Cost-effectiveness of avelumab first-line maintenance therapy for adult patients with locally advanced or metastatic urothelial carcinoma in France.

BACKGROUND: This study evaluated the cost-effectiveness of avelumab first-line (1L) maintenance therapy plus best supportive care (BSC) versus BSC alone for adults with locally advanced or metastatic urothelial carcinoma (la/mUC) that had not progressed following platinum-based chemotherapy in France. METHODS: A three-state partitioned survival model was developed to assess the lifetime costs and effects of avelumab plus BSC versus BSC alone. Data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) were used to inform estimates of clinical and utility values considering a 10-year time horizon and a weekly cycle length. Cost data were estimated from a collective perspective and included treatment acquisition, administration, follow-up, adverse event-related hospitalization, transport, post-progression, and end-of-life costs. Health outcomes were measured in quality-adjusted life-years (QALYs) and life-years gained. Costs and clinical outcomes were discounted at 2.5% per annum. Incremental cost-effectiveness ratios (ICERs) were used to compare cost-effectiveness and willingness to pay in France. Uncertainty was assessed using a range of sensitivity analyses. RESULTS: Avelumab plus BSC was associated with a gain of 2.49 QALYs and total discounted costs of €136,917; BSC alone was associated with 1.82 QALYs and €39,751. Although avelumab plus BSC was associated with increased acquisition costs compared with BSC alone, offsets of -€20,424 and -€351 were observed for post-progression and end-of-life costs, respectively. The base case analysis ICER was €145,626/QALY. Sensitivity analyses were consistent with the reference case and showed that efficacy parameters (overall survival, time to treatment discontinuation), post-progression time on immunotherapy, and post-progression costs had the largest impact on the ICER. CONCLUSIONS: This analysis demonstrated that avelumab plus BSC is associated with a favorable cost-effectiveness profile for patients with la/mUC who are eligible for 1L maintenance therapy in France.

Impact of concurrent medications on clinical outcomes of cancer patients treated with immune checkpoint inhibitors: analysis of Health Insurance Review and Assessment data.

PURPOSE: Medications regulating immune homeostasis and gut microbiota could affect the efficacy of immune checkpoint inhibitors (ICIs). This study aimed to investigate the impact of concurrent medications on the clinical outcomes of patients with cancer receiving ICI therapy in South Korea. METHODS: We identified patients newly treated with ICI for non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), and malignant melanoma (MM) between August 2017 and June 2020 from a nationwide database in Korea. The effect of concurrent antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids prescribed within 30 days before ICI initiation on the treatment duration and survival was assessed. RESULTS: In all, 8870 patients were included in the ICI cohort (NSCLC, 7,128; UC, 960; MM, 782). The patients were prescribed ATBs (33.8%), CSs (47.8%), PPIs (28.5%), and opioids (53.1%) at the baseline. The median overall survival durations were 11.1, 12.2, and 22.1 months in NSCLC, UC, and MM subgroups, respectively, since starting the ICI mostly as second-line (NSCLC and UC) and first-line (MM) therapy. Early progression was observed in 34.2% of the patients. Opioids and CS were strongly associated with poor survival across all cancer types. A high number of concurrent medications was associated with early progression and short survival. Opioid and CS use was associated with poor prognosis in all patients treated with ICIs. However, ATBs and PPIs had a cancer-specific effect on survival. CONCLUSION: A high number of concurrent medications was associated with poor clinical outcomes.

Implementation and Assessment of No Opioid Prescription Strategy at Discharge After Major Urologic Cancer Surgery.

