Stefan Bergström

Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC : Satellite-A phase II study from the Swedish Lung Cancer Study Group

BACKGROUND Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. METHODS Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1>1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m² and cisplatin 75 mg/m² with 3 weeks interval. An initial dose of cetuximab 400 mg/m² was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m². TOXICITY was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. RESULTS Seventy-one patients were eligible for analysis as four were incorrectly enrolled. HISTOLOGY adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss>5%. TOXICITY esophagitis grade 1-2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. CONCLUSION Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. TOXICITY, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.

High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma: a pilot study

BackgroundHuman papilloma virus (HPV) in patients with esophageal carcinoma has previously been studied with an average detection rate of 15%, but the role of HPV in relation to survival is less clear. In cervical cancer, lung cancer and tonsil cancer HPV viral load is a predictive factor for survival and outcome of treatment. The primary aim was to study the spectrum of high-risk HPV types in esophageal tumors. Secondary, as a pilot study we investigated the association between HPV status and the survival rates.MethodsWe compared both the presence and the viral load of high-risk HPV types 16, 18, 31, 33, 39, 45, 52, 58, and 67 in relation to clinical data from patients with esophageal carcinoma. Survival data and tumor samples were retrieved from 100 patients receiving treatment at the Department of Oncology, Uppsala Hospital, Uppsala, Sweden. The tumor samples were investigated for HPV viral load using real-time PCR.ResultsHPV 16 was detected in 16% of the patients; no other HPV type was detected. HPV 16 infection had no significant effect on survival (p = 0.72). Also, HPV 16 did not improve survival after treatment (radiotherapy or chemotherapy).ConclusionOnly HPV 16 was detected among the patients. HPV 16 in esophageal carcinoma patients did not influence survival or improve therapy response. However, given the size of the study there is a need to examine a larger cohort in order to understand in more detail the effect of high risk HPV types in esophageal carcinoma.

Clinical Phase I study with an Insulin-like Growth Factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma.

Abstract Background. Inhibition of the Insulin-like Growth Factor-1 receptor (IGF-1R) has resulted in extensive anti-tumor effects. Picropdophyllin (PPP, AXL1717) is a small-molecule inhibitor of the IGF-1R without inhibition of closely related receptors including the insulin receptor and has shown extensive effects against a wide range of tumors in animals. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment. Patients and methods. The first part (Phase IA) consisted of single day BID dosing every three weeks with consecutive dose escalations. The second part (Phase IB) consists of seven days or longer BID dosing every three weeks, dosing range being 520–700 mg BID. Non-progressing patients could continue treatment within a compassionate use setting. Results and discussion. The present report describes our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with PPP. Despite more than seven months of PPP treatment as third or fourth line treatment, the reported patients did not develop any additional metastases. Furthermore, CT scans as well as 18FDG-Positron Emission Tomography (PET) scans of the patients demonstrated large central necrotic areas, which may suggest tumor response. At the same time, the study drug is so far well tolerated. The phenomenon of necrosis in the tumors suggestive of tumor response has not been reported before in anti-IGF-1R treatment and will be subject to further studies in the present clinical trial.

Erythropoietin Treatment in Metastatic Breast Cancer

Erythropoietin is an effective treatment for anemia in patients with various types of cancers, but few studies have evaluated the benefit of treatment in advanced breast cancer. In this multicenter study, we investigated the influence of two different doses of epoetin-beta on the level of hemoglobin, the need for blood transfusion, quality of life and safety aspects in patients with metastatic breast cancer. A total of 180 patients were randomized to receive either 1000 IE or 5000 IE epoetin-beta subcutaneously three times per week for 24 weeks. An increase of 20 g/L was defined as a positive hemoglobin response. Blood transfusions were given, if clinically indicated. Additional laboratory values and adverse events were recorded. Quality of life was measured with the aid of the EORTC QLQ-C30 questionnaire. Hemoglobin levels increased significantly in both groups. In the high-dose group, the initial mean Hb value was 98 g/L (64-110), which increased to 121 g/L (83-165) by week 24. In the low-dose group, the mean Hb value was 99 g/L (77-110.5) and by week 24 it was 116 g/L (81-144). The majority of patients who responded to treatment did so during the first four weeks. After 4 weeks, 7 patients in the low-dose group and 24 patients in the high-dose group had increased their Hb values by more than 20 g/L. The need for transfusion was low and did not differ between the groups. Quality of life was significantly enhanced in both groups, and there was no difference in the global quality of life between the two study arms. Epoetin-beta is a well-tolerated, safe and effective treatment of anemia in patients with metastatic breast cancer. There were significant improvements in Hb levels and quality of life in both groups.

