Comparative standards for the evaluation of clinical and epidemiological data in oncology: methodical development and verification on population data

Dissertation thesis in oncology Comparative standards for the evaluation of clinical and epidemiological data in oncology: methodical development and verification on population data Jan Mužík 2010 Masaryk University, Faculty of Medicine, Institute of Biostatistics and Analyses, Brno, Czech Republic Supervisor: doc. RNDr. Ladislav Dušek, Ph.D. Co-supervisors: prof. MUDr. Jan Žaloudík, CSc. prof. MUDr. Rostislav Vyzula, CSc.

Bibliographic identification Author: Title of dissertation: Title of dissertation (in Czech): Doctoral study program: Supervisor: Co-supervisors: Jan Mužík Comparative standards for the evaluation of clinical and epidemiological data in oncology: methodical development and verification on population data Srovnávací standardy pro hodnocení klinických a epidemiologických dat v sou asné onkologii: vývoj metodiky a její verifikace na popula ních datech. Oncology doc. RNDr. Ladislav Dušek, Ph.D. prof. MUDr. Jan Žaloudík, CSc. Year of defense: 2010 prof. MUDr. Rostislav Vyzula, CSc. Keywords: Keywords (in Czech): cancer, epidemiology, data analysis novotvary, epidemiologie, analýza dat

Content Content... 5 Abstract... 7 Abstrakt (Abstract in Czech)... 9 Aims of the dissertation thesis... 11 Acknowledgements... 12 A. Data and Information Background of Czech Cancer Care current status... 13 1 Introduction overview of the main sources of information... 15 2 The main information sources of Czech oncology available on-line... 17 3 Demographic data and the Czech National Cancer Registry... 19 3.1 Demographic data and the Death Records Database... 19 3.2 The Czech National Cancer Registry... 19 3.3 The system of maintenance and check of records in CNCR... 20 3.4 Ensuring quality of data on the epidemiology of malignant tumours in the Czech Republic... 20 3.5 The Czech National Cancer Registry On-line... 26 4 Czech clinical registries monitoring the use of monoclonal antibodies in cancer therapy 27 5 Use of population-based data for cancer care assessment in the Czech Republic... 29 References... 31 B. Author s contribution to the development of data standards for the evaluation of Czech cancer care... 33 C. Author s contribution to the development of software tools for automated analysis and reporting of cancer data... 41 Glossary of specific terms... 47 Enclosures... 49 Paper I. Cancer Epidemiology in the Czech Republic: Current Load and the Time Trends. Paper II. Historical data of the Czech National Cancer Registry: information value and risk of bias Paper III. Epidemiology of chronic myeloid leukemia. Paper IV. Data registries form indispensable information base of current oncology. Paper V. The Czech National Cancer Registry and reference standards for health care assessment. Paper VI. Colorectal cancer screening in Europe. Paper VII. Multivariate analysis of risk factors for testicular cancer: a hospital-based casecontrol study in the Czech Republic Paper VIII. Analysis of population cancer risk factors in national information system SVOD. Paper IX. Epidemiology of Malignant Tumours in the Czech Republic [online] Paper X. What is the information availability to the cancer epidemiology data? Paper XI. UROWEB - web portal for analysis and visualization of epidemiology, diagnosis and treatment of urologic malignancies [online]. XII. Appendix to paper I. Summary of cancer epidemiology in the Czech Republic XIII. Curriculum Vitae - 5 -

Abstract Malignant diseases are a serious health problem in the Czech population, particularly with regard to annually increasing numbers of newly diagnosed patients. In international comparisons, the Czech Republic is ranked in the top positions in the incidence and mortality of cancer. Causes of development of many types of cancer are not clearly known, despite a still more extensive knowledge of processes of tumor growth. One of the most important sources of information in understanding this issue still remains cancer epidemiology, which allows us to assess the population burden, to identify the risk populations, to evaluate the success of diagnosis and treatment and to predict the number of patients for the planning of cancer care, etc. An essential prerequisite for the use of cancer epidemiology is availability of sufficiently large and complete population data and representativeness and completeness of such information. The Czech Republic has such data available thanks to the population-based National Cancer Registry (NCR), which is consistently managed since 1976 until now. NCR contains data on all diagnosed neoplasms in the Czech population, including relevant data on the tumour diagnosis and primary treatment of cancer. The database of NCR currently contains over 1.6 million records. Even a few years ago this extensive data was not fully accessible for professionals; also its level of quality, completeness and informational value was unknown. Availability of data on the epidemiology of neoplasms in the Czech Republic was previously limited only to publications Cancer Incidence in the Czech Republic issued annually by Institute for Health Information and Statistics (IHIS). Due to the limited capabilities of these publications and the growing need to use the extensive data collected in the NCR in 2001 was this database made first time available (with agreement of IHIS) for the cancer care professionals (the steering committee of the Czech Society for Oncology). Institute of Biostatistics and Analyses, Masaryk University (IBA) was commissioned to process these data and the author of this dissertation started to develop standardized data management over full NCR data. In addition to the definition of data standards, new measures for data quality assessment and scientifically based analytic reporting had to be developed. This dissertation thesis summarizes original articles and contributions of the author to the development of procedures for processing of large epidemiology data sets, algorithms completing information on the disease stage according to the recorded values (TNM, ICD and ICD-O classifications with respect to their changes over time) and finally algorithms for stratification of patients according to their information value and completeness of the data. The results initiated definition of the reference data set of patients as the reference pool for comparative evaluation of health care outcomes in oncology at the population level. The comprehensive summary of the current epidemiologic situation in the Czech Republic was published and basic standards for the comparative assessment of the population burden by cancer were defined. The standards include quantification of trends in incidence, mortality and prevalence, procedures to prepare data for international comparisons, calculation of lifetime cumulative cancer risk, assessment of regional distributions and trends. With regard to the lack of availability of these highly valuable data for professionals and for the lay public as well, the author also contributed to the development of several software analytic tools, which made the NCR data available to the users in user friendly environment. The first generation of this software was system SVOD (System for Visualisation of Oncologic Data), which provided a complete set of epidemiological data and data on the diagnosis and treatment recorded in NCR. This software was designed mainly to professionals. In the second generation a new Portal of cancer epidemiology of the Czech - 7 -

