Economic analysis of granulocyte colony stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial.

Considerable morbidity, mortality, and economic costs result during remission induction therapy for elderly patients with acute myeloid leukemia (AML). In this study, the economic costs of adjunct granulocyte colony stimulating factor (G-CSF) are estimated for AML patients > 55 years of age who received induction chemotherapy on a recently completed Southwest Oncology Group study (SWOG). Clinical data were based on Phase III trial information from 207 AML patients who were randomized to receive either placebo or G-CSF post-induction therapy. Analyses were conducted using a decision analytic model with the primary source of clinical event probabilities based on in-hospital care with or without an active infection requiring intravenous antibiotics. Estimates of average daily costs of care with and without an infection were imputed from a previously reported economic model of a similar population. When compared to AML patients who received placebo, patients who received G-CSF had significantly fewer days on intravenous antibiotics (median 22 vs. 26, p = 0.05), whereas overall duration of hospitalization did not differ (median 29 days). The median cost per day with an active infection that required intravenous antibiotics was estimated to be $1742, whereas the median cost per day without an active infection was estimated to be $1467. Overall, costs were $49,693 for the placebo group and $50,593 for the G-CSF patients. G-CSF during induction chemotherapy for elderly patients with AML had some clinical benefits, but it did not reduce the duration of hospitalization, prolong survival, or reduce the overall cost of supportive care. Whether the benefits of G-CSF therapy justify its use in individual patients with acute leukemia for the present remains a matter of clinical judgment.

The potential for treatment of idiopathic thrombocytopenic purpura with anti-D to prevent splenectomy: a predictive cost analysis.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder affecting both children and adults that can be manifested by severe bleeding episodes. Adult ITP patients have a low rate of spontaneous remission, and symptomatic patients commonly undergo splenectomy; however, maintenance therapy may increase the rate of remission, allowing splenectomy to be avoided. Anti-D is a recently licensed treatment for ITP that has the potential to delay, and possibly avoid, the need for splenectomy. We used preliminary data from an ongoing clinical trial to evaluate the costs involved in using anti-D therapy for 1 year with the intent of avoiding the need for splenectomy. We accounted for different possible outcomes at the completion of the clinical trial. An economic model with a theoretical cohort of 100 patients was developed using the model of an ongoing clinical trial. The average wholesale price was used to determine the cost of an infusion of anti-D based on an average dose ($1,213 per infusion). The cost of splenectomy was determined by a literature review ($16,000). Costs were calculated for all known patient outcomes; where outcomes were unknown and likely to vary, all possible outcomes were accounted for (splenectomy or no splenectomy). In our theoretical cohort, 31 of 100 patients were taken off anti-D and received splenectomy, 32 of 100 were stable after receiving anti-D and would not need splenectomy, and 37 of 100 had Indeterminate outcomes after receiving anti-D. When compared with the cost of the hypothetical scenario of initially giving all 100 patients splenectomy ($1.6 million), a minimum of 47 patients would have to avoid splenectomy to result in a cost savings for our cohort of 100 patients. The group of 47 patients avoiding splenectomy would be composed of the 32 patients comprising the stable group and at least 15 of the 37 patients comprising the group with indeterminate outcomes. If all 37 of the patients in the group with indeterminate outcomes avoid splenectomy, $363,000 and 69 spleens would be saved. Our data suggest that in the phase III trial of maintenance anti-D therapy versus immediate splenectomy, anti-D therapy will be a cost-effective option if 47% or more of patients avoid splenectomy.

Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490).

PURPOSE: Considerable morbidity and mortality and costs occur during induction therapy for acute myeloid leukemia (AML). Colony-stimulating factors (CSFs) can shorten neutropenia, and may lower costs. We performed a cost-minimization analysis of granulocyte macrophage colony stimulating factor (GM-CSF) for AML patients > 55 to 70 years of age during an Eastern Cooperative Oncology Group Study. PATIENTS AND METHODS: Clinical data were from a randomized double-blind phase III trial of 117 AML patients. Estimates of costs were from financial accounts from seven participating institutions. Costs were reported from the third party payor perspective. Analyses were conducted utilizing a decision analytic model. The primary source of event probabilities was in-hospital care with or without an active infection. Sensitivity analyses were also reported. RESULTS: When compared to AML patients who received placebo. GM-CSF patients had fewer grade 4-5 infections (9.6% versus 36.2%, P = 0.002) and grade 3-5 infections (52% versus 70%. P = 0.07) and $2.310 in savings. Sensitivity analyses indicated that similar cost estimates applied over a range of clinical and economic assumptions. CONCLUSIONS: This analysis can serve as a template for cooperative group cost analyses. Cooperation on study methodologies may allow for results that are relevant to both clinicians and policy makers.

