• Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
SHORT COMMUNICATION
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 37-40

Effect of Irinotecan Combined with Cetuximab on Liver Function in Patients with Advanced Colorectal Cancer with Liver Metastases


1 Department of Blood Transfusion, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
2 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
3 Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, China
4 Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China

Date of Submission23-Feb-2016
Date of Acceptance05-Apr-2016
Date of Web Publication29-Apr-2016

Correspondence Address:
Dr. Yan Liang
Department of Blood Transfusion, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.181433

Rights and Permissions
  Abstract 

Aim: To explore the effect of irinotecan combined with cetuximab on liver function of advanced colorectal cancer patients with liver metastases.
Methods: A total of 97 advanced colorectal cancer patients with liver metastases admitted to our hospital from August 2008 to August 2011 were treated with irinotecan combined with cetuximab. Changes of tumor markers, liver metastasis diameter, and liver function were observed, and the response rate was analyzed.
Results: After the treatment, carcinoembryonic antigen, carbohydrate antigen 19-9, prothrombin time, albumin, and metastasis diameter significantly decreased (P < 0.05) and aspartate aminotransferase, alanine aminotransferase, and total bilirubin increased significantly (P < 0.05). Average length of stay was 16.2 ± 3.7 weeks. There were 0 case of complete remission, 25 cases of partial response, 41 cases of stable disease, and 31 cases of progressive disease. The response rate was 25.77% and disease control rate was 68.04%. Adverse reactions were present in 92 cases, with the incidence rate of 94.85%.
Conclusion: Although the liver function tests show that the damage is caused by irinotecan combined with cetuximab, the normal cells recover and therefore liver function returns to near baseline. The data from this trial suggests that the combination treatment with irinotecan and cetuximab for colorectal cancer patients with liver metastases is safe and effective, resulting in improved prognosis and quality of life.

Keywords: Advanced colorectal cancer, cetuximab, irinotecan, liver function, liver metastasis


How to cite this article:
Liang Y, Li Y, Li X, Zhao J. Effect of Irinotecan Combined with Cetuximab on Liver Function in Patients with Advanced Colorectal Cancer with Liver Metastases. Cancer Transl Med 2016;2:37-40

How to cite this URL:
Liang Y, Li Y, Li X, Zhao J. Effect of Irinotecan Combined with Cetuximab on Liver Function in Patients with Advanced Colorectal Cancer with Liver Metastases. Cancer Transl Med [serial online] 2016 [cited 2019 Nov 17];2:37-40. Available from: http://www.cancertm.com/text.asp?2016/2/2/37/181433


  Introduction Top


Colorectal cancer, the most common malignant tumor in China, poses a serious threat to the health. [1],[2],[3],[4],[5] Metastatic disease is often present at diagnosis, and in these patients, surgical resection is ineffective for cure. Therefore, choosing the appropriate chemotherapy regimen is the key to improve the survival. In addition, reasonable chemotherapy helps to reduce the size of the neoplastic foci in patients, besides offers opportunity for surgical resection. [6],[7] Since 2004, irinotecan, cetuximab, and other biotarget drugs have gradually been approved for clinical application. To investigate the effect of combined irinotecan and cetuximab on liver function in advanced colorectal cancer patients with liver metastases, this clinical trial was carried out.


  Methods Top


Clinical data

The study was reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of Jinan University. All participants provided informed consent. Totally, 97 advanced colorectal cancer patients with liver metastases, treated in the First Affiliated Hospital of Jinan University from August 2008 to August 2011, were selected as the research objects. They were diagnosed by colonoscopy and biopsy, [8] and liver metastases were discovered by imaging examination. The exclusion criteria were: (1) patients with abnormal white blood cells and platelets; (2) patients with diseases of other vital organs such as heart, lung, and kidney; (3) patients with hepatitis, cirrhosis and other liver diseases; (4) Karnofsky score < 70 or expected survival time ≤ 3 months. There were 53 males and 44 females, aged 39-76 (average 61.0 ± 8.4) years. The primary foci of 64 cases were in the colon and 33 cases in the rectum. Metastatic lesions of 50 cases were in the left liver and 47 cases in the right liver.

