|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology
Research of Complementary/Alternative Medicine Therapies in Oncology: Promising but ChallengingFrom the University of Texas Center for AlternativeMedicine Research in Cancer, Houston, TX. Address reprint requests to Mary Ann Richardson, DrPH, University ofTexas School of Public Health, Center for Alternative Medicine and Center for Health Promotion Research and Development, PO Box 21086, Houston, TX 77225; email marich{at}utsph.uth.sph.uth.tmc.edu AN ESTIMATED 50% OF cancer patients use complementary/alternative medicine (CAM), and most patients combine CAM with conventional medicine.1-5 A summary of 26 surveys conducted across 13 countries estimated the prevalence of use at 31.4% and ranging from 7% to 64%.6 A prospective study reported that 28.1% of breast cancer patients (n = 480) initiated CAM use within 12 months of treatment, but use was associated with greater psychosocial distress.5 In the general population, CAM use has literally exploded since the surveys conducted in the early 1990s. Between 1990 and 1995, CAM use rose from 33.8% to 42%, and visits to CAM practitioners increased from 427 to 629 million; out-of-pocket expenditures were estimated at $27 billion.7,8 Accompanying this increased public interest,7,9 however, is a growing demand for systematic evaluations of safety and efficacy.10-13 Rigorous scientific testing is of vital importance. In response to this demand, the Office of Alternative Medicine (OAM) was established at the National Institutes of Health (NIH) in 1991 by congressional mandate. In 1993, OAM funded 30 pilot studies at $30,000 each. Despite these limited resources, the response was the largest in the history of the NIH and resulted in over 6,000 requests for applications, 800 letters of intent, and 452 applications. Given the overwhelming interest by the research community and with continued congressional support, OAM expanded their research base in 1995 to 10 exploratory research centers at major medical centers. With continued public support, OAM was upgraded to the National Center for CAM (NCCAM) in 1998, and again, they expanded their infrastructure with three new centers using the P-50 funding mechanism. Since the first research initiative by OAM, a multidisciplinary team at the University of Texas M.D. Anderson Cancer Center (MDACC) and the School of Public Health has been dedicated to applying rigorous research methodology to systematically evaluate CAM approaches. In one of the first pilot studies, this team used the randomized controlled trial design to assess the impact of support groups versus imagery/relaxation on immune function, quality of life, and coping for women who had undergone treatment for breast cancer.14-16 Subsequently, The University of Texas–Center for Alternative Medicine (UT-CAM) was established as one of the exploratory research centers in 1995. The primary aims of the center were to evaluate the efficacy of biopharmacologic and herbal therapies for cancer prevention and treatment, establish a network of CAM practitioners and researchers for collaborative research, and improve self-assessment skills of CAM practitioners and researchers. The purpose of this article is to review the state of CAM research in cancer, summarize activities underway at UT-CAM, NCCAM, and the National Cancer Institute (NCI), and highlight positive and challenging aspects of investigating this area. ASSESSING THE STATE OF THE SCIENCE The first task for UT-CAM was to assess the state of the science and establish a research agenda. UFCAM used multiple sources to identify agents, including major reports by the NIH,17,18 comprehensive books on CAM approaches,19-21 national surveys of CAM use, and consultations with experts in the field. Subsequently, over 30 therapies were identified for review and categorized as either herbal, biologic, pharmacologic, or integrated regimens. The systematic review entailed an exhaustive search of library databases, including MEDLINE, Cancerlit, Embase, and Current Contents. These searches were expanded by information from the Internet, reviews of CAM journals and books, site visits, unpublished documents, and information from CAM proponents. The review yielded approximately 6,000 references; 58.8% were applicable to cancer. Approximately 2,400 articles (69.0%) were retrieved and categorized as human, animal, and in vitro studies, reviews, and other information (Table 1).
A working set of agents was classified by research methodology and the accumulation of evidence. We assume that the credibility of study results and, thus, their potential impact on therapeutic practice can be judged by the methods used to generate and interpret those results. Therefore, a continuum of research methods and treatment decisions exists. As the rigor of research methodology improves, the strength of evidence increases. Therefore, clinical studies were classified by research methodology (ie, randomized trials, prospective or retrospective cohort studies, case control, clinical series, care reports) and summarized in annotated bibliographies (Table 2).
