Main aspects of personalized approach to the treatment of patients with chemotherapy resistant metastatic colorectal cancer Текст научной статьи по специальности «Клиническая медицина»

South Russian Journal of Cancer. 2024. Vol. 5, No. 4. P. 29-37 4.0

https://doi.org/10.37748/2686-9039-2024-5-4-4

https://elibrary.ru/cfoldg

South Russian

Journal of Cancer ORIGINAL ARTICLE

Южно-Российский

онкологический журнал

Vol. 5

No. 4, 2024 Main aspects of personalized approach to the treatment of patients with

chemotherapy resistant metastatic colorectal cancer

O. Yu. Stukalova1, R. V. Ishchenko2,3, A. A. Polikarpov4, A. I. Farmonkulova3

1 ALLORO Medical Center, Fryazino, Russian Federation

2 V. K. Gusak institute of emergency and reconstructive surgery, Donetsk, Russian Federation

3 Lomonosov Moscow State University, Moscow, Russian Federation

4 Russian Scientific Center of Radiology and Surgical Technologies named after Academician A. M. Granov, St. Petersburg, Russian Federation

 [email protected]

ABSTRACT

Purpose of the study. To improve the results of treatment of patients with unresectable metastases of colorectal cancer in

the liver that are not controlled by systemic chemotherapy.

Materials and methods. The study includes clinical data on the treatment of 76 patients with metachronous metastases of

colorectal cancer in the liver that are not controlled by systemic chemotherapy. Patients underwent removal of the primary

tumor according to urgent indications at the first stage of complex treatment, followed by systemic chemotherapy in an

adjuvant mode. After 24.5 ± 0.2 months, patients were diagnosed with metastatic liver damage, and therefore systemic che-

motherapy was initiated. After changing two lines of drug therapy with a registered progression of the oncological process,

liver metastases were recognized as uncontrolled by systemic chemotherapy. After that patients were included in the given

study and divided into two groups. The study group included 40 patients who underwent regional chemotherapy. The control

group included 36 patients who continued systemic chemotherapy with subsequent line changes. The effectiveness was

evaluated according to the RECIST 1.1 and mRECIST scales, as well as the overall one-year, two- and three-year survival rates.

Results. The median overall survival of patients in the control and study groups was 30.0 ± 0.8 and 41.5 ± 0.5 months, respec-

tively, p < 0.05. The total one-year, two- and three-year survival of patients in the control and study groups was 94.4 %, 69.4 %,

33.3 % and 100 %, 82.5 %, 57.5 %, respectively, p < 0.05. The median life expectancy of deceased patients in the control and

study groups was 22.5 ± 0.4 and 27.0 ± 0.4 months.

Conclusions. As a result of a comparative analysis of the detection of adverse events and complications of the treatment,

patients of the study group underwent treatment much easier than patients of the control group – in patients in the group of

systemic chemotherapy, moderate and severe complications were detected in 44.4 % of cases, in the study group – in 2.5 %

of cases. According to the results of a clinical study, regional chemotherapy is an effective method of treating patients with

colon cancer metastases in the liver that are not controlled by systemic chemotherapy and is associated with a statistically

significant increase in overall survival (p < 0.05). For a more detailed study of the benefits of regional chemotherapy in this

category of patients, further prospective clinical studies are necessary.

Keywords: colorectal cancer, liver metastases, hepatic artery chemoembolization, chemotherapy resistant metastases

For citation: Stukalova O. Yu., Ishchenko R. V., Polikarpov A. A., Farmankulova A. I. Main aspects of personalized approach to the treatment of patients with

chemotherapy resistant metastatic colorectal cancer. South Russian Journal of Cancer. 2024; 5(4): 29-37. https://doi.org/10.37748/2686-9039-2024-5-4-4,

https://elibrary.ru/cfoldg

For correspondence: Oksana Yu. Stukalova – MD, coloproctologist, oncologist, ALLORO Medical Center, Fryazino, Russian Federation

Address: 9 Oktyabrskaya str., Fryazino 141195, Russian Federation

E-mail: [email protected]

ORCID: https://orcid.org/0000-0003-3748-4750

SPIN: 4109-2387, AuthorID: 934990

Compliance with ethical standards: the study was carried out in compliance with the ethical principles set forth in the Declaration of the World Medical

Association of Helsinki, 1964, ed. 2013. The study was approved by the Committee on Biomedical Ethics at the 4Russian Scientific Center of Radiology

and Surgical Technologies named after Academician A. M. Granov (extract from the minutes of the meeting No. 01-04/2024 dated 04/04/2024). Informed

consents were received from all participants of the study

Funding: this work was not funded

Conflict of interest: the authors declare that there are no obvious and potential conflicts of interest associated with the publication of this article

