Prostate cryotherapy: More questions than answers

Prostate cryotherapy: More questions than answers

REVIEW PROSTATE CRYOTHERAPY: MORE QUESTIONS THAN ANSWERS GREGORY S. MERRICK, KENT E. WALLNER, B ecause of the absence of prospective randomized tri...

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REVIEW

PROSTATE CRYOTHERAPY: MORE QUESTIONS THAN ANSWERS GREGORY S. MERRICK, KENT E. WALLNER,

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ecause of the absence of prospective randomized trials comparing the relative efficacy of various local treatments, the management of clinically localized prostate cancer remains one of the most controversial topics in oncology. Radical prostatectomy (RP), external beam radiotherapy (EBRT), and brachytherapy (BT) represent universally accepted local approaches. Recently, cryotherapy has been resurrected as an additional potential treatment option.1 This resurgence of interest in cryotherapy reflects increased interest in less-invasive forms of therapy and has been facilitated by a better understanding of cryobiology, improved cryotechnology, and a perception among some that the currently accepted treatment options are of suboptimal efficacy and/or significant morbidity.1– 4 Cryotherapy induces cell death by two main mechanisms: direct cellular toxicity from disruption of the cellular membrane by iceball crystals and vascular compromise from thrombosis and ischemia.5 The degree of cell destruction is dependent on rapid freezing, the lowest temperature achieved, and slow thawing and is maximized by two or more freeze-thaw cycles.5–9 During the initial freeze cycle, the complete eradication of malignant cells requires a minimal freezing temperature of ⫺40°C for at least 3 minutes.5,8 Tatsutani et al.10 demonstrated that complete cell death was unlikely at temperatures greater than ⫺20°C; temperatures less than ⫺40°C were required to destroy cells.10 However, cells not destroyed by initial freezing to ⫺20°C were eradicated with a second freeze cycle.10 Cryosurgery was first used in the treatment of G. S. Merrick is a study investigator funded in part by Theragenics Corporation. From the Schiffler Cancer Center, Wheeling Hospital; Wheeling Jesuit University, Wheeling, West Virginia; Puget Sound Healthcare Corporation; Group Health Cooperative; and University of Washington, Seattle, Washington Reprint requests: Gregory S. Merrick, M.D., Schiffler Cancer Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV 26003-6300. E-mail: [email protected] Submitted: September 29, 2004, accepted (with revisions): December 15, 2004 © 2005 ELSEVIER INC. ALL RIGHTS RESERVED

AND

WAYNE M. BUTLER

prostate cancer in 1968 with the advent of probes cooled by liquid nitrogen in a closed circulation system.11 First-generation cryosurgery was performed without transrectal ultrasound guidance or urethral warmers and was plagued by significant complications, including urinary incontinence, urethral sloughing, and rectourethral fistulas.5,6 These complications were attributed to a lack of accurate monitoring of the freezing process. Second-generation cryosurgery witnessed the development and implementation of transrectal ultrasound guidance and urethral warmers.5,8 Ultrasound guidance allowed for accurate probe placement and real-time monitoring, and urethral warmers decreased the risk of urethral sloughing. Most recently, the implementation of gas-driven probes in which pressurized gas is used to both freeze (argon gas) and actively thaw (helium gas) using the Joule-Thompson effect heralded the development of third-generation cryosurgery.5,6 The transition from liquid to gas permitted the use of smaller diameter probes (ie, 17-gauge cryoneedles) and facilitated a more conformal cryosurgical approach secondary to the placement of a greater number of probes.5,6 The goals for all minimally invasive prostate cancer therapies include eradication of local disease, a shorter recuperative period, minimal postoperative morbidity, and a reduction in overall cost.1 Although cryotherapy has the proven ability to ablate malignant and benign cells, it has not yet been established whether the prostate gland represents an ideal organ for cryoablative therapy. Although long-term results (ie, longer than 10 years) are available for RP, EBRT, and BT, minimal detailed information exists regarding optimization of the cryoablative technique. Long-term biochemical control and quality-of-life outcome data for a significant number of patients will not be available for at least another 5 years. Before the routine use of cryosurgery as a mainstream treatment of prostate cancer, questions regarding technique, patient selection, thermal dosimetry, local control rates, and morbidity should be addressed. UROLOGY 66: 9 –15, 2005 • 0090-4295/05/$30.00 doi:10.1016/j.urology.2004.12.039 9

