Surgery and OncologySurgery and OncologyХирургия и онкология2949-5857Publishing House ABV Press25810.17650/2220-3478-2018-8-3-36-41ORIGINAL REPORTОРИГИНАЛЬНОЕ ИССЛЕДОВАНИЕNeoadjuvant chemotherapy in the combination treatment for locally advanced rectal cancer: currently available optionsСовременные возможности применения неоадъювантной химиотерапии в комбинированном лечении местно-распространенного рака прямой кишкиKuzmichevD. V.КузьмичевД. В.
Russian Federation

Department of Surgery No. 3 (Proctology).

24 Kashirskoe shosse, Moscow 115478

Хирургическое отделение № 3 (проктологическое).

Москва 115478, Каширское шоссе, 24

https://orcid.org/0000-0002-9289-1247MamedliZ. Z.МамедлиЗ. З.
Russian Federation

Department of Surgery No. 3 (Proctology).

24 Kashirskoe shosse, Moscow 115478

Хирургическое отделение № 3 (проктологическое).

Москва 115478, Каширское шоссе, 24

PolynovskiyA. V.ПолыновскийА. В.
Russian Federation

Department of Surgery No. 3 (Proctology).24 Kashirskoe shosse, Moscow 115478

Андрей Владимирович Полыновский - хирургическое отделение № 3 (проктологическое).

Москва 115478, Каширское шоссе, 24

polynovskiy@gmail.comMadyarovZh. M.МадьяровЖ. М.
Russian Federation

Department of Surgery No. 3 (Proctology).

24 Kashirskoe shosse, Moscow 115478

Хирургическое отделение № 3 (проктологическое).

Москва 115478, Каширское шоссе, 24

https://orcid.org/0000-0001-8965-8172TkachevS. I.ТкачевС. И.
Russian Federation

Department of Surgery No. 3 (Proctology).

24 Kashirskoe shosse, Moscow 115478

Хирургическое отделение № 3 (проктологическое).

Москва 115478, Каширское шоссе, 24

AniskinА. A.АнискинА. А.
Russian Federation

Department of Surgery No. 3 (Proctology).

24 Kashirskoe shosse, Moscow 115478

Хирургическое отделение № 3 (проктологическое).

Москва 115478, Каширское шоссе, 24

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России031120188336410311201803112018Copyright ©; 2018, ABV-pressCopyright ©; 2018, АБВ-пресс2018ABV-pressАБВ-прессhttps://onco-surgery.info/jour/about/editorialPolicieshttps://onco-surgery.info/jour/article/view/258

Objective: to analyze treatment outcomes in patients with locally advanced rectal cancer that received various combinations of neoadjuvant chemotherapy and chemoradiotherapy.

Materials and methods. In this retrospective study, we analyzed a cohort of prospectively recruited patients with stage mrT3(CRM+)/ T4N0–2M0 locally advanced rectal cancer. Participants were divided into three groups. Patients in Group 1 received preoperative longcourse radiotherapy given concurrently with capecitabine, followed by 2–6 cycles of consolidation chemotherapy with capecitabine and oxaliplatin (CapOx). In Group 2, patients initially received 1–2 cycles of induction chemotherapy with CapOx, followed by radiotherapy + capecitabine, and then consolidation chemotherapy with CapOx (“sandwich” method). Participants in Group 3 were treated with 1–3 cycles of induction CapOx chemotherapy with subsequent long-course chemoradiotherapy. After the combination treatment, all patients underwent surgery. The primary endpoint of this study was therapeutic pathomorphosis. Secondary endpoints included complete clinical response, toxicity, local recurrence, distant metastasis, and relapse-free survival.

Results. This study included 155 patients (98 in Group 1, 44 in Group 2, and 13 in Group 3). Grade III toxicity was documented in 6.12 %, 4.55 %, and 23.08 % of cases in Groups 1, 2, and 3 respectively. None of the patients had grade IV toxicity. Grade III therapeutic pathomorphosis was achieved in 33.7 %, 22.7 %, and 23.1 % of patients in Groups 1, 2, and 3 respectively. Grade IV therapeutic pathomorphosis was observed in 14.3 %, 15.9 %, and 7.69 % of patients in Groups 1, 2, and 3 respectively. Complete clinical response was registered in 16.3 %, 11.4 %, and 0 % of cases in Groups 1, 2, and 3 respectively. Median follow-up was 47.2 months with no signs of progression. Relapses were observed in 1.02 % and 2.27 % of patients from Group 1 and Group 2 respectively, whereas Group 3 demonstrated no relapses. A total of 11.22 %, 13.64 %, and 23.1 % of participants from Groups 1, 2, and 3 respectively developed distant metastasis.

Conclusion. Polychemotherapy used within the consolidation and «sandwich» treatment regimens is a promising option for the treatment of locally advanced rectal cancer. The efficacy of induction chemotherapy should be further studied with a larger sample.

