Cryosurgical ablation of the prostate

High-risk patient outcomes

Authors

  • Kristofer L. Prepelica M.S.,

    Corresponding author
    1. Department of Urology, College of Physicians and Surgeons of Columbia University, Columbia-Presbyterian Medical Center, New York, New York
    • Department of Urology, College of Physicians and Surgeons of Columbia University, Columbia-Presbyterian Medical Center, Atchley Pavilion, 11th Floor, Room 1153, 161 Fort Washington Avenue, New York, NY 10032
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    • Fax: (212) 305-0106

  • Zephaniah Okeke M.D.,

    1. Department of Urology, College of Physicians and Surgeons of Columbia University, Columbia-Presbyterian Medical Center, New York, New York
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  • Alana Murphy B.S.,

    1. Department of Urology, College of Physicians and Surgeons of Columbia University, Columbia-Presbyterian Medical Center, New York, New York
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  • Aaron E. Katz M.D.

    1. Department of Urology, College of Physicians and Surgeons of Columbia University, Columbia-Presbyterian Medical Center, New York, New York
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Abstract

BACKGROUND

The authors report their experience with cryosurgical ablation of the prostate in men with high-risk features for prostate carcinoma who were unwilling to undergo radical surgery or radiation therapy.

METHODS

Between January 1998 and April 2002, 65 men underwent primary cryosurgery for prostate carcinoma with high-risk features. All patients had biopsy-proven prostate carcinoma without evidence for metastatic disease on magnetic resonance images, computed tomography scans, or radionuclide images of bones. High-risk parameters were defined as either a prostate-specific antigen (PSA) level ≥ 10 ng/mL, or a Gleason sum score ≥ 8, or both. Patients who had undergone prior surgery, radiation therapy, or cryoablation for prostate carcinoma were excluded from the study. Patients were monitored with physical examination and PSA screening every 3 months and with radiologic imaging when indicated.

RESULTS

The median patient age was 72 years (range, 41–86 years), and t he median follow-up was 35 months (range, 4–77 months). There were 2 patients (3.1%) with rectal pain and incontinence. Durable PSA biochemical disease-free survival was noted in 83.3% of patients according to the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria. A 6-year Kaplan–Meier analysis revealed an 81.7% ASTRO survival probability as well as PSA nadir < 4.0 ng/mL and PSA nadir < 1.0 ng/mL projections of 50% and 35%, respectively. One of 8 postcryosurgery biopsies (12.5%) were positive. No patient had progressed at last follow-up, and the overall survival rate was 100%.

CONCLUSIONS

Cryoablation was a feasible treatment option in patients with organ-confined prostate carcinoma who had high-risk features. Longer follow-up will be necessary to determine the effectiveness of this approach. Cancer 2005. © 2005 American Cancer Society.

Percutaneous cryoablation of the prostate has emerged from being an experimental treatment modality to becoming one of many tools available to urologists for the treatment of prostate carcinoma (CaP). Since the approval of prostate cryoablation by Medicare in 1999 as a viable therapeutic option in the management of CaP, there has been a significant resurgence in the level of interest and enthusiasm for the procedure. Several large studies have demonstrated that targeted cryoablation of the prostate (TCAP) provides a long-term, durable response with regard to disease control.1–3 In addition, cryoablation is associated with a lower incidence of overall morbidity compared with radical surgery and radiotherapy.4 Indications for the use of this approach initially were limited to salvage procedures after radiation therapy.5 A recently published, multicenter trial showed reasonable short-term successes with this procedure.6 Recent advances in the technology for cryoablation have produced significant decreases in the associated complications and morbidity. The use of cryoablation also has been extended to the treatment of other urologic malignancies, such as kidney carcinoma, with promising short-term results.

In this retrospective review, we assessed rates of biochemical disease-free survival, morbidity, and disease progression as a function of the efficacy of TCAP in the primary treatment of patients with high-risk CaP, which was defined as a pretreatment prostate-specific antigen (PSA) level ≥ 10 ng/mL and/or a Gleason sum score ≥ 8.

