Stereotactic Ablative Radiotherapy Non-Inferior to Surgery in Operable Stage I Non Small Cell Lung Cancer

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates are often treated with conventional Radiation Therapy, over a period of 4 to 6 weeks.

Dating back to the 1930’s, the only hope for curing lung cancer has been surgery. However, important advances in the field of medical physics, computer science, and engineering have enabled significant progress in the field of Radiation Oncology, by better targeting the tumor and escalating the daily treatment doses. Surgery for Stage I NSCLC is now being challenged by these new Radiation Therapy techniques.

Stereotactic Ablative Radiotherapy (SABR) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SABR include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized Hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SABR is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given.

In a previously published pooled analysis of two independent, randomized, Phase III trials of SABR in patients with operable, clinical T1–2a (<4 cm), N0M0, Stage I NSCLC (STARS and ROSEL), Overall Survival (OS) was higher after Stereotactic Ablative Radiotherapy (SABR) than with surgery. This analysis had notable limitations and was closed early due to slow accrual. In the present study, the SABR group in the STARS trial was re-accrued with a larger sample size and the authors reported long-term results of the revised STARS trial, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients, who underwent Video-Assisted Thoracoscopic Surgical Lobectomy with Mediastinal Lymph Node Dissection (VATS L-MLND).

This single-arm prospective trial done at the University of Texas MD Anderson Cancer Center did not include patients from the previous pooled analysis and enrolled 80 patients (N=80) with newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumor diameter of 3 cm or less. SABR dosing for peripheral lesions was 54 Gy in three fractions and 50 Gy in four fractions for central tumors, with simultaneous integrated boost to gross tumor totaling 60 Gy.

For the propensity-matching analysis, the researchers used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery’s prospectively registered, institutional review board-approved database of all patients with clinical Stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Propensity matching consisted of determining a propensity score using a several covariates such as age, tumor size, histology, Performance Status, and the interaction of age and sex. The Primary endpoint was the 3-year Overall Survival. Non-inferiority could be claimed if the 3-year Overall Survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the Hazard Ratio (HR) was less than 1.965.

At a median follow-up time was 5.1 years, the OS with SABR was 91% at 3 years and 87% at 5 years. The OS in the propensity-matched VATS L-MLND cohort was 91% at 3 years and 84% at 5 years. Non-inferiority was claimed since the 3-year OS after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in OS between the two patient cohorts from a multivariable analysis (HR=0.86; P=0•65). SABR was well tolerated with no Grade 4-5 toxicities.

It was concluded from this study that long term survival after SABR is non-inferior to VATS L-MLND for operable Stage IA Non Small Cell Lung Cancer. SABR remains promising for this patient group and the authors strongly recommend a multidisciplinary management approach .

Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery. Chang JY, Mehran RJ, Feng L, et al. Lancet Oncol. 2021;22:1448-1457.