Norifumi Tsubokawa

Objectives: Bevacizumab (Bev) improves the response and survival rates in patients with advanced non-small cell lung cancer (NSCLC). This phase II trial aimed to assess the feasibility of adding Bev to preoperative chemotherapy in resectable non-squamous NSCLC. Methods: Patients with clinical stage II/IIIA non-squamous NSCLC (n = 30) received three cycles of cisplatin (Cis), pemetrexed (Pem), and Bev, followed by surgical resection. The primary endpoint was the complete resection rate (CRR), defined as the proportion of all eligible enrolled patients who ultimately underwent complete (R0) resection. The sample size was set at 30 patients. Treatment was considered feasible if the CRR exceeded the predefined acceptable threshold of 65%. Results: Radiological tumour reduction was observed in 29 of 30 patients (97%). Twenty-eight patients (93%) completed all three cycles of chemotherapy, and 25 patients (83%) underwent surgery. Five patients discontinued treatment due to adverse events (n = 3), disease progression (n = 1), or patient refusal (n = 1). Complete resection was achieved in all resected patients, yielding an 83% CRR (two-sided 80% confidence interval, 71.3%–91.7%). The objective response rate was 37%, and pathological complete response of the primary tumour was achieved in 3 patients (12%). Grade 3 toxicities included neutropenia (7%), nausea (7%), hypertension (23%), and pulmonary embolism (3%). No grade 4/5 adverse events occurred within 28 days, and no treatment-related deaths occurred within 84 days. Conclusions: Preoperative Cis, Pem, and Bev for clinical stage II/IIIA non-squamous NSCLC met the predefined feasibility criterion, with acceptable safety in this selected population. These findings provide historical insights supporting perioperative anti-vascular endothelial growth factor-based systemic intensification.

BackgroundSegmentectomy has demonstrated favorable long-term outcomes compared with lobectomy in patients with small peripheral non-small cell lung cancer (NSCLC). However, whether similar benefits can be achieved in centrally located, small-sized, radiologically solid-dominant NSCLC remains uncertain. This study aims to confirm the non-inferiority of segmentectomy to lobectomy within this setting.MethodsJCOG2501 is a multi-institutional, open-label, phase III, randomized controlled trial designed to confirm the non-inferiority of segmentectomy to lobectomy in patients with centrally located (within the inner two-thirds of the lung field), small-sized (maximum tumor diameter ≤2 cm), radiologically solid-dominant (consolidation-to-tumor ratio, >0.5 to ≤1) NSCLC. Eligible patients are aged 18–85 years with an Eastern Cooperative Oncology Group performance status of 0–1 and adequate pulmonary function. A two-step registration system is adopted, with preoperative and intraoperative confirmation of patient eligibility. Following confirmation of eligibility at the second registration, patients are randomized 1:1 to either the lobectomy or segmentectomy arm. In both arms, systematic or lobe-specific lymph node dissection is mandatory, and nodal sampling alone is prohibited. The primary endpoint is overall survival, analyzed in all randomized patients. Assuming a non-inferiority margin of 6.5% for 5-year overall survival, 490 patients are required to achieve 70% power with a one-sided α = 5%. The planned sample size is 500 patients at the second registration. JCOG2501 was initiated in February 2026 and is registered with the Japan Registry of Clinical Trials (jRCT1030250727).ConclusionsJCOG2501 will clarify the role of segmentectomy in centrally located small-sized NSCLC and inform future surgical standards.

