Научная статья на тему 'Modern strategy of metastatic colorectal cancer treatment (literature review)'

Modern strategy of metastatic colorectal cancer treatment (literature review) Текст научной статьи по специальности «Клиническая медицина»

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Ключевые слова
review / metastatic colorectal cancer / liver resection / chemotherapy / targeted therapy / обзор / метастатический колоректальный рак / резекция печени / химиотерапия / таргетная терапия

Аннотация научной статьи по клинической медицине, автор научной работы — Oleg I. Kit, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Vladimir E. Kolesnikov, Olga K. Bondarenko

Metastatic lesions account for about 50–60 % of all cases of colorectal cancer (CRC). Currently, the prognosis for metastatic CRC has significantly improved due to the advent of effective drug therapy and the expansion of surgical treatment options. In this regard, the study of modern directions of treatment of metastatic CRC is of particular interest. In this study, both literature data and obtained treatment results of patients with metastatic colorectal cancer have been analyzed (PubMed, Scopus, eLibrary databases were used) at the National Medical Research Centre for Oncology. Currently, many factors should be taken into account when planning therapy for patients with metastatic CRC: the characteristics of the tumor itself (biology and localization of the tumor, tumor burden, RAS, BRAF mutational status), the patient (age, performance status, functional state of organs and systems, comorbidity, patient attitude, expectations and preferences) and the treatment itself (toxicity, flexibility of the treatment program, socio-economic factors, quality of life). With a resectable process, surgical treatment with adjuvant or perioperative chemotherapy, and with potentially resectable liver metastases, with massive prevalence, unfavorable prognosis – to carry out the most active drug therapy taking into account the mutational status of the tumor in order to transfer the process to a resectable one. In case of widespread colorectal cancer, drug therapy lines are consistently carried out, the selection of which is based on the goals of therapy, the type and time of primary therapy, the mutation profile of the tumor, and the toxicity of drugs. Patients with metastatic liver and/or lung lesions should be considered through the prism of surgical treatment, since it is surgical intervention that can significantly improve the results of treatment of patients. Therefore, patients with potentially resectable metastases should receive the most effective treatment and be operated on as soon as the process becomes resectable. At the same time, modern chemotherapy and targeted therapy are an integral part of the treatment of patients with metastatic colorectal cancer.

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Современные хирургические стратегии лечения метастатического колоректального рака (обзор литературы)

Метастатическое поражение составляет около 50–60 % всех случаев колоректального рака (КРР). В настоящее время прогноз в отношении метастатического КРР значительно улучшил-ся в связи с появлением эффективной лекарственной терапии и расширением возможностей хирургического лечения. В связи с этим особый интерес представляет изучение современных направлений лечения метастатического КРР. В данном исследовании был проведен анализ данных литературы (использовались базы данных PubMed, Scopus, eLIBRARY) и собственных результатов лечения больных метастатическим колоректальным раком в ФГБУ «Национальный медицинский исследовательский центр онкологии» Министерства здравоохранения Российской Федерации. В настоящее время при планировании терапии пациентов с метастатическим КРР следует учи-тывать многие факторы: характеристики самой опухоли (биология и локализация опухоли, tumour burden, мутационный статус RAS, BRAF), пациента (возраст, performance status, функ-циональное состояние органов и систем, коморбидность, отношение пациента к различным ме‑тодам лечения, ожидания и предпочтения) и самого лечения (токсичность, гибкость програм-мы лечения, социоэкономические факторы, качество жизни). При резектабельном процессе хирургическое лечение с адъювантной или периоперационной химиотерапией, а при потенци-ально резектабельных метастазах в печень, при массивной распространенности, неблагоприят-ном прогнозе – проводить максимально активную лекарственную терапию с учетом мутаци-онного статуса опухоли с целью перевода процесса в резектабельный. При распространенном КРР последовательно проводят линии лекарственной терапии, выбор которой основывается на целях терапии, виде и времени первичной терапии, мутационном профиле опухоли, токсично-сти препаратов. Пациенты с метастатическим поражением печени и/или легких должны рассматриваться через призму оперативного лечения, поскольку именно хирургическое вмешательство способно зна-чимо улучшить результаты лечения пациентов. Поэтому пациенты с потенциально резекта-бельными метастазами должны получать максимально эффективное лечение и оперироваться, как только процесс станет резектабельным. При этом современная химиотерапия и таргетная терапия являются неотъемлемой частью лечения больных метастатическим КРР.

