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CHOICE OF THE OPTIMAL METHOD OF TREATMENT OF LOCALLY
ADVANCED RECTAL CANCER.
Almuradova D.M.
1
, Yusupov A.A.
1
, Ismoilov Zh.Kh.
1
1
Tashkent State Medical University . Tashkent. Uzbekistan .
Email:
ORCID : 0009-0002-4147-9460
ORCID: 0009-0004-7088-3344
ORCID: 0009-0000-5523-2114
Abstract:
Rectal cancer is one of the most common forms of malignant neoplasms both in the
world oncological practice and in Uzbekistan. About 600,000 new cases of this disease are
diagnosed annually in the world. Over the past few decades, there has been a steady increase in
the incidence of rectal cancer. The data on the relative incidence of this nosology are
comparable among Russian and foreign authors according to Siegel R., Miller K., rectal cancer,
including anal canal cancer, accounts for about 50% of all colon tumors. In recent years, there
has been a tendency towards an increase in the incidence of rectal cancer worldwide, so its
share in the structure of oncological morbidity in men is 5.3% and in women 4.4%. Locally
advanced rectal cancer is a tumor of limited mobility or immobile with involvement or
destruction of its own fascia, without obvious signs of distant metastasis in patients who, due to
its spread beyond the organ, cannot undergo radical surgery without a high risk of local relapse
in the near future after surgery. One of the urgent tasks of modern oncoproctology is to improve
the long-term results of treatment of patients with locally advanced rectal cancer (LARC).
Key words:
locally advanced rectal cancer, chemoradiation therapy, neoadjuvant
chemotherapy, consolidation chemotherapy, induction chemotherapy, SANDWICH therapy,
pathomorphism. capecitabine; ox aliplatin.
Relevance.
In recent years, against the background of an increase in the overall incidence of
rectal cancer both in the world and in Russia, the proportion of patients with a locally advanced
tumor process at primary treatment is more than 30% [8]. The use of preoperative prolonged
chemoradiotherapy (CRT) in combination with fluoropyrimidine drugs, followed by total
mesorectumectomy and adjuvant chemotherapy (CT) is the standard of treatment for this group
of patients and is included in national recommendations of the USA (NCCN), Western
European countries (ESMO) and Russia (AOR). Colorectal cancer accounts for 15% of all
cancer cases, and rectal cancer (RC) accounts for 30%. More than 1 million cases of colorectal
cancer are registered worldwide every year. In most countries, mortality from RC ranks 5th or
6th [5]. Unfortunately, this goal is not always achievable in the treatment of RC, since the
radicalism of the operation is often achieved through extensive resections with the loss of the
locking apparatus of the rectum [7]. At the same time, expanding the scope of surgical
intervention does not prevent the risk of relapse, which requires combined treatment in various
modes.
Epidemiology
. The highest incidence of rectal cancer is recorded in Japan (Hiroshima: men -
23.3, women - 10.0), the Czech Republic (men - 18, women - 7). High incidence is recorded in
New Zealand, North America, Northern and Western Europe. Low
incidence
is noted in Africa,
South and Central America. In Russia, the incidence of rectal cancer is quite high (St.
Petersburg: men -13, women -8) [12]. The share of rectal cancer in the structure of morbidity
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from 13 malignant neoplasms in the male population is 5.2%, in women - 4.7%. Among the
CIS countries, it was minimal in Armenia, Uzbekistan and Kyrgyzstan (2-3%), and maximal in
Moldova (8% in men and 5.2 in women). Rectal cancer in Russia, Belarus, Uzbekistan is in
fifth place. On average, in men, rectal cancer in these countries is from 4 to 5%. The increase in
standardized incidence rates was 12–50% for both sexes in Azerbaijan and Armenia, and for
men in Kazakhstan and Belarus. The lowest increase was observed in Uzbekistan (3.3% for
men and 4.2% for women). A decrease in standardized incidence rates of rectal cancer was
noted in Kyrgyzstan (15.9% and -25%).
Etiology.
Most malignant neoplasms of the rectum develop against the background of
adenomatous polyps or adenoma. Polyps are histologically classified as tubular (5%
malignancy), villous (40% malignancy), or mixed (20% malignancy)[39]. The degree of
intestinal epithelial dysplasia also plays an important role in the etiology of rectal cancer and
ranges from 5% malignancy (low grade) to 35% (high grade). The risk of malignancy of benign
neoplasms also correlates with the size of adenomas: 90% are less than 1 cm in size (1% risk),
10% are more than 1 cm (10% risk). Despite advances in radiation and drug therapy, as well as
recent advances in molecular biology of cancer, the leading
The surgical method remains the treatment of this pathology [1]. However, despite the
abundance of modern surgical techniques, many fundamentally new designs of suturing devices
and modern high-tech equipment for operating rooms, the improvement of the surgical method
from an oncological standpoint has to a certain extent reached its limit, as evidenced by the lack
of significant improvements in the long-term results of surgical treatment in recent decades [1].
