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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

INTRODUCTION AND OBJECTIVE:Novel hormonal agents (NHAs) such abiraterone acetate (ABI) and enzalutamide (ENZ) are frequently used in metastatic castration-resistant prostate cancer (mCRPC). Despite...

PURPOSE: Several new drug therapies have been approved in CRPC in the past decade. However, little is known about their potential overuse at the end of life. Cancer therapy use at the end of life has been considered an indicator of overtreatment. The study objective was to describe CRPC drug use in the last month of life of CRPC patients in Quebec. PATIENTS AND METHODS: Using administrative databases from the province of Quebec in Canada, we identified patients who received medical or surgical castration treatment, received one or more CRPC drugs (chemotherapy, abiraterone, or bone-targeted therapy), and died between 2001 and 2013. CRPC drug use in the last month of life was the primary outcome. RESULTS: The cohort consisted of 1,148 patients with CRPC. A total of 316 men (27.5%) received a CRPC drug in the last month of life. For those who received chemotherapy, abiraterone, and bone-targeted therapy, 10.2%, 27.8%, and 31.8% received them in the last month of life, respectively. In multivariable analyses, age older than 75 years (odds ratio [OR], 0.75; 95% CI, 0.57 to 0.99), and prostate cancer diagnosis received less than 24 months earlier (OR, 0.43; 95% CI, 0.26 to 0.72) were associated with less CRPC drug use. Relative to dying between 2005 and 2011, dying between 2012 and 2013 (OR 1.60; 95% CI, 1.18 to 2.18) was associated with greater CRPC drug use. CONCLUSION: More than one quarter of patients received CRPC drug therapies in the last month of life. Persistent chemotherapy, abiraterone, bone-targeted therapies, and medical castration drugs in the last month of life may be an indicator of inappropriate and expensive end-of-life care.

Purpose Immune checkpoint programmed death-ligand 1 inhibitor therapy has shown response in metastatic muscle invasive bladder cancer (MIBC). We evaluated the safety and tolerability of atezolizumab (anti-programmed death-ligand 1) in combination with trimodal therapy in patients with localized MIBC. Methods and Materials A prospective nonrandomized phase 1 study using a 3 + 3 design was conducted in patients with localized MIBC (T2-T4a N0M0) treated on a bladder preservation program. After transurethral resection of bladder tumor, patients received concurrent radiation therapy at a fixed dose of 50 Gy in 20 fractions, gemcitabine (100 mg/m2, intravenously once weekly for 4 weeks) and atezolizumab (1200 mg intravenously every 3 weeks for 16 cycles). The primary endpoint was safety/toxicity profile. Results Between May 2018 and March 2019, 8 patients (6 male and 2 female) were enrolled. The first 5 patients received atezolizumab at 1200 mg, 3 of whom developed grade 3 side effects (2 of them dose-limiting toxicity). Atezolizumab dose was reduced to 840 mg for 3 additional patients. The study was terminated due to the presence of 3 grade 3 adverse events (2 of which were dose-limiting toxicity) despite the reduced atezolizumab dose. Gastrointestinal events were the main toxicity. No grade 4 to 5 adverse effects were observed. Conclusions Concurrent administration of atezolizumab with concomitant hypofractionated radiation therapy and gemcitabine appears to be associated with unacceptable gastrointestinal toxicity. Although the numbers studied are small, our results suggest considerable caution with its concurrent use with trimodal therapy for MIBC.

Background: Inaccurate risk classification and the burden of unnecessary biopsies are a challenge due to the limited ability of current risk assessment tools and modalities to diagnose prostate cancer (PCa) and distinguish indolent from aggressive disease. This systematic review assesses newly developed tests and interventions with high evidence of clinical utility that might be adopted in clinical practice during PCa management before initial and repeat biopsy, after positive biopsy, and after radical treatment. Methods: The Cochrane, Embase, MEDLINE, and Web of Science databases were searched for studies pertaining to the clinical utility of PCa diagnostic tests. Outcomes of interest were (1) a measure of the percentage of altered decision-making, (2) decrease in number of unnecessary biopsies, (3) decrease or increase in treatment intensity, and (4) risk reclassification after test results. Results: The search yielded 2,940 articles, of which 46 met the inclusion criteria. We found clinical utility evidence on the Prostate Health Index (PHI), 4Kscore test, MRI, OncotypeDX, Decipher test, Prolaris, ConfirmMDx, Progensa PCA3, NADiA ProsVue, and ProMark. No evidence was identified for Prostarix, ProstaVysion, Prostate Core Mitomic Test, and Mi-Prostate Score. The interventions demonstrated their clinical utility in terms of change in treatment recommendations, decrease/increase in interventional treatment, decrease in biopsy, and risk reclassification. At diagnosis after a positive biopsy, ProMark, OncotypeDX, Prolaris, and MRI guided the use of active surveillance. Use of NADiA ProsVue, Decipher, and Prolaris aided in the decision to add adjuvant therapy post-prostatectomy. PHI, 4Kscore, and MRI used prior initial and repeat biopsies, and ConfirmMDx and Progensa PCA3 used prior repeat biopsies to improve prediction of biopsy outcome, allowing a decrease in unnecessary biopsies. Conclusions: This systematic review suggests that implementation of these tests in clinical practice could effectuate personalized treatment of PCa. Further clinical and economic evaluation studies of long-term PCa outcomes are warranted to provide further guidance.

