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.

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.

[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.

[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.

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

Lymphocyte activation by phytohaemagglutinin and pokeweed mitogen. Identification of proliferating cells by monoclonal antibodies.

Using a two-colour immunofluorescence technique, we have investigated the mitogenic effects of phytohaemagglutinin-M (PHA-M) and of pokeweed nitrogen (PWM) on human lymphocyte subsets. These were identified by CD1, CD3, CD4, CD8, and CD16 monoclonal antibodies, and proliferation was demonstrated by a polyclonal anti-transferrin antibody. Evidence has been obtained for the generation of a population expressing both the CD4 and CD8 antigens simultaneously, in short-term cultures of peripheral blood mononuclear cells in the presence of PWM and of PHA-M.

HIV-Related Lymphoblastic Lymphoma.

The clinical records of 17 patients with HIV-associated lymphoblastic mostly Burkitt-type lymphomas, are reviewed (54% of a total of 31 patients with HIV-associated malignant lymphomas, treated between 1/85-1/90). The lymphomas were diagnosed histologically with additional immuno-histochemical analyses, or cytologically, with subsequent immunocyto-chemistry. All patients were homosexual and HIV antibody positive, and the average age was 39 y. At initial staging evaluation an Ann Arbor stage III or IV was present in 15 patients (88%); a CDC-stage II of HIV-infection was present in 10 patients, CDC-stage III in 5 patients, and CDC-stage IV in 2 patients. An extranodal or mixed nodal/extranodal pattern of organ involvement was seen in 14 cases, with predominance of the gastrointestinal tract (30%) and the bone marrow (30%). The response rate to chemotherapy (CR + PR) was 81%, a CR was achieved in 53% of the patients, and relapses within a few months after CR were common. Survival following relapses in the CR- and PR group was similar, namely 5.2 and 4.9 months respectively. 2 patients in the CR-group and 1 patient in the PR group have been alive for 13, 19 and 30 months. An optimal therapeutic regimen for this disorder does not seem to have been found yet.

Chemotherapy in bone and joint tuberculosis.

Bone and joint tuberculosis, as all other types of tuberculosis is generally treated with antituberculotic combination chemotherapy. This has to be continued for a minimum of six months, or nine months in case of extensive spreading. A two- to three-month initial phase with four or five different drugs (H, R, Z, and additionally E and/or S) is followed by a four- to six-month therapy with H and R alone, provided the pathogen is fully susceptible to a standard regimen. The main side effects are hepatotoxic or allergic reactions. A frequent contra-indication is existing, often toxicity-induced, liver damage. The main local complications requiring surgery are spinal instability or neurologic deficiencies.

[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.

[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.

[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.

[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.

[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.