High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after external beam radiation, brachytherapy or proton therapy

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Salvage HIFU is a promising treatment option for local recurrence after radiation therapy, with morbidity comparable with other forms of salvage treatment. This study showed a long‐term follow up of salvage HIFU in men with recurrence of localized prostate cancer following not only external beam radiation therapy but also brachytherapy or proton therapy.

OBJECTIVE

To investigate the use of high‐intensity focused ultrasound (HIFU) as a salvage therapy in patients with recurrence of localized prostate cancer after external beam radiation (EBRT), brachytherapy, or proton therapy.

PATIENTS AND METHODS

We retrospectively reviewed the charts of all patients who had undergone salvage HIFU for biopsy‐proven prostate cancer after primary radiation therapy. Patient characteristics and oncological outcomes were assessed.

RESULTS

Records of 22 patients with a median (range) follow‐up of 24 (5–80) months were reviewed. Patients were men with presumed organ‐confined disease who had been treated with salvage HIFU following recurrent disease after EBRT (fourteen patients), brachytherapy (five patients: four with high‐dose brachytherapy using In¹⁹²; and one with low‐dose brachytherapy using Au⁹⁸) or proton therapy (three patients). The median (range) age at salvage HIFU was 65 (52–80) years, with a median (range) prostate‐specific antigen (PSA) level before radiation therapy of 14.3 (5.7–118) ng/mL and a median (range) PSA level of 4.0 (1.2–30.1) ng/mL before HIFU. The median (range) period to HIFU after radiation therapy was 36 (4–96) months. The biochemical disease‐free survival (bDFS) rate in all patients at 5 years was 52%. Rates of bDFS in low‐, intermediate‐ and high‐risk groups were 100%, 86%, and 14%, respectively. One of the twelve patients who received post‐HIFU prostate biopsy showed malignancy. Side effects included urethral stricture in four patients, grade I urinary incontinence in four patients, rectourethral fistula and epididymitis in one of each patient.

CONCLUSION

Salvage HIFU is a promising treatment option for local recurrence after radiation therapy, with morbidity comparable with other forms of salvage treatment.     

Rectal fistulae after salvage high‐intensity focused ultrasound for recurrent prostate cancer after combined brachytherapy and external beam radiotherapy

OBJECTIVE

To report on the high rectal fistula rate associated with salvage high‐intensity focused ultrasound (HIFU) after the failure of combined brachytherapy and external beam radiotherapy (EBRT) for prostate cancer; salvage ablative therapy for prostate cancer is indicated when there is local recurrence after RT, brachytherapy or their combination.

PATIENTS AND METHODS

We retrospectively reviewed all men with prostate cancer treated with HIFU between 1 March 2005 and 31 May 2007, and identified five men treated after the failure of both brachytherapy and EBRT for localized prostate cancer.

RESULTS

Three of the five men had iodine‐seed implantation brachytherapy combined with EBRT as primary treatment, one had high‐dose rate brachytherapy combined with EBRT and one had salvage iodine‐seed brachytherapy for failed EBRT. Three of the five patients developed a recto‐urethral fistula after HIFU.

CONCLUSIONS

The high rate of recto‐urethral fistula formation in this group might reflect an impaired blood supply or HIFU‐associated near‐field heating of the rectal wall. Tissue viability and healing might affect this group regardless of the salvage method. Careful patient selection and avoidance of rectal diagnostic biopsies might minimize the risk. Emerging ablative therapies regarded as less invasive than traditional therapies must be used with caution.     

High‐intensity focused ultrasound for localized prostate cancer: initial experience with a 2‐year follow‐up

OBJECTIVE

To report on the short‐term functional and oncological results, from one institution, of high‐intensity focused ultrasound (HIFU) for treating localized prostate cancer.

PATIENTS AND METHODS

Over a 3‐year period, 43 patients with localized prostate cancer were scheduled for HIFU in the primary (31) and salvage (12) settings using a second‐generation Ablatherm^TM device (EDAP, Lyon, France). Oncological failure was defined by several criteria, including biochemical failure (assessed using both the Phoenix definition of the nadir + 2 ng/mL) and the current Food and Drug Administration (FDA) trial endpoint of a prostate‐specific antigen (PSA) level of ≥0.5 ng/mL, or starting salvage therapy, or the presence of cancer on biopsy after treatment.

RESULTS

Three patients had their procedures abandoned due to technical limitations/rectal wall thickness. The mean PSA levels in the primary and salvage groups were 9.2 and 5.1 ng/mL, respectively. The mean HIFU treatment time in the primary and salvage groups was 71.1 and 63.3 min, respectively. Using the Phoenix definition of biochemical failure, HIFU treatment failed in 13 patients in the primary group (46%) and five in the salvage group. Using the FDA trial endpoint, HIFU failed in 21 patients in the primary group (75%) and eight in the salvage group. One man died from metastatic prostate cancer 18 months after salvage HIFU. There were two urethral strictures in the primary (7%) and one in the salvage treatment group. There were two prostato‐rectal fistulae in the salvage HIFU group.

