Abstract

Patients with prostate cancer are commonly treated medically or undergo radical prostatectomy and/or radiation therapy. Radiation therapy is usually selected for patients with local or regional disease and patients for whom traditional surgery has failed. The local recurrence of cancer in patients treated with radiation therapy presents a difficult challenge regarding the selection of further treatment options. A commonly applied treatment is salvage prostatectomy, but it can be difficult and complicated, with positive surgical margins occurring in as many as 50 percent of patients and with significant postoperative morbidity. Hormonal therapy, which is not curative, has served as an alternative to surgery in patients who have failed to respond to radiation therapy. Cryosurgery, the destruction of diseased tissue by freezing, is increasingly used both as a first-line therapy and as a second-line therapy (salvage therapy) in patients for whom radiation therapy has failed. Recent reports suggest that cryosurgery may be a useful alternative procedure for treating some of these patients with recurrent cancers. Outcomes of cryosurgery are improving through better instrumentation, surgical technique, and experience. The available data suggest that some patients with radioresistant cancer appear to benefit from the use of cryosurgery as a salvage therapy. Use of this technique has resulted in biochemical disease-free survival for varying periods of some patients who had recurrent prostate carcinoma following radiation therapy; however, morbidity remains high and relatively few patients have had adequate followup. Salvage cryosurgery prospective clinical trials are warranted and would help determine long-term survival benefits and make possible the comparison of cryotherapy patient survival rates with those of untreated biopsy-positive patients.

Foreword

The Center for Practice and Technology Assessment (CPTA) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies. In most instances, assessments address technologies that are being reviewed for purposes of coverage by federally funded health programs.

The CPTA assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps ensure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

The CPTA analyzed and synthesized data and information received from experts and the scientific literature. The results are reported in this assessment. Each assessment represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies. If an assessment has been prepared to form the basis for a coverage decision by a federally financed health care program, it serves as the Public Health Service's recommendation to that program and is disseminated widely.

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Introduction

Patients with prostate cancer, the second most common cause of cancer-related morbidity and mortality in men, are commonly treated medically or undergo radical prostatectomy and/or radiation therapy. ¹ Radiation therapy is usually selected for patients with local or regional disease, and patients for whom traditional surgery has failed. Recurrent and residual local disease has been reported to exist in 25 to 93 percent of the cases, with the broad range seemingly being explained by patient selection or the diligence and thoroughness with which the biopsy process was performed.^2,3 However, the National Cancer Institute's CancerNet reports that only about 10 percent of patients treated initially with radiation will have local relapse only. ⁴ The local recurrence of prostate cancer presents a difficult challenge, because therapeutic options are limited. Salvage prostatectomy is a common surgical treatment, but it can be difficult and complicated. Hormonal therapy, which is not curative, has served as an alternative to surgery in some patients who have failed to respond to radiation therapy.

Cryosurgery, the destruction of diseased tissue by freezing, is being used increasingly as both a first-line therapy and as a second-line therapy (salvage therapy) in patients for whom radiation therapy has failed. The ultimate objective of prostate cryoablation is the destruction of the entire gland. Because the procedure is better tolerated than open surgery, it can be offered to men who would not be candidates for salvage surgery due to advanced age or comorbidity. Recent reports suggest that cryosurgery may be a useful alternative procedure for treating some patients with recurrent prostate cancers.^5,6 Because recent improvements in cryosurgical procedures have raised the prospects of effective treatment for recurrent cancer following radiation therapy, salvage cryosurgery is emerging as a therapeutic option for localized prostate cancer.

Methods

A list of references identified by computer search of the biomedical data bases compiled by the National Library of Medicine (1982-1998) and from references cited in these articles yielded 119 publications on the treatment of prostate cancer by cryosurgery. Limiting the search to the treatment of recurrent prostate cancer with cryosurgery yielded 14 publications, including prior radiation therapy reduced the yield to seven publications. Of the seven studies on the use of cryosurgery as a salvage procedure in patients with recurrent prostate cancer following radiation therapy, two studies reported outcomes only, three studies reported outcomes and complications, and two studies reported only complications. All studies consisted of uncontrolled case series of patients who had demonstrated evidence of cancer recurrence (and all had relatively short followup periods). The observations in these studies are reviewed in this report.

