Prostate Cancer: Emerging Concepts: Part II

Glossary

Brachytherapy: The direct implantation of radioactive seeds into the prostate gland to treat prostate cancer. Also called interstitial radiation therapy and seed implantation therapy.

Clinical and pathologic staging of cancer (cT1, cT2a, cT2b, cT3, pT1, pT2, pT3): A description of prostate cancer tumor size and degree of extension using clinical criteria, such as results of digital rectal examination. The letter “c” denotes staging using clinical criteria; “p” denotes pathologic staging, usually determined by the pathologist examining the radical prostatectomy specimen. T1, tumor not palpable; T2a, tumor limited to one lobe; T2b, tumor limited to both lobes; T3, tumor with regional extension.

Cryosurgery: A procedure that involved freezing and thawing the prostate gland by surgical implantation of probes containing liquid nitrogen. Also called cryotherapy.

Neoadjuvant hormonal therapy: Hormonal therapy used to decrease circulating androgen levels before radical prostatectomy or radiation therapy. Designed to shrink the tumor before definitive localized therapy is used.

Prostate-specific membrane antigen: A novel protein that may indicate the presence of prostate cancer.

Three-dimensional conformal radiation therapy: Sophisticated computer modeling used to delineate the volume of the prostate gland more precisely, allowing more accurate and higher doses of external-beam radiation therapy to be delivered.

Neoadjuvant Hormonal Therapy

The problem of clinical “understaging”—that the clinical stage of disease generally underestimates the extent of disease as determined on pathologic examination—has prompted the development of novel management practices, including the use of neoadjuvant hormonal therapy. The rationale for the use of hormonal therapy before either radical prostatectomy or definitive radiation therapy (neoadjuvant) rests on the hypothesis that systemic therapy may be able to downstage and downsize the primary tumor before definitive localized therapy is administered. In a series of prospective trials on the use of hormonal treatment, generally involving a luteinizing hormone-releasing hormone analogue plus an antiandrogen, positive margin rate has decreased and improvements have been noted in tumor size, prostate-specific antigen level, overall gland size, final pathologic stage, time to progressive disease, and disease-free progression [3-9]. In one multi-institutional intergroup study [8], patients who did not receive neoadjuvant hormonal therapy were six to seven times more likely to have a positive margin in the radical prostatectomy specimen than were patients who received hormonal therapy plus radical prostatectomy. In a single-institution study at Memorial Sloan-Kettering Cancer Center that involved more than 200 patients, the organ-confined rate in the surgery-only group was 49%; the rate in patients treated with neoadjuvant therapy was 77% [10].

Information on long-term overall survival and cancer-specific survival after neoadjuvant hormonal therapy is lacking. In one study, however, the rate of relapsing detectable prostate-specific antigen values for all patients with pathologically organ-confined disease (a stage less than equals pT2) at 26 months was identical in patients who received preoperative androgen deprivation and those who did not [10]. Similar data obtained after a shorter follow-up (12 months) have recently been reported [11]. These data lend credence to the hypothesis that neoadjuvant androgen deprivation therapy improves the pathologic staging of tumors in patients who receive it. These findings also support the observation that a pathologically confined tumor seen after androgen deprivation therapy is not an artifact resulting from difficulty in interpreting the histologic changes occurring after androgen deprivation therapy. Because the pathologic organ-confined rate is about 50% higher in patients receiving androgen deprivation therapy than in patients having surgery alone, the net result may be that more patients achieve a nondetectable prostate-specific antigen value. More importantly, prostate-specific antigen is only an intermediate (surrogate) end point; more data are needed on clinical disease recurrence (and, ultimately, on survival) before neoadjuvant androgen deprivation therapy can be considered standard therapy.

The optimal duration of neoadjuvant hormonal treatment is unknown. One study determined the duration of neoadjuvant hormonal therapy by monitoring prostate-specific antigen values: that is, treatment was continued until the monthly measured prostate-specific antigen value reached its nadir. Only 27% of patients had reached the lowest prostate-specific antigen value by 3 months; nearly 90% had reached the nadir by 6 to 7 months. More favorable pathologic results were seen when the duration of neoadjuvant treatment was determined by the lowest prostate-specific antigen value [12]. In the largest randomized study on neoadjuvant radiation therapy to date, which was done by the Radiation Therapy Oncology Group [6], hormonal treatment was administered for 2 months before radiation was started and was continued throughout the course of radiation. Although initial analysis showed no differences in overall survival, disease-free survival and time to the development of progressive disease were significantly and substantially improved in the group that received neoadjuvant hormonal therapy. Several radiation oncologists have noted that the pelvic field size may be able to encompass less normal tissue volume with neoadjuvant therapy, thus minimizing treatment-related toxicity in patients who had previously received hormonal therapy [13].

