Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or 4-week schedule?

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1 Acta Oncologica ISSN: X (Print) 65-6X (Online) Journal homepage: Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or schedule? Anne Birgitte Als, Lisa Sengelov & Hans Von Der Maase To cite this article: Anne Birgitte Als, Lisa Sengelov & Hans Von Der Maase (008) Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or schedule?, Acta Oncologica, 47:, 0-9, DOI: 0.080/ To link to this article: Published online: 08 Jul 009. Submit your article to this journal Article views: 464 View related articles Citing articles: 3 View citing articles Full Terms & Conditions of access and use can be found at

2 Acta Oncologica, 008; 47: 09 ORIGINAL ARTICLE Gemcitabine and cisplatin in locally advanced and metastatic bladder cancer; 3- or schedule? ANNE BIRGITTE ALS, LISA SENGELOV & HANS VON DER MAASE 3 Department of Oncology Aarhus University Hospital, Aarhus, Denmark, Department of Oncology, Copenhagen University Hospital: Herlev Hospital, Copenhagen, Denmark and 3 Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Abstract Background. Chemotherapy with gemcitabine and cisplatin (GC) is an active regimen in advanced transitional cell carcinoma (TCC). Traditionally, GC has been administered as a schedule. However, an alternative schedule may be more feasible. Long-term survival data for the alternative schedule and comparisons of the feasibility and toxicity between the two schedules have not previously been published. Material and methods. We performed a retrospective analysis of patients with stage IV TCC, treated with GC by a standard or by an alternative schedule. Results. A total of patients received GC (; n5, ; n6). We found no statistical differences in overall survival between the two schedules (hazard ratio.5, 95% CI ), p0.40). Five-year s were 4.9% and.8% for the 3- and schedule, respectively (p0.94). Response rates were 59.7% and 55.6%, respectively (p 0.6). Toxicity was less pronounced in the schedule with regards to neutropenia, thrombocytopenia, and transfusion rates. Hematologic toxicity at day 5 in the schedule was common, leading to dose omissions in 47% of cycles. Dose intensity for gemcitabine was accordingly lower in the 4 week-schedule. The higher dose intensity of cisplatin in the schedule, did not lead to increased renal toxicity. In 3 patients with impaired renal function, cisplatin was split into days, which was feasible and efficient. Conclusion. Efficacy parameters for the GC schedule were comparable to those for the schedule, whereas toxicity was less pronounced. The schedule may be an effective and feasible alternative GC-schedule. Cisplatin-containing combination chemotherapy is the standard treatment for patients with locally advanced and/or metastatic transitional cell carcinoma (TCC) of the urothelium. Presently, the two most widely used therapeutic regimens are GC (gemcitabine and cisplatin) and MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) with similar efficacy, but with a significantly better toxicity profile for the GC combination [,]. In the randomized phase III study of GC vs. MVAC [] as well as in three phase II studies [35], a schedule was applied with gemcitabine 000 mg/m on day, 8 and 5 and cisplatin 7075 mg/m on day. However, a high incidence of hematologic toxicity compromises the gemcitabine dose intensity. Gemcitabine doses were modified in 37% of cycles in the phase III study [], and in 3000% of cycles in the phase II studies [35]. Omission of day 5 gemcitabine is reported to be by far the most common dose modification []. According to standard protocols, omissions on day 5 in the schedule should lead to advancement of the next treatment cycle. If so, the treatment is practically administered as a 3- week regimen. The combination of gemcitabine and cisplatin is also an active regimen in advanced nonsmall cell lung cancer (NSCLC). In NSCLC, the combination has been given in both a and a schedule. The schedule has been preferred since it enables better treatment compliance while providing a dose intensity and response rate similar to that of the schedule [6,7]. In carcinoma of the cervix uteri [8], in nasopharyngeal carcinoma [9] as well as in pancreatic carcinoma [0], a regimen has been used and found feasible. Correspondence: Anne Birgitte Als, Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark. Tel: Fax: abals@as.aaa.dk (Received December 006; accepted 6 June 007) ISSN X print/issn 65-6X online # 008 Taylor & Francis DOI: 0.080/

