Cryotherapy is a technique to ablate tissue by local induction of extremely cold temperatures. Recently, the American Urological Association Best Practice Statement recognized cryoablation of the prostate as an established treatment option for men with newly diagnosed or radiorecurrent organ-confined prostate cancer. Emerging data suggest that, in select cases, cryoablation may have a role in focal ablation of prostate. The current state of the art of cryoablation in these applications is reviewed.
Cryotherapy is a technique to ablate tissue by local induction of extremely cold temperatures. This technology was pioneered in the 1960s by Cooper and Lee. Several years later, Gonder and colleagues performed transurethral cryoablation of the prostate with digital rectal guidance of the ice ball for benign prostatic hypertrophy. Initial forays were hampered by difficulty in accurate placement of cryoprobes and by imprecise monitoring of the ice ball, which resulted in incomplete treatment and high complication rates. During the past 40 years, however, considerable inroads have been made in cryotechnology and imaging, allowing for precision, safety, and efficacy. In 2005, approximately 6600 procedures were performed in the United States. Indeed, it has now been more than a decade since the American Urological Association (AUA) recognized cryotherapy as a therapeutic option for prostate cancer, removing the label of “investigational.” In 2008, an AUA Best Practice Statement recognized cryoablation of the prostate as an established treatment option for men with newly diagnosed or radiorecurrent organ-confined prostate cancer. In their analysis of the current state of the art, the panel identified a constellation of key advancements such as improved cryotechnology, advanced ultrathin cryoprobes with precise isotherm delineation, real-time ultrasonographic ice-ball monitoring, active urethral warming, and, in particular, the use of multipoint thermal sensors to protect nontarget tissues (eg, rectum, external urethral sphincter). Improved patient outcomes have been seen commensurate with refinement of surgical technique and evolution of technology.
Cryoinjury
The principles of cryotherapy, including the mechanisms of cell injury and cell death, have been well described. Cryotherapy induces cell damage by a variety of direct and indirect mechanisms, some immediate and others delayed. The end result is the induction of coagulative necrosis in the targeted tissue. The direct and immediate effects of injury occur because of the destructive effects of freezing and warming tissue. The indirect and delayed effects occur due to microcirculatory damage/ischemia, inflammation, and apoptosis. A full discussion of the mechanism of cryoinjury is beyond the scope of this article.
Factors affecting tissue destruction during cryotherapy
The key variables that affect cellular destruction include the rates of cooling and warming and the nadir temperature achieved in the tissue. Tatsutani and colleagues studied thermal parameters associated with prostate cancer destruction in an ND-1 cell line; they demonstrated that temperatures less than −40°C were required for complete cell death. In addition, the investigators noted a faster freezing rate (ie, 2°C/min vs 1°C/min or 5°C/min) resulted in optimal cellular destruction, a finding reported by other groups. In practice, however, the cooling rate proximal to the probe is much higher than that of peripheral tissue, resulting in differential rates of cooling. Others have suggested that the cooling rate is not the most important factor determining cell death. However, there is evidence to suggest that the subsequent thaw cycle is more destructive at slower rates. In addition, numerous investigators have reported that a double freeze/thaw cycle significantly increased cell destruction. A second cycle has been found to increase the extent of necrosis up to 80% of the previously frozen volume. A second cycle also results in a lower lethal isotherm of approximately −20°C, permitting a closer approach to the margins of the prostate without endangering the rectum. Clinically, double freeze-thaw cycles have been associated with lower posttreatment positive biopsy rates and improved prostate-specific antigen (PSA) results, compared with a single freeze-thaw cycle. For patients who had undergone focal cryoablation before radical prostatectomy (RP) with 2 consecutive 10-minute freeze cycles, pathologic examination revealed a larger area of coagulative necrosis than with a single 20-minute freeze. Fig. 1 shows an example of a 1.47-mm ablation needle (IceRod, Galil Medical) and the corresponding isotherm map. Fig. 2 depicts a typical needle insertion template.
- 1.
Nadir temperature: minimum of −20°C, preferably −40°C
- 2.
Freezing rate: as rapid as possible (ie, 25°C/min)
- 3.
Thawing rate: slow, passive thawing
- 4.