Republic (available from www.svod.cz) was developed based on web technology. In the last work the team headed by the author developed a specialized portal for analysis of data on urology malignancies (www.uroweb.cz). This novel tools makes accessible epidemiological data for the public, including presentations oriented abroad. - 8 -

Abstrakt (Abstract in Czech) Nádorová onemocn ní p edstavují závažný zdravotní problém sou asné eské populace, zvlášt s ohledem na stále rostoucí po ty nov diagnostikovaných pacient ro n. eská republika zaujímá v mezinárodním m ítku p edním místa v incidenci a mortalit t chto onemocn ní. P í iny vzniku ady nádorových onemocn ní nejsou známy, a to i p es stále rozsáhlejší znalosti proces nádorového zvratu a r stu. Jedním z velmi významných zdroj informací p i porozum ní této problematice tak stále z stává epidemiologie nádorových onemocn ní, která umož uje hodnotit popula ní zát ž a identifikovat její trendy, poukazovat na rizikové skupiny v populaci, hodnotit úsp šnost diagnostiky a lé by, predikovat po ty lé ených p i plánování pé e o nemocné atp. Zásadním p edpokladem využití nádorové epidemiologie je však dostupnost dostate n rozsáhlých a úplných popula ních dat, jejich reprezentativnost a informa ní úplnost. Díky celopopula nímu Národnímu onkologickému registru (NOR) standardizovan vedenému od roku 1976 až do sou asnosti má eská republika taková data k dispozici. Národní onkologický registr obsahuje údaje o všech zachycených novotvarech v eské populaci v etn relevantních údaj o diagnostice a primární protinádorové lé b onkologických pacient a v sou asné dob obsahuje p es 1,6 miliónu záznam. Ješt v nedávné dob však tato rozsáhlá data nebyla b žn dostupná odborné ve ejnosti a nebyla známa úrove jejich kvality, úplnosti a informa ní hodnoty. Dostupnost údaj o epidemiologii novotvar v eské republice byla d íve omezena pouze na publikace Novotvary každoro n vydávané Ústavem zdravotnických informací a statistiky R (ÚZIS R). Vzhledem k omezeným možnostem t chto publikací a k rostoucí pot eb využívat rozsáhlé údaje shromážd né v NOR byla v roce 2001 tato data se souhlasem ÚZIS poprvé zp ístupn na odborné onkologické ve ejnosti zastupované vedením eské onkologické spole nosti LS JEP ( OS) pro možnosti vlastního zpracování a využití. Zpracováním t chto dat byl pov en Institut biostatistiky a analýz Masarykovy univerzity (IBA) a v rámci IBA byl hlavním analytikem dat NOR a dat o epidemiologii nádor jmenován autor diserta ní práce RNDr. Jan Mužík. Disertace shrnuje originální práce autora a jeho p ísp vek k vývoji zcela nového, mezinárodn konkurenceschopného managementu popula ních onkologických dat R. Byly vytvo eny postupy pro zpracování t chto objemových dat, byly vyvinuty algoritmy kompletující informaci o stadiu onemocn ní dle zaznamenaných hodnot (TNM, MKN a MKN-O klasifikace i s ohledem na jejich zm ny v ase) a následn algoritmy stratifikující pacienty do skupin podle jejich informa ní hodnoty a úplnosti dat. Výsledkem je definice referen ního souboru pacient jako komparativního standardu pro hodnocení výsledk lé ebné pé e v onkologii na popula ní úrovni. Dále bylo provedeno kompletní vyhodnocení aktuální situace epidemiologie novotvar v eské republice a byly nastaveny základní komparativní standardy pro hodnocení popula ní onkologické zát že (standard obsahuje trendy incidence, mortality a prevalence, mezinárodní srovnání, kumulativní riziko, v kovou strukturu, regionální zát ž a trendy stadií). S ohledem na nedostate nou dostupnost t chto vysoce hodnotných dat pro odbornou i laickou ve ejnost byly dále vyvinuty softwarové analytické nástroje zp ístup ující data NOR v uživatelsky p ijatelné podob pomocí interaktivních analytických nástroj. V první generaci byl vyvinut software SVOD (Systém pro Vizualizaci Onkologických Dat) zp ístup ující kompletní sadu epidemiologických data, dat o diagnostice a lé b zaznamenané v NOR. Tento software byl ur ený p edevším odborné ve ejnosti. Ve druhé generaci byl následn vytvo en Portál epidemiologie nádor v eské republice (www.svod.cz), který v rozsahu základních komparativních standard pro hodnocení popula ní onkologické zát že zp ístupnil tato data nejširší ve ejnosti v etn prezentace do zahrani í. Nejaktuáln jším výsledkem práce - 9 -

týmu vedeného autorem diserta ní práce je nová generace webových analytických nástroj, publikovaná se zam ením na urologické malignity (www.uroweb.cz). - 10 -

