Chemotherapy In Metastatic Urothelial Cancer Research Articles

Identification of patients with metastatic urothelial cancer not able to receive maintenance avelumab.

702 Background: Maintenance avelumab following frontline platinum-based chemotherapy for metastatic urothelial cancer (mUC) is associated with survival benefit. Eligibility to receive avelumab maintenance requires receiving 4-6 cycles chemotherapy without disease progression. Not all patients complete 6 cycles of chemotherapy or meet eligibility to receive avelumab and these patients may need to have alternative therapies. Here we present real world data to assess whether baseline characteristics can be used to identify patients unable to complete 6 cycles of chemotherapy and whom may not be eligible for maintenance avelumab. Methods: This retrospective audit was performed at Barts Cancer Centre for consecutive patients from January 2010 until August 2023. Patients who received frontline gemcitabine and cisplatin/carboplatin chemotherapy for advanced mUC were included. Eligibility for avelumab is defined as completing 4-6 cycles of chemotherapy without disease progression (PD). Characteristics of patients completing 6 cycles of chemotherapy, versus those who do not were described. Chi-squared tests were conducted to compare characteristic between the two groups, using SPSS v28. Results: 265 patients receiving frontline systemic therapy were identified over a 13-year period. 242 (91%) received Gem/Cis or Gem/Carbo chemotherapy. 151 (63%) patients were eligible to receive maintenance avelumab. 91 (38%) patients were not eligible due to receiving less than 4 cycles chemotherapy (68%) or due to PD (75%), or both. 91 (38%) patients completed 6 cycles of chemotherapy. Having a low baseline Hb <100g/dl was the only baseline characteristic associated with receiving less than 6 cycles chemotherapy (p=0.002). 33% of patients who completed less than 6 cycles chemotherapy had a Hb <100g/dl, compared to 10% of the patients who completed chemotherapy (p=0.002). Any dose delays was associated with a lower likelihood of being eligible to receive avelumab (32% and 18% dose delays in avelumab eligible vs ineligible cohorts, respectively (p<0.001). Patients with any dose delays had more frequently received carboplatin (65% vs 39%, p=0.012) and had visceral metastases including liver metastases (63% vs 39%, p=0.014), compared to those without dose delays. Conclusions: Specific baseline factors predispose to an inability to deliver 6 cycles of chemotherapy without complications or progression. These patients are less likely to receive maintenance avelumab. These data help the optimise number of cycles offered to patients in mUC.

Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer

To compare estimated survival times of patients who had received maintenance monotherapy with gemcitabine (GEM), or an immuno-oncology (IO) drug (i.e., pembrolizumab or avelumab) or both therapies (one after the other) following platinum-based combination chemotherapy for metastatic urothelial carcinoma (UC) in a real-world setting. For this retrospective study, we included consecutive patients with metastatic UC who had received first-line platinum-based chemotherapy followed by second-line treatment at our centre from March 2008 to June 2020. Of the 74 patients identified, 58 had received monotherapy as second line treatment, and 16 had received combination chemotherapy (i.e., non-monotherapy). The estimated median duration of survival was significantly longer in the monotherapy group compared with the non-monotherapy group (29 vs 7 months). Multivariate analysis showed that the outcome of the first-line chemotherapy treatment was the most important prognostic factor for survival. There was no significant difference in survival times between monotherapy with GEM or IO drugs. In addition, survival was significantly prolonged when GEM therapy was administered following IO drugs compared with GEM therapy alone. Monotherapy following primary chemotherapy for advanced UC significantly prolonged survival times, and IO drug therapy remained effective when followed by GEM single agent maintenance therapy.

Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial

Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636. Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1-17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5-8·3) in group A and 6·3 months (6·2-7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70-0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9-18·9) in group A and 13·4 months (12·0-15·2) in group C (0·83, 0·69-1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1-17·8) for group B and 13·1 months (11·7-15·1) for group C (1·02, 0·83-1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. F Hoffmann-La Roche and Genentech.

Effectiveness of durvalumab versus chemotherapy in metastatic urothelial cancer: an observational, indirect comparison.

Aim: To compare the overall survival of patients with metastatic urothelial carcinoma (mUC) who failed platinum-based chemotherapy and received durvalumab or chemotherapy. Patients & methods: In an indirect comparison of patients with mUC who failed platinum-based chemotherapy, those who received durvalumab in a single-arm study were matched to patients from the Flatiron oncology electronic medical record database who received chemotherapy (n = 158 for each cohort). Matching was based on propensity scores. Kaplan-Meier methods and Cox regression models were utilized. Results: Median overall survival was 11.2 months (95% CI: 7.2-16.9) for durvalumab versus 8.2 months (95% CI: 6.7-9.8) for chemotherapy (hazard ratio: 0.63; 95% CI: 0.48-0.84). Conclusion: As a second-line therapy for mUC, durvalumab was associated with longer overall survival than chemotherapy.