IS CANCERICIDAL DOSIMETRY ACHIEVED WITH PROSTATE CRYOTHERAPY? Urethral preservation is critical to prevent morbidity in patients treated with cryosurgery. The use of prostate parenchyma-sparing urethral warming devices has reduced the incidence of incontinence, urethral sloughing, and irritative voiding symptoms.12 In addition, the implementation of thermocouples to monitor temperatures at specific sites has improved tolerance and intraoperative monitoring during prostate cryotherapy. To ensure preservation of urethral function, a urethral warmer at a temperature of approximately 38°C should be used before, during, and after cryosurgery.13 In addition, four to six thermocouples are routinely placed in the region of the neurovascular bundles, apex, and Denonvilliers space.13 Typically, a double freeze-thaw technique is used; this includes freezing the neurovascular bundles to ⫺40°C, and the apex to a temperature of approximately ⫺10°C (greater than the ⫺20°C needed for cell death).13 The freezing cycle is complete when all prostatic tissue has been frozen as visualized on ultrasonography.13 However, Saliken and colleagues14 reported that “ultrasound provides no information about the temperature distribution within the ice, nor does it show the extent of freezing at the lateral or anterior aspects of the prostate,” and thermocouple-based dosimetry represents isolated “point” temperatures without providing information regarding temperature distributions throughout the target volume, with a resultant false sense of security regarding the actual temperature “dose cloud.” Specifically, blood vessels may act as “heat sinks,” with adjacent areas not achieving target temperatures, even though they are completely encompassed within the ultrasound target volume.15 “Modifications designed to reduce temperature side effects could conflict with efforts designed to improve eradication of prostate cancer.”16 In a review of Mayo Clinic RP specimens, it was demonstrated that the mean distance from the urethra to the nearest foci of cancer was 3 mm, with 17% of cancers abutting the urethra. A second study documented that 66% and 45% of prostate cancers were within 5 mm and 1 mm of the urethra, respectively.16,17 The urethra-cancer distance correlated with the preoperative prostate-specific antigen (PSA) level, biopsy Gleason score, biopsy Gleason grade 4 or 5, apical location of the prostate cancer, transition zone cancer, and greater prostate cancer volumes.16,17 Apical prostate cancer was present in 74% of the surgical specimens and was more likely to have a shorter urethra-cancer distance.17 Although sparing of periurethral tissues from cryoablation may affect the therapeutic efficacy of 10