Prostate cancer (PCa) is curable in most men but becomes lethal for patients with metastases at diagnosis and those who experience biochemical recurrence (BCR) after curative therapies. Androgen deprivation therapy is given upon BCR, but patients inevitably fail and become castration resistant (CRPC), dying from metastatic (m)CRPC despite receiving 2nd and 3rd line therapies (androgen receptor inhibitors/ARIs and/or taxanes). Drugs targeting other pathways have been tested in clinical trials. Few are implemented in practice due to low response rates, although some show a significant benefit in subsets of unselected patients. This clinical heterogeneity underscores the cellular and functional heterogeneity of malignant cells, highlighting the need for biomarkers of response to therapies. In line with the growing interest in using non-invasive liquid biopsies to monitor disease progression, we hypothesized that genes encoding proteins representative of prostate epithelial cell-subtypes may be detectable in blood as predictive biomarkers. Our objective was to identify such representative genes and test them in the blood of patients to determine whether they can stratify patients for optimal disease management. 14 genes pertaining to cell subtypes were chosen based on a thorough literature review. The panel was validated in transcriptomic datasets showing their predominant overexpression in metastases of mCRPC cases compared to primary tumours and benign prostate from diverse cohorts of patients. TaqMan assays were designed and optimized in serial dilutions of RNA from five prostate cancer cell lines. The panel was tested in the blood of healthy controls (n=9) and patients prior to prostatectomy (n=8), post-curative therapies (n=7), or mCRPC (n=19). In control men with no prostatic disease in their lifetime, we see low or no expression of most genes, with no correlation with age (29-71 years old). No association was seen between the proportions of different white blood cells and genes of interest expressed at varying levels in the blood of mCRPC patients. The threshold for overexpression in patients was defined as 2.58 standard deviation above the mean expression from controls (99.5% confidence interval). Phenotypic and functional diversity was seen in all categories of patients. Changes in genes patterns were significant in mCRPC cases based on current treatments (at time of blood draw) and the choice of initial curative therapy. For example, neuroendocrine genes were predominantly overexpressed in patients who underwent curative radiation therapy, whereas stem cell genes arose in cases under AR-Is at blood draw. In conclusion, we identified circulating genes that may be clinically meaningful to stratify and follow patients and predict response to therapies. Genes encoding drug targets may allow patient-tailored clinical trials for personalized treatments to impact on this unpredictable and lethal disease. Citation Format: Seta Derderian, Edouard Jarry, Arynne Santos, Mohanachary Amaravadi, Quentin Vesval, Lucie Hamel, Nathalie Cote, Marie Vanhuyse, Armen Aprikian, Simone Chevalier. Identifying therapeutic options for patients with advanced prostate cancer through genes in liquid biopsies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr CC06-01.

Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases. Patient selection was based on death from a pca-related cause or therapy used according to the Canadian Urological Association guidelines on mcrpc management. Treatments included chemotherapy (mitoxantrone before 2005 and docetaxel after 2005), abiraterone, bone-targeted therapy (zoledronic acid or denosumab, or both), and palliative radiation therapy (rt). During the study period, neither enzalutamide nor cabazitaxel was publicly reimbursed in Quebec, and as a result, no capture of their use was possible for this study. Multivariate logistic regression was used to identify factors associated with the probability of receiving chemotherapy, bone-targeted therapies, and palliative rt before death from pca. Overall, the database search identified 3106 patients who died of pca between January 2001 and December 2013. Median age of death was 78 years. Of those 3106 patients, just 2568 (83%) received mcrpc-specific treatments: chemotherapy, abiraterone, palliative rt, or bone-targeted therapy, the other 17% of the patients were managed solely with maximum androgen blockade (androgen deprivation therapy plus anti-androgens) despite a record of pca-related death. Logistic regression analyses indicate that patients dying after 2005 were more likely to have received chemotherapy [odds ratio (or): 1.51, 95% ci: 1.22 to 1.85] and bone-targeted therapy (or: 1.97, 95% ci: 1.64 to 2.37). Age was a significant predictor for the use of chemotherapy, bone-targeted therapy, and palliative rt (ors in the range 0.96&ndash, 0.98, p < 0.05). Patient age seems to be a strong determinant in the of selection mcrpc therapy, affecting the probability of the use of chemotherapy, bone-targeted therapy, or palliative rt. Although chemotherapy is still used only in a small percentage of patients, the introduction of new therapies&mdash, such as bone-targeted therapy, docetaxel, and abiraterone&mdash, affected treatment selection over time. The availability of enzalutamide since February 2014 will likely produce additional changes in mcrpc management.

Introduction In this study we determined self-perceived knowledge gaps and continuing medical education preferences among Canadian urologists and medical oncologists related to the treatment of patients with kidney cancer. Methods A needs assessment survey was created by the Quality Initiative group of the Kidney Cancer Research Network of Canada using an iterative feedback process. The survey determined knowledge gaps and continuing medical education preferences pertaining to 23 previously validated quality indicators of kidney cancer care. Topics included screening, diagnosis, prognosis, surgical management, systemic therapies and followup care. The survey was distributed via e-mail to Canadian urologists and medical oncologists. Results Among the 164 respondents 121 (74%) were urologists and 43 (26%) were medical oncologists. The majority of respondents practice in academic (72, 57%) or large urban community centers (40, 32%). Of the 23 quality indicators examined 14 were designated as priority continuing medical education topics based on perceived inadequate knowledge or high interest in the topic. Priority topics were similar for urologists and medical oncologists, and covered the spectrum of kidney cancer care with an emphasis on hereditary kidney cancer and management of advanced disease. Most respondents preferred that continuing medical education be delivered through in person, case based group discussions. Conclusions Canadian urologists and medical oncologists report similar knowledge gaps and continuing medical education preferences regarding kidney cancer care. Priority topics include screening for hereditary kidney cancer and management of advanced disease.

Background: Local control following trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC) requires further optimization. Objective: Evaluating the biologic endpoint, feasibility, and toxicity of integrating everolimus to TMT in patients with MIBC. Methods: This was a phase I trial in patients with MIBC who were not surgical candidates or who refused cystectomy. Following maximal transurethral tumor resection, patients were treated by radiotherapy (50 Gy/20 fractions), gemcitabine (100 mg/m2/weekly) and escalating doses of everolimus (2.5–5.0 mg/day). Everolimus was given daily for one month prior to radiation, during treatment, and one month post-radiation. Toxicity assessment followed the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. Biologic endpoint with downregulation of phospho-S6 (pS6) was assessed using immunohistochemistry. Local response was evaluated with imaging and bladder biopsy post-therapy. Results: 10 patients were recruited; 8 males, 2 females. Median age was 78 years (range: 63–85). Four patients entered everolimus 2.5 mg cohort. Six other patients entered everolimus 5.0 mg cohort. Toxicities were encountered in 2 patients (Grade I), 6 patients (Grade II), 9 patients (Grade III) and 1 patient (Grade IV), with some experiencing more than one toxicity. Most Grade III and IV toxicities were encountered from everolimus alone prior to combination testing. Trial was terminated early due to toxicity. Interestingly, 6/10 patients (60%) achieved a complete response with negative post-treatment biopsies. Significant decrease of pS6 was demonstrated post-therapy (p = 0.03). Conclusions: Although combining everolimus with TMT achieved a biological endpoint and complete response in a significant number of patients with MIBC and negative prognostic factors, it was associated with unacceptable increased toxicity.

