Neoadjuvant nivolumab plus chemotherapy in resectable non-small-cell lung cancer in Japanese patients from CheckMate 816.

In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB-IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8-not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5-NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30-1.24). The pCR rate was 30.3% (95% CI, 15.6-48.7) versus 5.7% (95% CI, 0.7-19.2), respectively; odds ratio, 7.17 (95% CI, 1.44-35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC.

The Role of Emphysema on Postoperative Prognosis in Early-Stage Nonsmall Cell Lung Cancer.

BACKGROUND: Emphysema is generally considered a poor prognostic factor for patients with nonsmall cell lung cancer; however, whether the poor prognosis is due to highly malignant tumors or emphysema itself remains unclear. This study was designed to determine the prognostic value of emphysema in patients with early-stage nonsmall cell lung cancer. METHODS: A total of 721 patients with clinical stage IA nonsmall cell lung cancer who underwent complete resection between April 2007 and December 2018 were retrospectively analyzed regarding clinicopathological findings and prognosis related to emphysema. RESULTS: The emphysematous and normal lung groups comprised 197 and 524 patients, respectively. Compared with the normal lung group, lymphatic invasion (23.9% vs. 14.1%, P = 0.003), vascular invasion (37.6% vs. 17.2%, P < 0.001), and pleural invasion (18.8% vs. 10.9%, P = 0.006) were observed more frequently in the emphysema group. Additionally, the 5-year overall survival rate was lower (77.1% vs. 91.4%, P < 0.001), and the cumulative incidence of other causes of death was higher in the emphysema group (14.0% vs. 3.50%, P < 0.001). Multivariable Cox regression analysis of overall survival revealed that emphysema (vs. normal lung, hazard ratio 2.02, P = 0.0052), age > 70 years (vs. < 70 years, hazard ratio 4.03, P < 0.001), and SUVmax > 1.8 (vs. ≤ 1.8, hazard ratio 2.20, P = 0.0043) were independent prognostic factors. CONCLUSIONS: Early-stage nonsmall cell lung cancer with emphysema has a tendency for the development of highly malignant tumors. Additionally, emphysema itself may have an impact on poor prognosis.

Differences in postoperative prognosis between early-stage lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND: Although prognosis and treatments differ between small-cell- and nonsmall-cell carcinoma, comparisons of the histological types of NSCLC are uncommon. Thus, we investigated the oncological factors associated with the prognosis of early-stage adenocarcinoma and squamous cell carcinoma. METHODS: We retrospectively compared the clinicopathological backgrounds and postoperative outcomes of patients diagnosed with pathological stage I-IIA adenocarcinoma and squamous cell carcinoma primary lung cancer completely resected at our department from January 2007 to December 2017. Multivariable Cox regression analysis for overall survival and recurrence-free survival was performed. RESULTS: The median follow-up duration was 55.2 months. The cohort consisted of 532 adenocarcinoma and 96 squamous cell carcinoma patients. A significant difference in survival was observed between the two groups, with a 5-year overall survival rate of 90% (95% confidence interval 86-92%) for adenocarcinoma and 77% (95% CI 66-85%) for squamous cell carcinoma (P < 0.01) patients. Squamous cell carcinoma patients had worse outcomes compared to adenocarcinoma patients in stage IA disease, but there were no significant differences between the two groups in stage IB or IIA disease. In multivariate analysis, invasion diameter was associated with overall survival in adenocarcinoma (hazard ratio 1.76, 95% confidence interval 1.36-2.28), but there was no such association in squamous cell carcinoma (hazard ratio 0.73, 95% confidence interval 0.45-1.14). CONCLUSIONS: The importance of tumor invasion diameter in postoperative outcomes was different between adenocarcinoma and squamous cell carcinoma. Thus, it is important to consider that nonsmall-cell carcinoma may have different prognoses depending on the histological type, even for the same stage.

A nomogram to predict the pathological complete response in patients with breast cancer based on the TILs-US score.

