BCBSMT may consider cryosurgical ablation of the prostate medically necessary as treatment of clinically localized (organ-confined) prostate cancer when performed as:
- Initial treatment; OR
- Salvage treatment of disease that recurs following radiation therapy.
BCBSMT considers subtotal cryoablation of the prostate experimental, investigational and unproven in the treatment of prostate cancer.
Cryosurgical ablation for treatment of prostate cancer has been demonstrated to be a safe and effective treatment modality for clinically localized prostate cancer. Data from many small non-randomized uncontrolled trials have established that cryosurgical ablation of prostate tumors demonstrates similar complication rates in terms of erectile dysfunction, obstruction, incontinence, and urethral stricture as does EBRT. The efficacy of cryoablation, as noted by post-operative biopsy results and recurrence rates, is similar to external beam radiation when treating prostate cancer. While the data supporting this procedure for use as a salvage technique is not extensive, there is data to demonstrate that this is a useful and safe therapeutic modality for patients who have previously failed radiation therapy. The level of evidence supporting this conclusion includes multiple case series studies.
Published studies have demonstrated that patients with low volume, localized, primary prostate cancer undergoing cryosurgery remain biochemically disease-free up to three years. Surgically related morbidities of cryosurgery of the prostate have compared favorably to those reported for radical prostatectomy and radiation therapy. The available data suggests that select patients with radio resistant cancer have benefited from the use of cryosurgery as a salvage therapy. To date, case studies indicate that at least, in the short-term, cryosurgery is better tolerated than open salvage surgery and can be considered a treatment option for men who would not be candidates for open surgery. Complication rates can be minimized through improvements in technique, instrumentation and utilization of experienced cryosurgeons.
Long et al. reported on the experience of five institutions with the use of cryoablation. The results were compared to those of conformal radiotherapy and brachytherapy. Patients with a previous history of failed radiotherapy were excluded and androgen deprivation was determined and categorized separately. Patients were classified as low risk, moderate risk or high risk according to the cancer characteristics (stage of the disease, Gleason grade and prostate-specific antigen [PSA] level). The procedure was not consistent at all institutions. Differences included the number of probes used, number of freeze cycles per patient, length of apical pullback maneuver, real-time monitoring during freezing and the system used for freezing. A total of 975 patients were studied, of whom 238 were low risk, 321 were moderate risk and 385 were high risk; risk was not determined in 38 patients. The five-year rate for non-rising postoperative PSA levels for low and medium risk patients ranged between 60 and 76 percent and for high-risk patients it was 41 percent. Only about 18 percent of the patients were found to have a positive biopsy following the procedure.
Another study by Long et al. presented a retrospective comparison of data from the cancer of the prostate strategic urologic research endeavor (CaPSURE™) database, a longitudinal observational database of patients with prostate cancer. Adjusted overall rates of second treatment indicate that patients receiving cryoablation are 1.9 times more likely to have a second treatment than those patients who received radical prostatectomy, and 1.4 times more likely than those patients who received EBRT. When rates of second treatment were stratified by various parameters of disease severity, the rates for cryoablation compared to radical prostatectomy tend to be significantly increased for low-risk disease but not for high-risk disease. The same is true for EBRT compared to radical prostatectomy, but to a lesser extent. Thus, these results do not suggest an advantage for cryoablation, and may indicate poorer outcomes for low-risk disease.
Perioperative mortality and acute life-threatening consequences of cryoablation appear to be negligible. Patients have the highest likelihood of impotence after cryoablation, compared to radical prostatectomy or three-dimensional conformal radiation therapy (3DCRT). The occurrence of incontinence appears comparable to 3DCRT and potentially less than radical prostatectomy. However, other genitourinary complications are peculiar to cryoablation. The adverse gastrointestinal consequences typical of 3DCRT are not noted after cryoablation.
Bahn et al. reported on a large single institution retrospective long-term experience with targeted cryoablation of the prostate (TCAP). A series of 590 consecutive patients underwent TCAP as primary therapy with curative intent for localized or locally advanced prostate cancer from March 1993 to September 2001. After a mean follow-up time of 5.43 years the rates of morbidity were modest, and no serious complications were observed. TCAP was shown to equal or surpass the outcome data of EBRT, three-dimensional conformal radiation, and brachytherapy. These seven-year outcome data provide compelling validation of TCAP as an efficacious treatment modality for locally confined and locally advanced prostatic carcinoma.
