PROGNOSIS AFTER DIAGNOSIS OF LIVER CANCER:
The Influence of Chinese Herbs
Reports about treatment of liver cancer have often included a statement that the disease has a "poor prognosis." Sometimes, this is more specifically stated, such as in a 1994 pathology textbook: "The outlook for hepatocellular carcinoma is not good, with death occurring within six months of diagnosis."
Patients diagnosed with cancer generally expect their physicians to provide them with a prognosis, an educated guess about what will happen to them. In the case of liver cancer, which has generally been associated with a poor outcome, the patients may want to know how long they have to live. While it is impossible to know the lifespan of any individual, the chances (probability) of passing a certain survival time can often be given. Factors that can alter this survival, including treatments with standard, experimental, and complementary therapies, can be taken into account, but also introduce uncertainty into the determination.
Currently, prognosis for life-expectancy is based on statistical data for prior cases that have been documented, analyzed, and summarized. In the case of cancer, survival time after the initial diagnosis is measured in median duration to death or in rate of survival past certain marker points, usually 1, 3, and 5 years. Median duration to death is the time at which 50% of patients have died; survival rate indicates the percent of patients surviving at a given time point after diagnosis of the disease. Data used for survival rates do not take into account the actual cause of death, which can include adverse effects of attempted treatments and death due to other diseases. Sometimes, prognosis is also given in terms of improvements versus disease progression within a limited treatment period without reference to survival duration.
Improvements in the accuracy of prognosis occur as a disease category (e.g., liver cancer) is subdivided according to parameters that affect overall outcomes. Liver cancer may be divided first into two broad categories: primary (hepatocellular carcinoma) and secondary (metastases from other cancers, such as colorectal carcinoma). The cancers are then staged (I through IV) based on tumor size, tumor number, and invasiveness into the organ's vascular system, with decreasing survival as the stage of disease progresses. Recent research, described below, provides a number of other determinants for survival.
There is relatively little data available for prognosis for untreated primary liver cancer because this type of cancer seldom goes untreated. Until recently, the effect of medical treatment on survival duration had often been minimal, so the accumulated data on survival rates with treatments given prior to the 1990's have closely reflected the survival rates without treatment. A 1992 report (based on data from the 1980's) indicated a survival curve that is not much different than that for pancreatic cancer: only about 20% survival at one year, and a very low 5-year survival rate of 6% (1). The five-year survival rate derived at that time was 15% when the cancer was localized and surgically removed (stage I), but only 2% when the cancer had already spread to other sites (stage IV).
Recently developed treatments, including improved surgical techniques and new chemotherapy drugs and delivery methods (e.g., catheterized chemo-embolization), may improve the outcomes, especially for the earlier stages of the disease. When delayed until the disease is in an advanced stage, available treatments have little effect on survival. Thus, for example, in a Chinese study using modern medical techniques (2), patients with advanced liver cancer were treated with either nolatrexed or with doxorubicin: it was reported that neither treatment had much effect. The median survival time was about 4 months.
In a French study (3), it was shown that five prognostic factors (other than those that had been used for staging the disease) could be combined to closely predict outcomes for primary liver cancer. The following were associated with poor prognosis:
By using these measures, the authors were able to describe three risk groups (low, medium, high) with markedly different average 1-year survival rates of 79%, 31%, and 4%, respectively. Patients with few of the adverse indicators would usually respond well to therapy and were likely to survive for at least one year, while the survival rate for those with several of the negative indicators (which correspond to advanced disease) was very limited, with short survival duration. Therefore, by collecting this detailed information, which involves a patient survey (Karnofsky), a blood test for indicators related to liver disease (alpha-fetoprotein is an indicator of certain cancers, especially liver and pancreatic cancer), and an ultrasound test of the liver, the prognosis for the first year can be given with more confidence than by simply using a diagnosis of liver cancer with or without metastases.
In a recent evaluation of surgical treatment of liver cancers secondary to colorectal cancer (which itself would have been previously treated by surgery plus chemotherapy), it was reported (4) that 5-year survival was 37% and 10-year survival was 22%. But, the ability to give a more specific prognosis for a patient could be improved by considering several individual factors. The following factors were associated with poor prognosis:
The last five criteria were said to be especially valuable for prognosis and could be used for determining what type of therapy to attempt; if up to 2 criteria were met, the outcome of standard treatment might be favorable; if more than 2, then new experimental therapies might be tried, as the outcome by current methods is unlikely to be favorable (meaning that the survival data for no treatment or ineffective treatment should apply).
A study (5) of surgical resection of primary liver cancer that was accompanied by underlying cirrhosis revealed a 5-year survival rate of 57% for those with small tumors (less than 5 cm), but only 32% for those with large tumors (>10 cm). Aside from tumor size, other factors that indicated poor outcome were high alpha-fetoprotein and vascular invasion of the tumor.
