2 The technologies
Gemcitabine
2.1 Gemcitabine (various companies) is a chemotherapeutic agent that inhibits DNA synthesis. It is a nucleoside analogue with anti‑tumour activity against a number of solid tumours. Gemcitabine, in combination with carboplatin, has a UK marketing authorisation for the treatment of 'patients with locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a recurrence‑free interval of at least 6 months after platinum‑based, first‑line therapy'.
2.2 Gemcitabine is administered by intravenous infusion. The recommended dosage is 1000 mg/m2 of body surface area administered on days 1 and 8 of each 21‑day cycle. After gemcitabine, carboplatin is given on day 1 consistent with a target area under curve of 4.0 mg/ml×min. The summary of product characteristics lists the following as the most common adverse reactions associated with gemcitabine treatment: leukopenia, thrombocytopenia, anaemia, dyspnoea, vomiting, nausea, elevation of liver transaminases and alkaline phosphatase, allergic skin rash, alopecia, haematuria, mild proteinuria, influenza‑like symptoms and oedema/peripheral oedema.
2.3 Gemcitabine is available in 200‑mg, 1‑gram and 1.5‑gram vials at net prices of £29.80, £154.82 and £213.93 respectively (excluding VAT; 'British national formulary' [BNF] October 2015). The cost of gemcitabine 1000 mg/m2 for 1 cycle (based on a body surface area of 1.7 m2) on day 1 and 8 of every 21 days is £487.46 (excluding administration costs). Costs may vary in different settings because of negotiated procurement discounts.
Paclitaxel
2.4 Paclitaxel (various companies) is a cytotoxic anticancer drug that belongs to the taxane group of drugs. Taxanes prevent the formation of mitotic spindles, interfering with the process of cell division and resulting in cell death. Paclitaxel has a UK marketing authorisation 'for the treatment of metastatic carcinoma of the ovary after failure of standard, platinum containing therapy'.
2.5 Paclitaxel is administered by intravenous infusion. The recommended dosage is 175 mg/m2 of body surface area administered over a period of 3 hours, with a 3‑week interval between treatment cycles. Paclitaxel has also been evaluated in randomised controlled trials with a weekly interval between treatment cycles, and this is in line with clinical practice for the treatment of platinum‑refractory or ‑resistant recurrent ovarian cancer. The summary of product characteristics lists the following as the most common adverse reactions associated with paclitaxel treatment: infection, myelosuppression, neutropenia, anaemia, thrombocytopenia, leukopenia, bleeding, mild hypersensitivity reactions, neurotoxicity, hypotension, diarrhoea, vomiting, nausea, mucositis, alopecia, arthralgia and myalgia.
2.6 Paclitaxel is available in 5‑ml (30‑mg), 16.7‑ml (100‑mg), 25‑ml (150‑mg) and 50‑ml (300 mg) vials at net prices of £66.85, £200.35, £300.52 and £601.03 respectively (excluding VAT; BNF October 2015). At list price, the cost of a dose of paclitaxel 175 mg/m2 (based on an average body surface area of 1.7 m2) is £601 per 3‑weekly cycle (excluding administration costs). The cost of paclitaxel 80 mg/m2 is £301 per weekly dose. However, the weekly regimen is currently unlicensed. Costs may vary in different settings because of negotiated procurement discounts.
Pegylated liposomal doxorubicin hydrochloride
2.7 Pegylated liposomal doxorubicin hydrochloride (Caelyx, Janssen‑Cilag; PLDH) is an anthracycline – a group of cytotoxic antibiotics that inhibit DNA synthesis. They also interact with cell membranes, altering their function and generating cytotoxic chemicals. PLDH has a UK marketing authorisation for the treatment of advanced ovarian cancer in women for whom a first‑line platinum‑based chemotherapy regimen has failed. It has been studied in combination with carboplatin for the treatment of platinum sensitive ovarian cancer but this combination does not have a marketing authorisation.
2.8 PLDH is administered by intravenous infusion. The recommended dosage is 50 mg/m2 of body surface area once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment. Using PLDH at lower doses in combination with other chemotherapeutic agents has been studied in clinical trials. The summary of product characteristics lists the following as the most common adverse reactions associated with treatment with PLDH: anorexia, nausea, stomatitis, vomiting, palmar–plantar erythrodysesthesia, alopecia, rash, asthenia, fatigue and mucositis.
2.9 PLDH is available in 10‑ml (20‑mg) and 25‑ml (50‑mg) vials at net prices of £360.23 and £712.49 respectively (excluding VAT; BNF October 2015). The cost per dose of PLDH 50 mg/m2 (based on an average body surface area of 1.7 m2) on day 1 of every 28‑day cycle is £1,425 (excluding administration costs). Costs may vary in different settings because of negotiated procurement discounts.
Topotecan
2.10 Topotecan (various companies) is a naturally derived chemotherapeutic agent that prevents DNA replication in cancer cells. It has a UK marketing authorisation for the treatment of women with 'metastatic carcinoma of the ovary after failure of first‑line or subsequent chemotherapy'. The recommended dosage is 1.5 mg/m2 of body surface area per day, administered by intravenous infusion over 30 minutes daily for 5 consecutive days, with 3 weeks between each course. If well tolerated, treatment may continue until disease progression. The summary of product characteristics lists the following as the most common adverse reactions associated with treatment with topotecan: febrile neutropenia, neutropenia, thrombocytopenia, anaemia, leukopenia, nausea, vomiting and diarrhoea, constipation, abdominal pain, mucositis, alopecia, anorexia, infection, pyrexia, asthenia and fatigue.
2.11 Topotecan is available in 1 mg and 4 mg vials at net prices of £87.88 and £261.55 respectively (excluding VAT; BNF October 2015). The cost of topotecan 1.5 mg/m2 (based on an average body surface area of 1.7 m2) on days 1–5 every 21‑day cycle is £1,308 per cycle (excluding administration costs). Costs may vary in different settings because of negotiated procurement discounts.
Trabectedin
2.12 Trabectedin (Yondelis, PharmaMar) is an anticancer agent that binds to the minor groove of the DNA and bends the helix to the major groove, which disrupts the cell cycle. It has a UK marketing authorisation, in combination with PLDH, for the treatment of women 'with relapsed platinum‑sensitive ovarian cancer'. The recommended dosage is 1.1 mg/m2 of body surface area, immediately after PLDH 30 mg/m2, administered every 3 weeks as a 3‑hour infusion. The summary of product characteristics lists the following as the most common adverse reactions associated with treatment with trabectedin: neutropenia; thrombocytopenia; anaemia; leukopenia; anorexia; headache; vomiting; constipation; hyperbilirubinemia; fatigue; increases in alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, gamma‑glutamyltransferase, blood creatine phosphokinase, and blood creatinine; and decrease in blood albumin.
2.13 Trabectedin is available in 250‑microgram and 1‑mg vials at net prices of £363.00 and £1,366.00 respectively (excluding VAT; BNF October 2015). The cost of trabectedin 1.1 mg/m2 (based on an average body surface area of 1.7 m2) is £2,732 per dose (excluding administration costs).
2.14 The company has agreed a patient access scheme with the Department of Health. If trabectedin plus PLDH had been recommended, this scheme would apply to patients who need more than 5 cycles of treatment, with the company authorising an appropriate rebate from cycle 6 onwards. An update to the patient access scheme was approved during the appraisal. If trabectedin had been recommended, this scheme would have provided a discount to the list price of trabectedin with the discount applied at the point of purchase or invoice, in addition to the existing dose cap. The level of the discount is not being published as trabectedin is not being recommended with the proposed revised patient access scheme. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.