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Background: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear., Patients and Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up., Results: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status., Conclusions: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a 'watch-and-wait' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and 'real-world' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of pretreatment factors on immune checkpoint inhibition in platinum-refractory advanced urothelial cancer (aUC) deserves further evaluation. The aim was to study the association of Bellmunt risk factors, time from last chemotherapy (TFLC), previous therapy and PD-L1 expression with atezolizumab efficacy in platinum-refractory aUC., Patients and Methods: This was a post-hoc analysis of patients who had received prior cisplatin or carboplatin in the prospective, single-arm, phase IIIb SAUL study (NCT02928406). Patients were treated with 3-weekly atezolizumab 1200 mg intravenously. The primary outcome was overall survival (OS). Relationships were analysed using Cox regression and long-rank test., Results: Of 997 patients in SAUL, 969 were eligible for this analysis. The number of Bellmunt risk factors was associated with OS (P < 0.001); median OS (mOS) for 0, 1 and 2-3 risk factors was 17.9, 8.9 and 3.3 months, respectively. Significant associations were also observed between OS and TFLC (P < 0.001), programmed death-ligand 1 (PD-L1) expression (P = 0.002), and prior perioperative chemotherapy (P = 0.013); mOS was 6.97 versus 11.63 months for TFLC ≤6 versus >6 months, 7.75 versus 11.6 months for PD-L1 expression on <1% of tumour-infiltrating immune cells (ICs) (IC0)/expression on 1% to <5% of tumour-infiltrating ICs (IC1) versus expression on ≥5% of tumour-infiltrating ICs (IC2/3) and 10.2 versus 7.8 months for prior versus no prior perioperative chemotherapy, respectively. The type of platinum compound and number of previous treatment lines were not associated with outcomes., Conclusions: Post-platinum atezolizumab is active in aUC, irrespective of previous platinum compound and lines of therapy. Bellmunt risk stratification, PD-L1 expression, TFLC and perioperative chemotherapy were identified as prognostic factors for OS with second-line atezolizumab, indicating the need for novel prognostic signatures for immunotherapy-treated patients with aUC., Competing Interests: Disclosure AB: honoraria, advisory and research funding from Roche, BMS, MSD, Ipsen, Debiopharm, Basilea, Pierre Fabre and Janssen; and steering committee member for Roche. ASM: lectures/speaker honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Astellas, Novartis, Pfizer and Roche; consultant for AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSA Pharma, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer and Roche; research and clinical trials support from AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSA Pharma, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer and Roche. YL: personal fees from Roche, Janssen, Astellas, MSD, Pfizer, Roche, BMS, Immunomedics, AstraZeneca, Sanofi and Seattle Genetics; grants from Janssen, MSD and Sanofi; non-financial support from Janssen, Roche, AstraZeneca and Sanofi. NJ: consultancy from Merck, Roche and AstraZeneca; trial funding (to institution) from Merck, Roche and AstraZeneca. EC: research grants from Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB; consultancy from AbbVie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm and Sanofi; and speakers fees from AbbVie, Amgen, Bristol Myer Squibb, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB. DC: personal fees for advisory boards/speaker engagements from Roche, Janssen, Astellas, MSD, Ipsen, Pfizer, Bristol-Myers Squibb, Bayer, AstraZeneca, Novartis, Lilly, Sanofi, Pierre Fabre and Boehringer Ingelheim. FL-R: honoraria from AstraZeneca, Bayer, BMS, Lilly, MSD, Pfizer, Roche and Thermo Fisher; and research funding from Lilly, Roche and Thermo Fisher. FC: advisory role for BMS, MSD, Pfizer and AstraZeneca. MK: honoraria/consultation for Bayer, BMS, EUSAI, Novartis, Merck, MSD, Pfizer and Roche; travel grants from Ipsen, Janssen, Merck and Novartis. GdeV: support for clinical trials and scientific projects for Pfizer, Roche and Ipsen; and speaker fees and consulting for Pfizer, Novartis, Roche, MSD, Astellas, Bayer, Ipsen, Janssen, Merck, EUSA Pharma and BMS. CNS: consultant for Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, BMS, Foundation Medicine, Immunomedics (now Gilead), Medscape, UroToday, CCO Clinical, Janssen and NCI. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases., Methods: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion., Results: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients., Conclusions: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.

EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% . The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.