Background: Androgen deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer (PCa); however, it accelerates the loss of bone mineral density (BMD), which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to assess baseline fracture risk properly. The objective of this study was to examine the proportion of BMD testing in men initiating ADT in Quebec and to identify factors associated with receipt of this testing. Methods: The study cohort consisted of men extracted from Quebec public healthcare insurance administrative databases who initiated continuous ADT from 2000 to 2015 for >12 months. The primary study outcome was receipt of BMD testing in the period from 6 months before through 12 months after ADT initiation. Multivariable generalized linear mixed regression modeling with a logit link was performed to identify variables associated with BMD testing. Results: We identified 22,033 patients, of whom 3,910 (17.8%) underwent BMD testing. Rates of BMD testing increased from 4.1% in 2000 to 23.4% in 2015. After multivariable analyses, prior history of osteoporosis (odds ratio [OR], 1.84; 95% CI, 1.32–2.57; PP=.006), use of bisphosphonates (OR, 1.47; 95% CI, 1.25–1.73; PP=.006) were associated with higher odds of BMD testing. Patient age >80 years (OR, 0.67; 95% CI, 0.59–0.76; PPPPConclusions: In our study population, BMD testing rates in men initiating ADT were low, although they increased over the years especially in the years after the publication of recommendations for BMD testing in these patients. Potential gaps identified include being older, more comorbid, and rural areas. Overall, additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.

Background Docetaxel-based chemotherapy has been the cornerstone of the management of symptomatic metastatic castration-resistant prostate cancer (mCRPC) since 2004. This study aimed to describe how real-world clinical practice was changed with the public funding of novel hormonal agents (abiraterone and enzalutamide) in Quebec. Methods We conducted a retrospective cohort study in two McGill University hospitals. Hospital-based cancer registries were used to select mCRPC patients in medical oncology departments from January 2010 to June 2014. Two groups according to mCRPC diagnosis year were built, with 2012 chosen as the cut-off year, corresponding to the year abiraterone was approved for public reimbursement in second-line in Quebec. Kaplan–Meier analysis was used to estimate time to first docetaxel prescription since mCRPC diagnosis before and after 2012. Cox regression was used to identify predictive factors of docetaxel and novel hormonal agent use. Results In our cohort, 308 patients diagnosed with mCRPC were selected with 162 patients in the pre-2012 group and 146 patients in the post-2012 group. The median age at mCRPC was 74.0 years old. At 12 months from diagnosis, 69% of patients received a prescription for docetaxel in the pre-2012 group comparatively to 53% in the post-2012 group. Factors that decreased the likelihood of docetaxel utilization were: age older than 80 at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3–0.7), mCRPC diagnosis after 2012 (HR: 0.6; 95%CI: 0.4–0.8), and asymptomatic disease at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3–0.7). Conclusion The introduction of novel hormonal agents reduced first-line and overall docetaxel utilization and delayed time to its initiation.

62 Background: Novel hormonal agents (NHAs) such abiraterone (ABI) and enzalutamide (ENZA) have demonstrated similar survival benefits against placebo groups in their respective clinical trials leading to their regulatory approval in both the pre- and post-chemotherapy settings in metastatic castration-resistant prostate cancer (mCRPC). Despite the overall tolerable risk profile, certain signals of cardiovascular toxicity were reported for these agents in clinical trials but little is known about their incidence in clinical practice. The objective was to assess the comparative cardiovascular safety of ABI and ENZA in patients with mCRPC in the real-world. Methods: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. Patients were selected on the basis of having received androgen deprivation therapy prior to initiating a novel hormonal agent (ABI or ENZA) between 2012 and 2016. The primary outcome of interest was cardiovascular-related hospitalization (composite outcome that included acute coronary disease, cerebrovascular disease, heart failure, arrhythmia and other cardiovascular causes). Inverse probability of treatment weighting (IPTW) with the propensity score was used to adjust for measured baseline confounders including pre-existing cardiovascular disease. Results: The cohort comprises 2,183 patients, with 1,773 (81.2%) in the ABI group and 410 (18.8%) in the ENZA group. Before IPTW, mean age of the ENZA group was higher than the ABI group (78 vs 76). There were more ENZA patients with pre-existing arrythmia (ABI: 10.7%, ENZA: 15.1%) and diabetes (ABI: 21.5%, ENZA: 25.1%). Crude incidence rates of cardiovascular-related hospitalization were of 10 events per 100 person-years (PYs) and of 7 events per 100 PYs for the ABI and ENZA groups, respectively. After applying IPTW, all baseline variables were well balanced across both groups with standardized differences < 0.05. The ABI group was at greater risk of cardiovascular-related hospitalization compared to the ENZA group (IPTW-hazard ratio (HR): 1.79, 95% confidence interval (95%CI): 1.04-3.09). The risk of hospitalization for heart failure was greater in ABI (IPTW-HR: 3.02, 95%CI: 1.17-7.78). Conclusions: In our study population, there was a greater risk of cardiovascular-related hospitalizations for ABI users relative to ENZA users, in particular for hospitalization for heart failure. Given the lack of evidence from randomized head-to-head comparisons of both agents, these results provide clinicians with additional insight on the cardiovascular risks of mCRPC patients treated with NHAs in the real-world and further large studies are required to corroborate these findings.

INTRODUCTION AND OBJECTIVE:Bladder preserving strategies such as trimodality therapy (TMT) remain associated with suboptimal local control of muscle invasive bladder cancer (MIBC). Recently, immune...

Objectifs La therapie trimodale (TMT), associant resection transuretrale etendue (RTUVe) et chimioradiotherapie, est une alternative de preservation vesicale pour les cancers de vessie infiltrant le muscle (TVIM) chez les patients refusant ou medicalement contre-indique a la cystectomie totale. L’objectif etait d’analyser les resultats oncologiques de la TMT chez les patients atteints d’une TVIM. Methodes Etude retrospective monocentrique incluant tous les patients atteints d’une TVIM (cT2-4aN0-2M0) traites par TMT a dose curative entre 2001 et 2017. Les resultats demographiques, pathologiques, d’imagerie et des cystoscopies ont ete collectes. Les patients ont beneficies d’une RTUVe, d’une radiotherapie a dose curative (> 45 Gy) associe a une chimiotherapie concomitante. Un suivi regulier par imagerie, cystoscopie et anatomopathologie etait realise. Les analyses statistiques etaient realisees par analyse de Kaplan–Meier et modele de Cox. Resultats Au total, 158 patients atteints d’une TVIM ont ete inclus dont 142 (90 %) cT2 patients, 12 (8 %) cT3, et 4 (2 %) cT4a. L’âge median etait de 75 ans [IQR 43–91]. Chez 60 (38 %) patients la chirurgie etait contre-indiquee et 30 (19 %) ont beneficies d’une chimiotherapie neoadjuvante. Les radio-sensibilisants majoritairement utilises etaient la gemcitabine (68 %) ou le cisplatine (23 %). La mediane de suivi etait de 43 mois [IQR 5–191]. Cinquante-deux patients (33 %) ont presente une recidive, la mediane avant recidive etait de 10 mois [IQR 5,7–20,2]. Durant la periode l’etude, 76 (48 %) patients sont decedes. Les probabilites de survie a 2 et 5 ans etaient de 0,71 (IC95 % : 0,64–0,79) et 0,52 (IC95 % : 0,48–0,66) respectivement. En analyse multivariee, l’âge (HR = 1,06 ; p = 0,026) et une cystoscopie suspecte ou une cytologie urinaire positive (HR = 3,10 ; p = 0,008) etaient predictifs d’une survie globale plus faible ( Fig. 1 , Fig. 2 ). Conclusion La TMT est associee a des resultats oncologiques satisfaisant et est une alternative valide a la cystectomie totale pour les patients atteints d’une TVIM ne pouvant ou ne souhaitant pas de chirurgie invasive. Nos resultats doivent etre valides par des etudes prospectives.

