The incidence and mortality of prostate cancer continue to rise and will continue to pose a major public health problem, especially with the increased longevity of the Western population. Prostate cancer has become the most common newly diagnosed cancer in American men, largely because of mass screening of asymptomatic individuals. In 1995, about 244,000 men in the United States will be diagnosed with prostate cancer, and 40,400 will die of it, a mortality rate second only to that of lung cancer [1]. The increase in incidence of prostate cancer primarily represents an increase in the proportion of patients with localized disease. Many such patients are curable with local therapy, and local treatments continue to evolve to minimize morbidity [2].
Despite progress in diagnosis and local therapy, fundamental questions remain with regard to the etiology, prevention, and treatment of prostate cancer. Most notably, treatment of metastatic disease is strictly palliative, and there is still no treatment for hormone-refractory disease that is demonstrated to improve survival. Significant breakthroughs await improved understanding of the biology of prostate cancer and development of novel therapeutic strategies built on that understanding.
Epidemiology
Prostate cancer incidence is strikingly related to age. The incidence of clinically diagnosed prostate cancer is also significantly affected by geographic and racial factors, ranging from 0.8 per 100,000 men in Shanghai, China, to 100.2 per 100,000 men among blacks in Alameda County, California [3]. Epidemiologic studies have shown that mortality rates among US whites and blacks continue to rise, with rates increasing more rapidly among males over 74 years old and reduced in nonwhite young males [4].
Despite these variations in the incidence of clinically detected prostate cancer, the prevalence of latent prostate cancers is actually quite similar across ethnic groups [5]. This suggests that there may be differences in factors required to cause a latent cancer to progress to a clinically detectable stage. Identification of these progression factors would have obvious therapeutic implications. Some of these factors may be environmental in origin because there is an increased incidence of clinical prostate cancer in men who have emigrated from countries with a low incidence to those with a high incidence [6–8].
Except for an association with chronic prostatitis, epidemiologic studies have found no association between prostate cancer and type of diet, prevalence of venereal disease, sexual habits, smoking, or occupational exposure [9]. Vasectomy is not a definite risk factor for the future development of prostate cancer, and individuals who have undergone this procedure should not be categorized as highrisk [10]. Although the role of benign prostatic hypertrophy in the development of prostate cancer remains unclear, it is generally believed that the benign, hypertrophic prostatic cells do not directly transform into malignant cells [11]. One possible contributory factor to the pathogenesis of prostate cancer is elevated serum testosterone concentrations. This hypothesis is supported by observations that prostate cancers are responsive to testosterone suppression, that black men have serum testosterone levels on average 15% higher than white men [12], and that the incidence of detectable prostate cancer in vegetarians and eunuchs, who have below-average or negligible levels of testosterone, is low [13].
The prevalence of latent or “incidental” tumors is characteristic of the prostate gland. Autopsies of men over the age of 50 years have revealed microscopic foci of well-differentiated adenocarcinoma in serial sections of prostate glands otherwise considered to be normal. Every decade of aging nearly doubles the incidence of microscopic prostate cancer: from 10% for men in their 50s to 70% for men in their 80s. It has been estimated that 9 out of 10 men who eventually develop clinically recognized prostate cancer had cancer that remained undetected for decades [14].
Significant clustering of prostate cancer within families, along with breast and central nervous system tumors, suggests a role for genetic factors in the etiology of this disease [15]. It is estimated that men from families in which two or more first- or second-degree relatives have prostate cancer may have as much as eight times greater risk of developing prostate cancer than the average male [16]. As with other malignancies, an inherited susceptibility to prostate cancer may lead to much earlier onset.
Pathogenesis
Despite the increasing incidence of prostate cancer, our knowledge of the molecular and cellular biology of prostatic adenocarcinoma remains significantly less than that of most other neoplasms. Nevertheless, over the past few years several important advances have been made [17]. Loss of heterozygosity studies and, more recently, comparative genomic hybridization techniques have suggested that chromosomes 6q, 8p, 9p, 10q, 13q, 16q, and 18q are potential sites for genes associated with the initiation of prostate carcinoma [18-20]. In one study 74% of the primary prostatic tumors showed evidence of DNA sequence copy number changes [20]. Losses were five times more common than gains. The most common abnormalities affected 8p and 13q. Furthermore, the pattern of genetic changes seen in recurrent tumors, with the frequent gain of chromosomes 7, 8q, and X, suggests that the progression of prostatic cancer and development of hormone-independent growth may have a distinct genetic basis [21].
Although several oncogenes (ras, myc, sis) are expressed with a higher frequency in prostatic cancer cell lines, their overexpression in localized (ie, early-stage) prostatic tumors is uncommon [21]. In contrast, loss of function of tumor-suppressor genes appears to play a significant role in prostatic carcinogenesis. The known tumor-suppressor genes, Rb on 13q and p53 on 17p, may play an important role in the progression of prostate cancer [22]. Mutations in the p53 gene are considered late events in prostatic carcinogenesis, associated with advanced stage, loss of differentiation, and conversion from a hormone-dependent to hormone-refractory state [23]. In contrast, loss of the Rb gene appears to be an early event in prostatic carcinogenesis [24]. Gao et al [25] found decreased expression of another tumor-suppressor gene, dcc (deleted in colon cancer), in 12 of 14 radical prostatectomy specimens.
