Measles-induced Acute Disseminated Encephalomyelitis in a Non-vaccinated Patient.

We reported a case of measles-induced acute disseminated encephalomyelitis (ADEM) in a 40-year-old immunocompetent adult. The patient presented a week after the development of respiratory symptoms and a cutaneous rash, and was admitted to hospital for altered mental status. Blood tests showed hyperleukocytosis, thrombopenia and cytolysis. A lumbar puncture was consistent with acute meningitis and the patient was initially treated with antiviral and wide broad-spectrum antibiotics. Serology and PCR for measles came back positive. LEARNING POINTS: Acute disseminated encephalomyelitis (ADEM) associated with measles infection is not uncommon.Clinical suspicion must be based on the presence of measles infection or recent vaccination.A normal CT scan does not rule out the disease but magnetic resonance imaging (MRI) is not required to confirm the diagnosis.

Abrupt Severe Chest Pain and Vomiting: Remember to Think of a Ruptured Oesophagus (Boerhaave Syndrome).

Boerhaave syndrome or spontaneous rupture of the oesophagus is a severe condition commonly misdiagnosed or unrecognized. Prognosis is poor even if the diagnosis is made promptly. We describe a case of Boerhaave syndrome diagnosed after the development of pneumomediastinum and cardiac arrest. Unfortunately, the patient died 48 hours after admission to the Intensive Care Unit. This entity requires a multidisciplinary management approach which may include conservative, surgical or endoscopic procedures. LEARNING POINTS: Boerhaave syndrome is a diagnostic and therapeutic challenge, and rapid diagnosis and management are crucial.A thoraco-abdominal CT scan with oesophageal opacification is the gold standard investigation.A multidisciplinary and individualized approach is needed in the management of this condition.

An Open-Label, Multicenter, Randomized, Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as a First-Line Therapy in Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer.

INTRODUCTION: Type 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting. METHODS: In this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m2 pemetrexed, and 75 mg/m2 cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed. RESULTS: The mean age of the intent-to-treat population (n = 172) was 59 years (range 32-83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81-1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64-1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred. CONCLUSIONS: Efficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported.

Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT).

INTRODUCTION: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor. METHODS: Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease. RESULTS: Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung. CONCLUSION: The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00339586.

Safety and Immunogenicity of MAGE-A3 Cancer Immunotherapeutic with or without Adjuvant Chemotherapy in Patients with Resected Stage IB to III MAGE-A3-Positive Non-Small-Cell Lung Cancer.

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.

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.

BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 µg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING: Merck KGaA (Darmstadt, Germany).

An open-label, multicenter, randomized, phase II study of pazopanib in combination with pemetrexed in first-line treatment of patients with advanced-stage non-small-cell lung cancer.

INTRODUCTION: This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer. METHODS: Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m(2) intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m(2) intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS). RESULTS: The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio = 0.75; 95% confidence interval, 0.43%-1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, -30.6% to 7.2%; p = 0.21). CONCLUSION: The combination of pazopanib/pemetrexed in first-line treatment of non-small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity.

The effect of clinical covariates on the diagnostic and prognostic value of soluble mesothelin and megakaryocyte potentiating factor.

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.

Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma.

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.

Randomised phase II study of amrubicin as single agent or in combination with cisplatin versus cisplatin etoposide as first-line treatment in patients with extensive stage small cell lung cancer - EORTC 08062.

PURPOSE: The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC). PATIENTS AND METHODS: Eligible patients with previously untreated ED-SCLC, WHO performance status (PS) 0-2 and measurable disease were randomised to 3 weekly cycles of either amrubicin alone 45mg/m(2) i.v. day(d) 1-3 (A), cisplatin 60mg/m(2) i.v. d1 and amrubicin 40mg/m(2) i.v. d1-3 (PA), or cisplatin 75mg/m(2) i.v. d1 and etoposide 100mg/m(2) d1, d2-3 i.v./po (PE). The primary end-point was overall response rate (ORR) as assessed by local investigators (RECIST1.0 criteria). Secondary end-points were treatment toxicity, progression-free survival and overall survival. RESULTS: The number of randomised/eligible patients who started treatment was 33/28 in A, 33/30 in PA and 33/30 in PE, respectively. Grade (G) ⩾3 haematological toxicity in A, PA and PE was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anaemia (10%, 15%, 3.1%) and febrile neutropenia (13%, 18%, 6%). Early deaths, including treatment related, occurred in 1, 3 and 3 patients in A, PA and PE arms, respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible patients who started treatment, ORR was 61%, (90% 1-sided confidence intervals [CI] 47-100%), 77% (CI 64-100%) and 63%, (CI 50-100%) for A, PA and PE respectively. CONCLUSION: All regimens were active and PA met the criteria for further investigation, despite slightly higher haematological toxicity.