CONCLUSIONS

HIFU is proposed to be a minimally invasive low‐morbidity ablative treatment for localized prostate cancer, and with good efficacy. The present limited series is unable to support these claims. There were significant rates of complications and oncological failure in both the primary and salvage setting. As a result we have suspended our programme pending further evidence of its safety and efficacy.     

Salvage radiotherapy after high-intensity focused ultrasound treatment for localized prostate cancer: feasibility, tolerance and efficacy

Background:

The objective of this study is to evaluate the feasibility, tolerance and efficacy of salvage external beam radiotherapy (EBRT) in persistent or recurrent prostate cancer after failed high intensity focused ultrasound (HIFU) therapy.

Methods:

We reviewed data on tolerance and oncologic outcomes for all patients with biopsy-proven locally recurrent or persistent prostate cancer who underwent salvage EBRT in our department between April 2004 and June 2008. Minimum follow-up for inclusion was 2 years. Failure with EBRT was defined as biochemical relapse (Phoenix definition) or introduction of androgen deprivation therapy (ADT). Gastrointestinal and urinary toxicity and urinary stress incontinence were scored at 12 and 24 months (Radiation Therapy Oncology Group and Ingelman Sundberg rating, respectively).

Results:

The mean age of the patients was 68.8 years (range: 60–79). Mean prostate-specific antigen (PSA) before EBRT was 5.57 ng/mL (range: 2.5–14.8). Median follow-up was 36.5 ± 10.9 months (range: 24–54). No patient received adjunctive ADT. The EBRT course was well-tolerated and completed by all patients. The mean PSA nadir was 0.62 ng/mL (range: 0.03–2.4) and occurred after a median of 22 months (range: 12–36). One patient experienced biochemical failure and was prescribed ADT 30 months after EBRT. The disease-free survival rate was 83.3% at 36.5 months. There was no major EBRT-related toxicity at 12 or 24 months.

Conclusions:

Our early clinical results confirm the feasibility and good tolerance of salvage radiotherapy after HIFU failure. Oncological outcomes were promising. A prospective study with longer follow-up is needed to identify factors predictive of success for salvage EBRT therapy after HIFU failure.     

Salvage robotic‐assisted radical prostatectomy: initial results and early report of outcomes

OBJECTIVE

To evaluate the initial results of salvage robotic‐assisted radical prostatectomy (SRARP) after recurrence following primary radiotherapy (RT) for localized prostate cancer.

PATIENTS AND METHODS

Between December 2002 and January 2008, 11 patients had SRARP with pelvic lymph node dissection by one surgeon from one institution. Six patients had brachytherapy, three had external beam RT (EBRT), one intensity‐modulated RT, and one received brachytherapy with an EBRT boost. All patients had prostate cancer on biopsy after RT, with negative computed tomography and bone scan. The mean (range) follow‐up was 20.5 (1–77) months.

RESULTS

The mean interval from RT to SRARP was 53.2 months; the mean preoperative prostate‐specific antigen (PSA) level was 5.2 ng/mL, the operative duration 183 min and the estimated blood loss 113 mL. One patient had prolonged lymphatic drainage, one had an anastomotic leak, and one had an anastomotic stricture requiring direct vision internal urethrotomy at 3 months. The mean duration of catheterization was 10.4 days and the hospital stay 1.4 days. Three patients had a biochemical recurrence, at 1, 2 and 43 months. In one of two patients with node‐positive carcinoma of the prostate the PSA level failed to reach a nadir of zero after surgery. In patients with a minimum follow‐up of 2 months, eight of 10 are continent (defined as zero to one pad per day) and two have erections adequate for intercourse with the use of phosphodiesterase‐5 inhibitors.

CONCLUSION

SRARP after RT‐resistant disease recurrence is feasible with minimal perioperative morbidity. Early functional outcomes appear to be at least equivalent with historical salvage RP series. Robotic extended pelvic lymph node dissection is safe and can improve the accuracy of surgical staging. A longer follow‐up is necessary to better assess the functional and oncological outcomes.     

Salvage high‐intensity focused ultrasound for biopsy‐confirmed local recurrence of prostate cancer after radical prostatectomy

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To present experience in high‐intensity focused ultrasound (HIFU) used as a salvage therapy for biopsy‐confirmed local recurrence at the vesico‐urethral anastomosis after radical prostatectomy (RP).

PATIENTS AND METHODS

From July 2006, four patients diagnosed with prostate cancer recurrence after RP were treated with HIFU, with or without salvage radiotherapy, using the Sonablate® 500 (Focus Surgery, IN, USA). Biochemical failure was defined as in increase in prostate‐specific antigen (PSA) level of >0.2 ng/mL. No patients received any adjuvant therapy after HIFU therapy before reporting failure.

