Pulmonary Toxicity In Patients Research Articles

A deep learning model for translating CT to ventilation imaging: analysis of accuracy and impact on functional avoidance radiotherapy planning.

Radiotherapy planning incorporating functional lung images has the potential to reduce pulmonary toxicity. Free-breathing 4DCT-derived ventilation image (CTVI) may help quantify lung function. This study introduces a novel deep-learning model directly translating planning CT images into CTVI. We investigated the accuracy of generated images and the impact on functional avoidance planning. Paired planning CT and 4DCT scans from 48 patients with NSCLC were randomized to training (n = 41) and testing (n = 7) data sets. The ventilation maps were generated from 4DCT using a Jacobian-based algorithm to provide ground truth labels (CTVI4DCT). A 3D U-Net-based model was trained to map CT to synthetic CTVI (CTVISyn) and validated using fivefold cross-validation. The highest-performing model was applied to the testing set. Spearman's correlation (rs) and Dice similarity coefficient (DSC) determined voxel-wise and functional-wise concordance between CTVI4DCT and CTVISyn. Three plans were designed per patient in the testing set: one clinical plan without CTVI and two functional avoidance plans combined with CTVI4DCT or CTVISyn, aimed at sparing high-functional lungs defined as the top 50% of the percentile ventilation ranges. Dose-volume (DVH) parameters regarding the planning target volume (PTV) and organs at risk (OARs) were recorded. Radiation pneumonitis (RP) risk was estimated using a dose-function (DFH)-based normal tissue complication probability (NTCP) model. CTVISyn showed a mean rs value of 0.65 ± 0.04 compared to CTVI4DCT. Mean DSC values over the top 50% and 60% of ventilation ranges were 0.41 ± 0.07 and 0.52 ± 0.10, respectively. In the test set (n = 7), all patients' RP-risk benefited from CTVI4DCT-guided plans (Riskmean_4DCT_vs_Clinical: 29.24% vs. 49.12%, P = 0.016), and six patients benefited from CTVISyn-guided plans (Riskmean_Syn_vs_Clinical: 31.13% vs. 49.12%, P = 0.022). There were no significant differences in DVH and DFH metrics between CTVISyn and CTVI4DCT-guided plan (P > 0.05). Using deep-learning techniques, CTVISyn generated from planning CT exhibited a moderate-to-high correlation with CTVI4DCT. The CTVISyn-guided plans were comparable to the CTVI4DCT-guided plans, effectively reducing pulmonary toxicity in patients while maintaining acceptable plan quality. Further prospective trials are needed to validate these findings.

Incidence of pulmonary toxicity in bleomycin-containing regimens for testicular cancer with and without the use of growth factor.

The concurrent use of bleomycin and granulocyte colony-stimulating factors (G-CSFs) has historically been debated as a risk factor for bleomycin-induced pulmonary toxicity in patients with both testicular cancer and Hodgkin's lymphoma. The purpose of this study is to evaluate the incidence of pulmonary toxicity in patients with testicular cancer who were treated with bleomycin and pegfilgrastim concurrently. This is a retrospective study that includes male patients over the age of 18 years old diagnosed with testicular cancer who received bleomycin-containing chemotherapy regimens with and without the use of G-CSF agents. There were a total of 33 patients identified as receiving bleomycin, with 30 of those patients having received concurrent G-CSF therapy. Of the patients who received G-CSF therapy, 11 patients (36.6%) experienced pulmonary toxicity leading to discontinuation of bleomycin or changes in chemotherapy regimens altogether. There were no major differences in patient demographics or risk factors between those who received G-CSF and developed pulmonary toxicity and those who received G-CSF but did not develop pulmonary toxicity. Further studies are needed in order to fully assess the risk of pulmonary toxicity with this chemotherapy regimen.

VMAT-Based Planning Allows Sparing of a Spatial Dose Pattern Associated with Radiation Pneumonitis in Patients Treated with Radiotherapy for a Locally Advanced Lung Cancer.

