• adjuvant therapy
• immune checkpoint inhibitor
• neoadjuvant therapy
• non-small cell lung cancer

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/therapy
• Lung Neoplasms/drug therapy
• Lung Neoplasms/therapy
• Lung Neoplasms/surgery
• Lung Neoplasms/pathology
• Lung Neoplasms/mortality
• Immune Checkpoint Inhibitors/therapeutic use
• Neoadjuvant Therapy/methods
• Perioperative Care/methods
• Chemotherapy, Adjuvant
• Cisplatin/administration & dosage
• Cisplatin/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Combined Modality Therapy
• Immunotherapy/methods

• National Cancer Center Research and Development Fund
• Japan Agency for Medical Research and Development

• adenocarcinoma
• computed tomography
• histopathological examination
• lung cancer
• small cell lung cancer
• squamous cell carcinoma

• Humans
• Lung Neoplasms/diagnosis
• Lung Neoplasms/prevention & control
• B7-H1 Antigen/genetics
• B7-H1 Antigen/therapeutic use
• Follow-Up Studies
• ErbB Receptors/genetics
• Carcinoma, Non-Small-Cell Lung/pathology

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Lung Neoplasms/drug therapy
• Neoplasm Staging
• Combined Modality Therapy
• Neoadjuvant Therapy

Neoadjuvant treatment (NT) with chemotherapy (Ch) is a standard option for resectable stage III (N2) NSCLC. Several studies have suggested benefits with the addition of radiotherapy (RT) to NT Ch. The International Association for the Study of Lung Cancer (IASLC) published recommendations for the pathological response (PHR) of NSCLC resection specimens after NT.

To contribute to the IASLC recommendations showing our results of PHR to NT Ch vs NT chemoradiotherapy (ChRT).

We analyzed 67 consecutive patients with resectable stage III NSCLC with positive mediastinal nodes treated with surgery after NT Ch or NT ChRT between 2013 and 2020. After NT, all patients were evaluated for radiological response (RR) according to Response Evaluation Criteria in Solid Tumours criteria and evaluated for surgery by a specialized group of thoracic surgeons. All histological samples were examined by the same two pathologists. PHR was evaluated by the percentage of viable cells in the tumor and the resected lymph nodes.

Forty patients underwent NT ChRT and 27 NT Ch. Fifty-six (83.6%) patients underwent surgery (35 ChRT and 21 Ch). The median time from ChRT to surgery was 6 wk (3-19) and 8 wk (3-21) for Ch patients. We observed significant differences in RR, with disease progression in 2.5% and 14.8% of patients with ChRT and Ch, respectively, and partial response in 62.5% ChRT vs 29.6% Ch (P = 0.025). In PHR we observed ≤ 10% viable cells in the tumor in 19 (54.4%) and 2 cases (9.5%), and in the resected lymph nodes (RLN) 30 (85.7%) and 7 (33.3%) in ChRT and Ch, respectively (P = 0.001). Downstaging was greater in the ChRT compared to the Ch group (80% vs 33.3%; P = 0.002). In the univariate analysis, NT ChRT had a significant impact on partial RR [odds ratio (OR) 12.5; 95% confidence interval (CI): 1.21 - 128.61; P = 0.034], a decreased risk of persistence of cancer cells in the tumor and RLN and an 87.5% increased probability for achieving downstaging (OR 8; 95%CI: 2.34-27.32; P = 0.001).

We found significant benefits in RR and PHR by adding RT to Ch as NT. A longer follow-up is necessary to assess the impact on clinical outcomes.

• Non-small cell lung cancer
• Chemotherapy
• Chemoradiotherapy
• Neoadjuvant treatment
• Resectable stage III
• Pathological response

Higher response may be achieved with induction therapy (IT) and better survival results could be expected after complete surgical resection for non-small-cell lung cancer (NSCLC) patients. Thus, locally advanced (LA)-NSCLC patients with pathological complete response (pCR) are optimal candidates to undergo surgery after IT, achieving good to very good long-term survival. Herein, we performed a retrospective analysis on a large cohort of locally advanced NSCLC patients who achieved pCR after IT and surgery, exploring long-term survival and factors affecting prognosis. We observed a rewarding 5-year overall survival (56%) with baseline N2 single-station disease and adjuvant therapy after surgery associated with better prognosis. These findings may be useful to better define the strategy of care in this highly selected subset of NSCLC patients.

