Stage IIIA-N2 Non-small Cell Lung Cancer Patients Research Articles

The prognostic value of postoperative radiotherapy in right tumor for lung related death: based on SEER database and real-world data.

Postoperative radiotherapy (PORT) is a therapeutic strategy for patients with non-small cell lung cancer (NSCLC). Nevertheless, some studies suggesting PORT does not improve overall survival (OS) including Lung ART phase III trial. The role of PORT and high-risk groups need to be confirmed. Patients from the Surveillance, Epidemiology, and End Results program (SEER) from 2004 to 2015 were eligible. Aged ≥18 years with stage IIIA-N2 NSCLC, accepted PORT or not were considered for the study. Cox regression analyses and multivariate competing risk model were performed. Propensity score matching (PSM) was conducted. Data from a single-center study in China were used for validation. In all patients with IIIA-N2 NSCLC, death from respiratory illness increased year by year, with right lung-related deaths accounting for the main proportion. In SEER database, PORT was detrimental for OS after PSM (hazard ratio [HR], 1.088; 95% CI, 1.088-1.174; P = 0.031), with a same trend for death from the lungs (HR, 1.13; 95% CI, 1.04-1.22; P = 0.005). Right tumor receiving PORT were prone to death from lung disease(HR, 1.14; 95% CI, 1.02-1.27; P = 0.018). In China single-center cohort, PORT was significantly correlated with deteriorated OS (HR 1.356; 95% CI 1.127-1.632; P <0.01), especially in the right laterality (HR 1.365; 95% CI 1.062-1.755; P = 0.015). PORT was a risk factor for stage IIIA-N2 NSCLC patients, particularly with characters of right laterality, male sex, age ≥65 years, and advanced tumor stage. These patients are more likely to death from lung disease after PORT.

Is Surgery Worthwhile in Locally-advanced NSCLC Patients with Persistent N2-disease After Neoadjuvant Therapy?

To explore the long-term survival in lung cancer patients with persistent mediastinal lymph nodal disease after neoadjuvant followed by surgical resection and to analyse prognostic factors in this specific subset of patients. Surgery in non-small-cell lung cancer (NSCLC) patients with N2-disease after neoadjuvant therapy (NAD) has been debated and has been even more questioned with the advent of immunotherapy. Describe long-term results of a multimodal approach in locally-advanced NSCLC patients with persistence of N2-disease and identify prognostic factors to target the strategy of care. We retrospectively reviewed data of 121 consecutive Stage IIIA-N2 NSCLC patients who underwent NAD (chemoradiotherapy or chemotherapy) from 01/00 to 12/19, focusing our analysis on 37 patients with persistent N2s status after surgery. Kaplan-Meier and Cox regression analysis explored the associations between mortality and potential risk factors. The 5-year survival was 29.8%. Cox regression analysis suggested that young age (HR=0.98, C.I.95%: 0.97- 1.00; p=0.062), male sex (HR=3.8,C.I.95%:1.06-13.73;p=0.04), and adjuvant therapy (HR=6.81,C.I.95%:0.96-53.94;p=0.06) influenced long-term outcomes in these patients. We herein observed suboptimal long-term results in this NSCLC patient subset, and, considering emerging results adopting immunotherapy following chemoradiotherapy, surgery should be carefully considered in very selected cases (young and clinically fit patients) and combined with adjuvant therapy after surgery.

Development and Validation of Deep Learning Model Based on CT Simulator Images to Predict 5-Year Recurrence of Stage IIIA-N2 Non–Small-Cell Lung Cancer Patients Treated with Surgery and Postoperative Radiotherapy

