Gemcitabine and cisplatin in locally advanced and/or metastatic bladder cancer

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Abstract

Although transitional cell carcinoma of the urothelium is chemosensitive, long-term disease-free survival is low. Accordingly, interest has focused on combining classically active agents like cisplatin with promising new drugs. Gemcitabine has evoked interest not only because of its intrinsic activity against this cancer, but also because of its effect of inhibiting repair of DNA that has been damaged by drugs like cisplatin. Four phase II studies have assessed the effect of a gemcitabine–cisplatin combination on advanced or metastatic bladder cancer. All the studies employed a gemcitabine dose of 1000 mg/m2 given on days 1, 8 and 15, whereas the cisplatin dose and schedule varied, with total doses ranging from 70 to 105 mg/m2. Overall response rates in these studies ranged from 42 to 66%, with complete responses from 15 to 28%. Toxicities, which were primarily haematological, were generally manageable. This promising two-drug combination has been compared with the standard MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) in a randomised phase III trial and the results are eagerly anticipated.

Introduction

Transitional cell carcinoma (TCC) of the urothelium is considered a chemosensitive tumour. None the less, chemotherapy confers only a modest survival benefit to these patients, and metastatic disease remains essentially incurable with only a small number of patients achieving long-term disease control.

A number of available drugs have significant single-agent activity against urothelial cancer, including cisplatin, methotrexate, doxorubicin, vinblastine, ifosfamide, and, more recently, gemcitabine and paclitaxel. Despite this activity, however, single-agent treatment generally achieves only partial responses (PRs) of short duration (median, 3–4 months).

Combination chemotherapy for advanced and metastatic TCC of the urothelium has been based most often on the most active single agents, cisplatin and methotrexate, which yield single-agent response rates of 30–35% [1]. As previously mentioned the MVAC combination (methotrexate, vinblastine, doxorubicin, cisplatin) is considered the standard for treatment of metastatic bladder cancer [2] with response rates of 40–72% 3, 4, 5, 6, 7, 8 and median survival times of 12–13 months 9, 10. In a recent long-term study, however, only 3.7% of patients randomised to MVAC were alive and continuously disease free at 6 years [11]. The regimen is also associated with considerable treatment-related toxicity.

For these reasons, developing more effective and less toxic drug regimens to treat patients with TCC of the urothelium is vital. In this regard, gemcitabine has shown promising activity, with overall response rates of approximately 25% and complete response (CR) rates of approximately 10% 12, 13, 14; toxicity, particularly myelosuppression, is mild.

Section snippets

Gemcitabine and cisplatin in patients with locally advanced or metastatic bladder cancer

The encouraging activity and tolerability of single-agent gemcitabine, coupled with its synergistic potential to inhibit DNA repair after a cell has been exposed to DNA-damaging agents like cisplatin [15], made it logical to study the combination of gemcitabine and cisplatin. Table 1 shows efficacy data from four phase II trials of this combination given to patients with locally advanced or metastatic TCC 16, 17, 18, 19.

In the first phase II study, a European study, our group administered

Conclusion

Gemcitabine and cisplatin represent an encouraging two-drug combination in patients with locally advanced or metastatic TCC of the urothelium. Toxicities are generally manageable although the weekly cisplatin schedule resulted in a high degree of grade 3–4 neutropenia and thrombocytopenia. Thus, cisplatin doses of 75 or 70 mg/m2 given every 28 days as opposed to the weekly schedule appears to be the optimal cisplatin schedule for the combination.

The four phase II studies of gemcitabine plus

References (19)

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