Locoregional Therapies for Early-Stage Prostate Cancer

Widespread use of prostate-specific antigen (PSA) as a screening tool has led to an increased incidence of biopsy-proven prostate cancer, as well as a shift toward more cases with clinically confined disease (stage T1 to T2). The two traditional therapeutic modalities, radical prostatectomy and external-beam radiation therapy, have undergone technical refinements. Other modalities, such as brachytherapy and cryosurgery, are also being used to treat early-stage disease. Comparisons between treatment results are difficult. Biochemical failure, based on PSA findings, is currently used to measure treatment efficacy, but the precise definition and clinical relevance of biochemical failure have yet to be established. The author presents current analyses of biochemical failure, cause-specific survival, distant metastasis, and morbidity rates following various treatment modalities.

Introduction

Use of prostate-specific antigen (PSA) as a screening tool has increased the incidence of biopsy-proven prostate cancer, as well as shifted the stage of presentation increasingly to early-stage disease. Of the estimated 244,00 patients with newly diagnosed prostate cancer in 1995 [1], approximately 75% will have disease clinically confined to the prostate gland (stage T1 to T2). The treatment of these patients with early-stage prostate cancer is highly controversial. The controversy centers around two general issues: (1) Which patients require treatment for their prostate cancer and which only need to be observed? (2) Once the decision for treatment has been made, which therapeutic modality is optimal?

Traditionally, the two modalities used to treat early-stage prostate cancer have been radical prostatectomy and external-beam radiation therapy. Recent technical advances in both modalities have led to decreased morbidity with the promise of improved results. In addition, new treatment approaches, such as brachytherapy and cryosurgery, are now being used for early-stage prostate cancer.

This review describes the various treatment options for early-stage prostate cancer and their technical refinements. It also analyzes treatment end points, compares results, and explores treatment-related morbidity.

Treatment Modalities

Radical Prostatectomy

Radical prostatectomy is the standard surgical treatment for prostate cancer. Using a retropubic or perineal approach, the prostate and seminal vesicles are removed and the bladder is reanastomosed with the urethra. In addition, a bilateral pelvic lymph node dissection is usually performed to identify patients who have lymph node metastases.

In 1982, Walsh and Donker introduced a modification of the standard retropubic prostatectomy, the nerve-sparing radical prostatectomy [2]. The major change came from a more precise anatomic identification of the prostate gland, which permitted excision of the prostate without injuring the neurovascular bundles containing the cavernous nerves and vessels that preserve sexual potency. In addition, Walsh demonstrated that, in patients with extracapsular tumor extension, these bundles could be sacrificed to obtain wider margins than are usually achieved with a standard retropubic or perineal prostatectomy [3].

External-Beam Radiation Therapy

Beginning in the 1970s, external-beam radiation techniques for treating prostate cancer were refined. These refinements included irradiation of the pelvis to treat the prostate, seminal vesicles, and primary draining lymph nodes, accomplished with the use of a four-field pelvic box technique. Following pelvic irradiation, a radiation boost to the prostate alone or prostate and seminal vesicles was delivered via a four-field technique or arcing beams.

Over time, the concept of treating the whole pelvis for early-stage prostate cancer fell out of favor. A Radiation Therapy Oncology Group (RTOG) randomized trial failed to show any benefit of irradiation of the whole pelvis plus prostate over irradiation of the prostate alone for stages A and B disease [4]. In addition, data from surgical series helped distinguish patients at low risk for pelvic lymph node metastases from those at high risk [5]. High-risk patients could then be selected for less invasive surgical procedures, such as laparoscopic pelvic lymph node dissection, to identify those with negative nodes for curative therapy.

These findings supported the concept of radiation treatment of the prostate and seminal vesicles alone. With advances in CT imaging and computer programming technology, three-dimensional conformal external-beam therapy was developed [6]. This new technique enables the prostate and seminal vesicles to be treated with a high degree of accuracy while greatly decreasing the dose delivered to surrounding normal structures, such as the bladder and rectum.

