Oncology Nutrition Connection

A publication of the ON DPG Volume 23, Number 2, 2016 ON DPG Website ISSN 1545-9896 www.oncologynutrition.org

Table of Contents ON DPG Message from the Chair For this issue of Oncology Nutrition Connection’s Message from the • Message from the Chair: CNM DPG Supporting ON DPG Chair, we are highlighting a letter from the Chair of a different DPG, the page 1 Clinical Nutrition Management (CNM) DPG. This all began at the ON DPG Breakfast at FNCE 2014, where Elaine Trujillo, MS, RDN, Past Chair • Brief Report: Fluoride Toxicity of ON DPG and Ann Yaktine, PhD, RD, Director of the Food and in Hematopoietic Stem Cell Transplantation Nutrition Board at the Institute of Medicine (IOM), presented ON DPG’s page 2 plan to hold an IOM workshop to address Access to Nutrition Care in Outpatient Oncology. One of our active ON DPG members, Terese • Pediatric Oncology Nutrition Scollard, MBA, RD, LD, also is an active member of CNM DPG. Terese Corner: Pediatric vs. Adult Cancer: Critical Differences had the tremendous vision to see how our workshop could lay the page 3 foundation for improved access to RDs in many settings, not just in outpatient oncology. She had the foresight to invite CNM DPG to • CPE Article: Miraculin and support our workshop, and ON DPG was amazed and grateful when The Miracle Berry: An Option for Dysguesia? CNM pledged some of their hard-earned budget to support our page 7 workshop. We say “Kudos!” to CNM DPG, and are pleased to share this letter from CNM DPG with you! • Medical Cannabis Comes Out from Underground To members of CNM DPG and ON DPG, page 14

The quality of operational practices and Common concerns to both Clinical level of service integration can vary widely Nutrition Management and the Oncology among cancer programs. Cancer programs Nutrition Practice Group are improving strive for quality; however, there remain patient access to nutrition care, improving inconsistencies within and between the quality of and timing of nutrition programs related to nutritional practices intervention, support for team nutrition and access. Operational practices can care planning for patients, and negatively or positively impact patients’ improvement of access to nutritional nutritional status and outcomes. services for all cancer patients.

(Continued on next page) 2 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016

National standards for cancer nutrition Every cancer patient deserves access to Oncology Nutrition services do not include quality metrics quality nutrition care provided by a with which to evaluate success or identify registered dietitian, embedded in cancer Connection improvement activities within cancer treatment programs. We must be A publication of Oncology Nutrition (ON), a nutrition programs. Reports in the advocates for our patients, and strive for dietetic practice group of the Academy of literature on practices, staffing levels, and the provision of quality nutrition care Nutrition and Dietetics. ISSN 1545-9896. training of professionals are inconclusive, within our organizations and our own Visit the ON DPG website at and therefore, challenging for program clinical practice. Attention to the basics of www.oncologynutrition.org leadership to identify the best workflows nutrition and hydration lessens suffering, Editor: or program practices. Few programs readmissions, delays in treatment, and Suzanne Dixon, MPH, MS, RDN include periodic nutrition risk screening gives hope to patients and families. For [email protected] with a validated and reliable screening tool these reasons, the CNM DPG is happy to Associate Editor: to identify patients who are struggling support this important first step of helping Jodie Greear, MS, RD, LDN [email protected] with nutrition before, during or after to finance the Nutrition and Cancer IOM treatment. Therefore, patients’ nutritional Workshop. Oncology Nutrition Connection (ONC) ISSN 1545-9896, is the official newsletter of the problems and needs may be missed or Oncology Nutrition Dietetic Practice Group inadvertently delayed until they result in We encourage our members to consider (ON DPG), a practice group of the Academy treatment dose reductions, serious side donating individually at: https://www. of Nutrition and Dietetics, and is published effects, and inability to heal and recover. oncologynutrition.org/get-involved/register- quarterly. All issues of ONC are distributed to to-become-a-member/iom-workshop/ members in electronic format only. The Oncology DPG has taken the major Articles published in ONC highlight specific step to plan for a collaborative workshop Sincerely, diseases or areas of practice in oncology with the Institute of Medicine to review the The Board of the Clinical Nutrition nutrition. Viewpoints and statements in each newsletter do not necessarily reflect the topic of nutrition care in cancer. The CNM Management Dietetic Practice Group policies and/or positions of the Academy of DPG, with a common concern for this Caroline Steele, MS, RD, CSP, IBCLC Nutrition and Dietetics or ON DPG. topic, has allocated $4,000 of member Chair, CNM DPG 2015-2016 Oncology Nutrition Connection is indexed in resources to support the IOM Workshop. the Cumulative Index to Nursing and Allied Health Literature. For inquiries regarding copyright, single-issue sales and past issues, contact the editor. Individuals interested in submitting a manuscript to ONC should Brief Report: Fluoride Toxicity in contact the editor or check the ON website for author guidelines. Individuals who are Hematopoietic Cell Transplantation ineligible for membership in the Academy of By Kerry McMillen, MS, RD, CSO Nutrition and Dietetics can order yearly subscriptions to ONC for $35.00 (domestic fee) and $40.00 (international fee), payable Many hematopoietic cell transplant (HCT) patients are treated for to the Academy of Nutrition and Dietetics/ invasive fungal infections. First line therapy for fungal pneumonia is ON DPG. Institutions can subscribe to ONC for $50.00 (domestic yearly fee) and $65.00 voriconazole, which is a fluorinated triazole compound (1). At standard (international yearly fee). ON DPG members voriconazole dosing, daily fluoride intake may be as high as 62.6 mg. The have access to archived back issues in pdf format. Non-members can order printed WHO guidelines document that fluoride intake of >6 mg/day increases copies of back issues (contact editor for risk of skeletal events, such as increased fracture risk, tingling and availability) at a cost of $10.00 each if mailed domestically and $20.00 each if mailed numbness in extremities, and joint pain (2,3). Because fluoride toxicity internationally. Send requests for symptoms include bone pain and weakness, which also are common in subscriptions or back issues to the editor. All ON DPG member mailing address changes many post-HCT patients, fluoride toxicity may be overlooked. and email address changes should be sent to the Academy using the address change card In an article by Gerber and colleagues, correlated to glomerular filtration rate in the Journal of the Academy of Nutrition contributors to fluoride-related, clinically (GFR) (1). Impaired renal function, and Dietetics or at eatright.org in the relevant skeletal disease in patients on common with immunosuppressive members-only section. voriconazole treatment include (1): medications such as tacrolimus, ©2016. Oncology Nutrition Dietetic Practice • Impaired renal function. Gerber et al. cyclosporine and sirolimus, is associated Group. All rights reserved. noted fluoride levels are inversely with higher circulating fluoride levels. Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 3

• Prolonged intake. Patients in the Gerber study developed toxicity symptoms Pediatric Oncology Nutrition Corner: Critical between 3 and 7.5 months. Differences in Pediatric and Adult Cancers • Individual differences in By Nancy Sacks, MS, RD, LD and Chelsea Schulman, MS, RD, LDN pharmacogenetics and drug-drug interactions. • Inflammatory processes, the symptoms of Introduction which may be masked when patients are Cancer is the leading cause of death by disease among children in the on systemic corticosteroids, commonly United States (1). Leukemia, brain, and other central nervous system used for Graft vs. Host Disease treatment. (CNS) tumors account for more than half of new diagnoses of major