Cost-effectiveness model of a phase II clinical trial of a new pharmaceutical for essential thrombocythemia: is it helpful to policy makers?

Essential thrombocythemia (ET) is a rare, chronic myeloproliferative disorder of unknown origin characterized by thrombocytosis, excessive megakaryocytes, hemorrhages, and thrombotic complications. Because of the high costs of care for persons with rare diseases, policymakers are concerned with both clinical effectiveness and cost-effectiveness of new treatments. Although the clinical efficacy of all new pharmaceutical agents for rare diseases is evaluated extensively in clinical trial settings before approval by the Food and Drug Administration (FDA), comparative phase III trials of a new agent with its major competitor are sometimes not possible to carry out, and estimates of cost-effectiveness are therefore difficult to obtain. We describe methodologic issues associated with the development of economic models of new pharmaceutical agents for rare diseases and illustrate these issues with an analysis of a new therapy for ET. Anagrelide is a newly approved platelet aggregation inhibitor that can be used as primary therapy for ET. The agent reduces platelet counts by 50% in more than 70% of ET patients. Economic models suggest that, over the first year of anagrelide therapy, monthly costs for therapy and complications decreased from $775 to $490, the effectiveness improved to 98%, and the cost-effectiveness improved to $1,505 per major complication (gastrointestinal bleed, transient ischemic attack or stroke, or preinfarction angina or myocardial infarction) prevented. Sensitivity analyses indicate that, after the first 3 months of treatment, total costs of anagrelide treatment were in the range of $1,505 to $1,615 per major complication prevented. To make well-informed therapeutic decisions, policymakers and physicians require head-to-head studies of a new pharmaceutical agent with its major competitor. However, economic models can be used to derive estimates of cost-effectiveness of new pharmaceutical agents when such data are lacking. The interpretation of these models raises general issues related to the perspective of the investigator, study design, estimation of costs of care, rates of response, toxicity, survival, and the ability to generalize the results to other settings, as well as methodologic issues that are unique to rare diseases. If a comparative study found better therapeutic outcomes, then cost-effectiveness models would be of limited usefulness. Almost all physicians would use the drug with the better therapeutic profile.

Cost-effectiveness analysis comparing liposomal anthracyclines in the treatment of AIDS-related Kaposi's sarcoma.

Liposomal formulations have been shown to alter the efficacy and toxicity profiles of anthracylines for patients with HIV-related advanced Kaposi's sarcoma (KS). Using decision-analysis models, the costs and cost-effectiveness of the two U.S. Food and Drug Administration (FDA)-approved liposomal formulations of these agents were estimated. Estimates of costs, effectiveness, and cost-effectiveness were derived from clinical trial data of separate, randomized phase III trials of pegylated liposomal doxorubicin (20 mg/m2 every 3 weeks) and liposomal daunorubicin (40 mg/m2 every 2 weeks). Clinical response rates were 59% for pegylated liposomal doxorubicin and 25% for liposomal daunorubicin. Despite higher acquisition costs for pegylated liposomal doxorubicin, total estimated costs of treatment for KS and chemotherapy-related hematologic toxicities were similar ($7,066 U.S. compared with $6,621 U.S. for liposomal daunorubicin). Cost-effectiveness profiles, defined as average costs per responder, favored pegylated liposomal doxorubicin ($11,976 U.S./responder versus $26,483 U.S./responder for liposomal daunorubicin), reflecting the higher reported response rate in the phase III trial. Sensitivity analyses suggested that the costs and cost-effectiveness results would not differ markedly when evaluated over a range of assumptions, including response rate, neutropenia rate, and dosage variations.

Accuracy of viscera slide detection of abdominal wall adhesions by ultrasound.

Viscera slide is the normal, longitudinal movement of the intraabdominal viscera caused by respiratory excursions of the diaphragm. By detecting areas of restricted viscera slide, ultrasonic imaging was used to identify anterior abdominal wall adhesions prior to laparotomy or laparoscopy. Transcutaneous ultrasound examination was performed on 110 patients. A prediction of adhesions was made for each patient and then compared to the findings during subsequent laparotomy or laparoscopy. Only patients with previous abdominal surgery or history of peritonitis demonstrated adhesions. Sensitivity and specificity of viscera slide ultrasound in predicting adhesions were 90% and 92%. Nine out of 10 false results involved misinterpretation of ultrasound images of the lower one-third of the abdomen. Ultrasonic imaging of viscera slide is highly accurate in detecting abdominal wall adhesions. This technique is most useful in guiding the insertion of trocar in laparoscopic surgery, and as a noninvasive method in studying the formation of adhesions.

