Clinical Investigation
Prospective, Risk-Adapted Strategy of Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer: Results of a Phase II Trial

https://doi.org/10.1016/j.ijrobp.2010.04.056Get rights and content

Purpose

Validation of a prospective, risk-adapted strategy for early-stage non–small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT).

Methods and Materials

Patients with a T1–3N0M0 (American Joint Committee on Cancer 6th edition) NSCLC were accrued. Using the Radiation Therapy Oncology Group definition, patients were treated to a total dose of 60,Gy in three fractions for peripherally located lesions and four fractions for centrally located lesions. The primary endpoint was toxicity, graded according to the Radiation Therapy Oncology Group acute and late morbidity scoring system, and the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Secondary endpoints were local control and survival.

Results

A total of 40 patients were included, 17 with a centrally located lesion. The lung toxicity-free survival estimate at 2 years was 74% and was related to the location (central vs. peripheral) and the size of the target volume. No dose volumetric parameters could predict the occurrence of lung toxicity. One patient died because of treatment-related toxicity. The 1-year and 2-year local progression-free survival estimates were 97% and 84%, respectively, and were related to stage (T1 vs. T2) related (p = 0.006). Local failure was not more frequent for patients treated in four fractions. The 1-year local progression-free survival estimate dropped below 80% for lesions with a diameter of more than 4 cm.

Conclusion

The proposed risk-adapted strategy for both centrally and peripherally located lesions showed an acceptable toxicity profile while maintaining excellent local control rates. The correlation between local control and tumor diameter calls for the inclusion of tumor stage as a variable in future study design.

Introduction

Lung cancer death rates remain a major health issue (1). This is related to the often advanced stage at diagnosis. Only a minority of lung cancer cases are diagnosed at an early stage, although in the future an increasing proportion can be expected from the more frequent use of computed tomography (CT) in patients at risk (2). Surgery has been the gold standard in the local treatment for non–small-cell lung cancer (NSCLC) Stages I and II, with less than 20% local failure rates (3). For medically inoperable patients or patients refusing surgery, radiation therapy is considered to be an alternative. The experience with conventional external beam radiotherapy has resulted in local failure rates ranging from 6% to 70%, and local failure was strongly dependent on tumor size (4).

An alternative for conventional fractionation is hypofractionated radiotherapy. Phase I/II trials assessing the stereotactic body radiotherapy (SBRT) approach have reported local progression-free survival (LPFS) rates between 85% and 100% 5, 6, 7, 8, 9. Various fractionation schedules and dose prescriptions have been applied, with a dose–response relationship in favour of a biologic equivalent dose of at least 100Gy (α/β=10) (10). An important notion of warning was issued by the Radiation Therapy Oncology Group (RTOG) with respect to the use of SBRT for centrally located lesions (8). Excessive toxicity was seen in treating tumors of any T size within or touching the zone of the proximal bronchial tree (2 cm in all directions around carina and both main bronchi, both upper and lower lobe bronchi, the intermedius bronchus, the right middle lobe bronchus, and the lingular bronchus). The idea of a location-dependent dose prescription was recently introduced in a large retrospective report. A total dose of 60 Gy was prescribed in three, five, or eight fractions depending on the location (11). We previously reported on the feasibility of 60 Gy isocentric in eight fractions over 3 weeks for centrally located lesions or tumors with involved hilar nodes (12). However, inasmuch as the reported LPFS of 65% at 2 years was disappointing with respect to the reported local control using higher doses, we thought that a risk-adapted approach called for a higher fraction size than 7.5 Gy, even for centrally located lesions. Considering the steep dose–response relationship (13) and the known concern about centrally located lesions, we combined both elements in a risk-adapted strategy of dose prescription.

We report on the first analysis, to our knowledge, of this prospective Phase II trial using 60 Gy in three or four fractions for peripherally and centrally located early-stage NSCLC, respectively. The primary endpoint was pulmonary toxicity; secondary endpoints were local control and survival.

Section snippets

Patient population

Patients eligible for inclusion were adults with a nonmalignant related life expectancy of at least 6 months and a cytologically or histologically proven diagnosis of NSCLC. Tumor staging had to reveal a solitary primary tumor of ≤6 cm, without nodal or metastatic involvement (T1–3N0M0) according to the American Joint Committee on Cancer 6th edition staging manual. Minimum staging procedure consisted of bronchoscopy, to exclude lesions closer than 2 cm from the carina, and 18

Patient and treatment characteristics

Between March 2007 and June 2009, 40 patients were enrolled in the present study protocol. The first-step analysis in July 2008 on the 19 patients allowed continuation of the study protocol, inasmuch as no Grade 3 toxicity was seen at that time and 81% of patients showed a complete metabolic response. Baseline characteristics and patient demographics are summarized in Table 1. In 22 patients a marker was implanted; 19 of them also received a gated treatment. Gating was more frequent for

Discussion

To our knowledge, we are the first to report on a prospective application of a location-dependent dose prescription. The notion of warning for centrally located tumors was derived from the prospective experience of the RTOG (7, 8). The use of fraction sizes of 20 Gy to 22 Gy for T1 and T2 tumors, respectively was derived from the local failure pattern in the preceding dose escalation trial. In 90% of cases, local failure developed when three fractions of 16 Gy or less were used (9). Although

Conclusion

We report on a risk-adapted strategy for SBRT in early-stage NSCLC. The LTFS estimate at 2 years was 74%, and dose reduction for centrally located lesions did not increase the risk of local failure. Toxicity remained location dependent even at lower doses, and local control diminished with tumor diameter.

References (36)

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Supported by grants G.0486.06 and G.0412.08 from the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, and by a grant from the Wetenschappelijk fonds Willy Gepts.

Conflict of interest: none.

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