Abstract
Background
The combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) has played a significant role in the improvement of tumor therapy, but the increased incidence of pneumonitis has greatly limited its application. To identify potential intervention targets, we analyzed risk factors for pneumonitis after combination therapy with ICIs and TRT.
Methods
Overall, 335 patients who received TRT and ICI therapy concurrently or sequentially were included in our study. Pneumonitis was assessed and the related factors were analyzed.
Results
After combined TRT and ICI therapy, among the 335 patients, 219 (65.4%) patients had no pneumonitis or Grade 1 pneumonitis, 77 (23.0%) patients had Grade 2 pneumonitis, and 39 (11.6%) patients had Grade 3 or above pneumonitis. The incidence of Grade 2 or above pneumonitis was significantly related to the patients’ age at diagnosis, sex, time interval and ipsilateral or bilateral lung dose‒volume parameters.
Conclusion
We first showed that older, male patients are more likely to suffer from pneumonitis of Grade 2 and above. We also found that, numerically, patients who received ICIs before radiotherapy (RT) were more likely to have pneumonitis than those who received RT before ICIs. Moreover, a longer interval between treatments, lower mean lung dose (MLD) and smaller ipsilateral or bilateral lung dose‒volume parameters are correlated with a lower incidence of pneumonitis of Grade 2 or above.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12890-025-03871-y.
Keywords: Risk factors, Combination treatment, Pneumonitis, Immune checkpoint inhibitors, Thoracic radiotherapy
Introduction
Radiotherapy (RT) has been considered one of the most significant and effective methods for treating various tumors locally. It is essential for the comprehensive treatment of malignant tumors. Statistics indicate that more than fifty percent of cancer patients receive radiation therapy during their treatment [1]. TRT generally refers to RT for thoracic primary or metastatic tumors in the thoracic region, including the lung, esophagus, mediastinum, clavicular region, axilla, and thoracic vertebra. Concurrent TRT, with or without chemotherapy, plays an important role in the treatment of inoperable lung cancer and esophageal cancer [2–4]. For metastatic cancers, local RT for all metastatic tumors, including TRT for metastatic lung tumors, can significantly improve treatment efficacy when combined with effective systemic treatment [3]. However, radiation pneumonitis (RP) resulting from RT is the main complication of TRT. The incidence rates of Grade 2 and above RP after RT for lung cancer ranges from 9 to 55%, whereas those of Grade 3 and above RP range from 5 to 10% [5–8]. In a retrospective study, the incidence rates of Grade 1–2 and 3–4 RP after RT for esophageal carcinoma were 46.2% and 4.5%, respectively [9]. Most reported cases of RP are asymptomatic or mild, but up to 12% of cases are still severe and potentially fatal [8].
ICIs represent a novel approach for treating cancer, and their development represent a major advance in the field of tumor immunology. Antibodies against programmed death 1/programmed death ligand-1 (PD-1/PD-L1) have recently become more commonly used. ICIs have been widely used in maintenance therapy for various advanced or recurrent or metastatic tumors, including lung cancer, esophageal carcinoma, melanoma, head and neck carcinoma, colorectal cancer, and triple-negative breast cancer [10–14]. The PACIFIC and GEMSTONE-301 trials were performed to assess consolidation therapy with ICIs after definitive chemoradiotherapy (CRT) as a standard of care for patients with unresectable, stage III non-small cell lung cancer (NSCLC) [15, 16]. Importantly, the results of the NADIM trial led to the emergence of ICIs as a hot topic in neoadjuvant immunotherapy [17, 18]. However, immune-associated pneumonitis caused by immunotherapy is also a major complication. The reported incidence of pneumonitis caused by ICIs treatment ranges from 1 to 19% [19–23].
An increasing number of clinical trials and theoretical studies have reported the synergistic effect of RT and immunotherapy in combination. RT can result in increased tumor antigen release, enhanced antigen presentation, and T-cell infiltration, thereby enhancing the efficacy of immunochemotherapeutic agents [24]. A secondary analysis of the KEYNOTE-001 study revealed that the overall survival (OS) of patients treated with pembrolizumab was significantly longer in patients who had previously received RT than in patients who had not received RT (10.7 months vs. 5.3 months) [25]. The results of the phase 2 KEYNOTE-799 nonrandomized trial also suggested the antitumor activity of pembrolizumab in combination with CRT. Moreover, Grade 3 or above pneumonitis occurred in up to 8.0% of patients, a significant increase from previous studies [26]. Although the combination of RT and ICIs is more effective than either treatment alone, the risk of pneumonitis caused by combination therapy cannot be ignored [27]. Theelen W et al. reported that after the treatment with pembrolizumab in combination with stereotactic body radiotherapy (SBRT) (8 Gy × 3 F), the incidence of RP was greater than that in patients receiving ICIs alone (26% vs. 8% [28]. A meta-analysis also revealed an increase in the incidence of grade pneumonitis following combination therapy with PD-1/PD-L1 inhibitors and RT [29]. The elevated incidence of pneumonitis has severely restricted the access of cancer patients to combination therapies.
To investigate the relevant risk factors for pneumonitis caused by treatment with RT and ICIs, we systematically reviewed information on patients receiving TRT combined concurrently or sequentially with ICIs. We analyzed the clinical characteristics of these patients, including RT-related dose‒volume parameters, immunotherapy-related parameters, the combination strategy and the interval between TRT and ICI therapy. This real-world study aims to determine the incidence and predictors of clinical pneumonitis in patients treated with TRT and ICIs and identify potential intervention targets for clinical practice.
Materials and methods
Study participants and design
A retrospective analysis was conducted on 335 patients who received TRT and ICI therapy concurrently or sequentially between June 1, 2018, and June 30, 2022. The inclusion criteria for patients were as follows: (1) had a history of primary or metastatic tumors requiring TRT, including those in the lung, mediastinum, clavicular region, axilla, and/or thoracic vertebra; (2) received TRT and ICIs concurrently or sequentially after diagnosis; and (3) had complete clinical and imaging data.
Radiation techniques and radiation parameters
All patients received a standard RT prescription dose and target volumes as determined by the treating physicians. The RT approach included conventional fractionated radiotherapy with a prescribed dose of 54–66 Gy in 25–30 fraction which was administered using a 6-MV X-ray. The treatment plan was designed to ensure that 100% of the prescribed dose covered 95% of the target volume. RT was delivered using intensity-modulated radiation therapy (IMRT) via a Varian linear accelerator.
Immunotherapy and agents
Immunotherapy agents mainly included camrelizumab, pembrolizumab, sintilimab, nivolumab, durvalumab, and tislelizumab, and the physicians determined the timing of ICI treatment. The strategies for combining ICIs and RT were divided into four categories. Given the substantial variability in the treatment timing between ICIs and RT observed in our retrospective study, we categorized patients into four groups on the basis of treatment sequence: (1) ICIs and RT concurrently: ICIs administered during RT, (2) ICIs before RT: RT following completion of ICIs, (3) RT before ICIs: ICIs following completion of all planned RT sessions, and (4) sandwich-like therapy: alternating ICIs and RT cycles.