Simple SummaryA sub-region localized in the posterior right lung was significantly associated with the risk of grade ≥ 2 acute pulmonary toxicity in patients with locally advanced lung cancer treated with radiotherapy. Avoiding this sub-region with volumetric-arctherapy-based planification leads to a significant reduction of the predicted APT risk by reclassifying 43.2% (19/44) of the patients.Introduction: In patients treated with radiotherapy for locally advanced lung cancer, respect for dose constraints to organs at risk (OAR) insufficiently protects patients from acute pulmonary toxicity (APT), such toxicities being associated with a potential impact on the treatment’s completion and the patient’s quality of life. Dosimetric planning does not take into account regional lung functionality. An APT prediction model combining usual dosimetry features with the mean dose (DMeanPmap) received by a voxel-based volume (Pmap) localized in the posterior right lung has been previously developed. A DMeanPmap of ≥30.3 Gy or a predicted APT probability (ProbAPT) of ≥8% were associated with a higher risk of APT. In the present study, the authors aim to demonstrate the possibility of decreasing the DMeanPmap via a volumetric arctherapy (VMAT)-based adapted planning and evaluate the impact on the risk of APT. Methods: Among the 207 patients included in the initial study, only patients who presented with APT of ≥grade 2 and with a probability of APT ≥ 8% based on the prediction model were included. Dosimetry planning was optimized with a new constraint (DMeanPmap < 30.3 Gy) added to the usual constraints. The initial and optimized treatment plans were compared using the t-test for the independent variables and the non-parametric Mann–Whitney U test otherwise, regarding both doses to the OARs and PTV (Planning Target Volume) coverage. Conformity and heterogeneity indexes were also compared. The risk of APT was recalculated using the new dosimetric features and the APT prediction model. Results: Dosimetric optimization was considered successful for 27 out of the 44 included patients (61.4%), meaning the dosimetric constraint on the Pmap region was achieved without compromising the PTV coverage (p = 0.61). The optimization significantly decreased the median DMeanPmap from 28.8 Gy (CI95% 24.2–33.4) to 22.1 Gy (CI95% 18.3–26.0). When recomputing the risk of APT using the new dosimetric features, the optimization significantly reduced the risk of APT (p < 0.0001) by reclassifying 43.2% (19/44) of the patients. Conclusion: Our approach appears to be both easily implementable on a daily basis and efficient at reducing the risk of APT. Regional radiosensitivity should be considered in usual lung dose constraints, opening the possibility of new treatment strategies, such as dose escalation or innovative treatment associations.

MEDB-75. Treatment-induced pulmonary toxicity in patients with medulloblastoma: a retrospective analysis on 2 Italian institutions’ cohorts

BACKGROUND: Incidence of iatrogenic pulmonary toxicity is around 20%. Apart from bleomycin fibrosis, the role of lomustine, HD-thiotepa, autologous stem-cells transplantation(APBSCT) and their synergy with craniospinal irradiation(CSI) are unclear. To elucidate their role in lung-function impairment, we retrospectively evaluated 39 medulloblastoma patients treated at INT-Milan and OPBG-Rome. METHODS: 39 patients (17 females, median RT age 8 years) treated for localized(29) or metastatic(10) medulloblastoma in 2000-2020 and with spirometric assessment, were considered. Treatment included: SIOP-like-PNET IV(19), high-risk protocol(19), infant protocol without RT(1). CSI doses were: 23.4Gy(20), 31.2Gy(8), 36Gy(6) and 39Gy(4); 4 received protons and 34 photons(9 VMAT, 25 3D), 11 hyperfractionated-accelerated-RT; 33 had 6 median CCNU cycles; 6 APBSCT. RESULTS: Median follow-up: 98 months. All patients performed at least one spirometry at median 5 years after RT. Eight (20.6%) had mildly pathological spirometries, 8 Forced Vital Capacity (FVC%)<90%. RT age was not associated with FVC%/ PEF% (p=0.319 and 0.405). A lower Peak Expiratory Flow(PEF%) was marginally associated to APBSCT group (p=0.062) with FVC%(≤90% vs >90%) similar but less significant(p=0.163). Median FVC%/PEF% were higher in the CCNU-group without reaching significance (p=0.436 and 0.062): this was a standard-risk group not receiving APBSCT nor higher RT doses. Even though the lung volume encompassed by 5-10 Gy isodoses was greater in VMATvs3D RT(p<0.001 and p=0.015), there were no significant differences in ventilatory parameters. FVC%/PEF% were negatively associated to CSI dose. Since no relevant lung volume is involved in high doses, a multifactorial etiology could be speculated. CONCLUSIONS: Preliminary data show no significant FVC%/PEF% reduction. Small sample size and differences in spirometry techniques impose larger cohorts accrual to elucidate potential treatment-induced pulmonary impairment in the pediatric population thus validating the use of spirometry during treatment/follow-up.

