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Incidence and treatment outcome of radiation pneumonitis in limited-stage small-cell lung cancer patients treated with concurrent accelerated hyperfractionated radiotherapy and chemotherapy

Open AccessPublished:November 22, 2022DOI:https://doi.org/10.1016/j.adro.2022.101129

      ABSTRACT

      Purpose

      : To clarify the characteristics of and evaluate the risk factors for radiation pneumonitis (RP) induced by chemoradiotherapy (CRT) using accelerated hyperfractionated radiotherapy (AHF-RT) in patients with limited-stage small-cell lung cancer (LS-SCLC).

      Materials and Methods

      : Between September 2002 and February 2018, 125 LS-SCLC patients were treated with early concurrent CRT using AHF-RT. Chemotherapy comprised carboplatin/cisplatin with etoposide. Radiotherapy was administered twice daily (45 Gy/30 fr). We collected data regarding onset and treatment outcomes for RP and analyzed the relationship between RP and total lung dose-volume histogram (DVH) findings. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors for ≥Grade 2 RP.

      Results

      : The median age was 65 years, and 73.6% of the participants were men; 20% and 80.0% of the participants presented as Stage II and III, respectively. The median follow-up was 73.1 months. Grades 1, 2, and 3 RP were observed in 69, 17, and 12 patients, respectively. Grades 4–5 RP were not observed. RP was treated with corticosteroids in patients with ≥Grade 2 RP, without recurrence. The median time from the initiation of radiotherapy to onset of RP was 147 days. Three patients developed RP within 59 days, six within 60–89 days, 16 within 90–119 days, 29 within 120–149 days, 24 within 150–179 days, and 20 within ≥180 days. Among the DVH parameters, the percentage of lung volume receiving >30 Gy (V30) was most strongly related to the incidence of ≥Grade 2 RP; the optimal threshold for predicting RP incidence was V30 ≥20%. On multivariate analysis, V30 ≥20% was an independent risk factor for ≥Grade 2 RP.

      Conclusion

      : The incidence of ≥Grade 2 RP correlated strongly with a V30 of ≥20%. Contrarily, the onset of RP induced by concurrent CRT using AHF-RT may occur later. RP is manageable in patients with LS-SCLC.

      Keywords

      INTRODUCTION

      Small-cell lung cancer (SCLC) is one of the most aggressive tumor types. Nevertheless, limited-stage SCLC (LS-SCLC) is curable with a combination of radiotherapy and chemotherapy.1,2 Concurrent chemoradiotherapy (CRT) using accelerated hyperfractionated radiotherapy (AHF-RT) is the standard treatment for patients with LS-SCLC.3,4 In a previous study of LS-SCLC patients treated with CRT, the reported incidence of radiation pneumonitis (RP) of any grade as well as RP of ≥Grade 2 was 83.0–100% and 18.6–25.8%, respectively.5,6
      RP is one of the most common dose-limiting adverse events in thoracic radiotherapy.5,7 In locally advanced non-small-cell lung cancer (LA-NSCLC) patients treated with CRT, several factors, including the percentage of lung volume receiving >20 Gy (V20), V30, and the mean lung dose (MLD; as derived from dose-volume histograms [DVHs]), have recently been reported as indicators for the occurrence of RP.8-15 Among the DVH parameters, V20 correlated well with the incidence of symptomatic RP in previous study populations.8-11,13,14,16,17 Meanwhile, age, diabetes mellitus (as a comorbidity), and smoking status have been reported as the clinical factors most strongly associated with symptomatic RP in patients with LA-NSCLC.17-21
      The risk factors for RP have not yet been thoroughly investigated in LS-SCLC patients treated with CRT using AHF-RT. To our knowledge, no reports have focused on the treatment and outcomes for RP in this population. Therefore, the aim of this retrospective study was to clarify the characteristics of RP and to evaluate the risk factors for RP, including DVH parameters, in patients with LS-SCLC treated with concurrent CRT using AHF-RT.

      MATERIALS AND METHODS

      This retrospective study was approved by the Institutional Review Board at our institution, and this work was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained in the form of an opt-out via the official institutional website.

