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Antioxidants & Chemotherapy for Advanced Prostate Cancer: The Latest Research on Specific Interactions

PSFJA — Thu, 21 Jun 2007 20:00:51 +0000

INTRODUCTION
It has been commonly assumed that all chemotherapy drugs are incompatible with all antioxidants, but there is a growing body of evidence that suggests this might not always be the case (Lamson and Brignall 1999).

While some antioxidants are clearly not beneficial and can even decrease effectiveness of some chemotherapeutic treatments for certain cancers, there are many other antioxidants that do not interfere and may even enhance specific chemotherapy drugs, while also decreasing their side effects.

For this article, we investigated treatments for advanced metastatic prostate cancer, for which there are a limited number of chemotherapy treatments available. Although we focus on metastatic disease, some of the antioxidants discussed in this article are relevant for men with localized prostate cancer as well as for those who are at high risk for developing prostate cancer.

PROSTATE CANCER AND ITS TREATMENT
Prostate cancer is the second most common cancer in men after skin cancer. The most common form of prostate cancer occurs in men age 65 or older, and is often a slow growing, localized disease limited to the prostate gland. For this type of prostate cancer, there are a variety of treatments, including “watchful waiting,” radiation (including seeds), cryotherapy, surgery, High Intensity Focused Ultrasound (HIFU), hormone suppressing drugs (Androgen Deprivation Therapy), as well as other novel treatments. (See Glossary at the end of this article for brief descriptions of these terms.)

If cancer of the prostate gland goes untreated or undiagnosed, it can begin to metastasize, either slowly over many years or, in some cases, very rapidly. When prostate cancer metastasizes, it can spread locally to the pelvic bones, bladder, and other nearby organs. Advanced metastatic prostate cancer commonly progresses to distant sites in the bones but can also spread to other organs.

The first line of treatment for metastatic prostate cancer is usually hormone suppression therapy. This is called Androgen Deprivation Therapy (ADT) and includes drugs such as leuprolide (Lupron), goserelin (Zoladex), flutamide (Eulexin), bicalutamide (Casodex), nilutamide (Nilandron), or cyproterone (Androcur, Cyprostat). Secondary hormone therapy may be used if and when the first treatment does not work. This would include a combination of the same drugs listed above and may include others as well.

When Androgen Deprivation Therapy stops working, patients move on to chemotherapy, starting with drugs such as paclitaxel (Taxol), docetaxel (Taxotere), or mitoxantrone (Novantrone). Off-label or clinical trial chemotherapy drugs are sometimes added, such as carboplatin (Paraplatin), cisplatin (Platinol), satraplatin, epothilone, or doxorubicin (Adriamycin). Research has shown that chemotherapy has limited potential for controlling progression of metastatic prostate cancer, leading to the addition of newer therapies (in combination with chemotherapy or not) and clinical trials.

Some of the newer therapies, which can be considered, include: anti-angiogenesis drugs, such as bevacizumab (Avastin) or sunitinib (Sutent), which stop new blood vessels from growing; immune therapy, which stimulates the immune system to fight cancer; and gene therapy, which uses genetic material in the treatment of disease, including GVAX, ipilimumab (MDX -010), Granulocyte-Macrophage Colony-Stimulating Factor (GMCSF), and sipuleucel-T (Provenge).

RESEARCH ON HOW ANTIOXIDANTS AND CANCER THERAPIES WORK TOGETHER
As new approaches to treating advanced prostate cancer in conjunction with chemotherapy are being developed, it becomes more and more useful to explore approaches that involve increasing the effectiveness of chemotherapy while decreasing its side effects. There are antioxidants that, when properly combined with chemotherapy, have been shown to produce this effect. Although it is not commonly known, these combinations have been investigated as early as the 1980’s (Lamson and Brignall 1999) and one published scientific review reported on the results of over 180 studies specifically investigating antioxidant/chemotherapy and antioxidant/radiation combinations (Lamson and Brignall 1999).

