Hiroyuki Ito

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.

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.

Background: Uterine malignancies frequently metastasize to the lungs. Pulmonary metastasectomy has demonstrated survival benefits in some malignancies; however, its efficacy for uterine malignancies remains unclear. Methods: We retrospectively analyzed 38 patients who underwent pulmonary metastasectomy for uterine malignancies at the Kanagawa Cancer Center between 2010 and 2020. The primary endpoint was recurrence-free survival (RFS) after pulmonary resection. Results: The median patient age was 63 years. The primary sites were the cervical uteri (n = 22) and corpus uteri (n = 16). The FIGO stages at the time of treatment for the primary tumor were I, II, III, IV, and unknown in 20, 7, 9, 1, and 1 patient, respectively. The median disease-free interval (DFI), defined as the interval between primary treatment and first recurrence, was 26.5 months. Most patients had single metastasis (n = 32). The procedures for metastasectomy included lobectomy, segmentectomy, and wedge resection (n = 15, 8, and 15, respectively), and two cases resulted in microscopically incomplete resection. The median follow-up period after pulmonary metastasectomy was 57 months, with 16 patients experiencing recurrence after pulmonary metastasectomy (5-year RFS rate: 55.6%). Univariate analysis identified FIGO stage ≥ III, DFI < 12 months, presence of synchronous extrapulmonary recurrence, and uterine sarcoma as poor prognostic factors. No prognostic differences were found between cervical and corpus uteri cancers. Conclusions: Pulmonary metastasectomy may confer prognostic benefits in patients with uterine malignancies. Careful consideration is warranted for patients with advanced-stage primary tumors, early recurrence after primary treatment, synchronous extrapulmonary recurrence, and uterine sarcoma.

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.

Background: Visceral pleural invasion (VPI) has traditionally been regarded as a negative prognostic indicator in non-small-cell lung cancer (NSCLC). However, with the increasing adoption of sublobar resection for small-sized NSCLC, the clinical significance of VPI is being fundamentally reassessed. Specifically, it remains uncertain whether VPI is indicative of tumor size or represents distinct metastatic behavior. Methods: We conducted a retrospective comprehensive multicenter study involving 2464 patients with pathologically confirmed NSCLC ≤ 3 cm who underwent complete resection at three Japanese institutions. The prevalence, metastatic patterns, and prognostic impact of VPI were systematically evaluated, with particular focus on histological growth patterns. Results: VPI was identified in 370 patients (15%). Notably, VPI-positive tumors demonstrated a doubled incidence of lymph node metastasis (31% vs. 15%, p < 0.001) and a distinct metastatic profile characterized by preferential hilar spread (#12, 16.9%) and an increased risk of skip N2 metastasis (4.0% vs. 2.0%). Five-year recurrence-free survival was significantly reduced in the VPI group (33.7% vs. 50.6%, respectively). Conversely, adenocarcinomas with lepidic characteristics demonstrated a minimal risk of VPI or nodal metastasis, with incidences of 2% and 1%, respectively. This finding highlights the heterogeneity in the biological aggressiveness of small-sized NSCLC. Conclusions: Our findings suggest that VPI is not merely a histopathological descriptor but also acts as a clinically significant indicator of aggressive metastatic behavior, potentially enhancing surgical and staging approaches beyond just considering tumor size. With the increasing adoption of sublobar resection for small-sized NSCLC, recognizing that VPI appears to be associated with predominant hilar involvement and an elevated risk of skip N2 metastasis may help refine decisions on the extent of lung and lymph node resection.

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 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.

OBJECTIVES: Despite clinical trials supporting the efficacy of segmentectomy for early-stage non-small cell lung cancer (NSCLC), a previous report indicated its limited efficacy in younger patients, raising concerns about its indication. METHODS: Patients aged <70 years with radiologically solid-dominant clinical stage IA NSCLC ≤2 cm who underwent lobectomy or segmentectomy at three institutions between 2010 and 2017 were enrolled. Propensity scores were estimated to adjust for confounding variables (age, sex, smoking history, tumour location, size, ground-glass opacity, maximum standardized uptake value and histological type). To elucidate the prognostic impact of surgical indications in the late postoperative phase, restricted mean survival time (RMST) from 0 to 5 and 8 years was also determined. RESULTS: Overall, 388 patients with a median age of 63 years were enrolled. Overall survival (OS) (hazard ratio [HR], 0.447; 95% confidence interval [CI], 0.152–1.316) and recurrence-free survival (RFS) (HR, 0.638; 95% CI, 0.335–1.216) did not differ significantly between the segmentectomy (n = 114) and lobectomy groups (n = 274). In the propensity score matching of 100 pairs, OS (HR, 0.577; 95% CI, 0.162–2.056) and RFS (HR, 0.945; 95% CI, 0.408–2.191) were comparable between the segmentectomy and lobectomy groups. Regarding OS in the segmentectomy and lobectomy groups, the 5- and 8-year RMST were 4.95 years versus 4.92 years (difference: 0.02 years; 95% CI, −0.09–0.13; P = 0.699) and 7.82 years versus 7.69 years (difference: 0.12 years; 95% CI, −0.17–0.42; P = 0.420), respectively. CONCLUSIONS: Segmentectomy is a viable option for younger patients with early-stage NSCLC, suggesting that indications for segmentectomy need not vary by age.