RESULTS

The mean age and initial PSA level before RP was 74 years and 10.0 ng/mL, respectively. After RP, one patient was stage T2aN0M0, two were stage T3N0M0 and the last had an unknown pathological stage. Three patients received external beam radiotherapy as salvage therapy after RP. The mean PSA level before HIFU, tumour volume at the vesico‐urethral lesion and operative duration were 4.3 ng/mL, 4.6 mL and 27 min, respectively. Adenocarcinomas were confirmed by biopsy of the tumour at the vesico‐urethral anastomotic lesion before HIFU. At 24 months of follow‐up, patients 2 and 4 were classified a biochemically disease‐free. Biopsies at the anastomotic site after HIFU in three patients showed no malignancy, with fibrosis. There were no complications.

CONCLUSION

Salvage HIFU for patients with recurrence after RP is feasible, even though they received salvage radiotherapy before HIFU. More patients and a longer follow‐up are needed to evaluate the safety and oncological adequacy of this new approach.     

Accuracy of multiparametric magnetic resonance imaging in detecting recurrent prostate cancer after radiotherapy

OBJECTIVE

To assess the role of multiparametric magnetic resonance imaging (mp‐MRI) of the prostate in evaluating local recurrence of prostate cancer, using transperineal template‐guided 5 mm‐spaced biopsies as a reference standard, in men treated with external beam radiotherapy (EBRT) for prostate cancer.

PATIENTS AND METHODS

The study included 13 patients with evidence of biochemical recurrence after EBRT who had undergone mp‐MRI and prostate mapping. Each MRI scan (consisting of T1/T2 weighting, dynamic contrast enhancement and diffusion weighting) was reported by two expert uro‐radiologists. Each prostate was divided into four regions of interest (ROI), generating 52 paired datasets for analysis.

RESULTS

The mean (range) age of the men was 65.5 (55–70) years, the mean prostate‐specific antigen (PSA) level before EBRT was 36.6 (4.5–150) ng/mL, the mean time from EBRT to biochemical recurrence was 5.7 (3–10) years and the mean PSA level at the time of recurrence was 7.1 (0.83–27.9) ng/mL. Eleven men had histological evidence of recurrence, with 23 of 52 ROIs involved with cancer. Overall accuracy, as expressed by the area under a receiver‐operator curve, was 0.77 and 0.89 for all cancer, with accuracies of 0.86 and 0.93 for those cancers with ≥3 mm biopsy core length. Inter‐observer variability was measured by calculating κ coefficients, which showed fair and moderate agreement between radiologists.

CONCLUSIONS

Interpretation of mpMRI of the prostate after previous EBRT is challenging. Our results show that the accuracy is good using an accurate reference standard. These results need verification in more patients, but have implications for determining presence or absence of local recurrence and subsequent local salvage therapy.     

Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations

OBJECTIVE

To assess the effects of testosterone supplementation in men with testosterone deficiency syndrome (TDS) after external beam radiotherapy (EBRT) for localized prostate cancer.

PATIENTS AND METHODS

Five men with significant signs of TDS after treatment for localized prostate cancer with EBRT were treated with testosterone once their prostate‐specific antigen (PSA) level had reached the nadir.

RESULTS

The mean (range) level of testosterone before supplementation was 5.2 (1.1–9.2) nmol/L and the duration of follow‐up while on supplementation was 14.5 (6–27) months. At the last visit, the testosterone levels were 17.6 (8.5–32.4) nmol/L. One of the five patients had a transitory increase in PSA level but none had levels of >1.5 ng/mL. All patients reported a marked response in the manifestations of TDS, i.e. four each reported decreased hot flushes, decreased fatigue and improved libido, and two reported improved erectile function.

CONCLUSION

Men with TDS after EBRT for localised prostate cancer are candidates for testosterone therapy. The patients must be aware of the advantages and disadvantages of the treatment. PSA levels must have reached a nadir before starting treatment and the follow‐up must be particularly close. In these few patients there were no adverse effects from testosterone supplementation. There is a need for more information about the safety and efficacy of testosterone therapy in men successfully treated for localized prostate cancer, because there is evidence indicating hypogonadism in these patients, compromising their quality of life and longevity, independent of the cancer.     

Salvage permanent perineal radioactive‐seed implantation for treating recurrence of localized prostate adenocarcinoma after external beam radiotherapy

OBJECTIVE

To assess our experience with salvage permanent perineal radioactive‐seed implantation (SPPI) as a possible therapeutic option for recurrent prostate adenocarcinoma, as salvage therapies for recurrences after definitive external beam radiotherapy (EBRT) for localized adenocarcinoma of the prostate are associated with significant morbidity and biochemical failure.

PATIENTS AND METHODS

We retrospectively analysed on patients who had SPPI for localized recurrent prostate adenocarcinoma from 1996 to 2007 after primary treatment with EBRT. Excluded were patients who had other primary treatment or had no follow‐up. Primary outcomes were time to biochemical relapse‐free survival, using the Phoenix definition of a prostate‐specific antigen (PSA) nadir +2 ng/mL, and cancer‐specific survival. Secondary outcomes were the International Prostate Symptom Score (IPSS), the International Index of Erectile Function‐5 score (IIEF‐5), and complications based on Common Terminology Criteria for Adverse Events (version 3).