the procedure, the optimal warming regimen remains unknown.18 To date, no studies have determined the volume of periurethral tissue that must be spared from freezing, and no data exist regarding the depth of penetration of the urethral warmer. During transurethral microwave hyperthermia, Larson et al.19 demonstrated that urethral cooling resulted in sparing tissue from necrosis for a distance of 5 mm from the urethral mucosa. In conjunction with the Mayo Clinic RP data, this suggests that periurethral prostate cancer may be “spared” in as many as 84% of patients treated with a urethral warming device.17,19 Because the incidence of periurethral and apical malignancy is high, it is likely that the currently accepted thermographic dose distributions at the periurethral and apical locations may result in a “cancer-sparing” procedure in which prostate cancer cells may be “stunned,” but not eradicated and may likely represent a source of late prostate cancer failure. Future research must evaluate the depth of tissue penetration by the urethral warmer, the absolute minimal temperature and duration necessary for urethral preservation, and the potential integration of combined modality therapies (ie, chemical sensitization/protection and/or biologic response modifiers) to minimize the need for urethral warming. In addition, the development of cryotechnology to measure temperature distributions throughout the target volume and not just at specific points will significantly improve dosimetric evaluation. DOES THE CURRENTLY AVAILABLE CRYOABLATIVE TECHNIQUE RESULT IN OBLITERATION OF MALIGNANT AND BENIGN ELEMENTS WITHIN THE PROSTATE GLAND? After cryosurgical ablation, few studies have evaluated the long-term histopathologic findings. Residual malignant cells have been reported in 7% to 23% of patients, with focal areas of viable benign glands present in 45% to 70% of patients.15 In patients receiving neoadjuvant androgen deprivation therapy (ADT) in conjunction with salvage cryotherapy for biopsy-proven EBRT failure, residual prostate cancer, viable benign prostate glands, and viable stroma were present in 14%, 42%, and 27% of the specimens, respectively.20 These bothersome follow-up biopsy results were demonstrated despite an inadequate biopsy core technique (four core) and likely underestimated the actual incidence of residual malignancy.20,21 In two contemporary cryosurgical series, positive biopsies were documented in 13% and 18% of patients after definitive cryosurgery with or without ADT.22,23 Although an attractive aspect of cryotherapy is the ability to repeat the procedure in the presence of UROLOGY 66 (1), 2005

biopsy-proven residual disease, to date the available data have not supported the contention that prostate cryosurgery is an ablative process. It is possible that modifications in the cryotherapeutic procedure, including a greater number of freezethaw cycles and placement of additional cryoprobes/needles, may enhance the cryoablative process. ARE ALL REGIONS TREATED ADEQUATELY? Periurethral and apical cancers are the rule, rather than the exception, and are especially common in patients with higher risk features.16,17 After second-generation cryosurgery, persistent or residual cancer was most likely to be detected in either the apex (10%) or seminal vesicles (44%) compared with the mid-gland (4%) or base (0%).24 Although third-generation cryotherapy results are not yet available, more inclusive cytotoxic iceball thermographic distributions may be possible with the use of multiple cryoneedles and pull-back procedures in prostates longer than 27 mm, with a resultant decrease in geographic misses.25 DOES CRYOTHERAPY ADEQUATELY TREAT THE PERIPROSTATIC REGION? Inadequate periprostatic dose distributions may represent an additional source of possible late prostate cancer failure. During active cryoablation, iceballs are normally extended 2 to 4 mm beyond the capsule, with the posterior iceball extended into, but not beyond, the rectal muscularis propria.15 The hyperechoic edge of the iceball visualized on ultrasonography has a temperature of 0° to ⫺2°C, with temperatures of ⫺20° to ⫺40°C located approximately 3.1 mm inside the iceball.26 As such, it is likely that the prostate gland is frozen with little, if any, margin, which is particularly important in patients with a significant risk of extracapsular extension. Previous RP studies have demonstrated that 99% of extracapsular extension is limited to within 5 mm of the prostatic capsule.27 Future studies should target temperature gradients in the immediate periprostatic region to determine whether cryosurgery is, and/or can be, safely administered with 5-mm periprostatic margins. CAN CRYOSURGICAL ABLATION BE SAFELY COMBINED WITH SUPPLEMENTAL THERAPIES TO TREAT REGIONAL LYMPH NODE INVOLVEMENT? Although pelvic lymph node dissection is often recommended for high-risk patients, those patients remain at significant risk of locoregional failure even if the resected lymph nodes are free of UROLOGY 66 (1), 2005