Brachytherapy

The use of brachytherapy with permanent radioactive seed implants to treat early-stage prostate cancer gained popularity in the 1970s and '80s. Based on work done by Whitemore and Hilaris, an open laparotomy exposed the prostate gland, calipers measured the prostate volume, and freehand placement of needles guided seed placement into the gland [7]. Improved dosimetric evaluation and long-term follow-up often revealed a poor distribution of seeds with a corresponding inadequate radiation dose coverage. Also, patients with inadequate im- plants had high local recurrence rates based on digital rectal examination [8]. Due to these findings, brachytherapy fell out of favor as a treatment for prostate cancer.

Recent refinements in ultrasound and CT imaging led to the development of a transperineal implantation technique and spurred a renewed interest in this procedure [9-11]. The new technique achieves accurate seed placement within the gland and improved dose coverage.

Cryosurgery

Cryosurgery was pioneered as a treatment for prostate cancer in the early 1960s but was abandoned due to a high rate of complications stemming from an inability to adequately control the freezing technique [12]. Transrectal ultrasound and percutaneous tissue accessing techniques subsequently enabled the accurate placement of cryoprobes and, thus, an enhanced ability to control freezing.

Radical cryosurgical ablation is currently defined as the freezing of the entire prostate gland, periprostatic tissue, neurovascular pedicles, and proximal seminal vesicles [13]. Current cryosurgery involves a transperineal technique with placement of cryoprobes into the gland under ultrasound guidance. A urethral warming device is used to prevent freezing of the urethra, and formation of an ice ball is monitored by ultrasound imaging.

Comparing Treatment Results

It is difficult to compare results of the two most common treatment modalities, external-beam radiation therapy and radical prostatectomy. In a randomized trial comparing the two modalities conducted by the Uro-Oncology Research Group [14], radical prostatectomy was superior in terms of time to treatment failure, but the trial was faulty in many respects, including small numbers of patients and inherent methodologic problems. In addition, outcomes in the radiation therapy arm were inferior to results reported in other large single- and multi-institutional radiation oncology studies for T1 to T2 cancers, and were more consistent with results for stage T3 to T4 cancers reported by the same group [15]. Further attempts to run a comparison trial failed due to poor patient accrual [16].

Selection Bias

Difficulties in comparing the results of radical prostatectomy and radiotherapy stem, in part, from biases in selecting patients for the two modalities. In general, patients with higher PSA levels, grade, and stage are referred for radiation therapy. Emerging data suggest that pretreatment PSA is one of the most important determinants of outcome [17-19].

Recent radiation oncology series from both Massachusetts General Hospital and the Mayo Clinic show the typical PSA ranges of patients referred for radiation therapy. In the series by Zeitman et al, 53% of patients had PSA levels 10 ng/mL or less[19]. The series by Pisansky et al revealed that 50% of patients receiving radiation therapy had PSA levels < 13 ng/mL [20]. Of the patients selected for radical prostatectomy by Catalona and Smith [21] and Partin et al [22], 67% and 75%, respectively, had PSA levels 10 ng/mL or less. Within one institution, a selection bias has been demonstrated, with a larger percentage of patients with advanced-stage and higher PSA being selected for radiation therapy than for surgery [19].

In addition, patients with positive pelvic lymph nodes are thought by many to be destined to develop distant metastases [23,24].Radical prostatectomy is often abandoned if positive nodes are found, and therefore, prostatectomy series often do not include node-positive patients in treatment reports. In contrast, since patients receiving radiation do not benefit from surgical staging of their lymph nodes, radiation therapy series more often include node-positive patients. In a Stanford study, patients undergoing radiation therapy were staged surgically; 19% of patients with T1 or T2 disease had positive nodes [25].

Different End Points

Another obstacle to comparing studies stems from the different end points used to define outcome. There are methodologic differences in the detection of local recurrence following radiation therapy and radical prostatectomy. Some reports require biopsy-proven recurrence to signify local failure, whereas others use only the digital rectal examination.

Historically, most radiation therapy series have reported local failure based on digital rectal findings, which can be unreliable, rather than the more accurate method of post-treatment ultrasound-guided prostate biopsies. Post-treatment prostate biopsies have only recently been used routinely to assess local control [26].

In addition, local failure following radical prostatectomy is often difficult to detect by digital rectal examination, and prostate bed biopsies are not routinely performed. In a series by Lightner et al, 42% of patients with an elevated PSA and a normal digital rectal examination had biopsy-proven local recurrence at the site of anastomosis [27].For this reason, disease-free survival, which is also affected by local recurrence, is not the optimal end point for use in comparing treatment modalities.

