Incidence Of Pneumonitis Research Articles

Research Progress on Radiotherapy Combined with Immunotherapy for Associated Pneumonitis During Treatment of Non-Small Cell Lung Cancer.

Radiation pneumonitis is a common and serious complication of radiotherapy for thoracic tumours. Although radiotherapy technology is constantly improving, the incidence of radiation pneumonitis is still not low, and severe cases can be life-threatening. Once radiation pneumonitis develops into radiation fibrosis (RF), it will have irreversible consequences, so it is particularly important to prevent the occurrence and development of radiation pneumonitis. Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumour types, providing unprecedented survival in some patients, especially for the treatment of non-small cell lung cancer (NSCLC). However, in addition to its remarkable curative effect, ICls may cause immune-related adverse events. The incidence of checkpoint inhibitor pneumonitis (CIP) is 3% to 5%, and its mortality rate is 10% to 17%. In addition, the incidence of CIP in NSCLC is higher than in other tumour types, reaching 7%–13%. With the increasing use of immune checkpoint inhibitors (ICls) and thoracic radiotherapy in the treatment of patients with NSCLC, ICIs may induce delayed radiation pneumonitis in patients previously treated with radiation therapy, or radiation activation of the systemic immune system increases the toxicity of adverse reactions, which may lead to increased pulmonary toxicity and the incidence of pneumonitis. In this paper, the data about the occurrence of radiation pneumonitis, immune pneumonitis, and combined treatment and the latest related research results will be reviewed.

Analysis of deep inspiration breath-hold technique to improve dosimetric and clinical advantages in postoperative intensity-modulated radiation therapy for thymomas.

BackgroundRadiation therapy is one of the essential treatment modalities for invasive thymomas. Clinically, respiratory motion poses a challenge for the radiotherapy of thoracic tumors. One method to address this issue is to train patients to hold their breath at the end of deep inspiration. The purpose of this retrospective cohort study was to investigate the dosimetric and clinical advantages of the deep inspiration breath-hold (DIBH) technique in postoperative intensity-modulated radiation therapy (IMRT) for thymomas.MethodsThymoma patients undergoing postoperative IMRT were included. Each patient underwent two computed tomography (CT) scans, one under free breath (FB) and the other under DIBH. Dosimetric parameters of organs at risk (OARs) were evaluated in three series plans. Dose analysis and volume comparisons were conducted during FB-3 mm (FB with 3 mm internal target volume margin), FB-10 mm (FB with 10 mm internal target volume margin), and DIBH and compared using a paired sample Student’s t-test. Normal tissue complication probabilities (NTCP) for lungs and heart were calculated and compared.ResultsThe total lung volume significantly increased by 31% (4,216±198 vs. 2,884±166 mL) and the heart volume reduced by 12% (552±25 vs. 636±35 mL) between DIBH acquisitions compared to FB. A significant improvement was observed in all the dosimetric parameters (Dmean, V20, V5) of the lung on DIBH compared to FB-3 mm (54%±2.85% vs. 47%±2.90%, P<0.001; 15%±1.37% vs. 12%±1.32%, P=0.004; and 10.28±0.58 vs. 8.76±0.57 Gy, P<0.001, respectively), as well as in the Dmax and D2% of the esophagus and spine. The lung volume increment was related to a reduction in the mean dose of lungs, with a correlation coefficient of r=0.27, P=0.03. The NTCP values for pneumonitis significantly reduced with DIBH compared to the FB state (0.6% vs. 1.1%, P<0.001).ConclusionsThe radiation dose to the OARs can be significantly reduced by using the DIBH technique in postoperative IMRT for thymomas. The increased volume of lungs using DIBH acquisitions can significantly reduce the incidence of pneumonitis.

THE INCIDENCE OF RADIATION PNEUMONITIS IN BREAST CANCER PATIENTS WHO RECEIVED RADIOTHERAPY USING 3-DIMENSIONAL TECHNIQUES

