Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group

Annals of Oncology 12: 1417-1422.2001. © 2001 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group

1 First Department of Medical Oncologv. Metaxas Memorial Cancer Hospital. Piraeus; 2 Third Department of Medical Oncology. Agii Anargiri Cancer Hospital, Athens: ^Oncologv Section. Department of Medicine. University of Patras. Patras: *Department of Clinical Therapeutics. University of Athens. School of Medicine. Athens. i Second Department of Medical Oncology. Meta.xas Memorial Cancer Hospital. Piraeus: 6 Department of Medicine. Evangelismos Hospital. Athens: 7Medical Oncology Department, loannina University, loanmna. Greece

Summary Purpose: The aim of the study was to evaluate the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced urothelial cancer. Patients and methods: Thirty-four patients with metastatic urothelial cancer previously treated with cisplatin (CDDP)/ carboplatin (CBDCA) and/or taxanes-based chemotherapy were studied. Gemcitabine was administered at a dose of 800 mg/m 2 on days 1 and 8 and ifosfamide at a dose of 2 g/m 2 on days 1 and 8 with adequate amount of Mesna, every three weeks. Hematopoietic growth factors were given between days 3 to 5 and 12 to 16 to maintain the treatment schedule. Results: On an intent to treat basis, there was one complete response (CR) (3%) (95% confidence interval (95% CI): 0% to 10%) and six partial responses (PR) (18%) (95% CI: 7% to 34%), inducing an objective response rate (RR) of 21'Mi (95% CI: 9% to 38%); 12 (35%) patients achieved a stable disease (SD) and 15 (44%) a progressive disease (PD). The median time to tumor progression (TTP) was four months (range, 0.52

Introduction Urothelial cancer is the fourth most common cancer in men and the ninth in women [1]. Thus locally advanced, inoperable and metastatic disease is considered as a relatively 'chemosensitive tumor'. The most active single agents include the cisplatin (CDDP), methotrexate (MTX), doxorubicin (ADR), vinblastine (VLB) and taxanes; paclitaxel or docetaxel. The combination of CDDP with MTX and VLB (CMV) or these agents with ADR (M-VAC) have been associated with objective responses in 56%-72% of patients [2, 3]. The prognosis of patients with advanced urothelial cancer refractory to CDDP-based chemotherapy is very poor. Second-line chemotherapy may be administered to such patients with the aim to induce reduction of tumor load and to ameliorate symptoms such as hematuria, dysuria, pain and leg oedema. Unfortunately, there is no standard

to 21.6 months) and the median survival nine months (range 0.52 to 28 months). This regimen also provided the opportunity for symptomatic improvement of pain, dysuria. haematuria and leg oedema. Grade 3-4 neutropenia was experienced by 9 (27%) patients, grade 3-4 anemia by 6 (18%) and grade 3-4 thrombocytopenia by 4 (12%). Six patients were hospitalized due to febrile neutropenia. Despite the prophylactic use of hematopoietic growth factors, 8 (23.5%) patients required dose reduction due to myelosuppression. Grade 3 alopecia occurred in 14 (41%) patients, grade 3-4 nausea in 1 (3%), grade 2 fever in 3 (9%), grade 2-3 diarrhea in 2 ( 6%) and grade 2 allergic reaction in 1 (3%). Conclusion- We conclude that the combination of gemcitabine and ifosfamide is an active salvage regimen for the treatment of urothelial cancer and that the treatment also has a tolerable toxicity profile; it warrants further investigation in combination with CDDP in chemotherapy-naive patients. Key words: gemcitabine. ifosfamide, metastatic urothelial cancer, salvage chemotherapy

salvage regimen for patients who relapse or who are refractory to CDDP or taxanes-based chemotherapy. In particular, drugs with good tolerability and easy administration are chosen as second-line treatment. Thus, a number of new agents and combinations have been explored. Several new agents have been already investigated in urothelial cancer patients, including gemcitabine [4, 5], ifosfamide [6, 7], gallium nitrate [810], trimetrexate [11], paclitaxel [12, 13], and docetaxel [14, 15]. Whereas ifosfamide has been extensively investigated insofar as several solid tumors are concerned, few clinical trials have been conducted in urothelial cancer. Authors who have performed such studies, especially in the treatment of squamous cell carcinoma of the bladder, report impressive objective responses for ifosfamide when used either as single or in combination with anthracycline [16]. A Japanese study which evaluated ifosfamide in

