Prophylactic effect of tissue flap in the prevention of bronchopleural fistula after surgery for lung cancer.

PURPOSE: Bronchopleural fistula (BPF) is a serious complication of lung resection. To avoid BPF, the bronchial stump/anastomotic site is often covered with a flap of surrounding tissue. One risk factor for BPF is radical lung resection after induction chemoradiotherapy for lung cancer. We retrospectively reviewed our database to elucidate the characteristics of tissue flaps that prevent BPF. METHODS: This retrospective study included 152 patients treated between 1999 and 2019. We examined the clinicopathological characteristics, including the type and thickness of the tissue flap used to cover the bronchial stump/anastomotic site, and postoperative complications, including BPF. RESULTS: BPF occurred in 5 patients (3.3%). All 5 patients had complications that could have affected delayed wound healing, such as pneumonia. The covering tissue flap thickness was significantly greater in patients without BPF than in those who developed BPF (p = 0.0290). Additionally, the tissue flap thickness was significantly greater than in those with BPF (p = 0.0077), even in high-risk patients who developed pneumonia or radiation pneumonitis on the operative side within 6 months postoperatively. CONCLUSION: Perioperative management is crucial to avoid complications affecting the healing of the bronchial stump/anastomotic site, and the covering tissue flap thickness may be an important factor in avoiding or minimizing BPF.

Impact of the neutrophil-to-lymphocyte ratio on patients with locally advanced non-small cell lung cancer who suffer radiation pneumonitis during the course of induction chemoradiotherapy followed by surgery.

PURPOSE: Radiation pneumonitis (RP) is an obstacle for patients after surgery following induction chemoradiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). We performed a comparative analysis of the association between clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and prognosis, in LA-NSCLC patients with or without RP during induction chemoradiotherapy followed by surgery. METHODS: The subjects of this analysis were 168 patients undergoing trimodality therapy for LA-NSCLC between January, 1999 and May, 2019. Patients were divided into two groups: the RP group (n = 41) and the non-RP group (n = 127). We compared the clinicopathological factors including the NLR between the groups and analyzed the association between the NLR and prognosis. RESULTS: The RP group had more patients with tumors located in the lower lobe, more bilobar resections, shorter operative times, no implementation of postoperative adjuvant chemotherapy, and a higher postoperative NLR than the non-RP group. There were no significant differences in serious postoperative complications and the prognosis. Patients with a low postoperative NLR had a significantly better prognosis in the non-RP group, and a trend toward a better prognosis even in the RP group. CONCLUSION: Postoperative NLR may be a useful prognostic factor, even for patients who suffer RP after trimodality therapy for LA-NSCLC.

Successful Bronchoscopic Treatment for Postoperative Bronchopleural Fistula Using N-butyl-2-cyanoacrylate (NBCA): Report of a Post-completion Pneumonectomy Case with a History of Induction Chemoradiotherapy Followed by Bilobectomy for Advanced Lung Cancer.

Bronchopleural fistula (BPF) is a severe complication following lung resection. We present the case of a patient with a history of advanced lung cancer, who had undergone induction chemoradiotherapy followed by right middle and lower lobectomy, and who developed BPF after completion right pneumonectomy. Although we had covered the bronchial stump with an omental pedicled flap, BPF was found on postoperative day 19. We covered the fistula with n-butyl-2-cyanoacrylate (NBCA) using bronchoscopy. Although we had to repeat the NBCA treatment, we ultimately cured the patient's BPF and no recurrence was observed up to 15.2 months after surgery.

The impact of early tumor shrinkage on conversion surgery and the survival in patients with unresectable locally advanced pancreatic cancer.

