Utilisation of radiotherapy in lung cancer: A scoping narrative literature review with a focus on the introduction of evidence-based therapeutic approaches in Europe.

Background and purpose: The aim of this study was to review the published studies on the utilisation of radiotherapy in lung cancer (both small and non-small cell lung cancer, SCLC and NSCLC) patients in European countries with a population-based perspective. Material and methods: A literature search since January 2000 until December 2022 was carried out. Only English-published papers were included, and only European data was considered. PRISMA guidelines were followed. A scoping narrative review was undertaken due to the hetereogeneity of the published papers. Results: 38 papers were included in the analysis, with the majority from the Netherlands (52.6%) and the UK (18.4%). Large variability is observed in the reported radiotherapy utilisation, around 40% for NSCLC in general and between 26 and 42% in stage I NSCLC. Stereotactic body radiotherapy (SBRT) shows a wide range of utilisation across countries and over time, from 8 to 63%. Similary, in stage III lung cancer, chemoradiotherapy (CRT) utilisation varied considerably (11-70%). Eleven studies compared radiotherapy utilisation between older and younger age-groups, showing that younger patients receive more CRT, while the opposite applies for SBRT. An widespreadlack of data on relevant covariates such as comorbidty and health-services related variables is observed. Conclusion: The actual utilisation of radiotherapy for lung cancer reported in patterns-of-care studies (POCs) is notably lower than the evidence-based optimal utilisation. Important variability is observed by country, time period, stage at diagnosis and age. A wider use of POCs should be promoted to improve our knowledge on the actual application of evidence-based treatment recommendations.

Changes in Treatment Patterns and Costs for Lung Cancer Have Not Resulted in Relevant Improvements in Survival: A Population-Based Observational Study in Catalonia.

OBJECTIVE: Few published studies have described multidisciplinary therapeutic strategies for lung cancer. This study aims to describe the different approaches used for treating lung cancer in Catalonia in 2014 and 2018 and to assess the associated cost and impact on patient survival. METHODS: A retrospective observational cohort study using data of patients with lung cancer from health care registries in Catalonia was carried out. We analyzed change in treatment patterns, costs and survival according to the year of treatment initiation (2014 vs. 2018). The Kaplan-Meier method was used to estimate survival, with the follow-up until 2021. RESULTS: From 2014 to 2018, the proportion of patients undergoing surgery increased and treatments for unresectable tumors decreased, mainly in younger patients. Immunotherapy increased by up to 9% by 2018. No differences in patient survival were observed within treatment patterns. The mean cost per patient in the first year of treatment increased from EUR 14,123 (standard deviation [SD] 4327) to EUR 14,550 (SD 3880) in surgical patients, from EUR 4655 (SD 3540) to EUR 5873 (SD 6455) in patients receiving curative radiotherapy and from EUR 4723 (SD 7003) to EUR 6458 (SD 10,116) in those treated for unresectable disease. CONCLUSIONS: From 2014 to 2018, surgical approaches increased in younger patients. The mean cost of treating patients increased, especially in pharmaceutical expenditure, mainly related to the use of several biomarker-targeted treatments. While no differences in overall patient survival were observed, it seems reasonable to expect improvements in this outcome in upcoming years as more patients receive innovative treatments.

Innovation, value and reimbursement in radiation and complex surgical oncology: Time to rethink.

BACKGROUND AND PURPOSE: Complex surgery and radiotherapy are the central pillars of loco-regional oncology treatment. This paper describes the reimbursement schemes used in radiation and complex surgical oncology, reports on literature and policy reviews. MATERIAL AND METHODS: A systematic review of the literature of the reimbursement models has been carried out separately for radiotherapy and complex cancer surgery based on PRISMA guidelines. Using searches of PubMed and grey literature, we identified articles from scientific journals and reports published since 2000 on provider payment or reimbursement systems currently used in radiation oncology and complex cancer surgery, also including policy models. RESULTS: Most European health systems reimburse radiotherapy using a budget-based, fee-for-service or fraction-based system; while few reimburse services according to an episode-based model. Also, the reimbursement models for cancer surgery are mostly restricted to differences embedded in the DRG system and adjustments applied to the fees, based on the complexity of each surgical procedure. There is an enormous variability in reimbursement across countries, resulting in different incentives and different amounts paid for the same therapeutic strategy. CONCLUSION: A reimbursement policy, based on the episode of care as the basic payment unit, is advocated for. Innovation should be tackled in a two-tier approach: one defining the common criteria for reimbursement of proven evidence-based interventions; another for financing emerging innovation with uncertain definitive value. Relevant clinical and economic data, also collected real-life, should support reimbursement systems that mirror the actual cost of evidence-based practice.