Downloaded from https://academic.oup.com/annonc/article-abstract/12/10/1417/147856 by guest on 31 January 2019

D. Pectasides,1 G. Aravantinos,2 H. Kalofonos,3 C Kiamouris, 4 D. Bafaloukos,5 N. Xiros,6 C. Nicolaides,7 A.Visvikis1 & M. A. Dimopoulos 4

1418

Patients and methods Eligibility criteria included: histologically or cytologically proven urothelial cancer, mclastatic disease recurrent or refractory to CDDP/ carboplalin (CBDCA) and/or taxanes-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. measurable or assessable disease outside prior radiotherapy ports, life expectancy of at least 12 weeks, adequate haematological (WBC ^3500/ul. absolute granulocyte count (AGC) ^ 1500/ul. platelet count ^ 100,000/ul). renal (serum creatinine $1.5 ml/dl) and liver functions (bilirubin $1.5 mg/dl. Lransaminases $ 3 times normal). Patients with brain metastases. congestive heart failure even if medically controlled, documented myocardial infraction and pre-existing motor or sensory neurotoxicity grade 5= 2 according to the WHO scale (intolerance paresthesias and/or marked motor loss) were excluded from the study. Patients with active infection or other serious underlying medical conditions that would impair the ability of the patient to receive the protocol treatment were also ineligible for the study Informed consent was obtained from all patients. Before entering the study, all patients underwent physical examination, full blood count (FBC). blood chemistry, chest X-ray, bone scan, abdominal computed tomography (CT) scan and urine cytology. Bimanual examination under general anesthesia and cystoscopy were mandatory for patients with locally advanced disease. CTscan of the chest and other specific tests were performed when indicated. Responses were assessed every two cycles of treatment and included clinical examination. FBC. blood chemistry, chest X-ray. CT scan of the abdomen and pelvis and urine cytology and cystoscopy for patients with locally advanced disease.

Treatment plan Treatment was administered on an out-patient basis. All patients received the following chemotherapy dose schedule. Gemcitabine 800 mg/m 2 was given by intravenous infusion over 30 minutes on days 1 and 8 and ifosfamide 2 g/m" by intravenous infusion over two hours on days 1 and 8 with adequate amount of Mesna (1/3 Mesna i.v. push slowly - 10-minule infusion - before the administration of ifosfamide and 2/3 Mesna p o. four and eight hours post-ifosfamide administra-