PURPOSES: Owing to recent advances in induction chemo(radio)therapy, patients with unresectable locally advanced pancreatic ductal adenocarcinoma (UR-LA PDAC) are sometimes indicated for conversion surgery (CS). However, the predictors for proceeding to CS are unclear. We investigated the predictive factors for CS, especially at the early stage of induction therapy, and evaluated the impact of CS on the survival. METHODS: We analyzed 49 UR-LA PDAC patients retrospectively and investigated the predictive factors for proceeding to CS, including early tumor shrinkage (ETS). ETS in this study was defined as shrinkage of tumors by ≥ 15% at 8-12 weeks after the induction of treatment. RESULTS: CS was performed in 21 patients (43%). In a multivariate logistic regression analysis, ETS was an independent predictive factor for successfully proceeding to CS (P = 0.046). The median overall survival (OS) was not reached in the CS group but was 17.2 months in the non-CS group (P < 0.0001). A multivariate analysis by the Cox proportional hazard model identified CS as the only significant independent determinant of the OS (hazard ratio: 0.26, 95% confidence interval: 0.07-0.94, P = 0.004). CONCLUSIONS: ETS by induction therapy is a significant predictor of proceeding to CS among patients with UR-LA PDAC. CS was the only independent prognostic factor for this population.

Prognostic nutrition index affects the prognosis of patients undergoing trimodality therapy for locally advanced non-small cell lung cancer.

PURPOSE: Trimodality therapy, comprised of induction chemoradiotherapy (iCRT) followed by surgery, is a highly invasive treatment option for locally advanced non-small cell lung cancers (LA-NSCLCs; defined as a heterogenous disease). We conducted this study to investigate the prognostic nutritional index (PNI) of LA-NSCLC patients undergoing trimodality therapy, which has not been studied in detail before. METHODS: The subjects of this retrospective study were 127 patients who underwent trimodality therapy between 1999 and 2016. We measured the PNI at three points: before iCRT (pre-iCRT), before the operation, and after the operation. RESULTS: PNIs decreased significantly as treatment progressed. Patients with clinical T3/4 (cT3/4) disease had a significantly lower PNI than those with cT1/2 disease, but the extent of lymph-node metastasis did not affect the PNI at any point. Using the cut-off values of receiver-operating curve analyses, multivariable analyses revealed that a high PNI pre-iCRT correlated significantly with a better survival of LA-NSCLC patients, especially those with cT3/4 disease (hazard ratio 3.84; 95% confidential interval 1.34-12.5, P = 0.012). CONCLUSIONS: Measuring the PNI before trimodality therapy is important for predicting the clinical outcome of patients with LA-NSCLC, with differing predictive ability according to the disease extent. Perioperative intensive nutritional intervention must be considered for patients who undergo trimodality therapy for LA-NSCLC.

Ribcage procedure after neoadjuvant chemoradiotherapy for non-small cell lung cancer involving the chest wall.

PURPOSE: Non-small cell lung cancer (NSCLC) involving the chest wall is usually treated with en bloc rib resection or parietal pleurectomy; however, the former causes chest wall deformity and the latter is associated with local recurrence. To prevent both these sequalae, we performed the "ribcage" procedure for tumors involving the chest wall after induction chemoradiotherapy. METHODS: This was a single center retrospective study conducted from 2012 to 2018. The "ribcage" procedure is designed to preserve the ribs of patients with lung tumors involving chest wall and involves peeling the intercostal muscles and periosteum from the ribs, resulting in a birdcage-like appearance. Seventeen patients with NSCLC clearly involving the chest wall, but not destroying the ribs, were treated with induction chemoradiotherapy, followed by the ribcage procedure. A negative margin at the ribs was confirmed by intraoperative frozen sections in 16 of these patients, who then underwent the ribcage procedure. RESULTS: Complete resection was achieved in all 16 patients, none of whom experienced major postoperative complications. After a median follow-up period of 37 months, there was no evidence of local recurrence in any of the patients. CONCLUSION: Our findings suggest that the ribcage procedure is the preferable surgical option as it can prevent chest wall deformities as well as local recurrence.

Dose-volume parameters predict radiation pneumonitis after induction chemoradiotherapy followed by surgery for non-small cell lung cancer: a retrospective analysis.