Freeze/thaw cycles: a double freeze-thaw cycle (ie, 10 min freeze/5 min thaw)
Primary Cryotherapy
In general, patients with clinical stage T1c-T2 disease, who have no evidence of metastatic disease, greater than 10-year life expectancy, and who are not concerned with potency are candidates for whole-gland primary cryotherapy. The AUA Best Practice Policy Statement of cryosurgery proposed that the role of cryosurgery remains undetermined for patients with clinical stage T3 disease. Cryotherapy represents a good option for many patients who do not wish to undergo RP or radiation therapy (RT). Many patients who are candidates for external beam radiotherapy (EBRT) may consider primary cryotherapy because treatment can be conveniently administered as an outpatient procedure as opposed to 1 to 2 months of treatment. High-risk patients may require multimodal therapy. Patients with gross extracapsular extension or seminal vesicle invasion are treated with neoadjuvant hormone therapy to reduce the tumor volume and allow for easier inclusion within the ice ball. Due to limitations in isotherm coverage based on currently available probes, prostates larger than 50 cm 3 may be incompletely enveloped by the ice ball; neoadjuvant hormone therapy is indicated in these cases to reduce the target volume to allow for complete coverage. To date, there are no data to suggest that neoadjuvant or concurrent androgen deprivation therapy (ADT) improves postcryosurgery cancer control outcomes.
Absolute
- –
Metastatic disease
- –
Anorectal fistula
Relative
- –
Gland size >50 cm 3
- –
Prior transurethral resection of prostate (TURP) (particularly for salvage cryotherapy)
- –
PSA >20 ng/mL
- –
cT3 disease
- –
Prior pelvic surgery/trauma with distorted anatomy
Data from Miller DC, Pisters LL, Belldegrun AS. Cryotherapy for Prostate Cancer, Chapter 101. In: Wein AJ, Kavoussi LR, Novick AC, et al, editors. Campbell-Walsh Urology, 9th edition. Saunders, 2007.
Cryotherapy may offer certain advantages to patients with comorbidities that may preclude them from candidacy for RP or RT (eg, men with Crohn disease, ulcerative colitis, prior pelvic irradiation or pelvic surgery, cardiac disease, morbid obesity, or body habitus unfavorable for RP or RT). Finally, cryosurgery can also be considered in a salvage setting (ie, radiation failure) in patients who have negative metastatic workup.
Factors affecting tissue destruction during cryotherapy
The key variables that affect cellular destruction include the rates of cooling and warming and the nadir temperature achieved in the tissue. Tatsutani and colleagues studied thermal parameters associated with prostate cancer destruction in an ND-1 cell line; they demonstrated that temperatures less than −40°C were required for complete cell death. In addition, the investigators noted a faster freezing rate (ie, 2°C/min vs 1°C/min or 5°C/min) resulted in optimal cellular destruction, a finding reported by other groups. In practice, however, the cooling rate proximal to the probe is much higher than that of peripheral tissue, resulting in differential rates of cooling. Others have suggested that the cooling rate is not the most important factor determining cell death. However, there is evidence to suggest that the subsequent thaw cycle is more destructive at slower rates. In addition, numerous investigators have reported that a double freeze/thaw cycle significantly increased cell destruction. A second cycle has been found to increase the extent of necrosis up to 80% of the previously frozen volume. A second cycle also results in a lower lethal isotherm of approximately −20°C, permitting a closer approach to the margins of the prostate without endangering the rectum. Clinically, double freeze-thaw cycles have been associated with lower posttreatment positive biopsy rates and improved prostate-specific antigen (PSA) results, compared with a single freeze-thaw cycle. For patients who had undergone focal cryoablation before radical prostatectomy (RP) with 2 consecutive 10-minute freeze cycles, pathologic examination revealed a larger area of coagulative necrosis than with a single 20-minute freeze. Fig. 1 shows an example of a 1.47-mm ablation needle (IceRod, Galil Medical) and the corresponding isotherm map. Fig. 2 depicts a typical needle insertion template.
- 1.
Nadir temperature: minimum of −20°C, preferably −40°C
- 2.
Freezing rate: as rapid as possible (ie, 25°C/min)
- 3.
Thawing rate: slow, passive thawing
- 4.
Freeze/thaw cycles: a double freeze-thaw cycle (ie, 10 min freeze/5 min thaw)
Primary Cryotherapy
In general, patients with clinical stage T1c-T2 disease, who have no evidence of metastatic disease, greater than 10-year life expectancy, and who are not concerned with potency are candidates for whole-gland primary cryotherapy. The AUA Best Practice Policy Statement of cryosurgery proposed that the role of cryosurgery remains undetermined for patients with clinical stage T3 disease. Cryotherapy represents a good option for many patients who do not wish to undergo RP or radiation therapy (RT). Many patients who are candidates for external beam radiotherapy (EBRT) may consider primary cryotherapy because treatment can be conveniently administered as an outpatient procedure as opposed to 1 to 2 months of treatment. High-risk patients may require multimodal therapy. Patients with gross extracapsular extension or seminal vesicle invasion are treated with neoadjuvant hormone therapy to reduce the tumor volume and allow for easier inclusion within the ice ball. Due to limitations in isotherm coverage based on currently available probes, prostates larger than 50 cm 3 may be incompletely enveloped by the ice ball; neoadjuvant hormone therapy is indicated in these cases to reduce the target volume to allow for complete coverage. To date, there are no data to suggest that neoadjuvant or concurrent androgen deprivation therapy (ADT) improves postcryosurgery cancer control outcomes.