In a study of prognosis for primary liver cancer treated by surgery, it was shown that getting a clean margin, even if two surgical attempts were necessary, was very influential in overall survival. In the general case, it was reported that 1-, 2- (not 3-), and 5-year survival rates were 75%, 56%, and 29% for surgical treatment. Certain factors were found to be associated with a poor prognosis: vascular invasion, metastatic disease, and positive margin. For those who had two surgeries in order to get a clean margin, the risk of death was 5 times that of those who got a clean margin the first time; if there was no clean margin the second time, the risk of death was 15 times higher. Thus, taking into account the surgical outcome-by examining the removed mass-could greatly improve the ability to give an accurate prognosis.
Comparing outcomes of diverse treatments, an Italian study (6) involving 178 patients indicated the following survival rates:
|
Treatment |
1-year Rate |
3-year Rate |
5-year Rate |
|
Chemotherapy or no specific therapy |
13% |
3% |
0% |
|
Chemo-embolization |
55% |
26% |
13% |
|
Hepatectomy |
72% |
58% |
58% |
|
Liver transplant |
81% |
74% |
74% |
These data give very favorable prognosis for certain treatments, but must be viewed cautiously: the number of patients per group that resulted in favorable outcome was low (e.g., liver transplant: 22 patients; hepatectomy: 11 patients) and the treatments were selected on the basis of the nature of the cancer condition. In general, liver transplant is a therapy limited to those who have a well-defined tumor mass but in a location (or within a particular liver condition) that precludes successful hepatectomy (resection). The 13% survival rate at one year for simple chemotherapy described in this study was consistent with the Chinese report that standard systemic chemotherapy had little effect and resulted in median survival of only about 4 months. Systemic chemotherapy is often applied when there is metastatic cancer (stage IV).
In a U.S. study (7) involving liver metastasis from colorectal carcinoma, chemo-embolization (doxorubicin, mitomycin C, and cisplatin; followed-up by 5-FU with leucovorin) yielded a 1-year survival rate of 58% (consistent with above 55% rate for chemo-embolization) and the median survival time was 14 months. The authors of this study did not find that this outcome was better than that obtained with systemic chemotherapy (the 5-FU plus leucovorin) for this type of disease.
In a German study (8) involving liver metastases from colorectal cancer, all patients were first treated by surgery to remove the tumors. Some patients then received hepatic artery infusion of mitomycin C and 5-FU. The strongest factor in determining outcome was the disease status at the initiation of therapy: there was a 5-year survival rate of 64% for those with no mesenteric lymph-node metastases, but only 29% for those with the metastases. There was no advantage found with the arterial chemotherapy. Overall, 5-year survival rates for the patients were on the order 25-31%.
Liver cancer has a poor prognosis with a low chance of survival past one year, whether the cancer is primary or secondary, when untreated or treated by simple systemic chemotherapy, or when treated by any means when the cancer is advanced (large tumor, significant impact on serum indicators of liver involvement, rapid metastasis). The best indicator of survival outcome is the initial condition of the cancer at the time of diagnosis, more so than the type of treatment applied. When the initial conditions are good (small tumor, little or no vascular invasion, liver condition good), certain therapies are effective, notably surgical resection. The best survival outcome reported in the literature involves cancer that is limited to the liver, with transplantation of the affected organ. However, liver transplantation is itself risky and involves long-term immunosuppressive chemotherapy; further, there are not enough livers available for transplant, requiring an extended wait until the surgery can be done. The next best treatment reported is removal of the tumor and affected part of the liver. If the surgery shows no cancer at the margins and no lymph node spread, then the prognosis is very good. Chemotherapy is reported to have varying effects and the search for a reliable chemotherapy regimen is being actively pursued. Chemo-embolization, an intensive localized chemotherapy method, is currently being used as a means of improving the prognosis. However, this intensive chemotherapy has severe side effects and the long-term survival rates remain low, with positive outcome mainly for those with the favorable prognostic factors at the time of diagnosis, including ability to remove small tumors by surgery.
Primary liver cancer is much more common in the Orient than in the West. This difference is now understood to be due to the much higher incidence of viral hepatitis infection in the Orient, as this infection leads to liver cirrhosis, a major contributor to primary liver cancer. Some areas within the Orient have especially high rates of liver cancer, with Shanghai, Canton, and Hong Kong being among the highest. In China, about 100,000 patients die each year of primary liver cancer; the World Health Organization estimates the worldwide total number of annual cases at 430,000 (15). By contrast, primary liver cancer is rare in the U.S., though its incidence is increasing as the result of spread (which occurred mainly during the past 30 years) of hepatitis B and C.
