Darbepoetin alfa: in patients with chemotherapy-related anaemia

Darbepoetin alfa, novel erythropoiesis stimulating protein closely related to human erythropoietin, has been developed for the treatment of chemotherapy-related anaemia in patients with non-myeloid malignancies. In three 12-week, phase II studies in patients with cancer and chemotherapy-related anaemia, subcutaneous darbepoetin alfa, administered in once-weekly or 2-, 3- or 4-weekly regimens, dose-dependently increased the mean haemoglobin levels. In a randomised, double-blind, phase III study in 320 patients with lung cancer and chemotherapy-related anaemia, recipients of subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly, received red blood cell (RBC) transfusion approximate, equals 2-fold less frequently than placebo recipients (p < 0.001). In the same study, patients receiving darbepoetin alfa also received fewer standard units of RBC for transfusion and had greater haematopoietic response rate than placebo recipients (both p < 0.001). Subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly also reduced patient-reported fatigue (assessed by a quality-of-life questionnaire) [p = 0.019 vs placebo]. black triangle Darbepoetin alfa was generally well tolerated in clinical trials. The most frequent darbepoetin alfa-related adverse events were: body oedema, arthralgia and skin rash.     

Treating anaemia with epoetin alfa is associated with improvements in quality of life in cancer patients receiving chemotherapy

Anaemia is an important factor in the fatigue experienced by many patients receiving chemotherapy. A recent large-scale, randomised, placebo-controlled trial has shown that treatment with epoetin alfa raises haemoglobin levels, reduces fatigue and improves overall quality of life (QoL). In order to examine the relationship between anaemia and QoL more closely, we performed multiple regression analyses, adjusting for possible differences in demographic and clinical characteristics between the treatment groups on the trial data derived from FACT, CLAS and SF-36 QoL assessments. This confirmed that QoL is correlated with haemoglobin levels and that treatment with epoetin alfa is associated with a significant improvement in QoL as measured by validated cancer-specific instruments such as FACT and CLAS. However, the sub-group of patients who suffer disease progression during treatment are not predicted to experience an improvement in QoL, confirming the sensitivity of these scales. Race and tumour type were significantly related to changes in QoL scores, but other factors such as age and gender did not show significant effects on QoL.     

Epoetin Beta: a review of its clinical use in the treatment of anaemia in patients with cancer

Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit. Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy. Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials. Patients with haematological malignancies and a baseline platelet count > or =100 x 10(9)/L, Hb levels of > or =9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of <1 g/dL or an increase in Hb with epoetin beta during the first chemotherapy cycle indicated a low transfusion need in subsequent cycles in patients with ovarian carcinoma. In general, the efficacy of epoetin beta is not limited by tumour type. Response to the drug occurred irrespective of the nature (platinum- or nonplatinum-based) or presence of chemotherapy treatment in randomised trials. CONCLUSION: Epoetin beta has shown efficacy in the management of cancer-related anaemia in patients with haematological malignancies and of chemotherapy-induced anaemia in patients with solid tumours. Once-weekly administration provides added convenience for patients and may be cost saving, although additional research into the potential pharmacoeconomic benefits of this regimen are required. The drug is well tolerated in patients with cancer and is associated with little injection-site pain when administered subcutaneously. Epoetin beta is an important option in the prevention of chemotherapy-induced anaemia, and a valid and valuable alternative to blood transfusion therapy for the treatment of cancer-related or chemotherapy-induced anaemia.     

Darbepoetin alpha as treatment for anemia in patients receiving chemotherapy: a single-center experience

