Potentially Useful Predictors of Risk for Developing Postradiation Pneumonitis

ROCHESTER, New York—Interleukin-6 (IL-6) and interleukin 1-alpha (IL-1a) are potentially useful predictors of risk for development of postradiation pneumonitis, according to Yuhchyau Chen, MD, PhD. "Delayed peak of pneumonitis occurs at 6 to 9 months, and we expect that there will be a role for radioprotective agents in this setting," she said. Dr. Chen is assistant professor of radiation oncology, University of Rochester Medical Center, New York.

"There is significantly increased risk with higher levels of IL-1a and IL-6, regardless of pneumonitis grade, and suggests a common mechanism for both asymptomatic (grade 1) and symptomatic (grade 2 or above) pneumonitis. Circulating IL-1a and IL-6 are potential predictors and markers for radiation pneumonitis," Dr. Chen said. Preliminary data also show a delayed peak of TGF-beta at 6 months postradiotherapy.

Adhesion molecules, the selectins, are the cytokines responsible for lymphocyte adherence to endothelium. "They get cells out of the vascular system and enable them to home in to the site of inflammation," Dr. Chen said.

Prospective Protocol

Dr. Chen reported that 75 patients are enrolled in a prospective translational protocol in which serial blood samples, blood counts, radiographs, SoMA scoring of respiratory symptoms, and pulmonary function tests are being used to study radiation pulmonary injury. Over 600 plasma and serum specimens have been collected, plus 250 mRNA extracts from peripheral lymphocytes. Analysis includes the proinflammatory cytokines IL-1a, IL-6, and TNF-alpha, the fibrotic cytokines TGF-beta and basic-FGF, the angiogenic cytokines basic-FGF and vascular endothelial growth factor (VEGF), the chemokine MCP-1, and adhesion molecules L-selectin, P-selectin, and E-selectin. Pneumonitis is graded using the National Cancer Institute Common Toxicity Criteria.

The first set of analysis of 24 patients included 25% with grade 1 radiographic infiltrates only and 54% with grade 2 symptomatic pneumonitis. The second set included 59 patients, 40% of whom had grade 2 symptomatic pneumonitis.

Pneumonitis and Fibrosis

"Patients generally become symptomatic during the 6 to 13 week time window. We found that circulating IL-6 is significantly higher for patients with pneumonitis. We also suspect that pretreatment IL-6 may be a predictor for which patients will subsequently develop pneumonitis," Dr. Chen said. In contrast, levels of IL-1a did not change during radiotherapy, suggesting that IL-6 but not IL-1a has a mechanistic role in radiation-induced lung injury."

Before, during, and immediately after radiation treatment, levels of basic-FGF were relatively flat, but there was a delayed increase in those with pneumonitis. There was a similar delayed increase in levels of TGF-beta at about 6 months after radiation treatment, suggestive of a role in fibrosis.

There was a delayed decrease in selectins for the group as a whole. Dr. Chen said that this might be related to fibrosis.

Lymphocyte cell counts dropped dramatically following radiation by close to 20% of the pretreatment value, with a very slow recovery. "This was very similar to the L-selectin pattern," Dr. Chen said. There was also a slower recovery of CD4 than of CD8 cells after radiation.

"Our data show that the incidence of symptomatic radiation pneumonitis is 40% to 50% and that risk increases in patients who have elevated pre-treatment IL-1a and IL-6. Functional decline is seen primarily in the DLCO" (diffusing capacity of the lung for carbon monoxide).