Front. Oncol. Frontiers in Oncology Front. Oncol. 2234-943X Frontiers Media S.A. 10.3389/fonc.2023.1130406 Oncology Original Research A novel tool to evaluate and quantify radiation pneumonitis: A retrospective analysis of correlation of dosimetric parameters with volume of pneumonia patch Huang Jing-Wen 1 2 Lin Yi-Hui 1 Chang Gee-Chen 2 3 4 5 * † Chen Jeremy J. W. 2 * † 1 Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan 2 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan 3 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 4 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 5 School of Medicine, Chung Shan Medical University, Taichung, Taiwan

Edited by: Andrea Lancia, San Matteo Hospital Foundation (IRCCS), Italy

Reviewed by: Matteo Sepulcri, Veneto Institute of Oncology (IRCCS), Italy; Xingsheng Hu, Second Xiangya Hospital, Central South University, China

*Correspondence: Gee-Chen Chang, geechen@gmail.com; Jeremy J. W. Chen, jwchen@dragon.nchu.edu.tw

†These authors have contributed equally to this work

This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology

 13 03 2023 2023 13 1130406 23 12 2022 21 02 2023 Copyright © 2023 Huang, Lin, Chang and Chen 2023 Huang, Lin, Chang and Chen

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 Introduction

In lung cancer, radiation-induced lung injury (RILI) or radiation pneumonitis (RP) are major concerns after radiotherapy. We investigated the correlation between volumes of RP lesions and their RP grades after radiotherapy.

 Methods and materials

We retrospectively collected data from patients with non-small lung cancer that received curative doses to the thorax without undergoing chest radiotherapy before this treatment course. The post-treatment computed tomography (CT) image was used to register to the planning CT to evaluate the correlation between dosimetric parameters and volume of pneumonia patch by using deformable image registration.

 Results

From January 1, 2019, to December 30, 2020, 71 patients with non-small cell lung cancer with 169 sets of CT images met our criteria for evaluation. In all patient groups, we found the RPv max and RP grade max to be significant (p<0.001). Some parameters that were related to the dose-volume histogram (DVH) and RP were lung Vx (x=1-66 Gy, percentage of lung volume received ≥x Gy), and mean lung dose. Comparing these parameters of the DVH with RP grade max showed that the mean lung dose and lung V1–V31 were significantly correlated. The cut-off point for the occurrence of symptoms in all patient groups, the RPv max value, was 4.79%, while the area under the curve was 0.779. In the groups with grades 1 and 2 RP, the dose curve of 26 Gy covered ≥80% of RP lesions in >80% of patients. Patients who had radiotherapy in combination with chemotherapy had significantly shorter locoregional progression-free survival (p=0.049) than patients who received radiation therapy in combination with target therapy. Patients with RPv max >4.79% demonstrated better OS (p=0.082).

 Conclusion

The percentage of RP lesion volume to total lung volume is a good indicator for quantifying RP. RP lesions can be projected onto the original radiation therapy plan using coverage of the 26 Gy isodose line to determine whether the lesion is RILI.

 radiation pneumonitis NSCLC DVH radiotherapy pneumonia patch Introduction

In recent years, the global incidence of lung cancer has gradually increased (1), and radiation therapy has become a very important role in the treatment of lung cancer. Radiation therapy, a local treatment, is used for intervention in stage I–III lesions that are inappropriate for surgery, postoperative N2 nodal stage (2), oligometastasis (3), polymetastasis (4), or local recurrence/progression (5). However, radiation therapy used in treating the lung areas, including the mediastinal lymph nodes, can cause some damage to normal lung tissue. We refer to this as radiation-induced lung injury (RILI), or, more commonly, radiation pneumonitis (RP). Acute RILI mostly occurs within 6 months after thoracic radiotherapy (6, 7). The management of RP differs from that of other common lung lesions, for example, infection pneumonitis.

Distinguishing between the post-radiotherapy lung lesion and others can be used to direct the clinical treatment and avoid patient exposure to needless antibiotics use. To identify RILI radiation, oncologists need to correlate the post-RT CT images to the dose distribution map-related simulation image.

Since the correlation between volumes of RP lesions and their RP grades after radiotherapy has not been studied before and based on the advancement of modern planning software systems, we hope that in addition to a previous correlation between dose-volume histogram (DVH) and RP grades, fusion post-radiotherapy computed tomography and CT simulation can be used to explore the correlation between RP lesions and RP grading.

 Methods and materials

We retrospectively collected data from patients with non-small lung cancer who underwent curative doses to the thorax (lung tumor, mediastinum lymph nodes, et. al) without undergoing chest radiotherapy before this treatment course. Patients with other malignancies were excluded within five years before lung cancer or uncompleted planned radiotherapy. The CT sets were excluded if subsequent CT confirmed locoregional progression due to hard-to-distinguish lesions between progression and pneumonitis. Further, when sputum culture proved an infection, that was also excluded. This study was approved by the Institutional Review Board of Taichung Veterans General Hospital (approval no. CE22095B). Written informed consent for participation was not required in accordance with national legislation and institutional guidelines.

Treatment planning

The intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) planned to use multiple field technique that was delivered to each patient by a linear accelerator (Varian 21EX and Varian 21iX with Millennium MLC-120, Varian Oncology Systems, Palo Alto, CA, USA) using 6 MV photons. The planning design of the Varian Eclipse planning system (version 6.5) was based on the Acuros XB algorithm. The treatment planning system of Tomotherapy was the Accuray planning station (Hi-Art, version 5.1.7). The treatment dose was 2 Gy once daily, five days a week, and the total dose was ≥56 Gy. Gross tumor volume (GTV) included the primary lung tumor, regional lymph nodes, and/or spine. Clinical target volume (CTV) included GTV plus 5 mm margin. Planning target volume (PTV) included GTV plus 5–6 mm margin. PTV-H refers to the PTV region that was covered by the highest dose. If the treatment field included the lung and bone, the prescribed dose for the bone was 40 Gy in 20 fractions. All plans were optimized to cover 100% of the PTV by 95% of the prescribed dose while minimizing the doses to the organs at risk (OAR) as much as possible.

 RP evaluation

The CT images after radiotherapy were taken at a 5-mm thickness from the clavicular head to the second lumbar (L2) spinal vertebra level to cover the entire thorax, while the intravenous contrast enhancement was performed if there was no contraindication.

We included the deformable image registration of registered CT images after radiotherapy in the CT simulation set. The deformable image registration (DIR) software was embedded in the Varian Eclipse planning system (8, 9). Plan of Tomotherapy (Tomo) was also imported into the Varian Eclipse planning system to calculate the overlapping prescribed dose and pneumonia patch. Because the CT breathing status at follow-up was not the same as that of the CT simulation, the pneumonia patches contoured on the CT during the follow-up period cannot correctly correspond to the image originally planned. Furthermore, inconsistencies in respiratory status can also lead to errors in volume percentages calculation and area of overlap assessment using the dose curve ( Figure 1 ).

(A) Merged image of the post-radiotherapy CT and pre-treatment CT simulation based on a rigid registration process and showing significant inconsistency between respiratory status and lung volumes. (B) Lung volume of the pre-treatment CT simulation (blue: left lung, brown: right lung) projected on the post-radiotherapy CT (based on the rigid registration process). (C) Lung volume of the pre-treatment CT simulation projected on the post-radiotherapy CT (based on deformable image registration). CT, computed tomography.

