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Pii: s0959-8049(00)00079-4European Journal of Cancer 36 (2000) S34±S37 A phase II study of gemcitabine plus cisplatin chemotherapy in H.M. Khaled a,*, M.R. Hamza a, O. Mansour a, R. Gaafar a, M.S. Zaghloul b aDepartment of Medical Oncology, National Cancer Institute, Cairo University, Egypt bDepartment of Radiotherapy, National Cancer Institute, Cairo University, Egypt Bilharzial bladder cancer represents a distinct clinicopathological entity. To investigate whether gemcitabine±cisplatin is also active against bladder cancer of bilharzial origin, we performed a phase II study of previously untreated patients with stage III/IV disease. Standard eligibility criteria were used. Patients received gemcitabine (1000 mg/m2) on days 1, 8 and 15 and cisplatin (70 mg/ m2) on day 2 of every 28-day cycle. The 32 males and 5 females had a median age of 59 years (range: 29±81 years). Of 33 evaluable patients, 8 (24%) achieved complete responses, and 10 (30%) partial responses, for an overall response rate of 55%. 3 patients had minor responses. Responses were observed at all disease sites including lung and liver lesions. Myelosuppression was signi®cant but manageable. Non-haematological toxicity was limited mainly to nausea and vomiting and raised liver enzymes. Thus, these data suggest that gemcitabine plus cisplatin induces high response rates in patients with bilharzial bladder cancer with a moderate toxi- city pro®le. # 2000 Published by Elsevier Science Ltd. All rights reserved.
Keywords: Bladder cancer; Bilharzial-related bladder carcinoma; Transitional cell carcinoma; Chemotherapy-related toxicity; Gemcitabine; Cisplatin Gemcitabine (Gemzar), a new pyrimidine anti- metabolite active against a range of tumour types, has Bilharzial-related bladder carcinoma is the foremost been used against transitional cell bladder cancer with oncological problem in Egypt, constituting 30.3% of all promising results [7,8]. In the phase II study of Moore cancers of patients who present to the Cairo National and colleagues , gemcitabine was used as a single Cancer Institute . As most cases have invasive agent for patients with metastatic disease. There were 3 tumours, radical cystectomy with urinary diversion is complete responses (CR) and 6 partial remissions (PR) the only curative modality so far identi®ed. Patients in 37 evaluable patients, for an overall response rate of with operable disease have 5-year survival rates between 24%. Using a combination of gemcitabine and cisplatin, only 27 and 39% [2,3]. However, 25% have inoperable von der Maase and colleagues  reported a response rate of 39%, with 6 of 38 patients achieving a CR and 9 Inoperable patients, as well as those with recurrent and/or metastatic disease, are potential candidates for The aim of this work was to evaluate the ecacy of systemic therapy trials to identify the most active agents the gemcitabine±cisplatin drug combination against or drug combinations. In addition to the unique biolo- advanced bilharzial-related bladder cancer.
gical, epidemiological, pathological and clinical char- acteristics of bilharzial bladder cancer compared with the conventional transitional cell carcinoma seen in Western countries , the disease also has a dierent chemoresponsiveness pro®le, as reported in a series of The study included 37 patients with histologically phase II single-agent and combination chemotherapy proven inoperable, recurrent and/or metastatic bilharzial- related, measurable or evaluable disease. Bilharziasis was documented pathologically by the presence of bil- * Corresponding author. Tel.: +20-12-215-1040; fax: +20-236-35-083.
harzia ova in bladder tumour tissue obtained during E-mail address: [email protected] (H.M. Khaled).
0959-8049/00/$ - see front matter # 2000 Published by Elsevier Science Ltd. All rights reserved.
H.M. Khaled et al. / European Journal of Cancer 36 (2000) S34±S37 Inclusion criteria included age 518 years, good per- formance status (higher than 60 on the Karnofsky scale), adequate haematological, kidney and liver func- tions, no previous radiation therapy or chemotherapy The clinicopathological characteristics of the 32 Pretreatment and follow-up tumour measurement and (86%) males and 5 (14%) females included in the study staging were evaluated by complete physical examina- are shown in Table 1. Their ages ranged between 29 and tion, pelvi-abdominal and transrectal pelvic ultrasound, 81 years (median 59 years). 22 patients had transitional computed tomography scan of the abdomen and pelvis, cell carcinoma, 14 had squamous cell carcinoma and the chest X-ray and/or computed tomography scan, and remaining patient had adenocarcinoma of the bladder.
bone scan according to site and type of disease.
