Gastrointestinal and renal side effects of bisphosphonates: differentiating between no proof of difference and proof of no difference.

BACKGROUND: This study was aimed at comparing the safety of bisphosphonates in women with osteoporosis by application of equivalence testing. METHODS: Gastrointestinal and renal side effects were evaluated based on information published in randomized controlled trials. RESULTS: The data on gastrointestinal side effects (47 trials) indicated that alendronate, risedronate etidronate, and zolendronate have similar rates of the adverse effects; application of Bayesian network meta-analysis showed that equivalence was demonstrated according to margins around ±10%. The data on renal safety were more sparse and suffered from the use of different outcome measures; hence, a single trial could be evaluated. This trial showed a similar effect of alendronate and risedronate on renal function at 12 months; equivalence was based on differences between the two agents in renal function with margins of less than ±10.4 ml/min. CONCLUSION: Our study provided quantitative information to determine to what extent bisphosphonates can be considered equivalent in terms of gastrointestinal and renal side effects.

A retrospective cost-effectiveness analysis of interferon as adjuvant therapy in high-risk resected cutaneous melanoma.

To assess the cost per life year gained of alpha interferon (IFN) as adjuvant therapy for patients with high-risk resected melanoma, we conducted a retrospective, incremental cost-effectiveness analysis on clinical data from a previously published ECOG trial [9]. The Gompertz model was used to estimate the total lifetime values of patient-years of subjects receiving IFN in comparison with subjects given no adjuvant treatment. The ECOG trial involved 143 patients treated with high-dose IFN and 137 given no adjuvant treatment. Estimated drug expenditures were based on the assumption of a cost of $109.25 per 10 MU of IFN. Our analysis of the ECOG results showed that the adjuvant treatment of 100 subjects with high-dose IFN improved survival expectancy by 133.6 discounted life years or 308 undiscounted life years. The use of IFN (compared with no adjuvant treatment) implied an incremental cost of $16,467 per discounted life year saved (95% CI of $4752-50,000) or $7143 per undiscounted life year saved (95% CI of $3226-33,846). Sensitivity testing, in which variations were introduced in the main factors influencing cost and effectiveness, showed that this value always remained below $50,000. Our pharmacoeconomic analysis indicates that adjuvant treatment with high-dose IFN in patients with high-risk resected melanoma implies a favourable cost-effectiveness ratio. Because two other studies showed no significant survival benefit in patients receiving adjuvant IFN at lower values of total dose per patient, the controversy remains and confirmation data are needed for the ECOG trial's results. If these clinical results are confirmed, our analysis shows that the dosage of IFN given in this trial has a favourable pharmacoeconomic profile.

Retrospective survival analysis and cost-effectiveness evaluation of second allogeneic bone marrow transplantation in patients with acute leukemia. Gruppo Italiano Trapianto di Midollo Osseo.

The therapeutic options for patients with acute leukemia who relapse after the initial transplant include second bone marrow transplantation (2BMT) and conventional chemotherapy (CC). In this work, we conducted an analysis of published survival data and we evaluated the cost-effectiveness of 2BMT in comparison with CC. We retrieved survival information on 167 patients treated with 2BMT and 299 patients treated with CC. Survival figures were derived from individual patient data and were compared between 2BMT and CC. The mean lifetime survival (MLS) was estimated for each of the two patient cohorts using standard techniques of survival-curve extrapolation. The cost data of patients given 2BMT or CC were estimated from published data. Our analysis of individual survival data showed that 2BMT improved survival at levels of statistical significance (survival gain = 19.6 months per patient). Using an incremental cost of $90000 per patient, the cost-effectiveness ratio of 2BMT in comparison with CC was calculated as $52215 discounted dollars per discounted life year gained. Our results indicate that, in patients with acute leukemia who relapse after their first transplant, 2BMT significantly prolongs survival in comparison with CC and seems to have an acceptable cost-effectiveness profile.

A new method for expressing survival and life expectancy in lifetime cost-effectiveness studies that evaluate cancer patients (review).