Aims of the dissertation thesis The general objective of the dissertation was to develop procedures for the use of available sources of population data on the cancer epidemiology with focus on data of the National Cancer Registry of the Czech Republic (NCR) and setting the reference standards and comparative standards for assessing the cancer burden and for evaluating the results of medical care. Aims of this work were as follows: - development of standardized procedures for the processing of population-based data - evaluation of completeness and information usability of these population data - development of algorithms for stratification of records according to their completeness and information value - setting standards for the comparative assessment of the population cancer burden - definition of a reference group of patients and the comparative standard for assessing the outcomes of medical care on the population level (mainly for evaluation of survival) - publication of the results in articles in scientific journals and in electronic form via the software tools - 11 -

Acknowledgements First and foremost I would like to thank to my supervisor doc. RNDr. Ladislav Dušek, Ph.D. for the opportunity to work on this interesting and useful topic, for superior working conditions, for his motivation, professional guidance and assistance. I would like to thank also the steering committee of the Czech Society for Oncology, namely to prof. MUDr. Jan Žaloudík, CSc., prof. MUDr. Rostislav Vyzula, CSc. and to prof. MUDr. Jitka Abrahámová, DrSc. for valuable comments and suggestions to my work and for the help with orientation in this area. I would like to thank also to the management of the Institute for Health Information and Statistics and the board of Czech Society for Oncology for making the National Cancer Registry accessible for such extensive processing. Last, but not least, I would like to thank my colleagues from the Institute of Biostatistics and Analyses for creating an inspirational, creative and productive work environment and to my family and my friends for their support and patience. - 12 -

A. Data and Information Background of Czech Cancer Care current status Published in Dušek L. et al. Czech Cancer Care in Numbers 2008 2009. Praha: Grada Publishing, a.s., 2009. Shortened, updated. - 13 -

1 Introduction overview of the main sources of information A comprehensive quantitative assessment of health care must cover its inputs, the processes and the outputs. The health care inputs are represented primarily by patient numbers and their health condition, i.e. the health care load. The health care processes involve the distribution and availability of health care, and the standardization of diagnostic and treatment approaches, as well as their control. And finally, the health care outputs are generally perceived as health care quality and the results. Of course, all these components of health care are strongly linked to costs. The costs, in turn, primarily concern the extent of care needed (the health care load); well-adjusted processes should ensure correct and timely utilization of the financial resources, and health care quality assessment is essential to evaluate whether these resources have been utilized reasonably and cost-effectively. It is generally known that any meaningful assessment cannot be done without specific and representative data, and this particularly applies to health care. It is, therefore, inherent that a solid information platform be developed in the long term if we are to properly assess different areas of health care (hence the need for background information). The Czech health care system and its medical professionals are certainly able to assess the results at the level of individual patients, while there are often serious problems with such assessments at regional or even national levels. The analyses of population-based data on diagnostic and therapeutic processes and the results are not available, and the same applies to standardized export of data from the hospital information systems. With regards to the facts mentioned above, the Czech Society for Oncology has based its information strategy on the combination of population-based and clinical registries, and makes every effort to develop it further in cooperation with the health care payers. This would not be possible without the very helpful participation of doctors and their colleagues who collect data beyond their call of duty. It is only thanks to such professionals that the Czech Society for Oncology has data available for all strategic components of health care assessment. The system is based on real data which is collected directly at clinical practice. There is no point to analyze international data, since the contained information there is not helpful and/or compatible for assessing the actual results achieved in the Czech healthcare system. The following paragraphs provide an overview of the main data sources: The Czech Statistical Office processes data on the demographic structure of the Czech population within the monitoring of demographic trends. This data describes the main demographic characteristics noted for the Czech population, namely the total number of inhabitants, age structure, life expectancy, etc. The Death Records Database serves as a source of ascertaining population mortality from malignant neoplasms in the Czech Republic; this database is also maintained by the Czech Statistical Office in compliance with the international methodology and based on the data from the Death Certificate (ICD-10 classification). The Czech National Cancer Registry (CNCR) is the principal source of data on the epidemiology of malignant tumours. CNCR has become an indispensable part of the complex cancer care, containing more than 1.6 million records over the period 1976-2007 and covering the entire Czech population. The registration of malignant neoplasms is stipulated by the legislation and is obligatory. Three screening programmes of secondary prevention are currently in operation, focusing on breast cancer, colorectal cancer and cervical cancer. All these screening programmes - 15 -