The article was submitted 07.06.2024; approved after reviewing 11.11.2024; accepted for publication 17.11.2024

© Stukalova O. Yu., Ishchenko R. V., Polikarpov A. A., Farmankulova A. I., 2024

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Южно-Российский онкологический журнал. 2024. Т. 5, № 4. С. 29-37

https://doi.org/10.37748/2686-9039-2024-5-4-4

https://elibrary.ru/cfoldg

3.1.6. Онкология, лучевая терапия

ОРИГИНАЛЬНАЯ СТАТЬЯ

Роль регионарной химиотерапии в лечении больных с метахронными метастазами

колоректального рака в печени, не контролируемыми системной химиотерапией

О. Ю. Стукалова1, Р. В. Ищенко2,3, А. А. Поликарпов4, А. И. Фармонкулова3

1 Медицинский центр «АЛЛОРО», г. Фрязино, Российская Федерация

2 ФГБУ «Институт неотложной и восстановительной хирургии имени В. К. Гусака» Министерства здравоохранения Российской Федерации,

г. Донецк, Российская Федерация

3 ФГБОУ ВО «Московский государственный университет имени М. В. Ломоносова», г. Москва, Российская Федерация

4 ФГБУ «Российский научный центр радиологии и хирургических технологий имени академика А. М. Гранова» Министерства

здравоохранения Российской Федерации, г. Санкт-Петербург, Российская Федерация

 [email protected]

РЕЗЮМЕ

Цель исследования. Улучшить результаты лечения больных с нерезектабельными метастазами колоректального

рака в печени, не контролируемыми системной химиотерапией.

Пациенты и методы. В настоящее исследование включены клинические данные о лечении 76 пациентов с метахрон-

ными метастазами колоректального рака в печени, не контролируемыми системной химиотерапией. На первом этапе

комплексного лечения пациентам проведено удаление первичной опухоли по срочным показаниям с последующим

проведением системной химиотерапии в адъювантном режиме. Через 24,5 ± 0,2 месяцев у пациентов диагности-

ровано метастатическое поражение печени, в связи с чем начата системная химиотерапия. После смены двух

линий лекарственной терапии с зарегистрированной прогрессией онкологического процесса, метастазы в печени

были признаны не контролируемыми системной химиотерапией, после чего больные были включены в настоящее

исследование и разделены на две группы. В исследуемую группу включены 40 пациентов, которым проводилась

регионарная химиотерапия. В контрольную группы включены 36 пациентов, которым продолжена системная химио-

терапия с последующей сменой линий. Оценка эффективности проводилась согласно шкалам RECIST 1.1 и mRECIST,

а также оценивалась общая годичная, двух- и трехлетняя выживаемость.

Результаты. Медиана общей выживаемости больных контрольной и исследуемой групп составила 30,0 ± 0,8

и 41,5 ± 0,5 месяцев соответственно, p < 0,05. Общая годичная, двух- и трехлетняя выживаемость больных контрольной

и исследуемой групп составила 94,4, 69,4, 33,3 и 100, 82,5, 57,5 % соответственно, p < 0,05. Медиана продолжительности

жизни умерших больных контрольной и исследуемой группы составила 22,5 ± 0,4 и 27,0 ± 0,4 месяцев.

Заключение. В результате сравнительного анализа выявления нежелательных явлений и осложнений проводимого

лечения выяснили, что больные исследуемой группы перенесли лечение значительно легче, нежели больные кон-

трольной группы – у больных в группе системной химиотерапии осложнения средней и тяжелой степени выявлены

в 44,4 % случаях, в исследуемой группе – в 2,5 % случаях. По результатам проведенного клинического исследования,

регионарная химиотерапия является эффективным методом лечения больных с метастазами рака толстой кишки

в печени, не контролируемыми системной химиотерапией и ассоциирована со статистически значимым увеличением

общей выживаемости (p < 0,05). Для более детального изучения преимуществ регионарной химиотерапии в данной

категории больных необходимо дальнейшее проведение проспективных клинических исследований.

