The effect of diindolylmethane on the course of HPV-associated cervical intraepithelial neoplasia in women treated in routine clinical practice (CERERA study)
Apolikhina I.A., Zarochentseva N.V., Gorbunova E.A., Kedrova A.G., Mkrtchyan L.S., Belokrinitskaya T.E., Krasilnikov S.E., Shumeikina A.O., Pasman N.M., Suturina L.V., Islamidi D.K., Popandopulo V.A., Golubenko А.Е., Sokolov K.A., Verbitskaya Yu.S.
Objective: The primary aim of the study was to evaluate the effect of Cervicon-DIM (diindolylmethane) on cytological and clinical signs of HPV-associated LSIL/HSIL in real clinical practice. The secondary aim was to obtain additional data on the safety of Cervicon-DIM.
Materials and methods: This was an open observational study on the assessment of the dynamics of the cytological picture of cervical intraepithelial neoplasia in patients who received diindolylmethane in the form of vaginal suppositories in routine clinical practice (CERERA study). The study included patients with confirmed CIN I/LSIL or patients after excision for CIN II/HSIL who were treated with vaginal suppositories containing diindolylmethane for 6 months. The results of cytological examination, PCR HPV testing, and colposcopy findings were assessed before and after treatment.
Results: A total of 140 female patients were included in 10 study centres, 132 of whom completed a 6-month course of treatment with diindolylmethane. The results of the cytological examination showed that the regression of the disease was observed in 81% (39/48 patients) in the CIN I/LSIL group, and there were no signs of intraepithelial lesion and malignant process in the group of patients after excision and treatment with diindolylmethane suppositories according to the results of the cytological examination of all women who presented at the follow-up visit. The colposcopy findings revealed positive dynamics in 79/88 (89%) patients with CIN I/LSIL and in 39/44 (89%) patients with CIN II/HSIL. Elimination of HPV infection was noted in 80% (106/132) of patients in both groups after 6 months of therapy.
Conclusion: The results of the CERERA study demonstrated the therapeutic effects of diindolylmethane administered as vaginal suppositories in mild to moderate cervical dysplasia in women treated in real clinical practice.
Authors’ contribution. Apolikhina I.A., Gorbunova E.A., Zarochentseva N.V., Sokolov K.A., Verbitskaya Yu.S. – developing the design of the study, review of publications on the subject of the article, statistical analysis of the obtained data, writing the text of the article; Kedrova A.G., Mkrtchyan L.S., Belokrinitskaya T.E., Krasilnikov S.E., Shumeikina A.O., Pasman N.M., Suturina L.V., Islamidi D.K., Popandopulo V.A., Golubenko A.E. – obtaining the data for analysis, editing the text of the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The study was sponsored by Alcea LLC.
Ethical Approval: This study was approved by the Independent Interdisciplinary Committee for Ethical Review of Clinical Trials on 27.05.2022 and registered with Centre for Information Technologies and Systems of Executive Authorities of the Federal Service for Supervision in the Sphere of Education and Science of the Russian Federation in accordance with the Order of the Government of the Russian Federation dated 31 March 2009 No. 279, R&D number 122110300027-9.
Patient Consent for Publication: The patients signed informed consent for the publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Apolikhina I.A., Zarochentseva N.V., Gorbunova E.A., Kedrova A.G., Mkrtchyan L.S., Belokrinitskaya T.E., Krasilnikov S.E., Shumeikina A.O., Pasman N.M., Suturina L.V., Islamidi D.K., Popandopulo V.A., Golubenko А.Е., Sokolov K.A., Verbitskaya Yu.S. The effect of diindolylmethane on the course of HPV-associated cervical intraepithelial neoplasia in women treated in routine clinical practice (CERERA study).
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (3): 178-188 (in Russian)
https://dx.doi.org/10.18565/aig.2025.67
Keywords
cervical intraepithelial neoplasia
CIN
LSIL
HSIL diindolylmethane
Cervicon-DIM
References
- Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024; 74(3): 229-63. https://dx.doi.org/10.3322/caac.21834.
- Arbyn M., Weiderpass E., Bruni L., de Sanjosé S., Saraiya M., Ferlay J. et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob. Health. 2020; 8(2): e191-e203. https://dx.doi.org/10.1016/S2214-109X(19)30482-6.
- Ginsburg O., Bray F., Coleman M.P., Vanderpuye V., Eniu A., Kotha S.R. et al. The global burden of women's cancers: a grand challenge in global health. Lancet. 2017; 389(10071): 847-60. https://dx.doi.org/10.1016/S0140-6736(16)31392-7.
