Complementary Medicine, Chemoprevention, and Staging of Prostate Cancer

13TH INTERNATIONAL PROSTATE CANCER UPDATE Complementary Medicine, Chemoprevention, and Staging of Prostate Cancer E. David Crawford, MD University of Colorado Health Sciences Center, Denver, CO Additional Contributors Jonathan L. Epstein, MD, Daisaku Hirano, MD, M. Scott Lucia, MD, Arturo MendozaValdes, MD, Wael A. Sakr, MD, Bruce Sodee, MD The 13th International Prostate Cancer Update was held in Vail, Colorado, in February 2003. This article provides an overview of the high points in the areas of complementary medicine, chemoprevention, and staging that were discussed at this meeting. M. Scott Lucia, MD, addressed the use of various hormonal agents, antiproliferative or differentiating agents, antiinflammatory agents, and antioxidants in patients with prostate cancer. Wael A. Sakr, MD, provided an overview of prognostic markers for this disease. Arturo Mendoza-Valdes, MD, explored the potential role of exercise for patients with prostate cancer, and Bruce Sodee, MD, described some exciting new developments in prostate imaging. E. David Crawford, MD, discussed the ongoing Prostate Cancer Prevention Trial. [Rev Urol. 2003;5(suppl 6):S23-S32] © 2003 MedReviews, LLC Key words: Prostate cancer • Chemoprevention • Complementary medicine • Staging rostate cancer is the second leading cause of cancer-related death among men in the United States.1 There is growing evidence to suggest that approximately one third of all cancer deaths can be prevented by changes in diet and lifestyle and/or through the use of preventive drug therapy. In its strictest meaning, prevention of prostate cancer can be defined as the process of eliminating risk of developing the disease. However, the cause of prostate cancer continues to elude the research community, and most identified risk factors (age, P VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S23 Chemoprevention of Prostate Cancer continued ethnicity, and family history) are not modifiable. Therefore, a primary prevention strategy could focus on reduction of the incidence of the disease through the use of naturally occurring and synthesized chemical compounds, changes in lifestyle and diet, and the use of various vitamin and micronutrient supplements. Table 1 Epidemiologic, Clinical, and Molecular Clues to the Need for Chemoprevention of Prostate Cancer Risk factors • Age >50 years (oxidative stress?) • Family history of prostate cancer • High serum testosterone level and/or androgen supplementation • Diet Chemoprevention of Prostate Cancer High fat (oxidative stress? alteration of hormone balance? arachidonic acid?) M. Scott Lucia, MD, of the University of Colorado, discussed the broad aspects of chemoprevention of prostate cancer. Table 1 summarizes molecular clues to high risk of the disease and factors for chemoprevention. A number of agents are currently being evaluated for prevention or delay of progression of prostate cancer (Table 2). Low levels of selenium/antioxidants/isoflavonoids • Geographic locale Western culture (diet) • Low ultraviolet light exposure (vitamin D) • Prostatitis (oxidative stress?) • African-American ethnicity (androgen metabolism? vitamin D levels?) Molecular/biological characteristics • Early dependence on androgen; progression to androgen independence • Long latency Hormonal Agents: Antiandrogens and Estrogen Receptor Modulators Since the pioneering work of Huggins and Hodges,2 androgen—particularly the testosterone derivative 5-dihydrotestosterone (DHT)—has been recognized as the major regulator of growth in both normal and neoplastic prostate tissue. This knowledge forms the basis for total androgen ablation therapy for advanced prostate cancer. There is also evidence suggesting that • High prevalence of GSTP1 gene hypermethylation • High prevalence of telomerase expression • Overexpression of cyclooxygenase-2 • Altered growth factor responsiveness converts testosterone to DHT.3 Furthermore, men castrated when they are younger than 40 years have a lowerthan-average lifetime incidence of prostate cancer. There is growing evidence to suggest that about one third of all cancer deaths can be prevented by changes in diet and lifestyle and/or through the use of preventive drug therapy. reducing circulating androgen levels or interfering with androgen’s action on the prostate before the development of advanced prostate cancer might prevent or retard progression of the disease. The development of prostate cancer has not been reported in men with a congenital deficiency of 5--reductase, the enzyme that S24 VOL. 5 SUPPL. 