Treatment method

Combined chemotherapy

Before chemotherapy, 0.4 g cimetidine (GYZZ H20050727, Zhejiang Sanjiu Bangerkang Pharmaceutical Co., Ltd., China) by intravenous infusion, 50 mg ephedrine diphenhydramine tablets (GYZZ H23023598, Heilongjiang Dinghengsheng Pharmaceutical Co., Ltd., China) by oral way, and 5 mg dexamethasone acetate (GYZZ H31021298, Shanghai GM Pharmaceutical Co., Ltd., China) by intravenous injection were administered to patients to protect the gastric mucosa, inhibit allergic reactions, and prevent inflammatory symptoms. [9] The therapeutic regimen was [10] that cetuximab (Registration No. S20050095, Merck Group Ltd., Germany) of 400 mg/m 2 was infused intravenously within 120 min and then decreased to 250 mg/m 2 within 60 min. Cetuximab was infused once a week. Irinotecan hydrochloride (GYZZ H20020687, Jiangsu Hengrui Medicine Co., Ltd, China) of 180 mg/m 2 was injected intravenously every 2 weeks and 2 h after cetuximab infusion.

Surgical treatment

After 1-3 months of chemotherapy, partial hepatectomy was carried out depending on the recovery. General anesthesia and endotracheal intubation in the supine position were administered to patients. The incision approach was central flaw from the right costal margin. Tumor was removed conventionally for liver histopathological examination.

Outcome measures

Tumor changes

Fasting blood of 5 mL was collected 1 week after administration and at the end of treatment. Enzyme-linked immunosorbent assay method was used for detecting tumor markers including carcinoembryonic antigen (CEA) and serum carbohydrate antigen 19-9 (CA19-9 ). [11],[12] The mean diameters of tumor in liver metastases when patients were enrolled and at the end of treatment were recorded and compared.

Changes of liver function

Fasting blood of 5 mL was collected when patients were enrolled, 1 week after administration, and at the end of treatment. Prothrombin time (PT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), and total bilirubin (TBIL) of liver functions were observed by blood biochemical examination.

Response rate analysis

The response rate was analyzed referring to the WHO clinical evaluation standard, [13] including complete remission (CR), partial response (PR), stable disease (SD), and progressive disease (PD). CR + PR was used to calculate response rate, and CD + PD + SD was used to calculate disease control rate.

Adverse reactions observation

Side effects of patients were observed and recorded referring to the Adverse Reaction Grading of National Cancer Institute of United States. [14]

Statistical analysis

All data in this clinical study were analyzed using SPSS 15.0 (IBM Co., Ltd, Armonk, New York, USA). Mean ± standard deviation was calculated, and t-test and F-test were applied. Test level was set to α = 0.05. P < 0.05 was considered as statistically significant.


  Results Top


Changes of tumor

After treatment, CEA and CA19-9 and diameter of metastases reduced significantly (P < 0.05) [Table 1].
Table 1: Changes of tumor markers and metastases diameter in patients (x̄±s)


Click here to view


Changes of liver function

After the treatment, PT and ALB decreased significantly and AST, ALT, and TBIL increased significantly (P < 0.05) [Table 2].
Table 2: Changes of liver function in the 97 patients (x̄±s)


Click here to view


Response rate analysis

The average length of stay was 16.2 ± 3.7 weeks. After the treatment, there were 0 case of CR, 25 cases of PR, 41 cases of SD, 31 cases of PD. The response rate was 25.77% and disease control rate was 68.04%.

Adverse reactions

Adverse reactions presented in 92 cases, with the incidence of 94.85%. Although the incidence is very high, all the adverse reactions were mild, such as skin toxicity, diarrhea, leukopenia, decreased hemoglobin, and decreased platelets, which were relieved after symptomatic treatment.

Follow-up

All patients were followed up in a timely and effective manner for 3 years, with mean follow-up time of 2.8 ± 0.6 years. There were 29 cases died within 1 year, with 1-year survival rate of 70.10% and 58 cases died within 3 years, with a 3-year survival rate of 40.21%.


