QUESTIONABLE CANCER THERAPIES I:
Any cancer patient who has sought out alternative therapies is well-aware that there is an abundance of treatments claimed to be of benefit. Each remedy is accompanied by literature that sounds fully supportive, with numerous research reports and a variety of testimonials. Unfortunately, many cancer patients soon become bewildered and financially drained. Products that initially sounded so promising begin to be questioned, especially if the medical diagnosis is not markedly improved after using them, then the next item is tried, one after another or in groups. John Diamond, a prolific journalist in England, suffered from cancer and wrote about his various experiences following the diagnosis. His columns on the subject were compiled in a book called Snake Oil (2001 Vintage Press, London), in which he revealed the plethora of alternative remedies that people threw his way. He marveled at the lack of logic and investigation behind most of the claims associated with them and wondered about what circumstances led people to not question them more critically.
Practitioners of natural healing are usually asked by their patients for an opinion about the purportedly useful substances, but the practitioners are not necessarily well-informed about the myriad products that are presented nor are they in a good position to evaluate the validity of laboratory and clinical reports that are said to support them. The position taken by these practitioners is often to go along with having the patient use the product that has brought them some hope. One problem with this approach, which the medical profession has pointed to for decades now, is that by pursuing some of these therapies that are of questionable value other courses that are open to the patient may end up being ignored or underutilized until it is too late. Therefore, ineffective therapies may indeed turn out to be harmful to the overall therapeutic plan.
ITM has received numerous inquiries over the last two years about PC-SPES (PC for prostate cancer; SPES is said to be Latin for "hope"). PC-SPES is described as a Chinese herb formula, though it fits that description very loosely. It became especially popular recently, after a few medical doctors, passing on the information that this is a traditional Chinese herb remedy, proclaimed good results with cancer patients. According to a detailed medical study relayed here, PC-SPES appears to be effective for some kinds of prostate cancer, but its mechanism of action is entirely unlike what its proponents claim and it poses certain side effects that all users should be aware of. The content of the product is questionable and the product has been promoted by a single distributor in the U.S. In 2002, the U.S. FDA forced a product recall when it discovered that the product contained one or more pharmaceutical agents.
A detailed report "Clinical and biological activity of an estrogenic herbal combination (PC-SPES) in prostate cancer," was published in the September 17, 1998 issue of the New England Journal of Medicine (1). It conflicts with information provided by the product distributor (Botaniclab, in Brea, California). The NEJM article stimulated some controversy in the field of herbal medicine because it indicated that a purportedly natural Chinese herb product could not only accomplish what its proponents claimed-namely to inhibit prostate cancer-but that it did this via a strong estrogenic response that carried with it all the side effects and expected risks of estrogen therapy. As a result, the authors of the NEJM study cautioned, appropriately so, that this unregulated natural product was not a benign treatment.
A first question raised by proponents of PC-SPES is whether or not this report in NEJM was valid. The product distributors and promoters had described the formula as an immune enhancing and anticancer therapy, not a hormone treatment. Further, side effects had not been reported in the product literature. It should be noted that NEJM is one of the world's leading medical journals, having intensive peer review. The researchers had demonstrated estrogen-like activity of PC-SPES in three assays, including yeast, mice, and man, and the results were all consistent. The researchers searched for, but did not find, commonly-used estrogens in the mixture (these would have to be additives, as they do not occur in any significant quantity in plants). The researchers monitored the changes in the prostate cancer marker (PSA) in men with biopsy-verified prostate cancer, along with levels of testosterone (which went down during therapy with PC-SPES and back up after the herb use had stopped for several days). They monitored clinical responses and compared them to the effects of hormonal therapy based on leuprolide (comparison based on literature reports).
It is quite difficult to come to any conclusion other than this: the product, PC-SPES, when taken in the amounts usually recommended, has significant estrogenic and anti-testosterone effects sufficient to explain most (if not all) of the prostate cancer inhibitory action associated with it; further, it can produce the side effects that are common to hormone therapies of similar nature. The NEJM study included reports of impotence (which affected the entire group of 8 men in this evaluation) and breast tenderness (experienced by most); this could hardly have been missed by users of the product who were not enrolled in the study and were merely taking it as a natural supplement. Could the product distributor really be unaware of this response? Were the men who had taken it on their own too embarrassed to talk about it and report it? What does this apparent lack of awareness mean in terms of the monitoring of natural product safety and side effects?