      Patient characteristics

      We retrospectively evaluated patients with LS-SCLC who presented at our institute between September 2002 and February 2018. Patients with pathologically diagnosed SCLC, or combined SCLC who underwent concurrent CRT using AHF-RT, were eligible for study inclusion. Meanwhile, patients treated with late concurrent CRT (where RT was initiated after starting the third course of chemotherapy) or sequential CRT were excluded.
      LS-SCLC was defined as a disease with lesions limited to the ipsilateral thorax, contralateral mediastinum, and contralateral supraclavicular fossa lymph nodes, without malignant pleural effusion or pericardial effusion. Lesion distribution was assessed by computed tomography (CT) from the chest to the abdomen or by positron emission tomography (PET). The absence of brain metastases was confirmed by magnetic resonance imaging (MRI).
      For statistical analysis, we collected data on age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS) at diagnosis, baseline forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)%, smoking status, pack-years of smoking, history of diabetes mellitus, performance of PET-CT at diagnosis, clinical stage at diagnosis, chemotherapy regimen (cisplatin [CDDP]/carboplatin [CBDCA]+etoposide [ETP]), the reason for the discontinuation of chemotherapy, the initial date of radiation therapy, the last date of radiation therapy, total lung DVHs (V5-50), maximal lung dose (Dmax), MLD, RP grade, date of RP diagnosis, initial treatment of RP, and outcomes of RP. The follow-up period was calculated from the start of radiotherapy.
      RP was diagnosed by confirming the relationship between the infiltration shadow detected on CT and the distribution of the radiotherapy field, with evaluations conducted by one radiologist and one pulmonologist. The severity of RP was evaluated as the worst grade of pneumonitis according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0,22 which sets the following criteria for Grade 2 RP: symptomatic; medical intervention indicated; limiting instrumental ADL.

      Chemotherapy and radiation therapy

      All patients received chemotherapy with platinum-based regimens: CDDP (60 or 80 mg/m2 on day 1) and ETP (80 or 100 mg/m2 on days 1–3), or CBDCA (area under the curve [AUC] = 5 on day 1) and ETP (80 mg/m2 on days 1–3); these regimens were repeated for up to four courses. Radiation treatment planning was based on slow CT scans acquired while breathing freely in the treatment position. CT datasets were transferred into a commercial treatment planning system (Pinnacle3, Philips Medical Systems, Andover, MA, USA). The treatment course was planned by a board-certified radiation oncologist.
      Gross tumor volume (GTV) was defined as the total volume of the primary tumor and the metastatic lymph nodes, with a short-axis diameter of ≥1 cm on CT scanning and nodes of <1 cm on CT with high fluorodeoxyglucose uptake on PET scanning. The clinical target volume (CTV1) was defined as the GTV plus a uniform 5-mm margin and elective nodal regions. The second clinical target volume (CTV2) was defined as CTV1 minus elective nodal regions. Elective nodal regions included the affected lymph node stations, subcarinal region, and ipsilateral hilum; supraclavicular lymph nodes were included in elective nodal regions if metastasis was detected. Lymph nodes with pathological confirmation by endobronchial ultrasound-transbronchial needle aspiration, an increase in size over time, or PET/CT positivity were included in the elective nodal regions. The planning target volume (PTV) was defined as the CTV1 or CTV2 plus a uniform 5-mm margin, respectively. The treatment plans were calculated with heterogeneity correction using an adaptive convolution algorithm within Pinnacle3.
      Radiotherapy was delivered concurrently with chemotherapy and was initiated before the start of the third course of chemotherapy, which was delivered twice daily at 1.5 Gy per fraction to a total of 45 Gy (with an interfractional interval of at least six hours) using three-dimensional conformal radiation therapy. The photon energy of the external beam was set to 6, 8, or 10 MV. Dose calculations were performed using tissue density inhomogeneity correction.
      The treatment was delivered using a linear accelerator with a photon beam in the MV range. All treatment plans were based on volumetric CT. Radiotherapy consisted of anterior-posterior opposed fields to CTV1 for the first 30 Gy of 45 Gy, followed by irradiation of off-cord oblique opposing fields to CTV2 for the next dose of 15 Gy.

