Head of Department
Division of Medical Oncology
S.G. Moscati Hospital
Cancer is the second-leading cause of death in western countries, preceded only by cardiovascular diseases.(1) In recent decades standard treatments, including surgery, chemotherapy and radiotherapy, have significantly improved the outcome of cancer. However, in most cases these treatments have reached a plateau and new treatment strategies are needed.
Better knowledge of tumour biology and of the mechanisms of oncogenesis have allowed the singling out of several molecular targets.
New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumour growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors have been a major focus of basic research and drug development in the field of oncology. Approaches targeting VEGF include monoclonal antibodies (mAbs) and small-molecule VEGF receptor-tyrosine kinase inhibitors (VEGFR-TKIs). The humanised mAb bevacizumab, directed against VEGF, is the first and, currently, the only pure antiangiogenic agent approved for cancer therapy.(2)
This review will mainly focus on currently available data for angiogenic therapies in the treatment of non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC), the first and the third most common cancers, respectively, with more than one million new cases diagnosed worldwide each year.(3)
Bevacizumab is currently the only clinically available antiangiogenic agent licensed for use in combination with fluorouracil-based chemotherapy for first-line treatment of patients with metastatic CRC (mCRC) in the USA and Europe. Approval was based on the results of several large phase II and III studies in patients with previously untreated mCRC.(4-7) In the main phase III trial, patients were randomly assigned to one of three arms: IFL, or irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV); IFL/bevacizumab 5mg/kg intravenously (IV); or 5-FU/LV (Roswell Park regimen)/bevacizumab. The latter arm was used as a comparator to test the safety of irinotecan plus bevacizumab, and it was closed after about 100 patients had been enrolled into each arm with no difference observed in terms of safety. This trial showed a 30% increase in median overall survival (OS), from 15.6 to 20.3 months (p<0.001) and a 71% increase in progression-free survival (PFS), from 6.2 to 10.6 months (p<0.001); overall response rate (RR) was 34.8% and 44.8% for patients treated with IFL/bevacizumab and ILF alone, respectively. The most common side-effect attributable to bevacizumab therapy was hypertension (22.4% versus 8.3%, respectively), which was easily manageable, and a slight increase in thromboembolic events.(4) A recently completed phase III trial evaluated bevacizumab 10mg/kg IV alone or in combination with oxaliplatin/5-FU (FOLFOX4) versus FOLFOX4 alone in 829 previously treated mCRC patients. FOLFOX4/bevacizumab significantly improved OS (12.9 versus 10.8 months; p=0.0018), PFS (7.2 versus 4.8 months; p<0.0001) and RR (21.8% versus 9.2%;p<0.0001) compared with FOLFOX4. FOLFOX4/bevacizumab increased the incidence of grade 3/4 hypertension, bleeding, sensory neuropathy and vomiting events compared with FOLFOX4 alone.(8)
The clinical development of bevacizumab combined with chemotherapy in the treatment of advanced NSCLC has produced exciting results. Based on promising data from a phase II randomised trial,(9) a randomised phase III trial recently compared the combination of carboplatin plus paclitaxel with or without bevacizumab (15mg/kg IV) in the first-line treatment of advanced nonsquamous NSCLC. Squamous histology was excluded because of risk of grade 5 haemoptysis reported in a previous study.(9) Among the 878 patients enrolled, a statistically significant advantage in OS (12.3 versus 10.3 months; p=0.003), PFS (6.2 versus 4.5 months; p<0.001) and RR (35% versus 15%; p<0.001) was reported in favour of chemotherapy/bevacizumab. Rates of clinically significant bleeding were 4.4% and 0.7% (p<0.001), respectively. There were 15 treatment-related deaths in the bevacizumab group, including five from pulmonary haemorrhage.(10) This study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC. Table 1 summarises the main phase III, randomised trials performed in mCRC and NSCLC employing bevacizumab.
VEGFR-TKIs are low-molecular-weight agents that inhibit downstream signalling pathways rather than binding to VEGF directly. Some of these agents, such as sunitinib, sorafenib and ZD6474, are able to inhibit other receptors at the same time, so they are considered multitarget TKIs. Sunitinib and sorafenib have recently been licensed for the treatment of renal cancer pretreated with cytokines. Sunitinib has also been approved for the second-line treatment of gastrointestinal stromal tumours. ZD6474 is under investigation in phase III trials for the second-line treatment of NSCLC. Other agents are currently at different phases of clinical development and are being tested in various solid tumours.(11)
Bevacizumab is the first antiangiogenic agent demonstrating anticancer benefit with mild toxicity. In fact, when combined with a fluorouracil-based schedule, it represents a standard of care in clinical practice for first-line mCRC. Following the excellent results reported in mCRC and NSCLC, bevacizumab is being tested at the early stages of these diseases and in many other solid tumours, including breast cancer.
VEGFR-TKIs are being evaluated in prospective phase II and III trials for the treatment of several cancers. Potentially favourable toxicity profile and once-daily oral administration schedule make these drugs particularly suitable for cancer therapy.
- Ferlay J, Bray F, Pisani P, Parkin D. GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide, version 1.0; IARC Cancer Base No. 5. Lyon (France): IARC Press; 2001.
- Gridelli C, Rossi A, Maione P. New antiangiogenetic agents and non-small cell lung cancer. Crit Rev Oncol Hematol 2006;60:76-86.
- Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2006;55:10-30.
- Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med 2004;350:2335-42.
- Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al.Phase II randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.J Clin Oncol 2003;21:60-5.
- Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697-705.
- Mass RD, Fyfe G, Hambleton J, et al. Bevacizumab in combination with 5-FU/leucovorin improves survival in patients with metastatic colorectal cancer: a combined analysis. J Clin Oncol 2004;22 14S:273s (Abstract 3616).
- Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 2005;23 16S:1s (Abstract 2).
- Johnson DH,Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184-91.
- Sandler A, Gray R, Perry MC, et al. Paclitaxelï¿½ carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.
- Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 2006;11:753-64.