Цель исследования – изучить результаты комплексного лечения больных местно-распространенным раком прямой кишки с использованием различных вариантов последовательности неоадъювантной полихимиотерапии и химиолучевой терапии.

Материалы и методы. Проведен ретроспективный анализ когортной группы проспективно набранных больных местно-распространенным раком прямой кишки со стадиями опухолевого процесса mrT3(CRM+)/T4N0–2M0. Пациенты разделены на 3 группы. В 1-й группе на предоперационном этапе проводили курс пролонгированной лучевой терапии на фоне приема капецитабина, далее назначали консолидирующую химиотерапию по схеме CapOx от 2 до 6 курсов. Во 2-й группе перед началом химиолучевой терапии пациенты получали 1–2 курса индукционной химиотерапии по схеме CapOx, далее курс лучевой терапии + капецитабин, затем консолидирующую химиотерапию по схеме CapOx (методика «sandwich»). В 3-й группе проводили от 1 до 3 курсов индукционной ХТ по схеме CapOx, затем пролонгированную химиолучевую терапию. После комбинированной терапии планировалось хирургическое лечение. Основной оцениваемый показатель – лечебный патоморфоз. Дополнительные оцениваемые показатели – достижение полного клинического ответа, степень токсичности, частота развития местных рецидивов, отдаленных метастазов и безрецидивная выживаемость.

Результаты. В исследование включено 155 пациентов. В 1-ю группу вошло 98 больных, во 2-ю – 44, в 3-ю – 13. Токсичность III cтепени в группах зарегистрирована в 6,12, 4,55 и 23,08 % случаев соответственно. Токсичности IV степени не было зарегистрировано ни в одной из групп. Патоморфоз III степени в группах достигнут в 33,7; 22,7 и 23,1 % случаев соответственно, IV степени – в 14,3; 15,9 и 7,69 % случаев, полный клинический ответ – в 16,3; 11,4 и 0 % случаев. Медиана времени без прогрессирования составила 47,2 мес. В 1-й и 2-й группах зарегистрировано 1,02 и 2,27 % рецидивов соответственно, в 3-й группе – 0 %. Отдаленные метастазы возникли в 11,22, 13,64 и 23,1 % случаев соответственно.

Выводы. Использование полихимиотерапии в режимах консолидации и «sandwich» является перспективным направлением в лечении больных местно-распространенным раком прямой кишки. Вопрос о применении индукционной химиотерапии может быть решен после дальнейшего набора материала.