BACKGROUND: The relationship between lung dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) associated with induction concurrent chemoradiotherapy (CCRT) followed by surgery in patients with non-small cell lung cancer (NSCLC) is unclear, particularly when concerning irradiation of the whole lung prior to resection. We performed this study to identify factors associated with grade ≥ 2 RP in such patients. METHODS: Patients who received induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 46 Gy/23 fractions) between May 2003 and May 2017 were reviewed. The mean lung dose (MLD) and the percentage of the lung volume that received ≥5 Gy (V5) and ≥ 20 Gy (V20) were calculated. Factors associated with the development of grade ≥ 2 RP were analyzed. RESULTS: One hundred and eight patients were included in this study, 34 (31.5%) of whom experienced grade ≥ 2 RP. A V20 ≥ 21%, an MLD ≥10 Gy, and a lower lobe tumor location were significant predictors of grade ≥ 2 RP on univariate analysis (p = 0.007, 0.002, and 0.004, respectively). Moreover, an MLD ≥10 Gy and lower lobe location were significant predictors of grade ≥ 2 RP on multivariate analysis (p = 0.026 and 0.0043, respectively). The cumulative incidence rates of grade ≥ 2 RP at 6 months were 15.7 and 45.6% in patients with MLDs < 10 Gy and ≥ 10 Gy, respectively, and were 23.5 and 55.6% in patients with upper/middle lobe- vs. lower lobe-located tumors, respectively. CONCLUSIONS: MLD and lower lobe location were predictors of grade ≥ 2 RP in patients who received induction CCRT. It is necessary to reduce the MLD to the greatest extent possible to prevent the occurrence of this adverse event.

Clinical outcome of patients with recurrent non-small cell lung cancer after trimodality therapy.

PURPOSES: The purpose of this study was to review the clinical course of patients with recurrence after induction chemoradiotherapy followed by surgery (trimodality therapy) for locally advanced non-small cell lung cancer (LA-NSCLC) and to identify the factors associated with favorable clinical outcome after recurrence. METHODS: We analyzed the records of 140 patients with LA-NSCLC who were treated with trimodality therapy between 1999 and 2014. RESULTS: Recurrence developed after trimodality therapy in 48 patients. A yp-N positive status was associated with a high risk of recurrence (HR, 2.05; P = 0.048). Of the 45 of these patients able to be assessed retrospectively, 18 had oligometastatic recurrence and 20 underwent local treatment with curative intent. Local treatment was most frequently given to patients with oligometastatic recurrence (P < 0.001). The median post-recurrence survival (PRS) was 41.4 months, and the 2-year PRS rate was 62%. Patients who received local treatment showed better PRS (P = 0.009). The presence of liver metastasis (P = 0.008), bone metastasis (P = 0.041), or dissemination (P < 0.0001) were associated with worse PRS. CONCLUSION: The survival of patients who received aggressive local treatment for postoperative recurrence after trimodality therapy for LA-NSCLC was better than that of patients who did not.

Pneumonectomy after induction chemoradiotherapy for locally advanced non-small cell lung cancer: should curative intent pulmonary resection be avoided?

PURPOSE: We conducted a retrospective analysis to assess the practicality of pneumonectomy, especially after concurrent induction chemoradiotherapy (i-CRT), for locally advanced non-small cell lung cancer (LA-NSCLC). The operative risks vs. the survival benefit of this procedure for such patients is a subject of controversy. METHODS: The subjects of this retrospective study were 71 consecutive LA-NSCLC patients with cStage IIIA-C NSCLC, who underwent i-CRT followed by curative intent pulmonary resection between February, 2001 and March, 2013. RESULTS: Thirty-two patients underwent pneumonectomy (group P) and 39 patients underwent lobectomy (group L). In group P, 17 (54.8%) patients underwent right pneumonectomy. There was no 30-day postoperative mortality in either group and no significant difference in 90-day postoperative mortality between the groups (3.1% vs. 2.6% in groups P and L, respectively). The 5-year overall survival (OS) rate was 58.7% (95% CI: 41.5-75.9%) in group P and 57.3% (95% CI 41.2-73.4%) in group L, without a significant difference between the groups. CONCLUSION: Our findings suggest that i-CRT followed by pneumonectomy is feasible, with a similar survival benefit to lobectomy. Thus, pneumonectomy after i-CRT should not be avoided as it is a potentially curative intent strategy for carefully selected patients.

