Cumulative incidence and risk factors of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from IMpower130, IMpower131, and IMpower150.

BACKGROUND: The objective of this study was to explore the abilities of atezolizumab plus chemotherapy in preventing brain metastases (BMs) among metastatic non-small cell lung cancer (NSCLC) without initial BMs, as well as the risk factors of BMs. METHODS: Individual patient data from three trials involving first-line atezolizumab for metastatic NSCLC (IMpower130, IMpower131, and IMpower150) were pooled. Among patients without baseline BMs and without epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutations, those receiving atezolizumab + chemotherapy ± bevacizumab were classified as the atezolizumab plus chemotherapy group and those receiving placebo + chemotherapy ± bevacizumab were classified as the chemotherapy group. The cumulative incidences of BM (CI-BMs) between the two groups were compared. Other factors associated with the CI-BM were analyzed by Cox regression analyses. RESULTS: With a median follow-up of 17.6 months (range, 0.03-33.64 months), 74 (3.1%) of the 2380 enrolled patients developed BMs, including 50 (3.1%) and 24 (3.0%) in the atezolizumab plus chemotherapy group (n = 1589) and the chemotherapy group (n = 791), respectively. The CI-BMs at 6, 12, and 24 months were 1.7%, 2.8%, and 3.3%, respectively. After taking competing risk events into account, there was no significant difference in the CI-BMs between the two groups (p = .888). Nevertheless, the use of bevacizumab and the histology of nonsquamous NSCLC were found to be independently associated with the risk of BMs. CONCLUSIONS: In patients with metastatic EGFR/ALK wild-type NSCLC without baseline BMs, adding atezolizumab in the first-line treatment might not reduce the CI-BM. However, the administration of bevacizumab may reduce the risk of BMs.

Prognostic value of genomic mutation signature associated with immune microenvironment in southern Chinese patients with esophageal squamous cell carcinoma.

The genomic landscape of esophageal squamous cell cancer (ESCC), as well as its impact on the regulation of immune microenvironment, is not well understood. Thus, tumor samples from 92 patients were collected from two centers and subjected to targeted-gene sequencing. We identified frequently mutated genes, including TP53, KMT2C, KMT2D, LRP1B, and FAT1. The most frequent mutation sites were ALOX12B (c.1565C > T), SLX4 (c.2786C > T), LRIG1 (c.746A > G), and SPEN (c.6915_6917del) (6.5%). Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling. A 17-mutated gene-related risk model was constructed using random survival forest analysis and showed significant prognostic value in both our cohort and the validation cohort. Based on the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression (ESTIMATE) algorithm, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm, and the MCPcounter algorithm, we found that the risk score calculated by the risk model was significantly correlated with stimulatory immune checkpoints (TNFSF4, ITGB2, CXCL10, CXCL9, and BTN3A1; p < 0.05). Additionally, it was significantly associated with markers that are important in predicting response to immunotherapy (CD274, IFNG, and TAMM2; p < 0.05). Furthermore, the results of immunofluorescence double staining showed that patients with high risk scores had a significantly higher level of M2 macrophage than those with low risk scores (p < 0.05). In conclusion, our study provides insights into the genomic landscape of ESCC and highlights the prognostic value of a genomic mutation signature associated with the immune microenvironment in southern Chinese patients with ESCC.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy.

OBJECTIVES: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). RESULTS: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001). CONCLUSION: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

NGS-based Tissue-Blood TMB Comparison and Blood-TMB Monitoring in Stage-III Non-Small Cell Lung Cancer Treated with Concurrent Chemoradiotherapy.

In this study, we analyzed the blood-based TMB (b-TMB) and its dynamic changes in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received concurrent chemoradiotherapy. Baseline tissue and blood TMB from 15 patients showed a strong positive correlation (Pearson correlation = 0.937), and nearly all mutations were markedly reduced in the later course of treatment, indicating a treatment-related response. This study suggests that in patients with LA-NSCLC, b-TMB is a reliable biomarker, and its dynamic monitoring can help distinguish patients who might benefit most from the consolidated immunotherapy.