metastatic involvement.15 For high-risk patients, cryotherapists have relied on neoadjuvant ADT with or without pelvic lymph node dissection to address locoregional disease. However, prospective randomized trials evaluating the impact of neoadjuvant ADT before RP have not demonstrated any significant reduction in either seminal vesicle or pelvic lymph node involvement after such therapy.28 In contrast, the results of prospective randomized trials evaluating pelvic radiotherapy combined with ADT in high-risk patients have strongly suggested a synergistic effect between the two modalities.29 Roach and colleagues29 reported that in patients with a 15% or greater incidence of pelvic lymph node involvement, optimal diseasefree survival included a regimen of neoadjuvant ADT and pelvic radiotherapy. For cryotherapy to address locoregional concerns adequately in patients with higher risk features, studies to evaluate the efficacy and morbidity of neoadjuvant ADT, pelvic radiotherapy, and cryotherapy are warranted. WHAT IS THE MOST APPROPRIATE DEFINITION OF FREEDOM FROM BIOCHEMICAL PROGRESSION? Unlike after RP, the PSA level does not immediately decline to undetectable levels after cryotherapy. In addition, periprostatic PSA-producing cells remain viable and, as such, detectable PSA values can be expected. Akdas et al.30 demonstrated that a PSA level of 0.4 ng/mL is expected when 1 g of prostatic tissue has been preserved in men free of prostate cancer. After cryosurgery, the PSA nadir occurs at 3 months, with a nadir of 0.4 ng/mL or less associated with superior biochemical outcome.24,31 Multiple biochemical progression-free definitions for cryosurgery have been proposed, including the American Society for Therapeutic Radiology Oncology (ASTRO) consensus definition and PSA cutpoint definitions of 0.4 ng/mL or less, 0.5 ng/mL or less, and 1.0 ng/mL or less.13,22,24,25 In particular, the ASTRO consensus definition is not suitable for treatments that result in an early PSA nadir and in fact has only been validated for EBRT. The various biochemical disease-free survival definitions used after cryotherapy have resulted in markedly divergent biochemical control rates and have made multi-institutional comparisons questionable. The impact of various biochemical definitions is well illustrated by a review of an oftencited multi-institutional study in which 92% of the 590 patients received 3 to 12 months of ADT in combination with cryotherapy.22 With a median follow-up of 5.7 years, the 7-year biochemical progression-free survival rate for patients with low11

TABLE I. Cryotherapy complications by treatment type (primary or salvage) and by technology generation Primary Cryotherapy Complication Impotence Incontinence* Urethral sloughing Pelvic pain Paresthesias Scrotal edema Rectourethral fistula

Salvage Cryotherapy

Second Generation15 (%)

Third Generation25 (%)

Second Generation15 (%)

Third Generation25 (%)

40–95 4–27 4–23 1–11 2–10 0–5 0–3

87 8 5 6 2 2 0

⬃100 20–73 5–44 21–77 6–10 0–11 0–11

86 17 11 6 6 11 0

* Included urge incontinence for third-generation approaches.

risk prostate cancer (PSA level 10 ng/mL or less and Gleason score 6 or less and clinical Stage T2a or less) was 61%, 87%, and 92% using the biochemical progression-free definitions of PSA level of 0.5 ng/mL or less, PSA level of 1.0 ng/mL or less, and the ASTRO consensus definition, respectively.22 Comparable ranges in biochemical outcomes were reported for both intermediate-risk (PSA level greater than 10 ng/mL or Gleason score 7 or more or clinical Stage T2b or greater) and high-risk (two or three adverse features) patients. An unexplained observation was the relative lack of influence of risk group on biochemical outcome. Using a PSA cutpoint of 0.5 ng/mL or less, the biochemical disease-free survival rate was 61%, 68%, and 61% for low-risk, intermediate-risk, and high-risk groups.22 In a prospective second-generation cryosurgical study, Aus and colleagues32 reported that only 39% of patients remained free of biochemical progression at 5 years (failure was defined as either a positive posttreatment biopsy or PSA level greater than 1.0 ng/mL). Most disturbing was that only 30% of patients with low-risk features remained free of biochemical failure. After third-generation cryotherapy with a minimum of 12 months of follow-up, Han and colleagues25 reported that 78% of low-risk patients remained free of biochemical failure (PSA level 0.4 ng/mL or less). Because of the short follow-up and that 37% of these patients received ADT, their reported biochemical control rates were unrealistically optimistic. In addition, only 71% of a combined intermediate and high-risk group remained free of biochemical failure at 12 months. In our opinion, a PSA level of 0.4 ng/mL or less should be adopted as the standard definition of biochemical success after cryotherapy. Using such a definition, the biochemical outcomes after second-generation and third-generation cryosurgery (even in patients receiving ADT) compare unfavorably to those reported in the vast majority of the RP or BT studies.33 After either RP34 or BT, using a PSA 12