Endorectal Coil Magnetic Resonance Imaging of the Prostate Gland

In addition to probability curves, endorectal coil magnetic resonance imaging may also help to predict the presence of organ-confined disease, extracapsular extension, or presence of lymph node involvement. In one multi-institutional evaluation of nearly 500 patients who had radical prostatectomy for clinically localized disease [14, 15], adding the results of a magnetic resonance imaging study to the Gleason score and the prostate-specific antigen value provided important discriminating information with which to predict whether patients were likely to have prostate-specific antigen relapse within 2 years after radical prostatectomy. With the use of multiple logistic regression analysis, patients could be separated into groups with low, moderate, and high risk for prostate-specific antigen failure on the basis of the Gleason score of the biopsy specimen and the serum prostate-specific antigen values. Patients with a Gleason score less than 4 and a prostate-specific antigen value less than 10 ng/mL made up the low-risk group; these patients had a prostate-specific antigen failure rate of 2% to 3% at 2 years. In contrast, high-risk patients had a prostate-specific antigen value greater than 20 ng/mL and a Gleason score of 8 or more. These patients had a 70% likelihood of developing prostate-specific antigen failure within 2 years after radical prostatectomy. Most patients were in the moderate-risk group, with Gleason scores of 3 to 7 and prostate-specific antigen values of 10 to 20 ng/mL. In this group, an endorectal magnetic resonance image positive for extracapsular extension or seminal vesicle involvement indicated a high likelihood of predicting prostate-specific antigen failure. However, the likelihood that magnetic resonance imaging, or any currently available imaging technique, will be highly accurate in detecting microscopic extracapsular extension is low, because by definition such extensions are only found on microscopic examination. Current imaging technology is not sensitive enough to detect microscopic disease.

Circulating Prostate Cells

The development of polymerase chain reaction (PCR), which enables minute amounts of DNA to be amplified many times and thus improves detection, promises to become a major advance in the detection of micrometastatic disease [16, 17]. The two markers currently used in studies in which PCR is done to detect circulating prostate cancer cells are prostate-specific antigen and prostate-specific membrane antigen. In contrast to prostate-specific antigen, which is a secreted protein, prostate-specific membrane antigen is membrane bound and cannot be measured in serum by conventional assays. Every cell in the body contains the genes for these markers; however, PCR relies on the demonstration of messenger RNA, which is expressed most highly and specifically in prostate cells. Thus, only prostate cells should react to the prostate-specific antigen and prostate-specific membrane antigen primers. However, the detection of even minute amounts of prostate cell DNA reacting to probes for prostate-specific antigen or prostate-specific membrane antigen indicates the presence of circulating prostate cells.

The major controversy surrounding PCR centers on the significance of finding circulating cells in men with known cancer. There is no doubt that residual microscopic disease exists in men who have positive PCR results for cells containing prostate-specific antigen or prostate-specific membrane antigen 6 months after radical prostatectomy. However, in patients in whom the prostate is still in place—either before radical prostatectomy or after radiation therapy—the significance of circulating cells is uncertain. Thus, current data do not support a decision to deny curative treatment solely on the basis of the PCR-prostate-specific antigen or PCR-prostate-specific membrane antigen test. In the initial study describing the PCR-prostate-specific antigen assay [18], only 35% of patients with known metastatic disease had a positive test result. Other researchers have found positive results in nearly 80% of patients with stage D disease. Further clinical correlation and standardization of the probes used for PCR are needed before the assay can be considered a reliable clinical tool. A major potential disadvantage of the PCR-prostate-specific antigen test in patients with metastatic disease is the decrease in the prostate-specific antigen value that occurs with hormonal manipulation [19-21]. In contrast, prostate-specific membrane antigen is up-regulated after androgen deprivation therapy; thus, tests for the presence of this antigen may be more valuable in patients receiving hormonal therapy [22].

New Concepts in Radiation Therapy

Three-Dimensional Conformal Radiation Therapy

Recent advances in radiation therapy have allowed the delivery of larger doses to more precisely defined anatomical areas. Three-dimensional conformal radiation therapy uses sophisticated computer modeling to precisely outline the tumor and deliver larger tumoricidal doses of ionizing radiation while at the same time minimizing damage to surrounding normal tissues. In a recent study [23], 432 patients with stage T1 to T3 prostate cancer received three-dimensional conformal radiotherapy. Doses could be escalated to 81 Gy without significant increases in toxicity. Overall, minimally to moderately severe rectal and urinary symptoms were the principal toxic effects. Preliminary efficacy, as measured by the 3-year actuarial survival without prostate-specific antigen relapse (a prostate-specific antigen value less than 1 ng/mL), are also encouraging, especially in appropriately selected patients. Patients with a serum prostate-specific antigen value less than 20 ng/mL and a Gleason biopsy score less than 6 had a significantly higher survival rate than patients with a higher prostate-specific antigen value or Gleason score.