MATERIALS AND METHODS

Patient Selection

Patient records were reviewed for patients between January 1998 and April 2002. Sixty-five men with a median age of 72 years were identified who underwent cryoablation of the prostate for clinically localized, T1–T3 CaP with high-risk features. Inclusion criteria were patients with prehormone therapy high-risk features of CaP, which were defined as either a PSA level ≥ 10 ng/mL, a pathology report indicating a Gleason sum score ≥ 8, or both of these features. Patients who had undergone prior radical prostatectomy or radiation treatment for CaP were excluded from this analysis. Patients were required to have no evidence of metastatic disease by bone scan, computer-assisted tomography, or magnetic resonance imaging. Patients who were receiving androgen-deprivation therapy for CaP were eligible for the study.

Cryosurgical Techniques

All cryosurgery was performed by a single surgeon (A.E.K.) using argon and helium gases to freeze and thaw tissue, respectively. The procedure was performed under spinal anesthesia or general anesthesia according to anesthesiologist and patient preference. Patients received a Fleets enema on the morning of the procedure and 500 mg of metronidazole intravenously at the start of the procedure. A 10-French suprapubic catheter was placed under flexible cystoscopic guidance. The bladder was then filled with 0.9% normal saline and remained distended for the duration of the procedure. A urethral warming catheter was inserted before commencement of tissue freezing. The catheter was warmed to 38 °C and remained in place for 2 hours after the conclusion of the procedure. Using a brachytherapy template, cryoprobes were placed percutaneously into the prostate under transrectal ultrasound (TRUS) guidance. Thermocouple probes for temperature monitoring were placed adjacent to each of the two neurovascular bundles, the apex, Denonvilliers space, and in the external sphincter. Freezing was then initiated by activating the anterior probes, followed by the posterior probes. A double freeze-thaw technique was applied in all procedures. The outer edge of the ice ball had a hyperechoic appearance and was visualized readily on TRUS. Freezing was completed when the temperature was < − 40 °C at each neurovascular bundle, apical temperature was < − 10 °C, and all prostatic tissue was frozen, as visualized by ultrasound. Patients were discharged home the next morning. They received 500 mg of ciprofloxacin orally twice daily for 5 days.

Patient Follow-Up

The suprapubic tube remained open, and patients were instructed to clamp the tube on the fourth postoperative day. One week after the procedure, the suprapubic tube was removed. The external genitalia and perineum were examined to determine the extent of swelling, obstruction, urethral sloughing, urinary infection, rectal fistula, edema, and ecchymosis. Serum PSA was measured, and digital rectal examination was performed 6 weeks after cryosurgery and every 3 months thereafter. At each follow-up, the operating surgeon (A.E.K.) evaluated morbidities, including incontinence, which was defined as patient report of a lack of urinary control that required more than 1one pad daily. Patients also were questioned during the examination about other potential complications, such as rectal pain or perineal discomfort.

Statistical Analyses

Data were summarized as the means and ranges for continuous variables and, in frequency tables, for categorical variables. The statistical software package SPSS 12.0 for Windows (SPSS Incorporated, Chicago, IL) was used for all statistical analyses.

RESULTS

Patient Demographics

Sixty-five consecutive patients with a median age of 72 years underwent TCAP as primary therapy with curative intent for advanced, clinically localized CaP from January, 1998 to April, 2002. Patient characteristics are summarized in Table 1. Forty-four of 63 patients (67.7%) with available data received neoadjuvant androgen-deprivation therapy for 3 months and are stratified by clinical characteristics in Table 2.

Table 1. Patient Characteristics
CharacteristicNo. of patients (%)
  1. PSA: prostate-specific antigen.

No. of patients65 (100.0)
Age (yrs) 
 Mean70.86
 Median72
 Range41.0–86.3
Gleason score 
 Mean7
 Median7
 Range5–10
 ≤ 629 (45)
 720 (31)
 > 715 (23)
PSA (ng/mL) 
 Mean38.67
 Median21.70
 Range2.7–70.1
 < 10 ng/mL35 (54)
 > 10 ng/mL30 (46)
Neoadjuvant hormone therapy44 (67.69)
Table 2. Hormone Stratification
VariableNo. of patients (%)Hormones (%)
  1. PSA: prostate-specific antigen.

