Unresectable Urothelial Cancer Research Articles

SOGUG-vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.

TPS4606 Background: The current standard of care in non-progressors to first-line platinum-based chemotherapy for unresectable locally advanced or metastatic urothelial carcinoma (UC) is maintenance treatment with avelumab plus best supportive care (BSC). The Checkmate 032 trial showed that the highest ORR (42.4%) was achieved by the combination of Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg in refractory mUC (1), with a manageable safety profile and better outcomes compared to other treatment arms. The trial aims to consolidate the clinical benefit achieved from first-line chemotherapy with the combination of nivolumab 1mg/kg plus ipilimumab 3mg/kg followed by nivolumab. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of Ipilimumab and nivolumab followed by nivolumab maintenance therapy in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line chemotherapy. Main eligibility criteria include: Male or female subjects ≥ 18 yrs old with written informed consent, ECOG performance status 0 or 1, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (UCC), patient inclusion within 3-12 weeks after the last chemo dose, no progressive disease per RECIST v1.1, available tumor tissue at baseline, adequate normal organ and marrow function (Haemoglobin ≥ 9.0 g/dL, ANC > 1500 per mm3, platelets ≥ 100,000 per mm3, bilirubin ≤ 1.5 X ULN, transaminases ≤ 2.5X ULN, creatinine clearance > 30 mL/min). The primary endpoint is Progression Free Survival (PFS). Secondary objectives include: objective response rate (ORR), duration of response (DoR), overall survival (OS), chemotherapy overall survival (cOS), and chemotherapy progression-free survival (cPFS). Additionally, the study also has safety secondary objectives. Dynamic biomarker analysis will be performed. As of January 2023, 5 out of the planned 66 patients have been enrolled in the study. 1) Sharma P et al. J Clin Oncol. 2019. Clinical trial information: EudraCT 2021-005364-22 .

Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial

Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. Bristol Myers Squibb.

Alliance A032002 (ART): Phase II randomized trial of atezolizumab versus atezolizumab and radiation therapy for platinum-ineligible/refractory metastatic urothelial cancer.

TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .

Sequential enfortumab vedotin (EV) after platinum-based chemotherapy in metastatic or locally advanced urothelial cancer: Complete response, bladder preservation and survival.

529 Background: For metastatic or unresectable invasive urothelial cancer (UC), standard first-line platinum-based chemotherapy achieved progression-free survival (PFS) of 4–7 months. Complete response (CR) rate is <10%. The minority of patients downstaged after chemotherapy followed by cystectomy still suffer from loss of bladder function and a high risk of recurrence. To improve PFS, CR, and bladder preservation, we explored the use of EV after platinum-based chemotherapy in patients with metastatic or locally advanced UC who desired bladder preservation. Methods: Patients with metastatic or locally advanced unresectable UC who desired bladder preservation and received EV after platinum-based chemotherapy were identified. CR was defined as no evidence of disease identified on both radiology (MRI+CT) and cystoscopy; PFS were calculated from the date of initial treatment (first-line chemotherapy) to the date of last follow-up/death or recurrence via Kaplan-Meier analysis. Results: A total of 12 patients were identified: median age was 69.5 years (range, 52–83); 10 (83%) were men; 9 (75%) partial response and 3 (25%) disease progression were observed from platinum-based chemotherapy. EV was given after platinum-based chemotherapy to all 12 patients who subsequently achieved 100% of response: CR was achieved in 7 (58%) patients, and 4 (33%) remained disease free without ongoing treatment, their disease-free survival (DFS) was 9 months (range, 4–18); 2 patients who achieved CR then recurred as carcinoma in situ (CIS), one of whom had a cystectomy with TisN0 confirmed on final pathology. 2 (17%) patients received radiation to bladder and nodal area. Eleven (92%) patients retained their bladders and no patients died. Median follow-up was 19 months (range, 3.4–53.6). The median duration of EV was 7.5 months (range, 2–20). One-year PFS with bladder intact was 83%. Detailed clinical characteristics and outcome listed on Table. Conclusions: For patients with locally advanced or metastatic UC who desired bladder preservation, platinum-based chemotherapy followed by EV with or without pembrolizumab showed encouraging CR and PFS and deserves to be explored further. [Table: see text]

TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy.

TPS498 Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991.