6 2003 It is postulated that differences in androgen metabolism might contribute to racial differences in the incidence of prostate cancer in the United States. Therefore, inhibition of androgen-promoted carcinogenesis in the prostate might be an effective treatment strategy. There is accumulating evidence that estrogens act REVIEWS IN UROLOGY synergistically with the effects of androgens on the prostate. When combined with DHT, estrogen induces prostate growth in rats1 and dogs.4 Estradiol (E2) has been shown to increase androgen receptor content in dog prostate and in human prostatic carcinomas. The changing levels of estrogen relative to androgen that occur with aging are believed to play a role in the development of prostatic hyperplasia. When combined with androgen in rodent systems, E2 can potentiate carcinogenesis. This evidence suggests that a chemoprevention strategy using a selective estrogen receptor modulator (SERM) might be effective at inhibiting androgen-promoted prostatic carcinogenesis. Several SERMs that might be useful in prostate can- Chemoprevention of Prostate Cancer Table 2 Candidate Chemopreventive Agents for Prostate Cancer Hormonal agents • 5--reductase inhibitors (eg, finasteride—Prostate Cancer Prevention Trial) • Antiandrogens/LHRH antagonists (eg, flutamide, leuprolide) • SERMs (eg, tamoxifen, raloxifene, toremifene, SERM-3) • Aromatase inhibitors Phytoestrogens and protein kinase inhibitors • Isoflavonoids (eg, genistein, silibinin) • Angiogenesis inhibitors (eg, SU-101, SU-5416) • Farnesyltransferase inhibitors Antiproliferative or differentiating agents • Vitamin D analogs (eg, doxercalciferol) • Retinoids (eg, 4-HPR, 9cis-retinoic acid) • Polyamine inhibitors (eg, DFMO) • Short-chain fatty acids Anti-inflammatory agents • COX-2 inhibitors (eg, celecoxib, sulindac sulfone) • 5-lipoxygenase inhibitors • Leukotriene receptor antagonists Antioxidants • Vitamin E (SELECT) • Selenium (SELECT) • Carotenoids (eg, lycopene) LHRH, luteinizing hormone-releasing hormone; SERM, selective estrogen receptor modulator; 4-HPR, 4-hydroxyphenylretinamide; DFMO, difluoromethylornithine; COX-2, cyclooxygenase-2; SELECT, Selenium and Vitamin E Cancer Prevention Trial. cer chemoprevention have been developed. Tamoxifen, raloxifene, and toremifene have been shown to inhibit prostatic carcinogenesis in animal systems. Their mechanisms of action might involve regulation of stimulatory and inhibitory growth factors, inhibition of protein kinase C, and/or induction of p21/waf2/cip1. A phase 2 trial is underway to investigate the effects of toremifene, alone or in combination with flutamide, on prostatic intraepithelial neoplasia (PIN) and other biomarkers in patients scheduled for prostatectomy. Phytoestrogens and Protein Kinase Inhibitors The phytoestrogens, including isoflavonoids and lignans, are nonsteroidal substances that, like SERMs, act as weak estrogens or “antiestrogens." Evidence that isoflavonoids, such as genistein, might guard against the development of prostate cancer comes largely from epidemiologic dietary studies. There are marked geographic differences in prostate cancer incidence throughout the world, with high rates of prostate cancer mortality in the United States and Western Europe and relatively low mortality rates in Asia. Persons who emigrate from low-risk areas to high-risk areas tend to adopt the higher prostate cancer risk. Epidemiologic studies have identified a number of dietary factors that are partly responsible for these observations, including regional differences in dietary content of fat, selenium, lycopene, and isoflavonoids. The Asian diet is rich in soy, which is a major source of genistein and other isoflavonoids. In addition to inhibiting the growth of prostate cancer cell lines in vitro and in xenograft models,5 genistein also inhibits the development of advanced disease in a mouse transgenic model of prostate cancer.6 Mechanisms of action might include alterations in androgen signaling and metabolism (estrogenic properties), increased cell–cell adhesion, inhibition of tyrosine kinases, induction of p21,35, inhibition of angiogenesis, and potential antioxidant properties (see below). Other protein kinase inhibitors that target signaling pathways involved in angiogenesis include SU-101, which is a platelet-derived growth factor receptor antagonist, and SU-5416, which is a vascular endothelial growth factor receptor antagonist. These agents are being evaluated in phase 1 and phase 2 trials in patients with early or hormonerefractory prostate cancer, as well as in patients with other cancers. Antiproliferative and Differentiating Agents Antiproliferating and differentiation therapies are being evaluated for use in a number of solid tumors, including colon, breast, and prostate cancers. Agents such as vitamin D and its analogs, vitamin A derivatives VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S25 Chemoprevention of Prostate Cancer continued (retinoids), and polyamine inhibitors, such as difluoromethylornithine (DFMO), act by inducing cell-cycle arrest, apoptosis, and cell differentiation.7 Their potential for use as chemopreventive agents for prostate cancer is based on a growing body of experimental and epidemiologic evidence. The major role of vitamin D in humans is the regulation of calcium uptake and bone metabolism. press the development of prostatic and seminal vesicle carcinomas in rat models. Fenretinide is well tolerated; however, a recent phase 2 trial failed to demonstrate an effect of 3 weeks of therapy with fenretinide versus placebo on several end point biomarkers in patients who had prostatectomies for prostate cancer.9 