Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting.

INTRODUCTION: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities associated with immunotherapies, including T cell redirecting bispecific antibodies. Although cooperative group guidelines recommend the use of tocilizumab or other IL-6/IL-6R inhibitors for the management of CRS and ICANS, reports on the use of siltuximab, an IL-6 inhibitor, for the treatment of CRS are limited. CASE REPORT: We present the case of a 77-year-old male who received T cell redirecting bispecific antibody therapy with talquetamab for relapsed/refractory multiple myeloma (RRMM) and developed CRS with concurrent ICANS after receiving a second dose of talquetamab. MANAGEMENT AND OUTCOME: The patient received an infusion of siltuximab. The patient recovered from CRS within 1 h of siltuximab administration and ICANS within 7 h of siltuximab administration. Patient tolerated the subsequent dose of talquetamab with no evidence of CRS and continued on study. DISCUSSION: This case describes the successful use of siltuximab for the management of CRS in a patient treated with a T cell redirecting bispecific antibody for RRMM.

Health-related quality of life in patients with relapsed or refractory multiple myeloma: treatment with daratumumab, lenalidomide, and dexamethasone in the phase 3 POLLUX trial.

In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient-reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires. Changes from baseline are presented as least-squares mean changes with 95% confidence intervals (CIs) derived from a mixed-effects model. PRO assessment compliance rates were high and similar in both D-Rd and Rd groups through cycle 40 (week 156). In this on-treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ-C30 global health status, physical functioning, and pain scores in the D-Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health-related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D-Rd treatment. These findings complement the sustained and significant improvement in progression-free survival observed with D-Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009.

Health-related quality of life maintained over time in patients with relapsed or refractory multiple myeloma treated with daratumumab in combination with bortezomib and dexamethasone: results from the phase III CASTOR trial.

In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D-Vd) significantly extended progression-free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient-reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed-effects model. After Cycle 8, PROs were only collected for patients in the D-Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ-C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health-related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long-term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D-Vd in patients with RRMM and support its use in this patient population.

Protocole of a controlled before-after evaluation of a national health information technology-based program to improve healthcare coordination and access to information.

BACKGROUND: Improvement of coordination of all health and social care actors in the patient pathways is an important issue in many countries. Health Information (HI) technology has been considered as a potentially effective answer to this issue. The French Health Ministry first funded the development of five TSN ("Territoire de Soins Numérique"/Digital health territories) projects, aiming at improving healthcare coordination and access to information for healthcare providers, patients and the population, and at improving healthcare professionals work organization. The French Health Ministry then launched a call for grant to fund one research project consisting in evaluating the TSN projects implementation and impact and in developing a model for HI technology evaluation. METHODS: EvaTSN is mainly based on a controlled before-after study design. Data collection covers three periods: before TSN program implementation, during early TSN program implementation and at late TSN program implementation, in the five TSN projects' territories and in five comparison territories. Three populations will be considered: "TSN-targeted people" (healthcare system users and people having characteristics targeted by the TSN projects), "TSN patient users" (people included in TSN experimentations or using particular services) and "TSN professional users" (healthcare professionals involved in TSN projects). Several samples will be made in each population depending on the objective, axis and stage of the study. Four types of data sources are considered: 1) extractions from the French National Heath Insurance Database (SNIIRAM) and the French Autonomy Personalized Allowance database, 2) Ad hoc surveys collecting information on knowledge of TSN projects, TSN program use, ease of use, satisfaction and understanding, TSN pathway experience and appropriateness of hospital admissions, 3) qualitative analyses using semi-directive interviews and focus groups and document analyses and 4) extractions of TSN implementation indicators from TSN program database. DISCUSSION: EvaTSN is a challenging French national project for the production of evidenced-based information on HI technologies impact and on the context and conditions of their effectiveness and efficiency. We will be able to support health care management in order to implement HI technologies. We will also be able to produce an evaluation toolkit for HI technology evaluation. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02837406 , 08/18/2016.

Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia.

BACKGROUND: Outcomes for children with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are dismal. In an effort to improve outcomes, we performed a phase I/II study of a novel clofarabine based combination regimen called TVTC. Herein, we report the response rates of patients in the phase II portion of the study. PROCEDURE: Seventeen patients with R/R ALL, AML, or biphenotypic leukemia were enrolled. Sixteen patients were evaluable for response. Patients were treated at the maximum tolerated dose (MTD) from the phase I portion of the study (clofarabine 40 mg/m(2) /day IV × 5 days, topotecan 1 mg/m(2) /day IV continuous infusion × 5 days, vinorelbine 20 mg/m(2) /week IV × 3 weeks, thiotepa 15 mg/m(2)/day IV × 1 day). The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). RESULTS: The ORR was 69% (10 CR, 1 CRp). Among the 11 responders, 9 (82%) proceeded to hematopoietic stem cell transplantation. The most common grade 3+ non-hematologic toxicities were febrile neutropenia (82%) and transient transaminase elevation (47%). CONCLUSIONS: TVTC demonstrates significant activity in patients with R/R acute leukemia. The activity in R/R AML patients was very encouraging, with 8 of 12 (67%) patients achieving a CR/CRp. Patients with high risk de novo AML may benefit from incorporation of TVTC therapy into frontline treatment regimens. This regimen warrants further exploration in a larger cohort of patients with R/R leukemia.

