Kristina Lamberg

Phase III Trial of Gemcitabine Plus Carboplatin Versus Single-Agent Gemcitabine in the Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer: The Swedish Lung Cancer Study Group

PURPOSE This phase III study compared overall survival in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life. PATIENTS AND METHODS Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2 on days 1 and 8; gemcitabine arm) or with carboplatin (area under the curve 5 on day 1; GC arm) every 21 days. RESULTS Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%; P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months; P = .0001) and significantly higher objective response rate (29.6 v 11.3%; P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms. CONCLUSION In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity.

Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumours and poorer survival in non-small cell lung cancer patients

We have analysed the predictive and prognostic information in preoperatively collected serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients clinically evaluated as operable non-small cell lung cancer (NSCLC). Fifty-eight patients with operable NSCLC were included. VEGF and bFGF levels in serum were analysed using enzyme linked immunosorbent assays (Quantikine human VEGF and Quantikine HS human FGF basic, R&D Systems). Univariate analysis demonstrated that tumour volume, platelet counts, VEGF and bFGF were significant prognostic factors. However, only bFGF remained significant in the multivariate analysis (P=0.014). Significant correlations were demonstrated between VEGF levels and tumour volume (r=0.33; P=0.012) and platelet count (r=0.43; P=0.001). bFGF levels correlated significant with recurrent disease (r=0.34; P=0.01), platelet count (r=0.53, P<0.001) and performance status (r=0.29; P=0.029). Furthermore, bFGF levels and VEGF levels correlated significantly (r=0.44; P<0.001). We conclude that elevated circulating angiogenic cytokines correlate with tumour volume, higher relapse risk and poorer survival in patients with operable non-small cell lung cancer.

CD99 is a novel prognostic stromal marker in non-small cell lung cancer

The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour–stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non‐small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double‐staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer‐associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: A double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group

BACKGROUND Increased expression of cyclooxygenase-2 (COX-2) is common in non-small cell lung cancer (NSCLC) and has been associated with poor prognosis. Experimental and clinical phase II trials have indicated that the addition of the COX-2 inhibitor celecoxib to palliative chemotherapy might increase survival time in patients with advanced NSCLC. METHODS We performed a double-blind, placebo-controlled multicentre phase III trial at 13 centres in Sweden. Three hundred and nineteen patients with advanced NSCLC stage IIIB-IV and performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in addition to palliative chemotherapy. The primary objective was to compare overall survival. Other end-points were quality of life, progression-free survival, toxicity, cardiovascular events and biological markers. The trial is registered with ClinicalTrials.gov, No. NCT00300729. FINDINGS Three hundred and sixteen patients were included in the analysis, 158 in each treatment group. Median survival time was 8.5 months. There was no survival difference between the treatment arms. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group. INTERPRETATION This study failed to demonstrate a survival benefit of the addition of celecoxib to palliative chemotherapy.

Regional differences in treatment and outcome in non-small cell lung cancer: A population-based study (Sweden)

In the recent decade uniform treatment guidelines for non-small cell lung cancer (NSCLC) have been introduced in Sweden. The objective of this study was to examine time trends and differences in treatment intensity for NSCLC between county clinical centres in Central Sweden. A second aim was to investigate whether any differences in treatment of NSCLC were associated with differences in survival. 4345 patients with a diagnosis of NSCLC between 1995 and 2003 were identified in the population-based Lung Cancer Register of Central Sweden. Multivariate logistic regression was used to estimate odds ratios to analyse the likelihood of receiving different treatment modalities for NSCLC. Cox proportional hazard models estimating relative hazard ratios were used to identify factors related to death (by any cause). Of all patients, 33.4% received no treatment, and 17.5% underwent surgery. Between 1995 and 2003, the proportion of patients receiving chemotherapy rose from 14.6% to 55%. There were pronounced differences between county centres in treatment policies, especially concerning surgery and radiotherapy. The likelihood of receiving treatment for NSCLC was highest at county centre A where both surgical treatment and chemotherapy were given more often. Compared to this reference county, the risk of death was between 20% and 40% higher in the other counties after adjusting for age, stage, gender, time period, smoking status and histopathological type. When analyses were adjusted for treatment, county of residence was no longer a prognostic factor. Despite common guidelines there were marked differences in treatment activity between the counties. Treatment activity was associated with survival. Survival benefits may follow improvement in compliance to guidelines.

Gene copy number aberrations are associated with survival in histologic subgroups of non-small cell lung cancer.

Introduction: Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups. Methods: Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters. Results: Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively. Conclusion: Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.