Complicated course of cancer often does not allow preoperative RT, bringing to the forefront
the need for urgent surgical intervention. In this case, when metastases are detected in regional
lymph nodes, it is necessary to limit oneself to postoperative radiation therapy only. To
enhance the effectiveness of preoperative RT, local microwave hyperthermia began to be used
as a radiomodifier [15]. However, to develop an individualized approach, it is necessary to
develop a rational strategy that would facilitate the optimal choice of the combined treatment
method and the volume of surgical intervention to achieve the best oncological results.
Oncological and functional adequacy of treatment follows from the preference for a particular
volume of surgical intervention compared to other operations, depending on the combined
treatment method used, and consists in achieving, with minimal functional damage, a decrease
in not only the frequency of locoregional cancer recurrences, but also, if possible, distant
metastases.[5] Modern diagnostic methods (transrectal ultrasound, MRI of the pelvic organs)
make it possible to obtain information about the degree of local tumor spread and the state of
regional lymph nodes even before the start of treatment, which allows for advance planning of
the latter[17].
In recent years , a number of studies have been conducted on optimizing the choice of
combined treatment methods depending on the cancer localization [4], expanding the
indications for sphincter-preserving surgery in the context of combined treatment using radio-
modification.
In the past 20–30 years, the incidence of local recurrences and distant metastases in patients
with rectal cancer remains high, especially in cases where the tumor has spread beyond the
rectal wall and there is metastatic involvement of regional lymph nodes[30]. However, rectal
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cancer (histologically, it is usually adenocarcinoma) is a relatively radioresistant tumor, which
makes it advisable to search for effective radiomodifiers to increase the overall effectiveness of
treatment measures carried out at the neoadjuvant stage of complex treatment. [14].
In cases where complete tumor regression is achieved after neoadjuvant treatment, it is possible
to use the tactics of dynamic observation, without the surgical stage of therapy. This tactic is
very important in patients with tumor localization in the lower ampullar region, who require
extirpation of the rectum according to oncological principles [18]. Maximum sphincter-
preserving treatment, provided that adequate oncological results are achieved, is the ultimate
goal of the complex of treatment measures [12].
Adjuvant chemotherapy is one of the most important components of the complex treatment of
patients with locally advanced rectal cancer. First of all, this is due to the frequency of distant
metastases, which remains high in this category of patients [15]. The results showed that a
longer interval increases the frequency of complete morphological response (pCR) and does not
increase the frequency of surgical complications [10–14].
In a number of studies, local hyperthermia is used to increase the radiosensitivity of the tumor.
This method has received scientific justification in domestic and foreign studies both in the
study of fundamental radiobiological aspects of hyperthermic effects on normal and tumor
tissues, and in the analysis of the results of including a thermal component in the scheme of
treatment measures for tumors of various localizations [13]. The use of neoadjuvant
thermochemoradiotherapy is aimed at achieving maximum regression of the primary tumor,
and with a high initial probability of non-radical surgical intervention in prognostically
unfavorable areas, it increases the chance of performing R-0 resections and sphincter-
preserving operations when the tumor is localized in the lower ampullar region of the rectum
[13]. In cases where complete regression of the tumor is achieved after neoadjuvant treatment,
it is possible to use the tactics of dynamic observation, without the surgical stage of therapy.
This tactic is very important in patients with tumor localization in the lower ampullar region,
who require extirpation of the rectum according to oncological principles. Maximum sphincter-
preserving direction of treatment, provided that adequate oncological results are achieved, is the
ultimate goal of the complex of therapeutic measures [6].
Drug therapy for colorectal tumors is usually considered in one section; the general strategy of
therapeutic approaches to these tumors differs [32]. Radiation therapy has been an important
part of rectal cancer (RC) treatment for many decades, and the study of the optimal
combination and sequence of surgical , radiation, and drug treatment methods for tumors in this
location continues to this day [15]. At the first stage, it was established that adjuvant
chemotherapy based on 5-fluorouracil in combination with radiation therapy significantly
improves both relapse-free (RFS) and overall (OS) survival in patients with rectal cancer.
Unlike colon cancer, in RRC, the addition of leucovorin to 5-fluorouracil does not increase the
effectiveness of treatment [18]. In addition, it has been shown that radiation therapy combined
with continuous infusion of 5-FU is more effective than radiation therapy combined with jet
injection of fluorouracil [22,23]. In recent years, neoadjuvant chemoradiotherapy has attracted
the attention of researchers.
A significant advantage of neoadjuvant chemoradiotherapy compared to adjuvant
chemotherapy in terms of locoregional control and toxicity has been demonstrated[7].
According to the results of the study, preoperative chemoradiation therapy at stage II–III of the
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disease was recognized as preferable, although there were no differences in overall survival
[3,17]. One of the important indicators of the effectiveness of neoadjuvant chemoradiation
therapy for RCC is the frequency of complete pathologically confirmed tumor regressions, the
frequency of which, according to different authors, fluctuates within 10–25% [15,19, 20].
