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INTEGRATIVE NUTRITION
Audio-Digest Internal Medicine
Volume 60, Issue 33
September 7, 2013

Integrative Cancer Care – Donald I. Abrams, MD
Vitamin D Deficiency and Cardiac Risk – Brandi J. Witt, MD

  
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Internal Medicine Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Integrative Nutrition

Educational Objectives

The goal of this program is to improve the application of integrative nutrition in cancer care and explore the potential association between vitamin D deficiency and cardiac disease. After hearing and assimilating this program, the clinician will be better able to:

1. Counsel patients on nutritional strategies to reduce risk for cancer.

2. Summarize data supporting the potential impact of a diet high in omega-3 fatty acids on the progression of certain cancers and the efficacy of chemotherapeutic agents.

3. Identify mushrooms with potential therapeutic benefits for patients with cancer who undergo chemotherapy.

4. Consider prescribing cannabis for management of cancer-related symptoms.

5. Monitor and correct deficiencies of vitamin D in patients at risk for coronary artery disease.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Abrams presents information related to the off-label or investigational use of a therapy, product, or device.

Integrative Cancer Care

Donald I. Abrams, MD, Professor of Clinical Medicine, Integrative Oncologist, Osher Center for Integrative Medicine, University of California, San Francisco, School of Medicine; Chief, Hematology-Oncology, San Francisco General Hospital

Integrative oncology: rational, evidence-informed integration of conventional therapy and complementary and alternative medicine (CAM) methods of treatment and prevention into individualized therapeutic regimen that addresses whole person (body, mind, and spirit) with cancer; provides relationship-centered care; aims to activate body’s innate healing response, using natural and less invasive interventions when possible

Causes of avoidable cancers: 33% of avoidable cancers related to diet and obesity; equal number related to tobacco use (while most Americans can identify tobacco use as cause, only 50% recognize role of nutrition and obesity); 90% recognize ultraviolet light from sun as cause but responsible for only small percentage of avoidable cancers

American Cancer Society: comments on supplements — strong evidence that diet rich in vegetables, fruits, and other plant-based foods may reduce risk for cancer; no evidence at this time that supplements can reduce risk; some evidence indicates high-dose supplements can increase risk

Nutritional strategies: to reduce risk for cancer, eat more phytoestrogens (eg, soy, flax), cruciferous vegetables, garlic and onion, turmeric and ginger, Asian mushrooms (cooked), green tea, omega-3 fatty acids, and vitamin D

Vitamin D3 (cholecalciferol): only vitamin that body can manufacture from sunlight; increasing percentage of world’s population becoming deficient due to indoor living, heliophobia, and use of sunscreen products; long recognized as involved in bone health but now felt linked to other processes; increasing evidence that low levels associated with increased risk for certain malignancies, including of breast, prostate, colon, and pancreas

Risk for colorectal cancer (CRC): results of European Prospective Investigation into Cancer and Nutrition (EPIC) study (520,000 participants) show strong inverse association between prediagnosis levels of vitamin D and risk for CRC; however, high consumption of dietary vitamin D not associated with reduced risk; authors concluded optimal level of vitamin D supplementation unknown; retrospective cohort study of patients with stage IV metastatic CRC found patients with low vitamin D levels had survival outcomes 1.5 times worse than those with normal levels; unknown whether aggressive replacement of vitamin D would improve outcomes

Breast cancer (BC): study of 194 women treated for stage 0 to III BC who had vitamin D levels drawn within 3 mo of surgery and matched with cancer-free controls; patients with BC had mean level just above optimal (32 ng/mL) vs 37 ng/mL in controls and twice as likely to be deficient; mean levels lower in estrogen receptor-negative (vs positive), triple negative (vs not), and basal-like (vs luminal) disease

Aromatase inhibitor (AI)-induced bone loss: intervention study of 156 postmenopausal nonosteoporotic women receiving AIs for adjuvant therapy in early stage BC; all received daily oral calcium 1000 mg and vitamin D3 800 IU (additional given if deficient at baseline); each 10 ng/mL increase in 25-hydroxyvitamin D at 3 mo associated with decrease in bone loss

Nutritional sources of vitamin D: found in same fish rich in omega-3 fatty acids; mushrooms placed in direct sunlight synthesize vitamin D2 (ergocalciferol)