Measures of Treatment Outcome

Biochemical failure, as assessed by post-treatment PSA, has become an important measure of treatment outcome. In addition, the rate of development of distant metastases and cause-specific survival more accurately reflect the impact a therapy has on life expectancy.

Biochemical Failure

Following Prostatectomy--Levels of PSA following radical prostatectomy should approach zero, since this procedure should remove all prostate cancer as well as prostate tissue. Detectable PSA levels following surgery indicate that either prostate tissue has been left behind or prostate cancer cells remain. A rising PSA after surgery is an indication of recurrent cancer.

Different PSA assays have been used to determine biochemical failure after surgery, and various cutoff levels of PSA to indicate failure have been employed, ranging from 0.1 to 0.6 ng/mL [21,28-30]. Comparisons among these diverse assays and cutoff levels are difficult, as different end points often represent the minimal levels of PSA detection for a particular laboratory. Rates of freedom from biochemical failure in radical prostatectomy series are given in Table 1 [21,28-33].

In addition, preoperative PSA has been found to be an independent predictor of biochemical failure [30]. Zeitman et al showed that 28% of patients with preoperative PSA levels 7.5 or greater ng/mL had not experienced biochemical failure at 4 years, as compared with 74% of those with PSA levels 7.5 ng/mL or less[30]. Catalona found a 5-year biochemical cure rate of 71% for patients with PSA values 10 or greater ng/mL, compared to rates of 95% and 93% for patients with preoperative PSA values 4 or less ng/mL and 4.1 to 9.9 ng/mL, respectively [21]. Only 60% to 70% of patients thought to be clinically free of disease are biochemically free of disease as well [31,32,34].

Following External Radiation--Biochemical failure following radiation therapy is more difficult to assess, since the gland is not removed and viable prostate tissue remains in the body. It is not reasonable to expect PSA levels following irradiation to match those following radical prostatectomy.

Initially, biochemical failure rates after radiation therapy were defined by rising PSA profiles, but this failed to define a level representing a cure. In order to define such a level, retrospective analyses of patients clinically free of prostate cancer for extended periods were undertaken. Some investigators reported that PSA levels 1.0 or less ng/mL represent a biochemical cure [18,19], but others using a similar analysis designated 1.5 ng/mL as a cutoff point [35,36]. Approximately 40% to 75% of clinical cures are also biochemical cures [19,20,36,37].

In addition, as with radical prostatectomy, many authors consider the pretreatment PSA to be an important prognostic factor for biochemical failure after external-beam radiation [17-19,36]. For this reason, many studies define biochemical failure rates in terms of initial PSA levels rather than in overall terms. Freedom from biochemical failure rates following external irradiation are listed in Table 2.

Following Brachytherapy--Using modern transperineal techniques and guided by CT or ultrasound technology, permanent radioactive isotope implants yield freedom-from-biochem- ical-failure rates comparable to those of external-beam irradiation or radical prostatectomy. Due to the lack of long-term data to determine a true PSA nadir following implantation, early biochemical failure results most often were reported in terms of a rising PSA level. More recent analyses are starting to use a PSA nadir of 1.0 ng/mL, similar to that used for external-beam therapy, to define a biochemical cure.

Results from Mount Sinai Medical Center, using an interactive ultrasound- guided transperineal technique, showed an overall actuarial rate of freedom from biochemical failure (rising PSA) of 76% at 2 years for 97 patients with stage T1b to T2c disease. The 2-year freedom-from-biochemical-failure rate among 44 patients with an initial PSA equal to or less than 10 ng/mL was 83%. Corresponding rates were 82% for 29 patients with initial PSA levels between 10 and 20 ng/mL and 58% for 24 patients with PSA levels greater than 20 ng/mL [37].

In a study from Memorial Sloan-Kettering Cancer Center, 92 patients underwent CT-based transperineal implantation with iodine-125. At 4 years, these patients had an actuarial rate of freedom from biochemical failure (defined as a PSA level greater than 1.0 ng/mL) of 63%. Rates were 100% for 7 patients with pretreatment PSA 4 ng/mL, 80% for 43 patients with PSA levels between 4 and 10 ng/mL, and 50% for patients with levels greater than 10 ng/mL [38].