Intimal hyperplasia producing thrombus organization in an experimental venous thrombosis model.

PURPOSE: A venous thrombosis animal model demonstrated similarities between intimal hyperplasia and thrombus organization. This has prompted the evaluation of a hypothesis that intimal hyperplasia may be the mechanism for thrombus organization in veins with normal pressure. METHODS: Thrombi were produced in surgically exposed jugular veins of anesthetized, 18 to 20 kg pigs. Thrombosis was induced by a combination of devascularization, electric injury produced by a low amperage, direct current, and permanent partial ligation (50% diameter reduction). Vein segments were harvested at 0, 1, 2, 7, 14, and 60 days and histologically examined for fibrin, red blood cells, platelets, smooth muscle cells, endothelial cells, elastic fibers, and collagen deposits. RESULTS: Forty vein segments in 20 pigs were evaluated. Luminal thrombi with thickened walls developed in all specimens. All luminal thrombi demonstrated partial spontaneous thrombolysis over the period of observation. Intimal thickening consisting primarily of smooth muscle cells by day 2 was apparent and progressed until about 2 weeks, when collagen deposits became prominent within the neointima. The neointima frequently comprised half the cross-sectional area of the veins. Endothelial cells were present in the intima as single cells or as lining for clefts formed within the thickened intima. CONCLUSIONS: Smooth muscle cell proliferation with collagen deposition characteristic of intimal hyperplasia seemed to be the mechanism of thrombus organization in the experimental thrombosis model used in this study in which extensive stimulation was used to produce thrombosis.

Differentiation of breast tumors by ultrasonic tissue characterization.

The ability of ultrasonic tissue characterization to differentiate and classify benign and malignant breast tissues in vivo in patients with palpable breast masses and in vitro in excised breast tissue was evaluated. One-hundred and twenty-four in vivo and 89 in vitro studies were performed using a technique of UTC based on parameters from the power spectrum of backscattered echoes. Sensitivities and specificities for diagnosing carcinoma were 86 and 84% for in vivo studies and 94 and 92% for in vitro studies. These UTC parameters provided threshold values for color-coding breast lesion images. The results of this preliminary investigation suggest that UTC provides a basis for assessing more accurately lesions suspected of being malignant prior to biopsy and possibly for evaluating breast lesions noninvasively.

Age determination of experimental venous thrombi by ultrasonic tissue characterization.

PURPOSE: The ability of ultrasonic tissue characterization based on radiofrequency signal processing to detect compositional differences in thrombi of varying ages was evaluated in vivo. METHODS: Thrombi were produced in 49 jugular veins of 26 anesthetized 18 to 20 kg pigs by partial ligation and application of direct electric current. Thrombi were imaged 30 minutes after formation and 1, 7, and 14 days later with a color Doppler ultrasound scanner that identified the thrombi, and acquired radio frequency data for ultrasonic tissue characterization analysis. Ultrasonic tissue characterization used two parameters from the normalized power spectrum, slope, and intercept, which are related to scatterer size, scatterer concentration, and acoustic-impedance differences between scatterers and surrounding medium. Previous in vitro studies demonstrated that lower slope and higher intercept values correlated with greater cellularity and more-dense fibrin mesh. Histologic examination was performed for each time period. The values of slope and intercept for each timed observation were compared by a multilinear discriminant analysis. RESULTS: There were no statistical differences between day 0 and day 1. Statistically-significant differences in ultrasonic tissue characterization parameters were seen between all other time intervals with p values < 0.01. Older thrombi tended to demonstrate higher slope and lower intercept values. These ultrasonic tissue characterization changes correlated with a red cell and fibrin-mesh density reduction, which was confirmed by histologic findings and was indicative of partial spontaneous thrombolysis. The degree of spontaneous thrombolysis provides an estimate of the age of thrombi. CONCLUSION: Ultrasonic tissue characterization is capable of distinguishing age differences in thrombi in an animal model and has the potential for noninvasive application in clinical diagnosis.

Ultrasonic tissue characterization of experimental venous intimal hyperplasia.