Evaluation of radiation pneumonitis
RP diagnoses were confirmed by clinical manifestations, including fever, cough, expectations, respiration, etc., in medical records and follow-up chest CT. These diagnoses were agreed upon radiation oncologists and radiologists. The diagnosis and grading of severe pneumonitis in certain cases were determined through multidisciplinary discussions. Pneumonitis was assessed and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0: Grade 1: no symptoms, only imaging findings; Grade 2: symptomatic, but does not affect the ability in daily life, requiring drug treatment; Grade 3: symptomatic, affecting the ability in daily life, requiring oxygen inhalation; Grade 4: life-threatening respiratory symptoms, requiring mechanical ventilation; Grade 5: death. For patients with treatment-associated pneumonitis, the date of diagnosis of pneumonia, CT features of pneumonia, symptoms, treatment and outcome were recorded through medical records and telephone follow-up.
Statistical analysis
Statistical analysis was performed using SPSS software version 20.0. The characteristics of the patients and treatment were compared across the different groups. Statistical descriptions, including means, standard deviations (SDs), ranges and percentages, were used to characterize the eligible participants. The chi-square test was used to compare categorical variables, pairwise comparisons between multiple sample rates were performed using the Bonferroni method, and an independent sample t test was used to compare continuous variables. For patients who developed Grade 2 or above pneumonitis, the optimal cutoff values for the ipsilateral and bilateral lung dosimetry parameters, the percentage of the lung volume exceeding 5/10/20/30 Gy (V5, V10, V20, V30), and the MLD were determined using receiver operating characteristic (ROC) curve analysis. Area under the curve (AUC) values were calculated. The logistic regression model was used to identify the risk factors for Grade 2 and or pneumonitis. Factors with P < 0.05 in the univariate analysis were included in the multivariate logistic regression analysis. P < 0.05 indicated statistical significance.
Results
Patient characteristics
All 335 patients who met the inclusion criteria and had evaluable data were enrolled in this study. As shown in Table 1, 293 men (87.5%) and 42 women (12.5%) were included, with a median age of 68 years (range 25–83 years). The distribution of tumor types was as follows:NSCLC (177, 52.8%), small-cell lung cancer (42, 12.5%), esophageal carcinoma (53, 15.8%), head and neck carcinoma (27, 8.1%), thymic carcinoma (6, 1.8%), other cancers with pulmonary metastasis (14, 4.2%), other cancers with bone metastasis (7, 2.1%) and others (9, 2.7%). Among the 335 participants, 211 (63.8%) patients had a smoking history, and 124 (37.0%) patients had no previous smoking history. Simultaneously, we recorded the strategies of RT combined with ICIs for all patients: 20 patients (6.0%) received ICIs and RT concurrently, 91 patients (27.2%) received ICIs before TRT, 169 patients (50.4%) received TRT before ICIs, and 55 patients (16.4%) underwent sandwich-like therapy. In addition, the average time interval for the whole patients received combination therapy was 241.98 days (SD, 353.21). We also calculated the median of patients received ICIs before TRT (53, ranging from 1 to 770) and TRT before ICIs (287, ranging from 2 to 2066) in Table 1. Table 1 also summarizes the types of ICI drugs administered to these patients and the radiation dose parameters of normal tissues. After combined RT and ICI therapy, 219 (65.4%) patients had no pneumonitis or Grade 1 pneumonitis, 77 (23.0%) patients had Grade 2 pneumonitis, and 39 (11.6%) patients had Grade 3 or above pneumonitis.
Table 1.
Patient characteristics
| Age at Diagnosis Median(range) | 61(25–83) |
|---|---|
| Gender | N(%) |
| Female | 42(12.5) |
| Male | 293(87.5) |
| Smoking Status | N(%) |
| Never smoke | 124(37.0) |
| Previous or current smokers | 211(63.0) |
| Type of Tumors | N(%) |
| Small-cell lung cancer | 42(12.5) |
| Non-small-cell lung cancer | 177(52.8) |
| Esophageal cancer | 53(15.8) |
| Head and neck cancer | 27(8.1) |
| Thymic carcinoma | 6(1.8) |
| Other cancer with pulmonary metastasis | 14(4.2) |
| Other cancer with bone metastasis | 7(2.1) |
| Others | 9(2.7) |
| Ki67 Status | N(%) |
| ≤ 20 | 12(3.6) |
| > 20 | 76(22.7) |
| Unkown | 247(73.7) |
| CTCAE 5.0 Grade | |
| No pneumonitis or Grade 1 | 219(65.4) |
| Grade 2 | 77(23.0) |
| Above Grade 2 | 39(11.6) |
| Immunotherapy Drugs | N(%) |
| Camrelizumab | 131(39.1) |
| Durvalumab | 20(6.0) |
| Nivolumab | 26(7.8) |
| Pembrolizumab | 66(19.7) |
| Sintilimab | 46(13.7) |
| Tislelizumab | 29(8.6) |
| Toripalimab | 1(0.3) |
| Combination of two drugs | 16(4.8) |
| Strategy of ICIs and TRT | N(%) |
| ICIs and TRT concurrently | 20(6.0) |
| ICIs bofore TRT | 91(27.2) |
| TRT bofore ICIs | 169(50.4) |
| Sandwich-like therapy | 55(16.4) |
| Time Interval (Days) | |
| The whole (Mean (SD)) | 241.98(353.21) |
| ICIs bofore TRT | 53(1–770) |
| TRT bofore ICIs | 287(2–2066) |
| Ipsilateral lung dosimetry parameters | Mean(SD) |
| V5ipsi | 50.05(22.91) |
| V10ipsi | 38.02(19.95) |
| V20ipsi | 23.23(14.60) |
| V30ipsi | 14.13(10.58) |
| Ipsilateral MLD (Gy) | 12.32(6.54) |
| Bilateral lung dosimetry parameters | Mean(SD) |
| V5bi | 40.05(20.09) |
| V10bi | 27.74(15.30) |
| V20bi | 15.19(9.42) |
| V30bi | 8.40(6.00) |
| Bilateral MLD (Gy) | 8.86(4.57) |
Abbreviations: ICIs immune checkpoint inhibitors, TRT thoracic radiotherapy, Sandwich-like therapy ICIs-TRT-ICIs or TRT-ICIs-TRT, RT radiotherapy, V5ipsi percentage of ipsilateral lung volume exceeding 5 Gy, V10ipsi percentage of ipsilateral lung volume exceeding 10 Gy, V20ipsi percentage of ipsilateral lung volume exceeding 20 Gy, V30ipsi percentage of ipsilateral lung volume exceeding 30 Gy, MLD mean lung dose, V5bi percentage of bilateral lung volume exceeding 5 Gy, V10bi percentage of bilateral lung volume exceeding 10 Gy, V20bi percentage of bilateral lung volume exceeding 20 Gy, V30bi percentage of bilateral lung volume exceeding 30 Gy
Patient clinical characteristics and treatment strategy for pneumonitis of grade 2 or above
Among patients who received the combination of RT and ICIs, 116 out of 335 (34.07%) patients developed Grade 2 or above pneumonitis. There were differences between groups in terms of the different clinical characteristics of the patients. The morbidity of Grade 2 or above pneumonitis is significantly related to age, gender, immunotherapy agent, and strategies involving a combination of TRT and ICIs. The age at diagnosis for patients who developed pneumonitis of Grade 2 and above was greater (61.47 years old) than that (58.24 years old) for patients with Grade 1 or below pneumonitis (P = 0.008). The optimal age cutoff, as determined by the ROC curves (Table 3), was 57.5 years old, which provided a sensitivity of 72.4% and a specificity of 55.3%. The incidence rate of Grade 2 pneumonitis and above was 36.86% (108/293) in male patients and 19.05% (8/42) in female patients (P = 0.023). We found that males and older patients were more likely to suffer from Grade 2 and above compared with female patients and younger patients. In contrast, there was no correlation between smoking and the incidence of pneumonitis in these patients. The incidence rate of Grade 2 and or pneumonitis differed among patients administered different ICI agents and combination strategies of TRT and ICIs. Furthermore, our analysis revealed varying incidences of Grade 2 and or pneumonitis associated with different treatment strategies. Numerically, the ICIs before TRT strategy was associated with the highest incidence of Grade 2 and or pneumonitis (45/91, 49.5%), whereas the TRT before ICIs strategy led to the lowest incidence (47/169, 27.8%). However, further statistical analysis indicated that these differences were not significant (Table 2 and Supplementary Table).