Текст научной работы на тему «Modern strategy of metastatic colorectal cancer treatment (literature review)»

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South Russian

Journal of Cancer..

Vol. 5

No. 3, 2024

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South Russian

Journal of Cancer..

Vol. 5

No. 3, 2024

South Russian Journal of Cancer. 2024. Vol. 5, No. 3. P. 102-110

https://doi.org/10.37748/2686-9039-2024-5-3-9

https://elibrary.ru/lxyray

REVIEW

Modern strategy of metastatic colorectal cancer treatment

(literature review)

O. I. Kit, Yu. A. Gevorkyan, N. V. Soldatkina , V. E. Kolesnikov, O. K. Bondarenko, A. V. Dashkov

National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

snv-rnioi@yandex.ru

ABSTRACT

Metastatic lesions account for about 50�60 % of all cases of colorectal cancer (CRC). Currently, the prognosis for metastatic

CRC has significantly improved due to the advent of effective drug therapy and the expansion of surgical treatment options.

In this regard, the study of modern directions of treatment of metastatic CRC is of particular interest.

In this study, both literature data and obtained treatment results of patients with metastatic colorectal cancer have been

analyzed (PubMed, Scopus, eLibrary databases were used) at the National Medical Research Centre for Oncology.

Currently, many factors should be taken into account when planning therapy for patients with metastatic CRC: the characteristics

of the tumor itself (biology and localization of the tumor, tumor burden, RAS, BRAF mutational status), the patient (age,

performance status, functional state of organs and systems, comorbidity, patient attitude, expectations and preferences) and

the treatment itself (toxicity, flexibility of the treatment program, socio-economic factors, quality of life). With a resectable

process, surgical treatment with adjuvant or perioperative chemotherapy, and with potentially resectable liver metastases,

with massive prevalence, unfavorable prognosis � to carry out the most active drug therapy taking into account the mutational

status of the tumor in order to transfer the process to a resectable one. In case of widespread colorectal cancer, drug

therapy lines are consistently carried out, the selection of which is based on the goals of therapy, the type and time of primary

therapy, the mutation profile of the tumor, and the toxicity of drugs.

Patients with metastatic liver and/or lung lesions should be considered through the prism of surgical treatment, since it is

surgical intervention that can significantly improve the results of treatment of patients. Therefore, patients with potentially

resectable metastases should receive the most effective treatment and be operated on as soon as the process becomes

resectable. At the same time, modern chemotherapy and targeted therapy are an integral part of the treatment of patients

with metastatic colorectal cancer.

Keywords: review, metastatic colorectal cancer, liver resection, chemotherapy, targeted therapy

For citation: Kit O. I., Gevorkyan Yu. A., Soldatkina N. V., Kolesnikov V. E., Bondarenko O. K., Dashkov A. V. Modern strategy of metastatic colorectal cancer

treatment (literature review). South Russian Journal of Cancer. 2024; 5(3): 102-110. https://doi.org/10.37748/2686-9039-2024-5-3-9,

https://elibrary.ru/lxyray

For correspondence: Natalya V. Soldatkina � Dr. Sci. (Med.), MD, leading researcher of the Department of General Oncology, National Medical Research

Centre for Oncology, Rostov-on-Don, Russian Federation

Address: 63 14 line str., Rostov-on-Don 344037, Russian Federation

E-mail: snv-rnioi@yandex.ru

ORCID: https://orcid.org/0000-0002-0118-4935

SPIN: 8392-6679, AuthorID: 440046, Scopus Author ID: 23499757500

Funding: this work was not funded

Conflict of interest: Kit O. I. and Soldatkina N. V., have been the members of the editorial board of the South Russian Journal of Cancer since 2019, however

they have no relation to the decision made upon publishing this article. The article has passed the review procedure accepted by the journal. The authors did

not declare any other conflict of interest

The article was submitted 06.06.2023; approved after reviewing 01.06.2024; accepted for publication 19.06.2024