Platelet-to-Lymphocyte Ratio as an Indicator to Predict Decreased Carbon Monoxide Diffusion of the Lung in Patients with Testicular Cancer.

To investigate whether the use of diffusing capacity of the lungs for carbon monoxide (DLCO) and neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) could be used to predict bleomycin-induced pulmonary toxicity in patients with testicular cancer (TCa). Descriptive study. Ankara Oncology Training and Research Hospital, Turkey, between 2017 and 2020. Data of 40 patients with TCa, who were followed at cancer centre from 2017-2020 and received 3-4 cycles of BEP protocol were retrospectively screened and included who met the criteria for inclusion in the study. All patients with TCa, who were older than 18 years of age and had no secondary malignancy and comorbidity, were included in this study. A statistically significant negative correlation was found between DLCO change and NLR, PLR (r:-0.558, p:0.002 for NLR; r:-0.462 p:0.012 for PLR). A statistically significant positive correlation was found between DLCO change and lymphocyte level (r:0.436, p:0.018). The NLR and PLR were statistically higher in the group with a decrease of ≥10% in DLCO compared to the group with no decrease or a decrease of ≤10% in DLCO (for NLR; 3.03 ± 1.45 and 1.68 ± 0.73, respectively, p = 0.005; for PLR 187.72 ± 66.90 and 124.72 ± 47.99, respectively, p = 0.008). Multivariate regression analysis showed a statistically significant relationship between PLR increase and a decrease of ≥10% in DLCO. PLR and LDH could be used as independent predictive biomarkers for DLCO decline which is used to identify bleomycin-induced pulmonary toxicity. Key Words: Bleomycin, Markers of inflammation, Platelet-to-lymphocyte ratio (PLR), Pulmonary diffusing capacity, Testicular cancer.

Nitrofurantoin-induced interstitial lung disease

We report the case of a 55-year-old woman diagnosed with interstitial lung disease due to long-term nitrofurantoin therapy that was administered for recurrent urinary tract infection. Despite distorted pulmonary parenchymal architecture and patchy fibrosis confirmed by computed tomography of the thorax, the symptoms and radiographic findings disappeared within 3 months after the administration of prednisone. This case shows that nitrofurantoin-induced lung disease may run a benign course and respond favourably to corticosteroids, even when there is radiographic evidence of established lung fibrosis. This case report highlights the need for vigilance of pulmonary toxicity in patients taking long-term nitrofurantoin therapy.