Table 3.
ROC analysis of grade 2 and above penumonitis
| AUC | P | Cutoff Value | Sensitivity | 1-Specificity | |
|---|---|---|---|---|---|
| Age at Diagnosis | 0.600(0.537–0.663) | 0.003 | 57.50 | 0.724 | 0.553 |
| Dosimetric Parameters | |||||
| V5ipsi | 0.572(0.509–0.634) | 0.031 | 44.38 | 0.716 | 0.571 |
| V10ipsi | 0.581(0.517–0.644) | 0.015 | 39.58 | 0.603 | 0.466 |
| V20ipsi | 0.577(0.513–0.641) | 0.02 | 27.36 | 0.50 | 0.356 |
| V30ipsi | 0.578(0.514–0.642) | 0.019 | 18.96 | 0.414 | 0.269 |
| Ipsilateral MLD | 0.581(0.517–0.645) | 0.015 | 13.63 | 0.543 | 0.379 |
| Dosimetric Parameters | |||||
| V5bi | 0.580(0.514–0.645) | 0.021 | 42.86 | 0.594 | 0.44 |
| V10bi | 0.575(0.509–0.642) | 0.029 | 28.65 | 0.623 | 0.478 |
| V20bi | 0.579(0.512–0.646) | 0.022 | 17.97 | 0.519 | 0.367 |
| V30bi | 0.581(0.514–0.649) | 0.018 | 10.96 | 0.481 | 0.290 |
| Bilateral MLD | 0.587(0.521–0.654) | 0.012 | 10.95 | 0.472 | 0.309 |
| Time Interval (the whole) | 0.578(0.517–0.640) | 0.018 | 166.5 | 0.750 | 0.562 |
Abbreviations:V20ipsi percentage of ipsilateral lung volume exceeding 20 Gy, V30ipsi percentage of ipsilateral lung volume exceeding 30 Gy, MLD mean lung dose, V5bi percentage of bilateral lung volume exceeding 5 Gy, V10bi percentage of bilateral lung volume exceeding 10 Gy, V20bi percentage of bilateral lung volume exceeding 20 Gy, V30bi percentage of bilateral lung volume exceeding 30 Gy
Table 2.
Characteristics of patients by pneumonitis of grade 2
| N | Pneumonitis of Grade 1 and Below | Pneumonitis of Grade 2 and above | P |
|---|---|---|---|
| 219 | 116 | ||
| Age at Diagnosis Mean(SD) | 58.24(10.77) | 61.47(10.43) | 0.008 |
| Gender | 0.023 | ||
| Female | 34 (15.5) | 8 (6.9) | |
| Male | 185 (84.5) | 108 (93.1) | |
| Smoking Status | 0.158 | ||
| Never smoke | 87 (39.7) | 37 (31.9) | |
| Previous or current smokers | 132 (60.3) | 79 (68.1) | |
| Immunotherapy Drugs | 0.042 | ||
| Camrelizumab | 85 (38.8) | 46 (39.7) | |
| Durvalumab | 15 (6.8) | 6 (5.2) | |
| Nivolumab | 15 (6.8) | 11 (9.5) | |
| Pembrolizumab | 38 (17.4) | 28 (24.1) | |
| Sintilimab | 35 (16.0) | 11 (9.5) | |
| Tislelizumab | 16 (7.3) | 13 (11.2) | |
| Toripalimab | 1 (0.5) | 0 (0.0) | |
| Combination of two drugs | 15 (6.8) | 1 (0.9) | |
| Strategy of ICIs and TRT | 0.005 | ||
| ICIs and TRT concurrently | 13 (5.9) | 7 (6.0) | |
| ICIs bofore TRT | 46 (21.0) | 45 (38.8) | |
| TRT bofore ICIs | 122 (55.7) | 47 (40.5) | |
| Sandwich-like therapy | 38 (17.4) | 17 (14.7) | |
| Time Interval (the whole) | 290.81 (403.283) | 149.78 (202.266) | < 0.001 |
| V5ipsi | 47.99 (23.68) | 53.93 (20.93) | 0.019 |
| V10ipsi | 36.18 (20.21) | 41.49 (19.04) | 0.02 |
| V20ipsi | 21.96 (14.54) | 25.63 (14.39) | 0.028 |
| V30ipsi | 13.18 (10.36) | 15.93 (10.81) | 0.023 |
| Ipsilateral MLD (Gy) | 11.67 (6.50) | 13.54 (6.47) | 0.012 |
| V5bi | 38.29 (20.74) | 43.48 (18.38) | 0.03 |
| V10bi | 26.56 (15.80) | 30.02 (14.08) | 0.05 |
| V20bi | 14.45 (9.57) | 16.64 (9.00) | 0.047 |
| V30bi | 7.88 (5.99) | 9.43 (5.90) | 0.030 |
| Bilateral Pulmonary MLD (Gy) | 8.44 (4.63) | 9.70 (4.35) | 0.020 |
Abbreviations: ICIs immune checkpoint inhibitors, TRT thoracic radiotherapy, Sandwich-like therapy, ICIs-TRT-ICIs or TRT-ICIs-TRT, RT radiotherapy, V5ipsi percentage of ipsilateral lung volume exceeding 5 Gy, V10ipsi percentage of ipsilateral lung volume exceeding 10 Gy, V20ipsi percentage of ipsilateral lung volume exceeding 20 Gy, V30ipsi percentage of ipsilateral lung volume exceeding 30 Gy, MLD mean lung dose, V5bi percentage of bilateral lung volume exceeding 5 Gy, V10bi percentage of bilateral lung volume exceeding 10 Gy, V20bi percentage of bilateral lung volume exceeding 20 Gy, V30bi percentage of bilateral lung volume exceeding 30 Gy
The association of dose-volume parameters with the risk of pneumonitis of grade 2 and above
In clinical practice, dose‒volume constraints play an important role in helping us formulate RT plans to reduce or prevent pneumonitis [30, 31]. However, when ICIs are combined with RT, it is unclear whether the time interval of the whole patients is related to the incidence of pneumonitis. It also remains unknown how to control the radiation dose‒volume parameters to minimize the incidence of pneumonitis caused by combination therapy. Here, we compared two groups of patients, those with pneumonitis of Grade 2 and above and those with pneumonitis of Grade 1 or below. The time interval (the whole) between RT and ICI therapy in patients who developed pneumonitis of Grade 2 and above was much shorter (149.78 days) than that (290.81 days) in patients who developed Grade 1 or below pneumonitis (P < 0.001). The percentage of ipsilateral lung volume exceeding 5/10/20/30 Gy (V5ispi, V10ispi, V20ispi, and V30ispi) and the MLD of the ipsilateral lung were greater in patients who developed pneumonitis of Grade 2 or above pneumonitis than in patients with Grade 1 or below pneumonitis (53.93% vs. 47.99%, 41.49% vs. 36.18%, 25.63% vs. 21.96%, 15.93% vs. 13.18%, and 13.54 Gy vs. 11.67 Gy, P values = 0.019, 0.02, 0.028, 0.023 and 0.012, respectively). Similarly, the percentage of bilateral lung volume exceeding 5/10/20/30 Gy (V5bi, V10bi, V20bi, and V30bi) and the MLD of the bilateral lung were greater in patients who developed pneumonitis of Grade 2 and above than in patients with Grade 1 or below pneumonitis (43.48% vs. 38.29%, 30.02% vs. 26.56%, 16.64% vs. 14.45%, 9.43% vs. 7.88%, and 9.70 Gy vs. 8.44 Gy, P values = 0.03, 0.05, 0.047, 0.03 and 0.02, respectively). We observed that the effects of the interval between treatments and ipsilateral or bilateral lung dose‒volume parameters differed between the two groups. A longer interval between treatments, lower MLD and smaller ipsilateral or bilateral lung dose‒volume parameters were correlated with a lower incidence of pneumonitis of Grade 2 and above (Table 2).