Background: According to the 2018 Global Cancer Observatory from the World Health Organization (WHO), breast cancer is the most common cancer in Indonesia. 3-dimensional conformal radiotherapy (3D-CRT) is one of the breast cancer treatment planning. Effect of radiation on the lungs can cause radiation pneumonitis. The incidence rate of pneumonitis in breast cancer patients who received radiotherapy using 3D-CRT techniques from several researchers is still varied and there is no accurate data yet at RSUP Dr. Kariadi.Objective: To determine the incidence of pneumonitis in breast cancer patients undergoing breast cancer 3D-CRT.Methods: The research design used in this study was cross sectional. The subject is chosen by consecutive sampling methods. The independent variables of this study was 3D breast cancer radiation therapy, while the dependent variable was radiation pneumonitis. This hypothesis test on this study is analyzed with chi-square test.Results: Forty one subjects were included in this study, two subjects were found with a picture of pneumonitis on chest radiographs. The incidence of radiation pneumonitis in breast cancer patients who received radiotherapy using 3-dimensional techniques was 4.9%. There is no significant relationship between breast cancer radiation therapy 3-dimensional techniques on the incidence of pneumonitis. And there was no significant difference in the proportion of pneumonitis in patients with breast cancer locations on the right and left sides.Conclusion: The incidence of radiation pneumonitis in breast cancer patients who received radiotherapy using a 3-dimensional technique is 4.9%. Keywords: 3 Dimensional Technique Radiotherapy, Breast Cancer, Radiation Pneumonitis

Sensitization of GSH synthesis by curcumin curtails acrolein-induced alveolar epithelial apoptosis via Keap1 cysteine conjugation: A randomized controlled trial and experimental animal model of pneumonitis

IntroductionEpidemiological studies have reported an association between exposures to ambient air pollution and respiratory diseases, including chronic obstructive pulmonary disease (COPD). Pneumonitis is a critical driving factor of COPD and exposure to air pollutants (e.g., acrolein) is associated with increased incidence of pneumonitis. ObjectivesCurrently available anti-inflammatory therapies provide little benefit against respiratory diseases. To this end, we investigated the preventive role of curcumin against air pollutant-associated pneumonitis and its underlying mechanism. MethodsA total of 40 subjects was recruited from Chengdu, China which is among the top three cities in terms of respiratory mortality related to air pollution. The participants were randomly provided either placebo or curcumin supplements for 2 weeks and blood samples were collected at the baseline and at the end of the intervention to monitor systemic markers. In our follow up mechanistic study, C57BL/6 mice (n = 40) were randomly allocated into 4 groups: Control group (saline + no acrolein), Curcumin only group (curcumin + no acrolein), Acrolein only group (saline + acrolein), and Acrolein + Curcumin group (curcumin + acrolein). Curcumin was orally administered at 100 mg/kg body weight once a day for 10 days, and then the mice were subjected to nasal instillation of acrolein (5 mg/kg body weight). Twelve hours after single acrolein exposure, all mice were euthanized. ResultsCurcumin supplementation, with no noticeable adverse responses, reduced circulating pro-inflammatory cytokines in association with clinical pneumonitis as positive predictive while improving those of anti-inflammatory cytokines. In the pre-clinical study, curcumin reduced pneumonitis manifestations by suppression of intrinsic and extrinsic apoptotic signaling, which is attributed to enhanced redox sensing of Nrf2 and thus sensitized synthesis and restoration of GSH, at least in part, through curcumin-Keap1 conjugation. ConclusionsOur study collectively suggests that curcumin could provide an effective preventive measure against air pollutant-enhanced pneumonitis and thus COPD.

Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Once-daily Thoracic Radiotherapy: Predicting the Value of Clinical and Dose-volume Histogram Parameters.

Background and objectivesThe incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients.MethodsBetween 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0.ResultsIn total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20 < cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20 > cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P < 0.001).ConclusionPatients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.

Dosimetric predictors of pneumonitis in locally advanced non-small cell lung cancer patients treated with chemoradiation followed by durvalumab

ObjectivesThe incidence and predictors of pneumonitis for patients with unresectable, locally advanced non-small cell lung cancer (NSCLC) in the era of consolidation durvalumab have yet to be fully elucidated. In this large single institution analysis, we report the incidence of and factors associated with grade 2 + pneumonitis in NSCLC patients treated with the PACIFIC regimen. Materials and methodsWe identified all patients treated at our institution with definitive CRT followed by durvalumab from 2018 to 2021. Clinical documentation and imaging studies were reviewed to determine grade 2 + pneumonitis events, which required the following: 1) pulmonary symptoms warranting prolonged steroid taper, oxygen dependence, and/or hospital admission and 2) radiographic findings consistent with pneumonitis. ResultsOne-hundred ninety patients were included. The majority received 60 Gray (Gy) in 30 fractions with concurrent carboplatin and paclitaxel. Median number of durvalumab cycles received was 12 (IQR: 4–22). At a median follow-up of 14.8 months, 50 (26.3%) patients experienced grade 2 + pneumonitis with a 1-year cumulative incidence of 27.8% (95% CI: 21.9–35.4). Seventeen (8.9%) patients experienced grade 3 + pneumonitis and 4 grade 5 (2.1%). Dosimetric predictors of pneumonitis included ipsilateral and total lung volume receiving 5 Gy or greater (V5Gy), V10Gy, V20Gy, V40Gy, and mean dose and contralateral V40Gy. Heart V5Gy, V10Gy, and mean dose were also significant variables. Overall survival estimates at 1 and 3 years were 87.4% (95% CI: 82.4–92.8) and 60.3% (95% CI: 47.9–74.4), respectively. ConclusionWe report a risk of pneumonitis higher than that seen on RTOG 0617 and comparable to the PACIFIC study. Multiple lung and heart dosimetric factors were predictive of pneumonitis.

