Hypofractionated RT in Locally Advanced NSCLC: Phase I Trial Yields MTD

[[{"type":"media","view_mode":"media_crop","fid":"20939","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_8943494129151","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1377","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Dose-escalated hypofractionated radiotherapy yielded a maximum tolerated dose for patients with locally advanced non-small-cell lung cancer (NSCLC) and shed light on dangerous toxicity at higher doses, according to a new study. The toxicity was dominated by late radiation toxicity to the central and perihilar structures including the proximal bronchial tree and surrounding vasculature.

“In most of the randomized concurrent chemotherapy trials, patients were treated to doses of 60 to 66 Gy but nevertheless still experienced local failure rates of approximately 30%,” wrote authors led by Donald M. Cannon, MD, of the Mountain States Tumor Institute in Twin Falls, Idaho. “Given these suboptimal results, strategies of treatment intensification to improve outcomes continue to be explored.”

The new phase I study, published online ahead of print on October 21 in the Journal of Clinical Oncology, enrolled 79 patients with NSCLC at a single institution. After five patients were treated on a pilot study at a dose of 57 Gy of hypofractionated radiotherapy, the study’s dose escalation protocol (without any concurrent chemotherapy) proceeded. Forty-seven of the patients ended up receiving only the 57 Gy base dose; 11 patients received 63.25 Gy, 3 received 69.25 Gy, 12 received 75 Gy, 4 received 80.5 Gy, and 2 received 85.5 Gy. The median dose was 57 Gy in 25 fractions.

After a median follow-up period of 17 months, the median overall survival rate was 16 months; 29% of the cohort survived to 3 years. There was no difference seen in rates of local control between those treated at 69.25 Gy and higher and those treated at the lower 57 and 63.25 Gy doses (P = .81).

The maximum tolerated dose was established at 63.25 Gy. There were no cases of grade 3 or higher radiation pneumonitis, and 12 patients (16%) had grade 2 pneumonitis. There were also no instances of grade 3 or worse acute or late esophageal toxicities, though 48% of the cohort experienced grade 2 esophagitis.

Six grade 4 or 5 toxicities were deemed likely to be related to radiotherapy. One patient treated at 63.25 Gy died from progressive hypoxemia with bilateral lung infiltrates without disease progression 1 month after therapy. Three patients treated at 75 Gy and above died from massive hemoptysis 8 or more months after the therapy. Univariate analysis showed that higher delivered dose was significantly associated with development of any grade 4 to 5 toxicity, with a hazard ratio of 1.13 (95% CI, 1.04-1.23; P = .0036).

While the study suggests this therapy up to 63.25 is well tolerated, the authors noted that “our results are a reminder that the spectrum of toxicities from dose-intensified thoracic radiotherapy can be broad.” The results have implications for design of trials aiming to improve rates of local control. “In addition to controlling for pneumonitis risk, radiation dose-escalation studies in lung cancer should require strict limits to doses received by the proximal bronchial tree,” they concluded.