As explained in Experience in Treating Carcinomas with Traditional Chinese Medicine (10), traditional doctors have thought that liver cancer is mainly caused by "dietetic injuries, emotional disturbance, and accumulation of toxic materials and blood stasis, which lead to impairment of the liver and the spleen and stagnation of the liver qi." Other factors are "damp-heat, alcohol, emotional disturbance, water toxin, or malaria that adversely affect the liver and spleen." The tumor mass results from "prolonged stagnation of the liver qi, transforming into fire, which accumulates together with damp-heat. Stagnation of the liver qi will become more and more serious, the blood stasis more and more aggravated, and the lump larger and larger." The modern medical view is that repeated damage of the liver-with repair mechanisms brought into play-results in high levels of activation of the liver DNA, with increasing risk of transformation to neoplasm. Viral hepatitis and alcohol abuse are contributors to the liver damage; aflatoxin, a mold metabolite found in improperly stored foods, can also contribute to liver cancer.
Based on the traditional Chinese view, treatments are aimed at supporting the stomach/spleen function, regulating liver qi, dispersing stagnant blood, resolving toxin, and dissolving masses. Numerous formulas based on these principles of therapy have been suggested in the Chinese literature on treating cancer. An example is Gan Ai Tang (Liver Cancer Decoction) which is not a single formula but a basic approach to treatment. One version is: bupleurum, blue citrus, curcuma, corydalis, white peony, red peony, fu-shou, saussurea, eupolyphaga, leech, and pangolin scale. This decoction is to be taken with Rhubarb and Eupolyphaga Formula (Dahuang Zhechong Wan; a strong blood-vitalizing prescription containing several insect drugs) in pill form. Another version of Gan Ai Tang is produced from the above prescription by replacing red peony with zedoaria and sparganium, and adding the following herbs: lonicera, dandelion, zizyphus, tang-kuei, and atractylodes (also accompanied by Rhubarb and Eupolyphaga Formula).
Reliance on animal drugs, whether or not they are actually effective, is evident upon reviewing the herbal formulas recommended for treatment of liver cancer when traditional medicines are the sole or primary therapy. For example, cancer specialist Jia Kun (who developed the anti-cancer prescription Ping Xiao Dan) recommends a prescription that includes tortoise shell, turtle shell, oyster shell, earthworm, wasp nest, snake skin, and scorpion, along with just four plant-derived materials (18), as one of the formulas to accompany Ping Xiao Dan when treating liver cancer. In the book Illustrated Guide to Antineoplastic Chinese Herbal Medicine (19), five formulas from the Chinese medical literature are cited as treatments for primary liver cancer. These include one prescription that contains pangolin scale, oyster shell, and armadillidium (wood louse); another that contains the toxic insect mylabris; and another called the "Five Insect Pill," comprised of leech, tabanus (gadfly), eupolyphaga (beetle), gecko (lizard), and bufo (toad secretion). The term "chong," often translated as insect, as in the name of this formula, actually refers to small creatures. Two formulas without animal drugs are mainly comprised of high dosages (20-30 grams each) of "anti-cancer" herbs, such as scutellaria, oldenlandia, and lobelia (see Table 1). In Treating Cancer with Chinese Herbs (20), three prescriptions for liver cancer are described based on clinical work done in China; one contains pangolin scale, tortoise shell, and oyster shell; another contains tortoise shell and centipede; the third contains gallus (chicken gizzard lining).
An ancient concept that is still being relied upon in some of these formulations is that the animal drugs, especially insects, can deeply penetrate (because of their natural tendency to scurry about) into areas of swelling and obstruction and dissolve the accumulation. Advanced liver cancer is marked by hard swelling of the liver and ascites, which do not respond to most plant-based treatments; therefore, these animal agents are brought into play. Some of the materials, such as turtle shell, oyster shell, and gallus, are traditionally indicated for a wide range of swellings; others, such as centipede, scorpion, and mylabris (which are toxic), are selected for serious diseases.
In the book Anticancer Medicinal Herbs (32), the following is said about pangolin scales, which are frequently mentioned in prescriptions for liver cancer:
It is recorded in Records of Integrated Chinese and Western Medicine that: 'Pangolin scale, with a stinking smell which enables it to scurry actively through the whole human body, can activate the viscera, penetrate the channels and collaterals, reach joints and passages, and clear away blood stasis and stagnation. The drug can be used at will to treat furuncle and carbuncle with instant results. The drug is also effective in treating abdominal mass, paralysis, difficult urination and defecation, and abdominal pain.'
This section of the anticancer book includes a prescription for hepatocarcinoma that incorporates pangolin scale, oyster shell, and earthworm along with plant materials that vitalize blood circulation (i.e., persica, carthamus, curcuma, and moutan). According to specialists in the use of insect drugs, there are specific methods of applying them and cautions to observe (29):
Because the chong drugs are hard to dissolve in water, applying them in decoction form usually gives a poorer result; instead, clinical practice is usually based on baking them to dryness for preparing pills or making a powder to swallow directly. Since the chong drugs possess a strong penetrating and dispersing effect (just as they scurry about when alive), and some have drying, heating, and strong blood activating action, they should be administered carefully: it is better to start with small dosage and then increase by degrees, but never apply them in excessive dosage.
