Incidence and risk factors for pneumonitis among patients with lung cancer who received immune checkpoint inhibitors after palliative thoracic radiotherapy

Abstract

The aim of this study is to analyze the incidence and risk factors for pneumonitis when immune checkpoint inhibitors (ICIs) are combined with palliative thoracic radiotherapy (RT) for lung cancer. We retrospectively evaluated 29 patients with lung cancer who received ICIs after palliative thoracic RT (30 Gy in 10 fractions). Their ICIs were pembrolizumab (n = 17), nivolumab (n = 8) and atezolizumab (n = 4). Median follow-up period was 10 months. The median interval between starting RT and starting ICI was 25 days. Pneumonitis events were grade 1 (n = 10; 34%), grade 2 (n = 4; 14%) and grade 3 (n = 3; 10%). Obstructive pneumonia was significantly associated with grade ≥ 2 pneumonitis (P = 0.036). Age, sex, ICI agent, interval between RT and ICI and history of ICI before RT were not associated with grade ≥ 2 pneumonitis. Tumor volume; Brinkman index; dosimetric factors, such as lung V5, V10, V20, V30 and mean lung dose (MLD); lactate dehydrogenase; and C-reactive protein did not significantly differ between the grade ≤ 1 and grade ≥ 2 pneumonitis groups. Levels of sialylated carbohydrate antigen KL-6 were evaluated in 27 patients before RT; they significantly differed between patients with grade ≤ 2 pneumonitis (mean: 431 U/ml) and those with grade ≥ 3 pneumonitis (mean: 958 U/ml; P < 0.001). Patients who receive ICI after palliative thoracic RT should be carefully followed-up, especially those who have had obstructive pneumonia or high KL-6 levels.

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

“…In one study of 27 patients who received palliative thoracic radiation therapy (30 Gy in 10 fractions) followed by pembrolizumab (n = 17), nivolumab (n = 8) or atezolizumab (n = 4) immunotherapy, pre-radiotherapy levels of sialylated carbohydrate antigen KL-6 were shown to predict the likelihood of pneumonitis. 65 Pneumonitis events were grade 1 (n = 10; 34%), grade 2 (n = 4; 14%) and grade 3 (n = 3; 10%) after a median follow-up of 10 months. In that study, dosimetric factors, such as lung V5, V10, V20, V30, and mean lung dose (MLD) did not significantly differ between the grade ≤1 and grade ≥2 pneumonitis groups.…”

“…This relatively high incidence of pneumonitis makes it attractive to identify predictive biomarkers of severe toxicity aside from radiation dosimetric factors. In one study of 27 patients who received palliative thoracic radiation therapy (30 Gy in 10 fractions) followed by pembrolizumab ( n = 17), nivolumab ( n = 8) or atezolizumab ( n = 4) immunotherapy, pre‐radiotherapy levels of sialylated carbohydrate antigen KL‐6 were shown to predict the likelihood of pneumonitis 65 . Pneumonitis events were grade 1 ( n = 10; 34%), grade 2 ( n = 4; 14%) and grade 3 ( n = 3; 10%) after a median follow‐up of 10 months.…”

Safety and Tolerability of Metastasis-Directed Radiation Therapy in the Era of Evolving Systemic, Immune, and Targeted Therapies

“… 102 , 108 , 109 , 110 , 111 With a median follow-up of 10 months, similar radiation pneumonitis rates were reported when immune checkpoint inhibitors were given within a year of palliative RT (30 Gy in 10 fr) to the thorax. 112 Interestingly, 2 cases of radiation recall pneumonitis have been reported up to 2 years after radiation with nivolumab. 113 …”

Safety of thoracic radiotherapy after PD‐(L)1 inhibitor treatment in patients with lung cancer

“…Based on the fact that PD‐(L)1 inhibitor and TRT both can damage the lung, 7,8 there is a theoretical concern that PD‐(L)1 inhibitor combined with TRT irrespective of concurrent or sequential might result in enhanced pulmonary toxicities. Nowadays, available data, though showed a generally acceptable safety profile, mainly focused on the pulmonary toxicities of concurrent combination of PD‐(L)1 inhibitor with TRT or sequential combination of PD‐(L)1 inhibitor with a prior history of TRT 2,9‐12 . Whether regimen of TRT after multicycles of PD‐(L)1 inhibitor‐ induced tolerable pulmonary toxicities was scarcely reported.…”

“…Nowadays, available data, though showed a generally acceptable safety profile, mainly focused on the pulmonary toxicities of concurrent combination of PD-(L)1 inhibitor with TRT or sequential combination of PD-(L)1 inhibitor with a prior history of TRT. 2,[9][10][11][12] Whether regimen of TRT after multicycles of PD-(L)1 inhibitor-induced tolerable pulmonary toxicities was scarcely reported. With the increasing use of PD-(L)1 inhibitor particularly in first-line treatment, it is conceivable that a growing number of patients with lung cancer will be exposed to subsequent TRT.…”