Enhancing the prediction of symptomatic radiation pneumonitis for locally advanced non-small-cell lung cancer by combining 3D deep learning-derived imaging features with dose-volume metrics: a two-center study.

OBJECTIVE: This study aims to examine the ability of deep learning (DL)-derived imaging features for the prediction of radiation pneumonitis (RP) in locally advanced non-small-cell lung cancer (LA-NSCLC) patients. MATERIALS AND METHODS: The study cohort consisted of 90 patients from the Fudan University Shanghai Cancer Center and 59 patients from the Affiliated Hospital of Jiangnan University. Occurrences of RP were used as the endpoint event. A total of 512 3D DL-derived features were extracted from two regions of interest (lung-PTV and PTV-GTV) delineated on the pre-radiotherapy planning CT. Feature selection was done using LASSO regression, and the classification models were built using the multilayered perceptron method. Performances of the developed models were evaluated by receiver operating characteristic curve analysis. In addition, the developed models were supplemented with clinical variables and dose-volume metrics of relevance to search for increased predictive value. RESULTS: The predictive model using DL features derived from lung-PTV outperformed the one based on features extracted from PTV-GTV, with AUCs of 0.921 and 0.892, respectively, in the internal test dataset. Furthermore, incorporating the dose-volume metric V30Gy into the predictive model using features from lung-PTV resulted in an improvement of AUCs from 0.835 to 0.881 for the training data and from 0.690 to 0.746 for the validation data, respectively (DeLong p < 0.05). CONCLUSION: Imaging features extracted from pre-radiotherapy planning CT using 3D DL networks could predict radiation pneumonitis and may be of clinical value for risk stratification and toxicity management in LA-NSCLC patients. CLINICAL RELEVANCE STATEMENT: Integrating DL-derived features with dose-volume metrics provides a promising noninvasive method to predict radiation pneumonitis in LA-NSCLC lung cancer radiotherapy, thus improving individualized treatment and patient outcomes.

STING signaling activation modulates macrophage polarization via CCL2 in radiation-induced lung injury.

BACKGROUND: Radiation-induced lung injury (RILI) is a prevalent complication of thoracic radiotherapy in cancer patients. A comprehensive understanding of the underlying mechanisms of RILI is essential for the development of effective prevention and treatment strategies. METHODS: To investigate RILI, we utilized a mouse model that received 12.5 Gy whole-thoracic irradiation. The evaluation of RILI was performed using a combination of quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), histology, western blot, immunohistochemistry, RNA sequencing, and flow cytometry. Additionally, we established a co-culture system consisting of macrophages, lung epithelial cells, and fibroblasts for in vitro studies. In this system, lung epithelial cells were irradiated with a dose of 4 Gy, and we employed STING knockout macrophages. Translational examinations were conducted to explore the relationship between STING expression in pre-radiotherapy lung tissues, dynamic changes in circulating CCL2, and the development of RILI. RESULTS: Our findings revealed significant activation of the cGAS-STING pathway and M1 polarization of macrophages in the lungs of irradiated mice. In vitro studies demonstrated that the deficiency of cGAS-STING signaling led to impaired macrophage polarization and RILI. Through RNA sequencing, cytokine profiling, and rescue experiments using a CCL2 inhibitor called Bindarit, we identified the involvement of CCL2 in the regulation of macrophage polarization and the development of RILI. Moreover, translational investigations using patient samples collected before and after thoracic radiotherapy provided additional evidence supporting the association between cGAS-STING signaling activity, CCL2 upregulation, and the development of radiation pneumonitis. CONCLUSIONS: The cGAS-STING signaling pathway plays a crucial role in regulating the recruitment and polarization of macrophages, partly through CCL2, during the pathogenesis of RILI.