Liver cancer remains asymptomatic until it is relatively far advanced. Due to lack of diagnostic tools for detecting liver cancer in China, this disease was only diagnosed in the advanced stage (usually corresponding to the modern stage III and stage IV liver cancers). Symptom alleviation had become the primary outcome measure, and herbal formulas were recommended for and adjusted to the specific symptoms such as poor appetite, abdominal distention, pain, and fever. In 1973, a committee was formed to help coordinate research and treatment efforts for primary liver cancer. They found that the mean survival rate among 3,254 case reports available to them was 5.7 months (11). Mean (average) survival time is usually slightly longer than median survival time, because the figures may be skewed by a small number of long term survivors.
Earlier diagnosis of the disease, currently available in China only to a limited extent, has made it possible to attempt more comprehensive treatment, usually with Western medical intervention as the basis. Still, in a review article on integrated traditional Chinese and Western medicine for primary liver cancer (14), it was pointed out that advanced cases make up more than 90% of the total patients that come for treatment. A recent article on combined Western and Chinese therapies (27) pointed out that "90 percent of primary hepatocellular carcinoma patients were in the middle or advanced stage when they came for medical care. Because most of them missed the chance of surgical resection, and were insensitive [non-responsive] to systemic chemotherapy and radiotherapy, their prognosis usually was very bad and their survival period was, in general, 3 months." This survival duration is consistent with what has been reported when stage IV cancer patients were treated in China by herbal therapies prescribed on the basis of differential diagnosis (34). The median survival time was 2 months, mean survival time was 3.5 months, and the survival rate at 6 months was 11%.
Most Chinese clinical reports about treatment of primary liver cancer emphasize the value of surgical intervention for ultimate success in treating liver cancer. For example, one physician specializing in integrated traditional and Western medicine (28) wrote: "Generally, satisfactory results can be expected only for patients at the early stage treated by surgical intervention." Pan Mingji (11) describes some of the attempts to combine traditional Chinese herbs with surgery and other Western medical therapies. Among the suggestions for treatment:
Herbal prescriptions that are used when Western medical therapies are not applied are also suggested by Pan, based on syndrome differentiation according to traditional Chinese medical principles. The suggested formulas contain the following "anti-cancer" herbs: solanum, scutellaria, lobelia, oldenlandia. These herbs (see Table 1) are relatively non-toxic and can be used in substantial dosage (20-30 grams of each per day). Aside from these anti-cancer ingredients, the formulas are comprised of herbs that address the particular Chinese medical syndromes. As examples:
These suggestions are presented without accompanying evidence of efficacy.
Table 1: Anti-Cancer Herbs of Low Toxicity Used to Treat Primary Liver Cancer in China. The following materials are among those included in several Chinese herbal formulas used in the treatment of primary liver cancer. Their main functions are to "remove toxins, resolve swellings, and disperse accumulations of fluids or stagnant blood." The traditional actions mentioned in the table are quoted from Oriental Materia Medica (25). In contrast to toxic materials such as toad secretion and mylabris, these herbs are relatively non-toxic; some are listed in the Chinese texts as "slightly toxic" and others are considered toxic in the U.S. (based on the herb constituents) but not in China (based on clinical experience). When attempting to treat the tumor or its accompanying abdominal swelling (local liver swelling or ascites), these herbs are usually combined with others that regulate qi circulation (e.g., bupleurum, cyperus, saussurea, and various citrus materials) and that vitalize blood circulation (e.g., sparganium, zedoaria, tang-kuei, cnidium, salvia herb, pangolin scale, and eupolyphaga).