Patients complaining of bone pain and childhood cancers. Advances in treatment for childhood cancer, along weakness on voriconazole should be with supportive care and participation in clinical trials, have improved evaluated for fluoride toxicity. If fluoride survival. The combined five-year survival rate for all childhood cancers levels are high, patients should be has improved from less than fifty percent prior to the 1970s to eighty counseled to limit dietary and other fluoride percent currently (2-4). As of 2010, an estimated 379,112 survivors of sources; choosing fluoride-free toothpaste, avoiding fluoridated water and avoiding childhood cancer were living in the United States (5). Approximately 24 eating the bones of fish such as sardines are percent of these childhood cancer survivors are living more than thirty examples of steps a patient can take to years after their diagnosis, thus contributing to the growing number of lower fluoride intake. For the majority of long-term survivors (6). patients, symptoms of fluoride toxicity resolve after discontinuing voriconazole. Current therapies for pediatric cancer Bone pain resolves rapidly and skeletal include surgery, radiation, chemotherapy, Figure 1. International disease resolves over time (1). and hematopoietic cell transplantation, all Classification of Childhood of which may result in side effects that Cancer (11) It is important to include fluoride toxicity in adversely impact nutritional status (7-10). the differential of post-HCT patients on Leukemia Cancer and the associated treatment can voriconazole presenting with bone pain Lymphomas and Reticuloendothelial affect growth and development (weight Neoplasms and/or weakness, especially with loss/gain and attainment of appropriate Central Nervous System (CNS) concomitant renal insufficiency. Identifying linear growth) and contribute to altered fluoride toxicity early will allow the dietitian Sympathetic Nervous System Tumors body composition. The childhood cancer to adequately counsel the patient regarding Retinoblastoma survivorship population is unique, and appropriate medical nutrition therapy to Renal Tumors interpretation of indices used to assess limit fluoride exposure. Hepatic Tumors nutritional status in healthy children and Malignant Bone Tumors adults may not accurately reflect nutritional Kerry McMillen, MS, RD, CSO is a Clinical status because of abnormal growth Soft-Tissue Sarcomas Dietitian with the Seattle Cancer Care Alliance secondary to treatment. Germ-Cell, Trophoblastic and other in Seattle, Washington. Gonadal Neoplasms Childhood Cancer Compared to Carcinomas and other Malignant Epithelial Neoplasms References Adult Cancer 1. Gerber B, Guggenberger R, Fasler D, Nair G, Other and Unspecified Malignant Manz MG, Stussi G, Schanz U. Reversible The classification of childhood cancers differs Neoplasms skeletal disease and high fluoride serum from adult cancers. Unlike adult cancers, levels in hematologic patients receiving voriconazole. Blood. 2012 120: 2390-2394. which are usually tabulated by primary site, 2. U. S. Environmental Protection Agency. childhood cancers are classified by histologic together comprise roughly 60% of childhood Health and Ecological Criteria Division, Office cancer cases. Less common histologic types of Water. Fluoride: Dose-Response Analysis type and primary site based on the for Non-cancer Effects. Accessed September International Classification of Childhood and sites make up the remaining 40% of 7, 2015. childhood cancer cases; it is important to 3. http://water.epa.gov/action/advisories/ Cancer (ICCC) criteria (Fig 1) (11). The drinking/upload/skeletal_effects.pdf. predominant types of pediatric cancers (0-19 note exact percentages for disease types 4. Fawell J, Bailey K, Chilton J, Dahi E, Fewtrell L, differ when cases are separated by age for Magara Y. Fluoride in Drinking Water. years old) are leukemia (26%), cancers of the London, United Kingdom: World Health brain and central nervous system (CNS) children (0-14 years old) and adolescents Organization; 2006. (18%), and lymphoma (14%) (12), which (15-19 years old) (Fig 2) (12). (Continued on next page) 4 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016

Among adults, the leading new cancer is the inherited mutation of the RB1 gene, Compared with children, the incidence rate cases are prostate cancer (27%) for males which causes 25-30% of the retinoblastoma of adult cancer is much higher. According to and breast cancer (29%) for females. Lung cases in children (12). However, the National Cancer Institute’s Surveillance, and bronchus cancer (14%) is the second retinoblastoma only accounts for three Epidemiology, and End Results, 2,053 out of leading cancer type and colon and rectum percent of childhood cancers overall. Much 100,000 adults over forty years of age living is the third (12). more research on the genetic and in the United States were diagnosed with environmental causes of childhood cancers cancer each year from 2001-2007 (4). In that The etiology of most pediatric cancers is needed. same timespan, only 32 out of 100,000 currently is unknown, but is hypothesized American children (0-14 years of age) to be related to genetic mutations, similar Genetic mutations that cause cancer also developed cancer. In adults, environmental to adult cancers (13). These mutations lead can arise during the development of a fetus causes of cancer are better understood to rapid and uncontrolled cell growth, in the womb. For example, one in every 100 compared with childhood cancer, because eventually resulting in cancerous cells. children is born with a genetic abnormality childhood cancers are rare and the Increased cancer risk is associated with that increases the risk for leukemia, environmental exposures from prenatal to familial syndromes and genetic although only one child in 8,000 with that post-birth are difficult to ascertain abnormalities including Li-Fraumeni abnormality actually develops leukemia accurately (18). In adults, risk factors such as syndrome, Beckwith-Wiedemann syndrome, (16). Given these statistics, it is clear that tobacco use and secondhand smoke Fanconi anemia syndrome, Noonan genetic risk factors may be necessary, but exposures, asbestos, and ultraviolet syndrome, von Hippel-Lindau syndrome, not sufficient to cause any case of radiation are commonly known to cause and Down syndrome (14). Children with childhood cancer. Furthermore, cancer. This type of causal pathway has not Down syndrome are 10-20 times more likely environmental factors are difficult to been defined for most childhood cancers. to develop leukemia than children without identify due to the rarity of childhood Down syndrome; however, only a very small cancer. It is difficult to accurately assess Incidence and Mortality Trends proportion of childhood leukemia is linked environmental exposures occurring during The overall incidence for childhood cancer to Down syndrome (15). In childhood early prenatal and fetal time periods, and among all sites increased by 0.6% per year cancers, about five percent are due to gene into childhood as well (17). between 1975 and 1990 (12,19). However, mutations that are inherited. One example incidence varies by cancer site and is

Estimated New Cases of Childhood and Adolescent Cancer, United States, 2014 FigureFigure 2. 1. Estimated Cases for Childhood and Adolescent Cancers, US, 2014

Children (Ages 0-14) Adolescents (Ages 15-19)

Acute lymphocytic leukemia Hodgkin lymphoma 2,670 (26%) 800 (15%) Brain and CNS Thyroid carcinoma 2,240 (21%) 570 (11%) Neuroblastoma* Brain and CNS 710 (7%) 540 (10%) Non-Hodgkin lymphoma Testicular germ cell tumors 620 (6%) 430 (8%) Wilms tumor Non-Hodgkin lymphoma 510 (5%) 420 (8%) Acute myeloid leukemia Acute lymphocytic leukemia 500 (5%) 410 (8%) Bone tumors† Bone tumors† 450 (4%) 370 (7%) Hodgkin lymphoma Melanoma 380 (4%) 310 (6%) Rhabdomyosarcoma Acute myeloid leukemia 340 (3%) 230 (4%) Retinoblastoma Ovarian germ cell tumors 280 (3%) 110 (2%) All sites All sites 10,450 5,330 Estimates are for malignant cancers only and are rounded to the nearest 10. In addition, 730 children and 630 adolescents will be diagnosed with benign and borderline brain tumors in 2014. CNS = central nervous system * Includes ganglioneuroblastoma. †Bone tumors include osteosarcoma and Ewing sarcoma. ©2014, American Cancer Society, Inc.

How Do Childhood and Adolescent Cancers r Incidence and mortality rates for Asian American/Pacific Vary in the US Population? Islander children are lower than those for whites and generally similar to rates in African American children. Table 1 (page 28) summarizes differences in cancer incidence, mortality, and survival rates by sex and race/ethnicity. r American Indian/Alaska Native children have the lowest cancer incidence and mortality of all racial/ethnic groups. Sex Reasons for differences in incidence rates of childhood cancers r In children, incidence and mortality rates are lower in girls by race and ethnicity in the US are not well understood. Unlike than in boys, while survival rates are similar. many adult cancers, incidence is not consistently higher among r In adolescents, boys and girls have similar incidence rates, populations with lower socioeconomic status.3 In general, the while mortality rates are lower and survival is higher for incidence of pediatric cancer is higher in industrialized coun- girls. Some of these differences may reflect the different types tries than in developing countries, but patterns differ by cancer of cancers that occur in boys compared to girls in this age type. 4, 5 group. Racial and ethnic disparities in survival for childhood and ado- Race/Ethnicity lescent cancers have been noted previously.6, 7 Factors that may be associated with these survival disparities include socioeco- Cancer incidence, mortality, and survival rates show substantial nomic status, health insurance status, timely diagnosis and variability by race and ethnicity. quality of treatment and supportive care, and genetic factors.6 r Non-Hispanic white (white) and Hispanic children have the highest incidence rates for childhood and adolescent cancers. How Has the Occurrence of Pediatric Cancers r Although incidence rates are substantially lower for non- Changed over Time? Hispanic black (African American) children and adolescents Trends in incidence rates than for whites and Hispanics, death rates are similar due to lower survival rates in African Americans. From 1975 to 2010, the overall incidence of pediatric cancer in the US increased slightly, by an average of 0.6% per year.8 Specifi-