In addition, we analyzed the cutoff values of the time interval (the whole) and dose‒volume constraints in patients with pneumonitis of Grade 2 and above to provide a reference for clinical treatment (Fig. 1 and Table 3). The ROC curve revealed that the best cutoff values for V5ispi, V10ispi, V20ispi, V30ispi, ipsilateral MLD, V5bi, V10bi, V20bi, V30bi, bilateral MLD and the interval between ICI therapy and RT were 44.38%, 39.58%, 27.36%, 18.96%, 13.63 Gy, 42.86%, 28.65%, 17,97%, 10.96%, 10.95 Gy, and 166.5 days, respectively.
Fig. 1.
A The ROC curves of RT related ipsilateral pulmonary parameters in patients with pneumonitis of grade 2 and above; B. The ROC curves of RT related bilateral pulmonary parameters in patients with pneumonitis of grade 2 and above; V5ipsi = percentage of ipsilateral lung volume exceeding 5 Gy; V10ipsi = percentage of ipsilateral lung volume exceeding 10 Gy; V20ipsi = percentage of ipsilateral lung volume exceeding 20 Gy; V30ipsi = percentage of ipsilateral lung volume exceeding 30 Gy; MLD = mean lung dose; V5bi = percentage of bilateral lung volume exceeding 5 Gy; V10bi = percentage of bilateral lung volume exceeding 10 Gy; V20bi = percentage of bilateral lung volume exceeding 20 Gy; V30bi = percentage of bilateral lung volume exceeding 30 Gy
Univariate and multivariate logistic regression analysis of potentially prognostic factors for grade 2 or above pneumonitis
To supplement and improve the existing clinical guidelines, we used the optimal cutoff values obtained from the ROC curve as the classification standard for subsequent analysis of risk factors associated with pneumonitis of Grade 2 and above.
We categorized the patients on the basis of the cutoff values or categories for different clinical characteristics, the interval between treatments, and the ipsilateral lung dose‒volume parameters in the RT phase and conducted univariate logistic regression analysis. In the univariate logistic regression analysis, age at diagnosis > 57.5 years, male sex, interval ≤ 166.5 days, V5ispi > 44.38%, V10ispi > 39.58%, V30ispi > 18.96%, and ipsilateral MLD > 13.63 Gy were related to the risk of Grade 2 or above pneumonitis. Related factors with P < 0.05 were included in the multivariate logistic regression analysis. The final model results revealed that with P = 0.05 as the significance threshold, age at diagnosis > 57.5 years old (P = 0.011), male sex (P = 0.038), and time interval (the whole) ≤ 166.5 days (P = 0.003) were independent risk factors for pneumonitis of Grade 2 or above (Supplementary Table).
Similarly, univariate and multivariate logistic regression analyses were also conducted with the same cutoff values and categories for clinical characteristics and the interval between treatments. However, the model included the cutoff values of the parameters of the bilateral rather than the ipsilateral lung in TRT. In the univariate logistic regression analysis, age at diagnosis > 57.5 years, male sex, interval ≤ 166.5 days, V5bi > 42.86%, V10bi > 28.65%, V20bi > 17.97%, V30bi > 10.96%, and bilateral MLD > 10.95 Gy were related to the risk of Grade 2 or above pneumonitis. In the multivariate logistic regression analysis, the final model results revealed that with P = 0.05 as the significance threshold, age at diagnosis > 57.5 years old (P = 0.04) and time interval (the whole) ≤ 166.5 days (P = 0.002) were independent risk factors of pneumonitis of Grade 2 and above (Table 4).
Table 4.
Univariate and multivariate logistic regression analysis of the pneumonitis of grade 2 and above (Bilateral)
| Univariate logistic regression analysis | Multivariate logistic regression analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| B | SE | OR(95%CI) | P | B | SE | OR(95%CI) | P | |
| Age at Diagnosis > 57.5 | 0.754 | 0.248 | 2.126(1.307–3.458) | 0.002 | 0.552 | 0.269 | 1.736(1.025–2.942) | 0.04 |
| Male Gender | 0.909 | 0.411 | 2.481(1.108–5.555) | 0.027 | ||||
| Smoking Status | ||||||||
| Never smoke | Ref | |||||||
| Previous or current smokers | 0.342 | 0.242 | 1.407(0.875–2.263) | 0.159 | ||||
| Strategy of ICIs and TRT | ||||||||
| ICIs and TRT concurrently | Ref | |||||||
| ICIs bofore TRT | 0.597 | 0.514 | 1.817(0.664–4.971) | 0.245 | ||||
| TRT bofore ICIs | −0.335 | 0.499 | 0.715(0.269–1.903) | 0.502 | ||||
| Sandwich-like therapy | −0.185 | 0.552 | 0.831(0.282–2.452) | 0.737 | ||||
| Time Interval (the whole) > 166.5 days | −0.869 | 0.254 | 0.419(0.255–0.690) | < 0.001 | −0.819 | 0.275 | 0.441(0.257–0.756) | 0.002 |
| V5bi > 42.86% | 0.625 | 0.242 | 1.868(1.161–3.003) | 0.01 | ||||
| V10bi > 28.65% | 0.588 | 0.244 | 1.800(1.116–2.904) | 0.016 | ||||
| V20bi > 17.97% | 0.658 | 0.242 | 1.931(1.201–3.103) | 0.007 | ||||
| V30bi > 10.96% | 0.821 | 0.248 | 2.272(1.399–3.690 | < 0.001 | ||||
| Bilateral MLD > 10.95 Gy | 0.691 | 0.246 | 1.995(1.232–3.230) | 0.005 | ||||
Abbreviations: ICIs immune checkpoint inhibitors, TRT thoracic radiotherapy, Sandwich-like therapy ICIs-TRT-ICIs or TRT-ICIs-TRT, RT radiotherapy, V5bi percentage of bilateral lung volume exceeding 5 Gy, V10bi percentage of bilateral lung volume exceeding 10 Gy, V20bi percentage of bilateral lung volume exceeding 20 Gy, V30bi percentage ofbilateral lung volume exceeding 30 Gy, MLD mean lung dose
Discussion
In recent years, combining RT with ICIs for tumor treatment has become a hot topic in clinical practice. However, pneumonitis caused by RT and/or not ICI has always been a major factor limiting its therapeutic application. On the one hand, multiple studies have suggested that the incidence of pneumonitis after ICI therapy combined with RT is significantly greater than that after RT alone or ICI therapy alone. Shaverdian N et al. reported that the incidence of pneumonitis of any grade after ICI therapy in patients who had previously received RT was as high as 63%, whereas 40% of patients had not previously received RT [25]. On the other hand, some studies have reported no increase in the incidence of all-grade pneumonitis among TRT-treated patients compared with non-TRT-treated patients [32, 33].
