The liver is a frequent site of metastatic colorectal disease. Over the past 20 years, improvements in systemic chemotherapy and surgical techniques have improved the survival of patients with hepatic metastases. For 4 decades, fluorouracil and leucovorin were the only drugs available to treat metastatic colorectal cancer, but several new drugs and a variety of novel regimens are now available. Further improvements in results have been seen with the delivery of chemotherapy via the hepatic artery. Surgical resection of liver metastases has been encouraged when possible, and recent advances in surgery such as portal vein embolization, have made liver resection a possibility for more patients. This review considers the timing and sequence of chemotherapy and surgery in this setting, as well as the roles of cryoablation, radiofrequency ablation, and radiation therapy.
Dr. Kemeny has provided us with a current and comprehensive review of the management of liver metastases from colorectal cancer. The explosion of new oral and intravenous chemotherapy agents along with novel molecularly targeted agents have revolutionized the treatment of colorectal cancer but has challenged clinicians to develop new treatment algorithms that offer patients the most effective multidisciplinary treatment.
Despite the new chemotherapy agents, hepatic resection is still the most effective therapy for metastatic colorectal cancer confined to the liver. Multiple large series have shown that liver resections can be performed with low (< 5%) mortality and can offer long-term cure to about 30% of patients with metastatic cancer. As the safety of hepatic resection has evolved, major centers have adopted more aggressive surgical approaches to this disease. Patients with multiple, bilobar, and very large hepatic metastases now routinely undergo resection as long as there is no extrahepatic disease and adequate hepatic reserve.
With this expansion of surgical indications, scoring systems proposed by Dr. Fong and others looking at specific preoperative prognostic factors can predict long-term outcomes based on the size of the largest tumor, the preoperative carcinoembryonic antigen, the number of tumors, the nodal status of the primary tumor, and the disease-free interval. These scoring systems should not be used to exclude patients from hepatic resection, but rather, to stratify patients in clinical trials.
To compliment resectional strategies when complete resection of all metastases is not possible, a number of ablative techniques have been explored. Currently, the most widely used technique is radiofrequency ablation (RFA), which has been shown to be a safe, feasible treatment for hepatic metastases. RFA can be performed percutaneously or laparoscopically, alone or in combination with an open hepatic resection.
Due to the risks of biliary stricture, lesions near the central hepatic hilum should not be ablated. Tumors close to the diaphragm, near the dome, or abutting the stomach or colon should also not be ablated due to the risk of injury to these structures. A frustrating limitation of RFA is the inability to monitor the ablation in real time, necessitating a series of follow-up computed tomography scans to determine whether an adequate ablation has been accomplished.
Curley et al reviewed a series of 418 patients who underwent hepatic resection, RFA, or chemotherapy. Hepatic resection produced significantly better overall survival (65% at 4 years) compared to RFA and resection (36% at 4 years) or RFA alone (22% at 4 years). Intrahepatic and local recurrences were markedly increased in the RFA patients compared to those with hepatic resection. Despite the selection bias, hepatic resection and RFA produced superior survival compared to the group undergoing chemotherapy. This study supports the fact that RFA cannot be considered equivalent to hepatic resection but may complement surgical treatment of unresectable bilobar tumors or tumors in difficult locations.
Randomized trials examining the role of adjuvant fluorouracil (5-FU) and leucovorin after hepatic resection compared to no treatment have been negative. Current studies are addressing the use of new agents alone or with molecularly targeted agents, although many medical oncologists are already treating patients postoperatively with these systemic regimens. We await further objective evidence to justify treating these patients with adjuvant systemic therapy.
The role of adjuvant hepatic arterial infusion (HAI) of chemotherapy has been well study by Dr. Kemeny and colleagues at Memorial Sloan-Kettering Cancer Center. The trial published in 1999 comparing HAI floxuridine and systemic 5-FU vs systemic chemotherapy alone demonstrated a significant improvement in survival free of hepatic recurrence. A recent update revealed a 10-year survival rate of 41% for the combination treatment and 27% for systemic chemotherapy alone.
Further phase I and II studies looking at the role of HAI and systemic oxaliplatin (Eloxatin) and irinotecan (Camptosar) have confirmed the safety of this approach and shown surprisingly impressive response rates and overall survival in these small preliminary trials. The response rates for the combination of HAI and systemic chemotherapy seem higher than what would be anticipated for either type of therapy alone, suggesting that the benefits of HAI may be additive to systemic therapy. The true benefit of HAI adjuvant therapy after liver resection is currently being investigated through the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-09 trial.
As recently as 1986, patients with bilobar disease and/or more than four hepatic lesions were deemed unresectable-not necessarily due to technical constraints, but as a result of high tumor failure rates. Since the liver is the most likely location of subsequent recurrence, surgical failure after complete resection was presumably secondary to undetectable micrometastases dwelling in the remnant liver.
In 1996, Bismuth reported on 330 patients who presented with surgically unresectable hepatic metastases from colorectal cancer. A total of 53 (16%) were downstaged with 5-FU-based chemotherapy and eventually underwent hepatic resection, resulting in a 5-year survival rate of 40% for this select group, which was as good as any reported survival after resection alone. The underlying premise for this approach was that systemic therapy was more likely to provide a durable response against micrometastases than visible lesions; thus, combining resection with chemotherapy could improve the outcome. This neoadjuvant approach also provides a process for selecting patients more likely to benefit from resection by weeding out the patients who show disease progression on systemic therapy.
With the availability of newer chemotherapy regimens, increasing evidence supports the neoadjuvant approach, as is illustrated clearly by Dr. Kemeny. While enthusiasm for this approach has grown, a better understanding of the ill effects of chemotherapy on hepatic parenchyma is coming into view. Along with obesity, neoadjuvant chemotherapy appears to substantially increase hepatic steatosis (promoting use of the term CASH as an acronym for chemotherapy-associated steatohepatitis). Associated data suggest that marked steatosis is an independent predictor of complications following hepatic resection. Even a standard right hepatectomy in a patient with substantial fatty replacement can result in hepatic dysfunction and substantial postoperative complications.
Now more than ever, physicians treating patients with liver metastases from colorectal cancer need to coordinate therapy. Surgical and medical oncologists must personally discuss each patient on a case-by-case basis. Surgeons cannot be oblivious to the type and duration of therapy administered, and medical oncologists must be cautioned not to overtreat potential resection candidates.
At our institution, we present all potential resection candidates at a weekly multidisciplinary conference. Cross-sectional and nuclear imaging is reviewed, and health-care teams select therapy appropriate for each patient. Patients are characterized as low-risk (limited metastases with metachronous disease) or high-risk (mulifocal hepatic disease with synchronous disease). Low-risk patients can be resected or treated for two to four cycles of chemotherapy and high-risk patients are mostly treated with chemotherapy prior to resection. Once a response is detected, patients are referred back for surgical resection. This method provides an in vivo response assay but limits hepatic damage prior to resection.
Financial Disclosure: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.
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