The morphological evaluation of RP on CT appearance was judged according to Linda’s classification (10), while the labeling region included four patterns (1): diffuse consolidation (2), diffuse ground-glass opacity (GGO) (3), patchy consolidation and GGO, and (4) patchy GGO ( Figure 2 ). Initial manual labeling of the CT scans was performed by a radiation oncologist (J-WH) with subsequent review by a thoracic medical doctor (G-CC). RP lesions on the grade 1 of CT images after radiotherapy were defined as RP1 (radiation pneumonitis grade 1), and so on, including the RP2 and RP3 and the calculated total volume of the original lung (based on the CT simulation). The volume ratio was defined as RPv1 (RP1 volume/total lung volume), RPv2 (RP2 volume/total lung volume), and RPv3 (RP3 volume/total lung volume). The severity of RP was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), ver.4.0. Furthermore, the grades of RP, when the CT images were evaluated, were defined as RP1, RP2, and RP3 grades, in chronological order. RP at follow-up for each patient was defined as RP grade max (radiation pneumonitis grade max), which was the most severe degree. Moreover, RP max volume/total lung volume was defined as RPv max. The time interval from completion of radiation therapy to RP grade max was defined as the number of days after completion of therapy until the onset of RP grade max or the onset of RPv max (for the same RP grade).

(A) Diffuse consolidation in a 70-year-old man with T4 N3 M0 non-small cell carcinoma, 70 days after completing radiotherapy (sequential chemotherapy followed by radiotherapy). (B) Diffuse ground-glass opacity (GGO) in a 55-year-old woman with T2a N2 M1c non-small cell carcinoma, 27 days after completing consolidative radiotherapy (arrow). (C) Patchy consolidation and GGO in a 75-year-old man with T4 N2 M0 non-small cell carcinoma, 98 days after completing concurrent chemoradiotherapy. (D) Patchy GGO same patient as (B) but occurring in the right lung (arrowhead).

 Survival analysis

Locoregional progression-free survival (LRPFS) was defined as the time from the completion of radiotherapy to the treatment field which received radiotherapy recurrence. Progression-free survival (PFS) was the time from the completion of radiotherapy to disease progression. Overall survival (OS) was the time from the completion of radiotherapy to death of any cause. Combined treatment, such as immunotherapy, will affect disease progression and survival. Thus, for analysis, LRPFS, PFS, and OS were collected by combining target therapy or chemotherapy groups.

 Statistical analyses

Kruskal-Wallis test was used to determine if there were statistically significant differences between RP groups in independent variables, including DVH parameters and RPv max. Dunn-Bonferroni post hoc was used for pairwise comparison for the significant Kruskal-Wallis test. Mann-Whitney U test was used to compare the interval between grade 1 and grade ≥2 RP (symptomatic RP). The main application difference between the Mann-Whitney U and the Kruskal-Wallis H tests is that the latter can accommodate more than two groups (grade1, grade 2, and grade 3 pneumonitis). Spearman’s rank correlation coefficient was used to assess the relationship between RPv max (%) and lung Vx (x=1-66Gy, %). The log-rank test was applied to estimate LRPFS, PFS, and OS. The univariate Cox regression analysis was used to evaluate hazard ratio (HR) of prognostic factors on LRPFS, PFS, and OS. A p-value <0.05 was considered statistically significant. To predict symptomatic RP, the receiver operating characteristic (ROC) curve was used to compare the sensitivity versus specificity across a range of dosimetric parameters and RP volumes. All statistical analyses were performed by IBM SPSS Statistics for Windows, version 27 (IBM Corp., Armonk, NY, USA).

 Results

From January 1, 2019, to December 30, 2020, 71 patients with non-small cell lung cancer met our criteria for evaluation, with a total of 169 sets of CT images, including 71, 55, and 43 sets of first CT images after receiving radiotherapy, 3 months after CT follow-up in the first group, and another 3 months afterward, respectively.

The patient characteristics are described in Table 1 . The patients’ median age was 65 years (range, 42–86 years), the proportion of males was 60.56%, and the proportions of radiation therapy for curative, salvage, and consolidation purposes were 36.62%, 8.45%, and 54.93%, respectively. Doses ≥60 Gy accounted for 98.59% (n=70), while the lowest prescribed dose was 56 Gy. The dominant histological type was adenocarcinoma, accounting for 70%. The proportions of IMRT, VMAT, and Tomo in the treatment technology were 63.38%, 35.21%, and 1.41%, respectively. The combined treatment consisted mainly of target therapy and chemotherapy, with proportions of 49.30% and 35.21%, respectively. The treatment site was mainly the primary lung tumor, accounting for 56.34%. The proportions of RP grade max in grades 1, 2, and 3 were 51%, 45%, and 4%, respectively.

Patient characteristics.

Total (n=71)
Age, years 65 (42–86)
Age ≥65 years 36 (50.70%)
Sex
 Female 28 (39.44%)
 Male 43 (60.56%)
RT dose1(Gy)
 56 1 (1.41%)
 60 49 (69.01%)
 64 12 (16.90%)
 66 9 (12.68%)
RT dose ≥60Gy 70 (98.59%)
Histology
 Adenocarcinoma 50 (70.42%)
 Squamous 17 (23.94%)
 Ca. PD 3 (4.23%)
 Neuroendocrine 1 (1.41%)
Technique
 IMRT 45 (63.38%)
 VMAT 25 (35.21%)
 Tomo 1 (1.41%)
Treatment type
 No 8 (11.27%)
 Target2 35 (49.30%)
 C/T 25 (35.21%)
 C/T + IO3 3 (4.23%)
Purpose
 Consolidative 39 (54.93%)
 Curative 26 (36.62%)
 Salvage 6 (8.45%)
Treatment site group
 Lung 40 (56.34%)
 Lung+bone 3 (4.23%)
 Lung+regional LNs 21 (29.58%)
 Lung+regional LNs+bone 1 (1.41%)
 Regional LNs 6 (8.45%)
 PTV-H volume4(c.c) 199.20 (34.6-1020)
RP grade max5
 Grade 1 36 (51%)
 Grade 2 32 (45%)
 Grade 3 3 (4%)

1: highest prescribed dose.

2: Target therapy included tyrosine kinase inhibitor that targets EGFR and ALK, serine/threonine kinase (BRAF) inhibitor (dabrafenib) and mitogen-activated protein kinase (MEK) inhibitor (trametinib).

3: IO means immunotherapy.

4: PTV-H refers to the PTV region covered by the highest dose i.e., if the treatment field included the lung and bone, the prescribed dose for the lung was PTV-H and that for the bone was 40 Gy in 20 fractions.

5: RP grade max (radiation pneumonitis grade max) was defined as the most severe degree of RP at follow-up for each patient.

 Interval to RP grade max

The first set of CTs was performed from 5 to 190 days; the interval to symptomatic RP grade max (grade ≥2) was from 24 to 190 days, to grade 3 RP was 27 to 70 days, and RP grade 0 was from 17 to 50 days ( Table 2 ). If grade 3 RP occurs, it is usually distributed at ≤70 days after radiotherapy; on the contrary, for mild (grade <2) RP, especially grade 0 pneumonitis, intervals to RP grade 0 were from 17 to 50 days.

RP grade max and interval of days to RP.

RP grade max1 Interval to RP1 Interval to RP2 Interval to RP3 Interval to RP max grade
1 44 133 233 133
1 80 164 269 80
2 30 136 216 136
2 126 231 301 126
2 105 217 329 105
2 120 218 407 120
1 36 127 304 127
2 72 184 296 72
1 112 210 112
2 135 248 357 135
1 17 17
1 111 195 279 279
1 5 102 201 201
1 131 131
2 190 190
1 135 135
2 84 168 252 84
1 25 117 229 117
1 75 141 75
1 50 217 302 302
2 34 34
2 51 161 273 51
2 119 203 315 119
1 55 149 239 149
1 43 43
1 35 133 231 133
1 55 55
1 64 161 64
2 24 24
2 46 136 227 136
2 60 144 215 60
1 24 24
2 45 150 45
3 27 128 212 27
2 62 178 311 62
1 17 114 224 114
2 85 268 357 85
1 55 167 293 55
1 23 23
2 83 181 265 83
2 124 208 293 124
2 128 240 128
2 21 103 103
1 112 224 315 112
1 93 177 317 93
3 48 154 287 48
2 71 147 71
1 83 195 251 83
1 28 126 245 28
2 76 139 76
1 25 130 25
2 36 148 218 148
1 139 230 323 139
2 64 169 295 64
2 98 182 276 98
2 106 106
1 75 131 243 243
1 65 65
2 110 229 110
1 98 98
1 41 41
1 17 80 80
3 70 70
1 73 185 241 185
2 52 89 206 89
1 29 134 260 134
1 96 195 308 96
2 88 172 284 88
2 69 181 281 181
1 31 31
2 98 203 98

1: RP grade max (radiation pneumonitis grade max) was defined as the most severe degree of RP at follow-up for each patient.

