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
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 . 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 . 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.
KeywordsLate Toxicity Dose Finding Study Combine Treatment Modality Bone Marrow Depression Interstrand Cross Link
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