UNOFFICIAL TRANSLATION

NATIONAL PROGRAM FOR COLORECTAL CANCER PREVENTION

1. Introduction National Program for Colorectal Cancer Prevention (hereinafter: Program) is based on evidence and recommendations of good clinical practice of international associations and various groups for prevention, early detection and colon cancer treatment. It represents a continuity of the consensus conference „‟Colon Cancer Diagnostics and Treatment‟‟, former Society of Coloproctology of Yugoslavia, held in December in 2003, which set a path for a defined strategy for colon cancer detection in people without symptoms, registration of all people at increased risk and secondary prevention in these groups of the diseased. The Program is in accord with the Health Care Development Strategy and guidelines of the declaration: Europe against Colorectal Cancer (Europe against Colorectal Cancer). Program is harmonized with the resolution on Cancer Prevention and Control (WHA58.22, „‟Cancer Prevention and Control‟‟ enacted by the World Health Assembly at its meeting in Geneva in 2005 and the Council of the European Union (2003/878/EC) on 2nd December 2003). The Program significantly contributes to improving the health of the population, as through preventive measures malignant colon tumors can be discovered in early stadiums when chances of curing this disease are high. The scope of the Program will include the target population group, and citizens will have equal possibilities to participate. Good clinical practice recommendations on screening relate to the average morbidity risk population without symptoms. In the increased risk population, it is necessary to follow special rules, i.e. examinations should be started at an early age and performed in prior determined intervals. It is considered that in developed countries approximately 4.6% of men and 3.2% of women develop cancer during their lifetime. The use of fecal occult blood test as an initial test in early colon cancer detection has lead to a reduction of the relative morbidity rate by between 18% and 33%. Active program for early colon cancer detection is purposeful as colon cancer usually grows from benign tumors of the lining- adenoma, during the carcinogenesis process lasting not less than ten years. This long-term process enables timely detection and removal of these changes. Detection of the disease in pre-carcinogenic stadium- the stadium of benign polyp or in the stadium of localized disease gives the possibility of complete recovery in 85% (76%-90%) of the diseased.

2. Analysis of the current situation regarding colorectal cancer in the Republic of Serbia Compared with people of other nations, the citizens of Serbia are at an average risk of cancer morbidity and mortality, with exception to lung cancer and cervix cancer, where our country is the leader in the registered incidence rates in Europe. 2.1. Epidemiology of colorectal cancer in the Republic of Serbia In the Republic of Serbia, malignant colon tumors are second most common type of malignant tumors from which approximately 3800 people of both genders fall ill and 2300 die every year. In 2006 in the mortality structure of all malignant tumors, colon and rectum cancer were the second most common cause of death, following lung cancer in men and breast cancer in women. 2.2. Risk factors for colorectal cancer pathogenesis Colon cancer pathogenesis risk rises significantly after age 40 and 91% of all carcinoma is discovered in people who are aged over 50. Every person aged over 50 is at 4.8% risk that by 74 they would develop colon cancer, i.e. there is a 2.3% risk of colon cancer mortality. Symptoms indicating colon cancer are occult or manifest bleeding, changes in bowel motion, abdominal pain and anemia. A quarter (25%) of the diseased has a family colon cancer anamnesis, 15% of which in first degree relatives. Irregular nutrition (food high in animal fat and proteins, and low in fibers), overweightness, smoking, and a positive family anamnesis, polyps of the colon (the risk increases after age 50) and lack of physical activity are the risk factors for developing colorectal cancer. 3. Program Targets Targets of the Program are to decrease colon cancer morbidity and mortality of the population. The Strategy for enhancing colon cancer early detection entails the population which is more informed on the importance of colon cancer early detection and health care professionals with better education on the Program itself. 4. Methods of colon cancer early detection Several methods can be used for colon cancer early detection individually or which is most common in combination. The most frequently used are the fecal occult blood tests for detecting traces of blood (imperceptible to the naked eye) in the stool and flexible rectosigmoidoskopy or colonoscopy. Other diagnostic procedures such as determining specific DNA mutations in the stool and virtual colonoscopy are in the efficiency and reliability testing phase. 4.1. Fecal occult blood test Early colon cancer detection via tests for detection of occult blood in the stool in the asymptomatic, average-risk population has proved to be an appropriate method due to its simplicity of use and low cost. In large, population-based, controlled studies- 1% and 5% of the cases had evidence level B) positive test (in the pilot program at the territory of seven local communities of Vozdovac Municipality 3.6% of the cases). A positive test is an indication of the