- Lei J., Ploner A., Elfström K.M., Wang J., Roth A., Fang F. et al. HPV vaccination and the risk of invasive cervical cancer. N. Engl. J. Med. 2020; 383(14): 1340-8. https://dx.doi.org/10.1056/NEJMoa1917338.
- van de Sande A.J.M., Kengsakul M., Koeneman M.M., Jozwiak M., Gerestein C.G., Kruse A.J. et al. The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia: A systematic review and meta-analysis. Int. J. Gynaecol. Obstet. 2024; 164(1): 66-74. https://dx.doi.org/10.1002/ijgo.14953.
- Bulkmans N.W., Berkhof J., Bulk S., Bleeker M.C., van Kemenade F.J., Rozendaal L. et al.; POBASCAM Study Group. High-risk HPV type-specific clearance rates in cervical screening. Br. J. Cancer. 2007; 96(9): 1419-24. https://dx.doi.org/10.1038/sj.bjc.6603653.
- Santesso N., Mustafa R.A., Schünemann H.J., Arbyn M.., Blumenthal PD., Cain J. et al.; Guideline Support Group. World Health Organization Guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer. Int. J. Gynaecol. Obstet. 2016; 132(3): 252-8. https://dx.doi.org/10.1016/j.ijgo.2015.07.038.
- Министерство здравоохранения Российской Федерации. Клинические рекомендации. Цервикальная интраэпителиальная неоплазия, эрозия и эктропион шейки матки. 2024. [Ministry of Health of the Russian Federation. Clinical guidelines. Cervical intraepithelial neoplasia, erosion, and cervical ectropion. 2024. (in Russian)].
- Сухих Г.Т., Ашрафян Л.А., Киселев В.И., Аполихина И.А., Мальцева Л.И., Сутурина Л.В., Селиванов С.П., Леонидова Т.Н., Цхай В.Б., Радзинский В.Е., Ордиянц И.М., Бебнева Т.Н., Евтушенко И.Д., Удут В.В., Кулагина Н.В., Баранов А.Н., Хасанов Р.Ш., Гурьева В.А., Шамина И.В., Карахалис Л.Ю., Муйжнек Е.Л. Исследование эффективности и безопасности препарата на основе дииндолметана у пациенток с цервикальной интраэпителиальной неоплазией (CIN 1–2). Акушерство и гинекология. 2018; 9: 91-8. [Sukhikh G.T., Ashrafyan L.A., Kiselev V.I., Apolikhina I.A., Maltseva L.I., Suturina L.V., Selivanov S.P., Leonidova T.N., Tskhai V.B., Radzinsky V.E., Ordiyants I.M., Bebneva T.N., Evtushenko I.D., Udut V.V., Kulagina N.V., Baranov A.N., Khasanov R.Sh., Guryeva V.A., Shamina I.V., Karakhalis L.Yu., Muyzhnek E.L. Investigation of the efficacy and safety of a diindolylmethane-based drug in patients with cervical intraepithelial neoplasia grades 1-2 (CIN 1-2). Obstetrics and Gynecology. 2018; (9): 91-8. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.9.91-98.
- Краснопольский В.И., Зароченцева Н.В., Ашрафян Л.А., Киселев В.И., Джиджихия Л.К., Баранов И.И., Джавахишвили М.Г. CIN II: современные направления в диагностике и лечении. Акушерство и гинекология. 2020; 1 (Приложение): 18-25. [Krasnopol’skii V.I., Zarochentseva N.V., Ashrafyan L.A., Kiselev V.I., Dzhidzhikhiya L.K., Baranov I.I., Dzhavakhishvili M.G. Current diagnosis and treatment of CIN II. Obstetrics and Gynecology. 2020; 1 (Suppl.): 18-25 (in Russian)]. https://dx.doi.org/10.18565/aig.2020.1suppl.18-25.
- Bowring J., Strander B., Young M., Evans H., Walker P. The Swede score: evaluation of a scoring system designed to improve the predictive value of colposcopy. J. Low Genit. Tract. Dis. 2010; 14(4): 301-5. https://dx.doi.org/10.1097/LGT.0b013e3181d77756.
- Хельсинкская декларация Всемирной медицинской ассоциации. Принята на 18-й Генеральной Ассамблее ВМА, Хельсинки, Финляндия, июнь 1964 г., изменения внесены на 64-й Генеральной Ассамблее ВМА, Форталеза, Бразилия, октябрь 2013 г. [Declaration of Helsinki of the World Medical Association. Adopted at the 18th WMA General Assembly, Helsinki, Finland, June 1964, amended at the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. (in Russian)].
