Cancer cachexia affects between 50% and 80% of cancer patients, according to Nagi B. Kumar and colleagues at the University of South Florida College of Medicine. It is a primary cause of death in many patients. The condition is characterized by unintentional weight loss, muscle wasting, appetite loss, early satiety, anemia, edema, and debility. Eventually, the immune response collapses. Cachexia is believed to stem from metabolic changes that accompany cancer. Unfortunately, no conventional treatment has proved effective in preventing or reversing the condition. Simply increasing calorie intake does not halt or reverse muscle depletion; and appetite stimulants, 5-HT3 antagonists (to prevent nausea and vomiting), and COX-2 inhibitors (anti-inflammatories) have been unsuccessful in clinical trials. Doctors recognize that cachexia increases the likelihood of death, but they tend to ignore it – possibly because they do not know how to treat it.
Even if they have little to offer in the way of treatment, practitioners need to talk with patients and their families about cachexia. Ignoring the condition adds to patient and caregiver distress. In a 2009 article, J. Reid and colleagues report the results of a survey involving 15 patients with advanced cancer and cachexia and 12 family members. Survey participants reported that medical staff tended not to discuss noticeable weight loss. One patient's doctor responded by referring the man to a dietician whose treatment repertory consisted of a weight-loss diet. Overall, patients felt isolated and "devalued." Relatives were frustrated. They wanted to know what was happening. They wanted to know that their family members were getting "the best possible care."
Even though medicine has no definitive cachexia treatment, health-care professionals can acknowledge patient and family concerns. "[Practitioners] must recognize the psychological impact of progressive involuntary weight loss associated with primary cachexia, and the social meaning of food in the lives of these patients and their family members, to help support them through this emotive and difficult time,"write Reid et al.
Kumar and colleagues suggest that eicosapentaenoic acid (EPA) might be helpful in preventing and treating cancer cachexia. EPA, a polyunsaturated fat, is found in fish oils (e.g., cod liver, sardine, and salmon). EPA inhibits PIF, a tumor product produced by cachexia-inducing tumors. PIF activates the proteasome pathway, resulting in muscle protein degradation. These researchers believe that EPA can stabilize weight, increase muscle mass, and improve life quality in at least some patients if supplementation begins early in treatment.
Kumar NB, Kazi A, Smith T, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr Treat Options Oncol. 2010;11:107–117. Available at www.springerlink.com/content/1212v77137qj.6510/?MUD=MP. Accessed May 22, 2012.
Reid J, McKenna HP, Fitzsimons D, McCance TV. An exploration of the experience of cancer cachexia: what patients and their families want from healthcare professionals. Eur J Cancer Care. 2010:19:682–689. Available at CINAHL database. Accessed May 21, 2012.
Fermented Wheat Germ Extract (Avemar) and Cancer
Could the fermented wheat germ extract Avemar prevent cancer cachexia, as Thomas Mueller and Wieland Voigt suggest in their review article for Nutrition Journal? The cause of cachexia is still not clear. It appears that tumors emit chemicals that shift the body's terrain in their favor, producing metabolic dysfunction and suppressing immune response. Unintentional weight loss, muscle wasting, weakness, and appetite loss are among cachexia's symptoms.
Biochemist Máté Hidvégi developed Avemar by fermenting the nutrient-rich germ of the wheat berry with the yeast Saccharomyces cervisiae for 18 hours at 30 ºC. The dried extract, to which water is added before consumption, is a government-approved, nonprescription medical nutriment for cancer patients in Hidvégi's native Hungary. Avemar, made in a good manufacturing practices facility, is available in the US and other countries as a dietary supplement.
Avemar has been the subject of several laboratory studies. In vitro experiments with numerous cancer cell lines have shown that the fermented wheat germ extract slows cancer cell proliferation. Avemar inhibits cancer cells' uptake of glucose and interferes with enzymes that take part in anaerobic glycolysis. It also induces apoptosis via the caspase-PARP-pathway. In addition to slowing cancer growth, Avemar stimulates cellular immune response.
In most clinical studies involving Avemar, the supplement is given to cancer patients in addition to surgery, radiation, and/or chemotherapy. Several of the trials are comparative; only one (that I could find) is randomized, and none are blinded. A 2008 Russian randomized, phase II clinical trial investigated the use of Avemar in 58 patients with stage III malignant melanoma. All patients received chemotherapy. The treatment group also used Avemar for one year. Seven years after treatment, the Avemar group had an impressive mean progression-free survival time of 55.8 months compared with the control group's 29.9 months (p = 0.0137). Mean overall survival was 66.2 months for the Avemar group and 44.7 months for the control (p = 0.0298). Avemar use at therapeutic levels has no serious adverse effects. Mild diarrhea, flatulence, constipation, nausea, dizziness, and weight gain are the most common side effects.