The Presence of Anti-p53 Antibodies in Sera Prior to Thoracic Surgery in Non Small Cell Lung Cancer Patients: Its Implications on Tumor Volume, Nodal Involvement, and Survival

BACKGROUND During recent years, a correlation between the presence of antibodies in sera against p53 and survival has been reported. The aim of the present study was to analyze anti-p53 antibodies in sera from patients with non small cell lung cancer (NSCLC) prior to thoracic surgery and their correlation to survival, nodal involvement, and tumor volume. PATIENTS AND METHODS Serum samples from 58 patients with NSCLC admitted to the Department of Pulmonary Medicine in Uppsala were collected between 1993 and 1995 and analyzed for the expression of anti-p53 antibodies. RESULTS Antibodies against p53 were detected in 12 patients (21%). No association was found between increased levels of anti-p53 antibodies and tumor volume (P =.84). There was a numerical trend towards higher levels of anti-p53 antibodies in patients without nodal disease, when compared with patients with nodal involvement, although not statistically significant (P =.136). However, when patients with metastatic disease were included, statistically significantly lower levels of anti-p53 antibodies were demonstrated, in comparison to patients without any sign of nodal engagement or metastatic disease (P =.038). Anti-p53 antibodies and survival showed no correlation between increasing index levels of anti-p53 antibodies and survival (P =.18). Neither was a correlation found between using the cutoff (>1.1) described by the manufacturer and survival. CONCLUSION The presence of anti-p53 antibodies was correlated neither to survival nor to tumor volume in the present study. However, patients with either nodal or metastatic disease had lower levels of anti-p53 antibodies in comparison to patients without signs of either nodal or metastatic disease. These issues are discussed.

Treatment with paclitaxel 1-h infusion and carboplatin of patients with advanced non-small-cell lung cancer: a phase II multicentre trial

The primary aim of this phase II study was to determine the response rate of a combination of paclitaxel and carboplatin in advanced non-small cell lung cancer (NSCLC) in a multicentre setting. The secondary aim was to determine time to progression (TTP), 1-year survival rate and toxicity. 65 patients were treated and all of them were included in the follow up for survival and toxicity. 60 patients were followed for response rate and time to progression. 55% were stage IV patients and 45% stage IIIB patients. The treatment consisted of paclitaxel 200 mg/m2 given as a 1-h i.v. infusion and carboplatin given as a 30 min i.v. infusion and the latter was dosed by using the Calvert formula at an area under the concentration time curve (AUC) of 5. The glomerular filtration rate (GFR) was determined by iohexol clearance and was not calculated from the serum creatinine level. The chemotherapy courses were given every third week with a maximum number of six or eight courses for patients who responded late. As premedication we used 8 mg betamethasone 40 min prior to infusion and then 10 min later clemastin and cimetidine. One complete response and 18 partial responses were seen giving a response rate of 29%. 40% of the patients progressed during the treatment and 28% had stable disease. The median TTP was 22 weeks. At a minimum follow up of 1 year, the 1-year survival rate was 38% and the median survival rate was 41 weeks. Haematological toxicity was mild with no grade 4 leucopenia and only seven patients (11%) had grade 3 leucopenia. There was no grade 4 toxicity. Grade 3 toxicity was seen as myalgia 5%, allergic reaction 3% and peripheral neuropathy 6%. 15% of the patients had a dose reduction due to neurotoxicity. The haematological toxicity was much milder than we expected, probably because of more exact determination of the GFR. This trial confirms the results of earlier reported trials of the efficacy and the ease of the regimen as an out-patient treatment option in advanced NSCLC. The main problem with this treatment is peripheral neuropathy.

Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy

AIM OF THE STUDY The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. METHODS In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. RESULTS VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). CONCLUSION Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.

Etoposide Versus Methotrexate in Small Cell Bronchial Carcinoma a Randomized Study of Two Types of Four-Drug Chemotherapy Regimens

Seventy-nine patients with small bronchial carcinoma randomly received cyclophosphamide, doxorubicin, vincristine, and methotrexate, alternating after four cycles with cyclophosphamide, lomustine, vincristine and methotrexate or the same with replacement of methotrexate by etoposide in lomustine cycles. Patients with limited disease received radiotherapy with 40 Gy. In 34 patients with extensive disease the total response in the groups with and without etoposide was 89% and 69% and the median survival 10.9 and 8.2 months respectively. In 45 patients with limited disease, the complete remission rates in the groups with and without etoposide were 57% and 67%, partial remission rates 38% and 25%, and the median survival times 12.3 and 17.8 months respectively. The disease-free survival exceeding 5 years in the respective groups was 4.2% and 14.3%. A slightly better response in extensive disease and a tendency to better long-term survival in limited disease was noted but the price was increased toxicity in the latter group.