Chin and colleagues recently reported on a randomized trial of cryoablation (CRYO) compared to EBRT in patients with clinical stage T2C-T3B prostate cancer. These patients had node-negative disease and also received six months of hormonal therapy, starting three months before treatment. Only 64 of the planned 150 patients were accrued, entry was limited due to changes in practice and difficulty beginning cryosurgery at one of the sites. Twenty-one of 33 (64%) in the CRYO group and 14 of 31 (45%) in the EBRT-treated group were classified as treatment failure. The mean biochemical disease-free survival (bDFS) was 41 months for the EBRT group compared to 28 months for the CRYO group. The four-year bDFS for EBRT and CRYO groups were 47 and 13%, respectively. Disease-specific survival (DSS) and overall survival (OS) for both groups were very similar. Serious complications were uncommon in either group. EBRT patients exhibited adverse gastrointestinal (GI) effects more frequently. The authors concluded that taking into account the relative deficiency in numbers and the original trial design, this prospective randomized trial indicated that the results of CRYO were less favorable compared to those of EBRT and that CRYO was suboptimal primary therapy in locally advanced prostate cancer.
Aus recently commented that cryosurgical ablation is now using third-generation equipment and that long-term follow-up from these devices, which emerged around 2000, will be needed. These newer devices use more probes and argon gas (as opposed to liquid nitrogen) and create smaller ice balls. Finally, there is minimal evidence for use of a newer technique of subtotal prostate cryosurgery for treatment of localized disease.
Recent studies have described results from using cryosurgery for patients with recurrent, localized prostate cancer following a course of radiation therapy. Ng and colleagues reported on a series of 187 patients with locally recurrent prostate cancer after radiotherapy that underwent salvage cryoablation of the prostate, and were studied after a mean follow-up of 39 months. Serum PSA at cryoablation was a predictive factor for biochemical recurrence on univariate and multivariate analysis (p <0.001). Patients with a pre-cryoablation PSA value less than 4 ng/ml had a 5- and 8-year biochemical recurrence-free survival of 56% and 37%, respectively. In contrast, patients with a pre-cryoablation PSA of 10 ng/ml or greater had a 5- and 8-year biochemical recurrence-free survival of only 1% and 7%, respectively. Patients with a pre-cryoablation PSA in the range of four to 9.99 ng/ml had intermediate survival outcomes. Overall 5- and 8-year survival was 97% and 92%, respectively. The authors concluded that salvage cryoablation is a viable treatment option for patients with prostate cancer in whom radiation therapy has failed and that salvage cryoablation should be performed when the serum PSA level is still relatively low, because in these patients the procedure may potentially be curative. Similarly, Ismail and colleagues reported on 100 patients treated between May 2000 and November 2005 with CRYO for recurrent prostate cancer after radiotherapy; mean follow-up was 33.5 months. All patients had biopsy-confirmed recurrent prostate cancer. Biochemical recurrence-free survival (BRFS) was defined using a PSA level of <0.5 ng/mL and by applying the American Society for Therapeutic Radiology and Oncology (ASTRO) definition for biochemical failure. Patients were stratified into three risk groups, i.e., high-risk (68 men), intermediate-risk (20 men) and low-risk (12 men). There were no operative or cancer-related deaths; the five-year actuarial BRFS was 73%, 45%, and 11% for the low-, intermediate- and high-risk groups, respectively. Complications included incontinence (13%), erectile dysfunction (86%), lower urinary tract symptoms (16%), prolonged perineal pain (4%), urinary retention (2%), and recto-urethral fistula (1%). The authors concluded that salvage cryoablation is a safe and effective treatment for localized prostate cancer recurrence after radiotherapy.
While the data for treatment of recurrence after radiation therapy are also limited, these patients have few options; one option with recurrence is prostatectomy, which can be difficult in tissue that has been irradiated. Like primary prostate cancer, when to proceed with treatment is a complex issue. However, for patients with recurrence after radiation therapy who elect further treatment, based on the limited data available, cryosurgical treatment does appear to produce anti-tumor activity.
A literature search using MEDLINE was conducted through October 2011. One randomized trial on cryotherapy for prostate cancer was identified. Donnelly and colleagues reported on a randomized trial of 244 patients with newly diagnosed localized prostate cancer, during the period of December 1997 through February 2003, to compare cryoablation to external beam radiotherapy. All patients began neoadjuvant antiandrogen therapy prior to local treatment and continued for a period of three through six months. Median follow-up was 100 months. At 36 months, the biochemical failure rate (PSA nadir + 2ng/mL) was 17.1% in the cryoablation group versus 13.2% in the radiotherapy group. Overall survival at five years was 89.7% in the cryoablation group versus 88.3% in the radiotherapy group and did not differ statistically (p = .78). At 36 months, radiotherapy patients had significantly more positive prostate biopsies than the cryoablation group (22 of 76 vs. 7 of 91 patients respectively [p = <.001]). Observed failure rates at 60 months were equal in both groups but favored cryoablation at 84 months. Twelve cryoablation patients experienced 13 grade 3 adverse events versus 16 grade 3 adverse events in 14 radiotherapy patients using National Cancer Institute of Canada Common Toxicity Criteria. Urinary retention was the most common grade 3 adverse event in both treatment arms. The authors indicated they were unable to establish cryoablation was noninferior to radiotherapy at 36 months due to the wide confidence interval. However, they noted several issues which limit interpretation of the study results including the use of lower radiation dosages (68 Gy, 70 Gy and 73.5 Gy) than are common today and early trial closure due to lack of patient enrollment.