The following are brief summaries of more recently published evidence on the combination of antioxidants and chemotherapy specifically for advanced metastatic prostate cancer:

CURCUMIN
Curcumin is an active component of the Indian curry spice turmeric. Curcumin is known for its antitumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

Curcumin & Chemotherapy
Curcumin appears to block a protein that plays a role in the resistance to the chemotherapy drug mitoxantrone. It therefore may be compatible with mitoxantrone (Chearwae, Shukla et al. 2006). However, curcumin appears to block a pathway by which taxol based drugs (taxanes) cause tumor suppression and therefore should not be taken in combination with taxanes (Wang and Wieder 2004).

MELATONIN
Melatonin is a hormone released from the pineal gland and helps to improve quality of sleep. It is also known to reduce metastasis in cancer patients.

Melatonin & Chemotherapy
Melatonin’s antioxidant activity appears to counteract toxicity of common chemotherapy treatments for advanced prostate cancer, including cisplatin, mitoxantrone, and paclitaxel. Melatonin significantly reduces the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis, and asthenia related to chemotherapy. Additionally, melatonin promotes cancer cell death when combined with the same therapies (Lissoni, Barni et al. 1999). In a human clinical trial, melatonin at a dosage of 20mg combined with intra-muscular hormone therapy triptorelin (Trelstar, Depot, Trelstar LA) decreased levels of prostate specific antigen (PSA) and growth factors for metastatic prostate cancer (Lissoni, Cazzaniga et al. 1997).

GENISTEIN
Genistein is a soy extract that may help cancer prevention. It also inhibits proliferation of invasive prostate cancer.

Genistein & Chemotherapy
Genistein significantly improves the antitumor activity of docetaxel, doxorubicin, and cisplatin through several different mechanisms. Genistein, when used alone, also has anticancer activity without toxicity (Li, Ahmed et al. 2005; Li, Kucuk et al. 2006).

EPIGALLOCATECHIN-GALLATE (EGCG)
Epigallocatechin-gallate (EGCG) is one of the components of green tea extract, which is made from the dried leaves of an Asian evergreen shrub. EGCG is 25 to 100 times more potent an antioxidant than vitamin C. Research studies have found that in men who are at high risk for prostate cancer, EGCG reduces the incidence of those men developing the disease.

EGCG & Chemotherapy
An in vitro study found that when EGCG is used in combination with paclitaxel, hormone refractory prostate cancer cells developed resistance to treatment sooner than either paclitaxel or EGCG alone (Axanova, Morre et al. 2005).

CAPSAICIN
Capsaicin is a chili pepper extract, often topically used to reduce pain and inflammation. It is also used for anticancer treatment.

Capsaicin & Chemotherapy
An in vitro study showed that when capsaicin is used in combination with paclitaxel, hormone refractory prostate cancer cells developed resistance to treatment. When used in combination with cisplatin, it reduces the effectiveness of the cisplatin (Axanova, Morre et al. 2005).

CAPSIBIOL-T
Capsibiol-T is a combination of EGCG and capsaicin.

Capsibiol-T & Chemotherapy
In vitro studies show that when hormone refractory prostate cancer cells are pretreated with Capsibiol-T and then treated with paclitaxel, the combination has an additive effect in decreasing survival of cancer cells (Axanova, Morre et al. 2005).

VITAMIN D3
Vitamin D3 is metabolized into calcitriol. In one trial, researchers used a formulation of calcitriol called DN 101 that does not have as many problems with toxicity as vitamin D3 when used at high doses. High doses of calcitriol alone appear to inhibit hormone refractory metastatic prostate cancer cell growth and stimulate cancer cell death, as well as inhibit the invasiveness of prostate cancer cells (Schwartz, Wang et al. 1997). It has also been shown to increase differentiation of prostate cancer cells (Esquenet, Swinnen et al. 1996; Bauer, Thompson et al. 2003).

Vitamin D3 & Chemotherapy
In combination with docetaxel, vitamin D3 has an additive effect. In a recent study, docetaxel used with a specific formulation of calcitriol (DN 101) increased survival rate in hormone refractory metastatic prostate cancer patients (Beer, Ryan et al. 2007).

VITAMIN A
Vitamin A is an essential nutrient for humans and has many diverse functions in maintaining normal health. It has various different metabolites that are similar in structure and, with a few changes, can become vitamin A with the help of enzymes in the body.

Vitamin A & Chemotherapy
Retinoic Acid (an acidified form of vitamin A) has a synergistic effect in combination with docetaxel through two known
mechanisms therefore increasing docetaxel’s ability to stop tumor growth (Sun, Li et al. 2004).

