Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial

Summary

Background

Stereotactic ablative body radiotherapy (SABR) is widely used to treat inoperable stage 1 non-small-cell lung cancer (NSCLC), despite the absence of prospective evidence that this type of treatment improves local control or prolongs overall survival compared with standard radiotherapy. We aimed to compare the two treatment techniques.

Methods

We did this multicentre, phase 3, randomised, controlled trial in 11 hospitals in Australia and three hospitals in New Zealand. Patients were eligible if they were aged 18 years or older, had biopsy-confirmed stage 1 (T1–T2aN0M0) NSCLC diagnosed on the basis of ¹⁸F-fluorodeoxyglucose PET, and were medically inoperable or had refused surgery. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and the tumour had to be peripherally located. Patients were randomly assigned after stratification for T stage and operability in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumour was <2 cm from the chest wall) or standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5 Gy fractions, depending on institutional preference) using minimisation, so no sequence was pre-generated. Clinicians, patients, and data managers had no previous knowledge of the treatment group to which patients would be assigned; however, the treatment assignment was subsequently open label (because of the nature of the interventions). The primary endpoint was time to local treatment failure (assessed according to Response Evaluation Criteria in Solid Tumors version 1.0), with the hypothesis that SABR would result in superior local control compared with standard radiotherapy. All efficacy analyses were based on the intention-to-treat analysis. Safety analyses were done on a per-protocol basis, according to treatment that the patients actually received. The trial is registered with ClinicalTrials.gov (NCT01014130) and the Australia and New Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to new participants.

Findings

Between Dec 31, 2009, and June 22, 2015, 101 eligible patients were enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy (n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard radiotherapy group did not receive treatment, and a further four in each group withdrew before study end. As of data cutoff (July 31, 2017), median follow-up for local treatment failure was 2·1 years (IQR 1·2–3·6) for patients randomly assigned to standard radiotherapy and 2·6 years (IQR 1·6–3·6) for patients assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of 66 patients in the SABR group and 11 (31%) of 35 patients in the standard radiotherapy group, and freedom from local treatment failure was improved in the SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95% CI 0·13–0·77, p=0·0077). Median time to local treatment failure was not reached in either group. In patients treated with SABR, there was one grade 4 adverse event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one lung infection, one weight loss, one dyspnoea, and one fatigue) related to treatment compared with two grade 3 events (chest pain) in the standard treatment group.

Interpretation

In patients with inoperable peripherally located stage 1 NSCLC, compared with standard radiotherapy, SABR resulted in superior local control of the primary disease without an increase in major toxicity. The findings of this trial suggest that SABR should be the treatment of choice for this patient group.

Funding

The Radiation and Optometry Section of the Australian Government Department of Health with the assistance of Cancer Australia, and the Cancer Society of New Zealand and the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust).

Introduction

The standard of care for stage 1 non-small-cell lung cancer (NSCLC) is surgical resection, but many patients have smoking-related cardiac or respiratory comorbidities that make them unfit for an operation. For these patients, radiotherapy represents a safer and potentially curative option. Historically, a course of curative radiotherapy is given as 20 or more fractions delivered over a period of 4–6 weeks. Fractionating the treatment improves the therapeutic ratio by enabling escalation of the dose to tumouricidal amounts while allowing interfraction recovery of the incidentally irradiated dose-limiting normal tissues. Advances in radiotherapy technology, including image guidance and tumour motion management, have led to more precise conformal dose delivery to the tumour and substantially less dose delivery to the surrounding healthy tissues. As a result, safe delivery of extremely high (ablative) doses to smaller tumours without the need for protracted fractionation is possible. This technique, typically given as a hypofractionated course of one to five treatments over 1–2 weeks, is termed stereotactic ablative body radiotherapy (SABR), and its use for treating medically inoperable stage 1 NSCLC has increased rapidly since 2001.¹

Single-arm studies have consistently shown high local control with the use of SABR. For example, in one prospective trial² of SABR for inoperable early-stage NSCLC (RTOG 0236), the 3-year primary tumour control was 90%—far superior to the 30–40% control observed historically using fully fractionated techniques. Despite the high local control achieved, overall survival in RTOG 0236 was only 55·8% at 3 years, and no randomised trials have indicated that the high local control translates into improved overall survival compared with standard radiotherapy. The Scandinavian SPACE trial³ randomly assigned patients with medically inoperable non-central stage 1 NSCLC to SABR or standard fractionated radiotherapy. No significant differences in overall survival between the treatment groups were recorded, but any potential benefits of the SABR approach might have been masked by the inclusion of patients either with poor performance status, no pathological diagnosis, or incomplete staging due to omission of ¹⁸F-fluorodeoxyglucose (FDG)-PET in a substantial proportion of patients. We therefore did a randomised trial of SABR versus standard fractionated radiotherapy in patients with biopsy-confirmed FDG-PET stage 1 NSCLC that was either inoperable or the patient refused surgery to prospectively assess the effect of radiotherapy technique on local control, overall survival, toxicity, and quality of life.