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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4593-4602 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.8126 Hepatic Resection After Rescue Cetuximab Treatment for Colorectal Liver Metastases Previously Refractory to Conventional Systemic Therapy
From the Centre Hépato-Biliaire and the Departments of Medical Oncology, Pathology, and Pharmacy, Assistance Publique-Hôpitaux de Paris; University Paris-Sud, UMR-S 785, Inserm, Unité 785; and Inserm, Biological Rhythms and Cancers, Unité 776, Villejuif, France Address reprint requests to René Adam, MD, PhD, Paul Brousse Hospital, 12 Avenue Paul Vaillant Couturier, Villejuif, France 94800; e-mail: rene.adam{at}pbr.aphp.fr
Purpose In patients with unresectable colorectal liver metastases (CLM) resistant to first-line chemotherapy, the impact of cetuximab therapy on resectability is unknown. This study was performed to determine the post-cetuximab resectability rate and to examine postoperative outcomes for these heavily pretreated patients. Patients and Methods From February 2004 to April 2006, we evaluated 151 patients with unresectable CLM resistant to initial chemotherapy and subsequently treated with systemic cetuximab. Resectability rates, patient outcomes, and tumoral and nontumoral liver pathology were assessed. Results A total of 27 patients underwent surgery after a median of six cycles of cetuximab + irinotecan (20 of 27), oxaliplatin (four of 27), or both (one of 27). Eighteen patients (67%) had experienced treatment failure after at least two lines of chemotherapy before cetuximab. Twenty-five of the 27 patients who had surgery underwent hepatectomy: nine of 133 patients who were treated completely at our institution (resectability rate, 7%) and 16 of 18 patients who were referred from other institutions after systemic cetuximab therapy. Postoperative mortality was 3.7% (one of 27), with a complication rate of 50%. Histopathologic liver abnormalities were found in nine patients (36%), without specific lesions attributable to cetuximab. After median follow-up of 16 months, 23 of 25 patients who underwent resection (92%) were alive, and 10 patients (40%) were disease free. Median overall (OS) and progression-free survival (PFS) from initiation of cetuximab therapy were 20 and 13 months, respectively. Conclusion For CLM refractory to conventional chemotherapy, combination therapy with cetuximab increases resectability rates without increasing operative mortality or liver injury. The median OS and PFS of 20 and 13 months, respectively, suggest that this novel oncosurgical strategy benefits patients with previously refractory disease who respond subsequently to cetuximab.
The vast majority of colorectal cancer patients who present with liver metastases are not candidates initially for hepatic resection. This is due either to the distribution of tumors within the liver or to the presence of simultaneous extrahepatic disease. Systemic therapies for patients with unresectable disease typically include combinations of fluorouracil (FU) plus leucovorin (LV) and oxaliplatin or irinotecan. Using mainly systemic FU-LV and oxaliplatin-containing chronomodulated regimens, we have demonstrated the ability to convert 14% of patients from an unresectable status to a resectable situation, with a postoperative 5-year survival rate of 33%.1,2 Depending on the definition of initial unresectability and patient selection, other studies have reported resectability conversion rates as high as 60%.3-6 Although the combination of systemic chemotherapy and liver surgery can convert a significant proportion of patients from a palliative situation to a potentially curative situation, the majority of initially unresectable liver metastases do not respond sufficiently to initial chemotherapy to become resectable.1,6 Moreover, patients whose disease has progressed while receiving chemotherapy administered before hepatectomy experience a dismal prognosis, despite successful radical metastatic surgery.7 Failure to respond to first-line systemic therapy has frequently predicted poor response rates to subsequent lines of therapy.8-10 More recently, however, the addition of biologic agents (bevacizumab or cetuximab) to cytotoxic chemotherapy has increased the rate and extent of tumoral responses,11-13 suggesting that the addition of these agents to second-line or higher line regimens could improve resectability rates in treatment-refractory patients. This study provides a first assessment of the ability of systemic chemotherapy with cetuximab in second or subsequent lines to convert patients from an unresectable situation to a resectable status. This issue was examined in a cohort of patients with either initially unresectable or recurrent colorectal liver metastases, who were switched from their initial chemotherapy regimen to a combined regimen with chemotherapy and cetuximab, due to insufficient response. The purposes of our study were to determine the rate of cetuximab response sufficient enough to allow an attempt at margin-negative hepatic resection, and to examine the postoperative course in these heavily pretreated patients.