13-cis-retinoic acid (a vitamin A derivative) has been shown in in-vitro trials in combination with paclitaxel to have a synergistic effect in inhibiting the growth of prostate cancer cell lines (it enhances the effectiveness of paclitaxel in attacking cancer cells). However, in combination with carboplatin, it has an antagonistic effect (it diminishes effectiveness of carboplatin) (Cabrespine, Bay et al. 2005).

All-trans retinoic acid (a vitamin A derivative) helps Taxol-based drugs (taxanes) to increase cancer cell death (Wang and Wieder 2004).

SILIBININ
Silibinin is an extract from milk thistle seed that is known for its ability to protect the liver.

Silibinin & Chemotherapy
Silibinin and platinum-based compounds (cisplatin, carboplatin, satraplatin), when used together, have a substantially higher ability to inhibit prostate cancer cell growth and cause prostate cancer cell death, when compared with platinum-based compounds alone (Dhanalakshmi, Agarwal et al. 2003).

BETA-GLUCAN
Beta-glucans are natural soluble fiber polysaccharides found in the bran of cereal grains such as barley, oats, rye, and wheat. Beta-glucans can also be extracted from maitake mushrooms, as in the following study.

Maitake Beta-glucan & Chemotherapy
In combination with carmustine (BCNU), maitake beta-glucan enhances effectiveness of chemotherapy, with a 90% cancer cell viability reduction (Finkelstein, Aynehchi et al. 2002).

WHAT IF THERE IS INSUFFICIENT EVIDENCE FOR INTERACTIONS BETWEEN SPECIFIC CHEMOTHERAPY DRUGS AND SPECIFIC ANTIOXIDANTS?
When it is uncertain whether a specific antioxidant and chemotherapy drug treatment combination would conflict, then the possibility of combining them largely depends on the timing of their use. It is important to know that most water-soluble antioxidants usually stay in the blood for one day or less while oil-soluble antioxidants can stay in the blood for up to several days. This information, in combination with the known half-life of chemotherapy drugs (which is generally 72 hours or less), can allow patients and health care providers, working together in a process of shared decision-making, to make an informed decision on whether or not to combine certain antioxidants within the same treatment protocol. If a decision is made to use antioxidants intermittently, some healthcare providers will choose to separate their use by at least three days to allow time for chemotherapy drugs to complete their intended purpose before being metabolized.

CONCLUSION
Although this article only briefly touches on the possibility of combining some antioxidants with chemotherapy as an effective way for treating cancer, our hope is that it encourages both patients and health care providers to more seriously consider the importance of these various combinations. One must, of course, be judicial in determining which combinations are safe, but when the cancer research community is constantly looking for ways to make cancer treatments more effective and to help people live longer, antioxidant-chemotherapy combinations are worthy of further study and deeper understanding.

Special thanks to Johanna Altgelt and Jeremy Paster for their significant contributions to this article.

