Only retrospective data are available for low-dose-rate (LDR) salvage prostate brachytherapy for local recurrence after external beam radiation therapy (EBRT). The primary objective of this ...prospective phase 2 trial (NCT00450411) was to evaluate late gastrointestinal and genitourinary adverse events (AEs) after salvage LDR brachytherapy.
Eligible patients had low- or intermediate-risk prostate cancer before EBRT and biopsy-proven recurrence >30 months after EBRT, with prostate-specific antigen levels <10 ng/mL and no regional/distant disease. The primary endpoint was grade 3 or higher late treatment-related gastrointestinal or genitourinary AEs occurring 9 to 24 months after brachytherapy. These AEs were projected to be ≤10%, with ≥20% considered unacceptable. All events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Multivariate analyses investigated associations of pretreatment or treatment variables with AEs.
One hundred patients from 20 centers were registered from May 2007 to January 2014. The 92 analyzable patients had a median follow-up of 54 months (range, 4-97) and a median age of 70 years (interquartile range IQR, 65-74). The initial Gleason score was 7 in 48% of patients. The median dose of EBRT was 74 Gy (IQR, 70-76) at a median interval of 85 months previously (IQR, 60-119). Only 16% had androgen deprivation at study entry. Twelve patients (14%) had late grade 3 gastrointestinal/genitourinary AEs, with no treatment-related grade 4 or 5 AEs. No pretreatment variable predicted late AEs, including prior EBRT dose and elapsed interval. Higher V100 (percentage of prostate enclosed by prescription isodose) predicted both occurrence of late AEs (odds ratio, 1.24; 95% confidence interval, 1.02-1.52; P = .03) and earlier time to first occurrence (hazard ratio, 1.18; 95% CI, 1.03-1.34; P = .02).
This prospective multicenter trial reports outcomes of salvage LDR brachytherapy for post-EBRT recurrence. The rate of late grade 3 AEs did not exceed the unacceptable threshold. The only factor predictive of late AEs was implant dosimetry reflected by V100. Efficacy outcomes will be reported at a minimum of 5-year follow-up.
Abstract Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a ...pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery ( p = 0.024) and validation ( p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM , RB1 , and FANCC predicted pathologic response ( p < 0.001; 87% sensitivity, 100% specificity) and better overall survival ( p = 0.007). This test remained predictive for pathologic response in the validation set ( p = 0.033), with a trend towards better overall survival ( p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM , RB1 , and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.
To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for ...patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.
Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro and in xenograft tumors for cabazitaxel response.
The data herein show that (i) cabazitaxel exerts stronger cytostatic and cytotoxic response compared with docetaxel, especially in CRPC; (ii) cabazitaxel induces aberrant mitosis, leading to pyknotic and multinucleated cells; (iii) taxanes do not act through the androgen receptor (AR); (iv) gene-expression profiling reveals distinct molecular actions for cabazitaxel; and (v) tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to cabazitaxel.
Cabazitaxel not only induces improved cytostatic and cytotoxic effects, but also affects distinct molecular pathways, compared with docetaxel, which could underlie its efficacy after docetaxel treatment has failed in patients with CRPC. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization to taxanes, which could benefit up to 50% of CRPC cases.
Abstract Purpose For prostate cancer that is thought to be locally recurrent after prostatectomy, the optimal timing, dose and techniques for salvage radiotherapy (SRT) have not been established. ...Here we perform a systematic review of published reports including regression meta-analysis and radiobiologic modelling to identify predictors of biochemical disease control and late toxicity. Methods We performed a review of published series reporting treatment outcomes following SRT. Studies with at least 30 patients, median PSA before SRT of less than 2.0 ng/mL, and median follow-up of greater than 36 months were identified. Univariate and multivariate analyses were performed to test Gleason Score, SRT dose, SRT timing, pre-SRT PSA, whole pelvic irradiation and androgen deprivation therapy as predictors of 5-year biochemical progression-free survival (bPFS) and severe (grade ⩾ 3) late GI and GU toxicity. bPFS and toxicity data were fit to tumour control probability and normal tissue complication probability models, respectively. Results Twenty-five articles met the inclusion criteria for this analysis. Five-year bPFS ranged from 25% to 70%. Severe late GI toxicity rates were 0% to 9%, and severe late GU toxicity rates were 1–11%. On multivariate analysis, bPFS increased with SRT dose by 2.5% per Gy and decreased with pre-SRT PSA by 18.3% per ng/mL ( p < 0.001). Late GI and GU toxicity increased with SRT dose by 1.2% per Gy ( p = 0.012) and 0.7% per Gy ( p = 0.010), respectively. Radiobiological models demonstrate the interaction between pre-SRT PSA, SRT dose and bPFS. For example, an increase in pre-SRT PSA from 0.4 to 1.0 ng/mL increases the SRT dose required to achieve a 50% bPFS rate from 60 to 70 Gy. This could increase the rate of severe late toxicity by approximately 10%. Conclusion Biochemical control rates following SRT increase with SRT dose and decrease with pre-SRT PSA. Severe late GI and GU toxicity rates also increase with SRT dose. Radiobiological models suggest that the therapeutic ratio of SRT may be improved by initiating treatment at low PSA levels.
Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that ...incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.
A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).
Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included
and mismatch repair genes, with broader testing, such as
, for clinical trial eligibility.
was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for
carriers, with consideration in
, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.
This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
Provide evidence- and expert-based recommendations for optimal use of imaging in advanced prostate cancer. Due to increases in research and utilization of novel imaging for advanced prostate cancer, ...this guideline is intended to outline techniques available and provide recommendations on appropriate use of imaging for specified patient subgroups.