  Discussion Top


With the incidence of colorectal cancer increases year by year, people's quality of life has been seriously affected. Because of the hidden early symptoms and low specificity of the disease, most patients are diagnosed in middle or advanced stage and accompanied by metastasis. The liver is the most common site of colorectal cancer metastasis due to the venous drainage pattern from the colon toward the liver. Scholars have found that the 1-year survival in patients with unresectable liver metastasis was < 10%. [15],[16],[17],[18] Therefore, to ensure the quality of life of patients, it is important to safely and effectively eliminate liver metastases. In recent years, with the clinical use of a variety of molecular targeted drugs, the treatment of advanced colorectal cancer with liver metastasis has made progress. The launching of new modes of administration, chemotherapy options, and combination regimens has also laid a solid foundation for improving the survival rate.

In the present clinical trial, the effects of combined concurrent treatments with irinotecan plus cetuximab were explored in advanced colorectal cancer patients with liver metastases. Data indicated that the disease has been effectively controlled after the combined treatments. Tumor markers decreased significantly, disease control rate was acceptable, and the 3-year survival rate reached 40.21%. Although the incidence of adverse reactions in patients during treatment reached 94.85%, adverse reactions were mild and were effectively alleviated after drug withdrawal or symptomatic treatment, reflecting that the regime is safe. Irinotecan is an effective second-line regimen used in patients with tumors that are resistant to the first-line 5-fluorouracil-based chemotherapy regimens. In recent years, cetuximab has gained increasing attention in combination therapy with irinotecan. As a monoclonal antibody can specifically bind epidermal growth factor receptor, it plays a role by inhibiting cell proliferation, inducing apoptosis of tumor cells, and preventing tumor metastasis. It also has good effect on patients with drug resistance. In observation of liver function in patients, we found that 1 week after treatment, AST, ALT, TBIL increased significantly, by 2-10 times the baseline numbers at enrollment, and did not relapse at the end of treatment. PT and ALB significantly reduced, consistent with the changes of AST, ALT, and TBIL, demonstrating that liver function was affected. The main reason for these changes in laboratory values is that when drug is clearing cancerous cells, it also causes damage to the normal liver cells and blood flow for liver will also be affected, [19] which could induce hepatic ischemia-reperfusion injury. Excessive reactive oxygen leads to peroxidation damage of phospholipids, proteins, and nucleic acids, further aggravating the necrosis and injury of the normal liver cell, inducing elevated liver enzymes and decreased coagulation function. In addition, the stress effect of the body on the drug can also directly cause injury of tissue. However, over time with the removal of cancerous cells, liver compensatory function gradually recovers. Self-healing capabilities of the liver cell can alleviate the above damage to some extent, reflecting the favorable effect of the regime. In summary, irinotecan combined with cetuximab could cause some damage to liver function of advanced colorectal cancer patients with liver metastases. With the repair of hepatic cell injury, the influence of these liver function abnormalities could gradually decrease.

The results of our study demonstrate that irinotecan combined with cetuximab was safe and effective in the treatment of advanced colorectal cancer patients with liver metastasis, and it can improve the prognosis of patients and their quality of life.

Financial support and sponsorship

The study was supported by Natural Science Foundation of China (No. 81372895).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-Tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 2013; 14 (12): 1208-15.  Back to cited text no. 1
    
2.
Gong W, Lv N, Wang B, Chen Y, Huang Y, Pan W, Jiang B. Risk of ulcerative colitis-associated colorectal cancer in China: a multi-center retrospective study. Dig Dis Sci 2012; 57 (2): 503-7.  Back to cited text no. 2
    
3.
Zhang J, Yang S, Xie Y, Chen X, Zhao Y, He D, Li J. Detection of methylated tissue factor pathway inhibitor 2 and human long DNA in fecal samples of patients with colorectal cancer in China. Cancer Epidemiol 2012; 36 (1): 73-7.  Back to cited text no. 3
    