Importance: Postoperative opioid prescriptions are associated with delayed recovery, perioperative complications, opioid use disorder, and diversion of overprescribed opioids, which places the community at risk of opioid misuse or addiction. Objective: To assess a protocol for eliminating postdischarge opioid prescriptions after major urologic cancer surgery. Design, Setting, and Participants: This cohort study of the no opioid prescriptions at discharge after surgery (NOPIOIDS) protocol was conducted between May 2017 and June 2021 at a tertiary referral center. Patients undergoing open or minimally invasive radical cystectomy, radical or partial nephrectomy, and radical prostatectomy were sorted into the control group (usual opioids), the lead-in group (reduced opioids), and the NOPIOIDS group (no opioid prescriptions). Interventions: The NOPIOIDS group received a preadmission educational handout, postdischarge instructions for using nonopioid analgesics, and no routine opioid prescriptions. The lead-in group received a postdischarge instruction sheet and reduced opioid prescriptions at prescribers' discretion. The control group received opioid prescriptions at prescribers' discretion. Main Outcomes and Measures: Primary outcome measures included rate and dose of opioid prescriptions at discharge and for 30 days postdischarge. Additional outcome measures included patient-reported pain and satisfaction level, unplanned health care utilization, and postoperative complications. Results: Of 647 opioid-naive patients (mean [SD] age, 63.6 [10.0] years; 478 [73.9%] male; 586 [90.6%] White), the rate of opioid prescriptions at discharge for the control, the lead-in, and the NOPIOIDS groups was 80.9% (157 of 194), 57.9% (55 of 95), and 2.2% (8 of 358) (Kruskal-Wallis test of medians: P < .001), and the overall median (IQR) tablets prescribed was 14 (10-20), 4 (0-5.3), and 0 (0-0) per patient in the control, lead-in, and NOPIOIDS groups, respectively (Kruskal-Wallis test of medians: P < .001). In the NOPIOIDS group, median and mean opioid dose was 0 tablets for all procedure types, with the exception of kidney procedures (mean [SD], 0.5 [1.7] tablets). Patient-reported pain surveys were received from 358 patients (72.6%) in the NOPIOIDS group, demonstrating low pain scores (mean [SD], 2.5 [0.86]) and high satisfaction scores (mean [SD], 86.6 [3.8]). There was no increase in postoperative complications in the group with no opioid prescriptions. Conclusions and Relevance: This perioperative protocol, with emphasis on nonopioid alternatives and patient instructions, may be safe and effective in nearly eliminating the need for opioid prescriptions after major abdominopelvic cancer surgery without adversely affecting pain control, complications, or recovery.

Emerging agents for the treatment of metastatic urothelial cancer.

Over the past few decades, platinum-based combination chemotherapy (PBCC) has been the preferred initial therapy for metastatic urothelial cancer (mUC). However, despite a response rate of approximately 50%, a small proportion of patients with distant metastases may be cured by cisplatin-based combination chemotherapy (CBCC). In addition, up to 50% of patients are not eligible for CBCC due to age or comorbidities. Furthermore, adverse effects from PBCC are a major concern. The emergence of check-point inhibitors (CPIs), particularly those with antibodies directed against programmed cell death 1 protein (PD-1) or its ligand (PD-L1), advanced the treatment of mUC. Avelumab switch-maintenance therapy is recommended in patients with locally advanced or mUC who did not progress on initial PBCC. With the recent advances in tumor molecular biology and the discovery of actionable therapeutic targets, the clinical application of targeted therapy is now being explored for mUC. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown positive outcomes in patients with advanced UC with FGFR alterations. Another recent technological development is antibody-drug conjugates (ADCs), which are complex molecules composed of an antibody linked to a biologically active cytotoxic drug (payload) that targets and kills tumor cells while sparing healthy cells. Enfortumab vedotin, a monoclonal antibody targeting nectin-4 conjugated to monomethyl auristatin E, has demonstrated clinically significant efficacy in patients who do not respond to both cytotoxic chemotherapy and CPIs. In this review, we describe switch-maintenance therapies using CPI, various targeted agents, and ADCs that have been investigated for mUC treatment.

The cost effectiveness of pembrolizumab versus chemotherapy or atezolizumab as second-line therapy for advanced urothelial carcinoma in the United States.