Inclusion Criteria Prospectively collected institutional chemotherapy and hepatic surgery databases were examined to identify patients with the following criteria: metastatic colorectal adenocarcinoma to the liver; indication for chemotherapy, including unresectable liver metastases or marginally resectable liver metastases (owing to simultaneous potentially resectable extrahepatic disease, and/or recurrence after a previous hepatectomy); failure to respond to initial chemotherapy (in patients with recurrent liver metastases, initial chemotherapy refers to treatment of the recurrence); and subsequent treatment with a regimen containing cetuximab.
Cohort Description
Patients treated with cetuximab at our institution were imaged with computed tomography and/or magnetic resonance imaging of the chest, abdomen, and pelvis every 2 months and tumor responses were evaluated in a multidisciplinary conference setting using Response Evaluation Criteria in Solid Tumors Group version 1.0 criteria.14 Nine of the 133 patients (7%) treated with cetuximab-containing chemotherapy regimens at our institution had a tumoral response that permitted an attempt at resection. These nine patients were combined with 18 patients who were treated with cetuximab at outside institutions and met all study inclusion criteria prior to referral to our institution for resection of their liver metastases.
Methods
Statistical Considerations
Patient Characteristics The 27 patients who underwent liver surgery after combined treatment with cetuximab and chemotherapy included 13 men and 14 women. The median age was 53 years (range, 35 to 75 years). Most patients had advanced primary tumors, with 73% T3-4 and 74% N1-2. Liver metastases were synchronous (initially diagnosed within 3 months of primary tumor surgery) in 11 (41%) of the 27 patients. Six patients presented with solitary liver metastases (22%), 12 patients (45%) had two to three metastases, and nine patients (33%) had more than three metastases. Eight patients (30%) had at least one tumor with a diameter  5 cm. Prior to cetuximab therapy, 79% of patients had an elevated carcinoembryonic antigen (CEA) level (> 5 ng/mL). After cetuximab therapy, the proportion of patients with abnormal CEA decreased to 43%. The median pre-cetuximab CEA level was 23.0 ng/mL (range, 1.4 to 1,485.0 ng/mL) and the median preoperative CEA level was 5.7 ng/mL (range, 0.5 to 271.0 ng/mL; P = .001). Comparison of demographic and clinical characteristics of the patients treated with cetuximab at our institution and at referring centers revealed similar features in the two groups (Table 1).
Chemotherapy Details All study patients had received systemic chemotherapy during the interval between metastasis diagnosis and treatment with combined cetuximab and chemotherapy. In addition, all patients were confirmed immunohistochemically to have epidermal growth factor receptor expression in either the primary tumor or in at least one metastasis before receiving cetuximab. Nine (33%) of the 27 patients who underwent surgery had experienced treatment failure after one line of conventional systemic chemotherapy immediately prior to treatment with a cetuximab-containing regimen. The remaining 18 patients (67%) had experienced treatment failure after more than one line of conventional systemic chemotherapy immediately prior to cetuximab therapy, including 10 patients treated with two prior lines (37%), seven patients treated with three prior lines (26%), and one patient treated with four prior lines (4%) of pre-cetuximab chemotherapy. Cetuximab was most commonly combined with irinotecan (20 of 27 patients), oxaliplatin (four of 27 patients), or both drugs (one of 27 patients). The median number of chemotherapy cycles administered prior to cetuximab treatment was 17 (range, two to 30 cycles). Eleven of the 27 study patients (41%) reported grade I or II skin toxicity while being treated with cetuximab. The characteristics of systemic therapies were similarly distributed between patients treated with cetuximab inside compared with outside of our institution (Table 2).