Innovation, value and reimbursement in radiation and complex surgical oncology: Time to rethink.

BACKGROUND AND PURPOSE: Complex surgery and radiotherapy are the central pillars of loco-regional oncology treatment. This paper describes the reimbursement schemes used in radiation and complex surgical oncology, reports on literature and policy reviews. MATERIAL AND METHODS: A systematic review of the literature of the reimbursement models has been carried out separately for radiotherapy and complex cancer surgery based on PRISMA guidelines. Using searches of PubMed and grey literature, we identified articles from scientific journals and reports published since 2000 on provider payment or reimbursement systems currently used in radiation oncology and complex cancer surgery, also including policy models. RESULTS: Most European health systems reimburse radiotherapy using a budget-based, fee-for-service or fraction-based system; while few reimburse services according to an episode-based model. Also, the reimbursement models for cancer surgery are mostly restricted to differences embedded in the DRG system and adjustments applied to the fees, based on the complexity of each surgical procedure. There is an enormous variability in reimbursement across countries, resulting in different incentives and different amounts paid for the same therapeutic strategy. CONCLUSION: A reimbursement policy, based on the episode of care as the basic payment unit, is advocated for. Innovation should be tackled in a two-tier approach: one defining the common criteria for reimbursement of proven evidence-based interventions; another for financing emerging innovation with uncertain definitive value. Relevant clinical and economic data, also collected real-life, should support reimbursement systems that mirror the actual cost of evidence-based practice.

How public health services pay for radiotherapy in Europe: an ESTRO-HERO analysis of reimbursement.

Reimbursement is a key factor in defining which resources are made available to ensure quality, efficiency, availability, and access to specific health-care interventions. This Policy Review assesses publicly funded radiotherapy reimbursement systems in Europe. We did a survey of the national societies of radiation oncology in Europe, focusing on the general features and global structure of the reimbursement system, the coverage scope, and level for typical indications. The annual expenditure covering radiotherapy in each country was also collected. Most countries have a predominantly budgetary-based system. Variability was the major finding, both in the components of the treatment considered for reimbursement, and in the fees paid for specific treatment techniques, fractionations, and indications. Annual expenses for radiotherapy, including capital investment, available in 12 countries, represented between 4·3% and 12·3% (average 7·8%) of the cancer care budget. Although an essential pillar in multidisciplinary oncology, radiotherapy is an inexpensive modality with a modest contribution to total cancer care costs. Scientific societies and policy makers across Europe need to discuss new strategies for reimbursement, combining flexibility with incentives to improve productivity and quality, allowing radiation oncology services to follow evolving evidence.

First Report of Bacillary Angiomatosis by Bartonella elizabethae in an HIV-Positive Patient.

We present the case of an HIV-positive patient who developed polymorphous lesions in which the evidence in the skin biopsy corresponds to the diagnosis of bacillary angiomatosis, and further tests proved the pathological agent involved in this case is not the usual Bartonella species, B. henselae and B. quintana, but B. elizabethae. As far as we know, this is the first case of bacillary angiomatosis secondary to this etiological agent.

Estimating the number of fractions by tumour site for European countries in 2012 and 2025: An ESTRO-HERO analysis.