Aims: Pembrolizumab demonstrated significantly prolonged overall survival (OS) vs. chemotherapy in the Phase III KEYNOTE-045 trial, and is approved in the US for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who progressed after platinum-based chemotherapy. Using longer follow-up and individual patient-data from KEYNOTE-045, this study evaluates the cost-effectiveness of pembrolizumab vs. chemotherapy or atezolizumab from a US payer perspective.Materials and methods: A partitioned-survival model was developed over a 20-year time horizon. Progression-free survival (PFS) and OS for pembrolizumab and chemotherapy were extrapolated using a piecewise modelling approach, where patient-level data from KEYNOTE-045 were used for the initial period followed by parametric distributions. OS of atezolizumab was estimated by indirect treatment comparisons based on KEYNOTE-045 and IMvigor211. Different scenarios were explored in the absence of indirect comparisons on PFS and time-on-treatment (ToT) between pembrolizumab and atezolizumab. Drug acquisition/administration, disease management, adverse events, and terminal care costs were considered.Results: Compared with chemotherapy, pembrolizumab resulted in a mean gain of 1.33 life-years and 1.14 quality-adjusted life-years (QALYs) and an incremental cost of $106,299, yielding an incremental cost-effectiveness ratio of $93,481/QALY gained. Pembrolizumab dominated atezolizumab in extending patients' life by 0.89 years and 0.76 QALYs, while reducing costs by $26,458. Key drivers of cost-effectiveness included survival extrapolation, OS hazard ratio of pembrolizumab vs. atezolizumab, and time horizon. Pembrolizumab had a 66% and 100% probability of being cost-effective vs. chemotherapy and atezolizumab, respectively, at a $100,000 willingness-to-pay threshold.Limitations and conclusions: Uncertainties remain with extrapolated PFS and OS for pembrolizumab, OS indirect comparison, and ToT for atezolizumab. Despite these limitations, the model used robust methods to estimate key clinical endpoints with patient-level data from longer follow-up of KEYNOTE-045. Pembrolizumab dominates atezolizumab and is very likely cost-effective vs. chemotherapy in 2 L mUC at a $100,000 willingness-to-pay threshold.

Financial toxicity and its associations with health-related quality of life among urologic cancer patients in an upper middle-income country.

PURPOSE: This study examined the prevalence of financial toxicity (FT) and associated factors among urologic cancer patients. The association between FT and health-related quality of life (HRQoL) was also investigated. METHODS: A total of 429 respondents diagnosed with urologic cancers (prostate cancer, bladder and renal cancer) from Sarawak General Hospital and Subang Jaya Medical Centre in Malaysia were interviewed using a structured questionnaire. Objective and subjective FT were measured by catastrophic health expenditure (healthcare-cost-to-income ratio greater than 40%) and the Personal Financial Well-being Scale, respectively. HRQoL was measured with the Functional Assessment of Cancer Therapy - General 7 Items scale. RESULTS: Objective and subjective FT were experienced by 16.1 and 47.3% of the respondents, respectively. Respondents who sought treatment at a private hospital and had out-of-pocket health expenditures were more likely to experience objective FT, after adjustment for covariates. Respondents who were female and had a monthly household income less than MYR 5000 were more likely to experience average to high subjective FT. Greater objective FT (OR = 2.75, 95% CI 1.09-6.95) and subjective FT (OR = 4.68, 95% CI 2.63-8.30) were associated with poor HRQoL. CONCLUSIONS: The significant association between both objective and subjective FT and HRQoL highlights the importance of reducing FT among urologic cancer patients. Subjective FT was found to have a greater negative impact on HRQoL.

Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting.

PURPOSE: To determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. METHODS: ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. RESULTS: No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. CONCLUSION: Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy.

BACKGROUND: There is an unmet need for effective therapies for patients with advanced or metastatic urothelial cancer who cannot tolerate cisplatin-based chemotherapy. Cisplatin-ineligible patients experience a high frequency of adverse events from the most commonly used standard of care treatment, carboplatin plus gemcitabine, or alternative treatment with gemcitabine monotherapy. Pembrolizumab is a potent, highly selective humanised monoclonal antibody that releases checkpoint inhibition of the immune response system, and provides a new alternative for these patients. OBJECTIVE: To assess the cost-effectiveness of pembrolizumab for first-line treatment of urothelial carcinoma ineligible for cisplatin-based therapy in patients with strongly PD-L1-positive tumours in Sweden. DESIGN, SETTING, AND PARTICIPANTS: Parametric survival curves were fitted to overall survival, progression-free survival, and time on treatment data from KEYNOTE-052 to extrapolate clinical outcomes. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin plus gemcitabine and gemcitabine monotherapy. EQ-5D data from KEYNOTE-052 were used to estimate utility, while resource use and cost inputs were estimated using Swedish regional pricing lists and clinician opinion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The model reported costs, life years, and quality-adjusted life years (QALYs), and results were tested using deterministic and probabilistic sensitivity analysis. RESULTS AND LIMITATIONS: We estimated that pembrolizumab would improve survival by 2.11 and 2.16 years and increase QALYs by 1.71 and 1.75 compared to carboplatin plus gemcitabine and gemcitabine monotherapy, respectively. Pembrolizumab was associated with a cost increase of €90520 versus carboplatin plus gemcitabine and €95055 versus gemcitabine, with corresponding incremental cost-effectiveness ratios of €53055/QALY and €54415/QALY. CONCLUSIONS: At a willingness-to-pay threshold of €100000/QALY, pembrolizumab is a cost-effective treatment versus carboplatin plus gemcitabine and versus gemcitabine. PATIENT SUMMARY: This is the first analysis to show that pembrolizumab is a cost-effective option for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in Sweden.