benefit from a solid background comprising population data, making it possible to assess their nationwide impact. Moreover, specific information systems for cancer screening programmes have been developed, focusing on the collection of data on performed examinations and their results. This so-called data audit of screening programmes serves for regular assessment of screening performance. Clinical registries of the Czech Society for Oncology represent as the main source of clinical data. These registries provide a reliable description of the clinical practice, focusing on the collection and analysis of data on diagnostic and therapeutic procedures, or monitoring the results of a specific type of treatment. These clinical databases in combination with the Czech National Cancer Registry constitute a complex source of data, making it possible to assess not only the healthcare results, but also population-based indicators of quality, including the nationwide and regional availability of health care. Some information cannot be obtained from commonly available data sources; for example, the time trends in the probability of relapse/progression of primary malignant disease, or the probability of application of higher-line treatments in differently affected cancer patients. In these cases, predictions and assessments are made by an expert panel of the Czech Society for Oncology. Each year, the expert panel processes relevant data from the above-mentioned sources in order to answer clearly defined questions. In 2005, the concept and structure of electronic documentation of cancer patient was developed by another expert panel of the Czech Society for Oncology. Recently, this information system has been progressively implemented in everyday practice of the Czech health facilities; in this way, data previously reported to health care payers only will become available for analyses by the Czech Society for Oncology. The combination of these reports with diagnostic records within CNCR creates a brand new information system, making very detailed clinical data readily available. The project called Fusion of CNCR and health care payers data was successfully accomplished in two major hospitals and led to the analysis of more than 110,000 complete and comprehensive records on the treatment of cancer patients. In 2008, the Czech Society for Oncology commenced cooperation with the Czech National Reference Centre (CNRC) of health care payers; the CNRC is able to centralize data from health care payers and to monitor diagnostic and treatment procedures nationwide. Population-based data on diagnostic examinations within the cancer screening programmes are currently being analyzed in order to provide support for the assessment of Czech cancer screening programmes. The above-mentioned overview documents the fact that the extent of background information at the Czech Society for Oncology covers all needed levels with regard to the collection and assessment of data ranging from individual hospitals to the population level (Figure 1). - 16 -

3rd LEVEL INVESTIGATION Epidemiological reports Registration records for research purposes Clinical trials 2nd LEVEL ANALYSIS Diagnosisspecific records Continuous clinical records Records on complications Quality of life 1st LEVEL REGISTRATION Collection of clinical records Electronic case report forms Reports on provided health care Figure 1 The structure of background information as developed by the Czech Society for Oncology 2 The main information sources of Czech oncology available on-line The Czech Society for Oncology makes every effort to ensure unrestricted availability of important data sources on the internet: information and news for professionals and the lay public is made available here. The presented pages serve as a quick overview of the most important outputs. The NOP On-line project (http://www.onconet.cz) and the main communication portal of the Czech Society for Oncology (http://www.linkos.cz). These portals communicate, among others, the targets of the National Cancer Control Programmes and the way these targets are being accomplished. The portal http://www.linkos.cz contains a section for health professionals and a separate section for patients, their families and friends. The portal http://www.onconet.cz has been designed to provide an objective presentation of all cancer centres (CCs) and to provide information services to these centres in the respective regions (communication between CCs and their partners, regional data collection...). The individual CCs can use the portal to present their targets, the housed equipment and the quality of provided health care. The national web portal focused on the epidemiology of malignant tumours (http://www.svod.cz) This web portal graphically presents more than 1.6 million records from the Czech National Cancer Registry. The portal is primarily focused on epidemiological data and the related time trends, inclusive of the regional differences and population risks. Users can - 17 -

find here a number of interactive tools and automatic reporting systems, facilitating orientation in the complex database even for the lay users, who can assimilate the analyses and outputs according to their own preferences. The portal also analyzes the demographic data of the Czech population (this function has been made available thanks to the cooperation with the Czech Statistical Office) and the extensive databases on the condition of the environment. Cancer incidence and mortality in annual outputs of Institute of health information and statistics of the Czech Republic (IHIS) IHIS annually publish tabular overview of incidence and mortality of cancer in publications Cancer Incidence in the Czech Republic. They are available also in electronic form here http://www.uzis.cz/download.php?ctg=10&search_name=cancer%20incidence&region=1 00&kind=1&mnu_id=5300 Web portals of the national cancer screening programmes (http://www.mamo.cz; http://www.kolorektum.cz; http://www.cervix.cz) These web portals deal with organized population screening programmes in the Czech Republic. Apart from organizational and educational materials, detailed reports on data audits and their results are regularly published on these websites. The DIOS project (Dose Intensity as Oncology Standard, http://dios.registry.cz) This web portal deals with the parametric assessment and adherence to anticancer chemotherapy guidelines. Apart from several useful tools, which can be also used for educational purposes, the portal provides analytical and software support for its users, as well as the realization of multicentre projects. The most valuable tools involve the Central Library of Chemotherapy Regimens, and a set of automated software tools, such as Therapy Organizer, Dose Intensity Calculator, and reporting tools. The portal contributes to the standardization of diagnostic and therapeutic procedures. Methodical and data background for clinical and drug registries: http://www.registry.cz This methodical portal provides the background and maintenance data for the drug and clinical registries in the Czech Republic. The portal informs both the professionals and lay persons about the development of methods for registering clinical data, and describes the standards for on-line information systems and on-line available registries. This platform also led to the establishment of eight drug registries developed by the Czech Society for Oncology, which are focused on expensive anticancer pharmacotherapy (for instance, subportals of respective projects such as http://herceptin.registry.cz, http://tarceva.registry.cz, http://avastin.registry.cz), or on the assessment of data collected within individual hospitals or data describing selected diagnostic groups of malignant tumours (such as http://uranos.registry.cz, http://hardrock.registry.cz, http://pons.registry.cz). A specialized information portal oriented on urological malignancies (http://www.uroweb.cz) This portal is focused on the assessment of the epidemiological load, the diagnostic and therapeutic procedures, and the treatment results in urological malignancies in the Czech Republic. All population-based data from this domain is made available in an interactive manner, and reference survival rates are also provided. The project is the outcome of the cooperation between the Czech Society for Oncology and the Czech Urological Society. - 18 -