Evaluation of Pulmonary Toxicities in Lymphoma Patients Receiving Brentuximab Vedotin

Background: Brentuximab vedotin (Bv) is an anti-CD30 antibody conjugated via a protease-cleavable linker to the anti-microtubule agent monomethyl auristatin E (MMAE). It is FDA approved for the treatment of classic Hodgkin lymphoma (cHL) and CD30-expressing T-cell lymphomas in both upfront and relapsed/refractory (R/R) settings. The most common side effects in the original registration trials (ECHELON-1, ECHELON-2, AETHERA) include peripheral neuropathy and cytopenias. With its expanded use in real world settings, it is imperative to identify less-established adverse events which may also result in dose delays or reductions. Pulmonary toxicity is a rare but potentially life-threatening side effect of Bv, but few studies have characterized this toxicity in the adult and pediatric populations. Here, we characterize the incidence and risk factors of developing Bv-associated pulmonary toxicity in patients with lymphoma.Methods: We conducted a multicenter, retrospective, descriptive study of patients receiving Bv at University of California San Francisco Health in San Francisco, CA and Community Medical Center in Fresno, CA. Adult and pediatric patients were included if they received at least one dose of Bv between June 1, 2015 and September 30, 2020. Retrospective chart review was conducted to identify patients who developed respiratory symptoms concerning for Bv-induced pneumonitis. Past medical history, smoking history, and prior administration of pulmonary toxic agents were collected to assess for risk factors contributing to Bv-associated pulmonary toxicity. Respiratory symptoms were classified as likely related, possibly related, or not related to Bv.Patients were identified to have pulmonary toxicities likely related to Bv if they satisfied the following criteria: development of respiratory symptoms with a temporal relation to Bv, suggestive chest imaging or pulmonary function tests (PFTs), rule out of other etiologies including infectious causes, and relief of symptoms with steroid treatment and/or Bv discontinuation at the physician's discretion. Patients were identified to have pulmonary toxicities possibly related to Bv if they satisfied the following criteria: development of respiratory symptoms with a temporal relation to Bv, equivocal chest imaging or PFTs, inability to fully rule out other etiologies, and relief of symptoms with steroid treatment or Bv discontinuation at the physician's discretion. Data is reported using descriptive statistics. A consort flow diagram of the selection process is depicted in Figure 1.Results: A total of 123 patients were reviewed, of whom 27 were excluded due to pregnancy, prisoner status, or not having received Bv during the study period. 96 patients were included in the final analysis. Baseline characteristics are captured in Table 1. Following Bv administration, 19 of the 96 patients developed pulmonary symptoms (dry cough, shortness of breath, dyspnea on exertion, chest pain, or hypoxic respiratory failure not justified by a competing process). Based on the prespecified definitions, we identified four patients (4.2%) who developed respiratory symptoms concerning for Bv-induced toxicity. The mean age of the four patients was 51 (range 28-76) and one patient was female. One patient received Bv in the upfront setting for cHL, one had R/R cHL, and the remaining two had anaplastic large cell lymphoma (ALCL). One patient previously received pulmonary toxic agents (gemcitabine and carmustine) and two patients had a history of tobacco use. The cumulative doses of Bv the four patients received prior to developing respiratory symptoms ranged from 8.8 to 30.4 mg/kg (6-21 cycles). Three patients were classified as likely related based on supportive findings on chest imaging or PFTs and one patient was classified as possibly related given lack of definitive evidence to differentiate between pneumonitis and disease progression. Three of the four patients developed symptoms requiring steroid treatment and two required Bv dose reduction and/or discontinuation.Conclusions: This study is an effort to raise awareness of the incidence of Bv-induced pulmonary toxicity and describe the potential risk factors associated with this adverse event. Further real world studies in larger and diverse patient populations are necessary to better characterize the incidence and risk factors associated with Bv-associated pulmonary toxicities. [Display omitted] DisclosuresLo: EUSA Pharma: Consultancy; Oncopeptides: Consultancy. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Abdulhaq: BMS, Alexion, Oncopeptides, Morphosys, Pfizer, Norvartis: Honoraria; Oncopeptides, Alexion, Amgen: Speakers Bureau; Morphosys, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees. Fakhri: Loxo/Lilly: Research Funding.