In the 169 CT series, 3 CTs without pneumonitis or consolidation lesion were found, also all that presented at first follow-up CT (in RP1 grade). Overall, all patients developed radiation-related lung injuries that could be detected by clinicians on post-radiotherapy CT.

 Dosimetric parameters and volume of pneumonia patch

Symptomatic RP (grade ≥2) occurred more significantly in patients aged ≥65 years (p=0.006). Other factors such as sex, RT dose, or PTV-H volume did not differ between the two groups ( Table 3 ).

Patient characteristics in non-symptomatic and symptomatic RP.

Symptomatic RP p-value
No (n=36) Yes (n=35)
Age, years 60 (42–86) 69 (50–79) 0.009**
Age ≥65 years 12 (33.33%) 24 (68.57%) 0.006**
Sex 0.735
 Female 13 (36.11%) 15 (42.86%)
 Male 23 (63.89%) 20 (57.14%)
RT dose1 (Gy) 0.107
 56 0 (0%) 1 (2.86%)
 60 21 (58.33%) 28 (80.00%)
 64 8 (22.22%) 4 (11.43%)
 66 7 (19.44%) 2 (5.71%)
Histology 0.257
 Adenocarcinoma 25 (69.44%) 25 (71.43%)
 Squamous 8 (22.22%) 9 (25.71%)
 Ca. PD 3 (8.33%) 0 (0%)
 Neuroendocrine 0 (0%) 1 (2.86%)
Technique 0.281
 IMRT 25 (69.44%) 20 (57.14%)
 VMAT 10 (27.78%) 15 (42.86%)
 Tomo 1 (2.78%) 0 (0%)
Combined treatment 0.247
 No 3 (8.33%) 5 (14.29%)
 Target2 22 (61.11%) 13 (37.14%)
 C/T 10 (27.78%) 15 (42.86%)
 C/T + I/O3 1 (2.78%) 2 (5.71%)
Purpose 0.660
 Consolidative 20 (55.56%) 19 (54.29%)
 Curative 12 (33.33%) 14 (40.00%)
 Salvage 4 (11.11%) 2 (5.71%)
Treatment site group 0.341
 Lung 21 (58.33%) 19 (54.29%)
 Lung+bone 0 (0%) 3 (8.57%)
 Lung+regional LNs 12 (33.33%) 9 (25.71%)
 Lung+regional LNs+bone 0 (0%) 1 (2.86%)
 Regional LNs 3 (8.33%) 3 (8.57%)
Treatment site group 0.939
 Lung 21 (58.33%) 19 (54.29%)
 Lung+others 12 (33.33%) 13 (37.14%)
 Regional LNs 3 (8.33%) 3 (8.57%)
PTV-H volume4 (c.c) 176.30 (34.6–1020) 211.20 (53.4–924.1) 0.337

Chi-Square test *p<0.05, **p<0.01.

Categorical variables are presented as frequencies and percentages (%). Continuous variables are presented as medians (ranges).

1: highest prescribed dose.

2: Target therapy including tyrosine kinase inhibitor that targets EGFR and ALK, serine/threonine kinase (BRAF) inhibitor (dabrafenib), and mitogen-activated protein kinase (MEK) inhibitor (trametinib).

3: IO means immunotherapy.

4: PTV-H refers to the PTV region covered by the highest dose i.e., if the treatment field included the lung and bone, the prescribed dose for the lung was PTV-H and that for the bone was 40 Gy in 20 fractions.

We compared RPv max with RP grade max in all patient groups and found a significant difference between RPv max and RP grade max (p<0.001). Some parameters related to DVH and RP included lung Vx (x=1-66 Gy, percentage of lung volume received ≥x Gy) and mean lung dose. Comparing the two parameters, DVH with RP grade max, showed that the mean lung dose and lung V1–V31 were significantly correlated ( Table 4 ).

RP grade max in all patient group.

