Translational lung cancer research最新文献

Background: Uptake of new systemic therapy treatments among patients with advanced non-small cell lung cancer (NSCLC) occurred rapidly after FDA approval. Few studies have characterized the association of these therapies on survival in community settings. We assessed survival by type of systemic therapy received among patients diagnosed with advanced NSCLC who were treated in community-based settings.

Methods: In this retrospective cohort, patients diagnosed with de novo stage IV NSCLC between March 2012 and December 2020 were followed through December 31, 2021. Survival was ascertained with restricted mean survival time from treatment receipt through 12 and 60 months and compared by RMST differences adjusting for demographic and tumor characteristics. Trends in one-year survival probabilities were assessed using joinpoint regression.

Results: Of 945 patients receiving systemic therapy, 46% received cytotoxic chemotherapy (Chemo-Only), 15% bevacizumab +/- Chemo, 22% immunotherapy +/- Chemo, and 16% targeted therapies. Median days from diagnosis to treatment ranged from 32 to 42. Compared to those receiving Chemo-Only, patients receiving immunotherapy +/- Chemo survived 1.4 months longer [95% confidence interval (CI): 0.5 to 2.3 months; P=0.002] and 3.2 months longer (95% CI: -1.4 to 7.9 months; P=0.18) through 12 and 60 months follow-up, respectively. Relative to those receiving Chemo-Only, patients receiving targeted therapies survived 1.6 months longer (95% CI: 0.7 to 2.5 months; P<0.001) and 5.5 months longer (95% CI: 0.7 to 10.4 months; P=0.02) through 12 and 60 months follow-up. One-year survival significantly increased from 30% to 59% between 2012 and 2020 (P=0.007).

Conclusions: We found patients receiving targeted therapies and immunotherapy +/- Chemo survived longer than those on Chemo-Only. One-year survival probabilities significantly increased between 2012 and 2020. Additional research is needed to better understand the potential benefits and harms, including patient adverse events and financial toxicity.

Background: The timing of immune checkpoint inhibitor (ICI) administration may influence clinical outcomes in non-small cell lung cancer (NSCLC) patients. Previous studies have shown varying effects of chronotherapy on survival rates, with some suggesting that a higher percentage of doses administered in the morning improves overall survival (OS) and progression-free survival (PFS). This study aimed to evaluate the impact of the timing of the first dose and the percentage of doses administered in the afternoon on survival outcomes in advanced NSCLC patients, as well as explore seasonal variations.

Methods: We conducted a retrospective cohort study at a tertiary cancer centre of patients diagnosed with NSCLC and programmed cell death ligand 1 (PD-L1) expression ≥50% who received first-line palliative treatment with pembrolizumab or atezolizumab. Patients were categorized based on the timing of their first dose (before or after 14:30) and further stratified by the percentage of doses received after 14:30. To evaluate seasonal variance, patients were also stratified into two groups: those who received their first dose within three months before or after the winter solstice ("Winter group") and those who received it within three months before or after the summer solstice ("Summer group"). Survival analysis was conducted using the Kaplan-Meier method.

Results: We identified 349 patients who met the inclusion criteria. There was no significant difference in PFS or OS between patients receiving their first ICI dose before 14:30 (n=188) and those receiving it after 14:30 (n=161). However, a significant difference in OS was observed in patients who received more than 50% of their doses in the afternoon. Seasonal variations in dosing timing did not significantly impact survival outcomes.

Conclusions: Our study suggests that the timing of the first ICI dose does not significantly affect survival outcomes in advanced NSCLC patients. However, patients receiving a higher percentage of their doses in the afternoon may experience poorer OS. Further prospective research is needed to confirm these findings and understand the underlying mechanisms before any changes to clinical practice can be recommended.

Background: Combination regimens of immunotherapy plus chemotherapy have been approved as the first-line and standard of care for extensive-stage small cell lung cancer (ES-SCLC). Novel regimens are continuously being explored, with the ETER701 study being the representative randomized controlled trial (RCT). ETER701 study has assessed the efficacy and safety of chemotherapy with or without anlotinib (multi-target angiogenesis inhibitor) + benmelstobart (programmed cell death ligand 1 inhibitor) (Anl/Ben/CT). There is no evidence-based medicine available proving that Anl/Ben/CT is the optimal regimen due to the lack of direct or indirect comparisons among varying immunotherapy-based regimens. In this study, we aimed to identify the optimal regimen to assist in clinical decision-making.