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

Introduction: Clinical trial data has shown pazopanib to be noninferior in overall survival (OS) compared to sunitinib as first-line treatment for metastatic renal cell carcinoma (mRCC). The purpose of this study was to evaluate outcomes and compare dose-modifying toxicities of mRCC patients treated with suntinib or pazopanib in the real-world setting.Methods: Data were collected on mRCC patients using the prospective Canadian Kidney Cancer Information System (CKCis) database from January 2011 to November 2015. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.Results: We identified 670 patients treated with sunitinib (n=577) and pazopanib (n=93). There were no significant differences in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (p=0.807). Patients treated with sunitinib had improved OS compared with pazopanib (median 31.7 vs. 20.6 months, p=0.028; adjusted hazard ratio [aHR] 0.60; 95% confidence interval [CI] 0.38‒0.94). Time to treatment failure (TTF) was numerically, but not statistically, improved with sunitinib (medians 11.0 vs. 8.4 months, p=0.130; aHR 0.87; 95% CI 0.59‒1.28). Outcomes with individualized dosing on sunitinib were unavailable for this analysis. Patients treated with sunitinib had a higher incidence of mucositis, hand-foot syndrome, and gastroesophageal reflux disease; patients treated with pazopanib had a higher incidence of hepatotoxicity.Conclusions: In Canadian patients with mRCC, treatment with sunitinib appears to be associated with an improved OS compared to pazopanib in the first-line setting. Patient selection factors and the contemporary practice of individualized dosing with sunitinib may contribute to these real-world outcomes and warrant further investigation.

Introduction Late locoregional complications in prostate cancer (PCa) affect quality of life and require medical interventions. Our objective was to compare late locoregional complications in men dying of castration-resistant PCa (CRPC) who previously received external-beam radiotherapy (EBRT) to radical prostatectomy (RP). No group without previous primary local treatment was included. Patients and Methods The cohort consists of CRPC patients who died between 2001 and 2013 and who underwent previous EBRT or RP. The Regie de l'assurance maladie du Quebec administrative databases were used to identify late locoregional complications (urologic procedures, minor rectal procedures, and other major surgical procedures) and PCa-related hospitalizations occurring in the last 2 years of life. Multivariable logistic regression and negative binomial regression analyses were performed. Results The cohort comprised 1189 patients; 535 (45%) and 654 (55%) received EBRT and RP, respectively. Overall, 46.4% of patients experienced at least 1 late locoregional complication. Primary local treatment type was not associated with the odds of late locoregional complications (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.72, 1.16). RP was associated with greater odds of PCa-related hospitalization (OR, 1.63; 95% CI, 1.23, 2.17) relative to EBRT, as were the usage of a CRPC treatment (OR, 3.96; 95% CI, 2.83, 5.53) and the occurrence of a late locoregional complication (OR, 2.76; 95% CI, 2.05, 3.69). For the number of PCa-related hospitalization days, RP was not found to be significant (rate ratio, 1.09; 95% CI, 0.90, 1.32). Conclusion In this population-based cohort, the risk of late locoregional complications in CRPC was not associated with the type of primary local treatment (RP or EBRT).

Background Abiraterone acetate was introduced in Quebec in 2012 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who had received chemotherapy with docetaxel. This study describes abiraterone use in the early postapproval period and its clinical effectiveness in Quebec, for both patients who had received docetaxel chemotherapy and those who could not receive docetaxel therapy owing to medical reasons. Methods A retrospective cohort study was conducted using Quebec public health care administrative databases. Our cohort consisted of patients with mCRPC who received abiraterone between January 2012 and June 2013. Treatment groups were defined as patients who received abiraterone following docetaxel chemotherapy and those who received abiraterone without having had chemotherapy, under the "exception patient" measure. Study outcomes included overall survival, duration of abiraterone therapy and number of hospital days. Cox proportional hazard regression was used to estimate the effectiveness of abiraterone adjusted for several covariates. Results Our cohort consisted of 303 patients with mCRPC treated with abiraterone (99 after chemotherapy and 204 as exception patients). The median age at initiation of abiraterone therapy was 75.0 for the postchemotherapy group and 80.0 for the exception patient group. The corresponding median survival values were 12 and 14 months (log-rank test p = 0.8). Risk of death was similar in the 2 groups (adjusted hazard ratio 0.89 [95% confidence interval 0.57-1.38]). Interpretation The effectiveness of abiraterone in older patients who were ineligible for chemotherapy was similar to that of patients with prior docetaxel exposure. Overall, the real-world survival benefits of abiraterone were similar to those in the COU-AA-301 trial.