Absolute
- –
Metastatic disease
- –
Anorectal fistula
Relative
- –
Gland size >50 cm 3
- –
Prior transurethral resection of prostate (TURP) (particularly for salvage cryotherapy)
- –
PSA >20 ng/mL
- –
cT3 disease
- –
Prior pelvic surgery/trauma with distorted anatomy
Data from Miller DC, Pisters LL, Belldegrun AS. Cryotherapy for Prostate Cancer, Chapter 101. In: Wein AJ, Kavoussi LR, Novick AC, et al, editors. Campbell-Walsh Urology, 9th edition. Saunders, 2007.
Cryotherapy may offer certain advantages to patients with comorbidities that may preclude them from candidacy for RP or RT (eg, men with Crohn disease, ulcerative colitis, prior pelvic irradiation or pelvic surgery, cardiac disease, morbid obesity, or body habitus unfavorable for RP or RT). Finally, cryosurgery can also be considered in a salvage setting (ie, radiation failure) in patients who have negative metastatic workup.
Surveillance after cryotherapy
Generally, we follow patients with clinical examinations and serial PSA measurements every 3 months for the first year and then biannually thereafter along with routine biopsies. Initially following the procedure, serum PSA levels spike due to release of intracellular PSA from cellular necrosis. The PSA nadir is generally reached in 3 months. However, serum PSA levels after cryotherapy may not decrease to an undetectable level because of the necessary preservation of a thin rim of periurethral tissue for whole-gland ablation or from a more substantial spared portion of the gland with subtotal treatment. Although data have shown that a lower PSA nadir is associated with an increased chance of a stable PSA and negative biopsy (eg, residual cancer is found rarely among patients with a PSA nadir <0.5 ng/mL), the actual PSA nadir level that should be achieved after cryotherapy is unknown. There is no universally established definition of biochemical failure after cryotherapy. Some investigators use static PSA cutoffs, such as 0.3, 0.4, 0.5, and 1.0 ng/mL. The American Society for Therapeutic Radiology and Oncology (ASTRO) has put forth various definitions for biochemical failure: the traditional ASTRO definition of 3 consecutive PSA increases after the posttreatment nadir and the more recent Phoenix (ie, PSA nadir+2) definition for biochemical recurrence. Given this uncertainty, we strongly advocate performing routine prostate biopsy after cryotherapy to assess local control. If biopsies are considered, however, we recommend waiting approximately 6 months to allow for resolution of inflammation.
Primary cryotherapy
Following primary cryotherapy prostate biopsy has been routinely performed as part of a standard protocol 6 to 12 months after cryotherapy in a few studies; the positive biopsy rate ranges from 2% to 25%. Cohen and colleagues reported a 10-year positive biopsy rate of 23%. The investigators noted that higher baseline PSA levels and clinical T stage were independent risk factors for positive postcryosurgery biopsies. In a series of 168 men who underwent primary cryoablation with third-generation cryosurgical technology, Ellis and colleagues found that 10.1% of men had a positive biopsy at an average of 10 months postablation. Among a subset of 336 patients from the Cryo On-Line Data (COLD) Registry who underwent posttreatment biopsy, a positive biopsy rate of 38% (49/129) was observed for patients with evidence of biochemical recurrence, compared with only 14.5% (30/207) among patients with no clinical evidence for biochemical recurrence. These data underscore the important observation that rates of local control can vary significantly depending on whether biopsies are performed as part of a standard surveillance protocol (ie, independent of postcryotherapy PSA levels) compared with biopsy only in patients with a rising PSA after the procedure. In most series that have advocated routine postcryotherapy biopsies, positive biopsy rates are usually reported in less than 10% of patients treated with third-generation systems and a double freeze-thaw cycle. The areas of the prostate or seminal vesicles that have been reported to have the highest recurrence rates are at the apex and the seminal vesicles compared with the midgland and base because of their peripheral location.
