Transarterial chemoembolisation in the treatment of patients with metastatic colorectal cancer

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Liver is an organ which is most commonly damaged by metastatic tumor processes. In most cases the source for metastasis in the liver is colorectal cancer [1]. Colorectal cancer ranks fourth in the structure of oncological disease. In each third individual with colon cancer remote metastases are identified at the moment of making the diagnosis, first of all, in the liver (according to the international authors, in 20-50% of cases) [2]. Besides, up to 55% of patients who received potentially radical treatment of colon cancer, have risk of progress of the disease in the form of metastases. In 25% of observations, liver is the only organ damaged by metastases [3]. Speaking about prognosis, the only metastases that lead to the lethal outcome faster than damages to the liver, are metastases into the brain. [4, 5]. According to different authors, survival rate in metastatic damages to the liver without treatment is less than 12 months. The only effective method of treatment of liver metastases giving satisfactory results, is surgical intervention. It provides 5-year survival rate in 20-58% of patients [6], but however, resectability of liver metastases is not more than 10-30% [7].

The most effective method of treating patients with non-operable colorectal liver metastases is radio frequency ablation (RFA) which provides 5-year survival in 17-51% of cases [8-10]. One of disadvantages of this method is a high risk of local recurrences which reaches 25-50% with the size of lesion more than 3 cm and 16% with the size of lesion less than 3 cm. The main cause for a local recurrence is incomplete coagulation necrosis after ablation. The rate of complete necroses with the size of lesion more than 5 cm is less than 50% [11]. To increase the area of necrosis and reduce the risk of local recurrences a combination of RFA with chemoembolization of the hepatic artery (CEHA) is used [12, 13]. In studies conducted on VX2 rabbits this combination was shown to reliably increase the concentration of heat shock proteins (HSP) (p<0.01) in peritumorous tissues, in particular, of HSP70 protein, responsible for autocrine induction of chemokines by tumor cells (Fig. 1) [14].

 

Fig. 1. Study protocol for determining the optimal time for the second stage of treatment

 

HSP70 proteins obtained from tumor cells, function as cytokines which stimulate macrophages that produce anti-inflammatory cytokines and chemokines. Besides, HP70 can accompany antigens of damaged cells into T-cells, and induce in this way the antitumor immunity. Increase in the concentration of HSP70 in peritumorous tissues after application of RFA and CEHA combination also leads to a considerable increase in the concentration of T-cells in this zone [15].

The result of increased concentration of HSP70 and CD8+ Т-cells was a reliably higher parameter of completeness of tumor necrosis after application of a combination of RFA and CEHA [15]. A disadvantage of conducted studies was the fact that ablation was performed within one hour after embolization. Only ischemic effect of embolization was used because of the minimal time of action of chemoembolic agent on the tumor.

In the world literature the data have been published about use of a combination of RFA and CEHA only for treatment of patients with hepatocellular cancer (HCC) [12, 13]. A disadvantage of these studies is different time intervals between stages of treatment (from several days to 3 weeks). At present the effectiveness of application of hepatic artery chemoembolization in treatment of patients with colorectal metastatic cancer is not determined. Besides, the treatment protocol of inoperable malignant neoplasms of the liver by a combination of RFA and CEHA is not yes standardized.

Materials and Methods

The basis of the prospective comparative randomized study included the analysis of the results of treatment of 30 patients with the medium age of 61.33±10.7 years with resectable metastases of colorectal cancer in the liver who were under treatment in the department of surgery of liver and pancreas in the period from 2013 to 2014. Into the study the following patients were included: without severe concomitant pathology with resectable metachronous liver metastases of colorectal cancer; with the size of metastases from 3 to 5 cm; patients who did not receive systemic chemotherapy after liver metastases have been verified. To study therapeutic patho-morphism in different periods after regional chemotherapy the patients were divided into two groups. The first group included 15 patients with resection performed 1 week after CEHA with the subsequent histological examination and determination of the degreet of therapeutic pathomorphism. The second group included patients with resection performed 2 weeks after CEHA with the subsequent histological examination according to the protocol, with determination of the degree of therapeutic pathomorphism (Fig. 1). A chemoembolic agent was a mixture consisting of lipiodol 10 ml and mitomycin C 10 mg. The extent of therapeutic pathomorphism was evaluated according to Colorectal Cancer Structured Reporting Protocol (2nd Edition, 2012). Randomization of patients into groups was conducted by a method of «ballot box» (UD 2:1) at the stage of planning of regional chemotherapy.

A decision about resection operation was taken by the multidisciplinary oncocon-cilium. Resection of the liver was conducted according to conventional standards and indications. In the first group the following interventions were conducted: atypical resection – 10; segmentectomy – 2; right-sided hemi-hepatectomy (RSHH) – 2; left-sided hemi-hepatectomy (LSHH) – 1. In the second group the following operation were conducted: atypical resection – 10; segmentectomy – 1; right-sided hemihepatectomy (RSHH) – 3; left-sided hemihepatectomy (LSHH) – 1. In planning of resection of more than 3 segments of the liver, the volume of future liver remnant (FLR) was evaluated in all patients. In all patients the FLR was above the necessary values ((>25% in the absence of the liver pathology (hepatosis, cirrhosis), >35% with existing pathology)). In all patients single-stage resections of liver were performed.

