Translational lung cancer research最新文献

Background: Bone metastasis (BoM) is a prevalent occurrence in patients with non-small cell lung cancer (NSCLC), significantly impacting prognosis and diminishing both survival rates and patients' quality of life. More and more studies have demonstrated that immunotherapy can improve the prognosis of NSCLC patients with bone metastases. Previous investigations pertaining to BoM in NSCLC have generally suffered from small sample sizes, absence of propensity score matching (PSM) to equate baseline characteristics, and an omission of the examination of patterns of treatment failure. This study aims to evaluate the prognostic significance of BoM and potential clinical value of bone radiation in metastatic NSCLC patients receiving immunotherapy.

Methods: Metastatic NSCLC patients receiving programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors from three academic centers were enrolled in a prospective, observational trial (https://clinicaltrials.gov/study/NCT04766515) and those with measurable disease and adequate follow-up were retrospectively reviewed. Propensity score matched (PSM) patients with and without BoM were included in this study. Treatment efficacy, pattern of failure and clinical value of bone radiotherapy were extensively evaluated.

Results: A total of 544 out of 1,451 immunotherapy-treated NSCLC patients were included after PSM, including 272 with BoM and 272 without. Patients with baseline BoM had a median progression-free survival (PFS) of 7.8 months [95% confidence interval (CI): 7.0-8.7], lower than those without it (9.5 months; 95% CI: 8.9-10.0) (P<0.001). Patients with baseline BoM had a median overall survival (OS) of 14.5 months (95% CI: 12.6-16.4), lower than those without 27.6 months (95% CI: 25.1-30.1) (P<0.001). Patients with BoM also had lower objective response rate than those without it (11.1% vs. 15.8%, P<0.001). Initial disease progression in the bone was more common in those with BoM (56.5%) compared to those without it (31.7%) (P<0.001). Meanwhile, among patients with BoM, no significant difference of PFS was found between those receiving bone radiation or not, possibly due to a dominant use of palliative radiotherapy.

Conclusions: Baseline BoM correlated with worse prognosis and palliative bone radiation did not improve PFS in metastatic NSCLC patients receiving PD-1/PD-L1 inhibitors.

Background: Electromagnetic navigation bronchoscopy (ENB) has been widely used to mark small peripheral pulmonary nodules (PPNs) in video-assisted thoracic surgery (VATS) resection. This technique offers the advantages of a high accuracy and fewer complications. However, few studies have analyzed the learning curve of ENB-guided preoperative localization. We aimed to describe the learning curve and factors influencing ENB-guided thoracoscopic pulmonary nodule resection.

Methods: This study included 300 consecutive patients with PPNs who underwent ENB-guided localization by the same endoscopist in our department between November 2019 and December 2021. The cumulative sum (CUSUM) method was used to analyze the learning curve of ENB-guided localization and the learning curve in different lobes, while logistic regression was used to analyze the risk factors affecting ENB operative time (OT).

Results: In 184 patients with 300 nodules, three learning phases were identified through turning points of the learning curve: Phase I (the 16^th nodule), Phase II (the 17^th to the 107^th nodule), and Phase III (the 107^th to the 300^th nodule). No significant difference was found in the success rate of ENB-guided localization in each phase of the learning curve (100%, 96.7%, and 97.9%, P=0.78). The distance from the localization to the pleura in Phase I was statistically significantly shorter than that in Phase II and Phase III (0.6±0.4 vs. 1.1±0.6 vs. 1.0±0.5 cm, P=0.001 and P=0.003). Furthermore, the learning curves for nodules in different lobes were different. The learning curve for the upper lobe nodules was divided into two phases; the learning curve for the middle lobe disclosed more negative values; and the learning curve for the lower lobe nodules displayed no obvious pattern. Significant differences were found in nodule location, distance from the localization to the pleura and learning curve phase (P=0.003, P<0.001, P=0.02). The independent factors for OT included gender, smoking history, nodule type, distance from localization to the pleura, and learning curve phase.

Conclusions: ENB OT at the 107^th nodule leveled off and showed a downward trend. Different lobes have different learning curves, the middle lobe is the easiest lobe to learn with ENB and can be used as the first lobe of choice for beginners. The learning curve can objectively evaluate the accuracy of ENB location and help endoscopists identify areas for improvement.

