Original article. C. Shannon, C. Crombie, A. Brooks, H. Lau, M. Drummond & H. Gurney

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Annals of Oncology : 97-9.. Kluwer Academic Publishers. Printed in the Netherlands.

1 Annals of Oncology : Kluwer Academic Publishers. Printed in the Netherlands. Original article Carboplatin and gemcitabine in metastatic transitional cell carcinoma of the urothelium: Effective treatment of patients with poor prognostic features C. Shannon, C. Crombie, A. Brooks, H. Lau, M. Drummond & H. Gurney Department of Medical Oncology and Palliative Care, Westmead Hospital. Sydney, Australia Summary Purpose: To evaluate the activity and toxicity of gemcitabine and carboplatin in consecutive patients presenting with locally advanced or metastatic transitional cell carcinoma of the urothelium (TCC). Patients and methods: Seventeen consecutive patients referred to a single institution with locally advanced or metastatic TCC were treated with carboplatin AUC on day and gemcitabine mg/m on day and 8 of a -day cycle. All patients were assessable for response and toxicity. Minimal eligibility criteria were used to minimize patient selection. Results: Seventeen patients with measurable stage IV TCC of the urothelium were treated. The median age was 9 years (range -78), the median creatinine clearance was ml/min (range -9) and % of patients had an ECOG performance score of two. Nine patients (%) had visceral metastases and the majority of patients had multiple sites of metastases. There were three complete responses, seven partial responses, for an overall response rate of 8.8%. Responses were seen at all sites including the liver. One patient had a response within a previously irradiated field and three patients with prior chemotherapy had responses. Median overall survival was. months and median time to progression was. months. Toxicity was primarily haematologic with six patients having grade neutropenia and six patients with grade neutropenia. There were five cases of grade and three cases of grade thrombocytopenia. There were no episodes of febrile neutropenia and only one patient required admission for management of toxicity. Thirteen patients required dose reduction or delay due to neutropenia or thrombocytopenia. There were no treatmentrelated deaths. Conclusion: The combination of carboplatin and gemcitabine is active in metastatic transitional cell carcinoma of the urothelium with manageable toxicity in a relatively elderly group of patients with some poor prognostic features. Key words: carboplatin, gemcitabine, urothelial carcinoma Introduction Transitional cell carcinoma (TCC) of the urothelium mostly occurs in elderly men and women. The median age of patients presenting with TCC of the bladder in Australia in 99 was 7 years []. Often these patients have poor renal function and poor performance status []. For much of the last fifteen years the standard chemotherapy for this disease has been a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) which has an overall response rate of %- 7% and a median survival of months and is superior to cisplatin alone or other cisplatin-based combinations [-]. MVAC is toxic with a treatment-related death rate of up to % and a neutropenic sepsis rate of % and is difficult to give to patients who are elderly, and those who have impaired performance status or renal function []. Llado et al. recently predicted that approximately half of all patients presenting with TCC of the urothelium would be ineligible for cisplatin-based regimens based on their poor performance status and impaired creatinine clearance []. Carboplatin has several advantages over cisplatin in the palliative setting. Its more favourable toxicity profile and the ability to attain more predictable haematological toxicity by dosing to AUC make it a good alternative in patients with imperfect renal function. Single agent carboplatin has response rates ranging from 8%-8% in TCC of the urothelium [-8]. However, attempts have failed to make cisplatin combination treatment less toxic but with similar activity by replacing cisplatin with carboplatin in the combination [9,]. Gemcitabine, a new nucleoside analogue, has shown promising activity in TCC of the urothelium. Single agent response rates of % 8% have been reported even in previously treated patients [-]. Gemcitabine is well tolerated and therefore an ideal candidate for combination with other active agents. A recently published phase trial comparing gemcitabine and cisplatin with MVAC showed no significant differences in overall survival or response rates []. The cisplatin and gemcitabine arm had significantly better safety profile and tolerability prompting a call for this combination to become the standard of care for these patients. However, the presence of cisplatin in this combination still makes a significant proportion of patients with TCC ineligible for this treatment.