26 Cancer Facts & Figures 2014 Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 5 highest for acute lymphocytic leukemia ≤2 years (<10th percentile in weight for research, and identification of reputable (ALL) and brain/CNS cancers (Fig 3). Also of length) (23) and for >2 and ≤20 years (<5th resources, some of which are identified here. note is the increasing incidence of acute percentile of BMI for age and sex) (24). The The Academy of Nutrition and Dietetics myeloid leukemia (AML), non-Hodgkin’s incidence of malnutrition increases during Pediatric Nutrition Care Manual offers lymphoma (NHL), and testicular germ cell treatment and is related to the multi-modal specific oncology-related guidance for tumors. More positively, the overall nature of therapy (25,26). Malnutrition has practitioners (33). Topics covered include mortality rate for all childhood cancers has been associated with increased risk of nutritional management of nausea and continued to decline annually from 1975- infection, treatment toxicity, higher vomiting, nutrition therapy and support, 2010, with the most dramatic decrease in incidence of relapse, decreased rate of survivorship, and other key areas. The mortality rates seen for ALL and brain/CNS survival and poor tumor response to Children’s Oncology Group (COG), a National cancers (12). The improvement in survival therapy (8, 27-29). Suboptimal nutritional Cancer Institute supported clinical trials rates for children and adolescents with status, particularly when a child is very group, is the world’s largest organization cancer is shown in Figure 2. young, can affect a child’s ability to reach devoted exclusively to childhood and maximal cognitive and physical growth adolescent cancer research (34). The COG Advances in treatment for childhood cancer, even after therapy is completed (8). encompasses more than 9,000 childhood supportive care, and the high proportion of cancer experts from treatment and research patients participating in clinical trials have The Childhood Cancer Survivor Study facilities all over the world. More than 90% of resulted in improvements in survival (20). (CCSF) is a retrospective cohort study that children diagnosed with cancer annually are Although survival rates vary by cancer type, tracks the health status of adults who were treated at a COG institution. With a growing overall, more than eighty percent of diagnosed with childhood cancer between number of childhood cancer survivors living pediatric oncology patients diagnosed with 1970 and 1986 and compares the results into adulthood, it is important for oncology cancer live at least five years after their with those of their siblings. Findings from practitioners to have the available resources initial diagnosis, with an estimated 363,000 the CCSS reported that two out of three necessary to care for these children and best survivors of childhood cancer living in the survivors (at least five years post-diagnosis) manage the late effects related to cancer United States as of 2009 (4,18). Important develop a chronic health condition, and treatment. differences in survival exist between more than one-third develop a condition pediatric and adult cases of certain cancer that is severe or life-threatening (30). We have recently formed the Pediatric types that occur more commonly in Nutritional status and growth can be Subunit group within the ONDPG, which children. The 5-year survival rate for ALL in affected by many factors in children with will focus on the pediatric oncology children, for example, is greater than 85% cancer. It is well known that multi-modal population and childhood cancer survivors. (21). For adults with ALL, survival is strongly cancer treatment can have acute effects The Subunit has identified projects that associated with specific molecular and and chronic late effects in childhood cancer may help best meet the needs of Registered genetic factors, though the overall survivors. Cancer and its treatment can Dietitians Nutritionists (RDNs) working in 5-yearsurvival rate for the group as a whole impact hormones, growth rates, and this area. In the near future, the Pediatric is much lower, at around 40% (22). contribute to altered body composition Subunit will be reaching out to you for your (31). The survivorship population is unique, support and ideas. A webinar on Nutrition Approximately 24% of these childhood and interpretation of indices used to assess and the Pediatric Oncology Population, cancer survivors have survived more than normal growth in children and nutritional sponsored by the Academy and ONDPG, thirty years since their diagnosis, joining the status in adults can be challenging. These was presented on May 12, 2015, and is growing number of long-term survivors of population norms may not provide an available on the ON DPG website for childhood and adult onset cancer in the accurate assessment of nutritional status for members to review. This webinar provides United States (6). childhood cancer survivors. The late effects an excellent overview and a wealth of of treatment can progress into adulthood, resources and references. The next resource Nutrition Status in Cancer Patients therefore requiring multi-disciplinary teams that the Pediatric Subgroup will release is a and Survivors to monitor and manage medical conditions list of references and resources including At diagnosis, the incidence of malnutrition, long term (32). websites, books and additional information also called undernutrition, in children with for RDs working in this field. The Pediatric cancer ranges from 8-60%, depending on Available Resources subunit will update this resource list cancer type, stage of disease, and the The Pediatric Subgroup of the Oncology quarterly. We are interested in hearing criteria used to determine nutritional status Nutrition Dietetic Practice Group (ONDPG) is about topics of interest to you, the ON DPG (8). The nutrition indices used to document dedicated to providing direction and membership and any RDN working with malnutrition are based on age and specific leadership for quality pediatric oncology pediatric cancer survivors. criteria related to expected growth rates: for nutrition practice through education, (Continued on next page) 6 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016

Figure 3. Trends in 5 year Relative Survival Rates for Cancer in Children and Adolescents (0-19 years), 1975-2010

Nancy Sacks, MS, RD, LD is a Pediatric 1975-1995. National Cancer Institute, SEER Gastrointestinal Supportive Care Medications Program. 1999;99-4649. and Survivorship. In: American Society of Oncology Dietitian, and Chelsea Schulman, 4. Howlader N, Noone AM, Krapcho M, Garshell Parenteral and Enteral Nutrition - Nutrition MS, RD, LDN is a Pediatric Dietitian, both at J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl Support Pediatric Core Curriculum. ASPEN, the Children’s Hospital of Philadelphia (CHOP) J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Silver Spring, MD. 2015. Feuer EJ, Cronin KA (eds). SEER Cancer 11. Kramarova E, Stiller CA. The international in Philadelphia, Pennsylvania. Statistics Review, 1975-2012, National Cancer classification of childhood cancer. Int J Cancer. Institute. Bethesda, MD, http://seer.cancer. 1996; 68(6): 759-765. gov/csr/1975_2012/, based on November 12. Ward E, DeSantis C, Robbins A, Kohler B, Jemal To join the Pediatric Subunit of the Oncology 2014 SEER data submission, posted to the A. Childhood and adolescent cancer statistics, Nutrition Dietetic Practice Group, and to SEER web site, April 2015. 2014. CA: A Cancer Journal for Clinicians. 5. Ward E, DeSantis C, Robbins A, Kohler B, Jemal 2014;64(2):83-103. Accessed March 20, 2016: receive the latest group notifications, please A. Childhood and adolescent cancer statistics. http://onlinelibrary.wiley.com/doi/10.3322/ email [email protected]. For more CA: A Cancer Journal for Clinicians. 2014; 64: caac.21219/full#caac21219-fig-0001 83–103. 13. Cancer in Children and Adolescents. National information on the Pediatric Subunit, 6. Mariotto AB, Rowland JH, Yabroff KR, et al. Cancer Institute, National Institutes of Health. contact Pediatric Subunit Chair Rachel Hill Long-term survivors of childhood cancers in Accessed June 10, 2015. http://www.cancer. at: [email protected], or the United States. Cancer Epidemiol Biomarkers gov/cancertopics/types/childhoodcancers/ Prev. Apr 2009;18(4):1033-1040. child-adolescent-cancers-fact-sheet#r1. Pediatric Subunit Chair-elect Nancy Sacks at: 7. Berde CB, Billett AL, Collins JJ. Ch 43. 14. Moore SW. Developmental genes and cancer [email protected]. Symptom Management in Supportive Care. in children. Pediatric Blood and Cancer. 2009; In: Pizzo P, Poplack P. Principles and Practice of 52(7): 755-760. Pediatric Oncology. 6th ed. Philadelphia, PA: 15. Ross JA, Spector LG, Robison LL, Olshan AF. References Lippincott Williams and Wilkins; 2011. Epidemiology of leukemia in children with 1. American Childhood Cancer Organization. 8. Ladas EJ, Sacks N, Meacham L, et al. A Down syndrome. Pediatric Blood and Cancer. Childhood Cancer Statistics. 2015. http:// multidisciplinary review of nutrition 2005; 44(1): 8-12. www.acco.org/about-childhood-cancer/ considerations in the pediatric oncology 16. Ma X, Urayama K, Chang J, Wiemels JL, Buffler diagnosis/childhood-cancer-statistics. population: a perspective from children’s PA. Infection and pediatric acute Accessed June 9, 2015. oncology group. Nutr Clin Pract. Aug lymphoblastic leukemia. Blood Cells, 2. Armenian SH, Robison LL. Childhood cancer 2005;20(4):377-393. Molecules, and Diseases. 2009; 42(2): 117-120. survivorship: an update on evolving 9. Mauer AM, Burgess JB, Donaldson SS, et al. 17. Ward E. Childhood & Adolescent Cancer paradigms for understanding pathogenesis Special nutritional needs of children with Statistics. American Cancer Society. 2014. and screening for therapy-related late effects. malignancies: a review. JPEN J Parenter Enteral 18. Cancer in Children and Adolescents. National Curr Opin Pediatr. Feb 2013;25(1):16-22. Nutr. May-Jun 1990;14(3):315-324. Cancer Institute. National Institutes of Health. 3. Ries LAG, Smith MA, Gurney JG. Cancer 10. Sacks N, Henry D, Williams K, Kolp K, White- 2014. http://www.cancer.gov/types/ Incidence and Survival Among Children and Collins A, Olsen B, Hospodar K and Rheingold childhood-cancers/child-adolescent-cancers- Adolescents: United States SEER Program S. Oncology, Hematopoietic Transplant, fact-sheet. Accessed June 10, 2015. Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 7

19. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl CPE Article: Miraculin and The Miracle J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Berry: An Option for Dysguesia? Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, http://seer.cancer. By Doreen Renee Cudnik, MS, RD, LD gov/csr/1975_2012/, based on November 2012 SEER data submission, posted to the SEER web site, 2013. Purpose – This literature review provides an overview of the miracle berry and its unique 20. Armenian SH, Robison LL. Childhood cancer taste-modifying glycoprotein, miraculin, with particular reference to its history, function, survivorship: an update on evolving paradigms for understanding pathogenesis proposed mechanisms of action, limitations, and current and potential uses, including and screening for therapy-related late effects. potential applications in oncology nutrition practice. Curr Opin Pediatr. Feb 2013;25(1):16-22. 21. American Cancer Society. Survival rates for Design/methodology/approach – Database queries utilizing PubMed, the Web of Knowledge, childhood leukemias. Accessed March 5, 2016: Google Scholar, and Science Direct were conducted with combinations of the following http://www.cancer.org/cancer/ leukemiainchildren/detailedguide/childhood- keywords: miraculin, miracle berry, miracle fruit, Synsepalum dulcificum, and taste-modifier. leukemia-survival-rates. Findings – The miracle berry’s glycoprotein, miraculin, has a unique ability to sweeten sour 22. Marks DI. American Society of Hematology. tastes. Its applications are intriguing, particularly as an alternative sweetener and antioxidant, Hematology, The Education Program. Treating the “Older” Adult with Acute Lymphoblastic its expression in transgenic plants, and for improving the dysgeusia of chemotherapy patients. Leukemia. Accessed March 6, 2016: http:// Originality/value – To the author’s knowledge there is a deficiency of current literature asheducationbook.hematologylibrary.org/ content/2010/1/13.full. reviews on the miracle berry and miraculin. Its mechanism of action and applications need to 23. Motil KJ. Sensitive measures of nutritional be researched to a further degree. status in children in hospital and in the field. Int J Cancer Suppl. 1998;11:2-9. Keywords: Miracle berry, Miraculin, Synsepalum dulcificum, Miracle Fruit, Taste-modifier, 24. Centers for Disease Control and Prevention. Glycoprotein, Chemotherapy, Antioxidants, Alternative sweetener, Transgenics About BMI for Children and Teens. Accessed June 10, 2015: http://www.cdc.gov/ healthyweight/assessing/bmi/childrens_bmi/ about_childrens_bmi.html#How%20is%20 Introduction BMI%20calculated. Accessed June 10, 2015. 25. Rickard KA, Detamore CM, Coates TD, et al. The fruit of Synsepalum dulcificum—the miracle berry—is indigenous Effect of nutrition staging on treatment delays to the tropical rainforests of West Africa from Ghana to the Congo, and and outcome in Stage IV neuroblastoma. Cancer. Aug. 15, 1983;52(4):587-598. transforms the taste of sour food and drink into one of remarkable 26. Smith DE, Stevens MC, Booth IW. Malnutrition at diagnosis of malignancy in childhood: sweetness (1,2). This taste-modifying sensation is due to a glycoprotein, common but mostly missed. Eur J Pediatr. Mar 1991;150(5):318-322. fittingly named miraculin, found in the pulp of the miracle berry 27. Christensen ML, Hancock ML, Gattuso J, et al. (3). Chewing a miracle berry coats the tongue with miraculin. The Parenteral nutrition associated with increased infection rate in children with cancer. Cancer. combination of an acidic/sour food or drink of less than a pH of 7 along Nov 1, 1993;72(9):2732-2738. 28. Lange BJ, Gerbing RB, Feusner J, et al. with miraculin activates the sweet taste receptors for an approximate Mortality in overweight and underweight children with acute myeloid leukemia. JAMA. period of thirty minutes to two hours and lasting up to three hours in Jan 12; 2005;293(2):203-211. 29. Ward E, Hopkins M, Arbuckle L, et al. some cases (4,5). Nutritional problems in children treated for medulloblastoma: implications for enteral nutrition support. Pediatr Blood Cancer. Oct History of the Miracle Berry as kankies (sour cornbread), and before 2009;53(4):570-575. The English physician and botanist William drinking intensely sour palm wine and 30. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of Freeman Daniell provided the first pitto (beer) (1,7,8). More than a century childhood cancer. N Engl J Med. Oct 12 thorough description of the tropical passed before two research teams in Japan 2006;355(15):1572-1582. 31. Brouwer CA, Gietema JA, Vonk JM, et al. Body miracle berry in 1852 (6). While stationed and the Netherlands independently mass index and annual increase of body mass as an army surgeon in the Gold Coast (now isolated and purified the active substance index in long-term childhood cancer survivors; relationship to treatment. Support the country of Ghana), Daniell that makes the berry unique: the Care Cancer. Feb 2012;20(2):311-318. encountered the “miraculous berry” and glycoprotein miraculin (9-11). 32. Carlson CA, Hobbie WL, Brogna M, Ginsberg the West African natives who consumed it. JP. A multidisciplinary model of care for childhood cancer survivors with complex The berry was well known to the Description of the Miracle Berry medical needs. J Pediatr Oncol Nurs. Jan-Feb indigenous people as assarbah, tanté, or The miracle berry is approximately the size 2008;25(1):7-13. 33. Academy of Nutrition and Dietetics. Pediatric agbayun and was sold in local markets (0.75 inch) and shape (ellipsoidal) of a On-line Nutrition Care Manual. 2015. (1,7). Daniell explained that in order to Spanish peanut, and grows on the 34. The Children’s Oncology Group. http://www. childrensoncologygroup.org. Accessed June make some food more palatable, the Synsepalum dulcificum bush (12,13). The 10, 2015. natives often chewed the berry before whole berry is comprised of a thin-layered eating strong, “acidulated specialties,” such (Continued on next page) 8 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 pulp over a large seed (1). When ripe, the Additionally, miraculin is deactivated by known is that miraculin binds tightly to the berry turns red, likely due to anthocyanins heat and high or low pH conditions— lingual epithelium’s microvilli plasma present in the berry’s flesh (14). The plant below pH 2 and above pH 12 (4,10). membrane of sweet-taste receptors grows best in acidic soil (4.5 > pH > 5.8) (hT1R2-hT1R3) without activating them. It and frost-free conditions (15). When grown Hellekant et al. (33) reported that the is experienced as flavorless (4,35,39,40). from seedlings, fruiting occurs in potency of the miraculin-induced Miraculin does not activate these receptors approximately three to four years; the bush sweetness effect is contingent upon the until exposed to an acidic pH, generally grows slowly and reaches six to fifteen feet concentration of the miraculin along with between pH 3.0 and 6.0 (30,41,42). in height when fully mature (16). In 1919 the type of acid consumed. For example, the miracle berry was introduced into the Igarashi et al. (31) found that, in Kurihara and Beidler (43) first proposed the United States by Fairchild (17), founder of conjunction with miraculin, citric acid is theory that an acidic environment induces the Fairchild Tropical Gardens in Florida. perceived as tasting twice as sweet as a dynamic conformational change to the acetic acid, if all other factors are equal. shape of the miraculin molecule The miracle berry only has a slight cherry- Chen et al. (34) described that the sufficiently to allow the carbohydrate like flavor and some consider it nearly maximum sweetness intensity produced portion of the molecule to stimulate the tasteless. However, the taste of sour by miraculin is equivalent to 0.3 M of “sweet site.” Thus, only when the pH (acidic) food or drink is changed to a sucrose. For reference, a 0.3 M sucrose decreases within the mouth—when acidic perception of sweetness, when these foods solution has 0.3 moles of sucrose per liter food or drink is consumed—miraculin are consumed after the berry (4,18,19). The of solution, or 103 grams of sucrose per changes its structure and activates the berry modifies the overall flavor liter. This is 3.6 ounces of sucrose dissolved sweet-taste receptors (39,44). perception by, for example, changing sour into 4.2 cups of water. lemon juice into a sweet drink with a As previously mentioned, the acidity of the subtly altered lemon flavor. The taste- The taste-modifying effect of miraculin food or drink still exists, but it is modifying function is due to the active begins a few seconds after consumption, significantly attenuated by the sweetness substance found in the berry—miraculin. though several minutes of chewing the perception of the activated miraculin. Food berry’s pulp may be necessary to or drink that does not have acidity, Overview of Miraculin sufficiently coat the taste buds. The therefore, is not affected. One could liken Miraculin is a compound found within the duration of the taste-modifying effect this situation to a key and lock. A key (the thin-layered pulp of the miracle berry. It is typically lasts thirty minutes to two hours, miraculin) does not fit all the way into a a glycoprotein consisting of 191 amino or until the miraculin is thoroughly diluted lock (the sweetness receptors). However, acid residues with two glycosylated and dissociated by salivary amylase (30,35). once the key is exposed to acidity, it polypeptides, Asn-42 and Asn-186, cross- transforms its shape and fits perfectly. linked by a disulfide bond (15,20-24). It should be noted that although the taste Once unlocked, a person experiences the Miraculin is a macromolecule with a receptors require less than 0.1 mg of perception of sweetness. molecular mass of 24,600, and is “400,000 miraculin to induce a sweetening effect, the times sweeter than sucrose on a molar duration is dose-dependent (36). Kurihara Misaka (39) postulates that miraculin pivots basis” (20,25). It consists of up to 13.9% and Beidler (9) demonstrated that the taste- between its function as a sweetness agonist sugars, including glucosamine, mannose, altering effects of a 2.3 µM solution of and an antagonist dependent upon the pH galactose, xylose, and fucose (21,26,27). miraculin held in the mouth for five minutes value of the consumed food or drink. When lasted for more than three hours. the tongue is exposed to miraculin in an Once activated by sour food or drink, acidic environment, the molecule binds to miraculin displaces a portion of the acidity Miraculin’s Mechanism of Action the sweet-taste receptors and behaves as with sweetness. This dramatically reduces Miraculin’s specific mechanism of action an agonist for sweet flavor. When the the sour acuity and augments the remains an enigma (22,37). Typically, receptors detect a neutral pH, miraculin—as sweetness acuity, mimicking the effect of macromolecules do not influence taste or an antagonist—inhibits the activation of adding sugar to the acid (5,28). The natural smell (4). Anomalies exist, however, and the sweetness receptors. For a period of aroma and taste of the sour food or drink miraculin became the first known (and is time (typically thirty minutes to two hours), are still present, to some degree (8). The still recognized as the most well known) miraculin has the ability to reactivate the miracle berry does not modify purely macromolecule able to elicit a shift in taste sweet-taste receptors whenever an acidic bitter, salty, or other sweet tastes, (29-32) perception (30,38). pH is detected. and may or may not affect perceptions of metallic flavors commonly documented in Although speculative mechanisms have Another theory, proposed by Dzendolet individuals