Randomized Trials of Systemic Medically-treated Malignant Mesothelioma: A Systematic Review.

Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy mainly localized to the pleura. Malignant mesothelioma grows highly invasive into surrounding tissue and has a low tendency to metastasize. The median overall survival (OS) of locally advanced or metastatic disease without treatment is 4-13 months but, during recent years, improvement in survival has been achieved since treatment for patients with mesothelioma has improved with better palliative care, systemic medical treatment, surgery and improved diagnostics methods. The present review aims at describing available data from randomized trials considering systemic medical treatment for this patient category.

FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer.

PURPOSE: To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer. PATIENTS AND METHODS: Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor- and/or progesterone receptor-positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP). RESULTS: In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively. CONCLUSION: Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.

Fractionated irradiation of five human lung cancer cell lines and prediction of survival according to a radiobiology model.

BACKGROUND: This study evaluates a predictive radiobiology model by measurements of surviving fraction (SF) by the clonogenic assay or the extrapolation method and the proliferation rate in vitro. It is hypothesized that incorporating proliferation to intrinsic radiosensitivity, measured by SF, to predict radiation responsiveness after fractionated irradiation adds to the model's accuracy. Materials and Methods. Five lung cancer cell lines with known SF after 1 Gy (SF1), and also SF2 and SF5, were irradiated with three different fractionation regimes; 10 × 1 Gy, 5 × 2 Gy or 2 × 5 Gy during the same total time to achieve empirical SF. In addition, the SF1, SF2 and SF5 after fractionated irradiation was calculated for each cell line based on the already known single fraction SF and with or without a proliferation factor. The results were compared to the empirical data. RESULTS AND DISCUSSION: By using the clonogenic assay to measure radiosensitivity, prediction of radiosensitivity was improved after fractionated radiotherapy when proliferation was used in the radiobiology model. However, this was not the case in the cell lines where the extrapolation method was used to calculate SF. Thus, a radiobiology model including intrinsic radiosensitivity, measured by the clonogenic assay, as well as proliferation, is better at predicting survival after fractionated radiotherapy, compared to the use of intrinsic radiosensitivity alone.

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

BACKGROUND: 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. METHODS: Patients with laryngeal cancer during 1978-2004 in the Uppsala-Orebro region in Sweden were retrospectively studied. RESULTS: There were no significant differences in the 945 cases between age groups concerning major patient and tumor characteristics, such as male/female ratio, distribution of glottic/supraglottic tumors, stage, or site of recurrence. Overall survival (OS) and disease-specific survival (DSS) were worse among the oldest, although a significant proportion was cured. Relapse risk was lower among the oldest (12%) compared with the youngest (23%). The risk of never becoming tumor-free was 25% among the oldest and 7% in the youngest. Among the most elderly, only 1 late recurrence occurred. CONCLUSION: Elderly patients with laryngeal carcinoma cope well with treatment. Undertreatment may determine outcome more than age. The oldest group should be followed for a minimum of 2 years.

Serological and immunohistochemical analysis of S100 and new derivatives as markers for prognosis in patients with malignant melanoma.

The incidence of cutaneous malignant melanoma is rising, and tumour markers are attracting attention as a possible alternative to clinical examination in the follow-up situation. S100 is the preferred marker for malignant melanoma, and correlation between serum S100 and disease relapse and survival has been reported. S100 tests previously used in clinical studies were specified poorly regarding reactivity with S100A1B and S100BB. In this study, a newly designed S100 assay (designed to measure exclusively S100A1B and S100BB) and two newly developed serological assays, S100A1B, and S100BB, were investigated postoperatively in patients undergoing radical surgery for cutaneous malignant melanoma. Additionally, immunohistochemical analysis of S100A4 was performed on the primary malignant melanoma using tissue microarrays. The primary aim of the study was to investigate whether any of these assays, either singly or in combination, can contribute additional information concerning increased risk of relapse and death because of malignant melanoma. In total, 98 patients (54 males, 44 females) with malignant melanoma were included in the study. As a continuous variable, S100BB (P=0.016) was associated statistically with increased risk of relapse; this was not the case for increased values of either S100 (P=0.11) or S100A1B (P=0.92). The Kaplan-Meier overall survival as well as disease specific survival curve for the S100 serum level demonstrated a statistically significant association with better survival if the patient had a S100 level

Esophageal cancer: current and emerging therapy modalities.