Dose-Volume Parameters Predict Radiation Pneumonitis after Surgery with Induction Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.

To clarify the relationship between dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) after surgery in cases of non-small cell lung cancer (NSCLC) treated with induction concurrent chemoradiotherapy (CCRT). Patients with NSCLC treated with induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 2.0 Gy fractions once daily for a total of 46 Gy) before surgery were reviewed. We calculated the percentage of lung volume receiving at least 20 Gy (V20) and the mean lung dose (MLD) for the total lung volume and the lung remaining after resection. Factors affecting the incidence of RP at grade 2 or higher (≥ G2 RP) were analyzed. Eighteen of 49 patients (37%) experienced ≥G2 RP. The V20 and MLD for the lung remaining after resection (V20r and MLDr) were significant predictors according to the multivariate analysis (p=0.007 and 0.041, respectively). The incidence of ≥G2 RP was 8% in patients with V20r<10%, and 13% in patients with MLDr<5.6 Gy, respectively. The optimal approach to reduce the rate of postoperative RP in patients with induction CCRT for NSCLC is to keep the V20r below 10% and/or the MLDr below 5.6 Gy in the radiotherapy planning.

Avoiding Dosimetric Risk Factors for Complications in Neoadjuvant Chemoradiotherapy for Lung Cancer: Conventional Radiotherapy Versus Intensity-modulated Radiotherapy.

BACKGROUND/AIM: We compared three-dimensional conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) for avoiding dosimetric risk factors related to pulmonary complications after neoadjuvant chemoradiotherapy followed by surgery (NACRT-S) for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed simulations in 11 patients with dosimetric risk factors during their treatment with NACRT-S for NSCLC. Radiation treatment plans were generated using 3D-CRT and IMRT to avoid dosimetric risk factors. Regarding dose-volume histogram (DVH) parameters, we calculated the percentage of lung volume that received more than x Gy (Vx) using 1) the total lung volume minus gross tumor volume (DVHg), 2) the lung volume remaining after surgery (DVHr), and 3) the contralateral lung volume (DVHc). We analyzed the dosimetric differences between 3D-CRT and IMRT. RESULTS: V35g and V40g were significantly lower with IMRT than with 3D-CRT (p=0.001 each); the median V35g and V40g were 16.1% and 14.9% with 3D-CRT versus 12.0% and 9.2% with IMRT, respectively. Overall, 0% and 55% of the patients were able to avoid all dosimetric risk factors with 3D-CRT and IMRT, respectively (p=0.006). Even with IMRT, tumor location and length of the planning target volume (PTV) significantly affected the avoidance of all dosimetric risk factors (p=0.015 and 0.022, respectively). CONCLUSION: IMRT is more useful than 3D-CRT for avoiding dosimetric risk factors in NACRT-S for NSCLC. For further improvements in avoiding these factors, respiratory motion managements to reduce the length of the PTV may be required for patients with middle or lower lobe tumors.

Multimodality therapy for lung cancer invading the chest wall: A study of the French EPITHOR database.