      Dose-volume parameters

      The planned dose distributions were restored from the archived data of the treatment planning system and were confirmed to be clinically delivered through chart review.
      Lung V5-50 was defined as the percent volume receiving at least 5–50 Gy in increments of 5 Gy. The Dmax was defined as the maximal dose to the total lung, and the MLD was defined as the average dose to the total lung. The lung was defined as the total lung minus the GTV.

      Statistical methods

      Differences between groups were compared using Fisher's exact tests for categorical variables (according to the incidence of RP of ≥Grade 2). Continuous variables were analyzed using the Wilcoxon rank-sum test. Patients were divided into two groups based on median values for age, pack-years of smoking, and FEV1/FVC%. Analysis of V5-50, Vmax, and MLD using receiver operating characteristic (ROC) curves was used to select the most relevant threshold for predicting RP of ≥Grade 2 or 3.
      Univariate logistic regression analysis was used to evaluate the association between total lung DVH parameters (V5-50, Vmax, and MLD) and RP of ≥Grade 2. The DVH parameter with a minimal p-value and patient characteristics showing a p-value <0.1 on univariate analysis was included in the multivariate analysis for RP of ≥Grade 2. Multivariate analysis of risk factors related to ≥Grade 3 pneumonia was not performed because of the small number of patients in that category (n = 12). As DVH parameters are known to be correlated with each other,5,7,15,17 we included one DVH parameter, showing the maximum AUC on ROC analysis and the minimal p-value on univariate analysis, in the multivariate analysis for ≥Grade 2 RP. To confirm this correlation, Spearman's rank correlation analysis was used to determine correlations between DVH parameters.
      The cutoff value was determined by maximizing the Youden index. All p-values were derived from two-sided significance tests, and statistical significance was set to p < 0.05. Statistical analyses were performed using JMP statistical software (v.15; SAS Institute, Cary, NC, USA).

      RESULTS

      Patient characteristics

      Between September 2002 and February 2018, 173 patients with LS-SCLC were eligible for concurrent CRT at our medical center. Forty-eight patients were excluded from this study, as they were already receiving sequential radiotherapy (n = 40), late concurrent radiotherapy (n = 4), or conventional radiotherapy (n = 4). Five patients had not competed four courses of chemotherapy. Of the 125 patients eligible for this study, the median age was 65 years (range: 34–76 years). All enrolled patients had an ECOG-PS of 0/1 and 73.6% of the patients were men; 64.0% were current smokers, 12.8% had diabetes mellitus, and 80.0% presented at Stage III. The median pack-years of smoking was 48 years (range: 0–225) (Table 1).
      Table 1Patient medical and demographic characteristics.
      CharacteristicAll patients (n = 125)Grade 2 RP (n = 29)Grade 0-1 RP (n = 96)p-value
      Median age, years (range)65 (34-76)69 (51-75)65 (34-76)0.026
      <65 years54 (43.2)8 (27.6)46 (47.9)0.579
      ≥65 years71 (56.8)21 (72.4)50 (52.1)
      Sex, n (%)
      Male92 (73.6)22 (75.9)70 (72.9)0.815
      Female33 (26.4)7 (24.1)26 (27.1)
      ECOG PS, n (%)
      067 (53.6)16 (55.2)51 (53.1)1.000
      158 (46.4)13 (44.8)45 (46.9)
      Smoking status, n (%)
      Current80 (64.0)20 (69.0)60 (62.5)0.175
      Past44 (35.2)8 (27.6)36 (37.5)
      Never1 (0.8)1 (3.5)0 (0.0)
      Pack-years of smoking
      Median (range)48 (0-225)43 (0-120)50 (6.3-225)0.063
      <4861 (49.6)19 (65.5)42 (44.7)0.058
      ≥4862 (50.4)10 (34.5)52 (55.3)
      FEV1/FVC% (%)
      Median (range)70.0 (28.6-91.3)69.8 (47.5-84.5)70.4 (28.6-91.3)0.760
      ≥7050 (51.0)11 (44.0)39 (53.4)0.490
      <7048 (49.0)14 (56.0)34 (46.6)
      Diabetes mellitus
      Yes16 (12.8)7 (24.1)9 (9.4)0.055
      No109 (87.2)22 (75.9)87 (90.6)
      Pathological diagnosis, n (%)
      Small cell carcinoma119 (95.2)28 (96.6)91 (94.8)1.000
      Combined SCLC6 (4.8)1 (3.5)5 (5.2)
      Clinical stage (UICC-TNM 8th), n (%)
      IIB25 (20.0)7 (24.1)18 (18.8)0.678
      IIIA46 (36.8)10 (34.5)36 (37.5)
      IIIB38 (30.4)10 (34.5)28 (29.2)
      IIIC16 (12.8)2 (6.9)14 (14.6)
      T stage, n (%)
      Tx3 (2.4)0 (0.0)3 (3.1)0.996
      T132 (25.6)7 (24.1)25 (26.0)
      T240 (32.0)10 (34.5)30 (31.3)
      T317 (13.6)4 (13.8)13 (13.5)
      T433 (26.4)8 (27.6)25 (26.0)
      N stage, n (%)
      N07 (5.6)1 (3.5)6 (6.3)0.454
      N129 (23.2)10 (34.5)19 (19.8)
      N254 (43.2)11 (37.9)43 (44.8)
      N335 (28.0)7 (24.1)28 (29.2)
      PET-CT
      Performed88 (70.4)23 (79.3)65 (67.7)0.257
      Not performed37 (29.6)6 (20.7)31 (32.3)
      Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance status; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; LCNEC, large cell neuroendocrine carcinoma; PET-CT, positron emission tomography-computed tomography; SCLC, small cell lung carcinoma; UICC-TNM 8th, Union International for Cancer Control-TNM 8th edition
      Twenty-six patients developed RP of ≥Grade 2. Despite not reaching statistical significance, trends were observed. Specifically, diabetes mellitus (p = 0.055) and ≥48 pack-years of smoking (p = 0.058) were more frequent in patients with RP of Grade 2 or greater.

