International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer.

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial.

BACKGROUND: Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. PATIENTS AND METHODS: In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. RESULTS: Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. CONCLUSION: Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. REGISTERED CLINICAL TRIAL NUMBERS: EudraCT number 2010-022273-34, NCT01317615.

[Employing tyrosine kinase inhibitors in the first line treatment of EGFR-positive metastatic NSCLC - state of the art and recent developments]. / Der Einsatz von Tyrosinkinase-Inhibitoren bei aktivierenden EGFR-Mutationen in der Erstlinientherapie beim fortgeschrittenen nicht-kleinzelligen Lungenkarzinom (NSCLC) - aktueller Stand und Entwicklungen.

In this review article we present an overview of recent developments in EGFR TKIs in lung cancer therapy. Besides the approved drugs erlotinib and gefitinib, clinical data on second-generation irreversible TKIs including afatinib, dacomitinib, neratinib, pelitinib, and canertinib are mentioned; these drugs not only inactivate EGFR but show a broader range of activity. We also report on NSCLC data of TKI that are known and approved in other indications, such as lapatinib and vandetanib. We stress the importance of quality of life in the treatment of patients with TKIs, an important aspect of the treatment that should also be considered in the selection of the appropriate NSCLC therapy in advanced stages.

[Gender-specific difference in lung cancer]. / Geschlechtsspezifische Unterschiede beim Lungenkarzinom.

More and more differences in lung cancer are being detected between men and women. Lung cancer, at the beginning of the last century a rare disease in women, has a growing incidence in women, in particular in young females. Lung cancer is a leading cause of cancer death in women in developed countries with different histological types and adenocarcinomas are more frequent in women than in men. Cigarette smoking is the most prevalent cause of lung cancer in women, in addition susceptibility to carcinogens may differ between the sexes. As more non-smoking women than men develop lung cancer, it is likely that they are exposed to excessive environmental carcinogens such as second-hand-smoking, in-house-radon or cooking fumes. Furthermore, genetic and hormonal influences play a role in lung cancer etiology for women. Taken together, women have a better overall survival than men with lung cancer. Differences in molecular susceptibility patterns are observed between men and women, and show that molecular targets such as EGFR or ALK more frequent in women.

Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study.

BACKGROUND: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement. PATIENTS AND METHODS: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m(2) day (d)1 + 8) and vinorelbine (V: 25 mg/m(2) d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m(2) d1) and pemetrexed (Px: 500 mg/m(2) d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. RESULTS: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P < 0.001). CONCLUSION: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb.

A 62-year-old woman with bilateral pleural effusions and pulmonary infiltrates caused by extramedullary hematopoiesis.

A 62-year-old female presented with a 1-month history of irritating cough and increasing dyspnea. A chronic idiopathic myelofibrosis had been diagnosed 5 years ago. CT of the chest and abdomen showed bilateral pleural effusions with a thickened pleura, nodular infiltrations in both lungs, enlarged intraabdominal lymph nodes and splenomegaly. Pleuroscopy (medical thoracoscopy) on the left side revealed dense tumorous nodules mainly on the posterior chest wall pleura, but also on the diaphragm and the lung. Biopsies taken from the chest wall pleura revealed extramedullary hematopoiesis (EMH) with abnormal megakaryocytes as well as myeloid and erythroid precursors. After unsuccessful tetracycline pleurodesis, talcum slurry was instilled via the chest tube without recurrence of the pleural effusion. Furthermore, treatment with hydroxyurea was started, and the disease regressed and then remained stable over the next 24 months. In conclusion, the pleuropulmonary findings were caused by EMH due to chronic idiopathic myelofibrosis. The definite diagnosis was established by pleuroscopy followed by successful pleurodesis with talc slurry, after tetracycline pleurodesis had failed.

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive

[Modern endoscopic procedures for diseases of the respiratory tract]. / Moderne endoskopische Verfahren bei Erkrankungen der Atmungsorgane.

