Maximum Tolerated Dose - Results of Phase I Trial of Weekly Paclitaxel and Cisplatin with Radiation Therapy in Carcinoma Cervix

Abstract

Purpose/Objective(s)Cisplatin based chemoradiation therapy is the standard treatment for locally advanced carcinoma cervix. Recent studies have shown better response rates with treatment using newer regimens administered along with radiation therapy. We conducted a Phase I study, to establish the Maximal Tolerated Dose (MTD) of paclitaxel in combination with cisplatin as radiosensitizer in the treatment of carcinoma cervix and to analyze the toxicity profile of the combination regimen.Materials/MethodsPatients with squamous cell carcinoma cervix stage (FIGO) I B to III B with good Zubrod's score (ECOG 0, 1) and normal hepatic and renal parameters were accrued for the study. Enrollment was done in cohorts of 3 patients at each level. External beam pelvic radiation therapy (50 Gy/25#) was given by conventional 4 field box technique followed by a single LDR brachytherapy application (25-30 Gy). Concurrent chemotherapy was delivered with 4 weekly cycles of cisplatin (30 mg/m2) and an escalating dose (according to the modified Fibonacci series) of paclitaxel starting at 10 mg/m2 and increasing by 10 mg/m2/level. During treatment, weekly clinical and blood investigations for hematological and biochemical toxicity (according to CTCv3) evaluation was done. Full evaluation was done 6 weeks after completion of brachytherapy. The study was carried out after clearance by the Institution review board. Informed consent was obtained from each patient.ResultsBetween November 2006 and November 2007, 21 patients with newly diagnosed cervical cancer, were enrolled for the study. Patients had a median age of 43 years, range - 24-59 years and FIGO stage IB (n = 3), stage II B (n = 11), stage III B (n = 7). The MTD of weekly paclitaxel along with cisplatin was determined as 40 mg/m2. The dose limiting toxicities (DLT) that occurred at a dose of 50 mg/m2 weekly paclitaxel were grade 3 proctitis and vaginitis. The patient with grade 3 vaginitis discontinued the treatment at 44 Gy and was lost for follow-up. Treatment related diarrhea was grade 2 in all levels. Maximum hematological toxicity was grade 2 leucopenia and neutropenia. Grade 3 dermatitis was present in all levels (not considered as SAE). The maximum overall treatment time in the MTD level was 58 days. Complications considered unrelated to treatment were grade 3 diarrhea in 2 patients due to Vibrio cholera infection. One patient in level 5 developed non neutropenic pulmonary infection and died of septicemia.ConclusionsIn this Phase I trial of concurrent chemoradiation with weekly Paclitaxel and cisplatin (30 mg/m2) in patients with carcinoma cervix, the Maximum Tolerated Dose (MTD) of paclitaxel was identified as 40 mg/m2. This regimen had an acceptable toxicity profile and can be the recommended dose level in designing phase II studies. Purpose/Objective(s)Cisplatin based chemoradiation therapy is the standard treatment for locally advanced carcinoma cervix. Recent studies have shown better response rates with treatment using newer regimens administered along with radiation therapy. We conducted a Phase I study, to establish the Maximal Tolerated Dose (MTD) of paclitaxel in combination with cisplatin as radiosensitizer in the treatment of carcinoma cervix and to analyze the toxicity profile of the combination regimen. Cisplatin based chemoradiation therapy is the standard treatment for locally advanced carcinoma cervix. Recent studies have shown better response rates with treatment using newer regimens administered along with radiation therapy. We conducted a Phase I study, to establish the Maximal Tolerated Dose (MTD) of paclitaxel in combination with cisplatin as radiosensitizer in the treatment of carcinoma cervix and to analyze the toxicity profile of the combination regimen. Materials/MethodsPatients with squamous cell carcinoma cervix stage (FIGO) I B to III B with good Zubrod's score (ECOG 0, 1) and normal hepatic and renal parameters were accrued for the study. Enrollment was done in cohorts of 3 patients at each level. External beam pelvic radiation therapy (50 Gy/25#) was given by conventional 4 field box technique