arznei-telegramm 2005; 36: 57
The anti-tumour drug bevacizumab (AVASTIN) is on the market since February 2005. I have not yet found an evaluation of it in arznei-telegramm.
M. STEHLE (pharmacist)
D-68519 Viernheim
Conflict of interests: none
Beyond microscopic size, the growth of a tumour depends on the formation of new vessels (1). Attempts have been made for decades to use this therapeutically. With the recombinant monoclonal mouse-human antibody bevacizumab (AVASTIN), for the first time a drug is marketed since February, which is developed specifically to inhibit angiogenesis in tumour therapy. Bevacizumab is licensed for combination with intravenous 5-fluorouracil (5-FU; 5 FU LEDERLE etc.) plus folinic acid (FA; LEUCOVORIN etc.) plus irinotecan (CAMPTO) or with 5-FU/FA alone as first line therapy in metastatic colorectal carcinoma (1).
CHARACTERISTICS: Vascular endothelial growth factor (VEGF) plays a major part in the regulation of angiogenesis. Bevacizumab binds to VEGF and thus prevents binding of VEGF to its receptors on endothelial cells. The immunoglobulin (Ig) G1 antibody bevacizumab is infused intravenously. Its terminal half-life is about 20 days, corresponding to the terminal elimination half-life of human IgG (1).
BACKGROUND: For decades, 5-FU was the only effective chemotherapeutic agent available in colorectal cancer, but recently other drugs such as the topoisomerase I inhibitor irinotecan have been added (2). A regime consisting of 5-FU/FA with irinotecan or oxaliplatin (ELOXATIN) is now recommended as first line therapy in metastatic colorectal carcinoma (3), which prolongs the median survival time by several months compared to therapy with 5-FU/FA alone. The regimes used in Europe, in which 5-FU is given as an infusion (e.g. FOLFIRI with irinotecan and FOLFOX with oxaliplatin), appear to be both more effective and also less toxic than the regime established mainly in the USA with 5-FU as a bolus (IFL schedule with irinotecan) (1,3). However, the varying use of second line therapies in the available studies makes a definitive comparison of the benefits of these schedules (4-7) difficult.
CLINICAL EFFICACY: In a phase II study of 104 patients with previously untreated metastatic colorectal carcinoma, bevacizumab in two dosages (5 mg/kg and 10 mg/kg body weight i.v. every two weeks) was combined with 5-FU/FA (500 mg/sqm 5-FU as bolus, 500 mg/sqm FA i.v. weekly for six weeks, two weeks drug-free interval). The treatment was continued until progression of the disease or for a maximum of 48 weeks (1,9). With addition of the 5-mg dosage, the response rate and progression-free survival increased significantly compared to 5-FU/FA alone. There was a trend for prolonged overall survival time (13.6 versus 17.7 months). The non-licensed higher dosage yielded worse results in all endpoints than the recommended lower dose (1).
In the pivotal phase III studies, 813 patients with metastatic colon cancer received bevacizumab (5 mg/kg i.v. every two weeks) or placebo, in each case in combination with the IFL bolus schedule (500 mg/sqm 5-FU, 20 mg/sqm FA plus 125 mg/sqm irinotecan, i.v. once a week for four weeks, two weeks drug-free interval). The study medication was used until progression of the disease, occurrence of unacceptable side effects or for a maximum of 96 weeks. Clinically relevant cardiovascular diseases were among the exclusion criteria. The addition of bevacizumab prolonged the median survival time (primary endpoint) significantly from 15.6 months with IFL alone to 20.3 months. The progression-free survival time increased from a median 6.2 months to 10.6 months, and the response rate from 34.8% to 44.8% (1,8).
It is not known what benefit can be obtained with bevacizumab in combination with the 5-FU infusion schedules used here. With these regimes as first line treatment median survival times of about 20 months are described even without the antibody but with better utilization of the second line options (6,7).
ADVERSE EFFECTS: The benefit of bevacizumab is at a price of increased toxicity. Serious and life-threatening side effects (grade 3 and 4 according to NCI CTC*) occur 13% more often in combination with the IFL regime than with IFL alone (74% versus 87%); these include gastrointestinal perforations, sometimes with fatal outcome (2% to 4% vs. 0.3% with IFL alone) as well as delayed wound healing and postoperative haemorrhages (10% to 20% of those undergoing major surgery during the therapy). The risk of arterial thromboembolism such as stroke or myocardial infarction (3% to 10% vs. 1% to 5% in control groups) is roughly doubled with bevacizumab. Shortly after market introduction in the US, the manufacturer had to warn about the increased risk particularly in over-65 year olds and in those with a previous history of arterial thromboembolism (1,10,11).
Deep venous thrombosis affects 9% of patients on comedication with IFL versus 6% with IFL alone, and high blood pressure requiring treatment affects 12% versus 2%. Hypertensive encephalopathy has been described. Severe diarrhoea (34% versus 25%) and grade 3 and 4 leukopenia (37% versus 31%) occur more often. Proteinuria occurs in up to 38% of users. Mucosal haemorrhage such as nasal bleeding (20% to 40%) and also tumour-associated haemorrhages are also increased. Severe tumour haemorrhages were observed especially with non-licensed use in non-small cell bronchial carcinoma. Patients with untreated CNS metastases must not use the drug because of the risk of intracranial haemorrhages. After prior treatment with anthracyclines or radiation of the left chest wall, an increased incidence of heart failure was observed in women with metastatic breast cancer (not a licensed indication). Bevacizumab is teratogenic in animal studies and is contraindicated in pregnancy (1,10).
COSTS: Bevacizumab (AVASTIN; one ampoule of 100 mg 432.96 Euro, 400 mg 1,549.49 Euro) increases the cost of chemotherapy of metastatic colorectal carcinoma by 2,814 Euro to 3,357 Euro monthly for two-weekly 5 mg/kg in patients weighing 50 kg to 80 kg.
 | The angiogenesis inhibitor bevacizumab (AVASTIN) prolongs as first line therapy in combination with bolus 5-fluorouracil (5 FU LEDERLE etc.)/folinic acid (LEUCOVORIN etc.) plus irinotecan (CAMPTO) - a schedule not used in Germany - the survival of patients with metastatic colorectal carcinoma. |
| The addition of bevacizumab increases the toxicity of the chemotherapy markedly, in particular gastrointestinal perforations, haemorrhages, delayed wound healing and arterial thromboembolism. |
| The antibody increases the cost of therapy by about 3,000 Euro a month. |
| The benefits and risks of bevacizumab in combination with the 5-FU infusion regimes used in Europe, which are probably superior to 5-FU bolus therapy, are not known and require confirmation in controlled studies. |
| As long as the benefit of adding bevacizumab is not confirmed in further studies, the combination cannot - in our opinion - be regarded as a new therapeutic standard. |