Neoadjuvant chemotherapy is an accepted standard for locally advanced esophagogastric junction adenocarcinoma. However, the dysphagia frequently associated with this condition may interfere with patient tolerance of this treatment. In many centers, invasive tube feeding, placed either endoscopically, radiographically, or surgically, is used to address this issue, but it can cause significant morbidity. We sought to determine if an approach of goal-directed dietary counseling and appropriately timed neoadjuvant chemotherapy could obviate the need for invasive tube feeding.Patients with locally advanced (cT3 or N+) esophageal and esophagogastric junction adenocarcinoma undergoing neoadjuvant TCF [Taxotere, cisplatin 5-fluorouracil (5-FU)], ECF (epirubicin, cisplatin, 5-FU), or FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU) at the McGill University Health Center from March 2007 to September 2012 were identified from a prospective database. All received individualized goal-directed dietary counseling, were monitored for signs/symptoms of malnutrition with serial (baseline/presurgery) body mass index, albumin, and completed serial symptom scores (dysphagia), and quality-of-life questionnaires (Functional Assessment in Cancer Therapy with the esophageal subset, FACT-E). We assessed the response of dysphagia and nutritional status to neoadjuvant chemotherapy and the need for invasive tube feeding.Of 130 patients undergoing neoadjuvant chemotherapy, 78 had severe dysphagia (defined as dysphagia score ≥2 on a 5-point Likert scale), most of whom received TCF (91 %). Overall dysphagia scores improved in 75 (96 %) of 78 patients from a dysphagia score of 3-0, most of which improved after the first cycle of therapy. This was associated with an increase in quality of life (FACT-E scores 117 ± 23 to 140 ± 20). With maintenance of weight (70 ± 22 to 69 ± 24 kg), body mass index (24.5 ± 8 to 23.9 ± 7 kg/m(2)), and serum albumin (40 ± 5 to 37 ± 4 g/L). Only one patient required a stent, and none required jejunostomy or gastrostomy.Appropriately timed neoadjuvant chemotherapy with a highly effective regimen rapidly restores normal swallowing, maintains nutritional status, and obviates the need for invasive tube feeding in patients with significant dysphagia from esophageal adenocarcinoma.

40 Background: The approval of novel hormonal agents (NHAs), abiraterone and enzalutamide, have increased the therapeutic arsenal available in metastatic castration-resistant prostate cancer (mCRPC). However, the use of chemotherapy and other antineoplastics at the end of life has been suggested as an indicator of poor quality of care. In this study, we report the use of NHAs at the end of life in men with mCRPC in the province of Quebec, Canada. Methods: Using Quebec public healthcare administrative databases, we identified patients with prostate cancer who used an NHA (abiraterone or enzalutamide) after androgen deprivation therapy and who died between 2012 and 2016. The primary outcome was the use of an NHA in the 30 days before death. Use of an NHA in the 60 and 90 days before dying, and initiation (first prescription) of an NHA in the 30 days before death were evaluated as secondary outcomes. Multivariable analysis of the primary outcome was performed with logistic regression with results reported as odds ratios (OR) with 95% confidence intervals (95%CI). Results: The cohort consists of 1316 patients who used an NHA over the course of their disease and died at a median age of 78 years old, with 292 (22.2%), 464 (35.3%), and 575 (43.7%) having used an NHA in the 30, 60 and 90 days of life, respectively. Use of NHA 30 days before dying decreased over the study period, from 44.8% in 2012 to 17.0% in 2016 (Cochran-Armitage test p-value < 0.001). On multivariable analyses, later years of death remained associated with lower odds of NHA use 30 days before death (OR 0.74, 95%CI 0.66 to 0.81, p < 0.001). Fifty-eight (4.4%) patients initiated a NHA 30 days before dying. Conclusions: Rates of NHA use 30 days before dying were high initially but decreased over the study period. Further assessment of NHA use at the end of life is warranted to examine if the trend will be maintained given the recent approval of additional oral NHAs for prostate cancer.

38 Background: Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) treatment, however several side-effects are associated with its long-term use. Notably, loss of bone mineral density (BMD) is accelerated which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to properly assess baseline fracture risk. The objective was to examine the proportion of BMD testing in men initiating long-term ADT in Quebec. Methods: The cohort consists of men extracted from Quebec public healthcare insurance administrative databases who were diagnosed with PCa from 2001-2012 and treated by ADT for at least one continuous year. The primary study outcome was the receipt of baseline BMD testing (defined as a BMD test identified in the period from 6 months prior to and up to 12 months after ADT initiation). Multivariable generalized linear mixed with a logit link was performed to identify variables associated with baseline BMD testing accounting for physician clustering. Results: We identified 7,069 patients, of which 887 (12.6%) underwent baseline BMD testing. Baseline BMD testing varied by year of ADT initiation, from 7.7% in 2001-2003 to 12.3% in 2013-2012. Following multivariable analyses, later years of ADT initiation (2004-2006, 2007-2009, 2010-2012, 2013-2015) remained associated with higher odds of baseline BMD testing compared to the earlier years (2001-2003) (ORs ranging from 1.43-1.88; p < 0.001). Conversely, age > 80 (OR 0.73; 95% CI 0.57-0.94; p = 0.001), greater Charlson comorbidity score (OR 0.51; 95%CI 0.34-0.75; p = 0.001), and rural residence (OR 0.60; 95%CI 0.48-0.75; p < 0.001) were associated with lower odds of baseline BMD testing. Conclusions: In our study population, rates of baseline BMD testing in men initiating ADT are low, although the rates increased over the course of the study period. Potential gaps identified in baseline BMD testing include older, more comorbid patients, and rural residence. Additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.

Background We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA). Methods Data from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method. Results One hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR=0.58 [0.26-1.30], P =0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM ( P =0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR=0.53 [0.22-1.32]). Conclusion In this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Background: To evaluate the antitumour activity and safety of metronomic cyclophosphamide vs megestrol acetate in progressive and advanced cancer patients having exhausted all effective therapies under standard care. Methods: Patients were randomly assigned to receive orally metronomic cyclophosphamide (50 mg b.i.d) or megestrol acetate (160 mg only daily) until intolerance or progression (RECIST 1.0). The primary efficacy end point was a 2-month progression-free rate (PFR2m). According to Optimal Simon's design and the following assumptions, namely, P0=5%, P1=20%, α=β=10%, the treatment is considered as effective if atleast 5 out of 44 patients achieved PFR2m. Results: Between September 2006 and January 2009, 88 patients were enrolled. Two patients experienced grade 3–4 toxicities in each arm (4%). One toxic death occurred in the megestrol acetate arm as a consequence of thrombosis. The metronomic cyclophosphamide arm reached the predefined level of efficacy with a PFR2m rate of 9 out of 44 and a PFR4m rate of 5 out of 44. The MA arm failed to achieve the level of efficacy with a PFR2m of 4 out of 44 and a PFR4m of 1 out of 44. The median overall survival was 195 and 144 days in the metronomic cyclophosphamide arm and megestrol acetate arm, respectively. Conclusion: Metronomic cyclophosphamide is well tolerated and provides stable disease in such vulnerable and poor-prognosis cancer patients. This regimen warrants further evaluations.