BACKGROUND: The tumor-infiltrating lymphocytes-ultrasonography score is a calculation system for predicting lymphocyte-predominant breast cancers in surgical specimens. A nomogram based on the tumor-infiltrating lymphocytes-ultrasonography score was developed to predict the pathological complete response in breast cancer treated with neoadjuvant chemotherapy. METHODS: A retrospective evaluation was conducted on 118 patients with breast cancer treated with neoadjuvant chemotherapy at Hiroshima University Hospital. Tumor-infiltrating lymphocytes-ultrasonography scores ≥4 were classified as high. A nomogram was developed using a stepwise logistic regression model for pathological complete response (ypT0 ypN0), based on the smallest Akaike information criterion. The predictive ability and clinical usefulness of the nomogram were also evaluated. RESULTS: Among 118 patients, 34 (28.8%) achieved a pathological complete response, and 52 (44.1%) exhibited high tumor-infiltrating lymphocytes-ultrasonography. In multivariate logistic regression analysis, high tumor-infiltrating lymphocytes-ultrasonography (odds ratio, 6.01; P < 0.001), clinical complete response (odds ratio, 4.83; P = 0.004) and hormone receptor (odds ratio, 3.48; P = 0.038) were independent predictors of pathological complete response. A nomogram based on tumor-infiltrating lymphocytes-ultrasonography score, clinical complete response, hormone receptor and clinical N status was developed. The nomogram showed an area under the curve of 0.831 and a bias-corrected area under the curve of 0.809. The calibration plot showed a good fit between the expected and actual pathological complete response values. Decision curve analysis also showed the clinical utility of the nomogram for predicting pathological complete responses. CONCLUSIONS: A nomogram based on the tumor-infiltrating lymphocytes-ultrasonography score exhibited a favorable predictive ability for pathological complete response in patients with breast cancer, which can be useful in predicting the residual disease status after neoadjuvant chemotherapy.

Association between prognosis and lymph node status using 18F-fluorodeoxyglucose-positron emission tomography in esophageal squamous cell carcinoma treated with esophagectomy post-neoadjuvant chemotherapy.

BACKGROUND: There are few reports on the associations between lymph node (LN) status, determined by preoperative 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), and prognosis in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy post-neoadjuvant chemotherapy (NCT). Additionally, details on the diagnostic performance of LN metastasis determination based on pathological examination versus FDG-PET have not been reported. In this study, we aimed to evaluate the associations among LN status using FDG-PET, LN status based on pathological examination, and prognosis in patients with locally advanced ESCC who underwent esophagectomy post-NCT. METHODS: We reviewed the data of 124 consecutive patients with ESCC who underwent esophagectomy with R0 resection post-NCT between December 2008 and August 2022 and were evaluated pre- and post-NCT using FDG-PET. The associations among LN status using FDG-PET, LN status based on pathological examination, and prognosis were assessed. RESULTS: Station-by-station analysis of PET-positive LNs pre- and post-NCT correlated significantly with pathological LN metastases (sensitivity, specificity, and accuracy pre- and post-NCT: 51.6%, 96.0%, and 92.1%; and 28.2%, 99.5%, and 93.1%, respectively; both p < 0.0001). Using univariate and multivariate analyses, LN status determined using PET post-NCT was a significant independent predictor of both recurrence-free survival and overall survival. CONCLUSION: The LN status assessed using FDG-PET post-NCT was significantly associated with the pathological LN status and prognosis in patients with ESCC who underwent esophagectomy post-NCT. Therefore, FDG-PET is a useful diagnostic tool for preoperatively predicting pathological LN metastasis and survival in these patients and could provide valuable information for selecting individualized treatment strategies.

Risk factors for recurrence of esophageal squamous cell carcinoma after pathological complete response to neoadjuvant therapy followed by esophagectomy.

