Thayne R. Larson

Salvage brachytherapy for localized prostate cancer after radiotherapy failure

OBJECTIVES To evaluate the effectiveness and morbidity of salvage brachytherapy for locally recurrent or persistent prostate cancer after radiotherapy failure. METHODS In this retrospective study, 49 patients of median age 73.3 years (range 52.9 to 86.9) with biopsy-proven localized prostate cancer underwent interactive transperineal fluoroscopic-guided and biplane ultrasound-guided brachytherapy with either iodine 125 or palladium 103 after prior radiotherapy failure. Post-treatment follow-up was conducted for a median of 64.1 months (range 26.6 to 96.8) and included clinical assessment of disease status, assays of serum prostate-specific antigen (PSA) levels, and documentation of treatment-related symptoms and complications. Determination of biochemical treatment failure was based on two successive rising PSA values above the post-treatment PSA nadir value. RESULTS The actuarial rate of local prostate cancer control was 98% (95% confidence interval [CI] 94% to 99%). Actuarial disease-specific survival at 3 and 5 years was 89% (95% CI 73% to 96%) and 79% (95% CI 58% to 91%), respectively. At 3 and 5 years, actuarial biochemical disease-free survival was 48% (95% CI 32% to 63%) and 34% (95% CI 17% to 51%), respectively. Post-treatment PSA nadir was found to be a significant predictor of biochemical disease-free survival. Actuarial biochemical disease-free survival of patients who achieved a PSA nadir less than 0.5 ng/mL was 77% (95% CI 53% to 90%) and 56% (95% CI 25% to 78%) at 3 and 5 years, respectively. Of 49 patients, 23 (47%) achieved a post-treatment PSA nadir less than 0.5 ng/mL. The incidence of serious complications after salvage brachytherapy, such as incontinence and rectal complications, was lower than that reported after other types of salvage procedures. CONCLUSIONS Interactive transperineal fluoroscopic-guided and biplane ultrasound-guided brachytherapy is a novel, potentially curative salvage modality for patients in whom prior radiotherapy failed. In a population of patients with poor prognosis, this modality was associated with a high rate of local prostate cancer control and a 34% actuarial rate of biochemical disease-free survival at 5 years. The incidence of major complications after salvage brachytherapy appears to be lower than that after other potentially curative salvage procedures, such as radical prostatectomy and cryoablation. Salvage brachytherapy warrants further investigation.

Temperature-correlated histo pathologic changes following microwave thermoablation of obstructive tissue in patients with benign prostatic hyperplasia

Abstract Objectives To determine the intraprostatic pathologic changes following accurately measured doses of transurethral microwave thermal energy in patients with benign prostatic hyperplasia. Methods Eight patients scheduled for prostate surgery were treated for approximately 1 hour without anesthesia using a newly designed microwave treatment catheter that allows a close impedance match to prostate tissue and concentrates thermal energy preferentially in the anterior and lateral prostate gland. Interstitial, urethral, and rectal temperatures were continuously measured using a novel stereotactic thermal mapping technique. Serial sections of prostate tissue harvested during subsequent surgery were evaluated pathologically with prostate mapping. Results Microwave treatment resulted in marked and continuous intraprostate temperature elevation, while urethral and rectal temperatures remained low. Peak intraprostate temperatures in individual patients reached as high as 80 °C. Mean temperature reached a maximum of 54 ° C at a radial distance of approximately 0.5 cm from the urethra and remained 45 °C or higher up to a distance of 1.6 cm. The predominant pathologic findings were uniform hemorrhagic necrosis and tissue devitalization without significant inflammation. The mean distance from the urethra to the viable-necrotic tissue border was 1.6 ± 0.2 cm (range, 0.5 to 2.5). At this border, no more than 1 mm in thickness, temperature averaged 45.7 ± 0.6 °C, and there was a suggestion that pure stromal nodules were more resistant to thermal injury. Conclusions Microwave treatment can destroy obstructive prostate tissue while maintaining innocuous urethral and rectal temperatures. Temperatures of 45 °C or higher for approximately 1 hour cause uniform thermoablation of prostate tissue.

Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance

PURPOSE To evaluate the effectiveness and safety of interactive transperineal brachytherapy under biplane ultrasound and fluoroscopic guidance in patients with localized prostate cancer. METHODS AND MATERIALS Brachytherapy using 125I or 103Pd radioactive seeds either alone or in combination with adjunctive external beam radiotherapy (XRT) was administered to 490 patients at a single institution. Post-treatment follow-up included clinical assessment of disease status, assays of serum prostate-specific antigen (PSA) levels and documentation of treatment-related symptoms and complications. RESULTS Actuarial disease-free survival at 5 yr was 79% (95% CI, 71-85%), and the 5-yr actuarial rate of local control was 98% (95% CI, 94-99%). Post-treatment PSA nadir and pretreatment PSA level were found to be significant predictors of disease-free survival. In patients with a PSA nadir < 0.5 ng/ml, 5-yr disease-free survival was 93% (95% CI, 84-97%), compared with 25% (95% CI, 5-53%) in patients whose PSA nadir was 0.5-1.0 ng/ml and 15% (95% CI, 3-38) in patients with a PSA nadir > 1.0 ng/ml. Brachytherapy was well tolerated with few post-treatment complications. CONCLUSION A broad range of patients with localized prostate cancer can benefit from transperineal brachytherapy with minimal morbidity. A post-treatment PSA nadir below 0.5 ng/ml provides a useful prognostic indicator of favorable long-term outcome.

In vivo interstitial temperature mapping of the human prostate during cryosurgery with correlation to histopathologic outcomes.

OBJECTIVES To determine the critical temperatures below which human prostatic tissue can be cryoablated in situ and the comparative cryoablative efficacy of single versus double-freeze cryosurgery. METHODS Six patients with prostate cancer previously scheduled for prostatectomy underwent unilateral or bilateral cryosurgery using a single cryosurgery probe per hemiprostate. Intraprocedural interstitial prostatic temperatures were measured by thermocouple junctions placed at various radial distances from the probe. After subsequent prostatectomy, whole-mount sections of the prostate gland were subjected to histopathologic evaluation. RESULTS Uniform coagulative necrosis was observed in proximity to the cryosurgery probe. The percentage of the prostate volume falling within the zone of necrosis produced by a single probe was significantly greater (P = 0.048) after a double freeze (median 13%; range 8% to 20%) than a single freeze (median 4%; range 0% to 12%). The critical temperature for cryoablation with a double freeze was -41.4 degrees C (95% confidence interval -49.9 degrees to -33.0 degrees C) compared with -61.7 degrees C (95% confidence interval -74.5 degrees to -48.9 degrees C) for a single freeze (P <0.0005). CONCLUSIONS Uniform coagulative necrosis of human prostatic tissue in vivo can be accomplished throughout a significantly larger zone with a double freeze than with a single freeze. A double freeze at temperatures below approximately -40 degrees C results in necrosis. These findings provide a basis for more optimal use of temperature monitoring during cryosurgery, which is essential to ensure effective treatment of the entire prostate gland with minimum risk of damage to adjacent tissues such as the rectum and external sphincter.

The results of radical retropubic prostatectomy and adjuvant therapy for pathologic Stage C prostate cancer

PURPOSE The results of therapy in 288 men with pathologic Stage C prostate cancer who underwent radical retropubic prostatectomy (RRP) were analyzed to determine the effects of adjuvant therapy. METHODS AND MATERIALS Twenty-seven of the 288 patients received preoperative neoadjuvant hormonal therapy (leuprolide acetate). Postoperatively, 60 patients received adjuvant radiotherapy (RT) to the prostate bed. Follow-up ranged from 3 to 83 months (median = 32 months). Freedom from failure (FFF) was defined as maintaining a serum PSA level of < or = 0.3 ng/ml. RESULTS The FFF was 61% at 3 years and 45% at 5 years for the entire group. The FFF following RRP plus RT was 75% at 3 years and 57% at 5 years as compared to 56% at 3 years and 40% at 5 years for RRP without RT (p=0.049). The FFF following RRP plus neoadjuvant hormonal therapy was 58% at 3 years and 40% at 5 years as compared to 60% at 3 years and 45% at 5 years following RRP without hormonal therapy (p=0.3). In patients without seminal vesicle (SV) invasion, the FFF was 81% at 3 years and 5 years for RRP plus RT as compared to 61% at 3 years and 50% at 5 years for RRP without RT (p=0.01). In patients with SV invasion, the FFF was 61% at 3 years and 36% at 5 years for RRP plus RT as compared to 44% at 3 years and 23% at 5 years for RRP without RT (p=0.23). The projected local control rate was 83% at 5 years for those with RRP alone as compared to 100% for RRP plus RT (p=0.02). Survival at 5 years was projected to be 92% and was not significantly altered by the administration of adjuvant therapies. CONCLUSIONS Postoperative RT was associated with significantly improved local control and FFF rates, especially in patients with tumors which did not involve the seminal vesicles.