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South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 102-110

Kit O. I., Gevorkyan Yu. A., Soldatkina N. V. , Kolesnikov V. E., Bondarenko O. K., Dashkov A. V. Modern strategy of metastatic colorectal cancer treatment

(literature review)

INTRODUCTION

Colorectal cancer (CRC) is the third most common

type of malignant neoplasm worldwide and the second

leading cause of cancer death [1, 2]. In Russia,

the incidence of CRC was 124 per 100 thousand population

in 2022 [3]. Metastatic lesions are observed

in 50�60 % of all CRC cases, while metachronous

metastases occur in 20�50 %, and synchronous metastases

account for 15�30 % of cases, and there is

also a relationship between the latter and the worst

prognosis [4, 5]. The most common localization of

metastases is the liver, followed by the lungs, peritoneum

and distant lymph nodes.

At the same time, metachronous metastases

occurring after treatment are most often observed

(40 %), synchronous metastases account for 25 % of

cases and are associated with a worse prognosis.

In 30

% of patients, metastatic lesion is limited only

to the liver with a primary resectable process in 1/3

of these patients. In 70 % of patients with metastatic

CRC, liver damage is primarily unresectable or there

are extrahepatic metastases [6, 7]. These data indicate

that the majority of CRC patients will sooner or

later have distant metastases, and these will mainly

be liver metastases.

Nevertheless, the current situation is not so tragic,

since the prognosis for metastatic CRC has improved

significantly due

to the

advent

of effective

drug therapy and the expansion of surgical treatment

options [8, 9].

The purpose of the study was to study modern

treatment options for metastatic colorectal cancer.

Metastatic CRC drug therapy

Many studies have been devoted to the choice of

drug therapy for metastatic CRC. There are modern

chemotherapy and immunotherapy regimens (targeted

drugs, immune checkpoint inhibitors), as well as

methods of local exposure (radiofrequency thermal

ablation, chemoembolization).

The long-term results of using FOLFOX and

FOLFIRI schemes turned out to be comparable, but

the advantages of the FOLFOX scheme in line 1 in

terms of the frequency of liver resections were revealed

[10]. A retrospective

PRIME study conducted

in England among 512 patients showed that the addition

of EGFR inhibitors to chemotherapy regimens

increases the frequency of R0 liver resections by

60 % in patients with unresectable metastases, and

these patients can be cured [11]. This conclusion

was also confirmed by a meta-analysis conducted

by Petrelli

F. and

coauthors

[12]. The

FIRE-3

study

conducted among 353 patients compared the use of

different therapy regimens for metastatic CRC and

found that the best response was achieved in the

group of patients receiving cetuximab and FOLFIRI

after 3.5

months of treatment [13]. The meta-analysis

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also confirmed that for patients with metastatic

CRC with wild type RAS, the best treatment strategy

in the 1st line of therapy is chemotherapy + cetuximab

[14]. In wild type RAS/BRAF and left�sided localization

of the primary tumor, anti-EGFR should be

used, in right-sided � bevacizumab

[15]. Achieving

resectability of liver metastases increases the 5-year

survival rate from 9 to 42

% [16].

Surgical strategies for CRC metastatic

liver damage

The requirement for liver resection in CRC metastases

is currently beyond doubt and has been

proven by LiverMetSurvey International Registry data,

according to which, out of 23 thousand patients, the

5-year survival rate in the presence of liver resection

was 42 %, without resection � 9 %. In the review by

Simmonds

R.

S. et al. [17], based on the analysis

of 30 studies, it was found that the 5-year survival

rate of CRC patients with liver metastases with

liver resection R0/R1 was 30�32 %, with resection

R2

� 7

%, without

liver resection

� 0

%. A meta-analysis

conducted by Kanas

G.

P. et al. [18] showed that

the 5-year survival rate of patients with metastatic

CRC undergoing liver resection was 38 %. Therefore,

surgery should be the goal for the majority of these

patients [6].

