Medical Radiology and radiation safety Medical Radiology and radiation safety Медицинская радиология и радиационная безопасность 1024-6177 2618-9615 46735 10.12737/1024-6177-2021-66-5-50-58 Лучевая терапия Radiation therapy Лучевая терапия Role of Intensification of Neoadjuvant Treatment of Patients with Locally Expanded Rectal Cancer РОЛЬ ИНТЕНСИФИКАЦИИ НЕОАДЪЮВАНТНОГО ЛЕЧЕНИЯ БОЛЬНЫХ МЕСТНОРАСПРОСТРАНЕННЫМ РАКОМ ПРЯМОЙ КИШКИ Полыновский А. В. Polynovskiy A. V.

кандидат медицинских наук;

candidate of medical sciences;

 Кузьмичев Д. В. Kuz'michev D. V.

кандидат медицинских наук;

candidate of medical sciences;

 Мамедли З. З. Mamedli Z. Z.

кандидат медицинских наук;

candidate of medical sciences;

 Ткачев Сергей Иванович Tkachev Sergey Ivanovich

доктор медицинских наук;

doctor of medical sciences;

 Черных М. В. Chernich M. V. Сураева Ю. Э. Suraeva Yu. E. Мадьяров Ж. М. Madyarov J. M.

кандидат медицинских наук;

candidate of medical sciences;

 Анискин А. А. Aniskin A. A. Колобанова Е. С. Kolobanov E. S. Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Минздрава России Москва Россия N.N. Blokhin National Medical Research Center of Oncology Moscow Russian Federation Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Минздрава России Москва Россия N.N. Blokhin National Medical Research Center of Oncology Moscow Russian Federation Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Минздрава России Москва Россия N.N. Blokhin National Medical Research Center of Oncology Moscow Russian Federation Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Минздрава России Москва Россия N.N. Blokhin National Medical Research Center of Oncology Moscow Russian Federation Национальный медицнский исследовательский исследовательский центр онкологии им. Н.Н. Блохина Минздрава РФ, Москва Россия N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia Russian Federation ОРЦ ПЭТ Технолоджи, Подольск, Московская обл. Москва Россия PET-Technology, Podolsk, Moscow Region, Russia Moscow Russian Federation Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Минздрава России Москва Россия N.N. Blokhin National Medical Research Center of Oncology Moscow Russian Federation НИИ организации здравоохранения и медицинского менеджмента Департамента здравоохранения города Москвы Россия Research Institute of Healthcare Organization and Medical Management of the Moscow Department of Healthcare, Moscow, Russia Russian Federation ОРЦ ПЭТ Технолоджи, Московская обл., Подольск Россия PET-Technology, Podolsk, Moscow Region, Russia Russian Federation 66 5 50 58 01 11 2021 https://zh-szf.ru/en/nauka/article/46735/view