More rigorous clinical trials are needed to confirm Avemar's value as an antitumor agent or anticachexia treatment. Still, its known ability to normalize glucose metabolism and increase immune response makes this supplement a potentially useful treatment for preventing cachexia.
Demidov LV, Manziuk LV, Kharkevitch GY, Pirogova NA, Artamonova EV. Adjuvant fermented wheat germ extract (Avemar™) nutraceutical improves survival of high-risk skin melanoma patients: a randomized, pilot, phase ii clinical study with a 7-year follow-up. Cancer Biother Radiopharm. 2008;23(4).
Johanning GL, Wang-Johanning F. Efficacy of a medical nutriment in the treatment of cancer. Altern Ther. Mar/April 2007;13(2):56–63. Available at www.altcancerweb.com/osteosarcoma/avemar/53_johanning.pdf. Accessed June 2, 2012.
Mueller T, Voigt W. Fermented wheat germ extract – nutritional supplement or anticancer drug? Nutr J. 2011;10:89. Available at www.nutritionj.com/content/10/1/89. Accessed May 21, 2012.
Cancer Cell Contamination
For decades, scientists have taken cells from tumors, found the right combination of nutrients to foster the cells' growth, and shared the resulting cell lines with other researchers, says Amy Dockser Marcus in her Wall Street Journal article. Researchers use these cell lines to study how a specific type of cancer works. They also use them to test the effectiveness of new cancer treatments. More often than researchers want to admit, cell lines are not what they are believed to be. An estimated 20% of all cancer cell lines are misidentified or cross-contaminated; some research indicates that the actual number is 33% or more. Poorly sterilized pipettes, mislabeled or misread containers, cultures stored too close to one another, inexperienced or distracted technicians who use the same tool in different samples, and inadequately tested cell samples from colleagues all contribute to cross-contamination. Aggressive cell lines – such as the cervical cancer cells taken from Henrietta Lacks in 1951 (HeLa) – have contaminated and overwhelmed several breast cancer lines as well as cells used in adenoid cystic carcinoma research.
The problems of misidentification and cross-contamination first became public in 1966, when Stanley Gartler at the University of Washington (Seattle) used genetic markers to test 20 cancer cell lines. Instead of being distinct, 18 of the 20 lines consisted of Lacks's cervical cancer cells. Many scientists refuse to test the cell lines that they use, preferring to ignore the problem. "The prevailing attitude, according to researchers, is that the other lab's cell line may be contaminated but not mine," Marcus explains. Given that 1 in 5 cell lines has been misidentified, using unverified cell lines can waste money and time and produce flawed research.
At this point, researchers are simply encouraged to verify cell line identity voluntarily. An international science committee recommends routine use of a DNA technique used in forensics to identify cell lines used in research, but the committee has no authority to demand verification. The test costs about $200.
In his 2006 article, Roland M. Nardone, professor emeritus at the Catholic University of America, would like all journals to require cell line authentication before a study can be published. He also thinks that cell line verification should be required before researchers receive grant money. At this time, grants from the National Institutes of Health do not require cell line authentication. Journals of the American Association for Cancer Research, however, do ask authors to state how and when their cell lines have been tested.
Marcus AD. Lab mistakes hobble cancer studies but scientists slow to take remedies. Wall Street Journal. April 21–22, 2012;A1, A12.
Nardone RM. Eradication of cross-contaminated cell lines: a call for action. February 2006. Available at www.biotrac.com/pages/authentication.html. Accessed May 21, 2012.
Glutamine and Cancer
Cancer cells, like other rapidly dividing cells, use up glutamine, an amino acid. The extra demand for glutamine means less for normal body functions. Glutamine deficiency produces insulin resistance, hyperlipidemia, increased hepatic production of acute-phase proteins (a sign of inflammation), reduced gut-barrier function, adipose tissue loss, and muscle wasting. While glutamine is clearly necessary for health, concerns about its ability to fuel cancer growth – as demonstrated in in vitro experiments – have prevented oncologists from using glutamine supplementation in cancer treatment.