- Национальный стандарт Российской Федерации ГОСТ Р 52379-2005 «Надлежащая клиническая практика». [National Standard of the Russian Federation GOST R 52379-2005 "Good Clinical Practice". (in Russian)]
- Yi M., Li T., Niu M., Luo S., Chu Q., Wu K. Epidemiological trends of women's cancers from 1990 to 2019 at the global, regional, and national levels: a population-based study. Biomark Res. 2021; 9(1): 55. https://dx.doi.org/10.1186/s40364-021-00310-y.
- Yang M., Du J., Lu H., Xiang F., Mei H., Xiao H. Global trends and age-specific incidence and mortality of cervical cancer from 1990 to 2019: an international comparative study based on the Global Burden of Disease. BMJ Open. 2022; 12(7): e055470. https://dx.doi.org/10.1136/bmjopen-2021-055470.
- Tan N., Wu Y., Li B., Chen W. Burden of cancers in six female organs in China and worldwide. Chin. Med. J. (Engl). 2024; 137(18): 2190-201. https://dx.doi.org/10.1097/CM9.0000000000003293.
- Инструкция по медицинскому применению лекарственного препарата Цервикон-ДИМ. РУ № ЛП-004939. [Instructions for medical use of the drug Cervicon-DIM. RU No. LP-004939. (in Russian)].
- Киселев В.И., Друх В.М., Пчелинцева О.И., Кузнецов И.Н., Муйжнек Е.Л., Горбунова Е.А. Изучение эффективности новой фармацевтической композиции дииндолилметана в подавлении выживаемости опухолевых клеток in vitro. Вестник РУДН. Серия: Медицина. 2014; 2: 95-101. [Kiselev V.I., Drukh V.M., Pchelintseva O.I., Kuznetsov I.N., Muyzhnek E.L., Gorbunova E.A. Anticancer activity of a new pharmaceutical composition of diindolylmethane by inhibiting the cell viability in vitro. Bulletin of RUDN University. Series: Medicine. 2014; 2: 95-101. (in Russian)].
- Киселев В.И., Друх В.М., Кузнецов И.Н., Муйжнек Е.Л., Аполихина И.А., Горбунова Е.А., Пчелинцева О.И. Оценка эффективности медикаментозной терапии цервикальной интраэпителиальной неоплазии легкой и средней степени тяжести суппозиториями Цервикон-ДИМ (промежуточные результаты клинического исследования). Гинекология. 2014; 16(6): 58-62. [Kiselev V.I., Drukh V.M., Kuznetsov I.N., Muyzhnek E.L., Apolikhina I.A., Gorbunova E.A., Pchelintseva O.I. Assessment of the drug efficacy for treatment of cervical intraepithelial neoplasia grade I-II with pharmaceutical composition Cervicon-DIM in suppository form (Interim results of a clinical trial). Gynecology 2014; 16(6): 58-62. (in Russian)].
- Шумейкина А.О., Красильников С.Э., Кедрова А.Г., Мансурова А.С., Чернышова А.Л., Качесов И.В., Логашенко Е.Б. Риски и лечение рецидивов интраэпителиальных повреждений шейки матки. Опухоли женской репродуктивной системы. 2022; 18(3): 100-6. [Shumeykina A.O., Krasilnikov S.E., Kedrova A.G., Mansurova A.S., Chernyshova A.L., Kachesov I.V., Logashenko E.B. Risks and treatment for recurrent intraepithelial cervical lesions. Tumors of the female reproductive system. 2022; 18(3): 100-6. (in Russian)]. https://dx.doi.org/10.17650/1994-4098-2022-18-3-100-106.
- Зароченцева Н.В., Джиджихия Л.К. Возможности применения препарата Цервикон-ДИМ у пациенток с цервикальными интраэпителиальными неоплазиями. Вопросы практической кольпоскопии. Генитальные инфекции. 2022; (3): 40-6. [Zarochentseva N.V., Dzhidzhikhia L.K. Possibilities of using Cervicon-DIM in patients with cervical intraepithelial neoplasia. Issues of Practical Colposcopy & Genital Infections. 2022; (3): 40-6. (in Russian)]. https://dx.doi.org/10.46393/27826392_2022_3_40.