We evaluated Darbepoetin alpha (Aranesp; Amgen), a novel erythropoietic protein, in patients who developed anemia while receiving chemotherapy. Seventy-five patients (median age 62 years, range 40-81 years) undergoing different cancer chemotherapy regimens were treated with darbepoetin alpha. Therapy was started if hemoglobin (Hb) levels fell below 10 g/dl or if symptomatic anemia developed. Treatment effect was evaluated after 4 weeks, 8 weeks and at the end of therapy (up to 12 weeks). If no increase in Hb was seen after 4 weeks, the dose of darbepoetin alpha was increased to 300 microg. Patients were questioned about fatigue and any change during treatment, with evaluation according to a four-point scale, where 0 = no fatigue and 3 = severe fatigue. We observed a treatment response in 54 of 75 patients (72%). Dose escalation was necessary in 30 of 75 patients (40%) and blood transfusions were required in 13 of 75 patients (17.3%). Response was observed in 32 of 43 patients (74.4%) who had a baseline Hb < 10 g/dl and in 22 of 32 (68.8%) patients who had a baseline Hb > or =10 g/dl. At baseline, 60 of 75 patients (93.3%) reported fatigue of grade 2 or 3, but at the end of the 12-week follow-up period, only 26 of 68 patients (38.3%) reported fatigue at these levels. We conclude that darbepoetin alpha is a highly effective and well-tolerated drug in the treatment of chemotherapy-associated anemia. Patients benefited both in terms of Hb levels and control of chemotherapy-related symptoms.     

Darbepoetin alfa: an effective treatment with flexible and simplified dosing for anemia in patients with cancer

Anemia is common in patients with cancer or myelodysplastic syndrome. Erythropoietic therapy offers an effective way to manage anemia by increasing hemoglobin levels, decreasing transfusion requirements, and alleviating symptoms. We reviewed data showing the feasibility and effectiveness of treatment with the erythropoiesis-stimulating protein darbepoetin alfa at extended dosing intervals to treat anemia in patients with cancer receiving multicycle chemotherapy. We also explored the darbepoetin alfa's potential for treating anemia in patients with myelodysplastic syndrome. Data from clinical studies and drug therapy evaluations confirm that darbepoetin alfa administered weekly, every 2 weeks, and every 3 weeks corrects and maintains hemoglobin levels in patients with chemotherapy-induced anemia. In addition, the data demonstrate that both weight-based and fixed dosing with darbepoetin alfa are effective, and that early intervention to treat anemia has clinical benefits. Darbepoetin alfa also is an effective treatment for anemia in patients with cancer not receiving chemotherapy, at extended dosing intervals of at least 3 weeks. Extended dosing for anemia treatment can provide benefits for patients, caregivers, and clinicians because it reduces the number of clinic visits needed and permits synchronizing anemia treatment with chemotherapy cycles. Data from recent studies suggest that darbepoetin alfa is effective for treating anemia in patients with myelodysplastic syndrome; this potential use is being investigated further in ongoing studies. Thus, darbepoetin alfa is an attractive therapy option for patients with chemotherapy or cancer-induced anemia. It allows increased flexibility and simplified dosing and may offer some benefit in the treatment of anemia in patients with myelodysplastic syndrome.     

Sucrose-formulated octocog alfa: a review of its use in patients with haemophilia A

Sucrose-formulated octocog alfa (Kogenate Bayer, Kogenate FS, Helixate FS, Helixate nexgen) is a full-length recombinant human coagulation factor VIII (FVIII) product that is purified and formulated without the addition of human serum albumin and is stabilized with sucrose. The purification process of this formulation includes a solvent/detergent viral inactivation step. Sucrose-formulated octocog alfa is approved in the EU and US for the treatment of bleeding in patients with haemophilia A (congenital FVIII deficiency). Additionally, it is approved in the EU for the prophylaxis of bleeding in patients with haemophilia A and as a continuous infusion treatment in patients undergoing major surgery. Sucrose-formulated octocog alfa is effective and well tolerated as a FVIII replacement therapy in patients with haemophilia A, including those with severe disease undergoing major surgery. The therapeutic profile of this sucrose-formulated product cannot be compared with that of other octocog alfa or moroctocog alfa products because of a lack of head-to-head comparative studies. Pathogen transmission has not been reported with use of sucrose-formulated octocog alfa. Available data indicate that sucrose-formulated octocog alfa is an appropriate alternative to other recombinant FVIII products for the treatment and prophylaxis of bleeding episodes in adults and children with haemophilia A.     

Darbepoetin alfa: new preparation. Just a me-too: no advantage in anaemia of chronic renal failure

(1) Darbepoetin alfa, an epoetin, is slightly more glycosylated than epoetin alfa and beta. (2) The clinical file on anaemic patients with chronic kidney failure shows no advantage of darbepoetin alfa over other epoetins in terms of efficacy or side effects (subcutaneous injections of darbepoetin alfa are more often painful). (3) The dosing schedules of epoetins have not been compared adequately. Dosing schedules should be adapted for each patient.     