3 Demographic data and the Czech National Cancer Registry 3.1 Demographic data and the Death Records Database As a standard part of population monitoring, the Czech Statistical Office also administrates data on the demographic structure of Czech Republic and makes it available on its website (http://www.czso.cz/eng/redakce.nsf/i/population). This data describes the main demographic characteristics of the Czech population, such as the total population, the age structure, life expectancy, as well as predictions of the time trends up to 2050. The Czech legislation requires all deaths which occur in the Czech Republic to be registered in the Death Records Database; for this purpose, standardized Death Certificates have been designed to collect precise data on the cause of death in each individual. The causes of death are classified according to the International Classification of Diseases (ICD), which can be found on the WHO website (http://www.who.int/classifications/icd/en/); at the time of writing this publication, the 10 th revision of ICD was valid in the Czech Republic and worldwide. Moreover, the primary cause of death is further specified according to standard guidelines. Apart from detailed information on the cause of death, the data structure of the Death Records Database also contains information on birth certificate number, the sex and address of the deceased, as well as the dates of birth and death. The Death Records Database is administered by the Czech Statistical Office and outputs are available on-line in aggregate form at http://www.czso.cz/csu/2007edicniplan.nsf/p/4017-07 or http://www.czso.cz/csu/2009edicniplan.nsf/p/4019-09. 3.2 The Czech National Cancer Registry The Czech National Cancer Registry (CNCR) was established in 1976 in order to collect population-based and clinical data on newly diagnosed malignant tumours in the Czech Republic (or in Czechoslovakia, historically). More specifically, a database of individuals diagnosed with malignant tumours was set up, and its records also served for prospective monitoring during the follow-up period. Nowadays, the CNCR is an indispensable part of the Czech National Cancer Control Programme, containing more than 1.4 million records since 1976 and covering the entire Czech population. The CNCR is enshrined in the Czech legislation as part of the National Health Information System (NHIS) and is administered by the Institute of Health Information and Statistics of the Czech Republic (IHIS, http://www.uzis.cz). The Czech National Cancer Registry (CNCR) contains personal data on patients, data describing malignant tumours and diagnostic details, data on patients' treatment, as well as data on post-treatment follow-up. The parametric structure of the CNCR can be divided into several groups (according to the clinical significance of respective parameters) as follows: Identification of record on cancer case Identification and demographic characteristics of the patient Data on the diagnosis of malignant tumour (such as the date of diagnosis, clinical and histological characteristics) All treatment modalities of primary anticancer therapy Actual condition of the patient and his/her disease, as monitored with follow-up reports Additional parameters - 19 -

3.3 The system of maintenance and check of records in CNCR The registration of malignant tumours is enshrined in the Czech legislation and is obligatory. The Czech National Cancer Registry (CNCR) is administered by the Institute of Health Information and Statistics of the Czech Republic (IHIS), which is responsible for cohesion of the registry as regards its methodology and contents. The IHIS regularly checks the correctness of submitted data, distributes the methodology, processes, and provides and publishes statistical outputs, and defines access rights to authorized users. The Coordination Centre for Departmental Medical Information Systems (CCDMIS) processes data from the CNCR on nationwide level. The CCDMIS is responsible for smooth operation of the registry, the database status, technical support and data security. It also provides information technology (HW, SW, and communication), authentication and authorization. The CNCR Council is an advisory body and expert guarantor to CNCR. Members of the CNCR Council most typically include representatives of IHIS, the regional CNCR centres, the Czech Ministry of Health, and from the Czech Society for Oncology. Any health care facility in which a malignant tumour has been diagnosed, treated and followed-up, is legally obliged to report that tumour. Data on patients and their tumours are sent to CNCR by specifically instructed health care professionals. The health care facility fills in the so-called Report on Malignant Neoplasm, which forms an integral part of the obligatory medical documentation. In compliance with the legislation in force, this Report is submitted either in written or in electronic form, in a specified extent within one month from the date of diagnosis, to a respective regional CNCR centre. The reporting health care facilities are obliged to submit all data required to compile the complete Report on Malignant Neoplasm. The disease is then followed-up using the so-called Follow-up Report on Malignant Neoplasm, which must be filled in by the follow-up health care facility in the specified extent and within the defined time intervals; the Follow-up Report is then submitted to the regional CNCR centre for further processing. The regional CNCR centres are obliged to send this data to the national centre electronically, regularly (at least once a year), and before the deadline as stipulated by the CNCR administrator. The IHIS then ensures data check, and CNCR records are completed with data from the Death Records Database. 3.4 Ensuring quality of data on the epidemiology of malignant tumours in the Czech Republic Epidemiological data contained in the Czech National Cancer Registry (CNCR) present an essential source of information, which is employed for the predictive assessment of cancer load, among others. For this reason, the CNCR database undergoes regular quality audits, which include the assessment of data quality and credibility. The following part introduces the main principles and results of these audits. The Czech National Cancer Registry (CNCR) is based on the following fundamental principles, which clearly define its position and informational value: 1. CNCR is a nationwide registry focused on epidemiological data, i.e. it is not a collection of specific diagnostic and therapeutic records, which would only reflect development within individual diagnoses. 2. CNCR clearly defines the regional affiliation of each new record, assigning it unequivocally to a specific health care facility which is responsible for the patient's treatment, or later to a follow-up health care facility. These measures have made the registry ready for possible conversions should any changes in the administrative division occur, and have made it possible to sort the records by the type of health care facility. - 20 -

