Stage IIIA Non-small Cell Lung Cancer Research Articles

Perioperative chemotherapy and nivolumab in non-small-cell lung cancer (NADIM): 5-year clinical outcomes from a multicentre, single-arm, phase 2 trial

Perioperative immunotherapy improves short-term outcomes in resectable non-small-cell lung cancer (NSCLC). We now report 5-year survival from the NADIM trial to assess its long-term benefit. NADIM was a multicentre, single-arm, phase 2 trial conducted across 18 hospitals in Spain. Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had histologically or cytologically confirmed, treatment-naive, resectable stage IIIA NSCLC (American Joint Committee on Cancer, 7th edition criteria). The neoadjuvant treatment consisted of three cycles of intravenous paclitaxel (200 mg/m2) and carboplatin (area under the curve 6 mg/mL per min) with nivolumab (360 mg). After surgery, 1 year of adjuvant treatment with intravenous nivolumab monotherapy was administered (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was 24-month progression-free survival, with 5-year progression-free survival and overall survival as secondary endpoints, assessed in the intention-to-treat population (ie, all patients who received neoadjuvant treatment). Toxicity profile was also assessed as a secondary endpoint. This trial is registered at ClinicalTrials.gov (NCT03081689) and is complete; this is the final report of the trial. Between April 26, 2017, and Aug 25, 2018, 51 patients were assessed for eligibility, of whom 46 comprised the intention-to-treat population (34 [74%] male and 12 [26%] female, median age 63 years [IQR 58-70]). Follow-up was concluded at 60 months (data cutoff July 11, 2023; median follow-up 60·0 months [IQR 60·0-60·0]). 5-year progression-free survival in the intention-to-treat population was 65·0% (95% CI 49·4-76·9), and overall survival was 69·3% (53·7-80·6). Disease progression occurred in 11 (24%) patients; 14 (30%) patients died, including nine (20%) from disease relapse and five (11%) from non-tumour-related causes. Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 14 (30%) of 46 patients during neoadjuvant treatment and in seven (19%) of 37 during adjuvant treatment. The most common grade 3 or worse TRAEs were increased lipase and febrile neutropenia (three [7%] each) during neoadjuvant treatment, and elevated serum lipase (four [7%]) and elevated serum amylase (three [8%]) during adjuvant treatment. Serious TRAEs included elevated serum lipase and neutropenia (one [2%] each) during neoadjuvant treatment, and elevated serum lipase (one [3%]) during adjuvant treatment. No treatment-related surgery delays, deaths, or unexpected long-term toxicities were reported. Perioperative chemoimmunotherapy showed a promising long-term benefit with no concerning safety data, reinforcing its use in resectable stage IIIA NSCLC. Bristol-Myers Squibb, Spanish Ministry of Science, Instituto de Salud Carlos III, European Union.

Survivorship program including long-term toxicities and quality-of-life development over 10 years in a randomized trial in operable stage III non-small-cell lung cancer (ESPATUE).

Over 40% stage-III non-small-cell lung cancer (NSCLC) patients (pts) experience 5-year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality-of-life (QoL) in the further long-term follow-up. Therefore, we invited pts from our randomized phase-III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow-up imaging, laboratory parameters, cardio-pulmonary investigations, long-term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long-term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1-year follow-up. This is the first comprehensive SSP of very late survival follow-up reported in stage-III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option.

A Single-Center Experience in Combined Oncological-Surgical Treatment for Resectable Locally Advanced Non-Small Cell Lung Cancer (NSCLC).

Non-small cell lung cancer (NSCLC) is the most common pulmonary malignancy, frequently diagnosed at an advanced stage (III/IV). Patients in the Locally Advanced Stage Subgroup (IIIA) are relatively few, yet compose heterogenic phenotypes, posing a diagnostic and treating challenge, leading to a lack of clinical guidelines regarding the optimal standard of care. Several approaches exist, with a general agreement that a combined oncological and surgical modality approach is required. In this current retrospective descriptive study, patients with operable stage IIIA NSCLC who underwent surgery between 2013 and 2020 were evaluated on several aspects, including the initial diagnosis, neoadjuvant regimens, outcomes of surgical intervention, and overall survival at 2 years and 5 years following treatment. A total of 35 patients had neoadjuvant oncological treatment (mostly chemoradiation therapy) prior to surgery, out of which 28 patients were diagnosed with stage IIIA NSCLC. In post-operative assessment of pathological staging, downstaging was reported in 19 patients, of which 25% of cases were defined as a complete pathological response. The 2-year overall survival rate was 65% and the 5-year overall survival rate was 62%. The main pattern of disease recurrence was distant metastasis.