Purpose/Objective(s)Surgery followed by postoperative radiotherapy is a treatment choice for stage IIIA-N2 non–small cell lung cancer (NSCLC) patients recommended by NCCN guidelines. However, a large group of these patients develop recurrence within five years. Growing evidence suggests deep learning models constructed with computed tomography (CT) images have predictive power. Therefore, we developed and validated a deep learning model to predict stage IIIA-N2 NSCLC patients' recurrence within five years, to instruct treatment choices and follow-up strategies.Materials/MethodsThe CT simulator images from stage IIIA-N2 NSCLC patients, treated with surgery followed by postoperative radiotherapy between 2003-2015, were collected. A prognostic model for 5-year recurrence was developed, using a deep neural network (ResNet) to perform visual recognition and data analysis. Data containing different imaging scanners and protocols were used to create a robust model for the variations. The model's performance was expressed as accuracy and the area under the receiver operating characteristic curve (AUC), and assessed using cross-validation.ResultsA total of 212 patients were eligible. Further data curation resulted in a final cohort of 70 patients: the training dataset had 54 patients, and the validation dataset had 16 patients. The 5-year recurrence rate was 52.86%, and event rates were balanced between training and validation groups. Our model learned to classify patients with recurrence vs without recurrence within five years, with 92% accuracy and AUC = 0.81 in the validation group. The deep learning model performed better than other machine learning models.ConclusionThe deep learning model performed very well and accurately predicted the 5-year recurrence of stage IIIA-N2 NSCLC patients treated with surgery followed by postoperative radiotherapy. The model could support clinicians in treatment decision-making and follow-up planning. Surgery followed by postoperative radiotherapy is a treatment choice for stage IIIA-N2 non–small cell lung cancer (NSCLC) patients recommended by NCCN guidelines. However, a large group of these patients develop recurrence within five years. Growing evidence suggests deep learning models constructed with computed tomography (CT) images have predictive power. Therefore, we developed and validated a deep learning model to predict stage IIIA-N2 NSCLC patients' recurrence within five years, to instruct treatment choices and follow-up strategies. The CT simulator images from stage IIIA-N2 NSCLC patients, treated with surgery followed by postoperative radiotherapy between 2003-2015, were collected. A prognostic model for 5-year recurrence was developed, using a deep neural network (ResNet) to perform visual recognition and data analysis. Data containing different imaging scanners and protocols were used to create a robust model for the variations. The model's performance was expressed as accuracy and the area under the receiver operating characteristic curve (AUC), and assessed using cross-validation. A total of 212 patients were eligible. Further data curation resulted in a final cohort of 70 patients: the training dataset had 54 patients, and the validation dataset had 16 patients. The 5-year recurrence rate was 52.86%, and event rates were balanced between training and validation groups. Our model learned to classify patients with recurrence vs without recurrence within five years, with 92% accuracy and AUC = 0.81 in the validation group. The deep learning model performed better than other machine learning models. The deep learning model performed very well and accurately predicted the 5-year recurrence of stage IIIA-N2 NSCLC patients treated with surgery followed by postoperative radiotherapy. The model could support clinicians in treatment decision-making and follow-up planning.

Recurrence Dynamics After Complete Resection and Adjuvant Chemotherapy in Patients With Stage IIIA-N2 Non-Small Cell Lung Cancer

To investigate the timing and pattern of recurrence in stage IIIA-N2 non-small cell lung cancer (NSCLC) patients after complete resection and adjuvant chemotherapy.The study cohort included pathologically confirmed stage IIIA-N2 NSCLC patients treated with complete resection and adjuvant chemotherapy from 2003 to 2015 in our single institution. Recurrence was categorized as local-regional recurrence (LRR), distant metastasis (DM) and both LRR and DM. The risk distribution was assessed by using clinical and pathological factors. The hazard rate function and competing risk analysis were used to evaluate the recurrence dynamics. The Gray's test was employed to estimate the cumulative recurrence rates and compare the differences between groups.Among 854 patients, 61.9% had multiple station N2 involvement. The 1, 3 and 5-year cumulative incidence rates of recurrence was 16.85%, 50.74% and 67.37%, respectively. Of the 510 patients who experienced recurrence, 95 (18.6%) experienced LRR, 285 (55.9%) experienced DM, whereas 130 (25.5%) had both LRR and DM. The hazard rate function for overall recurrence revealed a continuous increase between 0-18 months after surgery, consistent high level during 8-48 months and marked decline thereafter. And the DM displayed a hazard rate curve similar to that of overall recurrence. However, a double-peaked pattern of hazard rate was present in LRR and both LRR and DM. What's more, the peak recurrence frequency of DM differed by organs. A comparison of clinical and pathological factors revealed that patients with lower pT stage, single pN2 station and postoperative radiotherapy had a lower recurrence risk but similar pattern of recurrence.The recurrence risk of IIIA-N2 NSCLC after complete resection and adjuvant chemotherapy increased to a high level in 18 months and maintained continuously high till 48 months after surgery, which hinted necessity of intensive follow-up during this period of time. This follow-up strategy implied an individualized surveillance for N2 disease which was different from clinical routine, and should be verified in further studies.

Social determinants and facility type impact adherence to best practices in operable IIIAN2 lung cancer.