The criteria for resectability of liver metastases

were determined by Adam R. They were divided into

technical and oncological [19]. The technical absolute

criteria are the impossibility of R0 resection with

less than or 30 % of the remaining liver tissue, as well

as the presence of unresectable extrahepatic metastases.

The technical relative criteria are the possibility

of R0 resection only using other procedures,

as well as R1 resection. The oncological criteria are

unresectable extrahepatic metastases, 5 or more

liver metastases, and tumor progression.

Prognostically unfavorable factors after liver resection

for

CRC metastases are: R1 resection, ex

����-���������� �������������� ������ 2024. �. 5, � 3. �. 102-110

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trahepatic metastases, more than 1 metastasis, size

more than 5 cm, CEA above 200 ng/ml, metastases

in the lymph nodes of the primary tumor, non-event

interval less than 12 months, bilateral liver dam

age [16, 19], BRAF mutation [20].

Oncological and surgical criteria are taken into

account when choosing treatment tactics for initially

resectable liver metastases. In the absence of surgical

difficulties

and

favorable

oncological

prognostic

factors. Surgical treatment without preoperative chemotherapy

is recommended (adjuvant therapy is possible).

In case of adverse oncological factors, pre- or

perioperative chemotherapy is necessary. In case

of surgical difficulties,

systemic

chemotherapy is

recommended regardless

of oncological factors [21].

Adam R. suggests determining the tactics of treatment

of CRC with liver metastases depending on the

presence of symptoms of

the primary

tumor:

with

an asymptomatic tumor with resectable metastases,

simultaneous resection of the liver and primary

focus is possible, however, if there are risk factors,

then chemotherapy is performed first, then liver resection,

and only then resection of the primary focus

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is

performed; with

symptomatic tumors

with

resectable

metastases undergo resection of the primary

lesion, followed by chemotherapy followed by liver

resection. In case of an asymptomatic tumor with

unresectable metastases, chemotherapy is recommended,

followed by step-by-step resection of the liver

and primary focus when the process is transferred

to

a resectable one. In case of a symptomatic

tumor

with unresectable metastases, resection of the primary

focus is performed, chemotherapy followed

by liver resection when the process is transferred to

a resectable one [7].

Aigner F. and co-author. They make their own adjustments

to the treatment regimen for metastatic

CRC: in an asymptomatic

resectable process with the

presence of risk factors after neoadjuvant chemotherapy,

simultaneous surgical interventions should

be performed instead of two-stage ones [22].

The views of oncologists are currently attracted by

a group of asymptomatic tumors with conditionally

resectable liver metastases, which is recommended

to undergo the most active neoadjuvant chemotherapy

with the maximum frequency of objective

response (duplets, triplets) using targeted drugs

(depending on the RAS status) with an assessment

of the effect every two months [11, 23].

At the same time, patients with conditionally resectable

liver metastases undergoing drug therapy

should undergo surgery immediately upon reaching

resectability, without

waiting for a full

response. This

position is due to several factors. Firstly, 83 % of metastases

that disappeared during chemotherapy will

cause the progression of the disease, and secondly,

there is also

a danger

of hepatotoxicity [18,

22],

to

reduce the development of which it is recommended

to limit preoperative therapy to 2�3 months [24].

In addition, the frequency of postoperative complications

directly depends on the number of therapy

courses

performed: 13.6

%

� without chemotherapy,

19 % � after 5 courses of therapy, 45.4 % � after 6�9

courses of therapy, 61.5 % � after 10 or more courses

of therapy [25, 26]. At the same time, early tumor

reduction (. 20

% or . 30

%) at 6�8

weeks of therapy

is an indicator of sensitivity to treatment and is

associated with a high frequency of liver

resections

and an increase in overall patient survival [11, 27].

The volume of surgical intervention

on the liver for CRC metastases

The question of an adequate amount of liver surgery

for CRC metastases is a matter of debate. Anatomical

and atypical resections are possible here.

Previously, the advantage was given to extensive

liver resections

with

a large

margin

from the

edge

of

metastasis due to the better results of extensive interventions.

However, the era of highly effective drug

therapy has made it possible to equalize the survival

of patients with anatomical and non-anatomical liver

resections for CRC metastases [28].