Predicting therapeutic response to neoadjuvant immunotherapy based on an integration model in resectable stage IIIA (N2) non-small cell lung cancer

ObjectiveAccurately predicting response during neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer (NSCLC) remains clinically challenging. In this study, we investigate the effectiveness of blood-based tumor mutational burden (bTMB) and a deep learning (DL) model in predicting major pathologic response (MPR) and survival from a phase II trial. MethodsBlood samples were prospectively collected from 45 stage IIIA (N2) NSCLC patients undergoing neoadjuvant chemoimmunotherapy. An integrated model, combining the CT-based DL score, bTMB, and clinical factors, was developed to predict tumor response to neoadjuvant chemoimmunotherapy. ResultsAt baseline, bTMB were detected in 77.8% (35 of 45) of patients. Baseline bTMB ≥11 Muts/Mb was associated with significantly higher MPR rates (77.8% vs. 38.5%, p = 0.042), and longer disease-free survival (DFS, p = 0.043), but not overall survival (p = 0.131), compared to bTMB < 11 Muts/Mb in 35 patients with bTMB available. The developed DL model achieved an area under the curve (AUC) of 0.703 in all patients. Importantly, the predictive performance of the integrated model improved to an AUC of 0.820 when combining the DL score with bTMB and clinical factors. Baseline circulating tumor DNA (ctDNA) status was not associated with pathological response and survival. Compared to ctDNA residual, ctDNA clearance before surgery was associated with significantly higher MPR rates (88.2% vs. 11.1%, p < 0.001) and improved DFS (p = 0.010). ConclusionsThe integrated model shows promise as a predictor of tumor response to neoadjuvant chemoimmunotherapy. Serial ctDNA dynamics provide a reliable tool for monitoring tumor response.

Triple-induction treatment for locally advanced non-small cell lung cancer: a case report of pathological complete response

BackgroundIn patients with resectable stage III non-small cell lung cancer (NSCLC), induction chemoimmunotherapy followed by surgical resection has shown unprecedented rates of pathological response and event-free survival. However, a triple-induction including radiochemotherapy and immunotherapy followed by surgical resection has not been routinely established in clinical practice.Case presentationWe report the case of a 47-year-old patient with stage IIIA NSCLC who was treated in a combined concept including induction concurrent radiochemotherapy, followed by 4 cycles of pembrolizumab and subsequent intrapericardial left-sided pneumonectomy. Histological analysis revealed a pathological complete response.ConclusionsThe case demonstrates that the combination of neoadjuvant chemo-, radio- and immunotherapy in advanced NSCLC may lead to a relevant down-staging and may enable a R0-resection of a borderline resectable tumor. However, the combination of four different treatment modalities requires resilience and a good performance status. A triple induction treatment may be a promising option for selected patients with locally advanced NSCLC and good performance status.

Abstract CT281: The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC)

Abstract Background: Pembrolizumab (pembro; anti-PD-1) is indicated as adjuvant monotherapy following resection and adjuvant chemotherapy in patients (pts) with stage IB (T2a ≥4 cm), II, or IIIA NSCLC (per AJCC v7). However, many pts experience disease recurrence, and have limited treatment options available. V940 (mRNA-4157) is a novel individualized neoantigen therapy that encodes up to 34 neoantigens that is specifically tailored and manufactured for each pt derived from their tumor. V940 as monotherapy and in combination with pembro has shown preliminary antitumor activity in the phase 1 KEYNOTE-603 study in several solid tumor types, including NSCLC. Additionally, in pts with completely resected, high-risk stage IIIB/C/D and IV cutaneous melanoma in the KEYNOTE-942 primary analysis, V940 plus pembro demonstrated significant improvements in recurrence-free survival (HR, 0.561 [95% CI, 0.309-1.017]; P = 0.0266) and distant metastasis-free survival (HR, 0.347 [95% CI, 0.145-0.828]; P = 0.0063) vs pembro alone. Here we present the design of the phase 3, randomized, double-blind INTerpath-002 study (NCT06077760) of adjuvant V940 plus pembro vs placebo plus pembro in pts with completely resected and chemotherapy-treated stage II-IIIB (N2) NSCLC (AJCC v8). Methods: Eligible pts aged ≥18 years with completely resected stage II, IIIA, or IIIB (N2) squamous or nonsquamous NSCLC (per AJCC v8.0) where EGFR-directed therapy is not indicated as primary therapy (ie, absence of sensitizing EGFR mutations e.g. DEL19 or L858R), who have received 1-4 doses of adjuvant platinum-doublet chemotherapy, have ECOG PS 0 or 1, and have available tumor tissue for next-generation sequencing and PD-L1 testing will be enrolled. Pts must not have received previous neoadjuvant therapy for NSCLC and must not have received or be candidates for adjuvant radiotherapy. Pts will be randomized 1:1 to receive V940 1 mg IM or placebo Q3W for up to 9 doses plus pembro 400 mg IV Q6W for up to 9 cycles or until disease recurrence, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (squamous vs nonsquamous), PD-L1 TPS (&amp;lt;1% vs 1%-49% vs ≥50%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). The primary endpoint is disease-free survival per investigator review. Secondary endpoints include distant metastasis-free survival per investigator assessment, OS, lung cancer‒specific survival, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter. Enrollment began in October 2023 and is ongoing globally (NCT06077760). Citation Format: Jonathan D. Spicer, Santosh M. Nair, Adnan Khattak, Jay M. Lee, Michelle Brown, Robert S. Meehan, Nazly Shariati, Xuan Deng, Ayman Samkari, Jamie E. Chaft. The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT281.