We aimed to identify patient- and facility-specific predictors of collective adherence to 4 recommended best treatment practices in operable IIIAN2 non-small-cell lung cancer (NSCLC) and test the hypothesis that collective adherence is associated with superior survival. We queried the National Cancer Database for clinical stage IIIAN2 NSCLC patients undergoing surgery during 2010-2015. The following best practices were examined: performance of an anatomic resection, performance of an R0 resection, examination of regional lymph nodes and administration of induction therapy. Multivariable regression models were fitted to identify independent predictors of guideline-concordance. We identified 7371 patients undergoing surgical resection for IIIAN2 lung cancer, of whom 90.8% underwent an anatomic resection, 88.2% received an R0 resection, 92.5% underwent a regional lymph node examination, 41.6% received induction therapy and 33.7% received all 4 best practices. Higher income, private insurance and treatment at an academic facility were independently associated with adherence to all 4 best practices (P < 0.01). A lower level of education and residence in a rural county were associated with a lack of adherence (P < 0.05). Adherence to all 4 practices correlated with improved survival (P < 0.01). National adherence to best treatment practices in operable IIIAN2 lung cancer was variable as evidenced by the majority of patients not receiving recommended induction therapy. Socioeconomic factors and facility type are important determinants of guideline-concordance. Future efforts to improve outcomes should take this into account since guideline concordance, in the form of collective adherence to all 4 best practices, was associated with improved survival.

Evaluation of Postoperative Radiotherapy Effect on Survival of Resected Stage III-N2 Non-small Cell Lung Cancer Patients

Objective: The role of postoperative radiotherapy (PORT) in resected stage IIIA-N2 non-small cell lung cancer (NSCLC) patients remains controversial. This study aimed to explore the effect of PORT on survival of resected stage IIIA-N2 NSCLC patients.Methods: Resected stage IIIA-N2 NSCLC patients aged 18 years or older were identified from the SEER (Surveillance, Epidemiology, and End Results) database from 2010 to 2015. Cox regression analysis was used to identify factors including PORT associated with survival time. A subgroup analysis of patients stratified by number of lymph node metastases was also performed. Overall survival (OS) and overall mortality were compared among the different groups.Results: A total of 3,445 patients were included in the study. Multivariate Cox analysis showed that PORT had no significant impact on survival of patients with <6 positive lymph node [hazard ratio (HR) = 1.012, P = 0.858, 95% CI: 0.886–1.156]. Postoperative chemotherapy (POCT) (HR = 0.605, P < 0.001, 95% CI: 0.468–0.783) and PORT (HR = 0.724, P = 0.007, 95% CI: 0.574–0.914) are both favorable prognostic factors for stage IIIA-N2 patients with ≥6 positive lymph nodes. In 2,735 patients who featured <6 number of positive regional lymph nodes, patients who received PORT had better survival and lower 3-years and 5-years overall mortality rate than patients who underwent surgery only (41 vs. 28 months, P < 0.015). There was no significant difference in the survival of postoperative patients who underwent POCT in view of whether received PORT (44 vs. 53 months, P = 0.176). A total of 710 patients who featured ≥6 number of positive regional lymph node metastasis were divided into two groups by PORT. PORT did not prolong survival for postoperative patients who did not receive chemotherapy (12 vs. 15 months, P = 0.632). PORT showed a significant advantage in influencing OS in patients who received PORT combined with POCT as compared with those who received POCT only (32 vs. 25 months, P = 0.006).Conclusions: For IIIA-N2 patients with <6 lymph node metastases, use of PORT can be encouraged to improve survival. For patients with ≥6 positive lymph nodes, PORT combined with POCT significantly improved OS and decreased overall mortality.

Bayesian network meta-analysis of efficacy and safety of neoadjuvant therapy for non-small-cell lung cancer.

Objective:Neoadjuvant chemotherapy has increased the survival benefit of non-small cell lung cancer (NSCLC) patients. The effects of different neoadjuvant therapies are still controversial. We carried out the study to evaluate the efficacy and safety of neoadjuvant therapy.Methods:We performed a search of electronic databases (PubMed, Embase, MEDLINE, Cochrane) for randomized controlled trials (RCTs) comparing neoadjuvant treatment. After literature screening and data extraction, efficacy, and safety were analyzed by the Bayesian network meta-analysis (NMA).Results:A total of 19 RCTs were included, covering 3276 patients and six kinds of neoadjuvant therapies, including immunotherapy, targeted therapy, chemotherapy drugs and radiotherapy. Erlotinib, the first-generation epidermal growth factor receptor tyrosine inhibitors (EGFR TKIs), neoadjuvant targeted therapy is best for improving overall survival (OS) and progression-free survival (PFS), which is superior to other neoadjuvant therapy, such as neoadjuvant chemotherapy with platinum drugs [hazard ratio (HR) 0.39, 95% confidence intervals (CIs) 0.16–0.96], neoadjuvant chemoradiotherapy (HR 0.37, 95% CI 0.14–0.96) and neoadjuvant chemotherapy with non-platinum drugs (HR 0.25, 95% CI 0.07–0.90). OS of all neoadjuvant therapies is superior to surgery alone, but only neoadjuvant chemotherapy with platinum drugs showed a significant advantage (HR 0.76, 95% CI 0.59–0.93). Besides, for the stage IIIA N2 NSCLC patients, no significant difference was found between neoadjuvant therapies.Conclusions:Targeted neoadjuvant therapy is the best treatment for prolonging PFS. The neoadjuvant chemotherapy with platinum drugs was associated with the better OS benefits for patients with NSCLC, compared with surgery alone. There is no significant difference in the efficacy of neoadjuvant therapy for the stage IIIA N2 NSCLC.