It is also essential that biopsies be done after external-beam radiation therapy because prostate-specific antigen levels in serum may be undetectable, even with immunohistologic evidence of profuse prostate-specific antigen production in malignant cells [18]. Although no long-term (> 5 years) prostate-specific antigen or postradiation biopsy results are currently available, the solid rationale for this approach and the observation that dose escalation can be both well tolerated and effective, are reasons to be encouraged. However, long-term follow-up must be done in this area before definitive conclusions can be drawn about the place of three-dimensional conformal radiation therapy [24-31].

Defining an Optimal Prostate-specific Antigen Value after Definitive Radiation Therapy

Although a prostate-specific antigen value reduced to within the normal range (≤ 4 ng/mL) after external-beam radiation therapy was initially associated with favorable outcomes, recent data have challenged this finding. The likelihood of cancer recurrence, either in a local-regional area or systemically, is substantial if the prostate-specific antigen value after therapy does not decrease to less than 1 ng/mL. Other investigators have suggested that values of 0.5 ng/mL and even lower are required to predict long-term disease-free status [32-36]. Thus, the prognostic significance of prostate-specific antigen values after radiation therapy seem to have the same qualitative and quantitative significance as do values after radical prostatectomy.

Brachytherapy

The direct implantation of radioactive materials (usually in the form of “seeds”), also called interstitial implantation, has been used to treat prostate cancer since the 1970s and 1980s. In early programs, radioactive seeds were implanted into the prostate without the ultrasonographic guidance commonly used today; this therapy was associated with poor local control. With external-beam radiation therapy, local failure occurs in 4% to 13% of patients with stage B disease. In contrast, the use of implanted seeds in two studies [37, 38] did not eradicate or control the cancer in the prostate gland area in 17% to 52% of patients. Local failure rates were nearly two- to threefold greater in patients with stage C disease who were treated with interstitial implantation than in patients who received external-beam therapy. Complications, including radiation damage to the bowel and urethral damage, were common.

As a result of technical improvements, brachytherapy has recently reemerged. With the use of both computed tomographic and magnetic resonance scanning techniques and the improvements in transrectal ultrasonography, the prostate anatomy of the urethra and extraprostatic tissues can be visualized more accurately. This accuracy allows more precise seed placement. Patient selection criteria have also improved. The ideal patient is generally sexually active and has nonpalpable cancer (usually detected by prostate-specific antigen-based screening), a Gleason score of 2 to 4, and a prostate-specific antigen value less than 10 ng/mL. The likelihood that this cancer is organ confined is about 75%. When this type of patient is selected, better results should be obtained. Indeed, nearly 70% to 80% of patients with early prostate cancer (patients with T1 disease and selected patients with T2 disease) may be free of cancer and have a normal prostate-specific antigen test result 3 years after the procedure. The selection of “favorable” patients and the few patients to whom these results pertain should be emphasized. The ability to maintain potency is also reported to be high in these patients; some rates are as high as 70%.

The most disturbing aspect of these studies, however, is the occurrence of bowel, urinary, and urethral complications that often require corrective surgery. Implanted seeds may also migrate within the prostate, raising the possibility that some areas of the prostate may receive a substantial underdosage. Microscopic disease penetration through the prostatic capsule, which would be included in an external radiation field, may receive insufficient dosage with brachytherapy. Finally, as with three-dimensional conformal therapy, no results from long-term follow-up after postradiation biopsy have yet been obtained in patients treated with the newer techniques of seed implantation. Overall, however, the rapidity of treatment and the minimal morbidity are appealing and should encourage further study.

Cryosurgery

Cryosurgery is another emerging treatment for clinically localized prostate cancer [39]. In the past few years, the techniques and machinery used to deliver freezing temperatures to the prostate gland have been greatly refined. Cryosurgery cannot be recommended with the sense of confidence that we can bring to the recommendation of radical prostatectomy, radiation therapy, or interstitial radiotherapy, because long-term data on local control and survival are not yet available [40].

