2642 Alternative Medicine Use in Patients with Localized Prostate Carcinoma Treated with Curative Intent Marguerite C. Lippert, M.D.1 Rebecca McClain, R.N., M.S.N.1 James C. Boyd, M.D.2 Dan Theodorescu, M.D., Ph.D.1,3 1 Department of Urology, University of Virginia Health Sciences Center, Charlottesville, Virginia. 2 Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia. 3 Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville, Virginia. Dan Theodorescu, M.D., Ph.D., is the recipient of a career development award from the American Cancer Society. This work was supported in part by Grant 97-64 from the Milheim Foundation. Address for reprints: Dan Theodorescu, M.D., Ph.D., Department of Urology, Box 422, University of Virginia Health Sciences Center, Charlottesville, VA 22908. Received April 1, 1999; revision received July 26, 1999; accepted August 31, 1999. © 1999 American Cancer Society BACKGROUND. Alternative medicine therapies are estimated to be used by 7– 64% of cancer patients but up to 72% do not inform their physician. To the authors’ knowledge little useful information is available regarding the prevalence of alternative medicine use by patients with prostate carcinoma. Thus, the authors attempted to evaluate the prevalence of alternative medicine use by prostate carcinoma patients treated with curative intent by either radical prostatectomy, brachytherapy alone, or a combination of brachytherapy and external radiation therapy. METHODS. Between January 1997 and May 1998, 234 men with clinically localized prostate carcinoma underwent radical prostatectomy (54 patients) or brachytherapy (180 patients) with (74 patients) or without (106 patients) external beam radiation therapy. In July 1998 a questionnaire was mailed to all patients comprised of multiple questions regarding alternative medicine use to which 190 patients (81%) responded. The overall prevalence and types of alternative medicine therapies used were assessed and the relation between age at procedure, pretreatment prostate specific antigen level, clinical stage, pretreatment Gleason score, and type of treatment with the use of alternative medicine therapies was evaluated using univariate and multivariate analysis. RESULTS. The prevalence of alternative medicine use by prostate carcinoma patients responding to the survey was 43% (81 of 190 patients). No significant differences in alternative medicine use were observed between the patients who received brachytherapy alone (38%), those who underwent radical prostatectomy (40%), and those treated with combined brachytherapy and external beam radiation therapy (51%). Vitamins, prayer or other religious practices, and herbal medicines were the most commonly used therapies in these patients. Higher pretreatment Gleason scores were associated with a greater use of alternative medicine therapies on both multivariate and univariate analyses. Finally, using multivariate analysis, younger prostate carcinoma patients were more likely to use alternative medicine therapies than older patients. CONCLUSIONS. Alternative medicine use is very prevalent among patients treated for localized prostate carcinoma. Because some of these treatments may have a potential biologic impact on tumor behavior and, consequently, on definitive or surrogate therapeutic endpoints, patients should be questioned carefully regarding alternative medicine use during routine tumor follow-up. Cancer 1999;86:2642– 8. © 1999 American Cancer Society. KEYWORDS: prostate neoplasms, alternative medicine, health surveys, prostatectomy, brachytherapy. P atients with other chronic diseases are increasingly seeking alternative medicine therapies. Thirty-four percent of Americans surveyed by phone in 1991 and 42% surveyed in 1997 reported using at least 1 type of alternative medicine. In addition, in 1991 33% of Alternative Medicine Use in Prostate Carcinoma/Lippert et al. alternative medicine users reported consulting a provider of alternative medicine, whereas in 1997 this figure rose to 46%.1,2 Extrapolation to the U.S. population suggested that the 629 million visits to providers of alternative medicine exceeded the 386 million visits to all U.S. primary care physicians in 1997.2 Of the $13.7 billion spent on alternative medicine in 1990, 75% was paid out of pocket1 whereas of the $21.2 billion spent in 1997, $12.2 billion was paid out of pocket.2 Increasing health insurance coverage of alternative therapies also supports increasing patient use.3 Because of such consumer demand, the U.S. Congress targeted 0.02% ($2 million) of the 