Lung Vx (x=1-66 Gy)
1 (n=36) 2 (n=32) 3 (n=3) p-value Dunn-bonferroni post hoc
Median (IQR) Median (IQR) Median (IQR) 1 vs. 2 1 vs. 3 2 vs. 3
Mean lung dose (Gy) 10.0 (7.5-11.6) 10.7 (9-12.9) 17.8 (12.7-) 0.008** 0.202 0.015* 0.116
RPv max1 (%) 2.9% (1.1%-5.5%) 6.6% (3.9%-8.9%) 30.4% (17.2%-) <0.001** 0.001** 0.002** 0.122
1 Gy 74.1% (51%-84.1%) 75.1% (56.1%-88.9%) 94.7% (89.8%-) 0.024* 1.000 0.020* 0.054
2 Gy 57.9% (38.9%-64.6%) 59.1% (39.7%-70.3%) 79.0% (75.4%-) 0.023* 0.903 0.021* 0.071
3 Gy 49.3% (33.7%-56.4%) 51.9% (33.2%-59.6%) 68.7% (65.5%-) 0.027* 0.902 0.025* 0.081
4 Gy 41.6% (29.9%-52.1%) 46.6% (30.9%-54.6%) 62.4% (59.1%-) 0.033* 1.000 0.031* 0.090
5 Gy 38.0% (26.2%-49%) 41.9% (29.1%-49.7%) 57.5% (54.2%-) 0.029* 1.000 0.026* 0.078
6 Gy 33.0% (23.7%-45.7%) 36.6% (26.1%-46.3%) 53.4% (50%-) 0.023* 0.815 0.022* 0.079
7 Gy 29.7% (21.7%-39.1%) 34.8% (23.5%-42.4%) 49.8% (45.8%-) 0.018* 0.593 0.020* 0.087
8 Gy 27.5% (19.5%-36.5%) 32.0% (22.5%-38.7%) 46.7% (42.1%-) 0.019* 0.575 0.021* 0.094
9 Gy 25.7% (18.3%-33.7%) 29.6% (20.9%-36%) 43.9% (39.3%-) 0.020* 0.557 0.023* 0.102
10 Gy 24.1% (17.5%-31.6%) 27.6% (20.4%-33.2%) 41.2% (36.9%-) 0.015* 0.424 0.020* 0.103
11 Gy 22.8% (16.5%-29.1%) 24.7% (19.9%-31.8%) 38.6% (34.5%-) 0.016* 0.464 0.020* 0.100
12 Gy 21.7% (15.2%-26.7%) 23.5% (19.3%-30.6%) 36.0% (32.4%-) 0.019* 0.473 0.024* 0.115
13 Gy 20.4% (14.9%-25.4%) 23.1% (18.3%-29.4%) 33.5% (30.5%-) 0.018* 0.409 0.025* 0.127
14 Gy 19.4% (14.6%-23.6%) 21.9% (17.7%-28.4%) 31.1% (28.7%-) 0.017* 0.328 0.025* 0.144
15 Gy 18.3% (14.3%-22.9%) 20.9% (16.9%-27.6%) 29.0% (27%-) 0.013* 0.217 0.025* 0.169
16 Gy 17.4% (14%-22.2%) 19.9% (16.1%-26.8%) 27.0% (25.4%-) 0.012* 0.156 0.029* 0.219
17 Gy 16.5% (13.7%-21.4%) 19.1% (15.4%-26.1%) 25.2% (24%-) 0.012* 0.130 0.035* 0.272
18 Gy 15.9% (13.4%-20.9%) 18.4% (14.7%-25.5%) 23.6% (22.7%-) 0.013* 0.124 0.038* 0.291
19 Gy 15.3% (13.2%-20.2%) 17.9% (14.2%-24.9%) 22.0% (21.6%-) 0.017* 0.113 0.059 0.413
20 Gy 14.8% (12.9%-19%) 17.3% (13.9%-23.8%) 20.6% (20.6%-) 0.020* 0.097 0.089 0.577
21 Gy 14.3% (12.5%-18.5%) 16.6% (13.5%-22.7%) 19.8% (19.3%-) 0.024* 0.097 0.117 0.700
22 Gy 13.7% (11.8%-18.2%) 16.2% (13.1%-21.8%) 19.1% (18.1%-) 0.024* 0.090 0.124 0.741
23 Gy 13.3% (11.3%-17.8%) 15.9% (12.5%-20.2%) 18.4% (16.9%-) 0.030* 0.117 0.130 0.714
24 Gy 12.9% (11%-17%) 15.7% (12.1%-19%) 17.7% (15.9%-) 0.033* 0.117 0.149 0.783
25 Gy 12.4% (10.7%-16.2%) 15.5% (11.8%-18.3%) 17.1% (14.8%-) 0.035* 0.101 0.187 0.952
26 Gy 11.9% (10.1%-15.6%) 15.2% (11.5%-17.8%) 16.5% (13.9%-) 0.031* 0.084 0.193 1.000
27 Gy 11.3% (9.1%-15.2%) 14.5% (11.1%-17.3%) 16.0% (13%-) 0.030* 0.067 0.238 1.000
28 Gy 11.0% (8.3%-14.9%) 13.9% (10.9%-16.9%) 15.4% (12.1%-) 0.036* 0.068 0.321 1.000
29 Gy 10.7% (8.1%-14.6%) 13.6% (10.8%-16.6%) 14.9% (11.2%-) 0.040* 0.065 0.399 1.000
30 Gy 10.5% (7.8%-14.4%) 13.3% (10.6%-16.3%) 14.4% (10.3%-) 0.043* 0.060 0.514 1.000
31 Gy 10.2% (7.6%-14.1%) 13.0% (10.3%-15.5%) 13.9% (9.3%-0%) 0.046* 0.054 0.682 1.000
32 Gy 9.7% (7.3%-13.9%) 12.7% (9.9%-14.8%) 13.3% (8.3%-) 0.057
33 Gy 9.3% (7%-13.5%) 12.3% (9.3%-14.3%) 12.7% (7.3%-) 0.069
34 Gy 9.0% (6.7%-12.9%) 11.9% (8.7%-14%) 12.2% (6.3%-) 0.073
35 Gy 8.7% (6.4%-12.3%) 11.3% (8.2%-13.8%) 11.6% (5.4%-) 0.086
36 Gy 8.4% (6.2%-11.8%) 10.8% (7.9%-13.5%) 11.0% (4.5%-) 0.098
37 Gy 8.2% (6%-11.4%) 10.5% (7.7%-13.3%) 10.6% (3.5%-) 0.092
38 Gy 7.9% (5.8%-11.1%) 10.1% (7.4%-13%) 10.2% (2.3%-) 0.109
39 Gy 7.5% (5.6%-10.7%) 9.7% (7.1%-12.7%) 9.8% (1.2%-) 0.106
40 Gy 7.2% (5.4%-10.4%) 9.3% (6.8%-12.2%) 9.4% (0.4%-) 0.107
41 Gy 6.9% (5.2%-10%) 8.9% (6.6%-11.7%) 9.0% (0.1%-) 0.114
42 Gy 6.7% (5%-9.7%) 8.5% (6.3%-11.2%) 8.6% (0%-) 0.115
43 Gy 6.4% (4.8%-9.5%) 8.2% (6.1%-10.8%) 8.3% (0%-) 0.092
44 Gy 6.1% (4.6%-9.2%) 7.9% (5.8%-10.5%) 7.9% (0%-) 0.085
45 Gy 5.9% (4.4%-9%) 7.6% (5.6%-10.2%) 7.6% (0%-) 0.077
46 Gy 5.6% (4.2%-8.6%) 7.3% (5.4%-9.9%) 7.2% (0%-) 0.072
47 Gy 5.3% (4%-8.2%) 7.0% (5.2%-9.5%) 6.8% (0%-) 0.083
48 Gy 5.1% (3.7%-7.9%) 6.7% (5%-9.2%) 6.4% (0%-) 0.079
49 Gy 4.9% (3.5%-7.5%) 6.5% (4.9%-8.8%) 6.0% (0%-) 0.083
50 Gy 4.7% (3.3%-7.2%) 6.3% (4.7%-8.5%) 5.6% (0%-) 0.079
51 Gy 4.5% (3.2%-6.9%) 6.0% (4.5%-8.2%) 5.3% (0%-) 0.074
52 Gy 4.2% (3%-6.5%) 5.7% (4.2%-7.8%) 4.9% (0%-) 0.073
53 Gy 4.0% (2.8%-6.1%) 5.3% (3.9%-7.5%) 4.6% (0%-) 0.081
54 Gy 3.8% (2.5%-5.7%) 4.9% (3.7%-7%) 4.3% (0%-) 0.098
55 Gy 3.4% (2.4%-5.4%) 4.3% (3.6%-6.5%) 4.0% (0%-) 0.123
56 Gy 3.2% (2.2%-5%) 3.9% (3.4%-6%) 3.6% (0%-) 0.149
57 Gy 3.0% (2%-4.5%) 3.7% (3%-5.7%) 3.2% (0%-) 0.167
58 Gy 2.8% (1.7%-4%) 3.3% (2.5%-5.2%) 2.9% (0%-) 0.180
59 Gy 2.5% (1.6%-3.6%) 3.0% (2%-4.6%) 2.4% (0%-) 0.207
60 Gy 2.2% (1.4%-3.4%) 2.5% (1.6%-4%) 2.0% (0%-) 0.261
61 Gy 1.9% (1.2%-2.9%) 2.1% (1.3%-3.5%) 1.5% (0%-) 0.336
62 Gy 1.6% (1%-2.5%) 1.4% (0.7%-2.7%) 0.9% (0%-) 0.363
63 Gy 1.2% (0.5%-2.1%) 0.9% (0.2%-2%) 0.5% (0%-) 0.254
64 Gy 0.9% (0.2%-1.7%) 0.5% (0%-1.4%) 0.3% (0%-) 0.108
65 Gy 0.6% (0.1%-1.3%) 0.2% (0%-0.6%) 0.1% (0%-) 0.089
66 Gy 0.4% (0%-1%) 0.1% (0%-0.4%) 0.0% (0%-) 0.059

Kruskal Wallis test. *p<0.05, **p<0.01.

1: the value of RP max volume/total lung volume.

When we differentiated between grades of RP with or without symptoms, there was also a significant difference in RPv max (p<0.001). Statistically significant differences in the lung mean dose, V10, V13–V46, and V48 were observed in the DVH portion of the lung ( Table 5 ). Because age is also a factor in the occurrence of symptomatic RP, we divided the participants by age into ≥65 years and <65 years. Within these age groups, RPv max was significantly different between symptomatic and asymptomatic patients ( Table 6 ), while mean lung dose only differed significantly between symptomatic and asymptomatic patients in the ≥65 years age group (p=0.041).

Symptomatic RP.