Background: The prognosis of patients with lung cancer and malignant pleural effusion (MPE) caused by carcinomatous pleurisy is poor. Chemical pleurodesis is commonly performed clinically, however, often has a high failure rate. Furthermore, prolonged sustained drainage and delayed introduction of systemic chemotherapy could increase the risk of worsening the Eastern Cooperative Oncology Group Performance Status (ECOG PS) in the treatment of patients with non-small cell lung cancer (NSCLC). Therefore, both systemic and local treatments are crucial to control MPE. Ramucirumab, an antibody targeting vascular endothelial growth factor receptor 2, is expected to be effective for treatment of MPE. However, there are no data supporting this hypothesis. Herein, we performed a prospective phase II study to evaluate the efficacy and safety of ramucirumab plus docetaxel in NSCLC patients with MPE.

Methods: A single-arm phase II study was conducted to elucidate the efficacy and safety of ramucirumab plus docetaxel as a combined treatment for patients NSCLC and MPE previously treated with platinum-based chemotherapy. The primary endpoint was the MPE control proportion at eight weeks after protocol treatment initiation. The secondary endpoints of the study were objective response rate (ORR), progression-free survival (PFS), one-year survival rate, overall survival (OS), and toxicity profile.

Results: Between September 2019 and March 2022, 15 patients were enrolled. The pleural effusion control proportion at eight weeks was 100% [90% confidence interval (CI): 84.0-100%, and 95% CI: 78.4-100%], and the primary endpoint of this study was met. The ORR was 6.7% (95% CI: 0.2-32.0%), the median PFS was 6.3 months (95% CI: 1.9-6.9), and the median OS was 10.4 months (95% CI: 3.2-16.5). No Grade 5 or unexpected adverse events were observed.

Conclusions: Ramucirumab plus docetaxel is a promising and safe treatment option for previously treated patients with NSCLC and MPE, showing a high pleural effusion control rate.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). TQB2450 (benmelstobart) is a novel humanized immunoglobulin G1 monoclonal antibody against programmed death-ligand 1 (PD-L1). Anlotinib, an oral multitargeted anti-angiogenic agent with potential synergy with ICIs, has shown efficacy in relapsed and advanced NSCLC. Accumulating preclinical data suggest a synergism between immunological and anti-angiogenic therapies through the improvement of the immune microenvironment of the tumor. In this study, we hypothesized that the combination of TQB2450 and anlotinib as maintenance treatment would enable further improvements in the outcomes of patients with locally advanced/unresectable NSCLC without driver mutations that have not progressed after definitive chemoradiotherapy.

Methods: The Radiotherapy and Anlotinib Let PD-L1 Superb (R-ALPS) study is a randomized, double-blind, placebo-controlled, multicenter phase III study (Clinicaltrials.gov identifier, NCT04325763). A total of 534 eligible participants will be randomized to receive TQB2450 (1,200 mg) plus anlotinib (8 mg), or TQB2450 (1,200 mg) plus placebo, or placebo as maintenance therapy. Progression-free survival (PFS), assessed by the independent review committee is the primary endpoint. The secondary endpoints include additional measures of efficacy, safety, and biomarkers. An interim analysis of the effectiveness will be conducted when 70% (286 cases) of the total PFS events have been reached.

Discussion: The development of the R-ALPS study will contribute to a deeper insight into the interplay between immunotherapy and anti-angiogenic therapy and thus might expand the treatment options available to patients with locally advanced or unresectable NSCLC.

Trial registration: Clinicaltrials.gov identifier: NCT04325763. Date of registration: May 27, 2020. Protocol version: Version 4.0, Sep 16, 2022 (https://classic.clinicaltrials.gov/ct2/show/NCT04325763).

[This corrects the article DOI: 10.21037/tlcr-23-98.].

Background: Different pathological stages of lung adenocarcinoma require different surgical strategies and have varying prognoses. Predicting their invasiveness is clinically important. This study aims to develop a nomogram to predict the invasiveness of lung adenocarcinoma manifesting as ground-glass nodules (GGNs) based on follow-up computed tomography (CT) imaging.

Methods: We retrospectively collected data of 623 GGNs from 601 patients who underwent two follow-up chest CT scans and were confirmed as lung adenocarcinoma by postoperative pathology between June 2017 and August 2023. These patients were randomly divided into training and testing sets in a 7:3 ratio. Eighty-seven GGNs from 86 patients who underwent surgery between September 2023 and April 2024 were prospectively collected as a validation set. The volume, mean density, solid component volume (SV), percentage of solid component (PSC), and mass of GGNs were evaluated using the InferRead CT Lung software. Patients were classified into Group A (atypical adenomatous hyperplasia, adenocarcinoma in situ, and minimally invasive adenocarcinoma) and Group B (invasive adenocarcinoma). Three predictive models were established: model 1 utilized clinical characteristics and morphological features on pre-surgical CT, model 2 incorporated clinical characteristics, morphological features and quantitative parameters on pre-surgical CT, and model 3 utilized all selected features on baseline and pre-surgical CT.