Pathologists should be experienced in interpretation of prostate tissue that has undergone cryoablation. Pathologic findings include stromal fibrosis, hyalinization, basal cell hyperplasia with ductal and acinar regeneration, hemosiderin deposition, squamous metaplasia, and stromal hemorrhage ; coagulative necrosis is seen up to 30 weeks following treatment. Although there is no definitive method to evaluate tumor viability following cryoablation, keratin 34βE12, p63 (basal cell–specific markers), and racemase expression persist after cryoablation which may be of adjunctive value.
Biochemical Recurrence-Free Survival
In 2008, collaborators of the COLD Registry reported on pooled multicenter PSA outcomes for 2558 patients treated with primary whole-gland cryosurgical ablation. Among this large group of men, the 5-year actuarial biochemical recurrence-free survival was 83.7 (ASTRO definition) and 82.7% (Phoenix definition). When stratified according to D’Amico risk categories, 5-year biochemical recurrence-free survival rates (by ASTRO) were 89.2% for patients in the low-risk group, 83.7% for moderate-risk patients, and 80.2% for patients in the high-risk group. According to the Phoenix (nadir+2) definition, the corresponding rates were 84.3%, 79.0%, and 69.6% for low-, intermediate-, and high-risk groups, respectively. Cohen and colleagues reported long-term outcomes of approximately 200 men treated with cryoablation of the prostate from 1991 to 1996. Their reported 10-year PSA recurrence-free survival rates (Phoenix) were 80.6%, 74.2%, and 45.5% for low-, intermediate-, and high-risk groups, respectively. Variables that were significantly associated with postcryosurgery biochemical recurrence by multivariate analysis included patient age, pretreatment PSA, and the posttreatment PSA nadir. Similarly, Shinohara correlated the rate of biochemical and biopsy failure with the PSA nadir after cryotherapy in 132 patients. Biochemical failure was lowest in patients who achieved a PSA nadir of less than 0.1 ng/mL (21%). In addition, biopsy failure was rare in patients with a PSA nadir of less than 0.1 ng/mL (1.5%). Yet, among patients with a PSA nadir greater than 0.5 ng/mL, 55% had a positive follow-up prostate biopsy. The investigators observed that biochemical and biopsy failure usually occurred within the first 12 months after treatment (96% and 88% of biochemical and biopsy failures, respectively).
As noted in the AUA Best Practice Policy Statement of cryosurgery, to date, there are no long-term data for disease-specific or metastasis-free survival. Given this dearth of information, oncologic comparison between cryosurgery and other treatment modalities are limited.
Focal cryotherapy
Definition
The 2008 report from the Consensus Conference on Focal Treatment of Prostatic Carcinoma defined focal cryotherapy as “an individualized treatment that selectively ablates known disease and preserves existing functions, with the overall objective of minimizing lifetime morbidity without compromising life expectancy.” Focal therapy can involve the local application of treatment to a specific focus, and the term, “image-guided focal therapy,” is used when it is done under real-time imaging. Focal therapy has been further subdivided into hemiablation when treatment involves a complete lobe, and subtotal ablation when both lobes are targeted with the exception of a rim of parenchyma close to the neurovascular bundle(s) ( Fig. 3 ).
Patient Selection
Conceptually, prostate-sparing focal therapy has the advantages of treating the index lesion while minimizing morbidity that occurs with more radical treatments. Although this strategy is attractive to men with minimal disease who are concerned about potential over-treatment with RP or under-treatment as with active surveillance, at the present time it should be limited to patients who meet rigorous selection criteria. Although no universally accepted selection criteria currently exist, the 2008 Consensus Panel proposed several specific selection factors. Eggener and colleagues also suggested a comprehensive set of selection factors for focal therapy.
- •
≥5-year life expectancy
- •
The primary consideration for focal therapy is the location of the cancer
- •
Stage T1 to T3 disease: ablation of all known cancer is possible in a minimally morbid fashion
- •
PSA <15 ng/mL
- •
M1 disease is considered a contraindication
- •
Nodal involvement is a relative contraindication
Data from Babaian RJ, Donnelly B, Bahn D, et al. Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol 2008;180:1993–2004.
Clinical
- •
Clinical stage T1 or T2a
- •
PSA <10 ng/mL
- •
PSA density <0.15 ng/mL/cm 3
- •
PSA velocity <2 ng/mL yearly in the year before diagnosis
Biopsy
- •
Minimum of 12 cores
- •
No Gleason grade 4 or 5
- •
Maximum percentage of cancer in each core (eg, 20%)
- •
Maximum length of cancer in each core (eg, 7 mm)
- •
Maximum percentage of total cores with cancer (eg, 33%)
Imaging
- •
Single lesion with a maximum size (eg, 12 mm)
- •
Maximum length of capsular contact (eg, 10 mm)
- •
No evidence of extraprostatic extension or seminal vesicle invasion
Data from Eggener SE, Scardino PT, Carroll PR, et al. Focal therapy for localized prostate cancer: A critical appraisal of rationale and modalities. J Urol 2007;178:2260–7.