Serial measurements of mesothelioma serum biomarkers in asbestos-exposed individuals: a prospective longitudinal cohort study.

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.

Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma.

RATIONALE: Soluble mesothelin (SM) is currently the reference serum biomarker of malignant pleural mesothelioma (MPM). Megakaryocyte potentiating factor (MPF), which originates from the same precursor protein, is potentially more sensitive, yet lacks validation. OBJECTIVES: To analyze the diagnostic performance of MPF as an MPM biomarker and compare this performance with SM. METHODS: A total of 507 participants were enrolled in six cohorts: healthy control subjects (n = 101), healthy asbestos-exposed individuals (n = 89), and patients with benign asbestos-related disease (n = 123), benign respiratory disease (n = 46), lung cancer (n = 63), and MPM (n = 85). Sera were analyzed for SM and MPF levels using the Mesomark and Human MPF ELISA kit, respectively. MEASUREMENTS AND MAIN RESULTS: SM and MPF levels differed significantly between patients with MPM and participants from each other cohort (P < 0.001). Receiver operating characteristics curve analysis did not reveal a significant difference between both markers in area under curve (AUC) for distinguishing MPM from all cohorts jointly (SM = 0.871, MPF = 0.849; P = 0.28). At 95% specificity, SM and MPF had a sensitivity of 64% (cutoff = 2.00 nmol/L) and 68% (cutoff = 12.38 ng/ml), respectively. Combining both markers did not improve the diagnostic performance. CONCLUSIONS: In this prospective multicenter study, MPF is validated as a highly performant MPM biomarker. The similar AUC values of SM and MPF, together with the limited difference in sensitivity, show that both serum biomarkers have an equivalent diagnostic performance.

The importance of accurate lymph node staging in early and locally advanced non-small cell lung cancer: an update on available techniques.

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).

A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956).

PURPOSE: The incidence of bronchioloalveolar carcinoma (BAC) has risen steadily over the last decades along with the increasing frequency of adenocarcinomas. BAC is relatively resistant to commonly used chemotherapy regimens. A phase II study with single agent paclitaxel in patients with stages IIIB, IV or recurrent BAC was performed. EXPERIMENTAL DESIGN: Patients with BAC with at least one target bidimensionally measurable lesion staged as unresectable stages IIIB, IV or recurrent disease, not previously irradiated; ECOG performance status 0-2; life expectancy greater than 3 months; age range between 18 and 75, received paclitaxel at a dose of 200 mg/m2 i.v. as 3h continuous infusion on day 1 every 21 days. Treatment was continued until progression or up to a maximum of six cycles. RESULTS: Nineteen patients were eligible. Median number of cycles was 3 (range 0-6); 35% of patients received the planned six cycles of chemotherapy. One patient died of unrelated cause before the start of treatment. Both hematological and non-hematological toxicities were generally mild. Only one partial response (PR) was observed among the 18 eligible patients who started protocol treatment, with a response rate of 5.6% (95% CI: 0.1-27.3%). After an independent review, two PR were confirmed, for a response rate of 11.1% (95% CI: 1.4-34.7%); nine patients had stable disease (50.0%), three patients had progressive disease (11.1%) and four patients were not assessable (22.2%). Median survival was 8.6 months (95% CI: 5.8-14.5) and 1-year survival was 35.0% (95% CI: 14.1-55.8). Median progression free survival for all patients was 2.2 months (95% CI: 1.5-6.0). The study was terminated due to the low response rate. CONCLUSIONS: Paclitaxel as single agent in stages IIIB-IV BAC was well tolerated and manageable but of limited efficacy. BAC should not be excluded from trials of new forms of chemotherapy.

Increased IL-6 and TGF-beta1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy.

PURPOSE: To assess, in lung cancer patients, the effects of thoracic radiotherapy (RT) on the concentrations of transforming growth factor-beta(1) (TGF-beta(1)) and interleukin-6 (IL-6) in the bronchoalveolar lavage (BAL) fluid. METHODS AND MATERIALS: Eleven patients with lung cancer requiring RT as part of their treatment were studied. BAL was performed bilaterally before, during, and 1, 3, and 6 months after RT. Before each BAL session, the patient's status was assessed clinically using pulmonary function tests and an adapted late effects on normal tissue-subjective, objective, management, analytic (LENT-SOMA) scale, including subjective and objective alterations. The National Cancer Institute Common Toxicity Criteria were used to grade pneumonitis. The TGF-beta(1) and IL-6 levels in the BAL fluid were determined using the Easia kit. RESULTS: The TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated areas were significantly increased by thoracic RT. The increase in TGF-beta(1) levels tended to be greater in the group of patients who developed severe pneumonitis. In the BAL fluid from the nonirradiated areas, the TGF-beta(1) and IL-6 concentrations remained unchanged. CONCLUSION: The observed increase in TGF-beta(1) and IL-6 concentrations in the BAL fluid recovered from the irradiated lung areas demonstrated that these cytokines may contribute to the process leading to a radiation response in human lung tissue.