in cancer treatment. been proposed in the literature, what is (45), suggests that miraculin blocks the sour Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 9 receptor sites, and allows a sweet taste to processed foods. Moreover, the miracle between miraculin and food additives, be generated by the anionic group of an berry also has limited availability due its because it is not necessary to add acid molecule. Also, miraculin could be short shelf life, and spoils in about two miraculin to the food itself” (8). Unlike the influencing the taste of acids primarily by days (50). Despite these limitations to FDA, the U.S. Department of Agriculture causing the excitation of sites that usually widespread availability, potential (USDA) does not maintain restrictions on mediate sweetness, and not by causing any preservation techniques are being the miracle berry. Growing, selling, and peripheral suppression of responses to acid researched, such as utilizing a coating of eating miracle berries in the United States (12). Miraculin in the presence of acid adds the polysaccharide chitosan (51). Currently, is legal (57). sweetness, while reducing sourness by the miracle berry can be stored at -20° F for mixture suppression (28,46). approximately three months before use Relevance without significant degradation (13). Science has numerous new avenues for Limitations for Practical research into the miracle berry’s botany, Applications of Miracle Berry Regulatory Issues horticulture, and miraculin’s biochemistry, For a period of time, sour food or drink Miraculin faces regulatory impedance from physiology, and chemical structure-taste (acidic pH) is perceived sweetly whether or the U.S. Food and Drug Administration relationships. Nevertheless, the miracle not a person desires this. As an example, (FDA) and the European Union where it is berry and miraculin ultimately will succeed when eating a mixed meal, a grapefruit not yet legally recognized as an approved or fail on the criteria of practicality and would be very pleasant, but pickled food additive. It has been recognized by utility, however academically interesting it vegetables, for instance, may not taste Japan’s Ministry of Health and Welfare (52). may be otherwise (15). Fortunately, there particularly appetizing with a sweet may be a variety of uses for this unusual overtone. In fact many sour tastes are In the late 1960s, a Massachusetts-based food. Although it is generally recognized desirable (47). After application of company—the Miralin Corporation—was as more of a novelty food item, the miracle miraculin, for instance, a sour green apple formed and established large-scale berry may provide certain health benefits. may no longer taste refreshing; it may plantations of Synsepalum dulcificum in the taste overly sweet, which some perceive as West Indies and Brazil, developing new Humans readily crave and ingest sweet- “artificially sweet,” as reported in hybrids and propagation techniques (53). tasting foods, and miraculin may be a experiments conducted by Litt and Shiv This company began to introduce an healthier alternative to some of the more (19). Essentially, affecting the overall flavor extract in tablet form called miracle fruit traditional sweeteners, such as table may not always be enjoyable. concentrate (MFC), consisting of a partially sugar—sucrose (47). At a calorically purified extract containing hydrolyzed negligible quantity of 100 µg of miraculin, One of the largest obstacles to potential cereal solids and a Miracle Fruit Drop a long-lasting sweetening effect can be applications of miraculin to address taste (54,55). Special diets and menus were achieved (39). Miraculin is “400,000 times perception abnormalities lies in the developed incorporating MFC as an aid to sweeter than sucrose on a molar basis,” and miracle berry’s availability. It is not sold reduce energy intake. Despite fairly provides many times its own weight in within a mass distribution retail chain (e.g., extensive toxicological evaluation and sucrose-equivalent sweetness (20,52). grocery stores) (48). As stated before, the considerable investment, of at least $5 Because miraculin can be used in minute miracle berry only grows well in specific million, the extract did not obtain FDA amounts, it is not a contributing factor in climates. It is not widely found in nature, approval. In 1974, the FDA issued a tooth decay (3). The sweetening effect of and not readily available to consumers at regulatory letter requesting the company miraculin could be useful in general, but this time. to cease “interstate shipments.” The particularly for chewing gums, company was liquidated in 1976, and in mouthwashes, and other oral product Another issue with access to the miracle May 1977, all products containing applications (58). berry is that it is highly perishable. Synsepalum dulcificum were denied food Miraculin is thermolabile and is inactivated additive status (56). Sun et al. (57) reports Miraculin has a similar sweetening effect below pH 3 and above pH 12 (1,30). The “BioResources International, Inc. compared with sucrose in controlled protein backbone of miraculin is evidently (Somerset, NJ, USA) currently is experiments (5,36,59). Participants stated important as proteolytic modification undertaking the commercial development that they could not detect a taste leads to loss in activity (49). While the of miraculin for use as a taste masking distinction between the two, and, unlike deactivation of miraculin from intense pH agent, low-calorie sweetener, and flavor sucrose, miraculin neither induced a values would not be an issue under normal enhancer.” subsequent craving for sucrose nor conditions, the deactivation from heating triggered a demand for insulin (37,41,60). can be a problem. For instance, the miracle It should be recognized, however, that Chen et al. (61) conducted a prospective berry cannot be used in cooking or in “there is a fundamental difference (Continued on next page) 10 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 study that demonstrated miraculin decreased treatment tolerance, secondary strawberries and transgenic tomatoes (57). improved insulin sensitivity in rats. to malnutrition, and decreases in general Consequently, people who suffer from well-being (65,66). Unlike the miracle berry, these plants are obesity and diabetes may find miraculin readily harvested in more temperate very useful for limiting sugar intake (48). In Soares et al. completed a trial with regions and substantial yields of miraculin addition to its potential as an alternative to oncology patients drawn from the Mount can be obtained (72). Transgenic tomatoes sugar, the miracle berry may be a healthy Sinai Medical Center in Miami, Florida. The appear to be the most promising of the fruit in its own right, namely for its authors led a randomized crossover pilot three transgenic options, because antioxidant properties. study of 23 participants in order to transgenic tomatoes yield higher levels of determine if the miracle berry improves recombinant miraculin when compared A study published in 2011 examined the dysgeusia (67). The miracle berries were with transgenic strawberries. Further, gene antioxidant properties of the miracle berry obtained from a botanical garden in Miami silencing from generation to generation (18). In regard to flavonoid and phenolic and stored under controlled temperature was not an issue in tomatoes, as it was with content, the results suggest that the skin, conditions prior to use in the study At transgenic lettuce (71,74-76). In fact, pulp, and seed of the miracle berry exhibit baseline, 87% of participants reported transgenic tomatoes can produce higher potent antioxidant activity. A 2014 study dysgeusia and 78% experienced no taste levels of miraculin per gram of fresh presented similar results, but at all. After using the miracle berry, 30% weight than the miracle berry itself (26,77). demonstrated that the highest reported improvements in taste. Moreover, miraculin expressed in concentrations of antioxidant-rich transgenic tomatoes appears to be more phytochemicals are found within the Another pilot study was conducted by stable due to the acidic environment of the miracle berry’s flesh. Even more intriguing Wilken and Satiroff (65) among eight tomato (21,72,78). Further studies will is that the miracle berry contains patients from a Nebraska oncology clinic. assess “toxicity, allergenicity, digestibility, substantially larger quantities of ascorbic This crossover study consisted of randomly thermal stability, insertion position in the acid and several significant (and relatively selected chemotherapy patients, and taste host genome, and processing status” (15). rare) phenolics when compared with other improvements were recorded for all commonly-known, antioxidant-rich berries, participants after consumption of the Conclusion such as blueberries, blackberries, miracle berry. Despite the positive results, The miracle berry, with its glycoprotein cranberries, red raspberries, and larger confirmatory research is warranted miraculin, is very unique. The full strawberries (14). Although the antioxidant due to the small sample sizes. mechanism of action of its flavor properties of the miracle berry are notable, modifying ability to convert sour to sweet its potential to help patients receiving Transgenics is not completely understood, and small chemotherapy may be significant. Despite miraculin’s relative stability, the study sample sizes in clinical trials must be miracle berry is limited mainly by its addressed with larger trials. Nonetheless, The miracle berry could benefit individuals availability and perishability (56). Thus, the miracle berry’s potential is promising receiving cancer chemotherapy and alternative means to provide a consistent as an alternative sweetener, as an radiation treatment who often experience supply would improve access. Research to antioxidant-rich food item, and for taste alterations (dysgeusia) or decreases produce recombinant miraculin protein improving dysgeusia in patients receiving in taste acuity (ageusia). Spielman (62) are underway using transgenic plants in chemotherapy. The miracle berry is limited notes “as a consequence of ionizing Japan (68-70). Transgenics involves the by availability and perishability, and radiation, there are changes in the salivary transfer of genes from one species into a researchers are producing recombinant flow rate and in the composition, oral different species. miraculin in transgenic plants, notably bacterial flora, and turnover rate of taste tomatoes, to address these issues. Further cells.” Serving as a flavor enhancer, Genetically modified Escherichia coli, research into the mechanisms of action of miraculin may have the ability to increase Aspergillus oryzae, and tobacco plants miraculin, the miracle berry’s potential the desire of cancer patients to eat. Some have been unsuccessful in expressing therapeutic uses, and efficient production chemotherapy treatments leave an active miraculin. In 2006 Japanese and enhanced availability are required for unpleasant, noxious taste in the mouth, for biotechnologists reported that they had this food to realize its full potential. which no standard remedy exists (63). succeeded in expressing recombinant Food aversions related to dysgeusia are miraculin in transgenic lettuce that Doreen Renee Cudnik, MS, RD, LD completed experienced by more than fifty percent of exhibited activity (22,72,73). Since that this review to fulfill a requirement of her patients receiving chemotherapy (64). This time, recombinant miraculin has also been graduate program in human nutrition. may lead to decreasing nutrient intakes, successfully expressed in transgenic Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 11