Comparison of Pneumonitis Rates and Severity in Patients With Lung Cancer Treated by Immunotherapy, Radiotherapy, and Immunoradiotherapy.

IntroductionRadiation pneumonitis (RP) is a common dose-limiting toxicity of radiotherapy to the chest in lung cancer patients. Similarly, the revolutionary use of immune checkpoint inhibitors (ICIs) to treat lung cancer can be complicated by immune-related adverse events (irAEs), particularly checkpoint inhibitor pneumonitis (CIP). Our study aimed to assess the effect of immunotherapy, with and without radiotherapy, on pneumonitis and other outcomes.MethodsWe performed a retrospective chart review of 680 lung cancer patients treated with either radiotherapy, immunotherapy, or both at St. Luke's University Health Network to determine the incidence rates of pneumonitis. Then, a more extensive review of 346 patients was completed, 181 of whom had pneumonitis, to investigate risk factors and outcomes.ResultsAll-grade pneumonitis incidence was 26.6% while more severe pneumonitis (grade 3 or higher) was 13%. Receiving programmed cell death-1 (PD-1) or ligand-1 (PD-L1) inhibitors, having squamous cell carcinoma (SCC), and having poorer performance status were independently and significantly associated with increased risk of pneumonitis, with AOR (adjusted odds ratios) of 8.32, 4.10, 2.91, and 1.71, respectively. Among those who had pneumonitis, more severe cases (grade 3 or higher) were related to immunotherapy, either alone (58.32%) or with radiation (55.7%), compared to radiation therapy alone (36.2%).Poorer performance status (defined as a higher Eastern Cooperative Oncology Group (ECOG) score) was the only covariate we found to be significantly and independently associated with reduced odds of 18-months survival. More of the patients treated with both lung radiation and immunotherapy had progressive disease (53.8%) compared to those treated with only radiation (30.4%) or immunotherapy (36.7). Progressive disease occurred more in patients with pneumonitis grade 3 or higher (48.3%) than those with no or low-grade pneumonitis (27.2%).ConclusionReceiving PD-L1 and PD-1 inhibitors, either with or without radiotherapy, was associated with a higher risk of more severe pneumonitis (PD-L1 > PD-1) than radiotherapy alone. Given its high incidence and complications, more about therapy-induced pneumonitis is yet to be studied. Learning more about pneumonitis' risk factors and complications is of great clinical importance, as it may result in better treatment planning and improved outcomes. Future studies are needed to investigate the suggested association between symptomatic pneumonitis and poorer response to treatment and whether SCC increases the risk of higher-grade pneumonitis.

The impact of COVID-19 infection on immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors.

2525 Background: Immune checkpoint inhibitors (ICIs) can cause a variety of inflammatory autoimmune tissue damage, referred to as immune-related adverse events (irAEs). COVID-19 is associated with increased amounts of proinflammatory cytokines, which may synergistically affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients. Methods: We retrospectively analyzed adult patients with malignant solid tumors treated with ICIs at AdventHealth Orlando between August 2020 and August 2021. All COVID-19 infections were confirmed by PCR. Patients who had the most recent ICI treatment over one month before or after the positive COVID-19 test were excluded from the study. For COVID-19 positive group, only the irAEs that developed after COVID-19 infection were considered as events. Results: A total of 579 patients were included in our study, with 46 (7.9%) in COVID-19 positive group, and 533 (92.1%) in COVID-19 negative group. The baseline characteristics of patients in the two groups were similar in terms of age, ethnicity, ECOG, cancer histology, and type of ICI. With a median follow-up of 10 months (1-73 months), no differences in the time from ICI initiation to irAE onset, corticosteroid use, or additional immunosuppressant use were seen. A trend in higher incidence of all-grade diarrhea/colitis (8.7% vs. 3.0%, p=0.07) and grade 3 and 4 hepatitis (4.3% vs. 0.8%, p=0.08) was noted in the COVID-19 positive group, however the difference was not statistically significant. No significant difference in the incidence of pneumonitis (2.2% vs. 1.1%, p=0.44), nephritis (2.2% vs. 0.8%, p=0.34) or dermatitis (6.5% vs. 6.4%, p=1.00) were noted between COVID-19 positive and negative groups. We noticed a higher incidence of all-grade irAEs in the COVID-19 positive group (30.4% vs. 19.9%, p=0.18), but the difference was not statistically significant. The incidence of grade 3 and 4 irAEs was significantly higher in the COVID-19 positive group (10.9% vs. 3.2%, p=0.02). Nine COVID-19 related death occurred while no irAE-related death was noted in the entire cohort. Conclusions: Our study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possible delaying ICI administration could be considered when cancer patients were infected with COVID-19. [Table: see text]

