Association of age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer.

PURPOSE: To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. RESULTS: pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6-37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary subtype. CONCLUSIONS: While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.

BACKGROUND: Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre. RESULTS: All men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA. CONCLUSIONS: Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research.

Elective intensive care unit admissions for organ donation in patients with terminal brain glioma: Case report.

Despite being eligible, only 26 patients with primary brain cancer became organ donors from 2009 to 2018 in Australia. We describe two patients with high grade gliomas who successfully donated their organs after obtaining first-person consent in the outpatient setting by careful multidisciplinary planning and an elective intensive care unit admission for organ donation. Barriers and facilitators were examined based on these experiences and suggestions for future practices are explored. The recommended practices include: 1. Systematic incorporation of organ donation into advance care planning. 2. Integrating organ donation organisation coordinators into advance care planning. 3. Standardization of donor care and clear communication and collaboration between treatment teams. 4. Support and involvement of the medical treatment decision maker. 5. Identification of clinical triggers for admission to hospital and intensive care unit. These two cases illustrate that with careful coordination and involvement from a multidisciplinary team, successful organ transplantation outcomes are possible.

Impact of sex on response to neoadjuvant chemotherapy in patients with bladder cancer.

OBJECTIVE: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC). METHODS: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses. RESULTS: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75-1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71-1.58, P = 0.77). CONCLUSION: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.

The prognostic value of the neutrophil-to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC. METHODS: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression. RESULTS: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02). CONCLUSION: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice.

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.

Neutrophil-Lymphocyte Ratio and Pathological Response to Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NC) improves overall survival in muscle-invasive bladder cancer (MIBC), but there are currently no predictive biomarkers of response to NC in MIBC. An increased peripheral blood neutrophil to lymphocyte ratio (NLR) is a marker of systemic inflammation and is linked to poor prognosis in some solid tumors. We evaluated whether NLR is associated with pathological response (pathR) in MIBC patients who receive NC. PATIENTS AND METHODS: MIBC patients treated with NC and radical cystectomy (RC) between July 2006 and April 2013 were retrospectively reviewed. The primary end point was to find variables associated with pathR in the RC specimen after NC. Potential predictive markers were analyzed using logistic regression. NLR values before NC, midway through NC, and before RC were collected and compared between patients who achieved pathR ('responders') and those who did not ('nonresponders'). RESULTS: In 26 evaluable patients, age, sex, performance status, smoking status, stage, hydronephrosis, NLR before NC, midway through NC, and before RC were not significantly associated with pathR, but the pattern of NLR change between responders and nonresponders was significantly different (P = .038). Responders exhibited a sustained decrease in NLR during NC until RC, and nonresponders exhibited a transient decrease in NLR which then increased to above its baseline before RC. CONCLUSION: The pattern of change in NLR during NC varied significantly between responders and nonresponders. We hypothesize that a sustained decrease in inflammatory burden during NC is associated with pathR. Despite limitations of a small retrospective study, our observations might have clinical implications and warrant further basic and clinical research.

Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer.

BACKGROUND: The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE: We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS: Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION: NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS: Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS: Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY: There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Abiraterone acetate in metastatic castration-resistant prostate cancer: a retrospective review of the Princess Margaret experience of (I) low dose abiraterone and (II) prior ketoconazole.

INTRODUCTION: Abiraterone (AA) is a CYP17 inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). Data suggest similar pharmacokinetics of 250-500 mg of AA with high-fat meals ('low-dose') and 1000 mg in the fasting state ('full-dose'). Ketoconazole (KT) is a less potent CYP17 inhibitor previously widely used in mCRPC. OBJECTIVE: To study outcomes of men with mCRPC treated with low-dose AA and/or with prior exposure to KT. PATIENTS AND METHODS: Retrospective chart review of all men treated with AA at the Princess Margaret Cancer Centre between November 2009 and March 2013. Outcome measures were prostate-specific antigen response rate (PSA-RR), biochemical progression-free survival (bPFS), treatment duration and overall survival (OS). Associations between AA dose or prior KT and outcomes were assessed using chi-square test for PSA-RR and log-rank test for bPFS, treatment duration and OS. RESULTS: In total, 111 men who received AA were evaluable, of which 21 received low-dose AA and 23 received prior KT. There was a non-significant difference in PSA-RR (43% versus 32%, p=0.37), but no significant differences in median bPFS, median treatment duration and median OS (18.7 versus 16.6 months, p=0.25) in the full and low-dose cohorts respectively, and for those who received prior KT or not (PSA-RR 48% versus 38%, p=0.4; median OS 24.2 versus 16.5 months, p=0.066, respectively). CONCLUSIONS: Low-dose AA or prior KT treatment were not associated with poorer outcome in men with mCRPC treated with AA. These observations may have implications for drug sequencing and dose in resource-limited settings.

Evaluation of second-line and subsequent targeted therapies in metastatic renal cell cancer (mRCC) patients treated with first-line cediranib.

INTRODUCTION: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing. METHODS: In this study we evaluated mRCC patients who were initially treated on the first-line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies. RESULTS: Twenty-eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%-47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib. CONCLUSION: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second-line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease.

Neoadjuvant chemotherapy should be administered to fit patients with newly diagnosed, potentially resectable muscle-invasive urothelial cancer of the bladder (MIBC): A 2013 CAGMO Consensus Statement and Call for a Streamlined Referral Process.

Neoadjuvant chemotherapy (NC) improves overall survival in patients with resectable muscle-invasive urothelial cancer of the bladder (MIBC). However uptake of NC in Canada is dis-appointingly low. Following a detailed literature review and in consultation with urologic oncology, the Canadian Association of Genitourinary Medical Oncologists (CAGMO) has developed a consensus statement for the use of NC in MIBC. Our primary goal is to increase the uptake of NC for MIBC in Canada and improve patient outcomes.

Mortality within 30 days of receiving systemic anti-cancer therapy at a regional oncology unit: what have we learned?

AIMS: Benefits to patients from systemic anti-cancer therapies (SACT) occur at a cost of significant toxicities that can be life threatening. Published data of SACT mortality outside clinical trials is limited with no published Australia data. We aim to establish local outcomes at a regional Victorian oncology center to allow comparison with limited international data. METHODS: An audit was undertaken at Ballarat Health Services to analyze all deaths occurring within 30 and 60 days of receiving SACT (cytotoxic chemotherapy and targeted therapy) for epithelial malignancies and hematological malignancies (excluding acute leukemia), over a 12-month period. Hormonal therapy was excluded. RESULTS: Between 1 January and 31 December 2008, 378 patients received SACT. In total 13 deaths (3.4%) occurred within 30 days following SACT. Three deaths (23%) were definitely treatment-related - neutropenic sepsis, pneumocystis pneumonia and bowel perforation, respectively. Eight deaths (62%) were definitely unrelated to treatment. Most deaths were due to disease progression (six patients) For two patients (15%), the cause of death was unknown. Most patients were treated with palliative intent. Most patients were receiving first-line treatment (seven patients, 50%). A further five deaths (1.3%) occurred 31-60 days after SACT, four of which were due to disease progression. CONCLUSION: Our local outcome data are comparable to limited current international data. This type of audit reviews local outcomes and identifies factors contributing to mortality in order to improve standards of care. We encourage similar audits to establish national benchmarks of 30-day mortality rate.