Jure Murgic

Lessons learned using an MRI-only workflow during high-dose-rate brachytherapy for prostate cancer

PURPOSE We report clinical observations of a technique using an MRI-only workflow for catheter insertion and treatment planning in patients receiving standard-care high-dose-rate brachytherapy before external beam radiotherapy for prostate cancer. METHODS AND MATERIALS Forty patients with intermediate or high-risk prostate cancer were enrolled on a prospective clinical trial approved by our institutions research ethics board. Multiparametric MRI with stereotactic navigation was used to guide insertion of brachytherapy catheters, followed by MRI-based treatment planning. RESULTS Sixty-two implants were performed. Median catheter insertion + imaging time was 100 minutes, and overall anesthesia time was 4.0 hours (range, 2.1-6.9 hours). MRI at the time of brachytherapy restaged 14 patients (35%) who were found to have a higher stage of disease. In 6 patients, this translated in directed insertion of brachytherapy catheters outside the prostate boundary (extracapsular disease [n = 2] or seminal vesicle invasion [n = 4]). Most patients (80%) had gross tumor visible on MRI, which influenced catheter insertion and treatment planning. MRI depicted postimplant anatomic boundaries clearly, with the exception of the apical prostate which was blurred by trauma after catheter insertion. Conventional dose-planning objectives for the rectum (V75 < 1.0 cc) were difficult to achieve, but toxicities were low (acute grade ≥ 2 genitourinary = 20%, late grade ≥ 2 genitourinary = 15%, and late grade ≥ 2 gastrointestinal = 7%). Urethral trauma visualized on MRI led to two transient Grade 3 events. CONCLUSIONS Despite a standard-care approach, MRI acquired throughout the procedure altered catheter insertion and dose-planning strategies. An MRI-only workflow is feasible but must be streamlined for broader acceptance.

Translating a Prognostic DNA Genomic Classifier into the Clinic: Retrospective Validation in 563 Localized Prostate Tumors

BACKGROUND Localized prostate cancer is clinically heterogeneous, despite clinical risk groups that represent relative prostate cancer-specific mortality. We previously developed a 100-locus DNA classifier capable of substratifying patients at risk of biochemical relapse within clinical risk groups. OBJECTIVE The 100-locus genomic classifier was refined to 31 functional loci and tested with standard clinical variables for the ability to predict biochemical recurrence (BCR) and metastasis. DESIGN, SETTING, AND PARTICIPANTS Four retrospective cohorts of radical prostatectomy specimens from patients with localized disease were pooled, and an additional 102-patient cohort used to measure the 31-locus genomic classifier with the NanoString platform. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The genomic classifier scores were tested for their ability to predict BCR (n=563) and metastasis (n=154), and compared with clinical risk stratification schemes. RESULTS AND LIMITATIONS The 31-locus genomic classifier performs similarly to the 100-locus classifier. It identifies patients with elevated BCR rates (hazard ratio=2.73, p<0.001) and patients that eventually develop metastasis (hazard ratio=7.79, p<0.001). Combining the genomic classifier with standard clinical variables outperforms clinical models. Finally, the 31-locus genomic classifier was implemented using a NanoString assay. The study is limited to retrospective cohorts. CONCLUSIONS The 100-locus and 31-locus genomic classifiers reliably identify a cohort of men with localized disease who have an elevated risk of failure. The NanoString assay will be useful for selecting patients for treatment deescalation or escalation in prospective clinical trials based on clinico-genomic scores from pretreatment biopsies. PATIENT SUMMARY It is challenging to determine whether tumors confined to the prostate are aggressive, leading to significant undertreatment and overtreatment. We validated a test based on prostate tumor DNA that improves estimations of relapse risk, and that can help guide treatment planning.

Single institution long-term efficacy and safety analysis of abiraterone acetate (AA) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in a named patient programme (NPP)

Abiretrone acetate (AA) administration in patients with metastatic castration-resistant prostate cancer (mCRPC) results in powerful androgen depletion and consequential reversal of the castrate-resistant state. This translates into the improved survival observed in large phase III trials, with AA given in combination with prednisone either before or after docetaxel chemotherapy.1 ,2 As wide-access studies regularly fail to replicate the same findings as those from large registrational trials, we sought to investigate the long-term efficacy and safety of AA in an unselected population of patients with mCRPC that may be more representative of a real-life clinical setting.3 After publication of the CUO-AA-301 trial in 2011, and before regulatory approval by the European Medicines Agency, AA was made available in Croatia through a named patient programme (NPP), approved by the local hospital ethics committee.1 Within our institution, we prospectively reviewed clinical records of patients with mCRPC treated with AA to …

Improved outcomes with dose escalation in localized prostate cancer treated with precision image-guided radiotherapy

