Journal of Surgical Oncology 2012;105:511–519 Peri-Operative Chemotherapy for Resectable Colorectal Liver Metastasis: Does Timing of Systemic Therapy Matter? HUGO PINTO MARQUES, MD, 1 EDUARDO BARROSO, MD, 1 MECHTELD C. DE JONG, MD, 2 MICHAEL A. CHOTI, MD, 2 VASCO RIBEIRO, MD, 1 ANA MARTA NOBRE, MD, 1 CARLOS CARVALHO, MD, 1 AND TIMOTHY M. PAWLIK, MD, MPH 2 * 1 Hepato-Biliary-Pancreatic and Transplantation Centre, Curry Cabral Hospital, Lisbon, Portugal 2 Department of Hepatobiliary Surgery, the Johns Hopkins Hospital, Baltimore, Maryland Background: The benefit of pre-operative chemotherapy in patients with resectable colorectal liver metastases (CRLM) remains ill defined. We sought to evaluate the impact of peri-operative systemic chemotherapy timing on outcome following resection of CRLM. Methods: 676 patients who underwent surgery for CRLM were identified from two hepatobiliary center databases. Data were collected and analyzed utilizing multivariate, matched, and propensity-score analyses. Results: Median number of metastases was 2 and median tumor size was 3.3 cm. 334 patients (49.4%) received pre-operative chemotherapy while 342(50.6%) did not. Surgical treatment was resection only (n ¼ 555; 82.1%; minor hepatectomy, n ¼ 399; 59.1%). While there was no difference in morbidity following minor liver resection (pre-operative chemotherapy: 17.9% versus no pre-operative chemotherapy: 16.5%; P ¼ 0.72), morbidity was higher after major hepatic resection (pre-operative chemotherapy: 23.1% versus no pre-operative chemotherapy: 14.2%; P ¼ 0.06). Patients treated with pre-operative chemotherapy had worse 5-year survival (43%) as compared to patients not treated with pre-operative chemotherapy (55%)(P ¼ 0.009). Controlling for baseline characteristics, pre-operative chemotherapy was not associated with outcome on multivariate (HR ¼ 1.04, P ¼ 0.87) or propensity-score analysis (HR ¼ 1.40, P ¼ 0.12). Conclusion: Pre-operative chemotherapy was associated with a trend toward increased morbidity among patients undergoing a major hepatic resection. Receipt of pre-operative chemotherapy was associated with neither an advantage nor disadvantage in terms of long-term survival. J. Surg. Oncol. 2012;105:511–519. ß 2011 Wiley Periodicals, Inc. KEY WORDS: chemotherapy; colorectal; liver; metastasis INTRODUCTION Although surgical resection remains the cornerstone of therapy for resectable colorectal liver metastasis, recurrence is common. In fact, roughly two-thirds of patients will suffer a recurrence within 5 years [1]. Systemic chemotherapy for patients with unresectable colorectal liver metastasis is well established with response rates of 40–55% and median survival now approaches 2 years [2–4]. There has been increasing interest in the use of peri-operative systemic chemotherapy for patients with resectable colorectal liver metastasis. The use of peri-operative chemotherapy in the treatment of colorec- tal liver metastasis has recently been reported in a large multi- institutional trial [5]. The EORTC Intergroup trial 40983 randomized patients to receive either six cycles of FOLFOX4 pre-operatively followed by surgery and then an additional six cycles of adjuvant FOLFOX4 versus surgery alone without any systemic chemotherapy. When only eligible paients were analyzed, peri-operative chemother- apy was associated with an overall 8% absolute improvement in progression-free survival at 3 years (surgery alone, 28.1% versus peri-operative FOLFOX, 36.2%) (HR 0.72, 95% CI 0.60–1.00; P ¼ 0.041) [5]. While the EORTC 40983 trial assessed peri- operative versus no chemotherapy for patients with resectable colorectal liver metastasis, many patients are routinely offered che- motherapy in conjunction with resection. As such, the question remains as how to best sequence systemic chemotherapy relative to the timing of surgery. Specifically, is there a benefit to giving all systemic therapy in the adjuvant setting or should should part of the systemic chemotherapy regimen be given in the pre-operative setting [6]? Despite the lack of level 1 data to support the routine use of pre-operative chemotherapy, some clinicians have advocated for pre- operative chemotherapy for resectable liver metastasis [7]. Other investigators have suggested that chemotherapy administered after but not before resection of colorectal liver metastasis is associated with improved outcomes [8]. Data comparing the outcomes of patients treated with or without pre-operative chemotherapy can be problematic as baseline differences in clinicopathological character- istics may confound the relationship between the effect of systemic chemotherapy timing and outcome. The objective of the current study was to evaluate the impact of peri-operative systemic chemo- therapy timing on outcome following surgical resection of colorectal liver metastasis. In addition to identifying factors associated with survival, we sought to examine comparative outcomes following sur- gery relative to the timing of chemotherapy using both multivariate and propensity index modeling to adjust for potential confounding. PATIENTS AND METHODS Study Population and Data Collection Utilizing an international database, 888 patients with colorectal liver metastasis who underwent surgical resection between April 1996 and October 2010 at one of two institutions (Hepato-Bili- ary-Pancreatic and Transplantation Center, Curry Cabral Hospital, Lisbon, Portugal and Johns Hopkins School of Medicine, Baltimore, *Correspondence to: Timothy M. Pawlik, MD, MPH, Associate Professor of Surgery and Oncology, Department of Surgery, Harvey 611, 600 N. Wolfe Street, Baltimore, MD 21287. Fax: (410) 502-2388. E-mail: tpawlik1@jhmi.edu Received 11 July 2011; Accepted 9 October 2011 DOI 10.1002/jso.22133 Published online 7 November 2011 in Wiley Online Library (wileyonlinelibrary.com). ß 2011 Wiley Periodicals, Inc.