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Introduction: To assess the safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with stage IB-III MAGE-A3-positive non-small-cell lung cancer (NSCLC) who were or were not undergoing standard cisplatin/vinorelbine chemotherapy., Methods: This open, prospective, multicenter, parallel-group phase I study (NCT00455572) enrolled patients with resected (cohorts 1-3) or unresectable (cohort 4) MAGE-A3-positive NSCLC. MAGE-A3 immunotherapeutic (300 μg recombinant MAGE-A3 formulated with AS15) was administered (eight doses, 3 weeks apart) concurrent with (cohort 1), after (cohort 2), or without (cohort 3) standard-adjuvant chemotherapy, or after standard radiotherapy and/or chemotherapy (cohort 4)., Results: Sixty-seven patients received greater than or equal to 1 dose of MAGE-A3 immunotherapeutic. Grade 3/4 adverse events (AEs) were reported for 16 out of 19 (84%), 2 out of 18 (11%), 5 out of 18 (28%), and 1 out of 12 (8%) patients in cohorts 1, 2, 3, and 4, respectively. Many grade 3/4 AEs in cohort 1 (e.g., neutropenia) were typical of chemotherapy. Six patients, including three in cohort 1, reported study treatment-related grade 3/4 AEs (injection-site reactions or musculoskeletal/back pain, which resolved within 5 days). One patient (in cohort 4) died, but this and the other serious adverse events were not study treatment related. MAGE-A3-specific antibody responses to immunotherapy were induced in all patients evaluated in all cohorts. MAGE-A3-specific CD4 T-cell responses to immunotherapy were detected in 4 out of 11 (36%), 4 out of 15 (27%), 2 out of 8 (25%), and 5 out of 6 (83%) evaluated patients in cohorts 1, 2, 3, and 4, respectively; and CD8 T-cell responses were only detected in four patients., Conclusion: In resected and unresectable NSCLC patients and irrespective of whether standard chemotherapy was concurrent or not, MAGE-A3 immunotherapeutic is well tolerated and induces MAGE-A3-specific immune responses.

Background: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study examined the effect of clinical covariates on biomarkers levels and their diagnostic and prognostic value., Methods: Five hundred ninety-four participants were enrolled in a multicenter study, including 106 patients with mesothelioma and 488 control subjects. Multiple linear regression analyses were used to identify which covariates were independently associated with SM and MPF levels. The effect of these covariates on the diagnostic accuracy was evaluated with receiver operating characteristics curve analysis. In patients with mesothelioma, survival analysis was performed with Cox regression., Results: SM and MPF levels were independently associated with age, glomerular filtration rate (GFR), and BMI in control subjects and with GFR and tumor stage in patients with mesothelioma. The diagnostic accuracy of SM and MPF was significantly affected by the distribution of these covariates in the study population. The patients with mesothelioma were best discriminated from the control subjects with either the youngest age, the highest GFR, or the largest BMI. Furthermore, the control subjects were significantly better differentiated from stage II to IV than from stage I mesothelioma. MPF, not SM, was an independent negative prognostic factor, but only if adjusted for the biomarker-associated covariates., Conclusions: SM and MPF levels were affected by the same clinical covariates, which also had a significant impact on their diagnostic and prognostic value. To improve the interpretation of biomarker results, age, GFR, and BMI should be routinely recorded. Approaches to account for these covariates require further validation, as does the prognostic value of SM and MPF.

Introduction: Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome., Methods: Sixty-two patients with malignant pleural mesothelioma were included in an observational multicenter study. Blood samples and matched computed tomography scans were collected at diagnosis and, when possible, during and after therapy. For each patient, the best overall radiological response was compared with the changes in serum SM, MPF, and plasma OPN levels across corresponding time points., Results: In five patients, blood sampling was done shortly before and after extrapleural pneumonectomy. SM and MPF levels markedly decreased after surgery, whereas OPN levels showed a median increase. Fifty-seven patients were surveilled during (and after) chemotherapy, of whom 27 (47%) had stable disease, 14 (25%) partial response, and 16 (28%) progressive disease. In patients with stable disease, SM and MPF levels did not change significantly across the corresponding time points, whereas OPN levels significantly decreased. In those with partial response, SM and MPF levels significantly decreased, whereas OPN levels showed no significant change. In patients with progressive disease, all three biomarker levels significantly increased. Patient responses correlated with a 15% change in all three biomarkers, although SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable progression-free survival and overall survival. Neither SM nor MPF showed prognostic value., Conclusions: SM and MPF levels were more closely associated with disease course than OPN and might prove useful in monitoring patient response in mesothelioma. Baseline OPN levels were an independent negative predictor of survival. These promising results require further validation.

