Dose-finding study of oxaliplatin associated to capecitabine-based preoperative chemoradiotherapy in locally advanced rectal cancer.

Gemma Bruera,Pierluigi Bonfili,Antonio Galvano,Mario Di Staso,Roberto Vicentini,Enrico Ricevuto,Ernesto Di Cesare,Gino Coletti,Rosa Manetta,Corrado Ficorella,Stefano Guadagni,Antonio Russo

doi:10.18632/oncotarget.24665

Gemma Bruera, Pierluigi Bonfili + Show 10 more

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https://doi.org/10.18632/oncotarget.24665

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Abstract

IntroductionProper administration timing, dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform two-drugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC). This dose-finding study investigated recommended oxaliplatin dose, safety of oxaliplatin/capecitabine regimen and preliminary activity.MethodsSchedule: oxaliplatin dose-levels, 35-40 mg/m2/week; capecitabine 825 mg/m2/ twice daily, radiotherapy on rectum/nodes, 50/45 Gy, 45 and 9 boost/45 Gy, in first 5 and subsequent patients, 5 days/week, respectively; for 5 weeks. Pathologic complete response (pCR) 10% was projected in order to positively affect clinical outcome.ResultsSeventeen fit <75 years patients enrolled: median age 60; young-elderly 4 (23%); T3/T4, 15/2, N0/N1/N2, 7/9/1. At first dose-level, no dose-limiting toxicity (DLT). At second, 2 DLT, G3 mucositis, G3 thrombocytopenia, in 2/6 patients (33%). Oxaliplatin recommended dose, 40 mg/m2/week. Cumulative G3-4 toxicities: mucositis 6%, thrombocytopenia 6%. Limiting toxicity syndromes 18%, 25% in young-elderly, all single site. Objective response rate intent-to-treat 94%. Sphinter preservation 87%, pCR 6%. After 17 months follow-up, progression-free survival and overall survival were not reached.ConclusionsOxaliplatin can be safely added to preoperative capecitabine-based chemoradiotherapy at the recommended dose 40 mg/m2/week, in LARC, with promising pCR and high activity.

Highlights

Proper administration timing, dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform twodrugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC)
Oxaliplatin can be safely added to preoperative capecitabinebased chemoradiotherapy at the recommended dose 40 mg/m2/week, in LARC, with promising Pathologic complete response (pCR) and high activity
Oxaliplatin and 5-fluorouracil- or capecitabine-based chemoradiotherapy was performed at different doses and schedules with significantly increased toxicity in randomized studies, limiting the favourable impact of the association, but, the expected effectiveness of radiotherapy [17,18,19,20]

Summary

Introduction

Dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform twodrugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC) This dose-finding study investigated recommended oxaliplatin dose, safety of oxaliplatin/capecitabine regimen and preliminary activity. Over the years researchers have studied the formulation of new platinum-based chemotherapeutic agents with the aim of reduce the incidence of drug related adverse events, based on the technological and biological improvement. These new compounds would be able to target specific cellular structures, carrying the pharmacological action only at the site of interest and reducing the involvement of healthy structures. Among the main examples of this strategy we find platinum A able to bind the oxygenase-2 cycle (COX-2) while platinum B is able to interact with mitochondrial DNA by interfering with tumor resistance mechanisms [1]

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