OBJECTIVES: According to a nation-based study, we intend to report the data of the patients operated on for lung cancer invading the chest wall, taking into consideration the completion of induction chemotherapy (Ind_CT), induction radiochemotherapy (Ind_RCT) or no induction therapy (0_Ind). MATERIALS AND METHODS: All patients with a primary lung cancer invading the chest wall who underwent radical resection from 2004 to 2019 were included. Superior sulcus tumors were excluded. RESULTS: Overall, 688 patients were included: 522 operated without induction therapy, 101 with Ind_CT and 65 with Ind_RCT. Postoperative 90-day mortality was 10.7% in the 0_Ind group, 5.0% in the Ind_CT group, 7.7% in the Ind_RCT group (p = 0.17). Incomplete resection rate was 14.0% in the 0_Ind group, 6.9% in the Ind_CT group, 6.2% in the Ind_RCT group (p = 0.04). In the 0_Ind group, 70% of the patients received adjuvant therapies. Overall survival (OS) analysis disclosed the best long-term outcomes in the Ind_RCT group (5-year OS probability: 56.5% versus 40.0% and 40.5% for 0_Ind and Ind_CT groups, respectively; p = 0.035). At multivariable analysis, Ind_RCT (HR = 0.571; p = 0.008), age > 60 years old (HR = 1,373; p = 0.005), male sex (HR = 1.710; p < 0.001), pneumonectomy (HR = 1.368; p = 0.025), pN2 status (HR = 1.981; p < 0.001), ≥3 resected ribs (HR = 1.329; p = 0.019), incomplete resection (HR = 2.284; p < 0.001) and lack of adjuvant therapy (HR = 1.959; p < 0.001) were associated with OS. Ind_CT was not associated with survival (HR = 0.848; p = 0.257). CONCLUSION: Induction chemoradiation therapy seems to improve survival. Therefore, the present results should be confirmed by a prospective randomized trial testing the benefit of induction radiochemotherapy for NSCLC invading the chest wall.

Role of fluorodeoxyglucose-positron emission tomography in predicting the pathological response and prognosis after neoadjuvant chemoradiotherapy for locally advanced non-small-cell lung cancer.

OBJECTIVES: The present study compared the utility of fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) for predicting the pathological response and prognosis following neoadjuvant therapy for locally advanced non-small-cell lung cancer (NSCLC). METHODS: This retrospective analysis included 72 patients in whom adjacent structures showed involvement and/or cN2 NSCLC who received induction chemoradiotherapy (ICRT) and subsequent surgery at our hospital from 2008 to 2019. FDG-PET and CT were performed in all patients before and after ICRT using the same scanner with similar techniques. We calculated the reduction in the maximum standardized uptake value in FDG-PET (ΔSUVmax) and tumour size on CT (ΔCT-size) before and after ICRT and investigated the relationship between the pathological response and prognosis. RESULTS: The disease response was classified as a major pathological response in 43 patients, and a minor response in 29 patients. ΔSUVmax 60% and ΔCT-size 30% were identified as the optimal cut-off values for predicting a major pathological response. ΔSUVmax was superior to ΔCT-size in terms of sensitivity, specificity, positive predictive value and negative predictive value. Furthermore, ΔSUVmax was superior to ΔCT-size for predicting the prognosis. CONCLUSIONS: Based on the results of the present study, FDG-PET appeared to have greater utility than CT in predicting the pathological response following ICRT and the postoperative prognosis in patients with locally advanced NSCLC.

Prognostic impact of pathologically confirmed rib invasion in patients with lung cancer requiring chest wall resection.

Background: Primary lung cancer that invades the chest wall is classified as T3 regardless of the depth of invasion. This study assessed the prognostic impact of pathologically confirmed rib invasion in patients with pT3N0-1 lung cancer requiring chest wall resection. Methods: We retrospectively analyzed the records of patients with non-small cell lung cancer (NSCLC) who underwent combined lung and chest wall resection with rib involvement from 2006 to 2019. The median follow-up period was 64.0 months. Results: In total, 42 patients (41 men, 1 woman) were enrolled. The median patient age was 64 years (range, 42-79 years). The median tumor size before treatment was 56.5 mm (range, 21-80 mm), and an osteolytic sign was identified on computed tomography (CT) in 42.9% (18/42). Among 27 patients who received induction chemoradiotherapy, 5 (18.5%) achieved a complete pathological response. The operations comprised 36 lobectomies, 5 segmentectomies, and 1 wedge resection with resection of 2.5 ribs on average. Pathological examination revealed rib invasion in 18 (42.9%) patients. The 5-year disease-free and overall survival rates with pathological rib invasion were 44.4% and 77.4% (P=0.0114), respectively and those without pathological rib invasion were 44.7% and 81.3% (P=0.0222), respectively. Pathologically confirmed rib invasion was the only factor identified to have a prognostic impact in the univariate and multivariate analyses [hazard ratio (HR), 5.98; 95% confidence interval (CI): 1.37-26.1]. Locoregional recurrence and distant metastases were more common in patients with than without pathologically confirmed rib invasion [4 (22.2%) and 6 (33.3%), respectively, among 18 patients with pathological rib invasion; 2 (8.3%) and 3 (12.5%), respectively, among 24 patients without pathological rib invasion] (P=0.0073). Conclusions: Pathologically confirmed rib invasion was found to have a significant unfavorable prognostic impact in patients with pT3N0-1 lung cancer requiring chest wall resection. Multimodal therapy may be preferable in these patients to prevent local and distant relapse.

