[Strategies to Overcome Acquired Resistance to EGFR-TKI Therapy Based on T790M Specific Substances using Osimertinib as an Example]. / Strategien zur Überwindung der erworbenen EGFR-TKI-Resistenz durch T790M spezifische Substanzen am Beispiel von Osimertinib.

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed.

Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Pulmonary adenocarcinoma occurring 5 years after resection of a primary pancreatic adenocarcinoma: a relevant differential diagnosis.

Ductal adenocarcinoma of the pancreas is a lethal disease. Surgical extirpation only offers the slim chance for long-term survival in localized disease. We report on a 73 year old female patient who initially underwent successful resection of pancreatic adenocarcinoma in May 2005. She was treated with adjuvant chemotherapy with gemcitabine. In October 2010 the patient noticed increasing dyspnea with haemoptysis. She was soon referred to our center. After the diagnosis of pulmonary adenocarcinoma with widespread metastasis, she was treated with systemic chemotherapy. For a period of next three years, she was treated with different chemotherapy regimens due to repeated episodes of tumor progression. To the best of our knowledge after reviewing the literature, this case represents an unusually clinical course with metachronous pulmonary adenocarcinoma arising after treatment of a primary pancreatic cancer after a long latency period.

Pleural mesothelioma presenting as periumbilical metastasis: the first clinical documentation.

Introduction. Pleural mesothelioma with metastasis to the subcutaneous tissue of the abdominal wall at first diagnosis and without penetration into the peritoneum is an extremely rare clinical presentation. Methods. Patients with pleural mesothelioma have low survival rate. Usually, the disease at presentation is confined to its site of origin (most often the pleural cavity). A 55-year-old man was referred to our center due to increasing dyspnea and a painful periumbilical mass in the anterior abdominal wall. CT scan revealed both advanced mesothelioma of the pleura and a tumor mass confined to the subcutaneous fatty tissue without penetration through the peritoneum. Results. Video-assisted thoracoscopy confirmed the diagnosis of epithelioid pleural mesothelioma, which was also confirmed by a biopsy of the periumbilical mass. Systemic chemotherapy with cisplatin and pemetrexed was initiated. Under the ongoing systemic chemotherapy, the evaluation revealed partial remission of pleura mesothelioma and its subcutaneous manifestation of the abdominal wall. Conclusion. Mesothelioma of the pleura with a simultaneous metastasis to the subcutaneous fatty tissue of the abdominal wall at presentation without penetration of peritoneum is a rare clinical presentation of mesothelioma disease. The knowledge of its natural history is very limited. This is the first ever clinical documentation of a patient with pleura mesothelioma and simultaneous subcutaneous manifestation of abdominal wall.

Lung metastasis of primary alveolar soft-part sarcoma occurring 20 years after initial treatment.

A 30-year old woman was referred to our center because of suspicion of a primary lung tumor of the right upper lobe. Histological examination of the lung lesion revealed lung metastasis of a previously treated alveolar soft part sarcoma of the musculus vastus medialis of the right femur, which was resected 20 years ago. Alveolar soft-part sarcoma is a rare malignant tumor that occurs most often in the soft tissue of lower limbs. It is a slow-growing malignant soft tissue tumor arising in muscle tissue, usually in young adults. Due to pleural and extensive mediastinal infiltration with bilateral lung metastases, a systemic treatment with chemotherapy doxorubicin and ifosfamide was initiated. Late metastases from previously treated alveolar part sarcoma should be considered in patients with suspicious lung lesions even if surgical treatment was performed a long time ago.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome.

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare clinical pathological syndrome. There have been only 49 cases of DIPNECH reported in the literature so far. We report a case of a 69-year-old nonsmoking man with a 7-year follow-up. METHODS: The initial CT scan from December 2003 showed persistent nonspecific bilateral reticulonodular infiltrates. In January 2004, the patient underwent a video-assisted thoracoscopic wedge resection of his right lower lobe for further diagnostic workup. Pathology of the resected wedge of the right lower lobe revealed a diffuse idiopathic pulmonary cell hyperplasia (DIPNECH) highlighted by staining for the neuroendocrine typical carcinoid markers, such as marker CD 56. RESULTS: All the performed CT scans over a 7-year period showed no progression of the bilateral pulmonary lesion. The bilateral pulmonary nodules were stable in terms of size, number and form. The yearly control with chest CT scans will be continued. CONCLUSIONS: The neuroendocrine cell hyperplasia is confined to the airway mucosa without penetration through the basement membrane and appears in a diffuse pattern, generally in close association with obliterative bronchiolar fibrosis. DIPNECH is characterized by a mixed obstructive and/or restrictive ventilation pattern with bilateral reticulonodular infiltrates and a predilection for middle-aged women. Little is known about the clinical course and treatment for DIPNECH.

[Bronchial aspergillosis]. / Bronchiale Aspergillosen.

Bronchopulmonary aspergillosis is becoming more frequent, is often hard to diagnose and with today's antimycotics better to treat than before. It is therefore of current interest. This also concerns bronchial aspergillosis which is less common than pulmonary aspergillosis and the topic of this paper. A total of 39 patients with bronchial aspergillosis are presented: 1) 4 cases with endobronchial aspergilla, two which are visual bronchoscopically, 2) one case with chronic necrotising pulmonary aspergillosis (CNPA), where a bronchus has necrotised, 3) an invasive aspergillosis in the region of a bronchial anastomosis, 4) 7 cases with an Aspergillus invasion from endobronchial tumour tissue and 5) 26 cases with allergic bronchopulmonary aspergillosis (ABPA). 37 of the 39 cases are part of a single centre study with a total of 116 bronchopulmonary aspergilloses, which were collected over seven years. The focus of attention in this paper is on the bronchoscopic and radiological results.