BACKGROUND: Prognosis of patients who achieve pathological complete response (pCR) with neoadjuvant therapy (NAT) is better than that of non-pCR patients. Currently, there is no indication for adjuvant immune checkpoint inhibitor therapy after achieving pCR. However, recurrence risk after pCR is reportedly 10%-20% with a poor prognosis. Therefore, we investigated the preoperative risk factors for recurrence in patients with pCR. METHODS: We analyzed 56 patients with esophageal squamous cell carcinoma who underwent esophagectomy after neoadjuvant chemoradiotherapy (NACRT) or neoadjuvant chemotherapy (NAC) and were histologically diagnosed with pCR. Preoperative factors were compared between patients with and without recurrence to identify the risk factors. RESULTS: Forty-eight patients who achieved pCR received NACRT and 8 received NAC. Ten patients who experienced recurrence (17.9%) had undergone NACRT. The cN2 lesions were more frequent, and pre-NAT blood hemoglobin (Hb) was lower in the recurrence group. In addition, the pre-NAT cross-sectional area (CSA) product of the major and minor diameters of the primary tumor before NAT was significantly higher in recurrent cases (p = 0.041). Multivariate analysis, including the cTNM stage, pre-NAT Hb, and pre-NAT CSA, identified high pre-NAT CSA as the only risk factor for recurrence (odds ratio 11.6, 95% confidence interval 1.3-104.1, and p = 0.028). Cox regression analysis of recurrence-free and overall survival identified only high pre-NAT CSA as a prognostic factor. CONCLUSIONS: The recurrence risk is relatively high even in patients who achieve pCR after NAT. High pre-NAT CSA of the primary tumor is a risk factor for recurrence necessitating close surveillance.

Prognostic factors for esophageal squamous cell carcinoma without pathological lymph node metastasis after neoadjuvant therapy and surgery.

BACKGROUND: Pathological lymph node metastasis (LNM) following multimodal therapy is an important indicator of poor prognosis in patients with esophageal cancer. However, a significant number of patients without LNM are still at high risk for recurrence. METHODS: We assessed prognostic factors in 143 patients without pathological LNM who were diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) and underwent neoadjuvant chemotherapy (NAC) or chemoradiotherapy (NACRT), followed by surgery. RESULTS: Using univariate and multivariate analyses of recurrence-free survival, carcinoembryonic antigen (CEA) levels (hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.12-4.23, and p = 0.02) and neutrophil-to-lymphocyte ratio (NLR) (HR: 1.22, 95% CI: 1.04-1.43, and p = 0.02) were significant independent covariates. Furthermore, pretherapeutic LNM (HR: 1.94, 95% CI: 1.003-3.76, and p = 0.049), NACRT (HR: 3.29, 95% CI: 1.30-8.33, and p = 0.01), poorly differentiated tumors (HR: 2.52, 95% CI: 1.28-4.98, and p = 0.01), and lymphovascular invasion (LVI) (HR: 2.78, 95% CI: 1.27-6.09, and p = 0.01) were also significant independent covariates. The recurrence rates among patients with 0/1, 2, 3, and 4/5 poor prognostic factors were significantly different (5.0%, 25.0%, 35.7%, and 53.8%, respectively; p = 0.001); the survival rates were stratified among these prognostic groups. CONCLUSIONS: Pretherapeutic CEA and NLR levels, pretherapeutic LNM, NACRT, poorly differentiated tumors, and LVI were significantly correlated with survivals in patients without pathological LNM after neoadjuvant therapy and surgery. Postoperative therapy should be considered in patients with ESCC with several indicators of recurrence, even in those without pathological LNM who underwent surgery following neoadjuvant therapy.

The treatment efficacy and prognosis of each treatment in early postoperative recurrence of esophageal squamous cell carcinoma.

PURPOSE: Various treatments are used for early postoperative recurrence of esophageal cancer, which has a poor prognosis. We evaluated the differences in outcomes and prognoses of each treatment modality between patients with early and late recurrence. METHODS: Early and late recurrence were defined as recurrence within and after six postoperative months, respectively. Of the 351 patients with esophageal squamous cell carcinoma who underwent R0 resection esophagectomy, 98 experienced postoperative recurrence (early recurrence, n = 41; late recurrence, n = 57). We evaluated the characteristics of patients with early and late recurrence and compared their treatment responses and prognoses. RESULTS: Regarding treatment responses for chemotherapy or immunotherapy, the objective response rate was not significantly different between the early- and late-recurrence groups. For chemoradiotherapy, the objective response rate was significantly lower in the early-recurrence group than in the late-recurrence group. The overall survival was significantly worse in the early-recurrence group than in the late-recurrence group. An analysis by treatment type showed that the early-recurrence group had significantly worse overall survival for chemoradiotherapy, surgery, and radiotherapy than the late-recurrence group. CONCLUSIONS: Patients with early recurrence had particularly poor prognoses with worse post recurrence treatment efficacy than those with late recurrence. The differences in the treatment efficacy and prognosis were particularly pronounced for local therapy.

Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. METHODS: Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. RESULTS: The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6 months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5 months with tislelizumab (n = 10) versus 2.9 months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7 months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6 months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. CONCLUSIONS: As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov: NCT03430843.

Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407.

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m2 every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m2 (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5-24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5-not reached) versus 11.0 (8.6-19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27-1.15). Median PFS (95% CI) was 8.3 (6.1-13.0) versus 7.2 (3.9-8.8) months (HR 0.65; 95% CI, 0.35-1.23). Grade 3-5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.

Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.

BACKGROUND: Lobectomy is the standard of care for early-stage non-small-cell lung cancer (NSCLC). The survival and clinical benefits of segmentectomy have not been investigated in a randomised trial setting. We aimed to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC. METHODS: We conducted this randomised, controlled, non-inferiority trial at 70 institutions in Japan. Patients with clinical stage IA NSCLC (tumour diameter ≤2 cm; consolidation-to-tumour ratio >0·5) were randomly assigned 1:1 to receive either lobectomy or segmentectomy. Randomisation was done via the minimisation method, with balancing for the institution, histological type, sex, age, and thin-section CT findings. Treatment allocation was not concealed from investigators and patients. The primary endpoint was overall survival for all randomly assigned patients. The secondary endpoints were postoperative respiratory function (6 months and 12 months), relapse-free survival, proportion of local relapse, adverse events, proportion of segmentectomy completion, duration of hospital stay, duration of chest tube placement, duration of surgery, amount of blood loss, and the number of automatic surgical staples used. Overall survival was analysed on an intention-to-treat basis with a non-inferiority margin of 1·54 for the upper limit of the 95% CI of the hazard ratio (HR) and estimated using a stratified Cox regression model. This study is registered with UMIN Clinical Trials Registry, UMIN000002317. FINDINGS: Between Aug, 10, 2009, and Oct 21, 2014, 1106 patients (intention-to-treat population) were enrolled to receive lobectomy (n=554) or segmentectomy (n=552). Patient baseline clinicopathological factors were well balanced between the groups. In the segmentectomy group, 22 patients were switched to lobectomies and one patient received wide wedge resection. At a median follow-up of 7·3 years (range 0·0-10·9), the 5-year overall survival was 94·3% (92·1-96·0) for segmentectomy and 91·1% for lobectomy (95% CI 88·4-93·2); superiority and non-inferiority in overall survival were confirmed using a stratified Cox regression model (HR 0·663; 95% CI 0·474-0·927; one-sided p<0·0001 for non-inferiority; p=0·0082 for superiority). Improved overall survival was observed consistently across all predefined subgroups in the segmentectomy group. At 1 year follow-up, the significant difference in the reduction of median forced expiratory volume in 1 sec between the two groups was 3·5% (p<0·0001), which did not reach the predefined threshold for clinical significance of 10%. The 5-year relapse-free survival was 88·0% (95% CI 85·0-90·4) for segmentectomy and 87·9% (84·8-90·3) for lobectomy (HR 0·998; 95% CI 0·753-1·323; p=0·9889). The proportions of patients with local relapse were 10·5% for segmentectomy and 5·4% for lobectomy (p=0·0018). 52 (63%) of 83 patients and 27 (47%) of 58 patients died of other diseases after lobectomy and segmentectomy, respectively. No 30-day or 90-day mortality was observed. One or more postoperative complications of grade 2 or worse occurred at similar frequencies in both groups (142 [26%] patients who received lobectomy, 148 [27%] who received segmentectomy). INTERPRETATION: To our knowledge, this study was the first phase 3 trial to show the benefits of segmentectomy versus lobectomy in overall survival of patients with small-peripheral NSCLC. The findings suggest that segmentectomy should be the standard surgical procedure for this population of patients. FUNDING: National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Hypoxia-inducible factor 1α modulates interstitial pneumonia-mediated lung cancer progression.