Lung Vx (x=1-66 Gy)
No symptoms (n=36) Symptomatic (n=35) p-value
Median IQR Median IQR
Mean lung dose (Gy) 10.0 (7.5-11.6) 11.0 (9.4-14.5) 0.020*
RPv max1 (%) 2.9% (1.1%-5.5%) 6.9% (5%-10%) <0.001**
1 Gy 74.1% (51%-84.1%) 76.1% (56.2%-89.8%) 0.175
2 Gy 57.9% (38.9%-64.6%) 63.9% (40.7%-71.5%) 0.121
3 Gy 49.3% (33.7%-56.4%) 55.0% (34.8%-64.7%) 0.123
4 Gy 41.6% (29.9%-52.1%) 49.6% (31.5%-59.1%) 0.144
5 Gy 38.0% (26.2%-49%) 44.6% (29.6%-54.2%) 0.141
6 Gy 33.0% (23.7%-45.7%) 41.9% (26.7%-50%) 0.107
7 Gy 29.7% (21.7%-39.1%) 36.0% (23.6%-45.3%) 0.073
8 Gy 27.5% (19.5%-36.5%) 34.1% (22.5%-41.5%) 0.071
9 Gy 25.7% (18.3%-33.7%) 32.2% (21.3%-39.3%) 0.069
10 Gy 24.1% (17.5%-31.6%) 29.2% (20.6%-36.9%) 0.049*
11 Gy 22.8% (16.5%-29.1%) 27.9% (20%-34.5%) 0.055
12 Gy 21.7% (15.2%-26.7%) 26.7% (19.3%-32.4%) 0.058
13 Gy 20.4% (14.9%-25.4%) 24.4% (18.6%-30.5%) 0.049*
14 Gy 19.4% (14.6%-23.6%) 22.9% (18%-29.4%) 0.038*
15 Gy 18.3% (14.3%-22.9%) 21.4% (17.5%-28.8%) 0.024*
16 Gy 17.4% (14%-22.2%) 20.8% (17%-27.3%) 0.017*
17 Gy 16.5% (13.7%-21.4%) 20.4% (16.7%-26.7%) 0.015*
18 Gy 15.9% (13.4%-20.9%) 19.3% (16.2%-26.1%) 0.014*
19 Gy 15.3% (13.2%-20.2%) 18.2% (15.6%-25.6%) 0.014*
20 Gy 14.8% (12.9%-19%) 17.8% (14.8%-24.4%) 0.013*
21 Gy 14.3% (12.5%-18.5%) 17.5% (14%-23.2%) 0.014*
22 Gy 13.7% (11.8%-18.2%) 17.3% (13.2%-22.2%) 0.013*
23 Gy 13.3% (11.3%-17.8%) 16.9% (12.6%-20.4%) 0.018*
24 Gy 12.9% (11%-17%) 15.9% (12.3%-19.1%) 0.018*
25 Gy 12.4% (10.7%-16.2%) 15.6% (12.1%-18.5%) 0.017*
26 Gy 11.9% (10.1%-15.6%) 15.2% (11.9%-17.8%) 0.014*
27 Gy 11.3% (9.1%-15.2%) 14.5% (11.8%-17.3%) 0.012*
28 Gy 11.0% (8.3%-14.9%) 14.2% (11.6%-17%) 0.013*
29 Gy 10.7% (8.1%-14.6%) 13.9% (11.2%-16.8%) 0.013*
30 Gy 10.5% (7.8%-14.4%) 13.6% (10.4%-16.5%) 0.013*
31 Gy 10.2% (7.6%-14.1%) 13.3% (10.2%-15.7%) 0.013*
32 Gy 9.7% (7.3%-13.9%) 12.8% (9.8%-14.8%) 0.017*
33 Gy 9.3% (7%-13.5%) 12.4% (9.2%-14.4%) 0.021*
34 Gy 9.0% (6.7%-12.9%) 11.9% (8.6%-14.1%) 0.022*
35 Gy 8.7% (6.4%-12.3%) 11.3% (8.1%-13.8%) 0.027*
36 Gy 8.4% (6.2%-11.8%) 10.8% (7.8%-13.6%) 0.032*
37 Gy 8.2% (6%-11.4%) 10.5% (7.6%-13.4%) 0.031*
38 Gy 7.9% (5.8%-11.1%) 10.1% (7.4%-13.2%) 0.040*
39 Gy 7.5% (5.6%-10.7%) 9.7% (7.1%-12.8%) 0.040*
40 Gy 7.2% (5.4%-10.4%) 9.4% (6.8%-12.2%) 0.043*
41 Gy 6.9% (5.2%-10%) 9.0% (6.5%-11.4%) 0.045*
42 Gy 6.7% (5%-9.7%) 8.5% (6.3%-10.8%) 0.048*
43 Gy 6.4% (4.8%-9.5%) 8.2% (6%-10.2%) 0.041*
44 Gy 6.1% (4.6%-9.2%) 7.9% (5.8%-10%) 0.040*
45 Gy 5.9% (4.4%-9%) 7.6% (5.5%-9.8%) 0.037*
46 Gy 5.6% (4.2%-8.6%) 7.2% (5.3%-9.6%) 0.041*
47 Gy 5.3% (4%-8.2%) 6.9% (5.2%-9.3%) 0.051
48 Gy 5.1% (3.7%-7.9%) 6.7% (5%-9.1%) 0.049*
49 Gy 4.9% (3.5%-7.5%) 6.4% (4.8%-8.8%) 0.053
50 Gy 4.7% (3.3%-7.2%) 6.2% (4.6%-8.4%) 0.054
51 Gy 4.5% (3.2%-6.9%) 5.9% (4.4%-8%) 0.054
52 Gy 4.2% (3%-6.5%) 5.5% (4.2%-7.6%) 0.051
53 Gy 4.0% (2.8%-6.1%) 5.1% (3.9%-7.2%) 0.055
54 Gy 3.8% (2.5%-5.7%) 4.7% (3.7%-6.8%) 0.070
55 Gy 3.4% (2.4%-5.4%) 4.2% (3.5%-6.5%) 0.090
56 Gy 3.2% (2.2%-5%) 3.8% (3.4%-5.9%) 0.119
57 Gy 3.0% (2%-4.5%) 3.4% (3%-5.7%) 0.146
58 Gy 2.8% (1.7%-4%) 3.0% (2.5%-5.2%) 0.212
59 Gy 2.5% (1.6%-3.6%) 2.8% (2%-4.5%) 0.314
60 Gy 2.2% (1.4%-3.4%) 2.4% (1.5%-3.8%) 0.577
61 Gy 1.9% (1.2%-2.9%) 1.9% (1.3%-3.4%) 0.913
62 Gy 1.6% (1%-2.5%) 1.4% (0.7%-2.6%) 0.538
63 Gy 1.2% (0.5%-2.1%) 0.8% (0.2%-1.9%) 0.192
64 Gy 0.9% (0.2%-1.7%) 0.4% (0%-1.2%) 0.047*
65 Gy 0.6% (0.1%-1.3%) 0.1% (0%-0.6%) 0.031*
66 Gy 0.4% (0%-1%) 0.0% (0%-0.4%) 0.018*

Mann-Whitney test. *p<0.05, **p<0.01.

1: the value of RP max volume/total lung volume.

Symptomatic RP in the <65 and ≥65 years age group.

