«Colorectal cancer screening in the regions of the Russian Federation:

Stanislav Konovalov Leading expert in HTSA Plus program Relevance of the problem

The structure of mortality rate in Russia from various diseases

1 place • Diseases of the circulatory system

2 place • Malignant neoplasms

3 place • Injuries and poisonings

Colorectal cancer (CRC) occupies leading positions in the oncology rates of all developed countries Relevance of the problem

Mortality rate from malignant neoplasms among the Russian population (both sexes, 13.6%)

Rectum 5,7 Pancreas 5,9 Trachea, bronchi, lungs 17,3

Breast 7,8

Stomach 10,3 Colon 7,9 Quantitative immunochemical FOBT (FIT) test HTSA (Hemoglobin Transferrin Simultaneous Assay)*

High-performance  Unique specimen collection container analyzer (Provides stability of Hb and Tf)

 Reagent containing colloid gold

 Fully automated  Performance: 300 tests/hour

* HTSA (Hemoglobin Transferrin Simultaneous Assay) - a combination of the quantitative detection of fecal hemoglobin (Hb) and fecal transferrin (Tf) currently has the highest accuracy level: 96% for patients with cancer and 88% for patients with precancerous stages. The first pilot project in the Russian Federation in Khanty-Mansiysk region, in which the CRC screening program was launched and has been successfully implemented since 2011

1400 км

Сургут Ханты-Мансийск Нефтеюганск Нижневартовск Test for Tf confirms false-negative test for Hb

Traverse colon Traverse colon Ascending colon Ascending colon

Descending colon Descending colon

Sigmoid colon Sigmoid colon Bleeding Hb, Tf

Rectum Rectum

Bleeding

Hb, Tf Denatured Hb, Tf Hb, Tf

The cancer of the ascending colon is virtually asymptomatic and at its early stages its detection is difficult. This neoplasm occurs mostly among people older than 50, and the incidence rate is growing each year. This calls for a need for new methods of detection of this type of cancer. Transferrin Test (Tf) can be an effective and reliable method for diagnosing colorectal cancer. HTSA Fecal Occult Blood Test using the immunochemical IFOBT/FIT method in Khanty-Mansiysk Region - Yugra

DETECTION Immunochemical fecal occult blood test OCCULT bleeding in various intestine areas iFOBT/FIT

Fecal Hemoglobin (Hb) – high levels of Hb indicate the damage of lower areas of intestine. Hb

Fecal Transferrin (Tf) - high levels of Tf indicate the Tf damage of higher areas of intestine . Besides, Fecal Tf allows avoiding the false-negative results for Hb.

© “Diagnosis” Yoshinori Takashima, Takao Shimada, Tamotsu Yokozawa – 2015; 2(1): 53-59.

(Hemoglobin Transferrin Simultaneous Assay) a combination of the quantification of fecal hemoglobin (Hb) and fecal transferrin (Tf) has the highest current accuracy level: 96% for patients with cancer and 88% for patients with precancerous conditions. Transferrin – in the LOINC system

 In may 2017 fecal transferrin was introduced to the international database and universal standard for identification of medical doctor’s and laboratory examinations – LOINC, and it was given a code 86271-4.

 LOINC is used for standardized presentation of medical terminology in the field of laboratory research and clinical observation for the purpose of electronic exchange and the collection of clinical data obtained from various information systems. Quantitative detection of fecal transferrin and hemoglobin (for occult blood) using a two-day HTSA method in the pilot project "colorectal cancer screening in the Khanty-Mansiysk region - Ugra" on the NS-Plus analyzer

Surgut Khanty-Mansiysk Nizhnevartovsk Nefteyugansk TOTAL

People examined 88685 19396 47309 25668 181058 Positive results («+»), people 10222 11,5% 3380 17,4% 7842 16,6% 4010 15,6% 25454 14,1% Positive results («+»), tests 16282 5261 12538 5900 39981 «+» for Hb (Day 1 and Day 2) 11880 73,0% 3703 70,4% 8602 68,6% 4295 72,8% 28480 71,2% «+» for Hb Day 1 6253 52,6% 1909 51,6% 4470 52,0% 2228 51,9% 14860 52,2% «+» for Hb Day 2 5627 47,4% 1794 48,4% 4132 48,0% 2067 48,1% 13620 47,8% «+»for Tf (Day 1 and Day 2) 4402 27,0% 1558 29,6% 3936 31,4% 1605 27,2% 11501 28,8% «+» for Tf Day 1 2178 49,5% 777 49,9% 1970 50,1% 831 51,8% 5756 50,0% «+» for Tf Day 2 2224 50,5% 781 50,1% 1966 49,9% 774 48,2% 5745 50,0% «+» for both markers 449 2,8% 160 3,0% 447 3,6% 145 2,5% 1201 3,0% «+»for Hb and Tf Day 1 1167 13,8% 398 14,8% 1078 16,7% 454 14,8% 3097 15,0% «+»for Hb and Tf Day 2 1106 14,1% 414 16,1% 1076 17,6% 389 13,7% 2985 15,4%