|
Common Name Pinyin |
Source Material |
Traditional Actions |
Dosage and Comments |
|
Armadillidium shufu |
Armadillidium vulgare |
disperses stagnant blood, promotes diuresis, removes toxin, controls pain |
3-6 grams; this is the wood louse, it is a rarely used item that is mentioned in several treatments for liver cancer |
|
Cremastra shancigu |
Cremastra variabilis; also from Pleione bulocodioides |
reduces heat, removes toxin, disperses accumulation, dissipates swelling |
up to 9-15 grams; listed as "slightly toxic" |
|
Lobelia banbianlian |
Lobelia chinensis |
promotes diuresis, removes swelling, removes toxin |
30-60 grams of fresh herb; 10-15 grams dried herb; used for ascites; not considered toxic in China but U.S. FDA lists lobelia as restricted due to toxicity of lobeline |
|
Oldenlandia baihuasheshecao |
Oldenlandia diffusa |
cleanses heat, removes stagnancy, removes toxin |
30-120 grams; usually along with scutellaria |
|
Paris zaoxiu |
Paris sp. |
dispels heat, removes toxin, resolves phlegm, disperses accumulated masses |
15-30 grams; listed as "slightly toxic" |
|
Scutellaria baizhilian |
Scutellaria barbata |
cleanses heat, removes toxin, disperses stagnancy, controls bleeding, controls pain |
15-30 grams; frequently combined with oldenlandia |
|
Solanum longkui |
Solanum nigrum; Solanum lyratum (shuyangquan) is also used |
dispels heat, removes toxin, promotes blood circulation, disperses swelling |
15-30 grams; not listed as toxic in China, but U.S. FDA restricts use of Solanum species (nightshades) due to content of solanine alkaloids |
A recent Chinese publication (12) compared treatment of primary liver cancer with radiation plus placebo or radiation plus Chinese herbal medicine. The herbal formula used was a modification of a traditional prescription for qi and blood stasis: Xuefu Zhuyu Tang. The traditional prescription includes the qi-regulating herbs bupleurum and chih-ko and the blood-vitalizing herbs persica, carthamus, tang-kuei, cnidium, red peony, and cyathula. According to the medical report, 1-, 3-, and 5-year survival rates improved by about 20% with the use of the Chinese herbs. The development of metastases outside the liver was not influenced by treatment. A 20% increase in survival rates is regarded as marginally significant (in terms of clinical outcomes as well as statistical significance) in the Western medical literature. Thus, for example, if a 1-year survival rate is 50% by radiation alone, the claimed benefit of adding Chinese herbs is a survival rate of 60%; similarly, a 5-year survival rate of 20% without herbs would improve to a survival rate of 24%. In addition to slight improvements in survival rate, this report indicates reduction of symptoms, with an improvement in quality of life.
In a review of treatment approaches to liver cancer (14), integrated radiation therapy plus Chinese herbs for middle-stage primary liver cancer was reported to yield 1-, 3-, and 5- year survival rates of 60%, 35%, and 25% respectively. Better rates were obtained when higher doses of radiation could be tolerated, which was the case for 70% of patients who also received Chinese herbs. In that circumstance, 1-, 3-, and 5-year survival rates increased to 100%, 68%, and 68% respectively. This is comparable to the results reported in Western clinics for hepatectomy and liver transplant, but the ability to tolerate high levels of radiation probably signifies a healthier patient at the initiation of treatment. It was suggested, by other liver cancer researchers mentioned in this review, that, as an accompaniment to radiation therapy, formulas comprised mainly of herbs that tonify spleen qi and regulate qi circulation (those that protect the body from damage) may produce a better result than formulas relying on herbs that vitalize blood and clear toxic heat (herbs used to treat the tumor mass). When advanced cases of liver cancer (with jaundice, ascites, and metastases) are treated by the combined method, there is some slight survival benefit reported compared to Western medical treatments alone. In one study, median survival for the group treated by combined therapy (24 patients) was 7.5 months, with 1-year survival at 21% and 3-year survival at 7%.
Administration of Chinese herbs was compared to use of standard chemotherapy in a study (17) of patients with primary liver cancer who were mainly in middle-stage liver cancer (classification: stage II and stage III). The patients had already undergone some standard medical therapies, but did not adequately respond. In the herbal treatment group (200 patients), syndrome differentiation pointed to about half the group being of the qi stagnation and blood stasis type, and the other half of the group belonging to the qi and yin deficiency type. The formula administered, called Qinglong Wan (Green Dragon Pill), was comprised of the qi and yin tonic herbs ginseng, astragalus, codonopsis, lycium fruit, adenophora, and atractylodes in a partial Rehmannia Six Formula base of rehmannia, moutan, and cornus, plus the blood-vitalizing herbs tang-kuei, salvia, pangolin scales, frankincense, myrrh, san-chi, and succinum (additionally, haematite and lonicera were included; proportions of the ingredients were not stated). The herbs were made (process not defined) into pills and taken 8 grams at a time with warm water, a half hour after meals, three times daily, for a total of 24 grams per day. The control group (70 patients) received chemotherapy (mitomycin C and adriamycin) through a hepatic artery catheter.
The authors of the study reported that the herb therapy helped alleviate several symptoms, including weariness, fever, pain, nausea, vomiting, and abdominal bloating. As a result, patients in the herb treatment group tended to consume more food (and maintain or even gain weight during the treament period) than those in the chemotherapy group. Further, the levels of hemoglobin (representing red blood cell levels), leukocytes, and platelets were better than in the control group. The study lasted two months and monitoring of patients was followed up for only a few months thereafter, so long-term survival data could not be reliably obtained. Early deaths occurred in about 7% of the herb group and 3% of the chemotherapy group, with mean survival time of about 100 days; the rest of the patients had a mean survival time of about 5 months at the end of follow-up (time of death after that was unrecorded). About 10% of patients in both the herb and control groups showed marked alleviation of symptoms. Most of the difference between the two groups, in terms of response to therapy, involved a larger proportion of patients being stabilized by the herbal treatment compared to a small proportion stabilized by the chemotherapy.