In a second article on the Donnelly study, Robinson et al. reported on quality of life outcomes in the same 244 patients. With only a few exceptions, the authors found study participants reported quality of life at high-levels in both the cryoablation and radiotherapy treatment arms. Acute urinary dysfunction, which eventually resolved, occurred more often with cryoablation as measured using the UCLA Prostate Cancer Index (mean urinary function in cryoablation was 69.4 vs. 90.7 in EBRT; P < .001; higher scores meaning better function and less bother). UCLA Prostate Cancer Index sexual function decreased in both arms at three months. However, reduced sexual function was reported more in the cryoablation arm (mean cryoablation = 7.2 vs. 32.9 in EBRT; P < .001). Decreased sexual function continued at the three-year evaluation with the mean score 15 points lower in the cryoablation group.
In one representative publication on focal therapy, Truesdale and colleagues reported on a retrospective chart review of 77 patients with unilateral prostate cancer treated with primary focal cryosurgery between 2002 and 2009. Using D'Amico risk classifications, 44 patients were considered low-risk, 31 were intermediate-risk, and two were high-risk disease. Patients were followed for a median time of 24 months and the biochemical (PSA) progression-free survival rate was 72.7% overall. Prostate cancer was confirmed by biopsy in 10 of 22 patients suspected of having recurrent disease (two ipsilateral, seven contralateral, and one bilateral disease). The overall pathological progression-free survival rate was 87%. Disease progression was correlated with pretreatment PSA levels, pretreatment Gleason scores, number of positive cores, and total tumor lengths. Comparative data from studies with longer follow-up are needed are needed to evaluate this technology. In another representative publication identified in the literature search, Williams and colleagues reported on a retrospective review of 176 patients receiving salvage cryotherapy for locally recurrent prostate cancer during the period of 1995 to 2004. Patients were followed a mean of 7.46 years with 52 patients having been followed for more than ten years. The ten-year, disease-free survival rate was 39%. The authors found risk factors for prostate cancer recurrence following salvage cryotherapy were presalvage PSA levels, preradiation, and presalvage Gleason scores. Early recurrence was highly predicted by PSA nadir >1.0 ng/dl after salvage cryotherapy.
www.ClinicalTrials.gov identified four studies on cryotherapy for prostate cancer. Biochemical failure and quality of life (QOL) outcomes will be evaluated in an estimated 800 patients in the prospective, multicenter registry of salvage cryotherapy in recurrent prostate cancer (SCORE) trial (NCT00824928A). This study began in January 2007 and is currently recruiting patients. Two single-institution studies (NCT00774436 and NCT00877682) will evaluate the effectiveness of focal cryotherapy in clinically-localized prostate cancer in 50 and 100 patients. These studies have completion dates of October 2011 and April 2012, respectively. A phase 1 study on the safety of focal cryotherapy in 100 low-risk, localized prostate cancer patients is being conducted in Italy and is enrolling patients by invitation only (NCT00928603).
Technology Assessments, Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (v.1.2011) indicate cryosurgery is appropriate for post-radiation recurrence in patients that have a positive prostate biopsy and negative studies for metastasis. However, the NCCN guidelines indicate cryotherapy as primary therapy is not recommended. The discussion notes that there is insufficient data available from long-term studies comparing cryotherapy with radiation and radical prostatectomy.
The 2008 American Urological Association Best Practice Statement has recognized cryoablation of the prostate as an appropriate treatment option for newly diagnosed or radiorecurrent organ-confined prostate cancer. However, this Best Practice Statement indicates cryoablation in patients with clinical T3 disease is undetermined. In addition, long-term results of subtotal prostate cryoablation are noted as being unavailable.
The available evidence for use of cryotherapy in the treatment of clinically localized (organ-confined) prostate cancer when performed as initial treatment or as salvage treatment of disease that recurs following radiation therapy is sufficient to demonstrate improvement in net health outcome. This conclusion is based on the extensive data from cohort studies and clinical input including an indirect chain of evidence and the recognition that the data for this long-used technique is similar to data for a number of accepted techniques. While the data for treatment of recurrence after radiation therapy are limited, these patients have few options; one option with recurrence is prostatectomy, which can be difficult in tissue that has been irradiated. Like primary prostate cancer, when to proceed with treatment is a complex issue. However, for patients with recurrence after radiation therapy who elect further treatment, based on the limited data available, cryosurgical treatment does appear to produce anti-tumor activity. Given the lack of long-term follow-up data, including a lack of comparative studies, subtotal prostate cryoablation is considered experimental, investigational and unproven.
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