One hundred and six patients were included, and their characteristics are listed in Table 1. The median age of the patients was 64 years (range, 38–82), and 84% were male. Most patients showed a good Eastern Cooperative Oncology Group Performance Status of 0–1. The mean values of PFT did not differ significantly between the two groups. Approximately half of the patients with squamous cell carcinoma and adenocarcinoma were enrolled in the study. Most of the recruited patients (90.6%) were stage III.
Table 1
Patient and disease characteristics
Characteristics | Total (n = 106) | ICI (n = 51) | Non-ICI (n = 55) | p† |
Median age (median, [range]) | 64 | (38–82) | 62 | (36–76) | 66 | (38–82) | 0.004 |
Sex (n [%]) | | | | | | | 0.051 |
Male | 89 | (84.0) | 40 | (78.4) | 49 | (89.1) | |
Female | 17 | (16.0) | 11 | (21.6) | 6 | (10.9) | |
ECOG PS before CCRT (n [%]) | | | | | | | 0.570 |
0–1 | 97 | (91.5) | 45 | (88.2) | 52 | (94.5) | |
2 | 7 | (6.6) | 5 | (9.8) | 2 | (3.6) | |
3 | 2 | (1.9) | 1 | (2.0) | 1 | (1.8) | |
ECOG PS before ICI (n [%]) | | | | | | | |
0–1 | | | 45 | (88.2) | | | |
2 | | | 3 | (5.9) | | | |
Unavailable | | | 3 | (5.9) | | | |
Underlying lung disease (n [%]) | 21 | (19.8) | 9 | (17.6) | 12 | (21.8) | 0.087 |
ILD | 1 | (0.9) | 1 | (2.0) | 0 | (0.0) | |
COPD | 13 | (12.3) | 4 | (7.8) | 9 | (16.4) | |
Asthma | 4 | (3.8) | 0 | (0.0) | 4 | (7.3) | |
TB | 8 | (7.5) | 4 | (7.8) | 4 | (7.3) | |
Smoking status (n [%]) | | | | | | | 0.255 |
(Ex-) smoker | 82 | (77.4) | 37 | (72.5) | 45 | (81.8) | |
Never-smoker | 24 | (22.6) | 14 | (27.5) | 10 | (18.2) | |
PFT (mean, [range]) | | | | | | | |
FVC, % | 83.0 | (54.0–118.0) | 85.0 | (57.0–118.0) | 82.0 | (54.0–110.0) | 0.202 |
FEV1, L | 2.00 | (0.89–3.61) | 3.00 | (0.89–3.57) | 2.00 | (1.05–3.61) | 0.076 |
FEV1, % | 76.0 | (24.0–118.0) | 78.0 | (24.0–118.0) | 74.0 | (33.0–114.0) | 0.221 |
DLCO, % | 75.0 | (36.0–124.0) | 81.0 | (48.0–132.0) | 71.0 | (36.0–124.0) | 0.013 |
Tumor histology (n [%]) | | | | | | | 0.710 |
SqCC | 52 | (49.1) | 22 | (43.1) | 30 | (54.5) | |
Adenocarcinoma | 50 | (47.2) | 29 | (56.9) | 21 | (38.2) | |
Others | 4 | (3.8) | 0 | (0.0) | 4 | (7.3) | |
Tumor location (n [%]) | | | | | | | |
Right upper lobe | 43 | (40.6) | 26 | (51.0) | 17 | (30.9) | 0.018 |
Right middle lobe | 4 | (3.8) | 3 | (5.9) | 1 | (1.8) | |
Right lower lobe | 15 | (14.2) | 5 | (9.8) | 10 | (18.2) | |
Left upper lobe | 32 | (30.2) | 14 | (27.5) | 18 | (32.7) | |
Left lower lobe | 12 | (11.3) | 3 | (5.9) | 9 | (16.4) | |
Stage (n [%]) | | | | | | | 0.657 |
IIA | 10 | (9.4) | 5 | (9.8) | 5 | (9.1) | |
IIIA | 27 | (25.5) | 10 | (19.6) | 17 | (30.9) | |
IIIB | 53 | (50.0) | 29 | (56.9) | 24 | (43.6) | |
IIIC | 16 | (15.1) | 7 | (13.7) | 9 | (16.4) | |