Bronchoscopy is the most important diagnostic procedure for the work-up of central bronchial processes and parenchymal lung diseases, such as lung cancer, pneumonias or diffuse lung diseases. Recent progress - ultrasound, navigation systems or ultrathin bronchoscopes - was made to achieve a better yield in the diagnosis of peripheral and peribronchial lesions. Bronchial recanalisation by thermal ablation or stenting is mainly performed with rigid instruments; these procedures as well as brachytherapy in local anaesthesia should be restricted to specialized centers. If pleuracentesis does not provide the etiology of pleural effusion, thoracoscopy in local anaesthesia is the method of choice. The procedure does not only provide a definite diagnosis for almost all of the patients, it also allows the immediate option for talcum poudrage in case of pleural malignancy.

[Diagnosis and staging of lung cancer]. / Lungenkarzinom: Diagnostik und Staging.

Despite medical advances lung cancer remains the leading cause of cancer deaths. Lung cancer is usually recognized late in its natural history and at presentation in 80 % unresectable. Smoking history is the most important risk factor. At present time, screening for lung cancer is not recommended. The only chance for cure is tumour resection in early stages, performed in about 20 % of all lung cancer cases. Histological subtypes are non-small cell lung cancer (NSCLC) (80 % of lung cancers) and 20 % small cell lung cancer (SCLC). TNM-staging has important influence on prognosis and therapy. After identification the tumour should be staged using the TNM system. Currently diagnosis and staging rely predominantly on chest radiography and computed tomography (CT) scanning. Positron emission tomography (PET) identifies the tumour by its metabolic activity and helps to find malignant nodal or systemic lesions. Flexible bronchoscopy is the key investigation in the diagnosis and staging of patients with suspected lung cancer. Endobronchial ultrasound guided transbronchial fine needle aspiration (TBNA) may be utilized to improve the bronchoscopic results in mediastinal staging. Internistic thoracoscopy or video assisted thoracoscopic surgery (VATS) may be used in malignant pleural effusions. Mediastinoscopy staging is the gold-standard for mediastinal staging.

[Multimodal therapy of small cell and non-small cell lung carcinoma]. / Multimodale Therapie des kleinzelligen und nichtkleinzelligen Lungenkarzinoms.

Lung cancer is divided into two types: non-small cell and small cell lung cancer. Small-cell lung cancer is a very aggressive rapid growing tumour type treated primarily with chemotherapy and, in the minority of patients with limited disease, with radiotherapy. Non-small cell lung cancer is treated in a multidisciplinary way with surgery, radiotherapy and chemotherapy depending on stage. Surgery is the mainstay of treatment for early stage non-small cell lung cancer patients. Adjuvant therapy has become state of the art in stage II and IIIA patients and must be considered in stage IB. Stage III patients should be treated in a multimodal way with radiotherapy and chemotherapy, and, if possible, with surgery. Treatment for every stage III patient should be discussed in a multidisciplinary team. Stage IV patients in good performance status will benefit from a combination chemotherapy, preferably platinum-based. Second line therapy has become standard and targeted therapies are under evaluation and are common in second line chemotherapy.

[Lung cancer: targeted therapy]. / Pharmakologische Therapie des Lungenkarzinoms.

An increased understanding of the biology of lung cancer has identified biological targets for rationally designed novel therapies. Most of these targets are components of signalling pathways or metabolic processes. EGFR-tyrosinkinase inhibitors have become standard in second- and thirdline therapy of NSCLC, the anti-VEGF-antibody Avastin combined with first-line chemotherapy showed a significant survival benefit over chemotherapy alone. There are ongoing studies with targeted therapies in all stages of lung cancer. Major advances of these new drugs are their low toxicity and, in part, the oral application.

[Pharmacologic treatment of bronchial cancer. Part 1: Standards]. / Pharmakologische Therapie des Bronchialkarzinom. Teil I: Standards.

In the last decade there have been important innovations in the treatment of lung tumors. New combined modality therapies are becoming standard and require a network of cooperating partners. New therapeutic agents are under investigation that will hopefully improve the outcome of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Principles of chemotherapy in non-small cell und small cell lung cancer depending on stage and combination in multimodal regimens are shown. In the second part single drugs are described with their typical effects and side effects from the viewpoint of a clinician. A following part II will discuss new "targeted" biologicals.