3. CNCR puts accent on the correctness and completeness of the diagnostic records. In most solid tumours, this involves particularly the identification of diagnosis and the location of primary tumour, as well as TNM and stage determination. 4. Records within CNCR are regularly checked and updated, particularly with data on patient's death. Each year, data within CNCR undergoes quality and completeness checks. Chronological order is checked as the minimum attribute of data consistency, and records are further checked with regard to their correctness and completeness. In the stage of input audit, incomplete or clearly incorrect records are marked as irrelevant for further processing, and are subsequently checked and updated. If a record cannot be completed retrospectively, it is marked by a code denoting that this record has various weights in various situations: summary code, defining the overall credibility and usability of the record, for example: a complete record, fully usable incomplete record for objective reasons, otherwise consistent record with serious problems and of compromised quality, incorrect and unusable record code denoting missing values in primary record code denoting record in which some values have been omitted due to their inconsistency code denoting the main reasons of record incompleteness (objective reasons / error) As explained above, the data audit detects all situations and reasons that might lead to incomplete diagnostic identification of records. However, many reasons are objective, and they often bring valuable information if detected properly. Here is a list of possible reasons for incomplete records: 1. In some diagnostic groups, the TNM classification has no sense, i.e. the incompleteness of those records is actually correct (in the Czech health system, this situation has been historically caused by the universal CNCR reporting form, which thus excluded the diagnostic identification of leukaemias, for example). 2. In other diagnostic groups, the respective TNM classification was not yet defined at the time of diagnosis. 3. Incomplete diagnostic identification due to diagnosis based on post-mortem examination (DCO records) or autopsy 4. Incomplete diagnostic identification due to early death of patients (shortly after diagnosis), or patients without the start of anticancer therapy. 5. Incomplete diagnostic identification due to unexpected development of a situation, moving the patient abroad, patient s refusal to treatment, etc. 6. Actually wrongly incomplete or otherwise problematic records which do not belong to any of the preceding categories. The above-mentioned coding system allows data administrators to sort the records by various degrees of incompleteness, without being obliged to remove the original records from registry: Records containing at least the diagnosis of malignant tumour can be included into basic epidemiological summarizations. Records containing the clinical stage only or TNM only can be retrospectively supplied with the missing item, using the rules which were valid at the time of diagnosis, and based on expert opinions. Records missing the clinical stage and TNM, whether this is wrongly incomplete or for objective reasons might be classified on the probability basis. - 21 -

stage or TNM available TNM and stage available Stage available only In some diagnoses, TNM only or stage only is available due to the status of TNM classification at that time (e.g., malignant tumours of the urogenital tract in 1982-1994). In other cases, the record is incomplete and can be updated retrospectively, based on TNM version at that time and expert opinions. All patients TNM available only stage and TNM not available TNM and stage not available because classification was not introduced Diagnosis based on autopsy / DCO Early death of patient Patient was not treated Incomplete record Stage and TNM is determined by the TNM classification valid at the time of diagnosis. The incompleteness of records (with respect to TNM and stage) in some diagnoses is due to the absence of rules of TNM and stage determination. Other objective reasons for incompleteness of records are related to the patient's condition at the time of diagnosis, or the patient's refusal to be treated, etc. All these objective criteria having been taken into account, there are also some truly incomplete records, where TNM classification and stage are missing. Figure 2 Basic classification of record completeness in the Czech National Cancer Registry Figure 2 presents the basic scheme of stratification of CNCR records with regard to their completeness in the diagnostic section. This scheme has been designed according to the above-described and justified categories in an effort to differentiate partly incomplete records from records incomplete for objective reasons, and from records which must be marked as incorrect. Figure 3 presents the assessment of all CNCR records. There is a clear improvement in the quality of CNCR data over time, which cannot be justified by the development in TNM classification only, but also by the development of the CNCR itself. Nevertheless, the development in TNM classification is a very important factor: recent data contains 6.3% of incomplete records due to missing TNM classification. One must bear in mind, however, that even nowadays, there are specific groups of neoplasms for which the TNM system has not been defined. These diagnoses are objectively incompatible with the majority standard for the registration of solid tumours, and so should be assessed separately (haemato-oncological malignancies, malignant tumours of the brain and the central nervous system, in situ tumours, rare tumours, unspecified sites). Provided that the clinical stage can be supplied in records containing TNM only, then particularly data from the period 1995-2007 are fully comparable with the highest-quality international data, as regards completeness of records. With respect to the incidence rates of DCO records and the findings during autopsy, such recent data is also acceptable from the international point of view. Figure 3 also documents the decreasing proportion of untreated patients and patients who died soon after diagnosis (early deaths). "Early death" in our analysis corresponds to death within one month of diagnosis, which corresponds to the criteria used in international analyses. - 22 -

Overall, CNCR records from the period 1995-2007 contain only 5.5% records which are unfoundedly missing both the TNM classification and the clinical stage (Figure 3). A very positive message is that the completeness of data increases in time and that the most recent period (which is the most relevant one for clinical analyses) provides high-quality data. In the period 2001-2007, only 4.9% of records were detected to be unfoundedly incomplete (Table 1). Furthermore, it is obvious that since 1995, the problem of incomplete diagnostic classification applies much less to the most frequent diagnoses, such as the breast cancer, colorectal cancer and lung cancer. Each year, the audit focusing on the correctness of CNCR data results in a dataset of credible records with properly defined diagnosis, and a dataset of incomplete records with clearly specified objective causes of the problems. Similar filtration procedures are employed by most population-based studies which monitor the survival of cancer patient with regard to their diagnosis or treatment. Even records lacking information on the clinical stage can be employed for routine assessments of incidence and mortality rates, because the diagnosis of malignant tumours is specified. On the other hand, these records can be omitted for the purpose of health care assessment, without making any systemic distortion or reducing the information value of outputs. Table 1 provides an overview of the results of CNCR data audit for the recent period 2001-2007. - 23 -