Influence of cisplatin-use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine.

BACKGROUND: We previously reported that treatment of patients with symptomatic advanced non-small cell lung cancer with single agent Gemcitabine (GEM) resulted in a superior clinical-benefit response rate (RR) compared to cisplatin-based combination chemotherapy. We now report the detailed individual symptom control analysis, and the influence of cisplatin-use, age, performance status (PS) and duration of treatment. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m(2), days 1, 8 and 15) or cisplatin (100 mg/m(2), day 1) plus Vindesine (3 mg/m(2), days 1 and 15) (PV), both every 4 weeks. Scores of 9 symptoms were listed weekly by the patient on visual analogue scales. Improvement of a symptom was defined as 2 consecutive cycles of improvement over baseline. RESULTS: Baseline symptoms in the 169 patients were well balanced between the 2 arms (84 GEM, 85 PV). Both patients with objective response and disease stabilisation had clearly better symptom control than those with disease progression. Symptom control in both arms was similar for 'disease-specific' symptoms such as cough, dyspnea, pain or haemoptysis. Compared to PV, a significantly larger number of GEM-patients had better scores for 'constitutional' items such as anorexia (P=0.007), ability to carry on with daily activities (P=0.04) and overall impression of quality-of-life (P=0.008). Symptom control was very similar in younger (<65 years) versus older (>/=65 years) patients, and only slightly better in those with a Karnofsky PS >/=80% compared to those <80%. Most of the symptom improvement occurred in the first 3 cycles, with some further symptom improvement in the following cycles in the GEM-arm only. CONCLUSIONS: Both GEM and PV yield a symptom control rate much higher than expected by the objective tumour RR. GEM is equally effective in controlling 'disease-specific' symptoms, but superior in controlling 'constitutional' symptoms. Most of the symptom control was achieved during the first 3 cycles of treatment, with some further improvement thereafter in the GEM-arm only.

European organization for research and treatment of cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as second-line treatment of refractory and sensitive small cell lung cancer.

PURPOSE: The purpose of this study was to assess the activity and toxicity of a combined regimen of topotecan and cisplatin in "sensitive" (s) and "refractory" (r) small-cell lung cancer (SCLC) patients treated previously. EXPERIMENTAL DESIGN: Patients with measurable SCLC and progressive disease after one first-line regimen were eligible for the study. Patients were enrolled in two separate groups: r group (patients who failed first-line treatment <3 months from treatment discontinuation) and s group (patients who responded to first-line treatment and progressed >or=3 months after treatment discontinuation). Cisplatin was given i.v. at the dose of 60 mg/m(2) on day 1, and topotecan was administered as a daily i.v. infusion at the dose of 0.75 mg/m(2) from day 1 to 5, every 3 weeks. RESULTS: A total of 110 eligible (68 s and 42 r) patients were enrolled from 24 institutions. The main patient characteristics were as follows: median age 60 (s) and 55 (r) years, median performance status 1 for both (s) and (r). Seventy-four percent (s) and 67% (r) had extensive stage disease, including 22% and 36%, respectively, with brain metastases. A total of 398 chemotherapy courses were administered [median 4 (s) and 3 (r) per patient]. The most frequent and serious toxicity was myelosuppression. Grade IV neutropenia occurred in 62% (s) and 49% (r) of patients, with a 19% (s) and 15% (r) incidence of febrile neutropenia, and grade IV thrombocytopenia in 54% (s) and 44% (r). Most of these toxicities occurred during the first chemotherapy course and led to topotecan dose reduction and/or delay in the following courses. Grade III-IV nonhematological toxicity was uncommon. Five deaths possibly related to toxicity occurred among s patients only. Objective responses have been documented in 20 s patients, 19 partial responses and 1 complete response, (29.4% response rate; 95% confidence interval, 19-42), whereas, among r patients, 10 partial responses have been observed (23.8% response rate; 95% confidence interval, 12-39). Median survival for s and r was 6.4 and 6.1 months, respectively. CONCLUSIONS: The combination of cisplatin and topotecan, at this dose and schedule, shows activity and promising results in patients with refractory SCLC, with reversible myelosuppression being the main side effect. Additional development of this regimen, using better-tolerated schedules, is warranted in patients with refractory SCLC.