Perioperative Chemotherapy for Colorectal Cancer Liver Metastases

In 2013, approximately 143,000 people will be diagnosed with colorectal cancer, and over 50,000 will die from the disease. While the majority of patients will not have detectable metastases at diagnosis, ultimately 35% to 40% of patients will develop metastatic disease. The liver is the most common site of metastases for colorectal cancer; however, more than two-thirds of patients with liver metastases will also have extrahepatic disease. Still, although the number of patients who have metastatic disease limited to the liver is relatively small, this population has gained increasing attention in the past 2 decades, as numerous cohort studies have reported a long-term disease-free period for those with limited metastases in the liver who undergo resection of their metastases. Despite the continued progress in overall survival that has been demonstrated for resection of colorectal liver metastases,[1] the disease will recur in most patients even after a margin-negative resection.[2] Early recurrence is a known risk with synchronous metastases,[3] and a disease-free interval of less than 12 months has been recognized as one of the main risks for tumor recurrence in a multivariate analysis of over 1,000 patients with colorectal liver metastases.[4]

The question of how best to manage potentially resectable liver metastases in colorectal cancer patients is complex, since the presentations of metastatic liver disease are many and varied. Patients can present with synchronous metastases at their initial diagnosis or develop metachronous metastases months to years later. Liver metastases can be solitary in number or multiple. Metastases can be limited to one segment, limited to one lobe, or bilobar. Metastases may be easily resectable at presentation or may be more complicated because of proximity to vascular structures. Patients may have received prior chemotherapy for their colorectal cancer or may be chemotherapy-naive. Given these possible variations, there is not one formula that can apply to all patients when considering resection of oligometastatic liver disease.

Weiser and colleagues present an excellent review of these issues[5]; they try to consider the different scenarios a clinician might encounter and provide guidance on how to approach them. We would agree with their ultimate conclusion that treatment of these patients requires a multidisciplinary team approach.

In this commentary, we would like to highlight a few issues related to the management of potentially resectable oligometastatic liver disease. First, the timing of chemotherapy administration in relation to liver surgery is particularly relevant in patients with synchronous or early metastases, and the goals of perioperative chemotherapy are worth consideration. As discussed by Weiser et al, chemotherapy has been shown to effect tumor “downstaging” in colorectal liver metastases, allowing margin-negative resection in patients previously deemed to have unresectable metastases.[6] Such “conversion” chemotherapy may be relevant in patients at risk for positive resection margins, such as those with tumors abutting vascular structures or those with bilobar disease and a limited functional liver remnant. The choice of chemotherapy in this setting remains controversial, since there are no randomized studies to define which combination of chemotherapeutics provides optimal downsizing.

In addition to tumor downstaging, however, preoperative chemotherapy has a number of theoretical benefits. For one, preoperative administration will ensure that all eligible patients receive systemic therapy, given the risk that some patients will miss postoperative therapy due to surgical morbidity. Perioperative morbidity, including bleeding, infection, and bile leak, can occur in 20% to 40% of patients,[7] potentially limiting the timing or duration of postoperative chemotherapy. Second, assessment of response to chemotherapy in the patient with a measurable disease burden may potentially guide postresection chemotherapy choices, although it is not clear whether evidence of tumor necrosis in a macroscopic tumor corresponds to elimination of microscopic disease (the goal of adjuvant therapy). Perhaps most importantly, a delay in surgery while preoperative therapy is administered serves a role in surgical selection, reserving the risk of surgery for those without interval disease spread, and allowing declaration of occult disease in high-risk patients. Response to chemotherapy is recognized as a predictor of outcome after resection[8]; patients with disease progression on chemotherapy have a poor prognosis.[9] Outcomes after metastasectomy in the setting of disease progression are significantly worse compared with those after radiographic response, with 5-year survivals of 8% vs 37%.[6]

The benefit of chemotherapy moved beyond the theoretical realm with the report of European Organisation for Research and Treatment of Cancer (EORTC) intergroup trial 40983. This study prospectively randomized 364 patients with colorectal liver metastases to perioperative chemotherapy with 6 cycles of preoperative therapy and 6 cycles of postoperative therapy, or to surgery alone. A significant impact in progression-free survival was evident at 3 years, with 43% of patients demonstrating an objective response via Response Evaluation Criteria In Solid Tumors (RECIST) criteria,[9] although overall survival was not significantly different. One concern with preoperative chemotherapy is the potential progression of disease while surgical resection is delayed. In the EORTC study, 12 of 182 patients (7%) showed progressive disease on chemotherapy. However, only four cases became unresectable due to progression of known liver lesions, and given the poor prognosis with disease progression on chemotherapy, it is likely that preoperative therapy rarely limits what would otherwise be a potentially curative operation.

Preoperative chemotherapy is not completely risk-free. As Weiser et al note, all current regimens have some associated hepatotoxicity, and prolonged preoperative administration could potentially limit surgical options or lead to unacceptable postoperative outcomes. Precise data on the incidence of chemotherapy-related hepatotoxicity are limited by variation in the type and duration of chemotherapy used in various studies, as well as by the extent of liver resection performed. While varying degrees of hepatotoxicity are described with irinotecan-containing regimens,[10] as well as with oxaliplatin-containing regimens,[11] the risks of chemotherapy do seem related to the duration of treatment and the delay prior to surgery.[12] Available data suggest that a limited course of preoperative chemotherapy may increase the morbidity but not mortality of liver resection.[9,13] In addition, preoperative suspicion for chemotherapy-related liver injury can be managed with preoperative portal vein embolization to induce contralateral hepatic hypertrophy.[14] Despite appropriate concerns for hepatotoxicity, it is not clear that a limited course of preoperative chemotherapy restricts liver resection in patients without preexisting liver dysfunction.

Considerations regarding chemotherapy notwithstanding, the simultaneous management of the primary tumor and the metastatic focus is a possible option in patients with synchronous metastases. Benefits of a simultaneous operation include the avoidance of a second operation and second anesthesia, as well as the avoidance of additional delay, during which metastases could theoretically progress.[15] Although studies are retrospective and involve heterogeneous patient populations, increased morbidity and mortality with synchronous operations have been suggested by some authors when liver resection includes major hepatectomy.[16] Absent solid data, most centers reserve synchronous resection for metastases that are small, unilobar, and few in number. In particular, the surgical access required for left-sided and rectal resections may not allow optimal access for formal hepatectomy. Most would agree that simultaneous liver resection is contraindicated in the setting of a surgical emergency, obstruction, or perforation.

In closing, Weiser and colleagues correctly emphasize the limited data available to guide decision making in the management of colorectal liver metastases. Despite a trend toward increased use of perioperative chemotherapy, others have questioned the role of this approach in patients with solitary lesions and a longer disease-free interval.[17] Treatment strategies must be highly individualized and take into account numerous factors, such as the anatomy of primary and metastatic lesions, the disease-free interval, prior chemotherapy exposure, prior surgery, and physiologic health. Until better data are available, local experience and available expertise will likely heavily influence management strategies.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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2. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715-22.

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17. Adam R, Bhangui P, Poston G, et al. Is perioperative chemotherapy useful for solitary, metachronous colorectal liver metastases? Ann Surg. 2010;252:774-84.