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A trial of 1974;22(4):595-601. production of the plant-derived high-value protein in a plant factory: photosynthetic photon fluxes affect the accumulation of recombinant miraculin in transgenic tomato fruits. Plant Signaling & Behavior. 2011;6(8):1172-79. Complete Meal Replacement or Protein/Calorie Supplement Help Patients Meet Protein and Calorie Needs Complete nutrition without added sucrose or corn syrup. 480-490 calories per 11 ounce serving

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of this case, today, health practitioners can Medical Cannabis Comes Out from be confident their recommendations for Underground medical cannabis will no longer carry the burden of federal prosecution (5). By Donna Shields, MS, RDN

The Obama Administration and the The use of cannabis for various health conditions is becoming a more Department of Justice issued a common topic of discussion in healthcare circles today. The cannabis memorandum on August 29, 2013 to plant has been used medicinally for thousands of years and is well United States attorneys in all fifty states, known to herbalists, naturopathic medicine practitioners, and other announcing it would take a “hands off” approach regarding cannabis in those non-conventional healthcare providers; however, today medical states with legalized use. The memo cannabis has moved into mainstream conversation. Since cannabis has directed federal prosecutors to focus on recently emerged as a trending topic in the medicinal arena, it could be eight areas of enforcement rather than considered as a part of comprehensive care plans for certain patients. spending time targeting individual users (6,7). New bills have been introduced into Congress, which would allow for increased The science in this area is continuing to without fear of legal reprisal (2). The federal acceptance. For instance, H.R. 1940 develop, and continued research is needed physician may not prescribe or dispense Respect State Marijuana Laws Act of 2015, to fully understand the risks as well as marijuana to a patient, or recommend it was sponsored to amend the Controlled benefits associated with different types, with the specific intent that the patient will Substance Act of 1970 (CSA) to provide doses, and forms of medical cannabis. The use the recommendation as a prescription provisions related to cannabis to cover any purpose of this article is to give the to obtain marijuana (2). person acting in compliance with state registered dietitian nutritionist (RDN) an laws (8). understanding of basic medical marijuana In states that have legalized medical issues and their impact on how to use this cannabis, a physician, and in some cases a However, even though state legislation has information to help educate and guide nurse practitioner, can recommend (not set policy for the legal status of medical patients. prescribe) the use of the cannabis for cannabis use in many locations, cannabis patients who meet an approved, qualifying remains a Schedule I drug under the CSA. State of the Industry medical condition (3). The patchwork of This means cannabis is listed alongside Currently, 23 states and the District of qualifying conditions varies state by state, drugs such as heroin and LSD, and is Columbia allow for the use of medical but will change over time as new defined as being highly addictive and cannabis. Of those 23, only four states and conditions are added. However, cancer is having no accepted medical use (9). With the District of Columbia currently permit currently a qualifying condition in all states new evidence emerging that cannabis may adult (21+ years of age) recreational use of and likely will remain on the list (3). offer therapeutic value, there is interest in cannabis: Colorado, Oregon, Washington, investigating it further. Unfortunately, the and Alaska (1). There is no uniform federal With the passage of California’s Proposition Schedule I classification has made it policy in place governing the legality of 215 in 1996, medically-approved patients difficult for researchers to adequately test medical cannabis use, however, in 2002, in that state began to purchase their the effects of cannabis on certain illnesses the Ninth Circuit Court of Appeals held, in cannabis from a dispensary; many could (9). Until and unless the federal Conant v. Walters, that the federal not cultivate their own cannabis, or locate classification changes, uncertainty around government could not punish, or threaten a caregiver to grow it for them (4). Prior to the legality of medical cannabis will to punish, a physician solely for telling a 2002, the Controlled Substance Act (CSA) remain. The Obama memorandum was a patient that his or her use of marijuana for promised to prosecute any physician who step forward toward clarifying legal issues medical purposes is proper (2). However, it prescribed or recommended cannabis to around medical cannabis use, but the remains illegal for a physician to “aid and patients by revoking their licensure. Any federal government also made it clear it abet” a patient to obtain marijuana or patient who used the prescribed cannabis, reserves the right to revisit its position in conspire with him or her to do so. This also could be prosecuted, as could those the future (6,9). means a physician may discuss the pros affiliated with dispensaries (5). In the and cons of medical marijuana with his or Conant v. Walters case, previously Because of changing state and federal her patient, and issue a written or oral mentioned, a group of California patients mandates, RDNs will need to familiarize recommendation to use marijuana within a and physicians sued the federal themselves with what is allowed in the bona fide doctor-patient relationship, government (2), and due to the outcome states where they practice. It is equally Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 15 valuable for practitioners to stay current (endocannabinoids) released by needed to determine whether on national policy regarding tolerance or postsynaptic neurons leads to inhibition of cannabinoids could be used as tumor prosecution of medical marijuana use. neurotransmission; this may explain the growth inhibitors, in conjunction with cognitive and memory deficits elicited by conventional palliative care approaches Cannabis as a Healing Tool these cannabinoids (14). All (13,15). The study was very small and One of the more recognized uses for endocannabinoids identified so far are additional research is sorely needed, but medical cannabis is cancer treatment derivatives (amides, esters, ethers) of long- unfortunately, because medical cannabis symptom management. The topic was chain polyunsaturated fatty acids and retains schedule 1 status, larger, more presented by Donald Abrams, MD and exhibit varying selectivity for the two long-term studies have yet to be Kelay Trentham, MS, RDN, CSO at the 2015 cannabinoid receptors; however, more ECS completed (9,15). Food & Nutrition Conference & Expo, during receptors continue to be identified, and an Oncology Nutrition Dietetic Practice are present in various tissues throughout However, not all medical cannabis research Group (ON DPG) Session. An article titled the body (12). Although research is limited, has ceased. At the Center for Medicinal Cannabis in Cancer Care was published this endocannabinoid system seems to Cannabis Research at the University of recently in Clinical Pharmacology & play an integral role in an ever-increasing California, San Diego, the analgesic effect Therapeutics, discussing the potential number of pathological conditions (12,13). of cannabis to manage chronic pain, the benefits of cannabis (10). Cannabinoids are Activation at the receptor level appears to most common indication for medical the physiologically active chemical mitigate nausea, vomiting, anorexia, cannabis use, is being investigated (17). constituents of cannabis that mimic the cachexia, chronic pain, and loss of While cannabis alone appears to be effects of the body’s own endocannabinoid appetite, many of which can accompany effective for some types of pain system (ECS) (11). The term chemotherapy (12,13). management, it also may provide the endocannabinoid came into use in the added benefit of reducing opioid use for 1990s after the discovery of cell membrane Although the use of cannabis currently pain relief (18). receptors to which the exogenous focuses on managing cancer-treatment cannabinoid known as delta-9- symptoms, some research indicates Beyond cancer management, cannabis tetrahydrocannabinol (THC) could bind cannabinoids may inhibit tumor growth as appears to hold promise for conditions (12). These findings