Abstract 4890: Mutational signatures as biomarkers of response to nivolumab in metastatic bladder cancer

Abstract Background: Metastatic or surgically unresectable urothelial cancer (UC) is a disease with high unmet need. Nivolumab monotherapy demonstrated clinical benefit in patients with platinum-resistant UC (CheckMate 275; NCT02387996). Because not all patients respond to nivolumab therapy, identifying biomarkers for response is of critical importance. In the CheckMate 275 cohort, higher tumor mutational burden (TMB) was associated with longer overall survival (OS) (1). Previous studies have shown that certain mutational signatures, combinations of mutation types arising from specific mutagenesis processes, were associated with mutational burden and clinical outcome in UC (2,3). We hypothesized that specific mutational signatures may be associated with response to nivolumab in CheckMate 275. Methods: Whole exome sequencing data and clinical annotations for 139 archival, tumor-normal paired samples from patients enrolled in the CheckMate 275 cohort were collected and analyzed. Sequencing reads were processed and somatic variants called as described previously (4). Percentage of mutations across 30 mutational signatures were generated using deconstructSigs, which infers signature activity with given known signatures (5). Association of the most prevalent mutational signatures with TMB, previously known clinical biomarkers, and clinical efficacy (OS, progression free survival [PFS], and objective response [OR]) were examined. Results: We identified age-related (signature 1), endogenous mutagenesis-related APOBEC (signatures 2 and 13) and UV-induced (signature 7) as the most prevalent mutational signatures in UC. When examining their correlations with TMB, signature 1 showed negative correlation, signatures 2 and 13 showed high positive correlation, and signature 7 showed low correlation. Higher signature 2 scores were associated with better OS, but were poor predictors for PFS and OR. Overall, while signature 2 added predictive value over previously known clinical biomarkers such as PD-L1 expression, serum hemoglobin level, and presence of liver metastasis, it did not improve on the predictive performance of TMB. Conclusions: An APOBEC-related mutational signature (signature 2) was associated with OS in patients with advanced UC treated with nivolumab. This signature was correlated with TMB and did not improve upon TMB as a predictive biomarker. Our work demonstrates the importance of including TMB as a covariate when analyzing mutational signatures.

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.

Abstract CT080: A phase II study of JNJ-42756493, a pan-FGFR tyrosine kinase inhibitor, in patients with metastatic or unresectable urothelial cancer (UC) harboring FGFR gene alterations

Abstract Background: Current treatment options for metastatic UC remain limited, and tolerability is a concern in many patients. Alterations in the fibroblast growth factor receptor (FGFR) pathway are implicated in development of non-muscle-invasive bladder cancer; FGFR3 mutations or FGFR translocations are present in ∼10-20% of patients with metastatic UC. Treatment with pan-FGFR (FGFR1-4) inhibitor JNJ-42756493 resulted in promising antitumor activity in a phase 1 trial in patients with advanced solid tumors, including 3 partial responses among 8 patients with UC (Tabernero J, et al. J Clin Oncol. 2015). Safety was manageable and as anticipated with a potent FGFR inhibitor. This phase 2 open-label study of JNJ-42756493 (NCT02365597) is being conducted to determine efficacy and safety of 2 different dose regimens in patients with metastatic or unresectable UC with specific FGFR translocations or mutations. Methods: Eligible patients must have disease progression following chemotherapy for metastatic or surgically unresectable UC or relapse within 12 months of the last dose of neoadjuvant/adjuvant chemotherapy. There is no limit on number of prior lines of treatment. Prior immunotherapy (eg, programmed-death 1/death-ligand 1 inhibitor) is allowed. Enrollment of cisplatin-ineligible (chemotherapy naïve) pts is allowed. Patients must have measurable disease (Response Evaluation Criteria In Solid Tumors version 1.1); Eastern Cooperative Oncology Group performance status ? 2; and adequate bone marrow, liver, and kidney function (creatinine clearance ? 40 mL/min). Patients with uncontrolled cardiovascular disease or baseline phosphate persistently above the upper limit of normal are not eligible. Eligible patients are randomized to 1 of 2 oral dose regimens of JNJ-42756493 in a 28-day cycle: an intermittent (10 mg/day for 7 days followed by 7 days off drug) or a continuous (6 mg/day) regimen until a dose regimen is selected. Approximately 110 patients will be treated at the selected dose regimen. Primary end point is objective response rate; secondary end points include progression-free survival, duration of response, overall survival, safety, biomarker, and pharmacokinetic assessments. This trial is currently enrolling in 14 countries. Citation Format: Arlene O. Siefker-Radtke, Begoña Mellado, Karel Decaestecker, John M. Burke, Anne O’ Hagan, Anjali Avadhani, Bob Zhong, Ademi Santiago-Walker, Peter De Porre, Sabine Brookman-May, Jesus Garcia-Donas. A phase II study of JNJ-42756493, a pan-FGFR tyrosine kinase inhibitor, in patients with metastatic or unresectable urothelial cancer (UC) harboring FGFR gene alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT080.