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GLOSSARY OF TERMS

Androgen Deprivation Therapy: Medications that work Bevacizumab (Avastin): A synthetic antibody often used Bicalutamide (Casodex): A drug used in combination with Carboplatin (Paraplatin): A platinum-containing anticancer Chemotherapy: The use of chemical agents in the treatment Cisplatin (Platinol): A platinum-containing anticancer Cryotherapy: The therapeutic use of cold, such Cyproterone: A synthetic steroid used in the form of Docetaxel (Taxotere): A semisynthetic antineoplastic Doxorubicin (Adriamycin): An anthracycline antibiotic Epothilone (Ixabepilone): A new type of drug with the Excretion: The act or process of separating or eliminating Flutamide: A nonsteroidal antiandrogen that is used Goserelin (Zoladex): A drug that is similar to luteinizing Granulocyte-Macrophage Colony-Stimulating Factor GVA X: An immunotherapy for prostate cancer, made from Half-life: The time required for half the amount of High Intensity Focused Ultrasound (HIFU): The therapeutic Interaction: The effect of one drug, food, or vitamin Leuprolide (Lupron): A synthetic analog of gonadotropin-releasing Metabolism: The sum of the processes by which a particular Metastatic: Having to do with the transfer of cancer Mitoxantrone: An antineoplastic drug that is used in Nilutamide (Nilandron): A drug used in combination with Provenge: A new vaccine currently in clinical trials Radiation: Energy radiated in the form of waves or particles Sunitinib (Sutent): A newly developed drug, which works Taxanes: A group of drugs that includes paclitaxel (Taxol) Watchful Waiting: An approach by which patients are by decreasing the amount of testosterone.
along with chemotherapy, first developed to treat colon and rectal cancer that has spread to other parts of the body. It works by blocking a protein called vascular endothelial growth factor (VEGF), which decreases the blood supply to the tumor.
hormone treatment to treat prostate cancer that has spread to other areas of the body. It works by blocking the action of testosterone in the prostate.
drug that is an analog of cisplatin with somewhat reduced toxicity and that is used in the treatment of various cancers.
or control of disease, especially cancer.
drug that functions by producing cross links in DNA between and within strands.
as in cryosurgery.
its acetate to inhibit androgenic secretions (as testosterone).
drug derived from the needles of the yew tree.
with broad antineoplastic activity that is obtained from a bacterium of the genus Streptomyces (S. peucetius) and is administered in the form of its hydrochloride.
same mechanism as the taxanes, which may have greater potency than paclitaxel, have activity in tumors that are resistant to paclitaxel, can stay in cancer cells longer, and can be useful in people who have already had several different types of aggressive therapies.
substances from the body.
in the treatment of prostate cancer.
hormone releasing hormone (LHRH), which is made by the body. It decreases the hormone testosterone, which can help slow or stop the growth of prostate cancer cells.
(GM-CSF): A hormone essential in augmenting the body’s immune response to vaccines.
two genetically-modified prostate cancer cell lines, currently in clinical trials for advanced-stage prostate cancer.
a substance (as a drug or radioactive tracer) in or introduced into a living system or ecosystem to be eliminated or disintegrated by natural processes.
use of ultrasound that is much more powerful and focused than ordinary diagnostic ultrasound.
on the effectiveness or metabolism of another drug. This can be synergistic, in which the effect of the drug is increased, or antagonistic, in which the effect of the drug is decreased or blocked.
hormone used to treat cancer of the prostate gland. It works by reducing the amount of testosterone that the body makes. This can help slow or stop the growth of prostate cancer cells and helps relieve symptoms like painful or difficult urination.
substance is handled (as by assimilation and incorporation or by detoxification and excretion) in the living body.
from one part of the body to another..
the form of its dihydrochloride either alone or in combination in the treatment of some leukemias and carcinomas.
surgery or other medications to treat prostate cancer. Testosterone, a natural hormone in men, stimulates the growth of prostate cancer cells. Nilutamide is an anti-androgen that works by blocking the effects of testosterone.
for advanced stage prostate cancer.
used, for example, in medicine to stop the growth of cancer cells.
by decreasing the blood supply to tumor cells.
and docetaxel (Taxotere), which are used in the treatment of cancer. Taxanes have a unique way of preventing the growth of cancer cells: they affect cell structures called microtubules, which play an important role in cell functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Taxanes stop the microtubules from breaking down; cancer cells become so clogged with microtubules that they cannot grow and divide.
given no immediate treatment until the tumor shows signs of progressing, often offered to men diagnosed with early stage prostate cancer. Less often recommended following recent publication of a study showing better 10-year survival rates in men who received either surgery or radiation therapy, compared to those who elected for watchful waiting approach. (Tewari, A., G. Divine, et al. 2007)

