High-dose chemotherapy with autologous stem-cell transplantation for relapsed metastatic germ cell tumors The Alberta experience.

INTRODUCTION: High-dose chemotherapy with autologous stem-cell transplantation (HDC-ASCT) is standard therapy for metastatic germ cell tumors (mGCTs) in patients whose disease progresses during or after conventional chemotherapy. We conducted a retrospective review of HDC-ASCT in relapsed mGCT patients in the province of Alberta, Canada, over the past two decades. METHODS: Patients with mGCTs who received HDC-ASCT at two provincial cancer referral centers from 2000-2018 were identified from institutional databases. Baseline clinical and treatment characteristics were collected, as well as overall survival (OS ) and disease-free survival (DFS). Relevant prognostic variables were analyzed. RESULTS: Forty-three patients were identified. The median age was 28 years (range 19-56). A majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty patients (47%) had poor-risk disease, as per The International Germ Cell Consensus Classification (IGCCC), at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% of patients, and 58% of ASCT patients received tandem transplants. Median followup after ASCT was 22 months (range 2-181). At last followup, 42% of patients were alive without disease, including 3/7 (43%) of patients with primary mediastinal disease. Two-year and five-year DFS/OS ratios were 44%/65% and 38%/45%, respectively. Median OS and DFS for all patients were 30.0 months (13.3-46.6) and 8.0 months (0.9-15.1), respectively. CONCLUSIONS: We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Patients appeared to benefit regardless of primary site. Although limited by small sample size, we found a numerical difference in DFS and OS between second- and third-line HDC-ASCT and single vs. tandem ASCT.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.

BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy.

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Defining cisplatin eligibility in patients with muscle-invasive bladder cancer.

The current treatment paradigm for muscle-invasive bladder cancer (MIBC) consists of cisplatin-based neoadjuvant chemotherapy followed by local definitive therapy, or local definitive therapy alone for cisplatin-ineligible patients. Given that MIBC has a high propensity for distant relapse and is a chemotherapy-sensitive disease, under-utilization of chemotherapy is associated with suboptimal cure rates. Cisplatin eligibility criteria are defined for patients with metastatic bladder cancer by the Galsky criteria, which include creatinine clearance ≥60 ml/min. However, consensus is still lacking regarding cisplatin eligibility criteria in the neoadjuvant, curative MIBC setting, which continues to represent a substantial barrier to the standardization of patient care and clinical trial design. Jiang and colleagues accordingly suggest an algorithm for assessing cisplatin eligibility in patients with MIBC. Instead of relying on an absolute renal function threshold, their algorithm emphasizes a multidisciplinary and patient-centred approach. They also propose mitigation strategies to minimize the risk of cisplatin-induced nephrotoxicity in selected patients with impaired renal function. This new framework is aimed at reducing the inappropriate exclusion of some patients from cisplatin-based neoadjuvant chemotherapy (which leads to under-treatment) and harmonizing clinical trial design, which could lead to improved overall outcomes in patients with MIBC.

Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.

IMPORTANCE: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial. OBJECTIVES: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC. DESIGN, SETTING, AND PARTICIPANTS: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function. INTERVENTIONS: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). RESULTS: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life. CONCLUSIONS AND RELEVANCE: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02033993.

Optimizing management of advanced urothelial carcinoma: A review of emerging therapies and biomarker-driven patient selection.

INTRODUCTION: Advanced urothelial carcinoma has been challenging to treat due to limited treatment options, poor response rates, and poor long-term survival. New treatment options hold the promise of improved outcomes for these patients. METHODS: A multidisciplinary working group drafted a management algorithm for advanced urothelial carcinoma using "consensus development conference" methodology. A targeted literature search identified new and emerging treatments for inclusion in the management algorithm. Published clinical data were considered during the algorithm development process, as well as the risks and benefits of the treatment options. Biomarkers to guide patient selection in clinical trials for new treatments were incorporated into the algorithm. RESULTS: The advanced urothelial carcinoma management algorithm includes newly approved first-line anti-programmed death receptor-1 (PD1)/ programmed death-ligand 1 (PD-L1) therapies, a newly approved anti-fibroblast growth factor receptors (FGFR) therapy, and an emerging anti-Nectin 4 therapy, which have had encouraging results in phase 2 trials for second-line and third-line therapy, respectively. This algorithm also incorporates suggestions for biomarker testing of PD-L1 expression and FGFR gene alterations. CONCLUSIONS: Newly approved and emerging therapies are starting to cover an unmet need for more treatment options, better response rates, and improved overall survival in advanced urothelial carcinoma. The management algorithm provides guidance on how to incorporate these new options, and their associated biomarkers, into clinical practice.