Objectives: Immunotherapy with Bacillus Calmette Guerin (BCG) has been widely used recently as primary option for treatment of high grade superficial (G3T1) carcinoma of the bladder. We describe our long term experience of therapy of G3T1 bladder cancer., Methods: From January 1982 to December 2000, 785 patients were diagnosed with superficial bladder cancer. All patients underwent preoperative CT scan and transurethral resection of the bladder. Eighty-six patients (11%) had histological high grade superficial bladder cancer infiltrating the lamina propria. This group was treated with the following schedule of BCG Pasteur strain plus maintenance. Four cycles BCG, 6 instillations per cycle, first cycle weekly x 6, second cycle every 2 weeks x 6, third cycle monthly x 6, fourth cycle (maintenance) every 3 months x 6 instillations., Results: The median follow-up is 91 months (30-197 months). The overall recurrence rate was 35% (30/86). The median time to recurrence was 29 months (5-128 months). Of these patients, 12 (14%) had progression at a median follow-up of 16 months (range 8-58 months). Cystectomy was needed in 8 (9%) patients. Death due to disease occurred in 5/86 (6%) patients. One patient died due to adenocarcinoma at the ureterosigmoidostomy site. Sixty-four (74%) patients are alive at a median follow-up of 71 months (range 28-197 months). Sixty patients (70%) are alive with an intact bladder., Conclusions: Treatment with BCG is a feasible conservative therapy for patients with primary G3T1 transitional bladder cancer. Long term results of BCG treatment are excellent. Cystectomy shouldn't be considered first line treatment for high grade superficial carcinoma of the bladder.

Background: An every-2-week regimen of gemcitabine and paclitaxel was adapted for patients with advanced transitional cell carcinoma (TCC) who had received prior cisplatin-based chemotherapy., Methods: Forty-one patients with advanced or metastatic TCC who had received prior cisplatin-based systemic chemotherapy were treated with an outpatient regimen of gemcitabine 2500-3000 mg/m(2) and paclitaxel 150 mg/m(2) every 2 weeks., Results: Forty of 41 patients had measurable disease. Response was observed in 24 patients (60%; 95% confidence interval [CI], 45-75%). Eleven (28%) achieved complete response, and 13 (33%) obtained partial response. Twenty of 25 patients (80%; 95% CI, 64-96%) who had been previously treated in the neoadjuvant or adjuvant setting responded versus 4 of 15 (27%; 95% CI, 5-49%) in patients who received prior methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) for metastatic disease. The median duration of survival for patients given gemcitabine and paclitaxel after failing neoadjuvant or adjuvant M-VAC was 12 months (range, 2-43+), as compared with only 8 months (range, 2-28) for patients who had been treated after failure of prior therapy for metastatic disease. For all patients, the median duration of response was 6.4 months (range, 2-43.3+ months), and the median survival was 14.4 months (range, 2-43+). Thirteen patients (32%) developed World Health Organization Grade 3-4 neutropenia, with febrile neutropenia in 3 (7%) patients. Granulocyte colony-stimulating factor was given to 10 (24%) patients. There was no Grade 3-4 anemia or thrombocytopenia., Conclusions: The combination of gemcitabine and taxol in previously treated patients with recurrent TCC is highly effective and produces objective durable responses. This every-2-week schedule is a well tolerated outpatient regimen with minimal toxicity., (Copyright 2001 American Cancer Society.)

Cisplatin-based combination chemotherapy such as methotrexate, vinblastine, adriamycin and cisplatin produces durable improvements in survival in only a minority of patients. Therefore, other therapeutic options and strategies are clearly needed. Strategies include increasing the dose of chemotherapy, modifying the sequencing of chemotherapy, and new therapeutic agents. This paper reviews recent work on high-dose chemotherapy, currently available chemotherapeutic agents and combinations, with an emphasis on gemcitabine and the taxanes. New strategies such as monoclonal antibody therapy and molecular targeted small molecule therapy are becoming a reality in the treatment of many diseases. The rationale for using epidermal growth factor receptor targeted therapies is also reviewed.