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REFERENCES

1. Axanova, L., D. J. Morre, et al. (2005). “Growth of LNC aP cells in monoculture and coculture with osteoblasts and response to tNO X inhibitors.” Cancer Lett 225(1): 35-40.
2. Bauer, J. A., T. A. Thompson, et al. (2003). “Growth inhibition and differentiation in human prostate carcinoma cells induced by the vitamin D analog 1alpha,24-dihydroxyvitamin D2.” Prostate 55(3): 159-67.
3. Beer, T. M., C. W. Ryan, et al. (2007). “Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCEN T Investigators.” J Clin Oncol 25(6): 669-74.
4. Cabrespine, A., J. O. Bay, et al. (2005). “In vitro assessment of cytotoxic agent combinations for hormone-refractory prostate cancer treatment.” Anticancer Drugs 16(4): 417-22.
5. Chearwae, W., S. Shukla, et al. (2006). “Modulation of the function of the multidrug resistancelinked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin.” Mol Cancer Ther 5(8): 1995-2006.
6. Dhanalakshmi, S., P. Agarwal, et al. (2003). “Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death.” Int J Cancer 106(5): 699-705.
7. Esquenet, M., J. V. Swinnen, et al. (1996). “Control of LNC aP proliferation and differentiation: actions and interactions of androgens, 1alpha,25-dihydroxycholecalciferol, all-trans retinoic acid, 9-cis retinoic acid, and phenylacetate.” Prostate 28(3): 182-94.
8. Finkelstein, M. P., S. Aynehchi, et al. (2002). “Chemosensitization of carmustine with maitake beta-glucan on androgen-independent prostatic cancer cells: involvement of glyoxalase I.” J Altern Complement Med 8(5): 573-80.
9. Lamson, D. W. and M. S. Brignall (1999). “Antioxidants in cancer therapy; their actions and interactions with oncologic therapies.” Alternative Medicine Review 4(5): 304-329.
10. Li, Y., F. Ahmed, et al. (2005). “Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells.” Cancer Res 65(15): 6934-42.
11. Li, Y., O. Kucuk, et al. (2006). “Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RAN K)/RAN K ligand/MMP-9 signaling in prostate cancer.” Cancer Res 66(9): 4816-25.
12. Lissoni, P., S. Barni, et al. (1999). “Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status.” Eur J Cancer 35(12): 1688-92.
13. Lissoni, P., M. Cazzaniga, et al. (1997). “Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone.” Eur Urol 31(2): 178-81.
14. Tewari, A., G. Divine, et al. (2007). “Long-term survival in men with high grade prostate cancer: a comparison between conservative treatment, radiation therapy and radical prostatectomy: a propensity scoring approach.” J Urol 177(3): 911-5.
15. Schwartz, G. G., M. H. Wang, et al. (1997). “1 alpha,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells.” Cancer Epidemiol Biomarkers Prev 6(9): 727-32.
16. Sun, M., H. Li, et al. (2004). “[The synergistic effects of docetaxol and retinoic acid on prostate cancer cell line PC-3].” Sichuan Da Xue Xue Bao Yi Xue Ban 35(6): 797-801.
17. Wang, Q. and R. Wieder (2004). “All-trans retinoic acid potentiates Taxotere-induced cell death mediated by Jun N-terminal kinase in breast cancer cells.” Oncogene 23(2): 426-33.

Chinese Herbal Medicine and Chemotherapy in the Treatment of Hepatocellular Carcinoma: A Meta-analysis of Randomized Controlled Trials

Pine Street Foundation — Fri, 01 Apr 2005 16:28:17 +0000

By Xiaojuan Shu, MPH (candidate), Michael McCulloch, LAc, MPH, Hang Xiao, MPH, PhD, Michael Broffman, LAc, and Jin Gao, MD, PhD

Click here to download this study (including tables) in PDF format.

BACKGROUND
Hepatocellular carcinoma (HCC), one of the most common malignancies worldwide, is highly resistant to standard therapy. It is unclear whether chemotherapy, arte- rial embolization, or arterial chemoembolization improve survival advantage enough to justify their high toxicity. Treatment with Chinese herbal medicine has been explored, combining herbs that stimulate host immune response with those that have cytotoxic activity against HCC cells. The au- thors sought to evaluate the effectiveness of Chinese herbal medicine combined with chemotherapy. The hypothesis was that Chinese herbal medicine added to chemotherapy for the treatment of HCC would improve survival and tumor re- sponse, when compared to treatment with chemotherapy alone. Methods: The authors searched the databases TCMLARS, PubMed, and EMBASE as well as the bibliogra- phies of studies identified in the systematic search for po- tentially relevant titles or abstracts of studies in any language. They retained those that (1) treated only HCC pa- tients, (2) were described as randomized or reported that there was no statistical difference between treatment groups, (3) gave patients either Chinese herbal medicine therapy combined with chemotherapy in the treatment group or chemotherapy alone in the control group, and (4) provided data on the number of enrolled subjects and re- sponders and nonresponders for tumor response and sur- vival. The authors used random effects meta-analysis to combine data. Results: Twenty-six studies representing 2079 patients met the inclusion criteria. Chinese herbal medicine combined with chemotherapy, compared to chemotherapy alone, improved survival at 12 months (relative risk [RR], 1.55; 95% confidence interval [CI], 1.39-1.72; P < .000), 24 months (RR, 2.15; 95% CI, 1.75-2.64; P < .000), and 36 months (RR, 2.76; 95% CI, 1.95-3.91; P < .000). Tumor re- sponse increased (RR, 1.39; 95% CI, 1.24-1.56; P < .000). Conclusions: These findings provide promising evidence that combining Chinese herbal medicine with chemotherapy may benefit patients with HCC. Because of the low quality of these studies, these findings should be confirmed through conducting high-quality, rigorously controlled trials.