The ultimate question of whether retinoids can inhibit the development of clinical Vitamin D is now recognized as a potent regulator of cell growth and differentiation in many tissues, including prostate. However, vitamin D is now also recognized as a potent regulator of cell growth and differentiation in many tissues, including prostate; these effects are mediated by specific vitamin D receptors. Some data suggest that an analog of vitamin D, Ro245531, inhibits the development of prostate and seminal vesicle carcinomas in experimental rat models.8 Epidemiologic data show an inverse relationship between the level of solar radiation and prostate cancer incidence and mortality. Furthermore, African American men have a higher incidence of prostate cancer and lower mean serum levels of vitamin D compared with Caucasian men. A recently activated phase 2 trial is designed to determine whether the vitamin D analog doxercalciferol modulates a variety of end point biomarkers for the development of prostate cancer in patients with localized disease who are scheduled for prostatectomy. Retinoids have also been shown to inhibit proliferation and induce differentiation of prostatic epithelial cells. In clinical studies, retinoids exhibited chemopreventive activity for carcinomas arising in the head and neck.8 Retinoids such as 4-hydroxyphenylretinamide (4-HPR, fenretinide) have also demonstrated the ability to sup- S26 VOL. 5 SUPPL. 6 2003 prostate cancer over time has yet to be addressed. DFMO and other polyamine inhibitors act by reducing levels of polyamines that are necessary for cell proliferation (eg, putrescine, spermidine, and spermine). DFMO irreversibly inhibits ornithine decarboxylase (ODC), an enzyme necessary for the initial step in synthesis of polyamines. Because levels of spermidine and spermine are particularly high in the prostate, DFMO has received much attention as a potential preventive agent for prostate cancer. The National Cancer Institute is currently sponsoring and/or funding several phase 2 clinical trials to Anti-inflammatory Agents A body of evidence suggests a role for prostaglandins (PGs) and other eicosanoids in the development and progression of human cancers.10 Cyclooxygenase (COX), which is a key enzyme in the synthesis of PGs and eicosanoids from arachidonic acid, exists in two isoforms. COX-1 is constitutively expressed in many tissues, whereas COX-2 is inducible by cytokines and growth factors and is highly expressed in a number of cancers, including prostate cancer. Overexpression of COX-2 is associated with increased tumorigenesis and alterations in cellular adhesion and apoptosis in epithelial cells. Prostaglandin E2 (PGE2), which is derived from COX-2, stimulates angiogenesis in tumors, whereas suppression of COX-2 suppresses angiogenesis and tumor growth. A recent study has demonstrated that human prostate cancer tissue produces markedly increased levels of PGE2 compared with surrounding normal prostate tissue. Because Western diets tend to be high in meat and animal fats that contain arachidonic acid, inhibition of COX-2 and PG synthesis might be an ideal target for prostate cancer chemoprevention, especially in light of the relative safety of oral anti- Overexpression of COX-2 is associated with increased tumorigenesis and alterations in cellular adhesion and apoptosis in epithelial cells. evaluate the effects of DFMO on ODC activity, polyamine levels, levels of prostate-specific antigen (PSA) and testosterone, histopathologic factors, and other markers of cell proliferation and differentiation in patients at high risk for prostate cancer or those scheduled for prostatectomy for prostate cancer or cystoprostatectomy (without prostate cancer). REVIEWS IN UROLOGY inflammatory agents. In vitro studies have shown that COX-2 inhibitors decrease growth and increase apoptosis in prostate cancer cell lines.11 The proapoptotic effect of COX-2 inhibition is likely a result of arachidonic acid metabolism being shunted to stimulate production of ceramide, a mediator of apoptosis. Several COX-2 inhibitors/anti-inflammatory Chemoprevention of Prostate Cancer agents are being studied (preclinical and phase 1 human trials) for use in prostate cancer chemoprevention; these include celecoxib, R-flurbiprofen, and exisulind, which inhibits cyclic guanosine monophosphate phosphodiesterases. Antioxidants Reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, peroxinitrite, and hydroxyl anions, are highly reactive molecules produced as byproducts of oxidative metabolism or by absorption of radiant energy (eg, x-rays, ultraviolet light). In addition, ROS are frequently generated during enzymatic metabolism of many known carcinogens. ROS can cause oxidative damage to cellular lipids, proteins, and DNA that can ultimately lead to carcinogenesis. For instance, ROS damage to DNA might result in mutagenesis or altered expression of transcriptional factors involved in carcinogenesis. Oxidative damage to critical DNA repair enzymes might affect their activity and, thereby, exacerbate mutagenesis. The cumulative result of these processes would be an imbalance between