International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationProspective, Risk-Adapted Strategy of Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer: Results of a Phase II Trial
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)
- et al.
Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition)
Chest
(2007) - et al.
Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame
Int J Radiat Oncol Biol Phys
(2005) - et al.
Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: Four-year results of a prospective phase II study
Int J Radiat Oncol Biol Phys
(2009) - et al.
Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study
Int J Radiat Oncol Biol Phys
(2005) - et al.
Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: Updated results of 257 patients in a Japanese multi-institutional study
J Thorac Oncol
(2007) - et al.
Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
(2008) - et al.
A feasibility study of image-guided hypofractionated conformal arc therapy for inoperable patients with localized non-small cell lung cancer
Radiother Oncol
(2007) - et al.
Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy
Int J Radiat Oncol Biol Phys
(2008) - et al.
Treatment delivery time optimization of respiratory gated radiation therapy by application of audio-visual feedback
Radiother Oncol
(2009) - et al.
Optimal control of set-up margins and internal margins for intra- and extracranial radiotherapy using stereoscopic kilovoltage imaging
Cancer Radiother
(2006)
Quality assurance of a system for improved target localization and patient set-up that combines real-time infrared tracking and stereoscopic X-ray imaging
Radiother Oncol
Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC)
Lung Cancer
Volumetric response analysis during chemoradiation as predictive tool for optimizing treatment strategy in locally advanced unresectable NSCLC
Radiother Oncol
Universal survival curve and single fraction equivalent dose: Useful tools in understanding potency of ablative radiotherapy
Int J Radiat Oncol Biol Phys
Toxicity analysis of RTOG 0236 using SBRT to treat medically inoperable early stage lung cancer patients. I
nt J Radiat Oncol Biol Phys
Benefit of respiration-gated stereotactic radiotherapy for stage I lung cancer: An analysis of 4DCT datasets
Int J Radiat Oncol Biol Phys
Four-dimensional CT scans for treatment planning in stereotactic radiotherapy for stage I lung cancer
Int J Radiat Oncol Biol Phys
Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients
Int J Radiat Oncol Biol Phys
Cited by (157)
Radiotherapy in the management of lung oligometastases
2024, Cancer/RadiotherapieStereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial
2024, International Journal of Radiation Oncology Biology PhysicsLocal Control After Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer
2021, International Journal of Radiation Oncology Biology Physics
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.