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Exercise for Cancer-Related Fatigue

Physical and psychological activities alleviate cancer-related fatigue (CRF) more effectively than pharmaceutical treatments, according to recent studies. CRF, a very common symptom of cancer and cancer treatment, impairs life quality--often for years after treatment. Its presence has also been associated with increased risk of cancer recurrence and decreased overall survival in breast cancer patients.


Karen M. Mustian, PhD, MPH, and colleagues recently published a meta-analysis comparing the four most common CRF treatments: exercise (aerobic and/or anaerobic), psychological (cognitive behavioral or psychoeducational), combined exercise and psychological, and pharmaceutical (methylphenidate, modafinil, armodafinil, or paroxetine). The researchers used data from 113 good quality studies (11,525 participants; 78% female; mean age 54; range, 35-72), published from January 1, 1999, through May 31, 2016, for the meta-analysis. They found that exercise or psychological interventions were significantly more effective than the pharmaceuticals. Combining exercise and psychological interventions did not produce greater benefit. They conclude: "Clinicians should prescribe exercise or psychological interventions as first-line treatments for CRF."

Another 2017 systematic review and meta-analysis, led by Roger Hilfiker, provides more specific recommendations for the type of non-pharmaceutical intervention that is most likely to relieve CRF during cancer treatment (115 studies) and after treatment (135 studies). The effectiveness of fatigue-relieving strategies differed in the two groups. Relaxation practices (including stretching, meditation, and gentle yoga) were particularly effective in relieving CRF for patients undergoing treatment: "... a strategy to tackle CRF efficiently during cancer treatment should include relaxation sessions besides the personalized exercise or other non-pharmaceutical interventions." After treatment, however, relaxation is less important. Instead, yoga appears to be the most effective choice. However, the researchers also found moderate effects for combined aerobic and resistance training, cognitive behavioral therapy (CBT), and combined CBT and Tai Chi. Other options such as dance therapy may also be helpful. This study gives patients and health-care professionals evidence-based non-pharmaceutical options for relieving CRF, "according to patients' preference and abilities."

"The influence of exercise on the inflammation-immunity axis is very complex," Hilfiker et al write. "Too much exercise may be detrimental for the inflammatory and immune reaction process while an optimal exercise dosage may positively regulate the inflammation-immunity system." More research on possible adverse events, patient preferences, adherence, and cost-effectiveness would be helpful. In the meantime, data show that non-pharmaceutical interventions can relieve cancer-related fatigue.

Hilfiker R, et al. Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med. May 13, 2017 (online).

Mustian KM, et al. Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue A Meta-analysis. JAMA Oncology. March 2, 2017 (online).

A Cancer Immunity Hypothesis

Some infectious organisms, such as strains of the human papillomavirus, are known to incite cancer (oncogenic); and others, such as West Nile virus, destroy tumor tissue (oncolytic). In a recent BMC Cancer article, French researcher Camille Jacqueline and colleagues urge readers to look beyond the dichotomy of cancer-causing/cancer-destroying organisms: "... the links between infectious organisms and carcinogenesis through the immune system are varied and complex, and cannot be restricted to the study of oncogenic and oncolytic agents." They point out that immune disorders, inflammatory diseases, and cancers have increased as the incidence of infectious disease has decreased with better sanitation, vaccines, and other public health strategies. They suggest that common infectious diseases may provide unexpected benefits as the body responds to the illness.

"Different infectious agents are known to selectively polarize the immune system towards a Th1 or a Th2 response," the authors explain. T helper 1 (Th1) lymphocytes produce cytokines (i.e., tumor necrosis factor) and phagocyte-dependent inflammation. Th1 cells respond to tumor-associated antigens (TAA), produced by cancer cells, by mobilizing cancer-killing cells and macrophages. Some infectious agents also express TAA or epitopes that are similar to antigens produced by cancer cells. Infections with such pathogens may "prime the immune response" and increase immunosurveillance against TAA-producing cancer cells, say Jacqueline et al. Immune systems geared toward Th1 production are protective against several cancers while "... patients with a Th2-polarized immune response have poor prognosis when suffering from lung, breast, colorectal, pancreatic cancers." Uncontrolled Th1 response can produce organ-specific autoimmune disease.

In contrast to Th1 cells, T helper 2 (Th2) lymphocytes produce cytokines involved in the antibody response and tend to inhibit some phagocyte functions, impairing the ability to destroy and remove pathogens and tumors. Human newborns have a stronger Th2 response. "The increase in antigenic exposure, after birth through viral/bacterial infections, may be essential for newborns to switch from a Th2 biased to a balanced Th1/Th2 immunity as well as to develop immunological memory," say Jacqueline et al. "Also, childhood diseases may activate specific anti-tumoral responses." In effect, common childhood diseases may provide long-term health benefits--if the child is basically healthy and survives the illness.