4.
Hu F, Li D, Wang Y, Yao X, Zhang W, Liang J, Lin C, Ren J, Zhu L, Wu Z, Li S, Li Y, Zhao X, Cui B, Dong X, Tian S, Zhao Y. Novel DNA variants and mutation frequencies of hMLH1 and hMSH2 genes in colorectal cancer in the Northeast China population. PLoS One 2013; 8 (4): e60233.  Back to cited text no. 4
    
5.
Dai Z, Zheng RS, Zou XN, Zhang SW, Zeng HM, Li N, Chen WQ. Analysis and prediction of colorectal cancer incidence trend in China. Zhonghua Yu Fang Yi Xue Za Zhi 2012; 46 (7): 598-603.  Back to cited text no. 5
    
6.
Prasad VG, Kawade S, Jayashree BS, Reddy ND, Francis A, Nayak PG, Kishore A, Nandakumar K, Rao CM, Shenoy RR. Iminoflavones combat 1,2-dimethyl hydrazine-induced aberrant crypt foci development in colon cancer. Biomed Res Int 2014; 2014: 569130.  Back to cited text no. 6
    
7.
Bose A, Elyagoby A, Wong TW. Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment. Int J Pharm 2014; 468 (1-2): 178-86.  Back to cited text no. 7
    
8.
Robertson DJ, Lieberman DA, Winawer SJ, Ahnen DJ, Baron JA, Schatzkin A, Cross AJ, Zauber AG, Church TR, Lance P, Greenberg ER, Martínez ME. Colorectal cancers soon after colonoscopy: a pooled multicohort analysis. Gut 2014; 63 (6): 949-56.  Back to cited text no. 8
    
9.
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381 (9863): 303-12.  Back to cited text no. 9
    
10.
Ychou M, Rivoire M, Thezenas S, Quenet F, Delpero JR, Rebischung C, Letoublon C, Guimbaud R, Francois E, Ducreux M, Desseigne F, Fabre JM, Assenat E. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann Surg Oncol 2013; 20 (13): 4289-97.  Back to cited text no. 10
    
11.
Wang RF, Song BR, Peng JJ, Cai GX, Liu FQ, Wang MH, Cai SJ, Ye X. The prognostic value of preoperative serum CEA and CA19-9 values in stage I-III colorectal cancer. Hepatogastroenterology 2014; 61 (132): 994-9.  Back to cited text no. 11
    
12.
Shibutani M, Maeda K, Nagahara H, Ohtani H, Sakurai K, Toyokawa T, Kubo N, Tanaka H, Muguruma K, Ohira M, Hirakawa K. Significance of CEA and CA19-9 combination as a prognostic indicator and for recurrence monitoring in patients with stage II colorectal cancer. Anticancer Res 2014; 34 (7): 3753-8.  Back to cited text no. 12
    
13.
Ducreux M, Adenis A, Pignon JP, François E, Chauffert B, Ichanté JL, Boucher E, Ychou M, Pierga JY, Montoto-Grillot C, Conroy T. Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). Eur J Cancer 2013; 49 (6): 1236-45.  Back to cited text no. 13
    
14.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008; 58 (2): 71-96.  Back to cited text no. 14
    
15.
Denève E, Riethdorf S, Ramos J, Nocca D, Coffy A, Daurès JP, Maudelonde T, Fabre JM, Pantel K, Alix-Panabières C. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin Chem 2013; 59 (9): 1384-92.  Back to cited text no. 15
    
16.
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30 (28): 3499-506.  Back to cited text no. 16
    
17.
Abdalla EK, Bauer TW, Chun YS, D′Angelica M, Kooby DA, Jarnagin WR. Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements. HPB (Oxford) 2013; 15 (2): 119-30.  Back to cited text no. 17
    
18.
Dixon MR, Haukoos JS, Udani SM, Naghi JJ, Arnell TD, Kumar RR, Stamos MJ. Carcinoembryonic antigen and albumin predict survival in patients with advanced colon and rectal cancer. Arch Surg 2003; 138 (9): 962-6.  Back to cited text no. 18
    
19.
Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284 (1): G15-26.  Back to cited text no. 19
    



 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
References
Article Tables

 Article Access Statistics
    Viewed1614    
    Printed45    
    Emailed0    
    PDF Downloaded174    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]