98 The current study was designed to examine the efficacy and toxicity of carboplatin and gemcitabine in patients with metastatic TCC of the urothelium.

2 98 The current study was designed to examine the efficacy and toxicity of carboplatin and gemcitabine in patients with metastatic TCC of the urothelium. Since carboplatin can be dosed using GFR and gemcitabine is not renally excreted, this combination is attractive in patients with urothelial cancer who often have impaired renal function. The combination of carboplatin and gemcitabine has been evaluated in the setting of nonsmall-cell lung cancer (NSCLC) and has demonstrated manageable toxicity [, 7]. Data from phase II trials in NSCLC show that a -day schedule with gemcitabine on day one and eight is less toxic than a 8-day schedule with gemcitabine on day, 8 and with no apparent compromise of efficacy and this schedule was selected for this study [8. 9]. priate. All patients who received at least one dose were assessable for toxicity and those receiving at least two cycles were assessable for response. Overall survival was measured from the date of study entry until death and time to progression was measured from the date of study entry until progression or death. Standard WHO criteria were used to assess response. Response criteria were as follows: ) complete response was defined as the disappearance of all known disease; ) partial response was defined as a decrease of % or greater in the total cross-sectional area of measurable lesions, and ) progressive disease was defined as a % or greater increase in the overall sum of measurable lesions compared with baseline. Patients who achieved a response were re-scanned after a further three cycles of chemotherapy to confirm their response. Criteria for stopping treatment included tumour progression, serious toxicity or patient request. Following completion of treatment patients were assessed every three months until disease progression or death. Patients and methods Patients This was a pilot study of patients had locally advanced or metastatic transitional cell carcinoma of the bladder, ureter or renal pelvis. Wide entry criteria were adopted in seventeen sequential patients referred for treatment. Patients were required to have histologically or cytologically proven TCC and measurable disease. Prior cytotoxic treatment either in the adjuvant setting or for metastatic disease was permitted if the treatment had been completed at least six months prior to enrollment in the study. Prior radiotherapy was permitted but must have been completed at least six weeks prior to enrollment. Patients were required to have a performance status (Eastern Cooperative Oncology Group) of three or less and have adequate bone marrow reserve (WBC count >. x IO 9 /, platelets > x 9 /l, and haemoglobin > log/dl). There were no restrictions with regard to hepatic function or creatinine clearance. Exclusion criteria included known CNS metastases, pregnancy and prior malignancy (except in situ carcinoma of the cervix or treated basal cell carcinoma of the skin) within five years. Treatment schedule Patients were treated on an outpatient basis. Gemcitabine. mg/m was given by intravenous infusion over minutes on day I and 8 of a -day cycle. Carboplatin dosed to an AUC of was given as an intravenous infusion over one hour on day I of a -day cycle. Creatinine clearance was determined by using serum creatinine and the Cockcroft and Gault formula [], Day eight Gemcitabine was omitted if the neutrophil count was <.x 9 /l or platelet count < x 9 /l Carboplatin dose was adjusted for renal function with each cycle. The dose of both drugs was reduced % % if the patient had developed grade or neutropema or thrombocytopenia in the previous cycle. Patients were reviewed every three weeks for toxicity. All toxicity was recorded according to WHO criteria A complete blood count and differential were performed on day and 8 of all cycles and on day of the first cycle. Dose of gemcitabine was increased by % to % if the nadir neutrophil count was >. x IO 9 /. Cycles were delayed one week if the absolute neutrophil count was <l. x 9 /l or platelets < x IO 9 /. Blood transfusions, anti-emetics and analgesics were administered as appropriate Patients received a maximum of six cycles unless they developed progressive disease or toxicity unacceptable to the patient Outcome evaluation Patients were evaluated for response after every three cycles with physical examination, computed tomography or chest X-ray as appro- Results Patient characteristics From June 998 to October 999, all patients seen at Westmead Hospital with advanced TCC were treated on this protocol. Seventeen patients were treated and all are assessable for toxicity and response. One patient had a resection of residual disease following a partial response and was not included in the survival analysis. This analysis was completed in July. Table provides a summary of patient's baseline characteristics. Patient age ranged from -78 years with a median age of 9 years. The majority (7.%) of patients had the bladder as the primary site of disease. Nine patients (.9%) had visceral sites of metastases (liver or lung) and eleven patients (.7%) had multiple sites of metastatic disease. Two patients had locally advanced tumour in the bladder as their only site of disease (both Tb). Three patients had previously received adjuvant or neoadjuvant chemotherapy and one patient had previously received chemotherapy for metastatic disease. Three patients had previously received radiotherapy to the pelvis. The study group included patients with relatively poor renal function. Calculated creatinine clearance ranged from ml/min to 9 ml/min with a median creatinine clearance of. ml/min. Fourteen of seventeen patients had a creatinine clearance of < ml/min. Study treatment Patients received a median number of five cycles of chemotherapy (range -). Of the seventeen patients entered on the study seven patients completed six cycles of treatment. Six patients stopped treatment due to disease progression, two patients stopped due to toxicity and two patients were deemed to have had adequate treatment after five cycles. The day 8 dose of gemcitabine was omitted on out of a total of 8 cycles due to neutropenia or thrombocytopenia. Two patients had cycle delays due to prolonged neutropenia or thrombocytopenia. Dose reductions