The absence of differences in overall survival in the German CAO/ARO/AIO-94 study, which
was confirmed by updated long-term results with a median follow-up of 11 years reported at
ASCO 2011 [26], is explained by the fact that neoadjuvant chemoradiation therapy regimens
use doses of cytostatics that are adequate only to achieve the radiosensitization effect and
insufficient to achieve systemic control and eradication of micrometastases [2]. That is why
neoadjuvant chemotherapy followed by chemoradiation therapy, then surgery and adjuvant
chemotherapy was recognized as the most optimal strategy for treating stage II–III rectal cancer
[2,5,7].
A further direction of clinical research was the search for more effective regimens of
preoperative and adjuvant chemotherapy based on the introduction of new drugs into treatment
regimens [20].
The basis for these programs was the results of clinical trials of capecitabine and oxaliplatin in
colon cancer. Thus, the X-ACT study demonstrated the advantages of adjuvant chemotherapy
with capecitabine compared with the combination of 5-fluorouracil / leucovorin in patients with
stage III colon cancer [4], and concluded that capecitabine is a justified alternative.
In addition, the MOSAIC (Multicenter International Study of Oxaliplatin, Fluorouracil and
Leucovorin in the Adjuvant Treatment of Colon Cancer) study assessed the efficacy of
oxaliplatin in adjuvant therapy for stage II–III colon cancer (
n
= 2246), comparing the
FOLFOX-4 and 5-FU/LV (De Gramon regimen) regimens[8 As early as 2006, a pilot phase I
study was presented in which, after 4 courses of neoadjuvant chemotherapy using the XELOX
regimen, patients with stage II and III rectal cancer received radiation therapy with capecitabine
as a radiosensitizer, and then, after surgery, capecitabine was used for another 12 weeks in an
adjuvant regimen [11]. Based on the study results, it was recommended to continue studying
capecitabine. The role of adding irinotecan to the standard combination of 5-fluorouracil with
leucovorin in adjuvant chemoradiotherapy of patients with stage II–III rectal cancer was
assessed in a randomized phase III study [12]. Unfortunately, the use of irinotecan was
accompanied by increased toxicity.
In June 2011, the ASCO congress discussed in detail the issues of further optimization of
treatment of patients with rectal cancer. In a large randomized study NSABP R-04, the
immediate efficacy of four different chemotherapy regimens, which were used concurrently
with preoperative radiation therapy, was compared [16]. The study included 1608 patients with
clinical stage II or III rectal cancer with the potential possibility of performing sphincter-
preserving surgery, who underwent preoperative RT (45 Gy in 25 fractions over 5 weeks +
boost 54-108 Gy fractionally over 3-6 days) and the following drug therapy:
−
long-term infusion of 5FU (225 mg/m2
5
days a week);
−
long-term infusion of 5FU (225 mg/m2
5
days a week) + oxaliplatin (50 mg/m2
once
a
week for 5 weeks);
−
capecitabine (825 mg/m2
twice
daily 5 days a week);
−
capecitabine (825 mg/m2
twice
daily for 5 days a week) + oxaliplatin (50 mg/m2
weekly
for
5 weeks).
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The objectives of the study were pathologically confirmed complete regression (pCR) rate,
sphincter-preserving surgery, and downstaging based on surgical material (local control rate
data expected in 2013)[16]. 5-FU versus capecitabine and oxaliplatin versus non-oxaliplatin
groups were compared. It was shown that the efficacy of capecitabine was not lower (and even
slightly higher) than 5-FU: the pCR rate was 22.2 and 18.8%, respectively (
p
= 0.12),
sphincter-preserving operations were performed in 62.7 and 61.2% of patients (
p
= 0.59), the
stage decreased in 23.0 and 20.7% of cases (
p
= 0.62) with comparable toxicity: grade 3/4
diarrhea was recorded in 10.8 and 11.2% of observations [16]. In contrast to capecitabine, the
results of adding oxaliplatin were not as positive: the addition of the drug did not affect the
immediate efficacy of treatment, but it did lead to a significant increase in the incidence of
grade 3–4 diarrhea from 6.6 to 15.4% (
p
< 0.0001) [16]. Although only immediate results of
the study have been reported so far, the authors conclude that capecitabine is at least as
effective as 5-fluorouracil and may become a new standard for chemoradiation therapy for
RCC. The inclusion of oxaliplatin based on the results of this program is not recommended [16].
Large randomized trials comparing capecitabine and 5-fluorouracil in perioperative
chemoradiotherapy for rectal cancer have convincingly proven that the use of capecitabine is
associated with improved clinical outcomes. The presented data were widely discussed at the
13th World Congress on Gastrointestinal Cancer, held in June 2020. Based on the discussion, it
was concluded that capecitabine can effectively and safely replace 5-fluorouracil in
chemoradiotherapy programs; the addition of oxaliplatin is currently not recommended. In
general, neoadjuvant radiotherapy in combination with chemotherapy based on the use of
capecitabine as a radiosensitizer, followed by surgery and adjuvant chemotherapy, can be called
a new standard of treatment for locally advanced rectal cancer.
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