INTRODUCTION
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer worldwide, with increasing incidence.1 The incidence ranges from 1 to 4 cases per 100 000 population in Western Europe and North America to 50 to 150 cases per 100 000 population in parts of Asia and Africa, where HCC is responsible for a large pro- portion of cancer deaths.2 Its treatment remains a con- troversial issue, despite the progress that has been made during the past decades, as most HCC patients are diagnosed at late stages and receive only palliative treatments not intended to extend survival.1 Untreated patients with advanced disease have a 1- year survival rate of 29%, a 2-year survival rate of 16%, and a 3-year survival rate of 8%.3

Arterial embolization, chemoembolization, and arterial chemotherapy are the major procedures in chemotherapy. Arterial embolization or chemoemboli- zation is a technique combining intra-arterial chemo- therapy and selective ischemia and was developed as an alternative to conventional systemic or intra-arterial chemotherapy. It is intended to induce tumor necrosis through administration of chemotherapy and an embolizing agent directly into the tumor by way of the feeding artery. The cytotoxic effect of arterial occlu- sion can be potentiated by labeling the infusion with radioactive isotopes or by adding cytotoxic drugs. Arterial embolization or chemoembolization includes procedures such as transcatheter arterial chemo- embolization, transarterial embolization, hepatic arterial chemoembolization, and hepatic arterial embolization. Arterial chemotherapy is not aimed to achieve arterial occlusion. It includes procedures such as transarterial infusion, hepatic arterial infusion, and intravenous chemotherapy. However, these proce- dures are associated with their own potentially life- threatening toxicities and complications, such as severe postembolization syndrome, hepatic insuffi- ciency, abscess, or infarction.4 In addition, they have shown only slightly improved survival or no survival advantages in previous studies.5-7 Meta-analysis of randomized controlled trials of treatment with chemoembolization or embolization has shown only a modest advantage in 2-year survival for patients with unresectable HCC, compared with conservative man- agement.8 The same meta-analysis revealed that tamoxifen provided no advantage in 1-year survival.8 Since the prognosis with existing therapy is so poor, we sought to evaluate the clinical evidence for effective- ness of Chinese herbal medicine in combination with systemic chemotherapy for the treatment of HCC.

In China, herbal medicine is frequently combined with chemotherapy in the treatment of liver cancer, usually in formulas that combine various Chinese herbs into one treatment strategy. In this meta-analysis, we sought to assess the effectiveness of this therapy for HCC by analyzing data from studies that compared treatment with Chinese herbal medicine combined with chemotherapy to treatment with chemotherapy alone.

METHODS

Systematic Search
Retrieval of studies in all languages was performed through systematic searching of the databases TCMLARS (1984-August 2004; www.cintcm.com), PubMed (1966-August 2004; www.pubmed.gov), and EMBASE (1974-August 2004; www.embase.com) using the keywords liver cancer, chemotherapy, Chinese medicine, and randomized controlled trials. We also searched the bibliographies of review papers and published ran- domized controlled trials identified in our systematic search.

Criteria for Inclusion
To be included in this meta-analysis, a study had to ful- fill the following criteria: (1) only patients with HCC were included, (2) studies were described as random- ized or had the design elements of quasi-randomized studies (studies did not mention adoption of random- ization but reported there was no statistical difference between 2 groups), (3) HCC patients were given ei- ther Chinese herbal medicine therapy in combination with chemotherapy in the treatment group or chemo- therapy alone in the control group, and (4) authors provided necessary data on the number of responders and nonresponders for the end points of tumor re- sponse and survival sufficient to calculate relative risks (RRs) and 95% confidence intervals (CIs).