the rate of mutagenesis and the ability to repair mutations (without error), allowing for their progressive accumulation. In support of this theory, the inactivation (usually via CpG island methylation) of the glutathione Stransferase (GST) gene, GSTP, has been detected in a high proportion of prostate cancer and PIN specimens. GSTP1, the primary GST gene in prostatic epithelial cells, is responsible for inactivating oxidant carcinogens via conjugation to reduced glutathione. Furthermore, lipid peroxidation of dietary fat might also lead to the formation of mutagenic carcinogens and ROS. A high intake of dietary fat, which is typical in Western cultures, is associated with a high relative risk of prostate cancer. Therefore, strategies aimed at reducing the generation or increasing the scavenging of ROS offer exciting promise for the prevention of prostate cancer. Epidemiologic studies provide evidence that increased dietary consumption of antioxidants, such as lycopene (from tomato products), selenium, and vitamin E, is associated with a decreased risk of prostate cancer. Although vitamin E inhibits lipid peroxidation, it might also induce apoptosis in cancer cells. Selenium might potentiate the production and activity of glutathione How should chemoprevention trials be designed? Proper attention to these questions is required for ultimate success in reducing the morbidity and mortality associated with prostate cancer. Prognostic Markers of Prostate Cancer Wael A. Sakr, MD, of Wayne State University, provided an overview of the prognostic markers of prostate cancer. Predicting the prognosis of patients with prostate cancer has tra- New markers have to compete with a fairly powerful set of traditional parameters that, when applied with expertise, have a great deal of prognostic value within this tumor system. peroxidase, a potent antioxidant. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a large, multi-institutional, phase 3, randomized, prospective, double-blind study that is currently evaluating the effects of these two agents on the incidence of prostate cancer in healthy men. Conclusions We are entering an exciting time in the study of prostate carcinogenesis and its chemoprevention. As more is learned about the multiple pathways involved in carcinogenesis, new targets for chemoprevention are being discovered. Eventually, we might see combination strategies that simultaneously target many pathways through the use of simple dietary modifications or supplementation. As exciting as these prospects are, a number of questions remain. For instance, are surrogate endpoint biomarkers an accurate means of predicting the development of prostate cancer? What are the optimal dosages of chemotherapeutic agents, and how should they be formulated? Who are the ideal candidates for chemopreventive therapy? ditionally been driven by the powerful morphologic parameters of Gleason score, an assessment of the “amount" of tumor in the biopsies (number of cores with cancers, percentage of core involvement, etc), and the pathologic stage of cancer (when it can be determined). These parameters continue to be the cornerstone of patient management, particularly when combined with serum PSA levels; additional information regarding a patient’s age and health status, often in the form of prognostic tables and nomograms, is sometimes integrated into patient management. However, considerable variabilities in response to therapy and in tumor progression within the same prognostic categories remain. Therefore, the search for additional prognosticators is aimed at refining and supplementing the information obtained from traditional parameters. When addressing the subject of prognostic markers, it is helpful to differentiate those that indicate an increased risk of “developing or having" prostate cancer from those that might help predict its course or response to a particular therapy. There VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S27 Chemoprevention of Prostate Cancer continued have been significant developments in the former category (addressed elsewhere in this supplement). Furthermore, there is a need to distinguish between characterizing the role of a marker in certain pathways of carcinogenesis and its potential utility as a prognosticator and/or an indicator of response to therapy. With respect to markers aimed at predicting tumor progression potential, a long list of older and more recent technologies and molecules continues to be explored. The value of most of these markers in clinical practice is uncertain. Published data concerning the added value of these markers are inconsistent and, therefore, they are viewed with justified on pretreatment samples from prostate biopsies? The need for new markers is mostly to guide the management approach before definitive therapy. Most of the available “molecular" data on prostate cancer have been derived from advanced tumors, because molecular abnormalities accumulate and tend to be easier to detect in more advanced cancers and obtaining tissue samples from larger tumors in more advanced-stage disease is easier, especially if fresh