Background: Based on the favorable results of the combination 5-fluorouracil (5-FU), cisplatin and interferon-alpha as second-line treatment in advanced metastatic transitional-cell carcinoma of the urothelial tract a confirmatory study was executed in a multicenter setting., Patients and Methods: In this open label phase II study 43 patients failing adequate previous chemotherapy were treated with IFN-alpha2b 5 MU/m2 subcutaneously for 5 consecutive days starting on day 1 and 22 simultaneous with 5-FU 500 mg/m2 daily as a continuous infusion. In between the same dose of IFN-alpha2b was given 3 times weekly with CDDP 25 mg/m2 on days 1, 8, 15 and 22. This cycle was repeated every six weeks., Results: In 40 eligible patients 5 PR were seen (12.5%; 95% confidence interval (95% CI): 4.1%-26.8%). The major toxicity was hematological. Two toxic deaths were seen due to gastrointestinal hemorrhage., Conclusions: In view of these results this combination can not be recommended as second line treatment for metastatic transitional-cell carcinoma of the urothelial tract.

Systemic chemotherapy is the only current modality that provides the potential for long-term survival in patients with advanced or metastatic transitional cell carcinoma of the urothelium. The methotrexate/vinblastine/doxorubicin/cisplatin combination is currently considered to be the standard treatment of this disease, with overall response rates of up to 72% and survival durations of approximately I year. With the addition of gemcitabine to the chemotherapeutic arsenal, approaches to bladder cancer are changing significantly. When administered as a single agent, gemcitabine produces response rates of 23% to 28% in both pretreated and chemonaive patients with an excellent toxicity profile. When combined with cisplatin, overall response rates increase to 66% with maintained tolerability. Other new gemcitabine combinations with agents such as taxanes or carboplatin also appear promising; however, these preliminary phase II data must be confirmed in the phase III setting. Effective management of transitional cell carcinoma also involves understanding the mechanisms of resistance to treatment, including the implications of the expression of p-glycoprotein, p53 proteins, and several other biochemical predictors of outcome, as well as overcoming resistance. Growth factors may enable us to maximize drug delivery.

Background: The possibility of bladder preservation as well as the utility of neo-adjuvant chemotherapy for invasive bladder cancer are controversial issues. The purpose of this study was the evaluation of neo-adjuvant M-VAC chemotherapy and bladder preservation in patients with locally advanced transitional cell carcinoma of the bladder., Patients and Methods: Eighty-seven consecutive evaluable patients with T2-T4aNxM0 TCC of the bladder were treated with three cycles of neo-adjuvant M-VAC chemotherapy. After three cycles of M-VAC, 42 patients had TURB alone, 13 patients underwent partial cystectomy, and 32 patients were to undergo radical cystectomy., Results: Forty (51%) patients were T0 at the TURB following M-VAC. Thirty (71%) patients who had chemotherapy and TURB alone are alive; at a median follow-up of 54+ months (8(+)-109+). Twenty-four (57%) have maintained an intact bladder. Of 13 responding patients with monofocal lesions who underwent partial cystectomy, 8 patients (62%) are alive with a functioning bladder, at a median follow-up of 80+ months (16-107+ months). At a follow-up of 32 months (7-121+ months), 20 (63%) patients in the radical cystectomy group are alive. In patients who had downstaging to T0 or superficial disease, median follow-up is 55 months (10-121+ months) and five-year survival is 71%. Patients who failed to respond (T2 or greater after chemotherapy), at a median follow-up of 24 months (7-103+ months), had five-year survival of only 29%., Conclusions: Bladder sparing in selected patients on the basis of response to neo-adjuvant chemotherapy is a feasible approach which must be confirmed in prospective randomized trials.

Objectives: To evaluate the sensitivity and specificity of the Bard BTA test compared with bladder washing cytology in patients with a history of transitional cell bladder cancer undergoing routine follow-up cystoscopy., Methods: During routine follow-up for transitional cell bladder cancer, 75 patients underwent cystoscopy, bladder washing cytology, and the Bard BTA test, a latex agglutination test that qualitatively detects basement membrane complexes in voided urine. From October 1994 to October 1995, a total of 104 Bard BTA test examinations were performed. The results of the Bard BTA test were compared with those attained with cystoscopy and bladder washing cytology., Results: Cystoscopy found tumors in 13 cases. The Bard BTA test was diagnostic in 7 (54%) cases; it was more sensitive than bladder washing cytology, which was positive in only 3 (23%) cases. However, the specificity of the Bard BTA was lower (9% clinically unconfirmed positive tests) than that attained with cytology. In 2 patients (2%) in whom the cystoscopy was negative, the Bard BTA test was predictive for a positive cystoscopy 3 and 5 months later., Conclusions: The Bard BTA test is a noninvasive test that may be an important addition to cystoscopy and cytology in the routine surveillance of patients with a history of transitional cell cancer of the bladder.