During the last few years, there has been a gradual increase in treatment options for patients with esophageal malignancies. Several clinical studies have been performed, covering not only radiation and chemotherapy, but also the introduction of novel biological agents into the treatment arsenal. Patients with esophageal carcinoma are now offered second-line and sometimes even third-line treatments, and the number of research protocols is increasing. Despite the newly awakened interest in this malignancy, the overall 5-year survival rate has remained at approximately 10% since the 1980s. This review contains a compilation of available studies of esophageal malignancies and discusses current treatment options as well as newly developed therapies targeted at growth factor receptors.

The role of circulating angiogenic factors in patients operated on for localized malignant melanoma.

Malignant melanoma is a disease capable of rapid progression and rapidly developing metastases. Angiogenesis is a key event signalling tumour progression and elevated levels of angiogenic markers may indicate metastatic disease. No previously published work has, so far, examined plasma vascular endothelial growth factor (VEGF) and its receptor, VEGFR-1, in melanoma. This study investigated circulating levels of the angiogenic factors, VEGF-A and -D, their receptors 1-3 and hepatocyte growth factor (HGF)/scatter factor, in patients shortly after primary surgery for localized malignant melanoma. Elevated circulating levels of VEGF and its receptors, and of HGF, were found postoperatively, possibly derived from the reactive stroma adjacent to the tumours. Using univariate analysis, a correlation between levels of VEGFR-1 and relapse was found, but a correlation between the investigated angiogenic factors and survival could not be established. The results of the present study indicate that production of these angiogenic factors may be due to sources other than malignant melanoma cells.

Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines.

The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.

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

BACKGROUND: Human 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. METHODS: We 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. RESULTS: HPV 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). CONCLUSION: Only 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.

Radiation-induced DNA-damage and gene expression profiles in human lung cancer cells with different radiosensitivity.

BACKGROUND: Measurements of DNA double strand breaks and their subsequent repair after in vitro irradiation has been suggested to be an alternative way of monitoring radiotherapeutic response. METHODS: In the present study, the DNA repair kinetics (using a neutral version of the Comet assay) up to 45 min after a single dose of 2 Gy was studied as well as the gene expression profiles, before and 45 min after the irradiation, in two human lung cancer cell lines with different radiosensitivity (U-1285 and U-1810). RESULTS: Immediately after the irradiation, both cell lines responded with increased levels of DNA damage. However, the induced damage was slightly higher in U-1810 (known to be radioresistant) than in U-1285 (known to be radiosensitive), and the latter cell line also seemed to have a slightly more efficient DNA-repair. The two different lung cancer cell lines were highly heterogeneous in gene expression, both before and after the irradiation, and there was no obvious relationship between the Comet data and the microarray data. CONCLUSION: Given the fact that U-1810 has been classified as radioresistant and U-1285 as radiosensitive in clonogenic assays, the results of the present study indicate that radiation-induced DNA double strand breaks and DNA-repair efficiency are poor indicators of the intrinsic radiosensitivity of human lung cancer cells irradiated with a single dose in vitro.

Novel agents in the treatment of non-small cell lung cancer: implications for neoadjuvant chemotherapy?

During recent years, we have seen an increasing awareness among physicians about the possibilities of helping patients stricken by non-small cell lung cancer using active intervention with chemotherapeutics. This has emerged mainly from the development of new chemotherapeutics and novel drug combinations with an improved therapeutic ratio better tolerated by the patients. However, these new combinations of chemotherapeutics have proved to be only marginally better in terms of survival than the earlier used cytotoxic agents. Thus, many clinicians consider the effects of systemic therapy on symptom control and improved quality of life to be at least as important as survival when evaluating new drugs or new combinations. It is also obvious that improvements using traditional cytotoxics are slow and that there is a need for novel approaches. The present review focuses on novel drugs that have recently been introduced, or soon await to be included, in the management of advanced lung cancer and which have a potential value for use in neoadjuvant treatment of patients with non-small cell lung cancer, i.e. pemetrexed, EGFR-inhibiting agents, anti-angiogenesis inhibitors and other small molecules.

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.

The presence of anti-p53 antibodies in sera from patients with oesophageal carcinoma: correlation to treatment, tumour volume and survival.