180 Background: Esophago-gastric cancers are aggressive malignancies requiring numerous investigations to plan complex multi-modal therapy. The path from initial diagnosis to treatment can be associated with a long delay. This delay and complex patient trajectory may impact quality of life. Given the poor prognosis and highly symptomatic nature of upper GI cancer, a clear and timely access to treatment of crucial importance. We sought to determine the impact of a newly implemented streamlined and structure interdisciplinary pathway for newly diagnosed esophageal and gastric cancer on access times to treatment and quality of life (QoL). Methods: A streamlined pathway for patients referred to a high volume Upper GI Cancer clinic was generated with input from physicians, nutritionists, specialized nurses, and social workers. New diagnosis of esophageal or gastric cancer from 2014-16 were enrolled in this program and consenting patients completed serial QoL questionnaires (ESAS) at baseline, pre-treatment, 1 month post treatment. Dysphagia (DS) was quantified on a 5 point scale. Time intervals (days) were evaluated at various points between diagnosis and start of treatment (diagnosis, CT imaging, first visit with upper GI program, start of treatment). Data presented as median(IQR), * p < 0.05. Results: Of the 251 patients with Upper GI cancer, 153 (61%) consented to participate including 140 esophageal/EGJ and 13 gastric cancer patients. Clinical stage distribution was 17.9% I, 30.7% II, 42.6% III, 8.7% IV. Of the 82 Esoph/EGJ patients with completed QoL questionnaires, 15 (18.3%) patients had severe dysphagia (DS = 3-4) and were prioritized for treatment. Patients with severe dysphagia had reduced time from index endoscopy to treatment (29 (16.3-39.3) vs 43 (32.8-68.0)days)* and first Upper GI clinic to treatment (15 (8.0-23.0) vs 25 (21.0-36.0)*. ESAS surveys showed increased QoL for both patients with and without dysphagia from baseline to pre-treatment indicating that simply entry into the streamlined program improved QoL. Conclusions: Structured interdisciplinary investigative and treatment programs for upper GI cancers can expedite time to treatment and improve QoL.

Background: The role of chemotherapy in metastatic esophageal carcinoma (MEC) remains a matter of debate. The aim of this retrospective study was to analyze the survival impact of chemotherapy after stratification for prognostic factors. Methods: Consecutive patients with MEC (1995 to 2008) were randomly assigned to a development (n = 171) and a validation cohort (n = 113). We had first identified prognostic factors using the Kaplan-Meier and Cox methods in the development cohort and then validated them in the validation cohort. Then, we analyzed the impact of chemotherapy after stratification for these prognostic factors. The majority of patients had squamous cell carcinoma (80%). Results: The Cox model has retained 2 prognostic factors only: associated cancers (hazard ratio = 2.77, range 1.39–5.54, p = 0.004) and grade 3–4 dysphagia (hazard ratio = 1.44, range 1.08–2.14, p = 0.007). Median survival was 10.9 in patients with 0 (n = 77), 6.2 in those with 1 (n = 65) and 1.8 months in those with 2 prognostic factors (n = 11/171; p = 0.025). The median survival times of the patients with 0, 1 and 2 prognostic factors were 13 versus 9 months (nonsignificant, NS), 6 versus 5 months (NS) and 5 versus 1.3 months (NS) in patients with and without chemotherapy, respectively. Conclusion: Our data suggest that chemotherapy has no significant effect on survival for unselected MEC patients, regardless of the prognostic factors we identified.

Lamellarin D (LAM-D) is a marine alkaloid endowed with potent cytotoxic activities against various tumor cells, in particular human prostate cancer cells and leukemia cells. Its cytotoxic action is dependent, at least in part, to its capacity to inhibit topoisomerase I. P388CPT5 murine leukemia cells resistant to the reference topoisomerase I poison camptothecin (CPT) are cross-resistant to LAM-D but the relative resistance index (RRI) is significantly reduced with LAM-D (RRI=21) compared to CPT (RRI=103). To comprehend further the mechanism of action of this novel marine antitumor agent, we have investigated the influence of the P glycoprotein (Pgp) on the cytotoxicity of LAM-D and the proapoptotic effects induced by the alkaloid. P388CPT5 cells, expressing a mutated top1 gene, display a functional Pgp, as judged from cytometry experiments performed with cells treated with rhodamine 123 or calcein-ester whereas no Pgp activity was detected with the parental P388 cells. P388CPT5 cells are also cross-resistant to the topoisomerase II poisons doxorubicin and etoposide but the resistance is abolished in the presence of verapamil or quinine (at non toxic concentrations) which reverse the multidrug resistance (MDR) phenotype. In contrast, the RRI measured with LAM-D and CPT remain unchanged in the presence of the two MDR reversal agents. The effects of LAM-D on the cell cycle progression were different in the parental P388 cells compared with the CPT-resistant which were blocked in the S and subsequently G2-M phases of the cell cycle. Cytometry experiments with the JC-1 fluorescent marker revealed that LAM-D and CPT promoted apoptosis in parental P388 cells via an activation of the mitochondrial pathway. In contrast, a massive depolarisation of the mitochondrial membrane potential and a nuclear fragmentation were detected only with LAM-D on P388CPT5 cells. This in vitro work identifies LAM-D as a potent pro-apoptotic agent and its cytotoxic action is fully maintained in multidrug-resistant cells compared to the sensitive parental cell line.

e16078 Background: Recent analysis using CKCis showed that mRCC patients receiving first-line sunitinib (S) had better survival than patients receiving pazopanib (P) and greater than expected survival for a real world sampling. We conducted further analyses to see if an individualized approach (treatment starting at standard dose/schedule with subsequent schedule/dose alterations based on toxicity) using S results in better outcomes in mRCC patients. Methods: Patients within CKCis diagnosed with clear cell mRCC treated with first-line S or P between January 2011 through December 2015 were analyzed by three treatment groups: 1) S as per individualized approach (SI) 2) S as per product monograph (SS) 3) P as per product monograph (PS). Overall survival (OS) and time-to-treatment failure (TTF) were calculated. Cox regression analysis allowed for adjustment of International Metastatic RCC Database Consortium (IMDC) criteria with age as a continuous variable. Results: A total of 598 patients were identified, 351 patients in SI, 151 patients in SS, and 92 patients in PS. Baseline characteristics are noted in Table 1. Median OS was improved in SI vs SS (37.9 vs 22.3 months (m), p