BACKGROUND AND PURPOSE: The optimal number of radiotherapy fractions is a relevant input for planning resource needs. An estimation of the total number of fractions by country and tumour site is assessed for 2012 and 2025. METHODS: European cancer incidence data by tumour site and country for 2012 and 2025 were extracted from the GLOBOCAN database. Incidence and stage data were introduced in the Australian Collaboration for Cancer Outcomes Research and Evaluation (CCORE) model, producing an evidence-based proportion of incident cases with an indication for radiotherapy and fractions by indication. An indication was defined as a clinical situation in which radiotherapy was the treatment of choice. RESULTS: The total number of fractions if radiotherapy was given according to guidelines to all patients with an indication in Europe was estimated to be 30 million for 2012; with a forecasted increase of 16.1% by 2025, yet with differences by country and tumour. The average number of fractions per course was 17.6 with a small range of differences following stage at diagnosis. Among the treatments with radical intent the average was 24 fractions, while it decreased to 2.5 among palliative treatments. DISCUSSION: An increase in the total number of fractions is expected in many European countries in the coming years following the trends in cancer incidence. In planning radiotherapy resources, these increases should be balanced to the evolution towards hypofractionation, along with increased complexity and quality assurance.

Hacia la concentración de la cirugía oncológica digestiva: cambios en la actividad, las técnicas y los resultados / Towards the centralization of digestive oncologic surgery: changes in activity, techniques and outcome

Objetivo: se examinaron los cambios en actividad, técnicas quirúrgicas y resultados del proceso de concentración de la cirugía oncológica digestiva compleja entre 2005-2012 en relación a 1996-2000. Material y métodos: se realizó un estudio de cohortes retrospectivo a partir del Conjunto Mínimo Básico de Datos (CMBD) al alta hospitalaria (1996-2012) de centros públicos de Catalunya. Población > 18 años intervenida de cáncer de: esófago, páncreas, hígado, estómago y recto. Los centros se clasificaron en: bajo, medio y alto volumen (≤ 5, 6-10 y > 10 procedimientos/año, respectivamente). Utilización del test tendencia Chi-cuadrado para valorar la concentración de pacientes en centros de alto volumen y la evolución de la mortalidad hospitalaria y regresión logística para estudiar la relación entre volumen y resultado en el periodo de concentración (2005-2012). Resultados: se ha producido una progresiva concentración de la cirugía oncológica digestiva compleja, mediante la reducción de entre un 10% (hígado) y 46% (esófago) del número de hospitales que realizan estas intervenciones y el aumento significativo del porcentaje de pacientes intervenidos en centros de alto volumen (todas las p tendencia < 0,0001, excepto esófago). También se observa una reducción significativa de la mortalidad, especialmente en esófago (de 15% en 1996/2000 a 7% en 2009/12, p tendencia = 0,003) y páncreas (de 12% en 1996/2000 a 6% en 2009/2012, p tendencia < 0,0001). Conclusiones: se ha producido una concentración efectiva de la cirugía oncológica digestiva en Cataluña en centros de alto volumen que se ha acompañado de una reducción de la mortalidad hospitalaria clara en esófago y páncreas, aunque sin cambios significativos en los otros cánceres estudiados (AU)

Aim: The objective of the present study was to examine changes in the activity, surgical techniques and results from the process of centralization of complex digestive oncologic surgery in 2005-2012 as compared to 1996-2000. Material and methods: A retrospective cohort study employing the minimum basic data set of hospital discharge (MBDSHD 1996-2012) from public centers in Catalonia (Spain) was performed. The population consisted of individuals aged > 18 who underwent digestive oncologic surgery (esophagus, pancreas, liver, stomach or rectum). Medical centers were divided into low, medium, and high-volume centers (≤ 5, 6-10, and > 10 interventions/year, respectively). The tendency Chi-squared test was used to assess the centralization of patients in high-volume centers and hospital mortality evolution during the study period. Logistic regression was performed to assess the relationship between volume and outcome. Results: A centralization of complex oncologic digestive surgery between 10% (liver) and 46% (esophagus) was obtained by means of a reduction in the number of hospitals that perform these interventions and a significant rise in the number of patients operated in high-volume centers (all types p ≤ 0.0001, except for esophagus). A significant decrease in mortality was observed, especially in esophagus (from 15% in 1996/2000 to 7% in 2009/12, p = 0.003) and pancreas (from 12% in 1996/2000 to 6% in 2009/12, p trend < 0.0001). Conclusions: A centralization of oncologic digestive surgery in high-volume centers and a reduction of hospital mortality in Catalonia were reported among esophageal and pancreatic cancers. However, no significant changes were found for others cancer types (AU)

Towards the centralization of digestive oncologic surgery: changes in activity, techniques and outcome.