Caution against simultaneous integrated boost radiotherapy for upper thoracic esophageal squamous cell carcinoma: results from a single-arm phase II trial.

PURPOSE: To explore the feasibility and safety of simultaneous integrated boost technology (SIB) with elective nodal irradiation (ENI) to the cervical and upper mediastinal lymph node (LN) regions in upper thoracic esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS: Patients with pathologically proven unresectable upper thoracic ESCC were assigned 50.4 Gy/28 fractions (F) to the clinical target volume (encompassing the ENI area of cervical and upper mediastinal LN regions) and a boost of 63 Gy/28 F to the gross tumor volume. Chemotherapy consisted of courses of concurrent cisplatin (20 mg/m2) and docetaxel (20 mg/m2) weekly for 6 weeks. The primary endpoint was toxicity. RESULTS: Between Jan 2017 and Dec 2019, 28 patients were included. The median follow-up time for all patients was 24.6 months (range 1.9-53.5). Radiation-related acute toxicity included esophagitis, pneumonia and radiodermatitis, all of which were well managed and reversed. Late morbidity included esophageal ulcer, stenosis, fistula and pulmonary fibrosis. Grade III esophageal stenosis and fistula was seen in 11% (3/28) and 14% (4/28) patients, respectively. The cumulative incidence rate of late esophageal toxicity was 7.7%, 19.2% and 24.6% at 6, 12 and 18 months, respectively. There was significant difference of the occurrence of severe late esophageal toxicity among the different volume levels of the esophagus, and cervical and upper mediastinal LNs which received ≥ 63 Gy stratified by the tertiles (p = 0.014). CONCLUSIONS: Despite the acceptably tolerated acute toxicity of SIB in concurrent CRT with ENI to the cervical and upper mediastinal LN regions for upper thoracic ESCC, the incidence of severe late esophageal toxicity was relatively high. Cautions are provided against easy clinical application of SIB (50.4 Gy/28F to the CTV, 63 Gy/28F to the GTV) in upper thoracic ESCC. Further exploration on dose optimization is warranted.

Overall survival benefit of osimertinib and clinical value of upfront cranial local therapy in untreated EGFR-mutant nonsmall cell lung cancer with brain metastasis.

Osimertinib, as a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), showed more potent efficacy against brain metastasis (BM) in untreated EGFR-mutant nonsmall cell lung cancer (NSCLC) in the FLAURA study. However, the overall survival (OS) benefit of osimertinib and clinical value of cranial local therapy (CLT) in these patients remain undetermined. Here we conducted a retrospective study involving untreated EGFR-mutant NSCLC patients with BMs receiving first-line osimertinib or first-generation EGFR-TKIs. Upfront CLT was defined as CLT performed before disease progression to the first-line EGFR-TKIs. Pattern of treatment failure and survival outcomes were extensively investigated. Among the 367 patients enrolled, first-generation EGFR-TKI was administered in 265, osimertinib in 102 and upfront CLT performed in 140. Patients receiving osimertinib had more (P < .001) and larger BMs (P = .003) than those receiving first-generation EGFR-TKIs. After propensity score matching, osimertinib was found to prolong OS (37.7 vs 22.2 months, P = .027). Pattern of failure analyses found that 51.8% of the patients without upfront CLT developed their initial progressive disease (PD) in the brain and 59.0% of the cranial PD occurred at the original sites alone, suggesting potential clinical value of upfront CLT. Indeed, upfront stereotactic radiosurgery (SRS) and/or surgery was associated with improved OS among those receiving first-generation EGFR-TKIs (P = .019) and those receiving osimertinib (P = .041). In summary, compared to first-generation EGFR-TKIs, osimertinib is associated with improved OS in untreated EGFR-mutant NSCLC with BMs. Meanwhile, upfront SRS and/or surgery may provide extra survival benefit, which needs to be verified in future studies.