Real-world treatment patterns and clinical outcomes in patients with stage III NSCLC in Korea: The KINDLE study.

KINDLE-Korea is part of a real-world KINDLE study that aimed to characterize the treatment patterns and clinical outcomes of patients with stage III non-small cell lung cancer (NSCLC). The KINDLE was an international real-world study that explores patient and disease characteristics, treatment patterns, and survival outcomes. The KINDLE-Korea included stage III NSCLC patients diagnosed between January 2013 and December 2017. A total of 461 patients were enrolled. The median age was 66 years (range: 24-87). Most patients were men (75.7%) with a history of smoking (74.0%), stage IIIA NSCLC (69.2%), and unresectable disease (52.9%). A total of 24.3% had activating EGFR mutation and 62.2% were positive for PDL1 expression. Broadly categorized, 44.6% of the patients received chemoradiation (CRT)-based therapy, 35.1% underwent surgery, and 20.3% received palliative therapies as initial treatment. The most commonly adopted approaches for patients with stage IIIA and IIIB disease were surgery and CRT, respectively. The median PFS was 15.2 months and OS was 66.7 months. Age >65 years, adenocarcinoma histology, and surgery as the initial treatment were significantly associated with longer OS. This study revealed the heterogeneity of treatment patterns and survival outcomes in patients with stage III NSCLC before durvalumab consolidation came into clinical practice. There is an unmet need for patients who are not eligible for surgery as an initial therapy. Novel therapeutic approaches are highly warranted to improve clinical outcomes.

Disparities in Access to Multidisciplinary Cancer Consultations and Treatment for Patients With Early-Stage Non-Small Cell Lung Cancer: A SEER-Medicare Analysis

PurposeDisparities in access to multidisciplinary cancer consultations (MDCc) persist, and the role of physician relationships remains understudied. This study examined the extent to which multilevel factors, including patient characteristics and patient-sharing network measures reflecting the structure of physician relationships, are associated with MDCc and receipt of stereotactic body radiation therapy (SBRT) versus surgery among early-stage non-small cell lung cancer (NSCLC) patients. Materials and MethodsIn this cross-sectional study, we analyzed Surveillance, Epidemiology, and End-Result (SEER)-Medicare data for patients diagnosed with stage I-IIA NSCLC in 2016-2017. We assembled patient-sharing networks and identified cancer specialists who were locally unique for their specialty, herein referred to as “linchpins”. The proportion of linchpin cancer specialists for each hospital referral region (HRR) was calculated as a network-based measure of specialist scarcity. We used multilevel multinomial logistic regression to estimate associations between study variables and the receipt of MDCc and multilevel logistic regression to examine the relationship between MDCc and patient's first treatment. ResultsOur study included 6,120 patients with stage I-IIA NSCLC, of which 751 (12.3%) received MDCc, 1,729 (28.3%) only consulted a radiation oncologist, 2,010 (32.8%) only consulted a surgeon, and 1,630 (26.6%) had no consultations with either specialist within two months following diagnosis. Compared with patients residing in an HRR with a low proportion of linchpin surgeons, those in an HRR with a high proportion of linchpin surgeons had a 2.99 (95% CI: 1.87-4.78) greater relative risk of exclusively consulting a radiation oncologist (vs. MDCc) and a 2.70 (95% CI: 1.68-4.35) greater relative risk consulting neither specialist (vs. MDCc). Patients who received MDCc were 5.32 (95% CI: 4.27-6.63) times more likely to receive SBRT (vs. surgery). ConclusionsPhysician networks are associated with receipt of MDCc and treatment, underscoring the potential for leveraging patient-sharing network analysis to improve access to lung cancer care.