Recognizing that in vitro studies do not necessarily reflect real life, Katharina S. Kuhn and colleagues reviewed in vivo experimental and clinical data to see if concerns preventing glutamine's use are well founded. The researchers found 24 oral/enteral and 12 parenteral clinical studies that investigated glutamine's use in diverse patient groups in Medline's database (as of June 2008). "In the great majority of these clinical studies, glutamine supplementation in cancer patients improves host metabolism and clinical situation without increasing tumor growth," they write.
In fact, supplemental glutamine slows tumor growth by enhancing the immune system. The extra glutamine provides fuel for enterocytes (needed to maintain the protective intestinal mucosal barrier) and for lymphocytes. Glutamine supplementation also increases natural killer cell activity, helps protect against oxidative stress, and increases anti-inflammatory activity (control of NO formation and decreased free radical availability due to glutathione synthesis). Glutamine supplementation has also increased chemotherapy's effectiveness while reducing its toxic effects. Parenteral administration is more effective than oral/enteral.
Kuhn KS, Muscaritoli M, Wischmeyer P, Stehle P. Glutamine as indispensable nutrient in oncology: experimental and clinical evidence. Eur J Nutr. 2010;49:197–210. Available at CINAHL PLUS with Full Text database. Accessed May 21, 2012.
Maitake D-fraction, a highly purified b-glucan extracted from the maitake mushroom (Grifola frondosa), stimulates natural killer (NK) cell activity. NK cells kill virus-infected cells and some tumor cells. People with cancer typically show a decline in NK cell activity and immune function as the disease progresses. Patient responses to D-fraction during a 2003 study indicate that "changes in NK cell activity may be an effective clinical marker of disease progression in cancer patients," according to Noriko Kodama and colleagues.
This small Japanese study followed six male and four female patients between ages 46 and 84 years, with stage II–IV lung, breast, lingual, or gastric cancer. None of the 10 patients were undergoing chemotherapy or radiotherapy, or taking prescribed food supplements. The patients took D-fraction twice per day for up to 63 months. Researchers measured CD4+ cell numbers, CD8+ cell numbers, and NK cell activity in all patients. CD4+ and CD8+ levels responded to D-fraction administration in most, but not all, patients. However, NK cell activity increased – sometimes dramatically – for all patients after treatment with D-fraction began, according to Table 4. "Although NK cell activity reached a maximum and then decreased slowly, activity was maintained at a higher level [and within normal range] than observed prior to D-Fraction administration, except for Patients D and H, who later died," the authors report. This outcome made the researchers speculate that NK cell activity might be an accurate predictor of death in cancer patients.
Both patients who died during the study showed a marked response to D-fraction at first, but the improvement was not sustained. Patient D was a 54-year-old man with stage IV squamous cell lung carcinoma that had metastasized to lymph nodes. His NK cell activity rose from 30% (April 2000) to a high of 67% (May 2000) and then fell to 25% (January 2002), one month before his death. Patient H was a 69-year-old man with stage III liver cancer that had also metastasized to lymph nodes. His NK cell activity rose from 15% in October 1996 to a high of 65 in December 1997 before falling to 38% at the last measurement (March 2001), 10 months before his death. (A measurement taken nearer the time of his death would have been helpful.)
This study is too small to prove that NK activity is an accurate predictor of death in cancer. It also does not prove that oral administration of D-fraction extends life or stalls progression in late stage cancer. It does, however, provide data about the immune-stimulatory effects of this form of b-glucan on patients with late-stage cancer. Larger, randomized controlled studies would be helpful for patients and physicians who are trying to find effective immune-stimulating therapies with no adverse effects.
Kodama N, Komuta K, Nanba H. Effect of maitake (Grifola frondosa) D-Fraction on the activation of NK cells in cancer patients. J Med Food. 2003;6(4):371–377.
Fullerton SA, Samadi AA, Tortorelis DG, et al. Induction of apoptosis in human prostatic cancer cells with b-glucan (maitake mushroom polysaccharide). Mol Urol. 2000;4(1):7–13.
Cancer and Cellular Environment
For decades, scientists have focused on the genetics of cancer: how the cells mutate and which genes are involved. Until recently, the idea that the tissue surrounding "rogue" cells plays a role in the disease was roundly disparaged, as Gina Kolata reports in her New York Times article (December 29, 2009). Years of frustration and dead ends have caused some researchers to take a look at cancer cells' environment. "The basic idea – still in the experimental stages – is that cancer cells cannot turn into a lethal tumor without the cooperation of other cells nearby," Kolata writes.
