (MAS); Bastyr University, Kenmore, WA (LS); National Natural Science Foundation of China, Beijing, China (RJS); University of California, Davis, Health Systems, Sacramento, CA (YYW); Beijing University of Chinese Medicine, Beijing, China (ALX); University of Miami Miller School of Medicine, Miami, FL (GW); University of Louisville, Louisville, KY (JY); Rutgers, The State University of New Jersey, Camden, NJ (CY); Tsinghua University, Beijing, China (SL); Chinese Academy of Sciences, Beijing, China (GBZ). The workshop organizers and authors would like to thank the Workshop Planning Committee; Office of Cancer Complementary and Alternative Medicine, Division of Cancer Treatment and Diagnosis, National Cancer Institute leadership; session moderators; and all of the invited speakers for their valuable contributions in helping to organize and make this meeting such a success. We would like to thank the National Cancer Institute’s funding support for the workshop and for this manuscript. Finally, we appreciate editorial assistance from Christina Seluzicki at the Memorial Sloan Kettering Cancer Center (in part supported by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748). References 1 Ndao DH , Ladas EJ, Bao Y, et al. Use of complementary and alternative medicine among children, adolescent, and young adult cancer survivors: A survey study . J Pediatr Hematol Oncol. 2013 ; 35 4 : 281 – 288 . 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Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.

Journal

JNCI Monographs – Oxford University Press

Published: Nov 1, 2017

Keywords: cancer; complementary therapies; national cancer institute

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