468 Background: Recent analysis using CKCis, a prospective database, showed that mRCC patients receiving first-line sunitinib (S) had better survival than patients receiving pazopanib (P) and greater than expected absolute survival in the real world setting. We conducted further analyses to see if an individualized approach (treatment starting at standard dose/schedule with subsequent schedule/dose alterations based on toxicity) using S results in better outcomes in mRCC patients. Methods: Patients within CKCis diagnosed with clear cell mRCC treated with first-line S or P between January 2011 to December 2015 were analyzed by three treatment groups: 1) S as per individualized approach (SI), 2) S as per product monograph (SS), or 3) P as per product monograph (PS). Overall survival (OS) and time-to-treatment failure (TTF) were calculated. Cox regression analysis allowed for adjustment of International Metastatic RCC Database Consortium (IMDC) criteria with age as a continuous variable. Results: A total of 573 patients were identified, 261 patients in SI, 201 patients in SS, and 111 patients in PS. Differences in baseline characteristics were noted (Table). Median OS was improved in SI vs. SS (40.8 vs. 22.6 months (m), p

134 Background: A better understanding of taxane sensitivity/resistance in mCRPC is needed to optimize treatment. Preclinically, taxane efficacy has been linked to the ability of microtubules (MT) to inhibit AR nuclear trafficking. In this prospective biomarker study, we used circulating tumor cells (CTCs) from patients (pts) in TAXYNERGY to perform real-time analysis of AR nuclear localization (ARNL) and MT stabilization (bundling; MTB) in order to predict taxane sensitivity. Methods: TAXYNERGY (NCT01718353) is a phase 2 trial randomizing chemo-naïve mCRPC pts 2:1 to docetaxel or cabazitaxel, with a switch to the alternative taxane in the absence of a ≥ 30% PSA drop by C4. Here we present the co-primary biomarker endpoints. CTCs at baseline (C1D1) were compared to CTCs after 1 week of taxane treatment (C1D8), and were analyzed by multiplex confocal microscopy for %ARNL (integrated AR intensity in the cell and nuclear areas) and MTB (assessed for increase compared to C1D1 on a scale from 0–3 from no to most MTB increase). Associations between %ARNL and MTB with clinical outcomes were sought. Results: Of 63 randomized pts, 26 had evaluable CTCs both at C1D1 and C1D8. At C1D8, mean %ARNL was significantly lower in pts achieving a ≥ 50% PSA drop by C4 vs those without (44% vs 64%; p = 0.004). A taxane-induced decrease in mean %ARNL (C1D8 vs C1D1) was associated with a higher rate of ≥ 50% PSA response (73% vs 13%; p = 0.009); mean %ARNL decreased by 18% in responders and increased by 2% in non-responders (p = 0.02). Finally, a taxane-induced increase in mean MTB trended higher in pts achieving a ≥ 30% PSA drop by C4 vs those without (0.69 vs 0.09; p = 0.09); increase in mean MTB score was indicative of response and observed in pts who did not require a taxane switch after C4 (0.75 vs 0.09; p = 0.06). Conclusions: We provide the first prospective data suggesting that taxane-induced shifts in ARNL and MTB (measured in CTCs) may serve as an early biomarker of taxane sensitivity. Consistent with preclinical data, AR nuclear exclusion caused by microtubule bundling may be a clinically-actionable marker of taxane efficacy. Funding: Sanofi Genzyme. Clinical trial information: NCT01718353.

Incidental pulmonary nodules are frequently identified during staging investigations for esophageal cancer patients. Their clinical significance is unclear and may bias treatment decisions towards palliative options. From 2005 to 2011, 423 esophageal cancer patients were treated at a tertiary hospital. Those with incidental pulmonary nodules were identified. Demographics, imaging, pathology and perioperative outcomes were analyzed. Ninety-two patients (22 %) had lung nodules. Twenty-nine (32 %) were palliative due to poor performance status or extra-pulmonary distant metastasis on imaging. Sixty-three had no evidence of extra-pulmonary metastasis and underwent curative-intent treatment comprising of neoadjuvant therapy [35 (55 %)] followed by esophagectomy [with lung resection, 33 (52 %) or without lung resection, 30 (48 %)]. Of those 33 lung resections, there were 27 benign lesions, 4 stage I lung cancers, and 1 esophageal cancer metastasis. Of 30 patients with lung nodules that underwent curative esophagectomy without lung resection, none showed interval size increase on follow-up imaging [median 9 months (3–40)]. There was no difference in perioperative complications or mortality between patients with combined esophagectomy and lung resection and those with esophagectomy alone. Incidental pulmonary nodules in the absence of extra-pulmonary metastases in esophageal cancer patients are rarely metastases and should not bias caregivers towards palliative therapy.

5007Background: TAXYNERGY (NCT01718353), a randomized phase II trial, evaluated early taxane switch with CTC biomarkers to study mechanisms of sensitivity/resistance in men with chemo-naive mCRPC. ...

5031 Background: Microtubule-targeted therapy with taxanes is the only chemo with survival benefit in advanced PC. Emerging molecular evidence suggests sensitivity/resistance to taxanes may relate ...

226 Background: Prostate cancer (PCa) death is mainly due to castration-resistant PCa (CRPC) which results from disease progression despite androgen ablation therapy (ADT). Little is known about clinical outcomes and trends of real-life CRPC management in the present era, which has become very complex. Our study aimed to analyze healthcare services use, clinical outcomes and survival trends in real-life management of CRPC in Quebec, Canada. Methods: The study cohort consisted of 7,123 patients which shown evidence of CRPC from January/2001 to July/2013, selected from the public healthcare insurance programs the Régie de l’Assurance Maladie du Québec (RAMQ) databases. Survival was evaluated by Kaplan-Maier and the difference in survival between pre-/post-docetaxel (Doc) (2002-2005 vs 2008-2011) era by log-rank test. The association between Doc exposure and survival was evaluated by Cox proportional hazards model adjusted for several co-variables. Results: Chemotherapy was offered to 17% of patients, while 45% were kept on maximal androgen blockade (MAB) alone, or offered Abiraterone (3%). Androgen targeted therapies (MAB or Abiraterone) were the treatment of choice for the elderly population (mean age 78.8 and 78 ±7, respectively) while chemotherapy was offered to younger patients (mean age 72 ±7.3). Survival rates at 1 and 2 years after the initiation of chemotherapy were 52% and 26% in post-Doc era vs 46% and 17% in the pre-Doc period. In patients receiving first line chemotherapy only, hospitalization due to PCa was a poor prognostic predictor (HR: 2.0; 95%CI: 1.5-2.6), as expected. In addition among patients without previous hospitalization the risk of death was higher in the pre- vs post-Doc era (HR: 1.7 CI: 1.003-2.851). Conclusions: Patient age seems to be a strong determinant in CRPC therapy selection. In patients without serious complications leading to hospitalization, survival was greatly improved in the post-Doc era. Our data also supports that patients older than those in the TAX327 trial (72 vs 68) may equally benefit from chemotherapy. This is encouraging as we hope to observe comparable results for new approved therapies for CRPC.