3 GC, 3 or schedule in bladder cancer In urothelial carcinoma, the alternative schedule has been tested in a phase II study []. It was reported that the safety profile was good and that only 8% of doses had to be modified as opposed to 3000% reported in the phase II studies using a schedule [35]. In the present study, we have retrospectively evaluated all patients in our institutions, who received GC for locally advanced and/or metastatic urothelial cancer. The aim was to compare overall and progression-free s, response rates, toxicity profile, dose modifications, and dose intensity for the 3- and schedule, respectively. Impairment of the renal function is a common obstacle in this patient category, which may hamper the possibility to initiate cisplatin-containing chemotherapy. In most protocols, a glomerular filtration rate (GFR) ]60 ml/min or a se-creatinin 5.5 upper normal limit is requested. However, patients with a slightly impaired renal function may apparently tolerate cisplatin if the dose is given within days instead of during one day. Several studies describe regimens with 50% doses administered on day and 8 [4] but this decreases the peakintensity of cisplatin, which may be important for the efficacy. Administration of cisplatin by use of a 50% dose on two subsequent days is another possibility. Data for the outcome of such a strategy have to our knowledge not previously been published. As part of the present study, we have evaluated the feasibility of this procedure. Material and methods Patients All patients with histological proven locally advanced (T4b / N-3) or metastatic (M) TCC of the urothelium, treated with gemcitabine and cisplatin (GC) in a 3- or schedule at the departments of oncology at Aarhus University Hospital and Herlev University Hospital were included in the study. Patients were required to have an ECOG performance status (PS) 5, an adequate bone marrow reserve (white blood cell (WBC) count ] /l, platelets ]000 9 /l, and hemoglobin ]0 g/dl), and patients should have no signs of CNS metastases. An adequate renal function ( 5 Cr- EDTA plasma clearance (GFR) ]60 ml/min) was a prerequisite for full dose cisplatin. However, patients with a GFR of 5060 ml/min were offered cisplatin 70 mg/m, but this dose was divided, and administered as 35 mg/m on day and in both and schedules. This was in accordance with the guidelines in the mentioned GC versus MVAC phase III protocol. Patients recruited for ongoing protocols fulfilled all protocol criteria and all gave informed consent. The scientific ethics committee of Aarhus County approved all protocols. Baseline evaluation consisted in a complete history and physical examination, determination of performance status, complete blood cell count and analysis of p-alkaline phosphatase. Chest x-ray and CT-scans of the abdominal cavity were baseline evaluation methods, supplementary radiological evaluation were performed according to location of metastases. Treatment Schedules The schedule: gemcitabine 000 mg/m repeated on day, 8 and 5, plus cisplatin 70 mg/m on day. Cycles were repeated every 8 days. The schedule: gemcitabine 000 mg/m on day and 8 plus cisplatin 70 mg/m on day. Cycles were repeated every days. Gemcitabine and cisplatin were both administered intravenously over 3060 minutes. Cisplatin was administered with adequate pre- and post-hydration. Supportive care, including anti-emetics, analgesics, blood transfusions and antibiotics, were administered if appropriate and similarly in the two regimens. Granulocyte colony stimulating factors were not used routinely. In both schedules, cycles were not initiated unless WBC was ] /L and platelets were ] /L. Gemcitabine doses on day 8 or 5 were omitted for WBC