No complete clinical responses were observed. Surgery was performed after the documentation of a partial response in 23 patients (85%) and disease stabilization in four patients (15%). All four patients with stable disease while receiving cetuximab therapy had disease progression during previous chemotherapy regimens. Three of these patients initially presented with simultaneous extrahepatic disease and one patient presented with recurrent liver metastases, explaining the rationale for preoperative chemotherapy in these patients with marginally resectable intrahepatic disease.
Operative Characteristics
Surgical Morbidity and Mortality One patient died during the 60 days after surgery, resulting in an operative mortality rate of 3.7%. This patient developed hepatic failure after repeat major hepatectomy with a prolonged inflow occlusion time. Including the patient who died, four patients experienced general complications (15%), nine patients experienced local complications (33%), and one patient experienced both local and general complications (4%). After resection, the rate of transient postoperative liver insufficiency (defined as an increase in the serum bilirubin > 50 µmol/L and a decrease in prothrombin time to < 50%15) was 8%. Four patients required postoperative percutaneous drainage of fluid collections and there were three repeat laparotomies (one each for hemorrhage, infected fluid collection, and persistent biliary leak; Table 3).
Pathology Examination Analysis of the non–tumor-bearing liver identified nine patients (36%) with significant levels of at least one of the abnormalities sought in the pathologic analysis. This includes the observation of greater than 30% macrovesicular steatosis in four patients (16%) and vascular abnormalities (sinusoidal congestion/peliosis/regenerative nodular hyperplasia) in five patients (20%). Veno-occlusive lesions were not observed (Table 4).
Short-Term Outcomes The median follow-up from the initiation of cetuximab therapy was 16.4 months (range, 6 to 31 months). At the most recent follow-up, 25 patients were alive, including 10 patients who were free of disease. Of the 15 patients who are alive with disease, five are under treatment for extrahepatic disease that was present prior to resection with no new metastases, and 11 patients are under treatment for recurrent tumors that developed postoperatively (one patient with intrahepatic recurrence, one patient with extrahepatic recurrence, and nine patients with both intra- and extrahepatic recurrences). From the date of initiation of cetuximab there were 19 1-year survivors and three 2-year survivors. Median OS and PFS from initiation of cetuximab therapy were 20 and 13 months, respectively. Absent the one patient who died postoperatively, all patients have initiated postoperative systemic therapy, including 18 patients who were treated with cetuximab-containing regimens.
Representative Case Reports
Case 2. A 37-year-old woman was referred with a transverse colon carcinoma and synchronous unresectable (multiple and bilobar) liver metastases (Fig 6). The disease progressed during first-line treatment with six cycles of intravenous FU, leucovorin, and oxaliplatin, and then stabilized during second-line treatment with seven cycles of intravenous FU, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI). One year after diagnosis, the patient underwent colectomy for a pT3N2 colon adenocarcinoma and placement of a hepatic arterial infusion pump. Subsequent third-line therapy consisted of eight cycles of intra-arterial FU, folinic acid, oxaliplatin, and irinotecan without appreciable response. In fourth-line treatment, intravenous cetuximab was added to the third-line regimen. During 11 cycles of this regimen, a partial response was observed that allowed an attempt at curative hepatic resection (Fig 7). The surgical procedure consisted of a left hepatectomy and a segment VII resection. Histopathologic examination of the specimen showed that two of the three large resected metastases contained viable tumor cells. After a repeat hepatectomy for recurrence, she is now free of disease, and is receiving systemic chemotherapy 39 months after initial diagnosis and 16 months after first hepatectomy (Fig 8).