RESULTS

In all, 37 patients had SPPI during this period; after applying inclusion and exclusion criteria, 24 remained for analysis. At the time of salvage therapy, the median time to the diagnosis of local recurrence was 49 months, the median PSA level was 3.36 ng/mL, the median PSA doubling time was 20 months, and all patients were clinically re‐staged at ≤T2 with negative transrectal ultrasonography and/or magnetic resonance spectroscopy. The original Gleason score was ≤6 in nine patients, 7 in eight and ≥8 in three (not recorded in two). The median follow‐up after SPPI was 30 months; the cancer‐free survival was 96% (one death) and biochemical relapse‐free survival was 88% (three patients). The PSA level was higher than the levels before SPPI at 3 months in all three failures, but lower in all 21 patients considered relapse‐free. Complications included one urethral stricture, one grade 3 rectal haemorrhage and five grade 2 gross haematuria that resolved with conservative management. Insufficient data were available to assess the IPSS or IIEF‐5 scores.

CONCLUSION

With a short‐term follow‐up SPPI appears to provide excellent prostate cancer control with an acceptable rate of complications for patients with local recurrence of prostate cancer after EBRT. An extended follow‐up is necessary to determine the long‐term durability and safety of SPPI.     

Single-session primary high-intensity focused ultrasonography treatment for localized prostate cancer: biochemical outcomes using third generation-based technology

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The experience with HIFU as a minimally invasive treatment for localized prostate cancer is relatively new and most reports are from European centres. Our study is unique in five regards: 1. Data was collected prospectively. 2. All patients were treated with contemporary technology. 3. Outcomes are reported after a single HIFU session using two definitions of biochemical failure that have the ability to predict longer‐term clinical failure after primary ablative therapies for prostate cancer (Stuttgart definition for HIFU and Horwitz definition for radiation). 4. All patients were treated in a single centre. 5. No patients underwent peri‐HIFU TURP. The present study represents the largest North American prospective cohort of primary HIFU for prostate cancer with mid‐term oncological outcome data.

OBJECTIVE

• ? To assess 4‐year biochemical failure (BCF) rates in patients after high‐intensity focused ultrasonography (HIFU) treatment using the Horwitz and Stuttgart definitions.

PATIENTS AND METHODS

• ? A total of 447 consecutive patients were treated with a single session of HIFU between May 2005 and December 2010.
• ? Follow‐up included prostate‐specific antigen (PSA) measurement every 3 months during the first year and every 6 months thereafter.
• ? Patients who had previously received radiation, androgen deprivation or HIFU therapy, and patients with <2 consecutive PSA measurements were excluded.
• ? BCF was reported using the Stuttgart (PSA nadir + 1.2 ng/mL rising) and the Horwitz (two consecutive increases of at least 0.5 ng/mL) definitions.

RESULTS

• ? In all, 402 patients met the inclusion criteria and the median (range) follow‐up was 24 (6–48) months.
• ? Of these patients, 183 (45.5%) had low and 219 (54.5%) had intermediate D'Amico's risk stratification disease.
• ? Mean and median absolute PSA nadir levels were 0.36 ± 0.69 and 0.1 ng/mL (Q₁:0, Q₃:0.37), respectively and these were achieved in median time of 3 months.
• ? Overall 4‐year mean (range) BCF‐free rates were 68 (61–75)% and 72 (68–77)% according to the Stuttgart and Horwitz definitions at 4 years, respectively.
• ? Mean (range) BCF‐free rates were significantly higher for a PSA nadir ≤0.5 ng/mL and prostate volume ≤30 mL for both definitions at 4‐year follow‐up [Stuttgart: 79 (72–86)% vs. 25 (13–38)%; Horwitz: 82 (77–87)% vs. 33 (21–44)%] and [Stuttgart: 72 (64–79)% vs. 56 (42–69)%; Horwitz: 75 (69–80)% vs. 63 (53–74)%], respectively.
• ? Pre‐treatment PSA and PSA nadir of >0.5 ng/mL were the predictors of BCF using both definitions.

CONCLUSIONS

• ? Primary HIFU appears to result in promising 4‐year BCF‐free rates in individuals with low‐ and intermediate‐risk prostate cancer who achieve PSA nadir <0.5 ng/mL.
• ? A prostate volume <30 mL is associated with PSA nadir levels of <0.5 ng/mL suggesting a potential role for pretreatment volume reduction (medically or surgically) in larger prostates.

     

Six years' experience with high-intensity focused ultrasonography for prostate cancer: oncological outcomes using the new 'Stuttgart' definition for biochemical failure

Study Type – Therapy (outcomes research) Level of Evidence 2b

OBJECTIVE

? To determine oncological outcomes after high‐intensity focused ultrasonography (HIFU) treatment in patients with localized prostate cancer using a new, more accurate, definition (‘Stuttgart’ definition) of biochemical failure.

