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Surgical Resection of Colon Cancer Liver Metastases
Robert G. Fenton, MD, PhD, Clinical Associate Professor, Clinical Research Committee Member, University of Maryland, Marlene and Stewart Greenebaum Cancer Center. Dr. Fenton reports no financial relationships relevant to this field of study.
Approximately half of colon cancer patients will develop liver metastases during the course of their disease, but only about 20% of patients with hepatic metastases are candidates for surgical resection. Criteria for resectability include no radiologic evidence of involvement of the hepatic artery, portal vein, or major bile ducts, no local lymph node involvement, and adequate reserve in the remaining liver. An analysis of 3,957 Medicare patients who had surgical resection of liver metastases from 2000-2004 demonstrated a 25% five-year survival, with 30- and 90-day mortality rates of 4% and 8%, respectively. Indicators for poor short- and long-term mortality were age > 80, comorbid disease, and synchronous colon/hepatic resection.1 Given that the five-year survival for patients with metastatic colorectal cancer after chemotherapy is only 10%, surgical removal of liver metastases should be attempted if there is a reasonable chance for complete resection.
With more active chemotherapy regimens and better surgery, patients with multiple, bilobar metastases can be candidates for resection, with five- and 10-year survivals in the 50% and 30% range, at least in a small series of highly selected patients.2 It is generally recommended that when four or more lesions are present, neoadjuvant chemotherapy should be used to determine the responsiveness and biologic behavior of the patient's cancer, and to improve chances of obtaining clear margins at surgery. Post-operative chemotherapy is imperative to reduce the high recurrence rates after surgery, especially in cases with large numbers of metastases (e.g., > 7). A randomized study comparing resection of hepatic metastases, with or without perioperative FOLFOX4, demonstrated a significant increase in progression-free survival of 7%-9% in the chemotherapy group.3 At 3.9 years of follow-up, there was a three-year DFS trend favoring the chemotherapy arm (35 vs. 28%, p = 0.058).3 The role of hepatic artery infusion (HAI) after the resection of hepatic metastases is being studied in NSABP C-09, which is comparing systemic capecitabine plus oxaliplatin alone or combined in alternating cycles with HIA infusion of FUDR.
For patients with four or fewer lesions that appear resectable, it is reasonable to either administer neoadjuvant chemotherapy or to perform surgery and then give adjuvant chemotherapy. Neoadjuvant chemotherapy with oxaliplatin or irinotecan-based regimens can cause liver toxicity (sinusoidal dilatation or steatohepatitis, respectively) that may increase the post-operative complication rate.4,5 Therefore, for healthy patients with four or fewer metastases, surgery should be performed first, followed by adjuvant chemotherapy. For patients with borderline or initially unresectable disease, neoadjuvant chemotherapy should be given to determine responsiveness and to render the patient operable if they respond. Using FOLFOX, FOLFIRI, or a hybrid, as many as 30%-40% of "unresectable" patients can be converted to the "potentially curable with surgery" category. In all cases, bevacizumab, or EGFR-targeting antibodies (cetuximab, panitumumab), should be combined with chemotherapy regimens to enhance the anti-tumor response, realizing that a 6-8 week interval between bevacizumab and surgery is recommended. Additionally, surgery should be delayed until four weeks after the last chemotherapy treatment to allow liver toxicities to abate.
When neoadjuvant chemotherapy with newer, active agents is used, it is not uncommon for some of the liver metastases to completely respond, as determined by CT imaging. The surgeon must then ponder the question as to how to deal with liver lesions that are no longer visible on preoperative-staging CT scans. Should these liver segments be excised, thereby expanding the operation and increasing morbidity, or can they be assumed to be free of disease, as suggested radiologically? Data from a study designed to directly answer this question will be reviewed, and their implications for the concept of colon cancer stem cells will be discussed.
Benoist et al prospectively studied 586 consecutive patients from 1998 to 2004, of which 38 patients met the inclusion criteria;6 fewer than 10 had liver metastases prior to chemotherapy; imaging showed the disappearance of at least one metastasis after chemotherapy; surgery with intra-operative ultrasound within four weeks of CT scanning; no extra-hepatic disease; no previous liver resection or radiofrequency ablation; and at least one year of follow-up after surgery. In the 38 eligible patients, 183 liver metastases were identified prior to the chemotherapy, of which 66 had completely responded on preoperative imaging. The average maximum diameter of these lesions was 2.2 ± 1.5 cm; no lesions greater than 4.5 cm completely responded. The goal of the study was to determine how many of these 66 lesions were really sterile.
During surgery, direct liver inspection and ultrasound found residual macroscopic disease in 20 of these sites (24%), which had a mean size of 12.1 ± 6.8 mm (range 3 to 25 mm). Eight of the nine patients with macroscopic residual disease had been considered unresectable prior to chemotherapy; of these, six were rendered NED and two could not be completely resected. Forty-six patients had no macroscopic residual tumor at sites of pre-treatment lesions. These lesions were treated in one of two ways: The site of the initial resection was resected (15 cases), or the site of initial metastasis was not removed and followed over the ensuing year of the study by CT imaging (31 patients). In the former group, viable tumor cells were detected in 12 of the 15 patients (80%), and only three were free of viable tumor; ten of the 15 patients recurred within one year of surgery. In the latter group, recurrence at the original site of metastasis occurred in 23 of the 31 patients (74%), and only eight remained free from recurrence at the initial site. Overall, in 55 of 66 (83%) of the liver metastases that had shown a CR on preoperative CT scans, residual microscopic or macroscopic disease, or early recurring disease, was identified.
Clearly, complete response by CT imaging does not equate to sterilization of the site for colorectal cancer hepatic metastases, and these liver segments must be included in the surgical resection plan. However, there are a few caveats to the data. It is not clear the patients in this study received optimal chemotherapy, since some patients received only six courses and others received 5-FU/LV without oxaliplatin or irinotecan. Furthermore, it is possible that the addition of bevacizumab or cetuximab would have significantly improved the data, although neither of these agents, when added to first-line chemotherapy, has been shown to be active against minimal residual disease. Furthermore, it is possible that the surviving tumor cells represented in minimal residual disease are not representative of the metastatic site as a whole. Dick et al have demonstrated the existence of colon cancer stem cells using murine xenograft transplantation studies in a manner analogous to experiments that led to identification of leukemia stem cells.7 Hence, one can postulate that viable cells remaining at metastatic sites after neoadjuvant chemotherapy are colon cancer stem cells, or cells with characteristics of stem cells, which render them resistant to current forms of chemotherapy. This hypothesis will be difficult to prove, since isolating and characterizing these cells from surgically resected tissue will be challenging, although, perhaps, not impossible. Understanding what these remaining viable tumor cells are, and characterizing the signaling pathways responsible for their survival, will be critical for the development of targeted therapies that can truly sterilize sites of colorectal cancer metastases.
1. Robertson DJ, et al. Survival after hepatic resection of colorectal cancer metastases: A national experience. Cancer. 2009;115:752-759.
2. Malik HZ, et al. Prognostic influence of multiple hepatic metastases from colorectal cancer. Eur J Surg Oncol. 2007;33:468-473.
3. Nordlinger B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): A randomized controlled trial. Lancet. 2008;371:1007-1016.
4. Kooby DA, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003;7:1034-1044.
5. Rubbia-Brandt L, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15:460-466.
6. Benoist S, et al. Complete response of colorectal liver metastases after chemotherapy: Does it mean cure? J Clin Oncol. 2006;24:3939-3945.
7. O'Brien CA, et al. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature. 2007;445:106-110.