As many as 14% of patients with initially unresectable colorectal liver metastases can be converted to a resectable status by neoadjuvant systemic therapy and undergo potentially curative hepatectomies.1,2 For the remaining patients, with disease that does not respond sufficiently to chemotherapy so that a successful hepatectomy could be performed (the vast majority), the prognosis traditionally has been worse.2 Recently, however, our group has reported significant chemotherapy response rates in patients unresponsive to first-line chemotherapy.16,17 The introduction of targeted biologic agents has provided additional hope that patients who do not respond to initial chemotherapy may have salvage therapy and undergo potentially curative hepatic resection. Regulatory organizations in many countries currently prohibit the inclusion of cetuximab in the first line of systemic treatment for colorectal liver metastases. Although response rates associated with cetuximab-containing regimens used in second and higher lines are favorable, survivals remain disappointing.12,13 Data regarding the ability of biologic agents in second or higher lines to convert patients to a resectable situation are lacking. Therefore, we examined our hepatic resection experience in patients with disease progression after conventional prehepatectomy chemotherapies (ie, initial treatment failure) who subsequently responded to systemic therapy with cetuximab (ie, rescue therapy). The significant finding of our study is that 7% of unselected patients treated at our institution with cetuximab after failure of conventional therapy experienced a treatment response that allowed us to attempt a curative hepatectomy. This study group included a majority of patients with technically unresectable liver metastases, and some patients with marginally resectable metastases (recurrent liver metastases and/or extrahepatic disease that progressed on conventional regimens). This is a remarkable percentage given the refractory nature of the disease treated. Patients in the surgical group received a median number of 18 cycles of insufficiently effective chemotherapy immediately prior to cetuximab therapy, and 67% of patients who underwent surgery had been unresectable after two or more lines of chemotherapy immediately prior to cetuximab therapy. To our knowledge, this is the first report to document a meaningful response rate to combined cetuximab and chemotherapy using resectability as the main end point in patients with colorectal liver metastases that were previously resistant to chemotherapy. This study indicates that the addition of cetuximab to chemotherapy in second or even higher lines can increase the proportion of patients who become eligible for curative resection from 14% to 20%—a nearly 50% increase in the resectability rate (ie, of 100 unresectable patients, 14 can be converted to resectability with conventional chemotherapy. Six of the remaining 86 treatment-refractory patients [7%], may be converted subsequently to resectability with cetuximab-containing regimens, yielding a total of 20 resected patients and an overall resectability conversion rate of 20%). Notably, these percentages are concordant with reported resection rates for patients with unresectable liver metastases treated with first-line regimens that included cetuximab, which ranged from 20% to 24%.18 Our study cohort was composed of patients treated with cetuximab-containing regimens both at our institution and at other centers. Of course, we are unable to determine the total number of patients treated with cetuximab outside of our institution who failed to respond and were not referred for resection. However, the characteristics of the two groups of patients who underwent surgery were similar, suggesting that our institutional experience is representative of a broader experience with this difficult clinical situation. Given the intensity of prehepatectomy chemotherapy delivered to these patients, we closely examined the surgical outcomes for signs of chemotherapy-induced hepatotoxicity. Although the overall morbidity rate was high (52%), the hepatic insufficiency rate (8%) and mortality rate (3.7%) were relatively low. Our 60-day mortality rate compares favorably with previously reported experiences in patients treated with prehepatectomy chemotherapy, including our own.1,19-21 A testament to the feasibility of this approach is the fact that a majority of the resected patients have recovered to a performance status that is permitting the delivery of postoperative systemic therapies. In addition to a careful review of clinical outcomes, we also closely examined the non–tumor-bearing liver, searching for evidence of chemotherapy-induced hepatotoxicity. This analysis identified histopathologic liver abnormalities in 60% of the resected patients. We and others have also demonstrated an association between oxaliplatin-based chemotherapy and the development of vascular changes in the non–tumor-bearing liver.19,21-23 In our cohort, vascular changes were a common histopathologic finding and were observed in 20% of patients. However, dominant histopathologic features directly related to treatment with cetuximab were not identified. This is likely because most patients were treated with several lines of chemotherapy containing multiple agents, leading to a pooling of potential hepatotoxicities in each patient. In summary, 7% of patients with colorectal liver metastases who respond insufficiently to conventional chemotherapy may undergo rescue therapy to achieve resectability with cetuximab-containing chemotherapy regimens. Potentially, this treatment strategy could increase the rate of initially unresectable patients who could be offered curative resection by nearly 50%. Short-term outcomes demonstrate that this approach is safe, with no appreciable increase in operative mortality, postoperative liver insufficiency, or specific histopathologic liver injury. Although determination of the durability of response awaits longer follow-up, the median OS and PFS of 20 and 13 months, respectively, suggest that this is a promising oncosurgical strategy.
