[Prevention, Diagnosis, Therapy, and Follow-up of Lung Cancer - Interdisciplinary Guideline of the German Respiratory Society and the German Cancer Society - Abridged Version]. / Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms.

The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥ 50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥ 50% stage IIIA and treatment options in PD-L1 ≥ 50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.

Clinical benefit and cost-effectiveness analysis of liquid biopsy application in patients with advanced non-small cell lung cancer (NSCLC): a modelling approach.

PURPOSE: Targeted therapies are effective therapeutic approaches in advanced stages of NSCLC and require precise molecular profiling to identify oncogenic drivers. Differential diagnosis on a molecular level contributes to clinical decision making. Liquid biopsy (LB) use has demonstrated its potential to serve as an alternative to tissue biopsy (TB) particularly in cases where tissue sampling is not feasible or insufficient. We aimed at evaluating the cost-effectiveness of ctDNA-based LB use (molecular multigene testing) according to German care guidelines for metastatic NSCLC. METHODS: A Markov model was developed to compare the costs and clinical benefits associated with the use of LB as an add-on to TB according to the guidelines for NSCLC patients. Usual care TB served as comparator. A microsimulation model was used to simulate a cohort of non-squamous NSCLC patients stage IV. The parameters used for modelling were obtained from the literature and from the prospective German CRISP registry ("Clinical Research platform Into molecular testing, treatment, and outcome of non-Small cell lung carcinoma Patients"). For each pathway, average direct medical costs, and QALYs gained per patient were used for calculating incremental cost-effectiveness ratios (ICER). RESULTS: The use of LB as an add-on was costlier (€144,981 vs. €144,587) but more effective measured in QALYs (1.20 vs. 1.19) for the care pathway of NSCLC patients (ICER €53,909/QALY). Cost-effectiveness was shown for EGFR-mutated patients (ICER €-13,247/QALY). CONCLUSION: Including LB as an add-on into the care pathway of advanced NSCLC has positive clinical effects in terms of QALYs accompanied by a moderate cost-effectiveness.

Real-world multicentre analysis of neoadjuvant immunotherapy and chemotherapy in localized or oligometastatic non-small cell lung cancer (KOMPASSneoOP).

Background: Recent clinical trials demonstrate the feasibility of neoadjuvant immuno(chemo)therapy and report high rates of pathological remission, a surrogate marker for overall survival. Patients and methods: This is a retrospective multicentre real-world analysis of patients with locally resectable NSCLC, including oligometastatic disease, who received neoadjuvant immuno(chemo)therapy and resection. Consolidating immunotherapy was applied following multidisciplinary board recommendation. Primary endpoint was the rate of complete pathological response (pCR, no residual vital tumour cells) or major pathological response (MPR, ⩽ 10% residual vital tumour cells). Secondary endpoints included the radiological response and survival. Results: Seven centres contributed 59 patients (56% stage IIB-IIIC, 44% in stage IVA-IVB with up to four oligometastatic sites). MPR was found in 68% including 53% with pCR. There were no radiological progressions. Median follow-up was 24.3 months. At 12 and 24 months, progression-free survival was 82.6% and 68.1%, and overall survival was 89.5% and 87.2%, respectively. Conclusion: To our knowledge, this study encompassed the largest NSCLC real-world cohort treated with neoadjuvant immuno(chemo)therapy to date. In routine clinical practice, resection after neoadjuvant immuno(chemo)therapy is feasible in patients with locally resectable NSCLC, including oligometastatic disease. In line with clinical trials, we found MPR in more than two-thirds of patients. Early data show encouraging survival.

Afatinib as first-line treatment in patients with EGFR-mutated non-small cell lung cancer in routine clinical practice.

BACKGROUND: Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive (EGFRm+). Head-to-head clinical trials have demonstrated superior efficacy with second-/third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) versus first-generation EGFR TKIs in EGFRm+ NSCLC. Data from routine clinical practice are necessary to confirm that clinical trial findings are transferable to real-world populations. METHODS: In NCT02047903, a prospective non-interventional study in Germany, patients with EGFRm+ NSCLC received first-line afatinib until disease progression or intolerable adverse events. Key objectives were progression-free survival (PFS) rate at 12 months, objective response rate (ORR) and overall survival (OS). Safety/tolerability was also assessed. RESULTS: Of 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommon EGFR mutation and 51 patients (33.6%) had brain metastases. A starting dose of <40 mg was received by 39 (25.7%) patients. Overall, the 12-month PFS rate was 50.2% while the median PFS was 12.2 months. The ORR was 74.6% and the median OS was 30.4 months. In patients with brain metastases and uncommon mutations, the median PFS was 10.5 and 10.7 months, and the ORR was 77.3% and 83.3%, respectively. Treatment effectiveness was similar in patients with a starting dose of <40 mg (median PFS: 16.4 months; ORR, 81.3%) and a starting dose of 40 mg (median PFS: 10.8 months; ORR, 72.1%). Adverse drug reactions were manageable and consistent with the known afatinib safety profile. CONCLUSION: The results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon EGFR mutations and in those with brain metastases. Treatment benefit was also seen in patients receiving a <40 mg afatinib starting dose, supporting patient-tailored dosing.