The methodology of cost-effectiveness studies that use a lifetime perspective is based on the extrapolation to infinity of the survival curves. However, the research in this methodological area is at an initial phase. Hence, adequate techniques for survival curve extrapolation still need to be devised for handling the different clinical settings that can be analysed by cost-effectiveness survival studies. After a brief overview of the two most commonly used extrapolation methods (Markov decision-tree model and Gompertz technique), we describe a new method for expressing lifetime survival in cost-effectiveness studies that evaluate cancer patients. Our method extrapolates to infinity a traditional survival curve by assigning a normal life expectancy to patients (or long-term survivors). In this way, the value of mean lifetime survival (MLS) for the patient cohort under study can be determined using a lifetime perspective. This value can be employed in lifetime cost-effectiveness analyses that compare different forms of intervention for that disease condition. A separate section of our method compares the overall survival pattern of cured and not cured patients with that of a reference healthy population to assess the impact of the disease on life expectancy. As an example of the application of our method, we reanalysed a survival data set reported by Spinolo et al in 1992, that refers to patients with acute leukaemia who relapsed after their first allogeneic bone marrow transplantation and who received a second transplant (n=17, mean age at relapse = 26 years). The use of our extrapolation method provided the following results: MLS for leukaemia patients = 105.9 months per patient or 8.8 years per patient; MLS for the reference cohort of healthy subjects = 583.8 months per patient or 48.6 years per patient. We conclude that the extrapolation technique described herein can be useful to handle lifetime survival data in cost-effectiveness analysis.

Treatments for newly diagnosed multiple myeloma: analysis of survival data and cost-effectiveness evaluation.

The main therapeutic options currently available to induce remission in newly diagnosed cases of multiple myeloma include: i) melphalan at conventional doses without concurrent administration of interferon; ii) melphalan at conventional dose combined with interferon; iii) autologous bone marrow transplantation (ABMT). We conducted an analysis of the survival data reported in five large-scale published clinical trials and we evaluated the cost-effectiveness ratio. We determined the mean lifetime survival (MLS) for each treatment group using the Gompertz model. The cost data of patients given ABMT or standard chemotherapy were estimated from published information. The values of MLS were 3.47 years per patient for melphalan at conventional doses without interferon, 3.74 years for melphalan at conventional doses combined with interferon, and 7.28 years for ABMT. As compared with conventional melphalan treatment, ABMT yielded a significantly better survival. Survival after melphalan combined with interferon was not significantly different from that following melphalan alone. Using melphalan at conventional doses without interferon as reference term, the marginal cost-effectiveness ratio of ABMT was of about $26,000 per life year gained. For the induction treatment in patients with newly diagnosed myeloma, ABMT seems to be more effective and more cost-effective than the standard treatment with melphalan at conventional doses.

Cost-effectiveness of neoadjuvant multimodal therapy in patients with esophageal adenocarcinoma.

We conducted an incremental cost-effectiveness analysis to evaluate an adjuvant multimodal therapy (chemotherapy + radiotherapy) in patients with esophageal adenocarcinoma undergoing surgery. We utilized the clinical data of a published controlled trial comparing preoperative chemotherapy + radiotherapy versus surgery alone. Information on costs was derived from local data and verified against reported values. Multimodal treatment was found to improve life expectancy by 196.9 discounted years every 100 subjects (survival gain of about 2 years per patient). Costs of this neoadjuvant therapy were estimated as $780,010 per 100 patients. Our cost-effectiveness analysis showed that the cost per life year gained was $3,961 for the multimodal therapy in comparison with surgery alone. The pharmacoeconomic profile of this therapeutic modality compares favorably with previous economic data calculated for other types of health care intervention.

Treatment of large cell lymphoma with the Fi2 regimen (doxorubicin, vincristine, cyclophosphamide, bleomycin and prednisone): 25-year experience.

The CHOP protocol is the reference treatment for large cell lymphomas, but several other schemes of different intensity have recently been studied with controversial clinical findings. We report here the results obtained at our institution with a CHOP-like regimen called Firenze 2 (Fi2), which is characterised by an original scheduling of chemotherapy administration. A total of 225 patients, who were diagnosed from 1974 to 1996, were included in this retrospective study. All patients received the Fi2 regimen as a first-line intervention. One-hundred and sixty-two (72%) achieved complete remission; the overall survival at 120 months was 51% with a disease-free survival of 67% (median follow-up = 78 months). The survival curve showed a stable plateau of 42% after 16 years, which remained stable for further 4 years. In a multivariate survival analysis, achievement of complete remission (p<0.001) and IPI index of 0 or 1 (p=0.05) were significantly associated with a better survival. Overall, the outcome of our patients was similar to that reported by others, but the distinguishing feature of our study is the very long follow-up of the patients. Our study confirms that first generation regimens are effective and can cure a substantial proportion of patients. The long-term results of our study are helpful to retrospectively identify high-risk patients whose prognosis is poor and who can be candidates for more aggressive schemes of chemotherapy.