Ключевые слова: колоректальный рак, метастазы в печень, химиоэмболизация печеночной артерии, химиорези-

стентные метастазы

Для цитирования: Стукалова О. Ю., Ищенко Р. В., Поликарпов А. А., Фармонкулова А. И. Роль регионарной химиотерапии в лечении больных

с метахронными метастазами колоректального рака в печени, не контролируемыми системной химиотерапией. Южно- Российский онкологический

журнал. 2024; 5 (4):29-37. https://doi.org/10.37748/2686-9039-2024-5-4-4, https://elibrary.ru/cfoldg

Для корреспонденции: Стукалова Оксана Юрьевна – врач-колопроктолог, онколог, Медицинский центр «АЛЛОРО», г. Фрязино, Российская Федерация

Адрес: 141195, Российская Федерация, г. Фрязино, ул. Октябрьская, д. 9

E-mail: [email protected]

ORCID: https://orcid.org/0000-0003-3748-4750

SPIN: 4109-2387, AuthorID: 934990

Соблюдение этических стандартов: в работе соблюдались этические принципы, предъявляемые Хельсинкской декларацией Всемирной медицин-

ской ассоциации (World Medical Association Declaration of Helsinki, 1964, ред. 2013). Исследование одобрено Комитетом по биомедицинской этике

при ФГБУ «Российский научный центр радиологии и хирургических технологий им. акад. А. М. Гранова» Министерства здравоохранения Российской

Федерации (выписка из протокола заседания № 01-04/2024 от 04.04.2024 г.). Информированное согласие получено от всех участников исследования

Финансирование: финансирование данной работы не проводилось

Конфликт интересов: все авторы заявляют об отсутствии явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи

Статья поступила в редакцию 07.06.2024; одобрена после рецензирования 11.11.2024; принята к публикации 17.11.2024

30

Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 29-37

Стукалова О. Ю., Ищенко Р. В., Поликарпов А. А., Фармонкулова А. И. Роль регионарной химиотерапии в лечении больных с метахронными метастазами

колоректального рака в печени, не контролируемыми системной химиотерапией

INTRODUCTION All patients at the first stage of complex treatment

underwent surgical treatment for urgent indications

Currently, colon cancer occupies one of the lead- due to the development of intestinal obstruction

ing positions among all oncological diseases [1–3]. (88.2 %) and the threat of massive bleeding (11,8 %),

One of the main causes of death in patients with aimed at removing the primary tumor of the colon.

malignant tumors of the colon is the prevalence of Right-sided hemicolectomy was performed in 25

the oncological process, which in 20–60 % of pa- (32.9 %) cases, sigmoid colon resection was per-

tients manifests itself in the form of metastatic liver formed in 17 (22.4 %) cases, anterior rectal resec-

damage [4–6]. Without special antitumor treatment tion was performed in 19 (25.0 %) cases, left-sided

of patients with metastatic liver damage, life expec- hemicolectomy was performed in 6 (7.9 %) cases and

tancy does not exceed one year [3]. transverse colon resection was performed in 9 (11.8 %)

The progressive development of oncology led to cases. After the surgical intervention, a histological

a deep understanding of the biology of colon tumors examination of the surgical material was performed,

and determined the need for immunohistochemical followed by the determination of the final stage ac-

and molecular genetic studies, which made it possible cording to the TNM classification (8th edition).

to apply a personalized therapeutic approach [7, 8]. Stage T1 was detected in 11 (14.5 %) cases, stage

However, systemic chemotherapy (SCT) remains the T2 was diagnosed in 29 (38.2 %) cases, stages T3

main method of treating patients with advanced forms and T4 were detected in 27 (35.5 %) and 9 (11.8 %)

of colorectal cancer (CRC) today [9–11]. cases, respectively. When assessing regional metas-

There is an extensive group of patients with bilo- tasis, stage N0 was established in 32 (42.1) cases,

bar metastatic liver damage who need to stop CT due N1 in 29 (38.2 %) cases, and N2 in 15 (19.7 %) cases

to the development of chemoresistance or adverse (Table 1). No distant metastasis was detected in

events [12, 13]. The question of possible treatment any patient.

options for these patients remains open today. As can be seen from Table 1, stage I was diag-

The study purpose was to improve the results nosed in 19 (25 %) patients, stage II was diagnosed

of treatment of patients with unresectable metas- in 11 (14.5 %) patients, and stage III in 46 (60.5 %)

tases of colorectal cancer in the liver that are not patients (Fig. 1).

controlled by systemic chemotherapy In all cases, patients underwent radical resection

of the primary tumor R0.

PATIENTS AND METHODS It was mandatory for all patients to undergo a mo-

lecular genetic study determining mutations in the

The study included 76 patients aged 40 to 81 KRAS, NRAS, and BRAF genes. KRAS mutations were

years with a morphologically confirmed diagnosis detected in 19 (25.0 %) patients. Wild types of KRAS

of colon cancer. The average age was 63.6 ± 8.7 and NRAS were diagnosed in 57 (75.0 %) patients.

years. The primary tumor is represented by adeno- Given the unfavorable prognosis and the need for

carcinoma of various degrees of malignancy – in 23 more aggressive treatment of patients with muta-

(30.3 %) cases, highly differentiated adenocarcinoma tions in the BRAF gene, the latter were not included

(G1) was diagnosed, in 48 (63.1 %) cases and in 5 in this study.