Darbepoetin alfa: new indication/new dosage. No proven advantage in chemotherapy-induced anaemia

(1) Current treatments for anaemia in patients receiving cancer chemotherapy include blood transfusion and epoetin alfa and beta. These epoetins correct anaemia in 40% to 65% of patients and reduce the number of patients who require transfusions during the second and third months of treatment by 12-35% in absolute terms. (2) Darbepoetin alfa is slightly more glycosylated than epoetin alfa and beta. It is no more effective than these two drugs in chronic renal failure. Darbepoetin alfa is now approved for the treatment of anaemia in patients who are receiving chemotherapy for non myeloid malignancies. (3) Two placebo-controlled dose-finding studies and two placebo-controlled trials involving nearly 1000 patients in total have shown that darbepoetin alfa decreases the number of transfused patients by 17-25% in absolute terms, and that it probably reduces fatigue. However, one-quarter of patients receiving darbepoetin were nonetheless transfused. (4) In the absence of reliable comparisons, there is no firm evidence that darbepoetin alfa is more effective than other epoetins. (5) According to relatively imprecise company reports, darbepoetin alfa increased the risk of thromboembolic events during clinical trials (6% versus 3%), including pulmonary embolism (1.3% versus 0%); the company also states that darbepoetin alfa does not increase the risk of arterial hypertension, a classical effect of epoetin that is mentioned in the summary of product characteristics (SPC). Placebo-controlled trials and dose-finding studies show no impact on the outcome of cancer, but follow-up is limited and a negative effect cannot be ruled out. The company states that no cases of erythroblastopenia have occurred among more than 70 000 treated patients. (6) According to the SPC, darbepoetin alfa can be given once a week. However, the optimal epoetin dosing schedule is unknown. Epoetin therapy takes several weeks to correct anaemia, whereas transfusion is immediately effective. (7) In practice, darbepoetin alfa seems a little easier to administer than epoetin alfa or beta, but the advantages and disadvantages of these drugs as compared with blood transfusion are not entirely clear.     

The use of darbepoetin alfa for the treatment of chemotherapy-induced anaemia

Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.     

Reductions in anaemia and fatigue are associated with improvements in productivity in cancer patients receiving chemotherapy

OBJECTIVE: Cancer-related anaemia is associated with fatigue that adversely affects patients' everyday functioning and wellbeing. We explore the impact of fatigue on patient productivity and caregiver burden. METHODS: The analyses are based on data from a randomised, open-label, active-controlled, dose-finding trial of darbepoetin alfa among solid-tumour cancer patients with anaemia, who are receiving chemotherapy. Fatigue is assessed with the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale score. Productivity and caregiver outcomes include time (hours) missed from usual activities, amount of assistance (hours) needed from others, overall ability to perform desired activities and ability to perform family responsibilities. These outcomes are assessed at baseline and the end of the 12-week treatment period. ANOVA and linear regression models are used to evaluate associations. RESULTS: Patients (n=300) were aged 61 years on average, with a mean (SD) baseline haemoglobin of 9.9 (0.9) g/dL. FACT-Fatigue subscale score improvements were significantly (p=0.003) associated with haemoglobin improvements. Over a 2-week period, after controlling for age, sex and disease progression, one-point improvements in FACT-Fatigue subscale scores corresponded to a 1-hour (95% CI 0.5, 1.5) gain in productive time, 0.7-hour (95% CI 0.4, 1.0) reduction in caregiver time and 1.6% (95% CI 1.4, 1.7) improvement in overall activity. CONCLUSIONS: Reducing fatigue is associated with gains in productive time, reductions in caregiver burden and enhanced ability to perform activities. These outcomes may have broader implications for patients' wellbeing and for the societal impact of cancer-related fatigue and anaemia.     