Further on systemic adjuvant therapy was conducted. Characteristics of the groups are given in Table 1.

 

Table 1. Characteristics of patients with the definition of therapeutic pathomorphosis after regional chemotherapy

Characteristics	1 group (n = 15)	2 group (n = 15)	p
Floor: male feminine	7 8	8 7	0,775
Age: <60 years > 60 years	6 9	6 9	0,806
Primary tumor: colon rectum	12 3	7 8	0,126
Primary tumor stage: Step 1-2 3 stage	2 13	3 12	0,624
N-status of primary tumor: N+ N-	2 13	3 12	0,775
The size of metastasis: 3-4 cm 4-5 cm	9 6	8 7	0,870
Level of REA: <60 ng / ml > 60 ng / ml	12 3	12 3	0,653
Localization of metastasis: central (S4,5,8) peripheral	8 7	7 8	0,486
Time to metastasis: <12 months > 12 months	9 6	8 7	0,089
ASA: Grade 1 Grade 2	9 6	6 9	0,367

 

 Description of the variables depended on their distribution. The kind of distribution was determined using Shapiro-Wilk test. If distribution of the variable approached the normal one (Gaussian distribution), for description of the quantitative data the mean value was used with the mean square deviation (M±s), and in comparison of groups by this variable, parametric methods were used (Pearson correlation analysis, Student’s t-test).

For analysis of the data by a variable, non-parametric Mann-Whitney criteria for independent groups were used. The obtained results were processed by Statistica program for Microsoft Windows, version 6.1, StatSoft Inc. (USA). Statistically significant level was taken p<0.05.

Results and Discussion

In all patients after CEHA, postembolization syndrome was observed. Pain syndrome was seen in 29 of 30 patients (hereinafter – 29/30) patients, hyperthermia – in 7/20, elevation in the level of transaminases – in 25/30 patients.

The average intensity of pain syndrome on the first day after CEHA determined by VAS test was 41.37±15.17 (0-75) mm. Administration of analgesics was required for 27/30 patients, in 26/27 patients pain syndrome was relieved by non-steroid anti-inflammatory drugs (NSAID), in 1/27 patient – by narcotic analgesics. On the second day after the procedure intensity of pain syndrome determined by VAS was 19.97±9.65 (0-43) mm. Administration of analgesics was required for 11/30 patients, pain syndrome in them was relieved by administration of NSAID. On the third day after the procedure some painful sensations were observed in 2/30 patients with the average intensity by VAS test 3.31±6.75 (0-21) mm. Administration of analgesics was not required (Fig. 2).

Fig. 2. Intensity of pain syndrome according to VAS for 1-3 days after regional chemotherapy

 

 Hyperthermia ≥ 38°С on the 1^st day after CEHA was in 1/30 patients, ≥ 37°С – in 6/30 patients. On the second day hyperthermia ≥ 37°С was in 3/30 patients, the temperature did not rise above 38°С. On the 3^d day all patients had normothermia.

In all patients before CEHA the level of transaminases was within the norm. On the 1^st day AsAT level increased in 24/30 patients, of AlAT – in 25/30 patients. On the 1^st day the average level of AsAT was 75.28±41.39 (16-201) Un/L, of AlAT – 59.78±36.47 (22-207) Un/L. On the 3^d day elevation of AsAT was noted in 21/30 patients, of AlAT – in 19/30 patients. On the 3^d day the average level of AsAT was 40.78±25.5 (20-138) Un/L, of AlAT – 56.13±39.05 (21-243) Un/L. On the 5^th day after the procedure AsAT was increased in 12/30 patients, AlAT – in 12/30 patients. On the 5^th day the average level of AsAT was 31.2±11.54 (18-69) Un/L (Fig. 6), of AlAT – 32.43± 9.26 (15-79) Un/L (Figs. 3 and 4). No complications and no lethality after CEHA were recorded.

 

Fig. 3. AST level on the 1-5th day after HEPA

 

Fig. 4. ALT level for 1-5 days after HEPA

 

 The degree of therapeutic pathomor-phism was traced in all patients included into the study.

In the first group where resection operation was conducted in 7 days after the regional chemotherapy, the therapeutic pathomor-phism was observed in 13/15 patients. In 11/13 patients the 2^nd degree of therapeutic pathomorphism was recorded that consisted in the existence of fibrosis fields and scarce inflammatory infiltration (Fig. 5) with the underlying preserved tumorous tissue.

In 2/15 patients no therapeutic patho-morphism was observed. In 2/13 patients the 1^st degree of therapeutic pathomorphism was determined: in one patients in the form of fibrosis of separately located glands and calcified foci (Fig. 6), in the other patient – in the form of myxomatosis, diffuse inflammatory infiltration and necrotic foci.