biochemical failure cutpoint of 0.4 ng/mL or less,35 biochemical progression-free survival rates in excess of 90% have been reported for low-risk hormone-naive patients. Unlike cryotherapy, highquality BT results in comparable biochemical outcomes whether a PSA cutpoint of 0.4 ng/mL or less or the ASTRO consensus definition is used.35 With long-term follow-up, biochemical diseasefree survival rates in excess of 80% have been reported for intermediate and high-risk patients undergoing BT.36,37 CAN CRYOTHERAPY SALVAGE RADIORECURRENT PROSTATE CANCER? After biopsy-proven local failure, the absence of adequate molecular markers and/or sensitive imaging modalities precludes the ability to select accurately the patients most appropriate for salvage therapy. Although it is impossible to determine with certainty whether the biochemical relapse is due to local and/or distant failure, the posttreatment PSA doubling time is a documented predictor of disease-specific survival.38,39 Patients who are most likely to require therapy are the ones least likely to benefit from a local approach. Although local failure after EBRT is a statistically significant predictor for distant metastases,40 biochemical failure is associated with a long natural history before the development of distant metastases and subsequent death.40,41 Kupelian and colleagues41 reported that biochemical failure after definitive EBRT for localized prostate cancer was not associated with increased mortality within the first 10 years after initial therapy and only 5% (49 patients) of the 936 patients died of metastatic prostate cancer. In addition, recent studies have demonstrated improved overall survival with EBRT dose escalation.41,42 In the Cleveland Clinic experience, a trend for improved overall survival was noted in patients receiving 72 Gy or more, with a 90% versus 70% 10-year overall survival rate in patients receiving the greater versus lower dosUROLOGY 66 (1), 2005

es.41 Greater EBRT doses have also been associated with a decreased rate of biochemical failure, fewer distant metastases, and improved overall survival.42 In the era of EBRT dose escalation, improved biochemical outcomes and overall survival are expected, with fewer patients developing isolated local failures. In addition, because of the prolonged natural history of radiorecurrent prostate cancer, proponents of salvage therapy must document efficacy (a relatively high probability of cure) with an acceptable morbidity profile before subjecting large numbers of patients to such therapy. Multiple investigators have reported salvage cryotherapy results after biopsy-proven EBRT local failure. The Columbia University approach included neoadjuvant ADT, negative seminal vesicle biopsies, negative pelvic lymph node dissection, and negative bone scan before cryoablation.13,43 Despite careful patient selection, only 79% and 66% of patients remained free of biochemical failure at 6 and 12 months, respectively. The M.D. Anderson Cancer Center experience demonstrated an even more sobering outcome.44,45 From 1992 through 1995, 131 patients underwent salvage cryosurgery with second-generation technology after biopsy-proven EBRT failure, with a postcryotherapy definition of failure of a PSA nadir plus 2.0 ng/mL or greater. Whether patients were stratified by either the precryotherapy PSA level (10 ng/mL or less versus more than 10 ng/mL) or Gleason score (2 to 7 versus 8 to 9), the biochemical disease-free survival curves converged at approximately 25% 6 years after treatment.44,45 The most bothersome findings revolved around the postcryotherapy histopathologic evaluation. Whether or not biopsy-proven postcryotherapy local control was obtained, only approximately 25% of patients remained disease free 6 years after treatment, suggesting that salvage cryotherapy may delay biochemical recurrence and results in cure in only a small minority of patients. Because of the long natural history of locally recurrent prostate cancer, these results illustrate that patients undergoing salvage cryosurgery may have relatively little expectation for cure while being placed at risk of potential complications.40,41 These patients would likely be better treated with active surveillance, early versus late ADT or, in select cases, salvage RP. In contrast, the results of a recent study have suggested significantly better outcomes after salvage cryotherapy.46 From 1993 through 2001, Bahn and colleagues46 evaluated 93 patients undergoing salvage cryotherapy at least 24 months after initial treatment with EBRT or BT. After biopsyproven local cancer persistence, treatment consisted of 3 months of neoadjuvant ADT followed by cryotherapy and was prescribed with biochemical disease-free survival defined as a PSA level of 0.5 UROLOGY 66 (1), 2005