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer

BackgroundLimited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown. ObjectiveTo compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy. Design, setting, and participantsWe conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record–derived database. Outcome measurements and statistical analysisThe primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score–based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness. Results and limitationsIPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0–45.3%] vs 46.1% [95% CI 43.4–48.8%]) but higher at 36 mo (28.3% [95% CI 21.8–34.7%] vs 13.3% [95% CI 11.1–15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15–1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30–0.85). Limitations include retrospective design and potential unmeasured confounding. ConclusionsIn the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy. Patient summaryTo determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.

Recent advances in medical therapy for metastatic urothelial cancer

Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice. The paradigm of medical treatment for patients with metastatic UC is dramatically changing through the introduction of this and other immune-checkpoint inhibitors. In this article, we provide a brief overview of these immune-checkpoint inhibitors and a comprehensive summary of the use of cytotoxic chemotherapy for metastatic urothelial cancer, including ongoing clinical trials.

Consolidative Radiotherapy in Metastatic Urothelial Cancer.

We report outcomes of a retrospective, single-institution experience with consolidative radiation after chemotherapy in metastatic urothelial cancer (MUC). From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with MUC who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. Overall survival (OS) was defined as time from start of chemotherapy to death or last follow-up. In the selected group of patients with MUC, the median age was 67 years; 59% had received previous cisplatin-based chemotherapy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases. Median survival from diagnosis to cystectomy was 48 months. Median PFS was 13 months and median OS was 29 months. Eight patients (36%) were alive and disease-free 6 years after radiation therapy. Patients who were rendered disease-free were those with nodal metastases and delivery of radiation to a single site of metastasis. In this highly selective cohort of patients with MUC treated with consolidative radiation after chemotherapy, 36% were rendered disease-free. This suggests that radiation is feasible and might contribute to long-term disease control. Further prospective studies are needed to better characterize the benefit of combined modality treatment.

Third-Line Chemotherapy for Metastatic Urothelial Cancer: A Retrospective Observational Study.

The prognosis of locally advanced (T3/T4 or N1) and metastatic disease urothelial carcinoma is poor. In this retrospective study, we reviewed data about patients receiving third-line chemotherapy for metastatic disease, in view of the lack of data in this setting.We retrospectively analyzed medical records of patients with a pathologic diagnosis of urothelial carcinoma treated with systemic chemotherapy for metastatic disease at 4 participating Institutions between January, 2010, and January, 2015. Cox proportional hazards regression was used to evaluate the association of the chemotherapy agent used versus others with overall survival, adjusted for 5 externally validated prognostic factors in advanced urothelial carcinoma.Of 182 patients that received first-line chemotherapy/adjuvant chemotherapy as defined above, 116 patients (63.73%) received second-line salvage treatment. Fifty-two patients were finally included in this analysis, whereas 9 were excluded due to missing data. Third-line chemotherapy was based on cyclophosphamide, platinum, vinflunine, taxanes, and gemcitabine in 16, 12, 11, 10, and 3 patients, respectively. Median PFS (progression-free survival) and OS (overall survival) of the population were 13 (10–17) and 31 (28–36) weeks. Single-agent cyclophosphamide was associated with a PFS of 18 (13–22) and an OS of 38 (33–41) weeks, whereas platinum-based combinations were associated with a PFS of 5 weeks and an OS of 8 weeks. Multivariate analysis showed improved survival in patients treated with cyclophosphamide (hazard ratio (HR) = 0.42; 95% CI: 0.20–0.89; P = 0.025) and a worse survival in those treated with platinum-based regimens (HR: 4.37; 95% CI = 1.95–9.77; P < 0.01).We observed a significantly longer overall survival in patients receiving single-agent cyclophosphamide, with few grade 3 to 4 toxicities. Further studies should assess the efficacy of metronomic single-agent cyclophosphamide in advanced lines of treatment, as it may yield a survival benefit with low costs and no detrimental effects on quality of life.