Neoadjuvant Chemotherapy Before Bladder-Sparing Chemoradiotherapy in Patients With Nonmetastatic Muscle-Invasive Bladder Cancer.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy improves survival in muscle-invasive urothelial bladder cancer (MIBC). The use of NAC before chemoradiation (CRT) has been limited, as these patients are often elderly, frail, and ineligible for cisplatin. However, the role of NAC in fit, cisplatin-eligible patients who opt for bladder preservation warrants further evaluation. PATIENTS AND METHODS: Patients with MIBC treated with NAC followed by CRT at the Princess Margaret and Durham Regional cancer centers from 2008 to 2017 were retrospectively reviewed. Gemcitabine-cisplatin NAC was given for 2 to 4 cycles, followed by reassessment for CRT. External-beam radiotherapy (60-66 Gy) over 6 weeks was given with concurrent weekly cisplatin at 40 mg/m2. Kaplan-Meier method was used for survival analyses. RESULTS: We identified 57 consecutive patients. Median age was 72 (range 45-87), and all had an Eastern Cooperative Oncology Group performance status of 0 (60%) or 1 (40%). Stage II disease (65%), stage III disease (25%), and regional nodal metastases (11%) were included. Most completed planned NAC (95%). All patients completed external-beam radiotherapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Median (range) follow-up was 19.3 (4.8-96.1) months. Median overall survival (OS) was not reached. Two-year OS and disease-specific survival rates were 74% (95% confidence interval, 57.7-84.9) and 88% (95% confidence interval, 78.5-98.1), respectively. Two-year bladder-intact disease-free survival was 64%. Salvage cystectomy was performed in 14%. Distant relapse occurred in 11%, and 9% died of metastatic disease. OS was associated with baseline hydronephrosis and with bladder-intact disease-free survival with residual disease on cystoscopy. CONCLUSION: NAC followed by CRT can result in encouraging outcomes and tolerability in cisplatin-eligible patients.

The Prognostic Role of the Change in Neutrophil-to-Lymphocyte Ratio During Neoadjuvant Chemotherapy in Patients with Muscle-Invasive Bladder Cancer: A Retrospective, Multi-Institutional Study.

BACKGROUND: The impact of the change in the neutrophil-to-lymphocyte ratio (NLR) during neoadjuvant chemotherapy (NAC) on outcomes in patients with muscle-invasive bladder cancer (MIBC) is poorly understood. OBJECTIVE: To evaluate the prognostic impact of the change in NLR during NAC for patients with MIBC. METHODS: Patients referred to academic, community, and quaternary referral centres in Alberta, Canada from 2005 to 2015, Ontario, Canada from 2005 to 2013, and Southampton, UK from 2004 to 2010 were evaluated. 376 eligible patients were treated with NAC for clinical T2-4aN0M0 disease, and 296 were evaluable for the change in NLR. A high NLR was defined as being an NLR > 3. Relationships between the change in NLR from baseline to mid-NAC (pre-cycle 3) and outcomes were analyzed using multivariable Cox regression. Kaplan-Meier analysis was used with the log-rank test for group comparisons. RESULTS: Median follow-up was 22.0 months (95% confidence interval [CI]: 14.9-30.0). Patients with a sustained high NLR had a median disease-free survival (DFS) of 12.6 months, compared to 34.8 months for those with a sustained low NLR (log-rank test p = 0.0025; hazard ratio [HR] 0.61 [95% CI: 0.44-0.84]). Median overall survival (OS) was 19.4 months for patients with a sustained high NLR, compared to 44.0 months for patients with a sustained low NLR (log-rank test p = 0.0011; HR 0.54 [95% CI: 0.38-0.77]). CONCLUSIONS: A sustained high NLR from baseline to mid-NAC is an independent prognostic factor for patients with MIBC.

Prognostic and predictive clinical factors in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel.

INTRODUCTION: Cabazitaxel is one of several treatment options available for patients with metastatic castration-resistant prostate cancer who have progressed on docetaxel. Little is known about clinical factors that influence prognosis or treatment response for patients receiving cabazitaxel. Identifying prognostic and predictive factors could contribute to the optimal selection of patients for treatment after docetaxel. METHODS: A retrospective review of patients enrolled on the cabazitaxel Canadian Early Access Program (C-EAP) was performed. Clinical factors were analyzed by univariable and multivariable Cox proportional hazards and logistic regression analysis to identify independent predictors of prognosis and response. RESULTS: Forty-five patients from five centres in Canada were included in this study. On multivariable analysis, lower hemoglobin was associated with shorter survival. No other factors were independently associated with survival, prostate-specific antigen (PSA) response, or primary PSA progression. CONCLUSIONS: Clinical factors predicting survival or treatment response were not identified for men with castration-resistant prostate cancer receiving cabazitaxel. Larger studies may be necessary to identify clinical factors and biomarkers that identify whether patients should or should not receive cabazitaxel.