Real-world incidence and impact of pneumonitis in patients with lung cancer treated with immune checkpoint inhibitors: a multi-institutional cohort study

BackgroundImmune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP)....

Optimization of treatment options for EGFR-mutant, stage III, unresectable NSCLC: A systematic review and meta-analysis.

8548 Background: The PACIFIC study established a new treatment standard for Stage III unresectable NSCLC, but CRT followed by durvalumab failed to bring survival benefit to patients with EGFR mutations. EGFR-TKIs have been successful in the setting of first-line treatment of advanced NSCLC and postoperative adjuvant treatment of NSCLC. We explored whether locally advanced inoperable patients with EGFR mutations can benefit from EGFR-TKIs and the possibly best treatment regimen through meta-analysis. Methods: Studies involving unresectable stage III NSCLC with EGFR mutations published in PubMed, Embase, Cochrane, ClinicalTrials.gov, and abstracts of important international conferences (ASCO, ESMO, WCLC) from January 1, 2000 to September 30, 2021 were screened. An integrative analysis was performed using STATA (version 16.0), and a network meta-analysis based on a Bayesian framework was performed using R (version 3.6.1) for the studies with a control group. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 3291 patients were identified in 17 studies, including 5 treatment measures including concurrent chemoradiotherapy (CRT), CRT followed by durvalumab (CRT+Durva), TKI monotherapy, radiotherapy combined with TKI (RT+TKI), and CRT combined with TKI (CRT+TKI). PFS with TKI-free treatments (CRT, CRT+Durva) was significantly shorter than TKI-containing ones (TKI, RT+TKI, CRT+TKI) (HR 2.17, 95%CI 1.47-3.19), but its advantage only translated into borderline OS benefit (1.27, 0.99-1.63). In detail, the PFS with TKI-containing measures, including TKI monotherapy (0.66, 0.50-0.87), RT+TKI (0.37, 0.28-0.50), or CRT+TKI (0.14, 0.03-0.75) were all significantly longer than CRT. Furthermore, the PFS with both RT+TKI (0.40, 0.21-0.76) and CRT+TKI (0.15, 0.03-0.74) were significantly longer than CRT+Durva, while no statistical difference existed in PFS between RT+TKI and CRT+TKI. However, TKI alone had significantly shorter PFS than RT+TKI (1.78, 1.17-2.67). There was no statistical difference in OS among all the treatments, with RT+TKI ranking first in the Bayesian ranking. The integrated analysis found that RT+TKI had the longest OS (65.7 months, 55.5-76.0 months) and PFS (21.8 months, 18.0-25.7 months) and the highest response rate (77.7%, 68.8%-86.6%). Severe neutropenia was the most common with CRT+TKI, while RT+TKI brought the highest incidences of radiation pneumonitis and esophagitis. Conclusions: For EGFR mutant Stage III unresectable NSCLC, RT and TKI are both essential. RT+TKI and CRT+TKI have significantly longer PFS than CRT±immunotherapy, and RT+TKI has OS benefit trends. Due to the lack of sufficient studies on CRT+TKI, it is urgent to conduct large randomized clinical trials to explore the optimal treatment for these patients.

Risk factors and clinical characteristics of pneumonitis among patients with ALK-rearranged non-small cell lung cancer who received alectinib and thoracic radiotherapy.