AIM: The objective of the present study was to examine changes in the activity, surgical techniques and results from the process of centralization of complex digestive oncologic surgery in 2005-2012 as compared to 1996-2000. MATERIAL AND METHODS: A retrospective cohort study employing the minimum basic data set of hospital discharge (MBDSHD 1996-2012) from public centers in Catalonia (Spain) was performed. The population consisted of individuals aged > 18 who underwent digestive oncologic surgery (esophagus, pancreas, liver, stomach or rectum). Medical centers were divided into low, medium, and high-volume centers (≤ 5, 6-10, and > 10 interventions/year, respectively). The tendency Chi-squared test was used to assess the centralization of patients in high-volume centers and hospital mortality evolution during the study period. Logistic regression was performed to assess the relationship between volume and outcome. RESULTS: A centralization of complex oncologic digestive surgery between 10% (liver) and 46% (esophagus) was obtained by means of a reduction in the number of hospitals that perform these interventions and a significant rise in the number of patients operated in high-volume centers (all types p ≤ 0.0001, except for esophagus). A significant decrease in mortality was observed, especially in esophagus (from 15% in 1996/2000 to 7% in 2009/12, p = 0.003) and pancreas (from 12% in 1996/2000 to 6% in 2009/12, p trend < 0.0001). CONCLUSIONS: A centralization of oncologic digestive surgery in high-volume centers and a reduction of hospital mortality in Catalonia were reported among esophageal and pancreatic cancers. However, no significant changes were found for others cancer types.

How many new cancer patients in Europe will require radiotherapy by 2025? An ESTRO-HERO analysis.

BACKGROUND: The objective of this HERO study was to assess the number of new cancer patients that will require at least one course of radiotherapy by 2025. METHODS: European cancer incidence data by tumor site and country for 2012 and 2025 was extracted from the GLOBOCAN database. The projection of the number of new cases took into account demographic factors (age and size of the population). Population based stages at diagnosis were taken from four European countries. Incidence and stage data were introduced in the Australian Collaboration for Cancer Outcomes Research and Evaluation (CCORE) model. RESULTS: Among the different tumor sites, the highest expected relative increase by 2025 in treatment courses was prostate cancer (24%) while lymphoma (13%), head and neck (12%) and breast cancer (10%) were below the average. Based on the projected cancer distributions in 2025, a 16% expected increase in the number of radiotherapy treatment courses was estimated. This increase varied across European countries from less than 5% to more than 30%. CONCLUSION: With the already existing disparity in radiotherapy resources in mind, the data provided here should act as a leverage point to raise awareness among European health policy makers of the need for investment in radiotherapy.

Long-term costs of colorectal cancer treatment in Spain.

BACKGROUND: Assessing the long-term cost of colorectal cancer (CRC) increases our understanding of the disease burden. The aim of this paper is to estimate the long-term costs of CRC care by stage at diagnosis and phase of care in the Spanish National Health Service. METHODS: Retrospective study on resource use and direct medical cost of a cohort of 699 patients diagnosed and treated for CRC in 2000-2006, with follow-up until 30 June 2011, at Hospital del Mar (Barcelona). The Kaplan-Meier sample average estimator was used to calculate observed 11-year costs, which were then extrapolated to 16 years. Bootstrap percentile confidence intervals were calculated for the mean long-term cost per patient by stage. Phase-specific, long-term costs for the entire CRC cohort were also estimated. RESULTS: With regard to stage at diagnosis, the mean long-term cost per patient ranged from €20,708 (in situ) to €47,681 (stage III). The estimated costs increased at more advanced stages up to stage III and then substantially decreased in stage IV. In terms of treatment phase, the mean cost of the initial period represented 24.8 % of the total mean long-term cost, whereas the cost of continuing and advanced care phases represented 16.9 and 58.3 %, respectively. CONCLUSIONS: This study is the first to provide long-term cost estimates for CRC treatment, by stage at diagnosis and phase of care, based on data from clinical practice in Spain, and it will contribute useful information for future studies on cost-effectiveness and budget impact of different therapeutic innovations in Spain.

