• © 2008 by American Society of Clinical Oncology

Perioperative or Adjuvant Therapy for Resectable Colorectal Hepatic Metastases

No one will deny that the only potential curative treatment for patients with hepatic metastases from colorectal cancer is surgical resection. Although no more than 10% to 15% of patients with colorectal cancer metastases are considered resectable for cure, the 5-year survival in this population approaches 35%. Nevertheless, relapse can occur in 75% of patients, generally occurring within the first 2 years after surgery; 50% of relapses are in the liver. With these data, it would seem prudent to consider in these patients administering systemic agents to reduce the risk of recurrence and to potentially improve overall survival, based on the model of eradicating micrometastases with chemotherapy in early-stage primary colorectal cancer. A dilemma that we face today is whether these agents be given before hepatic resection or after surgery. It is therefore important to clarify definitions. For example, neoadjuvant therapy is the administration of preoperative systemic therapy for resectable hepatic metastases. In general, neoadjuvant therapy does not include any treatment after hepatic resection. The administration of chemotherapy before and after hepatic resection is referred to as perioperative. Adjuvant therapy is the administration of systemic therapy after hepatic resection. Lastly, conversion therapy refers to systemic chemotherapy used for patients with unresectable hepatic metastases in an attempt to make the metastases resectable. This Editorial will only use the definitions of either adjuvant or perioperative therapy for resectable hepatic metastases from colorectal cancer.

This Editorial discusses two articles in this issue of Journal of Clinical Oncology. The first is by Mitry et al¹ and the second is by Nordlinger et al, which recently appeared in the Lancet.² Already, readers will detect that a major issue for resectable hepatic metastases is adjuvant therapy compared with perioperative chemotherapy. Mitry and associates have reported a pooled analysis based on individual data from two phase III trials (FFCD 9002 and the European Organisation for the Research and Treatment of Cancer [EORTC]/National Cancer Institute of Canada Clinical Trials Group/GIVO [ENG] trial) which showed a strong trend toward improved progression-free survival favoring adjuvant chemotherapy after hepatic resection compared with surgery alone. However, both trials had to be closed prematurely because of slow accrual, thus lacking statistical power to demonstrate a difference in survival. The chemotherapy used in each trial was identical: fluorouracil and leucovorin for six cycles at 28-day intervals post hepatic resection. With 278 patients included in the pooled analysis, the median progression-free survival was 27.9 months in the chemotherapy arm compared with 18.8 months in the surgery alone arm (P = .058). The median overall survival was 62.2 months in the chemotherapy arm compared with 47.3 months in the surgery alone arm (P = .095). Adjuvant chemotherapy as reported by Mitry and associates was independently associated with both improved progression-free survival and overall survival in multivariable analysis. The authors concluded that the results of this pooled analysis of two randomized trials support the use of systemic adjuvant chemotherapy after potentially curative resection of liver metastases from colorectal cancer. The authors also state that it is possible that a greater benefit of adjuvant treatment would likely be achieved with currently available chemotherapy regimens that are more effective in the adjuvant stage II or III colon cancer setting than fluorouracil and leucovorin alone.

Now let's turn our attention to the perioperative chemotherapy trial reported by Nordlinger and associates.² This phase III trial randomly assigned 364 patients with up to four resectable liver metastases to either six cycles of fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) before and six cycles after surgery or to surgery alone. It is important to emphasize that this trial design did not attempt to compare adjuvant to perioperative chemotherapy. The results demonstrated the absolute increase in rate of progression-free survival with perioperative chemotherapy at 3 years to be 7.3% (P = .058) in randomly assigned patients, 8.1% in eligible patients (P = .041), and 9.2% in patients undergoing resection (P = .025). The authors concluded that perioperative chemotherapy with FOLFOX-4 reduced the risk of progression in eligible and resected patients. It is also important to note that in this phase III randomized trial, the postoperative complication rate was statistically significantly increased in those patients who receive perioperative chemotherapy versus surgery alone. Several of these complications included biliary fistula, hepatic failure, intra-abdominal infection, and the need for re-operation. One would have to attribute this increase in postoperative complications to specific chemotherapy-associated hepatic toxicity. We know that oxaliplatin is associated with sinusoidal and vascular injury as opposed to the steatohepatitis associated with irinotecan. Such specific chemotherapy-associated hepatic toxicity was not seen to this degree in the fluorouracil and leucovorin era. The authors state that this moderate increase in the risks of liver surgery after chemotherapy does not compromise the potential benefits of the treatment. I respectfully disagree since hepatic failure, re-operation, and intra-abdominal infections are serious complications. These risks can be lessened by administering chemotherapy postoperatively.