Criteria for Exclusion
Randomized controlled trials were excluded if they (1) were not described as randomized or quasi- randomized, (2) did not provide information con- cerning survival or tumor response, (3) included patients with cholangiocellular carcinomas or liver metastases of primary cancers other than liver, (4) did not contain an experimental arm treated with Chinese medicine combined with chemotherapy and control arm treated with chemotherapy alone, or (5) were du- plicate publications of other studies previously identi- fied in our systematic search. Decisions on whether to include or exclude trials and how to group studies for analysis by end points reported were made before conducting the meta-analysis.

Criteria for Combinability
Since there is no successful standard treatment for HCC, there are few published trials using exactly the same chemotherapy treatments and same Chinese herbal formula. As has been done in previous meta- analyses of chemotherapy for HCC, we combined studies in which patients in the treatment group were treated with the new therapy being evaluated and those in the control group were treated with standard chemotherapy alone.7-9 We also sought to separately meta-analyze any subgroups of studies that all used the same herbal combination.

Data Collection and Abstraction
Two reviewers (X.S. and M.M.) independently re- viewed the retained studies. Since prior work has shown that blinding during study selection and data extraction does not result in either a clinically or a sta- tistically significant effect on the summary effect mea- sure of a meta-analysis,10 we chose a nonblinded design for data extraction.

Analysis of Outcomes
The primary outcome of interest was the proportion of patients surviving at 6, 12, 24, and 36 months. The secondary outcome of interest was tumor response.

Survival. We calculated survival using the propor- tion of subjects surviving among the total number of subjects, separately for each treatment group. The ratio for improvement in survival at each time point was calculated as the proportion of subjects alive in the Chinese herbal medicine combined with chemother- apy group divided by the proportion of subjects alive in the chemotherapy-only group.

Objective tumor response. We selected studies that reported tumor response using the World Health Organization scale.11 Following a method used in a previous meta-analysis of studies treating HCC patients with chemotherapy,12 we calculated tumor response as any response (complete response plus partial response) divided by the total (complete response plus partial response plus no change plus progressive disease), separately for each treatment group. The RR of tumor response was calculated as the probability of any tumor response in the herbal medicine combined with chemotherapy group divided by the probability of any tumor response in the chemotherapy-only group.

Pooled analysis. We used the Stata statistical software package (version 8.0; Stata Corp, College Station, Tex) for data management and analysis. All analyses were performed on an intention-to-treat basis. We used the random effects method to calculate pooled treatment effects.13 An RR value greater than 1.0 was considered to be consistent with a beneficial effect of Chinese herbal medicine combined with chemother- apy (vs chemotherapy alone) in the treatment of patients with HCC.

Qualitative Analysis

Study quality. To evaluate study quality, we used the Jadad scale, a validated 5-point scale developed to eval- uate the quality of reporting in studies included in a meta-analysis.14,15 The scale assigns a score of 0 or 1 for each of the following quality criteria, whether (1) the study was described as randomized, (2) the authors reported the method of randomization, (3) the use of blinding was reported, (4) the method for conceal- ment of allocation was reported, and (5) authors accounted for withdrawals and dropouts. Thus, a highest-quality study would receive a score of 5 and a lowest-quality study a score of 0.

RESULTS

Selection of Trials
After an initial screening of titles and abstracts, 385 potentially relevant clinical trials of HCC were identified. We then performed a second screening of these 385 studies and retained 126 published full papers, which were randomized controlled trials assessing Chinese herbal medicine in the treatment of HCC. After fur- ther evaluation, we excluded 9 studies because of nonrandomization, 13 studies because they lacked rel- evant end points, 24 studies because other cancers were included, 51 studies because they were missing either a qualified experimental group or controlled group, and 3 studies because they were duplicate pub- lications of other studies previously identified in our systematic search. This yielded a total of 24 random- ized controlled trials and 2 quasi–randomized con- trolled trials, which were identified as meeting protocol-specified inclusion criteria, totaling 2079 patients (Tables 1 and 2).