Of the 37 patients included in the present study, 19 Chemotherapy consisted of gemcitabine given on days (51%) had not had a radical cystectomy. The tumour 1, 8 and 15 at a dose of 1000 mg/m2 every 28 days. The was inoperable in 10 patients due to extensive pelvic drug was administered as an intravenous (i.v.) infusion disease, and the other 9 patients had distant metastases over approximately 30±60 min. After adequate hydra- (bone, 1 patient; lymph nodes, 5 patients; liver, 1 patient; tion, cisplatin was administered on day 2 at a dose of 70 and multiple sites, 2 patients). 18 patients (49%) had mg/m2 as a 3-h infusion. Before cisplatin administra- developed locally recurrent (3 patients) or metastatic tion, patients were hydrated with 1500 ml dextrose sal- disease (10 patients) or both (5 patients), which occur- ine over 3 h, with 10 mEq potassium chloride and 750 red after surgical removal, i.e. radical cystectomy of the mg magnesium sulphate added to each 500 ml. A 25-ml ampoule of 10% mannitol was also administered before and after each cisplatin infusion. After the cisplatin infusion, a 3-h infusion of 1500 ml dextrose saline together with 10 mEq potassium chloride and 750 mg 33 (89%) of the 37 patients included in the study were magnesium sulphate per 500 ml dextrose was also evaluable for treatment response. The median number of courses received was 3 (range: 1±6 courses). Variations in No new cycles of gemcitabine and cisplatin were star- the number of treatment cycles were due to dierent ted unless the total leucocyte count was 53Â109/l and reasons including discontinuation of treatment due to the platelet count was 5100Â109/l. A full dose of gem- disease progression at any time, disease stabilisation citabine was given on day 8 or 15 if the total white blood cell and platelet counts were 52 and 550Â109/l, respectively. The dose was omitted if these counts were Clinicopathological characteristics of the 37 bilharzial-related bladder less than 1.99 and 49Â109/l, respectively or if there was any evidence of bleeding complications.
For other non-haematological toxicities, the drugs were given at 50% of planned doses or omitted if Com- mon Toxicity Criteria grade 3 or 4 toxicities occurred.
The decision was based on the type of toxicity seen and the judgement of the treating physician-investigator.
Patients were considered evaluable for response if they had received at least one course of chemotherapy.
Inevaluable patients were those who refused further therapy (1 patient) after receiving only days 1 and 2 but not days 8 and 15 of the ®rst cycle of therapy, did not return after receiving the ®rst cycle (1 patient), or were considered un®t to continue treatment by the investi- gator (2 patients). The duration of treatment depended on patient response. Therapy was discontinued after one cycle if there was de®nite disease progression.
Treatment was also stopped if the disease remained stable for two cycles whether or not a response had The Mann±Whitney statistical test was used to com- pare results amongst the various patient subgroups .
All reported P values were two-sided. P values <0.05 H.M. Khaled et al. / European Journal of Cancer 36 (2000) S34±S37 Response to therapy in relation to disease status at presentation Toxicity evaluation for the 37 patients who received chemotherapy CR, complete response; PR, partial response; MR, minor response; SD, stable disease; ID, increasing disease.
after two cycles, refusal of further therapy or patients considered by the investigator to be un®t to continue 8 patients (24%) achieved a CR, and 10 patients (30%) had a PR, for an overall response rate of 55%. 3 more patients (9%) responded with minor responses common side-eect, with grade 1±2 occurring in 68% whilst disease stabilised in 6 patients (18%) during and grade 3±4 in 22% of the 37 patients. Grade 1±2 chemotherapy. Disease progressed in 6 (18%) patients.
anaemia occurred in 17 of 37 (46%), and grade 3 At a median observation time of 7.5 months (range: leucopenia was encountered in 8 patients (22%).
