Treatment

A. Localized Disease
1. General considerations - The optimal form of therapy for all stages of CaP remains a subject of great debate. Well-designed, randomized trials comparing various modalities for localized disease are lacking. Treatment dilemmas persist in the management of localized disease (T1 and T2) because of the uncertainty surrounding the relative efficacy of various modalities, including radical prostatectomy, radiation therapy, and surveillance. Currently, treatment decisions are based on the grade and stage of the tumor, the life expectancy of the patient, the ability of each therapy to ensure disease-free survival, its associated morbidity, and patient and physician preferences.

2. Watchful waiting - No randomized trial has demonstrated the therapeutic benefit of radical treatment for early-stage prostate cancer. Patients with prostate cancer are often older and may have concomitant illnesses. In addition, the small, well-differentiated prostate cancers commonly found in this population are often associated with very slow growth rates. Several studies have shown that surveillance alone may be an appropriate form of management for highly selected patients with prostate cancer (

Table 22-6). However, most patients in such series are older and have very small, well-differentiated cancers. Even in such a selected population, cancer death rates approach 10%. In addition, end points for intervention in patients on surveillance regimens have not been defined.

3. Radical prostatectomy - The first radical perineal prostatectomy was performed by Hugh Hampton Young in 1904, and Millin first described the radical retropubic approach in 1945. However, the procedure remained unpopular because of frequent complications of incontinence and impotence. The rebirth of radical prostatectomy has resulted from a better understanding of the surgical anatomy of the pelvis. Description of the anatomy of the dorsal vein complex resulted in modifications in the surgical technique leading to reduced operative blood loss. In addition, improved visualization made possible a more precise apical dissection, allowing better reconstruction of the urinary tract and improved continence. Eversion of the bladder mucosa before anastomosis ensures a mucosa-to-mucosa apposition. Anatomic dissections have led to a better understanding of the prostate apex anatomy and its relationship to the distal urethral sphincteric mechanism. Description of the course of the cavernous nerves enabled modifications of the surgical technique, resulting in preservation of potency.

The prognosis of patients treated by radical prostatectomy correlates with the pathologic stage of the specimen. Distant metastasis is inevitable in patients with positive lymph nodes. A high percentage of patients with seminal vesical involvement at radical prostatectomy are destined to distant failure. Fortunately, the number of patients with these adverse prognostic factors undergoing surgery is decreasing because of better candidate selection based on appropriate use of preoperative clinical parameters. Several investigators have established nomograms to predict final pathologic stage at radical prostatectomy based on the serum PSA level, clinical DRE stage, and Gleason sum derived from the biopsy.

Patients with organ-confined cancer have 10-year disease-free survival ranging from 70% to 85% in several series. Those with focal extracapsular extension demonstrate 85% and 75% disease-free survival at 5 and 10 years, respectively. Patients with more extensive extracapsular extension demonstrate 70% and 40% disease-free survival at 5 and 10 years, respectively. High-grade tumors (Gleason sum > 7) have a higher risk of progression than do low-grade tumors. Disease-free survival at 10 years for patients with Gleason sum 2-6 tumors is in excess of 70%; for Gleason sum 7, 50%; and for Gleason sum > 8, 15%. Positive surgical margins significantly affect only tumors with extensive extracapsular extension.

The role of neoadjuvant hormonal therapy in men with localized CaP is currently being studied. Several investigators have reported a decrease in the number of positive surgical margins and the incidence of extracapsular extension. However, the largest randomized study to date demonstrated comparable serologic relapse rates at 4 years. Long-term data are still needed, and trials are ongoing.

The management of patients with positive surgical margins at radical prostatectomy remains controversial. Not all such patients relapse, but the identification of appropriate candidates for adjuvant radiation therapy remains problematic. A large multicenter randomized trial was recently closed to accrual to determine whether adjuvant radiation therapy in this setting is superior to radiation therapy at the time of relapse. Results of this study will not be available for several years.