B.00 9 /L and for platelets B500 9 /L. Omitted doses were not given subsequently. If day 5 gemcitabine was omitted, the next cycle was started on day, i.e. as a schedule. Doses were adjusted for non-hematologic toxicity similarly in both schedules. Patients received a maximum of six treatment cycles unless they experienced disease progression, developed unacceptable toxicity, or the patient requested discontinuation. Blood counts were performed weekly, performance status (PS) and weight was assessed before each cycle. Renal function was evaluated by secreatinin before each cycle and by Cr-EDTA clearance every two cycles. Evaluation of patients Toxicity was graded according to the National Cancer Institute common toxicity criteria scale (CTCAE v3.0). For toxicity analysis, the worst grade for each patient in each treatment cycle was recorded. Response was classified according to World Health Organization (WHO) criteria [5]. Evaluation of response was performed radiologically

4 A. B. Als et al. with the same methods as for the baseline examination and by physical examination. Response evaluations were reassessed every two cycles. Progression-free and overall survival was measured from the day of start of chemotherapy until progression or death, respectively. Patients who were alive with no progression were censored at the date when they were last known to be progressionfree. Survival data were updated February, 006. Statistical methods The distribution of the frequency of baseline parameters was analyzed by the x -test. Clinical response was dichotomized as response (WHO complete response and partial response) versus no response (no change or progressive disease). Patients not evaluable for response were excluded from the response analyses. Response and toxicity ratios were evaluated by the x -test. Weighted ratios and x - values were constructed by the Mantel-Haenszel method. For transfusion rates the Mann-Whitney U-test was used. Dose intensity was calculated according to the methods of Hryniuk [6]. Survival curves were estimated using the Kapplan Meier method. The relationships between survival and pretreatment factors as well as treatment were analyzed with the log-rank test. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic impact of pretreatment factors in relation to survival, and the statistical significance of the hazard ratios was estimated by Walds test. Data for the schedule represented the baseline parameters. Factors with a p-value 50.0 in the univariate analyses were included in the multivariate analysis. The final model was determined by backward selection. All p-values are two-sided. All data calculations were performed using the SPSS Statistical Software (v. 3.0, Chicago, IL). Results A total of patients with locally advanced and/or metastatic bladder cancer were treated with GC in a 3- or schedule in the period from January, 997 to June, 004. Among this group of patients, 5 patients were treated with the schedule and 6 patients with the schedule. The clinical features of the patients are presented in Table I. Baseline parameters were not evenly distributed for all prognostic parameters. We found an uneven distribution of patients with and without visceral metastases, of patients with stages M0 vs. M and of patients with and without elevated P- alkaline phosphatase, with more patients with poor prognostic parameters in the schedule. For patients at risk at the time of analyses, the median follow-up-time was 48.5 months (range 88 months). No patients were lost to follow-up. Overall survival Survival data are summarized in Table II. At the time of analysis, 78 patients had died; 6(83.4%) Table I. Baseline clinical patient characteristics. n (%) n (%) p-value Age (years) median (range) 63.7 ( ) 6.4 ( ) 0.7 Sex male 4 (8.) 4 (68.9) female 7 (7.9) 9 (3.) PS (ECOG) 0 35 (89.4) 54 (88.5) ] 6 (0.6) 7 (.5) 0.85 Hemoglobin normal 59 (40.4) (35.0) low 87 (59.6) 39 (65.0) 0.47 P-alkaline phosphatase normal 07 (74.3) 34 (56.7) elevated 37 (5.7) 6 (43.3) 0.03 Stage M0 T4b, N-3 69 (44.4) 6 (6.) M extra-pelvine lymph nodes 3 (0.5) 7 (.5) B0.000 visceral metastases 5 (33.7) 38 (6.)

