Adding docetaxel to cisplatin and fluorouracil in patients with unresectable head and neck cancer: a cost-utility analysis.

BACKGROUND: Adding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost-utility of TPF in patients with unresectable disease. DESIGN: We developed a Markov model to represent patient's weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5-year temporal horizon was adopted and a 3.5% yearly discount rate was applied. RESULTS: When compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of €11,822/QALY for TAX 323 and €6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of €50,000/QALY saved. CONCLUSIONS: In our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions.

Long-term cost-effectiveness of low molecular weight heparin versus unfractionated heparin for the prophylaxis of venous thromboembolism in elective hip replacement.

BACKGROUND AND OBJECTIVE: Either low molecular weight heparin (LMWH) or unfractionated heparin (UH) may be used for the prophylaxis of post-operative venous thromboembolic disease (VTD) in elective hip replacement. This study was aimed at assessing the cost-effectiveness of LMWH over UH from the society perspective, which considers all the outcomes occurring in the life-long time horizon. DESIGN AND METHODS: A decision tree modeled the clinical outcomes and resources used in consequence of restricted (2 weeks) and extended (4 weeks) prophylaxis of VTD with LMWH or UH. RESULTS: In the studied population, that of 67 year-old patients, restricted prophylaxis with LMWH saved 25 quality-adjusted days and $75 over UH. Extended prophylaxis provided a small additional benefit with additional cost savings. The incremental outcomes of the model proved independent of most parameters. INTERPRETATION AND CONCLUSIONS: We conclude that LMWH has considerable advantages over UH in the prophylaxis of VTD following elective hip replacement, and should be recommended in clinical practice.

The Italian Consensus Conference on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia.

The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.

Cost-effectiveness of recombinant human erythropoietin in the prevention of chemotherapy-induced anaemia.

Recombinant human erythropoietin (rHuEPO) has been advocated for the treatment of anaemia in patients submitted to cancer chemotherapy. We used decision analysis to compare the cost-effectiveness of rHuEPO supplemented with red blood cell (RBC) transfusions with conventional treatment with RBC transfusions alone. At baseline, we analysed the use of rHuEPO as secondary prophylaxis according to effectiveness estimates from a community-based oncology study. In order to reduce the probability of transfusions from 21.9% to 10.4%, and the number of RBC units per patient per month from 0.55 to 0.29, 150 units kg(-1) s.c. rHuEPO three times per week for 4 months resulted in an incremental cost of $189,652 per quality-adjusted life year (QALY). In patients treated with cisplatin-containing chemotherapy, rHuEPO added $190,142 per QALY. In a hypothetical scenario of a transfusion pattern that maintained the same haemoglobin level of rHuEPO-responsive patients, the marginal cost of rHuEPO was always greater than $100,000 per QALY. Results were stable with regard to variations in the probability of blood-borne infections, quality of life of responding patients and cancer-related mortality. The additional cost could be lowered to less than $100,000 per QALY by saving 4.5 RBC units over 4 months for any patient treated. In conclusion, according to current use, rHuEPO is not cost-effective in the treatment of chemotherapy-induced anaemia. More tailored utilization of the drug and better consideration of predictive response indicators may lead to an effective, blood-sparing alternative.

Cost-effectiveness of interferon alfa in chronic myelogenous leukemia.