All CNCR records Stage and/or TNM available TNM and stage available Stage available only TNM available only TNM and stage not available because of missing classification 1977-1981 1982-1995 1995-2007 1977-2007 1977-1981 1982-1995 1995-2007 1977-2007 1977-1981 1982-1995 1995-2007 1977-2007 1977-1981 1982-1995 1995-2007 1977-2007 5.0% 6.4% 3.0% 7.1% 5.5% 3.4% 10.4% 8.4% 6.5% 10.4% 40.8% 27.5% 22.0% 33.7% 52.0% 70.7% Stage and TNM not available Diagnosis based on autopsy / DCO Early death of patient Patient was not treated 1977-1981 1982-1995 1995-2007 1977-2007 1977-1981 1982-1995 1995-2007 1977-2007 1977-1981 1982-1995 1995-2007 1977-2007 4.9% 5.2% 4.5% 4.8% 7.4% 4.3% 2.9% 4.0% 13.4% 6.5% 3.5% 5.8% Stage and TNM not known 1977-1981 1982-1995 1995-2007 1977-2007 2.6% 6.4% 5.5% 5.5% 100% TNM 2nd edition Validity of TNM classifications in CNCR data TNM 3rd TNM 4th edition edition TNM 5th edition TNM 6th edition 80% 60% 40% 20% 0% 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005-24 - 2006 2007 Figure 3 Classification of records on malignant neoplasms (C00-C97) in CNCR with respect to completeness of data on the stage of disease. Year

Table 1 Analysis of CNCR records from the period 2001-2007 with respect to the availability of clinical stage and TNM Stage or TNM available Stage and TNM available Diagnostic group of malignant tumours N Stage and TNM available Stage available TNM available TNM classification not introduced Diagnosis based on autopsy/dco Early death of patient Patient was not treated Stage and TNM not available unfoundedly Oral cavity and pharynx (C00-C14) 8,450 79.4% 4.0% 1.0% 0.5% 2.3% 3.1% 2.7% 7.1% Oesophagus (C15) 3,286 64.9% 4.2% 1.7% 5.8% 7.2% 10.0% 6.2% Stomach (C16) 11,923 68.5% 3.1% 1.6% 5.4% 7.7% 9.1% 4.7% Colon and rectum (C18-C21) 55,811 82.1% 2.5% 1.2% 3.1% 3.6% 3.4% 4.1% Liver and intrahepatic bile ducts (C22) 5,771 40.4% 3.6% 3.6% 18.9% 15.1% 13.5% 4.8% Gallbladder and biliary tract (C23,C24) 6,973 54.0% 4.5% 3.1% 9.8% 12.0% 10.2% 6.4% Pancreas (C25) 12,375 55.9% 3.5% 3.6% 10.0% 11.3% 11.2% 4.4% Larynx (C32) 3,719 85.4% 2.6% 1.0% 2.3% 2.0% 2.0% 4.6% Bronchus and lung (C33,C34) 43,362 71.6% 2.9% 2.1% 0.1% 7.0% 7.2% 5.1% 3.9% Melanoma of the skin (C43) 12,039 89.7% 2.3% 1.4% 0.5% 0.7% 0.5% 5.0% Other malignant neoplasm of the skin (C44) 108,641 94.1% 0.6% 3.5% 0.1% 1.5% Connective and soft tissues (C47,C49) 1,810 53.4% 5.2% 8.0% 22.8% 2.3% 3.5% 3.1% 1.9% Breast women (C50) 40,471 88.4% 2.6% 0.6% 1.3% 1.7% 1.4% 4.0% Cervix uteri (C53) 7,255 78.4% 8.8% 1.1% 1.1% 1.2% 2.7% 6.9% Uterus (C54,C55) 12,409 61.2% 5.8% 0.8% 0.8% 1.5% 1.5% 3.4% 24.8% Ovary (C56) 8,356 75.0% 6.6% 1.6% 3.4% 3.4% 2.7% 7.2% Prostate (C61) 29,774 71.5% 5.4% 1.3% 2.8% 2.1% 7.3% 9.6% Testis (C62) 3,007 88.8% 3.6% 0.6% 0.5% 0.3% 0.3% 6.0% Kidney (C64) 18,498 75.5% 3.2% 2.3% 6.2% 3.5% 3.8% 5.6% Bladder (C67) 16,220 76.1% 5.8% 1.0% 1.5% 2.0% 2.5% 11.2% Brain and spinal cord (C70-C72) 5,480 100.0% Thyroid gland (C73) 4,872 79.2% 3.3% 1.1% 3.1% 1.1% 1.1% 11.1% Hodgkin s lymphoma (C81) 1,836 100.0% Non-Hodgkin s lymphoma (C82-C85,C96) 8,228 100.0% Multiple myeloma (C90) 3,143 100.0% Leukaemia (C91-C95) 8,229 100.0% Other malignant tumours 19,536 33.7% 22.1% 2.3% 7.7% 7.4% 12.0% 8.5% 6.3% Malignant tumours in total 461,474 73.7% 3.5% 2.0% 6.3% 3.0% 3.3% 3.3% 4.9% Source: Czech National Cancer Registry (CNCR) - 25 -