Background

It is estimated that there will be 179,300 new prostate cancer cases in the United States during 1999, with an estimated 37,000 deaths due to the disease. ⁷ During 1991-1995, prostate cancer mortality rates declined significantly, with the 5-year relative survival rates (1989-1994) for all stages at 93 percent and 100 percent when the prostate cancer was local (confined entirely to the prostate). However, a survival rate of 33 percent is reported in patients who had metastatic lesions remote from the primary tumor site. ⁷

Radiation therapy, either external beam irradiation or brachytherapy, remains a popular therapeutic modality for clinically organ-confined (stages T1 and T2) or locally invasive (stage T3) prostate cancer. ⁵ It is estimated that as many as 22,000 patients undergo some form of radiation therapy for prostate cancer each year. ⁸ Biopsy and prostate-specific antigen (PSA) data following radiotherapy can diagnose and monitor clinical failure in these patients. Up to 75 percent of patients with a positive biopsy after irradiation develop local recurrence within 10 years of therapy, as do 25 percent of those with a negative biopsy. ⁹

Currently, usual treatment for recurrent prostate cancer following radiation therapy is salvage prostatectomy. A recent study by Rogers et al. ¹⁰ of patients undergoing salvage radical prostatectomy reported the biochemical disease-free rate at 5 and 8 years was 55 percent and 33 percent, respectively. Conventional salvage prostatectomy is associated with significant postoperative morbidity, and positive surgical margins have been reported in as many as 50 percent of patients.^11,12 In addition, while salvage radical prostatectomy can be attempted in patients who have had recurrent cancer that appears well localized and amenable to surgical removal, obliteration of the normal landmarks in patients treated by radiation makes the procedure extremely difficult in many patients.

The early investigation of cryosurgery (application of freezing temperatures for the destruction of prostate cancer) was done in the 1960s and 1970s. The use of this procedure decreased and was nearly abandoned because of poor outcomes, serious and frequent complications, and an imprecise monitoring of the procedure.^13,14 Refinements in the technique with transrectal ultrasonography, ¹⁵ improved cryosurgical instrumentation,^16-18 and the use of commercial urethral warmers ¹⁹ have led to a renewed interest in the procedure as both primary treatment of localized prostate cancer and as a salvage procedure for treating recurrent cancer after radiation therapy. Cryosurgery has many attractive features, including a relatively short surgical procedure (approximately 2 hours) that can be accomplished on an outpatient basis with minimal blood loss and with the patient under regional anesthesia.

Literature Review

The published studies on salvage cryosurgery performed on patients with recurrent prostate cancer following radiation therapy are listed in Tables 1 and 2. All patients had biopsy-proven recurrent cancer and a rising PSA level. During the followep period, PSA levels were monitored and biopsy samples examined. The results for some studies were not always stratified by previous receipt of radiation therapy. Differences in outcomes from one study to another may also have been due to differences in patient selection. Patients with known adverse prognostic features such as extracapsular disease, high PSA, and high-grade recurrent tumors were included in some studies but not in others. In many studies, a number of patients were lost to followup. Also, the lack of standard definitions for terms such as "incontinence" and "biochemical cure" limit the generalizeability of the results.

Table

Table 1. Outcomes of salvage cryosurgery for recurrent prostate cancer after radiation therapy.

Table

Table 2. Major complications following salvage cryosurgery for recurrent prostate cancer after radiation therapy.

Bales et al. ³ studied cryosurgical ablation of the prostate in 23 men, accrued from December 1992 to February 1994, with local recurrent prostate cancer following radiation therapy. At 17 months, the biochemical disease-free survival rate (defined as a PSA value less than 0.3 ng/mL) was 11 percent (7 percent). Major complications noted included impotence in all men who had been potent before treatment, unresolved incontinence in 73 percent, urinary obstruction in 55 percent, and renal complications in 50 percent. The authors considered this initial experience with cryosurgery disappointing in terms of cancer control and complications and suggested that this modality be considered experimental.