EGFR mutation (n [%]) | | | | | | | |
Positive | 11 | (10.4) | 5 | (9.8) | 6 | (10.9) | 0.334 |
Negative | 36 | (34.0) | 20 | (39.2) | 16 | (29.1) | |
Not checkable | 59 | (55.7) | 26 | (51.0) | 33 | (60.0) | |
PD-L1 test (n [%]) | | | | | | | |
Positive | | | 36 | (70.6) | | | |
Negative | | | 8 | (15.7) | | | |
Not checkable | | | 7 | (13.7) | | | |
Dosimetric parameters | | | | | | | |
PTV size, cm3 (Median, [range]) | 317.6 | (104.8–1250.6) | 329.9 | (136.8–1250.6) | 296.6 | (104.8–847.2) | 0.216 |
MLD, Gy (median, [range]) | 13.1 | (2.7–21.6) | 13.3 | (2.7–21.3) | 12.1 | (3.9–21.6) | 0.919 |
V5, %, (median, [range]) | 45.8 | (7.5–83.5) | 46.8 | (7.5–83.4) | 45.3 | (12.7–83.5) | 0.557 |
V10, %, (median, [range]) | 33.2 | (5.8–61.4) | 33.2 | (5.8–59.9) | 32.8 | (9.5–61.4) | 0.611 |
V20, %, (median, [range]) | 22.3 | (3.2–45.5) | 22.6 | (3.2–45.5) | 20.9 | (7.1–41.4) | 0.982 |
V30, %, (median, [range]) | 16.3 | (1.1–36.5) | 17.5 | (1.1–29.3) | 15.8 | (3.6–36.5) | 0.705 |
V40, % (median, [range]) | 12.3 | (0.3–25.1) | 13.2 | (0.3–25.1) | 11.2 | (2.0–24.0) | 0.399 |
ECOG PS Eastern Cooperative Oncology Group performance status, CCRT Concurrent chemoradiotherapy, ICI Immune checkpoint inhibitor, ILD Interstitial lung disease, COPD Chronic obstructive pulmonary disease, TB Tuberculosis, PFT Pulmonary function test, FVC Forced vital capacity, FEV1 Forced expiratory volume in 1 second, DLCO Diffusing capacity of the lung for CO, SqCC Squamous cell carcinoma, EGRF Epidermal growth factor receptor, PD-L1 Programmed death-ligand 1, PTV Planning target volume, MLD Mean lung dose, VD (V5, V10, V20, V30, V40) The percentage of lung volume receiving more than a threshold radiation dose (5, 10, 20, 30, 40 Gy |
†Significance value for the difference in the distribution of the ICI and non-ICI groups. |
Values are number (percentage) or median (range). Because of rounding, not all percentages total 100. |
The median follow-up period was 11.5 months (range, 3.0–28.2). During this period, RP ≥ grade 2 occurred in 47 patients (44.3%), and six (5.7%) presented with RP ≥ grade 3. Univariate analysis was performed to determine the prognostic factors predicting RP ≥ grade 2. The results are shown in Table 2, and no clinical factor was significant. For the dosimetric factor, a cut-off value was set, and the OR was derived for the occurrence of pneumonitis, by dividing the group into patients with a value higher or lower than this. In univariate analysis for the entire cohort based on the cut-off value derived here, at an MLD of 16 Gy, V20, V30, and V40 showed a significant OR, which might increase the occurrence of RP (MLD, p = 0.026; V20, p = 0.001; V30, p = 0.006; V40, p = 0.002).