Цель: Повышение эффективности лечения больных местнораспространенным раком прямой кишки (МРРПК) со стадией опухолевого процесса T3(MRF+)-4N0-2M0 путем разработки новой стратегии комплексной терапии. Материал и методы: В исследование вошло 414 пациентов МРРПК. Контрольная группа I включила 89 пациентов, которым проведена неоадъювантная ХЛТ, до СОД 52–56 Гр, на фоне приема капецитабина. Контрольная группа II – 160 пациентов, проведена неоадъювантная химиолучевая терапия (ХЛТ), до СОД 52–56 изоГр, с капецитабином и оксалиплатином один раз в неделю, в течение курса ЛТ. Исследуемая группа III – 165 пациентов. В данной группе сочеталась неоадъювантная ХЛТ в дозе 52–56 изоГр на фоне приема капецитабина с дополнительными последовательными курсами химиотерапии (ХТ) в режиме CapOx. Данная группа, в зависимости от варианта проведения ХТ была разделена на 2 подгруппы: подгруппа IIIa включает 106 пациентов с консолидирующей ХТ (после ХЛТ); подгруппа IIIb включает в себя 59 пациентов, которым было проведено «сэндвич»-лечение. Терапия заключается в проведении от 1 до 2 курсов индукционной ХТ (до ХЛТ) в режиме CapOx и от 1 до 2 курсов консолидирующей ХТ в режиме CapOx с интервалом 7 дней. В промежутке между курсами лекарственной терапии проводилась пролонгированная ХЛТ. По результатам контрольного обследования определялась дальнейшая тактика лечения. Результаты: Полный лечебный патоморфоз в опухоли достоверно чаще регистрировался у больных в исследуемой группе III (17,5 %; р=0,021) по сравнению с контрольными группами: в I – 8,0 % и II – 8,3 %. Всего рецидивы в исследовании зарегистрированы у 34 (8,3 %) из 410 пациентов. Сравнительный анализ пациентов в контрольных группах (I и II) лечения не определил достоверных различий в развитии рецидивов (11,4 % против 10,8 % соответственно; p=0,884). При анализе подгрупп (IIIa и IIIb) исследуемой группы также не определено достоверных различий в развитии рецидивов (4,8 % против 3,4 %; р=0,676). Отдаленные метастазы в различные сроки после проведенного лечения диагностированы у 100 (24,4 %) из 410 больных. Все метастазы возникли при медиане прослеженности 20,9 мес. (от 4 до 46 мес.). Метастазы достоверно реже регистрировались у пациентов в группе III (18,3 %) по сравнению с группой I (31,8 %; р=0,015) и II (26,6 %; р=0,037). Достоверных различий между пациентами в группе I и II не определено (р=0,382). Анализ лечебных подгрупп исследуемой группы (IIIa и IIIb) не определил достоверных различий в развитии метастазов (19,1 % против 17,0 %; р=0,456). Общая пятилетняя выживаемость у больных в группе III составила 90,5 %, в группе I – 71,8 % и в группе II – 78,3 %. Пятилетняя безрецидивная выживаемость у пациентов в изучаемых группах составила: III – 71,5 %,I – 56,9 % и II – 65,6 % соответственно. Заключение: Усиление неоадъювантного воздействия на опухоль и усовершенствование подходов к режимам лекарственной терапии позволили значительно увеличить безрецидивную выживаемость у данной категории пациентов.

Purpose: To improve the effectiveness of treatment of patients with locally advanced rectal cancer (LARC) stage T3(MRF+)-4N0-2M0 by developing a new strategy of therapy. Material and methods: The study included 414 patients with LARC. Control group I included 89 patients who underwent neoadjuvant CRT 52–56 Gy with capecitabine. Control group II included 160 patients, underwent neoadjuvant CRT 52–56 Gy with capecitabine and oxaliplatin once a week, during the course of RT. Study group III - 165 patients. This group combined neoadjuvant CRT 52–56 Gy with capecitabine and additional consecutive courses of chemotherapy (CT) in the CapOx mode. This group, depending on the variant of chemotherapy, was divided into 2 subgroups: subgroup IIIa included 106 patients with consolidating CT (after CRT); subgroup IIIb included 59 patients who underwent "sandwich" treatment. Therapy consists of conducting 1 or 2 courses of induction CT (up to CRT) in the CapOx mode and 1 or 2 courses of consolidating CT in the CapOx mode with an interval of 7 days. In the interval between the courses of drug therapy, prolonged CRT was performed. According to the results of the control examination, further treatment tactics were determined. Results: IComplete therapeutic pathomorphosis in the tumor was significantly more frequently registered in patients in the study group III (17.5 %; p=0.021) compared to the control groups: in I – 8.0 % and II – 8.3 %. In total, relapses in the study were registered in 34 (8.3 %) of 410 patients. A comparative analysis of patients in the control groups (I and II) of treatment did not determine significant differences in the development of relapses (11.4 % vs. 10.8 %, respectively; p=0.884). When analyzing the subgroups (IIIa and IIIb) of the study group, there were also no significant differences in the development of relapses (4.8 % vs. 3.4 %; p=0.676). In the present study, long-term metastases at various times after treatment were diagnosed in 100 (24.4 %) of 410 patients. All metastases occurred at a median follow-up of 20.9 months (4 to 46 months). Metastases were significantly less frequent in patients in group III (18.3 %) compared to group I (31.8 %; p=0.015) and II (26.6 %; p=0.037). There were no significant differences between patients in group I and II (p=0.382). The analysis of the treatment subgroups of the study group (IIIa and IIIb) did not determine significant differences in the development of metastases (19.1 % vs. 17.0 %; p=0.456). The overall five-year survival rate in patients in group III was 90.5 %, in group I – 71.8% and in group II – 78.3%. Five-year relapse-free survival in patients in the study groups was: III – 71.5%, I – 56.9% and II – 65.6%, respectively. Conclusion: The shift in the focus on strengthening the neoadjuvant effect on the tumor and the improvement of approaches to drug therapy regimens allowed to significantly increase the relapse-free survival in this category of patients.

