Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) 62012 study was a Phase III trial of doxorubicin versus doxorubicin-ifosfamide chemotherapy in 455 patients with advanced soft tissue sarcoma (STS). Analysis of the main study showed that combination chemotherapy improved tumor response and progression-free survival, but differences in overall survival (OS) were not statistically significant. We analyzed factors prognostic for tumor response and OS, and assessed histological subgroup and tumor grade as predictive factors to identify patients more likely to benefit from combination chemotherapy. METHODS: Central pathology review was performed by six reference pathologists. Gender, age, performance status, time from first presentation with sarcoma to starting palliative chemotherapy, tumor grade, histological subgroup, primary tumor site involvement, and sites of metastases were assessed as prognostic factors. RESULTS: Three hundred and ten patients were included in this study. Discordance between local and central pathology opinion of tumor histology and tumor grade was observed in 98 (32%) and 122 (39%) cases, respectively. In multivariate analysis, liposarcoma patients had improved tumor response compared to other histological subgroups, whilst patients with metastases other than lung, liver or bone had a poorer response [odds ratio (OR) 0.42, 95% confidence interval (CI) 0.23-0.78; p = 0.006]. Patients with bone metastases had reduced OS [hazard ratio (HR) 1.56, 95% CI 1.16-2.09; p = 0.003]. By central pathology review, patients with undifferentiated pleomorphic sarcoma (UPS) had improved tumor response and OS with doxorubicin-ifosfamide compared to single-agent doxorubicin (OR 9.90, 95% CI 1.93-50.7 and HR 0.44, 95% CI 0.26-0.79, respectively). Grade III tumors had improved response with combination chemotherapy but there was no interaction between chemotherapy and grade on OS. CONCLUSIONS: Prospective central pathology review of tumor histology should be integrated into future STS clinical trials. Doxorubicin-ifosfamide may be most appropriate for young, fit patients with poorly differentiated Grade III tumors including UPS.

Angiogenic growth factor expression in benign and malignant vascular tumours.

Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p=0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p=0.07) and inflammatory vascular lesions (p=0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p=0.001, p=0.001, p<0.001 and p<0.001 respectively). Notch1 also correlated with Tie2 expression (p=0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK.

Zoledronic acid to prevent and treat cancer metastasis: new prospects for an old drug.

Zoledronic acid (zoledronate, Zometa™; Novartis Pharmaceuticals, Basel, Switzerland) is a nitrogen-containing bisphosphonate. Zoledronate rapidly binds to bone mineral where it is then ingested by osteoclasts. Once internalized, zoledronate inhibits the mevalonate pathway, which stops osteoclast function, and thus slows bone resorption. Zoledronate is approved for the prevention of skeletal morbidity in metastatic bone disease from solid tumors and multiple myeloma. Zoledronate is also recommended as an option for the treatment of cancer therapy-induced bone loss. In recent large Phase III studies in early breast cancer, zoledronate reduced both local and distant recurrences in women with induced or established natural menopause. Postulated mechanisms underlying the anticancer properties of zoledronate include antiangiogenic and immunomodulatory effects. A clearer understanding of these mechanisms will enable the full potential of zoledronate to be realized.

Anti-angiogenic therapy: concept to clinic.

It has been 40 years since Folkman hypothesized the use of anti-angiogenic therapy as a strategy in the treatment of cancer. Since then, vascular endothelial growth factor (VEGF) has been identified as the most potent cytokine to induce angiogenesis and drugs targeting VEGF, principally the humanized monoclonal antibody bevacizumab and the tyrosine kinase inhibitors sunitinib and sorafenib, have proven therapeutic benefit. The initial high expectations of tumor vascular targeting agents, however, have yet to be fulfilled. In unselected patient populations, the benefits of these agents is often marginal, they cause harmful side effects, and drug resistance is quickly established. Biomarkers to identify patients suitable for anti-angiogenic therapy will be key to the future development of these drugs.

Angiosarcoma.

Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin that have a poor prognosis. They can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly white men, involving the head and neck and particularly the scalp. They can be caused by therapeutic radiation or chronic lymphoedema and hence secondary breast angiosarcomas are an important subgroup. Recent work has sought to establish the molecular biology of angiosarcomas and identify specific targets for treatment. Interest is now focused on trials of vascular-targeted drugs, which are showing promise in the control of angiosarcomas. In this review we discuss angiosarcoma and its current management, with a focus on clinical trials investigating the treatment of advanced disease.

CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

Efficacy of eribulin in breast cancer: a short report on the emerging new data.

Eribulin is a novel microtubule-targeting agent that is approved for the treatment of patients with locally advanced or metastatic breast cancer who have previously received treatment with an anthracycline and a taxane in either the adjuvant or metastatic setting. Eribulin induces mitotic catastrophe leading to cell death but has other important antitumor effects, including reversal of epithelial-mesenchymal transition and remodeling of the tumor vasculature. Eribulin was licensed for the treatment of advanced breast cancer based on results from two large randomized Phase III clinical trials. Current clinical trials of eribulin for breast cancer are evaluating response to treatment earlier in the patient pathway and in combination with other therapeutic agents. This review provides a short overview of emerging new data on the mode of action of eribulin in breast cancer.

Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update.

Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field.