How to improve loco-regional control in stages IIIa―b NSCLC? Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group

BACKGROUND A combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies. METHODS Inoperable stage III non-small cell lung cancer patients in good performance status (PS<2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m2 and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m2 with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m2 and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern. RESULTS Between June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43-78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb. HISTOLOGY adenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3-4 esophagitis, 1% grades 3-4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3-12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4-23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases. CONCLUSIONS Treatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of survival, toxicity and quality of life. The optimal treatment schedule for patients with locally advanced NSCLC is still to be decided and investigated in future clinical studies. Relapse pattern with distant metastases and especially brain metastases is a great problem and need further research for better therapy options and higher cure rate for this patient group.

PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas

The prognosis of high-grade glioma patients is poor, and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients, the epigenetic regulation of the expression of PTPN6, and the role of its expression in chemotherapy resistance in glioma-derived cells. PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6-overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite pyrosequencing, and demethylation of PTPN6 was done with decitabine treatment. The PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p = 0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increase resistance (p < 0.05) to the chemotherapeutic drugs bortezomib, cisplatin, and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis, or autophagy. Low PTPN6 promoter methylation correlated to protein expression, and the protein expression was increased upon demethylation in glioma-derived cells. PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients, and in glioma-derived cells, its expression is epigenetically regulated and influences the response to chemotherapy.

The Role of Cystatin C and the Angiogenic Cytokines VEGF and bFGF in Patients with Esophageal Carcinoma

Angiogenesis is the formation of new blood vessels out of the existing vascular bed. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent circulating angiogenic factors, whereas cystatin C is one of the most important extracellular inhibitors of several cysteine proteinases. Because proteases degrade interstitial connective tissue and basement membranes during tumor growth and metastasis, an association between cystatin C and the angiogenic factors seems plausible. The primary aim of the present study was to investigate if such a correlation exists between these serum markers. The secondary aim was to determine the prognostic value of these circulating cytokines and cystatin C, collected prior to therapy, in patients with esophageal carcinoma.A total of 42 patients with esophageal carcinoma donated serum samples prior to therapy. VEGF and bFGF were correlated to platelet and leukocyte counts and VEGF was correlated to tumor volume (p=0.04), whereas bFGF was not (p=0.08). VEGF was significantly correlated with cystatin C (p=0.027). Survival analysis showed that VEGF regarded as a continuous variable was associated with a significantly poorer survival in the univariate analysis (p=0.023); however, this was not found for bFGF (p=0.46). Neither of the angiogenic factors were associated with survival in the multivariate analysis. In the univariate analysis, cystatin c was correlated with survival (p=0.01), but this was not found in the multivariate analysis (p=0.28).In conclusion, VEGF was correlated with cystatin C, possible explanations being discussed in the present article. Results of the present study indicate that use of the angiogenic factors as prognostic factors, prior to therapy in patients with esophageal carcinoma, appears limited.

Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity.

Background. Leucine-rich and immunoglobulin-like domains 1-3 (LRIG1-3) proteins have been implicated in the regulation of EGFR signalling. In the present study, we investigated the clinical implications of the expression of EGFR and LRIG1-3 in oesophageal carcinoma, as well as the correlation between their expression levels and the chemosensitivity of oesophageal carcinoma cell lines. Patients and methods. Tumours from 80 patients with oesophageal carcinoma were investigated for the expression of EGFR and LRIG proteins by immunohistochemistry. Oesophageal carcinoma cell lines were investigated for their expression of EGFR and LRIG1, 2, and 3 by quantitative real time RT-PCR and for their sensitivity to commonly used chemotherapeutics by a cytotoxicity assay. Results and discussion: Based on a total score of intensity and expression rates, a trend towards survival difference was found for EGFR (p = 0.09) and LRIG2 (p = 0.18) whereas for LRIG1 and -3 there was no trend towards any association with survival. Correlation analysis revealed a correlation with the clinical expression of EGFR and LRIG3 (p = 0.0007). Significant correlations were found between LRIG1 expression levels and sensitivity to cisplatin (r = −0.74), docetaxel (r = −0.69), and vinorelbine (r = −0.82) in oesophageal carcinoma cell lines. EGFR and the LRIG proteins may be functionally involved in oesophageal carcinoma, but larger materials are needed to fully elucidate the clinical implication.

Swedish Lung Cancer Radiation Study Group: Predictive value of histology for radiotherapy response in patients with non-small cell lung cancer

The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (⩾50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded (n=141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma (n=323) or squamous cell carcinoma (n=596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma (p=0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA-IIB (p<0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis (p=0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables (p=0.037 and p=0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA-IIB.

Impact of age at diagnosis on prognosis and treatment in laryngeal cancer.

The aims of this study were to analyze how age affects treatment and treatment outcome, and to determine whether tumor characteristics differ between different age groups with laryngeal cancer.