The abnormal expression of peptide growth factors and their receptors may contribute to the growth and development of both local and metastatic prostate cancer. There is enhanced expression of epidermal growth factor (EGF) and coexpression of the epidermal growth factor receptor (EGFR) in human prostatic tumors, consistent with in vitro data supporting autocrine growth regulation by EGFR-mediated pathways [26]. Tissue containing benign prostatic hypertrophy and several prostate cancer cell lines express higher-than-normal levels of transforming growth factor (TGF)-beta [27], as well as TGF-alpha and EGFR [28]. The fibroblast growth factors (FGFs), which have been isolated from prostatic tissue, have also been implicated in prostate cell growth [29]. Moreover, male transgenic mice expressing int-2, a member of the fibroblast growth factor peptide family, develop prostatic hypertrophy [30]. Other members of the tyrosine kinase growth factor receptor family related to EGFR include the HER-2/neu (c-erbB-2) and c-erbB-3 oncogenes. The increased expression of HER-2/neu and c-erbB-3 has also been demonstrated in prostatic intraepithelial neoplasia and in primary prostatic cancers and matching metastases from the same patients [31]. Within the group of primary prostate tumors, there is a positive correlation between stage and Gleason grade of tumor and the immunohistochemical expression of HER-2/neu [32]. The progression of prostatic tumors to a hormone-refractory state is frequently associated with the expression of the anti-apoptotic gene bcl-2 [32,34].
The expression of the surface adhesion molecule E-cadherin was absent in almost 50% of prostatic tumor [35], which correlated with tumor grade and stage and overall survival [36].
Tumor-induced angiogenesis is an essential step in the progression of malignant neoplasms and the development of metastases. Weidner et al [37] noted that the mean microvessel count in the invasive primary prostatic specimen was significantly higher for patients with metastases than for patients without metastases. The microvessel count was also noted to be increased at higher Gleason scores. In a multivariate analysis in 74 patients, microvessel count remained significant, and Gleason score did not add additional predictive value [37]. The therapeutic potential of angiogenesis inhibitors is under active investigation.
Both benign and malignant prostatic disease are influenced by interactions between cells in the stromal and epithelial compartments [38]. It has been shown that the in vivo and in vitro behaviors of prostatic epithelial cells are affected by the presence or absence of mesenchymal cells, particularly fibroblasts, and/or their paracrine-acting products. The frequent metastases of prostate cancer to the axial skeleton and the production of osteoblastic metastases suggest a bidirectional paracrine interaction between prostate cancer and bone cells.
Recognition of premalignant lesions in the prostate may permit the identification of a high-risk population that might benefit from early screening. Because prostatic intraepithelial neoplasia is much more common in prostate glands with invasive carcinoma than in those without, this type of growth has been designated as a premalignant lesion. Another premalignant condition in the prostate is atypical adenomatous hyperplasia, or prostatic adenosis [39].
Pathology
Histologically, almost all prostate cancers are adenocarcinomas. Such entities as sarcomas and transitional cell, small-cell, and squamous cell carcinomas are rare. Nonetheless, it is important to recognize these pathologic subtypes because they have distinct clinical behaviors and require different therapy. For example, patients with unusual sites of metastases (such as liver, skin, or bone marrow), low or normal levels of serum prostate-specific antigen (PSA), and newly diagnosed tumors that display hormone resistance should be evaluated for possible anaplastic small-cell pathology. Such anaplastic tumors respond better to chemotherapy than to hormonal treatments [40]. Similarly, transitional cell carcinoma of the prostate does not respond to hormonal manipulations but is moderately sensitive to radiation and chemotherapy.
The Gleason system for histologic grading of prostate tumors, which is based solely on morphology, correlates with malignant potential. Low-power microscopic examination of biopsy specimens (not those obtained by fine-needle aspiration) usually reveals tumor patterns ranging from well-differentiated, small glands to poorly differentiated sheets or cords of malignant cells. Five distinct glandular patterns are graded progressively from most to least differentiated. The grades of the two predominant patterns present in a surgical specimen are added to yield the final Gleason score. Patients with well-differentiated lesions (ie, Gleason scores 2–4) usually have early-stage disease and a good prognosis. Gleason scores 8–10, however, are associated with a poor prognosis. Gleason score correlates well with other known prognostic factors, such as tumor size, presence of pelvic lymph-node metastasis, and PSA level. The M.D. Anderson Cancer Center grading system is a simpler method that depends only on the percentage of gland formation in the tumor. It also appears to reflect the biologic behavior of prostate cancer [41].
The DNA ploidy and S-phase fraction of prostatic tumors may provide additional prognostic information. Flow cytometric assessment of both DNA content and S-phase fraction is possible using small quantities of prostatic tissue obtained at biopsy [42]. Detection of a high S-phase fraction in a primary tumor may indicate lack of hormonal responsiveness and poor prognosis [43].
Diploid tumors are associated with improved survival [44].
