Effects on hepatic and renal biomarkers in patients of colorectal carcinoma treated with two different schedules of 5FU/LV

Nusrat Bano, Rahila Najam and Ahmed Mateen

Introduction:

Colorectal cancer (CRC) is the third most common cancer in men and women worldwide (1) and a leading cause of cancer related deaths (2). 5FU synthesized in 1957 by Heidelberger (3) is the mainstay in all current standard regimens for CRC (4). Chemotherapy induced hepatic toxicity in 5FU based regimens can be an acute or delayed outcome (5, 6); whereas steatosis is a hallmark of 5FU induced hepatic toxicity (7). Chemotherapy induced nephrotoxicity (8) is also an area of concern for oncologists. The antimetabolite 5FU is often linked with kidney damage (9). Therapeutic outcomes and toxicity of 5FU differs markedly in different doses, combinations, schedules of administration and routes of administration. Leucovorin (LV) incorporated in 5FU based regimen enhances the cytotoxicity of 5FU. In this study we opt to report abnormalities in hepatic enzymes and renal biomarkers biochemically assessed in the serum after alternate cycles of treatment in CRC patients subjected to 5FU/LV based chemotherapy.

Methods:

The study was designed in the Department of Pharmacology, University of Karachia and conducted in a leading cancer hospital in Pakistan. Following institutional authorisation, informed consent was obtained from patients being admitted during 2008-2011. The inclusion criteria was maintained on the following grounds:

1. Histologically confirmed advanced colorectal carcinoma
2. Adequate blood count before therapy
3. Age 20-80 years
4. ECOG score of < 3
5. Serum bilirubin < 5× normal
6. Serum creatinine < 135µmol/liter
7. Serum transaminases < ×2.5 normal

Twenty three patients (median age 59 years) who underwent surgery were included in the study. All the patients had measureable disease at CT scan, ultrasonography or clinical examination. Patient’s characteristics are shown in Table 1. Seventeen patients were treated with the adjuvant bimonthly regimen of 5FU/LV - high dose Folinic acid (de Gramont Regimen); whereas, six patients were treated with adjuvant monthly regimen of 5FU/LV –low dose Folinic acid(Mayo Clinic Regimen) as follows.

5Fluorouracil/ Leucovorin (de Gramont’s regimen)

5Fluorouracil: 400mg/m² IV followed by 600mg/m² CIV for 22 hours on day 1-2.
Leucovorin: 600 mg/m² IV as 2 hours infusion before 5FU on day 1-2.
Cycle repeated after 2 weeks.

5Fluorouracil/ Leucovorin (Mayo clinic regimen)

5Fluorouracil: 425mg/m² IV on day 1-5.
Leucovorin: 20 mg/m² IV before 5FU on day 1-5.
Cycle repeated after 4-5 weeks.

Premedication with oral phenothiazines, 5HT₃RA and 10-20 mg of dexamethasone was given.

The blood samples were collected before the initiation of the therapy and after each alternate cycle of treatment. The blood was drawn when the patient was rested and comfortable from the antecubital vein under minimal tourniquet pressure. The blood drawn was sampled and collected into vacutainers (BD). The biochemical profile of the pretreatment and subsequent treatment was comparatively assessed. SGOT, SGPT, bilirubin and alkaline phosphatase levels were measured after each cycle of treatment or on the clinical presentation of any hepatic adverse effect notified by the physician or oncologist and the levels were compared to the pretreatment values. The serum creatinine levels and BUN was measured before the start of chemotherapy and after each alternate cycle of treatment up to six times in each patient.

Table 1 Patient characteristics

Results:

Table 2shows that the SGOT levels are raised after each cycle of treatment and the difference between the SGOT levels of the patients before treatment and after subsequent cycle of treatment is significant in the patients treated with 5FU/LV (p value < 0.05). The difference in the SGPT levels of the patients from the pretreatment value is not highly significant (p value >0.05). The difference in the bilirubin levels of the patients after the sixth cycle of chemotherapy with 5FU/LV regimens is highly significant from the pretreatment level (p value < 0.05). The difference in the alkaline phosphatase levels of the patients after chemotherapy with the pretreatment value in the same patients is not significant (p value >0.05).The difference in the triglyceride levels is not significant before and after chemotherapy in the patients treated with 5FU/LV.

Table 2 Comparative changes in hepatic biomarkers in patients treated with 5FU/LV regimen

Table 3 shows that the creatinine levels are raised in patients following each subsequent cycle of treatment with 5FU/LV regimens. The difference in the serum creatinine levels after the fourth and the tenth cycle of treatment with the pretreatment levels was significant (p<0.05). The difference in the BUN levels measures before and after chemotherapy with 5FU/LV was not significant following alternate cycles of treatment.