Morbidity associated with radical prostatectomy can be significant and is in part related to the experience of the surgeon. Immediate intraoperative complications include blood loss, rectal injury, and ureteral injury. Blood loss is more common with the retropubic approach than with the perineal approach because in the former, the dorsal venous complex must be divided. Rectal injury is rare with the retropubic approach and more common with the perineal approach but usually can be immediately repaired without long-term sequelae. Ureteral injury is exceedingly rare. Perioperative complications include Deep venous thrombosis, Pulmonary embolism, lymphocele formation, and wound infection. Late complications include urinary incontinence and impotence. Although total urinary incontinence tends to be rare (< 3%), stress urinary incontinence may be seen in up to 20% of patients. The return of continence after surgery is gradual, with 50% of patients continent at 3 months, 75% at 6 months, and the remainder at 9-12 months. Age is the single most important factor in the restoration of continence. Preservation of one or both neurovascular bundles may allow maintenance of erectile function in men who are potent and sexually active before the procedure. However, the nerve-sparing procedure should be used selectively, for extracapsular extension is a common finding in patients with presumed localized CaP. If extracapsular extension is present, preservation of the neurovascular bundle may increase the likelihood that the tumor will recur. Preservation of potency varies as a function of age, preoperative sexual function, and preservation of one or both neurovascular bundles. Reported rates of potency preservation vary from 40% to 82% in men under the age of 60 when both nerves are preserved and drops to 20-60% when only one nerve is preserved. For men between the ages of 60 and 69, comparable rates are 25-75% with bilateral nerve-sparing and 10-50% with unilateral nerve-sparing. Recovery of sexual function generally occurs within 6-12 months following surgery.

4. Radiation therapy - external beam therapy - Traditional external beam radiotherapy (XRT) techniques allow the safe delivery of 6500-7000 cGy to the prostate. Standard XRT techniques depend upon bony landmarks to define treatment borders or a single CT slice to define the target volume. These standard XRT techniques generally involve the use of open square or rectangular fields with minimal to no blocking and are characterized by the use of relatively small boost fields. Often, these XRT techniques fail to provide adequate coverage of the target volume in as many as 20-41% of patients with CaP irradiated.

Improved imaging and the use of 3-dimensional treatment planning software can now guarantee that the treatment field is accurately placed. This software can also allow higher doses of radiation to be given without exceeding the tolerances of surrounding normal tissues by causing the high-dose envelope of radiation to conform to the shape of the prostate. Conformal radiotherapy involves designing blocks from reconstructed CT images as viewed from the vantage point of the beam source. When viewed from the central axis, they are usually referred to as a “beam’s-eye view.” Computer-assisted beam’s-eye views can be generated to design oblique and out-of-plane or noncoplanar beam arrangements. The approach is commonly referred to as 3-dimensional conformal radiotherapy. Additional benefits of this technique include the ability to calculate dose in 3 dimensions (to account more accurately for scattered radiation) and the ability to generate 3-dimensional dose displays and dose volume histograms. Three-dimensional dose displays allow so-called hot and cold spots (areas of overdosing and underdosing, respectively) to be recognized, while dose volume histograms allow different techniques to be compared and ranked for the relative sparing of surrounding normal tissues. Compared with standard XRT, considerably less normal tissue is irradiated because of the use of multiple complex fields.

Retrospective studies from several centers suggest that acute toxicity is reduced with the use of conformal radiotherapy compared with standard therapy. Possible improvement in PSA response rates has also been reported in several retrospective studies using 3-dimensional conformal radiotherapy. Although these results are encouraging, randomized trials and longer follow-up are required to determine if these improvements in PSA responses will translate into improved survival for these patients.

5. Radiation therapy - brachytherapy - A resurgence in the interest in brachytherapy has occurred because of the technologic developments making it possible to place radioactive seeds under TRUS guidance. Previously, freehand seed placement techniques were used; however, very high failure rates were observed and the technique was virtually abandoned. Currently, with the use of computer software, one can preplan a precise dose of radiotherapy to be delivered by TRUS guidance.