Natural History
Epidemiologic studies suggest that the probabilities of the early events leading to so-called histologic cancers are similar worldwide [45]. Low-grade tumors can grow very slowly and remain localized to the gland for relatively long periods of time, during which they remain clinically undetectable. Tumors that become clinically significant arise mainly (80% of the time) in the peripheral zone of the prostate gland and less frequently in the transitional zone (15%) or central zone (5%). Significantly, the latter two areas are also frequent sites of benign prostatic hypertrophy. Tumors in the peripheral zone are palpable during digital rectal examination (DRE) but are inaccessible to transurethral resection. In contrast, tumors in the transitional zone surrounding the prostatic urethra are not palpable but can be removed easily during transurethral resection of the prostate.
Prostate cancers typically grow peripherally through the capsule along perineural sheaths that perforate the capsule at the upper outer corner and at the apex. Such tumors often invade the seminal vesicles and the neck of the urinary bladder. Occasionally, a prostatic tumor may invade across the fascial planes into the rectal wall.
Distant metastatic spread is both lymphatic and hematogenous. Lymphatic spread is usually orderly, first affecting the obturator lymph nodes, then advancing contiguously into the external iliac and hypogastric nodes, and finally involving the common iliac and periaortic nodes. Hematogenous spread is also characteristically orderly. In general, the axial skeleton is involved as the first site of metastasis. This is followed by spread to the proximal appendicular skeleton. Only in advanced disease do pulmonary and hepatic metastases appear. Metastases to either liver or lungs, especially in the absence of extensive skeletal involvement, should alert the physician to the possibility of small-cell carcinoma of the prostate, for which therapy significantly differs from that for adenocarcinoma. Metastases to the brain and other visceral sites are uncommon. Characteristically, bone metastases are osteoblastic and readily detected by radionuclide bone scans. While metastatic bone disease is almost always present when the pelvic lymph nodes are involved, the converse is not always true; bone metastasis often occurs without evidence of nodal involvement. Spinal metastases may extend into the epidural space and cause extrinsic compression of the spinal cord and progression to paraplegia. It is therefore prudent to thoroughly evaluate patients with backache for impending spinal cord compression. Paraneoplastic syndromes have been associated with disseminated prostate cancer and include disseminated intravascular coagulopathy and neuromuscular abnormalities. It should be noted that hypercalcemia is very unusual with prostate cancer, and other causes should be explored when it occurs in the prostate cancer patient.
Diagnosis
Transrectal Ultrasonography
Adenocarcinoma of the prostate usually appears as a hypoechoic lesion and can be detected in the apex of the prostate. Transrectal ultrasonography (TRUS) may detect lesions as small as 5 mm in diameter. In addition, a TRUS-guided biopsy permits a more precise sampling of areas suggestive of cancer [46]. Since this procedure is associated with minimal morbidity and complications, it can be performed easily on an outpatient basis. It is important to keep in mind that only 20% of hypoechoic areas are actually cancerous because the hypoechoic appearance of prostatic tumors reflects their high cellular density and overlaps considerably with that of nonmalignant tissue that may be affected by inflammation. In addition, up to 30% of prostate lesions that are easily palpable during DRE can be missed by ultrasonic scanning because they are isoechoic rather than hypoechoic. In addition, cancers arising in the transitional zone of the prostatic gland, an area that is also the origin of benign prostatic hypertrophy, cannot be detected as hypoechoic tumors because of the heterogeneous texture of this region of the gland.
The role of TRUS in screening for prostatic cancer remains to be established. Advocates emphasize its ease and reliability in serial examinations and the limitations of the DRE. Skeptics, however, point to the relatively marginal specificity of the procedure and to the lack of proof that detection of early lesions actually improves the clinical outcome of affected patients.
Prostate-Specific Antigen
Prostate-specific antigen is a glycoprotein produced by both normal and malignant prostate cells. Although specific to the prostate in benign tissues, recent studies have shown that other human malignancies, such as breast and ovarian cancer, may also express PSA, albeit at significantly lower levels [47,48].
An enlarged prostate caused by benign prostatic hypertrophy, especially in older males, accounts for the majority of borderline PSA elevations encountered in community practice. However, levels above 10 ng/mL are unlikely to be due to benign prostatic hypertrophy alone, necessitating a proper urologic evaluation [49]. Hudson et al [49] showed that only 2% of patients with benign prostatic hypertrophy had PSA levels over 10 ng/mL and that 44% of patients with prostate cancer (including 36% of those with clinical stage A or B disease) had levels over 10 ng/mL. On the other hand, up to one third of patients with localized prostate cancers have normal PSA values [49,50]. Therefore, measurement of PSA should not replace DRE in the early detection of prostate cancers but rather should complement it. It should be noted that PSA assays from different manufacturers may yield discordant results [51].
Attempts to refine the predictive value of PSA have been reported. One approach uses the ratio of PSA to the prostatic volume [52]. This refinement adjusts for the fact that the upper range of normal PSA levels rises with age, due partly to the increasing size of the prostate gland. Using the 95th percentile, the upper limit of the normal range for the serum PSA concentration increases from 2.5 ng/mL for a 45-year-old man to 6.5 ng/mL for a 75-year-old man [50]. Another consideration in improving the diagnostic yield of PSA measurement is the “PSA velocity,” or slope. It has been observed that serum PSA increases more rapidly in prostate cancer than in benign prostatic hypertrophy [45]. Further, a rise in PSA compared with previous measurements may be highly predictive of prostate cancer even though the PSA remains in the “normal” range [50].