necessity of further gastroenterological testing i.e. colonoscopy. The sensitivity of the test is about 50% and specificity 98% (the sensitivity of the Guaiac-impregnated slide test is 30-50% therefore two samples from three successive stools should be tested following prior „‟white diet‟‟ and without prior rehydratation of the samples, while immunochemical test has a 90% sensitivity, therefore one sample being enough and nutritional restriction unnecessary. Predictive value of the positive test in early colon cancer detection is 5%-10%, and 20%-30% for adenomas. Serbian Gastroenterologist Association, Serbian Association for Gastroenterological Endoscopy and Serbian Association of Coloproctologists acting upon recommendation from World and European Endoscopic Association for Early Colon Cancer Detection recommend the fecal occult blood tests as an initial method in average risk population aged over 50. The initial test is for singling out people who are at the highest risk from having neoplastic disease from those at the lowest risk. Fecal occult blood testing is performed every year. Colonoscopy should be performed in people whose fecal occult blood tests are positive with the aim of determining the cause of occult bleeding. Early colon cancer detection program should be started earlier in people at an increased risk from developing colon cancer (inflammatory bowel diseases, genetic burden, family or personal history of adenoma or colorectal cancer). People tested for presence of occult blood in the stool should be warned that a negative result does not mean complete security that the person does not have a polyp or colon cancer. 4.2. Colonoscopy Colonoscopic examination, used as an initial method is significantly costlier, but at the same time it is very sensitive in detecting the smallest lesions. Apart from sensitivity, the advantage of endoscopic methods is that spotted changes can be removed during the examination itself thus saving time and money, and the procedure becomes a treatment method. With adequate preparation and if the endoscopist is trained to perform total colonoscopy, in 90%-95% cases colon cancer is detected via colonoscopy. People with a positive fecal occult blood test should be sent to colonoscopy with a view to endoscopic therapy (e.g. polypectomy). People at high risk from developing colon cancer are suggested colonoscopy at an early age and monitoring during an interval recommended for that disease without prior testing for occult blood presence in the stool. People, who wish to be examined endoscopically within the screening, should be sent to a secondary level institution for performing colonoscopy examination once in ten years or at least for rectosigmoidoskopy once in five years. 5. Measures of primary prevention (organizing programs for colon cancer early detection) Before the start and throughout the Program it is necessary to have a public health approach through spreading information via a media campaign on the importance of prevention, colon cancer early detection and on the measures in the scope of the Program. The included activities are: identification of the population, mobilization and motivation, calling and testing people aged 50-70. In implementing these activities participation of the following subjects is planned: primary health care, health care institutes, associations and counseling for preventive actions. Preconditions for coordinated functioning of all subjects in the campaign are: a harmonized content, manufacture, production and distribution of a uniform promotion material. General practitioners are the main foundation for the mobilization of the population, providing information on the screening recommendations, testing and analyzing test

