Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study

doi:10.1016/S0959-8049(99)00315-9

European Journal of Cancer

Volume 36, Issue 5, March 2000, Pages 592-600

https://doi.org/10.1016/S0959-8049(99)00315-9 Get rights and content

Abstract

The purpose of this work was to study the feasibility of concurrent chemoradiation in patients with inoperable non-small cell lung cancer (NSCLC). 40 patients with inoperable NSCLC were treated with escalating doses of radiotherapy and cisplatin (cDDP). The radiation dose was increased step by step from 60.5 to 66 Gy in daily fractions of 2.75 Gy. Chemotherapy was also increased step by step from 20 to 24 daily doses of cDDP 6 mg/m² and given concurrently with radiotherapy. A dose of 40 Gy/2 Gy/20 fractions (fx) was given to the EPTV (elective planning target volume) which included the gross tumour volume with a margin of 2 cm and part of or the entire mediastinum. During each session a boost dose of 0.75 Gy was given simultaneously to the BPTV (boost planning target volume), which encompassed the GTV (gross tumour volume) with a margin of 1 cm, for the first 20 fx, so the total dose to the tumour was 55 Gy. Cisplatin 6 mg/m² was given 1 h prior to radiotherapy at each fraction. From then on the dose of radiation to the BPTV and the dose of cDDP were increased step by step. In group I the BPTV was irradiated with two extra fractions of 2.75 Gy to a total dose of 60.5 Gy without cDDP. In group II the same total dose of 60.5 Gy was given but the last two fractions were combined with cDDP. In group III four extra fractions of 2.75 Gy were given to the BPTV to a total dose of 66 Gy, only two of these fractions combined with cDDP. Finally, in group IV a total dose of 66 Gy was given in 24 fractions, all fractions combined with cDDP. All patients were planned by means of a CT-based conformal treatment planning. The maximal length of the oesophagus receiving ⩾60.5 Gy was 11 cm. 40 patients were evaluable for acute and late toxicity and for survival. Acute toxicity grade ⩾3 (common toxicity criteria, CTC) was rarely observed; nausea/vomiting in 3 patients (8%), leucopenia in 2 patients (5%), thrombocytopenia in 2 patients (5%), whilst 2 patients (5%) suffered from severe weight loss. Late side-effects (European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group, EORTC/RTOG) were: oesophageal toxicity ⩾grade 3 in 2 patients (5%) and radiation pneumonitis grades 1 (3%) and 2 (3%) in 1 patient each. Overall actuarial 1- and 2-year survival was 53% and 40%, respectively. The 1- and 2-year local disease-free interval was 65% and 58% respectively. Radiotherapy at a dose of 66 Gy/2.75 Gy/24 fx combined with daily cDDP 6 mg/m² given over 5 weeks is feasible and results in a good local disease-free interval and a good survival rate. This treatment schedule is at present being tested as one of the two treatment arms of EORTC phase III study protocol 08972/22973.

Introduction

Inoperable non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in males in the Western world. As the percentage of smokers since the 1980s has been steady no major decrease of the incidence in men is expected. Female incidence is rising 1, 2. Overall the 5-year survival is less than 13%, and in patients with irresectable disease it is less than 5% [3].

Large studies have shown that a small percentage of the patients with irresectable, localised disease can be cured with radiotherapy [4]. However, even after using the best available radiation schedules, recurrences in the radiation field are observed in a substantial percentage of the patients 5, 6, 7, 8.

Patients with localised NSCLC presenting with good prognostic factors have a better local-disease free and overall survival 4, 9. Known treatment factors influencing local disease-free survival in localised NSCLC are total dose, overall treatment time and combined administration of chemotherapy 10, 11, 12, 13, 14, 15, 16.

