Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Atezolizumab Post Chemo-Radiation

Objective: The use of Durvalumab following chemoradiotherapy in patients with stage III NSCLC, considerably increased PFS (progression free survival) and OS (overall survival). Unfortunately, Durvalumab is currently not reimbursed for this indication in Lebanon so far. We have used Atezolizumab on a series of patients to the similar mechanism of action. We report in this paper the incidence of pneumonitis using this approach. Methods: We selected from our lung cancer registry, a group of patients diagnosed with stage III NSCLC, who received Atezolizumab (Tecentriq) as consolidation therapy following concurrent chemoradiation therapy. We specifically look at the incidence and severity of pneumonitis based on Common Toxicity Criteria and Adverse Events (CTCAE). Finally, we analyzed patient and tumor characteristics looking for predictive markers for pneumonitis. Result: Of the 14 patients who met our selection criteria, 8 developed pneumonitis and 6 did not. Age, gender and smoking status did not affect the probability of having pneumonitis, with p-values of 0.98,1 and 0.86 respectively. The impact of having PDL-1 status on pneumonitis could not be assessed due to our small sample size. The mean onset of pneumonitis after completion of chemoradiotherapy is 3.62 and after starting Atezolizumab is 2.45 months. Conclusion: The administration of Atezolizumab carries a significant risk of developing pneumonitis following chemoradiation therapy for NSCLC. The presence of certain factors and tumor characteristics might affect the chances of having pneumonitis. However due to our small sample size, definitive conclusions could not be drawn.     

Symptomatic Radiation Pneumonitis in Elderly Patients Receiving Thoracic Irradiation

PurposeAdvanced age has been associated with increased risk of radiation pneumonitis. The purpose of this study was to examine the clinical and dosimetric predictors of radiation pneumonitis in elderly patients relative to younger patients treated with thoracic radiation therapy for lung cancer.MethodsTwo hundred fifty-six consecutive patients with stage I-III small cell and non–small-cell lung cancer treated with definitive radiation with or without concurrent chemotherapy, between 2004 and 2009, were reviewed. Pneumonitis was graded by using the Common Terminology Criteria for Adverse Events version 4. Clinical parameters and dosimetric variables were assessed in univariate and multivariate analysis to evaluate predictors of grade ≥2 pneumonitis in patients age ≥70 years and age <70 years.ResultsThere were 99 patients age ≥70 and 157 patients age <70 years old. Pneumonitis occurred in 32 patients (grade 2 [22], grade 3 [7], grade 4 [3], grade 5 [1]). On multivariate analysis, the V₅ Gy (P = .005) and age ≥70 years (P = .001) predicted for grade ≥2 pneumonitis, whereas angiotensin converting enzyme inhibitor use was associated with decreased risk (P = .02). Pneumonitis grade ≥3 occurred in 10% (n = 10/99) of patients age ≥70 years and in 1% (n = 1/157) of patients <70 years (P = .001). In patients with a V₂₀ Gy >31%, the incidence of grade ≥3 pneumonitis was 33% (n = 4/12) in elderly patients compared with 2% (n = 1/44) in younger patients (P = .005).ConclusionsElderly patients were observed to have an increased risk of symptomatic pneumonitis. Radiation dose parameters remain useful in this population; however, the threshold for clinically acceptable pneumonitis may be lower than in younger patients. angiotensin converting enzyme inhibitors use may mitigate radiation pneumonitis.     

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.     