In the second group where resection operation was conducted in 14 days after regional chemotherapy, the therapeutic patho-morphism was observed in 12/15 patients. In all these patients the 2^nd degree of the therapeutic pathomorphism was identified. The 1^st degree of therapeutic pathomorphism was not recorded. In 3/15 patients the therapeutic pathomorphism was absent.

The above described experimental data concerning combination of regional chemotherapy and radio frequency ablation showed better results with combined approach than with monotherapy (CEHA or RFA) [14, 15]. In our opinion, a disadvantage of the conducted treatment was the fact that ablation was carried out within the first hour after embolization. Only ischemic effect was used, since the time of action of chemo-embolizate on the tumor was minimal. This can explain continued tumor growth (tumor growth rate – 126.74±24.46%) after treatment and incomplete necrosis in a part of experimental rabbits (tumor necrotic rate – 94.56±12.03 %) (Fig. 3).

At the beginning of 2013 there was published a meta-analysis of 7 randomized controlled studies that compared effectiveness of use of combination of CEHA and RFA with use of only ablation type in treatment of patients with hepatocellular cancer (HCC). It showed that combination of CEHA and RFA in patients with lesions more than 3 cm reliably (p<0.0001) improved the results of 1,3,5-year survival rate. However, this combination did not improve the treatment results for patients with lesions less than 3 cm in size [16]. Besides, the above mentioned meta-analysis did not find statistically reliable increase in the number of complications with use of combination of CEHA and RFA which evidences safety of their combined use. A drawback of the given studies is different time intervals between stages of treatment. Most common is the method with ablation conducted in 1-2 weeks after CEHA [17]. This permits to effectively relieve postembolization syndrome and thus reduce the number of complications [18]. Some authors prefer to conduct ablation in 4 weeks [19]. In some studies both stages of treatment were conducted in one day [21].

In our research the therapeutic pathomorphism was recorded in the majority (25/30) of patients. At the same time no reliable difference between the degree of metamorphism on the 7^th and 14^th day after CEHA was recorded (p=0.436).

Postembolization syndrome was recorded in all patients after regional chemotherapy, however, it was possible to manage it not later than on the 5^th-7^th day of postoperative period. Thus, on the 7^th day not a single patient had contraindications for further interventions.

Thus, therapeutic pathomorphism develops after chemoembolization of hepatic artery and reaches maximum on the 7^th day. Postembolization syndrome is effectively relieved in all patients on the 7^th day after CEHA.

 

Fig. 5. Metastasis of adenocarcinoma of intestinal type with the presence of fields of fibrosis (A) and inflammatory infiltration (B). The second degree of therapeutic pathomorphosis (color: hematoxylin and eosin, x 400)

 

Fig. 6. Metastasis of adenocarcinoma of intestinal type. Moderate therapeutic pathomorphosis (grade 1). Fibrosis of separately lying glands and the appearance of calcifications. (color: hematoxylin and eosin, x 400)

 

Conclusion

Chemoembolization of the hepatic artery is an effective method of treatment of patients with colorectal cancer with metastases into the liver. In combination of chemoembolization of the hepatic artery with methods of local destruction in treatment of patients with inoperable metastatic cancer of the liver, the optimal interval is 7 days.

About the authors

Alexey V. Shabunin

Russian Medical Academy of Continuous Professional Education

Email: dc.drozdov@gmail.com
ORCID iD: 0000-0002-4230-8033
SPIN-code: 8917-7732

Corresponding Member of Russian Academy of Sciences, MD, Grand PhD, Professor, Head of Surgery Department, Russian Medical Academy of Continuous Professional Education; Head of Botkin Hospital

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993

Michael M. Tavobilov

Russian Medical Academy of Continuous Professional Education

Email: dc.drozdov@gmail.com
ORCID iD: 0000-0003-0335-1204
SPIN-code: 9554-5553

MD, PhD, Associate Professor of Surgery Department, Russian Medical Academy of Continuous Professional Education; Head of the Department of Liver and Pancreatic Surgery, Botkin Hospital

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993

Oksana V. Paklina

Botkin Hospital

Email: dc.drozdov@gmail.com
ORCID iD: 0000-0001-6373-1888
SPIN-code: 4575-9762

MD, Grand PhD, Professor, Head of the Pathoanatomical Department

Russian Federation, Mosсow

Dmitriy N. Grekov

Russian Medical Academy of Continuous Professional Education

Email: dc.drozdov@gmail.com
ORCID iD: 0000-0001-8391-1210
SPIN-code: 6734-9727

MD, PhD, Associate Professor of Surgery Department

Russian Federation, 2/1, Barrikadnaya st., Moscow, 125993

Galia R. Setdikova

Botkin Hospital

Email: dc.drozdov@gmail.com
ORCID iD: 0000-0002-9524-3798
SPIN-code: 6551-0854

MD, PhD, Pathologist

Russian Federation, Mosсow

Pavel A. Drozdov

Botkin Hospital

Author for correspondence.
Email: dc.drozdov@gmail.com
ORCID iD: 0000-0001-8016-1610
SPIN-code: 8184-8918

Surgeon of the Department of Liver and Pancreatic Surgery

Russian Federation, Mosсow

References

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