Conditional Survival of Patients Treated With First-Line Chemotherapy for Metastatic Urothelial Cancer

BackgroundMeasures of prognosis for cancer patients are typically evaluated at the time of diagnosis. However, this study assessed the changes in 2-year CS rates after first-line chemotherapy for metastatic UC. Patients and MethodsConditional overall survival and CPFS probability were estimated using the Kaplan–Meier method. Adjusted survival functions were stratified according to age groups (< 70 years vs. ≥ 70 years), sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS; ECOG PS ≤ 2 vs. ECOG PS > 2), pretreatment Hb levels (< 12 mg/dL vs. ≥ 12 mg/dL) and pretreatment NLR (< 3 vs. ≥ 3). Pairs of CS curves were compared using the Mantel–Haenszel log-rank test. ResultsTwo hundred ninety-eight patients were included in this analysis, 233 were male, and their median age was 69 years. First-line median overall survival and progression-free survival were 10.7 months (95% confidence interval [CI], 9.6-12.6) and 6.0 months (95% CI, 5.5-7.1), respectively. CPFS and COS showed an increasing trend in the population considered (b = 0.35; P < .001 and b = 0.79; P < .001, respectively). A significant increase in terms of COS and CPFS trends was identified in patients with age < 70 years (P = .02 and P = .005, respectively) and pretreatment NLR ≤ 3 (P = .05 and P < .001, respectively). Patients with Hb levels < 12 g/dL showed a significantly poorer 2-year COS. ConclusionThe conditional probability of survival at 2 years from the start of first-line chemotherapy for advanced UC changes over time according to clinical characteristics.

Posttreatment prognostic nomogram for patients with metastatic urothelial cancer completing first-line cisplatin-based chemotherapy

BackgroundModels to predict the outcome of patients with metastatic urothelial cancer (UC), based on pretreatment variables, have previously been developed. However, patients often request “updated” prognostic estimates based upon their response to treatment. Patients and MethodsData were pooled from 317 patients enrolled in 8 trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Variables were combined in the Cox proportional hazards model to produce a nomogram to predict survival from the end of treatment. The nomogram was validated externally using data from a phase III trial. ResultsThe median survival from end of treatment was 10.65 months (95% confidence interval; 9.20–13.24); 69% of patients had died. Baseline and posttreatment variables were evaluated. Baseline performance status, baseline number of visceral metastatic sites, baseline white blood counts, and response to treatment were included in the final model. The nomogram achieved a bootstrap-corrected concordance index of 0.68. Upon external validation, the nomogram achieved a concordance index of 0.67. ConclusionsA model derived from pretreatment and posttreatment variables was constructed to predict survival from the completion of first-line chemotherapy in patients with metastatic UC. This model may be useful for patient counseling and for stratification of trials exploring “maintenance” therapy.

Treatment patterns and outcomes in “real world” patients (pts) with metastatic urothelial cancer (UC).

4525 Background: Most studies reporting outcomes of pts with metastatic UC are derived from clinical trial data, potentially limiting the breadth/generalizability of the findings. To explore patterns of care/outcomes in “real world” pts, we initiated an international retrospective cohort study. Methods: Data were collected via an electronic data capture platform from 23 centers. Eligible pts had UC (at least muscle-invasive) and were initially evaluated from 1/1/2006-1/1/2011. Parameters were subjected to regression analysis to identify prognostic variables. Results: By 12/18/12, 1905 pts were enrolled. Among 1077 with metastatic UC, median age was 67 (IQR 60-75), 80% were male, 87% had bladder primary tumors, and 33% received perioperative chemotherapy. Only 758 (70%) received 1st-line chemotherapy for metastatic UC: cisplatin-based (51%), carboplatin-based (29%), non-platinum single-agent (16%), and non-platinum multi-agent (4%). The median survival from date of diagnosis of metastatic UC was 5.2 months (95% CI 4.4-6.5) and 16.1 months (95% CI 15.1-17.5) for pts who did and did not receive 1st-line chemotherapy, respectively [13.9 months (95% CI 12.78-14.98) from start of chemotherapy for latter group]. Among pts receiving 1st-line chemotherapy, univariable analysis revealed gender, primary tumor site, removal of primary, creatinine clearance, LDH, and hgb were not significantly associated with survival whereas smoking status, performance status, perioperative chemotherapy, metastatic sites, study site and chemotherapy regimen were. The multivariable analysis is shown in the Table. Conclusions: The current analysis identifies previously unrecognized prognostic factors in an international cohort of “real world” pts with metastatic UC treated with 1st-line chemotherapy. A large subset of pts with metastatic UC receives no chemotherapy. [Table: see text]

Post-treatment prognostic model for patients (pts) with metastatic urothelial cancer (UC) treated with first-line chemotherapy.