In

2019, a

meta-analysis

of 18

studies

was

published, including 7,081 patients, comparing

parenchymal-preserving and extensive liver resections

[29].

It turned out that the overall and relapse-

free survival in these groups of patients was

comparable, which allowed the authors to conclude

that parenchymal-preserving surgery is an adequate

method of treating metastatic CRC. Parenchymalpreserving

and anatomical liver resections for metastases

were compared with the same results in

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12 studies involving 2505 patients [30].

Currently, the attitude towards the negative edge

of liver resection has also changed. Thus, Kokudo

N. [31] found CRC micrometastases in the liver

parenchyma in only 2 % of patients within 5 mm or

more of the macroscopic border of the tumor. Fur

South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 102-110

Kit O. I., Gevorkyan Yu. A., Soldatkina N. V. , Kolesnikov V. E., Bondarenko O. K., Dashkov A. V. Modern strategy of metastatic colorectal cancer treatment

(literature review)

ther studies have shown that there is no significant

difference in patient survival when the distance from

the resection line is less than and more than 1 cm.

Even a clearance of 1

mm did not increase the time

before the recurrence of liver metastasis, and the

5-year

overall survival rate was 33

%

[31].

In addition,

with modern chemotherapy, even R1 resection has

no prognostic value for patient survival [32].

Parenchymal-preserving liver resections have also

opened up wide opportunities for the successful

application of laparoscopic techniques in CRC metastases

[33�35].

Repeated liver resections for metastatic CRC

The point of preserving the liver parenchyma is

not only the possibility of chemotherapy, but also

repeated liver resections in the event of new metastases.

The expediency of repeated liver resections

has been proven in studies, in particular, in the work

of Schmidt

T.

[36],

in which,

when analyzing the data

of 578 patients, it was found that without repeated

liver resections with recurrence of metastatic lesion,

the 5-year overall survival was 36.7 %, with repeated

liver resections � 56.6 %, with resections for the third

time � 53.2 %.

At the same time, the established prognostic factors

for repeated resections are not applicable, only

the pT stage of the primary tumor and the metachronism

of the lesion are important [37]. A meta-analysis

of 7,200 patients from 27 studies showed that

repeated operations benefit patients with a long relapse-

free period with solitary, small, unilobar lesion

and

absence

of extrahepatic metastases

[36]. Therefore,

patients for repeated liver resections should be

carefully selected.

In cases of impossibility of resection or RTT of

metastatic liver damage, it is possible to use other

methods of local exposure such as regional intraarterial

chemoinfusion, embolization therapy, which

allow

achieving a median overall survival of

45.6

months compared with 40.5 months with systemic

therapy alone [38].

Metastatic lung and ovarian lesions in CRC

Metastatic lung disease is the second favorite localization

of distant CRC metastasis. The importance

of active surgical tactics in this case was demonstrated

in a study by Onaitis

M.

W.

et al.

[39],

in which

thoracic intervention made it possible to achieve 28 %

3-year recurrence-free and 78 % overall survival when

analyzing data from 378 patients. The factors of negative

prognosis

for lung metastases

are: a short

recurrence-

free interval, metastatic lymph node lesion,

the presence of more than 1 metastatic lesion in the

lungs, high CEA, lung resection R1, large metastases,

liver metastases

in the anamnesis

[39, 40].

Clinical recommendations for the treatment of

metastatic liver damage in CRC are also applicable

for metastatic lung damage

[39]. Combined and sequential

resections of the liver and lungs are possible

with encouraging results in a selected group of

patients with solitary metastatic lesion [41].

Metastatic ovarian lesions often occur in women,

while they are more often detected with damage to

other organs, a single lesion occurs only in 24

% of

women. The prognosis for ovarian metastases is

worse than in the liver, and the median survival is

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only 23 months [42].