(6.6 %) cases, moderate (G2) and low-differentiated In 51 (67.1 %) cases, patients underwent system-

(G3) adenocarcinoma, respectively. ic chemotherapy in adjuvant mode – in 48 (63.1 %)

Table 1. Distribution of patients according to T and N categories

Category N0 N1 N2

T1 8 (10.5 %) 3 (3.9 %) 0

T2 11 (14.5 %) 13 (17.1 %) 5 (6.6 %)

T3 9 (11.8 %) 11 (14.5 %) 7 (9.2 %)

T4 2 (2.6 %) 4 (5.3 %) 3 (3.9 %)

31

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 29-37

Stukalova O. Yu., Ishchenko R. V., Polikarpov A. A., Farmankulova A. I. Main aspects of personalized approach to the treatment of patients with chemotherapy resistant

metastatic colorectal cancer

cases in patients with the spread of the pT1–4N+ trast, a percutaneous transhepatic trepan biopsy was

tumor process and in 3 (3.9 %) cases in patients with performed under ultrasound guidance. In all cases,

pT3N0M0 who had negative prognosis factors (high the morphological picture of metastatic foci corre-

degree of malignancy of the primary tumor, perineu- sponded to the primary tumor.

ral and lymphovascular invasion). In 39 (51.3 %) cas- After receiving histological confirmation of sec-

es, patients underwent drug therapy in the XELOX ondary liver foci, a collegial discussion of further

mode, in 37 (48.7 %) cases the FOLFOX mode was therapeutic tactics was conducted with the partic-

used. On average, each patient underwent 6.4 ± 1.4 ipation of an oncologist, surgeon, chemotherapist,

courses of CT (Fig. 2). radiologist. As a result, patients were prescribed che-

As can be seen from Figure 2, in two cases, sys- motherapy in the following regimens: modified FOLF-

temic chemotherapy is limited to one and two cours- OX6 – in 22 (28.9 %) cases, XELOX – in 14 (18.4 %)

es. The treatment of patients was interrupted due cases, FOLFIRI – in 24 (31.6 %) cases, XELIRI – in

to the development of adverse events. In one case, 11 (14.5 %) cases, capecitabine in monotherapy in 5

on the 7th day after the first course of drug therapy (6.6 %) cases. Chemotherapy courses were conduct-

in XELOX mode, a myocardial infarction was diag- ed against the background of biotherapy. Taking into

nosed. In the second case, after the second course account the data of the molecular genetic study, bev-

of CT in FOLFOX mode, an acute stomach ulcer was acizumab was prescribed to patients in 19 (25.0 %)

detected. cases, and erbitux was prescribed in 57 (75.0 %)

All patients whose clinical data are included in cases. The effectiveness of the drug treatment was

this study underwent regular follow-up examinations evaluated after the fourth course.

according to clinical recommendations. The median When performing a control examination after the

before the progression of the tumor process was fourth course of PCT, 66 (86.8 %) patients showed

24.5 ± 0.2 months. All patients were diagnosed with progression of the tumor process, in 10 (13.2 %)

bilobar metastatic liver disease. On average, 5.1 ± 1.4 cases, adverse events were detected, and therefore

metastatic foci were diagnosed in each patient. The chemotherapeutic treatment was interrupted. In pa-

average sum of the diameters in the largest mea- tients with the progression of the tumor process,

surement of liver formations in each patient was an increase in targeted foci was diagnosed in 46

49.9 ± 12.7 mm (Fig. 3). (60.5 %) cases, the appearance of new foci was reg-

After the liver formations were detected, accord- istered in 17 (22.4 %) cases, and in 28 (36.8 %) cas-

ing to computed tomography with intravenous con- es, an increase in blood cancer markers (CA 19–9,

9

8

7

6

5

4

3

2

 I Stage 25 % 1

 II Stage 15 % 0

 III Stage 61 % XT

Fig. 1. Distribution of patients by tumor process stages according to Fig. 2. Distribution of patients by the number of SCT courses

TNM classification performed

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Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 29-37

Стукалова О. Ю., Ищенко Р. В., Поликарпов А. А., Фармонкулова А. И. Роль регионарной химиотерапии в лечении больных с метахронными метастазами