Zoledronic acid: a review of its use in patients with advanced cancer

Zoledronic acid (Zometa), a parenteral bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption and is used in the management of patients with cancer. Zoledronic acid 4 mg is administered as an intravenous infusion over 15 minutes. In the treatment of bone metastases, zoledronic acid is the first and only bisphosphonate to demonstrate efficacy in patients with a broad range of tumour types and in multiple myeloma. In well-designed trials, a single 4 mg dose of zoledronic acid showed good efficacy in the treatment of patients with hypercalcaemia of malignancy. Zoledronic acid 4 mg was superior to pamidronic acid 90 mg, administered as a 2-hour infusion, as assessed by normalised serum calcium concentrations 10 days after administration. In conjunction with antineoplastic therapy, zoledronic acid was an effective long-term (up to 25 months) treatment for skeletal-related events in patients with bone metastases associated with multiple myeloma or solid tumours. In patients with bone metastases secondary to breast cancer or bone lesions from myeloma, zoledronic acid was at least as effective as pamidronic acid, based on assessments of skeletal-related events 25 months after the start of treatment. In addition, compared with pamidronic acid, the overall risk of developing skeletal complications, including hypercalcaemia of malignancy, was significantly reduced in recipients of zoledronic acid. Compared with pamidronic acid, zoledronic acid reduced the risk of patients with breast cancer developing a skeletal-related event by an additional 20%. Zoledronic acid was significantly more effective than placebo on most efficacy measures in patients with bone metastases secondary to other solid tumours (e.g. lung, prostate) and showed sustained efficacy for up to 15 months. Preliminary data indicate that its efficacy in these patients is sustained for up to 24 months. Estimates of the cost effectiveness of zoledronic acid in the treatment of prostate cancer were consistent with those of other bisphosphonates, and cost-effectiveness ratios were within limits considered acceptable economic value. Zoledronic acid was generally well tolerated, with a tolerability profile similar to that of pamidronic acid and placebo. As with other bisphosphonates, deterioration of renal function has occasionally been reported in patients receiving zoledronic acid and monitoring of serum creatinine is recommended during treatment. The efficacy of zoledronic acid is therefore well established in patients with hypercalcaemia of malignancy and, for up to 25 months, in the treatment of complications arising from metastatic bone disease in patients with multiple myeloma or solid tumours. The clinical profile of zoledronic acid compares favourably with that of pamidronic acid in patients with cancer and zoledronic acid has a more convenient administration schedule with the potential for better compliance. Thus, zoledronic acid is an effective bisphosphonate and is positioned to play an important role in the management of advanced cancer patients with bone metastases.     

Epoetin alfa for the treatment of cancer- and chemotherapy-related anaemia: product review and update

Anaemia, often associated with chemotherapy, is a common and debilitating disorder in cancer patients. Recombinant human erythropoietin (epoetin alfa) was introduced in the 1990s for the treatment of chemotherapy-related anaemia. Data from randomised, double-blind, placebo-controlled studies and large, non-randomised, community-based studies have demonstrated that either of the FDA-approved dosing schedules of epoetin alfa 150 - 300 U/kg three times weekly or 40,000-60,000 U/week s.c., significantly increases haemoglobin levels, reduces transfusion requirements, and improves quality of life in anaemic cancer patients undergoing chemotherapy or chemoradiation therapy. Guidelines for the effective and safe use of epoetin alfa have been published by major oncology/haematology organisations and are reviewed in this article. Areas of recent and ongoing investigation with epoetin alfa are also covered in this review.     

Ondansetron: a pharmacoeconomic and quality-of-life evaluation of its antiemetic activity in patients receiving cancer chemotherapy