      Incidence of RP

      The median follow-up time from the start of CRT was 73.1 months (range, 5.0–177.5 months). Twelve patients developed Grade 3 RP, 17 patients developed Grade 2 RP, 69 patients developed Grade 1 RP, and 27 patients did not exhibit RP based on radiological findings (i.e., Grade 0) (Table 2). The median time to the incidence of RP from initiation of radiotherapy was 147 days. Three patients (2.4%) developed RP within 59 days from the start of radiotherapy, six (4.8%) developed RP within 60–89 days, 16 (12.8%) developed RP within 90–119 days, 29 (23.2%) developed RP within 120–149 days, 24 (19.2%) developed RP within 150–179 days, and 20 (16.0%) developed RP at ≥180 days (Figure 1).
      Table 2Grade, initial treatment, and outcomes for RP.
      All patients (n = 125)Number of patients (n)Percentage (%)
      Grade of RP
      02721.6
      16955.2
      21713.6
      3129.6
      400.0
      500.0
      Initial treatment of ≥Grade 2 RP
      Observation without any treatment32.4
      Treatment with corticosteroids (initial dose)2620.8
      mPSL 500–1000 mg/day64.8
      PSL 1 mg/kg/day43.2
      PSL 0.5 mg/kg/day1411.2
      PSL 0.3 mg/kg/day21.6
      Duration of treatment (days)89 (28-477) *
      Outcome
      Recovered2620.8
      Requirement for long-term oxygen therapy32.4
      Abbreviations: mPSL, methylprednisolone; PSL, prednisolone; RP, radiation pneumonitis
      *: Duration of treatment was shown by median (range)
      Figure 1
      Figure 1Timing and incidence rate for radiation pneumonitis (RP). (A) Grade and onset of RP. The timing of onset was measured from the start of radiation therapy. (B) Grade and onset of RP. The timing of onset was measured from the last date of radiation therapy.