BACKGROUND: A correlation between mutations in the p53 gene and the presence of anti-p53 antibodies in sera has been reported. The aim of the present study was to analyse anti-p53 antibodies in sera from patients with oesophageal carcinoma and their implications for clinical outcome and survival PATIENTS AND METHODS: Between 1996 and 2002, patients treated for oesophageal carcinoma at the Department of Oncology, Uppsala University Hospital, Sweden, were asked to donate serum samples during treatment and follow-up. A total of 42 patients, with serum samples collected prior to therapy, were analysed for expressions of anti-p53 antibodies using a commercially available sandwich ELISA (Dianova, Hamburg, Germany). RESULTS: Anti-p53 antibodies did not correlate with investigated laboratory parameters. No correlation between anti-p53 antibodies and tumour volume was found (n=31; r=0.08;p=0.66). Anti-p53 antibodies as a continuous variable was not associated with survival (p = 0.42). Neither was the presence of anti-p53 antibodies (according to defined cut-off of 1.1, provided by the manufacturer) associated with survival (p = 0.99). CONCLUSION: The presence of anti-p53 antibodies correlated neither to tumour volume nor to clinical parameters.

Serum semicarbazide-sensitive amine oxidase (SSAO) activity correlates with VEGF in non-small-cell lung cancer patients.

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme associated with vascular systems in mammals. SSAO catalyzes the deamination of primary monoamines and has been suggested to be a risk factor in vascular disorders, e.g., diabetic vascular complications. The primary aim of the present study was to investigate if serum SSAO activity is associated with clinical parameters in non-small cell lung cancer (NSCLC) patients. Secondary aims were to investigate if there is a correlation between SSAO activity and the angiogenic factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).Thirty-three patients donated 231 serum samples. Detectable levels of bFGF, VEGF, and SSAO were observed in all patients. Serum SSAO activity was not statistically associated with survival (p = 0.35). A highly significant statistical correlation was found between SSAO activity and VEGF (p < 0.0001). No significant correlation between SSAO and bFGF was observed. We conclude that SSAO was not associated with survival in patients with NSCLC. However, a strong correlation between serum SSAO activity and the angiogenic factor VEGF was found that might implicate new aspects of the mechanisms controlling angiogenesis.

The role of circulating anti-p53 antibodies in patients with advanced non-small cell lung cancer and their correlation to clinical parameters and survival.

BACKGROUND: Lung cancer causes approximately one million deaths each year worldwide and protein p53 has been shown to be involved in the intricate processes regulating response to radiation and/or chemotherapeutic treatment. Consequently, since antibodies against p53 (anti-p53 antibodies) are associated with mutations within the p53 gene it seems likely that these antibodies could, hypothetically, be correlated with prognosis. METHODS: Serum samples from patients with non-small cell lung cancer (NSCLC) admitted to the Department of Oncology, University Hospital, Uppsala, Sweden, during 1983-1996 were studied. Anti-p53 abs were measured using a sandwich ELISA (Dianova, Hamburg, Germany). RESULTS: The present study included 84 patients with stage IIIA-IV (advanced NSCLC). At least three serum samples from each patient were collected and altogether 529 serum samples were analysed for the presence of anti-p53 antibodies. The median value of anti-p53 antibodies was 0.06 (range 0 - 139.8). Seventeen percent of investigated NSCLC first serum samples (n = 84) expressed elevated levels of anti-p53 antibodies. Anti-p53 antibodies were not correlated to tumour volume or platelets. Survival analysis showed that anti-p53 antibodies were not associated with survival as revealed by univariate analysis (p = 0.29). However, patients with adenocarcinoma had a significantly poorer survival if they expressed anti-p53 antibodies (p = 0.01), whereas this was not found for patients with squamous cell carcinoma (p = 0.13). In patients where the blood samples were collected during radiation therapy, a statistically significant correlation towards poorer survival was found (p = 0.05) when elevated anti-p53 antibodies levels were present. No correlations to survival were found for serum samples collected prior to radiation therapy, during chemotherapy, or during follow-up. When anti-p53 antibodies were measured continuously, no increase in median anti-p53 values was observed the closer the individual patient come to death. CONCLUSION: The result of the present retrospective study indicates that anti-p53 antibodies are not suitable for predictions concerning selection of patients with a more favourable outcome. Further prospective studies are, though, needed to fully elucidate this issue.

Endothelial markers and circulating angiogenic factors and p53 may be potential markers for recurrence in surgically resected non-small cell lung cancer patients.