Postoperative Radiotherapy for Resected Stage IIIA-N2 Non-small-cell Lung Cancer: A Population-Based Time-Trend Study.

The value of postoperative radiotherapy (PORT) for resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial with few studies focusing on whether PORT always plays a part in clinical practice and generates benefits to patients across different time periods. We investigated this issue using the Surveillance, Epidemiology, and End Results Database (SEER) and assessed the temporal trends spanning 27years. Within SEER, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumonectomy and coded as receiving PORT or never receiving radiotherapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival analyses were performed and propensity score matching (PSM) was used in the potentially beneficial subgroup. 45.4% of 5568 eligible patients received PORT. The yearly PORT use rates varied largely from 27.8% to 74.4%. Overall survival (OS) was distinctly improved over the period. The application of PORT had a significant impact on survival only in period 1 and 3. In subgroup analysis, the OS benefit of PORT was significant in each period in patients with 50% or more lymph node ratio (LNR) both before (hazard ratios, and P values of 0.647, P = .002; 0.804, P = .008; 0.721, P < .001 for period 1, 2, 3, respectively) and after PSM (0.642, P = .006; 0.785, P = .004; 0.748, P = .003 for period 1, 2, 3, respectively). The benefits of PORT are lasting and stable throughout the years in patients with LNR of 50% or more. This might provide a clue on proper patient selection for PORT application.

Postoperative Radiation Therapy for Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer: A Population Study from 1988 to 2014 Using the Surveillance, Epidemiology, and End Results Database

The use of postoperative radiotherapy(PORT) after resection of stage IIIA-N2 non-small-cell lung cancer(NSCLC) remains controversial. Large real-world data studies are absent regarding the value of PORT across different time periods as all treatment methods develop. We explored the effects of PORT on the survival of patients with resected stage IIIA-N2 NSCLC and assessed the temporal changes spanning 27 years. Within the Surveillance, Epidemiology, and End Results Database, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumectomy and coded as receiving PORT or never receiving radiation therapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival rates were assessed with Kaplan-Meier method, log-rank test and multivariable hazard ratios were estimated from Cox proportional hazards models. A total of 5568 patients (718, 2020, 2830 in period 1, 2, 3 respectively) were included, 45.4% of which received PORT. The yearly PORT use varied largely with the highest 74.4% in 1994 and the lowest 27.8% in 2005. Overall survival(OS) was significantly improved over the periods ( p<0.001) in the whole cohort, PORT group and non-PORT group, respectively. Median survivals in the three periods were 20 vs 14, 26 vs 24, 39 vs 33 months for PORT vs non-PORT group. The use of PORT had significant impact on survival in period 1(p<0.001) and 3(p=0.001) but not in period 2(p=0.256). However, in subgroup analysis, the OS benefit of PORT was significantly in each period in patients with 50% or more lymph node ratio(LNR, defined as number of positive nodes/ number of resected nodes): Period 1: hazard ratio(HR), 0.646; 95% confidence interval(CI): 0.482-0.865, p=0.003. Period 2: HR, 0.846; 95% CI: 0.717-0.998, p=0.047. Period 3: HR, 0.773; 95% CI: 0.634-0.942, p=0.011). This population-based study demonstrates significant improvements in OS of these selected resected stage IIIA-N2 NSCLC patients from 1988-2014. The benefits of PORT are not significantly in each time period but are lasting and stable throughout the years in patients with LNR of 50% or more, although other integrated factors such as the progress of surgery and medication may contribute to a better survival. Further investigations in other cohorts and prospective studies are warranted.

P2.01-64 Prognostic Value of PET-CT after Induction Chemoradiotherapy and Curative Surgery in IIIA-N2 NSCLC: A Multi-Institutional Analysis