колоректального рака в печени, не контролируемыми системной химиотерапией

cancer- embryonic antigen, alpha-f etoprotein) was Patients of the study group underwent regional

revealed in comparison with the baseline level. The chemotherapy of secondary foci of the liver, i. e. the

patients underwent a change of the chemothera- hepatic artery chemoembolization (HACE) using Bio-

py line. FOLFIRI CT was prescribed in 26 (34.2 %) sphere microspheres 50–100 µm. Irinotecan was

cases, FOLFOXIRI in 27 (35.5 %) cases, irinotecan used as a cytostatic agent in the first line of RCT,

monotherapy was performed in 12 (15.8 %) cases, with the ineffectiveness of the latter, doxorubicin

and XELIRI in 11 (14.5 %) cases. After the control ex- was used as a line 2 drug.

amination, further progression of the tumor process HACE was performed in the following mode for

was revealed in 59 (77.6 %) patients, in 17 (22.4 %) all patients – the first two cycles were performed

cases, adverse events were diagnosed. Given the at intervals of 3 weeks, then 1 month after the sec-

ineffectiveness of two lines of systemic chemo- ond cycle, a control computed tomography was per-

therapy, metastatic foci are recognized as chemo formed to assess the effectiveness of the treatment

resistant. Considering the chemo resistant nature and then decide whether it was advisable to continue

of metastatic liver damage, a molecular genetic the RCT cycles when stabilization/response was ob-

study of biopsies of liver foci was performed. As tained or a cytostatic change was detected with the

a result, 5 (6.6 %) patients showed heterogeneity of progression of the tumor process (Fig. 4).

metastatic foci in comparison with the primary tu- Patients in the control group underwent a change

mor, which consisted in the detection of the mutant of systemic chemotherapy lines. The effectiveness

KRAS gene in the wild type of KRAS primary tumor. of treatment was evaluated after the fourth course

In this regard, the patients underwent correction of of SCT. The following regimens were used as 3 SCT

biotherapy. lines: FOLFIRI, XELIRI, irinotecan in monotherapy,

In patients with a pronounced degree of toxic capecitabine in monotherapy. Irinotecan in mo-

manifestations of drug therapy, metastatic foci are norode, capecitabine in monorode and FOLFOXIRI

recognized as uncontrolled by systemic chemother- were used as the 4th line of SCT.

apy. All the patients presented above are included in The obtained results of the study in both groups

this study and divided into two groups. were subjected to a comparative analysis. The ef-

The first study group included 40 patients with fectiveness of treatment in the study group was

chemo resistant liver metastases, including 17 pa- assessed using the response evaluation criteria in

tients with moderate and severe toxicity on the back- solid tumors (RECIST 1.1, 2009) and modified RE-

ground of CT. The second, control group included CIST (mRECIST) scales, in the control group – on the

36 patients with chemo resistant liver metastases. RECIST 1. 1 scale.

Fig. 3. 3D reconstruction of the liver in patients with CRC metastatic lesions

33

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 29-37

Stukalova O. Yu., Ishchenko R. V., Polikarpov A. A., Farmankulova A. I. Main aspects of personalized approach to the treatment of patients with chemotherapy resistant

metastatic colorectal cancer

When simultaneous progression on the RECIST metastatic lesion in the liver was registered, despite

1.1 scale and stabilization or response on the recist the local response of the observed foci, and therefore

scale were detected, that is, with local extrahepatic the result was regarded as progression according to

metastasis was diagnosed in the response, patients the RECIST 1.1 scale and stabilization according to

continued to undergo HACE against the background the mRECIST scale. There were no deaths within

of resumption of systemic chemotherapy. 12 months after the HACE.

In the control group, one year after inclusion in the

STUDY RESULTS present study, stabilization was noted in 16 (44.4 %)

patients after CT on the RECIST 1.1 scale, and 20

A year after the start of RCT in patients of the (56.6 %) patients were diagnosed with progression of

study group, a partial response on the RECIST 1.1 the tumor process, including extrahepatic metastasis.

scale was detected in 8 (20.0 %) patients, stabiliza- It is worth noting that 5 (13.9 %) patients included

tion of the tumor process in the liver in patients was in the control group with heterogeneous mutation-

diagnosed in 18 (45.0 %) patients, progression of the al KRAS status of primary and metastatic tumors

metastatic process was detected in 8 (20.0 %) pa- showed stabilization of the tumor process against

tients. In 6 (15.0 %) cases, the appearance of a new the background of a change in targeted therapy.