tissues are needed. In addition, there are statistical and reproducibility issues. Has the marker been tested on an adequate sample size? Has it been tested in multiple laboratories? Have the tests Table 3 Proposed Markers for Predicting Tumor Progression Under Study DNA ploidy Proliferation E-cadherins Morphometry Apoptosis Connxin 43 bcl-2 Integrin Angiogenesis Bax 12-lipoxygenase Neovascularity Interest in physical activity as a means for the primary prevention of cancer is increasing as the evidence for a protective effect accumulates. p21, p27 CD 44 Neuroendocrine cells skepticism. This might be because new markers have to compete with a fairly powerful set of traditional parameters that, when applied with expertise, have a great deal of prognostic value within this tumor system. Accordingly, a number of relevant questions need to be raised when assessing the potential utility of a new marker: 1. Does the new molecule provide an independent predictive value concerning outcome when tested in a multivariate analysis? Or is the claim of prognostic significance based on univariate analysis, which merely reflects a significant correlation with morphologic prognosticators such as stage and Gleason score? 2. Have the data on the marker been generated prospectively? Retrospective analysis in this setting is fraught with biases. 3. Has the marker been tested S28 VOL. 5 SUPPL. 6 2003 utilized consistent technical conditions with reproducible interpretational results? It is important to consider these questions when evaluating the growing number of proposed markers. Table 3 lists some of the markers that have been tested to varying extents— rarely, if at all, to the standard suggested earlier. It is common practice to group together some of these molecules in an attempt to investigate certain pathways, such as cell cycle regulators, growth factors, or histomorphometric analysis of cellular and nuclear alterations. With the increasing proportion of earlier-stage prostate cancer being confirmed after surgery, there is a potential for some of these markers to show significant prognostic value in a controlled-stage setting. In a series of organ-confined prostatic cancers, it was found that aneuploid tumors have lower rates of diseasefree progression than diploid tumors after controlling for Gleason score; REVIEWS IN UROLOGY p53 Epidermal growth factor receptor Fluorescent in situ hybridization for chromosomes HSP27 Transforming growth factor  Androgen receptor Proteases Glutathione S-transferase the same was true for proliferative index measured by flow cytometry. There is also considerable interest in cell adhesion molecules, telomerases, and methylation studies. Multiple centers within the United States and abroad are compiling large databases that include clinical records, pathology documentation, extensive molecular data, and outcomes in patients with prostate cancer. Comparing the data on well-characterized and thoroughly tested molecular markers in this setting will provide Chemoprevention of Prostate Cancer an opportunity to identify the badly needed markers that can help optimize the management of newly diagnosed prostate cancer. Exercise and Prostate Cancer Arturo Mendoza-Valdes, MD, of Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, reviewed the role of exercise in prostate cancer. The benefits of exercise for overall health are well known. There is no doubt that physical activity helps lower the risk of been established for several sites. In addition, central adiposity has been particularly implicated in promoting metabolic conditions amenable to carcinogenesis. Based on existing evidence, some public health organizations have issued physical activity guidelines for cancer prevention, generally recommending at least 30 minutes of moderate- to vigorous-intensity physical activity 5 days a week. Although most research has focused on the efficacy of physical activity in cancer prevention, evi- Evidence is increasing that exercise also influences other aspects of the cancer experience, including cancer detection, coping, rehabilitation, and survival after diagnosis. heart disease, high blood pressure, obesity, and many other conditions. Interest in physical activity as a means for the primary prevention of cancer is increasing as the evidence for a protective effect accumulates. There is some evidence that physical activity plays an etiologic role in the prevention of cancers of the colon, breast, prostate, testes, lung, endometrium, and ovary; studies have suggested a causal association for each of these sites. The evidence for an association between physical activity and prostate cancer is less consistent than that for colon cancer and breast cancer and can be classified only as probable. Several plausible, hypothesized, biologic mechanisms exist for an association between physical activity and cancer, including changes in levels of endogenous sexual and metabolic hormones and growth factors, decreased obesity and central adiposity, and, possibly, changes in immune function. Weight control might play a particularly important role because links between excess weight