3

results from the pilot project. Their task is to inform people from an age group that is recommended colorectal cancer screening on the program itself and testing methods, as well as to provide people‟s assent for participating in the program. It is necessary, when the need arises, to educate the primary health care and patronage service staff to suggest fecal occult blood tests to people aged over 50 and further testing i.e. colonoscopy to people with positive tests. A letter of invitation to testing is sent to home address of people aged between 50 and 70 on the basis of an updated population census from 2002, voting list, i.e. the data from health records of appointed practitioners and from the registration records of the insurees of the Republic Health Care Insurance Bureau. A brochure explaining the content and aim of the program and mode of implementation is sent with the invitation letter, as well as a questionnaire to determine whether the person belongs to one of the risk groups and possible risk factors for developing the disease. The invitation should contain a guide on performing the test and three fecal occult blood tests. Throughout the Program, the staff of the preventive centre, the teams of the appointed physician and patronage services staff should, within their daily activities, motivate and „‟remind‟‟ people from the target group on the significance of participation in the Program. Four weeks after the first letter is sent, a second invitation letter for participation in the Program is brought personally to the home address, unless the invitation has been made by phone. Thus invitation in “three intervals” is provided which increases the participation in the Program and its efficiency. A 12 hour telephone line for additional information regarding Program implementation will be introduced in the preventive centers‟ offices in medical centers (dom zdravlja) and in health care institutes. A portal of the Ministry of Health with all available information regarding the Program will be opened for the purposes of the Program. Pursuant to the contract with the Republic Health Care Insurance Bureau, GP specialists (appointed practitioners), nurses and patronage nurses, biochemical technicians, the staff of the Health Care Insurance Bureau, gastroenterology specialists trained for performing colonoscopy and surgeons will participate in the Program. Persons who wish to be tested perform home tests and send test charts for reading in an attached envelope to preventive centers of medical centers (dom zdravlja) one or two days after the test is performed. Preventive center staff schedules a colonoscopy on behalf of the patient in a referent secondary, i.e. tertiary center for the following cities: Belgrade, Novi Sad, Nis and Kragujevac and sends a notice with colonoscopy instructions to home address and to the appointed GP. Data from the questionnaire and the results of diagnostic examinations are gathered and analyzed in Public Health Institutes, Program implementation monitoring is performed by the Public Health Institute „‟Dr Milan Jovanovic-Batut‟‟ and the by the Republic Expert Committee for Colon Cancer Prevention and Early Detection on behalf of the Ministry of Health on the basis of the Reports of the Institutes. The Final Report is forwarded to the Ministry of Health. Information system prior tested in a pilot test in the territory of Vozdovac Municipality is used in the Program. Program Executives are: -medical centres (domovi zdravlja)( appointed prаctitioners and preventive centers‟ practitioners); - Public Health Institutes; -gastroenterologists endoscopists; -surgeons.

4

Public Health Institute „‟Dr Milan Jovanovic-Batut‟‟ continually organizes and coordinates activities related to Program implementation, monitoring and constant estimate of activities‟ implementation in cooperation with Public Health Institutes. 5.1. Questionnaire - Together with the invitation, all persons receive at their home address a questionnaire in which they are asked to provide basic demographic data and to specify whether they have any of the disease symptoms (changes in bowel movement, visible blood in the stool etc.), whether they belong to a risk group (family burden, chronic inflammatory bowel diseases, personal and family anamnesis of previously removed polyps or surgeries on other tumors) and what their hygienic and nutritional habits are. 5.2. Test Apart from receiving a questionnaire at home address, people from a target population group also receive three copies of fecal occult blood test with instructions on the testing mode which they send back to the address of the preventive centre of the medical centre (dom zdravlja) together with the questionnaire. People with a positive test are scheduled a colonoscopy and they are advised via a written notice on the examination date and time, application instruction and if possible of the name of the physician to perform the examination. A „‟blue‟‟ copy of the notice is forwarded to the appointed GP. 5.3. Colonoscopy Colonoscopy should be complete (over 90% of the examined), up to the caecum, and if necessary ileoscopy should be performed. Every pathological change should be noted in a special standard form made in four copies, and if possible the polyps should be removed completely during the first examination and sent to histopathological analysis. A specialist gastroenterologist endoscopist performing the examination is to provide an explanation of the pathological finding, the intervention and also give instructions on further procedures and monitoring interval. The diseased with localized colon cancer are additionally treated (ultrasound examination of abdomen, easy-to-consult heart and lungs image, abdomen CT) and sent to further therapy (surgical or depending on the decision of the council). 6. Program monitoring and evaluation (Indicators of Program monitoring and evaluation) At the level of the Republic of Serbia, the Public Health Institute „‟Dr Milan JovanovicBatut‟‟ performs Program monitoring and evaluation based on the reports from the Public Health Institutes and forwards a report to the Ministry of Health on a regular basis. For short-term evaluation of the Program implementation success the following will be evaluated: response, time which has passed from sending an invitation letter for examination to the patient, receipt of the notice on the positive finding to the examination (colonoscopy), what is attitude to further examination of the „‟positive‟‟ people and which is the usage rate of the applied resources (colonoscopy, analgosedation, endoscopic interventions- success of the examinations performed, monitoring for pathologic findings and treatment). Long-term estimate of Program implementation relates to the estimate of morbidity (morbidity and incidence) and mortality (death toll) rate reduction.

