Cryosurgery of the Prostate: Techniques and Indications

CRYOSURGERY AND BRACHYTHERAPY Cryosurgery of the Prostate: Techniques and Indications Jeffrey K. Cohen, MD Department of Urology, Allegheny General Hospital, Pittsburgh, PA Cryosurgical ablation of the prostate (CSAP) is indicated for patients with high-stage and high-grade tumors, patients with recurrent/persistent carcinoma of the prostate after external radiation therapy or brachytherapy, and others. At Allegheny General Hospital, CSAP is performed as follows: the patient is prepped in an exaggerated lithotomy position; a volumetric study of the gland is obtained with transrectal ultrasound; 5 to 15 cryoneedles are placed (in three to five horizontal rows) through a 17-gauge, stepper-mounted template; a cystoscopy is performed; and a urethral warming catheter is introduced. The rows of cryoneedles are then activated from anterior to posterior, and generally two freeze-thaw cycles are used. In longer glands, a pullback of the cryoneedles might be needed to completely cover the apical portion of the gland. The skills required for CSAP are identical to those required for brachytherapy needle placement, thus the training required for physicians already proficient in brachytherapy is minimized. [Rev Urol. 2004;6(suppl 4):S20–S26] © 2004 MedReviews, LLC Key words: Cryosurgery • Prostate cancer • 17-gauge cryoneedles • Indications he modern age of cryosurgery began in New York City when a neurosurgeon, Irving Cooper, tried to improve the life of patients with Parkinson’s disease.1 He used a liquid nitrogen-based system to eliminate the rigidity patients experienced by focally ablating brain tissue. Obviously, this predated the use of L-dopa. The use of hypothermic destruction demonstrated the concept of T S20 VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY Cryosurgery of the Prostate using a focally applied destructive force to improve patient quality of life. The concept was applied in many other disciplines, one of which was urology. In 1964, Gonder and collagues2 reported their work with cryosurgery to treat men with carcinoma of the prostate. A modified Van Buren Sound was attached to a liquid nitrogen delivery system. The probe was inserted transurethrally and positioned manually by palpating an identifying nodule on the probe and aligning it with what was felt to be cent tissues. A single-freeze technique was used with passive thawing that took 90 minutes to perform. The second improvement was the introduction of urethral preservation.6,7 Initially, this was performed with a continuous inflow of warm water supplied by positioning a flexible cystoscope at the external sphincter. Inflow was a continuous irrigation of warm water with outflow provided by a suprapubic cystostomy. A closed-loop, continuous-flow, temperature-controlled urethral catheter was developed, which When transperineal probe placement was combined with urethral preservation, the complication of sloughing decreased from almost 100% to less than 10%. the prostatic apex. Unfortunately, the complication of urethral sloughing doomed the procedure to historical relevance yet the concept mirrored Irving Cooper’s work. Development of the Cryoablation Technique In 1988, the concept of hypothermicinduced, localized tissue destruction was married to a real-time imaging technique, ultrasound.3 Animal studies ensued, and the first patient was treated at Allegheny General Hospital in Pittsburgh, PA in June 1990. The ability to observe probe placement and the destructive process with ultrasound was a major step forward. Once tissue temperature dropped below 4ºC, the intra- and extracellular water froze and reflected sound as it changed from a liquid to a solid.3 Two other adaptations minimized sloughing, thus making the procedure acceptable. The first improvement was probe placement. Multiple 3-mm liquid nitrogen probes were placed transperineally into the prostate under ultrasonic visualization.4,5 Accurate placement avoided direct damage to the urethra and adja- replaced the cystoscope. When activated, the irrigant distended a long, thin-walled balloon that coapted to the urethra. The warm fluid transmitted heat to the urethral mucosa, thereby preserving it. When transperineal probe placement was combined with urethral preservation, the complication of sloughing decreased from almost 100% to less than 10%.6 This improvement made the procedure more acceptable to both patients and physicians. These technical advances ushered in the modern era of cryosurgical ablation of the prostate (CSAP). Yet the primary concept, as demonstrated by Cooper and Gonder and colleagues, remains the use of a locally applied destructive force to improve an outcome. CSAP of today evolved over the last 2 decades, from the application of a single, first-generation (liquid nitrogen) cryoprobe, through the placement of multiple second-generation, gasdriven, large-diameter cryoprobes, to the placement of multiple-array, thirdgeneration, 17-gauge CryoNeedlesTM (Oncura, Inc., Plymouth Meeting, PA) (Figure 1). Currently, in a typical CSAP at our facility, we prep the Figure 1. A single 17-gauge (1.47 mm in diameter) CryoNeedleTM (Oncura, Inc., Plymouth Meeting, PA). Image courtesy of Oncura, Inc. patient in an exaggerated lithotomy position, obtain a volumetric study of the gland with transrectal ultrasound, place 5 to 15 cryoneedles (in three to five horizontal rows) through a 17-gauge, stepper-mounted template (Figure 2), perform a cystoscopy, and introduce a urethral warming catheter. We then activate the rows from anterior to posterior, and generally two freeze-thaw cycles are used. In the longer glands, a pullback of the cryoneedles might be needed to completely cover the apical portion of the gland. Evolution and Results of CSAP To prove efficacy and attempt to Figure 2. Typical placement of 17-gauge CryoNeedles. Image courtesy of Oncura, Inc. VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S21 Cryosurgery of the Prostate continued S22 VOL. 6 SUPPL. 4 2004 Table 1 Negative Biopsy After One CSAP Treatment Patients Having a Posttreatment Biopsy (%) Negative (%) Overall 70 Before 1996 65 65 1996 and onward 85 71 CSAP, cryosurgical ablation of the prostate. Data abstracted from the Allegheny General Hospital (Pittsburgh, PA) 10-year CSAP database. treatment biopsies demonstrated total fibrosis of the prostate. Residual carcinoma on biopsy directly correlated with the percentage of residual glandular elements on biopsy. Distant microscopic disease could only be inferred by the PSA level and lack of demonstrable local UPGE. In 1997, Partin and colleagues11 published their work correlating positive margins in RRP patients to preoperative PSA level, digital rectal examination (DRE) results, and initial Gleason score; those findings helped us base predictions of risk of extraprostatic disease on the patient’s initial presentation. PSA levels and biopsy results, although related, had somewhat independent outcomes based on the initial presentation and the success of local treatment. By 1994, CSAP was being used for multiple presentations of carcinoma of the prostate. Complications of CSAP When Gonder and colleagues2 initially applied transurethral cryosurgery, the high frequency of complications led to abandoning the procedure. Similarly, transperineal CSAP was Figure 3. Kaplan-Meier survival curve using disease-free survival definition of positive and negative biopsy results. 1.1 1.0 0.9 0.8 Proportion recurrence-free compare CSAP with the dominant treatment modalities of the early 1990s (radical retropubic prostatectomy [RRP] and external radiation therapy [XRT]), posttreatment biopsies were obtained from areas in and around the prostate. Unpublished data from Allegheny General Hospital demonstrated that the posttreatment negative biopsy rate at 10 years was approximately 70%. Interestingly, we also found that if a patient has a posttreatment positive biopsy, it will occur during the first 24 months after treatment (Figure 3). We assessed biopsy results for the years before 1996 and from 1996 and beyond and found that the use of better equipment resulted in negative biopsy rates increasing from 70% to 85% (Table 1). These biopsy samples were obtained from the prostate, seminal vesicles, and periprostatic tissues, from patients with all stages, grades, and complications from prior treatments. Specifically, patients had bulky local disease, high-grade disease, biopsy-proven recurrences after XRT, and local recurrences after RRP. If the area could be visualized by ultrasound, probes were placed and the area treated. Success rates were based on longitudinal prostate-specific antigen (PSA) levels and biopsy results at 3 months, 1 year, and 5 years.4,5,7,8 As we gained experience, success with a single liquid nitrogenbased freeze correlated with PSA levels (Figure 4). Successful local therapy resulted in a PSA level of less than 0.4 ng/mL, with the posttreatment biopsy showing tissue fibrosis. Conversely, a rising or persistent PSA level after treatment indicated either local or distant glandular PSA-producing elements. PSA failures correlated with unaltered prostatic glandular elements (UPGE) on biopsy.9,10 The presence of glandular elements was the result of technical failures. There were no local failures if the post- REVIEWS IN UROLOGY 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 60 72 84 96 Recurrence-free survival time to positive biopsy (months) 108 120 Cryosurgery of the Prostate A 1 PSA level (ng/mL) 0.8 (0.57) 0.6 (0.56) 0.4 0.2 Previous XRT & hormone ablation Previous XRT only 0 0 12 24 36 48 60 72 84 96 108 120 Time (months) 1 B 0.8 PSA level (ng/mL) (0.68) 0.6 (0.63) (0.50) 0.4 High-risk group 0.2 Intermediate-risk group Low-risk group 0 0 12 24 36 48 60 72 84 96 108 120 132 Time (months) 1 C 0.8 (0.63) PSA level (ng/mL) evaluated first by the rate of complications encountered and then by its lack of efficacy. The major complications of CSAP from 1990 to 1994 were incontinence, sloughing, and