256 Background: Models to predict the outcome of pts with metastatic UC, based on pre-treatment variables, have previously been developed. However, pts often request “updated” prognostic estimates based on their response to treatment. This is particularly relevant in first-line treatment of metastatic UC, a disease state for which a fixed number of cycles of chemotherapy are typically administered. Methods: Data were pooled from 317 pts enrolled on eight trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Variables were combined in a Cox proportional hazards model to produce a nomogram to predict survival from end of treatment. The nomogram was validated externally using data from a trial of MVAC versus docetaxel plus cisplatin (n=148). Results: The median survival from end of treatment was 10.65 months [95% CI 9.20 – 13.24]; 69% of patients had died. Baseline (white blood count, ECOG performance status, number of visceral metastatic sites) and post-treatment (treatment response, duration of treatment, reason for treatment discontinuation) variables were evaluated. The Cox proportional hazard model is shown in the Table. The duration of treatment and reason for treatment discontinuation were not significantly associated with survival. The four significant variables were included in a nomogram. The nomogram achieved a bootstrap-corrected concordance index of 0.68. Upon external validation, the nomogram achieved a concordance index of 0.67. Conclusions: A model derived from pre- and post-treatment variables was constructed to predict survival from the end of first-line chemotherapy in pts with metastatic UC. This model may be useful for pt counseling and for stratification of trials exploring “maintenance” treatment. [Table: see text]

Progression-free survival as an endpoint for clinical trials in first-line metastatic urothelial cancer.

251 Background: Advances in the first-line treatment of metastatic urothelial cancer (UC) have proven elusive. The lack of appropriate intermediate endpoints to screen the activity of novel regimens may be a barrier to progress, particularly in this disease state characterized by relatively high response rates but short response durations. Progression-free-survival (PFS) at fixed time points may overcome several of the limitations of response rate-based endpoints, but would be further supported by establishing benchmarks and demonstrating a correlation between PFS and overall survival (OS). Methods: Data were pooled from eight phase II and III trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Landmark analyses for progression at 3, 6, and 9 months after treatment initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. Results: 545 patients were included in the analysis. The median PFS was 7.75 months (95% CI, 7.06, 8.18) and the median OS was 12.35 months (95% CI, 10.97, 13.44). The results of the landmark analysis, adjusted for performance status ≥ 1 and presence of visceral metastases, is shown in the Table. By using the Fleischer model, the estimated correlation between PFS and OS was 0.86 (bootstrap standard error 0.001, 95% CI 0.83, 0.89). Conclusions: PFS at 3, 6, and 9 months predicted OS in this analysis of patients with metastatic UC treated with first-line cisplatin-based chemotherapy. This analysis provides benchmarks, and support, for the use of PFS as an endpoint for phase II trials screening the activity of novel regimens as first-line treatment for metastatic UC. [Table: see text]

Chemotherapie beim Harnblasenkarzinom

This review summarizes results of neoadjuvant and adjuvant trials for locally advanced bladder cancer as well as data on systemic chemotherapy for metastatic urothelial cancer. Increasing attention has been drawn to targeted cancer therapies in the treatment of urothelial cancer in recent years. In future, molecular profiling will play a major role as a means to tailor individual therapy.

A phase II study of single-agent nab-paclitaxel as second-line therapy in patients with metastatic urothelial carcinoma.

TPS231 Background: There is currently no standard second-line chemotherapy for metastatic urothelial cancer (UC) previously treated with a platinum-based regimen, representing a key unmet clinical need. In this setting, paclitaxel and docetaxel are commonly used despite overal response rates (ORR) of less than 20%. In this phase II multicenter study, we evaluated the efficacy and tolerability of nab-paclitaxel (Abraxane [ABI-007]), an albumin-bound nanoparticle formulation of paclitaxel as a single agent second-line chemotherapy for metastatic UC. Methods: Patients with unresectable locally advanced or metastatic urothelial cancer of the bladder, ureter or renal pelvis, who progressed on or after first-line platinum based chemotherapy were enrolled on this open-label, two-stage, multicenter clinical trial. Key eligibility criteria included measureable disease with predominantly transitional cell histology, ECOG performance status 0-2, and adequate organ function. Patients treated with prior taxanes for metastatic disease, pre-existing neuropathy ≥ grade 1 or uncontrolled brain metastases or other illnesses were excluded. All patients received a starting dose of 260mg/m2 IV every 3 weeks. Clinical evaluation, CBC and biochemistry were performed at baseline and before each cycle with CT scans of the chest, abdomen, and pelvis repeated every 2 cycles. The primary endpoint was RECIST- defined objective response. Responding patients had confirmatory CT scans performed at least one month following documentation of a response. Secondary endpoints were duration of response, disease control rate (stable disease ≥ 16 weeks, PR or CR), PFS, overall survival, safety and tolerability. All patients were treated until progressive disease or unacceptable toxicity. Abraxane will be considered active in this patient population if a response rate of ≥ 20% is observed. Using a two-stage design, a planned 21 patients will be accrued to stage 1. If more than 1 response is seen, an additional 20 patients will be accrued. Assuming a drop out rate of 10-15%, the planned total accrual is 48 patients. Currently stage 1 criteria have been met and there are 44 patients on study with accrual ongoing. No significant financial relationships to disclose.