BACKGROUND: The prognosis of patients with lung cancer accompanied by interstitial pneumonia is poorer than that of patients with lung cancer but without interstitial pneumonia. Moreover, the available therapeutic interventions for lung cancer patients with interstitial pneumonia are limited. Therefore, a new treatment strategy for these patients is required. The aim of the present study was to investigate the pathophysiological relationship between interstitial pneumonia and lung cancer and explore potential therapeutic agents. METHODS: A novel hybrid murine model of lung cancer with interstitial pneumonia was established via bleomycin-induced pulmonary fibrosis followed by orthotopic lung cancer cell transplantation into the lungs. Changes in tumor progression, lung fibrosis, RNA expression, cytokine levels, and tumor microenvironment in the lung cancer with interstitial pneumonia model were investigated, and therapeutic agents were examined. Additionally, clinical data and samples from patients with lung cancer accompanied by interstitial pneumonia were analyzed to explore the potential clinical significance of the findings. RESULTS: In the lung cancer with interstitial pneumonia model, accelerated tumor growth was observed based on an altered tumor microenvironment. RNA sequencing analysis revealed upregulation of the hypoxia-inducible factor 1 signaling pathway. These findings were consistent with those obtained for human samples. Moreover, we explored whether ascorbic acid could be an alternative treatment for lung cancer with interstitial pneumonia to avoid the disadvantages of hypoxia-inducible factor 1 inhibitors. Ascorbic acid successfully downregulated the hypoxia-inducible factor 1 signaling pathway and inhibited tumor progression and lung fibrosis. CONCLUSIONS: The hypoxia-inducible factor 1 pathway is critical in lung cancer with interstitial pneumonia and could be a therapeutic target for mitigating interstitial pneumonia-mediated lung cancer progression.

Distribution and prognostic impact of EGFR and KRAS mutations according to histological subtype and tumor invasion status in pTis-3N0M0 lung adenocarcinoma.

BACKGROUND: The prognostic impact of EGFR mutation as major targetable somatic gene variant on lung adenocarcinoma is controversial. KRAS is another major somatic variant in lung adenocarcinoma, and a therapeutic agent for KRAS G12C became available in clinical settings. These mutations represent clinicopathological features of lung adenocarcinoma and can guide the treatment choice after recurrence. We evaluated the prognostic impact of EGFR and KRAS mutations by considering other clinicopathological recurrence risks in resected pTis-3N0M0 lung adenocarcinoma. METHODS: Clinicopathological features related to recurrence and genetic status were estimated in consecutive 877 resected cases. Recurrence-free survival (RFS), cumulative recurrence rate (CRR), and overall survival (OS) were compared. Uni- and multivariate analyses for RFS were performed after excluding cases with little or no recurrence risks. RESULTS: EGFR mutation was more likely to be harbored in female, never-smoker, or patients accompanied by > 5% lepidic component. KRAS mutation was more likely to be harbored in patients with current/ex-smoking history, International Association for the Study of Lung Cancer (IASLC) grade 3, or accompanied lymphatic or vascular invasion. In IASLC grade 2 and 3 patients, EGFR or KRAS mutation cases had significantly worse 5-year RFS than wild type patients (76.9% vs. 85.0%, hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.62-6.41, P < 0.001). EGFR or KRAS mutation cases had significantly higher 5-year CRR than wild type patients (17.7% vs. 9.8%, HR = 1.69, 95% CI = 1.44-6.59, P = 0.0038). KRAS mutation cases had higher 5-year CRR than EGFR mutation cases (16.7% vs. 21.4%, HR = 1.62, 95% CI = 0.96-7.19, P = 0.061). There was no significant difference in OS between cohorts. Multivariate analysis revealed that a positive EGFR/KRAS mutation status was risk factor for worse RFS (HR = 2.007, 95% CI = 1.265-3.183, P = 0.003). CONCLUSION: Positive EGFR and KRAS mutation statuses were risk factors for recurrence in resected IASLC grade 2 and 3 patients. KRAS mutations were more likely to be confirmed in cases with an increased risk of recurrence. EGFR and KRAS mutation statuses should be evaluated simultaneously when assessing the risk of recurrence.

Preoperative predictors for recurrence sites associated with poor post-recurrence survival after surgery of non-small cell lung cancer: a multicenter study.

