Hypofractionated Image-Guided vs Conventional Radiotherapy in Patients With Stage II/III NSCLC Ineligible for Concurrent Chemoradiation

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In a phase III trial reported in JAMA Oncology, Puneeth Iyengar, MD, PhD, and colleagues found that accelerated hypofractionated image-guided radiotherapy (IGRT) did not improve 1-year overall survival vs conventional radiotherapy in patients with stage II/III non–small cell lung cancer (NSCLC) who could not receive concurrent chemoradiotherapy.

As stated by the investigators, “A significant subset of patients with stage II/III NSCLC cannot receive standard concurrent chemoradiotherapy owing to the risk of toxic effects outweighing potential benefits. Without concurrent chemotherapy, however, the efficacy of conventional radiotherapy is reduced.”

Puneeth Iyengar, MD, PhD

Puneeth Iyengar, MD, PhD

Study Details

In the open-label trial, 96 evaluable patients from nine sites in Texas with Zubrod performance status ≥ 2, > 10% weight loss in the previous 6 months, and/or who were ineligible for concurrent chemoradiotherapy after oncology consultation were randomly assigned between November 2012 and August 2018 to receive hypofractionated IGRT at 60 Gy in 15 fractions (n = 50) vs conventionally fractionated radiotherapy (CFRT) at 60 Gy in 30 fractions (n = 46). 

The primary endpoint was overall survival at 1 year.

Overall Survival

A planned interim analysis indicated futility in reaching the primary endpoint and the study was closed to additional accrual. Median follow-up was 8.7 months (range = 3.6–19.9 months). Overall survival at 1 year was 37.7% (95% confidence interval [CI] = 24.2%–51.0%) in the hypofractionated IGRT group vs 44.6% (95% CI = 29.9%–58.3%) in the CFRT group (P = .29). No significant differences were observed in median overall survival (8.2 vs 10.6 months, P = .17), progression-free survival (6.4 vs 7.3 months, P = .77), time to local failure (P = .34), or time to distant metastasis (P = .16).  

On multivariate analysis, subsequent systemic therapy was associated with improved overall  survival (hazard ratio [HR] = 0.51, 95% CI = 0.29–0.87, P = .01), and the biologically effective maximum dose to any 0.035 mL of the esophagus was associated with poorer survival (HR = 1.01, 95% CI = 1.00–1.02, P = .03).


  • Study accrual was stopped due to futility.
  • No difference in 1-year overall survival was observed between accelerated hypofractionated image-guided radiotherapy vs conventionally fractionated radiotherapy.


Grade ≥ 3 adverse events occurred in 36% of those in the hypofractionated IGRT group vs 41% of the CFRT group, with most common in both groups being dyspnea (10 vs 5 patients). Grade 2 toxicity occurred in 52% vs 24% (P = .006), with the most common being esophagitis (22% vs 9%). Adverse events led to death in two patients in the hypofractionated IGRT group (due to death–not otherwise specified and dyspnea) and three patients in the CFRT group (due to death–not otherwise specified in 2 and dyspnea in 1). 

The investigators concluded, “This phase III randomized clinical trial found that hypofractionated IGRT (60 Gy in 15 fractions) was not superior to CFRT (60 Gy in 30 fractions) for patients with stage II/III NSCLC ineligible for concurrent chemoradiotherapy. Further studies are needed to verify equivalence between these radiotherapy regimens. Regardless, for well-selected patients with NSCLC (ie, peripheral primary tumors and limited mediastinal/hilar adenopathy), the convenience of hypofractionated radiotherapy regimens may offer an appropriate treatment option.”

Robert Timmerman, MD, of the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by a grant from the Cancer Prevention and Research Institute of Texas. For full disclosures of the study authors, visit

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