Supplements with Demonstrated Efficacy
The following article is taken from 'Treatment Options for Glioblastoma and other Gliomas' prepared by Ben A. Williams
Glioblastoma Diagnosis, March, 1995
Last Updated: October 31, 2011
Copyright 2011, Ben Williams
Disclaimer: the information presented here is the opinion of Ben Williams. It is for informational purposes only, do not consider it medical advice. Discuss the ideas presented here with your own doctors.
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This is a naturally occurring hormone secreted by the pineal gland that regulates the body's diurnal rhythm. It is commonly used for the treatment of jet lag and for insomnia. It is readily available in any health food store and most drug stores. Its role in Cancer treatment has been based on the assumption that it boosts the Immune System, with the current hypothesis being that it augments the activity of T-helper cells. It recently also has been shown to inhibit angiogenesis (138). It may also have direct cytotoxic effects on some types of cancer cells, notably melanoma cells. It has no known toxic side effects.
Clinical research on the use of melatonin for cancer treatment has been done primarily in Italy, where it has been used either as a single agent after radiation treatments, or in combination with various Chemotherapy or immunotherapy regimens, most frequently interleukin-2. Part of the rationale for such combinations is that it decreases the side effects of the chemotherapy, especially with respect to blood counts. One of the clinical studies (139) randomly assigned GBM patients either to radiation-alone or to radiation concomitant with 20 mg/day of melatonin Melatonin was continued after completion of the radiation. Survival time was significantly longer for subjects receiving the melatonin. In terms of one-year survival rates, 6/14 patients receiving melatonin were alive, while only 1/16 patients without melatonin was alive.
This GBM study involved a relatively small number of patients, so that the effects should be considered tentative until a larger study is conducted. However, the effect of melatonin was statistically reliable even with the small number of subjects. Moreover, comparable effects have been reported in a similar design for the use of melatonin with advanced lung cancer (140). Like the GBM study, a substantial increase in Survival Rate occurred for the patients receiving melatonin.
To date there have been at least a dozen phase-2 clinical trials using melatonin either alone or in combination with other agents and five phase-3 trials involving random assignment of subjects to melatonin versus some type of control group. The majority of these has been relatively small and has involved patients in the terminal stages of their disease, which is perhaps why American oncologists have largely ignored them. However, some trials have been much larger and seem to leave little doubt that melatonin significantly increases the efficacy of chemotherapy. The most extensive randomized clinical trial involved 250 patients with advanced metastatic cancer of various types (141). Patients were randomly assigned to chemotherapy alone (using different chemotherapies for different types of cancer) or chemotherapy plus 20 mg of melatonin per day. Objective Tumor regression occurred in 42 (including 6 complete regressions) of 124 patients receiving melatonin but in only 19/126 (with zero complete regressions) of the control patients. A comparable difference occurred for survival rate: 63/124 of those receiving melatonin were alive after one year while only 29/126 were alive of those receiving chemotherapy alone. A different trial, involving 100 patients with metastatic nonsmall-cell lung cancer (142), compared chemotherapy alone with chemotherapy in combination with melatonin. With chemotherapy alone, 9 of 51 patients had a partial tumor regression, while 17 of 49 chemo + melatonin patients had either a complete (2) or partial (15) regression. Twenty percent of the chemo-alone patients survived for one year and zero for two years, while the corresponding numbers for chemo + melatonin were 40% and 30%. Melatonin not only increased the efficacy of chemotherapy, but also significantly reduced its toxicity. These trials leave little doubt that the effects of melatonin are robust and of major clinical significance. Moreover, a recent study has shown that using multiple components of the pineal gland secretions instead of melatonin alone enhances clinical effectiveness still further (143).
My one caveat about the use of melatonin is that a recent randomized trial compared radiation treatment for metastatic brain cancer with and without melatonin and found no benefit of the melatonin (144). Given that almost all of the supporting evidence for the use of melatonin has come from its addition to chemotherapy, it is possible that it offers no benefit when added to radiation, perhaps because of its strong anti-oxidant properties.