The aim of the present retrospective study was to assess long-term survival after cisplatin-based chemotherapy in 398 patients with advanced urothelial transitional cell carcinoma (TCC) treated at seven international oncological units. Various combinations of cisplatin, methotrexate, vinblastine (or vincristine) and doxorubicin were used. The complete response rate according to the WHO criteria was 17%. Partial responses were obtained in 42% of the patients. The overall cancer-related 2 year and 5 year survival rates were 21% and 11% respectively. Based on multivariate analyses, a good prognosis group could be identified comprising patients with a good performance status with disease confined to lymph nodes (14%) or patients with T4b disease only. These patients had a 28% 5 year survival rate, which, in part, has to be related to post-chemotherapy consolidation treatment in patients with pelvis-confined disease (radiotherapy, 26%; total cystectomy, 11%). Fifteen patients died of chemotherapy-related complications and in 16% of the patients toxicity led to discontinuation of treatment. Modern cisplatin-based chemotherapy leads to long-term survival and cure of selected patients with advanced urothelial transitional cancer. In routine clinical practice, chemotherapy should be offered to good prognosis patients; those presenting with a good performance status and a non-metastasising T4b tumour or with metastases confined to lymph nodes. Post-chemotherapy consolidation treatment by surgery or radiotherapy should always be considered. Such chemotherapy requires oncological expertise in order to avoid unnecessary toxicity.

Purpose: We performed a retrospective long-term study to evaluate the results of immunotherapy in the treatment of high grade superficial bladder tumors., Materials and Methods: Between 1981 and 1993, 593 patients with superficial transitional cell carcinoma of the bladder underwent transurethral resection. Of 64 patients with stage T1 grade 3 disease 50 received intravesical bacillus Calmette-Guerin after transurethral resection of all visible tumor., Results: At a median followup of 42 months (range 12 to 112) 36 patients (72%) are disease-free and have not required further treatment. Superficial recurrence was noted in 8 patients (16%). Disease progressed in 6 patients (12%), including 5 with locally invasive and 1 with metastatic disease. Cystectomy was performed for progression in 4 patients and for recurrent stage T1 grade 3 disease in 1. There was 1 disease related death (2%). The overall survival rate is 94%., Conclusions: Intravesical bacillus Calmette-Guerin appears to be the most effective conservative treatment for patients with stage T1 grade 3 bladder cancer.

Background: Based on the excellent results with combination chemotherapy such as M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in patients with advanced disease, neoadjuvant chemotherapy has been advocated to improve survival and in some cases to permit bladder conservation., Methods: A Phase II study of neoadjuvant M-VAC chemotherapy was performed in patients with T2-T4N0M0 bladder tumors. After clinical staging, three cycles of M-VAC were given. After patients underwent postchemotherapy clinical restaging, pathologic restaging (partial or radical cystectomy) was planned., Results: Forty-six patients are evaluable. A clinical response was attained in 78%. Six patients (13%) had stable disease, and four (9%) had progression. After chemotherapy, 17 patients underwent radical cystectomy, none of whom were pTO. In this group, 10 of the 17 (59%) are alive at a median follow-up of 37+ months (range, 8-62+ months). Eleven patients had a partial cystectomy; 7 of the 11 (64%) are alive, 6 (55%) with a preserved bladder. Eighteen patients had clinical restaging only, and did not have pathologic staging. Median follow-up for this group is 36+ months (11-65+ months). Twenty-one of the 29 (72%) patients managed with conservative surgery or transurethral resection of the bladder alone are alive with a functional bladder. Median survival for all patients has not yet been reached. Two-year survival is 82%, and 3-year survival is 70%., Conclusions: The current study is of interest in terms of bladder conservation. Assessment of the true success of any bladder-preserving treatment will require longer follow-up.