A phase 2 study of JNJ-42756493, a pan-FGFR tyrosine kinase inhibitor, in patients (pts) with metastatic or unresectable urothelial cancer (UC) harboring FGFR gene alterations.

TPS4575Background: Current treatment options for metastatic UC remain limited, and tolerability is a concern in many pts. Alterations in the fibroblast growth factor receptor (FGFR) pathway are imp...

A Phase II, single-arm study of nivolumab in patients with metastatic or unresectable urothelial cancer who have progressed following treatment with a platinum agent

Meeting abstracts Clinical trials in patients with advanced bladder cancer have reported response rates of up to approximately 30% and 60% with single-agent and multi-agent regimens, respectively, and minimal improvements in survival over best supportive care. Guidance on second-line treatment

Phase II Trial of Cisplatin, Gemcitabine, and Bevacizumab As First-Line Therapy for Metastatic Urothelial Carcinoma: Hoosier Oncology Group GU 04-75

Novel approaches are needed for patients with metastatic urothelial cancer (UC). This trial assessed the efficacy and toxicity of bevacizumab in combination with cisplatin and gemcitabine (CGB) as first-line treatment for patients with metastatic UC. Chemotherapy-naive patients with metastatic or unresectable UC received cisplatin 70 mg/m(2) on day 1, gemcitabine 1,000 to 1,250 mg/m(2) on days 1 and 8, and bevacizumab 15 mg/kg on day 1, every 21 days. Forty-three patients with performance status of 0 (n = 26) or 1 (n = 17) and median age of 66 years were evaluable for toxicity and response. Grade 3 to 4 hematologic toxicity included neutropenia (35%), thrombocytopenia (12%), anemia (12%), and neutropenic fever (2%). Grade 3 to 5 nonhematologic toxicity included deep vein thrombosis/pulmonary embolism (21%), hemorrhage (7%), cardiac (7%), hypertension (5%), and proteinuria (2%). Three treatment-related deaths (CNS hemorrhage, sudden cardiac death, and aortic dissection) were observed. Best response by Response Evaluation Criteria in Solid Tumors was complete response in eight patients (19%) and partial response in 23 patients (53%), for an overall response rate of 72%. Stable disease lasting ≥ 12 weeks occurred in four patients (9%), and progressive disease occurred in six patients (14%). With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months). The study-defined goal of 50% improvement in PFS was not met. CGB demonstrates promising OS and antiangiogenic treatment-related toxicities in the phase II setting of metastatic UC. The full risk/benefit profile of CGB in patients with metastatic UC will be determined by an ongoing phase III intergroup trial.

A phase II randomized four-regimen selection trial incorporating response for sequential chemotherapy in metastatic, unresectable urothelial cancer: Final results from the M. D. Anderson Cancer Center

5071 Background: We developed a clinical trial incorporating response into the treatment algorithm. Patients meeting a certain threshold of response continued with the same treatment; those with insufficient response were switched to alternative chemotherapy. We now report on final results from this trial. Methods: Patients were randomly assigned to one of four regimens: ifosfamide, doxorubicin, gemcitabine; ifosfamide, paclitaxel, cisplatin; gemcitabine, cisplatin; or cisplatin, gemcitabine, and ifosfamide. To continue with chemotherapy, patients must have had at least a 40% response after the first 6-week interval, and a >90% response after the second 6 weeks. Otherwise, they were re-randomized to alternate chemotherapy. Overall success (OSX) was defined as patients with a >90% response with either front-line or second-line therapy. Surgical consolidation was offered to patients at the discretion of their treating physician. Results: Median overall survival (OS) for 120 patients was 19.1 mo. (3 and 5-yr survival: 33% and 20%). OSX was achieved in 41 patients (median OS: 51 mo.); the median OS in the other 79 patients was 15 mo. (p = 0.0001), with a 5-yr survival of 42% and 10% respectively. Surgical consolidation was performed in 35 patients: 23 with nodal metastases to pelvic and/or RPLN, 6 with cT4b tumors, and an additional 6 patients with distant metastases. Their median OS from surgery was 23.7 months, (5-yr survival: 31%). Surgical consolidation in the setting of OSX was associated with a 42% 5-yr survival as compared to 11% in those undergoing surgery in the absence of OSX. Visceral metastases and poor performance status were associated with a worse prognosis. Conclusions: With sequential therapy, 34% of patients had a >90% response (OSX). A potential benefit in long-term survival was seen in patients who had surgical consolidation in the setting of OSX. This trial design provides a novel method for assessing the benefits of sequential chemotherapy, and enhancing the population of patients who may be offered surgical consolidation in the setting of initially unresectable, or metastatic urothelial cancer. No significant financial relationships to disclose.