In fact, men with prostate cancer turning to natural therapies are often hoping to avoid hormone therapy because they do not wish to experience the usual side effects of hormone therapy. In the Botaniclab literature, there is a report attributed to Dr. James Lewis (said to be a supporter of PC-SPES) that begins with describing the problems associated with hormone therapy for prostate cancer and leads to the recommendation for using PC-SPES as an alternative. Certainly, if faced with the decision between standard hormone therapy and an herbal therapy that produced essentially the same effects, those who prefer natural approaches might opt for the herbs. But, it would certainly be a more comfortable decision if one could be certain of the product's ingredients and if the promotional literature didn't contradict the research findings as indicated by the NEJM article.
The herb list for PC-SPES (see the section on reported constituents in PC-SPES) does not appear to match any traditional formulation style. Two of the herbs in the formula have some use as anti-cancer agents: isatis contains an ingredient, indirubin, that treats certain kinds of leukemia; and rabdosia contains oridonin, which is being investigated in China for cancer therapy. Rabdosia or its isolated ingredients, has been used clinically in China for treating some types of cancer, but not, apparently, prostate cancer. Further, the NEJM article suggests that the prostate cancer inhibition produced by this mix is mainly accomplished by an estrogenic effect, not a general anti-cancer activity that might be expected from indirubin and oridonin.
The Chinese are known for their abilities in finding herbs with hormonal action, and have a good reputation for being able to minimize the effects of menopause (see: The treatment of menopausal syndrome with Chinese herbs). In the West, menopause is the topic of the day, and natural treatments abound. Except for licorice, not one of the herbs in this formula is commonly used for menopause, and even licorice is rarely selected as a first choice by herbalists either in China or in the West. One would expect that any of the herbs in the formula that had such a huge estrogenic potential, as indicated by the PC-SPES study, would have been revealed before.
That leads to the question that must arise: what, exactly, is in PC-SPES? Are the herbs listed by the distributor the actual ones used? Why would these plants, comprised of large collections of notably different active constituents, yield just three major peaks-indicating three major ingredients-in the HPLC (high-pressure liquid chromatography) analysis conducted for the NEJM published study? In another study that included HPLC analysis of PC-SPES (2), the authors suggested that the peaks they observed represented mainly alkaloids and polyphenols. While polyphenols could come from several of the plants (though none of these herbs are reputed to have polyphenols as a major constituent), alkaloids are only present as indirubin and related constituents from isatis.
According to the promotional literature, a unique aspect of PC-SPES is that each of the herbs is extracted individually. Accordingly, extraction techniques can be used to isolate certain fractions from each herb. This could yield a small number of active constituents and require a lower dosage than would be the case if the herbs were all extracted together by one technique. Still, it would be surprising to be able to concentrate the herb materials so that only 1.28 grams per day would have a dramatic effect unless individual active ingredients had been specially isolated.
The minuscule clinical dosage-4 small capsules per day-could only yield such a huge effect if one or two potent individual chemical components, present at several hundred milligrams each, are the main part of the finished product. Mark Blumenthal of the American Botanical Council revealed (via personal communication) that he had learned that the compound being marketed contained herb extracts that were at a concentration factor of 100:1 or higher. What this means is that, in fact, individual active components from herbs, not whole herb extracts, were being provided. That would answer part of the question, namely, how it was possible for such a small dosage to have such a powerful effect. In fact, patients in one recent clinical trial of PC-SPES had experienced adverse effects including nipple tenderness (42%), breast swelling (8%), hot flashes (7%), and deep venous thrombosis (2%). PC-SPES has also been associated with increased rates of pulmonary embolism and, most recently, a case of hemorrhage.
This last incident (of hemorrhage) is what triggered a product recall in February 2002 when the FDA discovered a significant content of coumadin (Warfarin) in PC-SPES. As a prompt defensive reaction, it was speculated, by PC-SPES proponents, that this was a natural derivative, highly concentrated, from one of the ingredients (Scutellaria), rather than the addition of a drug, but researchers in the U.S. involved with the testing believe that the compound is, in fact, the synthetic drug. Routine testing of another of the SPES products revealed the prescription drug alprazolam (Xanax), confirming that the manufacturer uses drug materials. The product distributor claimed that this was not a normal ingredient of the product, but must have been an inadvertent contaminant. This explanation seems highly unlikely.
Independently, researchers at UC San Francisco's medical school confirmed that they had tested four different lots of PC-SPES and found that all contained diethylstilbestrol (DES), a hormone that was once used to prevent miscarriages but later was banned when it was shown to cause birth defects in children and blood clots and other side effects. This was one component that had been suspected to be present by the authors of the NEJM article, but had not been detected in their earlier test.
These revelations about the product have not fully explained what is in the product. The amounts of coumarin and diethylstilbesterol detected may not be sufficient to explain the therapeutic effects. There could be other drugs, as yet undetected, and the nature of the purified compounds from herbs remained unrevealed.