The records of 28 patients with transitional cell cancer who had brain metastases were retrospectively reviewed. Data from 19 patients were considered suitable for analysis and were included in this study. One patient was treated with surgery alone, 10 with radiation alone and 7 with radiation and surgery, while 1 received no treatment. Mean and median survival times, respectively, were 57 and 42 months from the initial diagnosis, and 11 and 4 months from diagnosis of central nervous system metastases. Patients treated with surgery and radiation demonstrated a mean survival time of 19 months compared to 6 months for patients treated with radiation alone (p = 0.03). There were 2 long-term survivors in the combined modality group at 50 and at 12 months. Enthusiasm for combined modality treatment should be tempered by the fact that selection bias favored the combined modality group; 13 patients with single lesions demonstrated a mean survival of 14 months compared to 3 months for 6 patients with multiple lesions (p = 0.009) and only patients with solitary lesions underwent surgical resection. Brain metastases have an ominous prognosis in patients with bladder cancer primaries. Considering the sum of the retrospective and prospective reports, we recommend that patients with solitary brain lesions and good performance status be aggressively managed with surgical resection and postoperative radiation therapy.

The optimal management of invasive bladder cancer remains controversial. Combination chemotherapy regimens have been increasingly advocated in association with definitive local therapy in an attempt at eradicating micrometastases and reducing the risk of recurrence. Chemotherapy used after radical cystectomy is referred to as "adjuvant" therapy. The term adjuvant is occasionally used for chemotherapy following an aggressive transurethral resection (TUR). Decisions concerning individual patients must be made after careful examination of the histologic specimen and cognizance of the known relapse rates per pathologic stage. No randomized trial has reported results on patients with pT 2 and pT 3a tumors. Studies have not clearly proven any advantage for adjuvant therapy based on muscle infiltration alone (pT 2, pT 3a). For patients with minimal extravesical extension (pT 3b), additional therapy may be useful. For patients with nodal metastases (pN+) and direct extension into the adjacent viscera (pT 4), the data suggest a trend toward improved survival. These patients may benefit from adjuvant chemotherapy. The difficulties of clinical trials following cystectomy, conducted in an elderly patient population, done over a long period, with changing standards of effective chemotherapeutic regimens are described. Adjuvant therapy following cystectomy or an aggressive TUR remains investigational and its benefit has not yet been proven. Patients should be entered into well-designed and carefully conducted clinical trials to evaluate the role of chemotherapy in invasive bladder cancer.

A Phase I-II trial of gallium nitrate was conducted in 40 patients with bidimensionally measurable urothelial tract tumors who had failed to respond to combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. Partial responses were observed in 4 of 23 patients (17.4%) who received 350 mg/m2/d or more for 5 days by continuous intravenous infusion. In two additional patients who received 350 mg/m2/d or more, a minor response and a mixed response were observed. The median duration of response was 4 months (range, 2 to 8 months). A dose-response relationship was suggested because no responses were observed in 17 patients who received less than 350 mg/m2/d. Myelosuppression was minimal. The dose-limiting toxic reaction was a reversible optic neuropathy that occurred in 3 of 11 patients who received 400 mg/m2/d. Further evaluation of infusional gallium nitrate is warranted in patients with urothelial tract malignant tumors.

Progress has been made in the management of patients with advanced metastatic and muscle-invasive urothelial tract tumors. Combination chemotherapy has proved effective, and, in those who attain complete remission it prolongs survival. Chemotherapy alone or combined with radiotherapy and TURB may now make less aggressive surgery and bladder conservation possible in selected patients. Improvements in perioperative care, coupled with surgical, radiotherapeutic and diagnostic achievements, have led to substantial progress. Recombinant DNA technology has led to the availability of sufficient quantities of hematopoietic factors, which are now available for clinical trials. Today, CSFs can complement therapy and ameliorate the myelosuppression and mucositis associated with chemotherapy, permitting safer administration of therapy and increased dose intensity of treatment programs. Investigations of the biology of bladder cancer aimed at defining the malignant and metastatic potential of an individual tumor are very promising. Immunohistochemistry of cell surface antigens, such as blood group antigens, monoclonal antibody technology, and assessment of the chromosomal complement or DNA content will have increasing importance for this aim in the future. Future trials will need to consider the biology of bladder cancer and more sophisticated prognostic variables than performance status. Mixed-histology tumors are probably less responsive. Why certain tumors metastasize and others remain restricted to the bladder or nodes is still a matter of conjecture. Hopefully, future studies will throw some light on these still-unexplained areas.

Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M-VAC regimen), significant tumor regression occurred in 72% +/- 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% +/- 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2-year and 3-year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non-TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T less than pathologic [P] restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3-4M0 patients who achieved CR versus 33% of 100 with N0-+M+ lesions. Toxicity was significant with 4 (3%) drug-related deaths, 25% incidence of nadir sepsis, 58% greater than or equal to 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens.

Of 50 patients with bladder cancer given 1 to 5 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin in a pilot phase I and II study 63 per cent of 41 with pure transitional cell stage T2-4 lesions responded. While significant downstaging occurred by transurethral resection of the bladder in 70 per cent and by cytology in 60 per cent of the patients, the final T response rate by all noninvasive clinical staging procedures, including sonography and computerized tomography, revealed complete remission in 24 per cent and partial remission in 39 per cent. Of 30 patients who underwent pathological staging 33 per cent achieved stage P0 and 17 per cent stage Tis disease or P less than T. Despite extensive re-evaluation by transurethral resection of the bladder and other noninvasive staging procedures, a clinical staging error (T versus P) of 38 per cent was observed. Of the other 9 patients 4 with mixed nontransitional cell histological findings at presentation never achieved complete remission, although 3 had resolution of all transitional cell elements and 5 (10 per cent) were inevaluable. The toxicity of the regimen was generally acceptable but 6 per cent of the patients required hospitalization for neutropenic fever. While this active regimen can clinically (T) and pathologically (P) induce downstaging in a significant number of patients with primary bladder tumors, this pilot study has raised serious questions concerning the design of future nonrandomized and randomized neoadjuvant studies.

We evaluated the ability of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to prevent chemotherapy-induced neutropenia or to accelerate recovery from this complication and thus allow patients to receive full doses of antineoplastic agents on time, according to protocol design. Twenty-seven patients with transitional-cell carcinoma of the urothelium who were undergoing treatment with methotrexate, doxorubicin, vinblastine, and cisplatin were given rhG-CSF (up to 60 micrograms per kilogram of body weight per day) before their first cycle of combination chemotherapy, during the first cycle, or at both points. Treatment with rhG-CSF before chemotherapy resulted in a dose-dependent increase in the absolute neutrophil count. Treatment with rhG-CSF after chemotherapy significantly reduced the number of days (91 percent) per patient on which the absolute neutrophil count was 1000 per microliter or less (P = 0.0039), reduced the number of days (1 vs. 35) on which antibiotics were used to treat fever and neutropenia, and significantly increased the percentage (100 vs. 29 percent) of patients qualified to receive planned chemotherapy on day 14 of the treatment cycle (P = 0.0015). In addition, the incidence of mucositis was significantly decreased (11 vs. 44 percent, P = 0.041), as was its severity. These findings demonstrate that rhG-CSF is a potent stimulus of normal neutrophil proliferation and maturation. In addition, its administration can reduce both the hematopoietic and oral toxicity of chemotherapy.

The M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen was used to treat 25 patients with transitional cell carcinoma of the urothelial tract. Treatment consisted of monthly cycles of 30 mg. per m.2 methotrexate, followed 24 hours later by 3 mg. per m.2 vinblastine, 30 mg. per m.2 doxorubicin and 70 mg. per m.2 cisplatin, and concluded with repeat vinblastine and methotrexate on days 15 and 22. Significant tumor regression was noted in 71 per cent of the patients. Complete clinical remission was observed in 12 of 24 patients (50 per cent, 95 per cent confidence limits 30 to 70 per cent) with bidimensionally measurable indicator lesions, 6 of whom had pathological confirmation. After surgical exploration 4 patients required downstaging to a partial remission. The median duration of response has not yet been reached at 9.5 plus months, range 4.5 plus to 16 plus. Five patients (21 per cent) had a partial clinical remission for 4 to 8 plus months, 1 had a minor response for 4 months and 1 had stable disease for 11 months. All metastatic sites responded, including bone (6 of 8 cases), liver (3 of 5), locoregional (12 of 17) and intravesical (6 of 7) disease. Toxicity included moderately severe myelosuppression that resulted in nadir sepsis in 4 patients and a drug-related death in 1, mild to moderate anorexia, vomiting, alopecia and renal dysfunction. These preliminary results suggest that treatment with methotrexate, vinblastine, doxorubicin and cisplatin is extremely effective against locoregional and disseminated urothelial tract tumors, with the expectation (95 per cent confidence limits) of inducing objective tumor regression in 53 to 89 per cent of the cases.

