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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3202-3204 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.106
Oxaliplatin Toxicity Masquerading As Recurrent Colon CancerPresbyterian Intercommunity Hospital, Whittier, CA To the Editor: A 69-year-old white male, while receiving bicalutamide, leuprolide acetate, and finasteride for locally recurrent prostate cancer was diagnosed with moderately differentiated adenocarcinoma of the rectum, Dukes' stage C. He underwent anterior abdominoperoneal resection and received 45 Gy in 25 fractions to the pelvis. While receiving radiation therapy he was given 500 mg/m2/d of capecitabine for 14 of 21 days. After radiation therapy, the patient was given capecitabine 1,000 mg/m2/d divided in two doses for 14 of 21 days, plus oxaliplatin 130 mg/m2 intravenously on day 1 every 21 days for a total of four 21-day courses. Shortly after the fourth course, the patient presented with abdominal distension and severe ascites. The ascitic fluid was a sterile transudate devoid of tumor cells. Prostate specific antigen, prostatic acid phosphatase, carcinoembryonic antigen, CA-19-9, AST, ALT, alkaline phosphatase (AP), lactate dehydrogenase, and gamma glutamyl transferase (GGT) were all within normal limits. Serum albumin was 3.3 g/dL (range, 3.8 to 5 g/dL). Renal function was normal. An exhaustive work-up for metastatic cancer included computed tomography imaging of the chest, abdomen, and pelvis and diagnostic laparoscopy. All studies revealed absence of recurrent cancer. On laparoscopy, the liver appeared grossly normal and no tumor was noted. Computed tomography imaging through the liver revealed a 5 cm hemangioma confirmed by magnetic resonance imaging, which on biopsy confirmed that diagnosis. Hepatic color flow Doppler evaluation of the hepatic and portal veins demonstrated that the portal vein was patent with hepatopetal flow, and a hepatic vein was identified which was patent with blood flowing toward the inferior vena cava and heart. An echocardiogram ruled out right heart failure and there was absence of pericardial effusion. Inferior venacavagram and hepatic venograms with pressure measurements revealed that the right and middle hepatic veins were devoid of stenosis, thrombosis, or web formation. The wedge hepatic vein pressure, a reflection of the portal vein pressure, was elevated to 18 to 20 mmHg, confirming portal hypertension. Transjugular liver biopsy revealed severe hepatic sinusoidal obstruction with central vein fibrosis and no evidence of cirrhosis (Figs 1 and 2). The sinusoidal lesions were morphologically identical to those described by Rubbia-Brandt.1 A transjugular intrahepatic portal-systemic shunt was placed. The ascitic accumulation decreased.
The patient's course in hospital was complicated by elevation of AP, GGT, and total bilirubin to four times the upper limit of normal (starting 4 weeks after hospitalization) while the AST and ALT remained within the normal range. The patient became encephalopathic, developed renal failure requiring dialysis, upper gastrointestinal bleed due to gastritis, atrial fibrillation, and bilateral bacterial pneumonia. He was unable to be weaned from a respirator and he died after a 7-week hospitalization. Our original pathologic review of the patient's liver biopsy revealed a histologic pattern similar to that described in the Budd-Chiari syndrome, or in children receiving radiation to the liver, or in those receiving high-dose chemotherapy with autotransplant. The hepatic Doppler and hepatic venogram studies confirmed the absence of vascular obstruction as found in the Budd-Chiari syndrome. The patient received no hepatic radiation and usual dose capecitabine and oxaliplatin. Serendipitously, a recent publication by Rubbia-Brandt et al1 described liver pathology in their patients undergoing neoadjuvant chemotherapy. Perisinusoidal fibrosis, severe sinusoidal obstruction, and fibrotic venular occlusion, as noted in our patient, was noted in liver biopsy specimens in 44 (51%) of 87 of their hepatectomies performed after neoadjuvant chemotherapy, and in 34 (79%) of 43 colorectal cancer patients receiving oxaliplatin. In some patients, these lesions were found to progress in the absence of continued chemotherapy. They gave no instances of clinical abnormality caused by such lesions in their patient population. They found a significant correlation between the presence of liver lesions and the use of oxaliplatin: 34 (79%) of the 43 patients treated with oxaliplatin developed lesions, as opposed to 10 (23%) of the 44 who did not (P < .001). The amount of oxaliplatin received was quantified as a cumulative dose expressed in mg/m2 and ranged from 280 to 1,600 mg/m2. Our patient received a total dose of 520 mg/m2. This case is important, because to our knowledge, it is the first clinical report of portal hypertension and ascites likely due to oxaliplatin hepatic toxicity. Toxicity occurred in a patient who did not have hepatic metastases, whose liver had never been subjected to surgical intervention, and within the context of adjuvant chemotherapy. The patient had no signs of nephrosis, right heart failure, pericarditis, peritonitis, Budd-Chiari syndrome, hepatitis, alcohol abuse, or cirrhosis, and at the time of presentation with clinical ascites the AST, ALT, AP, GGT, total bilirubin, and lactate dehydrogenase were normal. A search of the medical literature for similar clinical toxicity revealed a solitary case of clinical hepatotoxicity leading to death reported in a patient receiving ralti-trexed plus oxaliplatin.2 Details of this case were not given. The presentation of ascites in a patient receiving chemotherapy for colorectal cancer is often construed as recurrent cancer. In such cases when oxaliplatin has been administered we recommend an aggressive search for recurrent or progressive cancer with a low threshold for liver biopsy in an attempt to recover noncancerous tissue. The presence of portal hypertension should be investigated. The true frequency of clinically important oxaliplatin hepatic toxicity is unknown; however, histopathologic evidence for such toxicity was reported in 79% of patients.1 Physicians should be aware that oxaliplatin hepatic toxicity might confuse the clinical evaluation of patients receiving the drug by masquerading as progression of cancer. Since the pathologic changes may progress for several months after withdrawal of chemotherapy, it is possible that clinical signs of hepatic dysfunction may occur many months or possibly years after therapy. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Rubbia-Brandt L, Audard V, Sartoretti P, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004
2. Seitz JF, Bennouna J, Paillot B, et al: Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non-pretreated metastatic colorectal cancer patients. Ann Oncol 13:1072-1079, 2002
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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