CT pronounced mCRC 2 CT sessions not

toxicity effective

Cytostatic drug

change 2 RCT sessions

Progression Abdominal CT with Response /

IV dye infusion stabilization

Fig. 4. Algorithm of regional chemotherapy in patients of the research group

Kaplan-Meier Survival by group

1,0

40

0,8 35

30

0,6

25

0,4 20

15

0,2

10

0 5

0 20 40 60 80 0

 CG  SG Time SG CG

Fig. 5. Overall survival of patients in the study group (SG) and the Fig. 6. Life expectancy of deceased patients of the study group (SG)

control group (CG) and the control group (CG)

34

Fraction Surviving

Duration, months

Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 29-37

Стукалова О. Ю., Ищенко Р. В., Поликарпов А. А., Фармонкулова А. И. Роль регионарной химиотерапии в лечении больных с метахронными метастазами

колоректального рака в печени, не контролируемыми системной химиотерапией

The median overall survival of patients in the con- DISCUSSION

trol and study groups was 30.0 ± 0.8 and 41.5 ± 0.5

months, respectively, p < 0.05 (Fig. 5). A common form of colorectal cancer is one of

The total one-year, two- and three-year survival of the leading causes of death among patients with

patients in the control and study groups was 94.4 %, malignant tumors worldwide. The main organ of CRC

69.4 %, 33.3 % and 100 %, 82.5 %, 57.5 %, respective- metastasis is the liver [14].

ly, p < 0.05. Currently, methods of a personalized therapeutic

The median life expectancy of deceased patients approach have been developed and introduced into

in the control and study groups was 22.5 ± 0.4 and clinical practice, developed based on an understand-

27.0 ± 0.4 months (Fig. 6). ing of carcinogenesis and tumor biology. According

The indicators of cancer markers were monitored: to clinical recommendations, surgical intervention is

in the case of HACE, there was a decrease in the indi- the main method of choosing treatment for patients

cators of cancer markers in 57.5 % of cases, and an with metastatic colorectal liver cancer. However, liver

increase in their level was noted in 42.5 % of cases. resection is possible in no more than 30 % of cases

In the case of CT, 72.2 % of the subjects had an due to the prevalence of the tumor process, tech-

increase in cancer markers and only 27.8 % had sta- nical features or the burdened comorbid status of

bilization. There were no pronounced phenomena of patients. Therefore, chemotherapy remains the main

systemic toxicity, liver and kidney failure after HACE: method of treatment for patients of the presented

6 (15.0 %) patients had a  change in Child-P ugh cohort [15].

scores (an increase of maximum 1 point from the Systemic chemotherapy is associated with a high

initial 3–5 points). Postembolization hepatotoxicity risk of toxicity and chemoresistance, which requires

(increased activity of gamma- glutamyltraspeptidase discontinuation of drug treatment in the first case

(GGTP), alkaline phosphatase, aspartate aminotrans- or a change of the SCT session in the second case.

ferase (AST), alanine aminotransferase (ALT)) was Thus, the treatment of colon cancer patients with

noted in 9 (22.5 %) patients. chemoresistant or uncontrolled chemotherapy liver

In the control group, toxic reactions and compli- metastases is an urgent topic of discussion [15–17].

cations of varying severity were detected after sys- In the presented clinical study, a comparative

temic chemotherapy. Hepatotoxicity was detected in analysis was carried out between treatment with

22 (61.1 %) patients, 8 (22.2 %) of whom had a dete- systemic and regional chemotherapy in patients with

rioration in the functional state of the liver according multiple unresectable chemoresistant liver metasta-

to the Child- Pugh scale. Neurotoxicity was detect- ses. Before inclusion in the present study, patients

ed in 10 (27.8 %) cases, which manifested itself in underwent at least two lines of CT. As a result of the

the form of the development of peripheral polyneu- conducted clinical study, HACE showed high effec-

ropathy. The development of acute cardiovascular tiveness – in 26 (65.0 %) cases, a result was achieved

insufficiency against the background of systemic according to the RECIST 1.1 scale and in 32 (80.0 %)

chemotherapy was detected in one patient (2.8 %), cases according to the mRECIST scale, compared

this complication led to a fatal outcome. with 16 (44.4 %) cases of positive results in patients

In the study group, an assessment and analysis of of the control group. It is worth noting that the eval-

the developed complications were also carried out. uation of the results of regional chemotherapy sep-

All patients had a manifestation of postembolization arately on the RECIST 1.1 scale or on the mRECIST

syndrome (PES), which manifested itself as a mod- scale does not reliably reflect the effectiveness of

erate intensity pain syndrome and hyperthermia up the treatment. Thus, the appearance of new extra-

to 37.4 °C for three days after HACE was performed. hepatic metastases (progression according to the

The pain syndrome was completely stopped by a sin- RECIST 1.1 scale) does not correlate with the inef-

gle intramuscular injection with NSAID drugs. One fectiveness of HACE due to the limited local effect of

patient treated by us had a case of extrahepatic em- the latter, which may be accompanied by a response

bolizate injection into the cystic artery. In this regard, according to the mRECIST scale, which was record-

the patient was treated conservatively with a positive ed in 6 cases in patients of the study group. In this

effect. No surgical intervention was required. regard, the presented patients need to undergo both