PATIENTS AND METHODS

? We performed a retrospective review of all patients in our centre who received first‐line treatment with a second‐generation Ablatherm^TM device (EDAP‐TMS, Lyon, France). ? Oncological failure was given either by biochemical failure (prostate‐specific antigen, PSA, nadir plus 1.2 g/mL) (Stuttgart definition) or the start of salvage therapy because of a persistently positive biopsy after the HIFU procedure. ? The 5‐year biochemical‐free survival rate and 5‐year disease‐free survival rate were calculated.

RESULTS

? In total, 53 patients were included (mean age, 72.5 ± 4.5 years, range 60–79 years; 28 low risk and 25 intermediate risk). None had undergone previous hormonal therapy. Mean ±sd follow‐up was 45.4 ± 15.5 months (range 16–71 years). Mean (range) pre‐treatment PSA was 8.5 ± 4 (0.29–18) ng/mL. The median (range) PSA nadir value was 1 (0.01–14) ng/mL and occurred after a mean (range) of 5.09 (3–24) months. ? Overall, 36 patients (67.9%) experienced oncological failure. ? These included 33 cases (62.2%) of biochemical failure. A PSA nadir of ≤0.2, 0.21–1.0 and >1 ng/mL was reached in 20.8%, 30.2% and 49% of patients, respectively, and was associated with biochemical failure in 9.1%, 30.3% and 60.6%, respectively. ? The 5‐year biochemical‐free survival rate and disease‐free survival rate were 21.7% and 13.5%, respectively. In multivariate analysis, a PSA nadir of >1 ng/mL was significantly associated with a risk of biochemical and oncological failure (P= 0.002 and P < 0.001). ? Oncological failure was not associated with any risk group. ? No patient died from prostate cancer.

CONCLUSIONS

? In our experience, Ablatherm^TM treatment for clinically localized prostate cancer was associated with a high rate of biochemical failure as determined by the ‘Stuttgart’ definition, and did not achieve effective cancer control. ? The PSA nadir value after HIFU treatment was a significant predictor of treatment failure.     

Relationship between prostate cancer mortality and number of unfavourable risk factors in men treated with definitive brachytherapy

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To explore whether the number of unfavourable pretreatment risk factors predicts cause‐specific mortality in men treated with prostate brachytherapy.

PATIENTS AND METHODS

Between April 1995 and March 2006, 739 patients were treated who had at least one of the following adverse risk factors: pretreatment prostate‐specific antigen (PSA) level of >10 ng/mL, a Gleason score of ≥7, clinical stage ≥T2b, or a PSA velocity (PSAV) of >2 ng/mL/year. Supplemental external beam radiotherapy (EBRT) was delivered to 464 (62.8%) men and 301 (40.7%) received androgen deprivation therapy (ADT). Of men with more than two risk factors, 87% received EBRT and 62% received ADT.

RESULTS

The biochemical progression‐free survival (bPFS), cause‐specific survival (CSS) and overall survival for all patients were 95.0%, 97.9% and 70.0% at 12 years. Men with three or four risk factors had a prostate cancer‐specific mortality (PCSM) at 12 years of 5.3%, vs 1.7% for men with one or two risk factors (P= 0.006). When ‘percentage of positive biopsy cores >50%’ replaced PSAV as a risk factor, men with two or more risk factors had a PCSM of 8.9%, vs 1.0% for men with one or two risk factors (P= 0.001). There was no difference in all‐cause mortality between the groups in either analysis.

CONCLUSION

Multimodal brachytherapy results in high rates of bPFS and CSS, even for men with several unfavourable risk factors. Men with two or more unfavourable risk factors had a slightly greater risk of PCSM and no difference in all‐cause mortality. The presence of three or four unfavourable intermediate‐risk factors does not appear to clearly identify a group that requires further treatment intensification, although the percentage of positive cores might be more predictive than PSAV.     

An algorithm for managing the failure of external beam radiotherapy in prostate cancer

