Wieneke A. Buikhuisen

Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study.

BACKGROUND Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. METHODS In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. FINDINGS Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. INTERPRETATION No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. FUNDING Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.

Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

Summary Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

Second line therapy in malignant pleural mesothelioma: a systematic review

After the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent.

Clinical features of large cell neuroendocrine carcinoma : a population-based overview

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an orphan disease and few data are available on its clinical characteristics. Therefore, we analysed LCNEC registered in the Netherlands Cancer Registry, and compared data with small cell lung carcinoma (SCLC), squamous cell carcinoma (SqCC) and adenocarcinoma (AdC). Histologically confirmed LCNEC (n=952), SCLC (n=11 844), SqCC (n=19 633) and AdC (n=24 253) cases were selected from the Netherlands Cancer Registry (2003–2012). Patient characteristics, metastasis at diagnosis (2006 or later), overall survival (OS) including multivariate Cox models and first-line treatment were compared for stage I–II, III and IV disease. The number of LCNEC cases increased from 56 patients in 2003 to 143 in 2012, accounting for 0.9% of all lung cancers. Stage IV LCNEC patients (n=383) commonly had metastasis in the liver (47%), bone (32%) and brain (23%), resembling SCLC. Median OS (95% CI) of stage I–II, III and IV LCNEC patients was 32.4 (22.0–42.9), 12.6 (10.3–15.0) and 4.0 (3.5–4.6) months, respectively. Multivariate-adjusted OS of LCNEC patients resembled that of SCLC patients, and was poorer than those of SqCC and AdC patients. However, frequency of surgical resection and adjuvant chemotherapy resembled SqCC and AdC more than SCLC. Diagnosis of LCNEC has increased in recent years. The metastatic pattern of LCNEC resembles SCLC as does the OS. However, early-stage treatment strategies seem more comparable to those of SqCC and AdC. Outcome of LCNEC is poor and metastatic pattern resembles SCLC, yet stage I–II treatment corresponds more with NSCLC http://ow.ly/S37N9

Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.

PURPOSE/OBJECTIVE In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction. METHODS AND MATERIALS Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancer during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets. RESULTS Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and -2%, 15%, and 7% for the tumor if an online carina registration protocol replaced a protocol based on bony anatomy registration. CONCLUSIONS Detailed analysis revealed considerable lymph node position variability, differential motion, and respiratory motion. Planning target volume margins can be reduced up to 27% in lung cancer patients when the carina registration replaces bony anatomy registration.

Mediastinal lymph node position variability in non-small cell lung cancer patients treated with radical irradiation

BACKGROUND AND PURPOSE Detailed knowledge on mediastinal lymph nodes position variability is lacking. In this study we quantified the variability over the irradiation course in non-small cell lung cancer (NSCLC) patients. METHODS A 0.35×5 mm gold fiducial marker was inserted in mediastinal lymph nodes of 14 stage III NSCLC patients. A respiration correlated 4D-planning-CT (pCT) and daily 4D-Cone Beam (CB)CT-scans were acquired. To calculate the systematic and random baseline variations, and respiratory motion variability of the lymph nodes, all CBCT scans were registered to both the bony anatomy and marker in the pCT. Patient population statistics of the peak-to-peak amplitude and time averaged mean position relative to the bony anatomy were calculated. RESULTS The average peak-to-peak amplitude was 0.21 cm, 0.52 cm and 0.20 cm in the Left-Right, Cranial-Caudal and Anterior-Posterior direction respectively, while the amplitude variability was ≤0.1 cm in each direction. Inter-fraction lymph node baseline variation was 0.21/0.2 cm, 0.34/0.23 cm, and 0.17/0.15 cm systematic/random. PTV margins for these variations were 0.92 cm, 1.24 cm, 0.82 cm for an online bone match and could be reduced to 0.77 cm, 0.82 cm and 0.86 cm for an online carina match. CONCLUSIONS Substantial and anisotropic, systematic and random mediastinal lymph node baseline variations were found in NSCLC patients indicating that non-uniform margins could be beneficial.

Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial

BACKGROUND There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus. METHODS LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing. FINDINGS Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related. INTERPRETATION The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids. FUNDING Novartis Pharma AG.

A Randomized Phase II Study Adding Axitinib to Pemetrexed-Cisplatin in Patients with Malignant Pleural Mesothelioma: A Single-Center Trial Combining Clinical and Translational Outcomes

Introduction: Mesothelioma often presents with a high vessel count and increased vascular growth factors levels. Interference with angiogenesis may therefore improve outcome. This study reports on clinical and translational parameters in patients treated with the small molecule tyrosine kinase inhibitor axitinib and chemotherapy. Methods: Chemonaive patients with mesothelioma were eligible. Patients received pemetrexed (500 mg/m2 every 3 weeks) and cisplatin (75 mg/m2 every 3 weeks) and were randomized to receive axitinib daily (two 5‐mg tablets on days 2–19) or observation. Before treatment and after three cycles of chemotherapy, a thoracoscopy was performed to evaluate vascular changes. Results: Twenty‐five patients were randomized after a successful lead‐in with six patients who received axitinib. Median follow‐up was 45 months. In all but one patient, it was feasible to perform a second thoracoscopy. However, there was more grade 3 or 4 neutropenia leading to pneumonia in the axitinib group. The rates of partial response and stable disease in the axitinib arm were 36% and 43% compared with 18% and 73% in the chemotherapy‐only arm. Median progression‐free survival and overall survival (5.8 and 18.9 months versus 8.3 and 18.5 months) were not different between the two groups. Axitinib reduced vessel number and vessel immaturation. Yet, the mRNA levels of a number of vascular growth factors, their receptors, serum VEGF levels, and activation of tissue vascular endothelial growth factor receptor 2 were increased. Gene expression of platelet‐derived growth factor receptor beta, fms‐related tyrosine kinase 1, and fms‐related tyrosine kinase 4 even correlated with outcome. Conclusions: Axitinib was well tolerated in combination with cisplatin and pemetrexed. Despite the lack of a clinical benefit, axitinib reduced angiogenesis. Whether changes in differentially expressed growth factors in tissue and serum may serve as a biomarker needs further investigation.

Neuroendocrine Cancer of the Lung: A Diagnostic Puzzle

Here we report the case of a pulmonary neuroendocrine tumor (pNET) in which the pathological diagnosis was revised several times over the course of the patients disease because of atypical behavior of the tumor; consequently, the patient was treated with various treatment schedules.

Pemetrexed Pathway–Associated Germline Polymorphisms: A Useful Tool for Treatment Individualization?

However,pemetrexed is still costly and is considered an expensive drug by theDutch Healthy Authority, as it amounts to a cost of approximately€14,000 per patient and a total of €19 to 24 million per year in theNetherlands. Therefore, every effort should be undertaken to addi-tionally individualize lung cancer treatment with pemetrexed, andpharmacogenetictraitsareprimecandidates.ThestudybyAdjeietal