Background: Outcomes for locally advanced NSCLC with pathological complete response (pCR), i.e., pT0N0 after induction chemoradiotherapy (IT), have been seldom investigated. Herein, long-term results, in this highly selected group of patients, have been evaluated with the aim to identify prognostic predictive factors. Methods: Patients affected by locally advanced NSCLC (cT1-T4/N0-2/M0) who underwent IT, possibly following surgery, from January 1992 to December 2019, were considered for this retrospective analysis. Survival rates and prognostic factors have been studied with Kaplan-Meier analysis, log-rank and Cox regression analysis. Results: Three-hundred and forty-three consecutive patients underwent IT in the considered period. Out of them, 279 were addressed to surgery; among them, pCR has been observed in 62 patients (18% of the total and 22% of the operated patients). In the pCR-group, clinical staging was IIb in 3 (5%) patients, IIIa in 28 (45%) patients and IIIb in 31 (50%). Surgery consisted of (bi)lobectomy in the majority of cases (80.7%), followed by pneumonectomy (19.3%). Adjuvant therapy was administered in 33 (53.2%) patients. Five-year overall survival and disease-free survival have been respectively 56.18% and 48.84%. The relative risk of death, observed with the Cox regression analysis, was 4.4 times higher (95% confidence interval (CI): 1.632–11.695, p = 0.03) for patients with N2 multi-station disease, 2.6 times higher (95% CI: 1.066–6.407, p = 0.036) for patients treated with pneumonectomy and 3 times higher (95% CI: 1.302–6.809, p = 0.01) for patients who did not receive adjuvant therapy. Conclusions: Rewarding long-term results could be expected in locally advanced NSCLC patients with pCR after IT followed by surgery. Baseline N2 single-station disease and adjuvant therapy after surgery seem to be associated with better prognosis, while pneumonectomy is associated with poorer outcomes.

• NSCLC
• induction therapy
• pathological complete response

• IIIA(N2) NSCLC
• adjuvant therapy
• locally advanced
• neoadjuvant therapy

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.

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.

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).

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.

• Lung cancer
• induction chemoradiotherapy (ICRT)
• surgery

• Chemoradiation
• National cancer database
• Non–small cell lung cancer
• Perioperative mortality
• Salvage resection

• Non-small-cell lung cancer
• chemotherapy
• lobectomy
• locally advanced
• pneumonectomy
• radiation therapy

• brain metastases
• gene mutation
• non-small-cell lung cancer
• prophylactic cranial irradiation

• Biomarkers, Tumor
• Brain Neoplasms/genetics
• Brain Neoplasms/secondary
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Neoplasm Staging
• Oncogenes
• Risk Factors

• IIIA (N2)
• Non-small cell lung cancer (NSCLC)
• induction chemoradiotherapy
• induction chemotherapy
• meta-analysis

• adjuvant therapy
• induction therapy
• neoadjuvant therapy
• non-small cell lung cancer

The treatment of patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) is one of the most challenging and controversial areas of thoracic oncology. This heterogeneous group is characterized by varying tumor size and location, the potential for involvement of surrounding structures, and ipsilateral mediastinal lymph node spread. Neoadjuvant chemotherapy, administered prior to definitive local therapy, has been found to improve survival in patients with stage IIIA (N2) NSCLC. Concurrent chemoradiation has also been evaluated in phase III studies in efforts to improve control of locoregional disease. In certain instances, a tri-modality approach involving concurrent chemoradiation followed by surgery, may offer patients the best chance for cure. In this article, we provide an overview of the trials evaluating neoadjuvant therapy in patients with stage IIIA (N2) NSCLC that have resulted in current practice strategies, and we highlight the areas of uncertainty in the management of this challenging disease. We also review the current ongoing research and future directions in the management of stage IIIA (N2) NSCLC.

• induction chemotherapy
• mediastinal disease
• neoadjuvant chemoradiation
• neoadjuvant chemotherapy
• stage IIIA non-small cell lung cancer
• tri-modality

The local management of stage III non-small cell lung cancer is controversial. Although definitive chemoradiotherapy (CRT) is considered a standard-of-care in the curative management of the disease, inadequate local control outcomes have led to various treatment strategies that incorporate surgical resection. Surgery alone has long been recognized as insufficient for this stage, and thus neoadjuvant strategies have been developed to treat micrometastatic disease and increase the probability of a complete resection. The optimal induction strategy has not yet been defined, however, with arguments favoring either preoperative chemotherapy or CRT. In this article, the data supporting the use of neoadjuvant CRT and the randomized literature comparing the two approaches will be reviewed. The article will conclude with summary comparisons of these induction paradigms.