Methods: The eligible RCTs were identified by searching PubMed, Embase, Cochrane Library databases, and major international conferences. Then, the network meta-analysis was analyzed to compare the efficacy and safety among 15 first-line regimens in ES-SCLC. The Cochrane Risk of Bias Tool was used to assess the risk of bias in included studies.

Results: A total of 12 immunotherapy-related RCTs covering 15 interventions and 6,178 patients with ES-SCLC were included. Overall, most RCTs exhibited a low risk of bias across multiple domains. The results indicated that most immunotherapy-based regimens could significantly prolong progression-free survival (PFS) compared with chemotherapy alone, especially Anl/Ben/CT [hazard ratio (HR) 0.32, 95% confidence interval (CI): 0.25-0.40]. Similar results were observed regarding overall survival (OS), that is, most immunotherapy-related regimens dramatically reduced the risk of death in ES-SCLC, with Anl/Ben/CT being the most prominent (HR 0.61, 95% CI: 0.47-0.80). The Bayesian ranking probabilities showed that Anl/Ben/CT ranked first and serplulimab plus chemotherapy ranked second in both PFS and OS among 15 regimens. Regarding safety, Anl/Ben/CT ranked 3rd, and serplulimab plus chemotherapy ranked 7th.

Conclusions: Adding anlotinib and benmelstobart to chemotherapy significantly improved PFS and OS compared with chemotherapy alone or chemotherapy plus immunotherapy, with an acceptable safety profile in patients with ES-SCLC. In conclusion, Anl/Ben/CT could be a new, preferable first-line treatment option but further clinical studies are needed to validate its efficacy and safety.

Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly improves the prognosis of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, subsequently-acquired resistance limits its effectiveness. This study aimed to explore the efficacy of anlotinib, a multitarget inhibitor of angiogenesis, in combination with osimertinib using in vitro and in vivo EGFR-TKI-sensitive and EGFR-TKI-resistant models.

Methods: We established osimertinib-resistant cell lines (H1975-OR and PC9-OR) and evaluated the effects of osimertinib, anlotinib, and their combination on cell proliferation in vivo and in vitro. In addition, we used pleural fluid from nine patients with EGFR-mutant NSCLC who received osimertinib therapy in the clinic to successfully establish a zebrafish patient-derived xenograft (zPDX) model. The effect of the combined treatment in vivo was assessed by quantifying red fluorescent regions representing tumor cell growth in zebrafish embryos to assess tumor proliferation and migration.

Results: Combination osimertinib and anlotinib therapy did not have an obvious synergistic antiproliferative effect in parental H1975 and PC9 cells; however, anlotinib reversed osimertinib resistance in osimertinib-resistant H1975-OR and PC9-OR cells in vivo and in vitro. A similar phenomenon was observed in the zPDX model.

Conclusions: In conclusion, anlotinib did not significantly enhance the anti-tumor effects of osimertinib in osimertinib-sensitive NSCLC cell lines or a zPDX model. However, it partially reversed osimertinib resistance. This combination therapy may improve the outcomes of patients with advanced NSCLC showing osimertinib-resistance.

Background: Based on improvements in recurrence-free and overall survival, osimertinib is now widely used as an adjuvant treatment in stage II-IIIA non-small cell lung cancer (NSCLC) presenting with a common epithelial growth factor receptor (EGFR) mutation. Histological transformation is a well-known resistance mechanism to osimertinib in EGFR-mutated metastatic NSCLC, but we currently have insufficient data on recurrence mechanisms in the adjuvant context. We present here the case of a patient treated with adjuvant osimertinib and presenting a small cell lung cancer (SCLC) transformation as a recurrence.

Case description: A 54-year-old man, never-smoker and with no previous medical history, underwent right superior lobectomy with lymph node resection for a pT3N1M0 [stage IIIA, tumor-node-metastasis (TNM) 8^th edition] adenocarcinoma. Programmed death-ligand 1 (PD-L1) negative with an EGFR exon 19 deletion. The patient received 4 cycles of adjuvant chemotherapy before starting adjuvant osimertinib 80 mg. After 35 months of adjuvant osimertinib the patient had a local recurrence and the re biopsy showed an SCLC transformation, underlining the importance of careful surveillance and biopsy at the time of recurrence in EGFR-mutated NSCLC.