In a study of 133 patients who received iodine-125 implants using a transperineal ultrasound-guided technique at Boswell Memorial Hospital in Sun City, Arizona, 82% of patients showed normalization of PSA levels (less than 2.5 ng/mL by the Yang assay) at 21 months following implantation [39]. Similarly, the University Community Hospital in Tampa found that 94% of 120 patients implanted with palladium-103 achieved normalization of their PSA levels over a follow-up of 3 to 32 months [40].

The largest series, from Blasko et al at the Northwest Tumor Institute, encompassed 197 patients implanted with iodine-125 by an ultrasound-guided technique. The actuarial rate of freedom from biochemical failure (defined as a rising PSA profile) at 5 years was 93%. At 5 years, 80% of patients with initial PSA levels greater than 20 ng/mL were free of biochemical failure, as opposed to 98%, 90%, and 89% of patients with PSA levels less than 4 ng/mL, 4 to 10 ng/mL, and 10 to 20 ng/mL, respectively [41]. In an analysis of 97 patients from the Northwest Tumor Institute implanted with palladium-103, the 4-year actuarial rate of freedom from biochemical failure, using a PSA cutoff of 1.0 ng/mL, was 86% [42].

Following Cryosurgery--It is difficult to assess biochemical failure rates for stages T1 to T2 prostate cancer from available cryosurgical data. These series contain all stages of disease and frequently include patients who have previously failed to respond to irradiation. In addition, in some series almost all patients received hormonal ablative therapy prior to cryosurgery [43].

Actuarial biochemical failure rates after cryosurgery are not available. Prostate-specific antigen results are often defined in terms of mean post-treatment values for biopsy-positive vs biopsy-negative cases. Mean post-treatment PSA levels for biopsy-negative patients have ranged from 0.4 to 1.8 ng/mL [43,44].

Moreover, a post-treatment PSA nadir that represents a cure after cryosurgery is unknown. If cryotherapy destroys all prostate gland cells, PSA findings consistent with radical prostatectomy would be expected. This end point has not been achieved, however, and detectable PSA values have been found in 56% to 59% of patients treated with cryosurgery [45,46]. Although the goal of cryosurgery is to freeze the entire prostate gland and kill all the cells, one study found that 77% of patients had biopsy evidence of residual nonfrozen, viable prostate cells after therapy [47].

Distant Metastasis Rates

The presence of detectable or rising PSA after treatment signifies that prostate cancer cells are present but does not always signify a life-threatening event. The ability of a treatment to prevent distant metastases may be more clinically relevant than its ability to eradicate PSA. Long-term data on distant metastasis are available for both radical prostatectomy and external-beam radiation therapy.

Following Prostatectomy--In a study by van den Ouden, the actuarial rate of freedom from the development of distant metastases at 5 years was 50% in 56 patients with margin-positive disease after radical prostatectomy vs 85% in 116 patients with negative surgical margins [34]. An analysis of 1,058 men who underwent radical prostatectomy at Johns Hopkins found an 10-year actuarial rate of freedom from the development of distant metastases of 92% [29].

The study with the longest follow-up of the largest number of patients comes from the Mayo Clinic. Zincke et al reported that the rate of freedom from distant metastases for 3,170 men after radical prostatectomy was 82% at 10 years and 76% at 15 years [33].

Following External Radiation--Rates of freedom from distant metastasis following external-beam irradiation are similar to those following radical prostatectomy (Table 3) [48-53].

Following Other Modalities--Most treatment results available for transperineal prostate implantation and cryosurgery have 5 years or less of follow-up information; thus, outcome data concerning the development of distant metastases after these procedures are premature. Assessment of distant metastasis rates requires at least 10 years of follow-up, since undetectable micrometastatic disease may take a long time to manifest clinically.

Cause-Specific Survival

Due to the prolonged natural history of many prostate cancers, as well as the typically advanced age of patients at the time of diagnosis, cause-specific survival is a crucial end point for use in comparing treatment modalities. Although prostate cancer may not be eradicated in a given percentage of men after treatment, it may not become life threatening during the lifetime of these patients, since other medical problems that affect men in this age range may cause death. Cause-specific survival assesses survival in terms of prostate cancer-related death.

