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Hospices Civils de Lyon
Hôpital E Herriot
& Centre Léon Bérard, INSERM U590,
Département de Médecine
Institut Gustave Roussy Département de Médecine
Tumours are dependent on blood vessels for growth and metastases. Indeed, tumour cells cannot survive more than 200mm away from an existing blood vessel and tumours rarely exceed 2–3mm(3) without neovascularisation. This phenomenon,called angiogenesis, corresponds to the sprout of new capillaries from existing vessels and the creation of new vessels from circulating endothelial progenitor cells.(1) Numerous factors, mostly tyrosine kinase receptors, control angiogenesis. Advances in the knowledge of the mechanisms of angiogenesis have led to the development of antiangiogenic therapies that have shown efficiency in phase III studies (see Table 1) and several agents are now approved for clinical use. The use of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), leads to significantly improved overall survival (OS) in firstline therapy.
Bevacizumab is a monoclonal antibody against VEGF. In metastatic colorectal cancer (mCRC), bevacizumab significantly enhanced the response rate (RR) from 34.8 to 44.8% and the median overall survival from 15.6 to 20.3 months when added to an irinotecan/ 5-fluorouracil (5FU) combination.(2) The five-month benefit of bevacizumab was independent of the chemotherapy, as the result was similar to that obtained with a 5FU/folinic acid combination.(3–5) In second line the benefit was lower, and it even disappeared in the thirdline setting.
In advanced lung adenocarcinoma, addition of bevacizumab to the frontline carboplatin/paclitaxel combination significantly enhances OR from 10 to 27.2% and two-year OS from 16.9 to 22.1%.(6)
In the firstline setting of advanced breast cancer, bevacizumab was added to weekly paclitaxel in 715 patients. RR significantly increased from 14.2 to 28.2% and progression-free survival (PFS) from 6.11 to 10.97 months. From second line onward, bevacizumab did not bring benefit.(7)
In renal cancer after failure of cytokine-based treatment, bevacizumab increased PFS from 2.5 to 4.8 months (p<0.001) compared with placebo.(8)
These important studies also established the toxicity profile of bevacizumab (and generally of all antiangiogenic therapies): hypertension, thromboembolism and haemorrhage, mostly when tumour is located on, or close to, large vessels (several toxic deaths have also been reported in patients with lung squamous cell carcinomas).
While bevacizumab is efficient in first line, broad-spectrum tyrosine kinase inhibitors (TKIs) are active for pretreated cancerous conditions and also front-line situations, probably because they inhibit several pathways.
SU11248 (sunitimib, Sutent) inhibits VEGFR1 (VEGF receptor 1), PDGFR (platelet-derived growth factor receptor) and c-kit. In a phase II study, 63 patients with renal cell carcinoma (RCC) received SU11248 after failure of a cytokine. It resulted in 25 (40%) partial responses (PR) and 17 (27%) stabilisations (SD).(9) In this setting (second-line treatment in RCC), objective RRs are usually just above 5%. Median time to progression in the 63 patients was 8.7 months (95% CI, 5.5–10.7) and median survival was 16.4 months (95% CI, 10.8 to NA [not yet attained]). Based on these results, a phase III trial comparing SU11248 with interferon (INF) alpha in untreated RCC patients was initiated and is still ongoing. SU11248 showed high efficiency in gastrointestinal tumours after failure of imatinib treatment; preliminary data of a phase III study showed a time to progression of 6.3 months for SU11248 (95% CI, 3.7–7.6) and 1.5 months for placebo (95% CI, 1.0–2.3).(10)OS was about eight months for placebo, and was not attained for SU11248 after 12 months.
Sorafenib is a potent inhibitor of RAF-1, a key enzyme in the RAS/RAF/MEK/ERK signalling pathway, and an inhibitor of VEGFR-2 and PDGFR-β, which are involved in angiogenesis. The efficiency of sorafenib was demonstrated by a phase II study (a randomised discontinuation trial) in 202 patients (189 of which were evaluable) with RCC who received sorafenib for 12 weeks then stopped (51; 27%) if their tumour progressed more than 25%, continued (73; 39%) if their tumour decreased more than 25%, or were randomised between placebo or sorafenib for 12 weeks (65, 34%).(11) At 12 weeks postrandomisation, 50% of patients treated with sorafenib were progression-free compared with 18% in the placebo group (p=0.0077). For these progressive patients, sorafenib was restarted with benefit. The PFS with sorafenib was 24 versus 6 weeks (p=0.0087). The TARGET phase III trial confirmed the efficacy of sorafenib in 769 patients with RCC who failed prior treatment. PFS was 24 weeks in the sorafenib group and 12 weeks in the best supportive care group (p=0.00001),(12) although an objective response was observed in only 2% of the patients (independent review, 11% missing). Grade 3/4 toxicities included a hand-foot skin reaction (5%), diarrhoea (1%), fatigue (2%) and hypertension (1%). Sorafenib is now approved for the treatment of RCC.
AG 013736 inhibits VEGFR, PDGFR and c-kit TKIs. Impressive antitumour activity was demonstrated in 52 patients with metastatic RCC who failed prior cytokine-based therapy. AG 013736 (5mg twice daily) induced a PR in 40% of patients.(13) After one year, 69% of patients were still under treatment.
PTK/ZK inhibits the tyrosine kinase activity of VEGFR1, VEGFR2 and PDGFR, and is administered orally. PTK/ZK (1,250mg/day) combined with FOLFOX4 was subsequently compared with a placebo in the CONFIRM-1 phase III trial, reported at the 2005 ASCO meeting. One thousand one hundred and sixty-eight patients with untreated mCRC were randomised in the trial. Neutropenia, thrombocytopenia and neuropathy did not differ between the two groups. There were more cases of grade 3/4 hypertension (21 vs 6%), venous thrombosis (7 vs 4%) and pulmonary embolism (6 vs 1%) in the PTK/ZK arm but similar grade 3/4 bleeding and arterial thrombosis in the two groups. According to investigator-based assessment, there was a statistically significant increase in PFS in PTK/ZK-treated patients. However, a central review failed to document any significant difference.(14) Additional data should soon be available regarding OS in the CONFIRM 1 study as well as the CONFIRM 2 study, which is investigating the same combination as second-line therapy.
ZD6474 is an inhibitor of VEGFR-2, VEGFR-3 and HER1 (EGFR; epidermal growth factor receptor), albeit to a lesser extent. A clinical trial with docetaxel and ZD6474 has been conducted in patients with advanced nonsmall-cell lung cancer who had progressed after firstline platinum-based chemotherapy.(15) In this randomised phase II trial, 137 patients were randomised to three arms: docetaxel plus ZD6474 (100mg/day), ZD6474 (300mg/day) or a placebo. Partial results suggest efficacy with a difference in PFS of 18.8 weeks versus 17 weeks and 12 weeks, respectively.
Various TKIs are currently being tested in several solid tumours.(16) Sorafenib is being investigated in phase III trials in hepatocellular carcinoma and in metastatic melanoma (in combination with carboplatin and paclitaxel). Phase I–III trials are also ongoing in head and neck, lung, pancreatic and prostate cancer, as well as in melanoma and sarcoma.
Angiogenesis is a perfect example of translational research which nicely illustrates how the fundamental knowledge of cancer can lead to substantial therapeutic achievements. Indeed, rapid progress has been achieved in the understanding of angiogenesis, including signalling pathways and their regulation. This has enabled the development of numerous potentially interesting agents, many of which are oral agents. Angiogenesis targeting is now a clinical reality accessible to more patients, due to the approval of agents such as bevacizumab, sorafenib and sunitinib.