and increased cancer risk have dence is increasing that exercise also influences other aspects of the cancer experience, including cancer detection, coping, rehabilitation, and survival after diagnosis.12 Along with poor diet and tobacco use, lack of physical activity might be one of the main risk factors for cancer that can be modified through lifestyle/behavioral changes. Clear public health recommendations and health promotion campaigns have been established for diet and tobacco use that would, developments in prostate imaging. The application of three complementary nuclear imaging modalities to staging prostate cancer was discussed, with the objective of underscoring the optimum utility and potential pitfalls of each. The first of these is bone scintigraphy, which is the conventional method of identifying skeletal metastasis that might occur in as many as 90% of prostate cancer cases. Although planar bone scintigraphy has dominated this area for several decades, it has had increasing competition in the last several years from other nuclear imaging procedures. The two most dominant procedures are single photon emission computed tomography (SPECT) and positron emission tomography (PET). As the “tomography" in SPECT and PET indicates, these modalities provide three-dimensional imaging information, which is particularly critical when these modalities are used to localize primary prostate cancer or to identify the extent of its capsular penetration or metastases to lymph nodes. The innumerable images generated by SPECT and PET in a single scan require enormous computing power that simply was not available until the approach of the 21st century. This same computing power has facil- The most beneficial spinoff from bone scintigraphy might be the monoclonal antibodies that were developed to improve diagnosis but can be modified for targeted therapy. if adopted, result in a decreased incidence of cancer worldwide. A similar focus should now be directed to the role of physical activity as a means of reducing the risk of some of the major cancer sites. Prostate Imaging Bruce Sodee, MD, from The Cleveland Clinic, reviewed some exciting new itated multimodality imaging, which plays a key role in the optimal utilization of these functional imaging modalities with the complementary anatomic detail that computed tomography (CT) and magnetic resonance imaging (MRI) provide. Therefore, combination imaging modalities have now emerged, and whether SPECTMRI, PET-CT, or any other combina- VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S29 Chemoprevention of Prostate Cancer continued Prostate Prostate Cancer Rectum Figure 2. Three-dimensional ProstaScint rendering of same patient illustrating cancer (red) extending through prostate (green) to rectum. Prostate Rectum Figure 1. Two-dimensional ProstaScint imaging of a 65-year-old patient with prostate cancer. tion of functional-anatomic imaging modalities is used, the fused images of each provide a novel means to map cancer, both within and outside the prostate. Bone Scintigraphy Although conventional planar bone scintigraphy is in competition with SPECT and PET imaging, the threedimensional information that SPECT and PET provide does not generally have a distinct advantage in this application. Exceptions to this are provided in the next 2 sections; special note is made of the role that MRI and magnetic resonance spectroscopy (MRS) play in identifying intertrabecular vertebral metastasis. The most beneficial spinoff from bone scintigraphy might be the monoclonal antibodies that were developed to improve diagnosis but can be modified for targeted therapy. Molecular radiotherapy could be S30 VOL. 5 SUPPL. 6 2003 the most valuable byproduct that emerges from this targeted imaging. Positron Emission Tomography PET permits direct monitoring of metabolism occurring in malignant cells targeted by a compound labeled with a positron emitter. The most widely used compound is 2-[fluorine-18] fluoro-2-deoxy-D-glucose (FDG), in which fluorine-18 is the of 34 patients with biopsy-proven prostate cancer imaged with both FDG-PET and bone scans, FDG-PET was significantly less sensitive than bone scintigraphy.13 However, in a more recent study in which follow-up imaging studies were conducted, eight lesions that were initially identified by PET but not by bone scanning were detected on bone scans when the test was repeated 2 to 4 months later.14 In the previously cited study,13 such initial imaging results would have been regarded as falsepositive PET scans. ProstaScint Imaging ProstaScint imaging is based on using planar and SPECT imaging to map the ProstaScint imaging, when used with computer tomography or magnetic resonance imaging, appears to be the most accurate means currently available to identify prostate cancer and its metastasis. positron emitter. FDG can be used to image primary prostate cancer as well as metastases to lymphatic and skeletal sites; because there is no concern about an autoimmune response to FDG, it is amenable to monitoring therapy or recurrence. In a study REVIEWS IN UROLOGY uptake of capromab pendetide that has been labeled