Positive results («+»), people ОбследованоPeople examined человек положительныхPositive results результатов Positive results («+»), tests положительныхHb positive на Hb положительныхTf positive на Tf «+» на Hb «+» на Tf из них «+» наBoth оба markers маркера

3,0 % 181058 25454; 28480 14,1% 28,8 % 71,2 %

11501 Detection rate of early stages of tumor in Russia in 2011 - 2015* Malignant neoplasms registered Colon Rectum, recto-sigmoid junction, CRC

(С18) anus (С19-21) 2015 64 314 36 494 (56,7%) 27 820 (43,3%)

2014 61 874 35 089 (56,7%) 26 785 (43,3%) in year in

2013 58 406 32 931 (56,4%) 25 475 (43,6%) 3% 2012 58 099 32 528 (56,0%) 25 571 (44,0%) 2011 57 047 32 014 (56,1%) 25 033 (43,9%) Of those had the following stage of disease (%): Rectum, recto-sigmoid junction, anus (С19- Colon (С18) 21) I ll lll lV l ll lll lV 2015 8,0 37,3 25,1 27,7 10,6 40,3 24,2 22,6 2014 7,4 35,7 26,6 27,7 10,2 38,8 24,8 23,5 2013 6,8 35,1 27,6 27,6 9,3 38,8 25,1 23,7 2012 6,7 35,3 27,5 27,5 9,0 38,6 26,0 23,2 2011 5,6 34,4 28,4 28,0 8,8 39,3 25,2 23,4 Mortality in the first year after making a diagnosis: 2015 27,4 23,8 2014 28,4 24,9 Rectum, recto-sigmoid 2013 Colon (С18) 28,4 25,7 junction, 2012 29,6 25,8 anus (С19-21) 2011 30,5 27,7 * - «Condition of the oncology aid to the population in 2011-2015» – - edited by A.D. Caprin, V.V. Starinski, G.V. Petrova - Moscow, 2012-2016

Conclusions: In the tables there are data over the 5-year period. In comparison with Khanty-Mansiysk region in Russia the detection rate on the first stage has grown only by 2.4% in colon. In rectum detection rate of malignants has grown by 1.8%. Statistics after implementation of immunochemical iFOBT (FIT) test by HTSA method in Khanty-Mansyisk Malignant neoplasms registered Autonomous Okrug — Yugra Colon Rectum, rectosigmoid, anus CRC (С18) (С19-21) 2015 585 317 (54,2%) 268 (45,8%) 2014 476 258 (54,2%) 218 (45,8%) 2013 479 265 (55,3%) 214 (44,7%) 2012 447 246 (55,0%) 201 (45,0%) 2011 390 195 (50,0%) 195 (50,0%) Of those had the following stage of disease (%): Colon (С18) Rectum, recto-sigmoid junction, anus (С19-21)

I ll lll lV l ll lll lV 2015 25,6 26,5 17,7 29,3 19,8 33,6 22,8 21,6 2014 17,8 32,9 21,7 25,6 25,7 27,1 22,0 21,1 2013 12,6 33,2 19,6 24,9 12,6 33,2 19,6 31,8 2012 14,6 32,9 15,9 34,1 16,9 38,3 20,4 23,4 2011 8,2 37,4 23,1 25,1 11,3 40,5 20,0 21,5 Mortality in the first year after making a diagnosis: 2015 22,8 15,4 2014 19,0 23,0 Rectum, recto-sigmoid 2013 Colon (С18) 23,3 14,6 junction, 2012 24,9 13,8 anus (С19-21) 2011 26,3 30,5 * «Condition of the oncology aid to the population in 2013-2015» - edited by A.D. Caprin, V.V. Starinski, G.V. Petrova - Moscow, 2012-2016

Conclusions: The data over the 5 year period in Khanty-Mansiysk region are represented above. Due to the 2-days HTSA method use (fecal hemoglobin and transferrin simultaneous assay) detection of colon cancer at the 1 stage has grown three times. Two-days HTSA method helped to increase detection of rectum cancer two times. As a result CRC mortality rate remained at a low level. The test results conducted on a Discrete Automated Clinical Chemistry Analyzer NS-Plus C15 (Japan) in Nizhnevartovsk (2011 to 2018)

• Results of the two-days immunochemical test - iFOBT (FIT) using the HTSA method (fecal hemoglobin (Hb) and transferrin (Tf) simultaneous assay ) (for the entire period).