5 GC, 3 or schedule in bladder cancer 3 Table II. Survival parameters. (n5) No. (n6) No. Overall survival Events (death) 6 (83.5%) 5 (85.3%) Censored patients 5 (6.5%) 9 (4.7%) Median survival.50 (0.34.7) 4.7 (0.88.7) (95% CI) months 5.7% 54.% 36 months.%.8% 60 months 4.9%.8% HR* 0.87 (0.63.0) Walds p0.40 Progression-free survival Events (progression) 3 (86.8%) 56 (9.8%) Censored patients 0 (3.%) 5 (8.%) Median survival 9.77 (8.3.) 8.60 (7.00.) (95% CI) months 39.% 3.8% 36 months 8.5% 8.6% 60 months 3.% 8.6% HR* 0.79 ( ) Walds p0.4 Abbreviations: HR, Hazard Ratio; CI, Confidence Interval. *A HR B indicates a better outcome for the schedule. vs. 5(85.%) in the 3 week vs. the schedule, giving a censoring rate of 6% (6.5% vs.4.7%). Median overall survival for all patients independent of schedule was.7 months (range ). To assess the assumption of proportional hazards, we performed a regression analysis with time-dependent covariates and found no significant effect of the interaction term of time and schedule. There were no statistically significant differences in overall survival for patients in the two different GCschedules. Median overall survival was.5 months (95% CI ) vs. 4.7 months (95% CI ) for the and schedule, respectively. The hazard ratio (HR) was 0.87 (95% CI ; Walds p0.40). The survival curves are presented in Figure a. Adjusting for baseline prognostic parameters revealed no statistical significant differences in the survival for the vs. the schedule (Table III). Progression-free survival Data are summarized in Table II. At the time of analysis, 87 patients had progressed or died (3- week, n3, 86.8%;, n 56, 9.8%). This means 5 patients were alive without progression giving a censoring rate of.8% (3.% vs. 8.%). There were no statistically significant differences in the median progression-free s for patients in the two different GC-schedules. Median time to progression was 9.8 months and 8.6 months with the and schedule, respectively, HR 0.79 ( ; Walds p0.4). Figure b provides the progression-free survival curves for the two schedules. Adjusting the HR for prognostic parameters revealed no statistical significant differences in survival for the vs. the schedule (Table III). Analysis of effect of prognostic parameters Multivariate Cox proportional hazards analyses were performed to evaluate the impact of pretreatment prognostic factors in relation to overall and progression-free survival. Presence or absence of visceral metastases, PS, level of hemoglobin, and level of alkaline phosphatase all revealed a p-value B0. in the Cox univariate analyses and were included in the multivariate analysis. The final model included PS (HR.0; 95% CI.63.4), presence and absence of visceral metastases (HR.8; 95% CI.33.47) and level of hemoglobin (HR.57; 95%CI.6.3). Due to the uneven distribution of pretreatment prognostic parameters, and in order to evaluate the effect of the two different schedules on survival parameters adjusted for the independent prognostic variables, we included schedule in the final model. We found no statistically significant effect of the treatment schedule for overall survival (p0.39), nor for progression-free survival (p 0.98), see Table III. Response analyses Response evaluation was performed according to WHO criteria. All analyses were done by a skilled radiologist and if there were any doubt at the time of assessment, a reevaluation was performed. A total of 83 patients were evaluable for response (, n9, 85.4%;, n54, 88.5%). The overall response rate was 59.7% vs. 55.6% in the vs. the schedule, respectively (p0.6, x -test). The complete response rate was.7% vs..8% (p0.99). Mantel Haenszel weighted Risk Ratios (RR) and x -tests were computed with correction for absence and presence of visceral metastases. This analysis did not change the results (Table III). Toxicity and dose intensity National Cancer Institute CTC grades 3 and 4 toxicities are provided in Table IV. Significant less