We believe that advancing the level of systematic investigation for CAM agents will ultimately benefit the public as information becomes more reliable. The current assessment of the science is presented for the general public and medical community on the UT-CAM Web site (http://chprd.sph.uth. tmc.edu/utcam/ ). This site has been recognized as a premier source of reliable information on CAM therapies for cancer.22-24 
READINESS OF CAM FOR RESEARCH Regardless of their level of acceptance by mainstream medicine,11,13,25,26 these therapies have infiltrated every aspect of health care, and many believe that access should be part of standard oncologic treatment.27 At the most basic level, evidence of efficacy is required before these therapies are moved into clinical testing.28 For many CAM agents, characterization of the product, standardization, reproducibility, safety, and information on basic pharmacology are lacking, while evidence of efficacy rests on anecdotal reports. Others suggest that if the prior probabilities of CAM hypotheses are not higher than those of competing conventional hypotheses, a rationale for testing does not exist.26 Therefore, developmental work has been necessary to educate the CAM community on the requirements for clinical testing (ie, the Investigation New Drug Application) as well as standards of rigorous research. Furthermore, dialog between the conventional research and CAM communities is necessary because the CAM community must be involved in these investigations. We would not expect a researcher who has no experience with surgery to design a study without consulting a surgeon. Neither should we presume to design studies of CAM without involving CAM practitioners.29 Over the past 4 years, UT-CAM has worked with the CAM community to develop clinical protocols, initiate basic in vitro and in vivo testing, conduct epidemiologic historical cohort studies, and pilot test the prospective outcomes evaluation and monitoring system (POMES) process. Clinical studies ranging from small pilot feasibility studies to randomized phase III trials are in progress to test nutritional and herbal supplements that are widely used by cancer patients and have a rationale for assessment. A summary of this research is presented by category.
Epidemiologic Studies Pattern of use of an herbal tonic. In a population-based survey of North America, we assessed the characteristics of consumers of a popular herbal tonic (Flor•Essence; Flora Manufacturing and Distributing, Ltd, Burnaby, British Columbia, Canada). Preliminary results from responders (n = 4,708) indicate they are predominately white, married, college educated, and aged 61 years old (SD, 14.4 years). Most individuals are current or former cancer patients (75.5%) and use the tonic as a medical treatment (62.8%), for prevention (34.1%), or to control symptoms (21.3%). Among the 725 cancer patients (response rate, 52%) who responded to a more detailed survey, half (53.2%) reported that the tonic offered hope, whereas many expected the herbs to improve immune function (75.8%), prolong life (59.2%), improve quality of life (54.0%), or cure the cancer (48.9%). Retrospective comparison. With the appropriate documentation and follow-up, retrospective reviews are possible and allow testing for a signal that the treatment is of benefit. This epidemiologic study retrospectively compared the experience of patients treated with endotoxin therapy to that of patients treated with standard care.31 Using a Cox proportional hazards model with time-dependent covariates, the survival experience for patients treated with Coley toxins, as identified from monographs prepared by Helen Coley Nauts, was compared with that of patients from the Surveillance, Epidemiology, and End-Results database who received surgery only. Our results suggest that risk of death was not significantly higher for Coley toxin–treated patients in the following disease sites: kidney (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.2 to 6; P < .79), ovaries (HR, 0.9; 95% CI, 0.2 to 4.3; P < .94), breast (HR, 0.7; 95% CI, 0.4 to 1.3; P < .24), and soft tissue (HR, 1.3; 95% CI, 0.7 to 2.3; P < .38). Field investigations. Efforts by the UT-CAM and NCCAM resulted in over two dozen investigations nationally and internationally. Meeting in the CAM practice sites provided information on the feasibility of collecting relevant information from patient records and determining follow-up status. Two well-established CAM clinics—the Bio-Medical Clinic in Tijuana, Mexico, and the Livingston Clinic in San Diego, CA—were investigated by UT-CAM. Most patient records were complete at the Livingston Clinic, but they were not at the clinic in Mexico. However, follow-up at both clinics was below tumor registry standards, and comparison with Surveillance, Epidemiology, and End-Results data was not feasible (Richardson et al, unpublished data).