35

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 29-37

Stukalova O. Yu., Ishchenko R. V., Polikarpov A. A., Farmankulova A. I. Main aspects of personalized approach to the treatment of patients with chemotherapy resistant

metastatic colorectal cancer

systemic chemotherapy and influence extrahepatic lecular genetic research methods, as well as the

foci and continue regional chemotherapy. severity of adverse events of chemotoxicity and

As a result of a comparative analysis of the de- individual reactions, it is possible to develop an

tection of adverse events and complications of the individual treatment plan that will increase the

treatment, patients of the study group underwent overall and relapse-free survival of patients with

treatment much easier than patients of the control uncontrolled systemic chemotherapy metastases

group – in patients in the group of systemic chemo- of colorectal cancer in the liver. According to the

therapy, moderate and severe complications were results of a clinical study, regional chemotherapy

detected in 44.4 % of cases, in the study group – in is an effective method of treating patients with

2.5 % of cases. chemo resistant metastases of colon cancer in

the liver and is associated with a statistically sig-

CONCLUSION nificant increase in the overall survival of patients

compared with systemic chemotherapy (p < 0.05).

Thanks to a personalized approach, which in- For a more detailed study of the benefits of region-

cludes an assessment of the prevalence of the al chemotherapy in this category of patients, it is

tumor process, the degree of malignancy of the necessary to further conduct prospective clinical

primary tumor, the results of histological and mo- studies.

References

1. Abdulaev MA, Napolskaya EV, Tsikoridze MYu. The current state of the problem of minimally invasive methods of local

treatment of colorectal cancer metastases in the liver. Surgery and Oncology. 2016;6:43–47. (In Russ.).

https://doi.org/10.17650/2220-3478-2016-6-1-43-47, EDN: WAHYVF

2. Ionkin DA, Zhavoronkova OI, Stepanova YuA, Gavrilov YaYa, Vishnevsky VA, Zhao AV. Thermal methods of local destruction

(rfa, cryodestruction, microwave ablation) in metastatic liver cancer. Postgraduate Bulletin of the Volga region. 2018;(5-

6):127–145. (In Russ.). https://doi.org/10.17816/2072-2354.2018.18.3.127-145, EDN: BUCJUG

3. The state of cancer care for the Russian population in 2018. Ed. by A. D. Kaprin, V. V. Starinsky, G. V. Petrova. Moscow:

P. A. Herzen MNIOI – Branch of the National Medical Research Radiological Center, 2019, 236 p. (In Russ.).

4. Oskombaev MSh, Abdurasulov KD, Dzhekshenov MD. Immediate results of surgical treatment of colorectal cancer with syn-

chronous liver metastases. Healthcare in Kyrgyzstan. 2022;(4):163–167. https://doi.org/10.51350/zdravkg2022.4.10.23.163,

EDN: MYZKHQ

5. Stukalova OYu, Polikarpov AA, Ishchenko RV, Shugushev ZKh. X-ray-endovascular interventions in the treatment of patients

with liver metastases of colorectal cancer after the termination of systemic chemotherapy. Journal of Clinical Practice.

2022;13(2):59–65. (In Russ.). https://doi.org/10.17816/CLINPRACT108552, EDN: UYGVHW

6. Shubin VP, Achkasov SI, Sushkov OI, Tsukanov AS. Molecular-genetic features of colorectal tumors in peritoneal carcino-

matosis and liver metastases (review). Coloproctology. 2020;19 (4):177-87. 2020;19(4(74)):177–187. (In Russ.).

https://doi.org/10.33878/2073-7556-2020-19-4-177-187, EDN: XGMLSX

7. Fedyanin MYu, Tyulyandin SA. Optimal sequences and combination of chemotherapy and monoclonal antibodies in the

treatment of patients with metastatic colorectal cancer. Malignant tumors. 2018;8 (2):50–59. (In Russ.).

https://doi.org/10.18027/2224-5057-2018-8-2-50-59, EDN: BSITYS

8. Grozinsky-Glasberg S, Bloom AI, Lev-Cohain N, Klimov A, Besiso H, Gross DJ. The role of hepatic trans-arterial chemoem-

bolization in metastatic medullary thyroid carcinoma: a specialist center experience and review of the literature. European

Journal of Endocrinology. 2017 Apr 1;176(4):463–470. https://doi.org/10.1530/EJE-16-0960

9. Martin J, Petrillo A, Smyth EC, Shaida N, Khwaja S, Cheow HK, et al. Colorectal liver metastases: Current management and

future perspectives. World J Clin Oncol. 2020 Oct 24;11(10):761–808. https://doi.org/10.5306/WJCO.V11.I10.761