2±24+ months), the duration of response ranged Grade 3±4 thrombocytopenia occurred in 5 patients between 1 and 22+ months (median 5+ months). Dis- (14%). Other side-eects were generally mild or ease relapsed after 4, 6 and 8 months in 3 of the 8 patients (38%) who achieved CR whilst the remaining 5 patients are still alive and free of disease at 3, 5, 9, 12 Treatment outcome was analysed in relation to both pathological subtype and disease status at the start of Bilharzial bladder cancer represents a distinct clin- chemotherapy. Response rates were higher for patients icopathological entity that diers from the bladder can- with transitional cell carcinoma than for those with cer seen in Western countries in several aspects, squamous cell carcinoma, 60% (6/20 PR and 6/20 CR) including response to chemotherapy. In a series of phase and 50% (4/12 PR and 2/12 CR) respectively. However, II studies, beginning in 1976, several drugs were shown this dierence in response rates did not reach statistical to be active against the disease, including epirubicin (Ellence), vincristine (Oncovin), ifosfamide (Ifex), and In contrast, disease status at the start of chemother- etoposide (VePesid). However, very few durable CRs apy seemed to aect response to therapy (Table 2). 7 of were observed . A combination of the most active 16 evaluable patients whose primary tumour was not agents in bilharzial bladder cancer was also evaluated removed responded either partially (6 patients, 38%), or . Of 22 evaluable patients, only 1 (4.5%) had a CR completely (1 patient, 6%), for an overall response rate of 44%. However, 11 of 17 (65%) of those patients who To our knowledge, this is the ®rst investigation to presented with locally recurrent and/or metastatic dis- report the achievement of a 24% CR rate (8/33 patients) ease after surgical removal of the primary tumour amongst patients with advanced bilharzial-related blad- responded to therapy, partially in 4 (24%) and com- der cancer, although the overall response rate (55%) did pletely in 7 (41%) patients (P=0.4 and 0.02 for the dif- not dier markedly from that reported in the previously ferences in overall response and CR rates, respectively, mentioned phase II study, where a combination of the between the inoperable and resected patients).
drugs, epirubicin and vincristine alternating with eto- poside and ifosfamide  achieved an overall response However, the higher CR and overall response rates as Toxicity was analysed according to the Common well as the toxicity pro®le observed in our study are Toxicity Criteria scale. As shown in Table 3, the toxicity comparable with those reported using the same gemci- pattern was generally tolerable. No toxic deaths occur- tabine±cisplatin combination against advanced transi- red among the 37 patients. Vomiting was the most H.M. Khaled et al. / European Journal of Cancer 36 (2000) S34±S37 In the current study, pathological subtype did not signi®cantly aect response to therapy (P=0.5), although higher response rates were observed for 1. Sherif M, Ibrahim AS. The incidence of cancer in Egypt. In patients with transitional cell carcinoma compared with Sherif M, Ibrahim AS, eds. The Pro®le of Cancer in Egypt those who had squamous cell carcinoma. However, dis- (CRMCA). Cairo, Arab World Printing House, 1987, 179±190.
ease status at presentation signi®cantly aected the 2. El Sebai I. End results of treatment of cancer of the bilharzial ability to achieve CR, as patients with bulky disease bladder. In El Sebai I, ed. Bladder Cancer, vol. 2. Boca Raton, 3. Ghoneim M, El Mekresh M, El Baz M, El Attar I, Ashamallah One valuable observation that comes from the study A. Radical cystectomy for carcinoma of the bladder: critical eva- is the possibility that the gemcitabine±cisplatin com- luation of the results in 1026 cases. J Urol 1997, 158, 393±399.
bination may convert some patients' tumours from 4. Zaghloul MS. Distant metastasis from bilharzial bladder cancer.
inoperable to operable status. Moreover, the combina- 5. Gad El Mawla N, Hamza MR, Zikri ZK, et al. Chemotherapy in tion may be used as neoadjuvant as well as adjuvant invasive carcinoma of the bladder. A review of phase II trials in therapy in patients with T3 and T4 lesions. This might have a favourable eect on either the disease-free or 6. Khaled HM, Gad El Mawla N, El Said A, et al. Combination overall survival rates of patients with bilharzial bladder chemotherapy for advanced bilharzial bladder carcinoma. Ann cancer, or might at least increase the rate of bladder 7. Moore MJ, Tannock IF, Ernst DS, et al. Gemcitabine: a pro- preservation in such a group. To investigate these var- mising new agent in the treatment of advanced urothelial cancer.
ious possibilities, a randomised trial would be necessary in which gemcitabine±cisplatin neoadjuvant therapy is 8. von der Maase H, Anderson L, Crino L, et al. A phase II study of compared with radical surgery alone.
gemcitabine and cisplatin in patients with transitional cell carci- At the same time, gemcitabine-containing doublets or noma (TCC) of the urothelium. Proc Am Soc Clin Oncol 1997, triplets should be assessed in advanced cases to further 9. Hollander M, Wolfe DA. Nonparametric Statistical Methods.
increase response rates and improve treatment outcome
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