It has been shown in several studies that low-risk prostate cancers are unifocal in about 20% of cases at RP, a finding that provides a biologic basis for such a therapy. However, a major concern is our ability to accurately identify preoperatively the patients that harbor unilateral prostate cancer. Several studies have attempted to determine whether the prevalence of unifocal prostate cancer on RP specimens can be predicted by unilateral or unifocal prostate cancer at biopsy. Iczkowski and colleagues analyzed a series of 393 perineal RP specimens with preoperative biopsy (average of 11 cores) and observed that prostate cancers were unilateral in approximately 71% to 76% at prostatectomy when they were unilateral at biopsy. In addition, the ability of preoperative biopsy to assess unilaterality at prostatectomy correlated with the number of biopsy cores. Yoon and colleagues reviewed the prostatectomy specimens for which the preoperative biopsy predicted limited disease (Gleason score ≤6, <3 positive cores, <50% of cancer in any core). The investigators found 13% had a significant tumor (>0.5 cm 3 ) contralateral to the index tumor, half of which were located in the transition zone. At RP, 20% of the patients had an adverse pathologic feature on the contralateral side of the biopsy, described as tumor volume greater than 0.5 cm 3 , positive margin, extraprostatic extension, or Gleason score greater than 6. However, one limitation of that study was the lack of detail regarding the number of biopsy cores obtained preoperatively. The importance of accurately sampling the prostate has led some investigators to suggest a second biopsy or even saturation biopsies to reduce the risk of contralateral cancer at follow-up.
Outcomes of Focal Ablation
Table 1 summarizes the first pilot clinical trials of focal hemiablation for unilateral lesions and targeted cryoablation of a presumed unifocal lesion. In 2002, Onik and colleagues reported an initial pilot study of 9 men treated with focal, unilateral, nerve-sparing cryotherapy. Using this technique, they attempted to exploit the ability of cryotherapy to treat extracapsular extension while minimizing the sexual function morbidity associated with whole-gland ablation. At a mean follow-up of 36 months, all 9 men had stable PSA levels; the 6 patients who had posttreatment biopsies had no evidence of residual cancer. The same group reported more mature follow-up on a larger cohort of patients treated with focal ablation between June 1995 and December 2005. Before treatment, patients underwent three-dimensional mapping saturation rebiopsy. Approximately 50% of patients who were initially believed to have unilateral disease were found to have bilateral lesions and were excluded from the study. Although follow-up was short (mean 3.6 years), 95% had a stable PSA at last follow-up. The investigators determined that the postcryosurgery PSA stabilization level was at some fraction of the preoperative PSA level, depending on the extent of gland ablation; the mean preoperative PSA level for this cohort was 8.3 ng/mL, whereas the mean postoperative PSA was 2.4 ng/mL. Among the 4 patients noted to have an unstable PSA level in the first posttreatment year, prostate biopsy determined that each patient harbored cancer in an untreated portion of the gland. A subset of patients underwent routine biopsy at 1 year, all of which were negative. Although standardized questionnaires were not used, potency was reportedly maintained in 85% of patients. No patients developed de novo urinary incontinence.
| References | N | No. of bx Cores | Median FU (mo) | Cryounit | bDFS (%) | PSA Cutoff | Bx-proven Recurrence | Potency Preserved |
|---|---|---|---|---|---|---|---|---|
| Lambert et al | 25 | 12 | 28 | SeedNet b | 84 | <50% nadir, nadir+2 | 12% (8% untreated lobe, 4% treated lobe) | 71% |
| Bahn et al a | 31 | 6–12 | 70 | Cryocare c | 93 | ASTRO | 4% untreated lobe | 88.9% total (48.1% full recovery, 40.8% medically assisted) |
| Onik et al | 21 | 7–8 | 50 | Cryocare | 95 | ASTRO | 0 (1 case of CaP was found on MRIS in untreated lobe) | 80% |
| Ellis et al | 60 | ND | 12 | Cryocare | 80.5 | ASTRO | 23% d | 70.6% |
Related posts:
Prostate Cancer: To Screen or Not to Screen?
Chemoprevention of Prostate Cancer
Controversies Surrounding Lymph Node Dissection for Prostate Cancer
Neoadjuvant and Adjuvant Therapies in Prostate Cancer
Current Topics in the Treatment of Prostate Cancer with Low-Dose-Rate Brachytherapy
Immunotherapy for Prostate Cancer: An Emerging Treatment Modality
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