with indium-111. Capromab pendetide is a monoclonal antibody that targets prostate-specific membrane antigen, a transmembrane glycoprotein that has been thoroughly characterized because of its role as Chemoprevention of Prostate Cancer a marker for prostate cancer and metastases. In a multicenter study examining ProstaScint imaging in more than 2100 patients with prostate cancer, ProstaScint imaging was found to complement both PSA measurement and Gleason score.15 Concerted efforts to optimize ProstaScint imaging have played a key role in mapping both primary prostate cancer and its metastatic sites.16 Although reading ProstaScint images requires considerable expertise, many of the difficulties can be greatly alleviated by laying the images over anatomic images obtained from other modalities, such as CT or MRI. Examples of ProstaScint imaging in two and three dimensions are illustrated in Figures 1 and 2, respectively; the images were obtained from a 65-year-old patient with a Gleason score of 6 (3+3) and a PSA value of 2.91 ng/mL. The same patient also underwent imaging with endorectal MRI and MRS, which did not yield definitive results. In contrast, capsular penetration with invasion of the rectum was clearly seen with fused ProstaScint/CT imaging. The detailed mapping of the cancer that is illustrated in Figures 1 and 2 provides invaluable information for guiding treatment planning. Studies of ProstaScint-guided brachytherapy at The Cleveland Clinic have been reported.17 Although PET/CT imaging could be similarly applied to guiding therapy, a study comparing FDG-PET and ProstaScint images with prostate histopathology indicated that inflammation is a frequent confounding factor with PET imaging. Therefore, ProstaScint imaging, when used with CT or MRI, appears to be the most accurate means currently available to identify prostate cancer and its metastasis. The Prostate Cancer Prevention Trial E. David Crawford, MD, concluded the session on complementary medicine, chemoprevention, and staging with a discussion of the Prostate Cancer Prevention Trial (PCPT). The PCPT is the first phase 3 (randomized, placebo-controlled, prospective) population-based study to determine if prostate cancer risk can be reduced.18 In this trial, 18,882 men were randomized to receive either finasteride or placebo at 219 sites in the United States. Enrollment began in 1994 and was completed in 1997. The study design included annual digital rectal examination and PSA level determinations, with PSA measurement performed centrally. Because finasteride lowers PSA levels, PSA reports provided to the sites were corrected for the treatment arm. The endpoint of the study is prostatic cancer detection rates as determined by biopsy in all study subjects. Endof-study (EOS) prostate biopsies began in 2000, and the final biopsy is expected in 2004. Main Points • Studies of chemopreventive strategies targeting androgen’s action on the prostate are exploring the utility of selective estrogen receptor modulators, such as tamoxifen, raloxifene, toremifene, and acapodene, as well as phytoestrogens, including isoflavonoids and lignans. • Vitamin D and its analogs, retinoids such as fenretinide, and polyamine inhibitors are all promising in their potential to suppress the proliferation of cancer cells in the prostate; more research is needed to determine their role in chemopreventive therapy. • Oral anti-inflammatory agents and an antioxidant-rich diet might prove to be safe and important components of a cancer prevention strategy. • Traditional parameters for prognosis, including Gleason score, cancer stage, and prostate-specific antigen (PSA) levels, are useful but not absolute, so careful research into potential new markers of prostate cancer is needed to refine current prognostic information and optimize treatment for patients facing this diagnosis. • One of the main cancer risk factors that can be eliminated through behavioral changes is a sedentary lifestyle; although the benefits of exercise are usually reported in relation to cancer prevention, evidence is growing that exercise can positively influence coping with a cancer diagnosis, rehabilitation, and survival. • Combined functional-anatomic imaging modalities are now being used to map cancer, both within and outside the prostate, and hold the promise of being more advantageous than the currently available modalities used alone. • ProstaScint, an imaging modality based on using planar and single photon emission computed tomography to map the uptake of capromab pendetide (a monoclonal antibody that targets prostate-specific membrane antigen), has been found to complement both PSA measurement and Gleason score for evaluating prostate cancer and metastases. • The Prostate Cancer Prevention Trial, currently under way, is evaluating the effect of finasteride treatment on benign prostatic hyperplasia and will also explore the effects of ethnicity, age, diet, family history, and other variables on the predictive value of PSA measurement. VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S31 Chemoprevention of Prostate Cancer continued A number of factors