Natural History

Prognosis at the time of initial diagnosis is clearly based on stage at presentation, with those patients having locally advanced disease or metastases at presentation most likely to experience symptomatic progression. Patients with poorly differentiated tumors on Gleason histologic grading are likely to comprise a large proportion of men presenting with advanced disease; similarly, within each stage, the histologic Gleason score adds prognostic significance. The serum prostate-specific antigen level has been shown to correlate with stage, particularly at very low and significantly elevated levels, and may improve the predictive value of either clinical stage or histologic grade alone. Predicting the behavior of small, well- to moderately differentiated clinically localized tumors remains a challenge for physicians, with host factors such as patient age, general health, and significant comorbidities influencing outcomes. These factors are important when counseling individual patients about their treatment options.

Symptomatic Disease Progression

Symptomatic progression can be divided into local and distant manifestations of disease. Local symptoms include bladder outlet obstruction, hematuria, and ureteral obstruction. Distant manifestations of disease include those attributable to sites of bone metastases (pain, pathologic fracture, neurologic disturbance), and extraskeletal sites. Several factors together can contribute to anemia, azotemia, and failure to thrive in advanced disease states. The course of disease in men with newly diagnosed advanced prostate cancer was evaluated in a recent study Advanced stage was defined as either local disease too advanced for curative treatment, or metastatic disease not yet causing symptoms. There were 938 patients included in the study, randomized to either androgen deprivation at the time of diagnosis or deferred until an indication prompted treatment at the discretion of the patient or physician. Of 465 men randomized to deferred treatment, 141 (30%) required transurethral resection of the prostate for bladder outlet obstruction, 55 (12%) developed ureteral obstruction, and 211 (45%) developed symptomatic osseous metastases during the follow-up period. Pathologic fracture and cord compression were less common (4%), likely due in part to lack of adequate long-term follow-up, initiation of androgen deprivation for bone pain prior to development of these more serious complications, and to the fact that deferred treatment was initiated in many cases for local progression and others because of increasing levels of tumor markers (e.g., prostate-specific antigen [prostate-specific antigen]). It is interesting to note that deferred treatment was initiated almost as commonly for problems related to local progression as it was for metastatic disease. Twenty-nine patients died from prostate cancer and 51 from other causes. Although criteria for deferred therapy were not firmly established, and specifics regarding therapy were not provided (i.e., transurethral resection of the prostate [transurethral resection of the prostate] plus androgen deprivation therapy versus androgen deprivation therapy alone for bladder outlet obstruction), these findings during the contemporary accrual period of 1985 to 1993 provide a generalizable estimate of the preliminary outcome in prostate cancer patients with newly detected disease of similar stage.

Androgen Deprivation

There are currently five major methods of androgen deprivation employed in managing progression of prostate cancer: (1) bilateral orchiectomy to remove primary testicular androgen production; (2) estrogen therapy to reduce luteinizing hormone production; (3) luteinizing hormone-releasing hormone (luteinizing hormone-releasing hormone) therapy to reduce luteinizing hormone production; (4) antiandrogen therapy directed at the target organ androgen receptor; and (5) combined androgen deprivation, whereby androgen production by the testes is ablated and androgens are blocked at the receptor. Although approximately 10% of men treated with androgen deprivation will experience prolonged survival, particularly in the presence of favorable prognostic factors, the majority of men treated will experience disease progression with a median time to progression of 12 to 14 months and require further therapy.

Complications of Androgen Deprivation Complications of androgen deprivation include impotence, decreased libido, changes in muscle mass and resultant changes in weight distribution, muscular weakness, lack of endurance, and mood changes. These effects can have a profound impact on quality of life, self-esteem, and interpersonal relationships. Osteoporosis and osteoporotic fracture are a recognized consequence of androgen deprivation, and may become an important clinical factor in those men surviving for several years following androgen deprivation. In a recent investigation, androgen deprivation was shown to be associated with a significantly increased risk of osteoporotic fracture in men with prostate cancer compared to those not treated with androgen deprivation. Risk factors for the development of osteoporosis in men with prostate cancer undergoing androgen deprivation were preandrogen deprivation hypogonadal states, smoking, and slender body habitus; a large percentage of major fractures may be due to osteoporosis in this subset. It has also been reported that bone densities are higher in prostate cancer patients treated with estrogens than in those treated with orchiectomy. Approaches to preventing androgen deprivation induced osteoporosis are experimental and include intranasal calcitonin therapy and bisphosphonates.

Anemia is a recognized complication of androgen deprivation. This has been well documented in patients with benign prostatic hyperplasia (benign prostatic hyperplasia) receiving androgen deprivation, effectively controlling for the potential effect of marrow failure on hemoglobin production seen in patients with metastatic disease. Androgen deprivation associated anemia is normochromic, normocytic, and temporally related to the initiation of androgen blockade. Nadir hemoglobin levels are reached  at a mean of 5.6 months of androgen deprivation, with 90% of men experiencing a >10% decline and 13% of men experiencing a >25% decline. Anemia may be associated with symptoms such as dyspnea, fatigue, and weakness in over 10% of treated men. These symptoms have been shown to respond to administered recombinant human erythropoietin.

Osseous Metastases

Spinal Cord Compression and Other Complications of Osseous Metastases

Management of Pain from Osseous Metastases

Urinary Manifestations of Disease

Urinary symptoms such as retention of urine and hematuria can result from local disease progression and may be treated with cystoscopy and transurethral resection or fulguration. Ureteral obstruction may be treated with either percutaneous nephrostomy or internal stenting, but these procedures are associated with discomfort, infection, and other tube-related problems (nephrostomy obstruction, dislodgement and bleeding, and the need for periodic tube change). Frequent visits to the emergency ward, hos-pitalization, and heightened patient anxiety may result and must be weighed when considering these treatments.

Anemia

In patients with diffuse osseous metastases, replaced marrow results in decreased blood-cell counts. This is aggravated by the myelosuppressive effects of radiotherapy, the anemia of androgen deprivation, and in some cases, hematuria due to local progression. Anemia is generally not acute in most cases, and very low hemoglobin levels may be tolerated by the patient. The physician should remain astute to the potential role of transfusion, particularly in the symptomatic patient.

Anorexia and Cachexia

Anorexia and cachexia will affect over half of patients with advanced disease. Treatment often consists of a series of nutritional supplements and pharmacologic agents, most commonly megestrol acetate (800 mg per day) and dron-abinol (2.5 mg twice to three times per day).

Hospice Care

The primary goal of hospice care is palliation of the cancer patient with a life expectancy under 6 months. One significant advantage of hospice care is that it can be delivered in the patient’s home. More than 200,000 Medicare beneficiaries enter hospice programs annually; in one recent review, prostate cancer patients comprised 7.4% of enrolled individuals. Among prostate cancer patients, median survival was 46 days, with 14% expiring within 7 days of enrollment and 13.7% living more than 180 days following enrollment.

Conclusion

The clinician must bring a working knowledge of the anticipated progression of prostate cancer, available therapies, and potential complications of both the disease and its therapies to bear on decisions concerning treatment for patients with this disease.

Magnetic resonance imaging is frequently used to evaluate spinal cord compression, due to its high sensitivity and ability to image the vertebral bodies and paraspinal and intraspinal soft tissues. On Tl-weighted images, bone metastases tend to stand out as focal or diffuse hypointense (dark) lesions against a background of higher signal intensity marrow. Compared to myelography, magnetic resonance imaging is noninvasive, directly visualizes cord compression, and can measure the extent of tumor outside the thecal sac along the entire cord.

In the patient with spinal cord compression, outcome is most accurately determined by neurologic status at the time of presentation, making early diagnosis crucial. Of those patients who are ambulatory at presentation, the majority (60 to 100%) will remain so following therapy if it is instituted promptly. The recommended primary treatment in the setting of spinal cord compression remains controversial; radiation therapy appears preferable in most cases. Radiotherapy seems as beneficial as decompressive surgery, particularly in the individual with early spinal cord compression at a single level — both radiotherapy and laminectomy followed by radiotherapy show similar results. Surgery is generally reserved for selected patients who progress after initial treatment and for those with bone instability.

Most often a direct posterior radiotherapy field is used, including a margin of one to two vertebral bodies above and below the area of compression. Conventionally, 20 to 30 Gy is delivered over 1 to 2 weeks, although single dose treatments delivering 10 to 15 Gy have been reported to show equivalent results. Radiation is preceded by cor-ticosteroid administration, and a dexamethasone taper is frequently used. Corticosteroids have anti-inflammatory properties which reduce swelling and edema; they also suppress the pituitary production of ACTH, resulting in decreased adrenal steroid production (including the adrenal androgens androstenedione and dehydroepiandrosterone). Confirmation of the diagnosis of prostate cancer is ascertained. When necessary, needle biopsy of the prostate will provide a diagnosis, obviating the need for bone biopsy. In the patient who has not previously been treated with androgen deprivation, this is promptly initiated. Bilateral scrotal orchiectomy is an attractive option due to its simplicity, relatively low cost, and uniform ability to achieve castrate levels of testosterone. In the rare patient who cannot undergo orchiectomy, ketoconazole, an imidazole antifungal agent, may be equivalent to orchiectomy in the acute period due to its rapid onset of action. Ketoconazole is administered orally 200 to 400 mg three times per day to inhibit both testicular and adrenal androgens. Its mechanism of action involves inhibition of the cytochrome P-450-dependent 14-demethylation step in the steroid synthesis pathway and may have a direct cytotoxic effect. Side effects of ketoconazole include hepatic dysfunction and gastrointestinal disturbances.

The overall prognosis for the patient with spinal cord compression is poor. Reported median survival ranges from 6 to 12 months. In a recent report of 35 patients with suspected spinal cord compression, imaging studies in 26 demonstrated epidural spinal cord compression. Interestingly, in five patients this provided the first indication of prostate cancer. Ninety-six percent of patients presented with back pain; of twelve patients with back pain alone who were ambulatory, six had decreased sensation below the level of the lesion. Eleven patients were para-paretic, one was paraplegic, and one patient with a cervical lesion was quadriplegic. Nearly half the patients had varying degrees of urinary and bowel complaints. All patients were initially treated with steroids, androgen deprivation, and radiation therapy, and three ultimately underwent laminectomy. Radiation was found to be effective in all ambulatory patients and in 83% of paraparetic patients. Seven patients, however, experienced recurrent compression during the follow-up period. Of the patients presenting with paraplegia, only 20% regained function with radiation; despite surgical decompression, average survival was only 3.9 months in these patients. Similar poor results were reported in a study of 137 patients undergoing radiation therapy for advanced disease. In this cohort of men with hormone refractory prostate cancer, at a follow-up of 3 months, 29 had died of disease, and palliation was felt to be effective in only 25% of remaining patients.