A similar approach was taken by physicians at the Hunan Tumor Hospital (31). They compared the use of Chinese herbs with chemotherapy or radiation therapy for patients admitted with stage II or stage III primary liver cancer. Their prescription included astragalus, codonopsis, atractylodes, hoelen, bupleurum, pangolin scales, persica, salvia, sappan, paris, oyster shell, armadillidium, prunella, and other unspecified herbs. The formula would be modified according to syndrome presentation, with herbs for either qi and blood stasis, liver/spleen disharmony, or yin deficiency syndrome. In all treatment groups, most patients still had short-term survival (under one year), but in the herb treatment group, 12% of the patients survived more than 2 years, compared to none in the chemotherapy and radiation groups. It is possible that selection criteria for the different treatments might have influenced the outcome, but the authors reported that administration of the herbs produced obvious effects in terms of patient symptoms.
In another study (13), patients who had intermediate or advanced liver cancer previously treated by surgery (but where it was found that the tumors could not be excised) were then provided with new therapies. One group (the control) was treated by routine chemotherapy, which, as noted before, has minor impact on survival. The mean survival time for the control group was 5.3 months, consistent with the Chinese report from 1983 of 5.7 months. The other group was treated with Chinese herbs. The formula administered was a modification of the traditional Bupleurum and Turtle Shell Combination (Chaihu Biejia Tang), that was modified to include a number of herbs considered beneficial for inhibiting cancer and reducing abdominal swelling: solanum, eupolyphaga, scutellaria, and alum. In addition, herbs to promote digestion (shen-chu, malt, gallus, cardamon, atractylodes) were included. According to the medical report, the use of the Chinese herbs resulted in a longer mean survival time of 10 months. In terms of symptom alleviation, the Chinese herbs were reported to be markedly effective in 38% of patients, and of some effect in 45% of cases, while 17% had no evident improvement.
An early trial (patients treated from 1966-1984) was based on using differential diagnosis and herbal treatment for patients undergoing chemotherapy or radiation therapy (techniques that were, at the time, not very effective) for intermediate and late-stage primary liver cancer (28). A number of traditional formulas were given including Danggui Liuhuang Tang for a fire syndrome, Xiangsha Liujunzi Tang for stagnation of fluids, Buzhong Yiqi Tang, Pingwei San, Sijunzi Tang, and other spleen-stomach formulas for weak qi and poor digestion, and Chaihu Shugan San for liver qi stagnation. The total number of patients was 50, but the number in each group was quite small, so comparisons were difficult to make. Nonetheless, the authors claimed that patients who had a spleen-deficiency type of syndrome responded best to the combined therapies and had an improved survival time, as compared to those with yin-deficiency syndrome or other patterns. It was suggested that the reason for this benefit was that the herbal treatment had immunoregulatory effects that had clinical significance for this group of patients.
A trial involving transcatheteral arterial chemotherapy and embolization (known as TACE) included administration of Chinese herbs (27). Unfortunately, the number of patients involved was small, making a detailed analysis difficult, and the patients generally had advanced cancer, meaning that chances of prolonged survival were already small. The control group also used Chinese herbs, but a less effective Western medical therapy (transcatheteral artery infusion of chemotherapy, but not embolization). The basic formula provided included qi tonics (astragalus, atractylodes, polygonatum), qi- and blood-regulating herbs (cyperus, corydalis, peony, red peony, zedoaria, pangolin scales, san-chi), anti-cancer herbs (scutellaria and hongcaozi, a toxic species of Polygonum), and digestive aids (crataegus and shen-chu). According to the authors, the impact of the Chinese herbs was to "remit the patients" symptoms, increase the body's immunity, decrease toxicity effects of radiotherapy and chemotherapy, improve the liver function, and, to a certain extent, stop the tumor growth and prolong the survival period." Average survival duration with TACE plus Chinese herbs was 13 months compared to about 9 months for the control treatment.
In some cases, liver cancer patients treated by chemotherapy or by Chinese herbs are described solely in retrospect (case reviews) rather than in a designed clinical trial in order to gain some understanding of the effects. In one such report (24), 45 patients treated with Chinese herbs and 20 patients treated with chemotherapy were depicted. The overall outcomes in terms or survival time were not very different. These patients that were the subject of study had all died, with median survival time of about 6 months and mean survival time of about 8 months (note: other patients had survived at the time of the analysis and were not included in the evaluation). The herbal formula given included cyperus, curcuma, akebia fruit, sparganium, zedoaria, turtle shell, scutellaria, and salvia herb, and was modified according to syndrome presentation (the two primary syndromes were liver-qi stagnation with spleen deficiency and liver-qi stagnation with blood stasis). One of the apparent benefits of the herbal therapies, which included administration of san-chi in cases of digestive tract hemorrhage, was a lower incidence of such hemorrhage contributing to the cause of death.