e20591 Background: Alectinib and thoracic radiotherapy (TRT) are important modalities in the management of ALK-rearranged non-small cell lung cancer. We therefore aimed to assess the incidence and risk factors of pneumonitis when these two treatments were combined. Methods: Patients with ALK-rearranged non-small cell lung cancer, receiving alectinib and TRT from January 2018 to December 2020 were reviewed, and the clinical and dosimetry data were collected. Logistic regression analyses were performed to evaluate risk factors associated with treatment-related pneumonitis (TRP). The prediction ability of dosimetry parameters for pneumonitis were examined by receiver-operating characteristic (ROC) curve analyses. Results: Of the 25 enrolled patients, 16 (64%) developed pneumonitis, and 12 (48%) developed grade 2 or higher pneumonitis. Logistics regression analyses revealed chemotherapy (OR = 8.750, 95% CI 1.207 - 63.428, p = 0.032), higher ipsilateral V5 (OR = 1.060, 95%CI 1.002 - 1.122, p = 0.043) and total lung V5 (OR = 1.083, 95%CI 1.000 - 1.174, p = 0.05) to be risk factors for TRP. Total lung V10, total lung V5, and ipsilateral V5 were strong predictors of TRP among the dosimetry parameters (AUC = 0.800, 0.786 and 0.781, respectively). After developing pneumonitis, 52% of patients recovered or improved, but one patient died due to respiratory failure. Conclusions: The combined use of alectinib and TRT significantly increased the risk of pneumonitis. Clinicians should consider the elevated risks and related dosimetric factors when deciding on combination treatment for ALK-rearranged NSCLC patients.

Comparison of the checkpoint inhibitor pneumonitis incidence between immunotherapy alone or in combination with chemotherapy for lung cancer: An observational, retrospective pharmacovigilance study.

2655 Background: Clinical trials lack direct cross-comparison in safety between immune checkpoint inhibitor (ICI) as monotherapy and in combination with chemotherapy. The adverse event of checkpoint inhibitor pneumonitis (CIP) is an important factor influencing the treatment decision making. We performed a real-world pharmacovigilance study in the US Food and Drug Administration Adverse Event Reporting System (FAERS) to determine if ICI combination therapy is superior to monotherapy for lung cancer patients in terms of CIP incidence. Methods: The database of lung cancer patients receiving ICI between 2015 and 2020 was extracted for this study. The strategy-specific durations of the pneumonitis event were compared using the Kaplan-Meier method. Reporting odds ratio (ROR), a surrogate measure in disproportionality analysis, was used to assess the signal of CIP between ICI treatment strategies. Results: A total of 27,882 lung cancer patients with reported adverse events were involved. Among them, 1763 (6.3%) CIP after ICIs therapy were identified. In general, ICI usage was associated with over-reporting frequencies of CIP, but this association was no longer significant after adjustment (ROR: 1.14, 95%CI 0.86-1.49). The median times to CIP occurred early after therapy onset, either in ICI monotherapy or in combination with chemotherapy (41 days and 37 days, log-rank p&gt;0.05). Different reporting frequencies emerged when we further compared different ICI strategies. Combination therapy with anti-PD-1 and chemotherapy was associated with a higher CIP incidence compared with anti-PD-1 monotherapy (ROR: 1.86, 95%CI 1.37-2.51), whereas anti-PD-L1/ CTLA-4 medications had lower risks in combination with chemotherapy (ROR: 0.31, 95%CI 0.16-0.56 and ROR: 0.41, 95%CI 0.09-1.22). Subgroup analyses on those with recorded therapy duration also indicated that reports of CIP were significantly lower with combination therapy of PD-L1 and CTLA-4 (ROR: 0.52, 95%CI 0.36-0.74 and ROR: 0.22, 95%CI 0.09-0.51 respectively). Conclusions: Compared with ICI monotherapy, the combination with chemotherapy might have an acceptable risk of CIP. Anti-PD-1 medications with additional chemotherapy could increase the risk of pneumonitis, whereas the risk was lower in the combination strategy with anti-PD-L1/CTLA-4. The combination might be a better therapeutic strategy than ICI monotherapy in treating lung cancer, regarding the CIP incidence. [Table: see text]

Predicting immune checkpoint inhibitor-related pneumonitis using patient medical information.