BACKGROUND: The recurrence site that influences post-recurrence survival (PRS) in patients with non-small cell lung cancer (NSCLC) undergoing surgery and the preoperative predictors of recurrence remain unclear. METHODS: Cohorts 1 and 2 had 4520 (who underwent complete resection for p-stage 0-IIIA NSCLC) and 727 (who experienced recurrence after surgery) patients, respectively. The initial sites of recurrence were the lungs (309 cases), thoracic lymph nodes (225 cases), pleura (112 cases), bone (110 cases), central nervous system (86 cases), adrenal gland (25 cases), abdomen (60 cases), cervical and axillary lymph nodes (38 cases), chest wall (13 cases), skin (5 cases), and eye and tongue (3 cases). For cohort 2 analysis, the initial recurrence site that resulted in poor PRS was analyzed by multivariable analysis using a Cox proportional hazard model. For cohort 1 analysis, the preoperative predictors of recurrence patterns with poor PRS were analyzed by multivariable analysis using a logistic regression model. RESULTS: In cohort 2 analysis, recurrence in the central nervous system (hazard ratio [HR], 1.70; p < 0.001), bone (HR, 1.75; p < 0.001), abdomen (HR, 2.39; p < 0.001), and pleura (HR, 1.69; p < 0.001) were independent poor prognostic recurrent sites for PRS and they were high-risk sites (HRS). Intrathoracic lymph nodes, cervical and axillary lymph nodes, lungs, chest wall, adrenal gland, eye and tongue, and skin were low-risk sites (LRS) that did not affect PRS. Patients with multiple LRS without HRS recurrence had a worse prognosis than those with a single LRS without HRS recurrence (5-year PRS 20.2% vs. 37.7%, p < 0.001) and were comparable to those with HRS recurrence (p = 1.000). In cohort 1 analysis, preoperative predictors for HRS and multiple LRS recurrences were positron emission tomography (PET) maximum standardized uptake value (maxSUV) ≥ 3.2 (HR, 5.09; p < 0.001), clinical nodal metastasis (HR, 2.00; p < 0.001), tumor size ≥ 2.4 cm (HR, 1.96; p < 0.001) and carcinoembryonic antigen (CEA) ≥ 5 ng/ml (HR, 1.41; p = 0.004). The cumulative incidence rates of HRS and multiple LRS recurrences within 5 years were 55.9%, 40.9%, 26.3%, 11.1%, and 3.5% (p < 0.001) in patients with 4, 3, 2, 1 and 0 of the above risks, respectively. CONCLUSIONS: HRS and multiple LRS were vital recurrences associated with poor PRS. Preoperative PET maxSUV, clinical nodal metastasis, tumor size, and CEA level predicted the incidence of vital recurrence.

Clinicopathologic study of stage I adenosquamous carcinoma of the lung.

OBJECTIVE: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components. Adenosquamous carcinoma is reported to have an aggressive clinical course, but its clinicopathological features and prognosis are unclear in the early stage. METHODS: Patients who underwent surgical resection for pathological stage I non-small cell lung cancer between April 2009 and December 2014 were retrospectively reviewed. Preoperative and postoperative data, histologic characteristics and outcomes of patients with adenosquamous carcinoma (n = 40) were compared to adenocarcinoma (n = 598) and squamous cell carcinoma (n = 131) patients. Factors affecting prognosis, particularly on recurrence, were assessed via Cox regression analyses. RESULTS: Patients with adenosquamous carcinoma had a worse prognosis than did patients with adenocarcinoma and squamous cell carcinoma in terms of 5 year overall (66.7%) and recurrence-free survival rates (44.9%), as well as a significantly higher recurrence rate (13/40 patients, 32.5%). Multivariable Cox regression analysis for recurrence-free survival rates revealed that the histology of adenosquamous carcinoma was an independent factor for recurrence (hazard ratio: 2.473, 95% confidence interval: 1.328-3.367; P = 0.0004). High serum carcinoembryonic antigen levels (hazard ratio: 5.962) and vascular invasion (hazard ratio: 4.899) were identified as risk factors for recurrence, and patients with adenosquamous carcinoma tended to have distant relapses, such as in the brain. CONCLUSIONS: Early-stage adenosquamous carcinoma of the lung is a histological type associated with severe prognosis and postoperative recurrence, often in distant sites, in approximately one-third of cases. High serum carcinoembryonic antigen levels and vascular invasion might be risk factors of recurrence.