Everolimus-Induced Pneumonitis in Patients with Neuroendocrine Neoplasms: Real-World Study on Risk Factors and Outcomes

BackgroundEverolimus-induced pneumonitis (EiP) has been poorly studied in patients with neuroendocrine neoplasms (NEN) outside clinical trials. The aim of this study was to evaluate the incidence, risk factors, and outcomes of EiP in patients with NENs using real-world data.MethodsRetrospective study of everolimus-treated patients with advanced NENs. Imaging reports were systematically reviewed for the presence of pneumonitis. Clinical features and treatment profiles for EiP were summarized. Overall survival (OS) was calculated from the initiation of everolimus to the date of death or last follow-up using the Kaplan-Meier method.ResultsA total of 122 patients were included. Median age at start of everolimus was 62 (19-86) years, 62% (76/122) were male, and half were from pancreatic origin (62, 51%). Twenty-eight patients (23%) developed EiP: 82% grade (G)1 or G2, 14% G3 and 4% G4. The median time to EiP was 3.6 (0.8-51) months. Primary tumor site, concurrent lung disease, smoking history, and prior therapies were not associated with the onset of EiP. Patients who developed EiP had longer time on everolimus treatment (median 18 months vs 6 months; P = .0018) and OS (77 months vs 52 months; P = .093). Everolimus-induced pneumonitis was a predictor of improved OS by multivariable analysis (HR 0.39, 95% CI 0.19-0.82; P = .013).ConclusionEverolimus-induced pneumonitis in the real-world clinical setting is present in one quarter of patients with NENs receiving everolimus and often occurs early. While risk factors for EiP were not identified, patients with EiP had improved survival.     

Impact of Checkpoint Inhibitor Pneumonitis on Survival in NSCLC Patients Receiving Immune Checkpoint Immunotherapy

With increasing use of immune checkpoint inhibitors (ICIs) for advanced NSCLC, there is increasing recognition of immune-related adverse events associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of immune-related adverse events in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we used a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. We found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multivariate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy.     

Korean Real-World Data on Patients With Unresectable Stage III NSCLC Treated With Durvalumab After Chemoradiotherapy: PACIFIC-KR

IntroductionThis study aimed to investigate real-world evidence for efficacy and safety of durvalumab consolidation (DC) after chemoradiotherapy (CRT) in patients with unresectable stage III NSCLC.MethodsPatients with stage III NSCLC who started DC after CRT between September 2018 and December 2020 and were treated at five tertiary hospitals in the Republic of Korea were included. The primary end point was real-world progression-free survival (rwPFS). Secondary end points were overall survival, objective response rate, and adverse events including radiation pneumonitis (RP) and immune-related adverse events (irAEs).ResultsA total of 157 patients were enrolled. At the median follow-up of 19.1 months, median rwPFS of DC was 25.9 months (95% confidence interval: 16.5–35.4) and the 1-, 2-, and 3-year rwPFS rates were 59.4%, 51.8%, and 43.5%, respectively. The median overall survival was not mature, and objective response rate of DC was 51.0%. High programmed death-ligand 1 expression (≥50%) and development of RP requiring steroid treatment were significantly associated with longer (p = 0.043) and shorter rwPFS (p = 0.036), respectively. RP, RP requiring steroid treatment, and irAEs developed in 57 (36.3%), 42 (26.8%), and 53 (33.8%) patients, respectively. Among peripheral blood cell counts at the initiation of DC, a high derived monocyte-to-lymphocyte ratio was the most significant risk factor for the development of RP requiring steroid treatment (OR 44.76, 95% CI: 8.89–225.43, p < 0.001) and irAEs (OR 2.85, 95% CI: 1.27–6.41, p = 0.011).ConclusionsCompared with the outcome of the PACIFIC trial, these real-world data revealed favorable survival benefits of DC after CRT in patients with unresectable stage III NSCLC. Blood-based biomarkers could predict higher-grade RP and irAEs before the initiation of DC.     