PURPOSE: To evaluate the cost-effectiveness of interferon alfa (IFN alpha) treatment of patients with chronic myelogenous leukemia relative to conventional chemotherapy. MATERIALS AND METHODS: A decision-analysis model that involved a multistate Markov process was designed to estimate the expected cost and quality-adjusted life expectancies for two cohorts of patients to be administered conventional chemotherapy or IFN alpha. Two IFN alpha strategies were modeled: prolonged treatment for patients who achieved a hematologic response (scenario A) or only for patients who achieved a cytogenetic remission in a 2-year period (scenario B). Data on response and transition probabilities between health states were obtained from the literature by a MEDLINE search and pooled with a meta-analytic method. Costs were based on local charges. Expected survival was adjusted for quality of life on the basis of an expert panel judgment. RESULTS: Baseline analysis showed IFN alpha treatment to increase the quality-adjusted life expectancy by 15.5 and 12.5 months relative to conventional chemotherapy, in scenarios A and B, respectively. Marginal cost-effectiveness was $89,500 and $63,500 per quality-adjusted life-year (QALY) gained. Sensitivity analysis confirmed IFN alpha as the most effective approach. Cost-effectiveness results were sensitive to the cost of IFN alpha therapy and to the assumptions about the rate of cytogenetic remission. Reducing the drug dose, as suggested by a recent report, would decrease the marginal cost-effectiveness to less than $20,000. CONCLUSION: IFN alpha is substantially superior to conventional chemotherapy in terms of quality-adjusted survival, but, at the current doses, marginal cost-effectiveness ranges from $50,000 to $100,000 per QALY gained under most of our assumptions.

Autoimmune hemolytic anemia in multicentric Castleman's disease.

We report on a patient affected by multicentric Castleman's disease who developed an acute immunohemolytic anemia due to warm antibody. The clinical course was characterized by refractoriness to the steroidal treatment and by a dramatic improvement of the hematological and objective picture following combination chemotherapy (CHOP regimen). The possible existence of a link between the lymphoproliferative syndrome and the immunological derangement is also discussed.

Regulation of erythropoietin production in a case of congenital erythropoietin-dependent pure erythrocytosis.

In a patient with congenital erythropoietin-dependent pure erythrocytosis (EDPE) associated with hypersensitivity of erythroid progenitor cells to erythropoietin (Epo), the investigations planned to elucidate the mechanism responsible for hormone hyperproduction revealed that Epo synthesis was (1) independent of normal oxygen-mediated feedback induced by phlebotomy; (2) not modulated by adenosine as a second messenger (the treatment with the adenosine antagonist theophylline in fact left unchanged the serum Epo levels); and (3) uninfluenced by iron therapy. The Epo dose-response curve for growth of erythroid progenitor was similar to that of three age-matched thalassemia patients with increased serum Epo levels, (sEpo) suggesting that the observed erythroid progenitors hypersensitivity to Epo could represent an ex vivo artifact induced by the increased sEpo levels.

Serum erythropoietin and erythropoiesis in high- and low-fetal hemoglobin beta-thalassemia intermedia patients.

Clinical data suggest that in beta-thalassemia-intermedia patients, higher levels of circulating fetal hemoglobin (HbF) are associated with greater disease severity at comparable degrees of anemia. We assessed the influence of the amount of circulating HbF on serum erythropoietin (s-Epo) levels and on serum transferrin receptor, a measure of erythropoiesis, in 30 beta-thalassemia-intermedia patients. Twenty-four showed more than 40% HbF (21 of whom with beta (0)-thalassemia) and 6 presented lower HbF levels (beta(+)-thalassemia). The two groups of patients did not differ in age (15.3 v 19 years, respectively) or degree of anemia (Hb = 8.8 g/dL in both groups). Log (s-Epo) was correlated inversely with Hb (r = -0.47; P < .01), and directly with HbF (r = .55; P < .001). Multivariate regression analysis showed that Hb and HbF were independently correlated with s-Epo levels. High-HbF patients had greater s-Epo values at the same Hb level than low-HbF patients. Considering that iron-deficiency anemia control patients represented the predicted physiologic response of s-Epo to anemia, the observed/predicted s-Epo ratio in low-HbF thalassemic patients was no different from controls, but was increased in the high-HbF group. High-HbF patients also showed an expansion of erythropoiesis as much as four to nine times the normal value at the same Hb level as low-HbF patients. We conclude that HbF exerts an independent regulatory effect on erythropoietin production and erythropoiesis that is detectable only when HbF levels exceed 40%.

Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction.