Systematic endoscopic staging of mediastinum to guide radiotherapy planning in patients with locally advanced non-small-cell lung cancer (SEISMIC): an international, multicentre, single-arm, clinical trial

Systematic mediastinal lymph node staging by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) improves accuracy of staging in patients with early-stage non-small-cell lung cancer (NSCLC). However, patients with locally advanced NSCLC commonly undergo only selective lymph node sampling. This study aimed to determine the proportion of patients with locally advanced NSCLC in whom systematic endoscopic mediastinal staging identified PET-occult lymph node metastases, and to describe the consequences of PET-occult disease on radiotherapy planning. This prospective, international, multicentre, single-arm, international study was conducted at seven tertiary lung cancer centres in four countries (Australia, Canada, the Netherlands, and the USA). Patients aged 18 years or older with suspected or known locally advanced NSCLC underwent systematic endoscopic mediastinal lymph node staging before combination chemoradiotherapy or high-dose palliative radiotherapy. The primary endpoint was the proportion of participants with PET-occult mediastinal lymph node metastases shown following systematic endoscopic staging. The study was prospectively registered with Australian New Zealand Clinical Trials Registry, ACTRN12617000333314. From Jan 30, 2018, to March 23, 2022, 155 patients underwent systematic endoscopic mediastinal lymph node staging and were eligible for analysis. 58 (37%) of patients were female and 97 (63%) were male. Discrepancy in extent of mediastinal disease identified by PET and EBUS-TBNA was observed in 57 (37% [95% CI 29-44]) patients. PET-occult lymph node metastases were identified in 18 (12% [7-17]) participants, including 16 (13% [7-19]) of 123 participants with clinical stage IIIA or cN2 NSCLC. Contralateral PET-occult N3 disease was identified in nine (7% [2-12]) of 128 participants staged cN0, cN1, or cN2. Identification of PET-occult disease resulted in clinically significant changes to treatment in all 18 patients. In silico dosimetry studies showed the median volume of PET-occult lymph nodes receiving the prescription dose of 60 Gy was only 10·1% (IQR 0·1-52·3). No serious adverse events following endoscopic staging were reported. Our findings suggests that systematic endoscopic mediastinal staging in patients with locally advanced or unresectable NSCLC is more accurate than PET alone in defining extent of mediastinal involvement. Standard guideline-recommended PET-based radiotherapy planning results in suboptimal tumour coverage. Our findings indicate that systematic endoscopic staging should be routinely performed in patients with locally advanced NSCLC being considered for radiotherapy to accurately inform radiation planning and treatment decision making in patients with locally advanced NSCLC. None.

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.

NEOADJUVANT CHEMORADIOTHERAPY IN THE MULTIMODALITY TREATMENT OF STAGE IIIA(N2) NON-SMALL CELL LUNG CANCER (NSCLC)