So where does this leave us in determining whether a patient should receive perioperative chemotherapy or adjuvant chemotherapy in resectable hepatic metastases from colorectal cancer? Of course, the answer to this question could be answered with a prospective randomized phase III trial comparing perioperative chemotherapy to adjuvant chemotherapy. I am happy to report that representatives from the American College of Surgeons Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, and the North Central Cancer Treatment Group are in the planning process for such a trial. This trial would also include targeted agents with evaluation of tumor KRAS status in view of the results of the recent CRYSTAL trial demonstrating that the treatment effect of cetuximab in patients with KRAS wildtype is significantly enhanced compared with standard chemotherapy alone, whereas patients with KRAS mutant type could not be shown to benefit from cetuximab treatment in patients with metastatic colorectal cancer treated first line with fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without cetuximab.³ However, the trial will use FOLFOX instead of FOLFIRI in view of the recently reported phase III trial demonstrating no overall advantage in disease-free survival for the addition of irinotecan to fluorouracil and leucovorin as adjuvant treatment after complete resection of liver metastases from colorectal cancer.⁴ Of course, the real question is whether this developing phase III trial will be able to accrue patients. Have physicians already made up their mind as to the administration of perioperative or adjuvant chemotherapy after hepatic resection? Hopefully, the answer is no, and we will be able to solve this in a prospective randomized trial. The other concern is the chemotherapy-induced liver injury with preoperative chemotherapy. This is not just a matter of chemotherapy timing whether one administers the agents before surgery or after hepatic resection. It is a matter of maintaining a healthy, nontumor-bearing liver parenchyma before surgery to avoid the postoperative complications as demonstrated in the EORTC Intergroup trial 40983. Wouldn't it be better for the patient if one could avoid the hepatic toxicity and subsequent postoperative complications associated with the newer systemic agents by only administering these agents after hepatic resection? I submit that the answer is a definitive yes. Nordlinger and associates note that these complications were reversible. However, just because potential complications are reversible does not make the surgery appropriate. All of these issues emphasize the importance of a multicenter prospective randomized phase III trial of perioperative chemotherapy versus adjuvant chemotherapy in resectable hepatic metastases. However, as this potential trial goes through the usual process of evaluation, what recommendations can be given to physicians in discussing these treatment options with their patients? Perhaps at the present time, there can be a compromise between advocates of perioperative and adjuvant chemotherapy. For example, a patient with borderline resectable hepatic metastases who is a candidate for surgery, but in whom the surgeon is concerned about leaving a positive margin can be offered preoperative chemotherapy to potentially allow borderline resectable metastases to indeed become resectable with negative margins. Similarly, a patient with resectable multiple metastases where the functional remaining liver may be compromised with resection could potentially be offered preoperative chemotherapy to downsize the metastases and preserve more remaining liver parenchyma. If patients in this category progress during preoperative chemotherapy, there still may be an opportunity for surgical resection. Or if they become unresectable, second-line therapy could be administered. In contrast, there are patients in whom there is increased concerns about hepatotoxicity, such as diabetics, alcohol abusers, and patients who are obese, since know these individuals already have compromised liver parenchyma secondary to steatohepatitis, cirrhosis, or steatosis. Under these comorbid conditions, it might be more prudent for the surgeon to resect the metastases first and then make the decision postoperatively about adjuvant chemotherapy. The same train of thought could be used for a single metastasis where surgery could be performed first followed by adjuvant chemotherapy.

I haven't spend much time in this Editorial criticizing these specific trials. Certainly, advocates of perioperative chemotherapy may criticize the Mitry et al report as a pooled analysis of two trials that closed prematurely because of slow accrual, each with a lack of statistical power to demonstrate the defined difference in survival between surgery alone versus adjuvant chemotherapy. In contrast, advocates of adjuvant chemotherapy after hepatic resection will criticize the EORTC Intergroup trial 40983 because the absolute increase in rate of progression-free survival at 3 years for the perioperative intent-to-treat group was 7.3%, which was not statistically significant. They will also add concerns about chemotherapy-specific hepatic toxicity and the postoperative complications, which may be reduced with adjuvant chemotherapy. For physicians who require level I evidence for decisions, this controversy can only be solved with a multi-institution, adequately and realistically powered prospective randomized phase III clinical trial. Until that time, the decisions discussed above will depend on the best available data, as well as the comorbid conditions of the patient, borderline resectability of metastases, and the remaining functional liver post resection. Remember, sometimes we harm patients in an attempt to get them better and that is not good medicine.