Miller et al. ² retrospectively studied cryosurgical ablation of the prostate in 33 men treated between September 1990 and April 1994 for radiation-resistant prostate cancer. After cryoablation, 24 (73 percent) converted to biopsy-negative status. Repeat cryoablation in three patients converted an additional two patients to biopsy-negative status, for an overall success rate of 79 percent. However, of 10 patients with no androgen suppressive therapy and a biopsy-negative status for 1 year, three maintained a PSA of 0.4 ng/mL or less. Biochemical disease-free survival was defined as having a PSA level less than 0.4 ng/mL. Complications, such as incontinence, urethral stricture, and retention, occurred in 39 percent of the patients, with about half of the complications consisting of a sloughing syndrome, described as dysuria, retention, urinary debris, and urinary tract infection. Four of the six patients with this syndrome required transurethral debridement of necrotic prostate tissue.

Pisters et al. ⁶ compared the efficacy of salvage cryosurgery using a single freeze-thaw cycle to a double freeze-thaw cycle in 150 patients between July 1992 and March 1995. Patients had locally recurrent prostate cancer following radiation, hormonal therapy, and/or systemic chemotherapy. In the 110 patients who had received radiation therapy only, an undetectable (less than 0.1 ng/mL) post-cryotherapy nadir PSA was reported in 37 percent of the patients, and the risk of subsequent biochemical failure was significantly less for those who had undergone a double compared to a single freeze-thaw procedure (p<0.01). Overall, the frequency of subsequent biochemical failure was significantly greater in patients who had undergone a single versus a double-thaw cycle (p<0.03). Patients were considered to have biochemical failure if they had an increase in PSA of 0.2 ng/mL or more above the nadir PSA level. Overall, the negative biopsy rate for cyrotherapy following radiation therapy was only 82 percent, with the negative biopsy rate after a double freeze-thaw cryotherapy procedure (93 percent) significantly greater than after a single freeze-thaw procedure (71 percent, p<0.02). The 71 men who had undergone salvage cryotherapy using a single cycle were followed for an average of 17.3 months, while the 79 men treated by double freeze-thaw cycle were followed for an average of only 10 months. Major complications included urinary incontinence in 73 percent, obstructive symptoms in 67 percent, and impotence in 72 percent of the patients.

Von Eschenbach et al. ²⁰ reported similar results when 47 of 89 patients underwent a single freeze-thaw cycle and the remaining 42 patients underwent a double freeze-thaw cycle (when they received salvage prostate cryoablation after radiotherapy had failed). Of the 89 patients, 67 underwent biopsy 6 months after their cryoablation and 52 (78 percent) were negative. Biopsy findings were negative in 69 percent of patients who had the single freeze-thaw cycle compared to 92 percent of those who had the double freeze-thaw cycle.

Schmidt et al. ²¹ reported that among 21 patients who underwent prostate cryoablation for relapses after radiation therapy, 18 (86 percent) had negative biopsies following the procedure. PSA levels were in the normal range in 67 percent of these patients, and of these, 40 percent were in the undetectable range.

Cox and Crawford ²² emphasized complications in their review of 63 patient charts (11 patients with prior radiation therapy) treated between June 1993 and December 1994 with cryosurgical ablation of the prostate for localized cancer. They noted that 37 (59 percent) of the patients had at least one significant adverse event. Significant complications included prolonged urinary retention, incontinence, tissue sloughing, fistula formation, prolonged perineal pain, and bowel dysfunction. Such complications were observed to be more common in 9 of the 11 patients (82 percent) with prior radiation therapy.

Cepedes et al. ²³ retrospectively investigated the long-term complications of salvage cryosurgery ablation of the prostate performed following failed radiation therapy for localized prostate cancer. They found that the complication rate was lower when the salvage cryosurgical procedure was done with a commercial urethral warmer (recently approved by the FDA) than when it was performed with the use of a "homemade" device. Long-term or persistent incontinence occurred in 28 percent of the 107 patients who had the commercial warmer as part of the procedure, and in 89 percent of the 28 patients with the same procedure using a homemade warmer. Urinary obstruction symptoms were reported in 9 percent of the patients with a commercial warmer versus 46 percent of the patients with the homemade warmer. A similar reduction in the occurrence of complications with the use of a commercial warmer was noted by Cox and Crawford ²² and Pisters et al. ⁶