OBJECTIVE: To present a management algorithm for men with prostate cancer recurring after external beam radiotherapy (EBRT), based on a review of published reports, to assist clinicians in identifying men who are suitable for salvage therapy and to help them to decide which type of salvage treatment is most likely to confer the desired outcome with the minimum of harm. METHODS: Men with radiorecurrent prostate cancer require special consideration; they tend to be older, have more comorbidity and have worse disease than their contemporaries having primary treatment. Salvage treatment is compromised by the irradiated pelvis, resulting in increased treatment toxicity. Using the Pubmed database and reference lists of key articles, we identified studies relating to the management of radiorecurrent prostate cancer; the findings were incorporated into a management algorithm and summary table of treatments. RESULTS: The American Society for Therapeutic Radiology and Oncology criteria, which define biochemical failure has now been superseded by the Phoenix definition (nadir prostate-specific antigen [PSA] plus 2 ng/mL). Biochemical follow-up after EBRT should be 3-monthly until the PSA level has reached a stable nadir after withdrawing androgen suppression. Contrast-enhanced dynamic magnetic resonance imaging (MRI) is an accurate tool and can be used for both the diagnosis and staging of patients with prostate cancer, in conjunction with prostate biopsies. Prostate biopsies should only be considered >2 years after EBRT to avoid false-positive results. In addition to MRI, high-risk cases being considered for salvage therapy should be considered for laparoscopic lymph-node dissection to exclude micrometastases. Deferred androgen suppression, laparoscopic or open radical prostatectomy, cryotherapy and high-intensity focused ultrasound all seem reasonable salvage treatment approaches. CONCLUSION: Through improved methods of detection, including frequent PSA measurements, modern imaging and carefully obtained biopsies, those with radiorecurrent disease can be identified before their disease has spread. Rigorous staging will exclude those with micrometastases. The minimally invasive salvage therapies seem to offer an advantage over salvage surgery to patients in whom the benefits and harms are so finely balanced.     

Multicentric Oncologic Outcomes of High-Intensity Focused Ultrasound for Localized Prostate Cancer in 803 Patients

Background

High-intensity focused ultrasound (HIFU) is an emerging treatment for select patients with localized prostate cancer (PCa).

Objectives

To report the oncologic outcome of HIFU as a primary care option for localized prostate cancer from a multicenter database.

Design, setting, and participants

Patients with localized PCa treated with curative intent and presenting at least a 2-yr follow-up from February 1993 were considered in this study. Previously irradiated patients were excluded from this analysis. In case of any residual or recurrent PCa, patients were systematically offered a second session. Kaplan-Meier analysis was performed to determine disease-free survival rates (DFSR).

Measurements

Prostate-specific antigen (PSA), clinical stage, and pathologic results were measured pre- and post-HIFU.

Results and limitations

A total of 803 patients from six urologic departments met the inclusion criteria. Stratification according to d’Amico's risk group was low, intermediate, and high in 40.2%, 46.3%, and 13.5% of patients, respectively. Mean follow-up was 42 ± 33 mo. Mean PSA nadir was 1.0 ± 2.8 ng/ml with 54.3% reaching a nadir of ≤0.3 ng/ml. Control biopsies were negative in 85% of cases. The overall and cancer-specific survival rates at 8 yr were 89% and 99%, respectively. The metastasis-free survival rate at 8 yr was 97%. Initial PSA value and Gleason score value significantly influence the DFSR. The 5- and 7-yr biochemical-free survival rates (Phoenix criteria) were 83–75%, 72–63%, and 68–62% (p = 0.03) and the additional treatment-free survival rates were 84–79%, 68–61%, and 52–54% (p < 0.001) for low-, intermediate-, and high-risk patients, respectively. PSA nadir was a major predictive factor for HIFU success: negative biopsies, stable PSA, and no additional therapy.

Conclusions

Local control and DFSR achieved with HIFU were similar to those expected with conformal external-beam radiation therapy (EBRT). The excellent cancer-specific survival rate is also explained by the possibility to repeat HIFU and use salvage EBRT.     

Treatment failure and clinical progression after salvage therapy in men with biochemical recurrence after radical prostatectomy: radiotherapy vs androgen deprivation

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To compare the outcomes between salvage radiotherapy (RT) and androgen‐deprivation therapy (ADT), to investigate factors determining clinical progression (CP) in men with prostate cancer.

PATIENTS AND METHODS

The study comprised 121 patients with biochemical recurrence while on follow‐up by prostate‐specific antigen (PSA) measurement, without adjuvant therapy after radical prostatectomy, received RT (45) or ADT (76). Failure after salvage therapy was defined as a PSA level of >0.2 ng/mL. Clinical, pathological and treatment factors were analysed.

RESULTS

The clinicopathological characteristics were similar between the RT and ADT groups except that men in the RT group were younger (61.4 vs 65.4 years). After ADT, salvage failed in 10 (13%) after a mean (sd ) of 18.5 (4.5) months of treatment, and 6.7 months after salvage failed all patients progressed clinically. After RT, salvage failed in 22 (49%) after 30.7 (5.2) months of response. Upon RT failure, all patients received ADT, after which in three (14%) patients the treatment failed again after 20.1 months of treatment and progressed to CP after 6.5 months, while in the remaining 19 (86%) patients the PSA level remained undetectable for 37.6 (7.7) months. On multivariate analysis, pathological stage (≥T3b) and Gleason grade 5 disease were independently prognostic of CP.

CONCLUSION

Salvage RT alone and combined with subsequent ADT provided PSA control in most patients, significantly increasing CP‐free survival compared with initial ADT. Patients with a short PSA doubling time (<3 months) are at high risk of failed salvage treatment after RT, and initial ADT might be considered. Regardless of salvage method, advanced pathological stage and Gleason grade 5 were factors prognostic of CP.     