A high-efficiency microwave thermoablation system for the treatment of benign prostatic hyperplasia : Results of a randomized, sham-controlled, prospective, double-blind, multicenter clinical trial

OBJECTIVES To determine the effectiveness, safety, and impact on patient quality of life (QOL) of a novel transurethral microwave thermoablation system for the treatment of benign prostatic hyperplasia (BPH). METHODS A total of 169 patients with BPH were randomized to undergo a 1-hour microwave (n = 125) or sham (n = 44) procedure using the Urologix Targis thermoablation system on an outpatient basis, without general or regional anesthesia. Symptoms, flow rates, and QOL scores were determined before the study procedure and periodically thereafter up to 6 months. RESULTS Mean American Urological Association (AUA) score in the microwave group diminished 50% (P <0.0005) by the 6-month evaluation (10.5, 95% confidence interval [CI] 9.2 to 11.8) compared with baseline values (20.8, 95% CI 19.8 to 21.9). The sham group also exhibited lower postprocedural AUA scores; however, the magnitude of the postprocedural decline in AUA score in the microwave group was significantly greater (P <0.01) than that in the sham group. Half the microwave group had an AUA score of less than 9 by 6 months, and the decrease in symptoms was similar among patients with initially moderate versus initially severe symptoms. Mean peak urinary flow rate (Qmax) in the microwave group increased 51% (P <0.0005) by 6 months to 11.8 mL/s (95% CI 10.7 to 13.0) versus a pretreatment value of 7.8 mL/s (95% CI 7.4 to 8.2). The magnitude of the postprocedural increase in Qmax was significantly greater in the microwave than the sham group (P <0.05). In nearly half the microwave group (47%), Qmax increased 50% or more by 6 months compared with 24% of the sham group. Microwave treatment resulted in a significantly greater (P <0.05) positive impact on patient QOL than did the sham procedure. By 6 months, the QOL score in microwave-treated patients (2.2, 95% CI 1.9 to 2.4) averaged 48% lower (P <0.0005) than that at baseline (4.2, 95% CI 4.0 to 4.4). Significantly greater durability of treatment effects was also evident with microwave than with sham treatment, as judged by the higher proportion of microwave-treated patients (98.4%) requiring no further treatment during the 6-month study period versus 83.3% of sham control patients (P <0.0005). Microwave treatment was well tolerated, and complications were generally minor, readily manageable, and transitory. CONCLUSIONS The microwave thermoablation system proved to be an effective and safe treatment modality for BPH, with a positive impact on patient QOL.

Feedback microwave thermotherapy versus TURP for clinical BPH—a randomized controlled multicenter study

OBJECTIVES To compare the outcome of a microwave thermotherapy feedback system that is based on intraprostatic temperature measurement during treatment (ProstaLund Feedback Treatment or PLFT) with transurethral resection of the prostate (TURP) for clinical benign prostatic hyperplasia (BPH) in a randomized controlled multicenter study. The safety of the two methods was also investigated. METHODS The study was performed at 10 centers in Scandinavia and the United States. A total of 154 patients with clinical BPH were randomized to PLFT or TURP (ratio 2:1); 133 of them completed the study and were evaluated at the end of the study 12 months after treatment. Outcome measures included the International Prostate Symptom Score (IPSS), urinary flow, detrusor pressure at maximal urinary flow (Qmax), prostate volume, and adverse events. Patients were seen at 3, 6, and 12 months. Responders were defined according to a combination of IPSS and Qmax: IPSS 7 or less, or a minimal 50% gain, and/or Qmax 15 mL/s or greater or a minimal 50% gain. RESULTS No significant differences in outcome at 12 months were found between PLFT and TURP for IPSS, Qmax, or detrusor pressure. The prostate volume measured with transrectal ultrasonography was reduced by 30% after PLFT and 51% after TURP. Serious adverse events related to the given treatment were reported in 2% after PLFT and in 17% after TURP. Mild and moderate adverse events were more common in the PLFT group. With the criteria mentioned above, 82% and 86% of the patients were characterized as responders after 12 months in the PLFT and TURP groups, respectively. The post-treatment catheter time was 3 days in the TURP group and 14 days in the PLFT group. CONCLUSIONS The outcome of microwave thermotherapy with intraprostatic temperature monitoring was comparable with that seen after TURP in this study. From both a simplicity and safety point of view, PLFT appears to have an advantage. Taken together, our findings make us conclude that within a 1-year perspective microwave thermotherapy with PLFT is an attractive alternative to TURP in the treatment of BPH.