Differences between lung adenocarcinoma and squamous cell carcinoma in histological distribution of residual tumor after induction chemoradiotherapy.

AIMS: To facilitate dose planning for convergent beam radiotherapy in non-small cell lung cancer (NSCLC), tumor response and histological distribution of residual tumors after induction chemoradiotherapy (ICRT) were compared between adenocarcinoma (AD) and squamous cell carcinoma (SQ). METHODS: Ninety-five patients with N1-2 or T3-4 NSCLC were treated with ICRT followed by surgery; 55 had AD and 40 had SQ. For the evaluation of distribution of residual tumors, the location of the external margin of residual tumors was assessed on surgical materials as follows: radius of whole tumor ("a"); distance between the center of tumor and the external margin of residual tumor ("b"); and its location ("b/a"). RESULTS: Of the 55 AD cases, 8 (15%) showed pathological complete remission, which was significantly less frequent than 22 of 40 SQ cases (55%) (p < 0.001). AD showed the residual tumors at the most periphery of tumor (b/a = 1.0) more frequently than SQ, i.e., 39/55 (71%) versus 6/40 (15%), respectively (p < 0.001). Even in 65 cases other than the pathological complete remission, external margins in 47 AD cases located more periphery than those in 18 SQ cases, of which mean b/a values were 0.97 ± 0.17 and 0.70 ± 0.29, respectively (p < 0.001). CONCLUSION: AD showed worse tumor response to ICRT than SQ. After ICRT, AD remained at the periphery of primary tumor more frequently than SQ. It seems that, also in the convergent beam radiotherapy, the periphery part of AD would be more resistant than that of SQ.

Feasibility and prognostic benefit of induction chemoradiotherapy followed by surgery in patients with locally advanced non-small cell lung cancer.

BACKGROUND: The optimal treatment for patients with resectable non-small cell lung cancer (NSCLC) involving adjacent organs (T3 or T4) and/or cN2 remains unclear. We investigated whether or not induction chemoradiotherapy (ICRT) followed by surgery improves the survival. METHODS: We retrospectively analyzed 84 patients with NSCLC involving the adjacent organs and/or cN2 who underwent ICRT followed by surgery at our hospital from 2006 to 2018. Presurgical treatment consisted of 2 courses of platinum-doublet and concurrent radiotherapy (40-50 Gy) to the tumor and involved field. RESULTS: All 84 patients completed ICRT. One patient died after completion of ICRT due to bacterial pneumonia. Radiological responses to ICRT were a complete response (CR), n=1; partial response (PR), n=48; stable disease (SD), n=32; and progressive disease (PD), n=2 (overall response rate: 58.3%). Eighty-one patients underwent radical surgery. The procedures included lobectomy, n=66; bilobectomy, n=7; pneumonectomy, n=6; and segmentectomy, n=2 (including 49 extended resections). Seventy-three patients (90%) underwent complete resection. The postoperative morbidity rate was 30%. The 30- and 90-day mortality rates were 1.2% and 2.4%, respectively. A pathological CR (Ef3) and major response (Ef2) were achieved in 17 (21.0%) and 38 (46.9%) patients, respectively; a minor response (Ef1) was observed in 26 (32%). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were 58.0% and 45.6%, respectively. The median survival time was 73.2 months. Based on the response to ICRT, patients with radiological CR or PR showed better 5-year OS than those with SD (63.7% vs. 40.0%, P=0.020). Patients with Ef3 or Ef2 demonstrated a much better 5-year OS than those with Ef1 (65.0% vs. 24.4%, P=0.005). CONCLUSIONS: ICRT followed by surgery for patients with NSCLC involving the adjacent organs and/or cN2 was feasible and improved the survival. A CR/PR or Ef2/Ef3 after ICRT led to a better prognosis.