5

Program monitoring indicators are: lower rate of the colon cancer population, number of reports on performed preventive examinations planned by screening, number of educated health care professionals, number of health care institutions equipped for performing systematic medical examinations, printed promotional material and the number of sent individual invitation letters for screening. 6.1. Expected number of positives, further actions, cost and profitability of the Program According to the estimate of the Republic Statistical Bureau (30th June 2006) in the Republic of Serbia, with exemption of the data for AP Kosovo and Metohija, of the total population, 1.903.721 is aged between 50 and 69 and planned to be invited to testing. It is expected that 3%-4% of all examinees (3.6% in the pilot Program) will have positive findings of occult blood in the stool in the Republic of Serbia on the basis of the literary data and the results of the pilot research. 7. Program financing Financing Program implementation will be provided from the budget of the Republic of Serbia depending on the dynamics of resources spending for the previous year and the planned activities for the next. Resources for health care services and health care executives will be provided from the fund of the Republic Health Care Insurance Bureau. Pursuant to the law other sources of financing can be used for Program financing. 8. Profit gained from reducing the risk from malignant diseases and the prevention strategy for four basic risk factors Primary prevention factors Smoking Use of tobacco is individually the most common preventable cause of malignant diseases in the world. Smoking is estimated to be related to 30% of total cancer morbidity and mortality (with exception of skin cancer non-melanoma type). This habit is related to 80-90% of lung cancer morbidity. Dietary habits /Overweightness Dietary habits are related to 30% of cancer cases in developed countries. Overweightness, defined as the Body Mass Index (BMI) higher than 25 kg/m2, is related to 10% of all cancer cases.

Profit gained from reducing the risk from malignant diseases Epidemiological studies consistently confirm a relation between the smoking habit and lung, pharynx, mouth, larynx, esophagus, bladder, kidney, pancreas and cervical cancer. Several studies indicate a relation between gastric, liver, colon and rectum cancer.

Unhealthy dietary habits increase the risk from several cancer types: colon, esophagus, breast, womb and kidney cancer. The strongest proof level is determined for colon cancer. Overweightness as a special factor also rises the risk from esophagus, colon, womb, breast and kidney cancer. A certain type of food and modes of preparation raise the risk of cancer development. These are for example: fish preserved the Chinese way, aflatoxin (aflatoxin-fungal contamination sometimes found on granular food, e.g. peanuts) preserved meat, salt and salted food, as well as very hot liquids and food. High rate of tomato and tomato products use in

6

Physical inactivity. Physical inactivity as a risk factor, is connected with about 1% of all cancer cases.

Alcohol abuse Alcohol abuse is related to about 1-6% of all cancer cases in dev eloped countries.

everyday nutrition provides lycopene to the organism, which decreases the risk of several types of malignant diseases. Most often the protective effect of lycopene is connected with prostate, breast, lung and digestive organs‟ cancer. There is still not enough evidence to confirm the protective role of green tea, but there are several ongoing researches regarding this issue. The use of finished beta-carotene and vitamin E preparations is not connected to the reduction of cancer incidence and mortality in the general population. It is difficult to estimate the isolated contribution of physical activity to cancer prevention, mostly due to the fact that the benefits of exercising are related to the decrease of body weight. Physical activity is mostly related to colon, breast and prostate cancer prevention. Alcohol abuse is related to several types of malignant diseases. Consummation of two standard drinks related to liver, mouth, pharynx, esophagus (especially in people who are passionate smokers as well) and larynx. That is a risk factor for breast cancer in women and colon cancer, especially in men. The risk rises with the increase of alcohol intake.

9. Recommendations for average- risk people (people without symptoms aged 50 or more) Recommended activities

Stratification of risk depending on the family anamnesis necessary It is necessary to suggest all people over 50, who do not belong to any of the risk groups, to take part in the Colon Cancer Early Detection Program Optimum screening method is the fecal occult blood test * People without colon cancer family anamnesis should be submitted to fecal occult blood testing once a year People with a positive test should be sent to a secondary level institution for performing a complete colonoscopy examination.