Development and Validation of a Spatial Dose Pattern Based Model Predicting Acute Pulmonary Toxicity in Patients Treated With Volumetric Arc-Therapy for Locally Advanced Lung Cancer

<h3>Purpose/Objective(s)</h3> (Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment's compliance and patients' quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the lower right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arc therapy (VMAT) and to validate our findings prospectively. <h3>Materials/Methods</h3> For the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for <i>n = 10.000</i> permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (<i>P < 0.05</i>) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A dose cut-off was defined by maximizing the Youden-Index derived from the Receiver Operative Curve. For the validation cohort, we applied the predefined spatial dose pattern and the dose cut-off to an observational prospective cohort. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). <h3>Results</h3> 167 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.2% and 21.4%. In the training cohort, a cluster of voxels was identified in the lower right lung with a cut off of 30.3 Gy for the D_mean(mean-dose). This spatial-based model resulted in an AUC of 0.69 and a Bacc of 0.71. Using the same voxel cluster and the D_meancut-off on the validation cohort, the model resulted in an AUC of 0.74 and a Bacc of 0.69. <h3>Conclusion</h3> Our model corroborates previous findings regarding the possible role of the lower right lung regarding the development of APT and successfully evaluates its robustness in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints.

Development and prospective validation of a spatial dose pattern based model predicting acute pulmonary toxicity in patients treated with volumetric arc-therapy for locally advanced lung cancer

Introduction(Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment’s compliance and patients’ quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the posterior right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arctherapy (VMAT) and to validate our findings prospectively. MethodsFor the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for n = 10.000 permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (p < 0.05) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A prediction model (Pmap-Model) was then built using a neural network approach and then applied to an observational prospective cohort for validation. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). Results165 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.4% and 19.1%. In the training cohort, a cluster of voxels (Pmap-region) was identified in the posterior right lung. In the training cohort, the Pmap-Model combining 11 features among which the mean dose to the Pmap-region resulted in an AUC of 0.99 and a Bacc of 99.2 using an 8% probability threshold. Using the same voxel cluster on the validation cohort, the Pmap-model resulted in an AUC of 0.81 and a Bacc of 82.0. ConclusionOur APT-prediction model was successfully validated in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints, opening the possibility of easily implementable adaptive dosimetry planning.

PO-1158 Validation of a spatial dose pattern predicting pulmonary toxicity in patients treated with VMAT for a lung cancer

PO-1158 Validation of a spatial dose pattern predicting pulmonary toxicity in patients treated with VMAT for a lung cancer

Abstract 2376: Diagnostic and predictive biomarkers of radiation pneumonitis

Abstract Increased rates of treatment failure in lung cancer patients necessitate treatment with high doses of radiation, which often cause toxicities. However, normal tissue injury in lung may manifest as acute toxicities or as delayed radiation pneumonitis. Identification of early indicators of delayed toxicities will allow timely management and mitigation. In present study, using mouse model, we identified a set of circulating microRNAs as biomarkers that potentially allow early detection of radiation induced lung injury such as inflammation and pneumonitis. Longitudinal analysis of serum samples collected from mice exposed to whole thorax lung irradiation (WTLI) allowed discovery of a panel of evolutionary conserved miRNAs that are potential predictors of radiation pneumonitis. Among these, miR21 and miR29a, miR130a, and miR19a were found peaked between 2-4 weeks after radiation, while miR146a exhibited a peculiar biphasic expression. Some of these changes were found to be associated with concomitant changes in anti- and pro-inflammatory serum cytokines. Several of the biomarkers identified in WTLI model, showed overlapping response in a bleomycin mouse model of acute lung injury. We further tested the translational utility of these biomarkers in single drop blood collected from mice using a validated internal normalizer, miR23a (Yadav et al., Science Translational Medicine, 2020, PMID: 32669422). The response noted for several of the candidate biomarkers identified in mouse model are conserved in specimens collected from human patients who received radiation therapy. In conclusion, our study has identified a panel of microRNA biomarkers with potential to develop as early predictor of pulmonary toxicities in patients receiving therapeutic radiation, and in victims of radiation accidents for timely mitigation. Citation Format: Marshleen Yadav, Joseph Liu, Zahida Qamri, Naduparambil K. Jacob. Diagnostic and predictive biomarkers of radiation pneumonitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2376.