6 4 A. B. Als et al. a Overall Survival According to Schedule Proportion surviving p= No. at risk Overall survival, months b.0 Progression Free Survival According to Schedule 0.8 proportion surviving p=0.4 No. at risk Progression free survival, months Figure. Survival for all patients. a) Overall survival, vs. schedule; b) Progression-free survival, vs. schedule grade 3 and 4 thrombocytopenia and neutropenia was observed in the schedule compared with the schedule. For neutropenic fever, the RR was 0.40 but with only few events in both schedules. The RBC transfusion rate was significantly lower in the schedule. Renal toxicity leading to dose reductions was not more common in the than in the schedule. Mantel Haenszel weighted RR and x -tests were computed with correction for absence and presence of visceral metastases, without changing the results of the analyses. Patients on the schedule received a total of 799 cycles (88.% of planned), compared with 34 cycles (85% of planned) on the -schedule. The median number of cycles was six in both schedules. Dose intensity was 96.0% and 9.0% for gemcitabine and for cisplatin, respectively, in the schedule as opposed to 80.7% and 93.0%, respectively, in the schedule (Table V). Dose adjustments were necessary in 9% of cycles in the schedule compared to 6% in the schedule. The by far most common dose adjustment occurred on day 5 in the

7 GC, 3 or schedule in bladder cancer 5 Table III. Summary of efficacy outcomes. Treatment effect Treatment effect when adjusted for prognostic factors HR 3- vs. 95% CI p HR 3- vs. 95% CI p Median overall survival (95% CI) Median progression-free survival (95% CI).5 (0.34.7) 4.7 (0.88.7) (8.3.) 8.60 (7.00.) RR 3-/ RR 3-/ Overall response rate 59.7% 55.6% Complete response rate.7%.8% Abbreviations: CI, Confidence Intervals; HR, Hazard Ratio; RR, Risk Ratio. A HR B indicates a better outcome for the schedule. The final model included performance status (HR.0; 95% CI.6 3.4), presence and absence of visceral metastases (HR.8; 95% CI.33.47), level of hemoglobin (HR.57; 95%CI.6.3) and schedule. regimen, where doses were omitted in 47% of all treatment cycles (Table VI). According to protocol criteria, omissions on day 5 should lead to modification of the schedule by starting the next cycle on day. In 35 of 49 cases of day 5 omissions, the cycle was the last in the treatment course and there was no subsequent treatment to be advanced. In 59 of the remaining 4 cases (5%), the next cycle was accelerated as planned. In 55 cases (48%), acceleration of the next cycle was not possible due to logistic reasons (3%), ongoing hematologic toxicity (%), or due to the general condition of the patients (4%). Patients with GFR ml/min A slightly impaired renal function with a GFR of ml/min at admission was found in 3 patients. These patients were offered cisplatin as a split dose with 35 mg/m on day and 35 mg/m on day. Remarkably, ten out of these 3 patients had metastatic disease, hereof eight patients with visceral metastases. The for these few patients was similar to that for patients treated with cisplatin 70 mg/m in one day. Median survival was 3.3 months (95% CI ) in the split-dose schedule compared to.7 months (95% CI 0.35.) Table IV. Toxicity ratios, n. -schedule (n5) Cycles (n799) - schedule (n6) Cycles (n34) Correction for absence or presence of visceral metastases Numbers accessible for evaluation (/) RR 3 vs. 4 # 95% CI x p Corrected RR # 3vs.4 (95% CI) M-H weighted x p Neutropenia grade 3 and 4 % of patients Thrombocytopenia grade 3 and 4 % of patients Infection grade 3 and 4 % of patients Neutropenic fever % of patients Renal toxicity leading to dose-reduction % of patients Transfusions RBC % of all cycles Transfusions platelets % of all cycles 06 (45/6) 06 (45/6) (5/6) (5/6) (5/6) (5/6) (5/6) 54.9% 77.0% 0.7 ( ) 44.8% 7.% 0.6 ( ) 6.5% 3.% 0.85 ( ) 4.6%.5% 0.40 (0.4.0) 4.6% 8.0% 0.80 (0.4.56) ( ) B ( ) ( ) (0..0) ( ) % 4.6% B0.00* 0.00*.6%.9% 0.8* 0.6* Abbreviations: RR, Risc Ratio; CI, Confidence Intervals. # ARRB indicates a better outcome for the schedule. * Mann-Whitney U-test.