Chemotherapy in the post-MVAC era: the case for adjuvant chemotherapy.

Radical cystectomy for muscle invasive and locally advanced bladder cancer is the standard treatment modality in most of the Western industrialised countries. Rates of perioperative mortality from radical cystectomy have decreased to less than 2% over the past two decades due to advances in surgical technique and perioperative care. However, at least 40% of patients with pT3 bladder cancer and 70% of patients with lymph node-positive disease develop tumour recurrence after radical treatment within the first 5 years when treated with radical cystectomy alone. After the efficacy of combination chemotherapy for metastatic urothelial cancer using methotrexate, vinblastine, adriamycin and cisplatin (MVAC) was first described in 1985, several cisplatin-based systemic regimens have been investigated as adjunctive treatment before or after therapy for locally advanced bladder cancer by radical surgery or radiation therapy. Three randomised studies have reported superior results of postoperative adjuvant systemic chemotherapy compared to radical cystectomy alone for locally advanced bladder cancer. All three studies demonstrated a significant survival benefit for bladder cancer patients receiving adjuvant combination therapy. Studies have been criticised for small patient numbers and statistical shortcomings. New effective antineoplastic agents, such as paclitaxel and gemcitabine, have evolved during the past decade as promising substances for the treatment of urothelial cancer. This article reviews adjuvant studies from the era of MVAC combination chemotherapy, as well as contemporary studies that discuss new antineoplastic agents for systemic adjuvant chemotherapy of locally advanced bladder cancer.

Chemotherapy in Metastatic Urothelial Cancer

For more than a decade, the cisplatin plus doxorubicin and methotrexate plus vinblastine (MVAC) regimen has been the gold standard chemotherapy in bladder cancer, although the toxicity associated with this therapy has hampered its use in many older patients with metastatic disease. In recent years, new active agents have been identified, combinations of new agents with established drugs followed and results have become available on the combination of gemcitabine and cisplatin vs MVAC that have revealed an efficacy-toxicity profile in favor of the gemcitabine-cisplatin regimen. Other new doublet and triplet combinations, comprising new agents as well as incorporating one or two new agents into established regimens have demonstrated significant activity in phase II studies. However, there are no randomized data to show that any of these regimens improves patient survival as compared with either MVAC or cisplatin-gemcitabine. Advances in the understanding of the molecular biology of urothelial cancer will help to identify new biochemical targets for the development of novel therapeutic approaches to treat this cancer.

Predictive factors of response to cisplatin-based chemotherapy and the relation of response to survival in patients with metastatic urothelial cancer

To identify pretreatment variables predicting overall and complete response to cisplatin-based chemotherapy for metastatic urothelial cancer, and to study the relation between response and the duration of survival. A total of 119 evaluable patients with recurrent locally advanced or metastatic urothelial cancer received cisplatin-based combination chemotherapy in four consecutive phase II studies from 1987 to 1997. The relationship of pretreatment variables and response was evaluated with logistic regression, and prognostic factors for survival were analyzed with Cox's multivariate model. Response was achieved in 49% of the patients with a complete response rate of 15%. Good performance status and absence of bone metastases were independently predictive of overall response. Good performance status and normal hemoglobin were independently predictive of complete response. Median survival was 8.9 months. Performance status, alkaline phosphatase, s-creatinine, liver and bone metastases were independent prognostic factors for survival. Median survival was 12.4 months in responding patients and 6.3 in nonresponding patients. Response to chemotherapy was included in the multivariate model and was the strongest prognostic factor for survival. The presence of bone metastases, low hemoglobin or poor performance status predicts decreased chance of response to chemotherapy. Response to chemotherapy is an independent prognostic factor for prolonged survival in patients with metastatic urothelial cancer.