e13566 Background: Immune checkpoint inhibitors (ICI) have improved outcomes in tumor types allowing subgroups of patients to have longer, higher quality lives. However, potential life-threatening immunotoxicities can arise in susceptible patients, including pneumonitis. Identifying patients at high risk of immunotoxicity can help patients understand potential adverse events, improve clinical trial cohort selection, and inform therapy selection in clinical settings. Here, we use electronic health record (EHR) data to build a binary classification model that predicts the probability of developing pneumonitis after the first ICI administration. Methods: We utilized real-world EHR-derived structured and unstructured data from &gt; 2,700 patients from Vanderbilt University Medical Center obtained prior to December 31, 2018. Unstructured data were transformed into structured variables by expert curators, including labels for pneumonitis episodes following ICI initiation. Feature engineering involved aggregating lab measurements over a 60-day time window before the first ICI; other features (conditions, smoking status, etc.) used a 1-year window. To build a small, easily deployable model and assess its performance robustly, we utilized a sequential process. In each step, we decided between two versions of a random forest model, one with the original feature set (M1) and one extended with a candidate feature (M2). We identified candidate features using 90% of the data. We performed nested cross-validation on this partition and compared the inner loop results. If M2 was significantly better, we tested whether it performed better on the 10% partition. If it did, we chose M2 and assessed its performance on the outer loop. This procedure was created as our dataset was rather small and noisy, which is typical for EHR-derived data. Results: All-cause pneumonitis incidence following ICI initiation was 8.4%. Our final model includes only six features: frequency of lung-related ICD-10 codes, frequency of C34 code, frequency of C78 code, smoking status, interaction between smoking and C34/C78 indicators, and median of blood oxygen saturation. This model achieved a mean AUC of 0.66 (SD: 0.07). Our analysis on the outer loop predictions showed that selecting 50% of patients with the lowest predicted probabilities reduced the occurrence of pneumonitis in the cohort to 5%, compared to 8.4%, when we select patients randomly. The model achieved a mean positive predictive value of 0.3 and negative predictive value of 0.96. Conclusions: We utilized a real-world EHR dataset to identify patterns in patient medical history that could predict the development of pneumonitis. We demonstrated that a small number of easily obtainable clinical covariates can result in meaningful predictions. This model illustrates potential future use for identifying the patients with the highest and lowest risks for pneumonitis during treatment.

Hypofractionated Radiation Therapy Combined With Weekly Chemotherapy in Patients With Unresectable or Recurrent Thymic Epithelial Tumor: A Prospective, Single-Arm Phase 2 Study (GASTO-1042)

This prospective phase 2 study aimed to evaluate the efficacy and safety of hypofractionated radiation therapy (HRT) combined with concurrent weekly chemotherapy in patients with unresectable or recurrent thymic epithelial tumors (TETs). Patients with unresectable or recurrent intrathoracic TETs that could be encompassed within the radiation fields were enrolled. HRT using intensity modulated radiation therapy (IMRT) technique was administered with 3 different levels of radiation doses (51 Gy/17 fractions (fx), 48 Gy/12 fx, and 45 Gy/9 fx; biologically effective dose of 66.3-67.5Gy), combined with weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2). Weekly thymosin α1 (1.6 mg) was administered from the start to 2 months after radiation therapy. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), health-related quality of life (QOL), and toxicity were recorded. Fifty eligible patients enrolled from August 1, 2018, to July 1, 2020, were analyzed. Most patients (82.0%) had stage IVB tumors. Patients had IMRT-HRT (36-51 Gy in 9-17 fx, median biologically effective dose of 67.2 Gy) and concurrent weekly docetaxel/nedaplatin (2-4 cycles). During a median follow-up of 25.0 months (14.0-40.0), the ORR was 83.7%, the 2-year PFS was 59.1%, and the 2-year OS was 90.0%. There was 1 (2.0%) in-field recurrence while 19 (38.0%) patients developed out-of-field recurrence. Grade 3 pneumonitis was observed in 1 patient (2.0%). The ORR, 2-year PFS, 2-year OS, and toxicity were similar among 3 dose levels. Fourteen (28.0%) patients had 2 to 4 courses of radiation therapy because of recurrent diseases. Only 1 suffered from grade 1 pulmonary fibrosis during follow-up. Most patients (88%) maintained a stable QOL within 1 year after radiation therapy. IMRT-HRT and concurrent weekly docetaxel/nedaplatin was effective and well tolerated in unresectable or recurrent TETs. Considering the common out-of-field recurrence, this combined regimen could be an option for repeated radiation therapy. Thymosin α1 might help lower the incidence of pneumonitis and maintain the QOL.

Volumetric Estimation of Lung Dose and Its Association with Pneumonitis Following Radiotherapy in Breast Cancer Patients

