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CORRESPONDENCE
Year : 2014  |  Volume : 10  |  Issue : 3  |  Page : 745-748

Severe liver dysfunction and safe use of 5-fluorouracil leucovorin and oxaliplatin in one patient with metastatic colorectal carcinoma


Department of Internal Medicine, Division of Medical Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

Date of Web Publication14-Oct-2014

Correspondence Address:
Dr. Emre Akar
Cerrahpasa Medical Faculty, Istanbul University, TR - 34098, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.136034

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 > Abstract 

The liver is the most frequent site of metastases in colorectal cancer. Commonly used anticancer drugs in colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan 5-fluorouracil (5-FU) and oxaliplatin have very few numbers of studies that support their safety in hepatic dysfunction, but pharmacokinetic studies of anticancer drugs focused on the single-agents; however, there is lack of data about drug combinations such as 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) and 5-fluorourocil, leucovorin and irinotecan (FOLFIRI) regimens. We demonstrated one patient with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. Laboratory investigation on admission showed total bilirubin 22.5 mg/dl, alkaline phosphatase 1137 IU/l, aspartate amino transferase 254 IU/l, alanine aminotransferase 164 IU/l and carcinoembryonic antigen levels 863 ng/ml. We initiated a 5-FU/oxaliplatin-based combination chemotherapy. Our data supports the safety and feasibility of FOLFOX regimen in patients with severe liver dysfunction secondary to liver metastases of colorectal cancer.

Keywords: Colorectal carcinoma, fluorouracil leucovorin and oxaliplatin, hyperbilirubinemia, liver dysfunction


How to cite this article:
Tural D, Akar E, Öztürk MA, Yıldız &, Turna H, Serdengeçti S. Severe liver dysfunction and safe use of 5-fluorouracil leucovorin and oxaliplatin in one patient with metastatic colorectal carcinoma. J Can Res Ther 2014;10:745-8

How to cite this URL:
Tural D, Akar E, Öztürk MA, Yıldız &, Turna H, Serdengeçti S. Severe liver dysfunction and safe use of 5-fluorouracil leucovorin and oxaliplatin in one patient with metastatic colorectal carcinoma. J Can Res Ther [serial online] 2014 [cited 2019 Sep 18];10:745-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/745/136034


 > Introduction Top


Colorectal cancer is third most common cancer and the liver is the most frequent site of metastases in colorectal cancer. Patients with colorectal cancer have approximately %50-60 risk of liver metastases development during the course of their disease and 20-30% of patients having liver metastases at the time of diagnosis. [1],[2] Multiple and extensive liver metastases cause secondary severe liver dysfunction frequently as appeared by significant jaundice and exemplified by raised levels of serum bilirubin, aspartate amino transferase, alanine aminotransferase and alkaline phosphatase. Liver has very important role of metabolism of drugs; thus, options of chemotherapeutic agents are limited for treatment of these patients. 5-fluorouracil (5-FU) and oxaliplatin have very few numbers of studies that support their safety in hepatic dysfunction, but using of irinotecan need to be paid attention because of liver's role of irinotecan metabolism.

We report here, on a patient with extensive liver metastasis and secondary liver dysfunction that treated with fluorouracil leucovorin and oxaliplatin (FOLFOX) without any drug-related or hepatic toxicity.


 > Case Report Top


A 49-year-old female patient presented with 2 months history of nausea and vomiting after fatigue of ongoing for a year and recent jaundice. On physical examination, there were distension, tenderness and generalize ascites on her abdomen. Computerized tomography (CT) scan and ultrasonography of the abdomen and pelvis revealed multiple solid masses in the liver. F-18 fluorodeoxyglucose positron emission tomography confirmed hepatic metastases and showed a cecal mass. Colonoscopy revealed a fragile ulcerovegetan polypoid cecal mass. Mucinous adenocarcinoma metastasis identified on pathological examination of a Tru-cut biopsy from one of the liver metastases (Diastase Resistant Periodic Acid Schiff+, CDX2 protein staining+, cytokeratin 7 focal−, CK20+, thyroid transcription factor 1−). Laboratory investigation on admission showed total bilirubin 22.5 mg/dl (normal range: 0.20-1.0), alkaline phosphatase 1137 IU/l (normal range: 38-126), aspartate amino transferase 254 IU/l (normal

range: 15-41), alanine aminotransferase 164 IU/l (normal range: 10-40). Hepatobiliar ultrasonography showed minimal dilatation of intrahepatic bile ducts, but percutaneous transhepatic cholangiography was unsuccessful for drainage.