Objectives: Mediastinal lymph-node dissection (MLND) is recommended for resectable non-small-cell lung cancer (NSCLC); however, its prognostic impact remains controversial. We evaluated whether MLND improves prognosis in patients with radiologically solid-dominant clinical stage I NSCLC. Methods: We retrospectively reviewed 2212 patients who underwent lobectomy for solid-dominant clinical stage I NSCLC between 2010 and 2022. Prognosis and local control were compared between the MLND and non-MLND groups. Results: The MLND and non-MLND groups included 1912 and 300 patients, respectively. After propensity score matching, 5-year overall survival did not show a statistically significant difference between the groups (85.3% vs 79.3%, P = .089). MLND identified occult pN2 metastasis in 7.3% (138/1912) of patients. Notably, 3.6% (68/1912) of the entire MLND cohort had pN2 disease yet remained recurrence-free. Furthermore, the MLND group demonstrated significantly lower mediastinal lymph-node recurrence than the non-MLND group (P = .017). Among patients with pN2 disease in the MLND group, those with recurrence (n = 70) had a higher incidence of intrapulmonary metastases (P = .042), a higher number of mediastinal lymph-node metastases (P = .002), and a lower rate of skip-N2 involvement (P = .031). Conclusions: Mediastinal lymph-node dissection provides superior local control by reducing mediastinal recurrences and enables accurate pathological staging. While this advantage guides appropriate adjuvant therapy selection, the direct impact of MLND on overall survival remains uncertain. Its true survival benefit should be evaluated in future prospective randomized trials.

Objectives: Segmentectomy is a standard treatment for small-sized, peripherally located, and radiologically solid-dominant non-small cell lung cancer. However, its effectiveness in loco-regional control compared with lobectomy for such tumours remains undetermined. Methods: We evaluated the clinicopathological findings, recurrence patterns, and prognosis of patients with radiologically determined ≤2-cm sized, solid-dominant, and peripheral non-small cell lung cancer without lymph node involvement clinically. These patients underwent complete resections via segmentectomy (n = 332) or lobectomy (n = 609) between 2010 and 2020. Median follow-up duration for anonymized patients was 48.8 months. Results: Among the 941 patients, loco-regional recurrence occurred in 7 (2%) patients following segmentectomy and in 30 (5%) following lobectomy (P = .037). Surgical stump recurrences occurred in 3 (1%) patients in a segmentectomy group and in 5 (0.8%) patients in a lobectomy group. Among patients with pure solid tumours, no significant difference in loco-regional recurrence was noted between the segmentectomy (7 patients, 4%) and lobectomy (27 patients, 7%) groups (P = .11). Surgical stump recurrence occurred in 3 (1.5%) patients following segmentectomy and in 3 (0.7%) patients following lobectomy. Fine-Gray proportional hazard regression analysis with adjusted variables, including age, sex, Brinkman index, solid tumour size, presence of ground glass opacity, and SUVmax, revealed that the surgical procedure was not a risk factor for loco-regional recurrence. Conclusions: Regardless of tumour malignant grade, segmentectomy provides comparable local control with lobectomy for selected small-sized peripheral non-small cell lung cancer.

Objectives: Ground-glass opacity (GGO) component is a favourable prognostic factor in non-small cell lung cancer (NSCLC), whereas NSCLC with interstitial lung abnormalities (ILA) generally has poorer prognoses. We investigated the clinical significance of GGO in patients with NSCLC and ILA. Methods: Among 1319 patients who underwent pulmonary resection for clinical stage IA NSCLC at 2 institutions between 2010 and 2020, we retrospectively assessed 216 patients with ILA based on preoperative CT. Patients were divided into 2 groups: pure solid tumours without GGO and subsolid tumours with GGO. Results: Among 216 patients with ILA, 146 (68%) had pure solid tumours and 70 (32%) had subsolid tumours. Subsolid tumours had significantly better prognoses than pure solid tumours (5-year overall survival, 69.7% vs 48.6%, P = .0008; 5-year recurrence-free survival, 69.7% vs 42.3%, P < .0001). Recurrence occurred in 4 patients (6%) with subsolid tumours and 41 (28%) with pure solid tumours. Although the 5-year cumulative incidence of lung cancer deaths was significantly lower in subsolid tumours than in those with pure solid tumours (2.6% vs 23.6%, P = .0011), an increase in other causes of mortality after 2 years post-surgery in subsolid tumours resulted in a comparable 5-year cumulative incidence of other causes of death (28.4% vs 36.1%, P = .260). Conclusions: In clinical stage IA NSCLC with ILA, subsolid tumours have a lower lung cancer mortality than pure solid tumours; however, higher other-cause mortality after 2 years contributes to poorer overall survival. Optimizing comorbidity management may improve long-term prognosis.