3 99 Table I. Patient characteristics (n = 7) Characteristic Age Range -78 years Median 9 years Sex Male Female Performance status Primary site Bladder Renal pelvis Ureter Metastatic site Liver Lung Bone Para-aortic lymph nodes Pelvis/bladder Pleura/soft tissue Multiple sites of metastatic disease Creat clearance, range -9 ml/min (median ) > ml/min < ml/min Previous treatment Chemotherapy Pelvic radiotherapy Number of patients (%) 8 8 were required in seven patients due to grade or neutropenia or thrombocytopenia in the previous cycle. Fifteen patients (88.%) received at least 8% of the planned dose of carboplatin and eleven patients (%) received at least 8% of the planned dose of gemcitabine. One patient had a dose increase due to an inadequate nadir neutrophil count. Tumour response In the 7 patients assessable for response there were (7.%) complete responses and 7 (.%) partial responses for an overall response rate of of 7 or 8.8%. In addition three patients (7.%) had stable disease and four patients (.%) had progressive disease. Two patients who had previously had adjuvant chemotherapy had partial responses and the one patient who had previously had MVAC for metastatic disease had a partial response. Two of the three patients who had previously had pelvic radiotherapy had a partial response and one of these was confined to within the radiation field. Among the nine patients with visceral disease there were four partial responses, one stable disease and four patients with progressive disease. With a median follow-up of 8. months (range -9 months) there are eight patients still alive. The estimated median time to disease progression was. months (9% confidence interval (9% CI):.8-8. months) (Figure ). The Kaplan-Meier estimate of the median overall survival was. months (9% CI:.-.9 Number at Risk Figure I Time to progressive disease. Months