Age <65 years Age ≥65 years
Symptomatic RP p-value Symptomatic RP p-value
No (n=24) Yes (n=11) No (n=12) Yes (n=24)
Median IQR Median IQR median IQR Median IQR
Mean lung dose (Gy) 10.1 (8-12.1) 10.7 (9.4-11.9) 0.334 9.1 (6-11.5) 11.1 (9-14.9) 0.041*
RPv max1 (%) 3.1% (1%-5.5%) 5.9% (3.2%-10.4%) 0.025* 2.6% (1.7%-5.7%) 7.0% (5%-9.7%) 0.003**
1 Gy 72.6% (53.6%-84.2%) 69.5% (47%-89%) 0.930 78.5% (43.5%-84.1%) 77.9% (59.5%-90%) 0.199
2 Gy 58.4% (42.5%-64.6%) 58.5% (35.3%-70.7%) 0.930 52.8% (33.4%-64.5%) 66.2% (43.6%-74.8%) 0.090
3 Gy 51.4% (37.3%-56.1%) 48.2% (31.4%-58.2%) 0.820 42.6% (29.4%-57.5%) 56.9% (38.8%-67%) 0.097
4 Gy 42.8% (33.1%-51.3%) 41.9% (28.4%-51.8%) 0.875 37.8% (26.5%-54.1%) 51.0% (35.5%-61.9%) 0.128
5 Gy 39.4% (30.3%-47.2%) 38.4% (25%-48.1%) 0.930 32.8% (23.7%-51.6%) 46.0% (31.3%-56.1%) 0.097
6 Gy 33.4% (25.2%-43.7%) 36.0% (22.1%-44.3%) 1.000 28.8% (20.2%-46.7%) 42.7% (28.6%-51.7%) 0.084
7 Gy 29.7% (22.8%-38.3%) 34.1% (20.4%-40.8%) 0.903 26.5% (16.6%-44.5%) 39.8% (24.9%-47.7%) 0.097
8 Gy 27.8% (21.5%-36%) 31.7% (19.9%-37.8%) 0.740 24.5% (15.1%-42.5%) 36.7% (22.6%-45.1%) 0.104
9 Gy 25.7% (20.6%-33.3%) 28.5% (19.5%-35%) 0.793 22.8% (14.4%-37.2%) 33.7% (21.8%-42.1%) 0.078
10 Gy 24.1% (19.7%-30.8%) 26.4% (19.1%-32.1%) 0.636 21.5% (13.9%-32.8%) 32.2% (20.8%-39.4%) 0.062
11 Gy 22.8% (19.2%-28.5%) 24.1% (18.8%-29.3%) 0.713 20.5% (13.2%-30.1%) 30.0% (20%-37.3%) 0.057
12 Gy 21.7% (18.5%-26.7%) 22.2% (18.5%-26.8%) 0.687 19.1% (12.8%-27.5%) 28.0% (19.4%-35.3%) 0.053
13 Gy 20.7% (17.7%-25.4%) 21.8% (17.9%-25.7%) 0.713 17.8% (11.7%-25%) 26.6% (18.7%-33.5%) 0.041*
14 Gy 19.6% (17%-24.3%) 21.5% (16%-24.9%) 0.793 16.8% (11.1%-23.2%) 25.3% (18.1%-32.3%) 0.026*
15 Gy 18.7% (16.3%-23.3%) 21.1% (14.6%-24.1%) 0.687 16.0% (10.5%-22%) 24.1% (17.5%-31.3%) 0.020*
16 Gy 18.0% (15.7%-22.5%) 20.1% (14%-23.4%) 0.587 15.3% (9.9%-21.4%) 23.0% (17.1%-30.4%) 0.013*
17 Gy 17.4% (15.2%-21.9%) 19.0% (13.8%-22.6%) 0.587 14.6% (9.3%-20.9%) 22.0% (16.7%-29.2%) 0.011*
18 Gy 16.7% (14.7%-21.4%) 18.0% (13.5%-22%) 0.587 14.1% (8.9%-20.4%) 21.0% (16.3%-27.6%) 0.010*
19 Gy 16.1% (14.2%-20.8%) 17.2% (13.3%-21.4%) 0.563 13.6% (8.7%-19.6%) 19.9% (15.6%-26.2%) 0.009**
20 Gy 15.3% (13.7%-20.2%) 16.6% (13.1%-20.6%) 0.540 13.2% (8.4%-18.4%) 19.2% (14.9%-25.5%) 0.010*
21 Gy 14.6% (13.5%-19.7%) 16.4% (12.9%-19.8%) 0.517 12.8% (8.2%-17.3%) 18.6% (14.1%-24.6%) 0.010*
22 Gy 14.1% (13.1%-19.3%) 16.2% (12.7%-18.9%) 0.472 12.5% (7.9%-16.3%) 18.2% (13.3%-23.4%) 0.007**
23 Gy 13.6% (12.7%-18.8%) 16.0% (12.5%-18.3%) 0.472 12.1% (7.7%-15.4%) 17.7% (12.7%-22.5%) 0.009**
24 Gy 13.0% (12.3%-18.4%) 15.8% (12.3%-17.8%) 0.472 11.8% (7.6%-14.5%) 17.1% (12.3%-21.7%) 0.009**
25 Gy 12.7% (11.7%-18%) 14.8% (12.1%-17.2%) 0.430 11.5% (7.4%-13.8%) 16.4% (11.9%-21%) 0.009**
26 Gy 12.5% (11.2%-17.6%) 13.9% (11.9%-16.6%) 0.375 11.2% (7.2%-13%) 15.5% (11.6%-20.4%) 0.010*
27 Gy 12.3% (10.7%-17.2%) 13.6% (11.8%-16%) 0.299 10.9% (7%-12.4%) 14.7% (11.3%-19.8%) 0.011*
28 Gy 12.0% (10.2%-16.7%) 13.4% (11.6%-15.4%) 0.316 10.6% (6.8%-12%) 14.5% (10.9%-18.8%) 0.012*
29 Gy 11.6% (9.6%-16.2%) 13.2% (11.2%-14.9%) 0.299 10.2% (6.7%-11.5%) 14.2% (10.6%-18.1%) 0.012*
30 Gy 11.1% (9.2%-15.7%) 12.9% (10.4%-14.7%) 0.238 9.8% (6.4%-11.1%) 13.9% (10.1%-17.5%) 0.012*
31 Gy 10.6% (8.7%-15.3%) 12.7% (10.2%-14.5%) 0.252 9.5% (6.2%-10.7%) 13.5% (9.6%-16.9%) 0.012*
32 Gy 10.1% (8.3%-14.8%) 12.5% (10.1%-14.3%) 0.238 9.2% (5.9%-10.3%) 13.1% (9.2%-16.2%) 0.022*
33 Gy 9.7% (7.9%-14.1%) 12.3% (10%-14.1%) 0.238 8.8% (5.6%-10%) 12.6% (8.8%-15.6%) 0.029*
34 Gy 9.3% (7.6%-13.6%) 11.8% (9.8%-13.9%) 0.224 8.5% (5.3%-9.8%) 12.0% (8.4%-15.1%) 0.032*
35 Gy 8.9% (7.2%-13.1%) 11.3% (9.6%-13.8%) 0.224 8.2% (4.8%-9.7%) 11.4% (7.9%-14.6%) 0.032*
36 Gy 8.6% (6.9%-12.7%) 10.8% (9.4%-13.6%) 0.252 7.9% (4.4%-9.5%) 10.9% (7.5%-14.2%) 0.038*
37 Gy 8.2% (6.6%-12.2%) 10.3% (9.1%-13.4%) 0.252 7.6% (4.3%-9.3%) 10.5% (7.1%-13.7%) 0.038*
38 Gy 8.0% (6.3%-11.8%) 9.9% (8.8%-13.2%) 0.268 7.4% (4.1%-9.1%) 10.1% (6.9%-13.1%) 0.041*
39 Gy 7.7% (6%-11.4%) 9.5% (8.4%-13%) 0.252 7.1% (4%-9%) 9.8% (6.7%-12.7%) 0.038*
40 Gy 7.5% (5.8%-10.9%) 9.2% (8.1%-12.7%) 0.238 6.8% (3.9%-8.8%) 9.4% (6.4%-12.1%) 0.041*
41 Gy 7.3% (5.6%-10.5%) 8.8% (7.8%-12.5%) 0.224 6.6% (3.8%-8.6%) 9.0% (6.2%-11.4%) 0.049*
42 Gy 7.0% (5.4%-10.1%) 8.5% (7.5%-12.3%) 0.211 6.3% (3.7%-8.5%) 8.6% (6%-10.7%) 0.062
43 Gy 6.8% (5.2%-9.8%) 8.2% (7.2%-12%) 0.163 6.0% (3.5%-8.3%) 8.2% (5.8%-10.1%) 0.061
44 Gy 6.6% (5%-9.4%) 7.9% (6.9%-11.8%) 0.152 5.7% (3.4%-8.1%) 7.9% (5.6%-9.8%) 0.057
45 Gy 6.3% (4.8%-9.1%) 7.6% (6.6%-11.5%) 0.152 5.4% (3.3%-7.9%) 7.6% (5.4%-9.5%) 0.041*
46 Gy 6.1% (4.5%-8.8%) 7.4% (6.3%-11.2%) 0.154 5.2% (3.2%-7.7%) 7.2% (5.2%-9.1%) 0.035*
47 Gy 5.8% (4.3%-8.4%) 7.1% (6%-11%) 0.201 4.9% (3.2%-7.5%) 6.8% (5.1%-8.8%) 0.045*
48 Gy 5.6% (4.1%-8%) 6.8% (5.6%-10.7%) 0.188 4.6% (3.1%-7.3%) 6.4% (4.9%-8.4%) 0.057
49 Gy 5.3% (3.9%-7.6%) 6.6% (5.3%-10.4%) 0.188 4.4% (3%-7%) 6.0% (4.7%-8.1%) 0.062
50 Gy 5.0% (3.8%-7.3%) 6.3% (4.9%-10.2%) 0.176 4.1% (2.9%-6.8%) 5.7% (4.5%-7.7%) 0.072
51 Gy 4.7% (3.6%-7%) 6.1% (4.6%-9.9%) 0.165 3.8% (2.8%-6.4%) 5.3% (4.3%-7.2%) 0.067
52 Gy 4.5% (3.3%-6.7%) 5.8% (4.2%-9.6%) 0.134 3.5% (2.7%-6%) 5.0% (4.1%-6.8%) 0.078
53 Gy 4.3% (3%-6.4%) 5.6% (3.9%-9.3%) 0.125 3.2% (2.6%-5.6%) 4.7% (3.9%-6.5%) 0.078
54 Gy 4.1% (2.7%-6%) 5.3% (3.6%-9%) 0.144 3.0% (2.4%-5.2%) 4.4% (3.7%-6.2%) 0.097
55 Gy 3.8% (2.5%-5.5%) 5.0% (3.3%-8.7%) 0.201 2.7% (2.2%-4.8%) 4.1% (3.6%-5.9%) 0.084
56 Gy 3.5% (2.3%-5.1%) 4.8% (3.1%-8.4%) 0.213 2.6% (2%-4.4%) 3.7% (3.4%-5.6%) 0.097
57 Gy 3.3% (2.1%-4.7%) 4.5% (2.9%-8.1%) 0.241 2.3% (1.9%-4%) 3.3% (3%-5.1%) 0.120
58 Gy 3.0% (1.9%-4.3%) 4.1% (2.6%-7.1%) 0.256 2.1% (1.7%-3.7%) 3.0% (2.4%-4.5%) 0.156
59 Gy 2.8% (1.7%-3.9%) 3.8% (2.3%-6.2%) 0.271 2.0% (1.5%-3.3%) 2.7% (1.8%-4%) 0.224
60 Gy 2.6% (1.5%-3.4%) 3.3% (1.8%-5.4%) 0.356 1.8% (1.4%-3%) 2.4% (1.3%-3.6%) 0.436
61 Gy 2.1% (1.3%-3.1%) 2.8% (1.5%-4.6%) 0.414 1.6% (1.1%-2.7%) 1.9% (0.9%-2.7%) 0.908
62 Gy 1.8% (1%-2.9%) 2.0% (1.1%-3.9%) 0.569 1.5% (0.8%-2.1%) 1.0% (0.5%-2%) 0.608
63 Gy 1.3% (0.7%-2.6%) 1.3% (0.6%-3.1%) 0.668 1.2% (0.3%-1.6%) 0.7% (0.1%-1.5%) 0.166
64 Gy 1.0% (0.4%-1.9%) 0.8% (0.2%-2.1%) 0.799 0.9% (0.1%-1.4%) 0.3% (0%-0.9%) 0.067
65Gy 0.7% (0.2%-1.7%) 0.5% (0.1%-1.2%) 0.563 0.5% (0.1%-1.2%) 0.1% (0%-0.4%) 0.097
66 Gy 0.5% (0%-1.3%) 0.2% (0%-0.5%) 0.351 0.2% (0%-1%) 0.0% (0%-0.1%) 0.068