Discussion

There is no medical consensus regarding a standard approach to treating local prostate cancer.^24,25 While radical prostatectomy may be a primary treatment of choice for certain patients with localized prostate cancer, the optimal treatment for many patients with local recurrence after radiation therapy is uncertain. Salvage prostatectomy is performed in patients who are judged to have resectable recurrent cancers, but obliteration of the normal landmarks by radiation makes the procedure extremely difficult and ineffective in many patients. Removed tissues have shown positive margins in a high proportion of cases, indicating the incomplete removal of the cancer by surgery. However, some series have reported favorable outcomes.^10,26 Lerner et al. ²⁶ reported a 10-year cancer-specific survival rate of 72 percent in 132 patients after salvage surgery and Rogers et al. ¹⁰ reported a cancer-specific survival rate of 95 percent at 5 years and 87 percent at 8 years in patients. Similar survival data for patients undergoing salvage cryosurgery are not available at the present time.

Cryosurgical ablation of recurrent prostate cancer is being used as an alternative to conventional surgery for treating patients who have failed radiation therapy. For a small percentage of patients found to have evidence of persistent or recurrent prostate cancer following cryotherapy, a second attempt at the procedure was undertaken. It appears, from the short-term results in the studies cited and summarized in Table 1, that cryosurgery is able to convert these patients to biopsy- negative status in a high percentage of cases. Negative biopsy rates ranged from 68 to 86 percent and depended on a number of factors, including tumor load and the extensiveness of prior therapy. Whether negative biopsy status translates into better long-term survival is unknown, particularly since it appears that in most studies only a small percentage of patients achieve a durable "biochemical cure." Currently, the significance of detectable levels of PSA in the face of negative biopsies is not entirely clear and raises the question of the reliability of postoperative negative biopsies.

Some of the discrepancies in the biochemical disease-free survival rates and complications reported with salvage cryosurgery by the various investigators may have resulted from differences in the procedure, experience, patient populations (clinical stages), and variations in the definitions for incontinence, obstruction, and "biochemical cure." There is general agreement that an increased or rising PSA level indicates that the cancer is recurring and progressing, while a persistently low or undetectable level of PSA indicates a biochemical disease-free survival.

However, there appears to be some disagreement as to what PSA levels should be considered as an indication of a cure or a biochemical failure (Table 1).

Although outcomes of cryosurgery (negative biopsy and a biochemical disease-free status) are improving through better instrumentation, surgical technique, and experience, multiple different techniques are being used. Long ²⁴ has identified a number of these:

• Thermocouple monitoring.
• Neoadjuvant hormonal therapy.
• Multiple freeze-thaw cycles.
• Urethral warming systems.
• Apical pull-back.
• Transrectal ultrasound.
• Variable number cryoprobes.
• Variable positions cryoprobes.

In cryoablation, three different types of freezing techniques have been used, including single and double freeze-thaw cycles and a pullback freeze. Multiple freeze-thaw-freeze cycling appears to be cumulatively cytotoxic when compared to a single freeze or freeze-thaw sequence. Also, because the length of the prostate measured from the base to the apex can be highly variable, in longer glands this may leave areas of the apex of the prostate unablated following the first freeze-thaw cycle. Apical pull-back, a technique in which each cryoprobe is moved distally toward the apex following the first freeze-thaw cycle, is not uniformly performed or reported. ²⁴ To what extent this technique affects the success of the procedure remains to be determined.

Recent studies by Pisters et al. ⁶ and Von Eschenbach et al. ²⁰ stratified patients according to the use of single and multiple freeze-thaw cycling. Pisters et al. ⁶ found biochemical cure significantly greater in patients who had undergone a double freeze-thaw cycle versus a single-thaw cycle (p<0.03). They also found the negative biopsy rate after a double freeze-thaw procedure (93 percent) significantly greater than after the single freeze-thaw procedure (71 percent, p<0.02). Similar results were reported by Von Eschenbach et al. ²⁰ However, the double freeze-thaw cycle procedure may result in increased complications. ³

Similarly, the use of thermocouples (thermosensors) to monitor the freezing process has been reported to significantly increase the negative biopsy rate. ²⁷ The use of thermocouples has been advocated in target areas to enhance cell kill by ensuring that appropriate cytodestructive levels of temperature are achieved. No standard thermocouple device is available. Also, probe positions in each individual prostate may vary considerably from one patient to the next; and no objective data define the number of or specific distances between cryoprobes that achieve maximum cellular destruction.