4 9 o.x - - Q. CJ Nunibei al Risk I I Months Figure. Overall survival. months) (Figure ). One patient was excluded from the calculation of time to progression and overall survival because she had resection of residual disease in the bladder following a partial response to chemotherapy. She remains alive and free of disease. Adverse events The major toxicity encountered with this regimen was haematological. Table contains a list of the worst toxicity encountered for each patient. Twelve (7%) of seventeen patients had grade or granulocytopenia and eight (7%) of 7 patients had grade or thrombocytopenia. There were no admissions for neutropenic sepsis and no treatment related deaths. One patient had minor epistaxis but was concurrently anticoagulated for deep venous thrombosis. Four patients required platelet transfusions and eight patients required red blood cell transfusions. Only patient was admitted as the result of toxicity with prolonged emesis. There was no renal toxicity. One patient had moderate mucositis and two patients had grade emesis. Study treatment was discontinued in two patients because of toxicity. Discussion This phase study demonstrates that carboplatin and gemcitabine have significant activity against advanced TCC of the urothelium with manageable toxicity in a group of patients with relatively poor prognostic factors and that are typical for this disease. Patients on this study were elderly (median age 9 years), had relatively poor Table. Worst grade of toxicity (per patient) Toxicity Neutropenia Thrombocytopenia Anaemia Nausea and emesis Mucositis Lethargy Grade Grade Grade Grade renal function (median creatinine clearance ml/min), and a significant proportion had visceral metastases (%) and poor performance status (% ECOG ). All patients referred to Westmead Hospital with advanced urothelial TCC during the period of the study were treated on this protocol. No patient was excluded because of age or other prognostic feature and so this study group accurately reflects patients seen in clinical practice. Despite these relatively poor clinical characteristics the treatment was well tolerated. Although a significant proportion of patients had some haematological toxicity there were few clinical sequelae. Only one patient was admitted as a result of toxicity, attesting to the practicality of using this schedule in the outpatient setting. There were no cases of neutropenic sepsis. The median number of cycles given was and all 7 patients had at least two cycles of treatments. These data indicate that the doses selected for this combination were suitable for this group of patients. This data is distinct from published series of the 'gold standard' MVAC where patients are younger and have

9 Table. Comparison of M VAC and gemcitabine combination studies. Treatment Carboplatin + gemcitabine MVAC phase II [] MVAC phase III [] Cisplatin + gemcitabine phase II [] Cisplatin + gemcitabine vs.