• combined modality therapy
• lung cancer
• neoadjuvant therapy
• radiation therapy
• stage III non-small cell lung cancer

• Non-small cell lung cancer
• definitive chemoradiation
• mediastinal downstaging
• multimodality therapy
• neoadjuvant chemoradiation
• neoadjuvant chemotherapy
• stage III lung cancer

• neoadjuvant chemotherapy
• non-small-cell lung cancer
• surgery
• unexpected persistent N2 disease

• Non small cell lung cancer
• induction chemotherapy
• lymph nodes involvemnt
• stage IIIA

• Induction treatment plus surgery
• combined chemoradiotherapy
• stages IIIA-N2 NSCLC

Brain metastasis is a major complication of non-small cell lung cancer (NSCLC) and leads to most of the mortality of this disease. However, the biological mechanisms and molecular features in brain metastasis of NSCLC are poorly understood. In the present study, we compared whole-genome copy number variations (CNVs) between a primary lung adenocarcinoma and secondary metastatic brain lesion from the same patient using array comparative genomic hybridization (aCGH). The number of CNV regions was markedly higher in the secondary metastatic tumor than the primary tumor in the lung. In detail, the common CNVs in both tumors included gains of 7p22, 7p12-p11, 7q11, 7q22, 21q22, and 19q13; gains of 1p33-p34, 1q22, 5p13 and 14q11 whereas losses of 3p, 4q31, 5q, 11p15, Xp21-p22 and Xq21 were identified only in the secondary lesion. Gene Ontology enrichment analysis revealed that the genes with amplified copy numbers in both tumors were related to such processes as DNA replication and mismatch repair. Genes only amplified in the metastatic tumor were enriched in processes that include leukocyte migration and organ development, and genes with a lower copy number in the secondary tumor included the processes of proteolysis regulation, negative regulation of cell proliferation and cell adhesion. These findings provided new insight into the genomic mechanism of the spread of lung adenocarcinoma to the brain, and the candidate genes identified serve as novel indicators or putative targets in NSCLC brain metastasis.

• ESMO
• locally advanced
• non-small-cell lung cancer
• recommendations
• stage III

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bronchoscopy
• Carboplatin/administration & dosage
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Non-Small-Cell Lung/therapy
• Chemotherapy, Adjuvant
• Cisplatin/administration & dosage
• Disease Management
• Endoscopic Ultrasound-Guided Fine Needle Aspiration
• Etoposide/administration & dosage
• Europe
• Humans
• Lung/diagnostic imaging
• Lung/pathology
• Lung Neoplasms/diagnosis
• Lung Neoplasms/pathology
• Lung Neoplasms/therapy
• Lymph Nodes/pathology
• Mediastinum
• Multimodal Imaging
• Pneumonectomy
• Positron-Emission Tomography
• Radiotherapy, Adjuvant
• Societies, Medical
• Tomography, X-Ray Computed
• Vinblastine/administration & dosage
• Vinblastine/analogs & derivatives
• Vinorelbine

• 20465 Cancer Research UK

Outcome of consecutive patients with locally advanced non-small cell lung cancer and histopathologically proven mediastional lymph node metastases treated with induction chemotherapy, neoadjuvant radiochemotherapy and thoracotomy at the West German Cancer Center between 08/2000 and 06/2012 was analysed. A clinico-pathological prognostic model for survival was built including partial or complete response according to computed tomography imaging (CT) as clinical parameters as well as pathologic complete remission (pCR) and mediastinal nodal clearance (MNC) as histopathologic factors.

Proportional hazard analysis (PHA) and recursive partitioning analysis (RPA) were used to identify prognostic factors for survival. Long-term survival was defined as survival ≥ 36 months.

A total of 157 patients were treated, median follow-up was 97 months. Among these patients, pCR and MNC were observed in 41 and 85 patients, respectively. Overall survival was 56 ± 4% and 36 ± 4% at 24 and 60 months, respectively. Sensitivities of pCR and MNC to detect long-term survivors were 38% and 61%, specificities were 84% and 52%, respectively.