The use of androgen suppression therapy in patients before and after they have undergone radical prostatectomy, radiation therapy, or cryosurgery is considered palliative treatment and is increasingly used in managing localized prostate cancer. Androgen suppression therapy can lower PSA levels and prolong survival. ²² In patients who had salvage procedures performed for recurrent cancer, this treatment has added to the difficulty of interpreting the procedure's outcome data.

Consideration of cryosurgery as a therapeutic option for prostate cancer is due in large part to the development of high-resolution transrectal ultrasonography that allows prostate imaging in both the transverse and longitudinal planes. Effective cryoablation of the prostate requires transrectal ultrasonography to guide placement of the cryoprobes and to monitor the freezing process in real time. Two-dimensional (2-D) transrectal ultrasonography is, however, highly operator-dependent and subjective. Moreover, because the system uses a spatially flexible and variable 2-D imaging technique to visualize the 3-D anatomy, it can impose limitations on the proper alignment of the cryoprobes. Therefore, the incorporation of a 3-D transrectal ultrasound imaging system may improve accuracy of probe placement and treatment monitoring. ²⁸

A number of studies reported significant increases in urinary incontinence, as well as obstructive problems and tissue slough in patients undergoing cryotherapy without the commercial urethral warming catheter.^3,2,29Table 2 ²

Although the salvage cryotherapy procedure itself is well tolerated, it is clear that postoperative complications are significant. Major complications of salvage cryotherapy include incontinence, impotence, and obstructive symptoms (Table 2). Previous radiation therapy may have caused periurethral scarring and functional damage, such that the superimposed effects of further aggressive local therapy with prostatectomy or cryotherapy result in an alarmingly high rate of urinary incontinence (UI). Urinary incontinence is clearly a major problem with salvage cryotherapy or salvage prostatectomy. The challenge is to reduce the risk of UI and not compromise the effectiveness of the treatment. Rates of incontinence vary widely among different reports, with some as high as 89 percent (Table 2). However, according to Pisters et al, ⁶ incontinence can resolve (with time) in up to 50 percent of patients.

FDA Comments

These devices are pre-Amendment class II devices, which means that they were used in the United States prior to May 28, 1976. Thus, they are legally on the market for use in the treatment of prostate cancer. The urethral warmers are considered accessories to the cryosurgical systems and therefore are also classified as class II. Because these devices are pre-Amendment, manufacturers of newer cryosurgical systems for the treatment of prostate cancer need only provide data that demonstrate substantial equivalence to a system that is already on the market. To date, these substantial equivalence determinations have been based on functional performance and do not require clinical data. Although the peer-reviewed literature suggests that cryosurgery in the treatment of some prostate cancers is reasonably safe and effective, no manufacturer has provided FDA with data from well-controlled clinical trials to support this conclusion.

Conclusion

Cryosurgical ablation of recurrent prostate cancer is being used as an alternative procedure to conventional salvage surgery for patients who have failed radiation therapy. The available data suggest that some patients with radioresistant cancer have benefited from the use of cryosurgery as a salvage therapy. To date, studies indicate that at least in the short term, cryosurgery can result in negative post-treatment prostatic biopsies and low or undetectable serum PSA levels in some patients. Use of this technique has resulted in the biochemical disease-free survival of some patients. It may be reasonable to expect that some cancer-specific deaths of patients with radioresistant prostate cancer might be prevented or delayed by this procedure. Outcomes of salvage cryosurgery have tended to improve with improvements in instrumentation, technique, and experience; however, morbidity remains high and few patients have had long-term followup. Salvage cryosurgery prospective clinical trials are warranted and would help determine long-term survival benefits and make possible comparison of cryotherapy patient survival rates with those of untreated biopsy-positive patients.

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AHCPR Pub. No. 99-0004