The choice of treatment tactics for

metastatic CRC

The ESMO-ASIA 2019 consensus on the treatment

of metastatic CRC summarized current views and

recommended surgical treatment with adjuvant or

perioperative chemotherapy in a resectable process,

and with potentially resectable liver metastases, with

massive prevalence, and an unfavorable prognosis,

to carry out the most active drug therapy taking into

account the mutational status of the tumor in order

to transfer the

process

to a

resectable

one

[21]. In

case of unresectable CRC, drug therapy lines are

consistently carried out, the choice of which is based

on the goals, type and time of primary therapy, the

mutational

profile

of the

tumor, and the

toxicity of the

drugs. Studies

have

found

a

correlation

between

an

increase in the median survival of metastatic CRC

and the use of all three main cytotoxic agents (fluorouracil/

leucovorin, oxaliplatin, irinotecan) during

therapy [43].

At the same time, many factors should be taken

into account when planning therapy for patients with

metastatic CRC. These are the characteristics of the

tumor itself (biology and localization of the tumor,

tumour burden, RAS mutations, BRAF), the patient

(age, functional state of organs and systems, comorbidity,

patient attitude, expectations and preferences)

and the treatment itself (toxicity,

flexibility of the

treatment program, socio-economic factors, quality

����-���������� �������������� ������ 2024. �. 5, � 3. �. 102-110

���

�.

�., ��������

�.

�., ����������

�.

�. , ����������

�.

�., ����������

�.

�., ������

�.

�.

����������� ������������� ��������� �������

���������������� ��������������� ���� (����� ����������)

of life)

[21]. That

is, a

balance

is

needed

between

the

risks and benefits of metastatic

CRC therapy,

and

much attention was paid to this issue at ASCO 2020.

CONCLUSION

Therefore, patients with colorectal cancer with

metastatic liver and/or lung damage should be considered

through the prism of surgical treatment,

since

it

is

surgical

intervention

that

can

significantly

improve the results of treatment of patients. Therefore,

patients with potentially resectable metastases

should receive the most effective treatment and be

operated on as soon as the process becomes resectable.

At the same time, modern chemotherapy and

targeted therapy, depending on the mutation status

and localization of the tumor, are an integral part of

the treatment of patients with metastatic CRC.

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Information about authors:

Oleg I. Kit � Academician at the Russian Academy

of Sciences, Dr. Sci. (Med.), MD, professor, General Director, National Medical Research Centre

for Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0003-3061-6108, SPIN: 1728-0329, AuthorID: 343182, ResearcherID: U-2241-2017, Scopus Author ID: 55994103100

Yuriy

A. Gevorkyan � Dr. Sci. (Med.), MD, professor, head of the Department of Abdominal Oncology

No. 2, National Medical Research Centre for

Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0003-1957-7363, SPIN: 8643-2348, AuthorID: 711165

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Natalya V. Soldatkina

� Dr. Sci. (Med.), MD, leading researcher of the Department of General

Oncology, National Medical Research Centre for

Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0002-0118-4935, SPIN: 8392-6679, AuthorID: 440046, Scopus Author ID: 23499757500

Vladimir E. Kolesnikov � Dr. Sci. (Med.), MD, surgeon, Department of Abdominal Oncology

No. 2, National

Medical Research Centre of Oncology,

Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0002-9979-4095, SPIN: 9915-0578, AuthorID: 705852

Olga K. Bondarenko � Oncologist of the Abdominal Oncology

Department No. 2, National Medical Research Centre for Oncology, Rostov-on-Don,

Russian Federation

ORCID: https://orcid.org/0000-0002-9543-4551, SPIN: 7411-8638, AuthorID: 1223821

South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 102-110

Kit O. I., Gevorkyan Yu. A., Soldatkina N. V. , Kolesnikov V. E., Bondarenko O. K., Dashkov A. V. Modern strategy of metastatic colorectal cancer treatment

(literature review)

Andrey

V. Dashkov � Cand. Sci. (Med.), MD, oncologist, the Abdominal Oncology

Department No. 2, National Medical Research Centre of Oncology,

Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0002-3867-4532, SPIN: 4364-9459, AuthorID: 308799

Contribution of the authors:

Kit O. I. � concept and design of the study;

Gevorkyan Yu. A. � editing;

Soldatkina N. V., Kolesnikov V. E., Bondarenko O. K., Dashkov A. V. � collection and processing of materials;

Soldatkina N. V. � statistical processing, writing the text.

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