Preclinical Studies In vitro tests of the whole plant extract of mistletoe suggested that mistletoe lectin III, one of the primary active components in the whole plant extract, mediated cytotoxicity through distinct killing pathways. Mistletoe lectin III preferentially affected CD8+ cells with a memory phenotype but did not induce sister chromatid exchange–inducing DNA lesions. The extract reduced the intensity of telomeric signals, increased the frequency of telomeric association and C-anaphases, and reduced nuclear Bcl-2 and p53 proteins. The study cannot exclude the possibility that these effects were due to a decrease in nuclear p53 proteins.34 Over the past year, extensive developmental research on the water-soluble extract of oleander has led to characterization of the plant extract by HPLC and electrochemical detection of the carbohydrate content. A carbohydrate fingerprint has been developed to monitor quality control and stability by the CarboPac HPLC column (Dionex Corp, Sunnyvale, CA), and nonpolar compounds have been isolated to identify the two most potent cytotoxic molecules. Ginseng saponins. After a dose-finding study, two protocols tested the ability of Korean red ginseng saponins to modulate carcinogenic metabolism and have an impact on progression of established and developing precancerous lesions in the rat colon. Compared with the carcinogen-only controls, ginseng significantly (P < .05) reduced aberrant crypt foci, by 25%, in the low-dose group (0.1 g/kg) but not in the high-dose group (1 g/kg). Ginseng had no apparent impact on developing precancerous lesions. Purified plant-based products. Collaborative research with CAM proponents has assessed the potential role of purified plant-based herbal supplements and related products (ie, emodin, ellagic acid, resveratrol, and genistein) in the prevention or treatment of cancer. After determining their relative cytotoxicity in human breast and prostate cancer cell lines, these products will be combined in a logical effort to test the synergism between specific plant products. We plan to optimize the relative chemopreventive activity of the combined plant products. Although the project is an exploration of in vitro pharmacology, if promising, combinations of agents could be tested for chemopreventive or antitumor activity in vivo. Isolated marine-based biologic agents. In vitro studies of dolastatin-10, a product isolated from a shell-less mollusk, Dolabella auricularia, assessed chromosome morphology, telomeric associations, and induction of polyploidy and cell death in a metastatic murine melanoma cell line. The observations suggest that dolastatin-10 could be a potent antineoplastic agent against malignant melanoma based on (a) increased frequency of metaphases, with telomeric associations, (b) induction of clumping in metaphase chromosomes, (c) induction of polyploidy, (d) formation of multinucleated cells, and (e) induction of cell death. In addition to interaction with cell microtubules, the mechanism of action may be mediated by loss of telomeric repeats and the induction of chromosome aberrations.35 A series of experiments are underway to isolate and purify the active inhibitor of 5- and 12-lipoxygenase (LOX) enzymes from an extract of the sea cucumber (phylum Echinodermata, class Holothurioidea), a marine animal. Studies to evaluate the effectiveness in blocking the LOX enzymes are necessary, because these enzymes have been shown to accelerate cancer progression and metastatic formation in animal models. Inhibitors of the LOX enzymes, involved in the metabolism of arachidonic acid to leukotrienes, represent an exciting, novel therapeutic target for the treatment and prevention of cancer. Cell culture studies clearly implicate a role for inhibitors of 5-LOX in the treatment of prostate and lung cancer. Coenzyme Q10 (ubiquinone). A series of in vitro experiments tested the relative cytotoxicity of coenzyme Q10 (CoQ10) in a human breast cancer cell line and examined the impact of CoQ10 on the cytotoxicity of standard chemotherapeutic agents (ie, doxorubicin, paclitaxel, and cisplatin) and the new proteasome inhibitor (PS273). Preliminary results suggest that CoQ10 did not affect the relative toxicity of the standard agents; however, CoQ10 may augment activity of PS273. Additional studies are necessary, specifically testing the impact of CoQ10 on the doxorubicin apoptosis–mediated pathway.