Quality of life and utility in patients with non-small cell lung cancer. Quality-of-life Study Group of the Master 2 Project in Pharmacoeconomics.

BACKGROUND: Although several studies have determined quality of life in patients with lung cancer, there is still little information about the use of generic questionnaires [e.g. the 36-item Short Form health survey (SF-36)] and utility questionnaires [e.g. the EuroQOL instrument (EQ-5D)] in this disease. OBJECTIVES: To (i) measure quality of life and utility in patients with non-small cell lung cancer (NSCLC) using the SF-36 and the EuroQOL questionnaires; (ii) to evaluate the impact of some clinical variables on quality of life and utility; (iii) to assess the correlation between the measurements produced by the 2 questionnaires. STUDY DESIGN: Cross-sectional study. PARTICIPANTS: 95 patients from 15 Italian hospitals with NSCLC (93% male, mean age 62 years) completed both questionnaires. RESULTS: The mean scores for the 8 domains of the SF-36 ranged from 20.8 (physical role) to 63.0 (social functioning). The mean physical and mental summed scores of the SF-36 were 36.8 [standard deviation (SD) 9.8] and 43.0 (SD 11.5), respectively. The EuroQOL mean score was 0.58 (SD 0.32) in the self-classifier (SC) version and 0.58 (SD 0.20) in the visual analogue scale (VAS) version. Among the clinical variables that affected quality of life and utility, the presence of metastasis had the greatest impact: patients with metastasis had statistically significantly lower scores for 2 domains of the SF-36 (physical functioning, p = 0.009; bodily pain, p = 0.016), for the physical component summed score of the SF-36 (p = 0.015) and for both utility estimates (EuroQOL-SC, p = 0.027; EuroQOL-VAS, p = 0.038) than patients without metastasis. Both the SC and VAS EuroQOL scores showed a statistically significant correlation with each of the 8 domains of the SF-36. The scores for both the SF-36 and the EuroQOL in patients with NSCLC were considerably worse (relative differences ranging from -8 to -73%) than the corresponding values (normative data) previously reported for healthy individuals. CONCLUSIONS: Our study quantified the degree to which quality of life is impaired in patients with NSCLC, showed that the presence of metastasis had an important role, and indicated a strong correlation between the measurements produced by the 2 questionnaires. The EuroQOL measurements obtained from these patients will aid evaluation of the cost-utility ratio for NSCLC therapies.

Cost effectiveness of riluzole in amyotrophic lateral sclerosis. Italian Cooperative Group for the Study of Meta-Analysis and the Osservatorio SIFO sui Farmaci.

OBJECTIVE: In patients with amyotrophic lateral sclerosis, long term treatment with riluzole has been reported to improve survival or tracheostomy-free survival in comparison with placebo. We conducted a pharmacoeconomic analysis for estimating the cost per life-year gained using this drug. DESIGN: This study was an incremental cost-effectiveness lifetime analysis. SETTING: The clinical material was derived from 2 placebo-controlled randomised controlled trials comparing riluzole versus usual care without riluzole, which were identified through a literature search based on the IOWA and the Medline systems. PATIENTS AND INTERVENTIONS: The study included 633 patients with amyotrophic lateral sclerosis. Patient-level information was retrieved from 313 patients treated with riluzole and 320 patients assigned to placebo. Survival after randomisation was compared between the 2 groups using standard statistics (log-rank test and Cox analysis), whereas the lifetime survival gain was estimated using Gompertz extrapolation. Cost data relative to the expenditure for healthcare resources were obtained from published information (using the US average wholesale price for the acquisition cost of riluzole). Sensitivity testing assessed the impact of different cost-of-illness assumptions for treated and untreated patients. MAIN OUTCOME MEASURES AND RESULTS: Our primary analysis showed that treatment with riluzole significantly prolonged survival [death risk = 0.77; 95% confidence interval (CI): 0.62 to 0.96; p = 0.022]. The lifetime survival gain (including 3% annual discounting) was, on average, 2.3 months per patient, while the incremental cost was around $US12,000 per patient. Hence, the cost-effectiveness ratio of riluzole versus usual care without riluzole was $US62,609 per life-year gained (discounted dollars per discounted years; 95% CI: $US13,458 to $US205,714). The sensitivity analysis, considering different values of national cost for riluzole, suggested an interval for this parameter ranging from $US45,048 to $US62,609. CONCLUSIONS: Our study indicates that in patients with amyotrophic lateral sclerosis, riluzole has an unfavourable cost-effectiveness ratio or, at best, a borderline pharmacoeconomic profile.

Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials.

OBJECTIVES: To determine the effectiveness of ranitidine and sucralfate in the prevention of stress ulcer in critical patients and to assess if these treatments affect the risk of nosocomial pneumonia. DESIGN: Published studies retrieved through Medline and other databases. Five meta-analyses evaluated effectiveness in terms of bleeding rates (A: ranitidine v placebo; B: sucralfate v placebo) and infectious complications in terms of incidence of nosocomial pneumonia (C: ranitidine v placebo; D: sucralfate v placebo; E: ranitidine v sucralfate). Trial quality was determined with an empirical ad hoc procedure. MAIN OUTCOME MEASURES: Rates of clinically important gastrointestinal bleeding and nosocomial pneumonia (compared between the two study arms and expressed with odds ratios specific for individual studies and meta-analytic summary odds ratios). RESULTS: Meta-analysis A (five studies) comprised 398 patients; meta-analysis C (three studies) comprised 311 patients; meta-analysis D (two studies) comprised 226 patients: and meta-analysis E (eight studies) comprised 1825 patients. Meta-analysis B was not carried out as the literature search selected only one clinical trial. In meta-analysis A ranitidine was found to have the same effectiveness as placebo (odds ratio of bleeding 0.72, 95% confidence interval 0.30 to 1.70, P=0.46). In placebo controlled studies (meta-analyses C and D) ranitidine and sucralfate had no influence on the incidence of nosocomial pneumonia. In comparison with sucralfate, ranitidine significantly increased the incidence of nosocomial pneumonia (meta-analysis E: 1.35, 1.07 to 1.70, P=0.012). The mean quality score in the four analyses (on a 0 to 10 scale) ranged from 5.6 in meta-analysis E to 6.6 in meta-analysis A. CONCLUSIONS: Ranitidine is ineffective in the prevention of gastrointestinal bleeding in patients in intensive care and might increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. These findings are based on small numbers of patients, and firm conclusions cannot presently be proposed.

A uniform procedure for reimbursing the off-label use of antineoplastic drugs according to the value-for-money approach.

National healthcare systems as well as local institutions generally reimburse numerous off-label uses of anticancer drugs, but an explicit framework for managing these payments is still lacking. As in the case of on-label uses, an optimal management of off-label uses should be aimed at a direct proportionality between cost and clinical benefit. Within this framework, assessing the incremental cost/effectiveness ratio becomes mandatory, and measuring the magnitude of the clinical benefit (e.g. gain in overall survival or progression-free survival) is essential.This paper discusses how the standard principles of cost-effectiveness and value-for-money can be applied to manage the reimbursement of off-label treatments in oncology. It also describes a detailed operational scheme to appropriately implement this aim. Two separate approaches are considered: a) a trial-based approach, which is designed for situations where enough information is available from clinical studies about the expected effectiveness of the off-label treatment; b) an individualized payment-by-results approach, which is designed for situations in which adequate information on effectiveness is lacking; this latter approach requires that each patient receiving off-label treatment is followed-up to determine individual outcomes and tailor the extent of payment to individual results.Some examples of application of both approaches are presented in detail, which have been extracted from a list of 184 off-label indications approved in 2010 by the Region of tuscany in italy. these examples support the feasibility of the two methods proposed.In conclusion, the scheme described in this paper represents an operational solution to an unsettled problem in the area of oncology drugs.