fistula formation7 (Table 2). Impotence occurred in almost all men who were treated with CSAP and became an inevitability of the procedure. For some younger men, however, erectile function was regained 2 years after treatment. Incontinence was divided into total and urge-related events. The rate of total incontinence was similar to the results reported for RRP and XRT at the time (< 5%).12 The rate of urge-related incontinence was approximately 25% in patients who underwent CSAP, comparable to the rate in similar groups of patients undergoing RRP and less than the rate for those undergoing XRT.12 Anecdotal reports of high rates of incontinence paralleled the results of inexperienced physicians delivering both XRT and RRP. All three modalities had a wide range of reported outcomes, which were related to the training and performance levels of the physician. Rates of sloughing of the urethra were stable at 8% until mid 1994 when the US Food and Drug Administration removed the warming catheter from the market.7 The catheter was made available once again approximately 18 months later because the rates of sloughing had increased to 70%. Once reintroduced to the market and to practice, the sloughing level decreased, returning to the pre 1994 level of 8%.6 Rectal fistulas resulted from transmural freezing of the bowel wall. Two factors accounted for this outcome; inadequate ultrasound equipment and inadequate experience with prostate ultrasound. The predominant equipment available in 1990 consisted of mechanical sector scanners with 5- to 7.5-MHz crystals. 0.6 (0.62) (0.49) 0.4 0.2 High-risk group Intermediate-risk group Low-risk group 0 0 12 24 36 48 60 72 84 96 108 120 Time (months) Figure 4. 10-year prostate-specific antigen (PSA) trends in all patients treated with cryoablation with first-, second-, and third-generation devices (A) after external radiation therapy (XRT) with and without hormonal deprivation therapy, (B) after hormonal deprivation therapy, and (C) with no previous therapy. Success was measured as nadir PSA level < 0.4 ng/mL, and failure was defined as two consecutive rises in PSA level of 50% or more. VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S23 Cryosurgery of the Prostate continued Table 2 Complications of CSAP with First-, Second-, and Third-Generation Equipment Complications Sloughing First and Second Generation* Pre-1996 (%) 16 First and Second Generation* 1996–2001 (%) 14 Third Generation† After 2001 (%) 2 Incontinence 8.6 3.2 0 Fistulas 2 0 0 Prostate stone 3 4 0 CSAP, cryosurgical ablation of the prostate. *CMSI/Endocare, n = 865. † Oncura, n = 98. Data abstracted from Allegheny General Hospital (Pittsburgh, PA) 10-year CSAP database. Although adequate for a biopsy, this equipment did not give a longitudinal view of the rectal wall sufficient to visualize an iceball of 3 cm. The introduction of 4-cm, 7.5-MHz longitudinal piezoelectric crystals minimized this problem. The second issue, ie, inadequate experience, reflects the difficulty in mastering this technique even today. Most fistulas developed among the physician’s first 25 patients. For physicians who had successfully completed 25 cases, the frequency of rectal fistulas approached the level identified for RRP or XRT. The set of skills required to perform transrectal ultrasoundguided biopsy is not identical to CSAP, and the erroneous assumption that these skills are similar or that CSAP could be performed by an ultrasound technician led to bowel injury and fistula formation. The initial goal of CSAP was to provide an effective alternative treatment for patients with prostate cancer while avoiding the complications of RRP and XRT. Specifically, the hemorrhage rate and length of hospital stays associate with RRP and the length of treatment and cystitis/proctitis rates associated with XRT were to be avoided. The technical achievements of intensity-modulated radiation therapy (IMRT) have decreased radiation cystitis/proctitis rates from 12% to 2%. Surgeons performing high volumes of RRP report transfusion rates of less than 10%, and length of hospital stays of just 2 days. Outcomes associated with CSAP have also improved, with sloughing rates dropping from 8% to 2% and total urinary incontinence becoming a rare event (< 1%) when CSAP is performed by an experienced physician (Table 2). Indications for Cryosurgery Throughout the evolution of CSAP, we have identified patients best and least suited for the procedure. Even with the above-mentioned improvements, the indications for CSAP have remained constant at our institution and include: Main Points • In 1988, the concept of hypothermic-induced, localized tissue destruction was married to a real-time imaging technique, ultrasound. The ability to observe probe placement and the destructive process with ultrasound was a major step forward for cryosurgical ablation of the prostate (CSAP). • Cryosurgical equipment has evolved from using liquid nitrogen to using compressed helium and argon gases. The advantage of the compressed