Following Prostatectomy--Lepor et al, one of the first groups to examine cause-specific survival, reported on 57 patients who underwent radical perineal prostatectomy. They found a 15-year cause-specific actuarial survival rate of 86%.54 The largest radical prostatectomy series (by Zinke et al), involving 3,170 patients, reported an overall cause-specific survival rate of 90% at 10 years and 82% at 15 years [33]. In a study of 601 men who underwent radical prostatectomy, Trapasso et al found a cause-specific survival rate at 10 years of 94% [32]. Frohmuller et al followed 115 patients for 10 years after radical prostatectomy. The rate of tumor-related survival in these patients was 83.5% [55].

Following Other Modalities--Numerous reports of cause-specific survival rates after external-beam radiation therapy are available. These data are summarized in Table 4 [48-50,56-58].

Cause-specific survival data are not yet available for cryosurgery and brachytherapy because follow-up periods are still too short to determine these rates.

Treatment-Related Morbidity

Treatment-related morbidity is an important, often overriding factor to consider when choosing a therapeutic modality. The most significant difference between radical prostatectomy and the other treatment modalities is the risk of morbidity associated with the invasive surgical procedure, which is often quite high in elderly patients. The Prostate Patient Outcomes Research Team examined the outcome of 10,598 prostatectomies in patients 75 years of age or older: Within 30 days of the operation, almost 2% of the patients died and nearly 8% suffered major cardiopulmonary complications [59].

Urinary Complications

The major long-term treatment-related morbidity after radical prostatectomy is urinary incontinence, defined in most series as total or stress incontinence. Total incontinence represents the complete inability to control urinary flow, whereas stress incontinence is typically defined as a partial ability to control the urinary stream. The latter is usually characterized by urinary leakage during straining or coughing, for example, which requires the patient to wear pads.

Following Prostatectomy--The overall incidence of total incontinence following radical prostatectomy is very low. Stress incontinence rates from various series are given in Table 5 [34,60-66]. In general, the lower incontinence rates derive from a single institution, where a small number of skilled surgeons perform most of the reported surgeries. A more representative assessment of stress incontinence probably comes from reports that use questionnaires or surveys to assess continence in a large number of institutions or patients. This type of analysis reports stress incontinence rates ranging from 19% to 47% [60,62,64].

Following External Radiation--The incidence of stress incontinence following external-beam radiation therapy is low. Most series report rates that range from 0% to 4% [67,68], but some authors feel that the risk of stress incontinence is underestimated. In a series by Widmark et al of 200 patients, the risk of developing urinary leakage after radiation therapy was three times greater than the risk in a control group [69].

Jonler et al, using a questionnaire to assess continence in 133 patients, found the rate of stress incontinence to be 11% [70]. This rate was higher than rates previously reported but was still less than the rate found using the same questionnaire in patients who had undergone radical prostatectomy.

The other urinary complication observed after radiation therapy is urethral stricture. Reported urethral stricture rates range from 4% to 8% [51,68,71].

Following Brachytherapy--During the first few months following a brachytherapy prostate implant, the majority of radioactive decay occurs, and acute urinary symptoms of frequency, urgency, and nocturia are common. The acute swelling of the gland secondary to radiation can cause minor urinary outlet obstruction, which may require temporary Foley catheterization in 14% to 16% of cases [38,72]. Major outlet obstruction requiring a transurethral resection of the prostate (TURP) is less common, occurring in 1% to 4% of cases [39,40,72].

Blasko's technique involves an even spacial distribution of radioactivity throughout the gland (which can result in higher radiation doses to the central portion of the gland and urethra). This technique resulted in a 3% incidence of superficial urethral necrosis. The majority of patients experiencing this problem underwent a TURP before treatment. Necrosis was thought to be secondary to a compromised urethral vascular supply from the TURP, combined with the high central radiation dose delivered. This led to an overall rate of total urinary incontinence in the series of 6% [9].

Using a technique that interactively places seeds in the prostate under ultrasound guidance and actively avoids implanting seeds in the periurethral area, Stone et al reported no cases of superficial urethral necrosis stress or total incontinence [72].

Following Cryosurgery--The risk of urinary complications following cryosurgical treatment for early-stage prostate cancer is less certain, because of limited data and because of the inclusion of patients following radiation therapy failure, who have higher complication rates. In one series, approximately 50% of radiation failures who were treated with cryotherapy were incontinent [73]. The development of a urethral-rectal fistula has been reported in 1.4% to 3% of patients who have undergone cryosurgery [13,43]. Total urinary incontinence rates after cryosurgery have been reported to range from 2.9% to 8% [43-45]. There is little information available on the rates of stress incontinence.