A brief report on incidence, radiographic feature and prognostic significance of brain MRI changes after anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer.

INTRODUCTION: Neurologic immune-related adverse events (nirAEs) are uncommon but potentially lethal complications of immune checkpoint inhibitor (ICI) treatment. However, the incidence, radiographic features and prognostic significance of brain magnetic resonance imaging (MRI) changes after ICI treatment remain largely unknown. METHODS: Consecutive patients with advanced non-small cell lung cancer (NSCLC) at three participating institutions receiving anti-PD-1/PD-L1 therapy from June 2017 to September 2020 were screened, and those who received brain MRI within 6 weeks before ICI initiation and at least one follow-up brain MRI after ICI treatment were included. Serial brain MRI images were independently reviewed by two experienced radiologists. RESULTS: With a median follow-up of 13.2 months, 27 (20.0%) of the 135 enrolled patients developed certain kind of brain MRI aberration. The 1-, 2- and 3-year cumulative incidence of brain MRI aberration was 17.1%, 36.3% and 52.2%, respectively. Brain MRI aberration indicative of stroke, mimicking typical white matter lesions and presenting as T2-hyperintensity suggestive of CNS vasculitis or encephalitis, was documented in 11, 9 and 4 patients, respectively. Patients with brain MRI aberration had higher clinical benefit rate (p = 0.030), longer progression-free survival (p = 0.015) and a tendency of improved overall survival (p = 0.054). CONCLUSIONS: Brain MRI aberrations developed after ICI treatment are not uncommon, and their manifestations vary a lot. Patients developing brain MRI aberrations tended to have better prognosis, which needed to be further investigated.

Clinical outcomes of advanced non-small cell lung cancer patients harboring distinct subtypes of EGFR mutations and receiving first-line tyrosine kinase inhibitors: brain metastasis and de novo T790M matters.

BACKGROUND: The clinical features, survival outcomes and patterns of treatment failure of advanced non-small cell lung cancer (NSCLC) patients harboring distinct subtypes of EGFR mutations and receiving first-line EGFR tyrosine kinases inhibitor (TKIs) are not fully understood. METHODS: Consecutive metastatic EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs from October 2010 to March 2020 were enrolled and classified into two main groups based on the EGFR mutation subtypes: common mutation (L858R or exon 19 deletion), uncommon mutation (other EGFR mutations). RESULTS: Of the 1081 patients included, 74 (6.8%) harbored uncommon mutations. The baseline characteristics were generally balanced between the two groups, except that bone metastasis developed less frequently in patients with uncommon mutations (p = 0.02). No significant difference of survival outcomes was found between the two groups, except that among patients with baseline brain metastasis, the intracranial time to progression was significantly shorter in patients with uncommon mutations. Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). The patterns of treatment failure were generally consistent between the two groups, except which patients with uncommon mutations had a higher risk developing progressive disease in the brain. CONCLUSION: First-line EGFR-TKIs seemed to be less effective in controlling and preventing brain metastasis in patients with uncommon EGFR mutations and Osimertinib was associated with promising efficacy in patients with de novo T790M mutation, which warranted further validation.

Promoter Methylation-mediated Silencing of the MiR-192-5p Promotes Endometrial Cancer Progression by Targeting ALX1.