Overall survival, costs, and healthcare resource use by line of therapy in Medicare patients with newly diagnosed metastatic urothelial carcinoma.

Aims: Medicare patients with metastatic or surgically unresectable urothelial carcinoma (mUC) often receive platinum-based chemotherapy as first line of therapy (LOT), but invariably progress, requiring additional LOTs and healthcare resource use (HCRU). To better understand the evolving mUC treatment landscape, the economic burden of chemotherapy-based mUC treatments among US Medicare patients was estimated. Methods: Newly diagnosed Medicare patients with mUC were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were followed from diagnosis to death, disenrollment, or end of study to characterize LOTs (first [LOT1], second [LOT2], and third or greater [LOT3+]). Kaplan-Meier methods were used to estimate overall survival (OS) by LOT. HCRU and mean costs were reported over the follow-up period, LOT duration, and maximum LOT received. Results: Among 1,873 eligible patients with mUC (median age = 77 years; median follow-up = 7.5 months), 1,035 (55%) received no chemotherapy. Among chemotherapy-treated patients, 61% had LOT1 only, 25% had LOT1 and LOT2 only, and 14% had LOT3+. Median OS was 8.1 months, range was 4.3 (untreated) to 29.8 (LOT3+) months. HCRU frequency increased with additional LOTs. Mean cumulative per-patient cost was $82,912 for all patients, increasing with additional LOTs (untreated = $57,207; LOT1 = $99,213; LOT2 = $125,190; LOT3+ = $163,884). Mean per patient per month cost was $18,827 for all patients, decreasing with increasing number of LOTs received (untreated = $27,211; LOT1 = $9,601; LOT2 = $7,325; LOT3+ = $6,017). Limitations: Potential for treatment misclassification when using the algorithm defining LOTs and non-generalizability of results to younger patients. Conclusions: Over 50% of Medicare patients with mUC received no chemotherapy. Among chemotherapy-treated patients, most received only one LOT. Additional LOTs led to higher mean costs and HCRU, but as patients were followed longer, monthly costs decreased. As treatments evolve to include immuno-oncology agents, these findings provide a clinically relevant economic benchmark for mUC treatment across different traditional LOTs.

Pembrolizumab for Previously Treated Advanced or Metastatic Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician's choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. No indirect treatment comparison was performed. The clinical effectiveness was assessed using hazard ratios for overall survival (OS) and progression-free survival (PFS) of the intention-to-treat (ITT) population, together with the subpopulations positive for programmed cell death 1 ligand 1 (PD-L1) expression (combined positive score [CPS] ≥ 1%) and strongly positive for PD-L1 expression (CPS ≥ 10%). In the ITT population, OS improved with pembrolizumab (HR 0.73, 95% CI 0.59-0.91) while PFS outcomes showed no difference (HR 0.98, 95% CI 0.81-1.19). Pembrolizumab demonstrated a better safety profile than its combined comparators, with fewer patients experiencing adverse events (60.9 vs 90.2%). Similar results were observed in populations expressing PD-L1. MSD estimated the cost effectiveness of pembrolizumab using a de novo partitioned survival model. The model had three health states: pre-progression, post-progression and death, where OS and PFS estimates excluded patients who received vinflunine. The largest uncertainty was over the selection of the parametric models used to extrapolate OS and PFS and the time point for when to begin their extrapolation. The company preferences for extrapolation were not well supported and the ERG disagreed with their selection for OS. Utility values were also contentious, with the company preferring to use pooled time-to-death-based utilities pooled across treatment arms, whilst the ERG preferred pooled progression-based utilities. The company preferred to use data from patients receiving vinflunine when calculating the utility values, which the ERG disagreed with as this is not recommended treatment within the UK. The company assumed a lifetime treatment effect for their model; however, the lack of evidence made it difficult to confidently provide a realistic estimate of treatment effect duration. Various durations were explored (3, 5 and 10 years). The first appraisal committee meeting concluded that pembrolizumab was not cost effective, largely due to uncertainty in the OS and PFS extrapolations. The company's second submission included an additional 4 months follow-up to survival data. The company in this new submission maintained their original assumptions in their base-case analysis, changing only the choice of parametric curve for PFS. This change resulted in the OS and PFS curves intersecting at 6 years in the pembrolizumab arm, at which point PFS identically followed OS. This resulted in no patients in the post-progression health state beyond this time point, and therefore, the majority of pembrolizumab's benefit came from pre-progression survival. Given the unclear PFS benefit, the ERG found this implausible and maintained their original base-case model assumptions. Considerable uncertainty remained over the specification of the extrapolations and the duration of treatment effect. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.