Summary. The choice of optimal treatment for stage IIIA(N2) non-small cell lung cancer (NSCLC) remains controversial, since the five-year survival rate of this category of patients cannot meet modern medical requirements and patient expectations even after radical surgery and chemotherapy (CT). Accordingly, the analysis of available clinical data and the search for the most effective multimodal treatment option are constantly ongoing. The main treatment strategy for stage IIIA(N2) NSCLC is surgery with induction CT. As part of a comprehensive clinical approach, neoadjuvant CT (NCT) is used to eliminate distant micrometastases, leading to increased survival in an independent operation. Meanwhile, induction with concurrent chemoradiotherapy (CRT) followed by surgery resulted in a 30% to 40% improvement in 5-year survival. Aim: to evaluate the results of treatment of patients with stage IIIA(N2) NSCLC after the use of various methods of neoadjuvant and adjuvant therapy in case of surgical intervention. Object and methods: the effect of NCRT was performed in 37 patients with stage IIIA(N2) NSCLC in selected tumors of the lungs and the middle of the National Cancer Institute. This group of patients was planned for multimodal treatment, which included 3 or 4 cycles of chemotherapy with platinum-based drugs following the regimens of cisplatin + docetaxel or carboplatin + paclitaxel with one-hour radiotherapy (RT), consisting of sessions in the or classical fractionation with a single dose of 2 Gy, SOD up to 50 Gy with subsequent surgery. The number of CT cycles (3 or 4) depended on the result of the control observation of the dynamics of regression of the tumor process. In the core of the vicoristan group, there was the first control group of stage IIIA(N2) NSCLC patients with NCT (n = 194). This group of patients was given 3 or 4 courses of CT using a regimen similar to the main group: cisplatin / carboplatin + docetaxel / paclitaxel, and in the second control group – similar to the number of courses and drugs, neoadjuvant CT and RT in SOD 50 Gy in adjuvant regimen (n = 60) with further surgical treatments. All patients, depending on the prevalence of the tumor process, underwent radical surgery in the form of lobectomy, bilobectomy or pneumonectomy with mediastinal lymphodissection. Results: median survival in the main group was 30.12 months, in the first control group (NCT) – 23.68 months and the second control group (NCT + adjuvant RT) – 23.23 months, respectively. In the main group, 5 (14.7%) patients were diagnosed with a complete morphological response of the primary tumor and a complete morphological response of the tumor tissue in the regional lymph nodes. In addition to the complete morphological response of the primary tumor and metastatic mediastinal lymph nodes (tumor cells were not detected in histological preparations), in 5 (14.7%) cases, a pronounced morphological response of a highly differentiated tumor was detected (residual viability of tumor tissue to 12±5%). These patients had a higher median survival (45 and 39 months, respectively) compared to controls. Conclusion: the treatment regimen with NCRT is more promising for increasing patient survival.

Deep pathomics: A new image-based tool for predicting response to treatment in stage III non-small cell lung cancer.

Despite the advantages offered by personalized treatments, there is presently no way to predict response to chemoradiotherapy in patients with non-small cell lung cancer (NSCLC). In this exploratory study, we investigated the application of deep learning techniques to histological tissue slides (deep pathomics), with the aim of predicting the response to therapy in stage III NSCLC. We evaluated 35 digitalized tissue slides (biopsies or surgical specimens) obtained from patients with stage IIIA or IIIB NSCLC. Patients were classified as responders (12/35, 34.7%) or non-responders (23/35, 65.7%) based on the target volume reduction shown on weekly CT scans performed during chemoradiation treatment. Digital tissue slides were tested by five pre-trained convolutional neural networks (CNNs)-AlexNet, VGG, MobileNet, GoogLeNet, and ResNet-using a leave-two patient-out cross validation approach, and we evaluated the networks' performances. GoogLeNet was globally found to be the best CNN, correctly classifying 8/12 responders and 10/11 non-responders. Moreover, Deep-Pathomics was found to be highly specific (TNr: 90.1) and quite sensitive (TPr: 0.75). Our data showed that AI could surpass the capabilities of all presently available diagnostic systems, supplying additional information beyond that currently obtainable in clinical practice. The ability to predict a patient's response to treatment could guide the development of new and more effective therapeutic AI-based approaches and could therefore be considered an effective and innovative step forward in personalised medicine.

Rates of surgery and adjuvant chemotherapy use in patients with stage IB to IIIA non-small cell lung cancer: A provincial population-based study.

134 Background: The current standard of treatment for early-stage (IB to IIIA) non-small cell lung cancer (NSCLC) include surgery and adjuvant chemotherapy. The objective of this study is to identify rates of adherence to guideline recommended surgery and adjuvant chemotherapy treatment for early-stage NSCLC for patients living in Ontario, the most populous province of Canada. Methods: A retrospective population-based study using linked administrative data through ICES was completed that included all adult patients with a diagnosis of stage IB to IIIA NSCLC made from 2010 to 2020 in Ontario. Rates of surgery and chemotherapy completion were calculated using available OHIP (Ontario Health Insurance Plan) billing codes. Logistic multivariate regressions were completed to assess for any predictors for completion of surgery and chemotherapy. Results: A total of 24,237 eligible patients were included. By cancer staging, there were 6,495 (26.8%) stage IB, 7,156 (29.5%) stage II, and 10,586 (43.7%) stage IIIA NSCLC patients. Within 180 days of diagnosis, surgery was completed for 9,929 (41.0%) of patients, by cancer staging were 4090/6495 (63.0%), 3719/7156 (52.0%), and 2120/10586 (20.0%) for IB, II, and IIIA respectively. The median time from diagnosis to surgery was 49 days (IQR 23-77 days). Amongst patients who completed surgery, 3344/9929 (33.7%) underwent at least 1 cycle of adjuvant chemotherapy within 180 days. Having advanced age (p&lt;0.001), high Charlson comorbidity score (p&lt;0.001), and low income (p&lt;0.001) are predictors for poor uptake for both chemotherapy and surgery. Being male also reduces the likelihood of undergoing surgery (p&lt;0.001). Conclusions: In our population-based study, less than half of the patients with early-stage (IB-IIIA) NSCLC underwent surgical resection and chemotherapy. These low treatment rates are concerning and may be contributing to suboptimal outcomes. Our findings indicate that elderly individuals with multiple comorbidities and those with low incomes are at the highest risk of not receiving appropriate chemotherapy and surgery. Our data highlight the need for quality improvement strategies aimed at identifying and enhancing treatment uptake within this patient population.