People examined 47309

Positive results («+»), people 7842 16,6% Positive results («+»), tests 12538 «+» for Hb (Day 1 and Day 2) 8602 68,6% «+» for Hb Day 1 4470 52,0% «+» for Hb Day 2 4132 48,0%

«+»for Tf (Day 1 and Day 2) 3936 31,4% «+» for Tf Day 1 1970 50,1% «+» for Tf Day 2 1966 49,9%

«+» for both markers 447 3,6%

«+»for Hb and Tf Day 1 1078 16,7% «+»for Hb and Tf Day 2 1076 17,6%

Positive results («+»), tests Positive Results 16,6 both % Table 2 Quantitative two-days immunochemical test using the HTSA method

«+» for both «+» for Hb «+» for Tf markers Day 1 4470 1970 1078 Day 2 4132 1966 1076

Positive results for Hb: Day 1 and Day 2

Hb Day 1 Hb Day 2

Positive results for Tf: Day 1 and Day 2

Tf Day 1

Tf Day 2 Appendix 1. Test results. Quantitative simultaneous Hb and Tf tests using the HTSA method (2018) (two- days method) Hb Tf Hb Tf Day 1 Day 1 Day 2 Day 2

This patient showed a significant excess of Hb and Tf cut-off in both days. With a positive value in any of the days or both days, the doctor assigns an additional examination (for example, a colonoscopy), and the final diagnosis is reached based on its results. This patient would have been missed when only conducting a one-day Hb test. For small and uneven positive Tf values, the patient is most likely to have an initial form of an upper intestine disease, so additional tests are necessary. For example, a colonoscopy.

This patient had positive values only in day 2. With a one-day study, he would have been missed. The doctor assigns an additional examination, which leads to the final diagnosis. Quantitative detection of transferrin and hemoglobin in feces (FOBT) using two- days HTSA method in Moscow Central Polyclinic

474 people were examined. Percentage of positive 40 positive cases (8.4%) were detected, including: results - Women - 24; 8,4% - Men - 16.

Examination revealed: 1. Polyps - 20 people. (by results of cytology, tubular adenoma of various degrees of dysplasia) 2. Colon cancer - 4 people. 3. Diverticular disease of the large intestine - 6 people. 4. Colitis of various etiology - 5 people. 5. Nonspecific ulcerative colitis - 3 people.

6. Crohn's disease - 2 people. Полипы 7,5% 5,0% 50,0% 12,5% Рак ободочной кишки

Дивертикулярная болезнь толстого кишечника Колиты различной 15,0% этиологии Неспецифический язвенный колит 10,0% Болезнь Крона Quantitative detection of transferrin and hemoglobin in feces (FOBT) using two- days HTSA method in Moscow Central Polyclinic

Hb «+» Tf «+» Hb Tf «+»

Day 1 19 12 6 Day 2 20 12 7

Positive results for Hb 1 day and 2 days

48,7% «+» на Hb 1 дня «+» на Hb 2 дня 51,3%

Positive resultsfor Tf 1 day and 2 days

50,0%

«+» на Tf 1 дня «+» на Tf 2 дня 50,0% Quantitative detection of transferrin and hemoglobin in feces (FOBT) using two- days HTSA method in Moscow Central Polyclinic

Hb Tf Hb Tf Hb Tf Hb Tf № 1 день 1 день 2 день 2 день № 1 день 1 день 2 день 2 день 3 669 30 17 3 3 669 30 17 3 6 239 18 6 239 18 25 42 8 22 99 25 42 8 22 99 26 75 8 174 13 26 75 8 174 13 28 39 2 81 70 28 39 2 81 70 33 0 27 268 79 33 0 27 268 79 43 12 2 468 94 43 12 2 468 94 45 188 29 107 6 45 188 29 107 6 51 309 11 94 8 51 309 11 94 8 53 207 4 112 7 53 207 4 112 7 55 37 129 7 113 55 37 129 7 113 57 41 0 544 1 57 41 0 544 1 59 872 172 130 3 59 872 172 130 3 60 64 6 357 13 60 64 6 357 13 61 27 1 745 5 61 27 1 745 5 67 444 70 15 4 67 444 70 15 4 81 114 84 53 7 81 114 84 53 7 91 11 118 24 37 91 11 118 24 37 99 44 7 186 9 99 44 7 186 9 100 15 4 124 5 100 15 4 124 5

Выводы: For the final diagnosis, patients underwent a colonoscopy and other cytological tests at the second stage of the examination. Conclusions • The immunochemical iFOBT (FIT) test by HTSA method will significantly save public funds since detection of patients with early stages of cancer will allow to timely conduct low-cost preventive procedures, to preserve patients’ health, to improve the quality of their life and to avoid complex and expensive treatment and as a result to reduce the incidence (stage III and IV) and mortality related to colorectal cancer.