      DVH parameters as risk factors for RP

      Correlations between dosimetric factors were assessed using univariate analysis. Total lung DVH parameters (V5-45 and MLD), excepting V50 and Dmax, were statistically significantly associated with the incidence of RP of ≥Grade 2 or 3 (as a continuous variable; p < 0.05) (Table 3). On univariate analysis, V30 showed the minimal p-value with ≥Grade 2 RP (p < 0.0001), and V25 showed the minimal p-value with ≥Grade 3 RP (p = 0.0006). The optimal threshold for V30 in predicting RP of ≥Grade 2 was 20%, with a maximum AUC of 0.748, while that of V25 for predicting RP Grade 3 was 24% (with a maximum AUC of 0.789). In an analysis of DVHs related to ≥Grade 2 RP, the maximum AUC for the diagnosis of ≥Grade 2 RP on ROC analysis was observed using V30 (AUC = 0.748). Therefore, in this study, we selected V30 as a representative parameter for univariate and multivariate analyses for RP of Grade 2 or greater.
      Table 3Univariate analysis and ROC analysis of total lung DVH parameters related to ≥Grade 2 RP and Grade 3 RP.
      ≥Grade 2 RP (n = 29)<Grade 2 RP (n = 96)Spearman's rank correlationROC analysisUnivariate analysis
      VariableMedian (IQR)Median (IQR)p-valuersp-valueAUCOptimal thresholdCrude OR (95% CI)p-value
      V5 (%)42 (37.5-52)35 (25-44.75)0.00540.787<0.00010.671361.049 (1.008-1.092)0.0146
      V1034 (32-44)30 (24.25-37)0.00340.827<0.00010.680291.060 (1.013-1.111)0.0101
      V1530 (27.5-37)26.5 (22-32)0.00320.868<0.00010.681261.072 (1.015-1.132)0.0093
      V2027 (23.5-30)22 (18.25-27)0.00120.945<0.00010.699231.100 (1.022-1.829)0.0075
      V2524 (22-27)19 (16.25-23)0.00010.976<0.00010.736211.140 (1.047-1.241)0.0013
      V3020 (20-23.5)16 (13.25-20)<0.0001--0.748201.160 (1.058-1.271)0.0006
      V3516 (13-17)13 (10-15)0.00130.931<0.00010.697161.144 (1.034-1.265)0.0063
      V4013 (10-14.5)10 (7-12.75)0.00170.874<0.00010.692131.169 (1.043-1.311)0.0053
      V456 (4.5-10)5 (3-7)0.01030.672<0.00010.657101.202 (1.050-1.376)0.0063
      V500 (0-0.5)0 (0-0)0.35230.2000.02580.53811.264 (0.534-2.988)0.7348
      Dmax49.6 (48.7-50.75)49.6 (48.5-50.6)0.56080.3250.00020.53649.11.046 (0.808-1.354)0.6002
      MLD (cGy)1234 (1146-1461)1059 (895-1243)0.00080.939<0.00010.70511401.002 (1.001-1.004)0.0044
      ≥Grade 3 RP (n = 12)<Grade 3 RP (n = 113)
      V5 (%)44 (38-53)37.5 (31-45)0.01120.847<0.00010.715361.060 (1.006-1.117)0.0281
      V1037 (32-45)32 (25-37.75)0.00980.882<0.00010.719291.075 (1.011-1.144)0.0187
      V1533 (28.5-39)27 (22-32.75)0.00890.914<0.00010.722261.099 (1.020-1.185)0.0101
      V2027 (24.5-32.5)23 (19-27)0.00390.986<0.00010.745231.154 (1.038-1.284)0.0045
      V2524 (23-29)20 (17-23)0.0006--0.789221.205 (1.064-1.364)0.0012
      V3021 (20-24)17 (14-20)0.00090.976-<0.00010.781201.209 (1.062-1.377)0.0017