Clinical Studies Mistletoe. A pilot study (n = 10) at Wellesley Hospital, affiliated with the University of Toronto, is testing the feasibility of recruiting and administering a whole-plant mistletoe extract to patients with advanced, unresectable, or recurrent (stage IIB, III, or IV) esophagus cancer. Measures of quality of life, clinical benefit, and toxicity are being monitored, but no preliminary data are available. Herbal tonic. A randomized, parallel, phase II pilot study is being finalized for patients with advanced colon cancer who present for palliative chemotherapy (ie, fluorouracil and folic acid). The pilot study will be the first clinical assessment of the herbal mixture Flor•Essence, which is widely used by cancer patients with anecdotal reports of improved well-being and survival. The study will allow us to monitor the willingness of patients to accept randomization and to evaluate compliance, safety, and toxicity. Shark cartilage. In collaboration with a Canadian biotechnology company, a multicenter, phase I/II trial was completed of whole cartilage extract for the treatment of lung, prostate, and breast cancer. The phase II trial in refractory lung cancer reported a positive trend in favor of a dose-response (ie, there was an impact on analgesic consumption, weight loss, and tumor progression). The number of patients with stabilization of tumor was 38% higher at the upper dose levels, and median survival was superior to the expected 25 weeks.36 Prospective Monitoring Studies One possible approach to obtain data on CAM therapies is the POMES process proposed by the NCI and NCCAM. The process is comparable to a classic phase II trial but includes three components unique for CAM investigations. Practitioners of CAM deliver the therapy in the context of their clinical practice, a monitoring board of conventional oncologists confirms patient eligibility and assesses outcomes, and a research team monitors compliance, patient follow-up, and outcomes assessment. In a pilot study of patients (n = 10) who elected to be treated at an integrated CAM treatment facility in Vancouver, British Columbia, Canada, we will assess the feasibility of the POMES process in collaboration with the Tzu Chi Institute for Complementary and Alternative Medicine and clinicians from the British Columbia Cancer Agency. Patients with pathologically confirmed advanced cancer who consent to participate in the study will be monitored for safety, biologic markers, disease progression, survival, and performance status. RESEARCH PLANNED BY NCI AND NCCAM
Phase III Clinical Studies
Cancer Advisory Panel for Complementary Alternative Medicine. CHALLENGES FOR INVESTIGATIONAL CAM THERAPIES According to our experience over the past 4 years, the majority of herbal and nutritional supplements are not fully developed or ready for definitive trials, despite wide use by cancer patients. Most whole-plant extracts and commercial teas rarely have data on product characterization, standardization, or stability.39 Furthermore, the optimal dose, schedule, and route of administrative have rarely been determined. As indicated by the research activities of UT-CAM, preclinical, pharmacokinetic testing and developmental phase I/II studies are necessary before these products can be launched into definitive clinical trials. Studies in this area must be subjected to the highest standards for design, implementation, and evaluation. Clear hypotheses should be identified a priori and tested in methodologically sound studies with adequate sample sizes to provide sufficient power to detect an effect should it exist. Researchers may face problems accruing patients to randomized clinical trials, considered the gold standard of biomedical research. Strict exclusion criteria and barriers to participation may limit accrual, which will decrease the study power and limit generalizability of the findings.16 Several studies of CAM have reported difficulty with accrual. In a trial underway to test an herbal formula with placebo to mitigate the side effects of chemotherapy, women who want to use the herbs are refusing randomization. They can purchase these products in the market.40 In another trial comparing standard palliative therapy with a complex CAM regimen (ie, nutritional supplements, enzymes, diet, and detoxification), patients with pancreatic cancer are either willing to comply with this complex regimen or prefer the standard treatment. Thus, willingness of patients to accept randomization is a challenge. Should patients accept randomization, the availability of CAM agents in the open market may result in the contamination of the control group. Finally, with fewer than 3% of all cancer patients participating in clinical trials of conventional treatment, researchers designing trials of CAM may encounter limited access to patient populations. In contrast, options for patients with advanced disease should be expanded, as palliation is often the only treatment and quality of life the only therapeutic end point. Patients with advanced solid tumors often have a poor prognosis, and many are not candidates for curative approaches. Quality of life for these patients is often limited by the disease or toxicities associated with treatment. When cure is not an option, oncologists aim for palliation to relieve symptoms. CAM therapies may be beneficial for these patients. Regardless of the stage of disease, reliable information on CAM therapies is needed for the public, physicians, and other health care professionals. The challenge to the CAM community, therefore, is the acquisition of data