Estimación del coste hospitalario del cáncer colorrectal en Cataluña / Estimation of hospital costs of colorectal cancer in Catalonia (Spain)

Objetivo: Estimar el coste hospitalario del tratamiento del cáncer colorrectal (CCR) según estadio, tipo de coste y fase de evolución de la enfermedad en un hospital público. Métodos: Se realizó un estudio retrospectivo de costes de la atención hospitalaria del CCR de una cohorte de 699 pacientes con diagnóstico y tratamiento de CCR entre los años 2000 y 2006 en el Hospital del Mar, con seguimiento de hasta 5 años desde el diagnóstico de la enfermedad, a partir de bases de datos clínico-administrativas. Se analizó el coste medio por estadio, tipo de coste y fase de evolución de la enfermedad. Resultados: El coste medio por paciente en casos con diagnóstico in situ fue de 6573 Euros. Este coste aumentó en estadios más avanzados y llegó a los 36.894 Euros en el estadio III. Los principales componentes del coste fueron la cirugía-hospitalización (59,2%) y la quimioterapia (19,4%). En estadios más avanzados, el peso de la cirugía-hospitalización disminuyó, mientras que el de la quimioterapia aumentó. Conclusión: Este estudio proporciona el coste hospitalario del tratamiento del CCR calculado a partir de la práctica clínica habitual. La cirugía y el tratamiento quimioterápico son los principales componentes del coste. Los resultados obtenidos aportarán la información necesaria para los análisis de coste-efectividad de distintas iniciativas preventivas e innovaciones terapéuticas en nuestro entorno (AU)

Objective: To assess the hospital cost associated with colorectal cancer (CRC) treatment by stage at diagnosis, type of cost and disease phase in a public hospital. Methods: A retrospective analysis was conducted of the hospital costs associated with a cohort of 699 patients diagnosed with CRC and treated for this disease between 2000 and 2006 in a teaching hospital and who had a 5-year follow-up from the time of diagnosis. Data were collected from clinical-administrative databases. Mean costs per patient were analysed by stage at diagnosis, cost type and disease phase. Results: The mean cost per patient ranged from 6,573 Euros for patients with a diagnosis of CRC in situto 36,894 Euros in those diagnosed in stage III. The main cost components were surgery-inpatient care (59.2%) and chemotherapy (19.4%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs and an increase in chemotherapy costs. Conclusions: This study provides the costs of CRC treatment based on clinical practice, with chemotherapy and surgery accounting for the major cost components. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain (AU)

[Estimation of hospital costs of colorectal cancer in Catalonia (Spain)]. / Estimación del coste hospitalario del cáncer colorrectal en Cataluña.

OBJECTIVE: To assess the hospital cost associated with colorectal cancer (CRC) treatment by stage at diagnosis, type of cost and disease phase in a public hospital. METHODS: A retrospective analysis was conducted of the hospital costs associated with a cohort of 699 patients diagnosed with CRC and treated for this disease between 2000 and 2006 in a teaching hospital and who had a 5-year follow-up from the time of diagnosis. Data were collected from clinical-administrative databases. Mean costs per patient were analysed by stage at diagnosis, cost type and disease phase. RESULTS: The mean cost per patient ranged from 6,573 Euros for patients with a diagnosis of CRC in situ to 36,894 € in those diagnosed in stage III. The main cost components were surgery-inpatient care (59.2%) and chemotherapy (19.4%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs and an increase in chemotherapy costs. CONCLUSIONS: This study provides the costs of CRC treatment based on clinical practice, with chemotherapy and surgery accounting for the major cost components. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain.

The optimal utilization proportion of external beam radiotherapy in European countries: An ESTRO-HERO analysis.