We evaluate the correlation of clinical staging on positron emission tomography-computed tomography (PET-CT) and pathologic staging and the prognostic value of PET-CT after induction chemotherapy in patients with locally advanced Non-Small Cell Lung Cancer (NSCLC). We analyzed 42 cases of clinical stage IIIA-N2 NSCLC who receive 2 to 4 cycles of pre-operative chemotherapy with or without radiation followed by curative resection. The maximum standard uptake value (SUVmax) of the suspected lesion on PET-CT was recorded. PET-CT findings after induction chemotherapy were compared with those of initial PET-CT and pathology after surgery. The accuracy of PET-CT in restaging of the primary tumor after induction chemotherapy was 50.0%. 18 (42.8%) of 42 patients were underestimated ycT stage, and 3 (7.1%) of 42 patients was overestimated ycT stage by PET-CT scan. The accuracy of PET-CT in restaging of the nodal disease was 71.4%. 6 (14.3%) of 42 patients were underestimated ycN stage, and 6 (14.3%) of 42 patients were overestimated ycN stage as compared with pathologic staging. The 2-year overall survival (OS) and relapse-free survival (RFS) rate were 68.5% and 40.9%, respectively. Complete responders (ycT0N0M0) on PET-CT after induction chemotherapy had a significantly longer RFS time than did incomplete responders (28.3 months versus 9.1 months, P = 0.021). Complete response on PET-CT after induction chemotherapy with or without radiation was a good prognosticator for RFS in stage IIIA-N2 NSCLC patients who received surgery. However, response evaluation on PET-CT after induction chemotherapy should be interpreted with caution due to its unacceptable accuracy.

Neoadjuvant Treatment Followed by Surgery Versus Chemoradiation in Stage IIIA-N2 Non–small Cell Lung Cancer on Behalf of GOECP/SEOR-GICOR

A subset analyses of randomized intergroup trial (INT0139) published in 2009, suggested that surgery after neoadjuvant treatment in patients with stage IIIA (N2) non-small-cell lung cancer (NSCLC) may increase the survival. Due to the difficulty in recruiting this subset of patients in clinical trials, we have designed a retrospective multicenter observational study to compare neoadjuvant treatment based on chemoradiation or chemotherapy followed by surgery (CRTS) with definitive chemoradiation (CRT). 297 NSCLC patients with stage T1-T3N2M0 underwent CRTS or CRT between January 2005 and December 2014, in 15 hospitals in Spain. In both arms, chemotherapy was platinum-based. Minimum radiation dose was 45 Gy in the CRTS group and 60 Gy in the CRT group. It was delivered in daily fractions of 1.8-2 Gy/day, with 3D conformal radiotherapy (N=237), intensity modulated radiation therapy (N=3) or volumetric modulated arc therapy (N=5). Patient and tumor characteristics were balanced by propensity score analysis method. The primary endpoint was overall survival (OS). 117 patients (median age 62 years, range 41-78) were treated with CRTS and 180 patients (65 years, range 37-82) with definitive CRT. Comparing CRTS with CRT patients, performance status was 0-1 in 99.1% vs. 97.2%; 60.6% vs. 64.4% were T1 or T2 tumors, (p=0.014); 38.4% vs. 57.2% presented two or more positive nodal stations (p=0.005); and 6.8% vs. 14.4% showed a positive nodal size ≥ 3 cm (p=0.044). Histopathological confirmation of mediastinal lymph nodes was performed in 58.1% and 65% patients, respectively. In CRTS group, 52.13% patients were treated with neoadjuvant CRT and 82.0% underwent lobectomy. Median follow-up was 27 months (43 months in CRTS and 23 months in CRT). Median OS was 58 months in CRTS vs. 27 months in CRT (hazard ratio [HR] 0.36, 95% CI: 0.23-0.56; p<0.001) after propensity score adjustment. Lobectomy vs. neumonectomy, (111 vs. 35 months, p=0.004), pT0-T2 status vs. pT3-T4 (111 vs. 22 months, p<0.001), doses ≥60 Gy vs. <60 Gy (25 vs. 14 months, p=0.001) and no treatment interruptions or interruptions ≤1 week vs. >1 week, (37 vs. 30 months, p=0.03), were associated with higher OS in a regression analisys. Progression-free survival (PFS) was better in CRTS than CRT group, median 57 months vs. 14 months, HR 0.35, (95% CI 0.22-0.54; p<0.001). Although grade > 3 oesophagitis and pneumonitis were similar in both arms, grade >3 hematological toxicity was greater in CRT group (2.9% vs. 21.1%, p=0.001). Adjusted treatment-related mortality was 6.1% (2/77) in CRTS group vs. 7% (4/77) in CRT, (p=0.846). Neoadjuvant chemoradiation treatment followed by surgery in stage IIIA-N2 NSCLC patients showed a better PFS and OS compared with definitive CRT patients. Furthermore, treatment-related mortality was similar in both treatment arms.