Pathologic fractures may involve the ribs, pelvis, scapula, and vertebrae, generally as a result of diffuse replacement of bone by tumor insufficient to bear applied loads. Long bone pathologic fracture occurs due to an osseous metastatic defect; when it involves the humerus or femur, it is most likely associated with an area of metastasis characterized by a 2.5 cm bone defect and > 50% destruction of cortex. Long bone fractures are best treated surgically when technically possible and appropriate. Predicting the pathologic risk of fracture at pain sites based on size of defect and cortical loss, followed by prompt administration of radiotherapy, may be an effective way of avoiding this debilitating complication. Pathologic fracture involving the vertebrae may result in neurologic symptoms and must be diagnosed and treated promptly, as previously discussed. As with all cases of spinal evaluation, magnetic resonance imaging can reliably elucidate the cause of vertebral compression fracture. The appearance of the marrow of the involved vertebral body on Tl-weighted imaging (i.e., complete replacement, incomplete replacement, complete preservation) and the pattern of abnormality can be used to distinguish benign and malignant compression fractures in most cases.

In all cases involving neurologic symptoms, it is important to differentiate between disorders caused by bone infiltration and those caused by intrinsic brain metastases. In rare cases, bony skull base metastases will result in nerve entrapment and cranial nerve palsies. The most commonly involved nerves are the fifth, sixth, and seventh cranial nerves. Skull base irradiation may result in significant symptomatic improvement in select cases and symptom improvement in over 50% of patients, durable in 80% of respondents.

Wide-field therapy may be administered for patients with multiple painful bony metastases. This is most frequently administered as hemibody radiotherapy, usually as a single dose (6 to 8 Gy). Pain relief will occur within a few days in up to 70% of patients. Fractionated hemibody radiotherapy (30 Gy per 10 fractions) has been evaluated in this application. In a phase II study, fractionated hemibody radiotherapy was associated with improved pain control at 1 year (70% versus 15%) and decreased requirement for retreatment (13% versus 71%).

Alternatively, when multiple metastatic bony sites exist, administration of systemic bone-seeking isotope therapy such as strontium-89 (Sr) may be employed. This is a radiopharmaceutical that localizes to bone following intravenous administration. As a beta-emitting isotope, Sr localizes to areas of increased mineral turnover and decays with an approximate 40-day half-life. Evidence of the effect of Sr comes from a double-blind placebo controlled trial. In this study, improvement in symptoms was observed in 75% of the patients treated with Sr. Pain relief occurred 2 to 4 weeks following administration and reached maximal effect at 4 to 12 weeks. Results with Sr appear to be similar to those obtained with hemibody radiotherapy. Hematologic toxicity is similar with both treatments although nausea, vomiting, and diarrhea are generally not seen with Sr. Effectiveness of palliative radiotherapy appears to correlate with extent of disease at the time of treatment and is often difficult to measure due to problems in controlling for physician-based scoring systems, accounting for concurrent changes in analgesics, and controlling for simultaneous therapies.

Conventional methods of pain control become increasingly important as the disease advances and the patient becomes hormone refractory. In such cases, maintenance of primary testicular androgen ablation should be continued despite the patient’s “hormone refractory status.” In patients treated with total androgen blockade, the antiandrogen should be withdrawn. This is based on the observation that up to 50% of patients will experience a decrease in serum prostate-specific antigen level and stabilization of disease. In patients not receiving an antiandrogen, such an agent may be added with the potential for objective response rate in 15 to 20% of patients.

Despite these steps being taken, patients with hormone refractory disease will ultimately experience pain and require pain management. To address this, the World Health Organization has developed guidelines for pain treatment through use of a pain ladder. First-line therapy is with nonsteroidal agents. Nonsteroidal anti-inflammatory agents (ibuprofen, 600 to 800 mg every 6 to 8 hours) may relieve symptoms of inflammation associated with tumor growth and fracture and may involve the prostaglandins pathway. When required, an opiate is added to the anti-inflammatory agent. Opioids are administered around the clock, with tolerance overcome by an increasing dose. Advances in transdermal application of opioids (i.e., fentanyl) have made this approach extremely useful. Antidepressants are often used in concert with opioid therapy for maximal effect, particularly in cases of neuropathic pain states. Antidepressants are also useful in relieving the anxiety and clinical depression experienced by many patients with advanced disease.

As screening programs have matured and the performance characteristics of digital rectal examination and prostate-specific antigen have become considerably clearer, a parallel, somewhat unobtrusive, series of investigations have laid the foundation for the concept of chemoprevention of prostate cancer. As was elegantly described by Sporn, chemoprevention efforts (and clinical trials testing these hypotheses) for cancer are considerably different from traditional therapeutic efforts and trials.

The medical community has witnessed the development of many exciting new innovations that have identified major opportunities to prevent prostate cancer. Indeed, in October 1998, a Chemoprevention Conference was held in Brussels, cosponsored by the European Association of Urology, the European Association for Research and Treatment of Cancer, and the Chemoprevention Branch of the National Cancer Institute of the United States. At this conference, no fewer than 13 potential strategies to prevent prostate cancer were discussed. At the present time, a number of trials are being conducted; some have completed their accrual, and many are in the planning stage.

Why Chemoprevention?

The rationale for the chemoprevention of prostate cancer is quite simple. First, there appears to be a natural progression of the prostatic epithelium from normal, to hyperplastic, through various stages of premalignancy (to include prostatic intraepithelial neoplasiya) to frank malignancy and thereafter to invasive disease. Current management strategies of early diagnosis and therapy, even under the best conditions, will result in no better than an 80 to 85% disease-free survival (i.e., zero prostate-specific antigen after radical prostatectomy) at 10 years. As a policy of prevention could conceivably lead to less cost and less morbidity with an improved survival, this has become a very attractive alternative.

Until the 1990s, evidence of the potential efficacy of chemopreventive agents constituted only intriguing observations. With the development of finasteride, the first 5 a-reductase inhibitor, and an agent that mimicked an enzyme deficiency that effectively prevented both benign prostate hyperplasia (benign prostatic hyperplasia) and prostate cancer, the first large-scale prevention trial began. The publication of serendipitous findings of dramatic reductions in prostate cancer incidence in two other prevention trials, one using alpha tocopherol and one using selenium, set the stage for a substantial increase in interest in the concept of chemoprevention of prostate cancer.

We are currently on the brink of a veritable explosion of clinical trials of agents for the prevention of prostate cancer. This chapter will address the rationale behind many of these agents. It must be stressed that the list of agents discussed here is in no way exhaustive but provides a sense of the types of approaches currently being investigated.

TABLE . Differences between Trials for Chemoprevention and Therapy of Cancer

Progression of Prostate Carcinoma

Evidence is accumulating that prostate cancer develops over a period of years, occasionally decades, and that it may progress through a number of steps. Perhaps the most telling series of observations have come from autopsy studies of men who died without evidence of prostate cancer. Sakr and colleagues in Detroit, Michigan, have collaborated with the Medical Examiner’s office in that city for a considerable period of time and have performed whole-mount analyses of men in various decades of life, analyzing the prevalence of both prostate cancer as well as prostatic intraepithelial neoplasia.

Prostatic intraepithelial neoplasia is the best characterized, most common, and most commonly accepted precursor to prostate cancer. While concrete evidence linking it with all cases of carcinoma of the prostate is lacking, considerable data are accumulating that connect these two lesions. These pieces of evidence are given below.

1.  Pathologic characteristics of prostatic intraepithelial neoplasia and prostate cancer are similar. These characteristics include (1) the increasing loss of the basal cell layer with higher grades of prostatic intraepithelial neoplasia, ultimately leading to a loss of this cell layer in frank carcinoma, (2) the cytologic similarities of prostatic intraepithelial neoplasia and prostate cancer — most often of higher grade than transitional zone tumors and more akin to peripheral zone tumors, (3) a higher microvessel density in prostatic intraepithelial neoplasia and prostate cancer than in benign or hyperplastic epithelium, and (4) immunohistochemical similarities that are present in prostatic intraepithelial neoplasia and prostate cancer.

2.  Prostatic intraepithelial neoplasia and prostate cancer frequently coexist. In Sakr’s series, high-grade prostatic intraepithelial neoplasia was only noted in men over 40 years who had concomitant prostate cancer. Several series have demonstrated that repeat biopsy in men with isolated prostatic intraepithelial neoplasia on prostate biopsy will detect prostate cancer in between 51 and 100% of cases.

Thus, it appears that the transformation of normal prostatic epithelium to carcinoma of the prostate may progress through a number of steps that can be measured on a molecular level, on a histochemical level, and on a morphologic level. These changes appear to occur first within the prostatic epithelium while the prostatic cells remain confined by a normal basement membrane and normal basal cells and in a normal glandular arrangement. What appears to be a prolonged period of transformation may provide an extended-duration target for chemoprevention strategies. Figures 48-2 to 48-5 demonstrate the histologic changes from benign prostatic epithelium (2), through prostatic intraepithelial neoplasia (3), through moderately differentiated Gleason grade 2+3 carcinoma (4), to poorly differentiated Gleason grade 5+5 carcinoma (5).

Opportunities for Chemoprevention

Conclusion

There are many potential agents that demand testing as potential methods of preventing prostate cancer. It is almost certain that the next 10 years will be a period of dramatic increase in information and evidence in this area. At the present time, there is no evidence that any agent will affect prostate cancer risk. However, as some potentially effective agents may have other beneficial effects (e.g., vitamin E and cancer prevention as well as a possible reduction of cardiovascular disease; aspirin and heart disease reduction; and reduced-fat diet and colon cancer-heart disease-stroke reduction), it is reasonable for physicians to discuss these options with their patients.

The opinions expressed herein are those of the authors and do not necessarily reflect those of the United States Department of the Army or Defense.

The term “vitamin E” is used to refer to a group of naturally occurring substances that have vitamin E activity including a-, β-, δ-, and y-tocopherols (that have saturated side chains) and tocotrienols (that have unsaturated side chains). These agents have some degree of difference in biopotency with the naturally occurring d-a-tocopherol approximately 30% more potent than the synthetic forms — d- or d, l-a-tocopherol alone, acetate, or succinate. The principal food sources of vitamin E are vegetable and seed oils as well as alfalfa and lettuce.