on patient outcomes and the preparation of their products for clinical testing, when appropriate. To move this field forward, state-of-the-art, rigorous evaluations are needed with mutual respect and open dialog between CAM practitioners/proponents and the scientific community. The developmental, pilot work reported here reflects a step toward establishing those collaborative links and moving forward with trials. The investigations of mistletoe, melatonin, and the Flor•Essence herbal tonic are important because they represent the first clinical trials of their kind in North America. They should provide preliminary data on safety, efficacy, and the feasibility and rationale for further testing. The phase I/II and in vivo studies of cartilage were critical because they established a foundation and collaborative relationship to move forward with a definitive, phase III trial of this agent. The preclinical studies provide information on the efficacy of herbal and nutritional supplements and may serve as templates for examining possible chemopreventive activity or interaction with standard cytotoxic agents. In summary, investigations by UT-CAM represent the application of scientific, rigorous research by established, conventional oncologists and researchers. This preliminary data and field experience are prerequisites for larger, more definitive trials. The strategy of UT-CAM has been to move agents forward along the research continuum, from basic research to pilot/feasibility studies to phase I/II studies, that is, to increasingly more rigorous research designs. Although many are calling for definitive trials of efficacy, this field is in its infancy. In the meantime, the patients and public are eager for any information. They will continue to influence policy makers to allocate resources for CAM research. It is their money and their disease, and we must begin to build bridges between rigorous science and CAM.41 With continued support by the NCCAM and NCI, dedication of CAM research centers, and willingness of the oncology and CAM communities to do the research, we can move the field from alternative to evidenced-based medicine.
NOTES Presented at the ASCB/ASCO Satellite Symposium on Complementary/Alternative Medicine, Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999 REFERENCES 1. Cassileth BR, Lusk EF, Strouse TB, et al: Contemporary unorthodox treatments in cancer medicine: A study of patients, treatments, and practitioners. Ann Intern Med101:105-112, 1984
2.
American Cancer Society: Unproven methods of cancer management: Macrobiotic diets for the treatment of cancer. CA Cancer J Clin39:248-251, 1989 3. Lerner IJ, Kennedy BJ: The prevalence of questionable methods of cancer treatments in the United States. CA Cancer J Clin42:181-191, 1992[Abstract] 4. McGinnis LS: Alternative therapies, 1990. An overview. Cancer67:1788-1793, 1991[Medline] 5. Burnstein H, Gelber S, Guadagnoli E: Use of alternative medicine by women with early-stage breast cancer. JAMA340:1773-1739, 1999 6. Ernst E, Cassileth BR: The prevalence of complementary/alternative medicine in cancer: A systematic review. Cancer83:777-782, 1998[Medline]
7.
Eisenberg D, Davis R, Ettner S, et al: Trends in alternative medicine use in the United States: 1990-1997 results of a follow-up national survey. JAMA280:1569-1575, 1998
8.
Eisenberg D, Kessler RC, Foster C, et al: Unconventional medicine in the United States: Prevalence, costs, and patterns of use. N Engl J Med328:246-252, 1993
9.
Astin JA: Why patients use alternative medicine: Results of a national study. JAMA279:1548-1553, 1998
10.
Fontanarosa PB: Alternative medicine meets science. JAMA280:1618-1619, 1998 (editorial)
11.
Angell M, Kassirer P: Alternative medicine: The risks of untested and unregulated remedies. N Engl J Med339:839-841, 1998
12.
DiPaola RS, Zhang H, Lambert GH, et al: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med339:785-791, 1998 13. Tannock IF, Warr DG: Unconventional therapies for cancer: A refuge from the rules of evidence? Can Med Assoc J159:801-802, 1998[Medline] 14. Moye LA, Richardson MA, Post-White J, et al: Research methodology in psychoneuroimmunology: rationale and design of the IMAGES-P clinical trial. Alternative Ther Health Med1:34-39, 1995 15. Richardson MA, Post-White J, Grimm E, et al: Coping, life attitudes, and immune response to imagery and group support after breast cancer. Alternative Ther Health Med3:62-70, 1997 16. Richardson MA, Post-White J, Singletary SE, et al: Recruitment for complementary/alternative medicine trials: Who participates after breast cancer. Ann Behav Med20:190-198, 1998[Medline] 17. U.S. Congressional Office of Technology Assessment. Unconventional Cancer Treatments. Washington, DC, U.S. Government Printing Office, 1990 18. Workshop on Alternative Medicine: Alternative Medicine: Expanding Medical Horizons—A Report to the National Institutes of Health on Alternative Medical Systems and Practices in the United States. Washington, DC, U.S. Government Printing Office, 1992 19. Boik J: Cancer and Natural Medicine: A Textbook of Basic Science and Clinical Research. Princeton, MN, Oregon Medical Press, 1995 20. Lerner M: Choices in Healing: Integrating the Best of Conventional and Complementary Approaches to Cancer. Cambridge, MA, MIT Press, 1994 21. Moss RW: Cancer Therapy: The Independent Consumer's Guide to Non-Toxic Treatment and Prevention. New York, NY, Equinox Press, 1992 22. Stone VL, Fishman DL, Frese DB: Searching online and Web-based resources for information on natural products used as drugs. Bull Med Libr Assoc85:523-527, 1998
23.