Diagnostic Workup, Treatment Patterns, and Clinical Outcomes in Early-Stage IB-IIIA Non-Small-Cell Lung Cancer Patients in Denmark.

Despite recent improvements in early-stage non-small-cell lung cancer (NSCLC), disease relapse remains challenging. Moreover, real-world evidence on long-term follow-up of disease-free survival (DFS) and recurrence patterns in a large, unselected cohort of early-stage NSCLC patients is lacking. This cohort study aimed to assess clinical characteristics, diagnostic workup, treatment, survival, and risk of disease relapse among early-stage NSCLC patients. Adult patients with stage IB, II, or IIIA NSCLC diagnosed and/or treated at Aarhus University Hospital in Denmark from January 2010 to December 2020 were included and followed-up until May 2021. Comprehensive clinical data were collected from electronic medical records of eligible patients and linked to Danish register data. The study population comprised 1341 early-stage NSCLC patients: 22%, 40%, and 38% were diagnosed with stage IB, II, and IIIA disease, respectively. In total, 42% of patients were tested for epidermal growth factor receptor (EGFR), of whom 10% were EGFR-mutation-positive (EGFRm+). Half of all patients received surgery, and nine percent of patients received stereotactic body radiation therapy (SBRT). Disease-free survival 5 years post-diagnosis was 49%, 42%, and 22% for stage IB, II, and stage IIIA patients, respectively. DFS improved over time both for patients treated with surgery and SBRT. However, disease relapse remained a challenge, with approximately 40% of stage IIIA having relapsed 3 years post-diagnosis. This study contributes important knowledge that puts clinical trials on new perioperative treatment modalities for early-stage NSCLC patients into perspective. Our findings cover an essential evidence gap on real-world DFS and recurrence dynamics, confirming that despite an improvement in DFS over time and across different treatment modalities, disease relapse remains a monumental challenge. Therefore, better treatment strategies are needed.

Risk factor analysis of the development of severe radiation pneumonitis in patients with non-small cell lung cancer treated with curative radiotherapy, with focus on underlying pulmonary disease

BackgroundWe aim to identify the multifaceted risk factors that can affect the development of severe radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with curative high-dose radiotherapy with or without concurrent chemotherapy.MethodsWe retrospectively reviewed the medical records of 175 patients with stage-I-III NSCLC treated with curative thoracic X-ray radiotherapy at the Korea University Guro Hospital between June 2019 and June 2022. Treatment-related complications were evaluated using the Common Terminology Criteria for Adverse Events (version 4.03).ResultsThe median follow-up duration was 15 months (range: 3–47 months). Idiopathic pulmonary fibrosis (IPF) as an underlying lung disease (P < 0.001) and clinical stage, regarded as the concurrent use of chemotherapy (P = 0.009), were associated with a high rate of severe RP. In multivariate analyses adjusting confounding variables, the presence of IPF as an underlying disease was significantly associated with severe RP (odds ratio [95% confidence interval] = 48.4 [9.09–347]; P < 0.001). In a subgroup analysis of stage-I-II NSCLC, the incidence of severe RP in the control, chronic obstructive pulmonary disease (COPD), and IPF groups was 3.2%, 4.3%, and 42.9%, respectively (P < 0.001). The incidence of severe RP was 15.2%, 10.7%, and 75.0% in the control, COPD, and IPF groups, respectively (P < 0.001) in the stage-III NSCLC group.ConclusionsThis study revealed that IPF as an underlying lung disease and the concurrent use of chemotherapy are associated with a high rate of severe RP. In contrast, COPD did not increase the risk of pulmonary toxicity after receiving curative high-dose radiotherapy.