BACKGROUND AND PURPOSE Dose-escalated radiotherapy (DE) improves outcomes in localized prostate cancer (PCa). The impact of DE in the context of image-guided radiotherapy (IGRT) remains unknown. Herein, we determined outcomes of three sequential cohorts treated with progressive DE-IGRT. MATERIALS AND METHODS We analyzed data from 1998 to 2012. Patients treated with radical radiotherapy were included, with three sequential institutional schedules: (A) 75.6Gy, (B) 79.8Gy, (C) 78Gy, with 1.8, 1.9 and 2Gy/fraction, respectively. IGRT consisted of fiducial markers and daily EPID (A, B) or CBCT (C). RESULTS 961 patients were included, with median follow-up of 6.1y. 30.5%, 32.6% and 36.9% were treated in A, B and C, respectively. Risk category distribution was 179 (18.6%) low-, 653 (67.9%) intermediate- and 129 (13.5%) high-risk. PSA, T-category, androgen deprivation use and risk distribution were similar among groups. BCR (biochemical recurrence) was different (p<0.001) between A, B and C with 5-year rates of 23%, 17% and 9%, respectively (HR 2.68 [95% CI 1.87-3.85] and 1.92 [95% CI 1.33-2.78] for A and B compared to C, respectively). Findings were most significant in the intermediate-risk category. Metastasis, cause-specific-death and toxicities were not different between cohorts. CONCLUSION Our findings suggest continuous BCR improvement with progressive DE-IGRT. Prospective validation considering further DE with IGRT seems warranted.

Adjuvant treatment following radical cystectomy for muscle-invasive urothelial carcinoma and variant histologies: Is there a role for radiotherapy?

Comprehensive molecular characterisation of muscle-invasive urothelial carcinoma and variant histological subtypes has led to the identification of recurrent driver mutations that are distinct in these aggressive subgroups of bladder cancer. While distant metastasis dominates as a pattern of relapse following radical cystectomy or chemoradiotherapy, loco-regional control rates are also suboptimal with single modality local treatment, and likewise, harbour equivocal implications on the long-term prognosis of patients. The role of adjuvant radiotherapy for optimising disease control within the pelvis is controversial, with limited evidence to support its efficacy. Herein, we present a stepwise review on adjuvant radiotherapy post-cystectomy; first, discussing the evidence to date supporting the concept that adjuvant radiotherapy is effective in targeting occult metastases within the pelvis, and adds to the benefits of adjuvant chemotherapy. Next, we outlined the principles underlying the definition of radiotherapy target volumes. To conclude, we addressed the need for appropriate patient stratification for treatment intensification, based on existing clinical models and novel molecular indices of aggression in muscle-invasive urothelial cancers and variant histological subtypes.

Abstract 4339: Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Aim: Men with intermediate-risk prostate cancer represent a heterogeneous group of patients with varying prognoses. Intraductal carcinoma (IDC), cribriform architecture (CA), and high copy number alteration burden are novel pathological and genomic indices that predict aggressive disease and inferior clinical outcomes in patients with localised prostate cancer. We aimed to test the independent prognostic effect of these indices in a cohort of intermediate-risk prostate cancers. Experimental methods: We defined a set of clinical and genomic indices to test for their prognostic significance in a cohort of individuals with NCCN-defined intermediate-risk prostate cancer, who were treated with radical prostatectomy (RadP) or radiotherapy (RT) (N = 173, RadP; N = 358, RT). Clinical indices include primary T-category, pre-treatment PSA level, Gleasons score and pattern, and presence of IDC and/or CA. Pathological features were reviewed centrally by two expert pathologists. Copy number alteration burden was assessed in 215 tumours of the cohort using SNP array profiling (Affymetrix Oncoscan), and reported as percent genome aberration (PGA). Our primary endpoint was to test if a model incorporating IDC/CA and PGA stratifies patients with intermediate-risk disease for risk of biochemical relapse after primary treatment. Results: Biochemical relapse was associated with PGA on univariable and multivariable analysis for the sub-cohort of 215 patients (HR of High vs Low PGA defined by median = 1.61, 95% CI = 1.04-2.49, Walds p = 0.033). Based on modelling of the clinical indices, presence of IDC/CA was associated with biochemical relapse-free rate (bRFR) on univariable and multivariable analyses (HR = 1.90, 95% CI = 1.34-2.69, p = 0.00034), along with PSA level. Risk stratification considering both IDC/CA and PGA indicated an additive prognostic effect of IDC/CA to PGA for early biochemical relapse, with 18-month bRFR of 83% in High PGA, present IDC/CA vs 94% in Low PGA, absent IDC/CA subgroups (HR = 2.55, 95% CI = 1.49-4.39, p = 0.00069). A comparison of risk stratification models revealed that inclusion of PGA to IDC/CA yielded the strongest model for predicting 18-month bRFR in patients with intermediate-risk prostate cancer following treatment (area under the curve, AUC = 0.580, 95% CI = 0.456-0.675 [T-category, PSA, and IDC/CA] vs 0.649, 95% CI = 0.476-0.776 [T-category, PSA, IDC/CA, and PGA]). Conclusions: We herein demonstrate for the first time a novel risk stratification model integrating pathological (IDC/CA) and genomic (PGA) indices to identify patients with unfavourable intermediate-risk prostate cancer, who may benefit from intensification to conventional definitive treatment. Citation Format: Melvin Lee Kiang Chua, Jure Murgic, Melania Pintilie, Emilie Lalonde, Charlotte Kweldam, Winnie Lo, Alejandro Berlin, Alan Dal Pra, Michele Orain, Valerie Picard, Helene Hovington, Alain Begeron, Yves Fradet, Bernard Tetu, Julie Livingstone, Alice Meng, Jun Yan Zhang, Gaetano Zafarana, Neil Fleshner, Mike Fraser, Paul Boutros, Robert Bristow, Theodorus van der Kwast. Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4339.