Of 92 patients who received methotrexate, vinblastine, doxorubicin and cisplatin complete and partial remissions were observed in 69 +/- 10 per cent of 83 adequately treated measurable and evaluable patients with advanced stages (N+M0 and N0M+) transitional cell urothelial cancer. Complete remission was achieved in 37 +/- 10 per cent of the patients clinically, pathologically and after surgical resection of residual disease. With 17 of 31 complete responders (55 per cent) surviving for 26+ to 49+ months, the estimated probability of survival at 2 and 3 years was 71 and 55 per cent, respectively. Partial remission occurred in 31 +/- 10 per cent of the patients, while 8 per cent had a minor response and 23 per cent had progression with median survivals of 11, 11 and 7 months, respectively. Whereas all metastatic sites responded, including the bone and liver, complete tumor regression was observed more frequently with nodal, pulmonary and local-regional lesions. Brain metastases occurred within 6 to 42 months in 18 per cent of the responders, half of whom never had systemic relapse. Of the remaining 9 patients 2 with nontransitional cell histological tumors did not respond, 5 (5 per cent) were inadequately treated and 2 were excluded from response data because of inevaluable disease parameters but they were free of disease at 16+ and 31+ months. Toxicity was significant, with 20 per cent of the patients experiencing nadir sepsis, 4 per cent a drug-related death, 31 per cent +1 renal toxicity and 41 per cent +1 mucositis. The applications and advantages of the newly proposed international response criteria for bladder cancer are discussed in reference to 25 patients who underwent surgical re-staging, indicating that the disease was understaged clinically in 24 per cent (T less than P), as well as in reference to attainment of true (pathological) complete remission and to other urothelial tract trials. While this therapy seems to have limited antitumor activity against nontransitional cell histological cancer, stage Tis disease and later development of de novo lesions, the regimen is efficacious in selected patients with advanced urothelial tract transitional cell carcinoma.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered at a dose of 1-60 micrograms/kg of body weight to 22 patients with transitional cell carcinoma before chemotherapy as part of a Phase I/II study. In all patients, a specific dose-dependent increase in the absolute neutrophil count (ANC) of 1.8-12 fold was seen. In addition, this augmentation in the ANC was accompanied by an increase in leukocyte alkaline phosphatase, a marker of secondary granule formation. In six of eight patients analyzed, an increase in bone marrow myeloid to erythroid cell ratio was seen. Day 14 peripheral blood cell derived colony forming unit granulocyte macrophage were also increased by day 6 of rhG-CSF treatment. Circulating levels of eosinophils and basophils were unchanged; however, a 10-fold increase in monocytes was observed in patients treated at the highest doses. There was also a small increase in CD3+ lymphocytes that was not dose dependent. Hemoglobin, hematocrit, and platelet count remained near baseline throughout the period of rhG-CSF administration. These findings demonstrate that rhG-CSF is a potent stimulus for normal neutrophil proliferation and maturation.

The standard therapy for muscle-infiltrating tumors of the bladder remains radical cystectomy with or without radiation. Caution should be exercised about recommending newer regimens outside of clinical trials. However, combination chemotherapy programs can produce dramatic and durable remissions in a significant percentage of patients with advanced urothelial tract malignancies.

Twenty-one patients with superficial transitional cell carcinoma of the bladder received a total of 121 doses of intravesical methotrexate (MTX) at 11 different concentrations of drug, ranging from 40 mg/m2 (mean concentration of 2.9 X 10(-3) M) to 500 mg/m2 (4.9 X 10(-2) M). Biochemical evidence of absorption was minimal in all cases. The maximum serum level was observed within 0.5-2 h in all patients and ranged from 1.8 X 10(-8) M to 5.0 X 10(-7) M. By 24 h the serum levels were negligible and ranged from 5.5 X 10(-9) M (the lowest limit detectable by the assay) to 4.4 X 10(-8) M in the patient who received the highest dosage of 500 mg/m2. Biologic evidence of absorption was minimal. Myelosuppression, mucositis, and nausea were not observed. Eighteen patients received six consecutive weekly doses ranging from 40 to 500 mg/m2. All patients had repeat cytoscopy performed within 2-4 weeks after six consecutive doses to evaluate local toxicity and efficacy. Flow cytometry was performed on the bladder washings of 22 patients, illustrating the use of flow cytometry, in conjunction with conventional cytology, as an additional means of objectively quantifying results. Despite MTX's established activity in systemic treatment of advanced bladder carcinoma, this study failed to demonstrate any clinical response to intravesically administered MTX, in doses of up to 500 mg/m2, and in concentrations of up to 4.9 X 10(-2) M.