8 6 A. B. Als et al. Table V. Dose intensity and compliance. DI* (mg/m /week) gemcitabine (n5) (n6) (n5) cisplatin (n6) Planned dose Received dose Relative DI (%) Abbreviations: DI, dose intensity. in patients receiving cisplatin on one day (p 0.76). Survival curves are illustrated in Figure. The response rate was also similar to that of the group of patients receiving cisplatin in one day. Two patients had a CR and four had a PR yielding an overall response rate of 46%. The effect on renal function as indicated by changes in GFR is illustrated in Figure 3. Five patients had decrements of GFR below 50 ml/min and stopped cisplatin treatment before completion of the six cycles. Discussion Locally advanced and metastatic TCC is a disease with a poor prognosis. Cisplatin-containing combination chemotherapy is the treatment of choice and GC has proven to be efficient, well tolerated, and with long term s comparable to other combinations []. In the randomized phase III study of GC versus MVAC, a 8 day schedule was chosen to limit differences and biases since it allowed administration of cisplatin in the same schedule and dose as in the MVAC arm []. On the basis of this randomized study, GC became an alternative to MVAC as a standard regimen and, consequently, as a GC schedule. Since then, this GC Proportion surviving No. at risk Overall Survival According to Administration of Cisplatin Cisplatin in two days Overall survival, months p=0.79 Cisplatin in one day Figure. Overall survival for all patients according to the administration of cisplatin GFR ml/min schedule has been applied in clinical trials concerning advanced urothelial cancer. However, in many centers, especially outside the framework of a clinical trial, a GC schedule is often applied in patients with locally advanced and/or metastatic bladder cancer. Optimally, a non-standard schedule should be compared with the standard schedule in a randomized trial. Such a randomized study would require a very large number of patients and will-from a realistic point of view-probably not be initiated. Therefore, we present this non-randomized comparison of the versus the GC schedule in a group of consecutive and unselected patients with locally advanced and/or metastatic urothelial cancer. The effect and feasibility of a combination of GC has also been investigated in several other cancer types especially lung cancer, where the 3- week schedule is reported to be well tolerated and efficient [6,7,8]. Patients with lung cancer may be comparable to patients with bladder cancer regarding age and smoking related comorbidity, and the obtained feasibility data in lung cancer may thus be of importance for patients with bladder cancer. Data on efficacy, toxicity and compliance from phase II and phase III studies on GC in bladder cancer are presented in Table VII together with data Table VI. Treatment compliance. 3 4 Number of Cycles Figure 3. Effect of chemotherapy on renal function. Each line illustrates the pre-treatment GFR value and the GFR value after the last treatment cycle for each patient. (n5) (n6) p-value - x No. No. Planned cycles Delivered cycles 799 (88%) 34 (85%) 0.4 Modified in dose 53 (9%) 97 (6%) B0.000 Day 5 omissions 49 (47%) Modified in timing 37 (5%) 59 (9%) B

9 GC, 3 or schedule in bladder cancer 7 Table VII. Presentation of 3- and GC Schedules. grade 34 thrombo-cytopenia grade 34 neutropenia median survival (months) relative dose-intensity gemcitabine OR/CR dose adjustments cisplatin mg/m day gemcitabine mg/m day n GC schedule Kaufman et al. [3] ,8, % 4%/% % 60% Moore et al. [5] 3 000,8, % 69% 57%/% 3. 39% 55% Lorusso et al. [4] ,8, % 48%/5%.5 39% 0% von der Maase et al. [] 03 (405) 000,8, % 80% 49%/% 3.8 7% 57% Present study 6 () 000,8,5 70 6% 76.9% 55%/% % 7% Parra et al. [6] 54 (07) 000,8,5 70 5% 79% Lung cancer 7.8% 9.5% GC schedule Hussain et al. [4] ,8 3545,8 65%/3% % 47% Adamo et al. [] 7 00,8 75 8% 48%/0% % Flechon et al. [9] % 88% Adjuvant 73% 3% Present study 5 () 000, % 96% 59%/% % 44.8% Parra et al. [6] 53 (07) 000,8 70 9% 88.5% Lung cancer Abbreviations: OR, Overall response Rate; CR, Complete response Rate. from a randomized phase II study of GC administered in a schedule vs. a schedule in non-small-cell lung cancer published by Parra et al. [6]. The studies may have different criteria of dose adjustments and patient selection, which may reflect dose intensity and toxicity data. When comparing our results with those in other studies, these limitations should be taken into consideration. We found no significant differences in survival or response for the two treatment schedules. Survival and response rates were comparable to previously published data on bladder cancer [,36,,4,9] (Table VII). The results of the univariate and multivariate analyses of clinical prognostic parameters were also in accordance with previous findings [,0,]. We found that hematological toxicity was significantly lower in the schedule compared to the schedule. Toxicity data is in line with the findings by Parra et al. [6]. This randomized phase II study was