A multicenter propensity score-matched analysis of lymphadenectomy in N1-positve lung cancer.

OBJECTIVES: Selective mediastinal lymph node dissection based on lobe-specific metastases is widely recognized in daily practice. However, the significance of mediastinal lymph node dissection for N1-positive tumors has not been elucidated. METHODS: We retrospectively reviewed 359 patients with N1-positive lung cancer who underwent lobectomy with systematic mediastinal lymph node dissection (systematic lymph node dissection) (n = 150) and lobe-specific mediastinal lymph node dissection (lobe-specific lymph node dissection) (n = 209). The operative and postoperative results and their propensity score-matched pairs were compared. The factors affecting survival were assessed using competing risk and multivariable analyses. RESULTS: The cumulative incidence of recurrence and the cumulative incidence of cancer-specific death were not significantly different between systematic and lobe-specific lymph node dissection in entire cohort. In the propensity score-matched cohort (83 pairs), systematic lymph node dissection tended to detect N2 lymph node metastasis more frequently (55.4 vs. 41%, P = 0.087). Eleven patients (13.2%) in the systematic lymph node dissection group had a metastatic N2 lymph node 'in the systematic lymph node dissection field' that lobe-specific lymph node dissection did not dissect. The oncological outcomes between patients undergoing systematic lymph node dissection (5-year cumulative incidence of recurrence, 62.1%; 5-year cumulative incidence of cancer-specific death, 27.9%) and lobe-specific lymph node dissection (5-year cumulative incidence of recurrence, 60.1%; 5-year cumulative incidence of cancer-specific death, 23.3%) were similar. The propensity score-adjusted multivariable analysis for cumulative incidence of recurrence revealed that the prognosis associated with systematic lymph node dissection was comparable with the prognosis with lobe-specific lymph node dissection (hazard ratio, 1.17; 95% confidence interval, 0.82-1.67; P = 0.37). CONCLUSIONS: The extent of lymph node dissection can affect accurate pathological staging; however, it was not associated with survival outcome in the treatment of N1-positive lung cancer.

Long-term results of chemoradiotherapy with elective nodal irradiation for resectable locally advanced esophageal cancer in three-dimensional planning system.

BACKGROUND: We evaluated the long-term results of definitive chemoradiotherapy (CRT) with elective nodal irradiation (ENI) using a three-dimensional (3D) planning system for resectable, locally advanced esophageal squamous cell carcinoma (LA-ESCC). METHODS: This retrospective study included 65 patients with LA-ESCC who started CRT between 2006 and 2017. Patients with Stage I-IV LA-ESCC according to the Union for International Cancer Control TNM classification (eighth edition) were included. In stage IV, only supraclavicular lymph node (LN) metastasis was included. All patients received radiotherapy with ENI and concurrent chemotherapy with platinum and 5-fluorouracil. RESULTS: The median age of the patients was 70 years (range 52-83 years). Stage I, II, III, and IV diseases were observed in 3 (5%), 28 (43%), 22 (34%), and 12 patients (18%), respectively. The median prescription dose was 66 Gy (range 50.4-66 Gy). The median follow-up period for the survivors was 71 months (range 8-175 months). The 5-year overall survival (OS) and progression-free survival rates were 54 and 43%, respectively. The 5-year OS rates for stages I-II and III-IV were 67 and 42%, respectively. Recurrence occurred in 29 patients (45%), and recurrence of regional LNs only occurred in 2 patients (3%). Grade 3 or higher late adverse events were observed in 8 patients (12%). Grade 5 heart failure occurred in two patients (3%); both had cardiovascular disease before treatment. CONCLUSION: The long-term results of definitive CRT with ENI for resectable LA-ESCC were favorable. ENI with a 3D planning system may reduce regional LN recurrence and late adverse events.

Feasibility of repeated ipsilateral anatomical pulmonary resection.