For example, Dr. Kornelia Plyak at Harvard Medical School decided to investigate the difference between breast cancer cells found in aggressive cancer and breast cancer cells that remain harmless (DCIS). Both types of cells have the same gene expression patterns, mutations, and cell maturation patterns. Failing to see a genetic difference between the two, Plyak looked at the surrounding tissue. She observed that harmless cancer cells are enclosed in a milk duct. When the outer layer of the milk duct weakens and the cancer cells escape, the cancer turns aggressive.
Another example of the interaction between cancer cells and environment comes from a 2012 review article written by Ana M. Soto and Carlos Sonnenschein. The authors refer to a series of experiments in which normal epithelial cells were combined with stroma (supporting connective tissue) that had been damaged by exposure to a carcinogen. The normal cells became cancerous. However, when abnormal cells were placed in a normal environment, the cells returned to normal. "Thus, interactions among cells in a tissue determine normal and neoplastic behavior, and imply that the neoplastic phenotype is reversible," say the authors.
In a 2008 article, Cyrus M. Ghajar and Mina J. Bissell point out, "… despite containing the same genetic information, cells acquire unique functions depending on where they reside (e.g., hepatocytes secrete bile acids while, thankfully, tongue epithelial cells do not). For humans, once growth has ceased, approximately 10 trillion of these cells must somehow retain their specificity for decades." Ghajar and Bissell believe that cells continually receive information from their environment that "help dictate how specific genes will be expressed." If the tissue's architecture is damaged, if the extracellular matrix loses integrity, signals sent to nearby cells change. Without signals that reinforce specificity, "rogue" cells can change their genetic expression and turn cancerous. "The extracellular matrix, once thought to solely provide physical support to a tissue, is a key component of a cell's microenvironment responsible for directing cell fate and maintaining tissue specificity," say Ghajar and Bissell. Epigenetics, the idea that environmental factors affect gene expression, has finally infiltrated cancer research.
Ghajar CM, Bissell MJ. Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging. Histochem Cell Biol. December 2008;130(6):1105–1118. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2949356. Accessed May 30, 2012.
Kolata G. Old ideas spur new approaches in cancer fight. New York Times. December 29, 2009. Available at www.nytimes.com/2009/12/29/health/research/29cancer.html. Accessed April 4, 2011.
Soto AM, Sonnenschein C. Is systems biology a promising approach to resolve controversies in cancer research? Cancer Cell Int. 2012;12:12. Available at www.cancerci.com/content/12/1/12. Accessed May 29, 2012.
New Immune-Based Cancer Therapies
Jerome Groopman recently published an article in the New Yorker about new immunotherapies for cancer. One is Yervoy/ipilimumab, a CTLA-4 antibody, approved by the FDA in 2011. CTLA-4 (cytotoxic T-lymphocyte antigen-4) is a protein on a T-cell's surface that acts like a brake. In December 1996, Jim Allison, director of Memorial Sloan-Kettering's tumor-immunology program, led a research team who showed that inactivating CTLA-4 with an antibody caused tumors to stop growing and then disappear altogether in mice. The companies Medarex and, later, Bristol-Myers Squibb were recruited to support research and development. Clinical trials involving patients with malignant melanoma (a cancer that has responded to other immune-based therapies) showed that inactivation of CTLA-4 increased patient survival and caused some tumors to shrink. Scientists are now investigating other T-cell "brakes." They have found more than five other inhibitors like CTLA-4.
Unfortunately, cutting the restraints that inhibit T-cell activity produces adverse effects. The Yervoy website states that the most common side effects include tiredness, diarrhea, itching, rash. But serious side effects are also listed, including colitis that can progress to the point of causing tears or holes in the intestines, liver inflammation that can produce liver failure, skin inflammation that can lead to toxic epidermal necrolysis, nerve inflammation that can produce paralysis, eye inflammation, and possible inflammation of the hormone glands (especially the pituitary, adrenal, and thyroid glands). As Jedd Wolchok of Memorial Sloan-Kettering told Groopman, "‘You may need to cross the line to toxicity for the immune system to be effective against a cancer. It's not a free ride.'"
Another immune cancer therapy in Groopman's article is adoptive cell transfer (ACT), developed by Steven Rosenberg at the National Cancer Institute. This individualized treatment consists of harvesting T-cells found in a patient's tumor and stimulating their replication. The T-cells are then injected back into the patient. Before the injection, patients undergo an immunodepleting preparative regimen to eliminate competing T regulatory cells and lymphocytes.