76P - Interpretation and prognostic value of PET-CT after induction chemotherapy with or without radiation in IIIA-N2 non-small cell lung cancer patients who receive curative surgery

Background: We evaluated the correlation of clinical staging on positron emission tomography-computed tomography (PET-CT) and pathologic staging and the prognostic value of PET-CT after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). Methods: We analyzed 42 cases of clinical stage IIIA-N2 NSCLC who received 2 to 4 cycles of pre-operative chemotherapy with or without radiation followed by curative resection. The maximum standard uptake value (SUVmax) of the suspected lesion on PET-CT was recorded. PET-CT findings after induction chemotherapy were compared with those of initial PET-CT and pathology after surgery. Results: The accuracy of PET-CT in restaging of the primary tumor after induction chemotherapy was 50.0%. 18 (42.8%) of 42 patients were underestimated ycT stage, and 3 (7.1%) of 42 patients was overestimated ycT stage by PET-CT scan. The accuracy of PET-CT in restaging of the nodal disease was 71.4%. 6 (14.3%) of 42 patients were underestimated ycN stage, and 6 (14.3%) of 42 patients were overestimated ycN stage as compared with pathologic staging. The 2-year overall survival (OS) and relapse-free survival (RFS) rate were 68.5% and 40.9%, respectively. Complete responders (ycT0N0M0) on PET-CT after induction chemotherapy had a significantly longer RFS time than did incomplete responders (28.3 months versus 9.1 months, P = 0.021). Conclusions: Complete response on PET-CT after induction chemotherapy with or without radiation was a good prognostic indicator for RFS in stage IIIA-N2 NSCLC patients who received surgery. However, response evaluation on PET-CT after induction chemotherapy should be interpreted with caution due to its unacceptable accuracy. Legal entity responsible for the study: Jong Hoon Lee Funding: None Disclosure: The author has declared no conflicts of interest.

Is endobronchial ultrasound-guided transbronchial needle aspiration an effective diagnostic procedure in restaging of non-small cell lung cancer patients?

Background and Objectives:Selecting the diagnostic procedure for mediastinal restaging after chemotherapy and/or radiotherapy in Stage IIIA-N2 non-small cell lung cancer (NSCLC) patients remains a problem. The aim of the study was to determine the efficacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the evaluation of mediastinal lymph nodes in the restaging of NSCLC patients.Materials and Methods:The present multicentric study retrospectively analyzed the results of Stage IIIA-N2 NSCLC patients who had undergone EBUS for mediastinal restaging after preoperative chemotherapy or radiotherapy or both.Results:In 44 patients with 73 N2 nodes, malignant cells were identified in EBUS-TBNA from 23 patients (57.5%) and 25 lymph nodes (34.2%). Twenty-one patients (42.5%) and 48 lymph nodes (65.8%) were negative for nodal metastasis. All of these patients with negative results subsequently underwent mediastinoscopy or surgery (n = 9 and n = 12, respectively). Metastasis was detected in 5 (23.8%) of 21 patients and 6 (12.5%) of 48 lymph nodes. The diagnostic sensitivity, specificity, positive predictive value, negative predicted value and accuracy of EBUS-TBNA based on number of patients were 82.1%, 100%, 100%, 76.2%, and 88.6%, respectively.Conclusions:EBUS-TBNA should be done before invasive procedures in restaging of the mediastinum in patients previously treated with neoadjuvant therapy because of high diagnostic accuracy rate. However, negative results should be confirmed with invasive procedures such as mediastinoscopy and thoracoscopy.

Interpretation and Prognostic Value of Positron Emission Tomography-Computed Tomography After Induction Chemotherapy With or Without Radiation in IIIA-N2 Non-small Cell Lung Cancer Patients Who Receive Curative Surgery.

We evaluate the correlation of clinical staging on positron emission tomography-computed tomography (PET-CT) and pathologic staging and the prognostic value of PET-CT after induction chemotherapy in patients with locally advanced nonsmall cell lung cancer (NSCLC).We analyzed 42 cases of clinical stage IIIA-N2 NSCLC who receive 2 to 4 cycles of preoperative chemotherapy with or without radiation followed by curative resection. The maximum standard uptake value (SUVmax) of the suspected lesion on PET-CT was recorded. PET-CT findings after induction chemotherapy were compared with those of initial PET-CT and pathology after surgery.The accuracy of PET-CT in restaging of the primary tumor after induction chemotherapy was 50.0%. Eighteen (42.8%) of 42 patients were underestimated ycT stage, and 3 (7.1%) of 42 patients was overestimated ycT stage by PET-CT scan. The accuracy of PET-CT in restaging of the nodal disease was 71.4%. Six (14.3%) of 42 patients were underestimated ycN stage, and 6 (14.3%) of 42 patients were overestimated ycN stage as compared with pathologic staging. The 2-year overall survival (OS) and relapse-free survival (RFS) rate were 68.5% and 40.9%, respectively. Complete responders (ycT0N0M0) on PET-CT after induction chemotherapy had a significantly longer RFS time than did incomplete responders (28.3 vs 9.1 months, P = 0.021).Complete response on PET-CT after induction chemotherapy with or without radiation was a good prognosticator for RFS in stage IIIA-N2 NSCLC patients who received surgery. However, response evaluation on PET-CT after induction chemotherapy should be interpreted with caution due to its unacceptable accuracy.