Introduction: Lung is a major organ at risk during Post Mastectomy RadioTherapy (PMRT), because of the risk of Radiation Pneumonitis (RP). In countries like India 2D RT is widely used due to limited access to advanced technologies. We estimated the lung dose volumetrically in breast cancer patients treated with 2D tangential techniques, the incidence of acute RP and its association with lung dose. Methodology: Retrospective study of patients who underwent PMRT was done. The images with structure sets of cases planned using 2D technique were transferred to TPS and 3 D plans were generated. CLD, MLD, LL were measured from the 2D plan in the CT simulator. LDmean and V20 were measured from from DVH, in the TPS. Correlation between V20 and LDmean was done with CLD, MLD and LL. The incidence of radiation pneumonitis and its association with lung dose also was studied. Result: Total 50 patients were analyzed of which 3 patients had radiation pneumonitis. The mean CLD was 2.28 cm ± 0.54cm, MLD was 2.32 ± 0.6cm and LL was 12.52 ±2cm. V20 for two fields (MT+LT) was 17.04 ± 5.6 Gy and for three field (MT,LT and SCF) was 28.75 ± 8.6 Gy. Positive correlation was found between for V20 &amp; LDmean and CLD, MLD &amp; LL (p&lt;0.05) 6% of patients developed Radiation pneumonitis but did not have association with V20 or MLD. Conclusion: Radiation pneumonitis is major concern after chest wall irradiation and the incidence is expected to be high with conventional technique where the volume is not accurately measured. It is still an option in countries like India with resource constraints by planning cautiously with the indicators of irradiated lung, like CLD and MLD within limits thus minimizing the incidence of radiation induced lung injury.&#x0D; &#x0D;

Risk of Immune-Related Pneumonitis with PD-1/PD-L1 Inhibitors in Different Cancer Types and Treatment Regimens: A Systematic Review and Meta-Analysis of 22 Randomized Controlled Trials

Background: Pneumonitis, the specific toxicity associated with PD-1/PD-L1 inhibitors, is severe and potentially life-threatening, and its incidence and severity are poorly understood among different tumor types or treatment methods. This meta-analysis was performed to compare the incidence and severity of pneumonitis among different tumor types and treatment regimens. Methods: MEDLINE and Embase were retrieved until September 2021. Meta-analysis of the risk of pneumonitis was calculated using a fixed-effect model. Pooled analysis of the incidence of pneumonitis in different tumor types was performed using a metaprop function. Results: Twenty two randomized controlled trials (RCTs) (n = 10,700) were included for pool analysis, and eighteen RCTs (n = 8,852) were eligible for meta-analysis. For all-grade pneumonitis, the risk of the combination therapy (PD-1/PD-L1 plus CTLA-4 inhibitor) was 3.62 times significantly higher than that of monotherapy, and 4.06 and 1.78 times significantly higher than that of chemotherapy and placebo than monotherapy. The incidence of pneumonitis was not significantly different between PD-1/PD-L1 inhibitor versus ipilimumab or between low doses versus high doses. For high-grade (grade ≥3) pneumonitis, the risk in PD-1/PD-L1 inhibitors alone was 3.62 times significantly higher than chemotherapy. No significant difference was found in the incidence of pneumonitis between combination versus monotherapy, monotherapy versus placebo, combination versus ipilimumab alone, monotherapy versus ipilimumab alone, or low doses versus high doses. Conclusions: Compared with chemotherapy, PD-1/PD-L1 inhibitor monotherapy may cause more treatment-related pneumonitis. Increasing the dose of PD-1/PD-L1 inhibitor does not significantly increase the incidence of pneumonitis. Compared with the monotherapy, combination therapy does not increase the incidence of pneumonitis significantly.

Is Thoracic Radiotherapy an Absolute Contraindication for Treatment of Lung Cancer Patients With Interstitial Lung Disease? A Systematic Review

Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8–46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0–60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy.

Interleukin-10 Is a Promising Marker for Immune-Related Adverse Events in Patients With Non-Small Cell Lung Cancer Receiving Immunotherapy.

BackgroundImmune checkpoint inhibitors (ICIs) brought about a major paradigm shift in non-small cell lung cancer (NSCLC) treatment. However, the use of ICIs is related to an unforeseeable pattern of immune-related adverse events (irAEs). Hence, more precise biomarkers are needed to predict the incidence of irAEs to prevent overtreatment of ICIs and decrease occurrences of irAEs. This study was designed to identify capable clinical features and plasma inflammatory factors for predicting irAEs.MethodsA total of 67 patients who received ICI monotherapy or ICI-based combination therapy were retrospectively identified. Clinical characteristics and plasma inflammatory cytokines were collected and analyzed to screen potential biological markers associated with irAEs. The chi-square test, Fisher’s test, and the Mann–Whitney U test were performed for the primary analysis. The optimal cutoff value was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate logistic regression models were used to identify risk factors of irAEs. Univariate and multivariate Cox proportional hazards were also performed.ResultsOut of 67 patients, 40 (59.7%) experienced irAEs, and 7 (10.4%) experienced severe adverse events (grade ≥ 3). Among these analyzed immune profile biomarkers, only interleukin−10 (IL-10) was related to the risk of irAEs. A high baseline IL−10 plasma level (odds ratio (OR) = 5.318, 95% CI 1.174–24.081, p = 0.030) was found to be a tremendous and independent risk factor for the development of irAEs. Also, for the dynamic analysis, upregulation of IL-10 after one cycle of ICI treatment was positively related to the occurrence of irAEs (OR = 5.712, 95% CI 1.088–29.993, p = 0.039). When pneumonitis, the most common irAEs, was analyzed, only baseline high-expression IL-10 was accompanied with the incidence of pneumonitis (OR = 9.969, 95% CI 1.144–86.843, p = 0.037).ConclusionBaseline and dynamic IL-10 plasma levels are tremendously and independently related to higher risk in the development of irAEs and could be utilized for medical practice to monitor adverse events in patients with ICI treatment.