Real-world Outcomes in Advanced Urothelial Cancer and the Role of Neutrophil to Lymphocyte Ratio.

INTRODUCTION: In the first- and second-line metastatic urothelial carcinoma (mUC) treatment setting, we investigated real-world outcomes and evaluated the prognostic role of neutrophil to lymphocyte ratio (NLR). METHODS: A retrospective analysis was performed on patients with mUC treated with systemic therapy. Overall response rates (ORRs), median time to treatment failure (mTTF), and median overall survival (mOS) were calculated. The association between baseline NLR (using a literature-derived cut-off of 3, as well as the best cut-off NLR value of 5.45 as identified by X-Tile software from this dataset) and mTTF and mOS were evaluated using Cox regression analysis. RESULTS: We evaluated 233 patients. In the first-line, the ORR was 25%. mTTF and mOS were 6.9 months and 9.0 months, respectively. Low baseline NLR was significantly associated with improved 8.3-month mTTF, in contrast to 5.8 months for patients with high NLR (P = .046). Low NLR was significantly correlated with a longer mOS of 13.1 months, compared with high NLR (8.2 months; P = .007). In the second-line, an ORR of 22%, an mTTF of 4.1 months, and an mOS of 8 months were observed. Low NLR in the second-line was significantly associated with improved mTTF at 7.9 months versus high NLR patients (3.3 months; P = .023). Second-line low NLR was significantly associated with a longer mOS of 12.2 months, in comparison to 6.8 months with high NLR (P = .003). CONCLUSION: In this real-world analysis of patients with mUC, first-line outcomes were lower than expected. Low NLR in the first- and second-line is associated with improved mTTF and mOS.

Clinical Outcomes of First-line Abiraterone Acetate or Enzalutamide for Metastatic Castration-resistant Prostate Cancer After Androgen Deprivation Therapy + Docetaxel or ADT Alone for Metastatic Hormone-sensitive Prostate Cancer.

BACKGROUND: The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone. PATIENTS AND METHODS: A cohort of patients with mCRPC treated between 2014 and 2017 with first-line AA or E for mCRPC was identified from 3 hospitals' institutional review board-approved databases. Patients were classified by use of D for mHSPC. This time frame was chosen as ADT+D became a valid therapeutic option for mHSPC in 2014, and it inherently entailed a short follow-up time on AA/E. The endpoints included overall survival from ADT start, overall survival from AA/E start, and time to AA/E start from ADT start. Differences between groups were assessed using the log-rank test. RESULTS: Of the 102 patients with mCRPC identified, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT+D. No statistically significant difference in any of the evaluated outcomes was observed between the 2 cohorts. Yet, deaths in the ADT+D group were 12 versus 21 in the ADT alone, after a median follow-up of 24.4 and 29.8 months, respectively. CONCLUSION: In a cohort of ADT/ADT+D-treated patients with mCRPC with short times to first-line AA/E and follow-up, the efficacy of AA/E is similar regardless of previous use of D.

Options in metastatic urothelial cancer after first-line therapy.

PURPOSE OF REVIEW: The treatment of patients with metastatic urothelial carcinoma is evolving with recent advances holding promise for improved outcomes. Historically, patients with metastatic urothelial carcinoma had a poor prognosis with no standard treatment options in the second-line setting. Currently, with an increased understanding of the heterogeneity of clinical bladder cancer subtypes and molecular diversity of the disease, there is optimism that outcomes will start to improve. The present review will evaluate historical second-line treatment options and focus on emerging therapies in this setting. RECENT FINDINGS: Single-agent cytotoxic chemotherapy agents continue to be evaluated in patients with metastatic urothelial carcinoma with variable results. Targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have also been extensively evaluated in this disease. Early phase data have as yet failed to demonstrate improvements in survival; however evaluations of targeted agents in enriched patient populations and in combination with chemotherapeutic agents are ongoing. Novel immunotherapeutic approaches have shown encouraging results and are currently being evaluated extensively. SUMMARY: The optimal treatment for patients with metastatic urothelial carcinoma in the second-line setting is unknown. Recent advances in the field gives rise to optimism as the focus shifts to individualization of therapy based on clinical and molecular characteristics of the patient and the disease.