An Expert Panel was convened with members from ASCO and the Society of Abdominal Radiology, American College of Radiology, Society of Nuclear Medicine and Molecular Imaging, American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology to conduct a systematic review of the literature and develop an evidence-based guideline on the optimal use of imaging for advanced prostate cancer. Representative index cases of various prostate cancer disease states are presented, including suspected high-risk disease, newly diagnosed treatment-naïve metastatic disease, suspected recurrent disease after local treatment, and progressive disease while undergoing systemic treatment. A systematic review of the literature from 2013 to August 2018 identified fully published English-language systematic reviews with or without meta-analyses, reports of rigorously conducted phase III randomized controlled trials that compared ≥ 2 imaging modalities, and noncomparative studies that reported on the efficacy of a single imaging modality.
A total of 35 studies met inclusion criteria and form the evidence base, including 17 systematic reviews with or without meta-analysis and 18 primary research articles.
One or more of these imaging modalities should be used for patients with advanced prostate cancer: conventional imaging (defined as computed tomography CT, bone scan, and/or prostate magnetic resonance imaging MRI) and/or next-generation imaging (NGI), positron emission tomography PET, PET/CT, PET/MRI, or whole-body MRI) according to the clinical scenario.
To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP).
...Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms.
The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups.
The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer.
The optimal timing of postoperative radiotherapy (RT) after radical prostatectomy (RP) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into ...the development of clinical metastases in men receiving post-RP RT and inform decision making.
GC scores were calculated from 188 patients with pT3 or margin-positive prostate cancer, who received post-RP RT at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The primary end point was clinical metastasis. Prognostic accuracy of the models was tested using the concordance index for censored data and decision curve analysis. Cox regression analysis tested the relationship between GC and metastasis.
The cumulative incidence of metastasis at 5 years after RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (P = .002). In multivariable analysis, GC and pre-RP prostate-specific antigen were independent predictors of metastasis (both P < .01). Within the low GC score (< 0.4), there were no differences in the cumulative incidence of metastasis comparing patients who received adjuvant or salvage RT (P = .79). However, for patients with higher GC scores (≥ 0.4), cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared with 23% for patients treated with salvage RT (P < .01).
In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical and pathologic features. Although preliminary, patients with low GC scores are best treated with salvage RT, whereas those with high GC scores benefit from adjuvant therapy. These findings provide the first rational selection of timing for post-RP RT.
Data supporting neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma are scant. In this multi-institution, prospective, phase II trial we investigated pathological complete ...responses after neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma.
Patients with high grade upper tract urothelial carcinoma in whom nephroureterectomy was planned were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin and cisplatin in those with baseline creatinine clearance greater than 50 ml per minute or gemcitabine and carboplatin in those with creatinine clearance 30 to 50 ml per minute or less. The study primary end point was a pathological complete response (ypT0N0). The accrual goal was 30 patients per arm. An 18% pathological complete response was considered worth further study while a 4% pathological complete response would not have justified pursuing this regimen. With 28 eligible patients per arm success was defined as 3 or more pathological complete responses (10.7%) in a given arm. Secondary end points included safety, renal function and oncologic outcomes.
A total of 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm from 2015 to 2017. Six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Of the 29 patients eligible for accelerated methotrexate, vinblastine, doxorubicin and cisplatin, including 23 men and 6 women with a median age of 65 years (range 40 to 84), 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8). In 1 patient receiving accelerated methotrexate, vinblastine, doxorubicin and cisplatin nephroureterectomy was deferred due to grade 4 sepsis. The grade 3-4 toxicity rate was 23% in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm with no grade 5 event.
Accelerated methotrexate, vinblastine, doxorubicin and cisplatin neoadjuvant chemotherapy in patients with high grade upper tract urothelial carcinoma and creatinine clearance greater than 50 ml per minute was safe and demonstrated predefined activity with a 14% pathological complete response rate. Final pathological stage ypT1 or less in more than 60% of patients is encouraging. Together the results of this prospective trial support the use of neoadjuvant chemotherapy in eligible patients with high grade upper tract urothelial carcinoma.
Objective To report on assessments of face, content, and construct validity for the commercially available da Vinci Skills Simulator (dVSS). Methods A total of 38 subjects participated in this ...prospective study. Participants were classified as novice (0 robotic cases performed), intermediate (1-74 robotic cases), or expert (≥75 robotic cases). Each subject completed 5 exercises. Using the metrics available in the simulator software, the performances of each group were compared to evaluate construct validation. Immediately after completion of the exercises, each subject completed a questionnaire to evaluate face and content validation. Results The novice group consisted of 18 medical students and 1 resident. The intermediate group included 6 residents, 1 fellow, and 2 faculty urologist. The expert group consisted of 2 residents, 1 fellow, and 7 faculty surgeons. The mean number of robotic cases performed by the intermediate and expert groups was 29.2 and 233.4, respectively. An overall significant difference was observed in favor of the more experienced group in 4 skill sets. When intermediates and experts were combined into a single “experienced” group, they significantly outperformed novices in all 5 exercises. Intermediates and experts rated various elements of the simulators realism at an average of 4.1/5 and 4.3/5, respectively. All intermediate and expert participants rated the simulator's value as a training tool as 4/5 or 5/5. Conclusion Our study supports the face, content, and construct validation attributed to the dVSS. These results indicate that the simulator may be most useful to novice surgeons seeking basic robot skills acquisition.
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