A primary function of vitamin E is as an antioxidant, interacting with free radicals (e.g., singlet oxygen, superoxide anion, organic peroxide radicals, hydrogen peroxide, and others) that are generated as a normal part of cellular metabolism. These free radicals can interact with cellular structures, primarily membranes, and lead to cellular damage, generally through lipid peroxidation. Over time, the oxidative stress in humans increases and, similarly, with aging, the endogenous antioxidant capability (from glutathione, vitamins A, C, and E, superoxide dismutase, catalase, and glutathione peroxidase) decreases.’ In addition to the effects of free radicals on vascular and inflammatory diseases, the initiation and promotion of cancer have been attributed to these agents.

A variety of lines of evidence suggest that vitamin E can modulate prostate cancer risk. As noted above, an increase in antioxidant levels may reduce cumulative cellular damage from free radicals and thereby reduce the likelihood of the first steps in carcinogenesis. Evidence also suggests that elevated vitamin E levels are associated with enhanced immune function, perhaps leading to improved antineoplastic immune surveillance.In addition, changes in oxidative stress in cells have been demonstrated to alter the production of various transcription factors, altering gene expression.’ Kelloff’s exhaustive review lists several other potential actions including protection of cytochrome P-450 metabolism, induction of differentiation, gap junction intercellular communication, inhibition of proliferation, arachidonic acid metabolism, nitrosamine formation, and ornithine decarboxylase activity.

There is growing evidence suggesting that vitamin E may have efficacy in the prevention of, specifically, carcinoma of the prostate. Perez Ripoll studied the effect of doxorubicin, vitamin E, and the combination in the human prostatic cancer cell line DU 145. Vitamin E enhanced the cytotoxic effect of doxorubicin but also inhibited tumor growth when used alone. In another study using the Nb rat prostate cancer model, vitamin E not only enhanced the efficacy of doxorubicin but had a similar effect with cyclophos-phamide and methotrexate. In the same Nb rat prostate cancer model, Nesbit found that the doxorubicin-vitamin E combination had a lower final tumor volume than control animals. In a series of experiments using the CRL-1740 prostate cancer cell line, vitamin E was shown to have a potent suppressive effect on tumor growth at relatively low concentrations (0.1 mM), and at higher concentrations (> 0.25 mM), no cells survived to day 24. In this study, deoxyribonucleic acid (DNA) analysis demonstrated extensive apoptosis due to vitamin E supplementation.

Epidemiologic studies have generally observed that lower rates of vitamin E intake have been associated with higher prostate cancer risk. Plasma vitamin E levels were measured in 2974 men from Basel, Switzerland, between 1971 and 1973, and mortality and cancer diagnoses were summarized in 1990. While overall levels of vitamin E did not correlate with prostate cancer risk, within the group of men who were smokers, the relative risk of prostate cancer diagnosis was 3.2 times higher in those with low levels of vitamin E.

Selenium

Selenium is an essential trace element required for the normal function of glutathione peroxidase, a major intracellular antioxidant. Selenium is found in varying concentrations in soil and is incorporated into forage crops and thereafter into animals. Plants convert the inorganic selenium in the soil to organic selenium via a sulfur assimilatory pathway. Human intake is thereby from grains, vegetables including onions and garlic, and animal meat. While in the United States most agricultural areas have acceptable amounts of selenium in the soil, in various regions of the world including New Zealand and China, some areas are notable for very low levels of selenium. Previously, until selenium was incorporated into fertilizers, levels of selenium intake were very low in Finland. This may have confounded earlier studies in this population. In the United States, the recommended daily allowance for men is 70 pg. In areas with extremely low dietary selenium intake, various diseases have been reported. Keshan disease, a cardiomyopathy with diffuse necrosis of the myocardial cells, has been identified in China in areas with low selenium intake. Kashin-Beck disease, a disease associated with cartilage necrosis, compromised epiphyseal growth, short stature, and joint abnormalities, has also been found in selenium-deficient areas. While studies have demonstrated that daily intake of 200 pg is not associated with any toxicity, selenium can be associated with significant side effects with intake levels only slightly above these. Indeed, the maximum tolerated dose is 819 pg and the mean lethal dose (LD50) in rodents is 26 mg per kg. Turner and Finch have recently summarized the literature pertaining to selenium toxicity. They noted that examples of selenium poisoning have been reported on farms, commercial piggeries, and more recently in wildlife in a California sanctuary in which selenium-contaminated water led to poisoning of wildlife.

A variety of animal studies have suggested that selenium may prevent or reduce the development of a variety of neoplasms. Reddy and colleagues studied the ability of organoselenium compounds (p-methoxybenzyl seleno-cyanate and l,4-phenylenebis[methylene]selenocyanate) to impact on colon carcinogenesis in rats treated with a carcinogen and fed either a low-fat or high-fat diet. It has been observed that the impact of selenium is greatest when given during the early stages of cancer progression or during the period of carcinogen administration in some tumor models. Using the human prostate cancer cell line DU 145, Webber and colleagues found a 50% reduction in growth related to selenium supplementation. These effects were seen in concentrations analogous to those achievable in serum associated with selenium supplementation. The direct association between dietary selenium and rodent mammary and skin cancers has been best demonstrated through supplementation with onions or garlic grown in selenium-enriched soils or from eggs from hens given a selenium-enriched diet thereby reducing chemical-induced cancers. Perhaps the most intriguing study was conducted in a mammary carcinogenesis model in rodents in which garlic grown in selenium-enriched soil was used as a preventive agent. The authors found increases in glutathione peroxidase levels as well as concomitant reductions in cancer rates with increasing selenium intake.

Population studies have demonstrated that overall cancer rates are higher in populations with low selenium intake. No phase III trials of selenium have been conducted to assess the impact on prostate cancer incidence or mortality. However, there have been several observations made from other clinical trials that may have considerable import. Yoshizawa and colleagues conducted a case-control analysis of 181 men in the Health Professionals Follow-up Study who developed advanced prostate cancer compared to controls from within the study. All men in the study had contributed toenail clippings in 1987, and with these specimens, selenium levels were analyzed. Higher selenium levels in this study were associated with a reduced risk of advanced prostate cancer (the odds ratio comparing highest to lowest quintile of intake being 0.49). Hardell and colleagues conducted a case-control study of selenium levels in plasma and glutathione peroxidase in erythrocytes in 164 patients with prostate cancer and 152 controls with benign prostatic hyperplasia, all from a urology clinic. The authors found that among men who were not taking selenium supplementation, selenium levels in those men with cancer were 0.99 pmol per L compared with 1.08 pmol per L in controls (p = .0007). A similar study was conducted in the Hypertension Detection and Follow-up Program. In this study of 10,940 men and women aged 30 to 69 years with diastolic blood pressure > 90 mm Hg, baseline venous blood samples were obtained. During a 5-year period, 111 patients were diagnosed with cancer and two controls were identified for each case. Case-control analysis demonstrated significantly lower selenium serum levels in cancer cases than in controls. This difference was greatest for gastrointestinal and prostatic tumors. (Selenium levels in prostate cancer cases and controls averaged 0.128 and 0.139 pg/mL, respectively.) Supporting the antioxidant hypothesis of the mechanism of action of selenium, serum levels of retinol and vitamin E were strongly associated with this effect; the relative risk of cancer in the lowest tertile of selenium was 2.4 and 3.9 for the lowest tertiles of vitamin E and retinol, respectively. Another large case-control study was conducted within the Nurses’ Health Study, a prospective analysis begun in 1976 of 121,700 female registered nurses aged 30 to 55 years living in the United States. The authors studied toenail selenium levels and found that levels declined with age and were lower in smokers. At odds with other similar studies, the authors did not find an association between selenium and overall cancer levels. This study added to the observations that a greater association between selenium and cancer risk may occur in men compared to women.

Perhaps the most intriguing observation regarding selenium and prostate cancer was made by Clark and colleagues. With the hypothesis that selenium intake would reduce the incidence of carcinoma of the skin, a group of 1312 patients at seven dermatology clinics, primarily in areas of the United States with low selenium intake, were randomized to receive either 200 pg of selenium daily or placebo. Fortunately, the authors also collected information on other cancers as melanoma rates were identical and there was no difference in squamous or basal cell carcinoma in both the study arms. However, when the authors analyzed all carcinomas, there were 104 in the placebo arm compared to 59 in the selenium arm of the study (RR = 0.55). Additionally, 35 prostate cancers were detected in the placebo arm compared with only 13 in the selenium arm of the study (RR = 0.37). The authors found no toxicity from selenium supplementation. Also of interest was a significant reduction in total cancer mortality (29 versus 57 in the placebo arm, RR = 0.5).

The mechanism of action of selenium, if it is a chemopreventive agent in humans, is unknown. Like oc-tocopherol, selenium may function as an antioxidant, thereby preventing cumulative cellular damage from reactive oxygen species. Indeed, there are data that selenium and a-tocopherol may have synergistic effects and that in the presence of low intake of either, supplementation with the other may reduce the carcinogenic effect. A second postulated action is enhancement of immune response. This effect has evidence in the observation in a number of animal species that selenium deficiency is associated with decreased cell-mediated immune function. Evidence is also available that at higher than usual concentrations, selenium may protect against the action of a number of carcinogens.  Selenium supplementation has also been demonstrated to inhibit tumor growth and to stimulate apoptosis in cell culture.

A variety of methods exist to measure selenium intake. It is possible to extrapolate selenium deficiency in certain areas of the world, where low selenium soil concentrations exist and there is a low intake of animal protein; however, in the United States, with such diverse food sources, only by measurement of individual patient levels can selenium intake be determined. Serum selenium concentrations will provide estimates of current intake but a more relevant measure comes from toenail levels, which provide an approximation of the intake over the past year.