The kinetics of PSA release and clearance are important for its proper incorporation into therapeutic decision making in patients with prostate cancer. Routine DRE should not cause a significant elevation in PSA [53]. This is in contrast to the level of prostatic acid phosphatase (PAP), which is affected by DRE. Nevertheless, it is generally recommended that baseline levels of PSA be measured before DRE or any other prostatic manipulation. After major traumas, however, such as transurethral resection or needle biopsy of the prostate, PSA rises significantly, sometimes up to 50 times over baseline values, and remains elevated for weeks [54]. A markedly elevated serum PSA level caused by bacterial prostatitis may cause confusion in the diagnosis of prostatic cancer. Thus, serum PSA determination should be repeated after complete clinical resolution of inflammation to exclude prostatic malignancy [55]. The half-life of PSA has been calculated to be approximately 4.6 days [56].
Serum PSA levels are lowered in patients receiving finasteride(Drug information on finasteride), an inhibitor of 5-alpha-reductase, which is used in the treatment of patients with benign prostatic hypertrophy, and it is therefore prudent to exclude prostatic carcinoma before starting patients on this drug. Any persistent elevation of PSA levels while on finasteride should initiate the necessary workup to rule out prostate cancer. It is recommended that in patients taking finasteride, the age-adjusted reference range of normal serum PSA levels be reduced by 50% [57].
Screening for PSA leads to the detection of more organ-confined prostate cancers than does the use of other diagnostic methods such as DRE. The incidence of lymph-node involvement has decreased from 20% in historical series to less than 10% in contemporary studies [58]. Earlier studies have also shown that serum PSA can detect twice as many cancers as DRE in a screening situation [59] and that DRE may not be adequate to detect tumors in early stages [60]. Current consensus is that elevated serum PSA levels that lead to further evaluation with a prostate biopsy do not identify clinically unimportant prostate cancers [61].
Screening
At present, no adequately performed prospective study has demonstrated a reduction in mortality rate attributable to annual prostate cancer screening. Because of the slow doubling time of primary prostatic carcinoma, it is advisable to confine screening for prostate cancer to men with a life expectancy of greater than 10 years [62]. Preliminary reports have suggested that the proportion of men with organ-confined tumors increases with PSA-based screening and that a reduction in prostate cancer mortality by means of screening is feasible [63]. However, the adoption of widespread screening of men for prostate cancer will await further evidence, particularly from prospectively randomized studies. Currently an NCI-funded randomized trial is under way to determine the survival advantage of screening. In the meantime, current recommendations of the American College of Surgeons are that all men over age 50 years be screened for prostate cancer annually with a DRE and PSA test [64]. Moreover, it has been recommended that men in high-risk groups, including blacks and men with a family history of prostate cancer, be screened at an earlier age [64].
With the advent of screening the general population by PSA measurements, the diagnostic approach in asymptomatic individuals has been steadily evolving. A reasonable summary of the current approach is that if the serum PSA level is less than or equal to the upper limit of the age-specific reference range and the DRE results are unremarkable, the patient should be followed with annual evaluations. If the serum PSA level is greater than the age-specific reference range and the DRE yields normal results, a TRUS should be performed and any visible lesion should be biopsied. In addition, a systematic sextant biopsy of the remaining prostate tissue should be carried out. If none of these cores contain tissue from the transitional zone, two additional specimens from the anterior part of the prostate, one from each side, should be taken in order to completely sample the gland. If the DRE results are abnormal, irrespective of the serum PSA level, the patient should undergo TRUS. Using ultrasound guidance, the palpable abnormalities should be biopsied, as should all hypoechoic lesions. In addition, a systematic sextant biopsy of the remaining prostate gland should be performed.
Staging
The most commonly used staging system for prostatic carcinoma is shown in Table 1. This system incorporates features of the A-B-C-D system originally introduced by Whitmore and later revised by Jewett, as well as features of the tumor-node-metastasis (TNM) staging system devised by the American Joint Committee on Cancer and the International Union Against Cancer [61]. In general, the disease-specific mortality for untreated patients who have stage A disease is less than 2%. Of those with stage B or C disease, one fourth will die within 15 years of diagnosis. Unfortunately, about 70% of patients present with stage C or D prostate cancer. The 5-year survival rate for patients with stage D prostate cancer remains less than 20%.