424 Background: The proportion and characterization of patients (pts) with metastatic renal cell carcinoma (mRCC) who never start or delay starting targeted therapy (TT) is unknown. It is important to understand and characterize these pts. Methods: Data from the Canadian Kidney Cancer information system (CKCis) database were utilized. CKCis data were collected prospectively from 14 REB-approved academic centers in Canada. The study population included pts with mRCC managed from 2006 (when VEGFR TT became available) to 2014. Results: 920 pts met the inclusion criteria, but 67 pts had

265 Background: Measuring quality of care is required to improve patient outcomes. There are 23 established Quality Indicators in Renal Cell Carcinoma (RCC) (Wood LA et al, JOP 2013) including initiating targeted therapy (TT) at full dose. It is recognized that the dose of TT is important to optimize clinical outcomes. Methods: The Canadian Kidney Cancer Information System (CKCis) is a prospectively maintained database of RCC pts from 14 Canadian academic centers. CKCis data was used to determine the use of TT in metastatic pts, the initial dose in the first line setting, and factors influencing whether pts initiated full dose TT. Descriptive statistics were performed to characterize current practices and a multivariate logistic regression was performed to assess predictors of initiating full dose TT. Results: Between 2006 and 2014, 560 pts received first-line TT and make up the study cohort. 92% received VEGF TT (81% sunitinib; 9% pazopanib; 2% sorafenib) and 8% received mTOR TT (5% everolimus; 3% temsirolimus). All pts receiving mTOR inhibitors received full dose and are excluded from further analysis. Full dose VEGF TT was initiated in 87% on sunitinib, 78% on pazopanib, and 92% on sorafenib. The sunitinib schedule was 4/2 in 81%, 2/1 in 12%, and other in 7%. Pts were less likely to initiate full dose TT if they were older (OR: 1.10, 95% CI 1.06-1.15), female (OR: 2.23, 95% CI 1.09-4.55) or had a worse ECOG PS (2,3,4 vs 0,1) (OR: 2.30, 95% CI 0.95-5.59). Data on initial versus final dose of TT will also be presented. Conclusions: Maximizing exposure to TT is important in metastatic RCC which is why initiating full dose TT was prioritized as a key QI in RCC. In this study, 87% of pts were initiated on full dose VEGF TT in the first line setting, and 100% of pts on mTOR TT which is higher than predicted. Those less likely to start on full dose VEGF TT were older, female and had a lower ECOG PS. The gender discrepancy will be explored in future studies.

Background For Canadian men, prostate cancer (PCa) is the most common cancer and the 3rd leading cause of cancer mortality. Men dying of PCa do so after failing castration. The management of metastatic castration-resistant prostate cancer (mCRPC) is complex and the associated drug treatments are increasingly costly. The objective of this study was to estimate the cost of drug treatments over the mCRPC period, in the context of the latest evidence-based approaches. Methods Two Markov models with Monte-Carlo microsimulations were developed in order to simulate the management of the disease and to estimate the cost of drug treatments in mCRPC, as per Quebec’s public healthcare system. The models include recently approved additional lines of treatment after or before docetaxel (i.e. abiraterone and cabazitaxel). Drug exposure and survival were based on clinical trial results and clinical practice guidelines found in a literature review. All costs were assigned in 2013 Canadian dollars ($). Only direct drug costs were estimated. Results The mean cost of mCRPC drug treatments over an average period of 28.1 months was estimated at $48,428 per patient (95% Confidence Interval: $47,624 to $49,232). The mean cost increased to $104,071 (95% CI: $102,373 - $105,770) per patient when one includes abiraterone initiation prior to docetaxel therapy. Over the mCRPC period, luteinizing hormone-releasing hormone agonists (LHRHa) prescribed to maintain castrate testosterone levels accounted for 20.4% of the total medication cost, whereas denosumab prescribed to decrease bone-related events accounted for 30.5% of costs. When patients received cabazitaxel in sequence after abiraterone and docetaxel, the mCRPC medications cost per patient per month increased by 60.2%. The total cost of medications for the treatment of each annual Canadian cohort of 4,000 mCRPC patients was estimated at $ 193.6 million to $416.3 million. Conclusions Our study estimates the direct drug costs associated with mCRPC treatments in the Canadian healthcare system. Recently identified effective yet not approved therapies will become part of the spectrum of mCRPC treatments, and may potentially increase the cost.

e16029 Background: Medical or surgical castration are the treatments of choice for hormone-sensitive prostate cancer with a high-risk of disease recurrence or progression. In addition, androgen abl...

A 22-year-old woman presented in June 2006 with a massive hemoptysis, revealing a large pulmonary right tumour. An urgent right pneumectomy was required with a pericardiectomy extended to the left auricle. Brain, chest and abdominal CT-scan and 18 F-fl uorodeoxyglucose (FDG) Positron Emission Tomography (PET) did not reveal metastatic extension. The initial histopathology report showed a 12 cm pulmonary blastoma biphasic subtype with no lymph node involvement and the resection was complete. A second histological examination confi rmed the pulmonary blastoma diagnosis, well-differentiated with rhabdomyoblastic, chondroid, and osteoid differentiation. As the margins were clear, no adjuvant treatment was offered. On November 2006, CT-scan, PET scan and liver MRI showed a massive local recurrence with liver extension through diaphragm (Figure 1, size 44 mm x 39 mm). The fi rst-line treatment consisted of six cycles of combined chemotherapy (Ifosfamide 2.5 g/m 2 on day 1 plus Doxorubicin 20 mg/m 2 once daily for three consecutive days every 21 days with lenograstim support d6 to d13). Successive tumour assessments demonstrated major tumour shrinkage. After the sixth cycle, the size of the residual tumour was 21 mm x 14 mm (Figure 2). The patient then received two additional cycles of doxorubicin (70 mg/m 2 /d q3wks) followed with stereotactic radiotherapy on the residual tumour (40 Gy). At the end of radiotherapy, the largest size of the residual mass was 11 mm without FDG-fi xation. Nevertheless, a second local relapse with thoracic vertebra and scapula involvement was diagnosed in May 2008. The patient received three successive ineffective lines of chemotherapy (Carboplatin Vincristine/ Cyclophosphamide Actinomycine-D/docetaxel gemcitabine). She died in November 2008.