[Therapeutic options in malignant pleural mesothelioma]. / Therapeutische Optionen beim malignen Pleuramesotheliom.

Malignant pleural mesothelioma may be treated with surgery, radiotherapy and chemotherapy. In most patients, the treatment remains palliative with symptom relief and a moderate survival gain. Only a minority of patients with early stage mesothelioma may be cured by a multimodal approach including radical surgery, chemotherapy, and radiotherapy. We discuss the role of surgery with either radical extrapleural pleuropneumonectomy or less invasive palliative pleurectomy and decortication, and the role of radiotherapy, in which the main problem is how to deliver sufficient doses to the pleural surface, sparing radiosensitive structures such as the lung, heart, liver, and kidneys. Chemotherapeutic options are discussed with 'older' mono- and combination regimens and the new promising combination cisplatinum/pemetrexed, now the 'standard regimen' for malignant pleural mesothelioma. Experimental approaches such as hyperthermia, interferons or interleukins, and 'small molecules' or antibodies inhibiting the EGFR oder VEGF receptor are under clinical evaluation. For the majority of our patients we recommend talcum pleurodesis either by medical thoracoscopy or VATS, followed by chemotherapy with platinum/pemetrexed. Radiotherapy may be applied in case of local tumour growth. The individual therapeutic decision will depend on tumour stage, concomitant diseases, performance status, and on the patient's preference.

Medical thoracoscopy: hormone receptor content in pleural metastases due to breast cancer.

Pleural metastases are common in the course of breast cancer, but, to date, the role of oestrogen receptor (OR) and progesterone receptor (PgR) content in metastatic tissue has been poorly evaluated. A series of 50 consecutive patients with a history of breast cancer (median age 64 yrs, range 40-86 yrs), which presented with pleural effusion and therefore underwent medical thoracoscopy, was analysed. Metastatic pleural involvement was histologically confirmed in all patients. The hormone receptor status of the pleural metastases was investigated using the immunohistochemical method in 49 and the biochemical method in 31 cases. The immunohistochemical test was performed using monoclonal antibodies. Biochemical analysis was performed on specimens quick-frozen in liquid nitrogen. OR and PgR were measured with the dextran-coated charcoal assay and Scatchard analysis. Immunohistochemical analysis yielded 29 OR-positive and 25 PgR-positive cases and biochemical analysis yielded 16 OR-positive and four PgR-positive cases, sometimes discrepant to hormone status of the primary breast cancer. Using a semiquantitative immunoreactive score, there was a significant association between receptor positivity and survival, but only for PgR positivity. Immunohistochemical and biochemical detection of hormone receptors (oestrogen and progesterone) in pleural metastases of breast cancer is feasible based on medical thoracoscopy as the method of choice, by which sufficient specimens may be obtained. The receptor status may enable a decision on antihormonal treatment. Whether a positive receptor status in pleural metastatic tissue is associated with a better prognosis remains to be confirmed.

[Multimodality therapy concept in stage I-IIIA small cell bronchial carcinoma. Case follow-up over 15 years]. / Multimodales Therapiekonzept beim kleinzelligen Bronchialkarzinom im Stadium I-IIIA. Fallverlaufsstudie über 15 Jahre.

We analysed our results of multimodal therapy including chemotherapy, radiotherapy and surgery in 150 consecutive patients with SCLC stage I-IIIa operated on in our hospital between 1983 and 2000. Median age: 58 years, stages see Table 2. Patients with proven SCLC had induction chemotherapy prior to surgery. All patients received three cycles of adjuvant chemotherapy, some with additional radiotherapy. Perioperative mortality: 2%. Median survival: 22.4 months. R0 resection was possible in 84% of all patients. Pre- and post-surgery staging differed in the majority of the patients. Rotes of 1-, 2- and 5-year survival were 79%, 47%, and 32%, respectively. A median survival of 22.4 months in multimodally treated LD-SCLC, most of them stage IIb/IIIa appears promising. Randomized studies based on clinical staging procedures are not recommended. Survival data are promising.