Joseph L. Chin

Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.

BACKGROUNDnBone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer.nnnMETHODSnIn this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091.nnnFINDINGSn1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4-33·3] vs 25·2 [22·2-29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73-0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5-38·0] vs 29·5 [22·4-33·1] months; HR 0·84, 95% CI 0·71-0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1-not estimable] months vs placebo, 44·8 [40·1-not estimable] months; HR 1·01, 95% CI 0·85-1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo.nnnINTERPRETATIONnThis large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer.nnnFUNDINGnAmgen Inc.

Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone‐refractory prostate cancer

Atrasentan is a potent, oral, selective endothelin‐A (ETA) receptor antagonist that has clinical activity in patients with hormone‐refractory prostate cancer (HRPC). In this article, the authors report the results from a phase 3, randomized, double‐blind, placebo‐controlled trial of atrasentan in patients with nonmetastatic HRPC.

RESULTS OF SALVAGE CRYOABLATION OF THE PROSTATE AFTER RADIATION: IDENTIFYING PREDICTORS OF TREATMENT FAILURE AND COMPLICATIONS

PURPOSEnWe conduct a critical evaluation of cryoablation of prostate cancer after failure of full dose radiotherapy to identify predictors of treatment failure and complications.nnnMATERIALS AND METHODSnA total of 125 cryoablation procedures were performed in 118 patients with proved local recurrence after full dose radiotherapy. Followup includes serial prostate specific antigen (PSA) and biopsy at 6,12 and 24 months. Kaplan-Meier plots were constructed for different PSA cutoffs. We separately analyzed different cohorts based on T stage, Gleason score, PSA before cryoablation and endocrine therapy status.nnnRESULTSnOf the 118 patients 114 had serum PSA nadir less than 0.5 ng./ml. Median followup was 18.6 months (range 3 to 54). Of the biopsy cores 3.1% (23 of 745) from 7 patients contained persistent viable cancer. Kaplan-Meier plots showed patients free of histological failure leveling at 87% and free from biochemical failure at 68%, 55% and 34%, respectively, with PSA greater than 4, 2 and 0.5 ng./ml. PSA greater than 10 ng./ml. before cryoablation, Gleason score 8 or greater before radiation and stage T3/T4 disease appeared to predict an unfavorable biochemical outcome. Serious complications included 4 rectourethral fistulas (3.3%) and severe incontinence (6.7%). Strong predictors of complications included bulky disease for fistulas and prior transurethral surgery.nnnCONCLUSIONSnSalvage cryoablation after radiation can achieve reasonable biochemical and histological results with acceptable morbidity. Cryoablation appears to be a reasonable treatment option for this patient population with few viable therapeutic options, provided vigorous patient selection criteria are adhered to.

Multicenter Phase II Study of Combined Neoadjuvant Docetaxel and Hormone Therapy Before Radical Prostatectomy for Patients With High Risk Localized Prostate Cancer

PURPOSEnWe assessed pathological outcomes as well as the feasibility of combined docetaxel and androgen deprivation therapy in men with prostate cancer before undergoing prostatectomy.nnnMATERIALS AND METHODSnIn this phase II multicenter study of newly diagnosed patients with untreated clinically localized prostate cancer and high risk features, all patients received androgen deprivation therapy (6.3 mg buserelin acetate every 8 weeks for 3 doses and antiandrogen for 4 weeks) with docetaxel (35 mg/m(2) weekly for 6 of 8 weeks for 3 doses).nnnRESULTSnA total of 72 men with a median age of 59 years (range 46 to 78) were enrolled in the study. Baseline characteristics included clinical stage T1C, T2 or T3 in 14%, 47% and 39%, and Gleason score 7 or less, 8 and 9 in 40%, 29% and 31% of patients, respectively. Median baseline prostate specific antigen was 10.8 mug/l (range 1.6 to 65.6). Eight patients did not complete protocol therapy because of toxicity (4), withdrawal of consent (1) and other reasons (3). Of the 64 patients completing protocol therapy 2 had a complete pathological response. Pathological stage was T2 in 53% and T3 in 44% of patients. Four patients had N1 disease and positive surgical margins were identified in 27%. At a median followup of 42.7 months (range 25.6 to 65.6) 19 patients (30%) had disease relapse.nnnCONCLUSIONSnCombined androgen deprivation and docetaxel before prostatectomy was feasible, and resulted in encouraging recurrence-free survival. While pathological down staging was observed, pathological complete response rates were rare.