Notably, although many studies have revealed risk factors for adverse events after RT, the risk factors for adverse events after RT combined with ICIs still need further exploration. In this retrospective study, we focused on exploring and distinguishing the effects of radiation-related parameters (ipsilateral V5–V30, bilateral V5–V30, and MLD) on the incidence of pneumonitis in the affected or bilateral lung. We also investigated the ability of gender, the dosimetric parameters, age > 57.5 years, and time interval (the whole) between RT and ICI therapy ≤ 166.5 days to predict pneumonitis. These modifiable factors may help oncologists assess the risk of pneumonitis.
In this study, 335 patients receiving TRT in combination with ICIs were analyzed for the incidence of Grade 2 and higher pneumonitis. 116 out of 335 (34.62%) patients developed Grade 2 or above pneumonitis, and 39 out of 335 (11.60%) patients developed Grade 3 or above pneumonitis. The incidence rates of any-grade pneumonitis, Grade 2 or above pneumonitis and Grade 3 or above pneumonitis in clinical trials of ICIs after conventional TRT were 56–85%, 28–52% and 2–18.2%, respectively, according to real-world data [34–38]. This finding is consistent with our results.
We found that the incidence of Grade 2 or above pneumonitis was significantly related to the patients'clinical characteristics, treatment strategy, time interval (the whole), and ipsilateral or bilateral lung dose‒volume parameters. We observed that males and older patients are more likely to suffer from pneumonitis of Grade 2 and above. As reported in previous studies, age is a risk factor for the occurrence of pneumonia [35]. Our study also identified age > 57.5 years old as a risk factor for the incidence of pneumonitis. However, smoking status was not a related factor. These results are consistent with those of existing studies [22, 30, 39]. In addition, we found that the incidence of Grade 2 or above pneumonitis varies among patients receiving different strategies. Patients who received ICIs before RT had a greater incidence of pneumonitis than those who received RT before ICIs. A longer time interval, lower MLD, and smaller ipsilateral or bilateral lung dose‒volume parameters are correlated with a lower incidence of Grade 2 or higher pneumonitis. These results are consistent with existing findings from clinical practice and theoretical research [8, 30, 40, 41].
In recent years, immunotherapy has emerged as an important tool for the comprehensive treatment of cancers, and ICIs are widely used for this purpose. Multiple studies and clinical trials have shown that the incidence rates of pneumonitis and other complications caused by PD-L1 inhibitor ICIs are lower than those caused by PD-L1 ICIs [20]. In this study, we observed differences between groups in the incidence of Grade 2 pneumonitis and above pneumonitis in patients treated with various ICIs. The incidence of Grade 2 or above pneumonitis did not differ between the two groups treated with different types of ICIs, despite the large difference in patient numbers between the groups.
In clinical practice, physicians pay close attention to the treatment strategy, time interval (the whole), and ipsilateral or bilateral lung dose‒volume parameters. Here, we also considered the factors mentioned earlier. The effects of different ICI and RT strategies, interval times, and ipsilateral or bilateral lung dose‒volume parameters in the two groups were different.
Our study demonstrated the impact of different treatment strategies on the incidence of Grade 2 or above pneumonitis. Although the differences were not statistically significant, these findings offer valuable insights for clinical decision-making. Existing relevant clinical trials have shown that patients receiving RT before ICIs have a lower incidence of pneumonitis of grade 3 and above, as evidenced by the results of GEMSTONE-301 trial (2%) [16] and the PACIFIC trial (3.4%) [42]. Conversely, recent studies, including one from our center, indicated a higher incidence (approximately 6–8%) in patients receiving ICIs before RT [43, 44]. These findings are consistent with our real-world study. However, some clinical trials, including NICOLAS (11.7%) [45, 46] and KEYNOTE-799 Arm A (8%) [26], reported a higher incidence of pneumonitis of Grade 3 and above in patients receiving concurrent ICI and RT, which partially deviates from our findings. This discrepancy may be attributed to our focus on pneumonitis of Grade 2 or above rather than grade 3 or above. Moreover, the limited sample size of patients receiving concurrent ICI and RT in our study may have contributed to these differences, warranting further investigation in future studies.
Our study also suggested that a longer interval is associated with a lower Grade 2 or above pneumonitis incidence. A recent research reported a higher rate of pneumonitis among patients received ICIs within 3 months after RT when compared with those of more than 3 months. This study also found that the patients were slightly more likely to discontinue treatment because of pneumonitis vs no-RT patients [47]. This result is consistent with our findings, as the longer the time interval, the lower the incidence of the Grade 2 or above pneumonitis. We also calculated the cutoff value for time intervals, and the time interval (the whole) ≤ 166.5 days was an independent risk factor for Grade 2 or above pneumonitis. Some studies have suggested slightly longer intervals between TRT and ICI to balance survival benefits and pulmonary toxicity.
Importantly, owing to the dispersion of data in our study, this time interval (the whole) cutoff value may not apply to clinical treatment strategies.
In this study, we also focused on the dose‒volume parameters; we found that a smaller MLD and smaller ipsilateral or bilateral lung dose‒volume parameters were correlated with a lower incidence of pneumonitis of Grade 2 and above. In clinical practice, these modifiable risk factors may help evaluate RT plans and identify high-risk patients susceptible to pneumonitis during combined treatment. In addition, we analyzed the cutoff values of time interval (the whole) and dose‒volume constraints in patients with pneumonitis of Grade 2 and above to provide a reference for clinical use. These cutoff values align with those in previous CRT studies [34, 48, 49] and can facilitate the development of clinical treatment plans and the prevention of pneumonitis. The cutoff values were as follows: V5ispi 44.38%, V10ispi 39.58%, V20ispi 27.36%, V30ispi 18.96%, ipsilateral MLD 13.63 Gy, V5bi 42.86%, V10bi 28.65%, V20bi 17.97%, V30bi 10.96%, and bilateral MLD 10.95 Gy. The NCCN guidelines recommend that V20 does not exceed 35–40% and that the MLD should not exceed 20 Gy [50]. In addition, the PACIFIC study revealed that V20 Gy ≥ 25% and MLD ≥ 10 Gy were independent risk factors for symptomatic pneumonitis [34]. In addition, univariate and multivariate logistic regression analyses were conducted. The first model revealed that male sex, age > 57.5 years and time interval (the whole) ≤ 166.5 days were independent risk factors for Grade 2 or above pneumonitis. Similarly, the second model revealed that age > 57.5 years and time interval (the whole) ≤ 166.5 days were independent risk factors for Grade 2 or above pneumonitis. These results provide a reference for clinical treatment with RT combined with ICIs to reduce the incidence or prevent the occurrence of pneumonitis.
