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Subpleural fibrotic interstitial lung abnormalities are implicated in non-small cell lung cancer radiotherapy outcomes

Makoto Ito
Makoto Ito
, 
Takuma Katano
Takuma Katano
, 
Hiroaki Okada
Hiroaki Okada
, 
Ami Sakuragi
Ami Sakuragi
, 
Yoshitaka Minami
Yoshitaka Minami
, 
Souichiro Abe
Souichiro Abe
, 
Sou Adachi
Sou Adachi
, 
Yukihiko Oshima
Yukihiko Oshima
, 
Wataru Ohashi
Wataru Ohashi
, 
Akihito Kubo
Akihito Kubo
, 
Takayuki Fukui
Takayuki Fukui
, 
Satoru Ito
Satoru Ito
 und 
Kojiro Suzuki
Kojiro Suzuki
   | 20. Apr. 2023
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Article Category: Research Article
Online veröffentlicht: 20. Apr. 2023
Seitenbereich: 229 - 238
Eingereicht: 19. Feb. 2023
Akzeptiert: 02. Apr. 2023
DOI: https://doi.org/10.2478/raon-2023-0018
Schlüsselwörter
© 2023 Makoto Ito et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1

Examples of interstitial lung abnormality subcategories. (A) non-subpleural, (B) subpleural non-fibrotic, and (C) subpleural fibrotic. White arrows point to lesions.
Examples of interstitial lung abnormality subcategories. (A) non-subpleural, (B) subpleural non-fibrotic, and (C) subpleural fibrotic. White arrows point to lesions.

FIGURE 2

Cumulative incidence of grade ≥ 2 radiation pneumonitis by group (A) and subgroup (B).ILAs = interstitial lung abnormalities; ILD = interstitial lung disease; NS = non-subpleural; SF = subpleural fibrotic; SNF = subpleural non-fibrotic
Cumulative incidence of grade ≥ 2 radiation pneumonitis by group (A) and subgroup (B).ILAs = interstitial lung abnormalities; ILD = interstitial lung disease; NS = non-subpleural; SF = subpleural fibrotic; SNF = subpleural non-fibrotic

Characteristics of patients treated with radical-intent radiotherapy

Characteristic Normal (n = 87) ILA-SF (n = 24) p
Age (years) 69 (41–90) 73 (60–82) 0.09
Performance status – – 0.39
  0 41 (47%) 12 (50%) –
  1 36 (41%) 8 (33%) –
  2 6 (7%) 4 (17%) –
  3 4 (5%) 0 (0%) –
Pack year 45 (0–171) 53 (0–122) 0.38
KL-6 (U/mL) 294 (151–1607) 399 (208–705) 0.91
Pathology – – 0.09
  Adenocarcinoma 46 (53%) 7 (29%) –
  Squamous cell carcinoma 35 (40%) 14 (58%) –
  Others 6 (7%) 3 (13%) –
Lower-lobe primary lesion 19 (22%) 6 (25%) 0.79
T classification – – 0.36
  1 13 (15%) 1 (4%) –
  2 23 (26%) 10 (42%) –
  3 19 (22%) 5 (21%) –
  4 32 (37%) 8 (33%) –
Concurrent chemotherapy 58 (67%) 13 (54%) 0.33
Durvalumab 15 (17%) 1 (4%) 0.19
Mutation 8 (13%) 3 (18%) 0.70
Median follow-up: survivors (years) 2.8 (0.6–12.1) 1.5 (0.7–6.0) 0.46

Univariate and multivariate analyses for overall and progression-free survival rates