      V3517 (14.5-18)13 (10-16)0.01020.865<0.00010.717161.169 (1.018-1.341)0.0213
      V4013 (11.5-14.5)10 (7.25-13)0.01070.792<0.00010.716131.183 (1.015-1.380)0.0269
      V456 (4-10)5 (3-7)0.08420.589<0.00010.64691.170 (0.985-1.390)0.0767
      V500 (0-0)0 (0-1)0.22340.1900.03420.56911.606 (0.553-4.667)0.4064
      Dmax50.3 (48.35-51.2)49.6 (48.6-50.6)0.63600.2830.00150.54050.31.065 (0.747-1.518)0.7300
      MLD (cGy)1261 (1159-1499)1073 (905-1266)0.00550.961<0.00010.73611591.003 (1.001-1.005)0.0063
      Abbreviations: AUC, area under the curve; CI, confidence interval; Dmax, maximal lung dose; DVH, dose-volume histogram; IQR, interquartile range; MLD, mean lung dose; OR, odds ratio; ROC, receiver operating characteristic analysis; RP, radiation pneumonitis; rs, Spearman's rank correlation coefficients between V30; V5-40, percentage of lung volume receiving more than 5–40 Gy
      Table 4 summarizes the results of univariate and multivariate analyses for risk factors related to ≥Grade 2 RP in the enrolled patients. V30 ≥20% (p < 0.001) was an independent risk factor for RP of ≥Grade 2, with an odds ratio (OR) of 13.632 (95% confidence interval [CI], 4.695-39.579; p < 0.001). The incidence of RP stratified by V5, V20, and V30 is shown in Figure 2. The occurrence rates for RP of ≥Grade 2 in patients with V30 <20% and V30 ≥20% were 6.6% and 49.0%, respectively (Figure 2). The correlations between total lung DVH parameters and ≥Grade 2 RP requiring steroids were also evaluated. The results were the same as those obtained in the analysis of ≥Grade 2 RP and are presented in the Supplementary Table.
      Table 4Univariate and multivariate analyses of risk factors for ≥Grade 2 RP.
      Variables (total n = 125)UnivariateMultivariate
      OR (95% CI)p-valueOR (95% CI)p-value
      Age (<65 years/≥65 years)0.414 (0.167-1.026)0.04900.456 (0.164-1.270)0.133
      Sex (male/female)1.167 (0.446-3.056)0.751--
      ECOG-PS (0/1)1.086 (0.471-2.502)0.846--
      Smoking status (past/current)0.667 (0.266-1.670)0.387--
      Diabetes mellitus (yes/no)3.076 (1.031-9.174)0.04391.559 (0.423-5.742)0.505
      V30 (≥20%/<20%)13.632 (4.695-39.579)<0.00112.352 (4.127-36.973)<0.001
      Abbreviations: 95% CI, 95% confidence interval; ECOG, Eastern Cooperative Oncology Group; OR, odds ratio; PS, performance status; RP, radiation pneumonitis; V30, percentage of lung volume receiving >30 Gy
      Figure 2
      Figure 2Incidence rate of radiation pneumonitis (RP) stratified by total lung dose-volume histogram (DVH) findings. (A) Incidence rate for RP stratified by the percentage of lung volume receiving more than 5 Gy (V5). (B) Incidence rate for RP stratified by the percentage of lung volume receiving more than 20 Gy (V20). (C) Incidence rate for RP stratified by the percentage of lung volume receiving more than 30 Gy (V30).