Gastrointestinal Complications

Following Prostatectomy--Gastro-intestinal morbidity following radical prostatectomy usually stems from rectal injury sustained during the surgical procedure. Reported rates of rectal damage requiring either primary closure or colostomy are very low (1% to 3%) [34,60].

Following External Radiation--Gastrointestinal complications following radiation therapy have decreased as treatment has shifted from irradiation of the whole pelvis to small prostate fields to conformal techniques. Perez et al demonstrated a decrease in intestinal and rectosigmoid morbidity using prostate fields alone compared to whole pelvic irradiation [74]. The incidence of rectosigmoid proctitis following external-beam therapy ranges from 2% to 22% [68,71,74,75]. A significant increase in rectal damage occurs when the anterior rectal wall receives radiation doses greater than 75 Gy [75].

Three-dimensional conformal therapy enables doses to the rectum to be reduced while more accurately treating the prostate volume. Hanks et al have demonstrated decreased acute morbidity with conformal techniques, as compared with standard techniques [76]. Using three-dimensional conformal radiation therapy and dose escalation, Leibel et al achieved a low rate of late rectal complications (2-year actuarial rate of 2%) [6].

Following Brachytherapy--Theoretically, rates of rectal damage with permanent brachytherapy implants should be very low if the seeds are placed only in the prostate gland, because of the rapid dose fall-off of radioactive isotopes. If seeds are inadvertently implanted in the rectal wall, however, ulcerations can develop. Wallner et al achieved a 5% rate of rectal ulceration with a CT-based preplanned system [38]. Using an ultrasound-guided interactive technique, Stone et al reported only a 1.7% incidence of grade 2 proctitis and no cases of rectal ulceration [72]. Other series of ultrasound-based implants also have noted a low incidence of proctitis, approximately 1% [9,39].

Following Cryosurgery--Damage to the rectum from cryosurgery can be caused by freezing of the anterior rectal wall. In one series, this complication occurred in 5.9% of patients and was followed by the development of a urethral-rectal fistula in half of these cases [13].

Sexual Potency

Penile erectile function is an important consideration for patients choosing from among different therapeutic options for prostate cancer. Assessment of treatment effect on potency is complicated by the varying definitions of and methods for assessing potency. Many define potency as the ability to achieve vaginal penetration, whereas others characterize it as the ability to attain an erection.

To examine the effect of a treatment on potency, it is important to obtain a baseline potency level. Unfortunately, most assessments are done retrospectively; these can be subjective and unreliable. Of note, 17% to 27% of prostate cancer patients are impotent prior to any treatment [6,70,77]. In addition, patients in this age range often have age-related declining sexual function, which can complicate the assessment of treatment impact on potency.

Following Prostatectomy--Traditional radical perineal and retropubic prostatectomy was associated with loss of potency in almost all patients. Walsh and Donker investigated the etiology of impotence after surgery by tracing the autonomic innervation of the corpora cavernosa, and concluded that impotence was caused by cutting through the neurovascular bundles. The development of nerve-sparing radical prostatectomy was based on the concepts of identifying these structures and sparing them if possible [2].

At Johns Hopkins, the nerve-sparing technique ultimately permitted 68% of patients to achieve vaginal penetration 18 months to 8 years following surgery [78]. Catalona et al reported a potency rate of 39% following the sacrifice of one neurovascular bundle and 63% following preservation of both bundles [79]. Leandrei et al found that 71% of 106 men were able to have full or partial erections following nerve sparing radical prostatectomy [80].

While potency can be preserved in a select group of patients operated on by a small group of skilled surgeons, these results may not be representative of those achieved in all communities. A recent report from Stanford found that only 11% of 459 patients were able to have unassisted intercourse after radical prostatectomy surgery [81]. In a survey of 739 Medicare patients who underwent radical prostatectomy, only 39% could achieve a partial or full erection following surgery and only 11% had erections firm enough for intercourse [60]. A survey by Jonler et al of 72 patients who were potent prior to surgery had similar results; 46% of these patients were able to attain partial or full erections following surgery and only 11% had full erections [62].