tion). Treatment was repeated every three weeks. Hematopoietic growth factors were given prophylactically at a dose of 150 u g / n r subcutaneously between days 3 to 5 and 12 to 16. Antiemelic treatment was given at the discretion of the investigators. Patients received at least 6 cycles of chemotherapy unless tumor progression, serious toxicity or intercurrent illness occurred, or the patient requested discontinuation. Doses of drugs were adjusted according to WBC and platelet counts. Chemotherapy was given if the AGC was >2000/ul and the platelet count was > 100,000/ul on the day of treatment. Patients had a dose reduction of gemcitabine to 700 mg/m 2 and ifosfamide to 1.75 g/m 2 if they had an AGC nadir $1000/u] and/or platelet nadir =S75.000/ul (level 1). If the AGC nadir was <500/ul and the platelet nadir $ 50.000/ul, gemcitabine was reduced to 600 mg/m 2 and ifosfamide to 1.5 g/m" (level 2). On day 8. full doses of drugs were given, if on the day of treatment, the AGC was > 1500/ul. the platelet count 5= 100,000/ul and any non-hematologic toxicity grade was $ 2. In the event of AGC of 1000 to 1500/ul or platelet count of 75.000 to 99.000/ ul, drug doses were reduced to level 1. For AGC < 1000/ul. or platelet count < 50.000/ul, drug doses were withheld. If patients experienced a grade 3 or 4 non-hematological toxicity. the treatment was delayed until recovery to grade 1 or less. For the patients who required day-8 doses to be withheld because of toxicity. their drug doses were also reduced to level 2 at subsequent cycles. Patients were monitored weekly for FBC and were evaluated for toxicity weekly. The WHO scale was used for toxicity grading. Response assessment was based on the WHO criteria [20]. Methods to evaluate efficacy included the determination of the tumor response rate, both by 'standard analysis', which considers only patients completing at least two cycles of therapy, and by 'mlent-to-treat analysis', which considers all patients entered in the study as evaluable, thus viewing withdrawn patients for any cause as treatment failure. Patients who had achieved either complete or partial response after six cycles could continue treatment for two further cycles. Patients who were stable for six cycles were considered to have completed protocol therapy and were taken off treatment. Once outside of the study, further treatment was at the discretion of the investigator. Complete response (CR) was defined as the complete disappearance of all clinically detectable disease for at least four weeks. Partial response (PR) was defined as a > 50% reduction of all measurable disease for at least four weeks Stable disease (SD) was defined as a < 50% reduction of all measurable or assessable lesions Progressive disease (PD) was defined as an increase in any lesion or the appearance of new lesions. Survival was calculated from the day of initiation of treatment to the day of death using the Kaplan-Meier method [21], Duration of response was calculated from the date that partial or complete response was documented to the date of progression Time to progression (TTP) was defined as the time elapsed from the initiation of treatment to documentation of progression.

Results Patient characteristics From November 1997 to June 1999, 29 (85%) men and 5 (15%) women with a median age of 61 years (range 45 to 79 years) entered the study. All patients were assessable for toxicity and response. Two patients refused further treatment after the first course of chemotherapy due to fatigue and an allergic reaction, respectively. These two patients were considered as treatment failures. Patients' characteristics are shown in Table 1. The median duration of follow-up was 24 months (range 0.52-28 months). Patients had a good performance status (PS) (62% of patients had a PS of 0 to 1), 27% had persistent or recurrent local disease, 50% had regional nodal dis-

Downloaded from https://academic.oup.com/annonc/article-abstract/12/10/1417/147856 by guest on 31 January 2019

malignant urological tumors, reported 10 objective responses in 34 patients, inducing an overall response rate of 29% [7]. A recent ECOG phase II trial of ifosfamide (7,5 g/m 2 total dose) in 55 previously treated patients reported an objective response rate in 20% of patients [6]. Gemcitabine is a new pyrimidine antimetabolite structurally similar to cytarabine and inhibits DNA synthesis and ribonucleotide reductase. It has an established role as an active single agent in the treatment of advanced urothelial cancer inducing objective responses in 21,5% to 28% of patients and a survival time from 8 to 11.8 months [4, 17-19]. Gemcitabine is well tolerated, even in elderly patients, with toxicities usually resulting in such limited reactions as grade 1 or 2 neutropenia, low-grade fever, rashes and mild peripheral edema. Gemcitabine and ifosfamide, two active agents in advanced urothelial cancer, work by different mechanisms of action, have minimal overlapping toxicity and can be easily given on an-out patient basis. Based on these observations, the Hellenic Cooperative Oncology Group (HeCOG) conducted a phase II study to evaluate the efficacy and toxicity of the combination.

1419 Table 2. Response to treatment.

Table 1. Patient characteristics. Characteristic

No. of patients

Response

No.

Number of patients Age Median (years) Range (years) Sex Male Female Performance status 0

34

Complete response Partial response Overall response rale Stable disease Progressive disease

I 6 7 12 15

61 45-79

95% Cl 3% 18% 21% 35% 44%

0.0-10.0 7.0-34.0 9.0-38.0 20.0-53.0 22.0-56.0

29 (85%) 5(15%)

13 (38%)

Histology Transitional cell Squamous cell Adenocarcinoma Mixed Previous treatment Cystectomy Radiotherapy Chemotherapy CDDP/CBDCA Anthracyclines Taxanes

MTX VLB Treatment-free interval Median (months) Range (months) Sites of metastases Bladder Bones Liver Lung-pleura Lymph nodes Abdomen-pelvis-ascites Other