Gleason score  
 ≤ 615 (23.8)73.3
 723 (36.5)56.5
 > 725 (39.7)76.0
PSA  
 < 10 ng/mL6 (9.2)66.7
 > 10 ng/mL59 (90.8)67.8

Clinical Follow-Up

Using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure (3 consecutive increases in PSA level), 83.3% of patients were free of biochemical recurrence after a median follow-up of 35 months (range, 4–77 months). Of the 8 patients who underwent biopsy and radiographic evaluation, 1 patient (12.5%) had clinical evidence of disease postcryotherapy. At 2 years postcryoablation, 94.44% and 80.55% of patients had a PSA nadir < 4.0 ng/mL or < 1.0 ng/mL, respectively. The mean and median PSA nadirs were 2.5 ng/mL and 0.4 ng/mL, respectively. Overall, 87.3% of patients had a PSA nadir < 4.0 ng/mL. Stratified PSA nadir results for 3 months, 12 months, 24 months, and 36 months are shown in Table 3. The 6-year Kaplan–Meier analyses for ASTRO survival, PSA nadir < 4.0 ng/mL, and PSA nadir < 1.0 ng/mL are shown in Figures 1 and 2. Morbidity analysis (Table 4) revealed only 2 patients each with incontinence, which was defined as any daily pad usage; urinary retention; and rectal pain, which subsequently resolved. Voiding complications presented in 1.5% of patients. No patient developed hematuria or fistula. To date, no patient has demonstrated disease progression, and the overall survival rate is 100%.

Table 3. Stratified Biochemical Survival
VariableBiochemical survival (%)
ASTROTwo-yr < 1.0 ng/mL nadir (%)
  1. ASTRO: American Society for Therapeutic Radiology and Oncology; PSA: prostate-specific antigen.

Gleason score  
 ≤ 6100.090.9
 770.070.0
 > 776.578.6
PSA  
 < 10 ng/mL57.180.0
 > 10 ng/mL88.680.7
Hormones  
 Yes86.781.5
 No75.077.8
Figure 1.

These Kaplan–Meier curves indicate the cumulative survival of patients who underwent primary cryosurgery for prostate carcinoma with high-risk features according to prostate-specific antigen (PSA) nadir.

Figure 2.

These Kaplan–Meier curves indicate the cumulative survival of patients who underwent primary cryosurgery for prostate carcinoma with high-risk features according to the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria.

Table 4. Morbidity and Complication Rates
Complication%
Rectal pain3.1
Urinary retention3.1
Incontinence3.1
Perineal discomfort0.0
Rectourinary fistula0.0
Voiding complications1.5
Disease progression0.0

DISCUSSION

Organ-confined CaP traditionally has been treated with radical surgery, external beam radiation therapy, and brachytherapy. However, each treatment can result in a substantial risk of significant morbidity.7 Some recent studies showed minimal a survival benefit between no treatment and radical prostatectomy. Consequently, watchful waiting slowly is gaining wide acceptance as a viable management alternative in certain patient populations.8 The decision to treat CaP with surgical or medical modalities versus watchful waiting requires a careful assessment of the risks and benefits, if any, for that patient. Therapeutic decisions become easier when the complications and side effects of treatments are reduced. However, many patients who choose the watchful-waiting approach eventually end up seeking treatment.9

Since the first published application of cryosurgery to the prostate by Gonder et al.,10 cryoablation has undergone many advancements to make it available as a legitimate treatment modality for CaP. With the publication in 1982 of the study by Bonney et al.1 of their experience with this procedure, coupled with the recognition of cryosurgery as a therapeutic option by the American Urological Association in 1996, there has been renewed interest in this technology. In the study by Bonney et al., 229 patients were followed for up to 10 years after cryosurgery. Comparisons of these patients were made with patients who underwent radical prostatectomy and received radiation therapy. The authors found similar survival rates for all treatment modalities. Cryosurgery showed advantages in the treatment of large, bulky tumors. However, difficulties with monitoring of the freezing process, due to unavailability of yet-to-be-developed technology, resulted in major complications, such as urethrocutaneous and rectourethral fistulas, at much higher rates compared with the rates among men who received other the treatment modalities. These complications initially limited the acceptance of cryosurgery as a treatment modality for patients with CaP.