PD-1 restrains IL-17A production from γδ T cells to modulate acute radiation-induced lung injury.

BackgroundCombining radiotherapy (RT) with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has been shown to enhance anti-tumor effects in the treatment of non-small cell lung carcinoma (NSCLC). Pulmonary toxicity is a major adverse effect of thoracic RT in NSCLC patients, whether it is administered alone or in combination with PD-1/PD-L1 inhibitors. This study aimed to evaluate the potential pulmonary toxicity of RT combined with concurrent PD-1 inhibitor and to clarify the underlying mechanisms.MethodsRadiation-induced lung injury (RILI) was induced in C57BL/6 mice by given 24 Gy in three fractions on consecutive days, with or without concurrent injection of anti-PD-1 antibody. On days 3, 7, 14, and 28 after the first exposure to irradiation, lung tissue and peripheral blood samples were collected from the mice. Histological injury was analyzed, and inflammatory cell infiltration and interleukin (IL)-17A production in the lung tissues were quantified.ResultsMice that received irradiation with concurrent administration of anti-PD-1 antibody had the highest histological score for RILI. In the murine lung tissues, the levels of PD-1 and IL-17A expression were increased in γδ T cells but not in the other CD3+ T cells after irradiation. Concurrent blockade of PD-1 enhanced IL-17A production from γδ T cells in the lung tissues after irradiation. In the mice with acute RILI, concurrent administration of anti-PD-1 antibody exaggerated pulmonary inflammation, with significantly increased levels of neutrophilic infiltration and IL-17A detected in both the lung and blood.ConclusionsPD-1 could restrain IL-17A production from γδ T cells to modulate acute RILI. The concurrent administration of anti-PD-1 antibody aggravates the severity of acute RILI. More attention should be paid to pulmonary toxicity in patients undergoing thoracic RT with concurrent anti-PD-1 immunotherapy.

Oxaliplatin-induced Pulmonary Toxicity: A Rare but Serious Complication

The FOLFOX regimen (oxaliplatin, leucovorin, and 5-fluorouracil) is FDA approved for use in patients with colorectal cancer and other gastrointestinal malignancies. The initial phase III randomized controlled trials that led to FDA approval of oxaliplatin with leucovorin and 5-fluorouracil showed a less than 1% incidence of pulmonary fibrosis and grade IV pulmonary toxicities. Here we describe two cases of pulmonary toxicity in patients with metastatic colorectal cancer treated with FOLFOX and briefly review the literature regarding oxaliplatin-induced pulmonary toxicity.

Total Body Irradiation Using Intensity Modulated Radiation Therapy (IMRT) (VMAT or Tomotherapy) for the Prevention of Pulmonary Toxicities in Patients Undergoing Donor Stem Cell Transplant

Total Body Irradiation Using Intensity Modulated Radiation Therapy (IMRT) (VMAT or Tomotherapy) for the Prevention of Pulmonary Toxicities in Patients Undergoing Donor Stem Cell Transplant

Real-World Effectiveness and Safety of Nivolumab in Special Subgroups of NSCLC pts: A Multicenter-Retrospective Study

Abstract Background In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large-scale cohorts of patients with special backgrounds from Japan. Method Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report retrospective analysis of all 901 pts data and focus on effectiveness and safety in special subgroups of the Japanese NSCLC patients, from a multicenter, observational study; CA209-9CR (NCT03273790). Result Patients with EGFR mutations showed significantly shorter PFS as compared to EGFR wild-type patients. Among other special groups, 316 pts with high blood pressure, in which 272 pts was on antihypertensive, showed superior ORR as compared to 585 pts with normal pressure at baseline. Safety analysis showed higher pulmonary toxicity in patients with pulmonary infection at baseline and higher hepatotoxicity in a group of pts infected with hepatitis virus. In this presentation, further analysis on the other subgroups will be presented.

