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 |
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Authors: | M I Koukourakis A Giatromanolaki S Kalokyris M Froudarakis V Georgoulias G Retalis N Bahlitzanakis |
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Institution: | (1) Department of Radiotherapy and Oncology, University Hospital of Heraklion, Iraklion, Crete, Greece;(2) Schering-Plough SA, Athens, Greece;(3) Department of Pneumology, Venizelion General Hospital, Iraklion, Crete, Greece;(4) Tumor and Angiogenesis Research Group, 18 Dimokratias Avenue, Iraklion, 71306 Crete, Greece |
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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 (480μg) 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 (50mg/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 60mg/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. |
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Keywords: | docetaxel carboplatin amifostine GM-CSF radiotherapy non-small cell lung |
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