Hexyl aminolevulinate: in the detection of bladder cancer

Hexyl aminolevulinate, the hexyl ester of 5-aminolevulinic acid, is a photosensitising agent designed to enhance the detection of bladder cancer tumours, in particular highly malignant carcinoma in situ (CIS). After cellular uptake, hexyl aminolevulinate and/or hydrolysed 5-aminolevulinic acid enter the haem biosynthetic pathway and induce accumulation of the photoactive compound protoporphyrin IX (PpIX) in malignant as opposed to nonmalignant cells. PpIX emits red fluorescence when illuminated under blue light. Blue-light fluorescence cystoscopy with hexyl aminolevulinate (hexyl aminolevulinate cystoscopy) was more effective than standard (white-light) cystoscopy for detecting non-muscle-invasive ('superficial') disease in two European, multicentre, phase III trials, which evaluated hexyl aminolevulinate cystoscopy as an adjunct to standard cystoscopy in patients with known or suspected bladder cancer. In one trial, hexyl aminolevulinate cystoscopy detected 96% of the patients with CIS; it identified 28% more patients with CIS than standard cystoscopy. In the other trial, 17% of patients were selected to receive more complete treatment following hexyl aminolevulinate cystoscopy than standard cystoscopy, because of the improved tumour detection rate. Hexyl aminolevulinate cystoscopy is well tolerated as an adjunct to standard cystoscopy; adverse events were those typically associated with standard cystoscopy/biopsy (e.g. postoperative pain).     

Paclitaxel: as adjuvant or neoadjuvant therapy in early breast cancer

Paclitaxel is a antimicrotubule agent with established antitumour activity in a variety of cancers including breast cancer. The efficacy of intravenous paclitaxel as adjuvant therapy for early breast cancer has been investigated in two large, randomised trials; it was administered sequentially to standard doxorubicin-cyclophosphamide (AC) combination therapy and compared with cycles of AC alone. In both trials, the addition of sequentially administered paclitaxel to the AC regimen significantly improved disease-free survival at 5 years compared with AC alone. In one of the trials, women who received paclitaxel also had a significant improvement in overall 5-year survival time. In randomised trials of neoadjuvant therapy for women with early breast cancer, paclitaxel or paclitaxel-containing regimens showed efficacy in terms of response/remission rates, local breast tumour recurrence and proportion of patients eligible for breast-conserving surgery. The most frequently reported grade 3-4 adverse events with paclitaxel administered sequentially to AC were haematological events (neutropenia, thrombocytopenia, anaemia) and nausea/vomiting.     

Etanercept: a pharmacoeconomic review of its use in rheumatoid arthritis

Etanercept (Enbrel), which inhibits the activity of tumour necrosis factor-alpha, is indicated in the treatment of patients with active rheumatoid arthritis (RA). A lifetime cost-utility analysis in patients with severe disease-modifying antirheumatic drug (DMARD)-resistant RA in the UK suggested that etanercept is associated with acceptable cost-utility ratios relative to traditional nonbiological DMARDs. In a 12-month cost-utility study in Spain, etanercept was predicted to be dominant over infliximab plus methotrexate in patients with active, refractory RA with regards to the cost per QALY gained and cost per American College of Rheumatology (ACR) 20 response achieved. In short-term cost-effectiveness analyses conducted in the US, the cost effectiveness of etanercept relative to other treatments in patients with methotrexate-naive or -resistant RA depends on whether predicted incremental cost-effectiveness ratios of at least USD 41,900 per ACR 20 response or USD 34,800 per ACR 70 weighted response over a 6-month period are considered acceptable (1999 values). The relative efficacy and cost effectiveness of etanercept and other biological DMARDs will be clarified when appropriate data from directly comparative clinical and/or long-term pharmacoeconomic studies become available. Etanercept may prevent or delay disability, which may produce reductions in nondrug costs that could help offset its acquisition cost.     

