Phase I study of high-dose epirubicin and vinorelbine in previously untreated non-small-cell lung cancer stage IIIB-IV.

The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively

Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting

Purpose: To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity. Methods: Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the “Stichting Hemato-Oncologie voor Volwassenen Nederland” (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents’ willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR). Results: Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS. Conclusion: Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients.</p

Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality

BACKGROUND: Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide-degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). METHODS AND RESULTS: We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. CONCLUSIONS: Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD

Bronchoscopic treatment of intraluminal typical carcinoid: A pilot study

AbstractObjective: The curative potential of various bronchoscopic treatments such as Nd:YAG laser, photodynamic therapy, and brachytherapy for the treatment of intraluminal tumor has been reported previously. Bronchoscopic treatment can be used to treat small intraluminal tumor with curative intent, such as in patients with roentgenologically occult squamous cell cancer. In a retrospective study, we showed that bronchoscopic treatment provided excellent local control with surgical proof of cure in 6 of 11 patients with intraluminal typical bronchial carcinoid. Methods: In a prospective study, 19 patients (8 women and 11 men) with resectable intraluminal typical bronchial carcinoid have undergone bronchoscopic treatment under general anesthesia. Median age was 44 years (range, 20-74 years). If tumor persisted after 2 bronchoscopic treatment sessions, surgery was performed within 4 months after the treatment. Results: Bronchoscopic treatment was able to completely eradicate tumor in 14 of the 19 patients (complete response rate 73%, 95% CI: 49%-91%). Median follow-up of these patients is 29 months (range, 8-62 months). One patient had severe cicatricial stenosis after bronchoscopic treatment, and sleeve lobectomy was necessary. No residual carcinoid was found in the resected specimen. In the remaining 5 patients, bronchoscopic treatment did not result in a complete response and radical surgical resection was performed afterward with confirmation of residual carcinoid in the resected specimen. Median follow-up of the surgical group is 34 months (range, 12-62 months). Conclusions: Current data suggest that bronchoscopic treatment may be an effective alternative to surgical resection in a subgroup of patients with resectable intraluminal typical bronchial carcinoid. It alleviated the necessity of surgical resection in 68% (95% CI: 43%-87%) of the patients. (J Thorac Cardiovasc Surg 1998;116:402-6

A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer.

The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate

Video-Assisted Thoracoscopic Surgery in Patients With Clinically Resectable Lung Tumors

To investigate the feasibility of thoracoscopic resection, a pilot study was performed in patients with clinically resectable lung tumors. In 40 patients, Video-assisted thoracic surgery (VATS) was performed because of suspicion of malignancy. There were 29 men and 11 women with a median age of 54.8 years (range 18 to 78). Preoperative indications were suspected lung cancer and tumor in 27 patients, assessment of tumor resectability in 7 patients, and probability of metastatic tumors in 6 patients. The final diagnoses in the 27 patients with suspected lung cancer were 12 primary lung cancers, 6 lung metastases, and 9 benign lesions. The success rates for VATS (no conversion to thoracotomy) were 1 of 12 (8.3%) for resectable stage I lung cancer, 8 of 12 (66.7%) for metastatic tumors, and 9 of 9 (100%) for benign tumors. With VATS, 6 of 7 patients (85.7%), possible stage III non-small cell lung cancer, an explorative thoracotomy with was avoided, significantly reducing morbidity. The reasons for conversion to thoracotomy were 1) oncological (N2 lymph node dissection and prevention of tumor spillage) and 2) technical (inability to locate the nodule, central localization, no anatomical fissure, or poor lung function requiring full lung ventilation). The ultimate diagnoses were 19 lung cancers, 12 metastatic lung tumors, and 9 benign lung tumors. Our data show the limitations of VATS for malignant tumors in general use. These findings, together with the fact that experience in performing thoracoscopic procedures demonstrates a learning curve, may limit the use of thoracoscopic resection as a routine surgical procedure, especially when strict oncological rules are respected

1st ESMO Consensus Conference in lung cancer; Lugano 2010: Small-cell lung cancer

The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement in SCLC is reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final updat