gases is that with argon multiple, smaller-diameter probes (cryoneedles) can be used to sculpt the target with ice, and with helium the frozen probes can be actively thawed. • An evaluation of biopsy results at Allegheny General Hospital (with samples obtained from the prostate, seminal vesicles, and periprostatic tissues, from patients with all stages, grades, and complications from prior treatments) showed that with improvements in cryosurgical equipment, the negative biopsy rate increased from 70% to 85%. • With improvements in CSAP equipment and techniques, sloughing rates have dropped from 8% to 2%, and total urinary incontinence is a rare event (< 1%) when CSAP is performed by an experienced physician. • The best patients for CSAP are those with bulky local disease, high-grade disease, and local recurrence after radiation therapy. The patients not well suited for CSAP are those with prior transurethral resection of the prostate. • Training remains the single biggest issue related to obtaining good results with CSAP. The skills required for the placement of cryoneedles are identical to those required for brachytherapy needle placement; thus, the training required for physicians already proficient in brachytherapy is minimized. S24 VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY Cryosurgery of the Prostate 1. High-stage tumors. If the initial stage of the tumor is cT2b or more, the chance of margin involvement is significant. Anatomic prostatectomy with sacrifice of the neurovascular bundle is feasible and widely performed. Neoadjuvant hormonal therapy with XRT is also feasible. CSAP is effective in controlling local disease because of its ability to freeze tissue outside the surgical margins. Real-time control with ultrasound is superior to IMRT, which at best is abstracted from prior computed tomographic alignments or pretreatment ultrasound measurements. Preoperative lower urinary tract voiding symptoms are relieved by CSAP as opposed to IMRT. Finally, CSAP is a 1-day treatment that allows a rapid return to work. CSAP is an effective and minimally invasive way to control local disease for patients with high-stage disease. 2. High-grade tumors. Biopsy specimens with Gleason patterns 4 and 5 are difficult to eliminate owing to radioresistance and early extraprostatic spread. Local control with RRP or CSAP can be achieved, with systemic treatment being reserved for those who demonstrate need. The ability to gain local control with a 1-day, minimally invasive treatment remains a benefit of CSAP as opposed to RRP. 3. Recurrent/persistent carcinoma of the prostate after XRT or brachytherapy. The two options for definitive treatment are RRP or CSAP. RRP carries with it a significant risk of complications, specifically incontinence and rectal injury. The risk of incontinence with CSAP remains 2%, and rectal injury is rare with an experienced physician. The 10year undetectable PSA response is approximately 60% (Figure 4A). Clearly, CSAP is the best modality for patients who have failed radi- ation therapy. Early detection of failure is a key to overall success. PSA postradiation levels do not always correlate with a lack of residual disease. Evaluation should not be conducted until at least 18 months after treatment with radiation. If the DRE is abnormal or the PSA level has not dropped to less than 1.5 ng/mL, then biopsies should be performed. Even patients with PSA levels of 1.0 ng/mL can have extensive local disease. When biopsies are performed on treatment and CSAP will eliminate the symptoms. • Patients who need persistent anticoagulation; the risk of radiation proctitis/cystitis, although small, still remains. For patients needing continuous anticoagulation, CSAP is an effective alternative. Relative Contraindications for CSAP The largest group of patients who are not good candidates for CSAP is comprised of patients who have under- Clearly, cryosurgical ablation of the prostate is the best modality for patients who have failed radiation therapy. postradiation patients, the seminal vesicles should be sampled because the disease is commonly present. Once disease is identified, it helps to taper treatment with CSAP. Prior brachytherapy increases the difficulty in visualizing the prostate with ultrasound, owing to the multiple echoes created by seeds. Although not a contraindication, this difficulty requires significant experience to safely place probes and follow treatment with CSAP. 4. Other indications. CSAP is also indicated for the following patients: • Patients who have undergone prior radiation therapy for rectal carcinoma. • Patients who are Jehovah’s Witnesses; need for transfusion is a rare event, and to date we have not transfused anyone. • Patients who have undergone prior abdominoperineal resection; visualization can be obtained with a 7-MHz convex biopsy probe. • Patients who are nonsurgical candidates with significant lower urinary tract symptoms; the irritative effects of XRT/brachytherapy can be debilitating after gone prior