Introduction: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study aims to examine the longitudinal behavior of SM and MPF in controls to gain insight in the optimal use of these biomarkers in screening., Methods: Asbestos-exposed individuals, with no malignant disease at inclusion, were surveilled for 2 years with annual measurements of SM and MPF. Fixed thresholds were set at 2.10 nmol/L for SM and 13.10 ng/ml for MPF. Longitudinal biomarker analysis, using a random intercept model, estimated the association with age and glomerular filtration rate (GFR), and the intraclass correlation. The latter represents the proportion of total biomarker variance accounted for by the between-individual variance., Results: A total of 215 participants were included, of whom 179 and 137 provided a second sample and third sample, respectively. Two participants with normal SM and MPF levels presented afterward with mesothelioma and lung cancer, respectively. Participants with elevated biomarker levels were typically older and had a lower GFR. During follow-up, biomarker levels significantly increased. Longitudinal analysis indicated that this was in part due to aging, while changes in GFR had a less pronounced effect on serial biomarker measurements. SM and MPF had a high intraclass correlation of 0.81 and 0.78, respectively, which implies that a single biomarker measurement and fixed threshold are suboptimal in screening., Conclusions: The longitudinal behavior of SM and MPF in controls indicates that a biomarker-based screening approach can benefit from the incorporation of serial measurements and individual-specific screening rules, adjusted for age and GFR. Large-scale validation remains nevertheless mandatory to elucidate whether such an approach can improve the early detection of mesothelioma.

Medical oncologists are faced with multiple factors to consider when staging a patient with suspected or confirmed non-small cell lung cancer (NSCLC). Identifying pathological nodal (N2) disease is, however, of great importance because its presence significantly affects outcomes and potential treatment strategies. Recent data supporting the use of adjuvant or neoadjuvant therapies in these patients suggests that every reasonable effort should be made to assess the lymph node status accurately in patients with clinical early stage disease as well as in those with clinically staged N2 disease who have undergone preoperative treatments. Newer procedures such as integrated positron emission tomography computed tomography and esophageal or endobronchial endoscopic ultrasound with fine needle aspiration are minimally invasive techniques that may enhance the accuracy of mediastinal staging, traditionally devoted to mediastinoscopy. As their availability widens, they are likely to become an important part of staging and treatment paradigms. Intraoperatively, a growing body of evidence suggests that lymph node dissection can be performed safely, and should replace sampling as a more effective means of identifying unsuspected N2 disease. This paper will review the current literature on staging NSCLC with regard to the detection of nodal disease through preoperative staging of the mediastinum, the use of intraoperative lymph node sampling or dissection at the time of resection, and procedures for use in restaging patients with clinical stage IIIA N2 disease who have undergone preoperative chemotherapy (with or without radiotherapy).

Background: Both gemcitabine and etoposide are active in the treatment of small-cell lung cancer (SCLC), and are characterised by mild toxicity profiles. The combination of both drugs was found to be feasible and active in a phase I dose-finding study in solid tumours. Therefore, a phase II trial was initiated to examine the activity and toxicity of this schedule in extensive disease SCLC., Patients and Methods: Forty-two chemo-naïve extensive disease SCLC patients were enrolled to receive gemcitabine 1000 mg/m2, days 1, 8 and 15, and etoposide 80 mg/m2, days 8, 9 and 10 of a 28-day cycle., Results: Thirty-seven patients were evaluable for efficacy (five received less than one cycle). No complete responses were observed, but partial responses were seen in 17 patients, yielding an overall response rate of 46%. The median duration of response was 5.8 months. Disease stabilisation was obtained in another 10 patients (27%). The median survival of the 37 protocol-qualified patients was 10.5 months (95% confidence interval (CI): 7.5-12.0). The levels of WHO grade 3 and 4 toxicities were low and clinically manageable., Conclusion: In comparison with standard platinum-based regimens, this combination of gemcitabine and etoposide resulted in a somewhat lower response rate, but a similar median survival time. Haematological toxicity was more pronounced than expected from the toxicity data of each agent individually. However, because of its mild non-haematological toxicity, and its ability to be administered in an outpatient setting, this combination provides a reasonable palliative option for patients with extensive disease SCLC.

Background: The role of chemotherapy dose-intensification in small-cell lung cancer (SCLC) remains unclear. This phase I-II study evaluates feasibility and outcome of combination chemotherapy at moderately elevated doses with concomitant thoracic radiotherapy in limited-disease SCLC., Patients and Methods: Moderately elevated doses of ifosfamide-epirubicin (cycles 1 and 3) and of carboplatin-etoposide (cycles 2 and 4) were given with G-CSF and peripheral blood stem-cell (PBSC) support. Thoracic radiotherapy (40 Gy) was given once daily during the first five days of each cycle., Results: Overall toxicity was acceptable; most common side-effects were myelosuppression and asthenia. All 35 eligible patients responded (23 CR, 12 PR). Median time to progression was 15 months: median overall survival was 24.6 months. Only 6 of 25 relapsing patients (24%) presented with a locoregional recurrence while 12 of 25 (48%) relapsed in the central nervous system (CNS)., Conclusions: This regimen is a feasible dose-intensification with an acceptable toxicity profile. Its efficacy was demonstrated by a 100% response rate, an excellent local tumor control rate and a median survival of 24.6 months. In the absence of PCI, CNS relapse is a major problem if adequate local control is achieved.