 местнораспространенный рак прямой кишки химиолучевая терапия индукционная химиотерапия консолидирующая химиотерапия sandwich терапия locally advanced rectal cancer chemo radiotherapy induction chemotherapy consolidation chemotherapy sandwich therapy

Jung K., Kim H., Park J., et al. Adjuvant Chemotherapy after Neoadjuvant Chemoradiation and Curative Resection for Rectal Cancer: is it Necessary for All Patients? // J. Surgical Oncology. 2015. V.111, No. 4. P. 439-444. Jung K., Kim H., Park J., et al. Adjuvant Chemotherapy after Neoadjuvant Chemoradiation and Curative Resection for Rectal Cancer: is it Necessary for All Patients? // J. Surgical Oncology. 2015. V.111, No. 4. P. 439-444. Bosset J.-F., Calais G., Mineur L., et al. Fluorouracil-Based Adjuvant Chemotherapy after Preoperative Chemoradiotherapy in Rectal Cancer: Long-Term Results of the EORTC 22921 Randomised Study // Lancet Oncol. 2014. V.15, No. 2. P. 184-190. Bosset J.-F., Calais G., Mineur L., et al. Fluorouracil-Based Adjuvant Chemotherapy after Preoperative Chemoradiotherapy in Rectal Cancer: Long-Term Results of the EORTC 22921 Randomised Study // Lancet Oncol. 2014. V.15, No. 2. P. 184-190. Sainato A., Cernusco Luna Nunzia V., Valentini V., et al. No Benefit of Adjuvant Fluorouracil Leucovorin Chemotherapy after Neoadjuvant Chemoradiotherapy in Locally Advanced Cancer of the Rectum (LARC): Long Term Results of a Randomized Trial (I-CNR-RT) // Radiother Oncol. 2014. V.113, No. 2. P. 223-229. Sainato A., Cernusco Luna Nunzia V., Valentini V., et al. No Benefit of Adjuvant Fluorouracil Leucovorin Chemotherapy after Neoadjuvant Chemoradiotherapy in Locally Advanced Cancer of the Rectum (LARC): Long Term Results of a Randomized Trial (I-CNR-RT) // Radiother Oncol. 2014. V.113, No. 2. P. 223-229. Rödel C., Graeven U., Fietkau R., et al. Oxaliplatin Added to Fluorouracil-Based Preoperative Chemoradiotherapy and Postoperative Chemotherapy of Locally Advanced Rectal Cancer (the German CAO/ARO/AIO-04 Study): Final Results of the Multicentre, Open-Label, Randomised, Phase 3 Trial // Lancet Oncol. 2015. V.16, No. 8. P. 979-989. Rödel C., Graeven U., Fietkau R., et al. Oxaliplatin Added to Fluorouracil-Based Preoperative Chemoradiotherapy and Postoperative Chemotherapy of Locally Advanced Rectal Cancer (the German CAO/ARO/AIO-04 Study): Final Results of the Multicentre, Open-Label, Randomised, Phase 3 Trial // Lancet Oncol. 2015. V.16, No. 8. P. 979-989. Hong Y.S., Nam B.-H., Kim K.-P., et al. Oxaliplatin, Fluorouracil, and Leucov-Orin Versus Fluorouracil and Leucovorin as Adjuvant Chemotherapy for Locally Advanced Rectal Cancer after Preoperative Chemoradiotherapy (ADORE): an Open-Label, Multicentre, Phase 2, Randomised Controlled Trial // Lancet Oncol. 2014. V.15, No. 11. P. 1245-1253. Hong Y.S., Nam B.-H., Kim K.