Omega-3 fatty acids: docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) found in fish; α-linolenic acid found predominantly in flaxseeds, nuts, and vegetable oils; omega-3 fatty acids important for anti-inflammatory and thrombolytic effects; omega-6 fatty acids proinflammatory and platelet aggregating; dietary intake of fatty acids has shifted to higher omega-6 to omega-3 ratio (from 2:1 to 18:1) over past century and current diet much more proinflammatory; inflammation now felt related to number of chronic diseases of aging, eg, dementia, heart disease, cancer

Fats, fatty acids, and prostate cancer: in recent study (Aronson et al, 2011), 48 men undergoing radical prostatectomy randomized to low fat (15%) diet and 5 g fish oil (omega-6 to omega-3 ratio 2:1) or control Western diet (40% fat; omega-6 to omega-3 ratio 15:1); results showed no effect on serum levels of insulin-like growth factor 1 between groups; however, those with low fat and high omega-3 diet had lower omega-6 to omega-3 ratios in blood and prostate, less prostate tissue (benign and malignant), and reduced cancer cell proliferation

Risk for bleeding: omega-3 supplementation associated with increased risk for bleeding in patients with chemotherapy-induced thrombocytopenia only if dose >4 g/day; therefore, dose of 1 to 2 g/day recommended for patients with cancer

Fish oil in lung cancer (LC): preclinical studies suggest fish oil omega-3 fatty acids (EPA and DHA) may enhance activity of number of chemotherapeutic agents and may also inhibit angiogenesis and metastasis; in recent study (Murphy et al, 2011) of 46 patients with stage IIIB or IV nonsmall-cell LC receiving first-line platinum-based doublet palliative chemotherapy, participants enrolled in open-label trial of nutritional intervention with fish oil (2.2 g/day) or standard of care; group that received fish oil had greater percentage of patients responding to and receiving benefit from chemotherapy, able to receive more chemotherapy cycles, and spend more days on therapy

Turmeric (Curcuma longa): long cultivated in Asia for culinary and medical purposes; appears to have potential as chemopreventive agent for CRC and pancreatic cancer; to get adequate systemic absorption, must be given in high dose or in conjunction with black pepper (piperine [active ingredient] increases absorption of turmeric 1000-fold); safe in patients getting gemcitabine; appears synergistic with taxane in patients with LC in vitro and in vivo; recommended for patients with cancer, but be cautious if taken with black pepper as piperine affects cytochrome P450 (CYP450) and therefore may impact absorption and kinetics of other medications; potential interactions with chemotherapeutic agents — bleomycin (may decrease pulmonary toxicity); cisplatin (may decrease renal and neural toxicities); cyclophosphamide and doxorubicin (may decrease toxicity and effectiveness); taxanes (may chemosensitize malignant cells)

Medicinal mushrooms: long used in Eastern cultures for health-promoting effects; 300 species felt to have therapeutic potential; large US market for edible and medicinal mushrooms; mechanism of immune action — β-glucans in cell walls of mushrooms resemble molecules on bacterial cell walls; when ingested, β-glucans complex with complement on macrophages and mobilize immune response (stimulate cytokines active in tumor inhibition); differently branched glucans from different species stimulate T cells, natural killer cells, or others; anticancer activities — most mushrooms work as nonspecific immunostimulants; activity may require intact T cell function; especially beneficial when used in conjunction with chemotherapy; some components may have direct cytotoxic effects; more studies needed

Agaricus species: white button mushroom contains agaritine (carcinogen; partially inactivated with heating); all mushrooms must be cooked before eating; A bisphorus may have AI activity; therefore, cooked Agaricus species recommended for postmenopausal women; in Japan and Brazil, A blazei most common CAM therapy used for patients with cancer

Lentinus edodes: eg, shiitake; supplements derived from L edodes taken by cancer patients include L edodes mycelium, lentinan, and active hexose correlated compound; however, speaker encourages consumption of whole mushroom; dried version more potent

Grifola frondosa (maitake; hen of the woods): many patients take D-fraction (functions as adaptogen and immunomodulator; may decrease side effects related to chemotherapy)

Hericium erinaceus (lion’s mane): may stimulate brain-derived nerve growth factor; could be considered as neuroprotective agent in patient with cognitive impairment or neuropathy induced by chemotherapy

Trametes versiocolor (Coriolus versicolor; turkey tail): nonedible; extremely potent; proteoglycan compounds extracted from mushroom (polysaccharide-K and polysaccharopeptide); widely used in Japan and China; used adjunctively in patients with gastroesophageal malignancies; recently studied in Seattle, Washington, for use in patients with BC

Ganoderma lucidum (reishi; lingzhi [“mushroom of immortality”]): polysaccharides may have immune-enhancing activity; ganoderic acid triterpenoids may inhibit tumor cell growth; extract products extremely popular