While certainly there is a body of literature suggesting that selenium may indeed reduce cancer risk, a number of confounding factors mitigate this conclusion. First is the observation that most human sources of selenium are organic — principally selenomethionine and selenocysteine — while many of the animal and other studies have used inorganic sources such as sodium selenite, often using levels of supplementation many times greater than that seen in human populations. A second problem is the very small number of cases of prostate cancer summarized in previous studies. Until Yoshizawa and colleagues’ study of 181 men with advanced prostate cancer, four previous studies provided data on a total of only 123 men with prostate cancer.  Another concern is that while selenium levels differed significantly between cases and controls in Hardell’s study, there were no differences observed in levels of erythrocyte glutathione peroxidase. This brings into question whether serum selenium levels actually correlate with intracellular antioxidant activity. Thus, saturation of glutathione peroxidase levels occurs at relatively low selenium intakes, calling into question whether supplementation actually changes antioxidant concentrations in cells. An internal inconsistency is rarely mentioned in reviews of selenium activity. Yan and Spallholz have demonstrated that selenium can interact with sulfur-containing compounds (thiols) to yield substances that lead to the formation of superoxide and hydrogen peroxide free radicals. They speculate that this may be the mechanism whereby apoptosis can be promoted by selenium but is in direct conflict with one of the proposed methods of action: as an antioxidant. In addition, a very large trial from Linxian, China, found no reduction in prostate cancer incidence or mortality. An additional problem in case-control studies analyzing cancer cases is evidence suggesting that selenium levels in serum can be lowered by the presence of cancer. In advanced tumors or tumors with a long prediagnostic phase (e.g., prostate cancer), this can be a major confounding factor in such studies even if toenail assays for selenium are used. Dietary assessments of selenium can also be unreliable due to the wide variability of soil selenium levels. Animal study conclusions may also be confounded by different mechanisms of selenium metabolism among species. Finally, merely the observation that millions of Chinese have profoundly selenium-deficient diets and yet no dramatic increases in cancer rates give pause to those who attribute dramatic differences in cancer rates merely to selenium intake. Additionally, the doses used for chemoprevention (50 to 200 pg/d) are quite close to those at which toxic effects are seen. Side effects most commonly encountered are dermatitis, hair loss, and abnormal nails; growth failure, hepatic dysfunction, and anemia can also be seen.

Anti-inflammatory Agents

A wide range of anti-inflammatory agents have been demonstrated to have chemopreventive effects in a number of tumor systems. Generally referred to as nonsteroidal anti-inflammatory drugs, the mechanism of action leading to this chemopreventive effect is unknown, yet most frequently attributed to its inhibition of a key enzyme in the metabolism of  arachidonate-cyclooxygenase. Two isoforms of cyclooxygenase have been identified: COX-1, which is constituitively expressed in many tissues, and COX-2, an inducible and more recently discovered enzyme. Many nonsteroidal anti-inflammatory drugs and aspirin inhibit both COX-1 and COX-2; thus, due to the COX-1 effect, this results in a number of undesirable side effects including gastritis and risk of neurologic sequelae (hemorrhagic stroke). It is for this reason that the advent of COX-2 inhibitors have opened a new avenue for the prevention of a variety of tumors.

Inhibitors of prostaglandin (or prostanoid) synthesis have been observed to have chemopreventive effects in a number of preclinical and clinical trials. In experimental animal models, indomethacin, aspirin, and piroxicam have been demonstrated to reduce fibrosarcoma and colon cancer growth. Similar effects have been observed in animal models of prostate cancer. Viljoen and colleagues found that aspirin substantially reduced the growth of the human prostate cancer line DU 145. In the Nb rat prostatic ade-nocarcinoma model, Drago and Murray found that aspirin and indomethacin significantly reduced the number of metastases in animals. Providing further evidence that arachidonic acid metabolism is the etiology of this effect, Ghosh and Myers demonstrated that arachidonic acid replacement dramatically increased the growth of human prostate cancer cell lines. Using a variety of agents to alter metabolism at several levels (ibuprofen for cyclooxygenase, SKF-525A for cytochrome P-450, baicalein and BHPP for 12Tipoxygenase, AA861 and MK886 for 5Tipoxygenase), the authors found that the most significant degree of inhibition occurred with 5-lipoxygenase inhibition. Of interest, other evidence suggests that nonsteroidal anti-inflammatory drugs may actually increase apoptosis in rectal mucosa and in colon cancer cell lines. The observations provide evidence of a number of possible effects of these agents.

In a substantial number of observational studies as well as in clinical trials, aspirin and sulindac have been demonstrated to significantly reduce the incidence of colon cancer and adenomatous polyps. Interestingly, in patients with familial adenomatous polyposis or Gardner’s syndrome, polyp counts have usually returned to pretreatment levels after stopping NSAID treatment. At this time, there have been no observations from large-scale clinical trials of prostate cancer to suggest that COX-2 inhibitors may be effective in preventing this disease. Almost certainly, case-control studies from large NSAID trials as well as observations from case-control analyses of large trials such as the Prostate Cancer Prevention Trial should shortly provide evidence as to the effect of these agents in carcinoma of the prostate.

Isoflavonoids/Lignans

The observation that native Japanese have very low rates of clinical prostate cancer despite similar background rates of latent disease and that rates of clinical disease increase among Japanese who immigrate to the United States and develop the local dietary habits has led to the speculation that dietary factors prevent disease in native Japanese. While animal products are a major source of protein in the United States, soybean products represent a major component of Japanese and other Asian diets. In Taiwan, the average consumption of soy protein is 35 g per day. Major components of soy products are isoflavonoids including daidzein, daidzen, genistein, o-desmethylangolensin, and equol, with daidzein and genistein being the most common. Of these agents, perhaps the most interesting and promising is genistein. Daily intake of genistein in Japan is 1.5 to 4.1 mg compared to < 1 mg in the United Kingdom and little more in the United States. One major putative method of action of these isoflavones has been suggested to be estrogenic or antiestrogenic through increased sex-hormone-binding globulin, modulation of pituitary response to gonadotropins, or inhibition of aromatase and 17-beta-hydroxysteroid oxidoreductase.

The initial recognition of the estrogenic activity of genistein was in the investigation of “clover disease” — decreased fertility in sheep allowed to graze on clover. The estrogenic activity has since been observed in mice, rats, and guinea pigs, and there are some similar observations through epidemiologic studies in humans. Kelloff has suggested that the composite of observations in humans is that the effect of genistein depends on the existing hormonal environment — if endogenous estrogen levels are low, genistein functions as a weak estrogen. If endogenous estrogen levels are high, it acts as an antiestrogen.

As prostate carcinogenesis is intimately dependent upon androgens, it stands to reason that one of the putative explanations for the chemopreventive activity of isoflavones is through its estrogenic activity. Genistein has been reported to inhibit 5 a-reductase and P-450 aromatase. Similarly, one of the more important enzymes in estrogen metabolism, 17-beta-hydroxysteroid oxidoreductase, has been demonstrated in prostate cancer cells to be inhibited by exposure to flavonoids.

A number of preclinical studies have added to the body of evidence that isoflavonoids may be potential preventive agents for carcinoma of the prostate. Barnes and colleagues studied the effect of varying concentrations of genistein on the growth of LNCaP and DU 144 human prostate cancer cells. These authors found dramatic reductions of tumor growth even at levels of < 5pg per mL. Using the Lobund-Wistar rat model of spontaneous and metastasizing adenocarcinoma in the prostate-seminal vesicle complex, Pollard and Luckert found that not only was the incidence of tumors reduced by high isoflavone dietary supplements but the disease-free period was pro-

longed. Genistein has also been demonstrated to induce apoptosis in prostate cancer cells. This observation has been replicated in a second study of LNCaP cells.

A number of phase II clinical trials are currently ongoing to investigate the possible roles of isoflavones in the prevention of prostate cancer. Studies are primarily focusing on small groups of patients at a higher risk of disease using intermediate endpoints or evaluating the modulation of various biomarkers. At this time, a large-scale dietary intervention trial using a phase III design is not currently planned.

Hormonal Prevention

It has been said that only two criteria are universally required for the development of prostate cancer in man: aging and an intact hormonal axis. While the former is generally inescapable, evidence is accumulating that modulation of the latter may reduce the risk of prostate cancer development.

A number of observations support the concept that cumulative androgen exposure contributes to the risk of prostate cancer development. The first of these stems from observations of the results of androgen deficiency syndromes. Perhaps the most notable of these syndromes is associated with a single gene and, therefore, single amino acid defect in 5 a-reductase. In the prostate, the type II isoform of 5 a-reductase converts testosterone (T) into dihydrotestosterone. At the androgen receptor, dihydrotestosterone is as much as 4 to 5 times more potent as T. The syndrome of 5 a-reductase deficiency, first described by Imperato-McGinley in 1979 provided the first evidence that androgen modulation may reduce the risk of prostate cancer development. In a relatively isolated area of the Dominican Republic, a group of children were identified at birth with pseudovaginal hypospadias. At puberty, masculinization of the genitalia developed as well as male gender identity and a deep voice despite a persistent female escutcheon and an absence of body hair. Further study of the affected subjects during adulthood found a pancake-shaped rudimentary prostate and an undetectable prostate-specific antigen level in serum. Biopsy of these glands found no evidence of prostatic epithelium. These observations ultimately led to the development and eventual clinical availability of the first 5 a-reductase inhibitor, finasteride, for the treatment of benign prostatic hyperplasia. In the syndrome of absence of 5 a-reductase, not only is there an absence of 5 a-reductase and very low levels of dihydrotestosterone during adulthood but these two changes to the prostatic hormonal milieu are also operational during embryogenesis and puberty, two periods when androgens have a major action on the prostate.

A series of important observations have been made regarding the impact of androgen deprivation on normal and neoplastic prostatic epithelium. Androgen deprivation has a well-established apoptotic effect on normal and

neoplastic epithelium. This action probably accounts for the reduction in prostate gland volume in patients treated with finasteride. In patients with extant carcinoma of the prostate, androgen deprivation leads to a considerable fall in serum prostate-specific antigen levels, dramatic improvements in symptoms, a decrease in prostatic volume, and major improvements in survival in men who have an undetectable level of prostate-specific antigen as a nadir value after androgen deprivation.

A variety of epidemiologic observations further support the notion that cumulative androgen exposure increases prostate cancer risk. It is well established that native Japanese have one of the lowest prostate cancer rates in the world. By comparison, Caucasians in the United States have an intermediate rate, with African Americans having one of the highest rates in the world. The prostate cancer risk link with androgen levels arises from a series of observations:

1.  Some large population studies have found serum androgen levels to be highest in African American men.

2.  The activity of 5 a-reductase (and, thereby, the levels of the most active androgen, dihydrotestosterone) is highest in African Americans, intermediate in Caucasians, and lowest in Japanese.

3.  A small study of pregnant women found serum androgen levels to be highest in African American women. Conceivably, such higher in utero androgen levels may be responsible for a higher “gonadostat” set point, leading to higher cumulative androgen levels and thereby a higher prostate cancer risk in African American men.

