Oxaliplatin-Mediated Increase in Spleen Size As a Biomarker for the Development of Hepatic Sinusoidal Injury Michael J. Overman, Dipen M. Maru, Chusilp Charnsangavej, Evelyn M. Loyer, Huamin Wang, Priyanka Pathak, Cathy Eng, Paulo M. Hoff, Jean-Nicolas Vauthey, Robert A. Wolff, and Scott Kopetz From the Departments of Gastrointesti- nal Medical Oncology, Pathology, Diag- nostic Radiology, and Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Hous- ton, TX; and the Centro Oncologico de Hospital Sirio-Libanes, São Paulo, Brazil. Submitted December 11, 2009; accepted February 1, 2010; published online ahead of print at www.jco.org on April 20, 2010. Presented in part in abstract format at the 44th Annual Meeting of the Ameri- can Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: Michael J. Overman, MD, Department of Gastroin- testinal Medical Oncology, Unit 426, The University of Texas M. D. Ander- son Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: moverman@mdanderson.org. © 2010 by American Society of Clinical Oncology 0732-183X/10/2815-2549/$20.00 DOI: 10.1200/JCO.2009.27.5701 A B S T R A C T Purpose Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury, with resultant sinusoidal damage and portal hypertension. We sought to explore the relationship between oxaliplatin induced hepatic sinusoidal injury, increases in spleen size, and the subsequent development of thrombocytopenia. Patients and Methods We retrospectively assessed the relationship between chemotherapy exposure, changes in spleen size (determined by volumetric measurements), and platelet counts in 136 patients treated with adjuvant fluorouracil and oxaliplatin (FOLFOX) or fluoropyrimidine for stage II or III colorectal adenocarcinoma. Hepatic sinusoidal injury and changes in spleen size were graded in a separate population of 63 patients with metastatic colorectal cancer receiving fluoropyrimidine and oxaliplatin before liver resection. Results Spleen size increased in 86% of patients treated with adjuvant FOLFOX (P  .001), with a  50% increase in 24% of patients. Spleen size did not significantly increase in patients treated with adjuvant fluoropyrimidine. Increases in spleen size correlated with cumulative oxaliplatin dose (P = .003). Patients with splenic enlargement  50% had higher rates of thrombocytopenia in the first year after completion of chemotherapy (27% v 5%; P = .003). In patients with hepatic metastases treated with preoperative fluoropyrimidine and oxaliplatin, increases in spleen size was a predictor of higher histologic grades of sinusoidal injury in both univariate (P = .03) and multivariate (P = .02) analyses. Conclusion Increases in spleen size correlate with increasing grade of hepatic sinusoidal injury and can serve as a simple method for identifying patients at risk for this toxicity. Oxaliplatin-induced increases in spleen size should be recognized as a potential etiology of persistent thrombocytopenia after oxaliplatin treatment. J Clin Oncol 28:2549-2555. © 2010 by American Society of Clinical Oncology INTRODUCTION The US Food and Drug Administration first approved oxaliplatin for use in patients with metastatic colorectal cancer in 2002. Currently the majority of patients with colorectal cancer will receive oxaliplatin-based therapy in either the adjuvant or metastatic setting. 1 Oxaliplatin-based chemothera- py has also been increasingly utilized before the re- section of hepatic metastases, and the examination of nontumor bearing portions of resected liver specimens have revealed a high rate of sinusoi- dal injury. 2-7 This sinusoidal injury was first reported by Rubbia-Brandt et al in 2004. 2 In this retrospective study of 153 patients who underwent hepatic re- section of liver metastases, sinusoidal injury was seen in 51% of specimens after any preoperative chemotherapy and in none of the specimens ex- amined after surgery alone. Of the 43 patients who received oxaliplatin, 78% demonstrated some de- gree of sinusoidal injury. Since that initial report, subsequent studies have confirmed the association of oxaliplatin with sinusoidal injury, although the reported rates of injury have ranged from 19% to 52%. 3-7 These hepatic changes are oxaliplatin spe- cific, as liver specimens from chemotherapy-naïve and those from patients receiving preoperative treatment with other chemotherapy agents, such as irinotecan or fluorouracil, demonstrate dra- matically lower rates of sinusoidal injury. 5-7 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 28  NUMBER 15  MAY 20 2010 © 2010 by American Society of Clinical Oncology 2549 Downloaded from jco.ascopubs.org on August 18, 2016. For personal use only. No other uses without permission. Copyright © 2010 American Society of Clinical Oncology. All rights reserved.