A nomogram predicting survival of patients (pts) with metastatic or unresectable urothelial cancer (UC) treated with cisplatin-based chemotherapy

5055 Background: Cisplatin-based chemotherapy is the standard of care for pts with metastatic or unresectable UC with phase III studies reporting median survivals of 12–15 months. Even more survival variation exists in phase II studies and this disparity is most frequently due to prognostic factors and not individual regimens. Thus, better tools are needed to predict survival both for individual pts and to balance phase III trials. Nomograms have utility in predicting short- and long-term outcome in muscle-invasive UC treated by surgery but they have not been explored in more advanced UC. Methods: We identified 308 pts with metastatic and/or unresectable UC treated on prospective phase II MSKCC protocols of cisplatin-based therapy containing 3–5 total chemotherapy agents. 203 pts received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), 45 had ifosfamide, paclitaxel and cisplatin (ITP) and 60 pts received doxorubicin plus gemcitabine (AG) followed by ITP (AG-ITP). Survival distributions were compared across trials. Pre-treatment characteristics were then assessed for impact on survival and a nomogram from a fitted Cox model was created to predict 1-yr, 2-yr, 5-yr and median survival. Results: No difference in median survivals were seen among the 3 regimens; median survival was 14.8 months for MVAC, 18.0 months for ITP and 16.1 months for AG- ITP (p=NS). Median survival for all pts was 12.99 months; 268 pts died and 40 pts were censored. 288 pts had all pre-treatment data. Characteristics most associated with survival included visceral metastases (present versus absent, p=.00001) and Karnofsky poor performance status (≥ 80 versus < 80, p= .0005) followed by hemoglobin (normal versus < normal, p=.01) and albumin (actual values, p<.02). These characteristics were then used to construct a nomogram utilizing all 4 factors to predict probabilities of 1-yr, 2-yr, and 5-yr survival. Conclusions: The number and sequence of drugs utilized in cisplatin-based chemotherapy did not substantially impact survival of pts with advanced UC. A nomogram of pre-treatment clinical factors can predict probability of pt survival at 1 yr, 2yrs, and 5 yrs. This nomogram may also be useful to balance treatment arms in phase III trials. No significant financial relationships to disclose.

Recent developments in advanced urothelial cancer

Metastatic or unresectable urothelial cancer of the urinary bladder has traditionally been treated with systemic chemotherapy, which is most often platinum-based. The long-term survival data and the associated toxicities from this form of therapy have spurred continuing interest in finding novel treatment options for this malignancy. Recently, trials of new chemotherapy combinations, many incorporating platinum analogs or deleting platinum entirely, have been reported. None has yet been shown to be superior to cisplatin-based regimens. In addition, recent advances in imaging and laboratory technologies have provided new avenues to understand urothelial cancer behavior and prognosis. These advances provide optimism for improvements in the diagnosis, staging, and ultimately, selection of therapy for patients with urothelial cancer. This review will summarize recent developments (circa 2004) in the diagnosis and management of advanced bladder cancer.

Phase III Trial of Fluorouracil, Interferon Alfa-2b, and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Metastatic or Unresectable Urothelial Cancer

PURPOSE: Previously, we developed a novel biochemotherapy regimen combining interferon alfa-2b with fluorouracil and cisplatin (FAP). We now report the results of a prospective randomized trial comparing FAP with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), the standard chemotherapy regimen for locally advanced and metastatic urothelial cancer. The purpose of this study was to compare the response rates and overall survival of patients with metastatic or unresectable urothelial cancer treated with these two chemotherapy regimens. PATIENTS AND METHODS: Between October 1992 and September 1999, 172 previously untreated patients were registered and randomly assigned to treatment with either FAP or M-VAC. Patients were followed until their death. RESULTS: The pretreatment clinical characteristics of the groups were similar except for sex (P < .01). Sex did not affect prognosis or survival. The objective response rate for patients assigned to FAP was 42% (35 of 83 patients), with complete resp...