4.  Substantial interindividual variability was recently found in the CYP3A4 gene, a gene responsible for the oxidation of testosterone to several metabolic products. In a group of 230 Caucasian men with prostate cancer, an altered 5′ regulatory element was found in 46% of men with locally advanced (T3 to T4) prostate cancer compared to only 5% of men with Tl tumors. One hypothesis from this investigation may be that men with an altered ability to metabolize intraprostatic testosterone may be at a higher risk of prostate cancer and that reduction of intraprostatic androgens may reduce prostate cancer risk.

5.  Androgenic stimulation of the prostate is associated with cellular proliferation. Evidence from a number of other organ sites suggests that methods to decrease cellular proliferation may reduce the clinical development of cancer.

6.  Conditions associated with chronically low levels of androgens (e.g., cirrhosis) are associated with a low risk of prostate cancer.

Potential Interventions for Hormonal Prevention Historically, traditional hormonal therapy has not been an attractive option for the prevention of prostate cancer in a population of healthy men at risk of the disease. These traditional hormonal manipulations include bilateral simple orchiectomy, luteinizing hormone-releasing hormone agonist, and antiandrogens. These options are associated with considerable toxicity including impotence, decreased libido, muscle wasting, mood changes, hot flashes, gynecomastia, and osteoporosis. Even with antiandrogens, perhaps the alternative with the fewest side effects, over 50% of patients can expect side effects of some degree.

It is because of the toxicity of traditional hormonal therapy that the discovery of finasteride, the first 5 a-reductase inhibitor, heralded tremendous interest in a new opportunity to prevent prostate cancer. Finasteride competitively inhibits 5 a-reductase and principally affects the type II isoform, which is most active in the prostate gland. (By contrast, the type I isoenzyme is found primarily in the liver and scalp.) Approved by the U.S. Food and Drug Administration for the treatment of bladder outlet symptoms associated with benign prostatic hyperplasia, finasteride has a number of clinical effects: (1) serum prostate-specific antigen concentrations fall by 50%; (2) dihydrotestosterone concentrations fall by 70 to 80%; (3) peak urinary flow rate increases by approximately 20%; (4) urinary symptom scores improve by 23%; and (5) prostate volume decreases by 20%. Most germane to the concept of chemoprevention of prostate cancer, side effects seen with finasteride therapy are relatively uncommon. The three side effects that have been seen more commonly in finasteride-treated patients than in controls in randomized, double-blind trials have been decreased libido, impotence, and ejaculatory disturbances. In the Veterans Administration trial, these three side effects were seen in 5, 9, and 2% of patients receiving finasteride compared to 1, 5, and 1%, respectively, of patients receiving placebo. Of interest, two other studies had somewhat different findings. The PROSPECT Canadian benign prostatic hyperplasia trial which randomized 613 men to either finasteride or placebo, found these three side effects in 10, 7.7, and 15.8% of patients receiving finasteride compared to 6.3,1.7, and 6.3% in those receiving placebo. In the PLESS study of 3040 men randomized to either finasteride or placebo, the rates of these side effects in the first year of study were 6.4, 8.1, and 3.7% in patients receiving finasteride compared to 3.4, 3.7, and 0.8% in those receiving placebo. In the years 2 to 4, the rates dropped to 2.6, 5.1, and 1.5% in finasteride patients compared with 2.6, 5.1, and 0.5% in those receiving placebo. Thus, the composite of these very large studies suggests that while sexual toxicity will occur in some patients, the rate will be quite low and tends to disappear over time.

A number of observations in the preclinical realm provide insight as to the potential application of hormonal therapy in general and finasteride in particular in the prevention of prostate cancer. Tsukamoto and colleagues have explored the impact of 5 a-reductase inhibitors on the development of carcinoma of the prostate in the F344 rat prostate carcinoma model in two separate studies. In this model, prostate cancer is induced through a combination of a carcinogen (3,2′-dimethyl-4-aminobiphenyl [DMAB]) and exogenous testosterone proprionate. Animals were grouped into controls, high- and low-dose finasteride (15 and 5 mg/kg), and three doses of bicalutamide (15, 30, and 60 mg/kg) with all doses administered three times weekly. Despite relatively low doses of finasteride (5 mg/kg for rats while some studies have used as high as 25 to 160 mg/kg), the rates of all prostatic tumors were reduced from 68.6% in control animals to 40 and 50% in high-dose and low-dose finasteride-treated animals, respectively, and 45, 50, and 20% in animals receiving increasing doses of bicalutamide.

A variety of other conclusions have been reached by other investigators when analyzing the effects of 5 a-reductase inhibitors in animal prostate cancer models. Many of the conclusions are of questionable value for several reasons. (1) The metabolism of 5 a-reductase inhibitors in animal models is extremely variable, and rapid metabolism in rodents may lead to only transient effects. (2) Many studies have not designated which type of tumor line was used, an item of special importance when dealing with the R-3327 Dunning tumor. While prostate cancer has been reported to have relatively low levels of 5 a-reductase, in humans an almost two-log differential in 5 a-reductase activity has been found in various sublines of the R-3327 tumor. Thus, it is not surprising that in the H-tumor (with high intratumor 5 a-reductase levels), Lamb found little activity of the 5 a-reductase inhibitor SKF 105857 while in the G-tumor (with 5 a-reductase levels more like that found in human prostate cancer), inhibition was witnessed that was similar to the effect of castration. Nevertheless, several studies using additional 5 a-reductase inhibitors have demonstrated growth inhibition of various prostate cancer cells.

An observation that has been made on several occasions in animal models of prostate cancer is that 5 a-reductase inhibitors can affect both androgen-sensitive and -insensitive tumors. For example, Bologna found that finasteride inhibited both PC-3 and DU 145 human prostate cancer cells with inhibition being dose dependent. The explanation for this may lie in the observation of Wang that finasteride may actually regulate prostate-specific antigen gene expression at the transcriptional level, thereby contributing to the fall in prostate-specific antigen in patients treated with this agent. This observation, combined with the concept that prostate-specific antigen itself may exert a trophic influence in prostate cancer cells (e.g., LNCaP), may go far to explain its potential effect on prostate cancer development and progression.

Clinical trials with finasteride provide, as stated above, considerable evidence regarding the safety profile of the drug. However, the data regarding the potential of this agent to reduce the risk of prostate cancer are conflicting. In the PLESS trial of benign prostatic hyperplasia treatment, no significant difference in the rate of prostate cancer detection was observed. (Although 2.4% of patients with a baseline prostate-specific antigen < 4.0 ng per mL treated with finasteride compared to 2.8% treated with placebo were found on biopsy to have prostate cancer, this difference was not statistically significant.) In a very small study of 57 patients with elevated prostate-specific antigen and a negative prostate biopsy who were randomized to finasteride or no treatment, 30% of finasteride-treated patients ultimately developed prostate cancer compared with 4% of those receiving no treatment. In this study, the majority of positive biopsies occurred in men with a previous diagnosis of prostatic intraepithelial neoplasia, a condition for which a 30 to 50% positive-rebiopsy rate would be expected. Thus, while the 30% positive biopsy rate was not unexpected in men treated with finasteride, the aberrant 4% positive biopsy rate in controls was quite unusual.

On the basis of compelling evidence that cumulative androgen exposure is associated with prostate cancer risk and that methods to reduce this androgenic stimulus should reduce prostate cancer risk, in 1992, the Board of Scientific Counselors of the Division of Cancer Prevention and Control of the National Cancer Institute approved the concept of a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. The Prostate Cancer Prevention Trial opened for participant enrollment in October 1993 and over the subsequent 3 years randomized 18,884 men to either finasteride or placebo. The trial design is illustrated in Figure 48-6. Eligible participants were over age 55 years and had a normal digital rectal examination and a prostate-specific antigen < 3.0 ng per mL. The study endpoint is cumulative prostate cancer incidence over the course of the 7-year study with a prostate biopsy in all men at the end of 7 years. It is anticipated that results of the study will be available in late 2004.

Vitamin D

Vitamin D is an essential vitamin, obtained both from diet and from sunlight. Figure 48-7 displays the pathways of vitamin D metabolism. As can be seen, vitamin D is synthesized from 7-dehydrocholesterol in skin exposed to sunlight. Thereafter, passage through the liver converts vitamin D to 25 (OH) vitamin D and thereafter in the kidney to 1,25 (OH)2 vitamin D. A number of studies have suggested that vitamin D can have substantial chemopreventive effects in cancer cells. The mechanism of action of vitamin D is unknown but Kelloff has reviewed available literature that lists potential modes of action as inhibition of proliferation; modulation of signal transduction, modulation of oncogene expression; inhibition of ODC induction, lipid peroxidation, and angiogenesis; and induction of differentiation, transforming growth factor expression, and apoptosis.

Several pieces of evidence suggest that indeed vitamin D may have a preventive role in the development of prostate cancer. Hancette and Schwartz surveyed geographic distribution of ultraviolet radiation and prostate cancer mortality in 3073 counties in the United States. They found a strong north-south trend of prostate cancer mortality; death rates from prostate cancer were the highest in the most northern latitudes, with vitamin D levels being a potential cause of the effect. It is well established that the majority of vitamin D is obtained through exposure to the sun. As skin pigments can reduce the amount of ultraviolet radiation that reaches the skin layers containing 7-dehydrocholesterol, the degree of pigmentation is inversely related to vitamin D levels. This observation may explain the fact that African American men in the United States have the highest incidence of prostate cancer.

Two observations from the Health Professionals Follow-up Study provide clinical support for this hypothesis. The authors studied the impact of calcium and fructose intake on the risk of prostate cancer to include a subset analysis of advanced and metastatic prostate cancers. As calcium leads to inhibition of the parathyroid hormone and thus a reduction in vitamin D production, it would stand to reason that increased calcium intake might increase prostate cancer risk. Conversely, as fructose intake reduces serum phosphate levels and as hypophosphatemia leads to increased production of vitamin D production, increased fructose intake should reduce prostate cancer risk. These were exactly the findings of the authors with high calcium intake associated with a relative risk of 2.97 while high fructose intake was associated with a relative risk of 0.51.