Evidence Degree level of recomm endation А

J

B B

JJа JJа

People who express a desire to be examined endoscopically within the screening should be directed to a secondary level institution for performing flexible rectosigmoidoskopy at least once in every five years. Irigography with double contrast is not a method of choice in the screening. * The sensitivity of the Guaiac-impregnated slide test is 30-50% therefore two samples from three successive stools should be tested following prior „‟white diet‟‟ and without previous rehydratation of the samples. Immunochemical test has a 90% sensitivity, therefore one sample is enough and nutritional restrictions unnecessary.

10. Aims of Colon Cancer Early Detection Program Target group __________ Program targets ____________ Specific targets Men and women aged 50-70 Reduce colon cancer mortality by Determine colon cancer incidence

7

with the average risk from developing colon cancer annually.

at least 10% after five years of Program implementation

Cover at least 50% of people invited for testing

Program scope should include75% of people from risk groups in the course of the ten years of Program implementation

and prevalence in a healthy (asymptomatic) population aged over 50, and the influence of certain risk factors for developing, localization, degree of extension and operability of the tumor as well. Enable as many as possible secondary centers to perform colon examination with standard endoscopic procedure and complete colon cancer examination in not less than 90% of performed examinations Standardize surgical, medicamentous and radiological treatment of people with colon cancer

11. Activities for Program implementation Activities Motivation and mobilization of the population Testing and reading fecal occult blood tests charts Performing colonoscopic examination Further procedures (diagnostic and therapeutic) when necessary Participants in Program implementation

Financial resources

Sources of financing

Deadline

First half of 2009 Second half of 2009 2010 And beyond Public Health Institute „‟Dr Milan Jovanovic-Batut‟‟ Health Care Centers Republic Health Care Insurance Bureau Preventive centers of medical centers (домови здравља) Hospitals Clinics Polyclinics Depend on the number of people who would respond to the invitation for testing Depending on the number of positive persons who would decide to undergo colonoscopy Budget of the Republic of Serbia Resources of the Republic Health Care Insurance Bureau on the basis of a contract with institutions

Indicators of Program realization

Number of the tested Number of colonoscopies Number of polypectomies and discovered carcinoma Number of registered people who belong to one of the risk groups

Success indicators

Number of discovered colon carcinoma in localized stadium (short-term) Mortality rate reduction (long-term)

8

12. Dynamics of implementation of activities Activities Printing and distribution of informative brochure on colon cancer and on the importance of early detection Media campaign on colon cancer prevention and early detection

Deadline

4/4 2008-1/4 2009 Start 2009 and further in continuity during Program implementation

Drawing and printing of Instructions for fecal occult blood testing and preparation for colonoscopy

4/4 2008-1/4 2009

Procurement of fecal occult blood tests

Start 2009 and further in continuity during Program implementation 3/4-4/4 2009 and further in continuity 3/4-4/4 2009 and

Printing and sending invitations for fecal occult blood testing at home address

Introduction of a telephone line for information relating to the Program in preventive centers and Health Care Institutions Reading of tests in preventive centers of medical centers (domovi zdravlja)

Scheduling colonoscopic examinations for positive patients and advising them on the time and date of the examination

further in continuity 4/4 2009 and further in continuity 4/4 2009 and further in continuity

Procurement of necessary equipment for performing colonoscopy and interventions (polypectomy) Analysis of questionnaires

2/4 2009 4/4 2009 and further in continuity

Procurement of IT equipment and information system installations (tested in the previous pilot program) 2/4-3/4 2009 Education of primary health care staff 2009 and further Education of gastroenterologists endoscopists Drafting of the Quality Control Assurance Plan Introducing Colon Cancer Diagnostic and Treatment Centers Ministry of Health/ Republic Expert Committee for Colorectal Participants in Program Cancer Prevention implementation Public Health Institute „‟Dr Milan Jovanovic-Batut‟‟ Health Care Centers Republic Health Care Insurance Bureau Preventive centers of medical centers (домови здравља) Financial resources /

9

Sources of financing Program realization indicators

Success indicators

Budget of the Republic of Serbia Number of printed and distributed brochures Number of printed Instructions for testing and preparation for colonoscopic examination Functional software in the units for Program implementation installed Number of participants in the Program (min. 50%) Number of colon carcinoma discovered in localized stadium (short- term) Mortality rate reduction (long-term) from 10% five years after the start of Program implementation

10