Groopman reports that 9 of 25 patients with malignant melanoma who received ACT at the National Cancer Institute have been in complete remission for more than five years. Rosenberg has expanded his research to include other types of cancers by using a genetically altered version of a patient's T-cells. He is inserting a gene that targets the protein NY-ESO, found in about one-third of all common cancers. NY-ESO is uncommon in most tissue (except testes) after fetal development. "‘When T-cells are genetically engineered to target NY-ESO, there is no difference between melanoma and breast cancer or prostate cancer, or colon cancer, ovarian cancer, sarcoma, and so on,'" Rosenberg told Groopman.
The drawback of ACT is its expense. The treatment is labor intensive and must be personally designed for each patient. Presently, ACT is funded by federal research dollars because it is experimental.
These two therapies represent the beginning of a new interest in immune therapy for treating cancer, according to Groopman. The National Cancer Institute is now funding clinical trials at 27 universities and cancer centers.
Groopman J. The T-cell army. New Yorker. April 23, 2012;24-30.
Information on side effects of YERVOY (ipilimumab) [Web page]. www.yervoy.com/patient/side-effects.aspx. Accessed May 21, 2012.
Rosenberg SA, Restifo NP, Yang, JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. April 2008;8(4):299–308. Available at www.ncbi.nih.gov/pmc/articles/PMC2553205. Accessed May 21, 2012.
Psilocybin and Advanced Cancer Anxiety
Beginning in the late 1950s, scientists began investigating hallucinogens as treatments for existential anxiety, despair, and isolation associated with advanced-stage cancer. The results were promising. Patients had "psychospiritual epiphanies" that often resulted in a sustained decrease in anxiety, improved mood, and less need for narcotic pain medication. But the war on hallucinogens, which started in the early 1970s, prevented further research.
In 2011, Dr. Charles S. Grob and colleagues published the first study in over 35 years to assess the use of psilocybin as a treatment for reactive anxiety in patients with advanced-stage cancer. Psilocybin, found in hallucinogenic mushrooms, produces psychological effects similar to those of LSD (lysergic acid diethylamide) but with less chance of paranoia and fewer panic reactions. This double-blind, placebo-controlled study involved 12 patients with advanced-stage cancer and anxiety. Patients acted as their own control.
During two separate sessions, patients were given either a "moderate dose" (0.2 mg/kg) of psilocybin or 250 mg of niacin as a placebo. The six-hour sessions took place in a comfortable room decorated with fabric wall hangings and fresh flowers on a hospital clinical research unit. After taking the capsule containing psilocybin or niacin, the patient put on eyeshades, lay in bed, and listened to preselected music via headphones. Staff encouraged them to remain in bed for the first few hours. Treatment staff remained with the patient for the entire six-hour period to give support if needed. In addition, staff performed hourly check-ins, asking how the patient was doing and taking heart rate and blood pressure measurements. Monthly follow-ups for six months revealed decreasing anxiety after the psilocybin session.
Blinding for this study was ineffective. Most of the subjects and investigators could tell the difference between psilocybin sessions and niacin sessions. Subjects considered the niacin placebo "far less worthwhile." The authors say, "Many of the subjects suggested that future protocols provide the opportunity for a second psilocybin session several weeks after the first. The general consensus among subjects was that a follow-up experience with psilocybin would reinforce and extend the perceived therapeutic effects of the initial session."
The value of psilocybin treatment lies in its ability to help patients transcend ego and body identification. Patients report connecting with a "larger state of consciousness in which their personal worries and insecurities [vanish]," according to a New York Times article by John Tierney. "‘It was a whole personality shift for me,'" Dr. Clark Martin, a retired clinical psychologist with depression linked to kidney cancer, told Tierney. "‘I wasn't any longer attached to my performance and trying to control things. I could see that the really good things in life will happen if you just show up and share your natural enthusiasms with people. You have a feeling of attunement with other people.'" Tierney reports that he interviewed many patients who considered their treatment session with psilocybin "among the most meaningful events" of their lives.
After decades of repression, the federal government is now giving permission to use psychedelics in controlled clinical experiments, according to Tierney. Several large universities are now researching therapeutic use of hallucinogens with financial support from private sources such as the Heffter Research Institute and MAPS, the Multidisciplinary Association for Psychedelic Studies.
Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. January 3, 2011;68(1):71–78. Available at
http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2010.116. Accessed May 21, 2012.
Tierney J. Seeking medical uses, doctors tune back in to hallucinogens. New York Times. April 12, 2010;A1, A17.