Several investigators have reported their results using modern techniques. Data in men with low-volume, low-grade CaP are encouraging, but randomized studies comparing brachytherapy with other forms of radiotherapy are needed, as are studies assessing morbidity (impotence and urinary tract obstruction).

6. Cryosurgery - There has been a resurgence of interest in cryosurgery as a treatment for localized CaP in the past several years. This is due to an increased interest in less invasive forms of therapy for localized CaP as well as several recent technical innovations, including improved percutaneous techniques, expertise in TRUS, improved cryotechnology, and better understanding of cryobiology.

Freezing of the prostate is carried out by using a multiprobe cryosurgical device. Multiple hollow-core probes are placed percutaneously under TRUS guidance. Generally, 5 probes are placed: 2 anteromedially, 2 posterolaterally, and 1 posteriorly. Most surgeons routinely perform 2 freeze-thaw cycles in all patients, and if the iceball does not adequately extend to the apex of the prostate, the cryoprobes are pulled backwards into the apex and a third freeze-thaw cycle is undertaken. The temperature at the edge of the iceball is 0 to -2 °C, while actual cell destruction requires -25 to -50 °C. Therefore, actual tissue destruction occurs a few millimeters inside the iceball edge and cannot be monitored precisely by ultrasound imaging. Double freezing creates a larger tissue destruction area and theoretically brings the iceball edge and destruction zone edge closer together.

Studies to date indicate that, in the short term at least, cryosurgery can result in negative post-treatment prostatic biopsies and low or undetectable serum PSA levels. However, the morbidity of cryosurgery is significant and the long-term results are unknown. More recently, further refinement in the cryo technology has resulted in the development of smaller cryoprobes, which may result in a more controlled freezing. Currently, very few of these procedures are being performed, because other minimally invasive therapies are becoming more popular (brachytherapy).

B. Locally Advanced Disease
1. Radiation therapy - Most patients with T3 CaP are, at the present time, treated with neoadjuvant hormonal therapy followed by XRT. This approach has proved to be superior to XRT alone in several randomized trials. One study reported on 456 evaluable patients, with high-volume T2, T3, and T4 patients randomized to receive 4 months of neoadjuvant complete androgen blockade with XRT (2 months before and 2 months during XRT) compared with XRT alone. The study demonstrated an improvement in local control and disease-free survival in the patients treated with neoadjuvant therapy (Pilepich et al, 2001). Another study reported on 401 evaluable patients with locally advanced CaP (predominantly T3) randomized to receive 3 years of androgen ablation therapy and XRT compared with XRT alone. This study also demonstrated improved survival in patients receiving combination therapy (Bolla et al, 1997). The optimal duration of hormonal therapy, both before and after radiation therapy, still needs to be defined.

C. Recurrent Disease
1. Following radical prostatectomy - The likelihood of recurrence following radical prostatectomy is related to cancer grade, pathologic stage, and the extent of extracapsular extension. Cancer recurrence is more common in those with positive surgical margins, established extracapsular extension, seminal vesicle invasion, and high-grade disease. For those patients in whom a detectable PSA level develops after radical prostatectomy, the site of recurrence (local versus distant) can be established with reasonable certainty based on the interval from surgery to the detectable PSA concentration, PSA doubling time, and selective use of imaging studies.

Patients with persistently detectable serum PSA levels immediately after surgery, those with PSA levels that become detectable in the early postoperative period, and those with serum PSA levels that double rapidly are more likely to have systemic relapse. Patients with initially undetectable serum PSA concentrations that become detectable a long time after radical prostatectomy, especially if PSA doubling times are prolonged, are more likely to have local recurrence (Pound et al, 1999).

2. Following radiation therapy - A rising PSA level following definitive radiotherapy is indicative of cancer recurrence. Biopsies of the prostate can identify local recurrences, while imaging with bone scans and possibly CT scans can identify distant recurrences. Irrespective of the site of recurrence, most patients receive androgen ablation therapy. While patients with clinical evidence of only local recurrence might be considered candidates for salvage radical prostatectomy or cryotherapy, morbidity remains high in this setting as well as subsequent clinical failure.