Adjuvant versus salvage radiation therapy for prostate cancer and the risk of death

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To investigate whether salvage radiation therapy (RT) for prostate‐specific antigen (PSA) failure can provide the same result as adjuvant RT, which decreases the risk of all‐cause mortality (ACM) for men with positive margins (R1), or extra‐capsular or seminal vesicle extension (pT3).

METHODS

We studied 1638 men at Duke University who underwent radical prostatectomy for unfavourable‐risk prostate cancer and whose postoperative PSA was undetectable. Cox regression was used to evaluate whether salvage vs adjuvant RT in men with a rapid (<10 months) or slow (≥10 months) PSA doubling time (DT) was associated with the risk of ACM, adjusting for adverse features (pT3, R1, Gleason score 8–10), age, preoperative PSA level, comorbidity and hormonal therapy use.

RESULTS

Despite fewer men with two or more adverse features (61 vs 82%; P = 0.016), salvage for a rapid PSA DT vs adjuvant RT increased the risk of ACM [adjusted hazard ratio (AHR) = 3.42; 95% confidence interval (CI) = 1.27–9.20; P = 0.015]. There was no difference (AHR = 1.39; 95% CI = 0.50–3.90; P = 0.53) in the risk of ACM among men who received salvage for a slow PSA DT or adjuvant RT. Nearly all (90%) men with a slow PSA DT had Gleason score ≤7 and the majority (59%) had at most pT3 or R1 disease.

CONCLUSION

Radiation therapy after PSA failure as compared with adjuvant RT was not associated with an increased risk of ACM in men with Gleason score ≤7 and pT3R0 or pT2R1 disease.     

Development and internal validation of prediction models for biochemical failure and composite failure after focal salvage high intensity focused ultrasound for local radiorecurrent prostate cancer: Presentation of risk scores for individual patient prognoses

Purpose

Patient selection for focal salvage remains difficult. Therefore, we developed and internally validated prediction models for biochemical failure (BF) and a composite endpoint (CE) following focal salvage high intensity focused ultrasound (HIFU) for radiorecurrent prostate cancer.

Does hormonal manipulation in conjunction with permanent interstitial brachytherapy,with or without supplemental external beam irradiation,improve the biochemical outcome for men with intermediate or high‐risk prostate cancer?

OBJECTIVE

To determine whether hormonal manipulation improves the biochemical outcome for men with intermediate or high‐risk prostate cancer and undergoing permanent brachytherapy with or without supplemental external beam radiation therapy.

PATIENTS AND METHODS

From April 1995 to August 2000, 350 patients with intermediate‐risk (225 men; a Gleason score of ≥ 7 or a prostate specific antigen, PSA, level of ≥ 10 ng/mL or clinical stage ≥ T2b) or high‐risk features (125 men; two or three of a Gleason score of ≥ 7 or PSA ≥ 10 ng/mL or clinical stage ≥ T2b) underwent transperineal ultrasonography‐guided permanent brachytherapy. No patient underwent pathological lymph node staging. Of these patients, 293 received supplemental external beam radiation therapy (EBRT), 141 received hormonal manipulation, with 82 having hormonal therapy for ≤ 4 months (median 4) for cytoreduction, while 59 had neoadjuvant and adjuvant hormonal manipulation (median 8 and 12 months for intermediate‐ and high‐risk, respectively). The median patient age was 68.5 years. No patient was lost to follow‐up. The mean (sd ) and median follow‐up was 50 (18) and 49 months (calculated from the day of implantation). Biochemical disease‐free (BDF) survival was defined using a consensus definition. The clinical variables evaluated for BDF survival included risk group, Gleason score, patient age, clinical T‐stage and pretreatment PSA. Treatment variables included use of hormonal manipulation stratified into cytoreductive (≤ 4 months) vs adjuvant (> 4 months) regimens, supplemental EBRT, isotope and dosimetric variables.

RESULTS

For intermediate‐risk patients, the 6‐year actuarial BDF survival rates were 98%, 96% and 100% for hormone naïve, cytoreductive and adjuvant treatment, respectively (P = 0.693); for high‐risk patients the respective values were 79%, 94% and 92% (P = 0.046). When stratified by pretreatment PSA, hormonal manipulation improved the outcome for patients with a PSA of ≥ 10 ng/mL (P = 0.019), but not for those with < 10 ng/mL (P = 0.661). Hormonal status was not statistically significant in predicting biochemical outcome when stratified by Gleason score. The follow‐up in hormone‐naïve patients was significantly longer than that in hormonally manipulated patients, at 55 (20) vs 43 (15) months (P < 0.001). In a multivariate analysis only the Gleason score predicted failure in intermediate‐risk patients, while pretreatment PSA, the use of hormonal manipulation and Gleason score predicted the outcome in high‐risk patients (P = 0.035). For both hormone‐naïve and hormonally manipulated BDF patients, the median PSA level after implantation was < 0.1 ng/mL.

