Elsevier

Radiotherapy and Oncology

Volume 66, Issue 2, February 2003, Pages 119-126
Radiotherapy and Oncology

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy

https://doi.org/10.1016/S0167-8140(02)00377-8Get rights and content

Abstract

Purpose: To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy.

Patients and methods: The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status ≤2, weight loss <10% and no chemotherapy within 6 weeks prior to the start of the radiotherapy treatment. No elective nodal irradiation was given. Patients were treated 5 days a week with 2.25 Gy per fraction and a 6 weeks overall treatment time; two fractions a day were given if more than 30 fractions were prescribed. Five risk groups were defined according to the relative mean lung dose (rMLD). Within each group the dose was escalated with three fractions per step (6.75 Gy). The next dose level opened after a toxicity-free follow-up of 6 months in three patients. The maximum tolerable dose has been reached if two out of six patients experience a dose-limiting toxicity (pneumonitis ≥grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications).

Results: Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4.

Conclusion: Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.

Introduction

For inoperable non-small cell lung cancer (NSCLC) patients with localized disease, radiation therapy is the principal mode of treatment. The local control rates after conventional radiotherapy doses of 60–66 Gy are however disappointing. In a study by Arriagada et al. [1], tumor control was strictly defined as radiological, bronchoscopical and histological complete response. Local disease eradication was achieved in only 17% of the patients, at one year after radiotherapy. To achieve a 50% tumor control probability it is estimated that doses of 84 Gy might be necessary [19]. Better control of locoregional disease is important because uncontrolled disease is often the direct cause of death due to local effects within the lung and mediastinum. Increased survival rates have been observed for patients with complete tumor response [28]. Locally persistent or recurrent thoracic disease might also serve as a focus for distant metastases. A possibility to improve local control is to increase the radiation dose to the tumor.

The use of three-dimensional conformal radiotherapy (3D CRT) techniques allows the delivery of higher radiation doses to the tumor by sparing surrounding normal tissues. The policy of sparing normal tissue is discordant with the conventional irradiation of clinical and radiological uninvolved regional lymph nodes (elective nodal irradiation, ENI). The influence of ENI on lung toxicity was evaluated in several studies [3], [20] and it was concluded that ENI hampers dose escalation to the primary tumor (which is the site most at risk for local recurrence). The need for ENI has not been established. Several studies have been published in which the elective nodal irradiation has been omitted systematically [10], [12], [23], [26], [29]. Krol et al. [12] published retrospective data on 108 patients with stage I–II NSCLC, irradiated without ENI. A low isolated nodal relapse rate of 4% justified the policy to omit the ENI. Results of prospective dose escalation trials using 3D CRT [12], [16], [25] report that it is safe to exclude the clinical and radiological uninvolved nodal areas because of an incidence of isolated nodal relapse of less than 6%. Moreover, it has been reported that clinically uninvolved lymph node areas often receive an incidental dose that might be sufficient to control subclinical disease [18].

To date, several groups are conducting phase I/II dose escalation studies using 3D CRT to establish the maximum tolerable dose that can be delivered without major complications. Table 1 shows the design of dose escalation studies defining risk groups, by determining dose-volume parameters like the mean lung dose (MLD) or the percentage of lung volume receiving more than a threshold dose. The radiation dose is escalated within these risk groups but the fractionation schedules and overall treatment time differ. In the early dose escalation trials from the RTOG [8] and the University of Michigan [10], the overall treatment time increased with increasing radiation doses. Meanwhile several studies have demonstrated an adverse effect on outcome of a prolongation of overall treatment time [4], [27]. Fowler states that local control is strongly dependent on overall treatment time, averaged over all histologies [7].

Therefore, in the more recently started RTOG L-0117 dose escalation trial, the overall treatment time was restricted to a maximum of 7 weeks and the fraction size increases. In this trial no risk groups were defined but the volume of total lung receiving more than 20 Gy should be less than 30% (for 2 Gy fractions). In the Wisconsin dose escalation trial [21] the overall treatment time is fixed to 5 weeks and the dose per fraction increases. In the dose escalation trial ‘HI-CHART’ of the Radiotherapy Institute Limburg (The Netherlands) two fractions of 1.8 Gy per day are given and the overall treatment time is less than 4 weeks (D. De Ruysscher, personal communication 2002). For the phase I–II dose escalation trial that started in our institute in October 1998 it was decided to keep the overall treatment time fixed to 6 weeks. Since the dose per fraction is fixed at 2.25 Gy, two fractions a day are given if more than 30 fractions are prescribed.

The main objective of this study was to report on the trial design and clinical implementation of 3D CRT for patients with inoperable NSCLC. The results of the first 55 patients entered in the study with respect to toxicity and local control rates are presented.

Section snippets

Patients and methods

The patients were selected from a group of medically inoperable or locally advanced NSCLC patients with good prognostic features (Eastern Cooperative Oncology Group performance status (ECOG)≤2 and weight loss <10% in the last 3 months) with visible tumor on a computed tomography (CT) scan of the thorax. Inoperable patients with a progressive lesion on CT scan of the thorax that could not be diagnosed with invasive transthoracic needle aspiration, were accepted only in case an

Patient characteristics

Fifty-five patients were included in this trial between October 1998 and December 2000. In three trial candidates the diagnostic 18FDG PET scan revealed distant metastases and these patients were not included in the trial. The pretreatment characteristics are enlisted in Table 3. Nearly half of the patients had a medical history of chronic obstructive pulmonary disease and 32 patients had cardiac problems in their medical record (angina pectoris, myocardial infarction, or bypass operation).

Discussion

Dose escalation for lung cancer patients with the concept of a fixed overall treatment time of 6 weeks is feasible. The administration of high-dose radiotherapy within this short period of time is new since other dose escalation trials reported had prolonged treatment times [8], [10]. The radiation dose was safely escalated using 3D conformal radiotherapy, omitting the elective nodal irradiation and stratifying the patients into risk groups, based on the mean lung dose. Doses up to 87.8 Gy for

Conclusion

For non-small cell lung cancer patients the use of 3D conformal radiation therapy, no elective nodal irradiation and stratifying the patients into risk groups (based on the mean lung dose), enables a significant escalation of radiation dose with acceptable toxicity. The maximum tolerable dose has not yet been reached in any of the defined risk groups.

Acknowledgements

K. De J. and Y.S. are supported by the Dutch Cancer Society (Grant 99-2043).

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