contributed to the design and implementation of this large clinical trial. At the time of study design, national attention was directed at prostate cancer because of the dramatic increase in the number of diagnoses secondary to the widespread implementation of PSA screening. Evidence existed that androgens play a role in the development of the disease. Concurrently, finasteride was approved by the FDA for the treatment of benign prostatic hyperplasia (BPH). Evidence existed that genetic variations leading to low levels of 5--reductase activity were related to a phenotype that was devoid of prostate cancer. Because finasteride is well tolerated and has the ability to alter the hormonal milieu, it became the focus treatment of the first large study of prostate cancer prevention. The PCPT is rapidly reaching completion. It is anticipated that study results will be available shortly after completion of EOS biopsies in May 2004. In addition to the prostate cancer prevention, a number of other issues will be evaluated. Because biopsies will be performed in all subjects, the true sensitivity and specificity of PSA testing for the detection of prostate cancer at PSA levels lower than 4.0 ng/mL will be ascertained. Data will be analyzed to evaluate the effect of ethnicity, age, family history, and other variables on the predictive value of PSA measurement for prostate cancer as determined by prostate biop- S32 VOL. 5 SUPPL. 6 2003 sy. Dietary history data also is being collected and will provide information on diet and prostate cancer. The recently completed Medical Therapy of Prostatic Symptoms (MTOPS) study identified the value of finasteride and an -blocker in preventing the progression of BPH.19 The PCPT will evaluate the effect, if any, of 7 years of treatment with finasteride on BPH. Perhaps the most important series of observations will be the opportunities for development of case-control studies that were heretofore not possible. Previous studies have selected cancer-free controls from groups of men with normal PSA levels or with elevated PSA levels and negative biopsy results. PCPT participants, on the other hand, have undergone prostate biopsy regardless of PSA level. This will provide valuable information about the rates of prostate cancer in relation to different PSA levels. References 1. 2. 3. 4. 5. REVIEWS IN UROLOGY Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5-26. Huggins C, Hodges CV. Studies on prostatic cancer: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5 alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974;186:1213–1215. Habenicht UF, el Etreby MF. Rationale for using aromatase inhibitors to manage benign prostatic hyperplasia: experimental studies. J Androl. 1991;12:395–402. Zhou JR, Gugger ET, Tanaka T, et al. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr. 1999; 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 129:1628–1635. Mentor-Marcel R, Lamartiniere CA, Eltoum IE, et al. Genestein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP). Cancer Res. 2001;61:6777–6782. Walczak J, Wood H, Wilding G, et al. Prostate cancer prevention strategies using antiproliferative or differentiating agents. Urology. 2001(4 suppl 1);57:81–85. Lucia MS, Anzano MA, Slayter MV, et al. Chemopreventive activity of tamoxifen, N-(4hydroxyphenyl)retinamide, and the vitamin D analogue Ro24-5531 for androgen-promoted carcinomas of the rat seminal vesicle and prostate. Cancer Res. 1995;55:5621–5627. Urban D, Myers R, Manne U, et al. Evaluation of biomarker modulation by fenretinide in prostate cancer patients. Eur Urol. 1999;35:429–438. Cuendet M, Pezzuto JM. The role of cyclooxygenase and lipoxygenase in cancer chemoprevention. Drug Metabol Drug Interact. 2000; 17:109–157. Kirschenbaum A, Liu X, Yao S, Levine AC. The role of cyclooxygenase-2 in prostate cancer. Urology. 2001;58(2 suppl 1):127–131. Friedenreich CM. Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev. 2001;10:287–301. Shreve PD, Grossman HB, Gross MD, Wahl RL. Metastatic prostate cancer: initial findings of PET with 2-deoxy-2-[F-18]fluoro-D-glucose. Radiology. 1996;199:751–756. Morris MJ, Akhurst T, Osman I, et al. Fluorinated deoxyglucose positron emission tomography imaging in progressive metastatic prostate cancer. Urology. 2002;59:913–918. Chang SS, Gaudin PB, Reuter VE, Heston WD. Prostate-specific membrane antigen: present and future applications. Urology. 2000;55:622–629. Sodee DB, Malguria N, Faulhaber P, et al. Multicenter ProstaScint imaging findings in 2154 patients with prostate cancer. The ProstaScint Imaging Centers. Urology. 2000;56:988–993. Ellis RJ, Kim EY, Conant R, et al. Radioimmunoguided imaging of prostate cancer foci with histopathological correlation. Int J Radiat Oncol Biol Phys. 2001;49:1281–1286. Feigl P, Blumenstein B, Thompson I, et al. Design of the Prostate Cancer Prevention Trial (PCPT). Control Clin Trials. 1995;16:150–163. McConnell J for the MTOPS Research Group. The impact of medical therapy on the clinical progression of BPH: results of the MTOPS trial. Presented at: American Urological Association Annual Meeting; May 29, 2002; Orlando, FL.