The Frequency and Clinical Implication of ROS1 and RET Rearrangements in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Patients.

To evaluate the frequency and clinicopathological features of ROS1 and RET rearrangements in N2 node positive stage IIIA (IIIA-N2) non-small cell lung cancer (NSCLC) patients, we retrospectively screened 204 cases with a tissue microarray (TMA) panel by fluorescent in situ hybridization (FISH), and confirmed by direct sequencing and immunohistochemistry (IHC). The relationship between ROS1 or RET rearrangements, clinicopathological features, and prognostic factors were analyzed in resected stage IIIA-N2 NSCLC. Of the 204 cases, 4 cases were confirmed with ROS1 rearrangement, but no RET rearrangement was detected. All 4 ROS1-rearranged cases were adenocarcinomas. The predominant pathological type was acinar pattern in ROS1-rearranged tumors, except for 1 case harboring a mixture acinar and mucous tumor cells. Variants of ROS1 rearrangement were SDC4-ROS1 (E2:E32), SDC4-ROS1 (E4:E32) and SDC4-ROS1 (E4:E34). There was no significant association between ROS1 rearrangement and clinicopathological characteristics. In this cohort, multivariate analysis for overall survival (OS) indicated that squamous cell carcinoma and lobectomy were independent predictors of poor prognosis; R0 surgical resection and non-pleural invasion were independent predictors of good prognosis. In resected stage IIIA-N2 NSCLC patients, ROS1-rearranged cases tended to occur in younger patients with adenocarcinomas. The prognosis of resected stage IIIA-N2 is generally considered poor, but patients with ROS1 rearrangement will benefit from the targeted therapy.

Neoadjuvant and adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer.

The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or lymph node biopsy). On the other hand, case reports and several phase II clinical trials with small sample size tried to elbow their way on respect of preoperative TKI treatment and advised that TKI tended to improve response rate. However, no data on survival rate was present. The first phase II study of biomarker-guided neoadjuvant therapy for stage IIIA-N2 NSCLC patients stratified by EGFR mutation status, sponsored by CSLC0702, showed erlotinib tended to improve response rate, but failed to show benefits of disease-free survival (DFS) or OS. Subsequently, CTONG1103 was designed to investigate efficacy of erlotinib vs. combination of gemcitabine/cisplatin (GC) as neoadjuvant treatment in stage IIIA-N2 NSCLC with sensitizing EGFR mutation in exon 19 or 21. All these ongoing trials should be worthy of our expect to provide convincing evidences for customized therapy for patients with resectable NSCLC.

Predictive factors for survival in stage IIIA N2 NSCLC patients treated with neoadjuvant CCRT followed by surgery.

To assess the impact of imaging, surgical, histopathologic and patient-related factors on the risks of recurrence and overall survival (OS) in stage IIIA-N2 non-small cell lung cancer (NSCLC) patients undergoing definitive resection after neoadjuvant concurrent chemoradiotherapy (CCRT). We retrospectively examined 104 consecutive patients with stage IIIA-N2 NSCLC who received neoadjuvant CCRT followed by surgery between 2008 and 2011. While reviewing the clinical and surgical data, we also assessed histopathologic and imaging (CT and PET/CT) factors. Disease-free survival (DFS) and OS were estimated with predictors for recurrence and survival. The 3-year OS for patients with and without recurrence was 37.1 and 63.3 %, respectively (p < 0.001). Size decrease of target lesion(s) ≥36 % on post-neoadjuvant CCRT CT (p = 0.048) and viable tumor size on surgical specimen <9.4 mm (p = 0.035) were related to longer OS. Regarding shorter DFS, tumor size on post-neoadjuvant CCRT CT (p = 0.046), SUV(max) of the primary tumor (p = 0.011), male gender (p = 0.023), total tumor size on surgical specimen (p = 0.041) and viable tumor size on surgical specimen (p = 0.043) were the significant predictors. OS is prolonged with greater extent of size decrease of target lesion(s) on post-neoadjuvant CCRT CT and smaller viable tumor size on surgical specimen. Larger tumor size on post-neoadjuvant CCRT CT, higher SUV(max), male gender, larger total tumor size and larger viable tumor size on surgical specimen may herald the higher probability of recurrence and the necessity of more attention.

Survivin mRNA Level in Blood Predict the Efficacy of Neoadjuvant Chemotherapy in Patients with Stage IIIA-N2 Non-Small Cell Lung Cancer.