Parameter Overall survival Progression-free survival
Univariate Multivariate Univariate Multivariate
HR (95% CI) P HR (95% CI) p HR (95% CI) p HR (95% CI) p
ILA-SF 2.59 (1.51–4.43) <0.001 3.07 (1.17–8.10) 0.02 1.88 (1.16–3.05) 0.01 1.95 (0.91–4.14) 0.08
Age (years) 1.02 (0.99–1.04) 0.09 0.95 (0.91–0.99) 0.04 1.01 (0.98–1.03) 0.59 – –
Sex (men) 1.21 (0.70–2.10) 0.49 – – 0.91 (0.58–1.45) 0.71 – –
Performance status (0,1 vs. 2,3) 1.90 (1.07–3.39) 0.03 0.82 (0.19–3.38) 0.78 2.81 (1.66–4.78) <0.001 1.35 (0.46–3.93) 0.59
Pack year 1.01 (1.00–1.01) 0.04 1.01 (0.99–1.02) 0.14 1.00 (0.99–1.01) 0.67 – –
%VC (%) 0.99 (0.98–1.01) 0.56 – – 0.99 (0.98–1.01) 0.51 – –
FEV1 (L) 0.84 (0.55–1.29) 0.43 – – 0.92 (0.62–1.36) 0.68 – –
FEV1/FVC (%) 0.99 (0.97–1.02) 0.92 – – 1.01 (0.98–1.02) 0.75 – –
KL-6 (U/mL) 1.00 (0.99–1.01) 0.11 1.00 (0.99–1.01) 0.34 1.01 (1.00–1.02) 0.03 1.00 (0.99–1.01) 0.40
Pathology (adenocarcinoma) 0.46 (0.31–0.69) <0.001 0.18 (0.08–0.44) <0.001 0.54 (0.36–0.79) 0.002 0.34 (0.18–0.65) 0.001
Lower-lobe primary lesion 1.60 (1.02–2.53) 0.04 1.03 (0.39–2.68) 0.95 1.09 (0.72–1.65) 0.69 – –
T classification (T4 vs. others) 1.15 (0.74–1.79) 0.53 – – 1.47 (0.99–2.17) 0.05 1.53 (0.78–2.99) 0.21
N classification (positive) 1.02 (0.49–2.12) 0.95 – – 0.88 (0.48–1.60) 0.67 – –
Concurrent chemotherapy 0.51 (0.33–0.80) 0.004 0.19 (0.07–0.56) 0.002 0.60 (0.41–0.89) 0.01 0.65 (0.31–1.30) 0.22
Durvalumab 0.22 (0.08–0.60) 0.003 0.43 (0.11–1.69) 0.22 0.34 (0.18–0.65) 0.001 0.40 (0.17–0.93) 0.03
PD-L1 (positive) 0.77 (0.39–1.50) 0.44 – – 1.03 (0.59–1.79) 0.92 – –
Mutation 0.76 (0.47–1.22) 0.26 – – 0.96 (0.64–1.42) 0.83 – –
Radiotherapy method (IMRT) 0.75 (0.43–1.30) 0.31 – – 0.86 (0.55–1.34) 0.50 – –
ENI 0.83 (0.49–1.38) 0.47 – – 0.99 (0.64–1.56) 0.99 – –
Lung dose
V5 (%) 0.45 (0.12–1.72) 0.24 – – 0.56 (0.19–1.66) 0.30 – –
V10 (%) 0.37 (0.06–2.27) 0.29 – – 0.44 (0.10–1.92) 0.28 – –
V20 (%) 0.36 (0.02–5.27) 0.46 – – 0.23 (0.02–2.27) 0.21 – –
Mean (Gy) 0.98 (0.93–1.04) 0.48 – – 0.97 (0.93–1.02) 0.29 – –

Univariate and multivariate analyses of the cumulative incidence of grade ≥ 2 radiation pneumonitis

Parameter Univariate analysis Multivariate analysis
HR (95% CI) p HR (95% CI) p
ILA 2.95 (1.81–4.82) <0.001 2.33 (1.18–4.61) 0.01
Age (years) 1.02 (0.99–1.05) 0.14 0.99 (0.95–1.03) 0.78
Sex (men) 1.02 (0.57–1.84) 0.94 – –
Performance status (0,1 vs. 2,3) 1.17 (0.56–2.44) 0.68 – –
Pack year 1.01 (0.99–1.01) 0.27 – –
%VC (%) 0.99 (0.98–1.01) 0.96 – –
FEV1 (L) 1.01 (0.64–1.55) 0.99 – –
FEV1/FVC (%) 0.99 (0.97–1.01) 0.67 – –
KL-6 (U/mL) 1.00 (0.99–1.01) 0.09 1.00 (0.99–1.01) 0.13
Pathology (adenocarcinoma) 0.58 (0.35–0.96) 0.04 0.85 (0.42–1.72) 0.65
Lower-lobe primary lesion 1.22 (0.69–2.12) 0.49 – –
T classification (T4 vs. others) 0.81 (0.47–1.39) 0.44 – –
N classification (positive) 1.18 (0.51–2.72) 0.70 – –
Concurrent chemotherapy 1.17 (0.72–1.88) 0.53 – –
Durvalumab 1.32 (0.72–2.40) 0.37 – –
PD-L1 1.11 (0.54–2.25) 0.78 – –
Mutation 1.24 (0.62–2.49) 0.54 – –
Radiotherapy method (IMRT) 0.69 (0.39–1.19) 0.18 0.38 (0.16–0.91) 0.03
ENI 1.06 (0.65–1.75) 0.81 – –
Lung dose
  V5 (%) 2.14 (0.67–6.82) 0.19 * *
  V10 (%) 3.93 (0.85–18.2) 0.08 * *
  V20 (%) 34.8 (3.05–396.4) 0.004 54.8 (1.52–1977.0) 0.03
  Mean (Gy) 1.10 (1.04–1.17) <0.001 * *