The author(s) indicated no potential conflicts of interest.
Conception and design: René Adam, Thomas Aloia, Francis Levi, Bernard Paule Administrative support: Dennis A. Wicherts, Robbert J. de Haas, Denis Castaing Provision of study materials or patients: René Adam, Francis Levi, Bernard Paule, Marie-Pierre Bralet, Mohamed Bouchahda, David Machover, Michel Ducreux, Vincent Castagne, Daniel Azoulay, Denis Castaing Collection and assembly of data: Thomas Aloia, Dennis A. Wicherts, Robbert J. de Haas, Bernard Paule, Marie-Pierre Bralet, Vincent Castagne Data analysis and interpretation: René Adam, Thomas Aloia, Dennis A. Wicherts, Robbert J. de Haas, Bernard Paule, Marie-Pierre Bralet, Mohamed Bouchahda, Michel Ducreux, Daniel Azoulay Manuscript writing: René Adam, Thomas Aloia, Francis Levi, Marie-Pierre Bralet Final approval of manuscript: René Adam, Thomas Aloia, Daniel Azoulay, Denis Castaing
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004[Medline] 2. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663-669, 1999 3. Alberts SR, Horvath WL, Sternfeld WC, et al: Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol 23:9243-9249, 2005 4. Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15:933-939, 2004 5. Zelek L, Bugat R, Cherqui D, et al: Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial). Ann Oncol 14:1537-1542, 2003 6. Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol 16:425-429, 2005 7. Adam R, Pascal G, Castaing D, et al: Tumor progression while on chemotherapy: A contraindication to liver resection for multiple colorectal metastases? Ann Surg 240:1052-1061, 2004[CrossRef][Medline] 8. Ahlgren JD, Trocki O, Gullo JJ, et al: Protracted infusion of 5-FU with weekly low-dose cisplatin as second-line therapy in patients with metastatic colorectal cancer who have failed 5-FU monotherapy. Cancer Invest 9:27-33, 1991[Medline] 9. Bertrand M, Doroshow JH, Multhauf P, et al: High-dose continuous infusion folinic acid and bolus 5-fluorouracil in patients with advanced colorectal cancer: A phase II study. J Clin Oncol 4:1058-1061, 1986 10. 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 11. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 12. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 13. Saltz LB, Meropol NJ, Loehrer PJ Sr., et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 14. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 15. Balzan S, Belghiti J, Farges O, et al: The "50-50 criteria" on postoperative day 5: An accurate predictor of liver failure and death after hepatectomy. Ann Surg 242:824-828, 2005; discussion 828-829[CrossRef][Medline] 16. Garufi C, Brienza S, Pugliese P, et al: Overcoming resistance to chronomodulated 5-fluorouracil and folinic acid by the addition of chronomodulated oxaliplatin in advanced colorectal cancer patients. Anticancer Drugs 11:495-501, 2000[CrossRef][Medline] 17. Van Cutsem E, Cunningham D, Ten Bokkel Huinink WW, et al: Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer 35:54-59, 1999[CrossRef][Medline] 18. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treatment of unresectable colorectal liver metastases: Correlation between tumour response and resection rates. Ann Oncol 16:1311-1319, 2005 19. 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 20. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-318, 1999[CrossRef][Medline] 21. Karoui M, Penna C, Amin-Hashem M, et al: Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1-7, 2006[CrossRef][Medline] 22. 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 23. Aloia T, Sebagh M, Plasse M, et al: Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 24:4983-4990, 2006 Submitted January 24, 2007; accepted June 12, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact tests. Differences were considered as statistically significant if the P value of the corresponding test was 
.05. Overall survival (OS) and progression-free survival (PFS), calculated from diagnosis and from initiation of cetuximab therapy, were determined using the Kaplan-Meier method. All statistical calculations were performed using SPSS software (version 12.0; SPSS Inc, Chicago, IL). 