Epidemiologic studies have found associations between common childhood infectious diseases and reduced cancer incidence. In a 2010 study, Daniel W. Cramer et al looked at a possible association between mumps and ovarian cancer. Their meta-analysis of all published studies found "... the pooled odds ratio estimate (and 95% Cl) for the mumps and ovarian cancer association was 0.81 (0.68-0.96) (p=0.01)." Cramer et al also found a significantly higher level of anti-MUC1 antibodies in the blood of people with mumps. MUC1 is an antigen expressed by ovarian cancer cells. Women with ovarian cancer who have anti-MUC1 antibodies at diagnosis tend to have better outcomes than those who do not. Cramer et al suggest, "Mumps parotitis may lead to expression and immune recognition of a tumor-associated form of MUC1 and create effective immune surveillance of ovarian cancer cells that express this form of MUC1." (Given that a complication of mumps in older males is testicular inflammation and atrophy, I wonder if mumps as a child might provide some protection against testicular cancer.)

Chickenpox is another childhood illness that may provide cancer protection. In 2016, E. Susan Amirian et al found reduced incidence of glioma in people who had chickenpox by using data from the Glioma International Case-Control Study: "... a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (Cl): 0.65-0.96)." Their findings corroborated other studies. In addition, patients with a history of chickenpox were less likely to have high-grade gliomas. Amirian et al point out that chickenpox was a very common childhood illness before the licensing of the live attenuated varicella zoster virus vaccine in the 1990s (1995 in the US). The vaccine may not provide the same protection: "Prior serologic analyses have demonstrated that antibody composition differs between children who experience a wild-type VZV infection versus those who... received the vaccine."

"Infectious organisms, that are not oncogenic neither oncolytic, may play a significant role in carcinogenesis, suggesting the need to increase our knowledge about immune interactions between infections and cancer," write Camille Jacqueline et al. The predominate view that seeks to eradicate all infectious-disease-causing pathogens, instead of honoring their possible role in strengthening and balancing immune system responses, needs to be questioned and studied. As Jacqueline et al note, "... very few studies have explored whether traits that help to limit the cost of infection might promote carcinogenesis later in life."

Amirian ES, et al. History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC). Cancer Medicine. 2016; 5(6): 13S2-1358.

Cramer DW, et al. Mumps and ovarian cancer: modern interpretation of an historic association. Cancer Causes Control. August 2010: 21(8): 1193-1201.

Jacqueline C, et al. Infections and cancer: the "fifty shades of immunity" hypothesis. BMC Cancer. 2017: 17: 257.

Romagnani S.T-cell subsets (Th1 versus Th2). Annals of Allergy, Asthma, and Immunology. July 2000; 85(1):9-18, 21.

Johanna Budwig's Flax Oil Diet

I first came upon the work of German biochemist Johanna Budwig in the "Port Townsend Health Letter" (Autumn 1990), a small publication that Jonathan Collin printed at that time for his patients. Two years later, I reviewed the North American edition of Dr. Budwig's Flax Oil as a True Aid Against Arthritis, Heart Infarction, Cancer and Other Diseases, a 58-page booklet that held three of her lectures. (German and French editions were originally published in 1959.) Dr. Budwig was the first person to develop methods for distinguishing between saturated and unsaturated fats. Throughout her life, she recommended using flaxseed oil ('food grade' linseed oil) and nutrition to cure serious illnesses, including cancer. Dr. Budwig died in 2003, at age 94.

Budwig asserted that impaired fat metabolism contributes to cancer as well as diabetes, skin ailments, kidney disease, liver and gall bladder ailments, behavior problems, and early sexual maturation. Commercially processed fats and oils and food preservatives that prevent oxidation (allowing a longer shelf life) destroy the reactive bonds in unsaturated fatty acids, impairing assimilation. Some links in natural, unsaturated fat chains react easily with protein. When combined with protein, the fats become water soluble and are easily transported throughout the body.

To address the problem of impaired fat metabolism, Dr. Budwig recommended adding flaxseed oil to the daily diet and deleting commercially preserved foods. Flaxseed is a rich source of the polyunsaturated fat alpha-linolenic acid and the richest-known dietary source of lignans (phytoestrogens), particularly secoisolariciresinol diglucoside (SDG). The Budwig diet has several components, but the primary one is twice-daily consumption of cottage cheese or its equivalent (Greek yogurt or quark) blended with cold-pressed flaxseed oil and freshly ground flaxseed.

Patient interest in flaxseed and its oil has instigated several laboratory and clinical studies over the past decade or so--as I learned during a recent Google Scholar search. So far, researchers have found evidence that flaxseed has preventive and anti-tumor effects for some cancers. A 2013 review article by Julie K. Mason and Lilian U. Thompson looked at the effect of flaxseed on breast cancer risk and tumor growth. Most rodent studies showed reduction in tumor growth when flaxseed lignans or oil was added to the diet. Flaxseed (lignans and/or oil) has also reduced tumor growth in a few clinical trials involving women with breast cancer. In addition, flaxseed consumption has decreased cancer risk in trials with premenopausal women and observational studies with postmenopausal women. Laboratory research indicates that the components in flaxseed decrease angiogenesis and cell proliferation and increase cancer cell death by modulating estrogen metabolism and estrogen receptor and growth factor receptor signaling pathways. Mason and Thompson note that flaxseed's beneficial effect may be "... more specific to ER+ tumours with low HER2 expression as the 2 studies conducted in HER2-overexpressing breast cancer have shown no effect of [flaxseed] or [flaxseed] oil alone."