Effectiveness comparison of third-generation EGFR-TKI as initial and sequential therapy in adjuvant treatment for EGFR mutation-sensitive stage IIIA non-small cell lung cancer after surgery

IntroductionAlthough third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) Osimertinib has been approved as adjuvant therapy for resected stage IIIA non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations, the optimal treatment sequencing of EGFR-TKIs, particularly whether Osimertinib should be the initial or sequential therapy following the first-generation EGFR-TKIs remains uncertain. MethodsA retrospective analysis was conducted on a cohort of patients with EGFR-mutated stage IIIA NSCLC who received treatment with either first-generation EGFR-TKIs or Osimertinib (third-generation) alone, or in sequential combination, at a single institution. The data analysis involved using the Kaplan-Meier method, log-rank test, and Cox regression. ResultsOut of the total 148 patients with stage IIIA NSCLC included in the study, 76 individuals underwent treatment with either first-generation EGFR-TKIs (referred to as subgroup “1″) or exclusively Osimertinib (subgroup “0 + 3″), or a sequential combination of the two (subgroup “1 + 3″) following surgery. Both univariate and multivariate analyses demonstrated that there were no discernible disparities in terms of disease-free survival and overall survival between subgroup " 1″ and " 1 + 3,” nor between subgroup " 0 + 3″ and “1 + 3". ConclusionThe findings from this study indicate that the introduction of third-generation EGFR-TKI Osimertinib did not yield enhanced survival benefits when compared to the first-generation drug in patients with stage IIIA completely resected NSCLC who were administered EGFR-TKIs as part of their postoperative adjuvant treatment. Additionally, within the observed sample size of this cohort, the sequential use of Osimertinib alongside first-generation EGFR-TKI did not demonstrate superiority over using either the first-generation EGFR-TKI or Osimertinib alone in terms of postoperative survival.

Prognostic value of lymph node ratio in stage III non-small-cell lung cancer: A retrospective cohort study.

A growing number of studies have found that the lymph node ratio (LNR) is an important indicator of prognosis in non-small-cell lung cancer (NSCLC). Impact analysis for LNR was performed for survival in patients undergoing surgery for stage III NSCLC compared to the surveillance, epidemiology and end results databank. Clinicopathological variables, such as cancer-specific survival (CSS), were taken from the surveillance epidemiology and end result databank of stage III NSCLC patients who underwent surgery, and the LNR threshold stratification of NSCLC patients was computed by X-tile. CSS was assessed by the Kaplan-Meier method with CSS-independent risk factors calculated by multivariate Cox regression analysis. In total, 7011 lung cancer patients were included. Multifactorial analysis showed that LNR and positive node category had predictive value for stage III NSCLC. In patients with stage IIIA NSCLC, Kaplan-Meier analysis demonstrated that patients with T1-2N2 stage had clearly superior CSS than those with T3-4N1 stage (P < .001), which conflicted with the results from the assessment of primary tumor, lymph nodes, and metastasis/N stage. The cutoff values for LNR were 0.31 and 0.59. Kaplan-Meier analysis demonstrated that the CSS was substantially better in patients with LNR-low than in those with LNR-medium or LNR-high (P < .001), which was also proven by multivariate competing risk regression. Subgroup analysis suggested that the survival advantage of a lower LNR was achieved in all subgroups (sex, race, etc). In stage III NSCLC, the LNR is a valuable factor for assessing prognosis, in which a higher LNR indicates a worse prognosis.

Stage IIIA Non-Small Cell Lung Cancer Treatment and Outcomes: A Single Institution Retrospective Analysis