D. Metastatic Disease
1. Initial endocrine therapy - Since death due to CaP is almost invariably a result of failure to control metastatic disease, a great deal of research has concentrated on efforts to improve control of distant disease. It is well known that most prostatic carcinomas are hormone dependent and that approximately 70-80% of men with metastatic CaP respond to various forms of androgen deprivation. Testosterone, the major circulating androgen, is produced by the Leydig cells in the testes (95%), with a smaller amount being produced by peripheral conversion of other steroids. Although 98% of serum testosterone is protein bound, free testosterone enters prostate cells and is converted to DHT, the major intracellular androgen. DHT binds a cytoplasmic receptor protein and the complex moves to the cell nucleus, where it modulates transcription. Androgen deprivation may be induced at several levels along the pituitary-gonadal axis using a variety of methods or agents (

Table 22-7). Use of a class of drugs (LHRH agonists) delivered as depot injections either monthly or, more recently, at 3-month or 4-month intervals has allowed induction of androgen deprivation without orchiectomy or administration of diethylstilbestrol. Currently, administration of LHRH agonists and orchiectomy are the most common forms of primary androgen blockade used. Because of its rapid onset of action, ketoconazole should be considered in patients with advanced prostate cancer who present with spinal cord compression or disseminated intravascular coagulation. Although testosterone is the major circulating androgen, the adrenal gland secretes the androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Some investigators believe that suppressing both testicular and adrenal androgens (complete androgen blockade) allows for a better initial and a longer response compared with those methods that inhibit production of only testicular androgens. Complete androgen blockade can be achieved by combining an antiandrogen with the use of an LHRH agonist or orchiectomy. Antiandrogens appear to act by competitively binding the receptor for DHT, the intracellular androgen responsible for prostatic cell growth and development. When patients with metastatic prostate cancer are stratified with regard to extent of disease and performance status, those patients with limited disease and a good performance status who are treated with combined androgen blockade (an LHRH agonist and antiandrogen agent) seem to survive longer than those treated with an LHRH agonist alone (Crawford et al, 1989). However, another study comparing the use of an antiandrogen with and without an orchiectomy failed to demonstrate a survival difference between the two arms (Eisenberger et al, 1998). Ongoing trials are studying the use of intermittent androgen deprivation to determine whether this might result in a delay in the appearance of the hormone-refractory state.

The timing of initial endocrine therapy in CaP has been an area of great debate for many years. Data from the Veterans Administration Cooperative Studies from the 1960s did not demonstrate a clear survival advantage for early intervention with androgen ablation therapy in patients with advanced CaP. However, a randomized study from the Medical Research Council comparing early with delayed endocrine therapy in patients with advanced CaP demonstrated improved survival as well as lower complication rates (cord compression, ureteric obstruction, bladder outlet obstruction, and pathologic fractures) in patients treated with early endocrine therapy (Medical Research Council, 1997). In patients who undergo radical prostatectomy and are found to have microscopic lymph node involvement, early endocrine therapy has also resulted in a survival advantage (Messing et al, 1999).

2. Early manipulations for endocrine therapy failure - Patients receiving complete androgen blockade therapy who demonstrate a rise in serum PSA levels are currently managed by discontinuing the antiandrogen. Approximately 20-30% of such patients have a secondary PSA response. Responses are not just serologic, as regression of soft tissue disease has been reported. The pathophysiology underlying this secondary response, referred to as the antiandrogen withdrawal syndrome, is not understood. Some investigators have postulated that emergence of the hormone-refractory state results from mutations in the androgen receptor. Typically, antiandrogens competitively inhibit the androgen receptor, but it is possible that these agents actually stimulate a mutant androgen receptor. Removal of this stimulus (stopping the antiandrogen), thus leads to a secondary response.

Patients receiving monotherapy (LHRH agonist or orchiectomy) whose PSA level starts rising may respond to the addition of an antiandrogen. Response rates are approximately 20-30% in this setting.