Weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) as first-line chemotherapy for elderly patients with advanced gastric cancer: results of a phase II trial.

BACKGROUND: Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. METHODS: Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. RESULTS: A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%-56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 - 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 - 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 - 11.82). CONCLUSION: OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer.

COX-2 expression in DCIS: correlation with VEGF, HER-2/neu, prognostic molecular markers and clinicopathological features.

AIMS: There is considerable evidence that links COX-2 to the development of cancer. The aim of our study was to assess, by immunohistochemistry, COX-2 expression in ductal carcinoma in situ (DCIS) and its possible correlation with HER-2/neu, vascular endothelial growth factor (VEGF) expression and other common immunohistochemical parameters (p53, ER, PGR, Ki67). METHODS AND RESULTS: Tissue samples of 49 archival cases of DCIS without any invasive component were analysed for COX-2, HER-2/neu, VEGF, oestrogen and progesterone receptors, Ki67 and p53 by immunohistochemistry using specific antibodies. COX-2 expression was detected in 43 (87.8%) tissue samples, of which 12 (24.5%) were graded as weak, 22 (44.9%) as moderate and nine (8.4%) as high expression. Only six (12.2%) lesions were negative for COX-2 expression. VEGF expression was detected in 93.8% of samples; 66.7% of lesions were found to be positive for HER-2/neu expression. Furthermore, COX-2 expression was significantly correlated with VEGF expression (P = 0.003). A significant positive correlation was also observed between COX-2 and HER-2/neu expression (P < 0.0001). CONCLUSIONS: Our results suggest that COX-2 is highly expressed in DCIS and takes part in the molecular pathway implicated in progression of breast cancer and may provide a rationale for targeting COX-2 in preinvasive breast cancer therapy.

The antineoplastic role of bisphosphonates: from basic research to clinical evidence.

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and Paget's disease. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due also to direct antitumor effect, exerted at different levels. Here, after a brief analysis of the chemical structure, we will review the antineoplastic and biological properties of bisphosphonates. We will start from well estabilished mechanisms of action and go on to discuss the latest evidence and hypotheses. In particular, we will review the antiresorptive properties in malignant osteolysis and the recent evidence of a direct antitumor effect. Furthermore, this review will analyze the influence of bisphosphonates on cancer growth factor release, their effect on cancer cell adhesion, invasion and viability, the proapoptotic potential on cancer cells, the antiangiogenic effect, and, finally, the immunomodulating properties of bisphosphonates on the gammadelta T cell population.

Prevention of radiotherapy-induced emesis.

In this minireview the authors examine and discuss the radioprotective compounds and the new combination therapies for the prophylaxis of radiation-induced emesis. Radiation-induced emesis is an important secondary effect of this anticancer treatment and it represents one of the causes of therapy interruption and decay of life quality before the introduction of optimal control of radiation-induced emesis with new antiemetic drugs which ensure the continuance of radiotherapy and avoid time breaks, that could negatively influence the efficacy of anticancer treatment. The incidence, the severity or the latency of radiotherapy-induced nausea and vomiting are correlated both with the treatment features (fractions, total dose, irradiation site) and with the main clinical characteristics of the patients. In contrast to the very extensive literature on the prevention of chemotherapy-induced emesis, relatively few studies about the prevention of nausea and vomiting in patients submitted to radiotherapy have been published. Among antiemetic drugs for the prevention of emesis, benzamides and in particular metoclopramide, are widely used in clinical practice. The introduction of selective 5-HT3 antagonists in clinical practice produced an important improvement in control of chemotherapy induced emesis, but few published studies were aimed at evaluating the efficacy of these drugs in the prophylaxis of nausea and vomiting due to radiation exposure. We herewith present a brief summary of Clinical practice guidelines for the use of antiemetics in anticancer therapy recently published by ASCO (American Society of Clinical Oncology).

The antineoplastic treatment in the elderly.

More than 550,000 American people died for cancer only in 1998 and more than third of them were over 65 years of age. According to recent data in next decade more than 70% of all the deaths for tumour will be verified in the population over 65 years. The cancers mostly frequently associated with the deaths in the elderly population are the tumour of the lung, colon, prostate and breast. Therefore the geriatrics oncology is progressively assuming a central and essential role within the medical oncology. One of the aspects of great interest in the treatment of the cancers of the elderly patient (> 65 years) is the study about some pharmacokinetic modifications of the antitumour medicines in such band of age, and the study about some pattern of toxicity characteristics in the elderly patients. In this ambit there are a few studies in literature devoted specifically to such aspect. This study represents an attempt of revision of the literature finalized to analyse the toxicological and pharmacokinetic characteristics of the principal chemotherapeutic agents used in the therapy of elderly patients affected with cancer. In the last part of the review we have tried to synthesize the state of the art of the achieved results about the medicines that have shown a better therapeutic index and a better impact on the clinical benefit in such population of patients.

Oxaliplatin may induce cytokine-release syndrome in colorectal cancer patients.

INTRODUCTION: Oxaliplatin, a third-generation platinum analogue, is a novel compound with proven anti-tumor activity in colorectal cancer. Moreover, oxaliplatin appears to be relatively well tolerated and easy to handle, even on an outpatient basis. PATIENTS AND METHODS: Five advanced colorectal cancer patients treated with oxaliplatin-based chemotherapy developed, after the end of oxaliplatin infusion, similar idiosyncratic reactions characterized by chills, high fever, hypotension, abdominal pain, nausea and often diarrhoea. Venous blood for IL-6 and TNF-alpha assessment was drawn just after the beginning of the reaction and 15 and 30 minutes later. After drawing the third venous sample, intravenous dexamethasone (8 mg) was administered and the drawing of other two venous samples was performed (180 and 360 minutes after the beginning of the reaction). RESULTS: TNF-alpha and IL-6 serum concentrations significantly decreased after steroid therapy administration. The decrease of TNF-alpha and IL-6 levels went along with the clinical complete regression of symptoms and signs in all the 5 patients. No statistically significant correlation was found between other laboratory parameters and basal cytokine levels or cytokine decrease after steroid therapy. DISCUSSION: Our results clearly show that that idiosyncratic reaction observed in colorectal cancer patients after oxaliplatin infusion may be due to a massive release of cytokines such as TNF-alpha and IL-6. Symptom regression following steroid therapy administration went along with significant decrease of cytokines levels, confirming that TNF-alpha and IL-6 play a role in the pathogenesis of this reaction.