Results: Model 3 achieved a satisfying area under the curves values of 0.911, 0.893, and 0.932 in the training, testing, and validation sets, respectively, demonstrating superior predictive performance than model1 (0.855, 0.858, and 0.816) and model2 (0.895, 0.891, and 0.903). A nomogram was constructed based on model 3. Calibration curves showed a good fit, and decision curve analysis showed that the nomogram was clinically useful.

Conclusions: The nomogram based on morphological features and quantitative parameters from follow-up CT images showed good discrimination and calibration abilities in predicting the invasiveness of lung adenocarcinoma manifesting as GGNs.

Background: Detailed clinical data about combination treatment with MET inhibitor (METi) and EGFR inhibitor (EGFRi) is lacking in patients with EGFR-mutant, MET-amplified, and EGFRi-resistant non-small cell lung cancer (NSCLC). This study aimed to report longitudinal data on the efficacy and safety of this combination treatment.

Methods: We retrospectively analyzed 44 patients with advanced EGFR-mutant and MET-amplified NSCLC who were treated with any types of METi plus EGFRi after progression with EGFRi at the National Cancer Center Hospital. Longitudinal clinicogenomic data and plasma circulating tumor DNA (ctDNA) data were collected.

Results: The overall response rate was 74.4% and median progression-free survival (PFS) was 5.3 months [95% confidence interval (CI): 3.3-7.3]. Twenty-three patients (52.3%) required either or both treatment discontinuation due to adverse effects. The main cause of discontinuation was pneumonitis (69.2%). There was no significant difference in the PFS of patients with or without METi discontinuation [hazard ratio (HR), 0.93; 95% CI: 0.49-1.78; P=0.83]. Median clearance time of MET amplification in plasma ctDNA was measured as 63 days. Patients who stopped METi within 63 days of initiation showed poorer PFS compared to those who discontinued after (HR, 2.78; 95% CI: 1.00-7.75; P=0.050). Diverse resistance mechanisms including on-target mutations in MET (D1246H) and EGFR (C797S or T790M) were detected in 14 patients. One MET D1246H-mutant case and one EGFR C797S-mutant case responded to sitravatinib and amivantamab, respectively.

Conclusions: A combination of METi and EGFRi showed a promising anti-tumor effect in advanced EGFR-mutant and MET-amplified NSCLC. Pneumonitis was the main adverse effects leading to treatment discontinuation. Early discontinuation of METi negatively affected the survival outcomes.

Background: Lung cancer screening with low-dose computed tomography has been started in some high-income countries and is being considered in others. In many settings uptake remains low. Optimal strategies to increase uptake, including for high-risk subgroups, have not been elucidated. This study used a system dynamics approach based on expert consensus to identify (I) the likely determinants of screening uptake and (II) interactions between these determinants that may affect screening uptake.

Methods: Consensus data on key factors influencing screening uptake were developed from existing literature and through two stakeholder workshops involving clinical and consumer experts. These factors were used to develop a causal loop diagram (CLD) of lung cancer screening uptake.

Results: The CLD comprised three main perspectives of importance for a lung cancer screening program: participant, primary care, and health system. Eight key drivers in the system were identified within these perspectives that will likely influence screening uptake: (I) patient stigma; (II) patient fear of having lung cancer; (III) patient health literacy; (IV) patient waiting time for a scan appointment; (V) general practitioner (GP) capacity; (VI) GP clarity on next steps after an abnormal computed tomography (CT); (VII) specialist capacity to accept referrals and undertake evaluation; and (VIII) healthcare capacity for scanning and reporting. Five key system leverage points to optimise screening uptake were also identified: (I) patient stigma influencing willingness to receive a scan; (II) GP capacity for referral to scans; (III) GP capacity to increase patients' health literacy; (IV) specialist capacity to connect patients with timely treatment; and (V) healthcare capacity to reduce scanning waiting times.

Conclusions: This novel approach to investigation of lung cancer screening implementation, based on Australian expert stakeholder consensus, provides a system-wide view of critical factors that may either limit or promote screening uptake.