Clinical details of eight patients with grade 5 radiation pneumonitis

Case Age ILA subcategory Radiotherapy method Concurrent chemotherapy Durvalumab Lung V20 (%) Mean lung dose (Gy) Days to death
1 64 SF IMRT Yes No 19.2 12.8 104
2 73 SF 3DCRT Yes No 21.4 13.9 210
3 73 SF IMRT No No 30.6 15.7 123
4 76 SF IMRT Yes Yes 34.1 17.9 155
5 77 SNF 3DCRT No No 33.2 16.5 155
6 79 SF IMRT Yes No 31.5 17.3 160
7 79 SF 3DCRT No No 19.4 9.7 40
8 80 SF 3DCRT No No 27.6 15.2 99

Patient characteristics

Characteristic Normal (n = 105) ILA (n = 64) ILD (n = 6) p
Age (years) 71 (41–90) 72 (60–86) 74 (63–86) 0.01
Sex (men) 82 (78%) 52 (81%) 6 (100%) 0.70
Performance status – – – 0.42
0 53 (50%) 37 (58%) 4 (66%) –
1 41 (39%) 19 (30%) 1 (17%) –
2 7 (7%) 7 (11%) 1 (17%) –
3 4 (4%) 1 (1%) 0 (0%) –
Pack year 45 (0–171) 47 (0–122) 48.5 (20–84) 0.98
Pulmonary function test
%VC (%) 99.1 (41.8–144.2) 103.0 (41.8–147.5) 86.9 (55.7–98.8) 0.08
FEV1 (L) 1.9 (0.6–3.6) 2.2 (0.9–3.5) 2.0 (1.5–2.1) 0.12
FEV1/FVC (%) 69.2 (34.1–98.1) 69.8 (36.0–85.0) 74.8 (62.2–86.8) 0.36
KL-6 (U/mL) 282 (151–3957) 370 (172–896) 393 (204–859) 0.65
Pathology – – – 0.01
Adenocarcinoma 59 (56%) 21 (33%) 2 (33%) –
Squamous cell carcinoma 40 (38%) 38 (59%) 4 (67%) –
Others 6 (6%) 5 (8%) 0 (0%) –
Lower-lobe primary lesion (radical-intent) 19 (22%) 14 (33%) 3 (75%) 0.20
TNM classification (radical-intent)
T classification – – – 0.53
  1 13 (15%) 3 (7%) 0 (0%) –
  2 23 (26%) 12 (28%) 2 (50%) –
  3 19 (22%) 13 (30%) 0 (0%) –
  4 32 (37%) 15 (35%) 2 (50%) –
N classification – – – 0.32
  0 7 (9%) 8 (19%) 0 (0%) –
  1 16 (18%) 8 (19%) 1 (25%) –
  2 42 (48%) 16 (37%) 2 (50%) –
  3 22 (25%) 11 (26%) 1 (25%) –
Stage – – – 0.40
  II A 3 (3%) 1 (2%) 0 (0%) –
  II B 5 (6%) 6 (14%) 0 (0%) –
  III A 34 (39%) 15 (35%) 3 (75%) –
  III B 36 (41%) 14 (33%) 0 (0%) –
  III C 9 (11%) 7 (16%) 1 (25%) –
Concurrent chemotherapy 65 (62%) 33 (52%) 2 (33%) 0.20
Carboplatin + paclitaxel 30 (46%) 18 (55%) 2 (100%) –
Cisplatin + docetaxel 22 (34%) 8 (24%) 0 (0%) –
Cisplatin + vinorelbine 13 (20%) 7 (21%) 0 (0%) –
Durvalumab 17 (16%) 9 (14%) 0 (0%) 0.83
PD-L1 (positive) 36 (34%) 23 (36%) 0 (0%) 0.99
Mutation – – – 0.99
EGFR 8 (7%) 5 (8%) 1 (17%) –
ALK 6 (6%) 2 (3%) 1 (17%) –
None/unknown 91 (87%) 57 (89%) 4 (66%) –
Radiotherapy method – – – 0.08
3DCRT 80 (76%) 40 (63%) 5 (83%) –
IMRT 25 (24%) 24 (37%) 1 (17%) –
ENI 77 (73%) 38 (59%) 4 (67%) 0.06
Hypofractionated radiotherapy 3 (3%) 3 (5%) 0 (0%) 0.67
Dose escalation 6 (6%) 5 (8%) 0 (0%) 0.75
Lung dose
V5 (%) 34.5 (4.3–90.8) 40.3 (5.8–95.7) 34.6 (10.6–66.8) 0.18
V10 (%) 27.1 (2.7–67.7) 32.4 (3.7–81.4) 27.8 (8.8–49.9) 0.19
V20 (%) 19.8 (1.1–44.8) 22.0 (1.0–48.0) 22.6 (7.3–33.0) 0.59
Mean (Gy) 10.8 (1.7–23.5) 11.8 (2.0–19.6) 12.3 (3.8–18.0) 0.53
Median follow-up (years) 1.8 (0.1–12.1) 1.3 (0.1–9.9) 0.9 (2.1–3.9) 0.06
Median follow-up: survivors (years) 2.9 (0.6–12.1) 1.9 (0.6–9.9) 0.9 (0.9–0.9) 0.51
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