Treatment Effectiveness
Chemotherapy combined with Chinese herbal medi- cine, compared with chemotherapy alone, signifi- cantly improved survival at 12 months (RR, 1.55; 95% CI, 1.39-1.72; P < .000; Figure 1), 24 months (RR, 2.15; 95% CI, 1.75-2.64; P < .000; Figure 2), and 36 months (RR, 2.76; 95% CI, 1.95-3.91; P < .000; Figure 3). Tu- mor response was also significantly improved (RR, 1.39; 95% CI, 1.24-1.56; P < .000; Figure 4). There were no reliable data indicating significant survival improve- ment at 6 months since there was significant between- study heterogeneity (Table 3; figure not shown).

We identified 2 studies that used the exact same herbal formula (Hua Chan Su) and conducted a sepa- rate meta-analysis.16,17 The result also showed survival benefits of Hua Chan Su at 12 months (RR, 1.67; 95% CI, 1.38-2.02; P < .000; Table 3; figure not shown). It should be noted that Hua Chan Su contains bufotoxin, a digoxin-like substance that must be pro- vided in carefully measured dosages to avoid cardiac glycoside toxicity.

A Chinese-English translation table is provided as an appendix, which identifies the original names of herbal formulas as identified in included studies and the names as translated into English.

CONCLUSIONS
Our meta-analysis data suggest promising evidence that Chinese herbal medicine in the treatment of HCC may have potential therapeutic value. Herbal medicine combined with chemotherapy for the treat- ment of HCC can improve survival at 12, 24, and 36 months when compared with chemotherapy alone. There is additional evidence that 6-month survival may also be improved; however, this finding is limited by the presence of between-study heterogeneity. Tu- mor response was also improved by the addition of Chinese herbal medicine to chemotherapy.

In a separate meta-analysis of the only 2 studies using the exact same herbal medicine, Hua Chan Su, we found that 12-month survival was also increased.16,17

Limitations

Publication bias. We found evidence for publication bias in the data for meta-analysis of survival at 6 and 12 months for all herbal formulas combined. We also found evidence for publication bias in the data for meta-analysis of tumor response.

Research techniques used in Chinese studies. Because the studies we found were of generally poor quality, we are unable to make definite conclusions from our data. Published studies from China were found to be more highly condensed than typical articles published in the Western literature, with key details of study design omitted, especially details concerning blinding of subjects and clinicians. In addition, since most stud- ies did not describe subject withdrawals or dropouts, it is not possible to adjust the analysis for censoring, and therefore pooled estimates of survival should be inter- preted with caution. However, inadequate reporting of specific details of randomization is also found in many Western medical journals. In 2004, 8 years after publication of the CONSORT Statement (intended to improve the quality of reporting of results in random- ized controlled trials), more than 40% of trials published in Western medical journals failed to use

adequate randomization methods or failed to report the method for concealment of allocation.18 In 1994, this figure was as high as 70% to 80%.19

An additional comment on the issue of blinding in these studies is warranted. Most of the studies (20 of 26) assessed in this meta-analysis provided the treat- ment group with orally administered Chinese herbal medicine combined with intravenous chemotherapy and the control group only intravenous chemother- apy. Therefore, blinding of subjects and clinicians was not possible. In such a study design setting, blinding could be achieved only if the treatment and control groups received both oral and intravenous trial medi- cations (ie, the treatment group was given true orally administered herbal medicine and intravenous che- motherapy and the control group was given placebo orally administered herbal medicine and intravenous chemotherapy).

In future trials, we propose that Chinese investiga- tors employ relatively simple measures such as ran- dom number–generating software for use in

randomization and placebo trial drugs for use in com- paring different therapies or in evaluating new and emerging extracted active components of Chinese herbal medicines. More thorough reporting of patients’ characteristics and accounting for patient withdrawals and dropouts would also be helpful.

Standardized herbal formulas. Since there is no stan- dard Chinese formula for the treatment of HCC, it is hard to identify the active components in the treat- ments. Further investigation is needed on effects of Chinese herbal medicine on HCC, on the identity of active components of Chinese herbal medicine, and on the therapeutic mechanisms underlying possible survival benefits of combining Chinese herbal medicine with chemotherapy for HCC.

Acknowledgments
Administrative and methodological support provided by the Pine Street Foundation (San Anselmo, Calif; www.pinestreetfoundation.org).