1992 National Institutes of Health (NIH) budget to evaluate alternative medicine by creating the NIH Office of Alternative Medicine (OAM). The OAM defines “alternative medicine” as therapies that are unproven. If these popular unproven therapies are found to be effective, they could become accepted as conventional medicine and no longer be considered “alternative.” The use of alternative medicine therapies for cancer patients varies from 7– 64% in published studies, with an average prevalence of 31.4%.4 It is interesting to note that it appears that up to 72% of those patients using alternative therapies do not inform their physicians.1 Because alternative therapies may alter the results of standard cancer therapies,5 produce side effects, and confound results of clinical trials, new patient evaluations should include questions concerning any herbal preparations or the practice of any alternative methods of cancer treatment. The potential confounding effects due to alternative medicine use are particularly relevant in diseases such as prostate carcinoma, in which status is assessed by biochemical markers. Unfortunately, to our knowledge, little information is available regarding the prevalence of alternative medicine in prostate carcinoma patients and this limits our ability to understand the magnitude of the issue. To address this important gap in the current literature, we sought to compare the prevalence of alternative medicine use in patients with localized prostate carcinoma treated with curative intent. In addition, we studied the patterns of use as a function of the treatment modality employed, such as radical prostatectomy, brachytherapy alone, or a combination of brachytherapy and external beam radiation therapy (EBRT). METHODS Study Population Between January 1997 and May 1998, 234 men with clinically localized prostate carcinoma underwent either radical prostatectomy (54 patients) or brachyther- 2643 apy (180 patients) with (74 patients) or without (106 patients) EBRT at 1 university medical center. These patients were undergoing routine management of their localized prostate carcinoma and were not enrolled in any clinical trials. Clinical stage of the prostate tumor was assessed retrospectively by review of the medical records using the 1992 TNM system.6 Serum prostate specific antigen (PSA) levels also were obtained for all patients prior to any treatment. The grade of each neoplasm was determined using the Gleason scoring system7 on pretreatment core needle biopsies. Our pathologists reviewed all biopsy materials not generated at our hospital. Selection of Patients for Therapeutic Procedure Patients underwent either radical prostatectomy (perineal or retropubic approach) or brachytherapy after thorough discussion of options and description of the advantages and disadvantages of each approach by the attending urologist. Radical prostatectomy patients did not undergo any pretreatment androgendeprivation therapy. Those patients who underwent brachytherapy were recommended for additional EBRT if their pretreatment PSA level was $ 10 ng/mL, clinical T classification was $ T2c, or pretreatment Gleason score was $ 7. Patients who underwent brachytherapy alone received either flutamide, 250 mg, three times daily or bicalutamide, 50 mg daily, and finasteride, 10 mg daily, beginning 2 months prior to brachytherapy and continuing for a total of 8 months from the initiation of therapy. Patients who underwent both brachytherapy and EBRT received leuprolide instead of finasteride for the same duration. No firm criteria or guidelines were used to assign patients to the three treatment groups, instead, this decision was made by the patient and physicians involved. Questionnaire In July 1998, a questionnaire was mailed first class with a cover letter stating the goals of the project. No financial reimbursement was given to the patients for filling out the questionnaire. Our institutional review board provided us with an exemption and did not require individual informed consent to be obtained because completion of the survey was considered as providing informed consent. Within 30 days of the initial mailing a reminder letter was sent to patients who did not respond. The questionnaire was comprised of an extensive survey regarding alternative therapy use (Fig. 1). Patients indicated whether they used alternative medicine and could chose from 18 types of alternative medicine treatments. More than one treatment could be chosen. 