CLO19-024: Risk of Atrial Fibrillation and Pulmonary Toxicities in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Treated With Ibrutinib

Background: Bruton’s tyrosine kinase (BTK), a kinase downstream of the B-cell receptor, involves in the B cell survival and proliferation and has become an attractive therapeutic target. Ibrutinib is an oral potent, covalent inhibitor of BTK and hence employed in many hematologic malignancies. We performed a systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of atrial fibrillation (AF) and pulmonary toxicities among patients treated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase 3 RCTs that mention AF and pulmonary toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 4 phase III RCTs with a total of 1,383 patients with chronic lymphocytic leukemia or small lymphocytic lymphoma were eligible. Studies comparing Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B)+ rituximab (R) vs placebo + B+ R, and I vs R were included in the analysis. The AF incidence was 41 (5.686%) in the ibrutinib group vs 8 (1.208%) in the control arm. The relative risk (RR) for AF was statistically significant at 3.825 (95% CI: 1.848–7.917; P&lt;.0001) and RD was 0.041 (95% CI: 0.023–0.059; P&lt;.0001). The RR of all-grade side effects was as follows: cough, 1.133 (95% CI: 0.724–1.773; P=.584); edema, 1.375 (95% CI: 0.943–2.006; P=.098); pneumonia, 1.227 (95% CI: 0.884–1.703; P=.221); and upper respiratory infections (URI), 1.075 (95% CI: 0.809–1.429; P=.616). The RR of high-grade side effects was as follows: cough, 0.373 (95% CI: 0.063–2.209; P=.277); edema, 1.232 (95% CI: 0.199–7.649; P=.822); pneumonia, 1.277 (95% CI: 0.847–1.926; P=.243); and URI, 1.555 (95% CI: 0.239–10.127; P=.644). Conclusion: Our meta-analysis demonstrated that patients on ibrutinib noted a significant increase in the risk of atrial fibrillation with a relative risk of 3.825. However, the risk of pulmonary toxicities was not statistically increased in the ibrutinib group.

Dosimetric Correlates of Pulmonary Toxicity in Patients with Malignant Pleural Mesothelioma Receiving Radiation Therapy to the Intact Lungs

PurposeWe aimed to determine dose-volume constraints that correlate with severe (grade ≥3) radiation pneumonitis (RP) in patients diagnosed with malignant pleural mesothelioma, treated using volumetric modulated arc therapy. Methods and MaterialsData from 40 patients with malignant pleural mesothelioma who underwent pleurectomy decortication and adjuvant radiation therapy at our institution between December 2010 and October 2016 were retrospectively analyzed. Dosimetric variables for the absolute volume and percentage volume of the ipsilateral lung, contralateral lung, and heart were recorded. Events of RP were assessed using the Common Terminology Criteria for Toxicity and Adverse Events, version 4.0. The statistical analysis with Wilcoxon rank-sum, Spearman rank correlation, and receiver operating characteristic curves was computed using MATLAB V9.1, RV3.4, and SAS V9.4. ResultsOf the 40 patients, 26 patients (65%) were male. The median age at the time of diagnosis was 66.5 years (range, 44-84 years). The median prescription dose was 45 Gy (range, 30-54 Gy). Five patients (12.5%) had grade ≥3 RP. The incidence of grade≥ 3 RP showed a significant correlation (P < .05) with the absolute volume and percentage volume of the ipsilateral lung spared of ≥20 Gy (55 cc; 7%) and spared of ≥30 Gy (200 cc; 23%). Dosimetric variables of the contralateral lung, total lung, and heart did not show a correlation with incidence of grade ≥3 RP. ConclusionsIn our cohort, sparing the ipsilateral lung of at least 55 cc of 20 Gy and 200 cc of 30 Gy correlated with a reduced incidence of severe (grade ≥3) RP.