Grade 3 or above pneumonitis is generally considered severe and life-threatening. Therefore, we also analyzed the relationships between the incidence of Grade 3 or above pneumonitis and the factors mentioned earlier. We found that 39 of 335 (11.6%) patients had Grade 3 or above pneumonitis, which is close to the previously reported results [37]. However, we could not identify any meaningfully related factors, so we did not investigate the risk factors in detail. The collected data revealed that some patients with Grade 3 or above pneumonitis also suffered from relatively severe pulmonary infections. Considering that infection is also closely associated with severe pneumonitis [51], we did not consider it feasible to determine whether Grade 3 or above pneumonitis was caused by infection or treatment with the available data.
Our study also has some other limitations. First, this was a retrospective and single-center study, which may have distorted the results because of some factors, such as selection bias, patient heterogeneity, and a relatively limited sample size. Second, multiple factors, such as infection and comorbidities, affect the incidence of pneumonitis. Identifying risk factors for pneumonitis on the basis of clinical symptoms and imaging findings can be challenging. However, we did our best to evaluate and grade pneumonitis in each patient and adopted the most consistent diagnosis from multidisciplinary team members. Third, owing to the wide variety of ICI drugs and the varying number of patients treated with different ICIs, we did not evaluate the impact of each ICI drug on the treatment of associated pneumonitis. A subsequent multicenter randomized controlled trial is needed to confirm the results and generate additional data.
Conclusion
We first showed that older, male patients are more likely to suffer from pneumonitis of Grade 2 and above. We also found that, numerically, patients who received ICIs before RT were more likely to have pneumonitis than those who received RT before ICIs. Moreover, a longer interval between treatments, lower mean lung dose (MLD) and smaller ipsilateral or bilateral lung dose‒volume parameters are correlated with a lower incidence of pneumonitis of Grade 2 or above.
Supplementary Information
Acknowledgements
We thank Prof Wen Li, Fen Lan, Lixia Xia from department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China for supporting our study.
Abbreviations
- AUC
Area under the curve
- CRT
Chemoradiotherapy
- CTCAE
Common Terminology Criteria for Adverse Events
- ICIs
Immune checkpoint inhibitors
- IMRT
Intensity-modulated radiation therapy
- MLD
Mean lung dose
- NSCLC
Non-small-cell lung cancer
- OS
Overall survival
- PD-1/PD-L1
Programmed death 1/programmed death ligand-1
- ROC
Receiver operating characteristic
- RP
Radiation pneumonitis
- RT
Radiotherapy
- SBRT
Stereotactic body radiotherapy
- TRT
Thoracic radiotherapy
- V10bi
Percentage of bilateral lung volume exceeding 10 Gy
- V10ipsi
Percentage of ipsilateral lung volume exceeding 10 Gy
- V20bi
Percentage of bilateral lung volume exceeding 20 Gy
- V20ipsi
Percentage of ipsilateral lung volume exceeding 20 Gy
- V30bi
Percentage of bilateral lung volume exceeding 30 Gy
- V30ipsi
Percentage of ipsilateral lung volume exceeding 30 Gy
- V5bi
Percentage of bilateral lung volume exceeding 5 Gy
- V5ipsi
Percentage of ipsilateral lung volume exceeding 5 Gy
Authors’ contributions
Yang Tang and Haifeng Yu contributed to the collection and analysis of data and wrote the original draft. Siyu Guo, Yihan Yao and Jing Zhao contributed to the data collection and investigation. Bingbing Zheng and Dang Wu contributed to the manuscript review and editing. Qichun Wei and Yang Xia contributed to the the methodology of the work and manuscript review and editing. Ting Zhang was responsible for the conceptualization, methodology and manuscript review and editing. Yang Tang and Haifeng Yu contributed equally to this work.
Funding
This work was supported by the grant from the National Natural Science Foundation of China (82173089, T. Z.; 82073332, Q. W.; 82073142, D. W.;), Natural Science Foundation of Zhejiang Province (LY21H100004, T. Z.; LY19H160050, D.W.), Medical Science and Technology Project of Zhejiang Province (2021RC063, T. Z.) and Chinese Society of Clinical Oncology (Y-2020Sciclone/ms-0099, T. Z.; Y-2019Sciclone-019, T.Z).
Data availability
The data that support the findings of this study are available from Second Affiliated Hospital of Zhejiang University. The authors do not own these data and hence are not permitted to share them in the original form.
Declarations
Ethics approval and consent to participate
This study has been approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (ID: I20221288). In addition, this study utilized medical records obtained from previous clinical diagnosis and treatment, so the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine waived the requirement for consent.
Consent for publication
All the authors approved for the publication of the article.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yang Tang and Haifeng Yu contributed equally to this work.
Contributor Information
Yang Xia, Email: yxia@zju.edu.cn.
Qichun Wei, Email: qichun_wei@zju.edu.cn.
Ting Zhang, Email: zezht@zju.edu.cn.
References
- 1.Schaue D, McBride WH. Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol. 2015;12(9):527–40. 10.1038/nrclinonc.2015.120. (Epub 2015/07/01. PubMed PMID: 26122185. PubMed Central PMCID: PMCPMC8396062). [DOI] [PMC free article] [PubMed]
- 2.Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). radiation therapy oncology group. Jama. 1999;281(17):1623–7. 10.1001/jama.281.17.1623. (Epub 1999/05/11. PubMed PMID: 10235156). [DOI] [PubMed]
- 3.Zhu H, Zhou Z, Wang Y, Bi N, Feng Q, Li J, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer. 2011;117(23):5423–31. 10.1002/cncr.26206. (Epub 2011/05/13. PubMed PMID). [DOI] [PubMed] [Google Scholar]
- 4.Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015;385(9962):36–42. 10.1016/s0140-6736(14)61085-0. (Epub 2014/09/19. PubMed PMID: 25230595). [DOI] [PubMed]
- 5.Yamashita H, Nakagawa K, Nakamura N, Koyanagi H, Tago M, Igaki H, et al. Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol. 2007;2(1):21. 10.1186/1748-717x-2-21. (PubMed PMID: 17553175. PubMed Central PMCID: PMCPMC1894806). [DOI] [PMC free article] [PubMed]