- Ткаченко Л.В., Свиридова Н.И., Костенко Т.И., Гриценко И.А., Шишиморова С.Г. Современный подход к тактике ведения пациенток с цервикальной интраэпителиальной неоплазией легкой степени. Гинекология. 2020; 22(6): 56-61. [Tkachenko L.V., Sviridova N.I., Kostenko T.I., Gritsenko I.A., Shishimorova S.G. Modern approach to tactics of management of patients with cervical intraepithelial neoplasia of easy degree. Gynecology. 2020; 22(6): 56-61. (in Russian)]. https://dx.doi.org/10.26442/20795696.2020.6.200504.
- Киселев В.И., Ашрафян, Л.А., Друх В.М., Муйжнек Е.Л., Кузнецов И.Н., Пчелинцева О.И., Андрианова Е.А., Барановский П.М. Клиническое исследование по изучению эффективности суппозиториев «Цервикон-ДИМ» при лечении цервикальной интраэпителиальной неоплазии легкой и средней степени. Вестник Российского научного центра рентгенорадиологии Минздрава России. 2014; (3): 6. [Kiselev V.I., Ashrafyan, L.A., Drukh V.M., Muyzhnek E.L., Kuznetsov I.N., Pchelintseva O.I., Andrianova E.A., Baranovsky P.M. Clinical study on the effectiveness of suppositories "Cervicon-DIM" in treatment mild to moderate cervical intraepithelial neoplasia. Bulletin of the Russian Scientific Center for X-ray Radiology of the Ministry of Health of Russia 2014; (3): 6. (in Russian)].
- Ashrafian L., Sukhikh G, Kiselev V., Paltsev M., Drukh V., Kuznetsov I. et al. Double-blind randomized placebo-controlled multicenter clinical trial (phaseIIa) on diindolylmethane’s efficacy andsafety in the treatment of CIN: implicationsfor cervical cancer prevention. The EPMA Journal. 2015; 6: 25 https://dx.doi.org/10.1186/s13167-015-0048-9.
- Carter T.H., Liu K., Ralph W. Jr., Chen D., Qi M., Fan S. et al. Diindolylmethane alters gene expression in human keratinocytes in vitro. J. Nutr. 2002; 132(11): 3314-24. https://dx.doi.org/10.1093/jn/132.11.3314.
- Yuan F., Chen D.Z., Liu K., Sepkovic D.W., Bradlow H.L., Auborn K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999; 19(3A): 1673-80.
- Sepkovic D.W., Stein J., Carlisle A.D., Ksieski H.B., Auborn K., Bradlow H.L. Diindolylmethane inhibits cervical dysplasia, alters estrogen metabolism, and enhances immune response in the K14-HPV16 transgenic mouse model. Cancer Epidemiol. Biomarkers Prev. 2009; 18(11): 2957-64. https://dx.doi.org/10.1158/1055-9965.EPI-09-0698.
- Куценко И.И., Боровиков И.О., Горринг Х.И., Магай А.С., Горбулина А.А. Опыт клинического применения дииндолилметана в лечении ассоциированного с вирусом папилломы человека цервикального поражения низкой степени. Медицинский совет. 2020; (3): 25-31. [Kutsenko I.I., Borovikov I.O., Gorring Kh.I., Magai A.S., Gorbulina A.A. Experience of clinical use of diindolylmethane in the treatment of HPV-associated low-grade cervical lesions. Medical Council. 2020; (3): 25-31. (in Russian)]. https://dx.doi.org/10.21518/2079-701X-2020-3-25-31.
- Reyes-Hernández O.D., Figueroa-González G., Quintas-Granados L.I., Gutiérrez-Ruíz S.C., Hernández-Parra H., Romero-Montero A. et al. 3,3'-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int. 2023; 23(1): 180. https://dx.doi.org/10.1186/s12935-023-03031-4.
- Patel A.R., Spencer S.D., Chougule M.B., Safe S., Singh M. Pharmacokinetic evaluation and in vitro-in vivo correlation (IVIVC) of novel methylene-substituted 3,3' diindolylmethane (DIM). Eur. J. Pharm. Sci. 2012; 46(1-2): 8-16. https://dx.doi.org/10.1016/j.ejps.2012.01.012.