In Vitro Assessment of the Efficacy of Thermal Therapy in Human Benign Prostatic Hyperplasia

The successful management of BPH with minimally invasive thermal therapies requires a firm understanding of the temperature–time relationship for tissue destruction. In order to accomplish this objective, the present in vitro study assesses the cellular viability of human BPH tissue subjected to an experimental matrix of different temperature–time combinations. Hyperplastic prostate tissue was obtained from 10 radical prostatectomy specimens resected for adenocarcinoma. A portion of hyperplastic tissue from the lateral lobe of each prostate was sectioned into multiple 1 mm thick tissue strips, placed on a coverslip and thermally treated on a controlled temperature copper block with various temperatures (45–70°C) for various times (1–60 min). After heat treatment, the tissue slices were cultured for 72 h and viability was assessed using two independent assays: histology and dye uptake for stromal tissue and using histology alone for the glandular tissue. The hyperplastic human prostate tissue showed a progressive histological increase in irreversible injury with increasing temperature–time severity. The dye uptake and histology results for stromal viability were similar for all temperature–time combinations. In vitro thermal injury showed 85–90% stromal destruction (raw data) of human BPH for temperature–time combinations of 45°C for 60 min, 50°C for 30 min, 55°C for 5 min, 60°C for 2 min and 70°C for 1 min. Apoptosis was also identified in the control and milder treated tissues with the degree of glandular apoptosis (about 20%) more than that seen in the stromal regions (<5%). The Arrhenius model of injury was fitted to the data for conditions leading to a 90% drop in viability (normalized to control) obtained for stromal tissue. The activation energies (E) were 40.1 and 38.4 kcal/mole for the dye uptake study and histology, respectively, and the corresponding frequency factors (A) were 1.1 × 1024 and 7.78 × 1022/s. This study presents the first temperature–time versus tissue destruction relation for human BPH tissue. Moreover, it supports the concept that higher temperatures can be used for shorter durations to induce tissue injury comparable with the current clinically recommended lower temperature–longer time treatments (i.e. 45°C for 60 min) for transurethral microwave thermotherapy of the prostate.

Rationale and assessment of minimally invasive approaches to benign prostatic hyperplasia therapy

Benign prostatic hyperplasia affects quality of life, with most patients complaining of symptoms related to urination. For this reason, successful treatments can be defined by (1) their effect on lower urinary tract symptoms, (2) their impact on quality of life, and (3) their ability to unobstruct the flow of urine through the prostate. Minimally invasive therapy (MIT), which includes transurethral microwave thermotherapy, water-induced thermotherapy, interstitial devices (eg, transurethral needle ablation), and interstitial laser treatments, offers physicians and their patients cost-effective alternatives for achieving a substantially improved quality of life at an acceptable level of risk. Evidence-based medicine indicates that MIT is safe and achieves significant symptomatic improvement. Compared with long-term medical management, minimally invasive procedures offer effective, well-tolerated 1-time intervention with lasting effects that can be achieved on an outpatient basis. This article reviews the options for MIT.

Increased prostatic blood flow in response to microwave thermal treatment: preliminary findings in two patients with benign prostatic hyperplasia.

OBJECTIVES To determine the effects on prostate blood flow of heat generated by microwave thermal treatment in patients with benign prostatic hyperplasia. METHODS Prostate blood flow was evaluated by continuous transrectal color Doppler ultrasonography in 2 patients at baseline, after implantation of interstitial needles used for thermal mapping, and during microwave thermal treatment. Temperatures at 30 prostatic, periprostatic, urethral, and rectal sites were continuously monitored. In 1 patient, transrectal prostate compression was applied and the blood flow and temperature response to this maneuver noted. RESULTS Microwave thermal treatment achieved maximum prostate temperatures of 59 degrees C at 5 mm radially from the urethra. Urethral and rectal temperatures remained low. Marked increases occurred in prostate blood flow in response to microwave thermal treatment. These increases were apparent throughout the prostate gland, with the greatest increase in perfusion occurring in the peripheral zone and the posterior half of the transitional zone. After 15 minutes of microwave treatment, peak systolic blood flow increased 99% and 70% in patients 1 and 2, respectively, while end-diastolic blood flow climbed 50% and 112%, respectively. Prostate compression resulted in a prompt quenching of blood flow and an increase in prostate temperature. CONCLUSIONS Based on these preliminary findings in 2 patients, prostate blood flow increases markedly in response to microwave thermal treatment. This compensatory increase in blood flow is likely to be a significant treatment-limiting factor in achieving effective thermoablation.