transurethral resection of the prostate (TURP). The sloughing rate in these patients is higher than in nonresected patients, in part because of the inability to adequately warm the urethral lumen. Coaptation of the warming catheter to urethral mucosa is not complete because of the luminal defect created by the TURP. Training for Cryoablation Training remains the single biggest issue related to obtaining good results with CSAP. Two components of CSAP that have improved are ultrasonic visualization and the cryosurgical equipment. CSAP and brachytherapy have stimulated the development of ultrasound equipment. To perform either procedure well, it is necessary to have a biplanar piezoelectric ultrasound probe with 5- to 7.5-MHz transducers. The longitudinal probe should be at least 4 cm long. It is a clear violation of the standards of care to perform these procedures with equipment that does not meet these standards. Visualization of the near field, specifically the anterior rectal wall, cannot be compromised by inadequate equipment because such com- VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S25 Cryosurgery of the Prostate continued promising leads to rectal injury. Cryosurgical equipment has evolved from using liquid nitrogen to using compressed helium and argon gases. The advantages of using these compressed gases are that argon permits the use of multiple smaller-diameter probes (cryoneedles) to sculpt the target with ice, and helium permits the frozen probes to be actively thawed.13 Cessation of argon gas-flow and the activation of active warming limits iceball growth, thus increasing the level of control and shortening the procedure time.14,15 The 17-gauge, template-based CryoNeedles (Figures 1 and 2) are placed similarly to brachytherapy needles.13 The skills required for the placement of these cryoneedles are identical to those required for brachytherapy needle placement, thus the training required for physicians already proficient in brachytherapy is minimized. Summary CSAP is an effective and safe procedure that can treat and eliminate carcinoma of the prostate in a minimally invasive fashion. The best patients for S26 VOL. 6 SUPPL. 4 2004 this procedure are patients with bulky local disease, high-grade disease, and local recurrence after radiation therapy. The patients not best suited for CSAP are those with a prior TURP. The equipment needed to perform CSAP has been simplified, which shortens the learning curve and minimizes complications. Active warming with helium gas has also shortened the time needed to perform the procedure. Future progress will continue to improve the results associated with and shorten the time required to perform CSAP. 7. 8. 9. 10. 11. References 1. 2. 3. 4. 5. 6. REVIEWS IN UROLOGY Cooper I, Lee A. Cryostatic congelation. A system for producing a limited controlled region of cooling or freezing of biological tissue. J Nerv Ment Dis. 1961;133:259–266. Gonder M, Sloanes W, Smith V. Experimental prostate cryosurgery. Invest Urol. 1964;1:610619. Onik G, Cobb C, Cohen J, et al. US characteristics of frozen prostate. Radiology. 1988;168:629-631. Wong WS, Chinn DO, Chinn M, et al. Cryosurgery as a treatment for prostate carcinoma. Results and complications. Cancer. 1997;79:963-974. Chin JL, Downey DB, Mulligan M, Fenster A. Three-dimensional transrectal ultrasound guided cryoablation for localized prostate cancer in non surgical candidates. A feasibility study and report of early results. J Urol. 1998;159:910-914. Cohen JK, Miller RJ. Thermal protection of ure- 12. 13. 14. 15. thra during cryosurgery of the prostate. Cryobiology. 1994;31:313-316. Cohen JK, Miller RJ, Shuman BA. Urethral warming catheter for use during cryoablation of the prostate. Urology. 1995;45:861-864. Koppie TM, Shinohara K, Grossfeld GD, et al. The efficacy of cryosurgical ablation of prostate cancer: the University of California, San Francisco experience. J Urol. 1999;162:427432. Long JP, Fallick ML, LaRock DR, et al. Preliminary outcomes following cryosurgical ablation of the prostate in patients with clinically localized prostate carcinoma. J Urol. 1998;159:477-484. Derakhshani P, Neubauer S, Braun M, et al. Cryoablation of localized prostate cancer. Experience in 48 cases, PSA and biopsy results. Eur Urol. 1998;34:181-187. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997;277: 1445-1451. Long JP, Fallick ML, LaRock DR, et al. Preliminary outcomes following cryosurgical ablation of the prostate in patients with clinically localized prostate carcinoma. J Urol. 1998; 159:477-484. Han KR, Belldegrun AS. Third-generation cryosurgery for primary and recurrent prostate cancer. BJU Int. 2004;93:14-18. Zisman A, Pantuck AJ, Cohen JK, Belldgerun AS. Prostate cryoablation using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template—technique and preliminary results. Urology. 2001;58:988-993. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with 3rd generation cryosurgery: preliminary multi-center experience. J Urol. 2003;170:1126-1130.