Guidance
3 The technologies
3.1 Bevacizumab
3.1.1 Bevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that inhibits the formation of blood vessels (angiogenesis inhibitor). It targets the biological activity of human vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation in the tumour. Bevacizumab in combination with IFN-α has a UK marketing authorisation for first-line treatment of people with advanced and/or metastatic RCC.
3.1.2 Bevacizumab is contraindicated in pregnant women, people with untreated central nervous system metastases, and people who have hypersensitivity to the active substance or to any of the excipients, to products derived from Chinese hamster ovary cell cultures or to other recombinant human or humanised antibodies. The summary of product characteristics (SPC) lists the following conditions that may be associated with bevacizumab treatment: gastrointestinal perforation, fistulae, wound healing complications, hypertension, proteinuria, arterial thromboembolism, haemorrhage, congestive heart failure and neutropenia. For full details of side effects and contraindications, see the SPC.
3.1.3 Bevacizumab is administered as an intravenous infusion. The recommended dosage for advanced and/or metastatic RCC is 10 mg/kg body weight once every 14 days. The initial dose of bevacizumab should be delivered over 90 minutes and if the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. IFN-α (Roferon-A, Roche Products) is administered by subcutaneous injection three times per week at a dose of 3 MIU for 1 week, 9 MIU for the following week and 18 MIU thereafter; if 18 MIU is not tolerated then the dose should be reduced to 9 MIU. Bevacizumab treatment is licensed for use in advanced and/or metastatic RCC until there is underlying disease progression. The price for a 400-mg vial of bevacizumab is £924.40 and the price of IFN-α is £45.19 for 9 MIU (excluding VAT; 'British National Formulary' [BNF] edition 55). Assuming an average weight of 76.5 kg and no wastage, the average daily cost of bevacizumab plus IFN-α is £151.42. Over a 6-week cycle, the average total cost of drug acquisition is £5982 per patient for the first cycle and £6117 for subsequent 6-week cycles. These figures assume a typical dose of IFN-α of 9–10 MIU. The manufacturer of bevacizumab (Roche) has agreed a patient access scheme with the Department of Health for advanced and/or metastatic RCC. Costs may vary in different settings because of negotiated procurement discounts.
3.2 Sorafenib
3.2.1 Sorafenib (Nexavar, Bayer) is a multikinase inhibitor that inhibits the development of tumour blood vessels and tumour cell proliferation. It has a dual action, inhibiting the raf cascade and VEGF/platelet-derived growth factor (PDGF) receptors on tumour cells, vascular endothelial cells and pericytes. Sorafenib has a UK marketing authorisation for the treatment of people with advanced RCC in whom IFN-α or interleukin-2-based therapy has failed or who are considered unsuitable for such therapy. Sorafenib has designated EU orphan drug status for RCC.
3.2.2 Sorafenib is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients. The SPC lists the following conditions that may be associated with sorafenib treatment: dermatological toxicities, hypertension, haemorrhage, cardiac ischaemia and/or infarction, hepatic impairment and wound healing complications. For full details of side effects and contraindications, see the SPC.
3.2.3 Sorafenib is administered orally. The recommended dosage for advanced RCC is 400 mg twice daily. Sorafenib treatment is licensed for use in people with advanced RCC as long as clinical benefit is observed or until unacceptable adverse events occur. The current price for a pack of 200-mg tablets (112 tablets per pack) is £2980.47 (excluding VAT). The average daily cost of sorafenib treatment is £106.45, with an average 6-week cycle costing £4471. The manufacturer of sorafenib (Bayer) has agreed a patient access scheme with the Department of Health for advanced RCC. Costs of treatment cycles may vary in different settings because of negotiated procurement discounts.
3.3 Sunitinib
3.3.1 Sunitinib (Sutent, Pfizer) is an inhibitor of a group of closely related tyrosine kinase receptors. It inhibits VEGF/PDGF receptors on cancer cells, vascular endothelial cells and pericytes, inhibiting the proliferation of tumour cells and the development of tumour blood vessels. Sunitinib has a UK marketing authorisation for the treatment of people with advanced and/or metastatic RCC.
3.3.2 Sunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The SPC lists the following conditions that may be associated with sunitinib treatment: skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC.
3.3.3 Sunitinib is administered orally. The recommended dosage is 50 mg once daily for four consecutive weeks with a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5 mg according to tolerability (dose range 25–75 mg). The price for a pack of 50-mg capsules (30 capsules per pack) is £3363.00 (excluding VAT; BNF edition 55). The average daily cost of sunitinib is £74.74, with an average 6-week cycle costing £3139. The manufacturer of sunitinib (Pfizer) has agreed a patient access scheme with the Department of Health for advanced and/or metastatic RCC. Costs of treatment cycles may vary in different settings because of negotiated procurement discounts.
3.4 Temsirolimus
3.4.1 Temsirolimus (Torisel, Wyeth Pharmaceuticals) is a selective inhibitor of the mammalian target of rapamycin (mTOR), a serine threonine kinase that regulates a signalling cascade controlling growth factor-induced cell proliferation. Temsirolimus inhibits mTOR-dependent protein translation induced by growth factor stimulation. Tumour growth may also be affected indirectly by the inhibition of other factors such as VEGF. Temsirolimus has a UK marketing authorisation for the first-line treatment of people with advanced RCC who have at least three of the six following prognostic risk factors:
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less than 1 year from time of initial RCC diagnosis to randomisation or initiation of treatment
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Karnofsky performance status of 60–70
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haemoglobin less than the lower limit of normal
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corrected calcium greater than 10 mg/100 ml (or 2.5 mmol/litre)
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serum lactate dehydrogenase more than 1.5 times the upper limit of normal
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more than one metastatic organ site.
Temsirolimus has designated EU orphan drug status for RCC.
3.4.2 Temsirolimus is contraindicated in people who have hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80 or to any of the excipients. The SPC lists the following conditions that may be associated with temsirolimus treatment: intracerebral bleeding, renal failure, hyperglycaemia, infections, interstitial lung disease, hyperlipaemia and wound healing complications. Pre-medication with intravenous antihistamine is also recommended to minimise allergic reactions. For full details of side effects and contraindications, see the SPC.
3.4.3 Temsirolimus is administered by intravenous infusion. The recommended dosage is 25 mg over a 30- to 60-minute period once a week. Treatment with temsirolimus should continue until there is no clinical benefit or until unacceptable toxicity occurs. The net-price for a 30-mg vial of temsirolimus is £620 (excluding VAT; BNF edition 57). Costs may vary in different settings because of negotiated procurement discounts.