BACKGROUND: Early stage lung cancer is potentially curable by resection, but 30-50% of patients will relapse within five years after surgery. Therefore, the search for a predictive method capable of estimating the risk of recurrence in this population of patients is important. MATERIAL/METHODS: We analysed, on the one hand, the predictive powers for recurrent disease of the immunohistochemical expressions of p53 and the endothelial markers CD34 and CD105 in 53 NSCLC tumor samples, and, on the other hand, their correlations to serum VEGF and bFGF levels. Moreover, we sequenced the whole coding region of the p53 gene in 32 tumor samples for the presence of p53 mutations (exons 2-11) using a cDNA technique. RESULTS: The two endothelial markers correlated with each other. CD105 expression correlated with p53 expression, which was overexpressed in 49%. No other significant correlations between markers could be demonstrated. A significant correlation between p53 overexpression and recurrent disease was demonstrated (p=0.029). The mutational status of p53 correlated to p53 protein overexpression, but did not correlate with either of the immunohistochemical markers. The mutational status could not confirm an immunohistochemical correlation between p53 and recurrences (p=0.068). CONCLUSIONS: The present study demonstrates that p53 expression correlates with CD105 expression, and that p53 overexpression may indicate a lower recurrence risk in patients undergoing surgery for NSCLC stage I-IIIA, although future larger prospective studies are needed to fully elucidate this finding.

A retrospective study focusing on clinical predictive factors in 126 patients with oesophageal carcinoma.

In Sweden, approximately 400 patients are diagnosed each year with oesophageal carcinoma. Despite the introduction of different treatment schedules, only modest improvements in survival have been accomplished. To be able to select patients in whom a more favourable outcome of radiation/-chemotherapeutic treatment could be expected, the present study reviewed the charts from 126 consecutive patients with oesophageal carcinoma. All patients were treated at the Department of Oncology, Uppsala University Hospital, Sweden, between 1990 and 2000. The charts were reviewed with focus on known and potential prognostic factors. Performance status, smoking habits, swallowing function, localisation of the tumour, leucocytes and albumin levels at first admittance, and stage of the disease were prognostic factors. However, performance status and stage of the disease only remained as significant independent prognostic factors in the multivariate analysis (both with p-values < 0.001). The results imply that further characterisation of tumour biology in oesophageal carcinoma is needed to find additional predictive factors for survival and future treatment strategies.

HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer.

The incidence of lung cancer is increasing throughout the world and is the most common cause of cancer-related death. Early detection followed by surgery has a reasonable, curative potential, but 30-50% of patients experience relapses. The immunohistochemical expressions of HER-2, EGFR and COX-2 were investigated in 53 resected non-small cell lung carcinomas and correlated to microvessel density and clinical data. HER-2, EGFR and COX-2 overexpressions were demonstrated in 15%, 30% and 40% of the tumours, respectively. In adenocarcinomas, HER-2 and COX-2 overexpression were more common, whereas in squamous cell carcinomas, EGFR overexpression was more common. COX-2 expression correlated with HER-2 expression (p = 0.002), and demonstrated a trend towards a correlation with microvessel density (p = 0.10). None of the markers alone had any impact on survival. However, HER-2+/EGFR- tumours proved to have a poor prognosis. In conclusion, adjuvant treatment with HER-2 antagonists might be a future treatment option in resected non-small cell lung cancer patients, especially when HER-2 is overexpressed without a concomitant overexpression of EGFR.

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.

p53 status and its in vitro relationship to radiosensitivity and chemosensitivity in lung cancer.

The following study was designed to investigate if mutations within the p53 gene are associated with radiation responsiveness or response to different cytotoxic drugs. Nine human lung cancer cell lines were examined (four SCLC and five NSCLC cell lines). cDNA-based sequencing of the entire p53 gene was performed. All cell lines were characterised with respect to drug-sensitivity towards eight cytotoxic drugs using the FMCA method and data from the clonogenic assay were studied to obtain information concerning radioresponsiveness. All the cell lines expressed mutations; six were missense mutations and three were deletions. A statistically significant increase in radiosensitivity was found for mutations in exon 7 (p = 0.019), compared with the other mutations localised within different exons of p53. Further statistical analyses using Fisher's two-tailed exact test confirmed that mutations in exon 7 were significantly associated with radiosensitivity, p = 0.047. No correlation concerning mutations in separate exons and response towards different chemotherapeutic agents could be found. Our results indicate that p53 mutations in exon 7 might be associated with increased radiation sensitivity in these human lung cancer cell lines, but our data should be interpreted with caution since several other explanations might exist regarding what determines the response towards radiation.