Given her poor performance status (Eastern Cooperative Oncology Group: 1) and liver dysfunction, initial treatment started with oxaliplatin 85 mg/m 2 . After 2 weeks, her liver function tests and total bilirubin levels showed improvement and modified regimen of FOLFOX6 with oxaliplatin 85 mg/m 2 and continuous infusion of 5-FU 2400 mg/m 2 over 46 h without 5-FU bolus injection started on her second cycle of therapy. She was subsequently treated with this regimen for eight cycles. After the six cycles, her total bilirubin level was 1.3 mg/dl and CT scans showed partial response to chemotherapy [Figure 1] and [Figure 2]. Her carcinoembryonic antigen levels decreased to 126 ng/ml from 863 ng/ml. The therapy was well-tolerated and no treatment-related grade 3 or 4 toxicity was noted.
Figure 1: Computerized tomography before chemotherapy

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Figure 2: Computerized tomography after six-cycle chemotherapy

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 > Discussion Top


Commonly used first line chemotherapeutic agents in colorectal cancer are 5-FU, oxaliplatin and irinotecan. Bevacizumab (a humanized antibody against vascular endothelial growth factor A) and cetuximab (a chimeric immunoglobulin G1 monoclonal antibody against epidermal growth factor receptor) are relatively new developed immunotherapeutic agents and our knowledge about safely use of bevacizumab and cetuximab in liver dysfunction needs to be an increase. Bevacizumab was avoided due to perforation risk caused by fragile mass and obstruction symptoms. [3] Cetuximab was not commenced because of her K-Ras status.

5-FU is a fluorinated pyrimidine analog and effects through irreversible inhibition of thymidylate synthase. [4] Toxicities caused by 5-FU are diarrhea, stomatitis and hand-foot syndrome. [5] Approximately, 90% of a dose of 5-FU is eliminated by metabolism with dihydropyrimidine dehydrogenase in liver. [6] There is lack of data about pharmacokinetics of bolus injection, on the other hand, safety of infusional 5-FU has been showed and 5-FU is feasible to use on patients with severe liver dysfunction due to no correlation between serum bilirubin level and 5-FU clearance. [7]

Oxaliplatin is a diaminocyclohexane platinum derivative and effects thorough blocking deoxyribonucleic acid (DNA) transcription and replication by covalently binding to form interstrand and intrastrand DNA cross-links, finally causes to cell death. Single-agent oxaliplatin is generally well-tolerated and its predominant clinical side-effects are myelosuppression, nausea and vomiting, cold sensitivity and peripheral neuropathy. Studies about pharmacokinetics of oxaliplatin demonstrated that oxaliplatin is cleared from plasma by covalent binding to tissues and renal elimination. The liver has no role on oxaliplatin metabolism. Furthermore, another study showed that dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction. [8],[9]

Irinotecan, a topoisomerase I inhibitor effects through generating intermediate forms of drug-stabilized covalent DNA-topoisomerase-I complexes. The dose-limiting toxicities of irinotecan are diarrhea and myelosuppression. Unfortunately, irinotecan is metabolized in the liver and pharmacokinetics of irinotecan directly depends on liver function and serum bilirubin levels. [10],[11] For these reasons, in severe liver dysfunction with high bilirubin levels, which can reach up to 20 mg/dl, safely use of irinotecan is a critical issue that needs dosage adjustment.

Combined chemotherapy is frequently used in the treatment of metastatic colorectal cancer because of the unsatisfactory results of the single-agent-chemotherapies. After all, the problem of insufficient knowledge about safety use of combined chemotherapy in severe liver dysfunction is encountered. Pharmacokinetic studies of anticancer drugs focused on the single-agents; however, there is lack of data about drug combinations such as FOLFOX and FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimens.