28 2 I 3

(82%) (6%) (3%) (9%)

14 (41%) 10 (29%) 34 (100%) 34(100%) 12 (39%) 18 (58%) 10(32%) 11 (35%) 4 0.4-32 9 (27%) 7 (21%) 7 (21%) 8 (23%) 17 (50%) 8 (23%) 7(21)

ease, 23% had lung-pleura metastatic disease and 21% metastases to the liver. Other sites of metastatic disease included the pelvis, the adrenal gland, the abdomen with ascites and the bones. Fourteen patients were previously treated with cystectomy and 10 with radiation therapy. All patients had prior treatment with CDDP/CBDCAbased chemotherapy. Anthracyclines had been administered to 12 (39%) patients, taxanes to 18 (58%), MTX to 10 (32%) and VLB to 11 (35%). The response to first-line chemotherapy was 2 CRs (6%), 6 PRs (20%) (objective response: 26%) and 8 SDs (26%). Thus, 8 (26%) patients were relapsing after prior response and 26 (74%) patients were considered to have primary refractory disease. The median time between the first-line chemotherapy and this salvage combination was four months (range 0.4 to 32 months).

Months

Figure I Time to tumor progression and overall survival.

were 1 (3%) CR (95% CI): 0% to 10%) and 6 (18%) PRs (95% CI): 7% to 34%), for an overall response rate (RR) of 21%, (95% CI): 9% to 38%); 12 (35%) patients achieved a SD and 15 (44%) a PD (Table 2). Among the seven patients who had an objective response, three patients had primary refractory disease and 4 had recurrences after prior CR or PR resulting from in first-line treatment. The median duration of response was 9.5 months (range 3.2 to 17.5 months), the TTP for all patients was four months (range 0.52 to 21.6 months) and the median survival was nine months (range 0.5 to 28 months). Figure 1 depicts overall survival and TTP for all patients in the study. It is of note that there were responses in all involved sites including the liver. Among patients who were symptomatic, clinical benefit response, including pain relief was observed in 39% of the patients with reduction of administered analgesic, improvement of dysouria; hematuria was also observed in 18% of the patients and reduction in leg oedema in 9%. The median number of cycles per patient was 4 (range 1 to 7 cycles) and the total administered cycles were 149. The median relative dose intensity was 0.85 for gemcitabine and 0.84 for ifosfamide. Despite the prophylactic use of hematopoietic growth factors, eight (23.5%) patients required dose reduction due to myelosuppression. Toxicity

Response On the basis of an intent-to-treat analysis, the overall responses to chemotherapy are listed in Table 2. There

Treatment was generally well tolerated (Table 3). Myelosuppression was the only toxicity that resulted in dose reduction. No patient had a dose reduction or treatment delay due to any other grade 3 and 4 toxicity. Grade 3-4

Downloaded from https://academic.oup.com/annonc/article-abstract/12/10/1417/147856 by guest on 31 January 2019

12 (35%) 9 (27%)

1420 Table 3. Ibxicity. Grade 1 n

Grade 3

Grade 4

%

n

%

n

%

n

23.0 6.0 6.0 3.0 90 60 18.0 150 _

9 5 2 3

27 0 15.0 6.0 9.0 15.0 3.0 6.0 9.0 3.0

6 1 4 1 14 1 _

18.0 3.0 12.0

3 5 _ _

5 1 2 3 1

neutropenia was observed in 9 (27%) patients, grade 3-4 thrombocytopenia in 4 (12%) and grade 3-4 anemia in 6 (18%>). There were 6 (18%) episodes of febrile neutropenia that required hospitalization. All these patients were successfully treated with broad spectrum antibiotics. No thrombopenic episodes were complicated by hemorrhage. Five (14.7%) patients required platelet transfusions and 12 (35.3%) patients required blood transfusions. Alopecia grade 3 was observed in 14 (41%) patients. Nausea/vomiting grade 3-4 occurred in 1 (3%) patient, grade 2 fever in 3 (9%), grade 2-3 diarrhea in 2 (6%i) and allergic reaction grade 2 in 1 (3%). None of the patients developed CNS toxicity. There were no treatment related deaths.

