Hypofractionated Image-Guided Versus Conventionally Fractionated Radiotherapy Shows No Treatment Advantage in NSCLC With Poor Performance Status

The use of hypofractionated image-guide radiotherapy was not found to improve overall survival for patients with non–small cell lung cancer and poor performance status versus conventional fractionated radiation techniques.

Hypofractionated image-guided radiotherapy (IGRT) was not superior to conventionally fractionated radiotherapy (CFRT) for the treatment of patients with stage II or III non–small cell lung cancer (NSCLC) who could not receive concurrent chemoradiotherapy, according to results of a phase 3 trial (NCT01459497) published in JAMA Oncology

There were no significant differences in 1-year overall survival (OS) between the hypofractionated IGRT group (37.7%; 95% CI, 24.2%-51.0%) or the CFRT group (44.6%, 95% CI, 29.9%-58.3%; P = .29). Investigators also found no significant differences between median OS, progression-free survival (PFS), time to local failure, time to distant metastasis, or toxic effects of grade 3 or higher.

“To our knowledge, this is the first phase 3 trial comparing hypofractionated vs conventional radiotherapy for stage II/III NSCLC in this patient population,” wrote the studies investigators. “Despite the fact that the study reached futility, our data provide thoracic oncologists a window on the role of 2 different fractionation schemas on a patient population with poor performance status, absent concurrent therapies.”

This study randomized 103 patients with a performance status of 2 or greater, and after 50% of patients were enrolled, the planned interim analysis suggested futility in reaching the primary end point with conditional power of 20.6%, which led to study accrual closure. The median follow-up was 8.7 months (range, 3.6-19.9). When the trial was randomized, 50 patients were assigned to the hypofractionated IGRT group and 46 patients for assigned to the CFRT group.

Patient characteristics showed that 54.0% of patients (n = 27) in the IGRT group and 63.0% (n = 29) in the CFRT group had squamous histology and versus 46.0% (n = 23) and 37.0% (n = 17; P = .41), respectively, who had nonsquamous histologic features. There were significantly more patients in the IGRT group (24.0%) with N1 disease vs the CFRT group (6.5%; P = .02). Conversely, fewer patients in the IGRT group than the CFRT group has N3 disease (8.0% vs 23.9%; P = .02).

In addition, most patients completed their planned radiotherapy in both groups, at 88.0% (n = 44) for IGRT and 89.1% (n = 41) for CFRT (P > .99). Receipt of systemic therapy before enrollment was well balanced for IGRT at 8.0% (n = 4) compared with 6.5% (n = 3) for CFRT (P > .99) as well as therapy received between enrollment and completion of radiotherapy and last follow-up at 26.0% (n = 13) for IGRT and 37.0% (n = 17) for CFRT (P = .28).

The median OS for the IGRT group was 8.2 months (95% CI, 29.9-58.3) compared with 10.6 months (95% CI, 8.4-15.3) for CFRT (P = .17). The median PFS for IGRT was 6.4 months (95% CI, 4.1-7.8) versus CFRT at 7.3 months (95% CI, 5.0-10.6; P= .77).

There were 5 patients who died during treatment, 4 who died after receiving fewer than 4 fractions, and 1 who died after a traumatic fall from altered mental status after 8 fractions.

The exploratory analysis of 77 patients allowed for follow-up imaging and time to local relapse. However, neither group reach the median time to local relapsed, with a 24-month probability of relapse-free survival of 85.8% (95% CI, 66.2%-94.5%) in the IGRT group and 66.1% (95% CI, 40.0%-83.0%; P = .34) in the CFRT group. Time to distant metastases was not reached in the IGRT group versus 18.0 months (95% CI, 4.4-36.0) in the CFRT group (P = .16).

More patients in the CFRT group (26.3%) developed distant metastases than in the IGRT group (51.3%; P = .04), possibly a reflection of more patients with N3 disease in the CFRT group. Overall, 11 patients (28.9%) in the IGRT group and 19 (48.7%) in the CFRT group died of NSCLC (P = .10).

There were no differences in grade 3 or greater toxic effects between the treatment groups. Grade 2 toxic effects occurred in 52.0% of patients (n = 26) in the IGRT group and 23.9% (n = 11) in the CFRT group (P = .006). The most common grade 2 effect was esophagitis found in 22.0% (n = 11) of the IGRT group and 8.7% (n =4) of the CFRT group (P = .09).

Additionally, other grade 2 effects were observed in 40.0% (n = 20) of the IGRT group and 15.2% (n = 7) in the CFRT group. The most common grade 2 respiratory toxic effect was dyspnea found in 14.0% of patients (n = 7) in the IGRT group and 2.2% (n = 1) in the CFRT group (P = .06).

“Our results show that hypofractionated IGRT did not improve overall survival compared with CFRT. In a subgroup analysis of patients from the primary enrolling site, there was a trend toward improvement with hypofractionated IGRT in times to local recurrence and distant metastasis, resulting in a trend of fewer patients dying of NSCLC. However, there was overall an almost 3-fold increase in grade 2 toxic effects with hypofractionation,” concluded investigators.


Iyengar P, Zhang-Velten E, Court L, et al. Accelerated hypofractionated image-guided vs conventional radiotherapy for patients with stage II/III non-small cell lung cancer and poor performance status: a randomized clinical trial. JAMA Oncol. Published Online August 12, 2021. doi:10.1001/jamaoncol.2021.3186