This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ribero, D. Articles by Vauthey, J.-N. Search for Related Content PubMed Articles by Ribero, D. Articles by Vauthey, J.-N. Social Bookmarking                            What's this?

In Reply

Department of Surgical Oncology, the University of Texas M.D. Anderson Cancer Center, Houston, TX

In recent years, several studies have reported the potential hepatotoxicity of chemotherapy administered to treat stage IV colorectal cancer. However, there was no systematic analysis by type of chemotherapy-associated injury—namely steatosis, steatohepatitis, and sinusoidal dilation—of correlation, if any, between the injury and specific preoperative chemotherapy drugs and the impact of the injury on outcome after hepatectomy. Our study was designed to address these questions.¹ The most important methodologic aspect of our study was the clear separation of steatosis, the mildest manifestation of nonalcoholic fatty liver disease, from steatohepatitis using the reliable scoring system proposed by the pathology committee of the National Institutes of Health Nonalcoholic Steatohepatitis (NASH) Clinical Research Network.²

Obesity is one of the most common risk factors for the metabolic syndrome associated with nonalcoholic fatty liver disease, and obesity has been shown to correlate with increased incidence of moderate-severe steatosis (> 30%).³ Therefore, in accordance with the two-hit theory of steatohepatitis pathogenesis,⁴ the oxidative stress induced by chemotherapy⁵ may be the second hit in patients with the highest incidence of underlying steatosis. Nevertheless, it is important to recognize that steatohepatitis can occur even with minimal fatty infiltration of the liver. Whereas radiographic findings may be suggestive of steatosis, histologic evaluation remains the only means of differentiating steatohepatitis (steatosis with hepatocytic damage) from simple steatosis (without inflammation and cellular ballooning). Our observation that among patients with a body mass index less than 25 kg/m², none of the chemotherapy-naïve patients had steatohepatits whereas 12% of those who received irinotecan did, strongly suggests that irinotecan plays a role in steatohepatitis development. In addition, in our study population, a negligible proportion of patients had a history of heavy alcohol intake (two patients in the no chemotherapy group and one patient in the fluorouracil group—none of them developed steatohepatitis); patients with diabetes were equally distributed among the control group and the various chemotherapy-regimen groups. Gentilucci et al raise the possibility that selection bias could have influenced our findings regarding a link between irinotecan-based preoperative chemotherapy and subsequent steatohepatitis. However, the large number of patients studied, the presence of a control group of patients who did not undergo chemotherapy, and the inclusion of individuals from two different countries reduces to a minimum the likelihood of selection bias for the innumerable minor known and unknown risk factors for metabolic syndrome.

We agree with Gentilucci et al that there is a need for improved individualization of preoperative chemotherapy and for further studies to clarify whether the incidence, type, and grade of clinical toxicity during chemotherapy might predict which patients are at risk for the development of steatohepatitis. However, this study was not designed to establish detailed recommendations for preoperative chemotherapy. In the meantime, until new studies refine selection criteria, we believe that irinotecan should be administered with caution in patients with high body mass index or features suggesting the presence of the metabolic syndrome who are likely to undergo postchemotherapy hepatic resection. Oxaliplatin may be a good alternative to irinotecan in such patients because the response rates for treatment with these two drugs are similar⁶ and resection after oxaliplatin administration for 3 months, as in our study, appears to be safe. Finally, as more is learned about the clinical impacts and interactions of all the treatments for stage IV colon cancer, adverse effects as well as response rates must be considered as first-line and second-line treatments are defined.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Jean-Nicolas Vauthey Sanofi-Aventis; Genetech Sanofi-Aventis

REFERENCES

1. Vauthey JN, Pawlik TM, Ribero D, et al: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065-2072, 2006[Abstract/Free Full Text]

2. Kleiner DE, Brunt EM, Van Natta M, et al: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313-1321, 2005[CrossRef][Medline]

3. Behrns KE, Tsiotos GG, DeSouza NF, et al: Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg 2:292-298, 1998[CrossRef][Medline]

4. Day CP, James OF: Steatohepatitis: A tale of two "hits"? Gastroenterology 114:842-845, 1998[CrossRef][Medline]

5. Laurent A, Nicco C, Chereau C, et al: Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res 65:948-956, 2005[Abstract/Free Full Text]

6. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ribero, D. Articles by Vauthey, J.-N. Search for Related Content PubMed Articles by Ribero, D. Articles by Vauthey, J.-N. Social Bookmarking                            What's this?