Clinical Briefs

With Comments from Russell H. Greenfield, MD, Dr. Greenfield is Medical Director, Carolinas Integrative Health, Carolinas HealthCare System, Charlotte, NC, and Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC.

Juiced About Pomegranates

Source: Pantuck AJ, et al. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 2006;12:4018-4026.

Goal: To determine the effects of drinking pomegranate juice on progression of prostate-specific antigen (PSA) in men who continued to have a rising PSA despite conventional therapy for prostate cancer (PC).

Design: Single-center, open-label, phase II, Simon two-stage clinical trial.

Subjects: Forty-eight men with rising PSA following surgery or radiotherapy for PC (data evaluable on 46). PSA had to be > 0.2 and < 5.0 ng/mL and documented as rising following surgery or radiotherapy, and Gleason score ≤ 7.

Methods: Subjects received 8 oz of commercially available (POM Wonderful®, LLC) pomegranate juice daily and were followed at three-month intervals. Clinical endpoints included effect on serum PSA variables (including doubling time) and serum lipid peroxidation and nitric oxide levels, among others. In vitro assays were also performed to determine the effect of subjects' sera on androgen-dependent LNCaP prostate tumor cell growth and apoptosis.

Results: Estimated mean PSA doubling time (PSADT) at 33 months increased from a baseline mean of 15 months to 54 months posttreatment, with 83% of participants experiencing a prolongation in PSADT. A decrease in PSA was seen in 16 men (35%). In vitro assays revealed a 23% increase in nitric oxide, significant reductions in serum lipid sensitivity to oxidation and measurements of oxidative stress, a 17% increase in apoptosis, and a 12% decrease in LNCaP cell proliferation. No differences between pre- and posttreatment hormone levels were found.

Conclusion: In men with recurrent prostate cancer following conventional curative approaches to treatment, regular ingestion of pomegranate juice produces statistically and potentially clinically significant effects on PSADT, as well as in vitro lessening of cell proliferation, and pro-apoptotic effects. Further study is required.

Study strengths: Dosing based on antioxidant effect in human dose-response studies; in vivo and in vitro effects documented; close follow-up.

Study weaknesses: Small sample size; as yet unvalidated assays were employed to assess antiproliferative and proapoptotic effects.

Of note: Subjects had no evidence of metastatic disease and had not received hormone therapy prior to entering the trial; the 8 ounces of pomegranate juice was equivalent to 570 mg/d total polyphenol gallic acid equivalents (flavonoids comprise 40% of total polyphenols in pomegranate juice); a significant improvement in PSADT may correlate with delay in disease progression, and may prove to be a surrogate marker for prostate cancer mortality (men with a greater PSADT could expect longer survival); radical prostatectomy is the most commonly used therapy for curative intent of PC, however, approximately one-third of men with clinically confined disease will develop biochemical recurrence; epidemiologic and basic science data suggest that dietary interventions and plant-derived phytochemicals may play a role in prevention or treatment of PC; African American men have the highest prostate cancer rate in the world while Chinese and Japanese men native to their countries who eat the typical low-fat, high-fiber diets of the region have the lowest rates; the pattern of slowing of PSA progression rather than achieving significant PSA declines is consistent with a cytostatic rather than cytotoxic mechanism; pomegranate phytochemicals have previously been shown to inhibit the in vitro proliferation of LNCaP, PC3, and DU145 prostate cancer cell lines.

We knew that: Adenocarcinoma of the prostate comprises 29% of all cancers, is the most common malignancy in men, and remains the second most common cause of cancer death in men despite significant improvements in survival rates over the past 20 years; limited options exist for men with progressively rising PSA levels following primary therapy for curative effect and without evidence of metastatic spread; hormonal ablation therapy is associated with significant side effects and adverse effects on quality of life; a wide variety of phytochemicals called polyphenols can be found in fruits and specific food products, and some of these polyphenols appear to have anticancer activity; commercial pomegranate juice possesses potent antioxidant and antiatherosclerotic properties due in large part to its polyphenol content; studies have shown that mild levels of oxidative stress stimulate cancer cell proliferation and increase DNA damage; commercial pomegranate juice is often quite high in sugar and potassium content; soy isoflavones, red wine resveratrol, and green tea catechins may also stimulate apoptosis and lessen cell proliferation.

Clinical import: This preliminary trial of pomegranate juice for men with recurrent prostate cancer offers reason for excitement. Imagine being able to share with a man recently found to have a rising PSA level after having gone through surgery or radiation therapy that simply developing a taste for pomegranate juice might extend his life. Excitement in this case must be tempered by the study limitations of sample size and the nature of some of the tests employed, but the data are certainly compelling if not downright amazing. Results of the new trial recently initiated by the authors evaluating dose response using two dosing regimens and a placebo control will doubtless shed additional light on the potential use of pomegranate juice as a chemopreventive agent. In the meantime, it appears there may be reason to recommend that men enjoy pomegranate juice regularly (with at least some attention paid to managing sugar and potassium intake).