High-dose cyclophosphamide for the treatment of refractory T-cell acute lymphoblastic leukemia in children.

Despite an almost 80% overall survival rate in pediatric T-cell acute lymphoblastic leukemia (T-ALL), there is a subset of patients who are refractory to standard chemotherapy regimens and could benefit from novel treatment approaches. Over a 2-year period, we treated 5 pediatric patients with refractory T-ALL, aged 3 to 15 years, with high-dose cyclophosphamide (CY) at a dose of 2100 mg/m for 2 consecutive days either alone (n=1) or in combination with other chemotherapy agents (n=4). Four of these 5 patients had a 1.5 log decrease in disease burden. Three of the 5 patients had no evidence of minimal residual disease (MRD) after high-dose CY. One patient developed transient grade 4 transaminitis and 1 patient developed grade 3 typhlitis. All 5 patients ultimately proceeded to hematopoietic stem cell transplant when MRD levels were <0.01%. Pediatric T-ALL patients with persistent MRD after treatment with conventional chemotherapy may respond to CY at escalated dosing.

GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review.

Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell-redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell-redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell-redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary.

Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab.

BACKGROUND: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described. DISCUSSION: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies. CONCLUSION: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence.

Comparative Efficacy of Talquetamab vs. Current Treatments in the LocoMMotion and MoMMent Studies in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.

INTRODUCTION: Talquetamab, a bispecific antibody targeting GPRC5D × CD3, is approved for the treatment of patients with triple-class -exposed (TCE) relapsed/refractory multiple myeloma (RRMM) on the basis of the results from the phase I/II MonumenTAL-1 trial. The relative effectiveness of talquetamab vs. real-world physician's choice of therapy (RWPC) was assessed using adjusted comparisons. METHODS: An external control arm for MonumenTAL-1 (subcutaneously administered talquetamab 0.4 mg/kg weekly [QW] and 0.8 mg/kg every other week [Q2W]) was created from two observational real-world studies: LocoMMotion and MoMMent. Imbalances in baseline covariates were adjusted using inverse probability weighting. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR), and ≥ complete response (CR); odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional hazards model. RESULTS: After reweighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, patients treated with talquetamab QW (n = 143) had significantly improved outcomes vs. RWPC; RRs were ORR 2.67, p < 0.0001; ≥ VGPR 4.70, p < 0.0001; ≥ CR 78.05, p = 0.0002; and HRs were PFS 0.52, p < 0.0001; TTNT 0.48, p < 0.0001; OS 0.36, p < 0.0001. Patients treated with talquetamab Q2W (n = 145) also had significantly improved outcomes vs. RWPC; RRs were ORR 2.62, p < 0.0001; ≥ VGPR 5.04, p < 0.0001; ≥ CR 101.14, p = 0.0002; and HRs were PFS 0.40, p < 0.0001; TTNT 0.39, p < 0.0001; OS 0.37, p < 0.0001. CONCLUSION: Effectiveness of talquetamab for both schedules was significantly better than RWPC for ORR, ≥ VGPR, ≥ CR, PFS, OS, and TTNT, highlighting its clinical benefit for patients with TCE RRMM. TRIAL REGISTRATION: MonumenTAL-1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584.

Successful treatment of refractory metastatic histiocytic sarcoma with alemtuzumab.

BACKGROUND: Histiocytic sarcoma (HS) is an exceedingly rare tumor and carries a dismal prognosis when patients present with advanced-stage disease. Because of the poor response rates to conventional chemotherapy and the rarity of the disease, no standard of care exists for patients with HS. The authors report the single-agent use of the anti-CD52 antibody alemtuzumab in 2 patients who had advanced-stage HS. METHODS: Two patients with chemotherapy-refractory, metastatic HS with tumors that expressed the CD52 antigen received a prolonged course of treatment with the anti-CD52 monoclonal antibody alemtuzumab. RESULTS: Resected tumor samples from both patients demonstrated CD52 expression. Both patients had marked responses to single-agent alemtuzumab. One patient had a complete response with no evidence of disease for >5 years. The second patient had a major response to alemtuzumab and also remained alive with no evidence of disease for >4 years. CONCLUSIONS: Further studies need to be performed to examine CD52 expression and function in HS as well as the role of alemtuzumab in a larger cohort of patients. However, the clinical impact of single-agent alemtuzumab in the 2 patients described in this report was very encouraging. Given the toxicity and frequent inefficacy of conventional chemotherapy, patients with incompletely resected HS should be strongly considered for alemtuzumab therapy.