Many patients with advanced liver cancer have difficulty consuming both food and herbs. One of the approaches developed by Chinese physicians is to apply herbs topically in an effort to reduce cancer pain, alleviate some of the swelling, and, according to reports, improve the survival time.
As an example, a medicinal plaster containing the following herbs was developed for patients with liver cancer (21): cremastra, zedoaria, realgar, eupolyphaga, san-chi, rhubarb, toad venom, borax, euphorbia, borneol, and musk. Additional herbs might be added in response to specific symptoms. The individual herbs are finely powdered then combined and mixed with a sticky material to make a plaster. It is applied over the liver region or area of pain (about 25 x 15 cm area) in a layer about 0.5 cm thick on a non-toxic plastic membrane. The plaster is changed once per week. According to the authors of the report, the herbal plaster had these actions: improve blood circulation, dissipate blood stasis, and soften masses. They explained that: "Most of the medicinal materials for topical use are similar to those used orally. However, since it is necessary for topical drugs to be absorbed by the skin or mucous membrane, the action is necessarily slow and prolonged. The skin exposed to the drug should be as extensive as possible and some penetrating drugs need to be added. Musk, being an example with a pungent odor and bitter taste, has a good analgesic effect." They recommend the plasters for treating pain and swelling, as an adjunct to chemo- or radiotherapy.
Another example was described in a report of topical powder used for treating cancer pain (22). The patients treated had various kinds of cancers with primary liver cancer being the most prevalent type. The plaster was made with more than 20 ingredients, including fresh arisaema, raw aconite, liquidambar, pteropus, musk, borneol, paris, huangyaozi (a potentially toxic species of Dioscorea), phragmites, pangolin scale, and gleditsia spine. A paste was made by combining the fine herb powder with tea, which was then applied to the affected area with a thickness of at least 0.2 cm. The paste was covered with gauze which was affixed with adhesive tape and left in place for 6-8 hours; after about 12 hours without the plaster, another batch was applied. It was claimed that there was a high rate of good analgesic effect for patients who had become refractory to standard drug pain relievers.
In these two plasters, musk and borneol are included to induce penetration of the herbs and they provide some analgesic effect; toxic materials such as toad venom, realgar, fresh arisaema, and raw aconite are powerful agents that have analgesic and anti-cancer actions (they must be used very cautiously internally and are inappropriate for use in Western clinics). In the second formula, phragmites is added, it was said, in order to help reduce the toxicity of raw aconite and raw arisaema.
In a review of various herbal treatments for liver cancer pain (23), the section on external therapies included a dozen prescriptions that had been reported on in Chinese medical literature. Generally, they contained ingredients such as those described above, with emphasis on toad venom, aconite, realgar, raw arisaema, myrrh, frankincense, musk, and borneol. Several formulas contained the anti-cancer herb paris. As the reviewer of the treatments stated: "The severe pain seriously affects the quality of life, leading to disrupted internal homeostasis and immunologic functions, which, in turn, adversely affect prognosis of the patient. Better analgesic modalities are urgently needed." At the Sandong Provincial Hospital, it was reported that by applying Putuo Plaster (ingredients not specified) for patients with primary liver cancer, there was remarkable pain relief in 83% of the patients (35). The author of the study claimed that the patients experienced improved quality of life and could, as a result of the alleviation of pain, survive longer than those who did not receive the plaster.
In the West, morphine and morphine derivatives are the drugs of choice for severe pain. One of the problems that is then encountered is severe constipation and impairment of mental function. Therefore, if the analgesic drug dosage can be minimized by combination with topical herbal treament, it may be possible to better manage the case. In the Western clinic, a combination of selected ingredients mentioned in the above formulas, such as paris, myrrh, frankincense, and borneol, could be easily made from available materials and would be of very low toxicity. Still, without the toxic analgesics used by Chinese doctors, the effect of herbs on pain will be somewhat limited and the extent of pain relief to be expected should not be overestimated.
The constipating effect of high morphine dosage can be counteracted with Chinese herbs (30). A formula based on Major Rhubarb Combination (Da Chengqi Tang), with rhubarb (added to the decoction late in order to preserve the laxative action), magnolia bark, chih-shih, raw rehmannia, scrophularia, ophiopogon, pseudostellaria, raphanus, and mirabilitum (taken separately, dissolved in water), was reported effective for morphine-induced constipation if taken twice daily. The formula could be modified to treat various deficiency syndromes (e.g., add astragalus for qi deficiency, tang-kuei for blood deficiency, cistanche and cuscuta for yang deficiency). Among the patients treated were those with primary liver cancers and other types of cancer. It was reported that use of the decoction in high dosage (most of the herbs in amounts of 15-20 grams per day), could yield a lasting effect even though the opioids were continued but the herbs discontinued. If constipation recurred, then the herbs would be taken again.