RENAL AUTOTRANSPLANTATION FOR THE LOIN PAIN-HEMATURIA SYNDROME: LONG-TERM FOLLOWUP OF 26 CASES

PURPOSEnWe review the long-term results of renal autotransplantation as a form of nephron sparing renal denervation for patients with the loin pain-hematuria syndrome.nnnMATERIALS AND METHODSnFrom 1985 to 1997, after exclusion of other urological, nephrological and psychiatric causes for severe intractable flank pain and recurrent hematuria, 22 patients with severe debility and heavy narcotic dependency underwent 26 renal autotransplantations for pain control. Postoperative pain relief, narcotic use, level of function in daily activities and status of the autograft were assessed.nnnRESULTSnMedian and mean followup was 78.5 and 84.7 months (range 30 to 138), respectively. There were 2 technical failures. Pain recurred within 2 years after 6 procedures, of which 3 resulted in transplant nephrectomy and 3 were managed with a reduced analgesic requirement. Of the 16 patients with minimum 5 years of followup 12 (75%) were pain-free after surgery with 3 additional patients pain-free after transplant nephrectomy. Overall, 18 of the 26 autotransplant procedures (69.2%) resulted in pain relief, in some cases beyond 10 years, with patients returning to normal daily activities.nnnCONCLUSIONSnRenal autotransplantation results in durable narcotic-free favorable results in the majority of meticulously screened loin pain-hematuria syndrome patients. Although some failures, which usually occur within 2 years after surgery, can be expected, autotransplantation is justified as a nephron sparing denervation therapy for select loin pain-hematuria syndrome patients.

THREE-DIMENSIONAL TRANSRECTAL ULTRASOUND GUIDED CRYOABLATION FOR LOCALIZED PROSTATE CANCER IN NONSURGICAL CANDIDATES: A FEASIBILITY STUDY AND REPORT OF EARLY RESULTS

PURPOSEnA 3-dimensional (D) transrectal ultrasound imaging system was incorporated into the cryoablation routine for prostate cancer to assess its feasibility and use. The objective was to improve visibility for probe placement and for intraoperative monitoring.nnnMATERIALS AND METHODSnA commercially available transrectal ultrasound unit was coupled with a custom designed software system to construct 3-dimensional prostate images. A total of 52 patients with clinically localized prostate cancer, in whom radiotherapy had failed (45) or who were otherwise judged to be nonsurgical candidates (7) were treated with cryoablation, using 3-D transrectal ultrasound for intraoperative guidance.nnnRESULTSnIn all cases the intraoperative 3-D transrectal ultrasound images provided a unique coronal view of the prostate, revealing useful information and facilitating more precise probe placement and treatment monitoring. Early postoperative histological and biochemical results and complication rates compare well with other contemporary series.nnnCONCLUSIONSnAlthough the precise role of cryoablation in the management of prostate cancer remains unclear and long-term results are pending, incorporation of a 3-D transrectal ultrasound imaging system into the cryoablation routine proved to be feasible and appeared to be a worthwhile effort to facilitate the procedure, and deserves further evaluation.

High-intensity Focused Ultrasound for Prostate Cancer: a Systematic Review

High-intensity focused ultrasound (HIFU) has recently been promoted as a non-invasive treatment option for prostate cancer. This systematic review sought to evaluate the evidence comparing it with standard treatment in patients with localised prostate cancer. The literature review included searches of MEDLINE, EMBASE, the Cochrane Library, annual meetings abstracts and websites of evidence-based practice guideline producers. Studies were included if they were randomised controlled trials comparing HIFU with current management approaches, or were meta-analyses, systematic reviews or practice guidelines addressing HIFU. No randomised controlled trials or meta-analyses were identified. Seven systematic reviews and two practice guidelines were identified; neither contained randomised controlled trials. Adjusting the selection criteria to include case series found 34 clinical studies of HIFU. Twenty-nine evaluated HIFU as the primary treatment and five examined HIFU as salvage treatment for recurrence after radiotherapy. In most studies the outcomes used to determine efficacy were negative biopsy rates or prostate-specific antigen (PSA) levels. Among the 29 studies of HIFU as the primary treatment, negative biopsy rates ranged from 35 to 95% in 21 studies, a PSA nadir of ≤0.5 ng/ml ranged from 55 to 91% in 10 studies and mean PSA nadirs ranged from 0 to 1.9 ng/ml in 17 studies. Five studies reported 5-year disease-free survival rates ranging from 55 to 95%. Among five studies of HIFU as salvage treatment, negative biopsy rates ranged from 73 to 84% in four studies, a PSA nadir of ≤0.5 ng/ml ranged from 57 to 66% in three studies and mean PSA nadirs were 1.97 and 2.38 ng/ml in two studies, respectively. Current evidence on HIFU use in prostate cancer patients is of low quality, rendering it difficult to draw conclusions about its efficacy. Until results from case series are confirmed in prospective studies, the widespread use of HIFU is not supported.