How well do diagnosis-related groups explain variations in costs or length of stay among patients and across hospitals? Methods for analysing routine patient data.

We set out an analytical strategy to examine variations in resource use, whether cost or length of stay, of patients hospitalised with different conditions. The methods are designed to evaluate (i) how well diagnosis-related groups (DRGs) capture variation in resource use relative to other patient characteristics and (ii) what influence the hospital has on their resource use. In a first step, we examine the influence of variables that describe each individual patient, including the DRG to which the patients are assigned and a range of personal and treatment-related characteristics. In a second step, we explore the influence that hospitals have on the average cost or length of stay of their patients, purged of the influence of the variables accounted for in the first stage. We provide a rationale for the variables used in both stages of the analysis and detail how each is defined. The analytical strategy allows us (i) to identify those factors that explain variation in resource use across patients, (ii) to assess the explanatory power of DRGs relative to other patient and treatment characteristics and (iii) to assess relative hospital performance in managing resources and the characteristics of hospitals that explain this performance.

Diagnosis related groups and variations in resource use for child delivery across 10 European countries.

Childbirth is one of the main causes of hospitalisation for women, accounting for about 5% of hospital activity in most Organisation for Economic Co-operation and Development countries. We analysed the factors that explain variations in resource use for child delivery in ten European countries. We compared the performance of three models for explaining the variations in resource use (log cost or length of inpatient stay) at patient and hospital level. The first model used only the DRGs to which child deliveries were coded (M(D) ), the second used a set of 'patient-level' and delivery specific explanatory variables (M(P) ), and the third model combined both sets of variables (M(F) ). Countries vary both in the number of DRGs and the criteria used to classify cases of child delivery (range: 3-8) and in the percentage of deliveries classified as 'delivery without complication' (range: 53-90%). The capacity of DRGs and patient level variables to explain cost variation for child birth ranges from 48% in Sweden to over 70% in Spain. There is room for improving current DRG classification in most countries, but this does not necessary imply multiplying the groups and/or complicating criteria. Countries with a higher number of DRGs do not always perform better.

How well do diagnosis-related groups for appendectomy explain variations in resource use? An analysis of patient-level data from 10 European countries.

Appendectomy is a common and relatively simple procedure to remove an inflamed appendix, but the rate of appendectomy varies widely across Europe. This paper investigates factors that explain differences in resource use for appendectomy. We analysed 106,929 appendectomy patients treated in 939 hospitals in 10 European countries. In stage 1, we tested the performance of three models in explaining variation in the (log of) cost of the inpatient stay (seven countries) or length of stay (three countries). The first model used only the diagnosis-related groups (DRGs) to which patients were coded, the second model used a core set of general patient-level and appendectomy-specific variables, and the third model combined both sets of variables. In stage two, we investigated hospital-level variation. In classifying appendectomy patients, most DRG systems take account of complex diagnoses and comorbidities but use different numbers of DRGs (range: 2 to 8). The capacity of DRGs and patient-level variables to explain patient-level cost variation ranges from 34% in Spain to over 60% in England and France. All DRG systems can make better use of administrative data such as the patient's age, diagnoses and procedures, and all countries have outlying hospitals that could improve their management of resources for appendectomy.

Does integrated care mean fewer hospitalizations? An evaluation of a French field experiment.

This study aims to evaluate the impact of an experimental healthcare policy on hospital use among elderly patients. From 2015 to 2017, French public authorities implemented an integrated care model, the Digital Health Territories (Territoire de Soins Numérique (TSN)) programme designed to improve healthcare coordination and sustain the use of health information (HI) technologies. The TSN programme was expected to reduce hospital healthcare utilization. In the Aquitaine region, the TSN programme was implemented in part of the Landes district and primarily consisted of the creation of a support platform (PTA). Part of the Lot-et-Garonne district was chosen as a "control area" due to its similarities to the experimental district in terms of the population structure and healthcare supply characteristics. In the control area, no integrated care model innovation was implemented over the study period. Using claims data from the French National Health Insurance (Système National d'Information Inter-Régimes de l'Assurance Maladie (SNIIRAM)), the healthcare utilization of the populations living in the experimental and control areas was tracked from 2012 to 2017. To estimate the impact of the TSN programme on three hospitalization outcomes, we used a combination of matching and difference-in-differences (DiD) approaches. The TSN programme shows a significant but weak negative impact on emergency department (ED) visits and no significant impact on 30-day re-hospitalizations (R30) or potentially avoidable hospitalizations (PAHs).