Received 10.03.2025
Accepted 19.03.2025
About the Authors
Inna A. Apolikhina, Dr. Med. Sci., Professor, Head of the Department of Aesthetic gynecology and Rehabilitation, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4; Professor at the Department of Obstetrics, Gynecology, Perinatology, and Reproductology, Institute of Professional Education, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), i_apolikhina@oparina4.ru, https://orcid.org/0000-0002-4581-6295Nina V. Zarochentseva, Dr. Med. Sci., Professor of the Russian Academy of Sciences, Deputy Director for Research, Academician V.I. Krasnopolsky Moscow Regional Research Institute of Obstetrics and Gynecology, 101000 Russia, Moscow, Pokrovka str., 22A, ninazar11@mail.ru, https://orcid.org 0000-0001-6155-788X
Elena A. Gorbunova, obstetrician-gynecologist, Researcher at the Department of Aesthetic Gynecology and Rehabilitation, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, el_gorbunova@oparina4.ru,
https://orcid.org/0000-0002-4723-4299
Anna G. Kedrova, Dr. Med. Sci., gynecologist-oncologist, Head of Oncology Department, Head of the Educational Part of Department of Obstetrics and Gynecology, Federal Scientific and Clinical Center of Special Types of Medical Care and Technologies of FMBA of Russia, 115682, Russia, Moscow, Orekhovy Boulevard, 28, +7(916)135-96-00, Kedrova.anna@gmail.com
Liana S. Mkrtchyan, Dr. Med. Sci., Leading Researcher, A. Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre, Ministry of Health of Russia, 249036, Russia, Kaluga region, Obninsk, 4 Koroleva St., 4, +7 (909) 251-28-49, liana6969@mail.ru, https://orcid.org/0000-0002-5027-5331
Tatiana E. Belokrinitskaya, Dr. Med. Sci., Professor, Head of the Obstetrics and Gynecology Department of the Pediatric Faculty and Faculty of Professional Retraining, Chita State Medical Academy, Ministry of Health of Russia, 672000, Russia, Chita, Gorky str., 39a +7(3022)32-30-58, tanbell24@mail.ru,
https://orcid.org/0000-0002-5447-4223
Sergey E. Krasilnikov, Dr. Med. Sci., Professor, Chief Researcher, Federal Research Center for Fundamental and Translational Medicine, 630060, Russia, Novosibirsk,
Timakova str., 2, SPIN: 4030-8868, https://orcid.org/0000-0003-0687-0894
Anastasia O. Shumeikina, PhD student, specialty "Oncology," Federal Research Center for Fundamental and Translational Medicine, 630060, Russia, Novosibirsk,
Timakova str., 2, https://orcid.org/0009-0008-1839-071X
Natalia M. Pasman, Dr. Med. Sci., Professor, Head of the Department of Obstetrics and Gynecology of the Institute of Medicine and Medical Technologies, Faculty of Medicine and Psychology, Novosibirsk State University, 630090, Russia, Novosibirsk, Pirogov str., 2, +7(913)916-25-91, nmpasman@gmail.com,
https://orcid.org/0000-0002-6095-1954
Larisa V. Suturina, Dr. Med. Sci., Professor, Head of the Department of Reproductive Health, Scientific Center for Family Health Problems and Human Reproduction,
664003, Russia, Irkutsk, Timiryazeva str., 16, +7(3952) 20-76-36, lsuturina@mail.ru, https://orcid.org/0000-0002-6271-7803
Diana K. Islamidi, PhD, Associate Professor, Department of Obstetrics and Gynecology with a course in Medical Genetics, Ural State Medical University, Ministry of Health of Russia, 620028, Russia, Yekaterinburg, Repin str., 3, +7(922)208-40-77, dishader@yandex.ru
Victoria A. Popandopulo, Dr. Med. Sci., Chief Physician, Center for Mother and Child (Clinic of Kuban State Medical University), 350010, Russia, Krasnodar, Zipovskaya str., 4/1, 4/3, +7(918)436-69-93, vik-krutova@yandex.ru, https://orcid.org/0000-0002-9907-7491
Aleksei E. Golubenko, MD, CEO and Head of Orel Colposcopy Center, gynecological oncologist, 302040, Russia, Orel region, Orel, per. Kinoprokatny, 2,
+7(910)308-84-89, golubr@mail.ru302040, https://orcid.org/0000-0001-7197-4812
Kirill A. Sokolov, MD, obstetrician-gynecologist, Medical Director of Alcea LLC, 129110, Moscow, Olimpiysky Ave., 16, bld. 5, kirill.sokolov@alceapharma.ru,
https://orcid.org/0000-0002-8358-3963
Yulia S. Verbitskaya, MD, PhD, Medical Advisor of Alcea LLC, 129110, Moscow, Olimpiysky Ave., 16, bld. 5, Yulia.verbitskaya@alceapharma.ru,
https://orcid.org/0000-0002-8358-3963
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