Treatment of locally advanced non-small cell lung cancer (NSCLC) remains challenging, with a multitude of treatment options available for Stage III patients. We hypothesized that Stage IIIA outcomes differ by treatment received. We performed a retrospective review of NSCLC patients ≥18 years old with Stage IIIA disease treated 1/1/2010-03/01/2022. Demographics, treatment received, treatment outcomes, and failure patterns were collected. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Kruskal-Wallis ANOVA was used to compare groups. Of 352 patients identified, 160 had Stage IIIA NSCLC with a median follow-up of 29.1 months. Patients had a median age of 63 years, 79 (49.4%) were male, and 137 (85.6%) were current/former smokers (with 30 median pack-years). Patients were treated as follows: 17 (11%) surgery alone (S), 91 (57%) definitive radiation ± chemotherapy (CRT), 52 (33%) neoadjuvant therapy followed by surgery (Neo). 6 (12%) of the Neo group received chemoimmunotherapy, and 21 (51%) of the 41 CRT patients received adjuvant immunotherapy. Between the three groups, there were no significant differences in tumor size as measured by T-staging (p = 0.83) and baseline FEV1/FVC (p = 0.92). Median PFS was 33.5mo (95% CI 13.2-NA) for group S, 18.4mo (95% CI 12.7-42.2) for CRT, and 19.7mo (95% CI 13.9-NA) for Neo with no significant intergroup difference (p = 0.72). Median OS was 33.5mo (95% CI 13.2-NA) for S, 48.7mo (95% CI 36.0-88.9) for CRT, and 50.9mo (95% CI 41.9-NA) for Neo with no significant intergroup difference (p = 0.94). Among the 17 primary surgical patients, 11 (65%) experienced failure: 6 (35%) local, 5 (29%) regional, and 7 (41%) distant. Among the 91 CRT patients, 57 (63%) experienced failure: 40 (44%) local, 35 (38%) regional, and 28 (31%) distant. Among the 52 Neo patients, 26 (50%) experienced failure: 14 (27%) local, 15 (29%) regional, and 17 (33%) distant. There were no significant differences in rates of local failure (p = 0.26), regional failure (p = 0.59), distant failure (p = 0.79), or any failure (p = 0.41) among the three treatment groups. The most common locations for distant failure were pleural effusions (n = 15, 29%), CNS (n = 14, 27%), and bone (n = 11, 21%). In this single institution retrospective study, we find no significant differences in PFS, OS, and failure patterns between patients with Stage IIIA NSCLC treated with definitive (chemo)radiation and neoadjuvant therapy. Numeric improvement in PFS in surgery-only patients is consistent with expected patient selection of this group. Further work in the immunotherapy era is needed.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC.

DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated the profile of DDR gene mutations in early-stage non-small cell lung cancer (NSCLC) and their prognostic values. We first examined 74 DDR genes involved in seven DDR pathways and then focused on six specific genes: ATM, BRCA1, BRCA2, CHEK1, BARD1, and BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis. A total of 167 eligible patients were finally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and six genes, respectively. Mismatch repair (MMR) and nucleotide excision repair (NER) alterations were observed more frequently in lung squamous cell carcinoma (LUSC) and smokers were more likely to develop the selected six DDR gene mutations than those who never smoked. Deleterious mutations in the six genes were independent prognostic indicators of significantly longer disease-free survival and overall survival. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage infiltration in tumor area. However, numbers of mutations were significantly increased among patients with DDR alterations. Deleterious mutations of these six genes were common in resected NSCLC and could serve as prognostic biomarkers.

Impact of pathological nodal staging and tumour differentiation on survival and postoperative radiotherapy in completely resected stage IIIA Non-small-cell lung cancer

BackgroundTumour differentiation is an important index for adjuvant therapy in many cancers; however, non-small cell lung cancer (NSCLC) is an exception. Furthermore, postoperative radiotherapy (PORT) is controversial in patients with NSCLC with N0-1 and N2 disease. We aimed to evaluate the impact of tumour-related factors on overall survival (OS), cancer-specific survival (CSS), and distant control (DC) in patients with completely resected stage IIIA NSCLC. Materials and MethodsPatients with stage IIIA non-metastatic NSCLC who underwent complete resection and adjuvant chemotherapy were identified from the Taiwan Cancer Registry (January 2007–December 2017). Logistic regression analysis was performed to determine the factors associated with PORT. Survival and relapse outcomes were compared using log-rank tests and Cox regression analysis. Sensitivity analysis was performed using propensity score-matched pairs. ResultsIn total, 1,897 patients were included and stratified according to PORT use (PORT vs. non-PORT). After adjusting for covariates, PORT was not found to be associated with improved survival outcomes. In patients with poorly differentiated tumours and N2 disease, absolute benefits for OS (adjusted hazard ratio [aHR] 0.76), CSS (aHR 0.80), and DC (aHR 0.74) were observed. Multivariable hazard models of propensity score-matched pN2 disease and poorly differentiated tumour subgroups also showed significant survival benefit with PORT treatment. ConclusionsPatients with poorly differentiated tumours and receiving PORT for pN2 disease showed a lower risk of distant recurrence and more favourable survival outcomes in stage IIIA NSCLC with R0 resection.