Chinese medical literature is relatively silent on treatment of prostate cancer; published clinical trials involving this cancer site are virtually absent. In the book Anticancer Medicinal Herbs (4), there is an appendix that lists herbs according to the type of cancer for which they are deemed useful. While lung cancer has a listing of 50 herbs, prostate cancer has only one herb mentioned (geranium leaf); this listing apparently comes from the following statement contained in that book's description of the herb: "For cancers of the lung, the rectum, the throat, the prostate, the breast, and leukemia, the liquid extract of geranium is taken orally with an arbitrary dose." In three books that depict Chinese approaches to treating cancer prior to the recent focus on integrated therapy (where Chinese herbs are used as an adjunct to Western medicine), prostate cancer isn't even mentioned (14, 15, 16), despite the inclusion of several rare cancers, such as of the penis and testes. Thus, it does not appear that PC-SPES evolved from extensive prior work on prostate cancer therapy by herbal treatment in China.
In a recent article, brucea fruit (a somewhat toxic herb) was used in intravenous administration and local injection to treat advanced prostate cancer (10). The authors noted that: "At the present, there is no useful method in the treatment of patients with prostate carcinoma of stage 3 and stage 4." Of course, they presented their new therapy as being of potential use, as revealed by their study. One would expect that PC-SPES (or any of its constituent herbs) would have been reported on favorably, if it were generally deemed a viable option among experts in traditional Chinese medicine.
Following is a brief analysis of the herbs that the PC-SPES product distributor claims are in the product, including research from China about the major active components.
Ganoderma lucidum (lingzhi) is a well-known mushroom (the whole mushroom, or just the fruiting body, or the mycelium grown in culture is used today) that has been used in China for many centuries and adopted in modern times to many uses. It contains two basic types of active constituents: ganoderic acids and polysaccharides. Ganoderic acids are triterpenes that are bitter compounds thought to promote blood circulation and enhance oxygen utilization. Immunologically-active polysaccharides are a neutral tasting component, not soluble in alcohol, which have notable immune-enhancing actions. Although these polysaccharides promote the immune system attack against transplanted tumors in laboratory animals, there is no evidence of anti-tumor action in spontaneously occurring tumors in humans. The polysaccharides are used clinically to protect against the immunosuppressive effects of chemotherapy and radiation. The amount of polysaccharide needed to get an effect has been estimated to be 0.4-2.4 grams per day (see: Physiological responses to immunologically-active polysaccharides). These polysaccharides are very difficult to purify and typical concentrated extracts from ganoderma contain only about 10% polysaccharides (thus, the amount of extract to ingest in one day is at least 4 grams; this is far more than the total dose of PC-SPES. There are no substantive reports of hormonal effects from either polysaccharides or the ganoderma triterpenes.
Rabdosia rubescens (donglingcao), formerly called Isodon rubescens, is a rarely-used Chinese herb (the entire plant is used). Its traditional use is as a digestant and anti-inflammatory agent, but it has been a folk remedy for carcinomas of the heart and esophagus in Hunan Province (4). Laboratory animal studies demonstrate notable antineoplastic properties. The main active components are oridonin (the main one studied) and similar compounds such as ponicidin (these active constituents are tetracyclic diterpenoid compounds). Little toxicity has been noted (5, 6). Early clinical reports indicated benefits of the herb for esophageal cancer and it has been tried with some other types of cancer. More recently, the active constituent oridonin has been evaluated as adjunct to standard cancer therapies, such as cisplatin, in tissue culture and in laboratory animal studies (7, 11). In a review of investigations on rabdosia (12) spanning the 1950s to the present, no mention is made of hormonal effects. In the book Anticancer Medicinal Herbs, rabdosia is mentioned under its earlier botanical name Isodon. Recommended dosages are 90-120 grams of the fresh herb (this corresponds, roughly, to 30-40 grams of dried herb), and 30 grams of the dried herb. It is mentioned, at the latter dosage, as being useful for cancer of the breast (when combined with other herbs). The author of the book mentioned that "The Tumor Department of the First Teaching Hospital of Henan Medical College has used the tablets [of ginseng plus rabdosia] for years and their experience indicates that the tablet is one of the best drugs for breast cancer." Panax notoginseng, a relative of ginseng, is reportedly contained in the PC-SPES formula. Despite this glowing report from more than a decade ago, the limited discussion of Chinese herbal treatments for breast cancer does not seem to follow-up on it. Nonetheless, rabdosia appears interesting since it purportedly benefits the digestive system, inhibits cancer, and is low in toxicity. As a reflection of this interest, in the book Chinese Drugs of Plant Origin (17), of 120 herb entries, rabdosia has one of the largest sections. There are two dozen pages of chemical constituent illustrations, obtained as a result of efforts to find the most useful antitumor agents from the many species of Rabdosia that grow in China.