Nivolumab for Treating Metastatic or Unresectable Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo®) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naïve comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were £58,791, £78,869 and £62,352 per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.

Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company's health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG's probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.

Current status of systemic chemotherapy for octogenarians with advanced urothelial cancer in Japan: a Japanese multi-institutional study (CURE study).

BACKGROUND: The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80 years. METHODS: Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80 years was reviewed before and after 2008 and compared with 315 young patients. RESULTS: There were only 7 (4.6 %) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12 %) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5 %) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis. CONCLUSION: Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.

Adjuvant chemotherapy for upper-tract urothelial carcinoma treated with nephroureterectomy: assessment of adequate renal function and influence on outcome.

OBJECTIVES: Upper-tract urothelial carcinoma (UTUC) is associated with poor outcomes. Our aim was to assess adequacy of renal function and evaluate the role of adjuvant chemotherapy (AC) in patients with UTUC treated by radical nephroureterectomy (RNU) in a universal health care system. MATERIALS AND METHODS: Retrospective data from 1,029 patients treated with RNU across 10 Canadian academic centers were collected. Tested variables included various clinico-pathological parameters, the use of perioperative chemotherapy, preoperative and postoperative creatinine values, and estimated glomerular filtration rates (eGFR). Univariable and multivariable Cox regression models addressed overall survival and disease-specific survival after surgery. Kaplan-Meier survival curves were used to compare outcomes in patients who received or did not receive AC. RESULTS: Median age of patients was 70 years with a median follow-up of patients who were alive of 26 months. The median preoperative and postoperative eGFR rates were 59 mL/min/1.73 m(2) and 47 mL/min/1.73 m(2), respectively. Using a cutoff eGFR of 60, 49% of all the patients and 48% of the patients with ≥ pT3 or pTxN+ or both diseases would have been eligible for cisplatin-based chemotherapy preoperatively and only 18% and 21% of the patients, respectively remained eligible postoperatively. Of the patients who received AC, 75% had an eGFR<60. On multivariate analysis, AC was not prognostic for improved overall survival or disease-specific survival. CONCLUSIONS: Chronic kidney disease is common in patients with UTUC. Following RNU, 57% of the high-risk patients with good preoperative renal function became ineligible for cisplatin-based chemotherapy. Use of AC did not translate into improved survival. Whether this is due to inherent biases of retrospective analysis, limited efficacy of AC in patients with UTUC, or use of suboptimal regimen or dose because of poor postoperative renal function requires further evaluation.

The impact of gender on outcomes in patients with metastatic urothelial carcinoma.

BACKGROUND: Although urothelial cancer is more common in men, women with urothelial cancer have inferior survival outcomes. The potential existence of gender-related disparities in patients with metastatic urothelial cancer has not been extensively explored. PATIENTS AND METHODS: Individual patient data were pooled from 8 phase II and phase III trials evaluating first-line cisplatin-based combination chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between male and female patients. RESULTS: Of the 543 patients included in the analysis, 100 patients (18%) were women. There was no significant difference in the number of cycles of chemotherapy administered or in the proportions of patients experiencing severe toxicities when comparing male and female patients. There was no difference in the survival distributions between male and female patients (P = .08); the median survival of male patients was 11.7 months (95% confidence interval [CI], 10.5-13.2) compared with 16.2 months for female patients (95% CI, 12.8-20.4). There was no significant difference in survival between men and women when controlling for baseline performance status and/or the presence of visceral metastases. CONCLUSION: Female patients with metastatic urothelial cancer tolerate cisplatin-based chemotherapy similarly to male patients and achieve comparable clinical outcomes. Although gender-associated survival disparities in patients with metastatic urothelial cancer cannot be completely ruled out, if such disparities exist, they are unlikely related to tolerability or efficacy of chemotherapy.