Mann-Whitney test. *p<0.05, **p<0.01.

1: the value of RP max volume/total lung volume.

The area under the ROC curve was used to evaluate the cut-off point for the occurrence of symptoms in all patient groups, the RPv max value was 4.79% while the mean lung dose was 8.4 Gy; the areas under the curve were 0.779 and 0.662 ( Figure 3 ), respectively. Sensitivity, specificity, and the p values for the ROC curves of RPv max cutoff values were 0.77, 0.69, and <0.001, respectively. Sensitivity, specificity, and the p values for ROC curves of the mean lung dose cutoff values were 0.86, 0.42, and 0.02, respectively. Therefore, RPv max may have a better identification rate than the previous pulmonary dose curve distribution map for symptomatic RP.

ROC curve of (A) RPv max (B) mean lung dose for predicting symptomatic RP.

 Relationship between RP lesions and DVH

We found that V1-V12 and V25-V54 were significantly correlated to RPv max ( Supplementary Table S1 ). The characteristic of the dose curve distribution is lower the dose, larger the coverage to the body, and vice versa. Therefore, in addition to the relationship between RPv max and lung Vx, when selecting a dose curve, we should use the curve with a higher dose as the principle. Finally, considering the comprehensive correlation and curve coverage to the largest patient population (>80% patients in grades 1 and 2 radiation pneumonitis, Supplementary Table S2 ) whose RP area is greater than 80%, V26 was selected.

When we evaluated the correlation between RP lesions and DVH, in the grades 1 and 2 RP groups, the dose curve of 26Gy covered ≥80% of RP lesions ( Figure 4 ) in the majority (80.6% and 81.3%, respectively) of patients ( Table 7 ).

(A) RP lesion. (B) RP lesion covered by different isodose curve: blue – 5 Gy, brown – 20 Gy, red – 26 Gy, orange – 30 Gy, green – 60 Gy; pink – RP field projected to planning CT. (C) Demonstrated volume of RP 1 lesion covered by 26 Gy equal to 95.66%. (D) The percentages of RP1, 2, and 3 coverage drop rapidly when it exceeds 26 Gy (red: RP1, blue: RP2, green: RP3).

Percentage of pneumonia patch covered by 26 Gy in grade 1 and 2 radiation pneumonitis patients.

Grade 1 (n=36) Grade 2 (n=32)
99.9% 100.0%
99.4% 91.8%
99.5% 89.1%
100.0% 94.7%
99.5% 96.3%
100.0% 98.9%
100.0% 97.7%
99.6% 81.0%
89.9% 52.3%
100.0% 30.9%
86.0% 100.0%
100.0% 100.0%
58.0% 80.8%
72.8% 96.7%
98.5% 93.2%
100.0% 99.8%
99.2% 85.1%
99.8% 93.7%
96.3% 95.9%
69.8% 99.1%
77.4% 79.0%
100.0% 97.5%
99.5% 86.0%
100.0% 89.7%
95.0% 31.5%
79.6% 95.7%
87.6% 63.6%
100.0% 99.5%
98.4% 100.0%
98.2% 96.3%
59.2% 78.1%
89.8% 91.6%
98.6%
99.9%
0%
100.0%
≥80%, n=29 ≥80%, n=26

Therefore, from the results presented in Tables 4 – 6 , the ratio of RP lesion volume to the original lung volume after treatment was significantly correlated with the grade of RP; an RPv max value of 4.79% and mean lung dose of 8.4 Gy were the best indicators that were also significantly positively correlated with the RP grade.