In a previous study, survivin mRNA expression in non-small cell lung cancer (NSCLC) tissue had been demonstrated to be associated with unfavorable prognosis of patients treated with chemotherapy. In this study, we investigated the survivin mRNA levels in blood of patients with stage IIIA-N2 NSCLC and their association with the efficacy of neoadjuvant chemotherapy (NCT) and disease-free survival (DFS) and overall survival (OS). Blood specimens were collected from 56 patients with stage IIIA-N2 NSCLC before (N0) and after the complete of NCT (N1). Survivin mRNA was measured by real-time quantitative-PCR assay. Receiver operating characteristics curve analysis was undertaken to determine the best cutoff value for survivin mRNA. Results showed that high blood survivin mRNA levels at N0 and N1 were significantly associated with clinical (P = 0.01 and P = 0.008, respectively) and pathologic response (both P = 0.004, respectively). Moreover, the change of blood survivin mRNA levels in these NSCLC patients is associated with the clinical and pathologic response to NCT. Patients with high survivin mRNA levels at N0 and N1 had significantly shorter DFS and OS than those with low survivin mRNA levels (P = 0.021 and P = 0.014, respectively for DFS; P = 0.009 and P = 0.005, respectively for OS). Multivariate analysis demonstrated that high blood survivin mRNA level was an independent predictor for worse DFS and OS in the NSCLC patients receiving NCT. In conclusion, survivin mRNA level in blood from stage IIIA-N2 NSCLC patients receiving NCT is predictive of cancer outcome.

Value of surgery for stage IIIa non-small cell lung cancer

背景与目的对于Ⅲ期非小细胞肺癌（non-small cell lung cancer, NSCLC），目前普遍倡导手术、化疗、放疗的多学科综合治疗，但许多研究者对是否应该手术提出了质疑。该研究探讨了手术对于Ⅲ期NSCLC患者的价值。方法回顾性分析2002年3月-2012年10月北京协和医院收治的经病理学确诊的Ⅲ期NSCLC患者310例。根据最初确诊时是否手术可分为手术组和非手术组。Ⅲa期根据N分期的不同可分为T4N0/T3-4N1M0期和T1-3N2M0期。采用χ2检验比较计数资料，Kaplan-Meier方法比较总生存期（overall survival, OS）和无进展生存期（progression free survival, PFS），并绘制生存曲线。结果ECOG评分0分和Ⅲa期NSCLC患者更倾向于手术治疗。Ⅲa期手术与非手术组的中位OS分别为38.9个月和21.8个月，中位PFS分别为19.2个月和11.9个月。两组OS的差异有统计学意义（P=0.041），PFS的差异无统计学意义（P=0.209）。Ⅲa期中的T4N0/T3-4N1M0期手术与非手术组的中位OS分别为48.7个月和20.1个月，中位PFS分别为14.6个月和10.5个月，两组OS和PFS的差异均无统计学意义（P>0.05）；T1-3N2M0期手术与非手术组中位OS分别为38.9和30.8月，中位PFS分别为19.8个月和12.7个月，两组OS和PFS的差异亦无统计学意义（P>0.05）。肿瘤最大径和辅助化疗对Ⅲa-N2期患者的OS和PFS的影响有统计学意义，而肿瘤的病理类型仅影响患者的OS（P < 0.05）。结论ECOG评分0分和Ⅲa期NSCLC患者更适于手术治疗。手术可延长Ⅲa期尤其是T4N0/T3-4N1M0期NSCLC患者的OS，但对PFS无改善作用。肿瘤最大径和辅助化疗对Ⅲa-N2期患者的OS和PFS均有明显影响，而肿瘤的病理类型只影响其OS。

MIS2-3 - A Prospective Phase II Study of Induction Erlotinib Therapy in Stage IIIA-N2 Non-Small-Cell Lung Cancer

ABSTRACT Background Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small-cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study was to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587). Study design Factorial Assignment, non-randomized, safety/efficacy; primary outcome measures: response to induction therapy. Results From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30–42 days), while 12 cases harboring wild-type EGFR received the GC regimen (three cycles). The most common side-effects in the erlotinib arm were rash (90%) and diarrhea (40%). The primary end point of the response rates were 58% (7 of 12) for the erlotinib arm and 33% (4 of 12) for the GC arm (P = 0.49). The pathological N2 complete response rates were 16.7% for the erlotinib arm and 25% for the GC arm (P = 0.64). In the erlotinib arm, the most common failure model was distant metastases (9 of 10), especially brain metastases (3 of 9). The median progression-free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P = 0.27). The median overall survival was 27.3 months for the erlotinib arm and 23.2 months for the GC arm (P = 0.52). In addition, four cases in the erlotinib arm got partial response to the second EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoractomy. Conclusions Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib versus GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR activating mutations (NCT01407822) is currently recruiting participants.