locally advanced rectal cancerchemoradiotherapyneoadjuvant chemotherapyconsolidation chemotherapyinduction chemotherapy“sandwich” therapypathomorphosisместно-распространенный рак прямой кишкихимиолучевая терапиянеоадъювантная химиотерапияконсолидирующая химиотерапияиндукционная химиотерапия«sandwich»-терапияпатоморфозDavydov M. I., Aksel E. M. Statistics of malignant tumors in Russia and CIS countries in 2009. Vestnik RONC im. N. N. Blokhina RAMN = Journal of N. N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences 2011; 22(3 annex. 1). (In Russ.).Давыдов М. И., Аксель Е. М. Статистика злокачественных новообразований в России и странах СНГ в 2009 г. Вестник РОНЦ им. Н. Н. Блохина РАМН 2011;22(3 прил. 1).National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Rectal Cancer(v. 3, 2017). Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf.Glynne-Jones R., Wyrwicz L., Tiret E. et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(Suppl 4):iv22–40. PMID: 28881920. DOI: 10.1093/annonc/mdx224.Clinical guidelines “Rectal cancer”. (2017). Available at: http://oncologyassociation.ru/files/clinicalguidelines_adults/rak_pryamoy_kishki.pdf. (In Russ.).Клинические рекомендации «Рак прямой кишки» от 2017 г. Доступно по: http://oncology-association.ru/ files/clinicalguidelines_adults/rak_ pryamoy_kishki.pdf.Berardi R., Maccaroni E., Onofri A. et al. Multidisciplinary treatment of locally advanced rectal cancer: a literature review. Part 1. Expert Opin Pharmacother 2009;10(14):2245–58. PMID: 19640208. DOI: 10.1517/14656560903143776.Berardi R., Maccaroni E., Onofri A. et al. Multidisciplinary treatment of locally advanced rectal cancer: a literature review. Part 1. Expert Opin Pharmacother 2009;10(14):2245–58. PMID: 19640208. DOI: 10.1517/14656560903143776.Benson A. B., Bekaii-Saab T., Chan E. et al. Rectal cancer. J Natl Compr Cancer Netw 2012;10(12):1528–64. PMID: 23221790.Lee M., Gibbs P., Wong R. Multidisciplina ry management of locally advanced rectal cancer – an evolving landscape? Clin Colorectal Cancer 2015;14(4):251–61. PMID: 26210575. DOI: 10.1016/j.clcc.2015.06.002.Smith J. J., Garcia-Aguilar J. Advances and challenges in treatment of locally advanced rectal cancer. J Clin Oncol 2015;33(16):1797–808. PMID: 25918296. DOI: 10.1200/JCO.2014.60.1054.Sauer R., Becker H., Hohenberger W. et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351(17):1731–40. PMID: 15496622. DOI: 10.1056/NEJMoa040694.Cercek A., Roxburgh C. S.D., Strombom P. et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol 2018;4(6):e180071. DOI: 10.1001/jamaoncol.2018.0071.Cercek A., Roxburgh C. S.D., Strombom P. et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol 2018;4(6):e180071. DOI: 10.1001/jamaoncol.2018.0071.Dewdney A., Cunningham D., Tabernero J. et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk cancer (EXPERT-C). J Clin Oncol 2012;30:1620–7.Chua Y. J., Barbachano Y., Cunningham D. et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol 2010;11:241–8.Schou J. V., Larsen F. O., Rasch L. et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol 2012;23(10):2627–33. PMID: 22473488. DOI: 10.1093/annonc/mds056.Bujko K., Wyrwicz L., Rutkowski A. et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol 2016;27(5):834–42. PMID: 26884592. DOI: 10.1093/annonc/mdw062.Bujko K., Wyrwicz L., Rutkowski A. et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol 2016;27(5):834–42. PMID: 26884592. DOI: 10.1093/annonc/mdw062.Schrag D. PROSPECT: Chemotherapy alone/chemotherapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery. Available at: https://clinicaltrials.gov/ct2/show/NCT01515787.Taylor F. G., Quirke P., Heald R. J. et al. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg 2011;253:711–9.Bhoday J., Balyasnikova S., Wale A., Brown G. How Should Imaging Direct/ Orient Management of Rectal Cancer? Clin Colon Rectal Surg 2017;30(5):297– 312. DOI: 10.1055/s-0037-1606107.Habr-Gama A., Perez R. O., Sabbaga J. et al. Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period. Dis Colon Rectum 2009;52:1927–34.Xiao J., Chen Z., Li W. et al. Sandwichlike neoadjuvant therapy with bevacizumab for locally advanced rectal cancer: a phase II trial. Cancer Chemother Pharmacol 2015;76(1):21–7. DOI: 10.1007/s00280-015-2763-2.Lavnikova G. A. Histological method for quantitative assessment of therapeutic tumor damage. Moscow: Methodical recommendations, 1979. 13 p. (In Russ.).Лавникова Г. А. Гистологический метод количественной оценки терапевтического повреждения опухоли. М.: Методические рекомендации, 1979. 13 с.Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet 1996;48(9042):1605–10.Wong R. K., Tandan V., De Silva S., Figueredo A. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev 2007;(2):CD002102. PMID: 17443515. DOI: 10.1002/14651858.CD002102.pub2.McCarthy K., Pearson K., Fulton R. et al. Pre-operative chemoradiation for nonmetastatic locally advanced rectal cancer. Cochrane Database Syst Rev 2012;(12): CD008368. PMID: 23235660. DOI: 10.1002/14651858.CD008368.pub2.McCarthy K., Pearson K., Fulton R. et al. Pre-operative chemoradiation for nonmetastatic locally advanced rectal cancer. Cochrane Database Syst Rev 2012;(12): CD008368. PMID: 23235660. DOI: 10.1002/14651858.CD008368.pub2.Bosset J. F., Collette L. Calais G. et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355(11):1114–23. PMID: 16971718. DOI: 10.1056/NEJMoa060829.Land S. R., Ritter M. W., Costantino J. P. et al. Compliance with patient-reported outcomes in multicenter clinical trials: methodologic and practical approaches. J Clin Oncol 2007;25(32):5113–20. PMID: 17991930. DOI: 10.1200/JCO.2007.12.1749.Fernandez-Martos C., Pericay C., Aparicio J. et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol 2010;28(5):859–65. DOI: 10.1200/JCO.2009.25.8541.Gerard J. P., Conroy T., Bonnetain F. et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24(28):4620–5. PMID: 17008704. DOI: 10.1200/JCO.2006.06.7629юChau I., Brown G., Cunningham D. et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006;24:668–74. PMID: 16446339. DOI: 10.1200/JCO.2005.04.4875.Perez K., Pricolo V., Vrees M. et al. A phase II study of complete neoadjuvant therapy in rectal cancer (CONTRE): The Brown University Oncology Group. J Clin Oncol 2013;31: abstr 335. DOI: 10.1200/jco.2013.31.4_suppl.335.Gao Y. H., Zhang X., An X. et al. Oxaliplatin and capecitabine concomitant with neoadjuvant radiotherapy and extended to the resting period in high risk locally advanced rectal cancer. Strahlen ther Onkol 2014;19092):158–64. PMID: 24408055. DOI: 10.1007/s00066-013-0500-5.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;90(5):1153–60. DOI: 10.1016/j.ijrobp.2014.07.021.