Lower Incidence of Esophagitis in the Elderly Undergoing Definitive Radiation Therapy for Lung Cancer

IntroductionMost patients with lung cancer are elderly and poorly represented in randomized clinical trials. They are often undertreated because of concerns about their ability to tolerate aggressive treatment. We tested the hypothesis that elderly patients undergoing definitive lung radiation might tolerate treatment differently than younger patients.MethodsA total of 125 patients who underwent definitive lung radiotherapy were identified from a prospective institutional database (University of Michigan cohort). Logistic regression modeling was performed to assess the impact of age on esophagitis grade 2 or higher or grade 2 or higher and pneumonitis grade 3 or higher or grade 2 or higher, with adjustment for esophageal and lung dose, respectively, as well as for chemotherapy utilization, smoking status, and performance status. The analysis was validated in a large cohort of 691 patients from the Michigan Radiation Oncology Quality Consortium registry, an independent statewide prospective database.ResultsIn the University of Michigan cohort, multivariable regression models revealed a significant inverse correlation between age and rate of esophagitis for both toxicity levels, (adjusted OR = 0.93 for both models and 95% confidence intervals of 0.88–0.98 and 0.87–0.99), with areas under the curve of 0.747 and 0.721, respectively, demonstrating good fit. This same association was noted in the Michigan Radiation Oncology Quality Consortium cohort. There was no significant association between age and pneumonitis.ConclusionsThere is a lower incidence of esophagitis with increasing age even after adjustment for use of chemotherapy. This is a novel finding in thoracic oncology. No age dependence was noted for pulmonary toxicity. The elderly are able to tolerate definitive thoracic radiation well and should be offered this option when clinically warranted.     

三维适形放疗肺癌患者的放射性肺炎的相关因素分析

 目的 探讨放射性肺炎的相关性因素,为临床治疗计划的制定提供参考标准。方法 78例未经手术治疗的肺癌患者在放疗开始前1周进行肺功能检测,应用χ2和Logistic多元回归分析方法研究肺癌患者临床资料、剂量体积参数及肺功能指标与放射性肺炎的关系。临床资料：性别、年龄、临床分期、病理类型、是否化疗、是否合并慢性阻塞性肺病、是否合并肺不张和阻塞性肺炎、放疗方式及肿瘤位置;剂量体积参数包括双肺V10、V15、V20、V25、V30、V35、V40,肺Dmean、Veff、GTV大小、射野数。肺功能指标分析Fvc、Fev1.0、DLco。结果 ①放射性肺损伤2级以上有18例（23.08%）;②单因素分析有统计学差异的相关因素是放疗前合并有慢性阻塞性肺病,GTV大小、V30,DLco（P〈0.05）;③经过Bi-naryLogistic回归模型分析,放疗前合并有慢性阻塞性肺病和V30〉18%为放射性肺损伤发生的独立因素（P=0.018和0.037）。结论 放射性肺损伤是个多因素综合影响的结果,对肺部有慢性疾病患者和基础肺功能异常（弥散功能为主）的患者应优选治疗方案,且肺V30控制在18%以下。     

不同放化疗治疗模式对肺癌患者放射性肺炎发生的影响

目的 比较肺癌放疗患者不同放化疗治疗模式下2级以上放射性肺炎（RP）发生的差异,以及临床治疗特征对RP发生的影响。方法 回顾性分析自2014年1月至2016年1月在我院行放化疗综合治疗的肺癌患者136例,按期随访并复查肺功能、胸部CT,按RTOG急性放射肺炎评价标准对肺损伤分级进行评价,分析临床特征及治疗模式对RP发生的影响。结果 ≥2级RP 36例,发生率为26.5%。临床特征方面,粉尘接触史和病理类型与RP发生有一定相关性（P=0.048, 0.047）,其余指标方面差异均无统计学意义。治疗模式方面,序贯放化疗与同步放化疗比较,在总RP发生、2级和3级RP发生率方面差异均无统计学意义,而≥4级RP发生率两组比较差异有统计学意义（6.7% vs. 0, P=0.05）。不同化疗方案之间比较在≥2级RP发生方面差异无统计学意义。RP严重程度与总化疗周期数及诱导化疗周期数呈显著正相关（P=0.000）。结论 粉尘接触史和病理类型是临床特征方面增加RP发生的独立因素。不同治疗模式对RP的发生有一定的影响,其中与患者化疗周期数密切相关,特别是总化疗周期或诱导化疗周期。     

Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy

IntroductionWe have suggested that major pathologic response (MPR) could serve as a surrogate endpoint for survival and provide rapid means of comparing different neoadjuvant treatment regimens. Here, we confirm that MPR is predictive of long-term overall survival (OS) in patients with non–small-cell lung cancer (NSCLC) who underwent neoadjuvant chemotherapy and surgical resection, to assess agreement on MPR between 2 observers, and to determine the minimum number of slides needed to obtain an accurate determination of MPR.Patients and MethodsWe identified 151 patients with NSCLC who had been treated with neoadjuvant chemotherapy followed by complete surgical resection from 2008 to 2012. Tissue specimens were retrospectively evaluated by 2 pathologists who had been blinded to patients’ treatment and outcome. We assessed the relationships between MPR and OS, the levels of agreement between the pathologists, and determined the number of slides needed to obtain an accurate determination of MPR.ResultsOur results reveal that MPR examined by either observer 1 (experienced) or by observer 2 (trained) was significantly predictive of long-term OS after neoadjuvant chemotherapy. MPR was associated with long-term OS in patients with NSCLC undergoing neoadjuvant chemotherapy on multivariable analysis (hazard ratio 2.68; P = .01). The levels of agreement between 2 pathologists were high after direct in-person training by one pathologist or the other (R² = 0.994). Our data suggest that at least 3 slides should be read to accurately determine MPR.ConclusionsMPR is significantly predictive of long-term OS in neoadjuvant chemotherapy–treated patients with NSCLC. MPR may serve as a surrogate endpoint for evaluating novel chemotherapies and immunotherapy response in biomarker-driven translational clinical trials.     

放疗前肺功能参数对非小细胞肺癌放射性肺炎的预测价值

目的 观察肺癌患者三维适形放疗后放射性肺炎的发生情况,探讨放疗前肺功能参数在预测非小细胞肺癌放射性肺炎方面的价值.方法 对81例接受三维适形放射治疗并符合入组条件的非小细胞肺癌患者进行放疗前基础肺功能测定,并记录剂量体积参数,观察放疗后放射性肺炎的发生情况,对患者临床资料、肺功能参数、剂量体积参数等指标进行单因素及多因素分析,评价肺功能参数预测放射性肺炎的价值.结果 全组患者中17例出现≥2级放射性肺炎,占21.0%(17/81),其中2级15例,3级2例,无4、5级放射性肺炎发生.单因素分析结果显示,放疗前肺功能指标FEV1.0、FEV1.0/FVC、DLCO及放疗计划指标PTV体积、双肺MLD、V5、V20、V30,均影响患者≥2级放射性肺炎的发生(P<0.05).≥2级放射性肺炎组患者肺功能参数FEV1.0、FEV1.0/FVC、DLCO指标值均低于0、1级放射性肺炎组,且有统计学意义(P<0.05).多因素分析结果显示:FEV1.0、FEV1.0/FVC、DLCO等相关肺功能指标值并非≥2级放射性肺炎的独立影响因素,仅双侧肺脏MLD、V5、V20及V30为患者≥2级放射性肺炎发生的独立影响因素(P<0.05).结论 基础肺功能参数FEV1.0、FEV1.0/FVC、DLCO在≥2级急性放射性肺炎预测方面具有一定价值,肺功能受损是放射性肺炎的高危因素,但并非影响放射性肺炎的独立因素.     

Excess Incidence of Lung Cancer among Pulmonary Tuberculosis Patients

Reviewing the epidemiological studies on coexistent pulmonarytubuerculosis and lung cancer since 1960, it was confirmed thatpatients with active pulmonary tuberculosis have a higher riskof dying from lung cancer or other malignancies, in spite ofa very high mortality from tuberculosis per se. Females showeda higher risk than males. An antagonistic hypothesis betweenthe above two diseases since 1854 seemed based on the factsthat tuberculosis patients had mostly died in young age groupsand had had little chance of surviving to cancer age groupsbefore the advent of modern treatments, and that the lack ofan adequate disease registration system might have caused afailure to reveal any association between the two diseases.Specific causative factors of the excess incidence of canceramong active pulmonary tuberculosis patients, however, haveso far not be clarified.     