Advances, such as improved TRUS of the prostate and the development of urethral warmers, significantly have reduced the rates of complications, such as incontinence, urethral sloughing, and fistulas.11–13 In a recently published, multicenter study of 975 patients3 that compared cryosurgery with published series on radiotherapy using similar risk-stratification and failure criteria, cryosurgery yielded results similar to both external-beam radiation therapy and brachytherapy. The low-risk group was defined as patients with Stage ≥ T2a CaP, PSA level ≤ 10.0 ng/mL, and Gleason sum score ≤ 6. The moderate-risk group was defined as patients with any 1 of the following: Stage ≥ T2b, PSA level > 10.0 ng/mL, or Gleason sum score ≥ 7. The high-risk group included men with at least two of the factors described above. For the low-risk group, the 5-year biochemical recurrence-free survival rate was 76% with cryosurgery, 75–87% for brachytherapy, and 67–81% for conformal radiation therapy. Comparable results also were noted for the medium-risk and high-risk groups. Those investigators also noted a higher incidence of rectal complications for the radiation therapy group, whereas the rate of impotence was greater with cryosurgery. In the study by Ragde et al.,14 the authors noted that the biochemical disease-free survival rates among 178 higher risk patients who were treated with palladium-103 brachytherapy at 3 years, 5 years, 10 years, and 13 years were 87%, 82%, 80%, and 80%, respectively. These rates are comparable to the observed rate of 80% in the current study for high-risk patients. A retrospective, nonrandomized, multiinstitutional, pooled analysis of patients who were treated with external beam radiation therapy alone between 1988 and 1995 at 6 United States medical centers, with follow-up as much as 9 years, showed that 5-year estimates of overall survival, disease-specific survival, and freedom from biochemical failure were 85.0%, 95.1%, and 65.8%, respectively. PSA failure-free rates at 5 years and 7 years after treatment for patients who presented with a PSA level < 10 ng/mL were 77.8% and 72.9%, respectively. The rates of survival free of biochemical failure at 5 years were estimated at 29–69% for patients in the moderate-risk and high-risk groups.15 It should be noted that several studies have shown that biopsy characteristics may be stronger independent predictors of disease recurrence after therapy than serum PSA levels.16, 17 Stratifying outcomes by biopsy parameters, such as extent of disease and the number of cores involved, may improve patient selection.

With results from the studies described above showing disease control with cryosurgery similar to that achieved with radiation therapeutic modalities, the focus of investigators shifted to reducing the complications associated with this technology as well as improving disease control by gaining better control over total ablation of the prostate. However, total gland ablation is associated with significantly higher impotence rates compared with radiation therapy and radical surgery.18, 19

The rationale for adjuvant or neoadjuvant androgen-deprivation therapy in high-risk patients is the theory that these patients eventually fail because they already have local or distant micrometastatic disease at the time of diagnosis. On this basis, improving local control of disease will have very little impact on recurrence-free survival. There is also the distinct possibility that some patients likely develop metastatic disease due to inadequate local treatment. Adjuvant or neoadjuvant androgen-deprivation therapy in high-risk patients, thus, has become an important strategy. When combined with radiation, a short course of androgen-deprivation therapy appears to improve local-regional control as well as distant metastatic disease in patients with T2–T4 disease.20 Long-term adjuvant hormonal therapy in addition to radiation therapy also appears to improve survival in patients with Gleason scores > 7.21 In the current series, the differences in biochemical recurrence-free survival did not differ significantly between patients who received androgen-ablation therapy and patients who did not. Han et al.6 recently reported a multicenter series on 122 patients in a pooled, multiinstitutional analysis using third-generation cryosurgery. Seventy-one percent of the high-risk patients in their study remained free of biochemical recurrence at 12 months of follow-up. The most common complication was scrotal swelling and pelvic pain (5.9%). Those patients had no episodes of fistula or infection. Their results are consistent with our series, in which the overall complication rate was 2%, with most complications accounted for by 2 patients each with rectal pain, urinary retention, and incontinence. None of our patients had infectious complications; and, to date, none has developed a rectourethral fistula. This is similar to rates published by Han et al.6

Most of the data available on outcomes after cryosurgery of the prostate have been from patients who failed radiation therapy, with PSA levels and biopsies that were indicative of locally recurrent prostate carcinoma. Advances in this technology have allowed its extension as primary treatment in patients with T1–T3 disease. High-risk patients often are regarded as poor candidates for radical prostatectomy. Cryosurgery offers these patients another treatment option in addition to radiation treatment. Our study demonstrates biochemical disease-free survival comparable to similar studies using the same modality in high-risk patients. Our study results indicate that, with short-term follow-up, cryosurgery offers improved survival compared with radiation therapy alternatives. Longer follow-up will be needed to assess the durability of these responses.

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