3.5 The Czech National Cancer Registry On-line Data from the Czech National Cancer Registry can be viewed and analyzed by anyone thanks to the project SVOD (System for Visualization of Oncology Data), which is available on-line at http://www.svod.cz. The objective of this comprehensive website is to provide a set of useful tools for performing analyses of several data sources which are automatically aggregated according to the user's choice (cancer epidemiology, demographic data, data on the risk status of the Czech population, etc.). All analytical tools provide clear outputs in the form of graphs or tables that are easy to understand; based on the results, the user can further specify or modify his/her analysis by setting a number of parameters to obtain the desired output. The software tools on this portal are primarily aimed for health care managers as well as professionals working in the field of human and ecological risk assessment. All graphical outputs (e.g. trends in incidence and mortality rates) have been prepared in a very safe way to be widely accessible to the general public. Automated analyses represent the core functions of the entire system. These analyses can be very straightforward, the results being displayed after just several mouse clicks, or they can be rather elaborate, depending on the users' experience and professional knowledge. Thanks to these software tools, anyone can analyze the epidemiological trends over the last three decades, stratify and filter cohorts of patients, and assess population risks in absolute or ageadjusted numbers. Some of the tools even offer stratification of cancer cases according to the clinical stage or TNM. Major epidemiological trends can be readily compared with the international data (GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide). The portal http://www.svod.cz is equipped with the following automated analytical tools: Incidence and mortality: overall time trends in incidence rates, mortality rates, and mortality/incidence ratio. The user can choose from the absolute numbers of cases, crude rates (number of cases per 100,000 population) or age-standardized rates (ASR): European ASR (ASR-E) or World ASR (ASR-W) is available. Time trends: changes in time trends in the incidence and mortality rates over time. The user can choose from the growth indices relevant to a specific year, or year-on-year changes. Both parameters can be viewed as absolute numbers or as proportional changes (expressed in percents). Regional overviews: comparison of the incidence and mortality rates in individual regions of the Czech Republic. The user can choose from the crude rates and age-standardized rates, and the graphical output can be displayed either as a map or as a bar chart. Age of patients: age structure of living and deceased patients diagnosed with a specific type of cancer. The user can choose from the absolute numbers of cases, recalculation per 100,000 population (age-specific rate), and percentage of cases according to age categories (age structure). Clinical stages: time trends in the proportion of cancer patients diagnosed at different clinical stages. The user can choose from the absolute numbers, percents, and crude rates (recalculation per 100,000 persons); the graphical output can be displayed as bar chart, line graph or pie chart over a selected time period. Comparison with foreign countries: comparison of incidence and mortality rates in the Czech Republic with international data. All these analyses are based on data obtained from the IARC database GLOBOCAN 2002. Comparative analyses: time trends in the incidence or mortality rates in selected region(s) in comparison with the overall epidemiological situation in the Czech Republic. Summary presentation: a comprehensive overview of the basic analyses for individual diagnostic groups. - 26 -

4 Czech clinical registries monitoring the use of monoclonal antibodies in cancer therapy Apart from population-based data, the Czech Society for Oncology has been using a set of clinical registries to collect real clinical data on cancer patients in the form of medical documentation. The principal objectives of these projects involve monitoring and retrospective evaluation of the treatment results and safety in areas where treatment effectiveness and health care improvements are of particular importance. Special attention is paid to the modern treatment approaches based on monoclonal antibodies, which are specifically targeted at cancer cells. These clinical registries have been developed as noninterventional studies within the Czech National Cancer Control Programme (http://www.onconet.cz) and have been running in compliance with the Czech legislation in force, meeting all requirements with respect to security of the collected data (for more details, see http://www.registry.cz). The primary and secondary objectives of clinical registries are listed below. Primary objectives of clinical registries Monitoring the number of patients treated with monoclonal antibodies Assessing the treatment safety in terms of standardized toxicity scoring Assessing the treatment effectiveness in terms of treatment response and survival Secondary objectives of clinical registries Analysis of patients' survival in relation to the monitored clinical parameters Analysis of data from patients treated with monoclonal antibodies in relation to the reference population data The network of clinical registries is well organized and fully functional, covering all main Czech health care facilities dealing with cancer patients. Data collection is representative enough, bringing significant added value to both the doctors and patients: Clinical registries inform the public about the incidence rates of a given cancer type (or disease in general) and provide informational support to public health care facilities and physicians. Oncologists get a better overview of their patients and receive regular reports on the number of patients involved in the entire project. Due to the overall assessment of nationwide data, health care providers obtain statistically relevant information on the treatment results. Moreover, a clinical registry can promote more effective exchange of information and experience among doctors. The clinical registries are based on electronic databases which meet high security standards. The security of individual records within the registry is guaranteed via de-identified data collection. Each patient's identity is replaced with a number (ID) which does not allow any retrograde identification of that person. Data security is further ensured via user accounts and encrypted communication channels. Authorized users can only access the system after entering a valid username and password. Users can be assigned various levels of authorization so that they have access to selected functions or parts of the system. An encryption protocol is used for data transfer between the user and central database to prevent tapping into the communication between the client and server. For this reason, any communication between - 27 -