Changing Management Strategies for Hepatic Colorectal Metastasis

With approximately 150,000 new cases annually, colorectal carcinoma is a major cause of cancer-related morbidity in the United States. Nearly 50% of these patients will develop metastatic liver disease at sometime in the course of their illness, and approximately one-third of this group will have disease confined to the liver. Thus, over 20,000 patients annually will potentially be candidates for liver-directed therapy, a figure that is on a par with the annual incidence of pancreatic carcinoma.

Treatment Evolution
Since the 1980s, overwhelming clinical evidence has shown that resection is the most effective therapy for patients with hepatic colorectal metastases. Contemporary series that include large numbers of patients have reported 5-year survival figures from 40% to > 50%.[1,2] Even within this selected subgroup of patients with resectable disease, there is wide variability in recurrence rates and survival following resection. In the absence of reliable and prognostically accurate molecular markers, disease-related clinical variables are currently used to stratify patients with respect to outcome.[2,3] Indeed, using such prognostic indicators, which often comprise some type of clinical scoring system, stark differences are often highlighted between patients in good-risk and poor-risk categories, with 5-year survival rates ranging between 60% and < 15%, respectively.[2-4]

Over the past few years, marked improvement in the efficacy of systemic chemotherapeutic agents has dramatically changed clinical management of patients with hepatic colorectal metastases. These new agents have not only improved survival rates in patients with advanced disease, but have likely also resulted in improvements in the results of resection and may well narrow the gap between good-risk and high-risk patients who undergo surgery. Furthermore, contemporary systemic regimens have markedly changed the definition of what constitutes resectable disease, resulting in increasing numbers of patients potentially being considered for complete resection.

Clearly, contemporary management of hepatic colorectal metastases has changed dramatically over a very short period of time, and the review by Wagman and Byun highlights many of these important developments and areas of continued controversy. Prominent among these has been the change in the surgical approach, which has undergone significant evolution. A major change in this regard has been in the area of patient selection for operation. In the not-too-distant past, patients were considered poor candidates for operation (or not considered at all) if they had more than three tumors or tumors involving both right and left hemilivers. Over time, it has become increasingly clear that such oversimplified selection criteria are no longer appropriate. Indeed, it is now commonplace for patients with multiple, bilobar tumors to undergo surgery. The advent of the two-stage partial hepatectomy in order to achieve an R0 resection has extended the indications for operation and has allowed increasing numbers of patients to be considered for potentially curative resection-patients who previously would never have been considered operative candidates.[5] Another area of persistent controversy includes the optimal management of patients with concomitant metastases to the liver as well as extrahepatic sites. Previously, extrahepatic metastasis was considered an absolute contraindication to hepatic resection. However, mounting evidence suggests that selected patients may enjoy long-term survival with complete resection of both the liver and extrahepatic disease.[6]

Chemotherapy
The authors correctly devote a large portion of their review to chemotherapy issues. This is only fitting since the changes in surgical management have evolved hand in hand with advances in systemic agents. There is little doubt that without the latter, the emergence of new and more aggressive surgical approaches almost certainly would not have taken place-a point that requires emphasis.

Particularly noteworthy in this regard has been the increasingly frequent use of neoadjuvant chemotherapy in patients with potentially resectable tumors, the advantages of which are nicely summarized by the authors. One of the major arguments in favor of this approach is that neoadjuvant chemotherapy provides an in vivo chemoresponsiveness assay that may potentially identify patients at high risk for recurrence and may help direct postoperative therapy. However, given the very low proportion of patients who experience disease progression while on treatment-as documented in the recently reported European Organisation for Research and Treatment of Cancer (EORTC) trial-this argument has increasingly become untenable.[7] On the other hand, providing therapy for radiographically occult microscopic disease without delay is a more plausible and attractive argument but is unproven clinically.

The issue of how to manage patients with lesions that disappear from imaging studies is a byproduct of contemporary systemic therapy and is a particularly vexing problem. In the majority of cases, viable residual disease is present at these sites, and tumor recurrence is the rule after chemotherapy is discontinued. However, a small proportion of these will represent complete responses. Such cases, while few in number, are challenging for surgeons, in terms of both patient selection and operative planning. In many instances, the lesions can be localized intraoperatively and resected, although this is not always true, and one should be cautious of performing a “blind resection” based on prior imaging.