138. Lissoni, P., et al. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinology Letters, 2001, Vol. 22, 45-47
139. Lissoni, P., et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with Radiotherapy plus melatonin compared to radiotherapy alone. Oncology, 1996, Vol. 53, pp. 43-46
140. . Lissoni, P., et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced non-small cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology, 1992, Vol. 49, pp. 336-339
141. Lissoni, P., et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. European Journal of Cancer, 1999, Vol. 35, pp. 1688-1692
142. . Lissoni, P. et al. Five year survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. Journal of Pineal Research, 2003, Vol. 35, 12-15
143. Lissoni, P., et al. Total pineal endocrine substitution therapy (TPEST) as a new neuroendocrine palliative treatment of untreatable metastatic solid tumor patients: a phase II study. Neuroendocrinology Letters, 2003, 24, 259-262
144. Berk, L., et al. Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain Metastases (RTOG 0119). Int. J. Radiat. Oncol. Biol. Phys., 2007, 68 (3) 852-57
PSK is the abbreviation for polysaccharide krestin (sometimes known simply as krestin), which is an extract from the mushroom, Coriolus Versicolor. It has become a standard component of cancer treatment protocols in Japan (a Chinese version of the same extract is known as PSP) for many different kinds of cancer, predicated on the assumption that it is an immune-system enhancer. Among the effects on the immune system that have been identified are gamma-interferon production, interleukin-2 production, and in increase in T-cell activity. Other effects include inhibition of matrix-degrading enzymes that underlie tumor invasion of adjacent tissue, and the inhibition of angiogenesis. Dozens of clinical trials have been conducted in Japan comparing chemotherapy regimens with the same regimens with PSK added, for a variety of different cancers, most frequently stomach and colon cancer.
In one representative study, with non-small cell lung cancer (145), stage I patients receiving PSK (3 g/day) had a five-year survival rate of 39% compared to 22% for patients not receiving PSK. For stage III patients, the 5-year survival rate with PSK was 16% versus only 5% for those not receiving PSK. Both differences were statistically significant. A second example involved patients with either stage II or stage III colorectal cancer, who were randomized to receive either the standard chemotherapy or the standard chemotherapy in combination with 3.0 g/day of PSK. The three-year disease-free survival rate was 81% for patients receiving PSK, compared to 69% for those receiving only chemotherapy.. I have found only one study that used PSK in the treatment of Glioma, in combination with ACNU (a chemical cousin of BCNU) and vincristine (146). The survival rate after one, two, and three years was 77%, 49%, and 47%, respectively. No control condition was studied that did not receive PSK, so exactly what its effect was is unclear. Note, however, that the two-year and three-year survival rates are substantially greater than that typically seen for GBM following traditional treatment with chemotherapy alone. However, the abstract of the study (the study was in an inaccessible Japanese journal) did not report the results separately for glioblastomas versus grade III gliomas.
The source for PSK that I have used is JHS Natural Products in Eugene, Oregon (phone # 541-344-1396 or 888-330-4691; website:www.jhsnp.com). Other sources undoubtedly can be found through a web search. Other mushroom extracts that also have the longchain polysaccharides (beta-glucans) that appear to be the active ingredient in PSK are more readily available. These include maitake, reisha, and shitake mushrooms. However, none of these has the same level of scientific evidence for treatment efficacy in human clinical trials. Maitake D-fraction seems an especially promising mushroom extract based on a recent laboratory study of chemically-induced tumors in mice (147). Tumor growth was inhibited 90% when the mushroom extract was combined with chemotherapy versus an inhibition of only 50% when chemotherapy was used alone for control subjects.
145. . Hayakawa, K., et al. Effect of krestin (PSK) as adjuvant treatment on the Prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer research, 1993, Vol. 13, pp. 1815-1820
146. . Kaneko, S., et al. Evaluation of radiation immunochemotherapy in the treatment of Malignant glioma. Combined use of ACNU, VCR and PSK. Hokkaido Journal of Medical Science, 1983, Vol. 58, pp. 622-630
147. Nanba, H. and Kubo, K. Effect of maitake D-fraction on cancer prevention. Annals of New York Academy of Sciences, 1997, Vol. 833, pp. 204-207
GLA is an essential fatty acid found in evening primrose oil, borage seed oil, and blackcurrant seed oil. At least 100 laboratory studies have shown it to be highly cytotoxic to many different kinds of cancer cells, with the presumed mechanism that metabolism of GLA by the cancer cells creates high levels of free radicals that are lethal to the cells. Iron and zinc potentiate this cytotoxic effect; Vitamin E (and perhaps other anti-oxidants) counteracts it. GLA is harmless to normal cells and has been shown to have clinical utility for a variety of disorders, notably rheumatoid arthritis and as a topical treatment for Superficial bladder cancer. It also has been shown to lower LDL cholesterol and increase insulin sensitivity. GLA is also known to change the structure of cell membranes, which is believed to underlie the finding that it increases the effectiveness of both chemotherapy and radiation. At the same time GLA has been shown to protect normal cells from radiation damage.