2644 CANCER December 15, 1999 / Volume 86 / Number 12 FIGURE 1. Questionnaire comprised of an extensive survey regarding use of alternative therapies. The effects of age at procedure, pretreatment PSA level, clinical stage, pretreatment Gleason score, and type of treatment on the prevalence of use of alternative medical therapies and types of therapies were evaluated univariately using the Mann–Whitney U test for quantitative and semiquantitative variables and chi-square tests of association for the categoric variables. The SAS program CATMOD (SAS Institute, Cary, NC) was used to evaluate these variables multivariately in a logistic model using maximum likelihood estimation. The relative importance of each variable in influencing the use of alternative medical therapies was evaluated using chi-square values derived by the Wald test based on the information matrix from the likelihood calculations. The overall goodness-of-fit of the multivariate logistic model was evaluated using a likelihood ratio statistic comparing the specified model with the unrestricted model. P values , 0.05 were considered significant. All mean values shown are 6 the standard deviation. tients at 7.8 6 1.5 ng/mL and 7.5 6 1.3 ng/mL, respectively, was lower than that of patients undergoing combination radiation, who had a mean PSA level of 13.4 6 2.7 ng/mL. Mean Gleason scores ranged from 5.7 6 0.5 for brachytherapy patients to 6.4 6 0.6 for the radical prostatectomy patients to 7.1 6 0.8 for combination radiation patients. The distribution based on clinical T classification was very similar for the 40 radical prostatectomy patients and the 77 brachytherapy patients with approximately 50% of the patients classified as T1 and 50% as T2. However, in the combination radiation patients, 14 (29%) were classified as T1, 32 (65%) were T2, and 3 (6%) were classified as T3. The 190 patients surveyed had a median follow-up of 6 months (range, 2–17 months). We detected 3 biochemical failures (PSA . 0.2 ng/mL) in patients treated by radical surgery and 5 in the radiotherapy group, defined as 3 consecutive increases in PSA after achieving a nadir as recommended by the American Society of Therapeutic Radiology and Oncology Consensus Panel.8 RESULTS Prevalence and Types of Alternative Medicine Used Patient Demographics and Tumor Characteristics In the survey, 81 patients (42.6%) reported use of alternative medicine therapies. Differences in the rates of use of alternative medicine were not statistically significant between the treatment groups, with a rate of use in the brachytherapy patients of 38% (35 patients), 40% in the radical prostatectomy patients (16 patients), and 51% in the combination radiation patients (30 patients). The three most commonly used therapies were vitamins (34% rate of use), prayer or religious practices (25%), and herbal medicines (13%). Statistical Methods Of the 190 patients responding to the survey, 40 (21%) underwent radical prostatectomy, 91 (48%) underwent brachytherapy alone, and 59 (31%) underwent a combination of EBRT and brachytherapy (Table 1). The mean patient age was 60 6 6 years for the radical prostatectomy patients, 67 6 7 years for the brachytherapy alone patients, and 69 6 7 years for the combination radiation group. The mean PSA level for both the radical prostatectomy and the brachytherapy pa- Alternative Medicine Use in Prostate Carcinoma/Lippert et al. 2645 TABLE 1 Patient and Tumor Demographics Radical prostatectomy Brachytherapy Brachytherapy and EBRT Parameter Mean SD No. Mean SD No. Mean SD No. Gleason score PSA Age 6.35 7.78 60.1 1.1 5.46 6.27 40 40 40 5.71 7.48 66.5 1.04 7.08 7.1 87 85 91 7.09 13.4 68.7 1.07 11.4 6.6 55 55 59 Tumor classification T1 T2 T3 Total Alternative medicine use No Yes Total Count Percent Count Percent Count Percent 20 20 50 50 42 35 55 45 40 100 77 100 14 32 3 49 29 65 6 100 24 16 40 60 40 100 56 35 91 62 38 100 29 30 59 49 51 100 EBRT: external beam radiotherapy; SD: standard deviation; PSA: prostate specific antigen. TABLE 2 Univariate Analysis of Alternative Medicine Use and Patient and Tumor Variables Users of alternative treatments Nonusers of alternative treatments Parameter Mean SD No. Mean SD No. P value Age PSA Gleason score 64.6 9.75 6.5 7.5 9.95 1.3 81 79 80 66.7 9.05 6.1 7.3 7.69 1.1 109 101 102 NSa NSa , 0.02a Radical prostatectomy Brachytherapy Brachytherapy and EBRT Tumor classification T1 T2 T3 Count Percentage Count Percentage 16 35 30 19.8 43.2 37.0 24 56 29 22.0 51.4 26.6 NSb 30 42 0 41.7 58.3 0 46 45 3 48.9 47.9 3.19 NSb SD: standard deviation; NS: not significant; PSA: prostate specific antigen; EBRT: external beam radiotherapy. a