      Treatment and outcomes for RP

      Of the 29 patients with RP of ≥Grade 2, 26 received corticosteroids. The initial dose was as follows: methylprednisolone at 500–1000 mg/day (n = 6), prednisolone (PSL) at 0.3 mg/kg/day (n = 2), PSL at 0.5 mg/kg/day (n = 14), and PSL at 1 mg/kg/day (n = 4). The median duration of treatment was 89 days (range: 28-477). The three patients who did not receive any treatment were considered to have Grade 2 pneumonitis because they showed abnormal lung shadows in and around the radiation field and experienced increased shortness of breath and coughing. Oxygen desaturation was also observed in two of the three patients. From these patients, two recovered with observation alone, while one showed radiation fibrosis on lung CT. Twenty-six patients recovered, one patient required long-term oxygen therapy, and no treatment-related deaths were observed.

      DISCUSSION

      To the best of our knowledge, we conducted the largest retrospective study in LS-SCLC patients treated with CRT using AHF-RT in order to evaluate DVH parameters for risk factors and to investigate the onset, treatment, and outcomes for RP.
      V20 was previously reported as a risk factor for RP in LA-NSCLC patients treated with CRT.9,10,13,14,16 In LS-SCLC patients receiving CRT using AHF-RT, V20 was also verified as a predictor of RP in several retrospective studies.5,23,24 Only one retrospective study, which enrolled a small number of patients with LS-SCLC, evaluated various DVH parameters.5 In the present study, V30 was considered a higher-level risk factor for RP among the evaluated DVH parameters. Therapeutic efficacy is expected to be maximized with the administration of radiation twice daily while reducing the dose per fraction and maintaining a larger tolerance dose to normal tissues.24,25 Therefore, it is thought that V30, which represents a higher dose range than V20, is a risk factor for RP in LA-NSCLC treated with CRT; moreover, V30 was verified as a risk factor for RP in LS-SCLC treated with AHF-RT. The impact of each DVH parameter on RP may differ between AHF-RT and conventional irradiation. In this study, we found that a V30 of ≥20% could consistently distinguish symptomatic RP overall. According to our findings, a V25 of ≥22% may potentially distinguish RP of ≥Grade 3.
      Moreover, we found that the incidence of RP gradually increased 60 days after the start of radiation, with the highest rate evidenced at 120-150 days. The median time to the onset of RP was 147 days after the initiation of RT. Previous studies on CRT-induced RP in LA-NSCLC patients showed that the median time to the onset of RP from the time of initiation of RT was 92-123 days,11,19,25 and that the median time to the onset of RP in LS-SCLC patients treated with concurrent CRT (CCRT) using AHF-RT was five months from the initiation of RT.24 Although the median time from the last date of RT to the onset of RP was 123 days in the present study, previous studies evaluating RP in LA-NSCLC patients showed a median onset time of 2.0-3.4 months.10,26 Therefore, the onset of RP induced by AHF-RT in LS-SCLC patients may be later than that induced by conventional irradiation in LA-NSCLC patients. There may be a difference in the incidence of RP between LS-SCLC patients treated with AHF-RT and in LA-NSCLC patients treated with conventional irradiation, according to tumor location or chemotherapy regimen.
      Recent randomized phase II or III trials of LS-SCLC patients treated with CRT have reported the following rates in the AHF-RT group: 5-20% for Grade 1-2 RP and 0-1% for Grade 3 RP.3,27,28 A previous Chinese randomized Phase II trial found a relatively high incidence of RP, with the following reported rates: 14.1% for Grade 2 RP, 2.2% for Grade 3 RP, and 1.1% for Grade 5 RP.29 Possible reasons for the higher frequency of RP detected in this study may be attributed to different ethnic backgrounds as well as the effects of elective nodal irradiation (ENI). It is, however, important to note that AHF-RT for LS-SCLC can be performed safely despite the high frequency of RP observed in this study.
      Although SCLC is one of the most aggressive tumors, LS-SCLC is curable with CRT.1,2 Among LS-SCLC patients treated with CRT, the reported rates of locoregional recurrences and distant metastases were 15-26% and 44.6-54.6%, respectively.23,30,31 Inhibiting distant metastasis by additional systemic therapy on the administration CRT could be important to improving the prognosis of patients with LS-SCLC. An ongoing randomized clinical study is evaluating the efficacy of the addition of immune checkpoint inhibitors (ICIs) to CRT.32 Our study results, the addition of ICI to CRT for patients with LS-SCLC may be tolerable.
      To our knowledge, this is the first study to report on the treatment of and outcomes for RP in patients with LS-SCLC treated with CCRT using AHF-RT. The severity of RP in our enrolled patients was relatively mild, and no deaths due to RP were recorded. Patients with RP responded well to steroid therapy and improved without sequelae, with the exception of one patient who required oxygen therapy. Remarkably, RP was not exacerbated during treatment.
      We acknowledge some limitations of this study. First, the single-center retrospective design may confer some level of bias and may likewise impact generalizability. Second, RP treatment was based on each physician's discretion. Additional prospective studies are necessary to evaluate the optimal dose and/or treatment duration for corticosteroid treatment in order to standardize the treatment of RP.

      CONCLUSION

      Radiation pneumonitis was observed in 78.3% of LS-SCLC patients treated with CCRT using AHF-RT, and RP of Grade 2 or greater was observed in 21.6% of our enrolled patients. The onset of RP induced by CCRT using AHF-RT in LS-SCLC patients might occur later than that induced by conventional irradiation in LA-NSCLC patients. Among the evaluated DVH parameters, V30 was most strongly associated with RP in LS-SCLC patients treated with AHF-RT. There were no deaths due to RP within the present study and a good response to steroid therapy was observed, indicating that RP induced by CRT using AHF-RT is manageable in LS-SCLC patients.

      Author responsible for statistical analysis

      Takanori Kawabata

      Funding

      None.