A Phase 3, Double-blind, Randomised, Parallel-group, Placebo-controlled Study of Oral Weekly Alendronate for the Prevention of Androgen Deprivation Bone Loss in Nonmetastatic Prostate Cancer: The Cancer and Osteoporosis Research with Alendronate and Leuprolide (CORAL) Study

BACKGROUNDnAndrogen-deprivation therapy (ADT) induces loss of bone mineral density (BMD) and increases the risk of fractures in patients with prostate cancer (PCa). We sought to determine whether a weekly dose of alendronate, an oral bisphosphonate, could reduce this unwanted side-effect.nnnOBJECTIVEnTo assess whether once-weekly oral alendronate therapy would maintain or improve BMD in men initiating ADT for localised PCa.nnnDESIGN, SETTING, AND PARTICIPANTSnA multicentre, double-blind, randomised, placebo-controlled study, we included hormonally naïve PCa patients initiating ADT with leuprolide acetate 30 mg intramuscularly every 4 mo.nnnINTERVENTIONnPatients were randomised to receive either oral alendronate 70 mg once weekly or placebo for 1 yr. Both groups received daily calcium 1g and vitamin D 400 international units.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnChanges in BMD (at the lumbar spine [LS] and total hip [TH]) and bone markers.nnnRESULTS AND LIMITATIONSnOne hundred ninety-one subjects were enrolled, and 186 were randomised between alendronate (n=84) and placebo (n=102). The alendronate group demonstrated a mean spine BMD increase of 1.7% compared with -1.9% in the placebo group (p<0.0001). Alendronate also increased the BMD at the hip (percent change: 0.7%) compared to placebo (-1.6%). Median urinary N-terminal crosslinking telopeptide of type I collagen (Ntx) values decreased by 3.5% in the alendronate group and increased by 16.5% in the placebo arm, even after adjusting for centre (p=0.510) and baseline urinary Ntx (p<0.0001). Bone-specific alkaline phosphatase (BSAP) decreased a median of 2.25% in the alendronate group and increased a median of 3.12% in the placebo arm, regardless of centre or baseline BSAP or other covariates (p<0.0001). The safety and tolerability profile was similar for the two treatment groups.nnnCONCLUSIONSnAlthough the study was closed early because of slow accrual, it showed that weekly oral alendronate prevented bone loss and increased bone mass in addition to decreasing bone turnover in patients initiating ADT for localised PCa, with few related side-effects.

Design and evaluation of a 3D transrectal ultrasound prostate biopsy system.

Biopsy of the prostate using ultrasound guidance is the clinical gold standard for diagnosis of prostate adenocarcinoma. The current prostate biopsy procedure is limited to using 2D transrectal ultrasound (TRUS) images to target biopsy sites and record biopsy core locations for postbiopsy confirmation. Localization of the 2D image in its actual 3D position is ambiguous and limits procedural accuracy and reproducibility. We have developed a 3D TRUS prostate biopsy system that provides 3D intrabiopsy information for needle guidance and biopsy location recording. The system conforms to the workflow and imaging technology of the current biopsy procedure, making it easier for clinical integration. In this paper, we describe the system design and validate the system accuracy by performing mock biopsies on US/CT multimodal patient-specific prostate phantoms. Our biopsy system generated 3D patient-specific models of the prostate with volume errors less than 3.5% and mean boundary errors of less than 1 mm. Using the 3D biopsy system, needles were guided to within 2.3 +/- 1.0 mm of 3D targets and with a high probability of biopsying clinically significant tumors. The positions of the actual biopsy sites were accurately localized to within 1.5 +/- 0.8 mm.

Salvage HIFU for recurrent prostate cancer after radiotherapy.

Recurrent disease following primary radiotherapy for localized prostate cancer is a common problem, occurring in up to 46% of patients. For these patients, therapeutic options include salvage prostatectomy, salvage cryotherapy, salvage high-intensity focused ultrasound (HIFU), hormonal therapy or observation. This review will focus on the emerging evidence for salvage HIFU. There are no randomized or prospective studies in this area. Efficacy results of 17–57% have been reported from retrospective case series, with reported toxicity including rectal fistula in 0–16%, and incontinence in 10–50%. The ideal patient, while yet to be clearly defined, should have preradiotherapy low or intermediate risk disease. Salvage HIFU appears most appropriate for those patients with histologically proven local recurrence only, with a life expectancy of at least 5 years and with some medical comorbidities rendering them not ideal for salvage prostatectomy.