Ultrasonic tissue characterization (UTC) employing slope and Y-intercept parameters from the normalized power spectrum of backscattered echoes was employed in vivo to study compositional changes in the walls of pig jugular veins in which thrombi were experimentally induced. Light microscopy revealed these changes to be intimal hyperplasia with an early predominance of smooth muscle cells and a later mixture of smooth muscle cells and collagen deposits. UTC distinguished intimal hyperplasia from previously reported data from luminal thrombosis UTC. Furthermore, UTC was able to discriminate between early (predominantly smooth muscle cells) and older (smooth muscle cells plus collagen deposits) intimal hyperplasia. The study suggests that intimal hyperplasia in the experimental model used may be organized thrombus and that UTC may be able to follow both the development of wall changes as well as luminal changes occurring in venous thrombosis.

Effect of perfusion and blood content on ultrasonic backscattering of liver tissue.

The purpose of this study was to determine the effect of blood flow perfusion and red cell content on ultrasonic scattering by liver tissue. Data acquisition for ultrasonic tissue characterization (UTC) employing analysis of the backscattered echoes from the power spectrum was obtained from the same region of pig liver tissue under four conditions: 1) normal perfusion in situ, 2) ischemia in situ in the living pig, 3) ischemia in situ immediately postmortem, and 4) immediately after excision of the liver. Discriminant function analysis was used to evaluate differences in the two basic parameters from the normalized power spectrum: slope and intercept. Normal perfused liver had significantly higher intercept values and lower slope values than liver under the other three conditions. Excised liver showed the lowest intercept and highest slope values (p < 0.01). These experiments indicate that differences in perfusion produce significant differences in ultrasonic scattering by liver tissue (ischemia caused a 3 dB drop in intercept amplitude). Normal or ischemic in vivo and in vitro liver tissue is associated with different patterns of ultrasonic scattering, and scattering data under these various circumstances are not equivalent.

Ultrasonic detection of viscera slide as an indicator of abdominal wall adhesions.

Real-time ultrasonography can detect the movement of viscera immediately deep to the abdominal wall. This motion of abdominal contents is called viscera slide, and is produced by the force of respiratory motion (spontaneous viscera slide) or by manual ballottement of the abdomen (induced viscera slide). Viscera slide was observed in 18 "normal" subjects (no history of previous abdominal surgery or peritonitis) and in 24 subjects at "risk" for abdominal wall adhesions because of previous abdominal operations or past history of peritonitis. In 14 of the 24 "risk" group subjects, spontaneous and induced viscera slide was restricted to excursions of less than 1 cm (58.3%). Operations were performed on 18 patients, which confirmed the fact that restriction of ultrasonically detected viscera slide identified abdominal wall adhesions in all cases, but no adhesions were found in patients with normal viscera slide. This ultrasonic finding of restricted viscera slide may be useful in the preoperative discovery and localization of abdominal wall adhesions prior to laparoscopy or laparotomy.

Cellularity and fibrin mesh properties as a basis for ultrasonic tissue characterization of blood clots and thrombi.

This in vitro study was designed to evaluate the ability of ultrasonic tissue characterization (UTC) based on power spectrum analysis of backscattered radio-frequency echo signals to distinguish two prominent variables of thrombi: cellularity (primarily red cell content) and fibrin-mesh density. Six types of clots simulating thrombus components were prepared by varying red-cell and platelet concentrations and shear forces during clotting. Data were acquired with a linear-array transducer, digitized, and analyzed in terms of slope and intercept parameters obtained from normalized power spectra of radio-frequency echo signals. Increased cellularity and fibrin-mesh density both produced lower slope and higher intercept values, which permitted statistically significant discrimination of cellularity and mesh density in the six types of clots analyzed. Shearing forces and (to a lesser degree) platelet concentrations increased fibrin-mesh density. This study suggests that UTC based upon the power spectrum of echo signals may be used to detect and follow compositional differences that have clinical relevance in the diagnosis and follow-up of thrombi.

Technique of ultrasonic detection and mapping of abdominal wall adhesions.

A technique for noninvasive ultrasound examination to detect and map abdominal wall adhesions is described. The examination is based on the demonstration of movement of abdominal viscera during real-time imaging. This movement is called viscera slide and either occurs spontaneously as a result of respiratory movement or may be induced by manual compression. Abdominal wall adhesions produce a restriction of viscera slide. Ultrasonic demonstration of restricted viscera slide has been used for the precise localization and mapping of abdominal wall adhesions prior to abdominal surgery. The technique may be particularly useful in providing safe initial access in patients undergoing laparoscopy who are at increased risk for trocar injury of viscera due to abdominal wall adhesions resulting from previous surgery or peritonitis.