Objectives: Although a novel tumour-node-metastasis (TNM) classification (ninth edition) for N staging was recently proposed, there is still room for improvement. We assessed whether classifying N stage based on zones and the number of involved lymph node stations could better predict postoperative recurrence risk. Methods: We included 671 patients with pathological N1 or N2, M0 non-small-cell lung cancer (NSCLC). Lymph node zones were categorized as peripheral and hilar for N1 nodes, and upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal for N2 nodes. The N category was subdivided according to the location and number of involved lymph node stations: N1a (single-zone/single-station N1), N1b (multiple-zone/multiple-station N1), N2a1 (single-zone/single-station N2 without N1 involvement), N2a2 (single-zone/single-station N2 with N1 involvement), and N2b (multiple-zone/multiple-station N2, regardless of N1 involvement). Results: Recurrence-free survival (RFS) and cumulative incidence of recurrence (CIR) were stratified according to the pathological N1, N2a, and N2b groups based on the TNM (ninth edition) N descriptors. RFS (P < .001 for both) and CIR (P < .001 for both) were effectively stratified using both station- and zone-based classifications. Station- and zone-based N2a1 exhibited RFS (hazard ratio [HR], 1.04; 95% CI, 0.66-1.63 and HR, 1.12; 95% CI, 0.66-1.89, respectively) comparable to those of N1b. Considering station-based N2b, zone-based N2a2 (HR, 1.98; 95% CI, 0.69-5.66) and N2b (HR, 1.99; 95% CI, 0.72-5.52) tended to have worse RFS than zone-based N2a1. Conclusions: Both station- and zone-based nodal classifications effectively stratify recurrence risk and are good candidates for further N category stratification in NSCLC.

Background: Small-sized, peripherally located, and radiologically solid-dominant or pure solid nonsmall cell lung cancer (NSCLC) tumors are related to lymph node metastasis at a certain frequency. The aim of this study is to disclose the validity of lymph node dissection on oncological local control during segmentectomy for such tumors. Methods: We investigated the clinicopathological findings, the distribution of the involved lymph nodes, the patterns of lymph node recurrences, and the prognosis of 1921 patients with radiologically-determined ≤3 cm-sized, solid-dominant or pure solid NSCLC tumors without clinical lymph node involvement following complete resections with lobectomy (n = 1472) or segmentectomy (n = 449) between 2010 and 2020. The median follow-up duration for anonymized cases was 51.8 months. Results: The median age, solid tumor size, whole tumor size, and maximum of standardized uptake value were 72/69 years, 1.5/1.8 cm, 1.6/2.1 cm, and 2.0/3.5 in patients undergoing segmentectomy/lobectomy, respectively. Hilar lymph node metastases were recognized in 13 (3%) patients who underwent segmentectomy, and in 110 (8%) patients who underwent lobectomy, respectively. No patients experienced a recurrence of hilar lymph node metastasis in either adjacent or nonadjacent areas without distant metastasis after segmentectomy, while three patients experienced recurrence after lobectomy. Conclusions: Lymph node dissection can be adequately performed during segmentectomy for selected small and peripherally located NSCLC tumors.