Cryosurgery is the freezing of tissues; the extremely cold temperatures destroy the exposed tissue. During this procedure, a transrectal ultrasonographic probe is inserted to visualize the prostate gland; probes containing liquid nitrogen are then implanted through the perineum. After the probe is in place, the liquid nitrogen delivers freezing temperatures to the gland. An important step is to prevent freezing of the urethra by simultaneously introducing a warming solution into the urethra. Researchers have recently observed that after the gland has been frozen and allowed to thaw, destruction of the cancer can be improved when the tumor is frozen again under the same anesthesia. The increased effectiveness of the “double freeze” technique appears to occur without appreciably increasing side effects.

The rate of positive biopsy results is about 15% at 2 years after the procedure. Unlike radiation therapy (with which patients cannot be re-treated), patients who initially had cryosurgery can be retreated with freezing. This refreezing often further reduces the rate of positive biopsy results [41].

Complications from cryosurgery include damage to the urethra and, in rare cases, urethral stricture, urethral fistula, and prostatitis. Overall, more than 50% of treated patients experience at least one significant adverse effect [42]. Incontinence is reported to occur in about 3% of cases. When cryosurgery is used after radiation failure, the overall incontinence rate may be as high as 20% to 30%; the incontinence is thought to result from the cumulative effects of radiation and cryosurgery on the external sphincter. The incontinence rate is also higher in patients whose tumor involves the apex of the prostate in proximity to the external urethral sphincter. About 20% of patients who were potent before the procedure are potent at 6 to 12 months of follow-up. Nearly 6000 patients have been treated with cryosurgical ablation of the prostate gland for prostate cancer.

Antiandrogens

Since 1989, the antiandrogen flutamide has been available for managing metastatic carcinoma of the prostate, in combination with either a luteinizing hormone-releasing hormone analogue or orchiectomy. Recent studies suggest that patients who have received complete androgen blockade (an antiandrogen plus a luteinizing hormone-releasing hormone analogue) and then become refractory to this therapy may have a temporary remission if the antiandrogen is withdrawn [43]. This phenomenon occurs with the withdrawal of flutamide as well as another antiandrogen (bicalutamide) [44], estrogens [45], and progestational agents [46]. The response to hormonal withdrawal is usually a decrease in the prostate-specific antigen value and, occasionally, objective radiologic alleviation of disease. This improvement is thought to result from molecular alterations in the androgen receptor, in which the antiandrogen (or other hormone moiety) assumes agonist rather than antagonist properties. Responses are usually short lived.

The Food and Drug Administration recently approved a second antiandrogen, bicalutamide, for the management of metastatic prostate cancer in combination with a luteinizing hormone-releasing hormone agonist. Although flutamide and bicalutamide appear similar in their mechanisms of action, overall survival data for patients receiving bicalutamide with a luteinizing hormone-releasing hormone agonist have not yet been reported [47]. The two antiandrogenic drugs appear to cause similar hepatotoxicity and liver function abnormalities; these side effects underscore the necessity of close monitoring of liver abnormalities, especially during the first months of therapy.

The potential benefit of adding antiandrogens to orchiectomy or a luteinizing hormone-releasing hormone analogue has recently been examined [48]. Although this meta-analysis questioned the net clinical benefit of this addition, methodologic flaws of the analysis (the inclusion of many short-term studies and studies that did not use pure antiandrogens) limit the strength of its conclusions [49].

The molecular biology of androgen resistance is becoming better understood. A recent study [50] reported that hormonally refractory prostate cancer was associated with a mutation in the androgen receptor of prostate cancer cells. This marker for hormonally refractory disease will be important as novel treatment strategies emerge.

Advances in Treating Erectile Dysfunction

Several general types of treatment are now available for sexual dysfunction that develops after radical prostatectomy or radiation therapy [51]. These treatments are described in order of increasing complexity. One treatment involves a vacuum device that can inflate the penis by the use of suction. A second treatment, pharmacologic injection therapy (also known as intracavernous vasoactive injection therapy), uses intrapenile injections of alprostadil (prostaglandin E₁). A third treatment is the implantation of a penile prosthesis or tube that makes the penis rigid.

Most experts use the vacuum device as the initial therapy for patients who have had prostatectomy because the procedure is simple and noninvasive. Pharmacologic injection therapy is much more likely to be successful if the patient and his partner are fully informed about the injection technique. The physician who trains the patient in injection therapy must be properly empathetic and must take the time necessary to adequately explain the proper technique. With this treatment, the physician's impatience and the patient's subtle reluctance are often the main reasons for loss of compliance and abandonment.

Improvements continue to occur. For example, some of the medicines may now be administered directly into the urethra through a suppository or urethral cream specifically made for this purpose. Although only preliminary data are available on effectiveness in achieving an erection, the avoidance of injection is seen as desirable.