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP.

Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. 211 patients were registered by 90 German centres. Data were collected retrospectively by questionnaire and queries. 56 centres reported data on 126 patients who actually received at least one cycle of durvalumab. In contrast to the PACIFIC-trial population, some patients with oligometastatic disease and a history of autoimmune disease are included in the EAP population. Information on PD-L1 status was obtained for 111 patients. Baseline data include age, gender, ECOG, stage (IASLC 8th ed.), and smoking history. Treatment data include mode of chemoradiotherapy, used chemotherapy agent, and duration of durvalumab therapy. Adverse evants were documented according to CTAEC 5.0. Data were analysed for progression-free survival (PFS), overall survival (OS), and adverse events (AE). The results were published in Lung Cancer [1].

Durvalumab after definitive chemoradiotherapy in locally advanced unresectable non-small cell lung cancer (NSCLC): Real-world data on survival and safety from the German expanded-access program (EAP).

BACKGROUND: Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. METHODS: Data from 56 centres were analysed for adverse events (AE), progression-free survival (PFS), overall survival (OS). RESULTS: 126 patients actually received at least 1 cycle durvalumab. Compared to the PACIFIC trial, the EAP population had more advanced stage and included "oligometastatic" stage IV patients and patients with autoimmune disease. PFS (20.1 months) and OS (not reached) were similar in the EAP and the PACIFIC trial. 42.9 % completed 12 months of durvalumab without deaths during FU. Stage IV patients (n = 7) had encouraging OS (not reached at 27 months). Autoimmune disease did not affect survival. PFS and OS were similar in PD-L1-negative patients (n = 32) and PD-L1-positive patients (n = 79). CONCLUSIONS: Survival in the EAP was comparable to the PACIFIC trial. Selected stage IV patients and patients with autoimmune disease may benefit from durvalumab consolidation and should be included in future immuno-oncological trials. PD-L1 did not predict survival challenging the exclusion of PD-L1-negative patients from durvalumab consolidation. In summary, durvalumab consolidation is safe and effective in a European real-world setting.

Advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations: first-line treatment with afatinib and other EGFR TKIs.

INTRODUCTION: Based on the results of several randomised controlled trials, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have now replaced platinum-based chemotherapy as first-line therapy for advanced non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation. Areas covered: This review describes the EGFR pathway and its abnormalities in NSCLC and discusses the differential molecular and clinical activity of first and next-generation EGFR TKIs in the first-line treatment of tumors with an activating EGFR mutation, with a special focus on the second-generation agent afatinib. A comprehensive literature search was conducted to identify all relevant clinical trials including abstracts from most recent meetings to provide up-to-date information on this topic. Expert commentary: While the first-generation EGFR TKIs erlotinib and gefitinib exhibited good tolerability and improved progression-free survival compared with a platinum doublet, they failed to improve overall survival (OS). In contrast, clinical trials of afatinib (LUX-Lung 3 and 6) demonstrated a significant OS advantage over a platinum doublet, particularly in patients whose tumors harbored the Del19 mutation. Moreover, in a head-to-head comparison afatinib improved efficacy versus gefitinib in patients with common EGFR mutations across a range of clinically relevant endpoints. Afatinib is therefore a promising first-line option in these patients.

Cdc2 as prognostic marker in stage UICC II colon carcinomas.