10. Shubin VP, Ponomarenko AA, Tsukanov AS, Maynovskaya OA, Rybakov EG, Panina MV, et al. Heterogeneity in Colorectal

Primary Tumor and Synchronous Liver Metastases. Russian Journal of Genetics. 2018;54(6):698–702.

https://doi.org/10.1134/S1022795418060091, EDN: YCHHAL

36

Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 29-37

Стукалова О. Ю., Ищенко Р. В., Поликарпов А. А., Фармонкулова А. И. Роль регионарной химиотерапии в лечении больных с метахронными метастазами

колоректального рака в печени, не контролируемыми системной химиотерапией

11. Dobrodeev AYu, Kostromitsky DN, Tarasova AS, Afanasyev SG, Babyshkina NN, Ponomaryeva AA, Larionova IV, et al. Multi-

modal therapy for metastatic colorectal cancer: a case of complete clinical and radiological response of liver metastases.

Siberian journal of oncology. 2024;23(1):162–169. (In Russ.). https://doi.org/10.21294/1814-4861-2024-23-1-162-169,

EDN: JSQZJV

12. Adenis A, de la Fouchardiere C, Paule B, Burtin P, Tougeron D, Wallet J, et al. Survival, safety, and prognostic factors for

outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a

multicenter study (REBECCA) nested within a compassionate use program. BMC Cancer. 2016 Jul 7;16:412.

https://doi.org/10.1186/S12885-016-2440-9

13. Metastatic colorectal cancer is a guide for doctors. Ed. by O. G. Skipenko, Yu. A. Shelygin, S. I. Achkasov. Moscow: Delta

Plus, 2020, 421 p.

14. Practical recommendations for the treatment of malignant tumors of the Russian Society of Clinical Oncology. 2021.

(In Russ.). Available at: https://www.rosoncoweb.ru/standarts/RUSSCO/2021/, Accessed: 12.11.2024.

15. Ishchenko RV, Dzhansyz IN, Fesak IV. Surgical technology catheterization hepatic arteri under selective intra-arterial che-

motherapy. Malignant tumours. 2016;(3):60–66. (In Russ.). https://doi.org/10.18027/2224-5057-2016-3-60-66

16. Ishchenko RV. Selective intraarterial chemotherapy for liver metastases of colorectal cancer. Bulletin of Emergency and

Reconstructive Surgery. 2016;1(1):43–47. EDN: XICNWL

17. Polikarpov AA, Tarazov PG, Kagacheva TI, Granov DA. Regional chemotherapy of unresectable liver metastases of colorec-

tal cancer resistant to systemic chemotherapy. Questions of Oncology. 2018;64(4):499–503. (In Russ.).

https://doi.org/10.37469/0507-3758-2018-64-4-499-503, EDN: VKVTEQ

Information about authors:

Oksana Yu. Stukalova  – MD, coloproctologist, oncologist, ALLORO Medical Center, Fryazino, Russian Federation

ORCID: https://orcid.org/0000-0003-3748-4750, SPIN: 4109-2387, AuthorID: 934990

Roman V. Ishchenko – Dr. Sci. (Med.), MD, Director, V. K. Gusak institute of emergency and reconstructive surgery, Donetsk, Russian Federation;

Professor of the Department of Surgical Diseases, Faculty of Fundamental Medicine of Lomonosov Moscow State University, Moscow, Russian

Federation

ORCID: https://orcid.org/0000-0003-0260-6922, SPIN: 9021-7370, AuthorID: 1045336

Alexey A. Polikarpov – Dr. Sci. (Med.), MD, Leading Researcher of the Department of Interventional Radiology and Operative Surgery, Professor of

the Department of Radiology and Surgical Technologies, Russian Scientific Center of Radiology and Surgical Technologies named after Academician

A. M. Granov, St. Petersburg, Russian Federation

ORCID: https://orcid.org/0000-0002-7683-5042, SPIN: 4641-0720, AuthorID: 690524

Amira I. Farmonkulova – student, Faculty of Fundamental Medicine of Lomonosov Moscow State University, Moscow, Russian Federation

ORCID: https://orcid.org/0009-0007-2851-2226

Contribution of the authors:

Stukalova O. Yu. – participation in the concept of clinical research, writing the source text, final conclusions;

Ishchenko R. V. – scientific guidance, development of the concept of clinical research, revision of the text, final conclusions;

Polikarpov A. A. – scientific guidance, development of the concept of clinical research, revision of the text, final conclusions;

Farmankulova A. I. – writing the source text.

37