Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Behaviour of metastasis in relation to vascular index in patients with node-positive breast cancer treated with adjuvant tamoxifen.

Some experimental studies suggested that one possible oestrogen-receptor-unrelated mechanism of action of tamoxifen involves inhibition of angiogenesis. We evaluated the correlation of the degree of vascularisation of the primary tumour and we assessed it by using the panendothelial marker anti-CD31 and immunohistochemistry with microvessels count, performed at the vascular 'hot spot' of each single cancer, with the risk of recurrence in time. A cohort of 176 consecutive patients with node-positive invasive breast cancer treated with adjuvant tamoxifen (30 mg/daily for 3 years) and a median follow-up of 72 months was studied. Sixty-two patients developed metastasis (30 visceral, 18 skeletal and 14 in soft tissues) during the time of observation. The study of the hazard function for metastasis was performed by a generalized linear modelling approach with a binomial error according to Efron. The risk of first recurrence was strictly associated with vascular index, having the patients with the highest microvessel counts the highest risk of metastasis during all the period of observation. We did not find an interaction of vascularity with oestrogen receptor (ER) status. However, in the subgroup of patients with ER-positive tumours the hazard of metastasis was almost constant in time, while in that with ER-negative tumours it increased rapidly up to 20 months and, thereafter, decreased sharply. The results of our study are an indirect evidence that the patients with highly vascularized breast cancers may gain poor benefit of adjuvant tamoxifen and, therefore. that this antioestrogen is unlikely to retain a clinically relevant antiangiogenic activity in human breast cancer. Our data need confirmation by a prospective randomized clinical trial.

Endogenous interleukin-12: relationship with angiogenic factors, hormone receptors and nodal status in human breast carcinoma.

Interleukin-12 (IL-12) is known to be a key cytokine for regulating immune response, but it is also known to provide some other biological function including inhibition of angiogenesis. We have determined using an enzymatic immunoassay the endogenous levels of IL-12 in 390 cytosols of primary breast cancers previously tested also for the angiogenic peptides, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). The concentration of IL-12 ranged from 0 to 7.6 ng/mg protein, and 124 (31.8%) out of 390 cancers showed a detectable dose (>0.1 ng/ml). There was no statistical association of IL-12 levels with tumor size and menopausal status. IL-12 levels tended to be higher in the tumors of node-positive patients as compared to those of node-negative ones (t-test, p=0.082). In addition, IL-12 levels were inversely associated with hormone receptor status, particularly progesterone receptor expression (p=0.0013). There was a significant inverse association between IL-12 and TP concentration (p=0.0007). The proportion of tumors with detectable levels of IL-12 and low levels of either VEGF or TP was higher among the patients with node-negative as compared to those with node-positive disease. On the contrary, the proportion of tumors with no detectable IL-12 and high levels of either VEGF or TP was higher in node-positive versus node-negative cancers. In conclusion, our study evaluated the balance between pro-angiogenic factors (TP and VEGF) and IL-12, as a detectable naturally occurring inhibitor of angiogenesis, in the same series of node-negative and node-positive breast cancers. Further studies are warranted to investigate the biological and clinical significance of the co-determination of pro and contra angiogenic factors in human breast carcinoma.

Rationale for the use of gemcitabine in breast cancer (Review).

Many active cytotoxic drugs and several regimens exist for breast cancer therapy. However, these conventional treatments have not changed the outcome of patients with locally advanced and metastatic disease. As a consequence, the dynamic balance between chemotherapy-induced side effects and benefits attributable to relief of cancer-related symptoms must be carefully considered in this setting. Gemcitabine is a pyrimidine nucleoside antimetabolite that has shown activity in a variety of solid tumors, a good toxicity profile, and non-overlapping toxicity with other chemotherapeutic drugs. As a single agent, gemcitabine yields response rates ranging from 14 to 37% as first-line treatment for advanced breast cancer and 12-30% as salvage therapy for patients previously treated with anthracycline and/or taxane treatment. Combined with vinorelbine, platinum, anthracyclines, and taxanes as doublets or triplets, response rates of 50 to 80% have been reported in phase II clinical studies. Gemcitabine in combination with anthracyclines and taxanes has been evaluated in the neoadjuvant setting in patients with early-stage breast cancer with interesting clinical and pathological response rates. Preliminary results of gemcitabine in combination with the biologic agent, trastuzumab, are encouraging. Phase III trials of gemcitabine combinations compared to standard regimens are ongoing with the aim to assess the independent contribution of gemcitabine.

Assessment of tumor vascularization: immunohistochemical and non-invasive methods.

Growth of solid tumors beyond a certain mass is dependent on the vascular bed from pre-existing host vasculature. The process of angiogenesis is essential not only for primary tumor growth but also for metastasis. The number of microvessels within the invasive component of a primary tumor reflects the degree of tumor angiogenesis. At present the most widely used method to assess neovascularization is the quantitation of intratumoral microvessel density (IMD) by immunohistochemical methods in which specific markers for endothelial cells are employed. In this paper we analyze the different methods used to assess IMD, as well as their advantages and potential methodological pitfalls. Several studies have shown a close correlation between IMD, tumor growth and the occurrence of metastasis, suggesting that IMD is a prognostic indicator of clinical relevance. Furthermore, preliminary studies suggest that determination of angiogenesis may predict responsiveness to some forms of conventional anticancer therapy. Although the histological microvessel density technique is the current gold standard to characterize tumor angiogenesis, it may not be the ideal tool for clinical purposes because it needs to be performed on biopsy material and does not assess the functional pathways involved in the angiogenic activity of tumors. Non-invasive assessment of tumor vascularity is possible in vivo by means of Doppler sonography, dynamic contrast-enhanced magnetic resonance imaging (MRI) and positron emission tomography (PET). These methods may be preferable to histological assay because they are non-invasive, survey the entire tumor, reflect both anatomic and physiologic characteristics, and may be useful to monitor the activity of antiangiogenic therapies.

Clinical significance of angiogenic factors in breast cancer.

Growth, progression, and metastasis of breast cancer, as well as of most of the other tumors, are angiogenesis-dependent processes. Several pro-angiogenic growth factors and endogenous inhibitors of angiogenesis have been identified and sequenced, and experimental studies suggest that angiogenic activity of a tumor may result from downregulation of inhibitors of angiogenesis or up-regulation of endothelial growth factors. The mechanisms leading to the alteration of the balance between positive and negative modulators of angiogenesis are only partially known. We are at the beginning of research to identify the more active angiogenic factors in human breast cancer, and little information is presently available on their clinical significance. Preliminary results suggest that among the known angiogenic peptides, both vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor / thymidine phosphorylase (PD-ECGF/TP) have promising prognostic and, perhaps, predictive value. No data are available on the clinical value of co-determination of positive and negative regulators of angiogenesis to look at the angiogenic balance of each single tumor. Only a few studies have assessed the role of endogenous inhibitors of angiogenesis in human breast cancer, with results available only on thrombospondin-1 and -2 (TSP-1, -2). Finally, the determination of some integrins such as alpha6 and alphavbeta3 and of some other endothelial-adhesion molecules seems to be of potential prognostic value. Recognizing which are the more biologically active positive and negative angiogenic factors is the key for the identification not only of new prognostic markers but also of targets for antiangiogenic therapy in human breast cancer.