-P., et al. Oxaliplatin, Fluorouracil, and Leucov-Orin Versus Fluorouracil and Leucovorin as Adjuvant Chemotherapy for Locally Advanced Rectal Cancer after Preoperative Chemoradiotherapy (ADORE): an Open-Label, Multicentre, Phase 2, Randomised Controlled Trial // Lancet Oncol. 2014. V.15, No. 11. P. 1245-1253. Schmoll H.J., Stein A., Hofheinz R.D., et al. Preoperative Chemoradiotherapy and Postoperative Chemotherapy with Capecitabine and Oxaliplatin vs. Capecitabine Alone in Locally Advanced Rectal Cancer: Final Analyses // Ann. Oncol. 2016. V.27 (suppl 6). Available at: https://academic.oup.com /annonc/article/ 27/suppl _ 6/467PD/2799263 Last Accessed November 21, 2019. Schmoll H.J., Stein A., Hofheinz R.D., et al. Preoperative Chemoradiotherapy and Postoperative Chemotherapy with Capecitabine and Oxaliplatin vs. Capecitabine Alone in Locally Advanced Rectal Cancer: Final Analyses // Ann. Oncol. 2016. V.27 (suppl 6). Available at: https://academic.oup.com /annonc/article/ 27/suppl _ 6/467PD/2799263 Last Accessed November 21, 2019. Hu X., Li Y.-Q., Li Q.-G., Ma Y.-L., Peng J.-J., Cai S.-J. Adjuvant Chemotherapy Seemed not to Have Survival Benefit in Rectal Cancer Patients with YpTis-2N0 after Preoperative Radiotherapy and Surgery from a Population-Based Propensity Score Analysis // Oncologist. 2019. V.24, No. 6. P. 803-811. Hu X., Li Y.-Q., Li Q.-G., Ma Y.-L., Peng J.-J., Cai S.-J. Adjuvant Chemotherapy Seemed not to Have Survival Benefit in Rectal Cancer Patients with YpTis-2N0 after Preoperative Radiotherapy and Surgery from a Population-Based Propensity Score Analysis // Oncologist. 2019. V.24, No. 6. P. 803-811. Fernandez-Martos C., Garcia-Albeniz X., Pericay C., et al. Chemoradiation, Surgery and Adjuvant Chemotherapy Versus Induction Chemotherapy Followed by Chemoradiation and Surgery: Long-Term Results of the Spanish GCR-3 Phase II Randomized Trial // Ann. Oncol. 2015. V.26, No. 8. P. 1722-1728. Fernandez-Martos C., Garcia-Albeniz X., Pericay C., et al. Chemoradiation, Surgery and Adjuvant Chemotherapy Versus Induction Chemotherapy Followed by Chemoradiation and Surgery: Long-Term Results of the Spanish GCR-3 Phase II Randomized Trial // Ann. Oncol. 2015. V.26, No. 8. P. 1722-1728. Kim C.W., Kang B.M., Kim I.Y., et al. Korean Society of Coloproctology (KSCP) Trial of CONsolidation Chemotherapy for Locally Advanced Mid or Low Rectal Cancer after Neoadjuvant Concurrent Chemoradiotherapy: a Multicenter, Randomized Controlled Trial (KONCLUDE) // BMC Cancer. 2018. V.18, No. 1. P. 538. Kim C.W., Kang B.M., Kim I.Y., et al. Korean Society of Coloproctology (KSCP) Trial of CONsolidation Chemotherapy for Locally Advanced Mid or Low Rectal Cancer after Neoadjuvant Concurrent Chemoradiotherapy: a Multicenter, Randomized Controlled Trial (KONCLUDE) // BMC Cancer. 2018. V.18, No. 1. P. 538. Glynne-Jones R., Grainger J., Harrison M., et al. Neoadjuvant Chemotherapy Prior to Preoperative Chemoradiation or Radiation in Rectal Cancer: Should We Be More Cautious? // Br. J. Cancer. 