Ondansetron is more effective than high-dose metoclopramide in the prevention of acute nausea and vomiting due to highly emetogenic chemotherapy, and, unlike metoclopramide, is rarely associated with extrapyramidal effects. Pharmacoeconomic analyses have demonstrated that, in specified clinical settings, ondansetron (8mg 4-hourly for 3 doses or 8mg followed by 1 mg/h for 24 hours) is equally cost-effective as high-dose metoclopramide (3 mg/kg followed by 0.5 mg/kg/h for 8 hours) in the prophylaxis of emesis in patients receiving highly emetogenic chemotherapy, at an acquisition cost 4- or 5-fold higher than that of the metoclopramide regimen. Furthermore, the combination of dexamethasone plus ondansetron has been shown to be more effective than ondansetron monotherapy in controlling emesis. In patients receiving high-dose ( greater than 50 mg/m2) cisplatin-based chemotherapy, antiemetic therapy with ondansetron (8mg intravenously as a single dose) plus dexamethasone (16mg total intravenous dose) was shown to be more cost-effective than the combination of high-dose metoclopramide (11 mg/kg total intravenous dose), dexamethasone (8mg intravenously as a single dose) plus lorazepam (1 to 1.5mg intravenously as a single dose). In a limited number of studies, quality-of-life scores, as assessed using the Rotterdam Symptom Checklist or the Functional Living Index--Emesis instrument, were significantly higher with ondansetron than with other antiemetic agents, including metoclopramide. Together, these results suggest that ondansetron, as an alternative to antiemetic regimens including high-dose metoclopramide, is appropriate cost-effective therapy for the prevention of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy. Ondansetron is effective in controlling acute emesis associated with moderately emetogenic chemotherapy, and its use in this clinical setting may best be reserved for patients who have not responded well to previous antiemetic therapy with more traditional agents. However, poorly controlled emesis can lead to anticipatory nausea and vomiting in subsequent courses of chemotherapy, thus, consideration should also be given to the use of ondansetron in patients receiving moderately emetogenic chemotherapy, although further pharmacoeconomic investigations are required to clarify its use in this clinical setting.     

Chronic vaccination with a therapeutic EGF-based cancer vaccine: a review of patients receiving long lasting treatment

Therapeutic vaccines continue to be one of the most active fields in cancer research. However, despite clear evidence of antitumor effect in laboratory animals, and despite the ability of current vaccine candidates to elicit tumor specific antibodies and T-cells in humans, objective responses in the clinical trials are rare. The role of therapeutic vaccines in advanced cancer patients, if any, would be to decrease the rate of disease progression and to increase survival and quality of life. Due to the redundant regulatory loops contracting the immune response to antigens that cannot be eliminated, such a role would require chronic vaccination, which is at first sight at odds with the classic experience of vaccinology. During the last decade our team has been developing a therapeutic vaccine for advanced lung cancer, which consists in human recombinant Epidermal Growth Factor (EGF) chemically conjugated to a carrier protein from Neisseria meningitides. Several clinical trials have been carried out, showing increase in anti-EGF antibody titters, decrease in plasma EGF concentration and survival advantage in vaccinated patients. In the present paper we review data from 58 patients who were vaccinated monthly for more than one or two years. Long term vaccination was feasible and safe, and there was no evidence of cumulative toxicity. Patients kept high anti-EGF antibody titters during all the time of vaccination, without evidence of immune response exhaustion. Continued vaccination increased the probability to get a high antibody response, which has been previously shown to be, in turn, associated with a better survival. Observations done in this series of patients suggest that long term therapeutic vaccination is a feasible strategy, worth to be further explored in the aim of transforming advanced cancer into a chronic disease.     

Drotrecogin alfa (activated): a pharmacoeconomic review of its use in severe sepsis