indicated there likely well (13,15). The first human clinical study that also may respond to nutrition was an endogenous cannabinoid system assessing the anti-tumor activity of intervention, such as gastrointestinal (ECS). This system now is known to be cannabinoids, a small pilot trial, was issues (e.g., GERD, IBS), immune disorders, comprised of cannabinoid receptors and published in the British Journal of Cancer in diabetes, Crohn’s disease, ADHD, enzymes for biosynthesis and inactivation 2006 (15). Nine patients with recurrent inflammation, multiple sclerosis, of endocannabinoids, and two key glioblastoma multiforme were neurodegenerative disorders (Parkinson’s endocannabinoids identified to date are administered THC intratumorally. Legal disease, Huntington’s disease, Tourette’s anandamide (AEA) and and ethical concerns dictated that the pilot syndrome, Alzheimer’s disease), epilepsy, 2-arachidonoylglycerol (2-AG) (10,11,12). study be conducted in a cohort of terminal osteoporosis, cardiovascular disorders, Furthermore, endocannabinoids appear to patients who had failed the standard obesity, and metabolic syndrome-related be involved in the control of cell therapies, including surgery and/or disorders (10-14). RDNs interested in metabolism, differentiation, proliferation, radiotherapies (15). Patients underwent offering a holistic approach to disease and and death (12). physical, neurological, biochemical, and condition management need to become hematological examinations as well as more knowledgeable about the Exogenous cannabinoid action occurs at magnetic resonance and CT scans of the mechanisms of action of medical cannabis the receptor level; and cannabis produces brain to measure tumor size changes (15). and how this may be utilized by patients, its psychotropic and peripheral effects The plasma and urine concentration of in conjunction with medical nutrition through activation of CB1 and CB2 THC was determined daily, and western therapy. receptors (11). CB1 receptors are located blot methodology was used on tumor primarily in the central nervous system biopsies. This was not only the first clinical Dosage & Delivery Systems (see (CNS), whereas CB2 receptors are located study to assess cannabinoid antitumor Disclosure) primarily in blood and/or immune-related action but also the first human study in Appropriate dosage recommendations for cells (12,13). Interestingly, the activation of which a cannabinoid was administered medical cannabis can be challenging to the CB1 receptors on axon terminals by intracranially. The study concluded THC determine. Numerous variables, including exogenous cannabinoids (delta-9- has a fair safety profile, and THC does not differences in plant strains, strain potency, tetrahydrocannabinol (THC)) and by facilitate tumor growth nor decrease delivery route, and individual differences endogenous cannabinoids patient survival. Additional trials are (Continued on next page) 16 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 in absorption, tolerance, and response to Many delivery options are available for person. Like most plants, the cannabis can dramatically alter response to those who prefer not to smoke cannabis. phytochemistry of cannabis is complex. the drug. These variables, in turn, will One of the more popular is vaporizing. More than 480 cannabis compounds have affect the amount and frequency of use an Vaporizing allows for the release of active been identified, including amino acids, individual will require to obtain optimal chemical compounds in an inhalant form. fatty acids, steroid compounds, symptom relief. For most patients, a very The vapor form eliminates taking in cannabinoids, flavonoids, stilbenoids, low dose is initiated, and effects are unwanted particulate matter and terpenoids, lignans, and akaloids (10,24). carefully monitored to determine potentially toxic compounds which can be The distribution and concentrations of response. Dr. Mary Lynch, a pain researcher generated with combustion (10,21). these compounds vary by plant part used, and head of the Canadian Consortium for Additionally, for many people, vaporizing age of the plant, plant varietal, growth Investigation of Cannabinoids in Human allows for more consistent and accurate conditions, harvest time, and storage Therapeutics, suggests it is best to start out dosing than smoking; ultimately, it can conditions. with the lowest dose possible, particularly result in less cannabis required to achieve for the naive, first-time user. Using the desired therapeutic effects (22). Edibles can be a difficult delivery protocols she and colleagues are mechanism for patients new to medical developing for research on medical use of Tinctures, topical products, and edibles cannabis due to the delayed response smoked cannabis, she recommends naive also are common routes for medical time; a patient may be inclined to consume users begin with 1 puff (or toke) usually cannabis delivery. Tinctures are absorbed more cannabis food product than is before bed, to help with pain, with rapidly through the oral mucosa, allowing needed for a therapeutic effect. Because of increasing intake as required for the for rapid systemic effects and drug varied titration and psychoactive desired outcome (19). response. Topical cannabis products, in the metabolites, a cannabis naive patient may form of salves, oils, creams, and not want to start with edibles; they may Experienced users often know what dose is transdermal patches, can be applied want to assess their response from the most effective for them; however, directly on the skin. Topical treatments smoking or vaporizing first, before moving Lynch recommends that a dose of 2 to 4 may be used to relieve inflammatory joint forward with oral cannabis options (23). puffs, 3 times a day is reasonable, pain, muscle soreness, and conditions such depending on response. The dose can be as psoriasis or eczema (23). Topicals tend For more seasoned medical cannabis titrated accordingly. Those who prefer to have few, if any, psychoactive effects patients, with proper knowledge, non-smoked cannabis may start with a because the active constituents do not preparing edibles at home may be a less small quantity of an edible product. A reach significant concentration in the sugared, higher nutritional value common recommendation is to consume bloodstream due the reduced absorption alternative to low nutritional value one-quarter to one-half of an edible rate (23). products typically sold at local product that is considered to be one dose, dispensaries. Tinctures and oral sprays also or use approximately 0.25 grams of dried Another delivery option is cannabis- allow oral delivery without excess sugar cannabis flower in a vaporizer, prior to infused edibles. These items are available and calories. each meal (19). Regarding edibles, primarily as baked goods, candies, and however, it should be noted that different beverages. Oral ingestion of THC or Why Should RDNs Be Concerned? products may list different milligram cannabis has different pharmacokinetics Patients are becoming more interested and amounts as equivalent to “one dose”; one compared with the inhalation route. The willing to incorporate various quarter of an edible item containing 10 mg onset of action is delayed, making titration non-conventional modalities into of THC per serving would be a higher dose more difficult (19). When consumed treatment plans, which will require a than one quarter of an edible listing 5 mg through food-related items, cannabinoids paradigm shift in healthcare for proper of THC per serving. Consultation with a are absorbed through the intestinal tract management. Medical cannabis can have a knowledgeable medical resource is, and then undergo first-pass metabolism place in the healing toolbox. Being therefore, essential. Further, a where the liver intercepts the majority of knowledgeable and confident regarding knowledgeable practitioner must the cannabinoids consumed; THC and its education of patients on the therapeutic understand a low oral dose for one person metabolites are lipophilic compounds and effects of cannabis can enhance the may not be low for another individual. their tissue distribution is governed by registered dietitian nutritionist’s practice, Extreme caution is always warranted with their physiochemical properties (10). and may provide a competitive edge for ingested cannabis, because individual Because cannabinoids are fat soluble, the private practitioners. tolerance of secondary metabolites, such processing of these secondary metabolites as 11-hydroxy THC (20), varies. by the liver can vary from person to Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 ❙ 17