What to do with this article: Make copies to hand out to your peers (and buy stock in pomegranates).

CAM, PPO, POS, and HMO (!)

Source: Lafferty WE, et al. Insurance coverage and subsequent utilization of complementary and alternative medicine providers. Am J Manag Care 2006;12:397-404.

Goal: To evaluate how insured people use complementary and alternative medicine (CAM) providers and to what extent such use impacts health care utilization and expenditures.

Design: Cross-sectional analysis of western Washington health insurance enrollees for 2002.

Subjects: Data were available for review on more than 600,000 enrollees aged 18-64 years who were continuously engaged with a single private health insurance plan for 12 months.

Methods: Review of insurance data from three large health insurance companies (covering 75% of western Washington state's private insurance market) that included demographics, diagnoses, CAM and conventional provider utilization, provider type, line item charges, pharmacy files, claims files, benefit information, and health care expenditures. These data were compared to those obtained from the 2002 National Health Interview Survey supplemental survey on CAM use to provide a U.S. comparison.

Results: Just more than 80% of enrollees made claims, while nearly 14% of enrollees made CAM claims (11% for chiropractic, 2% for massage therapy, 2% for naturopathy, and 1% for acupuncture). Available expenditure data revealed that CAM services accounted for almost 18% of outpatient provider visits but only 2.9% of total medical expenditures. In contrast, prescription drug (23%) and inpatient hospital expenditures (22%) were high. Musculoskeletal complaints were the most common diagnoses for both CAM and conventional medical visits. With the exception of visits to naturopathic physicians and massage therapists (both much lower), U.S. CAM use in 2002 was comparable to that seen in western Washington. In both the United States and the Washington state subset, enrollees in preferred provider organizations (PPO) and point-of-service (POS) programs (that typically offer greater consumer choice) utilized CAM more than those enrolled in health maintenance organizations (HMOs).

Conclusions: Specifically regarding enrollees in three large western Washington health insurance companies during 2002, the number of people using CAM insurance benefits was substantial, yet impact on insurance expenditures was modest. Insurance coverage of licensed CAM providers does not lead to runaway utilization and costs.

Study strengths: Large sample size; modeled predictors of CAM use employing logistic regression analysis; made use of adjusted clinical groupings to counter selection bias.

Study weaknesses: No assessment of therapeutic efficacy of CAM therapies; one of the three companies did not provide expenditure data and only provided information on their HMO product line, not including the one-third of clients using POS products; those covered by self-insured employer plans and Medicaid and Medicare recipients were not included in the analysis.

Of note: In 1996, Washington state implemented a law mandating that all commercial health insurance companies cover the services provided by every category of licensed provider (a mandatory chiropractic benefit has been in place since 1983); insurance company selection was based on willingness to participate, data retrieval capacity, and market penetration; CAM providers were defined as chiropractors, naturopathic physicians, acupuncturists, and massage therapists; osteopaths were included under the heading of conventional providers; in this study HMO coverage was most common, followed by PPO coverage; predictors of CAM use included female sex and age 31-50 years; in Washington, CAM use was lowest in urban areas due to lower utilization of chiropractic services than in rural areas, where chiropractic has historically played a significant role; two of the three companies treated massage therapy as a rehabilitation benefit with associated visit limits; the number of CAM providers is expected to double over the next 10 years in response to consumer demand.

We knew that: All 50 states license chiropractors; a 2004 survey found that 87% of covered employees had chiropractic coverage, whereas 47% had acupuncture coverage; 67% of HMOs offer some type of alternative care; in 2000, Washington state also mandated the ability to self-refer to chiropractic care for up to 10 visits, but all other referrals to CAM providers need to come from a physician; the requirement for referral from a physician for massage therapy likely impacts utilization rates in Washington; approximately one-third of all licensed naturopaths in the United States practice in Washington state; patients likely self-select available insurance products based not only on affordability, but also on expected need for specific medical services; requiring a gatekeeper's recommendation limits insurance-financed CAM utilization.

Clinical import: In the face of increasing consumer demand for CAM therapies, relatively little data exist with which to assess the impact of insurance coverage of CAM therapies on health care costs. Carriers have largely avoided blanket coverage of specific CAM therapies both out of fear of over-utilization and associated cost escalation, and due to the perception that insufficient data exist to execute cost-benefit analyses with respect to therapeutic efficacy. The present study results serve to quell fears over the issue of utilization to some degree, but not that of efficacy, leaving us with important but incomplete information. Though data on a significant number of people and associated expenditures were not fully captured, six years after CAM benefits were mandated in Washington state expenditures appear to be controlled. In addition, enrollees with high utilization rates were often identifiable in advance (responsible for 34% of CAM, 41% of outpatient conventional, and 50% of total expenditures). Such information should be of interest to insurers. Lack of assessment of clinical benefit of CAM therapies to enrollees severely limits the scope of conclusions that can be made, but from an economic standpoint this study offers a rare glimpse into the potential impact of insurance coverage for select CAM therapies.

What to do with this article: Keep a hard copy in your file cabinet.