5 9 Table. Comparison of M VAC and gemcitabine combination studies. Treatment Carboplatin + gemcitabine MVAC phase II [] MVAC phase III [] Cisplatin + gemcitabine phase II [] Cisplatin + gemcitabine vs. MVAC [] Median age (years) ECOG > Response rate Median survival (months) 9 % 8.7%. ns 7% ns ns 9%. 9 % 7%. 9% a.7%-9.%.8-.8 Abbreviation: ns - not stated. a Karnofsky performance score < 8. a better performance status than an unselected TCC population. The median age of patients in phase II and III studies of MVAC is to years and patients with moderately poor performance status were excluded from these studies [-, ]. Table compares selected prognostic and outcome data from the current study and the major studies of MVAC and gemcitabine/cisplatin [,,, ]. Although the median survival is lower in the current study, age and performance status, two major prognostic factors, are also worse. These results using carboplatin and gemcitabine are also similar to published phase II response rates using other combination of the newer agents such as carboplatin/paclitaxel (.7%-%) or gemcitabine/paclitaxel (%-%) [-]. This pilot study clearly shows significant activity and an acceptable toxicity profile of this combination in an unselected group of patients with this disease. Of considerable importance is that all patients had a sufficient cumulative dose to adequately test the chemosensitivity of their tumour, which would be difficult to achieve using a more toxic regimen. This combination warrants further study as it can be applied to patients with poor performance status and those with imperfect renal function. Given the relatively short overall survival and time-to-disease progression from this regimen, it may not be suitable for patients with good performance status and renal function who may withstand more aggressive treatment. A larger randomized phase II study of carboplatin and gemcitabine or docetaxel and gemcitabine is underway at this institution. References. Australian Institute of Health and Welfare. Cancer in Australia 99.. Llado A, Bellmunt J, Kaiser G et al A dose finding study of carboplatin with fixed doses of gemcitabine in 'unfit' patients with advanced bladder cancer. Proc Am Soc Clin Oncol (Abstr ).. Sternberg CN, Yagoda A, Scher HI et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer 989; Loehrer PJ, Einhorn LH, Elson PJ et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine. and doxorubicin in patients with metastatic urothelial carcinoma. A cooperatinve group study. J Clin Oncol 99; (7) Logothetis CJ, Dexeus FH. Finn L et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 99; 8: -.. Raabe NK, Fossa SD, Paro G. Phase II study of carboplatin in locally advanced and metastatic transitional cell carcinoma of the urinary bladder. Br J Urol 989; : WaxmanJ. Barton C. Carboplatin-based chemotherapy for bladder cancer. Cancer Treat Rev 99: 9 (Suppl C): Bellmunt J, Albanell J. Gallego O et al. Carboplatin. methotrexate, and vinblastine in patients with bladder cancer who were ineligible for cisplatin-based chemotherapy. Cancer 99; 7: Bellmunt J, Ribas A, Eres N et al. Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 997: 8: 9-7. Small EJ, Fippin LJ, Ernest JL, Carroll PR. A carboplatin-based regimen for the treatment of patients with advanced transitional cell carcinoma of the urothelium. Cancer 99: 78: Petrioli R, Frediam B. Manganelh A et al. Comparison between a cisplatin-containing regimen and a carboplatin-contaimng regimen for recurrent or metastatic bladder cancer patients. Cancer 99; Moore MJ, Tannock IF. Ernst KS et al. Gemcitabine: A promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 997; : -.. StadlerWM. Kuzel T. Roth B et al. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer J Clin Oncol 997: : Pollera CF, Ceribelli A. Crecco M. Calabresi F. Weekly gemcitabine in advanced bladder cancer: A preliminary report from a phase I study. Ann Oncol 99; : 8-.. Lorusso V. Pollera CF, Antimi M et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum Eur J Cancer 998; : 8-. Von der Maase H, Hansen SW. Roberts JTet 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 ; 7: Carmichael J, Allerheiligen S, Walling J. A phase study of gemcitabine and carboplatin in non-small-cell lung cancer. Semin Oncol 99; IaflTaioli RV, Tortoriello A. Facchim G et al. Phase I II study of gemcitabine and carboplatin in stage IIIB-IV non-small-cell lung cancer. J Clin Oncol 999; 7: Carrato A, Alberola V, Massuti B et al. Combination of gemcitabine and carboplatin as first line treatment in non-small-cell lung cancer (NSCLC) Ann Oncol 998; 9: 89 (Abstr P).. Langer CJ. Gandara DR. Calvert P et al. Gemcitabine and carboplatin in combination: An update on phase I and phase II studies in non-small-cell lung cancer. Semin Oncol 999: -8.. Cockcroft DW. Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 97; (): -.

6 9. Moore MJ, Winquist EW, Murray N et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer' A phase II trial of the national institute of Canada clinical trials group. J Clin Oncol 999; 7: Redman BG. Smith DC, Flaherty L et al. Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma J Clin Oncol 998; : Small EJ. Lew D, Redman BG et al. Southwest oncology group study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: The importance of survival as a clinical trial end point. J Clin Oncol ; : 7-.. Vaughn DJ, Malcowicz SB, Zoltick B et al. Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: An active and tolerable outpatient regimen. J Clin Oncol 998; : -. Meluch A, Greco A. Burris H et al. Gemcitabine and paclitaxel in combination for advanced transitional cell carcinoma of the urothelial tract: A trial of the Minnie Pearl Research Network. Proc Am Soc Clin Oncol 999; 8: 7a (Abstr 8). 7. Marim L, Sternberg C, Sella A et al. A new regimen of gemcitabine and paclitaxel in previously treated patients with advanced transitional cell carcinoma Proc Am Soc Clin Oncol 999; 8: a (Abstr ). Received November ; accepted March. Correspondence to H. Gurney, MB, BS, FRACP Department of Medical Oncology and Palliative Care Westmead Hospital Westmead, Australia howardg@westgate.wh.usyd.edu.au

symposium article introduction symposium article

symposium article introduction symposium article Annals of Oncology 17 (Supplement 5): v118 v122, 2006 doi:10.1093/annonc/mdj965 Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/ vinblastine/doxorubicin/cisplatin