- 6.Baker R, Han G, Sarangkasiri S, DeMarco M, Turke C, Stevens CW, et al. Clinical and dosimetric predictors of radiation pneumonitis in a large series of patients treated with stereotactic body radiation therapy to the lung. Int J Radiat Oncol Biol Phys. 2013;85(1):190–5. 10.1016/j.ijrobp.2012.03.041. (Epub 2012/08/30. PubMed PMID: 22929858). [DOI] [PubMed]
- 7.Ueki N, Matsuo Y, Togashi Y, Kubo T, Shibuya K, Iizuka Y, et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol. 2015;10(1):116–25. 10.1097/jto.0000000000000359. (Epub 2014/11/08. PubMed PMID: 25376512). [DOI] [PubMed]
- 8.Liu Y, Wang W, Shiue K, Yao H, Cerra-Franco A, Shapiro RH, et al. Risk factors for symptomatic radiation pneumonitis after stereotactic body radiation therapy (SBRT) in patients with non-small cell lung cancer. Radiother Oncol. 2021;156:231–8. 10.1016/j.radonc.2020.10.015. [DOI] [PubMed] [Google Scholar]
- 9.Pan X, Liao M, Ma H, Jiang X, Huang H, Wei M, et al. Chemoradiotherapy and increased prescription dose in esophageal squamous cell cancer: a retrospective study. Biomed Res Int. 2021;2021:3834040. 10.1155/2021/3834040. (Epub 2021/02/26. PubMed PMID: 33628778. PubMed Central PMCID: PMCPMC7884139). [DOI] [PMC free article] [PubMed]
- 10.Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. 10.1056/NEJMoa1003466. (Epub 2010/06/08. PubMed PMID: 20525992. PubMed Central PMCID: PMCPMC3549297). [DOI] [PMC free article] [PubMed]
- 11.Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. 10.1056/NEJMoa1504627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46. 10.1016/s0140-6736(16)00587-0. [DOI] [PubMed] [Google Scholar]
- 13.Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29. 10.1056/NEJMoa1709937. [DOI] [PubMed] [Google Scholar]
- 14.Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. 10.1056/NEJMoa1801005. (Epub 2018/04/17. PubMed PMID: 29658856). [DOI] [PubMed]
- 15.Hui R, Özgüroğlu M, Villegas A, Daniel D, Vicente D, Murakami S, et al. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(12):1670–80. 10.1016/s1470-2045(19)30519-4. (Epub 2019/10/12. PubMed PMID: 31601496). [DOI] [PubMed]
- 16.Zhou Q, Chen M, Jiang O, Pan Y, Hu D, Lin Q, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022;23(2):209–19. 10.1016/s1470-2045(21)00630-6. (Epub 2022/01/18. PubMed PMID: 35038429). [DOI] [PubMed]
- 17.Provencio M, Nadal E, Insa A, García-Campelo MR, Casal-Rubio J, Dómine M, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(11):1413–22. 10.1016/s1470-2045(20)30453-8. (Epub 2020/09/28. PubMed PMID: 32979984). [DOI] [PubMed]
- 18.Provencio M, Serna-Blasco R, Nadal E, Insa A, García-Campelo MR, Casal Rubio J, et al. Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA non-small-cell lung cancer (NADIM phase II trial). J Clin Oncol. 2022;40(25):2924–33. 10.1200/jco.21.02660. (Epub 2022/05/17. PubMed PMID: 35576508 PubMed Central PMCID: PMCPMC9426809 [DOI] [PMC free article] [PubMed]
- 19.Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, et al. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res. 2016;22(24):6051–60. 10.1158/1078-0432.Ccr-16-1320. (Epub 2016/08/19. PubMed PMID: 27535979; PubMed Central PMCID: PMCPMC5161686). [DOI] [PMC free article] [PubMed]
- 20.Khunger M, Rakshit S, Pasupuleti V, Hernandez AV, Mazzone P, Stevenson J, et al. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials. Chest. 2017;152(2):271–81. 10.1016/j.chest.2017.04.177. (Epub 2017/05/14. PubMed PMID: 28499515). [DOI] [PubMed]
- 21.Delaunay M, Cadranel J, Lusque A, Meyer N, Gounant V, Moro-Sibilot D, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J. 2017. 10.1183/13993003.00050-2017. Epub 2017/08/12. PubMed PMID: 28798088. [DOI] [PubMed]
- 22.Suresh K, Voong KR, Shankar B, Forde PM, Ettinger DS, Marrone KA, et al. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol. 2018;13(12):1930–9. 10.1016/j.jtho.2018.08.2035. (Epub 2018/09/30. PubMed PMID: 30267842). [DOI] [PubMed]
- 23.Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31. 10.1056/NEJMoa1910231. (Epub 2019/09/29. PubMed PMID: 31562796). [DOI] [PubMed]
- 24.Teng F, Li M, Yu J. Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications. BMC Med. 2020;18(1):275. 10.1186/s12916-020-01718-3. (Epub 2020/09/19. PubMed PMID: 32943072; PubMed Central PMCID: PMCPMC7499987). [DOI] [PMC free article] [PubMed]
- 25.Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7):895–903. 10.1016/s1470-2045(17)30380-7. (Epub 2017/05/30. PubMed PMID: 28551359; PubMed Central PMCID: PMCPMC5538772). [DOI] [PMC free article] [PubMed]
- 26.Jabbour SK, Lee KH, Frost N, Breder V, Kowalski DM, Pollock T, et al. pembrolizumab plus concurrent chemoradiation therapy in patients with unresectable, locally advanced, stage iii non-small cell lung cancer: the phase 2 KEYNOTE-799 nonrandomized trial. JAMA oncology. 2021;7(9):1–9. 10.1001/jamaoncol.2021.2301. Epub 2021/06/05. PubMed PMID: 34086039; PubMed Central PMCID: PMCPMC8446818 [DOI] [PMC free article] [PubMed]
- 27.Li M, Gan L, Song A, Xue J, Lu Y. Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy. Biochim Biophys Acta Rev Cancer. 2019;1871(2):323–30. 10.1016/j.bbcan.2019.02.004. (Epub 2019/03/04. PubMed PMID: 30826426). [DOI] [PubMed]
- 28.Theelen W, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts J, et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5(9):1276–82. 10.1001/jamaoncol.2019.1478. (Epub 2019/07/12. PubMed PMID: 31294749IF: 20.1 Q1 B1; PubMed Central PMCID: PMCPMC6624814IF: 20.1 Q1 B1 [DOI] [PMC free article] [PubMed]
- 29.Geng Y, Zhang Q, Feng S, Li C, Wang L, Zhao X, et al. Safety and efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Cancer Med. 2021;10(4):1222–39. 10.1002/cam4.3718. (Epub 2021/01/20. PubMed PMID: 33465302; PubMed Central PMCID: PMCPMC7926021). [DOI] [PMC free article] [PubMed]
- 30.Dang J, Li G, Ma L, Diao R, Zang S, Han C, et al. Predictors of grade ≥ 2 and grade ≥ 3 radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with three-dimensional conformal radiotherapy. Acta Oncol. 2013;52(6):1175–80. 10.3109/0284186x.2012.747696. (Epub 2012/12/04. PubMed PMID: 23198719). [DOI] [PubMed]
- 31.Kong FS, Moiseenko V, Zhao J, Milano MT, Li L, Rimner A, et al. Organs at risk considerations for thoracic stereotactic body radiation therapy: what is safe for lung parenchyma? Int J Radiat Oncol Biol Phys. 2021;110(1):172–87. 10.1016/j.ijrobp.2018.11.028. (Epub 2018/11/30. PubMed PMID: 30496880; PubMed Central PMCID: PMCPMC9454379). [DOI] [PMC free article] [PubMed]