PURPOSE: This study aimed to elucidate the feasibility of repeated ipsilateral anatomical pulmonary resection. METHODS: The subjects of this retrospective analysis were 50 patients who underwent ipsilateral anatomical pulmonary resection after major lung surgery. The patients were divided into two groups according to the type of primary operation performed: a repeated anatomical pulmonary resection group (RA group; n = 24) and an anatomical pulmonary resection after wedge resection group (AW group; n = 26). We compared the perioperative outcomes of the two groups. RESULTS: Completion lobectomy was performed in 9 of the 24 patients (38%) from the RA group and adhesion of the pulmonary hilum was more severe in this group (P = 0.004). Although the operative time was significantly longer in the RA group (P = 0.030), there was no significant difference in the amount of blood loss (P = 0.217) between the groups. A significantly higher rate of severe postoperative complications was observed in the RA group (42%) than in the AW group (12%) (P = 0.024). None of the patients who underwent repeated surgery died within 90 days postoperatively. CONCLUSION: Although repeated anatomical pulmonary resection is a more challenging procedure than anatomical resection after wedge resection, it does not increase short-term mortality; therefore, it is a feasible treatment option.

[Dawn of Radical Segmentectomy for Small Sized Peripheral Non-small Cell Lung Cancer].

The result of prospective, randomized, controlled, trial, Japan Clinical Oncology Group (JCOG) 0802/ West Japan Oncology Group( WJOG) 4607L, has been published in April 2022. The superiority in overall survival for patients who underwent segmentectomy for small sized peripheral non-small cell lung cancer( NSCLC)( whole tumor size≤2 cm, C/T ratio>0.5) compared with those undergoing lobectomy has been demonstrated for the first time in the world. Segmentectomy might become a standard surgical procedure for such tumors. Consequently, the opportunity to perform segmentectomy will increase. Developing techniques for segmentectomy is an urgent issue for general thoracic surgeons because segmentectomy generally requires more advanced surgical technique than lobectomy. In particular, the radical segmentectomy is an anatomically limited resection with hilar and mediastinal lymph node dissection. That means anatomically accurate resection of the pulmonary segment. There are a lot of points to be mastered in operative indications based on tumor size, phenotype, and location, understandings of anatomy, surgical techniques, transition to lobectomy, and so on. In this article, we would like to share some tips on segmentectomy primarily focusing on the surgical techniques.

Effectiveness of taxanes following nivolumab in patients with advanced esophageal squamous cell carcinoma: a retrospective chart review of patients in ATTRACTION-3.

BACKGROUND: The phase III ATTRACTION-3 study showed that second-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma prolonged overall survival (OS) but did not improve progression-free survival (PFS). Subsequent systemic therapy after discontinuing nivolumab may affect these outcomes. To test this possibility, we evaluated the outcomes of treatment with taxanes after nivolumab in ATTRACTION-3. METHODS: We reviewed the charts of Japanese patients who had discontinued second-line nivolumab in ATTRACTION-3 and started subsequent third-line taxanes between January 7, 2016, and November 12, 2018. The primary endpoint was objective response rate (ORR) to third-line taxanes. RESULTS: Of the 75 patients included in this study, 54 (72%), 18 (24%), and 3 (4%) patients received either paclitaxel, docetaxel, or combination therapy comprising docetaxel, cisplatin, and 5-fluorouracil, respectively. The ORR in the overall, paclitaxel, and docetaxel groups was 29.6%, 36.5%, and 12.5%, respectively; these numbers were comparable to those (20-44%) in patients receiving taxanes as first- and second-line therapy. The median OS in the overall, paclitaxel, and docetaxel groups was 9.9, 9.9, and 9.3 months, respectively, whereas the corresponding median PFS was 4.9, 4.7 and 6.5 months, respectively. Treatment-related adverse events were observed in 65 (87%) patients, of which grade 3-4 occurred in 37 (49%) patients. CONCLUSIONS: Favorable effectiveness and safety profile of taxanes following second-line nivolumab was observed in Japanese patients with advanced esophageal squamous cell carcinoma. When a patient with advanced esophageal squamous cell carcinoma receiving nivolumab becomes refractory or intolerant, subsequent taxane treatment may be a promising option.