| Primary tumor (T) | |
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| T1 | Clinically inapparent tumor not palpable or visible by imaging |
 T1a | Tumor incidental histologic finding in 5% or less of tissue resected |
| T1b | Tumor incidental histologic finding in more than 5% resected tissue |
| T1c | Tumor identified by needle biopsy (eg, because of elevated PSA) |
| T2 | Palpable tumor confined within prostateª |
| T2a | Tumor involves half of a lobe or less |
| T2b | Tumor involves more than half of a lobe, but not both lobes |
| T2c | Tumor involves both lobes |
| T3 | Tumor extends through the prostatic capsule |
| T3a | Unilateral extracapsular enlargement |
| T3b | Bilateral extracapsular extension |
| T3c | Tumor invades seminal vesicle(s) |
| T4 | Tumor is fixed or invades adjacent structures other than seminal vesicles |
| T4a | Tumor invades external sphincter and/or bladder neck and/or rectum |
| T4b | Tumor invades levator muscles and/or is fixed to pelvic wall |
| Lymph node (N) | |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph-node metastasis |
| N1 | Metastasis in a single lymph node, 2 cm or smaller in greatest dimension |
| N2 | Metastasis in a single lymph node, larger than 2 cm but not larger than 5 cm in greatest dimension, or multiple lymph nodes, no larger than 5 cm in greatest dimension |
| N3 | Metastasis in a lymph node larger than 5 cm in greatest dimension |
| Distant metastasis (M) | |
| MX | Presence of distant metastasis cannot be assessed |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| M1a | Nonregional lymph nodes |
| M2a | Bone |
| M3a | Other sites |
| PSA = prostate-specific antigen ª Tumor found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c. Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3, but as T2. | |
Patients with newly diagnosed, biopsy-proven prostate cancer are investigated to determine the presence or absence of locoregional and distant metastases. Nuclear bone scans are performed in most patients. A positive bone scan correlates with a high level of PSA and identifies patients with stage D2 disease, rendering elaborate local therapy unnecessary. If the bone scan is negative, computed tomography should be performed to look for involvement of the pelvic lymph nodes. The extent of local disease may be defined better by TRUS as an adjunct to the DRE because clinical staging of the primary tumor is relatively imprecise. To date, no single modality such as DRE, TRUS, PSA measurements, or magnetic resonance imaging can accurately predict which tumors are organ confined and presumably curable by local therapeutic modalities. Preoperative measurement of the prostatic acid phosphatase level is often done. If elevated, this suggests the presence of advanced disease, again obviating the need for prostatectomy [65]. Several studies are currently evaluating the role of molecular staging using an enhanced reverse transcriptase-polymerase chain reaction assay for the detection of prostatic tumor cells in the blood [66]. However, at present there is no evidence of whether the increased sensitivity in detecting micrometastases of prostate cancer has any bearing on the management of patients who are upstaged with this procedure.
Tumor volume in advanced disease appears to influence response to therapy. Investigators at M.D. Anderson Cancer Center have devised a stratification for patients with metastatic disease based on the extent of metastatic involvement. Osseous I (OI) is metastatic axial skeletal involvement only. Osseous II is axial disease plus extremity skeletal involvement. Visceral I (VI) is pulmonary metastases, and visceral II (VII) denotes metastases in other viscera [67].
Treatment
Early-Stage Prostate Cancer (Stages A and B)
The optimal method for managing patients with early-stage prostate cancer remains controversial. Evaluating response is difficult because early detection may increase the interval between diagnosis and death, regardless of the effectiveness of treatment (lead-time bias). In addition, the diagnosis and treatment of latent, rather than clinical, prostate cancer may seemingly achieve therapeutic efficacy when, in fact, these tumors were intrinsically innocuous. There is rising use of radical prostatectomy to treat patients with early stage prostate cancer. Nevertheless, valid comparisons between radiation therapy, radical prostatectomy, and “watch and wait” approaches are lacking, and no final consensus exists on the most appropriate treatment for patients with newly diagnosed early-stage prostate cancer. Further confounding the problem, approximately 30% of patients with clinical stage B and 60% of patients with clinical stage C disease have positive lymph-node involvement upon staging lymphadenectomy [68,69]. Lymph-node involvement may even be higher in patients with higher grade tumors.
Watchful Waiting: Difficulties arise in prospectively identifying patients in whom a deferred-treatment approach can be safely employed without jeopardizing survival or adversely affecting quality of life. Several investigators have questioned whether definitive therapy is necessary for all men with clinically localized prostate cancer [70,71]. However, many of the observational studies that recommended a watchful-waiting strategy had patients with predominantly well-differentiated tumors of low volume. In addition, many such studies included patients over the age of 70 years. In contrast, series recommending radical prostatectomy or radiation involved a larger proportion of younger men with moderately or poorly differentiated tumors.
At present it seems reasonable to offer curative therapy to men judged to have a life expectancy of 10 years or more, though there is no compelling evidence that a close watchful-waiting policy, with treatment deferred until the time of clinical progression, would produce inferior results. Certainly, patients with stage A1 well-differentiated prostate cancer may be simply followed up clinically. For other patients, although local progression is common, if not inevitable, how it affects quality of life in patients managed by watchful waiting requires further study.
Surgery vs Radiation for Localized Disease: In patients with early-stage disease limited to the prostate (stage A2, B1, or B2), both radical prostatectomy and radiation therapy can be curative but are associated with considerable morbidity. In a prospective randomized study by the Veteran Affairs Oncology Group, in which patients were assigned to either radiation therapy or surgery after confirmation that lymph-node metastases were absent, a higher percentage of surgically treated patients were free of recurrence after 5 years [72]. On the other hand, the results of a retrospective analysis of the long-term outcome of radiation therapy were comparable with those of surgical treatment in the cohort prospectively studied by the Veteran Affairs group [73]. Thus, neither approach has proved statistically superior in efficacy [74].
Since neither surgery nor radiation therapy is clearly preferable for treating localized prostate cancer, each patient's therapy must be individually chosen after consideration of the potential benefits and risks. Currently, patients with a 10- to 15-year life expectancy, good performance status, and clinically localized prostate cancer that is not of high Gleason grade nor associated with a PSA level above 15 ng/mL are considered ideal candidates for radical prostatectomy.