- 32.Hwang WL, Niemierko A, Hwang KL, Hubbeling H, Schapira E, Gainor JF, et al. Clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy. JAMA Oncol. 2018;4(2):253–5. 10.1001/jamaoncol.2017.3808. (Epub 2017/10/04. PubMed PMID: 28973343; PubMed Central PMCID: PMCPMC5838581 [DOI] [PMC free article] [PubMed]
- 33.Voong KR, Hazell SZ, Fu W, Hu C, Lin CT, Ding K, et al. Relationship between prior radiotherapy and checkpoint-inhibitor pneumonitis in patients with advanced non-small-cell lung cancer. Clin Lung Cancer. 2019;20(4):e470–9. 10.1016/j.cllc.2019.02.018. (Epub 2019/04/30. PubMed PMID: 31031204; PubMed Central PMCID: PMCPMC8767572). [DOI] [PMC free article] [PubMed]
- 34.Saito G, Oya Y, Taniguchi Y, Kawachi H, Daichi F, Matsumoto H, et al. Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON). Lung Cancer. 2021;161:86–93. 10.1016/j.lungcan.2021.08.019. (Epub 2021/09/21. PubMed PMID: 34543942). [DOI] [PubMed]
- 35.Wang Y, Zhang T, Huang Y, Li W, Zhao J, Yang Y, et al. Real-world safety and efficacy of consolidation durvalumab after chemoradiation therapy for stage III non-small cell lung cancer: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2022;112(5):1154–64. 10.1016/j.ijrobp.2021.12.150. (Epub 2021/12/30. PubMed PMID: 34963558). [DOI] [PubMed]
- 36.Jang JY, Kim SS, Song SY, Kim YJ, Kim SW, Choi EK. Radiation pneumonitis in patients with non-small-cell lung cancer receiving chemoradiotherapy and an immune checkpoint inhibitor: a retrospective study. Radiat Oncol. 2021;16(1):231. 10.1186/s13014-021-01930-2. (Epub 2021/12/06. PubMed PMID: 34863244; PubMed Central PMCID: PMCPMC8642976). [DOI] [PMC free article] [PubMed]
- 37.Jung HA, Noh JM, Sun JM, Lee SH, Ahn JS, Ahn MJ, et al. Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer. Lung Cancer. 2020;146:23–9. 10.1016/j.lungcan.2020.05.035. (Epub 2020/06/07. PubMed PMID: 32505077). [DOI] [PubMed]
- 38.Miura Y, Mouri A, Kaira K, Yamaguchi O, Shiono A, Hashimoto K, et al. Chemoradiotherapy followed by durvalumab in patients with unresectable advanced non-small cell lung cancer: management of adverse events. Thorac Cancer. 2020;11(5):1280–7. 10.1111/1759-7714.13394. (Epub 2020/03/12. PubMed PMID: 32160383; PubMed Central PMCID: PMCPMC7180558). [DOI] [PMC free article] [PubMed]
- 39.Kato T, Masuda N, Nakanishi Y, Takahashi M, Hida T, Sakai H, et al. Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer. Lung Cancer. 2017;104:111–8. 10.1016/j.lungcan.2016.12.016. Epub 2017/02/19. PubMed PMID: 28212992. [DOI] [PubMed]
- 40.Barriger RB, Fakiris AJ, Hanna N, Yu M, Mantravadi P, McGarry RC. Dose-volume analysis of radiation pneumonitis in non-small-cell lung cancer patients treated with concurrent cisplatinum and etoposide with or without consolidation docetaxel. Int J Radiat Oncol Biol Phys. 2010;78(5):1381–6. 10.1016/j.ijrobp.2009.09.030. (Epub 2010/03/17. PubMed PMID: 20231061). [DOI] [PubMed]
- 41.McFarlane MR, Hochstedler KA, Laucis AM, Sun Y, Chowdhury A, Matuszak MM, et al. Predictors of pneumonitis after conventionally fractionated radiotherapy for locally advanced lung cancer. Int J Radiat Oncol Biol Phys. 2021;111(5):1176–85. 10.1016/j.ijrobp.2021.07.1691. (Epub 2021/07/28. PubMed PMID: 34314815). [DOI] [PubMed]
- 42.Melosky B, Juergens R, McLeod D, Leighl N, Brade A, Card PB, et al. Immune checkpoint-inhibitors and chemoradiation in stage III unresectable non-small cell lung cancer. Lung Cancer. 2019;134:259–67. 10.1016/j.lungcan.2019.05.027. (Epub 2019/07/20. PubMed PMID: 31319991). [DOI] [PubMed]
- 43.Wang Y, Zhang T, Wang J, Zhou Z, Liu W, Xiao Z, et al. Induction immune checkpoint inhibitors and chemotherapy before definitive chemoradiation therapy for patients with bulky unresectable stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2023;116(3):590–600. 10.1016/j.ijrobp.2022.12.042. (Epub 2023/01/10. PubMed PMID: 36623605). [DOI] [PubMed]
- 44.Zhao J, Miao D, Zhou J, Guo S, Tang Y, Lan F, et al. A retrospective comparison of induction chemoimmunotherapy versus chemotherapy followed by concurrent chemoradiotherapy and consolidation immunotherapy in stage III non-small cell lung cancer. Front Oncol. 2024;14:1432954. 10.3389/fonc.2024.1432954. (Epub 2024/10/23. PubMed PMID: 39439959; PubMed Central PMCID: PMCPMC11493535). [DOI] [PMC free article] [PubMed]
- 45.Peters S, Felip E, Dafni U, Belka C, Guckenberger M, Irigoyen A, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung Cancer. 2019;133:83–7. 10.1016/j.lungcan.2019.05.001. (Epub 2019/06/16. PubMed PMID: 31200833). [DOI] [PubMed]
- 46.Passiglia F, Leone G, Olmetto E, Delcuratolo MD, Tabbò F, Reale ML, et al. Immune-checkpoint inhibition in stage III unresectable NSCLC: challenges and opportunities in the post-PACIFIC era. Lung Cancer. 2021;157:85–91. 10.1016/j.lungcan.2021.05.009. (Epub 2021/05/18. PubMed PMID: 33994198). [DOI] [PubMed]
- 47.Anscher MS, Arora S, Weinstock C, Amatya A, Bandaru P, Tang C, et al. Association of radiation therapy with risk of adverse events in patients receiving immunotherapy: a pooled analysis of trials in the US Food and Drug Administration database. JAMA Oncol. 2022;8(2):232–40. 10.1001/jamaoncol.2021.6439. (Epub 2022/01/07. PubMed PMID: 34989781; PubMed Central PMCID: PMCPMC8739815). [DOI] [PMC free article] [PubMed]
- 48.Palma DA, Senan S, Tsujino K, Barriger RB, Rengan R, Moreno M, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2013;85(2):444–50. 10.1016/j.ijrobp.2012.04.043. (Epub 2012/06/12. PubMed PMID: 22682812; PubMed Central PMCID: PMCPMC3448004). [DOI] [PMC free article] [PubMed]
- 49.Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial. J Clin Oncol. 2017;35(1):56–62. 10.1200/jco.2016.69.1378. (Epub 2016/12/31. PubMed PMID: 28034064; PubMed Central PMCID: PMCPMC5455690). [DOI] [PMC free article] [PubMed]
- 50.Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, et al. Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(5):497–530. 10.6004/jnccn.2022.0025. (Epub 2022/05/12. PubMed PMID: 35545176). [DOI] [PubMed]
- 51.Musher DM, Abers MS, Bartlett JG. Evolving understanding of the causes of pneumonia in adults, with special attention to the role of pneumococcus. Clin Infect Dis. 2017;65(10):1736–44. 10.1093/cid/cix549. (Epub 2017/10/14. PubMed PMID: 29028977; PubMed Central PMCID: PMCPMC7108120). [DOI] [PMC free article] [PubMed]
Associated Data
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Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from Second Affiliated Hospital of Zhejiang University. The authors do not own these data and hence are not permitted to share them in the original form.