CONCLUSION

In patients treated by permanent prostate brachytherapy, hormonal manipulation improved the biochemical outcome for those at high‐risk and those with an initial PSA of ≥ 10 ng/mL, but not for those with intermediate‐risk features. The use of hormonal therapy for> 4 months conferred no additional biochemical advantage over short‐course regimens. Because the follow‐up in hormone‐naïve patients was longer than that for those receiving hormonal manipulation, additional follow‐up will be mandatory to confirm the durability of these findings.

     

Extracorporeal high intensity focused ultrasound for renal tumours: a 3‐year follow‐up

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To determine whether primary extracorporeal high‐intensity focused ultrasound (HIFU) is safe, feasible and effective for managing small renal tumours.

PATIENTS AND METHODS

Although surgery currently remains the standard treatment for localized renal cell carcinoma (RCC), the increasing incidence of small renal cancers has led to a shift towards nephron‐sparing surgery, with associated morbidity in 20–25% of cases, and minimally invasive ablative therapies present an alternative management. HIFU results in ‘trackless’ homogenous tissue ablation and when administered via an extracorporeal device, is entirely noninvasive. The study comprised 17 patients (mean tumour size 2.5 cm) with radiologically suspicious renal tumours who underwent extracorporeal HIFU using the Model‐JC System (Chongqing HAIFU^TM, China), under general anaesthesia with one overnight hospital stay. Real‐time diagnostic ultrasonography was used for targeting and monitoring. Patients were followed with a clinical review and gadolinium‐enhanced magnetic resonance imaging at 12 days and every 6 months for a mean of 36 months. The outcomes measures were patient morbidity and oncological efficacy of HIFU treatment.

RESULTS

Of the 17 patients, 15 were treated according to protocol; two procedures were abandoned due to intervening bowel. There were no major complications related to HIFU. Radiological evidence of ablation was apparent at 12 days in seven of the 15 patients. Before the 6‐month follow‐up one patient had surgery due to persisting central enhancement. Fourteen patients were evaluated at the 6‐month follow‐up; eight tumours had involuted (mean 12% decrease in tumour area). Four patients had irregular enhancement on imaging and had alternative therapies. Ten patients remain on follow‐up at a mean (range) of 36 (14–55) months after HIFU (mean 30% decrease in tumour area). There was central loss of enhancement in all.

CONCLUSIONS

Renal HIFU achieves stable lesions in two‐thirds of patients, with minimal morbidity, and might be appropriate in selected cases. Further trials with accurate histological follow‐up are essential to fully evaluate this novel technique.     

Salvage Radiotherapy After High-Intensity Focussed Ultrasound for Recurrent Localised Prostate Cancer

Background

Radiotherapy is a treatment option in the case of local failure following treatment for localised prostate cancer with high-intensity focussed ultrasound (HIFU).

Objective

Our aim was to evaluate tolerance and oncologic control with salvage radiotherapy (SRT) after HIFU failure and to identify predictive factors of success.

Design, setting, and participants

From March 1995 to March 2008, all patients who presented with histologically proven persistent local disease following HIFU and were treated with curative intent SRT (with or without hormonal treatment) were included in this single-centre retrospective study.

Intervention

Patients underwent conformal radiotherapy. The median dose of conformal treatment was 72 Gy (65–78 Gy).

Measurements

The primary outcome measure was progression-free survival (PFS) defined as no biochemical relapse (three consecutive rises in prostate-specific antigen [PSA] with a velocity >0.4 ng/ml per year or PSA >1.5 ng/ml) and no additional treatment. Predictive factors of failure were examined in univariate and multivariate analyses. Adverse events in terms of urinary and digestive toxicity, urine incontinence, and erectile dysfunction (ED) were reported.

Results and limitations

The median (range) and mean (standard deviation) follow-up of the 100 patients analysed was 33 mo (5–164 mo) and 37.2 mo (23.6 mo), respectively. Eighty-three patients received SRT alone, and 17 received SRT and androgen-deprivation therapy. For the 83 patients treated with exclusive radiation therapy, PFS was 72.5% at 5 yr and 93%, 67%, and 55% for the low-, intermediate-, and high-risk groups, respectively. In the univariate analysis, PSA level prior to SRT, risk status, PSA nadir after SRT, PSA nadir after SRT >0.2 ng/ml, and time to achieve this nadir were all predictive of failure. In the multivariate analysis, PSA nadir post-SRT with a threshold at 0.2 ng/ml and time to achieve this nadir were the significant predictive factors of failure. Gastrointestinal toxicity was low; urinary toxicity grade ≤2 was 34.5%. Four were grade 3 (4.7%), one was grade 4 (1.2%), and one was grade 5 (1.2%). The incidence of severe ED (International Index of Erectile Dysfunction–5 score 5–10) was 14% pre-HIFU, and 51.9% and 82.3% pre- and post-SRT, respectively. Because our study was retrospective, results have to be interpreted cautiously.

Conclusions

SRT provides satisfactory oncologic control after HIFU failure with little (or mild) additional toxicity. These results warrant further investigation.