Radical Prostatectomy: Radical prostatectomy involves the removal of the entire prostate, including the capsule, a layer of surrounding connective tissue, and the attached seminal vesicles. Newer techniques have significantly reduced impotence and hemorrhage, but urinary incontinence may occur in a small proportion of patients. Using the nerve-sparing technique pioneered by Walsh [75], potency returns in 50% to 80% of patients after 1 year. Whether this technical modification compromises the overall effectiveness of the surgery with regard to local tumor control awaits longer periods of follow-up. Only selected patients, those with tumors that do not involve the neurovascular bundle in the pelvic plexus and branches innervating the corpora cavernosa lateral to the prostate gland, are eligible for this procedure [76]. Prostate-specific antigen must become undetectable after curative radical prostatectomy, and its presence after this procedure indicates residual prostatic cancer cells.
Zincke et al [2] reported the experience using radical prostatectomy for clinically organ-confined disease at the Mayo Clinic. Of the 1,143 patients followed up after radical prostatectomy, the 10- and 15-year disease-specific survival rates were 90% and 83%, respectively. Only the tumor grade was a significant predictor for disease outcome. For the more recent 1,000 patients, hospital mortality was 0% and severe urinary incontinence had declined so that it only affected 1.4% of patients.
Radiation Therapy: External beam radiation from high-energy linear accelerators is used in the treatment of patients with localized prostate cancer that may be encompassed within a radiotherapy field. The treatment involves up to 50 Gy of wide-field radiation that includes the pelvic lymph nodes, followed by an additional booster dose to the prostate and surrounding tissues, for a total dose of 70 Gy [7]. Complications such as delayed impotence occur in approximately 40% of patients. Urinary incontinence, however, is relatively uncommon. Radiation-induced rectal damage may also be a troublesome side effect of radiation therapy.
The presence of residual tumor after radiation therapy has been a cause for concern. Systematic biopsies of tissue from patients treated with radiation therapy have shown a 35% to 91% incidence of apparently viable tumor [78,79]. The detection of viable tumor 1 year after radiation therapy predicts for the subsequent development of distant metastases [80,81]. PSA levels should fall to normal within 6 to 12 months after radiation therapy, and persistence of elevated levels may indicate residual disease and poor prognosis.
The recent introduction of high-precision three-dimensional conformal radiation therapy (3D-CRT) in the treatment of prostate cancer provides a promising approach for overcoming the problems of local tumor failure after radiation therapy [82]. In addition, 3D-CRT attempts to circumvent the problems associated with exposure of normal pelvic tissues to external beam radiation. 3D-CRT uses sophisticated computer-aided treatment planning to accurately conform the distribution of a prescribed radiation dose to the anatomic boundaries of the prostatic target volume.
Stage C Prostate Cancer
Surgical cure is unlikely in patients with stage C prostate cancer given that over 50% of patients have pelvic lymph-node involvement, and there is a significant chance of leaving residual tumor behind [83]. Long-term disease-free survival is possible for some patients who only have capsular penetration (clinical stage C1). However, in most patients simply extending the surgical margin of resection has no impact on disease-free survival [84].
The use of adjuvant radiation and/or endocrine therapy in stage C disease remains controversial. A retrospective analysis of patients treated at the Mayo Clinic revealed that adjuvant therapy with radiation or orchiectomy for high-risk men decreased both the local and systemic progression rates but had no impact on survival [85]. This study result provides additional support for a deferred-treatment approach.
Radiation therapy has been the primary mode of treatment for patients with stage C prostate cancer [86]. In a series of patients treated with radiation and followed up for 20 years, 44% died of intercurrent illnesses and 47% died of prostatic cancer [87]. Hormonal therapy has also been used in the treatment of patients with stage C disease with the aim of local tumor control and downstaging of the tumor. Conversion from stage C to stage B or A may allow curative resection of the primary prostate cancer. Macfarlane et al [88] reported on 22 patients with stage B2 and C cancers who received preoperative combined androgen blockade. Although the PSA level became normal in the majority, only 33% showed a decrease in tumor size, based on ultrasonography volumes, and only 15% showed a decrease in clinical stage. In another study of 30 patients with stage C disease treated with preoperative hormonal therapy, 47% were downstaged to clinical stage B after therapy [89]. Pathologic staging, however, revealed organ-confined disease in only 10% of the patients. It appears that survival is identical for patients treated initially with hormonal therapy and those treated first with radiation and subsequently with hormonal therapy at the time of tumor progression.
Metastatic Prostate Cancer
Antiandrogen Therapy: Androgen deprivation remains the primary therapy for patients with metastatic prostate cancer, including stage D1 disease (N1-N3 M0). Androgen ablation is not curative therapy in patients with metastases to lymph nodes or beyond but is usually associated with significant disease control. Nevertheless, the duration of response is variable and the effect on the overall survival unclear. Up to 80% of patients with metastatic disease will respond initially to androgen ablation, but within 1 to 2 years, most of them will develop hormone-refractory disease [90]. Antiandrogen therapy should take into account the two sources of androgens in humans. The testes produce most of the testosterone, which is converted in the target cells by 5-alpha-reductase to dihydrotestosterone (DHT). In addition, the adrenal cortex produces androstenedione and dehydroepiandrosterone, which constitute about 5% of the circulating androgens.