Concurrent chemoradiotherapy using cisplatin and S-1, followed by surgery for stage II/IIIA non-small cell lung cancer.

OBJECTIVES: Because chemoradiotherapy using cisplatin and S-1, an oral fluoropyrimidine, is effective for unresectable non-small cell lung cancer (NSCLC), an induction setting was used in a multicenter phase II study (Clinical trial number: UMIN000008205). The correlations of relapse and clinicopathological factors were analyzed. METHODS: We defined locally advanced NSCLC as pathologically proven chest wall invasion or hilar and/or mediastinal lymph node metastases by endobronchial ultrasound-guided transbronchial needle aspiration. The patients received two courses of S-1 administration for 14 days and intravenous cisplatin injection on day 8. A total dose of 40 Gy radiotherapy was concurrently received. Surgical resection was performed after completion of the treatment. RESULTS: Of the 23 eligible patients, 18 had stage IIIA and 5 had stage IIB NSCLC. Twenty of the eligible patients (87.0%) completed the regimen. Six (26.1%) complete responses were identified and 12 cases (52.2%) were histopathologically downstaged by induction chemoradiotherapy (ICRT). The 3-year overall survival rate was 58.1% and relapse-free survival (RFS) rate was 52.0%, respectively. Among several clinicopathological parameters, univariate RFS analysis identified that only downstaging was significantly associated with longer RFS times (p = 0.003). The radiological response did not reflect pathological response. When the variables of preoperative pathologically proven N2 metastasis, pathological ICRT effectiveness, and downstaging were included in the Cox proportional hazard modes, only the parameter of downstaging displayed significant hazard ratio (hazard ratio 0.13, p = 0.010). CONCLUSION: This protocol is considered an option among preoperative therapies and has obvious benefits for pathologically downstaged cases. CLINICAL TRIAL NUMBER: UMIN000008205. TRIAL REGISTRATION DATE: June 19, 2012.

PD-L1 expression, CD8+ and CD4+ lymphocyte rate are predictive of pathological complete response after neoadjuvant chemoradiotherapy for squamous cell cancer of the thoracic esophagus.

BACKGROUND: Neoadjuvant chemoradiotherapy (CTRT) can effectively downstage esophageal squamous cell carcinoma (SCC) in patients with locally advanced disease and prolonged survival have been observed in patients with a pathological complete response (ypCR). AIMS AND METHODS: This exploratory study aimed to identify immunological predictors of pCR after neoadjuvant CTRT within SCC microenvironment. The tumor regression after neoadjuvant therapy was measured according to the Mandard score system. Eighty-eight consecutive patients with SCC of the thoracic esophagus who received neoadjuvant CTRT were included in this retrospective study. Inclusion criteria were neoadjuvant CTRT and the availability of representative histological samples taken at diagnosis. We investigated immunohistochemical expression of CD4, Tbet, FoxP3, CD8, CD80, PD-L1, and PD-1, in the pretreatment biopsies and correlated the immunohistochemical profiles to patients' outcomes. RESULTS: After neoadjuvant CTRT, 23 patients had pCR, while 65 ones had partial response, stable disease or progression. PD-L1 expression and CD8+ and CD4+ lymphocyte rate were significantly higher in patients who had ypCR compared to those who had not (10 (0-55) vs 0 (0-0), P = 0.004, 73 (36-147) vs 21 (7-47), P = 0.0006 and 39 (23-74) vs 5 (0-13), P < 0.0001 respectively). The accuracy of expression of PD-L1+, CD8+, and CD4+ lymphocyte rate in identifying responders was AUC = 0.76 (P = 0.001), AUC = 0.81 (P = 0.0001) and AUC = 0.75 (P = 0.0001), respectively. Within the ypCR group, all patients with high infiltration of CD4+ T cell recurred/relapsed while only the 38.9% of those with low CD4+ T cell infiltration did the same (P = 0.058). CONCLUSIONS: PD-L1 expression and CD8+ and CD4+ lymphocyte rate were predictive of ypCR after neoadjuvant CTRT for SCC of the thoracic esophagus with adequate accuracy. Furthermore, recurrence/relapse was associated with high level of CD4+ T cell infiltration. However, the small sample size prevented to draw definitive conclusions; further studies are necessary to evaluate the prognostic role of these markers.