Following External Radiation--Although the exact mechanisms for radiation-induced impotence are unknown, radiation is known to cause small blood vessel damage. Damage to the microvasculature that supplies the neurovascular bundle could result in erectile dysfunction.

In a study of 434 patients who were potent prior to external-beam radiation treatment, Bagshaw et al found that 50% remained potent at 7 years following treatment [68]. Shipley et al reported a 39% rate of impotence 3 years after radiotherapy [52]. Perez et al noted that 39% of 210 patients became impotent following radiation treatment [51]. The rate of impotence among patients enrolled in RTOG 77-06 over a median follow-up of 7 years was 53% [4].

Banker used a questionnaire to assess sexual function in 100 patients who underwent external-beam radiation therapy. He found that 54% maintained potency after treatment, but half of these patients reported significantly decreased libido or sexual performance [82]. Using the questionnaire developed by Fowler to assess potency in Medicare patients following prostatectomy, Jonler et al evaluated 133 patients after external-beam irradiation. Of these, 63% could achieve an erection following treatment (22% of whom could attain full erections and 41%, partial erections) [70].

Improved potency rates have been demonstrated with the use of con-formal therapy. Using this technique, Leibel et al reported a 30% actuarial rate of impotence at 2 years [6].

Following Brachytherapy--Since radiation-induced impotence is felt to be secondary to vascular changes, decreasing the radiation dose to the neurovascular bundles and pelvic vasculature should reduce the incidence of this complication. Permanent radioactive implants limit the dose to surrounding tissues due to the rapid dose fall-off of radioactive isotopes. In addition, the relatively lower dose rate of implants compared to external-beam therapy may further lessen radiation damage to the nerves and vasculature.

The open retropubic technique of implantation yielded high potency rates, with the largest series from Memorial Sloan-Kettering Cancer Center reporting a potency rate of 90% [7]. Results from modern transperineal series confirm these findings. In a series of 89 patients who underwent ultrasound-guided iodine-125 and palladium-103 implants, Stock et al assessed potency prior to treatment and at regular follow-up intervals. Among patients who were potent prior to treatment, 94% had preserved erectile function at 2 years; a subjective decrease in the quality of the erection was experienced by 39% [77]. Blasko et al reported a potency rate of 85% in patients under age 70 and 50% in patients over age 70, with a median follow-up of 3 years [9]. Results from Memorial Sloan-Kettering reveal an actuarial 3-year potency rate of 86% [38].

Following Cryotherapy--By definition, radical cryotherapy includes the freezing of the neurovascular pedicles [13]. In light of damage to the neurovascular bundles resulting from this technique, one would expect impotence in a significant percentage of patients. Indeed, the limited available data reveal impotence rates ranging from 41% to 86% [13,43,45,46].

Conclusion

Comparisons among the different treatments used in early-stage prostate cancer are difficult to make because of selection bias and the varying end points used to evaluate treatment results. A valid comparison between specific treatments can be made only through a well-designed randomized trial that stratifies patients based on prognostic factors. Since no such trial has been carried out, and the likelihood of this type of study being undertaken in the future is small, a comparison between treatments can be done only by examining existing single-treatment-modality reports. This type of comparison reveals a few important points:

• Biochemical failure, as defined by persistent or rising PSA levels after treatment, does not signify clinical disease progression in all cases. Approximately 45% to 75% of patients who are clinically disease free are also biochemically free of disease.
• Biochemical failure rates following treatment are similar for radical prostatectomy and external-beam irradiation, although different definitions of biochemical cure are currently being used in the radiation oncology literature. In addition, longer follow-up data for biochemical cure rates are available for radical prostatectomy series. Analysis of cause-specific survival and distant metastasis rates following treatment reveals similar results for external-beam irradiation and radical prostatectomy.
• Following brachytherapy, 2- to 5-year biochemical cure rates are comparable to results following external-beam irradiation and radical prostatectomy. Brachytherapy also is associated with very low morbidity. However, longer follow-up of brachytherapy series is needed to assess distant metastasis and cause-specific survival rates.
• Technical improvements in cryosurgery have markedly reduced morbidity. Data with longer follow-up are needed to assess the efficacy of this modality.

In summary, therefore, no single optimal therapy for early-stage prostate cancer can be identified at present. Treatment strategies must be individualized based on expected outcome and associated morbidity.

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