ng/mL or less. Thirty-six percent of the patients underwent salvage cryotherapy with a pretreatment PSA level of less than 4.0 ng/mL. At 7 years, 59% of patients remained free of biochemical failure. Surprisingly, very little difference in salvageability was detected whether patients underwent cryotherapy with a pretreatment PSA level of less than 4, 4 to 10, or greater than 10 ng/mL (biochemical disease-free survival rate of 61%, 62%, and 50%, respectively). The investigators did not report the actual number of EBRT or BT failures. It is likely that some of these “successfully” salvaged patients did not have cancer at the time of salvage cryotherapy. In a review of the early Seattle BT experience, Prestidge and colleagues47 reported that with a median follow-up of 40 months, 80% of biopsies were negative, 17% were indeterminate, and only 3% were positive. Of the patients with an indeterminate biopsy, additional biopsies demonstrated that 85% of the indeterminate biopsies converted to a negative biopsy, 9% remained indeterminate, and 6% converted to positive. As such, overall, only 4% of biopsies were ultimately positive for recurrent cancer. Similar to the biopsy information, posttreatment PSA values in the first few years after BT can present confusion regarding cancer status owing to the phenomenon of benign PSA spikes, which can be expected in approximately 25% of patients.48 Within the first 30 months after BT, the finding of a rising PSA level even when combined with a histologically positive biopsy does not necessarily indicate viable cancer persistence. The results of a recent study highlight that rebiopsy and PSA trends within the first 30 months after BT may be misleading.49 In 8 patients with low-risk iodine125 monotherapeutic BT with a rising PSA level (2.6 to 8.4 ng/mL), a posttreatment biopsy (obtained on average 22 months after BT) was positive for residual/recurrent prostate cancer. All patients were encouraged to proceed with salvage therapy, but ultimately decided for continued observation. With additional follow-up, in all patients, the PSA level subsequently normalized (median PSA 0.2 ng/mL) without any additional therapeutic intervention. As such, early salvage of BT “failures” may in fact represent the “salvage” of cured patients. Before the widespread acceptance of local salvage procedures, improvements in radiographic and/or biochemical determination of locoregional/ distant disease status and histopathologic analysis will assist in appropriate patient selection. DOES CRYOTHERAPY HAVE A FAVORABLE MORBIDITY PROFILE? Table I illustrates the ranges of commonly reported complications for second-generation and 13

