3-Drug Treatment for Transitional Cell Carcinoma: Determining Dose and Schedule

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Transitional cell carcinoma remains a fairly prevalent disease and, when locally advanced, or metastatic, effective drug combinations have been useful. However, these combinations have been quite toxic and also approximately 50% of patients do not respond. In the current trial, three drugs (cisplatin, gemcitabine and docetaxel) are investigated at two dose levels. The, lower dose level, although associated with some toxicity, was shown to have significant anti-tumor activity for the majority of patients. The dose and schedule presented seems reasonable to be forwarded as recommended for phase II and III investigation.

Source: Tinker A, et al. A phase I dose finding study of cisplatin, gemcitabine, and weekly docetaxel for patients with advanced transitional cell cancer. Am J Clin Oncol. 2006;29:3-7.

The aim of this study was to determine the toxicity of a 3-drug regimen (cisplatin, gemcitabine, and docetaxel) for patients with advanced transitional cell carcinoma. To this end, Tinker and colleagues report the results from a phase I trial in which 13 patients were enrolled. The first 3 were treated at one dose level (cisplatin 70 mg/m2 on day 1; gemcitabine 1000 mg/m3 days 1 and 8; and docetaxel 30 mg/m2 days 1 and 8 every 21 days) and when dose limiting toxicity occurred the subsequent 10 received a lower dose of one of the drugs (gemcitabine 800 mg/m2 on days 1 and 8) with the doses of cisplatin (70 mg/m2 on day 1) and docetaxel (30 mg/m2 days 1 and 8) were maintained. The order of chemotherapy administration was docetaxel followed by gemcitabine and then cisplatin. Docetaxel and gemcitabine were administered over 30 minutes and cisplatin was administered over 1 hour with hydration. The plan was to enroll 3 patients at each dose level and the dose limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity (except nausea or vomiting) or hematologic toxicity defined as any grade 4 thrombocytopenia, or neutropenia defined as grade 4 toxicity lasting > 5 days in total duration or febrile neutropenia. If 1 patient at a dose level experienced DLT, additional patients were entered at that level to a planned maximum of 6 patients. If 2 patients experienced DLT, then accrual stopped at that level, with the next lower dose level declared the maximum tolerable dose (MTD). It was planned to add additional patients at the MTD to reach 10 patients. Objective response was evaluated after every second cycle.

At the first dose level, one of three patients experienced hematologic DLT (febrile neutropenia) and 2 experience non hematologic DLT (grade 3 diarrhea). At the lower dose level, 1 (of 10) patients experienced febrile neutropenia and 1 had grade 3 diarrhea. Hematologic toxicity at the lower dose included 2 (of 10) with grade 3 and 4 (of 10) with grade 4 neutropenia. Three patients developed grade 3 and 1 developed grade 4 thrombocytopenia. Most nonhematologic toxicity was mild or moderate. The most common toxicity was fatigue, reported in 10 of 13 patients.

Of the 13 patients, 11 received a minimum of two cycles and were thus evaluable for treatment response. At the initial dose level, 2 (of 3) patients achieved a complete response (CR) and at the lower dose level 1 patient achieved CR, 5 patients had PR and 3 had stabilization of disease. Thus, for all evaluated patients, 8 out of 11 had a confirmed response. The median duration of response, measured from the first day of treatment until date of last follow-up, or to first evidence of disease progression was 10.3 months. AT the time of publication, eight patients were alive and median survival had not been reached.

Commentary

The trial was designed as an open label, multicenter, nonrandomized phase I dose finding study of gemcitabine and cisplatin with weekly docetaxel on a 21 day schedule in patients with advanced transitional cell carcinoma (TCC). Currently, the standard chemotherapy approach is a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) which has produced response rates of 40-50%1 but is associated with considerable toxicity (mucositis and neutropenia).2 Docetaxel and gemcitabine have single-agent activity and when combined with platinum analogues (cisplatin or carboplatin) response rates have been as high as 60% and with less toxicity.3-5 Thus, a strategy has been proposed to use the triplet (cisplatin, gemcitabine and docetaxel) as first line metastatic TCC treatment to improve overall response rate and survival. The drugs, however, have some overlapping toxicities and a dose finding trial, prior to phase II and III investigations was warranted.

This brief report is notable for several reasons. Among these are that the research achieved its goal of defining a reasonable dose and schedule for future investigation. The three drug combination seems a reasonable approach to realizing a more effective treatment for metastatic or locally-advanced TCC. However, it remains to be seen whether this provides advantage over doublets of cisplatin with either gemcitabine or docetaxel.

Additionally, the paper is a fine example of well articulated clinical trial methodology. This was a well conceived and designed investigation and the results were clearly presented. The paper is a fine example for those interested in the design of clinical trials and would be a useful, in this regard for medical oncology fellows and others who are learning the nuances of drug development and combination chemotherapy.

References

1. Loehrer PJ Sr, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066-1073; Erratum in: J Clin Oncol. 1993;11:384.

2. Saxman SB, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997;15:2564-2569.

3. Moore MJ, et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17:2876-2881.

4. Dreicer R, et al. Phase II study of cisplatin and paclitaxel in advanced carcinoma of the urothelium: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 2000;18:1058-1061.

5. Redman BG, et al. Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol. 1998;16:1844-1848.