Discussion An increasing number of patients with metastatic urothelial cancer who fail first-line chemotherapy and/or radiotherapy are candidates for second-line therapies. Over the last few years, a number of new chemotherapeutic agents have shown activity against urothelial cancer, including paclitaxel, docetaxel, gemcitabine, vinorelbine, liposomal doxorubicin and gallium nitrate. The present report describes the first phase II study combining gemcitabine and ifosfamide on a weekly basis in the treatment of patients with metastatic urothelial cancer who failed treatment with a platinumbased regimen with or without taxanes. It was designed on the basis that these agents represent two relatively active single agents in advanced urothelial cancer. Gemcitabine and ifosfamide work by different mechanism of action, have minimal overlapping toxicity and can be administered easily on an out-patient basis. Gemcitabine is an active agent in advanced TCC. When administered as a single agent, objective responses, ranging from 21,5% to 28% have been obtained in both pretreated patients and those who have not had prior therapy [4, 17-20]. Pollera et al. [4] reported 15 patients with metastatic urothelial cancer who had been included in an escalating-dose phase I study. All patients, apart from one, had been previously treated with

30 41.0 3.0

9.0 15.0

M-VAC chemotherapy. Gemcitabine was administered at a dose ranging from 875 mg/m 2 (1 patient) to 1370 mg/m 2 (11 patients) on days 1,8 and 15 of a four-week cycle. The response rate was 21.4% in 14 previously treated patients. Toxicity was generally mild. In the second trial, Lorusso et al. [19] treated 35 patients who had failed to respond to CDDP-based chemotherapy with gemcitabine at a dose of 1200 mg/m 2 on days 1, 8 and 15 every 28 days. The overall response rate was 22.5%, the median duration of response 11.8 months and the median survival five months. Myelosuppression was the main toxicity. Gemcitabine has been also evaluated in combination with CDDP/CBDCA and/or taxanes in the treatment of advanced TCC. Ifosfamide has been extensively investigated in a variety of malignant tumors including lung cancer, lymphomas, sarcomas, ovarian and testicular carcinomas. However, few clinical trials have been conducted with ifosfamide in urothelial cancer. In a Japanese study, ifosfamide was administered as a single agent in 34 previously treated patients with malignant urological tumors [7]. The reported response rate was 29%. In another study, ifosfamide was administered to 56 eligible patients who had progressive disease following prior systemic CDDP-based chemotherapy. Ifosfamide was administered every three weeks at a dose of 3750 mg/m 2 daily for two days (26 patients) or 1500 mg/m 2 daily for five days (30 patients) [22]. The two-day schedule changed to a five-day schedule due to severe renal and CNS toxicity. The overall response rate was 21%, the median TTP 9.6 weeks and the median overall survival 22 weeks. The toxicity was primarily myelosuppression, renal, CNS and gastro-intestinal. Ifosfamide at a dose of 1800 mg/m 2 daily for five days every three weeks has been also investigated in combination with epirubicin at a dose of 80 mg/m 2 on day 1 in 20 untreated patients with urothelial cancer (10 patients with squamous cell carcinoma and 10 patients with transitional cell carcinoma [TCC]) [16]. In 17 assessable patients the response rate was 64.7%. In another study ifosfamide at a dose of 2 g/m 2 daily of days 1-3 was investigated in combination with vinorelbine at a dose of 25 mg/m 2 days 1 and 8 and 5-fluoruracil at a dose of 400 mg/m 2 days 1-3, in 14

Downloaded from https://academic.oup.com/annonc/article-abstract/12/10/1417/147856 by guest on 31 January 2019

Anemia Thrombocytopenia Neutropema Nausea/Vomiting Alopecia Diarrhea Fatigue Fever Allergic reactions