Multivariable survival analysis revealed pCR, cN3 category, and gender, as prognostic factors at a level of α < 0.05. Considering only preoperative available parameters, CT response became significant. Classifying patients with a predicted hazard above the median as high risk group and the remaining as low risk patients yielded better separation of the survival curves by the inclusion of histopathologic factors than by preoperative factors alone (p < 0.0001, log rank test). Using RPA, pCR was identified as the top prognostic factor above clinical factors (p = 0.0006). No long term survivors were observed in patients with cT3-4 cN3 tumors without pCR.

pCR is the dominant histopathologic response parameter and improves prognostic classifiers, based on clinical parameters. The validated prognostic model can be used to estimate individual prognosis and forms a basis for patient selection for treatment intensification.

• Post-pneumonectomy
• accelerated radiotherapy
• salvage

• Locally advanced non-small cell lung cancer
• neoadjuvant chemoradiotherapy
• neoadjuvant radiotherapy

• Induction treatment
• Lymph node ratio
• Lymph nodes
• Mediastinal downstaging
• Non-small-cell lung cancer
• Persistent N2

• Chemotherapy
• Consolidation chemotherapy
• Non–small-cell lung cancer
• Radiotherapy
• Surgery
• Trimodal therapy

• Early-stage small cell lung cancer
• Lobectomy
• Lung resection
• Small cell lung cancer

• DNA methylation
• SHOX2
• lung cancer

The important role of combined chemoradiation for several groups of patients with non-small cell lung cancer (NSCLC) is reflected by the large number of scientific articles published during the last 30 years. Different measures of impact and clinical relevance of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Highly cited articles were identified through systematic search of the citation database Scopus. Among the 100 most often cited articles, meta-analyses (n = 5) achieved a median of 203 citations, guidelines (n = 7) 97, phase III trials (n = 29) 168, phase II trials (n = 21) 135, phase I trials (n = 7) 88, and others combined 115.5 (p = 0.001). Numerous national and international cooperative groups and several single institutions were actively involved in performing often cited, high-impact trials, reflecting the fact that NSCLC is a world-wide challenge that requires research collaboration. Platinum-containing combinations have evolved into a standard of care, typically administered concurrently. The issue of radiotherapy fractionation and total dose has also been studied extensively, yet with less conclusive results. Differences in target volume definition have been addressed. However, it was not possible to test all theoretically possible combinations of radiotherapy regimens, drugs, and drug doses (lower radiosensitizing doses compared to higher systemically active doses). That is why current guidelines offer physicians a choice of different, presumably equivalent treatment alternatives. This review identifies open questions and strategies for further research.

• chemoradiation
• chemotherapy
• citation
• non-small cell lung cancer
• radiotherapy
• research evaluation

To identify dose-volume parameters predictive for severity of acute esophagitis (CTC > grade 2) in locally-advanced non small-cell lung cancer (LA-NSCLC) patients treated with neoadjuvant concurrent hyperfractionated-accelerated chemoradiotherapy (HA-CRT) a retrospective analysis was performed. 88 patients were treated with HA-CRT followed by radical surgery. Predictive power of absolute oesophageal length, absolute and relative oesophageal volume included in the 95%-isodose, patient- and tumor-related factors for severity of acute esophagitis was assessed.

A total of 82 patients (93%) developed radiation-induced acute esophagitis. Grade 1 was documented in 1 (1%), grade 2 in 55 (67%), grade 3 in 23 (28%) and grade 4 in 3 (4%) patients, respectively. Absolute oesophageal volume included in the 95%-isodose (42.8 Gy) achieved 13.5 cm³ (range: 3 – 29 cm³). Of the tested variables in univariate analysis, absolute oesophageal volume included in the 95%-Isodose was found to be the only significant variable (p = 0.03) predicting severe acute esophagitis (CTC > grade 2). For this volume a gradation scale of the likelihood of severity was built.

Increase of absolute oesophageal volume included in the 95%-isodose correlates with severity of acute esophagitis in LA-NSCLC patients treated with neo-adjuvant concurrent HA-CRT.

• Aged
• Antineoplastic Agents/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carboplatin/administration & dosage
• Carcinoma, Non-Small-Cell Lung/mortality
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Non-Small-Cell Lung/therapy
• Chemoradiotherapy, Adjuvant/methods
• Dose Fractionation, Radiation
• Feasibility Studies
• Female
• Follow-Up Studies
• Humans
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Lung Neoplasms/therapy
• Male
• Middle Aged
• Neoadjuvant Therapy/methods
• Neoplasm Staging
• Paclitaxel/administration & dosage
• Pneumonectomy
• Prospective Studies
• Radiotherapy, Conformal/methods
• Survival Analysis
• Treatment Outcome