PURPOSE: Cyclin-dependent kinase 2 (cdc2) controls the G2-M checkpoint and, therefore, the entrance of cells into mitosis. It might play a crucial role during tumour progression in colon carcinomas (CCA). Thus, the prognostic value of cdc2 expression and connected markers relevant for proliferation and apoptosis has to be evaluated. EXPERIMENTAL DESIGN: Punch biopsies from the tumour centre and the invasion front of 0.6mm diameter from 392 CCA stage UICC II-IV were integrated in 14 recipient paraffin blocks. After immunohistochemical staining for cdc2, p53, caspase 3 and ki-67, a present (+) and absent (-) scoring was performed in the tissue arrays. The logrank test was used to compare distant metastasis and cancer-related survival. Multivariate Cox regression analysis was done to identify independent prognostic factors for parameters with significant influence on cancer-related survival (CRS) and distant metastasis (DM). RESULTS: The pT-category (p=0.007), nodal status (p<0.001), extramural venous infiltration (p<0.001) and lymphatic vessel invasion (p=0.003) were identified as independent histological parameters for CRS. Univariate analysis relating to stage UICC II-IV CCA showed caspase 3 in the tumour centre (p=0.047) to be a prognostic marker for CRS. In stage UICC II cdc2 (p=0.041) and caspase 3 in the invasion front (p=0.026) could be identified as independent prognostic factors for CRS and DM by multivariate analysis. CONCLUSIONS: Cdc2 and caspase 3 could be identified as independent prognostic markers in stage UICC II CCA. They might be of value to select patients who should receive adjuvant treatment.

Molecular signature for lymphatic metastasis in colorectal carcinomas.

PURPOSE: TNM-staging of colorectal carcinomas (CRC) relies on the histopathologic workup of the surgically removed specimen. If valid preoperative staging methods existed, patients could be selected for adequate individual therapy before surgery. Microarray techniques provide a promising tool to identify stage-specific molecular signatures on primary tumor biopsies. MATERIAL AND METHODS: Forty tumor samples of stage UICC I, II CRC, 40 samples of stage III CRC, and 25 biopsies of healthy mucosa (MC) were shock frozen in liquid nitrogen and underwent cryotomy after manual dissection for tumor tissue or MC enrichment. Isolated RNA was hybridized to GeneChips (HG-U133A, Affymetrix). Preprocessing of the microarray results was done by the robust multichip average method, and differentially expressed genes were selected by the maximum Wilcoxon statistic over 22,215 probe sets. The results were validated at an independent clinical study. RESULTS: Fifty differently expressed genes between stage UICC I, II versus III CRC were identified respecting the selection criteria by allowing for multiple testing. The data validation by the independent clinical study confirmed our results. In comparison to MC, the genes were over- or underexpressed. They belong to various functional groups such as cellular adhesion, transporters, signaling, metabolism, protein synthesis, gene control, and immune system. CONCLUSION: Our large patient cohort and the data validation on an independent study identified 50 differentially expressed genes between CRC of different histopathologic stages. These findings indicate that molecular staging of CRC may be possible, which could help to guide individual CRC treatment before surgery.

Transforming growth factor beta 1 dependent regulation of Tenascin-C in radiation impaired wound healing.

BACKGROUND: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial cell carcinomas of the head and neck region fibrocontractive wound healing disorders occur. Tenascin-C is significantly increased in fibrotic tissue conditions and can be stimulated by the transcription factor NF kappa B p65. Previous studies showed a reduction of irradiation induced fibrosis during the wound healing process by anti-TGF beta(1)-treatment. The aim of the study was to clarify the question whether Tenascin-C expression is elevated in radiation impaired wounds and whether anti-TGF beta(1)-treatment is capable to influence Tenascin-C and NF kappa B expression. MATERIAL AND METHODS: Wistar rats (male, weight 300-500 g) underwent preoperative irradiation of the head and neck region with 40 Gy, fractionated four times 10 Gy (16 animals), whereas 8 non-irradated animals served as a control. Four weeks after irradiation a free myocutaneous gracilis flap taken from the groin was transplanted to the neck. Eight animals additionally received 5 microg anti-TGF beta(1) into the graft bed by intradermal injection prior to each fraction of irradiation and on days 1-7 post-operation. On day 14 and 28 following surgery immunohistochemistry (ABC-POX method) was performed assessing the cytoplasmic NF kappa B and Tenascin-C staining in the transition area between transplant and graft bed. For quantitative considerations the labeling index (ratio: positive cells/total cells) was determined. RESULTS: A significantly altered expression of Tenascin-C in the preirradiated tissue was observed following anti-TGF beta(1)-treatment. NF kappa B protein was upregulated in irradiated animals and was significantly reduced in the anti-TGF beta(1) treated group on day 28 after transplantation. CONCLUSIONS: Tenascin-C expression is prolonged in irradiated animals as compared to non-irradiated tissue. Tenascin-C seems to be regulated by TGF beta(1) as the application of TGF beta(1)-neutralizing antibodies reduces Tenascin-C expression. Tenascin-C is a potentially useful marker for tissue remodeling due to its restricted distribution in adult and healthy tissue and a hallmark for developing fibrosis.