Grade 2

1421

Downloaded from https://academic.oup.com/annonc/article-abstract/12/10/1417/147856 by guest on 31 January 2019

patients with urothelial cancer, 10 of whom had failed to apy with gemcitabine, and it may be more toxic for respond to CDDP-based chemotherapy [23]. Of the 10 patients with advanced urothelial cancer. evaluated patients there were 1 CR and 2 PRs. Einhorn et al. [24] reported on the treatment of 27 previously untreated patients with metastatic urothelial cancer us- References ing vinblastine 0.11 mg/kg on days 1 and 2, ifosfamide 1. Wingo PA, Tong T. Bolden S. Cancer Statistics 1995. CA Cancer J 1.2 g/m 2 daily on days 1 to 5 and gallium nitrate 300 Clin 1995,45- 45-8. mg/m 2 daily as a 24-hour infusion on days 1 to 5. The 2 Harker WG. Meyers FJ. Freiha FS et al. Cisplatin. metholrexatc response rate was 67%, the median duration of response and vinblastine (CMV): An effective chemotherapy regimen for 20 weeks and the median survival 43 weeks. The toxicity metastatic cell carcinoma of the urinary iract. A Northern Calof this regimen was significant but manageable. ifornia Oncology Group Study. J Clin Oncol 1985: 3: 146.V70. 3. Stenberg CN. Yagoda A. Scher HL et al. M-VAC (mcthotrexale. The combination of gemcitabine at a dose of 1000 2 vinblastine, doxorubicin and cisplatin) for advanced transitional mg/m on days 1, 8 and 15 and ifosfamide at a dose of cell carcinoma of the urolhelium J Urol 1988; 341 461-9. 2 1500 mg/m daily on days 8 to 12, of a four-week cycle 4. Pollera CF. Cenbelli A. Crecco M et al. Weekly gemcitabine in was evaluated in a phase II study in the treatment of 56 advanced bladder cancer: A preliminary report from a phase 1 patients with advanced non-small-cell lung cancer [25]. study. Ann Oncol 1994: 5. 182-4. 5. De Luna M. Gridelli C. Lorusso V et al. Gemcitabine activity In 51 assessable patients, the RR was 22%. Grade 3 and (objective responses and symptom improvement) in resistant 4 neutropenia occurred in 35.8% and 24.5% of patients, stage IV bladder cancer. Proc Am Soc Clin Oncol 1996: 15: 246 respectively. To the best of our knowledge, there are no (Abstr622). published data on the combination of gemcitabine and 6 Witte R. Loehrer P. Dreicer R et al Ifosfamide in advanced ifosfamide for the treatment of metastatic urothelial urothelial carcinoma. An ECOG trial. Proc Am Soc Clin Oncol cancer. We administered this combination on days 1 and 1993; 13-23O(Abstr7O7). 7. Otarugo K. Ueda K. Niijima Tet al. Clinical evaluation of Z 4942 8 of a three-week cycle in order to reduce the hospital (ifosfamide) for malignant urological tumors. Hinyokika Kiyo visits of these already pretreated patients with meta1981,27-459-62. static cancer. We had not previously conducted a dose8. Crawford ED. Saiers JH, Baker LH ct al. Gallium nitrate in finding study, but we chose relatively low doses of both advanced bladder carcinoma. A Southwest Oncology Group gemcitabine and ifosfamide, since all the patients were Study. Urology 1991; 38: 355-7. 9. Seligman PA. Crawford ED. Treatment of advanced transitional previously exposed to chemotherapy and many of them cell carcinoma of the bladder with continuous-infusion gallium had received radiotherapy to the pelvis. Despite the nitrate. J Natl Cancer Inst 1991. 83: 1582-4. relatively low doses and the prophylactic administration 10. Sedman AD. Scher HI. Heinemann MH et al. Continuous infuof hematopoietic growth factors, dose reductions were sion gallium nitrate for patients with advanced refractory urolherequired in 23.5% of patients. We found that this combilial tract tumors. Cancer 1991:68: 2561-5. nation appeared to be relatively safe with a modest 11. Witte RS. Elson P. Khandaker J et al Eastern Cooperative Oncology Group phase II trial of trimetrexale in the treatment of activity in patients with advanced urothelial cancer, advanced urothelial carcinoma. Cancer 1994: 73: 688-91. who had failed first-line CDDP/CBDCA-based chemo12. Niel HB. Rangel C. Miller A et al. The activity of anlimicrotubutherapy. The objective response rate of 21%, the SD rate lar agents in human bladder tumor cell lines. Proc Am Assoc of 35% and the median survival of nine months would Cancer Res 1993: 34: 202. be rather modest. However, given that in most of our 13 Roth BJ. Dreicer R. Einhorn LH et al. Significant activity of paclitaxel in advanced transitional cell carcinoma of the urothcpatients, the response rate to first-line chemotherapy lium. A phase II trial of the Eastern Cooperative Oncology was quite low (26%), the duration of response was Group (E 1892). J Clin Oncol 1994; 12: 2264-70. satisfactory: the treatment free interval was only four 14. De Wit R. Stoter G. Blanc C et al. Phase II study of docetaxel months and a significant percentage of our patients (Taxotere) in patients with metastatic urolhelial cancer. Ann had visceral metastases. Our combination also showed Oncol 1994: 12. 5 (Suppl 8. Abstr 67). clinical benefit response in symptomatic patients. The 15. Me CafTrey J. Hilton S. Bajorin D et al Docetaxel in patients with advanced transitional cell cancer (TCC) who failed cisplatintolerability of this combination was acceptable and the based chemotherapy. A phase II trial. Proc Am Soc Clin Oncol toxicity moderate. Grade 3-4 neutropenia occurred in 1995; 14:233(Abslr607). 27% of patients, grade 3-4 thrombocytopenia in 12% 16 Nazli G. Khaled H. Abdlewareth A. Epirubicin, ifosfamide comand grade 3-4 anemia in 18%. Six patients required bination chemotherapy in invasive bladder cancer. Proc Am Soc hospitalization due to febrile neutropenia. All these Clin Oncol 1990: 9: 137 (Abstr 530). 17. Stadrel WM, Kuzal T, Roth B et al. Phase II study of single patients were successfully treated with broad spectrum agent gemcitabine in previously untreated patients with metaantibiotics. Other side effects including nausea/vomitstatic urothelial cancer. J Clin Oncol 1997; 15- 3394-8. ing, diarrhea, fatigue, alopecia, fever and allergic reac- 18. Moore MJ.Tannock IF. Ernst DSet al. A promising new agent in tions were mild and did not result in any clinically the treatment of advanced urothelial cancer. J Clin Oncol 1997: significant problem. 15: 3441-5. We conclude that the combination of gemcitabine 19. Lorusso V. Pollera CF. Antimi M el al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the and ifosfamide had modest activity as a salvage treaturinary tract previously treated with platinum. Eur J Cancer ment in advanced urothelial cancer. Based on this data, 1998:34: 1208-12. it is unlikely that the combination of gemcitabine and 20. WHO Handbook for Reporting Results of Cancer Treatment. ifosfamide is more active than single agent chemotherNo 48. The Hague- NijhofT 1979.