Conclusions: this case report provides evidence of SCLC transformation while on adjuvant osimertinib, in a pT3N1 EGFR, RB1 and TP53-mutated pulmonary adenocarcinoma. This highlights the importance of biopsy on recurrence and the transformation potential of the EGFR, RB1 and TP53-mutated adenocarcinomas.

Background: Three-dimensional (3D) is a useful tool for visualizing computed tomography (CT) scans, facilitating a clearer understanding of the spatial relationships between pulmonary lesions and the branching architecture of the bronchi and blood vessels. Several studies have demonstrated the benefit of preoperative 3D reconstruction in terms of intraoperative safety and short-term surgical outcomes after thoracoscopic surgery. However, evidence regarding the impact of 3D reconstruction on surgical planning of anatomical partial lobectomy (APL) is still lacking. This study aimed to evaluate the effect of 3D reconstruction in surgical planning and decision making compared with conventional clinical imaging.

Methods: This prospective self-controlled study included 49 patients with multiple lung nodules (MLNs). A 3D reconstruction model was created using thin-slice CT images with Mimics 21.0 software. Two novice surgeons and two experienced surgeons respectively conducted surgical planning based on the CT images and 3D reconstruction sequentially. The surgical plans based on the CT images and 3D reconstruction were compared with those after the evaluation of intraoperative inspection.

Results: Among the 49 participants enrolled to undergo sublobar resection (the patient level), 3D reconstruction significantly increased the surgical planning success rates both in novice surgeons (Surgeon A: 40.8% to 87.8%; Surgeon B: 49.0% to 89.8%) and experienced surgeons (Surgeon C: 83.7% to 100%; Surgeon D: 75.5% to 95.9%). For the entire 101 pulmonary nodules determined suitable for APL (the nodule level), all surgeons had higher surgical planning success rates with the help of 3D reconstruction and all success rates were above 90%. The gap in surgical planning success rates between novice surgeons and senior surgeons was closed. All patients were operated without intraoperative accident and without major postoperative complications.

Conclusions: The surgical planning success rates of both novice surgeons and experienced surgeons were significantly increased with the help of 3D reconstruction and reached a high level. 3D reconstruction also closed the gap of surgical planning between novice surgeons and experienced surgeons at patient level.

Background: The results of three modern randomized controlled trials have proved sublobar resection as an effective procedure for early-stage non-small cell lung cancer (NSCLC) up to 2 cm. We aimed to examine whether sublobar resection is oncologically feasible and what constitutes adequate lymph node assessment for hypermetabolic clinical stage IA (cIA) NSCLC.

Methods: A single-center retrospective study was conducted in 589 patients who underwent lobectomy (n=526) or sublobar resection (n=63) for hypermetabolic cIA NSCLC [maximum standardized uptake value (SUVmax) ≥2.6 g/dL]. The primary outcomes (lung cancer-specific death and tumor recurrence) were compared in a competing risks framework for all patients and the propensity score matched pairs. Random forests were used to examine the variable importance for lung cancer-specific survival and tumor recurrence. Factors affecting pathological upstaging and recurrence-free survival were assessed by logistic regression analysis and Cox regression analysis, respectively.

Results: Sublobar resection had significantly higher lung cancer-specific cumulative incidence of death (LC-CID) and cumulative incidence of recurrence (CIR) than lobectomy after matching (5-year LC-CID, 20.8% vs. 6.5%, P<0.001; 5-year CIR, 37.9% vs. 14.8%, P<0.001). Wedge resection was an independent risk factor for both lung-cancer specific death [hazard ratio (HR) =4.17; 95% confidence interval (CI): 2.07-8.36; P<0.001] and recurrence (HR =3.48; 95% CI: 1.91-6.33; P<0.001). Lymphadenectomy that failed to meet the lobe-specific nodal dissection (LSND) criteria correlated with decreased odds of pathological nodal upstaging [odds ratio (OR) =0.55; 95% CI: 0.34-0.87; P=0.01]. While patients with LSND had lower LC-CIR and CIR, there was no additional prognostic benefit of systemic nodal dissection (SND) over LSND.

Conclusions: Lobectomy was oncologically superior to sublobar resection as a curative-intent procedure for hypermetabolic cIA NSCLC. Lobectomy plus lobe-specific lymphadenectomy should be considered as the minimum standards of curative resection for hypermetabolic early-stage NSCLC in order to achieve more accurate pathological N staging and better cancer control.