2006. No. 94. P. 363-371. Glynne-Jones R., Grainger J., Harrison M., et al. Neoadjuvant Chemotherapy Prior to Preoperative Chemoradiation or Radiation in Rectal Cancer: Should We Be More Cautious? // Br. J. Cancer. 2006. No. 94. P. 363-371. Gao Y.H., Lin J.Z., An X. et al. Neoadjuvant Sandwich Treatment with Oxaliplatin and Capecitabine Administered Prior to, Concurrently with, and Following Radiation Therapy in Locally Advanced Rectal Cancer: a Prospective Phase 2 Trial // Int. J. Radiat. Oncol. Biol. Phys. 2014. V.90, No. 5. P. 1153-1160. Gao Y.H., Lin J.Z., An X. et al. Neoadjuvant Sandwich Treatment with Oxaliplatin and Capecitabine Administered Prior to, Concurrently with, and Following Radiation Therapy in Locally Advanced Rectal Cancer: a Prospective Phase 2 Trial // Int. J. Radiat. Oncol. Biol. Phys. 2014. V.90, No. 5. P. 1153-1160. Landry J.C., Feng Y., Prabhu R.S., et al. Phase II Trial of Preoperative Radiation with Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevaci-zumab in Patients with Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204 // Oncologist. 2015. V.20, No. 6. Р. 615-616. Landry J.C., Feng Y., Prabhu R.S., et al. Phase II Trial of Preoperative Radiation with Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevaci-zumab in Patients with Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204 // Oncologist. 2015. V.20, No. 6. R. 615-616. Maas M., Nelemans P.J., Valentini V., et al. Long-Term Outcome in Patients with a Pathological Complete Response after Chemoradiation for Rectal Cancer: a Pooled Analysis of Individual Patient Data // Lancet Oncol. 2010. V.11, No. 9. P. 835-844. Maas M., Nelemans P.J., Valentini V., et al. Long-Term Outcome in Patients with a Pathological Complete Response after Chemoradiation for Rectal Cancer: a Pooled Analysis of Individual Patient Data // Lancet Oncol. 2010. V.11, No. 9. P. 835-844. Habr-Gama A., Perez R.O., Nadalin W., Sabbaga J., Ribeiro U.Jr., Silva e Sousa A.H.Jr., Campos F.G., Kiss D.R., Gama-Rodrigues J. Operative Versus Nonoperative Treatment for Stage 0 Distal Rectal Cancer Following Chemoradiation Therapy: Long-Term Results // Ann. Surg. 2004. V.240, No. 4. P. 711-717. Discussion 717-718. Habr-Gama A., Perez R.O., Nadalin W., Sabbaga J., Ribeiro U.Jr., Silva e Sousa A.H.Jr., Campos F.G., Kiss D.R., Gama-Rodrigues J. Operative Versus Nonoperative Treatment for Stage 0 Distal Rectal Cancer Following Chemoradiation Therapy: Long-Term Results // Ann. Surg. 2004. V.240, No. 4. P. 711-717. Discussion 717-718. Petrelli F., Sgroi G., Sarti E., et al. Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer: A Meta-Analysis of Published Studies // Ann. Surg. 2016. V.263, No. 3. Р. 458-464. Petrelli F., Sgroi G., Sarti E., et al. Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer: A Meta-Analysis of Published Studies // Ann. Surg. 2016. V.263, No. 3. R. 458-464.