Role of oxygen-dependent mechanisms in monoclonal-antibody-induced lysis of normal T cells by phagocytes. II. Murine phagocytes.

In the first part of this study, we reported that antibody-dependent cellular cytotoxicity (ADCC) mediated by human polymorphonuclear (PMN) and mononuclear (MN) phagocytes against anti-T-cell monoclonal-antibody-(mAb)-coated T lymphocytes, is mainly dependent upon the generation of reactive oxygen intermediates (ROI) for PMN, whereas MN-mediated ADCC depends on both oxidative and non-oxidative cytolytic events. Using mouse effector cells from various organs and at various maturation or activation states, the present report shows that in this ADCC model against mAb-coated normal T cells, resident spleen (SPC) and peritoneal exudate (PEC) cells selectively bound and developed oxidative responses to these mAb-coated normal target cells but remained ineffective in ADCC. Similar data were obtained with inflammatory recruited (thioglycollate-elicited or Biogel granuloma-induced) macrophages, whereas immunologically activated macrophages (from BCG-treated mice) mediated both strong oxidative responses and potent ADCC reactions. In contrast, and as in the human system, both resident (from bone marrow) and inflammatory PMN phagocytes exerted significant lysis of these mAb-sensitized normal lymphoid cells. These findings, which are similar to those reported in ADCC against tumour target cells, strongly suggest that the nature (normal or tumoral) of the target cell does not influence the lytic mechanisms of macrophage-mediated ADCC and that these latter require activated macrophages and, like PMN, involve strong (if not exclusive) ROI participation.

Role of oxygen-dependent mechanisms in monoclonal antibody-induced lysis of normal T cells by phagocytes. I.--Human Phagocytes.

The present study investigates the lytic potential of the reactive oxygen species (ROS) which, as previously shown in our laboratory, are generated within the first minutes following the Fc-receptor-mediated interaction between phagocytic cells and anti-T-cell monoclonal-antibody (mAb)-coated T lymphocytes. A comparative study of ROS production (measured by chemiluminescence (CL] and the cytotoxic effect (evaluated in a 51Cr release antibody-dependent cellular cytotoxicity (ADCC) assay) of human polymorphonuclear (PMN) and mononuclear (MN) cells against mAb-coated autologous, allogeneic and xenogeneic (murine) thymocytes showed that the two reactions were closely interdependent for PMN and co-existed without significant correlation for MN cells. Catalase and superoxide dismutase did not modify ADCC results, suggesting that these ROS scavengers could not diffuse into the target cell destruction area. Colchicine treatment of PMN and MN cells at a dose inhibiting phagocytosis consistently impaired their CL generation and, in parallel, strongly reduced PMN-mediated ADCC but only weakly reduced that of MN cells. PMN and MN cells from 14 patients with chronic granulomatous disease (CGD) were not capable of producing CL after contact with mAb-coated T cells and showed significantly reduced ADCC activities, while PMN and MN cells from mothers carrying the X-linked type of CGD exhibited ADCC and oxidative responses of an intermediate level. We conclude that ADCC mediated by human PMN cells against T cells is mainly dependent upon the generation of ROS, whereas that induced by MN cells is most likely effected by both oxidative and non-oxidative events.

Effect of LPS on the oxidative metabolism of peritoneal and spleen cells from LPS sensitive and resistant mice.

The influence of LPS on peritoneal and spleen cell oxidative metabolism was investigated in LPS sensitive (C57BL/6) and LPS resistant (C3H/HeJ) mice following intraperitoneal or subcutaneous injection, by measurement of chemiluminescent (CL) responses to latex particles. In C57BL/6 mice, LPS induced a marked increase in peritoneal and spleen cell CL responses, regardless of the route of injection. On the 2nd day, the effect of LPS on peritoneal cells could be fully explained by an inflammatory reaction, while on the 4th day it could be related to an "activated state" of peritoneal macrophages. In contrast, such an in vivo effect of LPS in peritoneal or spleen cell CL responses was not found in C3H/HeJ mice except on the 2nd day following the injection and with the highest LPS dosage and could be totally due to the LPS induced inflammatory reaction. In vitro studies showed that extremely low concentration of LPS increased CL response capacities of C57BL/6 spleen cell to latex particles. In contrast, CL responses from C3H/HeJ spleen cells remained unaffected by LPS except when submitted to concentrations which proved toxic for the sensitive strain CL producing cells. These results lend additional evidence for the involvement of reactive oxygen species (ROS) in the metabolic consequences of LPS-induced macrophage activation.