Bilateral orchiectomy remains the definitive and most effective antitestosterone treatment. The procedure can be performed in an outpatient setting under local anesthesia with minimal morbidity. Estrogenic preparations, such as diethylstilbestrol(Drug information on diethylstilbestrol) (DES), have also been used for several decades. They exert their antitestosterone effect by inhibiting the secretion of pituitary luteinizing hormone through a negative-feedback loop. Side effects of estrogen therapy include gynecomastia and thromboembolism. Because of concerns about these side effects, daily doses of DES should not exceed 3 mg/d. At this dosage, complete suppression of testosterone is typical. A dose of 1 mg/d has also been advocated and is widely used. Although this dose probably produces fewer side effects, it effectively suppresses testosterone to castrate levels in only 70% of patients. Gynecomastia due to estrogens(Drug information on estrogens) may be prevented by superficial irradiation of the breast tissue at a dose of up to 15 Gy before the start of therapy.
Another class of antiandrogens includes the receptor antagonists, such as flutamide(Drug information on flutamide). The use of flutamide alone is associated with a rise in serum luteinizing hormone and testosterone concentrations as the negative feedback of androgens on the pituitary gland is inhibited. This secondary rise in circulating testosterone may decrease the efficacy of flutamide; it is not used as monotherapy because combination therapy with testicular suppression, described below, is more effective. It is also notable that there was no survival advantage for patients treated with luteinizing hormone-releasing hormone (LHRH) alone when flutamide was added at the time of disease progression [91].
The most commonly used approach in antiandrogen therapy involves the use of hypothalamic LHRH analogs. These synthetic peptides (leuprolide, buserelin(Drug information on buserelin), and goserelin(Drug information on goserelin)) are administered by parenteral injection. Through binding to the LHRH receptors in the pituitary, these agents initially stimulate the release of luteinizing hormone but then block the stimulation of LHRH receptors by the endogenous pulsatile secretion of LHRH. The eventual result is suppression of follicle-stimulating hormone and luteinizing hormone secretion by the pituitary gland. Depot preparations are now available that require only monthly injections to achieve castrate levels of testosterone. The advantages of LHRH analogs are that they avoid the minor trauma of orchiectomy and allow potentially reversible testicular suppression. The disadvantages include cost, the necessity for monthly injections, and the potential for rapid worsening of a patient's condition during the initial 2 weeks of therapy. In patients with involvement of the spinal column, LHRH analogs alone are strictly contraindicated because they can exacerbate spinal cord compression and precipitate paraplegia. This initial flare-up may be blocked by giving flutamide for several days before and for 2 weeks after the depot LHRH injection. The main disadvantage of these depot peptides is their high cost; they are much more expensive in the long term than orchiectomy.
Several studies have compared the efficacy of combined androgen blockade (LHRH agonists or orchiectomy plus antiandrogens) with that of antiandrogen therapy alone [92]. Several trials using an orchiectomy control arm showed a benefit for combined therapy. Janknegt et al [93] examined 433 patients and showed a 6-month advantage in median time to progression (20.8 vs 14.9 months), which was statistically significant, and an 8-month difference in the median time to death from prostate cancer (37.1 vs 29.8 months, P = .04). A study by the European Organization for Research Treatment of Cancer showed a longer time to progression (71 vs 41 weeks; P = .002), longer survival (median, 34 vs 27.1 months, P = .02), and longer prostate cancer-specific survival (43.9 vs 28.8 months; P = .001) for patients receiving combined therapy [94]. The modest survival advantage of total androgen blockade must be weighed against its side effects and considerable expense.
Hormone-Refractory Prostate Cancer
Patients with disease progression in the presence of proven castrate levels of testosterone pose a major therapeutic challenge to the practicing oncologist. Responses to second-line hormonal agents are typically poor, and the median survival of such patients remains less than 1 year [95].
It is important to note that most patients whose disease progressed despite hormonal therapy paradoxically remain sensitive to additional stimulation of tumor growth by androgens. A retrospective multivariate analysis of survival data on 341 patients with hormone-refractory prostate cancer revealed that continued androgen suppression was an important predictor of longer survival, as were weight loss, age, performance status, and disease sites [96]. Therefore, patients with hormone-refractory disease who have not undergone orchiectomy must continue their therapy with estrogen or LHRH analogs. Otherwise, they are at risk of severe, symptomatic exacerbations of their already terminal disease.
Flutamide Withdrawal: Several studies have demonstrated a favorable response to flutamide withdrawal in patients who have experienced a lengthy remission on combined antiandrogen therapy. In a recently reported study, flutamide was discontinued in 36 consecutive patients with disease progression despite castrate levels of testosterone [97]. Twenty-nine percent of patients experienced a significant decline in PSA levels (more than or equal to 80% in seven patients and less than or equal to 50% in three) from baseline after flutamide was discontinued. The duration of PSA response ranged from 2 to 10 or more months, with a median duration of 5 or more months [97]. Decline in PSA was associated with improvement in symptoms in all patients, and one patient had a partial response in an epidural mass with improvement in neurologic symptoms. All patients who responded to flutamide withdrawal received combined androgen blockade as their initial therapy.