Since according to the early studies, the outcome after splenectomy in the individual patient with myelofibrosis with myeloid metaplasia (MMM) is unpredictable, we assessed retrospectively the pre-intervention characteristics that best predicted adverse events, hematological consequences, and survival in 71 splenectomized MMM patients. The findings indicate that the operative risk of splenectomy for both mortality (8.4%) and morbidity (39.3%) was unpredictable. New hemorrhagic or thrombotic complications occurred in 16.9% of surviving patients and were predicted by age < 50 years, a normal to high platelet count (> 200 x 10(9)/l) and huge splenomegaly (> 16 cm from the costal margin). Massive liver enlargement occurred in 24% of patients and has to be expected in patients splenectomized for transfusion-dependent anemia. Anemia improved substantially in 45% and 52% of patients at 3 months and at 1 year, respectively, and was predicted by severe anemia, low platelet count (< 100 x 10(9)/l) or normal to high white blood cell (WBC) count (> 4 x 10(9)/l). Survival from splenectomy was superior in patients < 45 years with WBC < 10 x 10(9)/l count. An unexpectedly high rate of blastic transformation was observed. It accounted for 42.8% of the deaths. The results suggest trials for prophylactic cytoreductive treatment in young patients and when platelet count is normal to increased. Further study is needed for elucidating the possible role played by splenectomy in inducing blastic transformation.

Variations in erythropoiesis and serum ferritin during erythropoietin therapy for anaemia of end-stage renal disease.

In order to study the relationship between erythropoiesis and serum ferritin (SF) during erythropoietin (rHuEPO) therapy in the anaemia of end-stage renal disease (ESRD), 19 patients were followed without iron supplementation and at a fixed dose of the drug (40 U/kg). Twelve patients failed to attain the target haemoglobin (Hb) value, 7 of whom due to the appearance of iron deficiency. Erythropoiesis, as measured by the serum transferrin receptor concentration, increased from 12 to 120% of the basal value. This increment was not constantly associated with a proportional rise of Hb or reticulocyte count. SF decreased exponentially from a median value of 221 micrograms/dl (range 42-470) to a median value of 54 micrograms/dl (range 20-172). Halving of the basal SF value (SF-T50) was reached at the 18th-95th day of therapy (median = 43), representing a iron shift of 3.4-11.6 mg/day (median = 5.4). SF-T50 was not correlated with the Hb increase, but with that of erythropoiesis (r = 0.78; p = 0.003). The minimum SF (MSF) value attained was not correlated with the appearance of iron deficiency. The conclusion is that the rate of SF decrease during rHuEPO in ESRD is a reliable measure of iron mobilisation for erythropoiesis, but not for haematologic response. The MSF value reached during therapy is not representative of available iron for erythropoiesis.

Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial.

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.

Erythropoietin: biological aspects and clinical usefulness.

In the eighties there has been an enormous increase in our knowledge about erythropoietin, previously defined as "an elusive hormone". In this review we summarize the structural and molecular features, the mechanisms of production and of metabolism, the more important methods of assay, the mechanism of action and the biological effects, the main pathophysiological aspects and the therapeutic usefulness of the hormone.

POEMS syndrome with IgA lambda monoclonal gammopathy.

The various association of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes has been called the POEMS syndrome. Herein we report a case in which all the typical clinical and laboratory findings of the POEMS syndrome were present. We emphasize as the most striking features of our case the following: the similarity with scleroderma, the peripheral nerve demyelination without the presence of antibodies against nerve components, the occurrence of an IgA lambda monoclonal gammopathy and Castleman-like features at a single enlarged lymph node. To our knowledge, this is the first such case reported in Italy.

Myelofibrosis with myeloid metaplasia following essential thrombocythaemia.

We report a male patient in whom a diagnosis of essential thrombocythaemia was made at the age of 25. The clinical course was characterised by recurrent thrombotic episodes during the first few years of the disease, followed by a relatively benign course. He was treated with 32P, nitrogen mustard and plateletpheresis. A transformation into myelofibrosis with myeloid metaplasia was revealed 20 years after ET diagnosis. The length of the disease and the 32P therapy are discussed as factors favouring this metamorphosis.