Phase I/II dose escalation study of docetaxel and carboplatin combination supported with amifostine and GM-CSF in patients with incomplete response following docetaxel chemo-radiotherapy: additional chemotherapy enhances regression of residual cancer

Taxanes have been shown to interact with anti-apoptotic proteins. In the pr esent study we investigated whether the addition of taxane in combination w ith DNA damaging drugs can further enhance tumor shrinkage in cases with in complete response to radiotherapy. Since the dose of docetaxel in combinati on with carboplatin is not known, the above hypothesis was tested in the co ntext of a dose escalation phase I study. Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following docetaxel radio-chem otherapy, were recruited in a dose escalation protocol of docelaxel/carbopl atin supported with amifostine and GM-CSF. The starting dose of docetaxel w as 40 mg/m(2) every 2 weeks. Carboplatin dose was calculated using the Calv ert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel do se was increased to 50 and 60 mg/m(2), while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (60 0 mg/m(2)) was administered i.v. before carboplatin and GM-CSF (480 mu g) w as injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were giv en and response was assessed 2 weeks after the end of chemotherapy. None out of four patients treated in the 6th dose level cohort (50 mg/m(2) of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2-4 he matologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg e dema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4-12% of patients. Out of four patients treated in a 7th cohort (docetaxel 60 mg/m(2) and carboplatin AUC4), one developed grade IV neutro penia and two developed grade 3 severe asthenia requiring treatment delay f or 2 weeks. Out of 11 patients with PR following docetaxel radio-chemothera py, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy sho wed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m(2)) and carboplatin (AUC4) chemothera py can be safely administered on a two-weekly basis if supported with amifo stine and GM-CSF. Such an additional therapy may be important in patients w ith incomplete response after chemo-RT Broad spectrum cytoprotection with a mifostine and GM-CSF may also contribute to the reduction of incidence of n eurosensory reactions and asthenia In patients treated with taxanes.