1422 21. Kaplan EL, Meier P. Non-parametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 357-481. 22 White RS, Elson P. Bono B et al. Eastern Cooperative Oncology Group phase II trial of ilbsfamide in the treatment of previously treated advanced urothelial carcinoma J Clin Oncol 1997. 15: 589-93. 23. Mahjoubi M. Kalian J. Droz JP et al. Feasibility trial of a combination of vinorelbine. ilbsfamide, fluoruracil and folonic acid (VIF regimen) in advanced urothelial cancer Eur J Cancer 1993; 29A: 285-6. 24. Einhorn LH, Roth BR. Ansan A et al. Phase II trial of vinblastine. ifosfamide and gallium combination chemotherapy in metastatic urothelial cancer. J Clin Oncol 1994: 12: 2271-6.

25. Gatzemeier U, Manegold C. Eberhard Wet al. A phase II trial of gemcitabine and ifosfamide in non-small-cell lung cancer. Semin Oncol 1997; 24 (Suppl 8): S36-S38 Received 29 January 2001: accepted 15 May 2001. Correspondence to • D. Pectasides. MD HeCOG Data Office Laskaridou 1 and Kifissias str. 11524 Athens Greece E-mail: [email protected] Downloaded from https://academic.oup.com/annonc/article-abstract/12/10/1417/147856 by guest on 31 January 2019