Predicting factors of symptomatic radiation pneumonitis induced by durvalumab following concurrent chemoradiotherapy in locally advanced non-small cell lung cancer

BackgroundConcurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard of care for unresectable locally-advanced non-small cell carcinoma (LA-NSCLC). However, a major concern about administration of durvalumab after CCRT is whether the incidence of symptomatic radiation pneumonitis (RP) may increase or not. In the present analysis, we report the initial results of CCRT followed by durvalumab in patients with LA-NSCLC in a real-world setting with focus on predicting factors for symptomatic RP.MethodsPatients who were pathologically diagnosed as NSCLC and initiated treatment with CCRT followed by durvalumab between July 2018 to December 2019 were eligible for this study. Patients were included if they completed the planned CRT course and administered at least one course of durvalumab. We retrospectively investigated the preliminary survival outcome and incidence and predicting factors for symptomatic RP.ResultsOf the 67 patients who planned CCRT, 63 patients completed the entire CCRT course. Of these, 56 patients proceeded to consolidation with durvalumab. The median time to eternal discontinuation of durvalumab was 9.7 months. The cumulative proportion of the patients who exhibited symptomatic RP was 30, 40 and 44% at 3, 6 and 12 months, respectively. In multivariate analyses, pulmonary fibrosis score and lung V40 were significant predictive factors for symptomatic RP (p < 0.001, HR: 7.83, 95% CI: 3.38–18.13, and p = 0.034, HR: 3.17, 95% CI: 1.09–9.19, respectively).ConclusionsPulmonary fibrosis sore and lung V40 were significant predictive factors for symptomatic RP. We should be cautious about the administration of durvalumab for patients having subclinical pulmonary fibrosis. To our best knowledge, this is one of the first report showing the predictive value of high dose volumes to the lung in patients with LA-NSCLC who received CCRT followed by durvalumab.

Deciphering the clinical features of heterogeneous stage III non-small cell lung cancer in Japanese real-world clinical practice: Expanded cohort of the SOLUTION study

ObjectivesTo evaluate the actual treatment patterns with respective outcomes and the patient characteristics of stage III non-small cell lung cancer (NSCLC) in Japan. Materials and methodsPatients (aged ≥20 years at diagnosis) who were diagnosed with stage III NSCLC between January 2013 and December 2014 and underwent surgery, chemoradiotherapy (CRT), chemotherapy (CT), or radiotherapy (RT) at 11 institutions in Japan were consecutively registered in this retrospective, observational study (SOLUTION; UMIN000031385). Study measures included patient characteristics, first-line treatments, overall survival (OS), progression-free survival, objective response rate, and incidence of radiation-related adverse events. ResultsThe study population comprised 744 patients. The tumors were classified as stage IIIA and IIIB in 58.9% and 41.1% of patients, respectively. The tumors were considered resectable at diagnosis in 25.0% of patients. First-line treatments were surgery (20.0%), CRT (46.1%), CT (22.2%), and RT (11.7%). The median OS (mOS) in the overall population was 25.4 months and the 3-year OS rate was 38.7%. Among the four first-line treatment cohorts, OS most favored the surgery cohort: mOS was 43.4 months and the 3-year OS rate was 53.8%. Prognostic factors for OS in each treatment modality were analyzed using multivariable analysis and included the following: age, performance status, and histological type for the surgery cohort; sex, histological type, and primary lesion location (lower lobe) for the CRT cohort; and performance status and clinical stage for the RT cohort. The timing of peak incidence of pneumonitis from the start of first-line treatment was 18–20 and 12–14 weeks in the CRT and RT cohorts, respectively. ConclusionPatients with clinical stage III NSCLC received a variety of treatments selected to the clinical background and tumor status, and we clarified the outcome and prognostic factors. These findings will be a useful reference for future studies evaluating newly introduced treatments for stage III NSCLC.