Table 3 Comparative changes in renal biomarkers in patients treated with 5FU/LV regimen

Discussion:

The hepatocellular enzyme findings are indicative of deteriorating liver function. The levels of SGOT and SGPT both differ from the control values and point toward 5FU induced hepatic toxicity. Increase in SGOT and SGPT up to grade 2 (CTC of NIC) is reported by Hotta and colleagues (10) in a study based on clinicopathological assessment of 36 patients treated with 5FU/LV. They did not report grade 3 or grade 4 elevations in SGOT and SGPT ratio. In our data there is considerable difference in SGOT levels (mean value) after the second cycle of treatment as compared to the pretreatment levels (mean value). Similarly SGPT levels are perturbed following treatment and the difference in the SGPT levels from the pretreatment control value is statistically significant after the tenth cycle of treatment. The pooled data of all the patients cannot be used for prognostic or diagnostic assessment; however, it shows a pattern of drug induced alterations in hepatic functions. An early effect on SGOT level show mild progressive damages correlated with a prominent rise in SGPT levels. SGOT is found in cytosol whereas SGPT is in mitochondria. Any mild to moderate damage to the hepatic cells will result in a rise in SGOT levels even though SGPT levels may remain normalised. Moderate to Severe hepatic damage will give a rise in both SGOT and SGPT elevation. SGOT is located in red blood cells, kidneys, brain, skeletal muscle and cardiac tissues; hence a prompt rise in SGOT level is indicative of associated damages. SGPT is present in skeletal muscles and cardiac tissues and the serum levels are affected with myocardial and skeletal muscle damages. Cytotoxic chemotherapy is frequently associated with fatty liver disease, chemical hepatitis and reactivation of hepatitis B (11). The elevation in triglyceride levels is indicative of drug induced steatosis (fat globule deposition in hepatocytes) leading to postoperative hepatic insufficiency(8). A significant change in bilirubin from the pretreatment level is observed after the 6^th cycle of treatment. Biliary changes are detectable and persistent since the drug is excreted in the bile. Sclerosing cholangitis with elevation in alkaline phosphatase and bilirubin levels secondary to 5FU plus mitomycin therapy is reported by Fukuzumi et al (12). After intravenous administration, 5FU is converted into its active form ‘5-fluoro-deoxyuridine-monophosphate’ by anabolic reactions in the tissues. The drug undergoes catabolism primarily in the liver by reduction of the pyrimidine ring by enzymatic action of dihydrouracil dehydrogenase (13). The compound is then cleaved to urea, ammonia, carbondioxide and α-fluoro-β-alanine. The catabolic process in the liver amounts for 5FU induced hepatic toxicity. Hepatic and renal toxicity associated with 5FU is reported earlier with IV administration of 5FU (14). The risk of 5FU induced hepatic damages is increased in older patients (15). Older patients included in our study with increased post-treatment transaminase levels were more frequently presented with pruritus and hand and foot syndrome.This complexity of the situation is that altered hepatic function increases the risk of 5FU concentration (since it is catabolized in the liver cells), which in turn adds to the hepatic damage.

Creatinine clearance and blood urea nitrogen (BUN) are conventional biomarkers of renal function for convenient and cost-effective assessment (16). A detectable change in the creatinine levels of the patients ensue after the fourth cycle of treatment. Besides suggesting a decline in the renal function, it also indicates defect in hepatic functional status and progressive cachexia (muscle wasting), both of which are readily assessed in the patients during treatment. BUN levels are also affected by dexamethasone pretreatment, dehydration and azotemia besides renal function. Nephrotoxicity with 5FU chemotherapy is usually reported when it is combined with cisplatin with worsened creatinine levels (17, 18). Tubular damage induced by 5FU plus high dose leucovorin chemotherapy (similar to de Gramont’s regimen in our study) is reported by Kintzel, who also reported 50% decline in creatinine clearance in three patients (19). Chemotherapy induced renal damages are detected with abnormal creatinine and BUN levels, but in most cases the renal tubes remain intact and functional as the normal renal blood flow and GFR is reversibly attained (20). Adequate hydration and simultaneous treatment with mesna, which neutralises the toxic metabolites can effectively reduce chemotherapy induced renal damage (8).

Conclusion:

SGOT and bilirubin levels are raised after each cycle of treatment and the difference between the SGOT levels of the patients treated with 5FU/LV, before treatment and after subsequent cycle of treatment are highly significant indicative of mild to moderate progressive hepatic toxicity. Risk of clinical and subclinical renal damage is observed by a subsequent rise in serum creatinine and BUN levels. Renal toxicity marked by creatinine elevation is prominent after the fourth cycle of treatment.

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