Evidence that GLA is effective against gliomas comes from a study conducted in India (148, 149) in which GLA was infused directly into the tumor bed. Of the 15 patients treated, most had major tumor regressions, and 12 of the 15 were alive at the time of the report's publication (1-2 years later). The three who died were all quite elderly and probably would not have received any conventional treatment beyond radiation in this country. A subsequent study (150) involving patients with very advanced disease had notably less success but here too there were notable tumor regressions attributable to the treatment.
A critical question is whether oral ingestion of GLA has any clinical effects. A recent clinical trial involving its use for breast cancer substantiates that it does (151). Advanced breast cancer patients received the standard treatment of tamoxifen alone or tamoxifen in combination with GLA, in the form of 2.8 g of GLA/day. The source of GLA was borage seed oil, which is approximately 20-25% GLA, which meant that the patients were taking 12-15 g of borage seed oil per day. Borage seed oil is available in any health food store, usually in the form of 1000 mg capsules, although supposedly it can also be obtained in liquid oil form and makes tasty salad dressings. The measure of treatment effectiveness in the breast cancer clinical trial was the status of patients three months after the initiation of treatment. With tamoxifen alone, none of the patients had a complete response to treatment, 13% had partial regression of their tumors, while 81% had stable disease. For tamoxifen + GLA the corresponding percentages were 5, 37, and 55%, a significant improvement.
The use of GLA as a cancer treatment is controversial because one of its major metabolites is arachnidonic acid, which is the precursor to both the lipoxygenase and cyclogenase inflammatory pathways. These inflammatory pathways are believed to stimulate the growth of cancer cells, which seems to contraindicate using GLA. However, it should be noted that GLA has been used successfully as a treatment for rheumatoidarthritis because of its anti-inflammatory effects, so obviously the story is more complicated. Part of the source of confusion is that the effects of GLA are dose dependent. In laboratory studies low dosages have been shown to stimulate tumor growth, while at higher dosages the effect is clearly cytotoxic. (152, 153). A second important factor is the interaction with n-3 fatty acids (fish oil being the most common). When fish oil is also present, its metabolic pathway competes for enzymes that also are involved in GLA metabolism, thus preventing the formation of arachnidonic acid. The optimal use of GLA may therefore be in combination with fish oil, not as a single agent.
The major fatty acids found in fish oil, eicosapentenoic acid (EPA) and docosahexanoic acid (DHA), have also been demonstrated to have potent cytotoxic effects on cancer cells in numerous laboratory experiments. Part of their mechanism of action is similar to that of GLA, in that the metabolism of these fatty acids creates high levels of free radicals. In addition, a recent laboratory study has shown that EPA-treated tumors showed a significant arrest of cell division due to inhibition of cyclins at the G1 phase of cell division, which resulted in an increased rate of programmed cell death known as apoptosis (154).
A clinical trial comparing fish-oil supplements versus a placebo has also been reported, involving patients with several different types of advanced cancer (155). Thirty malnourished patients suffering from cachexia were randomly assigned to receive 18 g of fish oil per day in combination with 200 mg of Vitamin E, or a placebo sugar pill. An additional thirty subjects, adequately nourished, received a similar random assignment. For both groups the fish oil significantly increased survival. For the malnourished patients the Median survival times, as estimated from their survivor functions, were 110 days for the patients receiving placebo and 210 days for patients in the fish oil group. For the adequately nourished patients, the corresponding numbers were 350 versus 500 days. In laboratory studies (156) fish oil has also been shown to significantly increase the effectiveness of chemotherapy.