Economic vulnerability and unmet healthcare needs among the population aged 50 + years during the COVID-19 pandemic in Europe.

This study investigated the effect of economic vulnerability on unmet needs during the first wave of the coronavirus disease 2019 (COVID-19) epidemic in Europe among adults aged 50 years and older using data from the regular administration of the Survey of Health, Ageing and Retirement in Europe (SHARE) and the specific telephone survey administered regarding COVID-19 (SHARE Corona Survey). It addressed three main research questions: Did people who were in difficult economic situations before the epidemic face more barriers to accessing healthcare than others? If so, to what extent can these discrepancies be attributed to initial differences in health status, use of care, income or education between vulnerable individuals and non-vulnerable individuals or to differential effects of the pandemic on these groups? Did the effect of economic vulnerability with regard to unmet needs during the pandemic differ across countries? Unmet healthcare needs are characterised by three types of behaviours likely to be induced by the pandemic: forgoing care for fear of contracting COVID-19, having pre-scheduled care postponed and being unable to obtain medical appointments or treatments when needed. Our results substantiate the existence of significant differences in accessing healthcare during the pandemic according to economic vulnerability and of cumulative effects of economic and medical vulnerabilities: the impact of economic vulnerability is notably stronger among those who were in poor health before the outbreak and thus the oldest individuals. The cross-country comparison highlighted heterogeneous effects of economic vulnerability on forgoing care and having care postponed among countries, which are not comparable to the initial cross-country differences in social inequalities in access to healthcare. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-021-00645-3.

An evaluation of five regional health information technology-based programmes to improve health and social care coordination: A quasi-experimental controlled before/after mixed design.

OBJECTIVES: Health information technology (HIT) can help coordinate health and social actors involved in patients' pathways. We assess five regional HIT-based programmes ('Territoires de Soins Numériques' or TSN) introduced in France, covering the period 2012-2018. METHODS: This was a quasi-experimental controlled before/after mixed design. We used data from the French National Health Insurance database, qualitative and quantitative surveys, and information extracted from project documents and databases. We assessed the impact of TSN using four main impact indicators: emergency room visits, unplanned hospitalizations, avoidable hospitalizations and rehospitalization within 30 days. We also collected qualitative and secondary quantitative data covering perceived needs, knowledge, use, satisfaction, adoption and understanding of projects, pathway experience, impact on professional practices and appropriateness of hospitalizations. RESULTS: TSN implemented a heterogeneous mix of HIT. Implementation was slower than expected and was not well documented. Users perceived the HIT as having a positive but weak overall effect. There were no significant differences in trends for the main impact indicators, nor on the appropriateness of hospitalizations, but favourable trends on secondary polypharmacy indicators. CONCLUSIONS: If similar innovations take place in future, they should be based on a logical framework that defines causal, measurable links between services provided and expected impacts.

Childhood Cancer in Rhode Island.

The incidence rate of childhood cancer is increasing in the United States. We sought to describe the epidemiology of childhood cancer in the state of Rhode Island. Data from the Rhode Island Cancer Registry was reviewed to assess incidence and trends in childhood cancer for individuals age 0-19 years from 1995-2015. Cancer mortality was based on deaths with cause of deaths associated with malignant cancers filed with the Rhode Island Vital Records and CDC National Center for Health Statistics. We found that pediatric cancer is increasing in Rhode Island. Between 1995-2015, there were 1,090 new diagnoses of childhood cancer. Leukemia, tumors of the central nervous system, and lymphomas are the most common types of cancer in children in the state. Additionally, the overall mortality rate from childhood cancer is decreasing. In conclusion, the childhood cancer trends in Rhode Island are consistent with the national data. [Full article available at http://rimed.org/rimedicaljournal-2019-02.asp].

Cost of illness: an international comparison. Australia, Canada, France, Germany and The Netherlands.

OBJECTIVES: To assess international comparability of general cost of illness (COI) studies and to examine the extent to which COI estimates differ and why. METHODS: Five general COI studies were examined. COI estimates were classified by health provider using the system of health accounts (SHA). Provider groups fully included in all studies and matching SHA estimates were selected to create a common data set. In order to explain cost differences descriptive analyses were carried out on a number of determinants. RESULTS: In general similar COI patterns emerged for these countries, despite their health care system differences. In addition to these similarities, certain significant disease-specific differences were found. Comparisons of nursing and residential care expenditure by disease showed major variation. Epidemiological explanations of differences were hardly found, whereas demographic differences were influential. Significant treatment variation appeared from hospital data. CONCLUSIONS: A systematic analysis of COI data from different countries may assist in comparing health expenditure internationally. All cost data dimensions shed greater light on the effects of health care system differences within various aspects of health care. Still, the study's objectives can only be reached by a further improvement of the SHA, by international use of the SHA in COI studies and by a standardized methodology.