Background: Epigenetic regulation by promoter methylation-mediated silencing of cancer-related microRNAs plays vital roles in tumorigenesis. MiR-192-5p promotes tumor progression in various human cancers with conflicting biological effects. However, its expression levels and biological functions in endometrial carcinoma (EC) have not been reported. Methods: The methylation status of miR-192-5p in tissue samples and cell lines, was examined using bisulfite sequencing PCR. miR-192-5p expression was also measured. EC cell lines transfected with specifically designed vectors overexpressing miR-192-5p, its target gene ALX1 or both, were constructed. Tumorigenicity of these cell lines were examined by in vitro and in vivo experiments. Dual-luciferase reporter assay were employed to verify the target of miR-192-5p. Results: The promoter region of miR-192-5p gene was highly methylated and its expression significantly repressed in EC samples. Moreover, a higher level of promoter methylation as well as a lower expression of miR-192-5p, was significantly associated with advanced Federation of Gynecology and Obstetrics stage and shorter disease-free survival in patients with curatively resected EC. Functional studies demonstrated that miR-192-5p overexpression inhibited in vitro tumor progression, in vivo tumorigenicity and the expression of several oncoproteins that was highly related to epithelial-to-mesenchymal transition. ALX1 was verified as a direct target of miR-192-5p and demonstrated to mediate the tumor-suppressive function of miR-192-5p. Conclusion: miR-192-5p is a tumor suppressor miRNA that is epigenetically silenced by promoter methylation and may serve as a potential prognostic biomarker in EC.

Predicting the Value of Adjuvant Therapy in Esophageal Squamous Cell Carcinoma by Combining the Total Number of Examined Lymph Nodes with the Positive Lymph Node Ratio.

BACKGROUND: The value of adjuvant therapy for esophageal squamous cell carcinoma (ESCC) has been controversial, at least partially due to the lack of efficient criteria for selecting suitable patients. This study aimed to explore the existence of parameters related to lymph node (LN) status that can predict the value of adjuvant therapy in ESCC. METHODS: The study included 298 patients with ESCC who had undergone radical esophagectomy with lymphadenectomy. Adjuvant therapy was defined as reception of adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. For the study, LN ratio (LNR), total number of resected LNs (TLNs), and pN stage were selected for Cox regression analyses, including their correlations and prognostic values for survival. Log-rank tests were used to compare the survival rates of the patients with and without adjuvant therapy stratified by pN stage, TLNs, LNR, or their combinations. RESULTS: The independent prognostic factors for survival were TLNs, LNR, and pN stage. Whereas pN stage was significantly related to TLNs and LNR, TLNs were not correlated with LNR. The survival rates between the patients with and those without adjuvant therapy stratified by pN stage, TLNs, or LNR did not differ significantly. We used the median values of TLNs and LNR to group the patients into four groups. The patients in the group with fewer TLNs and higher LNR who had undergone adjuvant therapy showed a significantly better survival than those without adjuvant therapy (p = 0.030). CONCLUSIONS: In contrast to TLNs, LNR, and pN stage as single factors, the combination of TLNs and LNR can predict the value of adjuvant therapy.

Construction and characterization of regulated cycle inhibiting factors induced upon Tet-On system in human colon cancer cell lines.

A previous study has proven that cycle inhibiting factors (Cifs) inhibit Cullin E3 ubiquitin ligases, resulting in cell cycle arrest. More importantly, Cifs are also involved in cancer progression by deamidating Nedd8. Here we aimed to explore a novel insight into the treatment implications of Cifs in colon cancers by Tet-on system. The anticancer activity of Cif by doxycycline induction was investigated in the colon cell lines based upon Tet-On system. The expression of Cif in the colon cancer cells was determined by western blot. Furthermore, the cell viability and flow cytometry analysis were respectively performed to evaluate the cell proliferation and survival of colon cells. More importantly, the p21 and p27 levels were also evaluated after the induction of Cif with Tet-On system. Multiple clones of colon cancer cells for doxycycline-regulated Cif expression were constructed for maintenance purposes including HCT116 and SW480 cell lines. The result of western blot displayed good inducibility of expressing Cif in the cell lines. The clones with Cif preserved their transformed phenotype compared with the control group (clones with GFP or with Cif), in terms of the inhibition of cancer cell proliferation and survival. Furthermore, western blot analysis showed that p27 and p21 were accumulated in the clones with Cif, compared with the colon cancer cell lines with GFP or with Cif. Using the Tet-On system, we developed an efficient approach toward generation of colon cancer cells induced with Cif. These engineered colons tightly controlled Cif expression in vitro, which is a good inducible model system for cancer treatment.

Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma.

Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4+ and CD8+ T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Pamiparib as consolidation treatment after concurrent chemoradiotherapy of limited-stage small cell lung cancer: a single-arm, open-label phase 2 trial.

BACKGROUND: Small cell lung cancer (SCLC) is highly invasive with poor prognosis, and its treatment has historically been hindered due to the absence of targetable driver genomic alterations. However, the high genomic instability and replication stress in SCLC have made poly(ADP-ribose) polymerases (PARPs) inhibitors a focus of research. Pamiparib is an orally available PARP1/2 inhibitor with high selectivity, strong PARP trapping activity, and excellent brain penetration. Utilizing pamiparib as consolidation maintenance therapy in limited-stage SCLC holds promise for improving survival outcomes and offering a viable therapeutic approach. METHODS: This single-arm, open-label phase II trial will enroll patients aged 18-75 years with histologically/cytologically confirmed, limited-stage SCLC who have not progressed following definitive platinum-based cCRT and have an ECOG PS of 0 or 1. Patients will be excluded if they have histologically confirmed mixed SCLC or NSCLC, or have undergone previous tumor resection, or can be treated with surgery or stereotactic body radiation therapy/stereotactic ablative radiation therapy. Participants will receive pamiparib 40 mg twice daily every 3 weeks within 2 to 6 weeks after cCRT for up to 1 year or until disease progression according to RECIST v1.1. The primary endpoint is the 1-year progression-free survival (PFS) rate assessed by investigators per RECIST v1.1. Secondary endpoints include PFS, objective response rate, and duration of response assessed by investigators per RECIST 1.1, overall survival, time to distant metastasis, and safety. DISCUSSION: The study will provide valuable data on the feasibility, safety, and effectiveness of pamiparib as a consolidation therapy after cCRT in patients with LS-SCLC. The correlation between molecular typing or gene expression profile of the disease and curative response will be further explored. TRIAL REGISTRATION: NCT05483543 at clinicaltrials.gov.

Potential synergistic effects of cranial radiotherapy and atezolizumab in non-small cell lung cancer: an analysis of individual patient data from seven prospective trials.

Background: The impact of cranial radiotherapy (RT) on overall survival (OS) of patients with brain metastasis (BM) from non-small cell lung cancer (NSCLC) receiving programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors remains unclear. We aimed to examine the effect of previous cranial RT on the efficacy and neurological toxicity of PD-1/PD-L1 inhibitors in the treatment of patients with NSCLC. Methods: Patient-level data from seven prospective trials involving atezolizumab for the treatment of NSCLC [BIRCH (NCT02031458), FIR (NCT01846416), IMpower130 (NCT02367781), IMpower131 (NCT02367794), IMpower150 (NCT02366143), OAK (NCT02008227), and POPLAR (NCT01903993)] were pooled. Patients with baseline BM were divided into two subgroups based on previous cranial RT before initiation of treatment: patients with previously irradiated BM (iBM) and patients with non-irradiated BMs (niBM). Results: The per-protocol population consisted of 4,714 patients, including 3,176 in the atezolizumab group and 1,538 in the comparator chemotherapy group. In the atezolizumab group, OS was better in patients with BM (n=308) compared to patients without BM (n=2,868) [hazard ratio (HR): 0.83; 95% confidence interval (CI): 0.70-0.98; P=0.028]. Among patients with BM, patients with iBM (n=280) had a numerically longer OS (HR: 0.66; 95% CI: 0.41-1.07; P=0.090) than those with niBM (n=28). Intriguingly, OS was longer in patients with iBM than those without BM before (HR: 0.83; 95% CI: 0.70-0.99; P=0.043) and after (HR: 0.40; 95% CI: 0.32-0.49; P<0.0001) propensity score matching, while OS was similar between patients with niBM and those without BM. The survival advantage of patients with iBM over those without BM was not observed in the chemotherapy group. Atezolizumab-related serious neurological adverse events occurred in 16 (0.6%) patients without BM, none in those with niBM, and 2 (0.7%) patients with iBM. Conclusions: These data suggest potential synergistic effects of cranial RT and anti-PD-(L)1 therapy in NSCLC patients, which warrants further validation.