Deaza-aminopterin is a folate analog which is transported more rapidly than methotrexate into cells and appears to be more active than methotrexate against human and animal tumor in vitro. Fifteen patients with advanced urothelial tract cancer were given deaza-aminopterin 30-37.5 mg/m2 IV QW. In responding patients drug was given QOW after 4-6 consecutive doses. Doses were escalated or de-escalated by 7.5 mg/m2 depending on toxicity. Twelve patients had received prior chemotherapy which included methotrexate in nine. Three patients achieved a partial remission lasting 1, 3, and 3 months respectively: all responders had previously failed methotrexate after an initial response to a methotrexate containing regimen. None of the six patients who were methotrexate naive responded to deaza-aminopterin; 3 subsequently received methotrexate without response. Mild mucositis was universal and in 5 was severe. Six patients had an increase in liver transaminases probably secondary to anti-folate hepatotoxicity. Other toxicities included diarrhea, nausea, skin rash and fever. Further studies are needed to define the precise efficacy of deaza-aminopterin in patients with urothelial tract cancers.

Recently developed combination chemotherapy programs have now produced durable complete remissions in a significant percentage of patients with advanced urothelial tract malignancies. For advanced disease, efforts must still be directed at developing new agents but must also focus on understanding drug resistance. Some tumors appear to be resistant de novo; others respond for a period of time before a resistant population emerges. Clearly multiple factors come into play. In some cases, pharmacologic factors such as bioavailability metabolism, or toxicities predominate. In other cases, specific genes expressing surface proteins such as the p-glycoprotein identified in resistant ovarian tumors have been implicated. In the 1980s, it is no longer adequate to define tumors simply by pathologic inspection. As demonstrated by Russell and co-workers xenografts of phenotypically similar transitional cell tumors in nude mice demonstrated marked heterogeneity with respect to flow cytometric DNA analysis and immunocytochemistry. With the recent adoption of flow cytometric techniques, both from bladder washings and paraffin sections, insight into the biologic behavior of individual tumors may soon be possible. Blood group antigen expression and monoclonal antibodies to tumor-associated antigens may also help in this regard. For primary tumors, attention is now being focused on protocols aimed at bladder preservation. In some cases, radiation therapy alone can produce long-term survival, despite muscle infiltrating disease. Complete remissions have also been described with chemotherapy alone. The interaction of chemotherapy and radiation therapy has only recently begun to be investigated. In these trials, complete local control must still be the primary goal. Standard criteria for staging and response evaluation, including pathologic documentation of remission status, are crucial. To demonstrate a beneficial effect of therapy, long-term randomized trials will be required. The goal of individualized therapies may soon be possible, which will ideally translate into increased clinical benefit for patients with urothelial tract tumors.

A series of 71 patients with muscle invasive bladder cancer received a median of 3 cycles (range 1-6) of methotrexate, vinblastine, Adriamycin and cisplatin (M-VAC). Efficacy assessed by transurethral resection alone showed that 48% of patients were TO, 13% Tis and 54% had normalisation of initially positive urinary cytology after treatment. However, when considering transurethral resection of the bladder (TURB), cytology and non-invasive procedures (CT scan and/or ultrasound), only 21% had a clinical complete remission (cCR); 48 patients (68%) had pathological evaluation and 13 (27%) were PO after treatment. Non-responding patients had a poor prognosis: 14/30 (47%) developed metastatic disease and 13 died. In assessing the primary lesions, clinical understaging was significant. Of 15 patients who were TO cystoscopically prior to surgery, 6 (40%) had residual disease in the pathological specimen, including 4 with muscle infiltration; 23 patients (32%) remained clinically staged, only 8 of whom remain disease-free. With a median follow-up of 24 months (range 2-42+), 41 patients are alive and disease-free, including 20 with a functional bladder. The large staging error raises questions concerning studies using clinical rather than pathological endpoints as the sole criteria of efficacy.