Ketoconazole: Ketoconazole(Drug information on ketoconazole) is an antifungal drug that in sufficiently high doses inhibits the adrenal and testicular synthesis of androgens. An initial report showed that the level of PSA decreased on average by 49% from the pretreatment level in 12 (80%) of 15 patients treated with ketoconazole for a median duration of 4 months [98]. A larger study of 44 patients showed 1 complete and 5 partial responses (14% response rate) with a median response duration of 27 weeks [99]. Major side effects from ketoconazole include severe gastric intolerance and adrenal suppression, the latter requiring supplemental hydrocortisone(Drug information on hydrocortisone) to prevent hypoadrenocorticolism.
Chemotherapy: Interest in chemotherapy for hormone-refractory prostate cancer has been rekindled with the demonstration of significant antitumor activity of several drug-combination regimens. One of the most active agents against prostate cancer is doxorubicin(Drug information on doxorubicin) [100]. It is frequently administered at a dose of 20 mg/m² intravenously weekly. While doxorubicin can produce significant subjective improvement, significant prolongation of survival remains elusive [101]. The combination of doxorubicin and ketoconazole has been assessed in 39 patients with hormone-refractory disease [67]. Based on serial PSA measurements, 55% of patients experienced significant responses. Based on reduction of tumor size, objective partial responses occurred in 58% of patients with measurable disease. The combination of oral etoposide (50 mg/m²) and estramustine(Drug information on estramustine) (15 mg/kg/d) given for 21 days and repeated every 28 days has resulted in significant antitumor activity in patients with hormone-refractory prostate cancer [101]. Of the 18 patients with measurable disease, 3 and 6 patients had complete and partial responses, respectively. Ten of 42 patients experienced a greater than 75% reduction in PSA levels; 23 had a greater than 50% reduction. In contrast, single-agent oral etoposide(Drug information on etoposide) had minimal activity in hormone-refractory prostate cancer [102].
Another approach in the therapy of hormone-refractory prostate cancer involves the use of cytotoxic drugs plus hormonal agents. A randomized trial of combined vs sequential endocrine therapy and chemotherapy evaluated the effect of chemotherapy given early in the course of the disease. Patients were randomized to receive doxorubicin and cyclophosphamide(Drug information on cyclophosphamide) either at the time of initial hormonal therapy (combination arm) or at the time of tumor progression (sequential arm). Patients in the combination arm had a higher response rate than those in the sequential arm (63% vs 48%, respectively), but no significant difference in survival was observed [103].
Strontium-89: Strontium-89 is a beta-emitting radionuclide that may be used to deliver systemic radiation therapy to bone metastases [104]. Strontium-89, being chemically similar to calcium, is preferentially localized in bone. Over the past few years it has become recognized as a viable treatment option in the palliation of bone metastases secondary to prostate cancer. Occasionally, a transient increase in bone pain occurs within a few days of administration. In general, the major side effects of therapy with strontium-89 appear to be limited to hematologic toxicity, particularly thrombocytopenia.
A randomized phase III trial was performed in Canada to evaluate the effectiveness of strontium-89 in combination with local-field radiotherapy [105]. Patients with progressive disease after hormonal therapy were randomly assigned to receive local external beam radiation combined with either strontium-89 or a placebo. After 3 months, patients treated with strontium-89 plus radiation had significantly fewer new painful metastases and an increased interval of time to further radiotherapy, and on quality-of-life surveys they had superior improvement in pain and physical activity compared with the placebo group. There was no significant difference in the overall survival, but the strontium-89 treatment group had a greater number of patients with a 50% decline in PSA than the control group did. Investigators at M.D. Anderson Cancer Center are currently evaluating the efficacy of combining cytotoxic therapy (doxorubicin) with strontium-89.
Future Directions
Basic and clinical research in prostate cancer represent very active areas of research. Over the past few years, our understanding of the biology of prostate cancer has considerably increased. Some of the molecular changes during prostatic carcinogenesis may lend themselves to therapeutic interventions.
For patients with advanced hormone-responsive prostate cancer, a plateau has been reached with regard to antiandrogen therapy. One approach that may decrease the morbidity of androgen deprivation involves intermittent androgen suppression to induce multiple apoptotic regressions of prostate cancer [106]. For patients with hormone-refractory prostate cancer, cytotoxic therapy in various combinations is currently being actively investigated. However, in the absence of drugs with significant single-agent activity, this approach seems unlikely to produce significant improvements. Therefore, the search will continue for new drugs that target critical biochemical events involved in the progression of prostate tumors. One promising approach is to inhibit angiogenesis, a process that is crucial for disease progression and metastasis. TNP-470 is a semisynthetic analog of fumagillin with potent antitumor activity in animals bearing prostate tumors and is currently in early clinical trials [107,108].
Assessment of tumor response by bidimensionally measuring metastatic lesions is notoriously difficult in the majority of patients with prostate cancer, who have predominantly bone-only metastases. As such, only 10% to 20% of patients with metastatic disease are eligible for clinical trials based on the presence of measurable disease. Such obstacles have been partly overcome by the use of PSA as a marker for disease activity. A specific objective response may be categorized by the extent of PSA decline, such as 50% to 80% from baseline, and the duration of such a decline. Initial studies assessing the degree of PSA decline and its correlation with survival in patients receiving systemic therapy for hormone-refractory disease have shown that the median survival of patients with at least a 50% decline from the baseline PSA level is 20 months, in contrast to 8 months in patients with less than a 50% decline in the PSA level [109].