Several strategies for the chemoprevention of prostate cancer emerge from these observations. The first and simplest is a recommendation for increased intake of fruits, generally excellent sources of fructose. As fruits are also generally high in fiber, a number of other benefits may accrue. Observations from cell culture studies suggest that the amount of vitamin D3 required to cause cellular differentiation is associated with significant toxicity, generally through significant elevation in serum calcium levels. For this reason, a major effort has been made in the development of vitamin D analogues — agents that have activity at the vitamin D receptor yet do not have a similar effect on serum calcium. Finally, traditional dietary sources of vitamin D such as fish liver and milk can be maintained.

Retinoids

Retinoids are a class of compounds that are both natural and synthetic derivatives of vitamin A and function as regulators of cell growth and activity through action at the retinoid receptor. Retinol (vitamin A) is metabolized through nicotinamide-adenine dinucleotide (phosphate) (NAD [P])-linked dehydrogenase to all-trans-retinoic acid (RA); RA can be acted upon either by photoisomerization or enzymatic isomerization to 13-ris-retinoic acid (cRA) or via cytochrome P-450-dependent monooxygenase to trans-A hydroxy-retinoic acid. A quite promising agent, 9-cis-retinoic acid (9cRA), is a stereo- and photoisomer of RA. Carotenoids are a group of naturally occurring compounds that are found in vegetables and fruits that are metabolized to vitamin A and thereby to other retinoids. Included among this family are beta-carotene, crocetin, cryptoxanthin, lutein, astaxanthin, zeaxanthin, lycopene, and canthaxanthine. All these compounds are thought to affect cancer promotion by inhibiting cellular proliferation, leading to cellular differentiation, affecting apopto-sis, induction of transforming growth factor-beta expression, inhibition of arachidonic acid metabolism, antioxidant activity, and several other actions.  Retinoid receptors are classified into two types: RAR and RXR, with RXR perhaps the most active in the potential chemopreventive role. Epidemiologic studies have repeatedly noted a reduction in cancer risk among populations with a high intake of foods containing retinoids.

In preclinical studies, RA has been found to induce differentiation of the promyelocytic cell line HL-60. Similar differentiation effects have been seen in murine teratocarcinoma cell lines. As stated above, RA being a powerful inducer of transforming growth factor-beta production, it is notable that postandrogen-deprivation apoptosis is dramatically inhanced by increased levels of transforming growth factor-beta messenger ribonucleic acid (mRNA). Studies of animal tumor models have found that retinoids reduce mammary tumors, buccal pouch tumors, and 7, 12-dimethylbenz [a] anthracene (DMBA)-induced rat salivary gland tumors.

In the realm of prostate cancer, Pasquali et al. have studied levels of retinol and RA in normal tissue, benign prostatic hyperplasia, and prostate cancer. While retinol levels for these three tissues were 60, 146, and 77, respectively, interestingly, RA levels were 5, 8, and at or near the lower limit of detection (1 ng/g wet weight), respectively, suggesting a potential role of retinoids in either chemoprevention or therapy of carcinoma of the prostate. Studying three prostate cancer cell lines (PC-3, DU 145, and LNCaP), de Vos and colleagues found a variety of RAR and RXR heterodimers to have growth inhibitory activity for all cell lines. Liarizole, an imidazole derivative, has a variety of activities, one of which is postulated to be an increase in intracellular retinoid accumulation through inhibition of the catabolism of RA. In both androgen-dependent and -independent Dunning rat prostate tumors, liarozole inhibited cell growth. Finally, Pollard and Luckert have demonstrated that 4-hydroxyphenyl retinamide (4-HPR) retinoid, currently employed in a variety of clinical trials, not only substantially reduces the development of primary prostate tumors in the Lobund-Wistar rat model but also reduces the rate of metastasis in PA-III cells.

Despite the promise of these mechanisms of action and the epidemiologic observations suggesting the potential efficacy of retinoids in cancer chemoprevention, several observations call into question the efficacy of these agents. A recent study of vitamin A in the prevention of local recurrences and second primaries in patients with head and neck cancer found an increased risk of recurrence in those receiving vitamin A. In the realm of prostate cancer, two case-control studies, one in Hawaii and one in Utah, found higher vitamin A or carotenoid intake among cases than controls. In an analysis of the Physician’s Health Study (22,071 male physicians randomized in 2×2 fashion to beta-carotene or placebo and aspirin or placebo), after an average follow-up of 12 years Hennekens and colleagues found no significant effect on cancer risk. Of greater concern was the finding of an excess number of lung cancers in the ATBC trial of beta-carotene in Finnish smokers. Finally, Pienta and colleagues studied the effect of 4-HPR in men at a high risk of prostate cancer (elevated prostate-specific antigen) . With a mean prostate-specific antigen at study entry of 8.6 ng per mL, the study was actually terminated prematurely when 40% of patients were found to have a positive prostate biopsy.

Although epidemiologic and other evidences suggest that retinoids ought to have preventive activity in prostate cancer, there is little clinical evidence at this time of this effect, and more troubling is the evidence of an excess number of tumors in treated patients. For this reason, it is doubtful that there will be any large-scale trials using these types of agents until a better understanding of the mechanism of action and more selective agents are available. It is also reasonable for physicians to counsel patients as to the potential disadvantages of over-the-counter retinoid supplementation, especially among smokers.

Low-Fat Diet

While micronutrients, such as vitamins E and D, and selenium, have been suggested to be potential chemopreventive agents for prostate cancer, another major component of diet — fat — may play a major role. Such an association is not novel as high-fat diets have been associated with cancers of the colon, rectum, and breast. Overall population patterns support the association of high-fat (especially fat from animal sources) intake and prostate cancer. In general, Asian countries such as Japan and China have very low amounts of animal fat intake and have parallel low rates of clinical prostate cancer and prostate cancer mortality. Conversely, Western European and North American countries have some of the highest rates of animal fat consumption as well as rates of prostate cancer mortality.

Multiple observational studies support the notion that a low-fat diet is associated with a lower risk of prostate cancer. A population-based case-control study from Utah of 358 cases with prostate cancer and 679 controls matched by age and location of residence found dietary fat to be significantly associated with prostate cancer risk, most notably in older patients and those with aggressive tumors. The odds ratio was 2.9 for total fat and 2.2 for saturated fat. In a study of similar design (452 cases and 899 age-matched controls) from Hawaii, Kolonel and associates found a substantially increased risk of prostate cancer in men with the highest quartile of fat intake. The odds ratio was 1.7 for this group. A smaller study from Madrid, Spain came to a similar conclusion with an odds ratio of 2.56 for high animal fat diets. Giovannucci reported the results from the Health Professions Follow-up Study finding a high-fat diet to be associated with a greater risk of advanced prostate cancer. A more recent study from Canada analyzed a group of 427 men with prostate cancer, segregating patients into either local or advanced cases. While statistical significance was not reached, a positive trend to the development of advanced prostate cancer and total fat was noted while a negative trend was noted for total vegetable fat intake. Cases in the highest quartile of saturated fat had a significant odds ratio of 2.15 (95% CI, 1.14 to 4.04). Zhou and Blackburn reviewed all previously reported human studies of dietary fat and prostate cancer in 1997. Of the descriptive studies reviewed, 8 of 16 were positive and 8 showed no association. Of the 14 case-control studies surveyed, the results were similar: 8 of 12 reporting on total fat found a positive association, and 4 of 12 found no association; 4 of 6 reporting on total animal fat intake found a positive association, and 2 of 6 found no association; 4 of 5 reporting on saturated fat intake found a positive association, and 1 of 5 found no association; 2 studies reporting on monounsaturated fat intake found a positive association in both. Negative associations were found in 3 of 4 studies reporting on polyunsaturated fat intake. Most important is the lack of any epidemiologic observation of a negative association between prostate cancer and animal fat. Most recently, an international study of 59 countries comparing dietary patterns with prostate cancer mortality found an inverse relationship between prostate cancer mortality and intake of cereals, nuts and oilseeds, and fish, and a direct relationship with animal meat/fat intake.

Various mechanisms of action have been proposed to explain the association of prostate cancer and dietary fat.

Probably the best known is the association of animal fat and androgens. It has been observed in women that estradiol and estrone levels fall with dietary fat reduction; a similar effect has been seen in healthy men fed a low-fat diet, in whom excretion of urinary androgens increase with a high-fat diet. Investigators have hypothesized that the cumulative increased exposure to androgens by the prostate then leads to increased cellular proliferation and, eventually, an increased risk of cancer. Of interest, in a small study, African American women were noted to have higher androgen levels during the first trimester of pregnancy than their Caucasian counterparts. Ross and Henderson have merged this and other observations to develop a global hypothesis to explain the diet-prostate cancer link. In utero, a high-fat diet may lead to a “low-gonadostat set point,” leading to higher testosterone levels later in life. Such higher levels lead to earlier puberty (or menarche in girls), thus making the prostate in affected individuals “older” than chronologic age. Finally, a lifetime of increased serum testosterone levels leads to a state of relative hyperproliferation and decreased apoptosis in the prostate, unmasking or promoting other initiating events, thereby leading to a higher risk of prostate cancer.

Few studies in preclinical models have analyzed the impact of dietary fat on the growth of rodent and human prostate cancer lines. Wang and colleagues, using the human prostate cancer line LNCaP, studied the effect of various fractions of total calories of dietary fat (from 2.3 to 40.5% kcal% fat) on prostate cancer growth. As expected, tumor growth rates were highest in the 40.5% group and lowest in the 2.3% group. Serum prostate-specific antigen levels were similarly highest in the high-fat diet group and lowest in the low-fat diet group. In the Lobund-Wistar model of spontaneous prostate cancer development,* prostate cancer rates are reduced significantly with a reduction of dietary fat. Finally, a most intriguing observation was made by Kondo and associates in the ACI/Seg model of spontaneous prostate cancer. In this study, a high-fat (20% corn oil) or a low-fat (5% corn oil) diet was fed to mother rats and thereafter to their male offspring. At 100 weeks of age, adenocarcinoma of the prostate was found in 20% of the high-fat group compared with none of the low-fat group. Further supporting this conclusion, the rate of atypical hyperplasia was reduced from 73.3 to 20%, respectively. This observation has a close clinical parallel in several epidemiologic studies in that environmental factors (e.g., diet) have the most significant impact early in life rather than late.

Several parallel studies provide some commentary on the relationship of diet and fat. As diet and cholesterol are generally directly related, one might expect a higher risk of prostate cancer among men with higher cholesterol levels. Such has not been noted in two separate studies. Similarly, in a 1997 meta-analysis of 16 randomized trials of cholesterol lowering with statin drugs, no effect on cancer mortality was observed. Conversely, in two large studies, in populations of patients with a low rate of cardiovascular disease, prostate and overall cancer rates were reduced (perhaps again due to the relationship of dietary fat in both disease processes).