Mann–Whitney U test. b Chi-square test. The use of vitamins and herbal medicines was very similar in all treatment groups. However, only 17% of the patients treated with brachytherapy used prayer or religious practices compared with 30% of patients who underwent radical prostatectomy or received combination radiotherapy. Finally, 21% of the patients (40 patients) reported using more than 1 type of alternative therapy at the time the questionnaire was mailed. Variables Associated with Alternative Medicine Use Univariate analysis revealed a relation between increasing Gleason score and greater use of alternative medicine therapies in prostate carcinoma patients (P 5 0.02) (Table 2) (Fig. 2). The 80 patients who used alternative medicine therapies had a mean Gleason score of 6.5 6 1.3 compared with a mean Gleason score of 6.1 6 1.1 in the 109 patients who did not use alternative medicine therapies. However, patient age, 2646 CANCER December 15, 1999 / Volume 86 / Number 12 FIGURE 2. Variables related to the use and type of alternative medicine therapies in prostate carcinoma patients. Histograms depicting the relation between patient age at treatment and Gleason score and the overall use and specific type (prayer and religious practices) of alternative medicine therapies. TABLE 3 Multivariate Analysis of Alternative Medicine Use and Patient and Tumor Variables Parameter Degrees of freedom Chi-squarea P value Gleason score Age Procedure PSA T classification Likelihood ratiob 1 1 2 1 1 153 6.11 4.71 2.72 0.47 0.1 201.2 0.01 0.03 0.26 0.49 0.76 0.005 PSA: prostate specific antigen. a Chi-square values and associated P values were derived by the Wald test from the information matrix of the likelihood calculations. b Likelihood ratio statistic compared the specified model with the unrestricted model and provided a goodness-of-fit test for the model. type of treatment, higher pretreatment PSA level, and higher clinical T classification were not related to use of alternative medicine therapies. Use of multivariate analysis revealed an association between pretreatment Gleason score (P 5 0.0135) and younger patient age (P 5 0.03) (Table 3) and use of alternative medicine therapies. No association with alternative medicine use was observed with type of treatment, clinical stage, and pretreatment PSA level. Variables Associated with Specific Forms of Alternative Medicine Used Of the three most commonly used alternative medicine therapies, only the use of prayer and religious practices was associated with a higher Gleason score (P 5 0.0019) and younger patient age (P 5 0.066) by univariate analysis (Fig. 1). Patient age, type of treatment, higher pretreatment PSA level, and higher clinical stage were not related to the type of alternative medicine used. DISCUSSION An increasing proportion of the U.S. population is seeking alternative medicine therapies, with an increase from 34% in 1990 to 42% in 1997.1 Approximately 7– 64% of cancer patients in published studies used alternative medical therapies.4 Alternative medicine therapies offer hope to cancer patients who wish to leave no stone unturned and may enhance their sense of control over an illness that makes them feel helpless.9 In the study by Spiegel and Moore, 30 – 44% of newly diagnosed cancer patients were distressed enough to qualify for diagnosis of a psychiatric disorder.9 Although the significantly increased stress associated with initial cancer treatment decreases with time, 20% of cancer patients have been reported to remain psychiatrically distressed 6 months after initial cancer therapy.9 A longitudinal questionnaire-based study of cancer patients in Norway revealed that the majority of users started their use of alternative therapies , 3 months after becoming aware of their cancer.10 In this same study, only 17–27% of patients admitted to use of alternative therapies when questioned at a single point in time, whereas 40% of 252 patients used alternative medicine therapies during the entire 5-year study period.10 In view of the data presented earlier, because our study was of a crosssectional design, the 43% rate of use of alternative Alternative Medicine Use in Prostate Carcinoma/Lippert et al. medicine therapies by prostate carcinoma patients in our current study may be an underestimate of the actual prevalence. In addition, despite a very high response rate of 81%, our study may not be a completely accurate reflection of alternative medical therapy use in prostate carcinoma patients because our patients’ response to the questionnaire was voluntary