Cordyceps sinensis: used for vigor and stamina; some evidence it restores immune activity with chemotherapy; has prolonged survival of mice receiving chemotherapy and may improve anemia from chemotherapy

Mushrooms and green tea: case control study in southeast China of 1000 women with confirmed BC and 1000 controls found that, compared with nonconsumers, women with daily intake >10 g of fresh mushrooms had 66% decrease in risk for BC, and those with daily intake >4 g of dried mushrooms had 50% decrease; risk decreased even further if mushrooms consumed in association with green tea

Marijuana as medicine: contains >400 chemical compounds; main psychoactive component delta-9-tetrahydrocannabinol (THC), but many other cannabinoids and components of plant have medicinal benefits; secondary compounds enhance beneficial effects of THC and reduce some negative effects; in addition to cannabinoids, marijuana has terpenoids and flavonoids which also have medicinal potential; cannabis as anticancer agent — effective for managing cancer-related symptoms of weight loss, loss of appetite, early satiety, anorexia, pain, anxiety, depression, acute nausea, and vomiting; increasing body of preclinical evidence suggests cannabinoids themselves may have anticancer activity; National Cancer Institute Physician Data Query website on cannabis and cannabinoids (www.cancer.gov/cancertopics/pdq/cam/cannabis/) excellent source of information on preclinical and animal model activity of cannabis as anticancer agent, and on use of cannabis for symptom management in patients with cancer

Potential herbal supplement–drug interactions: interactions largely through CYP450 system (CYP3A4 isoform that metabolizes many different chemotherapeutic agents); patients on chemotherapy recommended not to take St. John’s wort (appears to induce CYP450, resulting in decreased levels of chemotherapeutic agents and decreased efficacy); ginko may inhibit CYP450, resulting in increased level of chemotherapeutic agents, which would increase toxicity

Role of antioxidants in cancer treatment: concern that supplemental antioxidants may interfere with mechanism of action of cytotoxic chemotherapy or radiotherapy; in meta-analysis (Block et al, 2007) of 19 randomized control trials, 17 showed either significant advantage or nonstatistically significant increase in survival or response to treatment in patients randomized to antioxidants; speaker’s approach — depends on goal of treatment; if goal to cure or give adjuvant chemotherapy, delay antioxidants until end of treatment; if goal palliation, consider use of supplemental antioxidants to protect normal tissue; antioxidant-rich foods safe to consume during chemotherapy or radiotherapy (do not interfere with antitumor effects of treatment)

Question and Answer

Potential of mercury contamination: in omega-3 fatty acid productsmercury toxic for pregnant and breastfeeding women and people with developing nervous systems; Consumer Reports or standard laboratory can probably advise brands less likely to be contaminated

Vitamin D Deficiency and Cardiac Risk

Brandi J. Witt, MD, Cardiologist, Lakeview Hospital Heart Center, HealthPartners Medical Group and Clinics, Stillwater, MN

Prevalence: 5% of US population has vitamin D level <10 ng/mL) and 60% has <25 ng/mL (>30 ng/mL considered sufficient)

Risk factors for vitamin D deficiency: distance from equator; winter; aging; darker skin pigmentation; use of sunscreen and barrier clothing; smoking; obesity; physical inactivity; malabsorption diseases of liver and kidneys; certain medications

Sources of vitamin D: most vitamin D taken through supplements (primarily in dairy products; also in cereal and orange juice); naturally occurring sources primarily fatty fishes

Metabolization and function of vitamin D: any type of vitamin D consumed hydroxylated in liver to form 25-hydroxyvitamin D, which further hydroxylated in kidney, resulting in breakdown into inactive and active form (1,25-dihydroxyvitamin D primarily involved in homeostasis in body, resulting in increased intestinal absorption, bone reabsorption, and decreased renal excretion of calcium); also binds to retinoic acid receptors and functions as transcription factor to regulate certain genomic functions

Physiologic results of vitamin D deficiency: upregulation of renin-angiotensin-aldosterone system; hypertrophy of smooth muscle cells as well as cardiac myocytes; hypertension; insulin resistance and diabetes mellitus; hyperparathyroidism; increased inflammation

Vitamin D deficiency and risk for coronary artery disease: numerous studies have shown U-shaped curve; ie, patients with lowest levels of vitamin D as well as those with extremely high (or supranormal) levels at increased risk for cardiovascular (CV) events and all-cause mortality; other studies have shown lower levels of vitamin D associated with increasing incidence of heart disease, myocardial infarction, heart failure, stroke, and total mortality