At the present time, there are no ongoing prospective studies on the impact of diet on overall prostate cancer incidence or mortality. Certainly, such studies cannot be blinded to the participant. However, the publication of a recent 2-year trial analyzing the impact of dietary fat on the radiographic appearance of the breast (patients were randomized to a low-fat diet or regular prestudy diet) illustrates that such studies are possible. Whether such studies are necessary may be open to debate as the bulk of evidence suggests that many additional benefits would accrue from such a dietary change (e.g., reduced breast and colon cancer, reduced cardiovascular disease). Perhaps the challenge for the cancer prevention community is to better “market” the message of the benefits of a reduced-fat (especially reduced animal-fat) diet and the potential salutary effect on the risk of various neoplasms including prostate cancer.

Miscellaneous Agents

A host of other agents have been suggested to have a possible preventive role in prostate cancer. Included among these are green tea, HMG-CoA inhibitors (cholesterol biosynthesis blocking agents), zinc, and DFM0. At this time, none of these agents have been sufficiently tested in prostate cancer to allow an objective evaluation. It is reasonable, however, to move these agents into preclinical trials or into models of cancer prevention (e.g., short-duration treatment prior to radical prostatectomy, treatment of patients with prostatic intraepithelial neoplasia, or treatment of men at high risk of prostate cancer [elevated prostate-specific antigen and negative biopsy]).

Successful outcomes in managing iatrogenic anorectal injuries incurred during prostate surgery begin with careful preoperative planning. The surgeon must thoroughly understand the technical aspects of the planned procedure and the challenges unique to his or her patient, such as prior surgeries or radiation therapy in the area being operated on. Preoperative planning should include an assessment of the functional status of the anorectum with respect to bowel function and continence to feces. The diagnosis, the patient’s history and functional status, and the experience and capabilities of the operating surgeon should all be considered when deciding on the operation best suited for the patient. Avoiding iatrogenic injuries is always preferable to repairing them.

It must be recognized that iatrogenic anorectal injuries can, have, and will occur during prostate surgery. With injury rates as high as 11% in some series, it seems prudent to include complete mechanical bowel preparation with broad spectrum antibiotics in the surgical process to provide coverage for gram negative and anaerobic enteric organisms. It is imperative that the surgeon look for and recognize injuries intraoperatively and in the postoperative period. An additional challenge in the current short-stay environment is to educate the patient, their family, and home healthcare providers to recognize complications and promptly bring them to the surgeon’s attention. The surgeon must also ensure easy access to follow-up for those patients who may need to have a postoperative problem evaluated. During follow-up, the surgeon should reassess anorectal function along with urinary and sexual function as some patients will benefit from consultation with other specialists to manage pre-existing dysfunction and those related to the procedure.

Finally, the surgeon may want to consider a multispecialty team approach. Iatrogenic anorectal injuries, especially major injuries, are encountered infrequently, so that most urologic surgeons do not have a great amount of experience managing them. Care for these patients may best be provided by involving colon and rectal surgery, general surgery, critical care, diagnostic radiology, and interventional radiology specialists. Most of these patients will be managed well by their urologic surgeons but the primary surgeon should not hesitate to seek the assistance of other specialists when deemed necessary.

Preoperative Evaluation of the Anorectum

Estimates of anal incontinence in elderly males range from 6 to 25%. In light of this frequency and because of the recently recognized association of fecal incontinence with perineal prostatectomy, the continence status of patients prior to prostate surgery should be documented. This assessment need not be complex, consisting of the patient’s history of anorectal injuries, and surgeries for fistulae, fissures, hemorrhoids, and cancers. Radiation therapy to the perineum, anus, or rectum should be recorded. Clinical assessment of anal continence can be obtained by recording a history of incontinence to gas, liquid, and solid, the frequency of such episodes, and the effect that these episodes have had on the patient’s lifestyle. The physical examination of the anorectum should evaluate for fissures, fistulae, hemorrhoids, scarring, or other deformation of the anus and perianal area, sensory changes or defects, and defects in the sphincter mechanism. Patients with alterations in continence or with significant findings on physical examination may require a more complete evaluation or referral. Any operative procedure carried out in proximity to the anus or distal rectum may exacerbate pre-existing conditions.

Recognition of Iatrogenic Anorectal Injuries

Many techniques and principles have been advocated to avoid intraoperative iatrogenic injuries and to recognize them when they do occur. The most important of these is a thorough understanding of pelvic and perineal anatomy, followed by the need for a detailed operative plan and knowledge of its relation to the patient’s anatomy. Proper patient positioning, adequate lighting (including headlights if required), appropriate instrumentation, adequate exposure, traction, and countertraction are all basic and crucial. As important as recognition of the proper plane of dissection is recognition of an improper plane. Injuries commonly occur when the surgeon strays from the proper dissection plane and tend to become more severe the longer it takes for this to be recognized.

Routine injection of difficult tissue planes in the confines of the perineum with dilute epinephrine solutions or normal saline may make the planes easier to recognize. If the plane of dissection is unclear at any time during prostate surgery, a finger in the rectum may serve as a reorienting tool.

Rectal wall integrity should be tested on completion of prostatectomy. Air insufflation via a red rubber catheter or proctoscope will detect a defect if the wound or pelvis is filled with saline prior to insufflation. This technique can also be used to evaluate rectal repairs. It is helpful to occlude the colon proximal to the suspected injury to prevent dilation of the entire colon from air insufflation.

Repair of Rectal Injuries

Permanent Fecal Diversion

Some patients will require permanent fecal diversion as treatment for rectal injuries or rectourinary fistulae. Significant radiation therapy damage, multiple failed repair attempts, poor physical condition, fecal incontinence not amenable to surgical repair, and locally aggressive or recurrent malignancy may all lead the surgeon to choose diversion over repair. If urine leak is a prominent symptom, the surgeon must be aware that fecal diversion will do little to improve it. Urine leak may in fact become a more difficult problem to manage effectively if it is felt that the patient is not a candidate for repair of the rectal injury.

The choice of the type of stoma with respect to temporary diversion has been discussed above. Additional considerations come into play with planned permanent stomas. The patient must be educated as to the purpose of the stoma. He must realize that the stoma is intended to be permanent, that some mucus discharge per rectum is expected, that it will not alleviate problems with urine leak, if present, and that complications such as prolapse, retraction, necrosis, stenosis, and hernia may result.

The surgeon should involve an enterostomal therapist in any planned permanent colostomy formation. The enterostomal therapist will introduce the patient to care of the stoma, to the various types of appliances available, and to troubleshooting. The therapist can mark the patient preoperatively for the best location for a permanent stoma. Many enterostomal therapists will see patients on a long-term basis to assist with routine management and problems that may arise.

Some of the advantages of the loop colostomy were noted above. Another advantage of a loop colostomy and of the mucus fistula created in association with an end colostomy is relief of backpressure. If a rectal stricture develops secondary to radiation therapy or from a massive inflammatory process, backpressure from mucus accumulation and retained intestinal contents may lead to rectal stump blowout and pelvic sepsis if there is no route available for relief.

Fecal Incontinence

Management of Fecal Incontinence

Appropriate management of fecal incontinence is determined by cause, degree, physical and functional status of the patient, and by the results of anorectal physiology studies. Diarrheal disorders, overflow incontinence secondary to constipation, and problematic dietary habits or food intolerances are treated by medical management. Therapies may include constipating agents, dietary counseling, laxative regimens, and antibiotics directed at enteric pathogens. Surgical treatments are directed at anatomic abnormalities of the perianum, anus, and external anal sphincter complex. Severe scarring of the perianum or anal canal may lead to fecal leakage and may be effectively treated by scar excision and flap advancements. Sphincter defects can be treated by overlapping external anal sphincteroplasty Patients may benefit from biofeedback to maximize muscular function and anorectal sensation. Combinations of the above therapies are often applied. In patients who do not respond to the above modalities, or who are not considered surgical candidates, fecal diversion may be beneficial. Further study is required in the area of fecal incontinence and its relationship to perineal prostatectomy.

TABLE. Indications for Anorectal Physiology Tests Associated with Prostate Surgery

H and P = history and physical examination; Electromyography = EMG

Conclusion

Anorectal complications of prostate surgery are challenging problems. Fortunately they are rare and can be avoided, or their ramifications minimized, with careful planning, meticulous surgical technique, and attention to detail in postoperative care. The surgeon should not hesitate to utilize a multispecialty approach in caring for patients with these complications. When they do occur, the evaluation and management guidelines outlined in this chapter can lead to a successful outcome.

TABLE. History and Physical Examination for Anorectal Function

Physical Examination

Management of rectal injuries noted in the postoperative period requires much more judgment than do repairs performed at the time of prostate surgery. Patient variables such as age, physiologic condition, degree of septic process, time from prostate surgery, and magnitude of leak noted weigh upon the decision-making process. In the case of minor leaks with little to no systemic manifestation, placing the patient on broad-spectrum antibiotics, bowel rest, and total parenteral nutrition, as well as using reliable urinary diversion and allowing free drainage to occur from the wound, will avoid the need for more invasive intervention in some patients. It is essential that these patients be closely monitored so that progression of the local septic process, if it occurs, can be appropriately managed by techniques such as fecal diversion and careful wound debridement.

Rectal injuries that fail nonoperative management or present initially as a significant local and systemic septic process require surgical therapy in addition to the measures outlined above. Wounds should be carefully debrided of dead and devitalized tissue, taking care not to enlarge the defect or unnecessarily damage the anal sphincter or levator ani musculature. Feces should be diverted and the colon and rectum distal to the stoma should be washed out.

The goals of fecal diversion should be satisfactory diversion of the fecal stream, appropriate stoma placement to allow for comfortable and reliable stoma appliance fit, and restoration of intestinal continuity without undue difficulty. Fecal diversion is best accomplished with the use of a temporary loop colostomy.  The greatest advantage of a loop colostomy is that it is a limited procedure that will restore intestinal continuity usually without requiring a celiotomy. The sigmoid colon is the most desirable site from which to create the loop colostomy; should this not be acceptable for technical reasons, however, a loop transverse colostomy is a good second choice. Loop transverse colostomies created from the left transverse colon may have a decreased incidence of prolapse compared to right-sided transverse loop colostomies. In the unusual event of a rectal injury of such magnitude that resection is required, a Hartmann procedure with rectal resection, oversew of distal rectal stump, and creation of an end sigmoid colostomy will be required.