148. Naidu, M. R., et al. Intratumoral gamma-linolenic acid therapy of human gliomas. Prostaglandins Leukotrienes and Essential Fatty Acids, 1992, Vol. 45, pp. 181-184
149. Das, U. N. et al. Local application of gamma-linolenic acid in the treatment of human gliomas. Cancer Letters, 1994, Vol. 94, pp. 147-155
150. Bakshi, A, et al. Gamma-linolenic acid therapy of human gliomas. Nutrition, 2003, Vol. 19, 305-309
151. Kenny, F. S. et al. Gamma linolenic acid with tamoxifen as primary therapy in breast cancer. International Journal of Cancer, 2000, Vol. 85, 643-648
152. Leaver, H. A., et al. Antitumor and pro-apoptotic actions of highly unsaturated fatty acids in glioma. Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002, Vol. 66, pp. 19-29
153. Bell, H. S., et al. Effects of N-6 essential fatty acids on glioma invasion and growth: experimental studies with glioma spheroids in collagen gels. Journal of Neurosurgery, 1999, Vol. 91, pp. 989-996
154. Palakurthi, S. S. et al. Inhibition of translation initiation mediates the anticancer effect of the n-3 polyunsaturated fatty acid eicosapentaenoic acid. Cancer Research, 2000, Vol. 60, pp. 2919-2925
155. Gogos, C. A., et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial. Cancer, 1998, Vol. 82, pp. 395-402
156. Hardman, W. E., et al. Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MPA-MB 231 breast cancer xenographs. Clinical Cancer Research, 2001, Vol. 71, pp. 2041-2049
Numerous laboratory studies have shown that Vitamin D is highly cytotoxic to cancer cells, due to several different mechanisms (although it is labeled a vitamin it more properly should be considered a hormone). While most research has focused on its ability to activate genes that cause cancer cells to differentiate into mature cells, other effects have also been identified, including cell cycle regulation, inhibition of the insulin-like growth factor, and the inhibition of angiogenesis (157). However the form of Vitamin D most commonly available is not readily usable for cancer treatments because the dosages producing anti-cancer effects also cause hypercalcemia, which can be life threatening (the major function of Vitamin D is to regulate calcium absorption and resorption from the bones and teeth). But like many vitamins/hormones, the generic designation refers not to a specific chemical structure but to a family of related molecules that may have different properties of various sorts. For Vitamin D several of these variants (commonly referred to as analogues) have been shown to effectively inhibit cancer cell growth but without the same degree of toxic hypercalcemia. In a 2002 paper in the Journal of Neuro-oncology (158), 10 patients with glioblastoma and one with a grade III AA tumor received a form of Vitamin D called alfacalcidol in a dosage of .04 micrograms/kg each day, a dosage that produced no significant hypercalcemia. The median survival was 21 months, and three of the eleven were long-term survivors (greater than 5 years). Although the percentage of patients who responded to the treatment was not high, the fact that any relatively non-toxic treatment can produce that number of long-term survivors is remarkable. There is also strong reason to believe that Vitamin D is synergistic with retinoids such as accutane (159). Its effectiveness is also increased in the presence of dexamethesome (160) and a variety of anti-oxidants, notably carnosic acid, but also lycopene, curcumin, silibinin, and selenium (161).
Unfortunately, alfacalcidol is not available in the USA. But it is available in Europe and Canada. For those in the USA it is possible obtain it from various online marketers. One source that several members of the brain tumor community have used is Masters Marketing. Its web address is http://www.mastersmarketing.com. Undoubtedly there is a number of other possible suppliers. It also should be noted that several other Vitamin D analogues are available, which also have much reduced hypercalcemic effects. One of these, paricalcitol, was developed for treatment of a disorder of the parathyroid gland, and recently has been the subject of several experimental studies (162, 163, 164) that have shown it to be highly cytotoxic to many different type of cancer. Given that other forms of Vitamin D have been shown to be highly cytotoxic to for glioblastoma cells, and that glioma cells are known to have receptors for Vitamin D, it seems likely that paricalcitol should have efficacy for glioblastoma as well. Unfortunately, its routine use is complicated by the fact it is available only in a form that requires intravenous injection.