Modern Chinese efforts of treating liver cancer with Chinese herbs is largely based on the "interventional" method, which often involves Western style approaches, but relies on Chinese herbs as substitutes for standard chemotherapeutic drugs (15). For example, bletilla powder, zedoaria oil, and brucea oil have been used (individually) for chemo-embolization therapy. These are injected into the hepatic artery. Other examples are: a combination of musk, borneol, and alum injected into liver tumors, which was reported to yield a 1-year survival rate better than a comparable chemotherapy group (but the trial size was small, with 11 patients receiving the herb therapy); injection of cinobufotalin (a toad secretion preparation) injected into the tumor in patients also given chemotherapy; and injection of zedoaria, frankincense, and myrrh extracts into the liver (which was said to produce less side effects than treatment by 5-FU). These treatment methods present many of the same risks as the embolization and perfusion techniques relying on Western drugs, and they are less well studied. Still, for the Chinese cancer specialists who face a very large number of cases of advanced primary liver cancer, the natural products provide a fertile ground for seeking out treatments with fewer side effects and equal or better results than the current chemotherapy methods.
One of the interventional treatments relying on a non-toxic herb is infusion of salvia extract into the hepatic artery (15, 16). This herb was chosen because patients with advanced liver cancer usually show several signs of blood stasis. According to authors of one study involving this method (16), salvia is able to prevent damage from hepatic autoimmunity, protect hepatic cells, and invigorate regeneration of damaged cells in patients who had failed to respond favorably to an initial treament by chemo-embolization (using Western drugs). It is possible that oral ingestion of salvia in high doses (20 grams per day is used orally in treatment of some other liver diseases, such as viral hepatitis) may confer some of the benefits claimed for the arterial injection method.
Another non-toxic method used as an adjunct therapy is injection of polysaccharide fractions from mushrooms (26). In a study of immune responses to the therapy, it was reported that: "Treatment [of primary liver cancer] by excision or embolization to reduce the tumor burden of patients is the prerequisite for restoring immune functions. The result of this study showed that the effect of MPI [mushroom polysaccharide injection] was more evident when applied to post-operations patients." The study, involving intramuscular injection of polysaccharides at 4 mg once daily for 60 days, resulted in a statistically significant improvement in CD4+ T-cells. Oral administration of polysaccharides usually involves 100 times the dosage (i.e., 400 mg daily) or more, in order to yield significant T-cell improvements. The higher oral dosage is required due to poor absorption of the very large polysaccharide molecules that are the most active fraction obtained from mushrooms. It was not established by the study of T-cell levels that longevity was improved by the treatment, but impaired immune functions can lead to lethal infections in cancer patients.
Similarly, a preparation made with earthworm as the main ingredient was reported to be "a non-toxic radiation sensitizer and chemotherapy enhancer," that could improve the outcome of liver cancer treatment (33). In a small study involving intra-arterial chemo-embolization therapy, patients that received capsules containing an earthworm preparation showed less bone-marrow suppression (measured by leukocyte and platelet counts), and had a more significant reduction in alpha-fetoprotein and CEA levels.
Chinese herbal therapies have been applied to treatment of liver cancer with and without Western medical treatment, but mostly in conjunction with Western medicine or used in a manner similar to that of Western medical drug treatments. Based on literature reports, for which the number of patients is relatively low and the reliability of the study has not been evaluated, the use of Chinese herbs in conjunction with Western therapies improves symptoms for many patients and increases mean survival time and survival rates. In the Chinese health care system, neither herbs nor Western medical therapies (alone or in conjunction) have a substantial effect on survival for advanced liver cancer, but the herbal therapies are reported to reduce pain and other symptoms.
Orally administered herbal therapies for liver cancer (as primary therapy or adjunct to Western medicine) include qi tonics, "anti-cancer" herbs of low toxicity, and a large selection of herbs that regulate qi circulation, vitalize blood, nourish yin, and promote digestive functions. Topically administered herbs generally include toxic analgesics and aromatic resins. Animal drugs are prevalent in both internal and external therapies, with particular emphasis on shells, scales, and skins of various animals, and whole insects, worms, and lizards. Injection of herbs for chemo-embolization therapy is one of the current areas of active research in China.
For the Western clinic, Chinese herb therapies as an adjunct to standard medical therapies appears to be a promising route towards making limited improvements in prognosis and for making significant improvements in the overall symptom picture (e.g., reducing nausea, improving appetite, inhibiting gastro-intestinal hemorrhage, alleviating pain). As a result of progress in modern medical treatments, slight enhancements in outcome attained by incorporating Chinese herbs may lead to significantly improved long-term survival rates and cure rates (5-10 years of cancer-free survival). Therefore, the Chinese method of therapy is of potential value beyond the limited effects attained in Chinese studies that involved advanced liver cancer treated with Western medical methods that were less-effective than those available now.
December 1999