Upfront Neoadjuvant Therapy Urged for All Colorectal Cancer Patients With Liver Metastases

BALTIMORE—Between 11,000 and 12,000 colorectal cancer patients present with liver metastases each year. Surgical resection is ideal but does not remove microscopic metastases and disease left behind after surgery. "Today, treatment should start with neoadjuvant therapy in all colorectal cancer patients that have liver metastases," Yehuda Z. Patt, MD, said.

The main approaches to colorectal cancer liver metastases include regional chemotherapy via hepatic arterial infusion (HAI), systemic chemotherapy, or combined modality therapy. Dr. Patt, who is chief of ambulatory care and of gastrointestinal oncology at the University of Maryland Greenebaum Cancer Center in Baltimore, said that little survival advantage has been seen in trials of HAI.

"HAI was an attempt to extract an extra mile from a marginally active drug floxuridine (FUdR) by increasing tumor drug exposure and improving specificity. Despite improved response rates, survival advantage has been equivocal, and administering floxuridine in this fashion was associated with significant biliary toxicity. Newer agents may accomplish improved tumor specificity without HAI."

Attempts to use monoclonal antibodies as drug carriers to increase specificity have been disappointing, but Dr. Patt said, "Use of enzymatic properties unique to the tumor, as with capecitabine (Xeloda), may provide the improved specificity we are looking for."

Resect When Possible

Dr. Patt outlined a suggested approach to metachronous liver metastases beginning with systemic fluoropyrimidine plus irinotecan (CPT-11, Camptosar) or oxaliplatin (Eloxatin) or all three agents. "Whenever possible we should then resect the responding metastases. Postoperatively, we should treat the patient with the regimen that produced the response and reserve HAI for liver metastases that do not respond," Dr. Patt said. "If the lesions respond to HAI, we should resect and give postoperative HAI as adjuvant treatment."

Current recommendations for patients with rectal cancer and resectable synchronous liver metastases are resection of the liver metastases and primary tumor with postoperative adjuvant fluorouracil (5-FU)/leucovorin or adjuvant radiation/5-FU plus two cycles of 5-FU/leucovorin. The current recommendations for rectal cancer with nonresectable liver metastases, include segmental rectal resection or laser ablation, diverting colostomy or radiotherapy/5-FU, and salvage chemoradiotherapy. However, Dr. Patt suggested "the use of neo-adjuvant therapy in nearly all patients."

A capecitabine/oxaliplatin combination regimen will be studied in a phase II trial in patients with asymptomatic colon cancer with synchronous liver metastases, while a separate trial will be conducted in patients with metachronous liver metastases. "With this drug regimen, response rates and median survival times formerly observed only with HAI, have been reported by European investigators," Dr. Patt said. He said that in a suggested national trial of preoperative capecitabine/oxaliplatin, "an attempt will be made to resect every one of the patients." He pointed out that postponing resection until after initial chemotherapy will rule out the risk of performing surgery on patients who have explosive disease and would not benefit from resection.

"Neoadjuvant therapy with capecitabine containing regimens may turn unresectable liver metastases into resectable ones. However, the addition of irinotecan and/or oxaliplatin may further increase the likelihood of resectability, and thus may make HAI for upfront therapy obsolete," Dr. Patt concluded.