Radiotherapy Combined with Daily or Weekly cis-Diammine Dichloroplatinum (II) in Inoperable Non-Metastasized Non-Small Cell Lung Cancer: A Toxicity Report of the Randomized Phase III Study of the EORTC Lung Cancer Cooperative and Radiotherapy Cooperative Groups

Abstract

The results of radiotherapy with curative intent (dose ≥ 50 Gy/5 weeks) have not improved in patients with inoperable non-metastasized non-small cell lung cancer (NSCLC) during the past years. This failure can be explained by two main reasons: 1) many patients suffer from distant metastases which are not detectable at the time of staging; an effective (adjuvant) chemotherapy against distant disease is lacking; 2) local failure has been observed in more than 50% of the patients treated with ≥ 50 Gy/5 weeks, 5 fractions a week. Local control is a necessary condition for cure and is related to survival. The local control rate is dose dependent. The higher the tumor dose the higher the chance of local cure [1,3]. As the radiotherapy dose applied is limited by damage to the normal tissues there is a need for selective potentiators of radiation induced damage in tumor cells. One of these potentiators might be cis-diammine dichloroplatinum II (cDDP), which shows a variable radiosensitizing effect in vivo [3,4]. These effects have been confirmed by some animal studies. The highest therapeutic gains were observed when cDDP was combined with fractionated radiation schemes daily [5,6]. Several mechanisms are considered to be responsible for some of the supra additive effects observed: 1) sensitization of hypoxic cells, 2) inhibition of cellular repair processes, 3) production of intra- and interstrand cross links in DNA, 4) depletion of endogenous radioprotectors [4,7]. The exact contribution of each of these influences is however still uncertain. Non-randomized phase I–II clinical studies using the combination cDDP and RT have been reported for a variety of tumor types. There is also a wide variety in treatment schemes applied, dose and sequence of the cDDP combined with the radiation [4]. A dose finding study was carried out for inoperable NSCLC. A high-dose split-course scheme was combined with cDDP once a week, given on the first of a series of five radiation days [8]. A weekly dose of 30 mg/m2 was found to be feasible. The most important toxicity observed was nausea and vomiting due to a general effect of the cDDP. No renal function damage was reported provided that the patients were hydrated well. No clinically important bone marrow side effects were seen.