third-generation cryotherapy.15,25 Although quality-of-life parameters depend greatly on the definitions used and the mode of data collection, it is clear that recent cryosurgical technologic advances have resulted in a dramatic decrease in the complication rates compared with those reported with first-generation cryosurgery. Preliminary results (12 months of follow-up) of third-generation cryosurgery have suggested a trend toward reduced morbidity compared with the second-generation outcomes.15,25 With third-generation cryosurgery, approximately 5% of patients have continued to experience each of the following: urethral sloughing, urinary incontinence, pelvic pain, and/or scrotal edema. Fortunately, with modern cryosurgical techniques, rectourethral fistulas have become relatively rare. As expected, salvage cryotherapy for EBRT failures has consistently been associated with greater complication rates.15,25 Cryotherapy impairs the penile arterial blood supply and damages the cavernosal nerves responsible for erectile function. In most series, even with third-generation techniques, nearly all patients develop impotence, and, as such, cryotherapy should not be offered to patients hoping for potency preservation. In an isolated report, Robinson and colleagues50 reported that 3 years after cryoablation, 13% of patients regained potency and that an additional 34% remained sexually active with the assistance of erectile aids. CONCLUSIONS Cryotherapy has not been demonstrated to be as effective as, or less morbid than, RP, EBRT, or BT in the treatment of localized prostate cancer. Although third-generation cryosurgery may ultimately prove to be an efficacious, minimally invasive treatment for prostate cancer, the criteria to support its use as a mainstream treatment have not been established. REFERENCES 1. Katz AE, and Rukstalis DB: Introduction. Urology 60: 1–2, 2002. 2. Rees J, Patel B, MacDonagh R, et al: Cryosurgery for prostate cancer. BJU Int 93: 710 –714, 2004. 3. Koppie TM, Katsuto S, Grossfeld GD, et al: The efficacy of cryosurgical ablation of prostate cancer: the University of California, San Francisco experience. J Urol 162: 427– 432, 1999. 4. Cox RL, and Crawford ED: Cryosurgical ablation of the prostate: the con side in 1996. Urology 48: 181–183, 1996. 5. Han K-R, and Belldegrun AS: Third generation cryosurgery for primary and recurrent prostate cancer. BJU Int 93: 14 –18, 2004. 6. Katsuto S: Prostate cancer: cryotherapy. Urol Clin North Am 30: 725–736, 2003. 7. Mazur P: Cryobiology: the freezing of biological systems. Science 268: 939 –949, 1970. 14

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40. Coen JJ, Zietman AL, Thakral H, et al: Radical radiation for localized prostate cancer: local persistence of disease results in late wave of metastases. J Clin Oncol 15: 3199 –3205, 2002. 41. Kupelian PA, Buchsbaum JC, Patel C, et al: Impact of biochemical failure on overall survival after radiation therapy for localized prostate cancer in the PSA era. Int J Radiat Oncol Biol Phys 52: 704 –711, 2002. 42. Jacob R, Hanlon A, Horwitz E, et al: The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer. Cancer 100: 538 – 543, 2004. 43. de la Taille A, Hayek O, Benson MC, et al: Salvage cryotherapy for recurrent prostate cancer after radiation therapy: the Columbia experience. Urology 55: 79 – 84, 2000. 44. Izawa JI, Madsen LT, Scott SM, et al: Salvage cryotherapy for recurrent prostate cancer after radiotherapy: variables affecting patient outcome. J Clin Oncol 20: 2664 –2671, 2002. 45. Izawa JI, Morganstern N, Chan DM, et al: Incomplete glandular ablation after salvage cryotherapy for recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys 56: 468 – 472, 2003. 46. Bahn DK, Lee F, Silverman P, et al: Salvage cryosurgery for recurrent prostate cancer after radiation therapy: a sevenyear follow-up. Clin Prostate Cancer 2: 111–114, 2003. 47. Prestidge BR, Hoak DC, Grimm PD, et al: Posttreatment biopsy results following interstitial brachytherapy in earlystage prostate cancer. Int J Radiat Oncol Biol Phys 37: 31–39, 1997. 48. Merrick GS, Butler WM, Wallner KE, et al: Prostatespecific antigen spikes after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 54: 450 – 456, 2002. 49. Reed D, Wallner K, Merrick G, et al: Clinical correlates to PSA spikes and positive repeat biopsies after prostate brachytherapy. Urology 62: 683– 688, 2003. 50. Robinson JW, Donnelly BJ, Saliken JC, et al: Quality of life and sexuality of men with prostate cancer 3 years after cryosurgery. Urology 60(2 suppl 1): 12–18, 2002.

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