 Survival in radiotherapy combined target therapy or chemotherapy

The combining target therapy and chemotherapy groups were 35 patients and 25 patients, respectively. Percentage of mean lung dose >8.4Gy was significantly higher in combining chemotherapy than combining target therapy (p=0.01, Supplementary Table S3 ). However, symptomatic radiation pneumonitis was not different (p=0.08). Patients who received a combination of chemotherapy had significantly shorter LRPFS (HR 4.68 [95% CI 1.01-21.75], p=0.049), and the p value of log-rank test was 0.03 ( Supplementary Table S4 ). Kaplan-Meier curves of LRPFS are presented in Figure 5 . PFS and OS were not significantly different between combined target therapy and combined chemotherapy ( Supplementary Tables S5, 6 ). Patients with RPv max >4.79% demonstrated a better trend of OS (HR 0.41 [95% CI 0.15-1.12], p=0.082) ( Supplementary Table S6 ).

Kaplan-Meier curves of LRPFS in the radiotherapy-combined target therapy or chemotherapy treatment group.

 Discussion

We selected the curative dose in line with the current trend for definite concurrent chemoradiation therapy (CCRT) (60 Gy +/-10%) (11) because the use of definite RT for oligometastasis from the primary or metastatic site is considered when considering current radiation therapy for lung cancer. In terms of the patient characteristics, only age (≥65 years) affected the development of symptomatic RP (12). Others, such as PTV volume, were not associated with RP grade. This result is consistent with other studies’ results (13–15). Although these studies were based on high-dose radiation therapy, the dose to the normal lungs that actually affects the severity of RP was also revealed.

RP occurred within 6 months of radiotherapy completion. It manifests as radiation pulmonary fibrosis during the chronic phase (16–18). According to this study, symptomatic RP occurred in less than 190 days, similar to the results of Itonaga’s study (19).

A previous study has been conducted on the relationship between DVH and RP, although it is still debatable which is the best predictor of RP (20). One of the major reasons is that the assessment of RP has always been based on CTCAE, which is mainly graded according to the patient’s symptoms. Therefore, there is no objective way to quantify the degree of RP. In this study, by linking the percentage of RP lesion volume to the total lung volume and the degree of RP, we found that RPv max and RP did have a statistically significant relationship.

Palma et al. proposed changes in Hounsfield unit (HU) values on CT but found there was a poor correlation between HU density changes in the entire lung and the severity of physician-graded radiological pneumonitis (21). Two studies discovered that the HU density became denser between 3 and 9 months, then stabilized across all the dose intervals after 12 months (18, 22). The time distribution supports a RILI model with early RP and late fibrotic changes. The HU density changes in previous studies are similar to our observation of RPv max.

Several classification systems of RP were not clinically useful to allow for detailed, quantitative analysis of the radiological changes observed following RT or that have known correlations with clinical or dosimetric measures (10, 13, 23–25). Although Chandy et al. proposed five different RP types, their model presents sophisticated techniques for analyzing RP. Furthermore, it was impossible to classify them intuitively from the CT images (26). Szejniuk et al. reported the RILI grading scale (RGS), and dosimetric parameters were found to be related to changes in RGS severity (27). However, although RGS ranged from 0 to 3, the drawback of poor quantification is also noted. Itonaga et al. reported the range of pneumonia patches after stereotactic body radiation therapy (SBRT), and the median RILI ranges of the acute phase were in the 80% (20–100%) dose regions (19). Our study found that 26Gy can contain ≥80% of RP lesions in most patients. The implementation of SBRT has some clinical limitations for lung tumors that are located in the periphery and are <5 cm in size. Thus, the 80% dose regions were limited to the same lung as the treatment. However, the RILI ranges in conventional radiotherapy did not occur only in the same lung as that in Itonaga’s study. Moreover, only 3% of grade 2 RP appeared after SBRT and it is difficult to correlate the severity of RP with RILI ranges. Our study is innovative in the use of simple and objective data to quantify the severity of radiation pneumonitis. Furthermore, because there is no previous research on the relationship between the distribution of pneumonia and that of lung dose curves in conventional radiation doses, our data can provide a good way to identify radiation-induced lung injuries.

In combining target therapy or chemotherapy groups, patients who combined with chemotherapy had significantly shorter LRPFS than those combined with target therapy (p=0.049). In stage III-IV NSCLC, a prospective trial found that concomitant EGFR TKIs with RT produced positive results (28). In a preclinical model, radiation-induced antiangiogenic effects, anti-proliferation, and apoptosis were significantly enhanced in ALK-positive NSCLC cell lines while combined crizotinib (29). Moreover, a meta-analysis showed that local consolidative therapy (radiotherapy or surgery) with systemic treatment showed favorable results in both EGFR mutation and wild-type group than systemic treatment alone. HR for PFS in EGFR mutation population was 0.29 and in the wild-type population was 0.31 (30). Our study showed no difference in PFS or OS in combining target therapy or chemotherapy groups similar with the meta-analysis. Patients with RPv max >4.79% demonstrated a better trend of OS (p=0.082). After radiation, the immune system is strengthened, with tumor antigens being encouraged to stimulate the immune system and T cell detection and killing being strengthened (31). Wolf also found a reduced rate of disease failure, with disease failure occurring in 25.0% of individuals with radiographic radiation pneumonitis (RRP) and 80% of those without RRP (p=0.02) after stereotactic body radiation therapy (SBRT) (32).

The limitations of this study included the retrospective analysis. The time of the first CT after the completion of radiotherapy varied greatly; however, we could observe the difference in the degree of lung injury at different time points and processes. Another limitation was that different doctors might differ in the selection of the pneumonia lesions’ images. Therefore, in the future, we hope to use artificial intelligence (U-net) to achieve automatic segmentation by the computer, reduce subjective errors and predict the grade of lung injury. Also, by building automated programs to help clinicians, they can identify whether the lesions are lung injuries caused by radiation therapy. Even though 26Gy can contain ≥80% of RP lesions in most patients, a few patients still remained where the range of RP and those ≥26 Gy overlapped very little (or was even 0%). This means that radiation therapy to the lungs may also cause lung injury in low-dose areas. In this case, it is difficult to determine whether lung injuries were caused by radiation therapy or whether V26 covered the pneumonia patch. Therefore, other clinical manifestations (such as features of infection) are required to make a differential diagnosis. Since the purpose of treatment in our study includes definite concurrent chemoradiotherapy (curative), recurrence (salvage), and metastatic (consolidative) patients and varies combined treatment with radiotherapy, too many factors could affect survival. Thus, combining target therapy or chemotherapy groups was included for survival analysis. More patient numbers and longer follow-up time was needed to clarify the correlation between radiation pneumonitis and survival.

In conclusion, based on this study, we know that the ratio of RP lesion volume to total lung volume is a good indicator for quantifying radiation pneumonitis. The cut-off point for the occurrence of symptoms, the RPv max value, was 4.79%. RP lesions can be projected onto the original radiation therapy plan using coverage of the 26Gy isodose line to determine whether the lesion is RILI.

 Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

 Ethics statement

The human study was reviewed and approved by Taichung Veterans General Hospital (approval no. CE22095B).

 Author contributions

J-WH conceptualized the study. J-WH. and Y-HL collected the data. J-WH drafted the manuscript. G-CC and JC revised the manuscript and supervised the study. All authors read and approved the final manuscript. All authors contributed to the article and approved the submitted version.

 Funding

The authors would like to thank the Biostatistics Task Force of Taichung Veterans General Hospital. This work was supported in part by the National Science and Technology Council, Taiwan under Grant of NSTC 111-2634-F-006-012.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1130406/full#supplementary-material

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