Table 2
Clinical and dosimetric factors predicting radiation pneumonitis ≥ grade 2 for patients treated with concurrent chemoradiotherapy
Variable | OR (95% CI) | p | Comparison group |
Clinical factors | | | | |
Age, ≥ 65 years | 1.12 | (0.52–2.41) | 0.778 | < 65 |
ECOG PS before CCRT, ≥ 2 | 3.03 | (0.60–15.33) | 0.180 | < 2 |
ECOG PS before ICI, ≥ 2† | 2.50 | (0.42–15.07) | 0.317 | |
(Ex-) smoker | 1.34 | (0.54–3.34) | 0.526 | Never-smoker |
Underlying lung disease | 1.14 | (0.40–3.23) | 0.806 | No underlying lung disease |
EGFR mutation | 1.20 | (0.31–4.65) | 0.792 | Wild type |
PFT | | | | |
FVC, % | 1.01 | (0.96–1.06) | 0.621 | [Continuous] |
FEV1, L | 1.22 | (0.51–2.92) | 0.661 | [Continuous] |
FEV1, % | 0.98 | (0.94–1.02) | 0.354 | [Continuous] |
DLCO, % | 1.01 | (0.98–1.03) | 0.708 | [Continuous] |
Clinical stage, ≥ IIIA | 1.29 | (0.35–4.73) | 0.706 | Stage II |
Tumor location, lower lobe | 0.43 | (0.17–1.10) | 0.079 | Tumor at RUL, RML, LUL |
Use of ICI | 1.97 | (0.91–4.28) | 0.088 | Non-ICI group |
Dosimetric factors | | | | |
Total dose, > 60 Gy | 1.06 | (0.491–2.31) | 0.876 | ≤ 60 Gy |
PTV volume, ≥ 280 cm3 | 1.49 | (0.68–3.27) | 0.320 | < 280 cm3 |
MLD, ≥ 16 Gy | 2.99 | (1.14–7.85) | 0.026 | < 16 Gy |
V5, ≥ 28% | 2.75 | (0.82–9.16) | 0.100 | < 28% |
V10, ≥ 23% | 2.31 | (0.87–6.17) | 0.094 | < 23% |
V20, ≥ 19% | 4.11 | (1.64–10.30) | 0.001 | < 19% |
V30, ≥ 18% | 3.08 | (1.38–6.85) | 0.006 | < 18% |
V40, ≥ 14% | 3.69 | (1.59–8.56) | 0.002 | < 14% |
OR Odds ratio, CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, CCRT Concurrent chemoradiotherapy, ICI Immune checkpoint inhibitor, EGRF Epidermal growth factor receptor, PFT Pulmonary function test, FVC Forced vital capacity, FEV1 Forced expiratory volume in 1 second, DLCO Diffusing capacity of the Lung for CO, RUL Right upper lobe, RML Right middle lobe, LUL Left upper lobe, PTV Planning target volume, MLD Mean lung dose, VD (V5, V10, V20, V30, V40) The percentage of lung volume receiving more than a threshold radiation dose (5, 10, 20, 30, 40 Gy) |
†Only 51 patients from the ICI group |
The incidence of RP ≥ grade 2 was 52.9% for the ICI group, which was approximately 16% higher than that of the non-ICI group, but there was no significant difference (p = 0.088) (Table 3). Severe RP ≥ grade 3 occurred in three patients in both groups, and the incidence in the ICI and non-ICI groups was 5.9% and 5.4%, respectively (p = 0.924). The interval between the end of CCRT and the occurrence of complications was 2.3 months for the ICI group and 3.7 months for the non-ICI group, with no significant difference (p = 0.782). In addition, the duration of steroid use due to pneumonitis was 56 days in the ICI group and 67 days in the non-ICI group, which was also similar in both groups with no significant difference (p = 0.848).
Table 3
Characteristics of radiation pneumonitis according to immune checkpoint inhibitor administration
Characteristics | ICI (n = 51) | Non-ICI (n = 55) | p |
Patients with RP ≥ grade 2 (n [%]) | 27 | (52.9) | 20 | (36.4) | 0.088 |
Patients with RP ≥ grade 3 (n [%]) | 3 | (5.9) | 3 | (5.4) | 0.924 |
Onset time from end of CCRT, month (median, [range]) | 2.3 | (0.0–15.4) | 3.7 | (0.0–7.5) | 0.782 |
Onset time from the start of ICI, month (median, [range])† | 1.4 | (0.0–5.8) | | - | - |
Duration of steroid use, day (median, [range]) | 56 | (16–238) | 67 | (6-114) | 0.848 |
RP Radiation pneumonitis, ICI Immune checkpoint inhibitor, CCRT Concurrent chemoradiotherapy |
†Only for patients with RT pneumonitis ≥ grade 2 |
To establish the dosimetric factors that can predict the RP in each group, a univariate analysis was performed with the same cut-off value used for the entire cohort, and the results are shown in Table 4. In the ICI group, at an MLD of 16 Gy, V30 and V40 could significantly predict the occurrence of RP, and in the non-ICI group, only V20 could significantly predict RP. Therefore, we plotted the cumulative incidence of RP with V40, which showed the most significant relationship in the ROC curve and univariate analysis. Moreover, it was found that the higher the value of V40, the greater the difference in the cumulative incidence between the two groups (Fig. 1). The cumulative incidence of patients with a V40 value of 0–20% was 45.1% in the ICI group and 34.5% in the non-ICI group, showing a difference of approximately 10.6%.