It is imperative to stress, as the authors do, that any potential advantage of neoadjuvant chemotherapy must be weighed against the very real risk of chemotherapy-induced liver damage, which can directly impact surgical morbidity. It has been well described that prolonged chemotherapy can result in significant liver damage, particularly steatosis and steatohepatitis, which is well known to increase perioperative complications and mortality rates. The potential ability for neoadjuvant chemotherapy to reduce the magnitude of the operative procedure, potentially resulting in the less extensive sacrifice of normal liver parenchyma, is a strong argument in favor of its use. In reality, however, this argument applies to very few patients, and in most instances the operation required to remove all disease is not altered. Before embarking on a course of neoadjuvant chemotherapy in a patient with a potentially resectable liver disease, the goals of such treatment must be carefully considered-when the risks and benefits are carefully weighed, any advantage of this approach often becomes inapparent.

Hepatic Arterial Infusion
The role of hepatic arterial infusion chemotherapy in this setting has similarly changed over the past few years. The authors provide a clear and succinct summary of the data regarding its use, pointing out that the in the era of contemporary systemic chemotherapy associated with high response, the role of hepatic arterial infusion is less clear. While this view is widely held, there is no data to support it. On the other hand, a great deal of published work clearly shows the efficacy of regional chemotherapy in patients with advanced disease, particularly in those who have failed first- or second-line systemic regimens. A recent report of patients with unresectable disease confined to the liver showed a response rate of 92% using a combined approach that included systemic plus hepatic arterial infusion chemotherapy.[8] This study documented a response rate of 85% in patients who had failed first-line systemic treatment in a conversion to resectability of 47% (and 57% in chemotherapy-naive patients). While the role of adjuvant hepatic arterial infusion chemotherapy remains to be defined, this approach combined with systemic agents is very effective in patients with advanced disease.

Ablative Therapy
There is also ongoing debate regarding the role of ablative therapy for metastatic colorectal cancer. While a number of different ablative techniques have emerged, radiofrequency ablation (RFA) remains the most commonly used technique and can be used percutaneously, laparoscopically, or at open operation. The authors correctly point out that RFA is being used increasingly in combination with resection in patients with advanced bilobar disease, with no apparent adverse impact in outcome. Indeed, the case report included in the Wagman/Byun article illustrates how such a combined approach might be applied, with resection of one lesion and RFA of a second, more centrally located and less accessible tumor.

While ablation may well be appropriate in some circumstances, it should in no way be considered a substitute for resection. This is particularly true for larger tumors and for tumors adjacent to large vascular structures, both of which are associated with high local recurrence rates.[9] Without the computed tomography scan images pertaining to the case at hand, it is difficult to make specific comments regarding the approach used. While that approach was certainly reasonable, one alternative consideration may have been to perform a right portal vein embolization in order to promote hypertrophy of the future liver remnant and to resect both of the liver lesions with a right hepatectomy.

Conclusion
In summary, the review by Wagman and Byun provides a complete and succinct summary of the changing management strategies that have taken place in the area of hepatic colorectal metastasis. With the burgeoning number of effective therapies and combinations of therapies, the management of these patients has become complex and requires clinicians with experience and mature clinical judgment. The authors correctly state that “rather than approaching the patient with sequential, independent therapies and handoff from specialist to specialist, a continuous interaction is required.” Now, more than ever, a multimodality treatment approach to patients with metastatic colorectal cancer is required in order to provide the best clinical outcomes.

References:

1. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al: Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 25:4575-4580, 2007.
2. Minagawa M, Yamamoto J, Kosuge T, et al: Simplified staging system for predicting the prognosis of patients with resectable liver metastasis: Development and validation. Arch Surg 142:269-276, 2007.
3. 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.
4. Rees MM, Tekkis PP, Welsh FK, et al: Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: A multifactorial model of 929 patients. Ann Surg 247:125-135, 2008.
5. Adam R, Laurent A, Azoulay D, et al: Two-stage hepatectomy: A planned strategy to treat irresectable liver tumors. Ann Surg 232:777-785, 2000.
6. Carpizo DR, D’Angelica M: Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease. Lancet Oncol 10:801-809, 2009.
7. Nordlinger B, Sorbye H, Glimelius B, et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): A randomised controlled trial. Lancet 371:1007-1016, 2008.
8. Kemeny NE, Melendez FD, Capanu M, et al: Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 27:3465-3471, 2009.
9. Mulier S, Ni Y, Jamart J, et al: Local recurrence after hepatic radiofrequency coagulation: Multivariate meta-analysis and review of contributing factors. Ann Surg 242:158-171, 2005.