Immunohistochemical expression of cyclooxygenase-2 in patients with advanced cancer of the larynx who have undergone induction chemotherapy with the intention of preserving phonation.

INTRODUCTION: Cyclooxygenase-2 (COX2) is an enzyme that plays a role in different stages of the carcinogenic process and has prognostic and predictive values that have not yet been established. The objective of this study was to evaluate the role of COX2 overexpression in advanced squamous cell carcinoma of the larynx that has been treated with a phonation conservation protocol. MATERIALS AND METHODS: This study included a retrospective analysis of 59 patients with resectable tumours that were treated with chemotherapy (CT) and/or radiation therapy (RT). The expression levels of COX2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor (VEGFR-2) in collected biopsy specimens were determined via immunohistochemistry. RESULTS: Forty-four percent of the included samples demonstrated overexpression of COX2. In the statistical analysis, COX2 overexpression did not correlate with other clinical or treatment efficacy prognostic factors; however, the median global survival (OS) of patients whose tumours expressed COX2 was 79 months, whereas COX2-negative patients had a median OS of only 38 months, although this finding did not reach statistical significance. The other analysed biological parameters did not demonstrate a significant relationship with COX2. CONCLUSIONS: COX2 overexpression was a common finding in our study. The results obtained did not reveal relationships with established prognostic categories; however, the difference in survival between patients with and without COX2 expression justifies the need for future prospective studies that utilise a larger patient sample size.

Limited impact of palliative chemotherapy on survival in advanced solid tumours in patients with poor performance status.

AIM: Oncologists should carefully weigh up the risks and benefits of palliative chemotherapy in patients with advanced solid tumours (AST) and poor general status from the standpoint both of medical and ethical issues and of healthcare resources required. This study is intended to assess the impact on overall survival of palliative chemotherapy in patients with AST and admitted to hospital as a result of their poor ECOG status. MATERIALS AND METHODS: We performed a retrospective analysis of 92 hospitalised patients with AST, ECOG 3-4, who were treated with palliative chemotherapy. Uni- and multivariate statistical analyses were conducted to determine the impact of clinical and disease variables (number of previous chemotherapy lines, presence of comorbidities, presentation of anorexia-cachexia syndrome, delirium, dyspnoea, ascitis, brain metastases, T-cell count, albumin, haemoglobin and LDH) on survival in this patient population. RESULTS: Mean age was 54 years (range 15-80). No chemotherapy had been given for advanced disease in 74%, 13% had received one line, 6% 2 lines and 7% ≥3 lines. Median survival, i.e., after initiation of chemotherapy to death, in these patients was 33 days (range 1-1390). The median of chemotherapy cycles was 1. In the multivariate analysis, no previous chemotherapy, and absence of anorexia-cachexia syndrome and of comorbidities was associated with significantly improved survival in patients. Forty-nine percent of patients died within 30 days of therapy, 28% died between days 30 and 90, and only 23% of patients lived longer than 90 days. Grade 3-4 toxicities mainly entailed blood disorders, namely anaemia 8%, neutropenia 13% and thrombocytopenia 8%. Six patients (5%) developed sepsis after therapy; of these, 3 died from this toxicity, 1 patient suffered cardiac toxicity, one patient leukoencephalopathy and 1 patient acute pulmonary thromboembolism. CONCLUSION: Palliative chemotherapy given to patients with AST and ECOG 3-4 with short life expectancy provided no benefit for survival. As a result, we may be over-treating these patients and contributing to poor-quality care.

Targeted therapy of metastatic breast cancer.

Breast cancer is a heterogeneous disease characterised by a dysregulation of multiple pathways related to cell differentiation, cell cycle control, apoptosis, angiogenesis and development of metastasis. Acting against these pathways provides therapeutic targets for new targeted biologic therapies, which, in the future, might constitute a key for fighting cancer. The development of molecular technology in recent years has allowed a further comprehension of these mutations and dysregulated pathways leading to oncogenesis. New targeted biologic therapies will block essential functions of cancer cells and tumour stroma. A growing number of therapy options, alone or in combination with background treatments (chemotherapy, hormone therapy, radiotherapy), will allow oncologists a better adaptation of treatment to patients and disease characteristics. Examples of approved targeted agents in breast cancer include agents targeting the human epidermal growth factor receptor 2 (HER2), such as trastuzumab, lapatinib and the anti-VEGF bevacizumab. In addition, there are other therapy classes under evaluation, including novel antiEGFR or antiHER2 therapies; agents fighting other tyrosine kinases, including the Src and the insulinlike growth factor receptor; agents interfering critically relevant pathways, such as PI3K/AKT/mTOR inhibitors; and agents promoting apoptosis, such as PARP inhibitors (for particular breast cancer subtypes, such as basal-like, or breast cancer with BRCA mutations) and others. The better selectivity against malignant cells of these therapies, when compared to conventional chemotherapy, gives, a priori, at least two advantages to biologic treatments: fewer side effects and a more individualised treatment of cancer depending on the tumour's molecular characteristics. The ability to identify patients' subgroups and response predicting factors will be crucial in obtaining the greatest benefit with minimal toxicity levels. Unsolved questions remain, such as appropriate patient selection based on the expression of the therapeutic target in the tumour, the study of the efficacy of the drug in not so extensively pretreated populations and with a greater chance of response, the use of new pharmacodynamic models to help to define new response predicting factors for a specific new biologic therapy, the combined and rational use of different biologic therapies having different molecular targets and fighting the same target through a complementary mechanism of action that might improve clinical efficacy.

Current status of anti-angiogenic agents in the treatment of ovarian carcinoma.

During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of molecular biology. One of the most promising strategies under investigation is antiangiogenic therapy. Bevacizumab is a monoclonal humanised antibody targeting vascular endothelial growth factor (VEGF), which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials, both in monotherapy and in combination with other therapies. Currently, ongoing phase III trials are testing bevacizumab as a front-line therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated with mild frequent toxicities (proteinuria, hypertension and bleeding). However, the drug may result in other uncommon, but potentially life-threatening side effects, such as arterial thromboembolism, wound healing complications, and gastrointestinal perforation or fistulae, which should be considered when the drug is administered. Other new therapeutic antiangiogenic strategies that include small-molecule tyrosine kinase inhibitors, antibodies neutralising the VEGF receptor (VEGFR) and soluble VEGFR hybrids (VEGF Trap) are being investigated with promising early results.