Drotrecogin alfa (activated) [Xigris] (DAA), the recombinant form of human activated protein C, is approved as an adjunctive therapy for patients with severe sepsis (sepsis associated with > or = 1 organ system failure [OSF]). In the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, the absolute reduction in 28-day all-cause mortality with intravenous DAA 24 micro g/kg/h for 96 hours plus conventional care versus conventional care alone was 6.1%.Although lacking statistical power, a prospectively planned subgroup analysis of this study suggested that the absolute reduction in mortality increased in patients with a baseline APACHE (Acute Physiology and Chronic Health Evaluation) II score of > or = 25 or > or = 2 OSFs, with no clear treatment effect in patients with an APACHE II score of < or = 24 or 1 OSF.Three fully published cost-effectiveness/cost-utility models of DAA plus conventional care relative to conventional care alone adopted a national healthcare payer's and/or societal perspective in North America. The base-case (baseline) discounted incremental cost per life-year gained (LYG) with DAA for all patients with severe sepsis was $US15,801-33,300 (year of costing 2000-2002). The results were more favourable for patients with an APACHE II score of > or = 25 ($US10,833-19,723 per LYG), but considerably worse for patients with an APACHE II score of < or = 24 based on a post hoc reanalysis by the US FDA.Among several fully or partly published cost-effectiveness/cost-utility models that adopted a national healthcare payer's perspective in continental Western European countries, the base-case (baseline) undiscounted incremental cost per LYG was broadly similar and more favourable for patients with > or = 2 OSFs (9660-11,300 euros; year of costing/publication 1998/1999, 2000, 2002 or 2003) than for all patients with severe sepsis (13,436-15,071 euros) in those studies that reported both analyses. The DAA acquisition cost accounts for up to 95% of the additional cost of using the drug.In conclusion, DAA is a major advance in the treatment of severe sepsis, based on the significant mortality reduction observed in the PROWESS study. From a hospital/hospital pharmacy perspective, the drug is associated with a high acquisition cost and a small increase in other short-term costs. From a societal or national healthcare payer's perspective, however, its administration to patients who meet the PROWESS study inclusion criteria, especially individuals with more severe disease (e.g APACHE II score of > or =25 and/or > or = 2 OSFs), has a lifetime cost-effectiveness profile that compares well to that of many widely accepted therapies.     

Paclitaxel: a pharmacoeconomic review of its use in the treatment of ovarian cancer.

Paclitaxel belongs to the group of antitumour agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomised 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-haematological 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 $US 6395 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 $US 13,135 (year of costs not reported) to $US 25,131 (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 $US 50,000 for new therapies and compare well with incremental costs reported for other oncological and life-saving therapies. Patient preferences and quality of life are important issues due to the short survival of patients with advanced 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 US $18,200 per additional quality-adjusted life-year (QALY) [1995 drug costs]. In a Canadian study the ICUR ranged from 11,600 Canadian dollars ($Can) to $Can 24,200 (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.     

Vinorelbine: a review of its use in elderly patients with advanced non-small cell lung cancer

Vinorelbine is a semisynthetic vinca alkaloid that is effective as monotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC). In the large comparative Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), patients receiving vinorelbine monotherapy achieved an objective response rate of 19.7%. The median survival time and the 1-year survival rate were significantly higher in recipients of vinorelbine plus best supportive care than in recipients of best supportive care alone. Vinorelbine recipients generally scored better than recipients of best supportive care on quality-of-life (QOL) functioning scales and experienced significantly fewer lung cancer-related symptoms; however, QOL scores were worse with vinorelbine for parameters relating to drug tolerability. Comparative phase III trials investigating the efficacy of combination therapy with vinorelbine and other agents specifically in elderly patients with advanced NSCLC have been conducted only for the combination of vinorelbine and gemcitabine [the Southern Italy Cooperative Oncology Group (SICOG) trial and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)]. Objective response rates for vinorelbine/gemcitabine combination therapy in these phase III trials were 22 and 20%, respectively. The SICOG trial was closed early when an interim analysis demonstrated a significant survival advantage for combination therapy with vinorelbine plus gemcitabine over vinorelbine monotherapy. However, a survival advantage for combination therapy versus vinorelbine monotherapy was not demonstrated in the larger MILES trial. The main adverse effect of vinorelbine monotherapy in the elderly is myelosuppression. Adverse events associated with most antineoplastic agents, such as mild alopecia, nausea, vomiting and mucositis, were reported in clinical trials; however, these events were rarely severe. Mild-to-moderate neurotoxicity, including constipation (presumably from autonomic neuropathy), was also reported. The addition of gemcitabine to vinorelbine increased the incidence of both haematological and nonhaematological adverse events. However, there was no significant increase in the incidence of life-threatening toxicity. Vinorelbine as a single agent is effective in elderly patients with NSCLC and is associated with improved survival and at least a trend towards improved QOL parameters compared with best supportive care alone. Vinorelbine was associated with a generally manageable tolerability profile. The benefit of adding gemcitabine to vinorelbine for the treatment of NSCLC in the elderly is equivocal; improved survival was reported in one comparative trial, but not in another larger one. Vinorelbine is an effective and well tolerated palliative treatment option for elderly patients with advanced NSCLC.