Four publications reported about FOLFOX chemotherapy is feasible in patients with severe liver dysfunction secondary to metastatic colorectal cancer. These publications including seven patients and our case are summarized on the [Table 1]. Taken together with our case, there are only two cases responded well to treatment in condition of extremely high bilirubin levels (>20 mg/dl). [12],[13],[14],[15]
Table 1: Previous publishings treated with FOLFOX in patients with severe liver dysfunction secondary to metastatic colorectal cancer

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Considering the safety of 5-FU and oxaliplatin as single agents in the setting of severe liver dysfunction, we decided to treat our patient with modified FOLFOX6. [16] Regarding the patient's very high bilirubin levels, treatment started initially only oxaliplatin at first cycle of chemotherapy. 46-h-infusion of 5-FU started at the second cycle of chemotherapy due to observation improvement of liver functions. With the aim of preventing the possibility of drug-related toxicity, bolus injection of 5-FU was not combined with mFOLFOX6 because of 5-FU's pharmacokinetic and metabolic characteristics.

In conclusion, our data supports the safety and feasibility of FOLFOX regimen in patients with severe liver dysfunction secondary to liver metastases of colorectal cancer. Further and prospective clinical studies are required to help understanding of the safety and utility of this combination.

 
 > References Top

1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.  Back to cited text no. 1
    
2.
Sasson AR, Sigurdson ER. Surgical treatment of liver metastases. Semin Oncol 2002;29:107-18.  Back to cited text no. 2
    
3.
Kabbinavar FF, Flynn PJ, Kozloff M, Ashby MA, Sing A, Barr CE, et al. Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: Results from a large treatment observational cohort study. Eur J Cancer 2012;48:1126-32.  Back to cited text no. 3
    
4.
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3:330-8.  Back to cited text no. 4
    
5.
Ardalan B, Chua L, Tian EM, Reddy R, Sridhar K, Benedetto P, et al. A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 1991;9:625-30.  Back to cited text no. 5
    
6.
Grem JL. 5-Fluoropyrimidines. In: Chabner BA, Longo DL, editors. Cancer Chemotherapy and Biotherapy. 2 nd ed. Philadelphia, PA: Lippincott-Raven; 1996. p. 146-211.  Back to cited text no. 6
    
7.
Fleming GF, Schilsky RL, Schumm LP, Meyerson A, Hong AM, Vogelzang NJ, et al. Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction. Ann Oncol 2003;14:1142-7.  Back to cited text no. 7
    
8.
Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, et al. Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: A National Cancer Institute Organ Dysfunction working group study. Clin Cancer Res 2007;13:3660-6.  Back to cited text no. 8
    
9.
Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E. Clinical pharmacokinetics of oxaliplatin: A critical review. Clin Cancer Res 2000;6:1205-18.  Back to cited text no. 9
    
10.
Venook AP, Enders Klein C, Fleming G, Hollis D, Leichman CG, Hohl R, et al. A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863. Ann Oncol 2003;14:1783-90.  Back to cited text no. 10
    
11.
Raymond E, Boige V, Faivre S, Sanderink GJ, Rixe O, Vernillet L, et al. Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 2002;20:4303-12.  Back to cited text no. 11
    
12.
Fakih MG. 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) in the treatment of metastatic colon cancer with severe liver dysfunction. Oncology 2004;67:222-4.  Back to cited text no. 12
    
13.
Grenader T, Goldberg A, Gabizon A. Combination therapy with oxaliplatin and 5-fluorouracil in a patient with severe hepatic dysfunction associated with metastatic adenocarcinoma of the large bowel. Anticancer Drugs 2009;20:845-7.  Back to cited text no. 13
    
14.
Shimura T, Kataoka H, Hirata Y, Mizushima T, Murakami K, Mabuchi M, et al. Metastatic colorectal cancer with severe liver dysfunction successfully treated using FOLFOX therapy. J Gastrointest Cancer 2011;42:68-72.  Back to cited text no. 14
    
15.
Roderburg C, do O N, Fuchs R, Bubenzer J, Spannbauer M, Luedde T, et al. Safe use of FOLFOX in two patients with metastatic colorectal carcinoma and severe hepatic dysfunction. Clin Colorectal Cancer 2011;10:E6-9.  Back to cited text no. 15
    
16.
Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006-12.  Back to cited text no. 16
    


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