Table 4
Dosimetric factors predicting radiation pneumonitis ≥ grade 2 for patients treated with concurrent chemoradiotherapy using ICI
Variable | ICI (n = 51) | Non-ICI (n = 55) |
OR (95% CI) | p | OR (95% CI) | p |
Total dose, > 60 Gy | 1.06 | (0.35–3.19) | 0.921 | 1.13 | (0.37–3.44) | 0.836 |
PTV volume, ≥ 280 cm3 | 1.18 | (0.37–3.73) | 0.782 | 2.21 | (0.71–6.86) | 0.172 |
MLD, ≥ 16 Gy | 11.5 | (1.33–99.33) | 0.026 | 1.71 | (0.48–6.08) | 0.404 |
V5, ≥ 28% | 4.17 | (0.75–23.06) | 0.102 | 1.86 | (0.34–10.24) | 0.475 |
V10, ≥ 23% | 2.37 | (0.60–9.40) | 0.221 | 2.27 | (0.54–9.47) | 0.262 |
V20, ≥ 19% | 2.88 | (0.74–11.19) | 0.128 | 4.75 | (1.32–17.11) | 0.017 |
V30, ≥ 18% | 3.53 | (1.10–11.36) | 0.034 | 2.67 | (0.86–8.29) | 0.090 |
V40, ≥ 14% | 4.36 | (1.31–14.51) | 0.016 | 2.67 | (0.79–9.03) | 0.115 |
ICI Immune checkpoint inhibitor, OR Odds ratio, CI Confidence interval, PTV Planning target volume, MLD Mean lung dose, VD (V5, V10, V20, V30, V40) The percentage of lung volume receiving more than a threshold radiation dose (5, 10, 20, 30, 40 Gy) |
We also examined whether the interval between the end of CCRT and the start of immunotherapy in the ICI group affected the occurrence of RP. As a result of comparing the incidence of pneumonitis with an interval of 3 months, 51.4% of those who started ICI within 3 months of CCRT and 57.1% of those who started after 3 months had RP ≥ grade 2, showing no significant difference (p = 0.712).
The survival and patterns of recurrence are shown in Additional File 2. In this analysis, only 90 patients were included; we excluded 16 patients who received immunotherapy with palliative and salvage aim within the ICI group. Of the 90 patients, 15 died, with a crude survival rate of 83.3%. LRF occurred in 27 patients (30%), and DM occurred in 17 patients (18.9%): 10 in the ICI group and 7 in the non-ICI group. The most frequent metastasis sites were the bone, the liver, and the brain, in order of frequency.
Toxicity data for all patients are shown in Additional File 3. For acute toxicity, 58 events occurred in 40 patients within the ICI group, and 39 events occurred in 23 patients within the non-ICI group. RP occurred most frequently, followed by esophagitis and dermatitis. In terms of late toxicity, 19 events occurred in 19 patients in the ICI group, and 21 events occurred in 21 patients in the non-ICI group. RP occurred most frequently, and peripheral neuropathy and pneumothorax were rare complications. Ten out of 106 patients (9.4%) had acute toxicity ≥ 3 grade, and three patients (2.8%) had late toxicity ≥ grade 3. Most patients with acute toxicity ≥ grade 3 recovered after various treatments such as antibiotics, steroid treatment, or esophageal stent insertion, but one patient who suffered brachial plexopathy did not improve despite the rehabilitation program. All three patients with late toxicity ≥ grade 3 experienced RP and seemed to improve with inpatient treatment, but two of them died from combined pneumonia and poor lung function.