BACKGROUND AND PURPOSE: The absolute number of new cancer patients that will require at least one course of radiotherapy in each country of Europe was estimated. MATERIAL AND METHODS: The incidence and relative frequency of cancer types from the year 2012 European Cancer Observatory estimates were used in combination with the population-based stage at diagnosis from five cancer registries. These data were applied to the decision trees of the evidence-based indications to calculate the Optimal Utilization Proportion (OUP) by tumour site. RESULTS: In the minimum scenario, the OUP ranged from 47.0% in the Russian Federation to 53.2% in Belgium with no clear geographical pattern of the variability among countries. The impact of stage at diagnosis on the OUP by country was rather limited. Within the 24 countries where data on actual use of radiotherapy were available, a gap between optimal and actual use has been observed in most of the countries. CONCLUSIONS: The actual utilization of radiotherapy is significantly lower than the optimal use predicted from the evidence based estimates in the literature. This discrepancy poses a major challenge for policy makers when planning the resources at the national level to improve the provision in European countries.

The impact of cancer incidence and stage on optimal utilization of radiotherapy: Methodology of a population based analysis by the ESTRO-HERO project.

BACKGROUND AND PURPOSE: The impact of differences in the distribution of major cancer sites and stages at diagnosis among 4 European countries on the optimal utilization proportion (OUP) of patients who should receive external beam radiotherapy was assessed within the framework of the ESTRO-HERO project. MATERIALS AND METHODS: Data from Australian Collaboration for Cancer Outcomes Research and Evaluation (CCORE) were used. Population based stages at diagnosis from the cancer registries of Belgium, Slovenia, the Greater Poland region of Poland, and The Netherlands were used to assess the OUP for each country. A sensitivity analysis was carried out. RESULTS: The overall OUP by country varied from the lowest of 48.3% in Australia to the highest of 53.4% in Poland; among European countries the variation was limited to 3%. Cancer site specific OUPs showed differences according to the variability in stage at diagnosis across countries. The most important impact on the OUP by country was due to changes in relative frequency of tumours rather than stage at diagnosis. CONCLUSIONS: This methodology can be adapted using European data, thus facilitating the planning of resources required to cope with the demand for radiotherapy in Europe, taking into account the national variability in cancer incidence.

Estimation of lung cancer diagnosis and treatment costs based on a patient-level analysis in Catalonia (Spain).

BACKGROUND: Assessing of the costs of treating disease is necessary to demonstrate cost-effectiveness and to estimate the budget impact of new interventions and therapeutic innovations. However, there are few comprehensive studies on resource use and costs associated with lung cancer patients in clinical practice in Spain or internationally. The aim of this paper was to assess the hospital cost associated with lung cancer diagnosis and treatment by histology, type of cost and stage at diagnosis in the Spanish National Health Service. METHODS: A retrospective, descriptive analysis on resource use and a direct medical cost analysis were performed. Resource utilisation data were collected by means of patient files from nine teaching hospitals. From a hospital budget impact perspective, the aggregate and mean costs per patient were calculated over the first three years following diagnosis or up to death. Both aggregate and mean costs per patient were analysed by histology, stage at diagnosis and cost type. RESULTS: A total of 232 cases of lung cancer were analysed, of which 74.1% corresponded to non-small cell lung cancer (NSCLC) and 11.2% to small cell lung cancer (SCLC); 14.7% had no cytohistologic confirmation. The mean cost per patient in NSCLC ranged from 13,218 Euros in Stage III to 16,120 Euros in Stage II. The main cost components were chemotherapy (29.5%) and surgery (22.8%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs but an increase in chemotherapy costs. In SCLC patients, the mean cost per patient was 15,418 Euros for limited disease and 12,482 Euros for extensive disease. The main cost components were chemotherapy (36.1%) and other inpatient costs (28.7%). In both groups, the Kruskall-Wallis test did not show statistically significant differences in mean cost per patient between stages. CONCLUSIONS: This study provides the costs of lung cancer treatment based on patient file reviews, with chemotherapy and surgery accounting for the major components of costs. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain.

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study.

The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.