Escitalopram: a pharmacoeconomic review of its use in depression

Escitalopram (Cipralex), a new highly selective serotonin reuptake inhibitor (SSRI), is the active S-enantiomer of RS-citalopram. It is effective in the treatment of patients with major depressive disorder (MDD) and may have a faster onset of therapeutic effect than citalopram. It has also been shown to lead to improvements in measures of QOL. Escitalopram is generally well tolerated, with nausea being the most common adverse event associated with its use. Modelled pharmacoeconomic analyses found escitalopram to have a cost-effectiveness and cost-utility advantage over other SSRIs, including generic citalopram and fluoxetine and branded sertraline, and also over the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine extended-release (XR). These studies used a decision-analytic approach with a 6-month time horizon and were performed in Western Europe (year of costing 2000 or 2001). Cost-effectiveness ratios for escitalopram, in terms of cost per successfully treated patient over 6 months, ranged from Euro 871 to Euro 2598 in different countries, based on direct costs and remission rates, and were consistently lower (i.e. more favourable) than the ratios for comparators (Euro 970 to Euro 3472). Outcomes similarly favoured escitalopram when indirect costs (represented by those associated with sick leave and loss of productivity) were included. The results of comparisons with citalopram, fluoxetine and sertraline were not markedly affected by changes to assumptions in sensitivity analyses, although comparisons with venlafaxine XR were sensitive to changes in the remission rate. The mean number of QALYs gained during the 6-month period was similar for all drugs evaluated, but direct costs were lower with escitalopram, leading to lower cost-utility ratios than for comparators. Incremental analyses performed in two of the studies confirmed the cost-effectiveness and cost-utility advantage of escitalopram. A prospective, 8-week comparative pharmacoeconomic analysis found that escitalopram achieved similar efficacy to venlafaxine XR, but was associated with 40% lower direct costs (Euro 85 vs Euro 142 per patient over 8 weeks; 2001 costs), although this difference did not reach statistical significance. In both the modelled and prospective analyses, the differences in overall direct costs were mainly due to lower secondary care costs (in particular those related to hospitalisation) with escitalopram. In the prospective analysis, escitalopram had lower estimated drug acquisition costs than venlafaxine XR. CONCLUSION: Escitalopram, the S-enantiomer of RS-citalopram and a highly selective SSRI, is an effective antidepressant in patients with MDD, has a favourable tolerability profile, and, on the basis of available data, appears to have a rapid onset of therapeutic effect. Modelled pharmacoeconomic analyses from Western Europe suggest that it may be a cost-effective alternative to generic citalopram, generic fluoxetine and sertraline. Although the available data are less conclusive in comparison with venlafaxine XR, escitalopram is at least as cost effective as the SNRI based on a prospective study, and potentially more cost effective based on modelled analyses. Overall, clinical and pharmacoeconomic data support the use of escitalopram as first-line therapy in patients with MDD.     

Spotlight on Paclitaxel in Non-Small Cell Lung Cancer

A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographic regions.Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomized trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin.A Canadian cost-effectiveness analysis incorporated data from one of the large randomized comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US22 181 (30 619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomized study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US30 769 vs $US29 592) and Spain ($US19 923 vs $US19 724) but lower costs per responder in Belgium ($US22 852 vs $US25 000) and France ($US28 080 vs $US34 747) [1995/96 costs].In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US10 000 in a US study (year of costing not reported) or $US11 200 in a Canadian analysis ($Can15 400; 1995 costs). Results were less favorable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can75 000 ($US54 526) per life-year saved or per quality-adjusted life-year gained (1995 values). Conclusions: Current treatment guidelines for advanced NSCLC recognize paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and effects on platelets. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.     

Spotlight on Paclitaxel in Ovarian Cancer

Paclitaxel belongs to the group of antitumor agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomized phase III clinical trials. When used in combination with cisplatin for first-line treatment of advanced ovarian cancer, it is superior to cyclophosphamide/cisplatin, with gains in median survival of around 1 year. Paclitaxel plus carboplatin has similar efficacy to paclitaxel plus cisplatin. There is now consensus that paclitaxel plus either carboplatin or cisplatin is the recommended first-line therapy for patients with advanced ovarian cancer. The particular combination employed may vary between institutions and geographical regions, although paclitaxel plus carboplatin is generally better tolerated (i.e. lower incidence of non-hematologic adverse events) than paclitaxel plus cisplatin and is widely used in many countries. Paclitaxel is also used as monotherapy in second-line (salvage) treatment of ovarian cancer.Pharmacoeconomic analyses performed to date have primarily focused on first-line therapy comparing the combination of paclitaxel/cisplatin with cyclophosphamide/cisplatin. All studies incorporated clinical outcomes data, most commonly from the Gynecologic Oncology Group (GOG) 111 trial, showing a survival advantage for paclitaxel/cisplatin. These studies report incremental cost-effectiveness ratios (ICERs) ranging from $US6395 per additional life-year gained (LYG) in Spain (1995/96 values) to US$44 690 per additional progression-free LYG in France (year of costs not reported). Five studies were based in the US and Canada and these reported very similar ICERs of $US13 135 (year of costs not reported) to $US25 131 (1993 costs) per additional LYG. In all of these studies the incremental costs of paclitaxel/cisplatin therapy fall well within the commonly cited threshold limit of $US50 000 for new therapies and compare well with incremental costs reported for other oncologic and life-saving therapies.Patient preferences and quality of life are important issues due to the short survival of patients with ovarian cancer. Two cost-utility studies reported similar incremental cost-utility ratios (ICURs). In the study based on US costs, the ICUR of paclitaxel/cisplatin treatment was $US18 200 per additional quality-adjusted life-year (QALY) [1995 drug costs]. In a Canadian study the ICUR ranged from 11 600 Canadian dollars ($Can) to $Can24 200 (1996 costs) per additional progression-free QALY depending on the choice of second-line treatment. Conclusions: Paclitaxel used in combination with cisplatin offers survival and utility gains versus cyclophosphamide plus cisplatin, when used as first-line treatment in patients with stage III or IV ovarian cancer. The incremental cost for these gains is within the accepted range for healthcare interventions. However, pharmacoeconomic analyses of paclitaxel plus carboplatin — a combination widely accepted for use in women with advanced ovarian cancer and with clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile — are currently lacking. Nevertheless, results of available pharmacoeconomic data support the clinical use of paclitaxel/platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced ovarian cancer.     

Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions.

The orally administered antianginal agent trimetazidine increases cell tolerance to ischaemia by maintaining cellular homeostasis. In theory, this cytoprotective activity should limit myocyte loss during ischaemia in patients with angina pectoris. Data from studies in patients with coronary artery disease indicate that, unlike the effects of other antianginals, the anti-ischaemic effects of trimetazidine 20 mg are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. Furthermore, limited evidence suggests trimetazidine may improve left ventricular function in patients with chronic coronary artery disease or ischaemic cardiomyopathy and in patients experiencing acute periods of ischaemia when undergoing percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20 mg 3 times daily reduces the frequency of anginal attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. Its clinical effects are broadly similar to those of nifedipine 40 mg/day and propranolol 120 to 160 mg/day but, unlike these agents, trimetazidine does not affect the rate-pressure product during peak exercise or at rest. Adjunctive trimetazidine 60 mg/day reduces the frequency of anginal attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antianginal agents. Furthermore, the drug appears to be more effective than isosorbide dinitrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranolol 120 mg/day. The tolerability profile of trimetazidine 60 mg/day was similar to that of placebo when used as add-on therapy in patients with angina pectoris insufficiently controlled by other antianginal agents and was superior to that of either nifedipine 40 mg/day or propranolol 120 to 160 mg/day when used as monotherapy. The most frequently reported adverse events in trimetazidine recipients were gastrointestinal disorders, although the incidence of these events was low. CONCLUSIONS: Trimetazidine is an effective and well tolerated anti-ischaemic agent which, in addition to providing symptom relief and functional improvement in patients with angina pectoris, has a cytoprotective action during ischaemia. The drug is suitable for initial use as monotherapy in patients with angina pectoris and, because of its different mechanism of action, as adjunctive therapy in those with symptoms not sufficiently controlled by nitrates, beta-blockers or calcium antagonists. The role of trimetazidine in other coronary conditions has yet to be clearly established.     

Prevention and Treatment of Osteoporosis in Postmenopausal Women

Postmenopausal osteoporosis is characterized by an increased rate of bone turnover accompanied by a reduction in bone mineral density (BMD) that results in an increased risk of fracture, especially of the vertebrae, hip, or wrist. Alendronate (Fosamax®, Fosamax Once-Weekly®), an oral bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism, is a first-line therapy for the management of postmenopausal women with, or at risk of developing, osteoporosis.Alendronate produces sustained increases in BMD and reductions in bone turnover from baseline, and reduces the risk of vertebral, hip, wrist, and other fractures in women with postmenopausal osteoporosis. It also prevents bone loss, and reduces the risk of radiographic or clinical vertebral fracture in postmenopausal osteopenia. Provided administration instructions are followed, alendronate is generally well tolerated. Adverse events are usually transient and are associated with the upper gastrointestinal tract (abdominal pain, nausea, acid regurgitation, dyspepsia); moreover, the incidence of these adverse events with alendronate was similar to those with placebo. More serious events (esophagitis, gastric or duodenal ulceration or bleeding) are uncommon. Once-weekly formulations are as effective and as well tolerated as once-daily alendronate in postmenopausal women.Pharmacoeconomic evaluations suggest that alendronate is a viable treatment option in postmenopausal osteoporosis. The reduction in fracture-related healthcare utilization seen with alendronate results in decreased direct costs, including inpatient or long-term care. Markov state-transition models suggest that this could at least partially offset costs incurred with alendronate therapy. Treatment of women with osteoporosis aged 65 years and older, and postmenopausal women with a previous osteoporotic fracture, are cost-effective strategies. Alendronate is also likely to increase quality-adjusted life-years in any postmenopausal women with osteoporosis.In conclusion, clinical and economic data support the use of alendronate in postmenopausal osteoporosis. It effectively reduces bone turnover, increases BMD, and reduces the risk of osteoporotic fracture in postmenopausal women with established osteoporosis, especially older women with a higher risk of fracture. Although its cost effectiveness in postmenopausal women with osteopenia is not clearly established, alendronate is clinically effective in these patients. In addition, it is generally well tolerated when taken as recommended. Consequently, alendronate should be considered a therapy of choice in the prevention and treatment of osteoporosis in postmenopausal women.