Fludarabine combined with radiotherapy in patients with locally advanced NSCLC lung carcinoma: a phase I study

Mirko Nitsche,Katinka Lederer,Olivier Pradier,Frank Griesinger,Heinz Schmidberger,Hans Christiansen

doi:10.1007/s00432-012-1185-3

Abstract

Background and purposeFludarabine is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. We designed a phase I trial exploring concurrent fludarabine and radiotherapy in patients with advanced non-small cell lung cancer (NSCLC) to determine the maximum tolerated dose (MTD) of fludarabine given with concurrent irradiation.Materials and methodsThirteen patients with stage IIIB NSCLC received thoracic irradiation of 60 Gy. Fludarabine was administered during the 5th and 6th week of radiotherapy. Doses started at 10 mg/m2 per day and increased by steps of 3 mg/m2 per day.ResultsAt a daily dose of 16 mg/m2, one out of six patients developed a grade 4 leukopenia, and one a grad 3 pneumonitis. Further grade III toxicity was not observed. The dose of 13 mg/m2 was identified as the MTD. All patients developed a fludarabine dose-dependent lymphocytopenia.ConclusionFludarabine can be safely administered concurrently with radiation at a daily dose of 13 mg/m2 during the final 2 weeks of radiotherapy. Further prospective clinical studies are required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of locally advanced inoperable NSCLC.

Highlights

Despite the advances in multimodal therapy, locally advanced stage IIIA and IIIB non-small cell lung cancer (NSCLC) remains a disease with a poor overall prognosis, and the optimal treatment still remains to be investigated (Buccheri and Ferrigno 1996; Spira and Ettinger 2004)
We designed a phase I trial exploring concurrent fludarabine and radiotherapy in patients with advanced non-small cell lung cancer (NSCLC) to determine the maximum tolerated dose (MTD) of fludarabine given with concurrent irradiation
Further prospective clinical studies are required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of locally advanced inoperable NSCLC

Summary

Introduction

Despite the advances in multimodal therapy, locally advanced stage IIIA and IIIB non-small cell lung cancer (NSCLC) remains a disease with a poor overall prognosis, and the optimal treatment still remains to be investigated (Buccheri and Ferrigno 1996; Spira and Ettinger 2004). The following seems to be the most promising therapy for the majority of patients with locally advanced inoperable stage IIIA and IIIB NSCLC: Several trials evaluated radiotherapy with concurrent cisplatin-based chemotherapy and revealed better survival rates than RT alone, even in comparison with sequential therapy (Le Chevalier et al 1991; SchaakeKoning et al 1992; Sause et al 1995; Furuse et al 1999; Curran 2002, O’Rourke et al 2010). The concurrent approach appears to increase the rate of adverse events, mainly esophagitis Providing support for these results, two meta-analyses showed a significant decrease in the relative risk of death at 1 and 3 years and a 24 % reduction in the risk of death at 1 year and a 30 % reduction at 2 years for radiotherapy with concurrent cisplatin-based chemotherapy in comparison with radiotherapy alone (Pritchard and Anthony 1996; Marino et al 1995). Doses started at 10 mg/m2 per day and increased by steps of 3 mg/m2 per day.

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