OBJECTIVES: This study aimed to compare the quality of mediastinal lymph node dissection (LND) during lobectomy for clinical stage I–II non-small cell lung cancer (NSCLC) between video-assisted thoracic surgery (VATS) and open thoracotomy, using data from the Japan Clinical Oncology Group (JCOG) 1413 phase 3, randomized, controlled trial. METHODS: This analysis draws information from JCOG1413, comparing the efficacy of lobe-specific versus systematic LND with standardized LND protocols. A total of 1685 patients were included in this exploratory analysis (1251 VATSs and 434 open thoracotomies). Propensity score matching (PSM) ensured a balanced distribution of patient characteristics. The study’s end-point was N2 upstaging, defined as the proportion of upstaging from clinical N0–N1 to pathological N2. RESULTS: Among 1685 patients, 141 (8.3%) and 118 (7.0%) had pathological N1 and N2, respectively. The PSM yielded 852 patients (426 per group). The N2 upstaging proportions (7.8% [VATS] vs 7.3% [open], P = 0.795) and the influence of the lobectomy type on N2 upstaging were not significantly different between the 2 groups. The median number of N2 lymph nodes dissected per defined LND extent was similar (systematic: 13 in both groups, P = 0.236; lobe-specific: 7 in both groups, P = 0.720). Additionally, no significant difference in N2 upstaging was observed between hybrid and complete VATS groups (6.7% in both groups, P =. 982). CONCLUSIONS: This study found no significant differences in N2 upstaging proportions between the VATS and open thoracotomy groups of patients with clinical stage I–II NSCLC. This suggests comparable quality of mediastinal LND in both surgical approaches. CLINICAL TRIAL REGISTRATION: This study is a sub-analysis of the JCOG1413 randomized controlled trial. The JCOG1413 trial is registered with the UMIN Clinical Trials Registry (UMIN0000025530).

OBJECTIVES: This study aimed to compare the oncological features of centrally and peripherally located small-sized (≤2 cm), radiologically solid-dominant, cN0 non-small-cell lung cancer (NSCLC). METHODS: We retrospectively reviewed 1240 patients who underwent lobectomy or segmentectomy for radiologically solid-dominant cN0 NSCLC tumours ≤2 cm in size. Tumours were categorized as centrally (inner two-thirds of the pulmonary parenchyma) or peripherally (outer one-third) located. Clinicopathological characteristics and prognoses were compared between the 2 groups. RESULTS: Among the 1240 patients, 299 had centrally located and 941 had peripherally located tumours. Centrally located tumours showed a significantly higher proportion of pure solid tumours and pathological lymph node upstaging than peripherally located tumours (P = 0.018 and P = 0.038, respectively). Multivariable logistic regression analysis identified central location as an independent predictor for pN1 (odds ratio, 1.91; 95% confidence interval, 1.09–3.36; P = 0.024), but not for pN2, upstaging. The cumulative incidence of loco-regional and distant recurrences did not significantly differ between the 2 groups (P = 0.455 and P = 0.383, respectively). Overall survival and recurrence-free survival rates were also similar among patients with central and peripheral tumours (P = 0.267 and P = 0.269, respectively). CONCLUSIONS: Patient prognosis following complete anatomical resection was comparable between centrally and peripherally located radiologically solid-dominant cN0 NSCLC tumours ≤2 cm in size. However, centrally located tumours were associated with a higher risk of pN1 upstaging, highlighting the importance of thorough hilar lymph node dissection in these patients.

Background: This study aimed to elucidate the significance of the maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) by radiological ground glass opacity (GGO) tumors of non-small cell lung cancer (NSCLC), particularly in tumors assumed to be pathologically non-invasive. Methods: Overall, 709 consecutive patients with GGO-dominant NSCLC who underwent complete resections at three institutions between 2017 and 2022 were included. GGO-dominant tumors and pure GGO tumors were evaluated based on the SUVmax. The adenocarcinoma subtypes were categorized into low, medium, and high grade. The correlation between the SUVmax, pathological malignant grade, and pathological invasive diameter was examined. Results: In GGO-dominant lung adenocarcinoma, the SUVmax correlated positively with the pathological malignant grade and the pathological invasive diameters (respectively, (P = .0001), (P < .0001)). Similarly, in pure GGO lung adenocarcinoma, the SUVmax correlated positively with the pathological malignant grade. The median pathological invasive diameter was higher in patients with SUVmax ≥ 1.0 compared to those with SUVmax < 1.0 [10 mm vs 0 mm, respectively, (P = .017)]. Conclusions: A higher accumulation of FDG than in the background lung reflects invasive components even in pure GGO areas where only non-invasive components are expected. An FDG-PET/CT can complement the qualitative diagnosis in predicting invasive components with limitations in high-resolution computed tomography alone.