A radiation dose of 60–66 Gy with conventional fractionation appears to be the maximal tolerated dose if large radiation fields are used [6]. As a dose–response relationship for NSCLC has already been established, phase II studies actually focus to administer higher doses by conformal radiotherapy techniques, and have so far shown promising results 17, 18, 19, which still are to be confirmed by phase III study data.

There is evidence that in NSCLC reduction of the overall treatment time might lead to better local control. Saunders and Dische prospectively randomised Continuous Hyperfractionated Accelerated Radiotherapy 54 Gy/in 36 fractions (fx) over 12 days (CHART) versus conventional radiotherapy (60 Gy/30 fx/6 weeks). A significant improvement in 2-year survival was seen in the CHART regimen (29%) compared with the conventional arm (20%). In addition, a significant reduction in local tumour progression was seen in the CHART arm [10]. A phase II study with hyperfractionated accelerated radiotherapy of 74.3 Gy/66–69 fx/33 days has also shown a favourable 2- and 3-year survival [20]. After retrospective analysis of data from RTOG studies, Cox found that prolongation of the overall treatment time in patients presenting NSCLC with good prognostic factors might result in decreased survival [21].

In the EORTC phase III study 08844 Schaake-Koning and colleagues demonstrated that radiotherapy combined with daily administration of 6 mg/m² cDDP resulted in an improved local control and actuarial survival in patients with inoperable NSCLC [12]. In this study a dose of 55 Gy was administered in an overall treatment time of 7–8 weeks (3–4 weeks split). A subsequent phase II study (EORTC 08912) demonstrated that the same dose of 55 Gy could be given in an overall time of 4 instead of 7–8 weeks without increasing toxicity [22]. As the toxicity of 55 Gy in 4 weeks combined with daily cDDP 6 mg/m² was considered acceptable in the previous study, a new feasibility prospective phase II study was undertaken which aimed to increase the dose of radiation from 55 Gy/2.75 Gy/20 fx to 66 Gy/2.75 Gy/24 fx and the cDDP doses from 20 to 24 times 6 mg/m² (120 to 144 mg/m² total dose). This study was performed under the auspices of the EORTC Radiotherapy and Lung Cancer Cooperative Groups. Primary endpoints were acute toxicity and late effects. Secondary endpoints were survival and local disease-free interval.

Section snippets

Patients and methods

Between October 1994 and January 1997 44 patients were registered. All patients were staged by physical examination, haematological counts and biochemical liver function tests as well as creatinine clearance, bronchoscopy, lung function tests including Vital Capacity (VC), Forced Expiratory Volume (FeV¹) and Carbon Monoxide Diffusion Capacity (DLCO), electrocardiogram (ECG), chest X-ray standard films and computed tomography (CT) scan of the thorax. Liver ultrasound, bone scan and CT scan of

Patient characteristics

44 patients were registered for the study. 4 patients were not eligible, 3 patients had N3 disease and 1 patient developed a lymphangitis carcinomatosa shortly before start of treatment. 40 patients were evaluable for acute and late toxicity, and for survival. A summary of patient characteristics is presented in Table 1. The mean age was 60 years (range: 39–70). 6 patients presented weight loss >5%. In 1 patient this could be attributed to an explorative thoracotomy and in the other 5 patients

Discussion

In conclusion, this study shows that it is tolerable to treat selected patients having inoperable locoregional NSCLC with 66 Gy in 24 fractions of 2.75 Gy, combined with daily administration of 6 mg/m² cDDP within a relatively short overall treatment time of 32 days. Severe acute toxicity is acceptable and severe late toxicity is rare. Survival and local control are promising. Data from randomised trials in squamous cell carcinoma of the head and neck and cervical carcinoma confirm the outcome

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Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study

Abstract

Introduction

Section snippets

Patients and methods

Patient characteristics

Discussion

Semin. Radiat. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Lancet

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Rad. Biol. Oncol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Eur. J. Cancer

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Biol. Oncol. Phys.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Eur. J. Cancer

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Biol. Oncol. Phys.