The most common version of Vitamin D found in health food stores is cholecalciferol, which is the precursor of calcitriol, the form of Vitamin D utilized by the body. A recent study of cholecalciferol with prostate cancer patients who had progressed after standard therapy (165) suggests that this common form of Vitamin D may be clinically beneficial. Fifteen patients who had failed standard treatments were given 2000 I.U daily. PSA levels were reduced or stayed the same for nine patients, and there were a reliable decrease in the rate of PSA increase for the remainder. No side effects of the treatment were reported by any of the patients.
Because serum Vitamin D levels have recently been shown to be inversely related to cancer incidence, there recently has been considerable discussion about the dosage that is toxic. Some have argued that doses as high as 5000 I.U.//day are safe. Nevertheless, it is important to note that all forms of Vitamin D can occasionally produce dangerous serum calcium levels, in part because there is a great deal of variability in their effects across individuals. It is thus important that blood calcium levels be monitored, especially while a nontoxic dosage is being established.
157. Van den Bemd, G. J., & Chang, G. T. Vitamin D and Vitamin D analogues in cancer treatment. Current Drug Targets, 2002, Vol. 3, 85-94
158. Trouillas, P, et al. Redifferentiation therapy in brain tumors: long-lasting complete regression of glioblastomas and an anaplastic astrocytoma under long-term 1-alpha-hydroxycholecalciferol. Journal of Neuro-oncology, 51, 57-66
159. Bollag, W. Experimental basis of cancer combination chemotherapy with retinoids, cytokines, 1, 25-hydroxyvitamin D3, and analogs. Journal of Cellular Chemistry, 1994, Vol. 56, 427-435
160. Bernardi, R. J., et al. Antiproliferative effects of 1alpha, 25-dihydroxyvitamin D (3) and vitamin D analogs on tumor-derived endothelial cells. Endocrinology, 2002, Vol. 143, 2508-2514
161. Danilenko, M., et al. Carnosic acid potentiates the antioxidant and prodifferentiation effects of 1 alpha, 25-dihydroxyvitamin D3 in leukemia cells but does not promote elevation of basal levels of intracellular calcium. Cancer Research, 2003, Vol. 63, 1325-1332
162. Chen, T. C., et al. The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1 alpha, 25-dyhydroxyvitamin D2 as therapeutic agents for prostate cancer. Clinical Cancer Research, 2000, Vol. 6, 901-908
163. Kumagai, T., et al. Vitamin D2 analog 19-nor-1, 25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma and colon cancer cell lines. Journal of the National Cancer Institute, 2003, Vol. 95, 896-905
164. Molnar, I., et al. 19-nor-1alpha, 25-dihydroxyvitamin D (2) (paricalcitol): effects on clonal proliferation, differentiation, and apoptosis in human leukemia cell lines. Journal of Cancer Research and Clinical Oncology, 2003, Vol. 129, 35-42
165. Woo, T.C.S, et al. Pilot study: Potential role of Vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutrition and Cancer, 2005, 51(1), 32-36
These closely related chemical compounds are derived from citrus oils, and have been extensively investigated as anti-cancer agents, including several early-stage clinical trials.
Unfortunately, the gastro-intestinal side effects of these compounds have retarded their clinical development. A recent clinical trial with recurrent glioma patients circumvented this problem by administering perillyl acid intranasally four times daily. Of the 37 patients in the trial, (29 with gbm) two had partial tumor regressions and 17 had stable disease (166). For the GBM patients, the PFS-6 value was 48%, one of the better outcomes for recurrent tumor patients in the literature. Moreover, there was minimal toxicity, even though treatment continued on a daily basis for the duration of the study. The clinical trial is continuing, now with dose escalation. Given its lack of toxicity, the treatment seems to be an excellent candidate for combinations with other forms of treatment.
In addition to the above, there are a significant number of other existing drugs that have impressive experimental data suggesting they may be effective for human glioblastoma patients. A partial list of such drugs includes sulfasalazine, a drug used for inflammatory conditions such as Crohn disease and rheumatoid arthritis, noscapine, a component of cough syrup, and digitoxin, a cardiac medicine. Some of these are currently being studied in clinical trials, but as yet no clinical results have been reported.
166. Da Fonseca, C. O. e al., Preliminary results from a phase I/II study of perilly alcohol intranasal administration in adults with recurrent malignant gliomas. Surgical Neurology, 2008, 70, 259-267
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