Predicting regional recurrence and prognosis in stereotactic body radiotherapy-treated clinical stage I non-small cell lung cancer using a radiomics model constructed with surgical data.

BACKGROUND: Risk stratification of regional recurrence (RR) is clinically important in the design of adjuvant treatment and surveillance strategies in patients with clinical stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). PURPOSE: To develop a radiomics model predicting occult lymph node metastasis (OLNM) using surgical data and apply it to the prediction of RR in SBRT-treated early-stage NSCLC patients. METHODS: Patients with clinical stage I NSCLC who underwent curative surgery with systematic lymph node dissection from January 2013 to December 2018 (the training cohort) and from January 2019 to December 2020 (the validation cohort) were included. A pre-operative CT-based radiomics model, a clinical feature model, and a fusion model predicting OLNM were constructed. The performance of the three models was quantified and compared in the training and validation cohorts. Subsequently, the radiomics model was used to predict RR in a cohort of consecutive SBRT-treated early-stage NSCLC patients from two academic medical centers. RESULTS: A total of 769 patients were included. Eight CT features were identified in the radiomics model, achieving areas under the curves (AUCs) of 0.85 (95% CI 0.81-0.89) and 0.83 (95% CI 0.80-0.88) in the training and validation cohorts, respectively. Nevertheless, adding clinical features did not improve the performance of the radiomics model. With a median follow-up of 40.0 (95% CI 35.2-44.8) months, 32 of the 213 patients in the SBRT cohort developed RR and those in the high-risk group based on the radiomics model had a higher cumulative incidence of RR (p<0.001) and shorter regional recurrence-free survival (p=0.02), progression-free survival (p=0.004) and overall survival (p=0.006) than those in the low-risk group. CONCLUSION: The radiomics model based on pathologically confirmed data effectively identified patients with ONLM, which may be useful in the risk stratification among SBRT-treated patients with clinical stage I NSCLC.

A PET/CT radiomics model for predicting distant metastasis in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy: a multicentric study.

OBJECTIVES: Stereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT. METHODS: Patients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups. RESULTS: In total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P < 0.001). CONCLUSIONS: The proposed PET/CT radiomics model can be used to predict distant metastasis in patients with early-stage NSCLC treated with SBRT and provide a reference for clinical decision-making. In this study, the model was established by combining CT and PET radiomics signatures in a moderate-quantity training cohort of early-stage NSCLC patients treated with SBRT and was successfully validated in independent cohorts. Physicians could use this easy-to-use model to assess the risk of distant metastasis after SBRT. Identifying subgroups of patients with different risk factors for distant metastasis is useful for guiding personalized treatment approaches.

A "Seed-and-Soil" Radiomics Model Predicts Brain Metastasis Development in Lung Cancer: Implications for Risk-Stratified Prophylactic Cranial Irradiation.