Isatis indigotica (daqingye, banlangen, qingdai) is a frequently-used herb (leaf and root are used), usually employed in treating infections (especially viral infections). It contains an anti-leukemic compound, indirubin, which is effective for granulocytic leukemias when taken in sufficient dosage. This herb is rarely used in treatment of other cancers, though it has been used experimentally as an ingredient in formulas for various cancers. In a review of antineoplastic Chinese herb compounds (8), rabdosia and isatis received only brief mention for esophageal cancer and leukemia, respectively. Another, more recent, review of this subject (9), included mention of isatis and indirubin for leukemia, but did not mention rabdosia. According to An Illustrated guide to Antineoplastic Chinese Herbal Medicine (13), the isatis extract called qingdai is administered in doses of 6-10 grams per day; the isolated indirubin is given in doses of 150-200 mg/day. When used in the amounts found helpful for leukemia treatment, qingdai and indirubin can cause intestinal irritation in some users.
Scutellaria baicalensis (huangqin) is a commonly-used Chinese herb (the root is used). It is found in hundreds of traditional herb formulas and is reputed to treat inflammation, infection, and bleeding. The active components have been identified as flavonoids, of which baicalein is a primary one. Usual dosing is 9-15 grams of the herb in decoction (as with other flavonoids, the isolated active constituents would be prescribed in amounts on the order of a few hundred milligrams per day). No hormonal effects have been noted. The whole plant of a related herb, Scutellaria barbata (banzhilian) is frequently used as an anticancer plant, but usually only in heavy doses of 30-60 grams per day. It is possible that this ingredient is used in PC-SPES and misidentified in the literature about the product.
Chrysanthemum morifolium (juhua) is a frequently-used herb (the flower is used), considered to be a cooling tonic, and employed in treatment of headaches, eye disorders, and skin eruptions. It is not known to have hormonal effects and is not typically given for treatment of cancers. The wild chrysanthemum (yejuhua), Chrysanthemum indicum, is briefly mentioned in Anticancer Medicinal Herbs, but testing has not gone beyond the stage of in vitro analysis. It is suggested as an ingredient for treatment of thyroma (thyroid adenoma). The main active constituents of both species of chrysanthemum are essential oils (sesquiterpenes) that give it the characteristic floral taste and fragrance, and flavonoids which contribute to the bitter taste.
Glycyrrhiza glabra (gancao), known commonly as licorice, is a substitute species for one of the most frequently-used herbs in Chinese medicine (the root of Glycyrrhiza uralensis is the main one), used both as a flavoring ingredient and medicinal agent. It does have some hormonal effects, including a very mild estrogen action, primarily through binding to estrogen receptor sites (3), though it is rarely used in China for treating menopausal syndrome or other estrogen-deficiency conditions. Tang-kuei (Angelica sinensis) yields a similar level of estrogen-binding site interaction and has actually been shown ineffective in treating menopausal symptoms when used as a single herb. Licorice is not used as an anticancer herb, though it is listed in Anticancer Medicinal Herbs as having been shown in animal experiments to inhibit some tumor lines. In Chinese herbal formulas for cancer, licorice is rarely present, and when it is present, it is usually only a minor ingredient. The main active constituents are flavonoids.
Panax pseudoginseng (sanqi) is a commonly-used Chinese herb that is most often employed to treat blood disorders, such as bleeding or blood stasis (bruises, restricted blood flow). It is often viewed specifically as an herb for injuries, though efforts have been made to broaden its applications. The active ingredients include saponin glycosides like those found in Panax ginseng. The herb is not known for hormonal activity nor for anticancer effects, except in laboratory experiments with tumor lines in vitro or in mice. However, it has been used as an adjunct to radiation therapy, with the idea that it makes tumors more susceptible to the radiation effects by altering the blood circulation, and it has been used as a minor ingredient in formulas for esophageal cancer and cervical cancer, probably for the purpose of treating bleeding.
Saw palmetto (Serenoa repens) is not a traditional Chinese herb, though it is now cultivated in China. It contains ingredients that inhibit 5-alpha-reductase, an enzyme involved in testosterone metabolism, inhibiting the production of dihydrotestosterone, which is a stimulant to prostate cells. This herb has recently been adopted in the Western herbal practice to treat benign prostatic hypertrophy (see: Herbal therapy for benign prostatic hypertrophy), but does not have the reputation of treating prostate cancer. Theoretically, it could contribute to inhibition of prostate cancer by reducing hormonal stimulus. The usual dosage of saw palmetto extract used for benign prostatic hypertrophy is 320 mg/day.