      Data Availability Statement

      The data that support the findings of this study are available from the corresponding author upon reasonable request.

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      Conflict of Interest Statement

      Dr. Doshita has nothing to disclose. Dr. Tabuchi has nothing to disclose. Dr. Kenmotsu reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Chugai Pharmaceutical Co., grants and personal fees from Daiichi-Sankyo Co., Ltd., grants and personal fees from Novartis Pharma K.K., grants from Loxo Oncology, personal fees from Ono Pharmaceutical Co, Ltd., Boehringer Ingelheim, personal fees from Eli Lilly K.K., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from Bristol-Myers Squibb, personal fees from Pfizer Inc., personal fees from Taiho Pharmaceutical., outside the submitted work. Dr. Omori reports grants and personal fees from Daiichi-Sankyo Co., Ltd., personal fees from Chugai Pharmaceutical Co., personal fees from AstraZeneca K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Novartis Pharma K.K., personal fees from Taiho Pharmaceutical, personal fees from Eli Lilly Japan K.K., personal fees from Daiichi Sankyo Co., Ltd., personal fees from Amgen K.K., outside the submitted work. Dr. Kawabata has nothing to disclose. Dr. Kodama has nothing to disclose. Dr. Hakkaku has nothing to disclose. Dr. Nishioka has nothing to disclose. Dr. Miyawaki has nothing to disclose. Dr. Iida has nothing to disclose. Dr. Mamesaya reports grants and personal fees from Boehringer Ingelheim, personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Taiho Pharmaceutical, personal fees from MSD K.K., personal fees from AstraZeneca K.K., personal fees from Ono Pharmaceutical Co., Ltd., outside the submitted work. Haruki Kobayashi reports personal fees from Eli Lilly K.K., personal fees from Novartis Pharma K.K., personal fees from Taiho Pharmaceutical., personal fees from AstraZeneca K.K., personal fees from Chugai Pharmaceutical Co., LTD., personal fees from Ono Pharmaceutical Co., LTD., outside the submitted work. Dr. Ko reports grants and personal fees from Boehringer Ingelheim, grants from MSD K.K., personal fees from Taiho Pharmaceutical, personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Eli Lilly K.K., personal fees from Boehringer Ingelheim, personal fees from Pfizer Inc., personal fees from AstraZeneca K.K., outside the submitted work. Dr. Wakuda reports grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from AstraZeneca K.K., grants from Novartis Pharma K.K., grants from Abbvie, grants from AMGEN, personal fees from Taiho Pharmaceutical, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from MSD, outside the submitted work. Dr. Ono reports personal fees from AstraZeneca K.K., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Ono Pharmaceutical Co., Ltd., outside the submitted work. Dr. Naito reports grants from Otsuka Pharmaceutical K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Helsinn Healthcare SA, outside the submitted work. Dr. Murakami reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Daiichi-Sankyo Co., grants from Abbvie, grants from IQvia, personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Bristol-Myers Squibb Japan, personal fees from MSD, personal fees from Pfizer Inc., personal fees from Novartis Pharma K.K., personal fees from Eli Lilly Japan K.K., personal fees from Taiho Pharmaceutical, outside the submitted work. Dr. Mori has nothing to disclose. Dr. Harada reports personal fees from AstraZeneca K.K., personal fees from Brainlab, personal fees from Pfizer Japan Inc., personal fees from MSD, personal fees from Eli Lilly Japan K.K., outside the submitted work. Dr. Kaneko reports grants and personal fees from Boehringer Ingelheim, grants from Eli Lilly Japan K.K., grants from Taiho Pharmaceutical, personal fees from GlaxoSmithKline, personal fees from AstraZeneca K.K., personal fees from Novartis Pharma K.K., personal fees from Nippon Kasei Chemical Co., Ltd., personal fees from Takeda Pharmaceutical Co., outside the submitted work. Dr. Takahashi reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from MSD, grants and personal fees from Pfizer Japan Inc., grants and personal fees from Boehringer Ingelheim Japan, grants from Merck Biopharma Co., Ltd., grants from Amgen Inc., personal fees from Roche Diagnostics K.K. personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Yakult Honsha Co. Ltd., outside the submitted work.

      Acknowledgments

      None.

      Appendix. Supplementary materials