Introduction: Brain is a major site of metastasis for lung cancer, and effective therapy for developed brain metastasis (BM) is limited. Prophylactic cranial irradiation (PCI) has been shown to reduce BM rate and improve survival in small cell lung cancer, but this result was not replicated in unselected non-small cell lung cancer (NSCLC) and had the risk of inducing neurocognitive dysfunctions. We aimed to develop a radiomics BM prediction model for BM risk stratification in NSCLC patients. Methods: 256 NSCLC patients with no BM at baseline brain magnetic resonance imaging (MRI) were selected; 128 patients developed BM within three years after diagnosis and 128 remained BM-free. For radiomics analysis, both the BM and non-BM groups were randomly distributed into training and testing datasets at an 70%:30% ratio. Both brain MRI (representing the soil) and chest computed tomography (CT, representing the seed) radiomic features were extracted to develop the BM prediction models. We first developed the radiomic models using the training dataset (89 non-BM and 90 BM cases) and subsequently validated the models in the testing dataset (39 non-BM and 38 BM cases). A radiomics BM score (RadBM score) was generated, and BM-free survival were compared between RadBM score-high and RadBM score-low groups. Results: The radiomics model developed from baseline brain MRI features alone can predict BM development in NSCLC patients. A fusion model integrating brain MRI features with primary tumor CT features (seed-and-soil model) provided synergetic effect and was more efficient in predicting BM (areas under the receiver operating characteristic curve 0.84 (95% confidence interval: 0.80−0.89) and 0.80 (95% confidence interval: 0.71−0.88) in the training and testing datasets, respectively). BM-free survival was significantly shorter in the RadBM score-high group versus the RadBM score-low group (Log-rank, p < 0.001). Hazard ratios for BM were 1.056 (95% confidence interval: 1.044−1.068) per 0.01 increment in RadBM score. Cumulative BM rates at three years were 75.8% and 24.2% for the RadBM score-high and RadBM score-low groups, respectively. Only 1.2% (7/565) of the BM lesions were located within the hippocampal avoidance region. Conclusion: The results demonstrated that intrinsic features of a non-metastatic brain exert a significant impact on BM development, which is first-in-class in metastasis prediction studies. A radiomics BM prediction model utilizing both primary tumor and pre-metastatic brain features might provide a useful tool for individualized PCI administration in NSCLC patients more prone to develop BM.

Pattern of failure and clinical value of local therapy for oligo-recurrence in locally advanced non-small cell lung cancer after definitive chemoradiation: Impact of driver mutation status.

INTRODUCTION: Considerable differences of treatment response and pattern of failure may exist between definitive chemoradiation (CRT) treated locally advanced non-small cell lung cancer (LA-NSCLC) patients. The clinical value of additional tyrosine kinase inhibitors (TKIs) before disease recurrence and salvage local therapy after initial recurrent disease remain controversial. METHODS AND MATERIALS: Consecutive LA-NSCLC patients receiving definitive CRT and having definite results about driver mutations (EGFR, ALK and ROS1) were retrospectively reviewed. Initial recurrent disease was classified as in-field recurrence, out-of-field recurrence and distant metastasis. Recurrent disease occurred only in the brain or limited to ≤3 extra-cranial organs and ≤5 extra-cranial lesions, was defined as oligo-recurrence. Progression free survival and overall survival (OS) were calculated from diagnosis to disease progression or death, and to death, respectively. OS2 was measured from initial disease recurrence to death among patients who had recurrent disease. RESULTS: Of the 153 enrolled patients, 39 had driver mutations and 13 received additional TKI therapy besides definitive CRT. Patients harboring driver mutations but without additional TKI therapy had a similar PFS and significantly longer OS (p = 0.032) than those without driver mutations. Additional TKI therapy prolonged PFS (p = 0.021) but not OS among patients with driver mutations. No significant difference of pattern of failure was observed between patient subgroups stratified by the status of driver mutations and the usage of additional TKI therapy. Furthermore, 57 of the 95 patients with initial recurrent disease developed oligo-recurrence and salvage local therapy significantly improved OS2 (p = 0.01) among patients with oligo-recurrence disease. CONCLUSION: LA-NSCLC patients receiving definitive CRT generally had similar PFS and pattern of treatment failure, regardless of driver mutation status. Additional TKI therapy besides definitive CRT could prolong PFS but not OS. The majority of recurrent disease after definitive CRT belongs to oligo-recurrence and salvage local therapy may provide survival benefit.