As with the injuries that respond to nonoperative management, some of the more severe rectal injuries that are treated with debridement, distal washout, and fecal diversion will close over time. There is a benefit to waiting 6 weeks to 3 months to give the injuries time to close spontaneously and allow time for the inflammatory response to resolve. If there is any question of ongoing inflammation in the area of the injury, waiting longer than 3 months is indicated. There have been a number of approaches described in the surgical treatment of rectourinary fistulae that have not responded to the above methods.

Restoration of intestinal continuity should not be performed until successful repair of a rectal injury can be verified. Verification can be challenging. Several modalities should be used in combination to overcome the difficulties of evaluation, especially of the more frequent, low-lying fistulae. These are not well demonstrated with barium enema studies as the balloon may occlude their internal opening. They may be very small, making them difficult to visualize by either colonoscopy or cystoscopy. Some healed fistulae may have a rather long blind tract that gives them the appearance of a fistula. Cystography offers perhaps the best visualization of these fistulae. If a blind tract is noted at the time of cystography, repeat cystography should be performed in 6 to 8 weeks. Examination of the anorectum, under anesthesia if necessary, may allow for gentle probing of possible tracts. Air may be insufflated into the anorectum with a proctoscope while the bladder is inspected with cystoscopy for air bubbles. Injection of methylene blue into possible tracts with the cystoscope and inspection of the rectum with proctoscopy are helpful. If the tract is relatively small and stable following repeat cystography, and if no tract can be confirmed by the above techniques, intestinal continuity may be restored. If there is any question regarding the functional integrity of the external anal sphincter complex prior to stoma closure, complete evaluation in an anorectal physiology laboratory should be performed and the problem treated appropriately before closure.

TABLE. Colostomy Type Advantages and Disadvantages

The high baseline rate of fecal incontinence in elderly males and the increased incidence of fecal incontinence following perineal prostatectomy were mentioned above. Bishoff et al. report that the association of fecal incontinence with perineal prostatectomy is not well understood. It may result from local muscle or nerve trauma or may be multifactorial and additive with the rather high baseline incontinence rate in this patient population. Fecal incontinence may result from aggressive wound debridement in the setting of postoperative perineal sepsis following perineal prostatectomy. Anorectal physiology testing is helpful in treating patients with fecal incontinence following prostatectomy and may assist in assessments of urinary continence.

Selected anorectal physiologic tests assist in the management of patients with fecal incontinence before and after prostate surgery. Manometry largely serves as a baseline from which to judge changes. It may be helpful in assessing patients with normal physical examinations but who relate a history of functional abnormalities. It is also helpful in assessing those patients whose functional history cannot be obtained, such as those who have undergone fecal diversion. Electromyography is helpful in evaluating patients who relate functional abnormalities but may or may not exhibit abnormalities on physical examination. Transanal ultrasound is helpful in evaluating patients who have undergone anorectal surgery or have sustained anorectal trauma and who relate a history of functional abnormalities. It is also helpful in the patient who has undergone fecal diversion and major debridement for perineal sepsis and is therefore not able to provide a relative functional history.

There has been much progress made in the diagnosis and staging of prostate cancer in recent years. The advent of biochemical techniques prostate-specific antigen testing, reverse-transcriptase polymerase chain reaction and imaging technologies (computerized tomography, radioisotape scans, magnetic resonance imaging) have greatly facilitated the diagnosis of TxN+ adenocarcinoma of the prostate. Surgical, radiotherapeutic, and hormonal treatments, either as monotherapy or in combination, have likewise progressed. The therapeutic dilemma in treating node-positive prostate cancer is compounded by a lack of prospective randomized trials pitting control populations against monotherapy, combinations of therapies, and observation or deferred treatment.

This chapter summarizes the available treatments for node-positive prostate cancer and compares the results of monotherapy, combinations of therapies, and deferred treatment. The case for observation of node-positive prostate cancer (with or without deferred treatment) will then be made. The value of pelvic lymph node dissection in the face of node positive disease, the survival benefit associated with the various therapies, and the expected outcome associated with observation will be addressed. The authors will attempt to identify or stratify TxN+ patients so that a subset of patients benefitting from initial (early) intervention may be selected.

The incidence of prostate cancer and the recent trend in stage migration of this disease are discussed elsewhere in this text. It is clear, however, that the incidence of TxN+ prostate cancer has decreased with the advent of biochemical tests and digital rectal examination coupled with ultrasonic techniques. Once the diagnosis of prostate cancer is made, then clinical staging becomes important in directing therapy and in establishing the patient’s prognosis regarding life expectancy and disease-free survival. The natural history of prostate cancer is less than clear. The median age at diagnosis has been stated to be 72 years. The average life expectancy from the age of 75 years in the United States remains approximately 11 years. These two figures should be kept in mind when planning therapy for patients with adenocarcinoma of the prostate, particularly when considering observation as a treatment for certain patients with node-positive prostate cancer.

Patients with TxN+ prostate cancer discovered incidentally at the time of surgical intervention as well as patients diagnosed through percutaneous biopsy are included in this group identified as candidates for observation as therapy (deferred treatment).

Treatment Options for TxN+ Prostate Cancer

The treatment options that will be discussed for this subset of patients include surgical extirpation, radiation therapy, endocrine therapy, and observation (deferred treatment). The intricacies and execution of these types of treatment will be discussed elsewhere in the book but the expected outcome variables, including survival and quality-of-life issues, will be addressed here.

Outcome variables in treating prostate cancer have traditionally included local progression (bladder outlet obstruction, ureteral obstruction, pathologic bone fracture, impotence, and incontinence), biochemical recurrence or progression, development of distant metastasis, and disease-free survival. More recently, the issue of quality of life has surfaced as an outcome measure and is being incorporated into research reports. The available data for and against each treatment option are examined below.

Surgical Extirpation

Surgery as a treatment for nonlocalized adenocarcinoma of the prostate is not considered effective. However, since a majority of patients are categorized as node positive postoperatively (historically), there are numerous reports of surgical intervention in this group of patients. The reported survival rate of stage Dl patients treated with surgery as monotherapy is generally below 50% at five years. There have been, however, reports of a small number of patients with low volume nodal metastasis with improved survival following surgery. Several of these studies have also employed adjuvant hormonal or radiation therapy, de Kernion et al. analyzed outcomes of patients who underwent radical prostatectomy with pelvic lymph node dissection for Dl prostate cancer, comparing results to those for patients who also received early endocrine therapy. The estimated cause-specific nine-year survival rate was 71% for those patients receiving no early endocrine therapy and 91% for those who received early postoperative hormonal therapy. Historically, the survival difference between these two groups of patients has not been statistically significant; the interval to progression (prostate-specific antigen), however, may be longer in the early adjuvant therapy group.

In a recent review of data from the Mayo Clinic, an overall survival advantage was shown for patients treated with radical prostatectomy and early androgen deprivation (orchiectomy) versus orchiectomy alone. The node-positive patients treated with extirpation and orchiectomy in this series demonstrated a 66% 10-year survival rate versus a 28% rate among patients treated with orchiectomy alone. Other institutions have corroborated the data supporting early adjuvant hormonal therapy in patients first treated surgically. The argument against radical prostatectomy in this setting is based on similar survival rates being obtained through early androgen ablation with or without surgical extirpation. Accepting the morbidity and mortality associated with surgery without clearly proven survival benefit seems unjustified.

Previous reports have refuted the therapeutic value of pelvic node dissection. Patients treated with pelvic node dissection only who then received delayed treatment (consisting of any modality) have generally demonstrated 5-year survival rates under 50%. Pelvic node dissection is regarded as a staging procedure by the authors’ institution.

Radiotherapy

External beam radiotherapy as a treatment for node-positive prostate cancer applied in an extended field technique has been evaluated. Patients with pathologically proven lymph node metastasis demonstrated a 50% 5-year survival rate in a large series of consecutive patients. In a more recent report, a slightly increased survival rate was noted in a similar group of patients treated with external beam radiation with a subsequent boost to the prostatic bed; not all patients in this report were staged surgically, however, therefore their exact pathologic stage may be in question. Gervasi et al. reported on a larger series of patients who underwent pelvic node dissection followed by radiation treatment. This series reported data that included node-positive and node-negative patients who received radioactive gold seed implantation and external beam radiotherapy. The cancer-specific survival rate for all N+ patients at 5 years was reported as 75% + 7%, decreasing to 43% at 10 years.

Endocrine Therapy and Observation

Discussion

The goal of therapy in treating TxN+ adenocarcinoma of the prostate is palliation of symptoms. When treating node-positive (advanced) prostate cancer, the goal of the chosen therapy must be clearly defined and kept in mind. The goal of palliative therapy is to limit the extent and minimize the symptoms of an already established disease process. At this time, extended survival cannot be demonstrated with any of the current therapies for advanced prostate cancer. The clinician and patient in this setting must discuss the therapeutic options and their attendant risks and benefits.

When comparing the therapies discussed in this post (observation, monotherapy, and combinations of therapy), it must be noted that frequently cited studies often compare noncongruent populations of patients. This fact and the sparseness of data regarding the true natural history of untreated node-positive prostate cancer (D1 disease) makes comparing therapies for this group of patients problematic.

TABLE. Morbidity of Hormonal Therapy

Clearly, some subset of patients may benefit from early intervention for node-positive prostate cancer. This subset of patients has yet to be defined although the patient with microscopic, low-volume node disease appears to be a likely candidate. Recently, Messing et al. reported a survival benefit for N+ prostate cancer patients treated with early hormonal therapy versus those for whom therapy was deferred. Their abstract, presented at the 1999 American Urological Association, showed an approximate three-to-one survival benefit for early hormonal therapy. The current authors anxiously await their full report. Each of the previously discussed treatment modalities has certain risks and benefits and each accomplish local disease control and biochemical regression to different extents. Early intervention of any sort uniformly results in side effects and will make an asymptomatic patient symptomatic. All of the therapies discussed, however, have immediate morbidity, with the exception of deferred treatment. The value of deferred treatment also becomes apparent when at the time of symptomatic progression the previously stated options then can be utilized. Deferred treatment for the patient with advanced prostate cancer is not resigning them to inevitable disease progression and mortality but is the art of maximizing their quality of life. Deferred therapy is not a passive process; it requires close and careful follow-up. Intervention must occur when the disease process progresses and begins to affect the patient’s health and quality of life.