References 10. Aggarwal S.K. MD, PhD. Cannabinergic Pain 22. Cavanaugh, J MD. ProCon. website. 2002. 1. Procon.org. 23 Legal Medical Marijuana Medicine. Clin J Pain. 2013; 29: 162-171. Available at http://medicalmarijuana. States and DC. Accessed December 15, 11. Abrams DI, Guzman M. Cannabis in cancer procon.org/view.answers. 2015: http://medicalmarijuana.procon.org/ care. Clin Pharmacol Ther. 2015; 97(6):575-86. php?questionID=000334. view.resource.php?resourceID=000881. 12. Di Marzo V, Maurizio B, & De Petrocellis L. 23. Czarnecka-Operacz M. Cannabinoid 2. United States Court of Appeals for the Ninth The Endocannabinoid System and its receptor agonists in topical anti-puritic and Circuit. No. 00-17222. D.C. No. CV-97- Therapeutic Exploration. Nature Reviews. anti inflammatory therapy. Postepy Derm. 00139-WHA. OPINION. Conant v. Walters. 2004; 3.9: 771-84. 2009; 26(2): 79. Accessed December 12, 2015: http:// 13. Guindon J & Hohmann AG. The 24. Sanchez IJF & Verpoorte R. 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Available at http:// at http://search.proquest.com. medicalmarijuana.procon.org/view.answers. contentproxy.phoenix.edu/ php?questionID=000636. docview/1702079418?pq- origsite=summon&accountid=458. 18 ❙ Oncology Nutrition Connection ❙ Volume 23, Number 2, 2016 2015-2016 Oncology Nutrition DPG Officers and Committee Chairs (* Voting member) EDUCATION TEAM SPECIAL PROJECT CHAIRS Continuing Education Chair Benchmarking Project Chair Chair* Tiffany Barrett, MS, RD, CSO, LD Elaine Trujillo, MS, RDN Tricia Cox, MS, RD, CSO, LD, CNSC Email: [email protected] Email: [email protected] Email: [email protected] Oncology Nutrition Connection Newsletter Editor Benchmarking Project Committee Members Chair-elect* Suzanne Dixon, MPH, MS, RD Suzanne Dixon, MPH, MS, RD Kelay Trentham, MS, RDN, CSO, CD Email: [email protected] Email: [email protected] Email: [email protected] Associate Editor Rhone M. Levin, MEd, RD, CSO, LD Secretary* Jodie Greear, MS, RD, CSO, LDN Email: [email protected] Katie Badgett, MS, RDN, CSP, LDN Email: [email protected] Jeannine Mills, MS, RD, CSO, LD Email: [email protected] Email: [email protected] Webinar Planning Committee Chair Treasurer* Amy Patton, RD, CSO, CNSD Katrina Claghorn, MS, RD, CSO, LDN Caitlin Benda, MS, RD, CSO, LDN Email: [email protected] Email: [email protected] Email: [email protected] Janet Mildrew, RD Webinar Planning Committee Email: [email protected] Past Chair* Bernadette Festa, MS, RD, CSO Andreea Nguyen, MS, RD, CSO, LD, CNSC Email: [email protected] Oncology Nutrition Symposium (Spring 2016) Email: [email protected] Project Chairs: Gretchen Gruender Heather Bell-Temin, MS, RD, CSO, LDN Nominating Committee Chair* Email: [email protected] Email: [email protected] Heidi Scarsella, RDN, CSO, LDN Email: [email protected] Amanda Ihmels Jeannine Mills, MS, RD, CSO, LD Email: [email protected] Email: [email protected] Western Area Representative (CA, TX, AZ, NM, WA, OR, NV, WY, ND, SD, HI, AK, ID, COMMUNICATIONS TEAM Andreea Nguyen, MS, RD, CSO, LD, CNSC MT, UT, CO, Asia, NZ, AU) Communications Coordinator Email: [email protected] Paula Charuhas Macris, MS, RD, CSO, FAND, CD Julie Lanford, MPH, RD, CSO, LDN Email: [email protected] Email: [email protected] Oncology Nutrition Symposium (Spring 2016) Planning Committee Eastern Area Representative Website Administrator Katrina Claghorn, MS, RD, CSO, LDN (VA, GA, PA, DE, NH, RI, NC, SC, NY, FL, NJ, MD, VT, ME, Heather Bell-Temin, MS, RD, CSO, LDN Email: [email protected] CT, MA, DC, PR, and Europe) Email: [email protected] Dianne Pippenburg, MS, RD/N, CSO Suzanne Dixon, MPH, MS, RD Email: [email protected] (primary) or Public Content Manager - ONDPG Website Email: [email protected] [email protected] (secondary) Erin Williams, RD, CSO, CNSC Email: [email protected] Kristen Lange, MS, RD, CSO, LD/N Central Area Representative Email: [email protected] (MI, IN, AR, AL, IA, KS, OH, KY, MO, MS, MN, OK, WV, Social Media Coordinator Denise C. Snyder, MS, RD, CSO, LDN TN, LA, IL, WI, NE and Canada) Lindsay Sappah, RD, CSO, LDN, CNSC Email: [email protected] Anita Vincent, RDN, CSO, LDN Email: [email protected] Email: [email protected] Kelay Trentham, MS, RDN, CSO, CD Electronic Mailing List (EML) Administrator Email: [email protected] Membership Chair Maureen Gardner, MA, RD, CSO, LDN Rhone M. Levin, MEd, RD, CSO, LD Michelle Bratton, RD, CSO Email: [email protected] Email: [email protected] Email: [email protected] EBlast Coordinator Maria Petzel, RD, CSO, LD, CNSC, FAND House of Delegates ONDPG Delegate Kristen Lange, MS, RD, CSO, LD/N Email: [email protected] Nicole Fox, RD, LMNT, CNSC, CSO Email: [email protected] Email: [email protected] Maureen Huhmann, DCN, RD, CSO Chair – Speakers Bureau Email: [email protected] Awards & Grants Committee Chair Anne Voss, PhD, RDN, LD Elaine Trujillo, MS, RDN Erin Gurd, RD Email: [email protected] Email: [email protected] Email: [email protected] or [email protected] PEDIATRIC SUBGROUP Jeannine Mills, MS, RD, CSO, LD Chair, Pediatric Subgroup Email: [email protected] Small Project Research Grant & Rachel Hill, RD, LD, CNSC Andreea Nguyen, MS, RD, CSO, LD, CNSC Research Award Coordinator Email: [email protected] Email: [email protected] Heidi Ganzer, DCN, RD, CSO, LD Email: [email protected] Pediatric Subgroup Committee Members Oncology Nutrition in Clinical Practice Project Chair Nancy Sacks, MS, RD, LD (Chair-Elect) Maureen Leser, MS, RD, CSO, LD Policy & Advocacy Leader Email: [email protected] Email: [email protected] Colleen Spees, PhD, MEd, RDN, FAND Email: [email protected] Katie Badgett, MS, RDN, CSP, LDN (Secretary) Chair – Speakers Bureau Email: [email protected] Anne Coble Voss, PhD, RDN, LD Reimbursement Chair Email: [email protected] Heidi Ganzer, DCN, RD, CSO, LD Paula Charuhas Macris, MS, RD, CSO, CD, FAND Email: [email protected] (PNPG Liaison) EAL Oncology Nutrition Guideline Revision Email: [email protected] Expert Workgroup Chair Project Chair Alliance Coordinator Laura Elliott, MPH, RD, CSO, LD Rhone M. Levin, MEd, RD, CSO, LD Jennifer Caceres, MS, RD, LD (Newsletter/ Email: [email protected] Email: [email protected] Communication Coordinator) Email: [email protected] SOP/SOPP Project Chair CDR/CSO Liaison Jodie Greear, MS, RD, CSO, LDN Academy Representative to CoC Chelsea Schulman, MS, RD, LDN (Webpage Content Email: [email protected] Kathryn Hamilton, MA, RD, CSO, CDN, FAND Manager) Email: [email protected] or Email: [email protected] ASCO Obesity Workgroup Liaision [email protected] Suzanne Dixon, MPH, MS, RD Jodie Greear, MS, RD, CSO, LDN (Cure4Kids Email: [email protected] Sponsorship Chair Administrator) Janet Mildrew, RD Email: [email protected] Academy DPG Relations Manager Email: [email protected] Carrie Kiley Email: [email protected]