Impact of induction chemoradiotherapy on pulmonary function after lobectomy for lung cancer.

OBJECTIVE: Our study aim was to determine whether there are differential changes in whole-lung and regional lung functions after lobectomy for lung cancer between propensity score-matched patients treated with and without induction chemoradiotherapy, by using single-photon emission computed tomography lung perfusion. METHODS: This study was a retrospective matched cohort study of consecutively acquired data. Pulmonary function test and perfusion scintigraphy were conducted before lobectomy and 6 months after lobectomy in patients treated with induction therapy (n = 72) and in those not treated (n = 170), for measuring functional changes of whole lung, contralateral lung, and lobes. After exact matching on resected lobe site, propensity scores for age, smoking status, preoperative pulmonary functions, and predicted postoperative pulmonary function were used to match the groups. RESULTS: After the matching, 46 patients were selected from the groups. Standardized mean differences of the 5 matched variables were <0.1. Whole lung function significantly decreased after lobectomy in the induction therapy group than in the noninduction therapy group (P < .001). Although ipsilateral preserved lobe function before surgery was not different between the groups (P = .33), postoperative value was significantly lower in the induction therapy group than in the noninduction therapy group (P < .001). Although both groups showed a significant increase of contralateral lung function after lobectomy (P < .01), the increases were not significantly different between the groups (P = .81). CONCLUSIONS: Induction chemoradiotherapy was associated with reduced pulmonary function after lobectomy because of a decrease in ipsilateral preserved lobe function, which could be caused by the chronic effects of the induction chemoradiotherapy.

Induction chemoradiotherapy versus induction chemotherapy for potentially resectable stage IIIA (N2) non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% to 90% of lung cancer cases. At diagnosis, around 30% of NSCLC patients are already at stage IIIA (N2). One standard treatment for this stage is induction chemotherapy followed by surgery, whether induction chemoradiotherapy is superior to induction chemotherapy remains uncertain. We therefore performed a systematic review and meta-analysis of published randomized control trials to evaluate the therapeutic efficacy and toxicity of induction chemoradiotherapy versus induction chemotherapy for potentially resectable stage IIIA (N2) NSCLC. METHODS: We systematically searched for relevant studies in PubMed, Embase, Web of Science and Cochrane Library from the inception of each database to September 10, 2017. The primary endpoints were objective response rate (ORR), pathological complete response (pCR) rate of mediastinal lymph nodes, toxicity (grade 3-4 adverse events, i.e., nausea and vomiting, infections, leukopenia and anemia), overall survival (OS) and progression-free survival (PFS). Statistical analyses were performed using Review Manager v5.3. RESULTS: Four studies, containing 461 patients in total, were included for meta-analysis. Our analyses suggest that compared with induction chemotherapy, induction chemoradiotherapy improved ORR [odds ratio (OR) =1.97, 95% confidence interval (CI): 1.25-3.10, P<0.05] and pCR rate of mediastinal lymph nodes (OR =1.97, 95% CI: 1.00-3.86, P=0.05); but it did not significantly improve OS [hazard ratio (HR) =0.91, 95% CI: 0.73-1.14, P=0.42] or PFS (HR =1.01, 95% CI: 0.81-1.26, P=0.91); also it did not exacerbate the toxicity. CONCLUSIONS: Induction chemoradiotherapy may have limited value concerning tumor response and pCR of mediastinal lymph nodes. However, current evidence does not support that addition of radiotherapy to induction chemotherapy followed by surgery can bring significant benefits to operable stage IIIA (N2) NSCLC patients. More studies are required to draw a better conclusion.