and no follow-up was undertaken of patients who did not return the questionnaire. To our knowledge little published information exists regarding the prevalence of alternative medicine use in prostate carcinoma patients alone. Of the prostate carcinoma patients responding to our questionnaire, 43% noted using alternative medicine therapies. Prostate carcinoma patients in combination with patients with testicular carcinoma have been found to have an 8.8% rate of use of alternative therapies in 1 study11 compared with a rate of 28% when prostate carcinoma patients were combined with testicular carcinoma and lung carcinoma patients.10 However, due to grouping of patients, such studies do not yield useful and practical information given the great differences between the ages of patients with prostate carcinoma and those with testicular carcinoma. Many studies have revealed a higher prevalence of alternative medicine use in younger cancer patients.2,3,12,13 Indeed, younger patient age was associated significantly with an increased use of alternative therapies in our study when evaluated with a multivariate logistic model. In addition, although we did not collect such data, other studies have shown that those patients using complementary therapies are more likely to be of higher socioeconomic status, female, and better educated than patients who did not try alternative therapies.2,11,13–16 A higher Gleason score was associated with greater use of alternative medicine therapies in our study by both multivariate and univariate analysis. However, other predictors of worse prognosis such as a higher pretreatment PSA level and clinical stage did not appear to be associated with a higher rate of use. In agreement with this finding, some studies have shown greater use of alternative medicine therapies in patients with more advanced disease,17 in patients receiving palliative treatment only,15,17 and in patients with prolonged illness11 whereas other studies revealed an equal rate of use in patients with advanced and early stage cancer.10,18 In further contrast, a recent study indicated that alternative medicine use was highest among men who were clinically disease free after radical therapy for localized prostate carcinoma.19 Although the clinical relevance of a difference of 0.4 in mean Gleason score between patients using alternative medicine and those who do not is debat- 2647 able, it nevertheless is interesting to speculate why this correlation exists. One possibility may be that physicians communicated less hope to those patients with higher Gleason scores, resulting in patients turning to alternative therapies to enhance their sense of control over an illness that makes them feel helpless. Although unlikely in our patient cohorts in view of their relatively low PSA levels, tumors with a Gleason score may be bulkier and as such could cause more local symptoms, which in turn would influence the patient’s interest in alternative medicine use. Not surprisingly, the prevalence of prayer and religious practices as an alternative therapy for cancer patients varies between countries and between geographic regions within a country.10,18 Approximately 34% of cancer patients have been found to become more religious after being diagnosed with cancer.20 In our study and those of others,20 there was a trend toward younger patients being more likely to use prayer and other religious practices, but the age difference between users and nonusers of prayer was not statistically significant. In the current study 13% of the prostate carcinoma patients responding indicated that they used herbal medicines. Because herbal medicines used to treat prostate carcinoma, such as PC-SPES, can reduce serum PSA levels and reduce serum testosterone levels, results of standard or experimental therapies can be confounded.5 Herbal medicines labeled to “promote prostate health” have been reported to have antiandrogenic and antiestrogenic activities such as saw palmetto21,22 or to inhibit in vitro growth of human prostate carcinoma cells such as a rye pollen extract, cernilton.23,24 In addition, herbal medications can cause side effects such as breast tenderness, decreased libido, and superficial venous thrombosis.5 Because up to 72% of patients using alternative medicine therapies do not inform their physicians,1 physicians who are not aware of a patient’s use of herbal therapies may terminate a concomitant effective conventional therapy because of such clinical or biochemical (i.e., PSA) effects. 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