Vitamin D supplementation and prevention of heart disease: little data supports efficacy of vitamin D supplementation; one study showed 7% reduction in all-cause mortality; another study showed 10% (nonsignificant) reduction in CV disease; lack of evidence of efficacy in lowering risk for heart disease may be at least partially due to tremendous variability in dosing in different trials and variability in recommended daily allowance of vitamin D; in addition, difficult to account for sources of vitamin D other than that supplemented by tablets or pills in studies

Bottom line: correcting any deficiency in vitamin D always advised; if level <30 ng/mL, supplement to normal range; however, no data to suggest supranormal levels of vitamin D beneficial (may be harmful)

Acknowledgements

Dr. Abrams was recorded at the 41st Annual Advances in Internal Medicine, held May 20-24, 2013, in San Francisco, CA, and presented by the University of California, San Francisco, School of Medicine. Dr. Witt was recorded at the 34th Annual Cardiovascular Conference: Current Concepts and Advancements in Cardiovascular Disease, held December 13-14, 2012, in St. Paul, MN, and presented by Regions Hospital Heart Center and HealthPartners Institute for Education and Research. For information about upcoming CME events presented by the University of California, San Francisco, School of Medicine, please visit their website at www.cme.ucsf.edu. For more about the 35th Annual Cardiovascular Conference, presented by HealthPartners Institute for Education and Research and scheduled for December 12-13, 2013, their web address is www.HealthPartnersInstitute.org. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Suggested Reading

Abrams DI: An overview of integrative oncology. Clin Adv Hematol Oncol 2007 Jan;5(1):45-7; Aronson WJ et al: Phase II prospective randomized trial of a low-fat diet with fish oil supplementation in men undergoing radical prostatectomy. Cancer Prev Res (Phila) 2011 Dec;4(12):2062-71; Block KI et al: Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials. Cancer Treat Rev 2007 Aug;33(5):407-18; Bostwick JM et al: Clinical decisions. Medicinal use of marijuana. N Engl J Med 2013 Feb 28;368(9):866-8; Carter GT et al: Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care 2011 Aug;28(5):297-303; Cre?u E et al: Plant-derived anticancer agents — curcumin in cancer prevention and treatment. Rev Med Chir Soc Med Nat Iasi 2012 Oct-Dec;116(4):1223-9; Deng GE et al: Evidence-based clinical practice guidelines for integrative oncology: complementary therapies and botanicals. J Soc Integr Oncol 2009 Summer;7(3):85-120; Frenkel M et al: Integrating Dietary Supplements Into Cancer Care. Integr Cancer Ther 2013 Feb 25 [Epub ahead of print]; Gupta SC et al: Curcumin, a component of turmeric: from farm to pharmacy. Biofactors 2013 Jan-Feb;39(1):2-13; Jenab M et al: Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. BMJ 2010 Jan 21;340:b5500; Liu L et al: Serum 25-hydroxyvitamin D concentration and mortality from heart failure and cardiovascular disease, and premature mortality from all-cause in United States adults. Am J Cardiol 2012 Sep 15;110(6):834-9; Liu WM et al: Cannabis-derived substances in cancer therapy — an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 2010 Nov;5(4):281-7; McCulloch M et al: Colon cancer survival with herbal medicine and vitamins combined with standard therapy in a whole-systems approach: ten-year follow-up data analyzed with marginal structural models and propensity score methods. Integr Cancer Ther 2011 Sep;10(3):240-59; Murphy RA et al: Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer 2011 Aug 15;117(16):3774-80; Patel S, Goyal A: Recent developments in mushrooms as anti-cancer therapeutics: a review. 3 Biotech 2012 Mar;2(1):1-15; Peppone LJ et al: The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol 2012 Aug;19(8):2590-9; Petrova RD: New scientific approaches to cancer treatment: can medicinal mushrooms defeat the curse of the century? Int J Med Mushrooms 2012;14(1):1-20; Pilz S et al: Vitamin D and cardiovascular disease: update and outlook. Scand J Clin Lab Invest Suppl 2012 Apr;243:83-91; Vacek JL et al: Vitamin D deficiency and supplementation and relation to cardiovascular health. Am J Cardiol 2012 Feb 1;109(3):359-6; Wang L et al: Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes 2012 Nov;5(6):819-29; Zittermann A et al: Future directions in vitamin D and cardiovascular research. Nutr Metab Cardiovasc Dis 2012 Jul;22(7):541-6.


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