Predictors of Physical and Functional Loss in Advanced-Stage Lung Cancer Patients Receiving Platinum Chemotherapy

Introduction

Muscle wasting has detrimental effects, including increased mortality. Identifying patients at risk can guide treatment efforts.

Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study

IntroductionThe phase 3 PACIFIC trial established consolidation therapy with durvalumab as standard of care for patients with unresectable, stage III NSCLC and no disease progression after definitive chemoradiotherapy (CRT). The observational PACIFIC-R study assesses the real-world effectiveness of durvalumab in patients from an early access program. Here, we report treatment characteristics and a preplanned analysis of real-world progression-free survival (rwPFS).MethodsPACIFIC-R (NCT03798535) is an ongoing, international, retrospective study of patients who started durvalumab (intravenously; 10 mg/kg every 2 wk) within an early access program between September 2017 and December 2018. The primary end points are investigator-assessed rwPFS and overall survival (analyzed by Kaplan–Meier method).ResultsAs of November 30, 2020, the full analysis set comprised 1399 patients from 11 countries (median follow-up duration, 23.5 mo). Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% confidence interval: 19.1–24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 versus 19.3 mo) and among patients with programmed cell death-ligand 1 expression greater than or equal to 1% versus less than 1% (22.4 versus 15.6 mo). Overall, 16.5% of the patients had adverse events leading to treatment discontinuation; 9.5% of all patients discontinued because of pneumonitis or interstitial lung disease.ConclusionsConsolidation durvalumab after definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was longer among patients who received concurrent versus sequential CRT and patients with higher programmed cell death-ligand 1 expression. Nevertheless, favorable rwPFS outcomes were observed regardless of these factors.     

Multicenter Real-World Study on Effectiveness and Early Discontinuation Predictors in Patients With Non-small Cell Lung Cancer Receiving Nivolumab

BackgroundReal-world (RW) evidence on nivolumab in pretreated patients with non-small cell lung cancer (NSCLC) by matching data from administrative health flows (AHFs) and clinical records (CRs) may close the gap between pivotal trials and clinical practice.MethodsThis multicenter RW study aims at investigating median time to treatment discontinuation (mTTD), overall survival (mOS) of nivolumab in pretreated patients with NSCLC both from AHF and CR; clinical-pathological features predictive of early treatment discontinuation (etd), budget impact (BI), and cost-effectiveness analysis were investigated; mOS in patients receiving nivolumab and docetaxel was assessed.ResultsOverall, 237 patients with NSCLC treated with nivolumab were identified from AHFs; mTTD and mOS were 4.2 and 9.8 months, respectively; 141 (59%) received at least 6 treatment cycles, 96 (41%) received < 6 (etd). Median overall survival in patients with and without etd were 3.3 and 19.6 months, respectively (P < .0001). Higher number, longer duration, and higher cost of hospitalizations were observed in etd cases. Clinical records were available for 162 patients treated with nivolumab (cohort 1) and 83 with docetaxel (cohort 2). Median time to treatment discontinuation was 4.8 and 2.6 months, respectively (P < .0001); risk of death was significantly higher in cohort 2 or cohort 1 with etd compared with cohort 1 without etd (P < .0001). Predictors of etd were body mass index <25, Eastern Cooperative Oncology Group performance status >1, neutrophile-to-lymphocyte ratio >2.91, and concomitant treatment with antibiotics and glucocorticoids. The incremental cost-effectiveness ratio of nivolumab was 3323.64 euros ($3757.37) in all patients and 2805.75 euros ($3171.47) for patients without etd. Finally, the BI gap (real-theoretical) was 857 188 euros ($969 050.18).ConclusionWe defined predictors and prognostic-economic impact of nivolumab in etd patients.