conducted in patients with lung cancer comparing GC administered as a vs. a schedule. Although toxicity was the main endpoint and the study had a limited number of patients, no statistical differences in survival between the two schedules were reported and compliance was improved in the schedule [6]. Both findings are in accordance with the results of the present study. We report that dose adjustments were necessary in 9% in the schedule compared to 6% of cycles in the schedule. As reported by von der Maase et al. [], and Parra et al. [6], the by far most common reason for dose adjustment was hematological toxicity on day 5, resulting in omission or reduction of gemcitabine. In our study, gemcitabine was omitted on day 5 in 47% of cycles. It is generally advised that the next treatment cycle is started on day in case of day 5 omissions. However, this was only possible in 5% of cases, and led to a significant decrease in dose intensity for gemcitabine in the schedule (Table V). Advancement of treatment may lead to logistic problems and frustrations for the patient as well as for the health care system. This may be illustrated by the fact that in 3% of the treatment cycles the subsequent cycle was not advanced due to logistic reasons. When comparing the schedule in the present study with the previously presented studies of the schedule (Table VII), we found higher toxicity rates regarding thrombocytopenia and number of dose adjustments. This may be due to the unselected character of our patient material and the high frequency of patients with poor prognostic parameters.

10 8 A. B. Als et al. In the schedules (Table VII), compliance was very similar to the results reported by Adamo et al. [] and Parra et al. [6]. In the study in an adjuvant setting by Flechon et al. [9], a higher dose of gemcitabine was used, which may also account for the higher frequency of neutropenia. Nephrotoxicity, indicated by a decrease in GFR below 60 ml/min during treatment, was observed in 9% of patients. Cisplatin was administered at higher dose intensity in the schedule but this did not lead to differences in nephrotoxicity between the two schedules. Differences in reporting renal toxicities make comparisons with previously published studies difficult. In patients with GFR 5060 ml/min, we report the administration of cisplatin split into two doses given on day and to be a feasible strategy. It was tolerable and efficient with s comparable to patients with a GFR ] 60 ml/min although eight of the 3 patients had visceral metastases. As only 3 patients had cisplatin divided in two doses on day and, the results should be interpreted with caution. Our results may be supported by the data reported by Hussain et al. [4] with a different GC schedule using cisplatin 35 mg/m on day and 8. In that study, 9 patients had an impaired renal function (GFR of 4060 ml/min). These patients did not experience a significant further decline in their renal function during treatment. Separate response and survival parameters for these 9 patients were not reported [4]. Our results have to be interpreted with caution due to the non-randomized and retrospective design. In our institutions GC was only applied as the presented or schedule. The choice of either the or the schedule was based on the running local protocols for that specific time period and not based on selected patient parameters. Thus during these specific time periods, all patients had the same schedule, which limits selection biases for the two schedules. In this present material we found a significant difference in the distribution of prognostic baseline parameters with more patients with poor prognostic features in the schedule, which may favor the schedule in terms of survival and tolerability. We adjusted the HR for overall and progression-free survival and the OR for toxicity for the uneven distribution of these parameters, which did not change the conclusions of the study. However, as the study was not randomized, unknown parameters may have influenced the outcome measures. In summary, we demonstrate that GC administered in a schedule is feasible and tolerable in locally advanced and/or metastatic bladder cancer. We found an improved compliance profile, adequate dose intensity and no differences in efficacy parameters for the schedule compared with the 4- week schedule. Thus with the proper reservations due to the retrospective data we find that the schedule may be an effective and feasible GC treatment schedule as an alternative to the schedule. Acknowledgements We wish to thank Professor Michael Vaeth, Department of Biostatistics, Institute of Public Health, University of Aarhus, Denmark for advice on survival analyses. The project was supported in part by grants from: Danish Cancer Society, Max og Inger Wörzners Fond, Frits, Georg og Marie Cecilie Gluds Fond. There are no conflicts of interest. References [] von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 000;/8:/ [] von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. 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