followed by a single LDR brachytherapy application (25-30 Gy). Concurrent chemotherapy was delivered with 4 weekly cycles of cisplatin (30 mg/m2) and an escalating dose (according to the modified Fibonacci series) of paclitaxel starting at 10 mg/m2 and increasing by 10 mg/m2/level. During treatment, weekly clinical and blood investigations for hematological and biochemical toxicity (according to CTCv3) evaluation was done. Full evaluation was done 6 weeks after completion of brachytherapy. The study was carried out after clearance by the Institution review board. Informed consent was obtained from each patient. Patients with squamous cell carcinoma cervix stage (FIGO) I B to III B with good Zubrod's score (ECOG 0, 1) and normal hepatic and renal parameters were accrued for the study. Enrollment was done in cohorts of 3 patients at each level. External beam pelvic radiation therapy (50 Gy/25#) was given by conventional 4 field box technique followed by a single LDR brachytherapy application (25-30 Gy). Concurrent chemotherapy was delivered with 4 weekly cycles of cisplatin (30 mg/m2) and an escalating dose (according to the modified Fibonacci series) of paclitaxel starting at 10 mg/m2 and increasing by 10 mg/m2/level. During treatment, weekly clinical and blood investigations for hematological and biochemical toxicity (according to CTCv3) evaluation was done. Full evaluation was done 6 weeks after completion of brachytherapy. The study was carried out after clearance by the Institution review board. Informed consent was obtained from each patient. ResultsBetween November 2006 and November 2007, 21 patients with newly diagnosed cervical cancer, were enrolled for the study. Patients had a median age of 43 years, range - 24-59 years and FIGO stage IB (n = 3), stage II B (n = 11), stage III B (n = 7). The MTD of weekly paclitaxel along with cisplatin was determined as 40 mg/m2. The dose limiting toxicities (DLT) that occurred at a dose of 50 mg/m2 weekly paclitaxel were grade 3 proctitis and vaginitis. The patient with grade 3 vaginitis discontinued the treatment at 44 Gy and was lost for follow-up. Treatment related diarrhea was grade 2 in all levels. Maximum hematological toxicity was grade 2 leucopenia and neutropenia. Grade 3 dermatitis was present in all levels (not considered as SAE). The maximum overall treatment time in the MTD level was 58 days. Complications considered unrelated to treatment were grade 3 diarrhea in 2 patients due to Vibrio cholera infection. One patient in level 5 developed non neutropenic pulmonary infection and died of septicemia. Between November 2006 and November 2007, 21 patients with newly diagnosed cervical cancer, were enrolled for the study. Patients had a median age of 43 years, range - 24-59 years and FIGO stage IB (n = 3), stage II B (n = 11), stage III B (n = 7). The MTD of weekly paclitaxel along with cisplatin was determined as 40 mg/m2. The dose limiting toxicities (DLT) that occurred at a dose of 50 mg/m2 weekly paclitaxel were grade 3 proctitis and vaginitis. The patient with grade 3 vaginitis discontinued the treatment at 44 Gy and was lost for follow-up. Treatment related diarrhea was grade 2 in all levels. Maximum hematological toxicity was grade 2 leucopenia and neutropenia. Grade 3 dermatitis was present in all levels (not considered as SAE). The maximum overall treatment time in the MTD level was 58 days. Complications considered unrelated to treatment were grade 3 diarrhea in 2 patients due to Vibrio cholera infection. One patient in level 5 developed non neutropenic pulmonary infection and died of septicemia. ConclusionsIn this Phase I trial of concurrent chemoradiation with weekly Paclitaxel and cisplatin (30 mg/m2) in patients with carcinoma cervix, the Maximum Tolerated Dose (MTD) of paclitaxel was identified as 40 mg/m2. This regimen had an acceptable toxicity profile and can be the recommended dose level in designing phase II studies. In this Phase I trial of concurrent chemoradiation with weekly Paclitaxel and cisplatin (30 mg/m2) in patients with carcinoma cervix, the Maximum Tolerated Dose (MTD) of paclitaxel was identified as 40 mg/m2. This regimen had an acceptable toxicity profile and can be the recommended dose level in designing phase II studies.