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

Abstract

Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in the context 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-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine and GM-CSF. The starting dose of docetaxel was 40 mg/m2 every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m2, while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m2) was administered i.v. before carboplatin and GM-CSF (480 microg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were given 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/m2 of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2-4 hematologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg edema, 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/m2 and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m2) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF. Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients treated with taxanes.

Phase II Randomized Study of Dose-Dense Docetaxel and Cisplatin Every 2 Weeks With Pegfilgrastim and Darbepoetin Alfa With and Without the Chemoprotector BNP7787 in Patients With Advanced Non-small Cell Lung Cancer (CALGB 30303)

“…6 Phase I and II studies of docetaxel plus another drug (carboplatin, vinorelbine, or gemcitabine) every 2 weeks have resulted in high objective response rates but dose-limiting neutropenia and neurosensory toxicity. [7][8][9] Although the use of filgrastim reduces the limitation of neutropenia, neurotoxicity remains a concern. BNP7787 (disodium 2, 2Ј-dithio-bisethane sulfonate) was developed as a novel putative chemoprotective agent.…”

<p>A Nomogram for the Prognosis of Nasopharyngeal Carcinoma with MR Imaging-Detected Tumor Residue at the End of Intensity-Modulated Radiotherapy</p>

“…15 Therefore, it is recommended that the curative effect be evaluated 3 months post-treatment, and the patients that are identified as having residual NPC should be treated again. 16 In this study, 162 patients with NPC had a local or regional residual tumor at the end of IMRT, 62 of which achieved complete remission within 3 months, and 51 of them achieved complete remission within 6 months. Some patients had complete remission for more than 6 months.…”

Concurrent administration of Docetaxel and Stealth® liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection

“…Grade 2 neutropenia was to be immediately followed by GM -CSF support (400 mg s.c. every Saturday and Sunday). This supportive regimen, established in previously published studies of ours (Koukourakis et al, 1998b(Koukourakis et al, , 2001), effectively protected from neutropenia patients receiving concurrent chemo -radiotherapy using a high dose of carboplatin fractionated regimen or docetaxel/carboplatin chemotherapy. In the present study, the adoption of this GM -CSF regimen immediately following the documentation of a grade 2 neutropenia, would potentially allow the elimination of neutropenia as a dose limiting toxicity factor.…”