Prostate-specific Antigen and the Increasing Incidence of Prostate Cancer

In August 1994, the Food and Drug Administration approved the use of prostate-specific antigen in association with digital rectal examination for the early diagnosis of prostate cancer. This new screening technique has already greatly increased the number of reported cases of prostate cancer [52]. The increase is likely to continue and seems to be largely related to increased awareness of prostate cancer and increased detection through the prostate-specific antigen test. In the past 5 years, the reported incidence of prostate cancer has nearly doubled, and these trends are expected to continue. Many have ascribed the increased incidence of prostate cancer solely to the increased detection that has resulted from prostate-specific antigen screening, and concern has therefore been raised that many patients will be diagnosed with and treated for slowly growing tumors that are unlikely to affect longevity. If this is true, many men may be subjected to unnecessary treatment-related illness and possibly death [53]. However, in Table 1, it is clear that the incidence of clinical prostatic carcinoma was increasing dramatically even before prostate-specific antigen detection was possible. These data contrast the incidence during two 5-year periods in three regions of the United States. The rate of clinically diagnosed prostate cancer in 1973 to 1977 was 6% to 36% greater than that reported in 1968 to 1972. Thus, appropriate understanding of the biology of prostate cancer and prostate cancer progression and optimal management of localized cancer became urgent priorities.

Funding for Research on Prostate Cancer

Agencies of the U.S. government are actively working to fund research in the biology and management of prostate cancer. The Specialized Programs of Research Excellence (SPORE) in Prostate Cancer will award $7.5 million annually for the next 3 to 5 years to enhance translational research approaches. Additional funding from other government sources should amount to $100 million to $130 million between 1996 and 1999. Private sources, such as Michael Milken's CaPCURE (Cure for Prostate Cancer), are providing much-needed support for basic science initiatives in prostate cancer research.

Funding also needs to be directed toward identifying prevention strategies. Nutritional modifications may help explain geographic and racial differences in the incidence of prostate cancer in different populations [55-58]. The recent observation [59] that the growth rate and prostate-specific antigen production of human prostate cancer cells implanted in nude mice can be significantly slowed by a diet consisting of no more than 20% total fat is intriguing. This finding suggests that dietary modification in humans may significantly slow tumor growth.

Legislation

The U.S. Congress has also been directly involved with legislation relevant to prostate cancer care. Pending as of this writing is the Prostate Cancer Diagnosis and Treatment Act of 1995. Key provisions are amendments of the Social Security Act to include Medicare coverage for the early detection of prostate cancer (including but not limited to digital rectal examination, testing for prostate-specific antigen, and transrectal ultrasonography) and reimbursement for oral anticancer agents, including antiandrogens, despite the limited information available on the effectiveness of several of these approaches.

Directions for Future Research

Gene Studies

As they have in patients with colon cancer, various chromosomal abnormalities have been identified in patients with human prostatic tumors. Most interest has centered on chromosomes 8p, 10q, and 16p, in which an increased rate of deletions and mutations has been observed. A putative prostatic cancer suppressor gene has been identified on chromosome 11q and on the KAII gene, related to invasion and metastases or chromosome 1q.

Although these findings may in the future shed some light on the cause of prostate cancer, the use of these data in treatment remains a promissory note for the clinician. Gene therapy to replace a specific abnormal gene may be of value in a disease such as cystic fibrosis, which results from a single genetic defect. However, the multiplicity of chromosomal defects in human solid tumors make it unlikely, if not impossible, that we will be able to usefully alter cell abnormalities in prostate cancer with gene therapy. A more promising approach is the transfection of irradiated human prostate cancer cells with cytokine-producing genes such as interleukin-2, interferon, granulocyte-macrophage colony-stimulating factor, or other appropriate immune-modulating agents. A particularly attractive concept is promoter-driven gene therapy, in which the transfected cell containing cytokines plus a specific promoter, such as prostate-specific antigen or prostate-specific membrane antigen, will direct the cytokine action specifically against prostate cancer cells—akin to Ehrlich's long-sought “magic bullet.”

Genetic Disorders

An investigation [60] of familial prostate cancer found that, overall, only about 9% of all prostate cancer may be familial. Of men younger than age 55 years who presented with prostate cancer, one third had evidence of an inheritable tendency. Other studies have shown a twofold increase in the incidence of prostate cancer in men with one first-degree relative having the disease; the risk increases four- to ninefold when two or more first-degree relative are afflicted. Thus, these men are candidates for more vigorous prostate screening, and some authorities recommend a prostate evaluation with an annual prostate-specific antigen assessment and digital rectal examination starting at age 40 years for men with this genetic background.

Dr. Fair: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.