In addition to breast cancer, flaxseed may be helpful for ovarian cancer. Supplementation with whole flaxseed reduced the frequency and severity of ovarian cancer in laying hens in a 2017 study. The researchers report: "Liver CYP1A1 expression was significantly increased by the whole flaxseed diet with a corresponding increase in 2-methoxygestradiol plasma levels," producing apoptosis in the cancer cells.

Other studies are investigating flaxseed's use as an adjuvant cancer treatment to reduce adverse effects of chemotherapy. For example, M.V. Varghese et al report that flaxseed oil reduced cardiac tissue damage caused by arsenic trioxide, a drug used to treat acute promyelocytic leukaemia, in their animal study. Flaxseed oil also improved cardiac glutathione content and reduced arsenic accumulation in the rats' hearts.

Decades after Dr. Budwig's lectures, mainstream research is beginning to document the benefits of consuming organic flaxseed and its cold-pressed oil.

Dikshit A, et al. Whole flaxseed diet alters estrogen metabolism to promote 2-methoxtestradiol-induced apoptosis in hen ovarian cancer (abstract). J Nutr Biochem. 2017; 42: 117-125.

Klotter J. Review: Flax Oil as a True Aid Against Arthritis, Heart Infarction, Cancer and Other Diseases. Townsend Letter. 1992; 113:1136.

Mason JK, Thompson LU. Flaxseed and its lignan and oil components: can they play a role in reducing the risk of and improving the treatment of breast cancer? Appl. Physiol. Nutr. Metab. 2014;39:663-678.

Varghese MV, et al. Attenuation of arsenic trioxide induced cardiotoxicity through flaxseed oil in experimental rats (abstract). Redox Rep. February 17, 2017 (online).

Cost-Benefit of Cancer Treatments

"The 'financial toxicity' of [cancer] treatments that can cost more than $100,000 a year is growing, and talks about that aren't happening enough," Dr. Rahma Warsame of the Mayo Clinic said in an Associated Press article. The bankruptcy rate among cancer patients is three times greater than that of people without cancer. Yet, doctors and patients seldom discuss treatment costs, according to doctor-patient conversations recorded at Mayo, Los Angeles County Hospital, and the University of Southern California (Norris campus) for a 2017 American Society of Clinical Oncology study. The topic of treatment cost arose in less than 30% of the conversations between newly-diagnosed patients and doctors; and patients were more likely to initiate the topic (106 by patient vs. 45 by doctor).

American Society of Clinical Oncology (ASCO) began seriously considering cost as a factor in cancer treatment choice back in 2015. The organization has developed a database of cancer drugs that includes a score indicating how well the drug works and how much it costs. In a June 2015 paper, Richard Schilsky (ASCO's chief medical officer) and colleagues explained the database plan, called the ASCO Value Framework (AVF). During a 2015 NPR interview, he gave Eli Lilly's Alimta as an example of how the database might help doctors and patients determine the treatment with the best cost-benefit. Alimta, a drug for lung cancer, did not work any better than standard treatment but cost ten times as much: $9193 per month. Alimta's AVF net health benefit score is zero for most patients; 16 for a particular subset. The net health benefit (summary) score is derived from prospective randomized clinical trials that compare oncology regimens.

The ASCO Value Framework is not the only cost-benefit assessment tool. National Comprehensive Cancer Network has developed NCCN Evidence Blocks (NEB) for assessing cancer drugs. Unlike the AVF, NEB provides scores for efficacy, safety, quality, consistency of evidence, and affordability that are determined by an expert panel. The European Society for Medical Oncology and the Institute for Clinical and Economic Review have also developed value assessment tools. All four of the tools are being tested for validity and reliability. In a June 2017 article, TGK Bentley et al say, "Continued use, analyses, and refinements of these frameworks will bring us closer to the ultimate goal of using value-based treatment decisions to improve patient care and outcomes."

Now, if only they would begin looking at the cost-benefit value of alternative treatments.

Bentley TGK, et al. Measuring the Value of New Drugs: Validity and Reliability of 4 Value Assessment Frameworks in the Oncology Setting. J Manag Care Spec Pharm. June 2017;23(6-a Suppl):S34-S48.

Kestenbaum D. Doctors Plan Database on Cancer Drugs, Showing Effectiveness and Cost. July 24, 2015.

Marchione M. Few doctors discuss cancer costs. (AP) Spartanburg Herald Journal. May 18, 2017.

Shah-Manek B, et al. Value Frameworks for the Patient-Provider Interaction: A Comparison of the ASCO Value Ramework Versus NCCN Evidence Blocks in Determining Value in Oncology. J Manag Care Spec Pharm. June 2017; 23(6-a Suppl): S13-S20.

briefed by Jule Klotter
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Title Annotation:treating cancer related fatigue with exercise; cancer immunity; and flax oil diet
Author:Klotter, Jule
Publication:Townsend Letter
Date:Aug 1, 2017
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