Sikorski R, Peters R: Researching alternatives. JAMA280:1631, 1998 (directory) 24. Eisenberg D: Hitting the books on herbal cures. Time November 23, 1998, p 67 25. Halperin EC: Let's abolish the office of alternative medicine of the National Institutes of Health. N C Med J59:21-23, 1998[Medline] 26. Stalker DF: Evidence and alternative medicine. Mt Sinai J Med62:132-143, 1995[Medline] 27. Coss RA, McGrath P, Caggiano V: Alternative care: Patient choices for adjunct therapies within a cancer center. Cancer Practice6:176-181, 1998[Medline] 28. Hawkins MG, Friedman MA: National Cancer Institute's evaluation of unconventional cancer treatments. J Natl Cancer Inst74:1699-1702, 1992 29. Vickers A, Cassileth B, Ernst E, et al: How should we research unconventional therapies? A panel report from the Conference on Complementary and Alternative Medicine Research Methodology, National Institutes of Health. Int J Technol Assess Health Care13:111-121, 1997[Medline] 30. Richardson MA, Ramirez T, Nanney K, et al: Alternative/complementary medicine: Implications for patient-provider communication. Proc Am Soc Clin Oncol 18:590a, 1999 (abstr 2279) 31. Richardson MA, Ramirez T, Russell NC, et al: Coley toxins immunotherapy: A retrospective review. Alternative Ther Health Med5:42-47, 1999 32. Pisters KMW, Newman RA, Goldman B, et al: Phase I trial of oral green tea extract (GTE) in adult patients with solid tumors. Proc Am Soc Clin Oncol 18:182a, 1999 (abstr 701) 33. Newman RA, Hutto T, Feliz E, et al: Clinical pharmacology of catechins and caffeine in adult solid tumor patients enrolled in a phase I trial of green tea extract. Proc Am Assoc Cancer Res40:82, 1999 (abstr 546) 34. Bussing A, Multani AS, Pathak S, et al: Induction of apoptosis by the N-acetyl-galactosamine-specific toxic lectin from Viscum album L. is associated with a decrease of nuclear p53 and Bcl-2 proteins and induction of telomeric associations. Cancer Lett130:57-68, 1998[Medline] 35. Pathak S, Multani AS, Ozen M, et al: Dolastatin-10 induces polyploidy, telomeric associations and apoptosis in a murine melanoma cell line. Oncol Rep5:373-376, 1998[Medline] 36. Riviere M, Alaoui-Jamali M, Falardeau P, et al: Neovastat: An inhibitor of angiogenesis with anticancer activity. Proc Am Assoc Cancer Res39:46, 1998 (abstr 317) 37. Muscat M: National Cancer Institute's OCCAM partners with NCCAM to expand research on unconventional cancer treatments. Alternative Ther Health Med5:26-30, 1999 38. Reuters Health Information: Federal panel focuses on alternative cancer therapies. Reuters Health July 12, 1999 39. Richardson MA, Tamayo C, Klein A, et al: Rationale for drug development of herbals in oncology: Clinical, industry, and regulatory perspectives. Drug Information J (in press) 40. Ness C: Alternative therapy for cancer welcomed. San Francisco Examiner-Chronicle, October 25, 1998, D, 1 41. Hoey J: The arrogance of science and the pitfalls of hope. Can Med Assoc J159:803-804, 1998 (editorial) [Medline]
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