Risk of health-related quality-of-life events and pulmonary toxicities in patients with cancer treated with poly adenosine diphosphate ribose polymerase inhibitors: A meta-analysis of seven phase III trials.

213 Background: Poly adenosine diphosphate ribose polymerase (PARP) enzymes aide in the repair of DNA damage. PARP inhibitors showed synthetic lethality in cancer cells and were utilized in many solid tumors with notable toxicities. Fatigue and pain are the major determinants of health-related quality of life (HRQOL) in cancer patients undergoing chemotherapy. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of HRQOL events and pulmonary toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018 were queried. Phase III RCTs that mention HRQOL events and pulmonary toxicities as adverse effects were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: 3188 patients from 7 phase III RCTs with breast, ovarian, and gastric cancer were eligible. Studies compared olaparib or niraparib or rucaparib versus placebo, olaparib vs single agent chemotherapy, iniparib + gemcitabine / carboplatin (GC) versus GC, veliparib + C versus C and olaparib + paclitaxel versus paclitaxel. The RR of all-grade side effects were as follows: fatigue, 1.26 (95% CI: 1.07 – 1.49, P = 0.006); decreased appetite, 1.42 (95% CI: 1.18 – 1.71, P &lt; 0.001); arthralgia, 1.05 (95% CI: 0.83 – 1.34, P = 0.65); headache, 1.35 (95% CI: 0.99 – 1.84, P = 0.05); cough, 1.75 (95% CI: 1.17 – 2.62, P = 0.006); dyspnea, 1.40 (95% CI: 0.90 – 2.18, P = 0.12); and upper respiratory infections, 1.70 (95% CI: 0.97 – 3.00, P = 0.06). The RR of high-grade side effects were as follows: fatigue, 1.94 (95% CI: 1.24 – 3.04, P = 0.004); arthralgia, 1.37 (95% CI: 0.29 – 6.51, P = 0.68); headache, 1.09 (95% CI: 0.47 – 2.55, P = 0.83); and dyspnea, 1.02 (95% CI: 0.44 – 2.36, P = 0.95). Conclusions: The risk of developing all grades of fatigue as well as any-grade cough and decreased appetite was high in PARP inhibitors group, compared to control arm. Recognizing these toxicities and providing good supportive care is vital in enhancing patients’ quality of life.

Real World Immunotherapy Response and Pulmonary Toxicity in Patients Treated with Chest Radiation Therapy

Real World Immunotherapy Response and Pulmonary Toxicity in Patients Treated with Chest Radiation Therapy

Risk of pulmonary toxicity of bleomycin and filgrastim.

To estimate the relative risk of pulmonary toxicity in patients exposed to a bleomycin-based chemotherapy including filgrastim compared to a similar chemotherapy without filgrastim. We conducted a nested case-control study of patients treated with BEP (bleomycin, etoposide and cisplatin) for germ cell cancer or with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) for Hodgkin's lymphoma at the Hôtel-Dieu de Lévis Hospital between 31 October 2000 and 30 June 2016. The relative risk was estimated by an adjusted odds ratio (aOR) using a propensity score-adjusted regression analysis. Thirteen cases of pulmonary toxicity, representing 14.7% of the 88 patients included in the study, were matched with 65 controls. A higher proportion of women (31.8%) than men (11.3%) developed pulmonary toxicity although the difference was not statistically significant (P = 0.08). Within the cohort, two deaths related to lung toxicity were observed among cases where no filgrastim was used. The risk of pulmonary toxicity associated with the addition of filgrastim was not statistically significant (aOR = 2.48 95% CI = 0.50 to 12.19). The results add further evidence that the concomitant use of filgrastim might not increase the risk of pulmonary toxicity of bleomycin. It also suggests that female patients might be more likely to develop this adverse effect. A clinical trial would be needed to confirm this result.