SAN FRANCISCO – Giving preoperative chemotherapy directly into the tumor-feeding artery and prophylactically into the common hepatic artery to target any liver micrometastases improves outcomes in patients with early colorectal cancer undergoing curative resection. But benefit is seen mainly in patients with stage III disease.
These were among the key findings of the randomized multicenter phase III PHRAC trial (Preoperative Hepatic and Regional Arterial Chemotherapy) conducted among 688 patients in China with stage II or III colorectal cancer.
Compared with curative resection alone, followed by adjuvant systemic chemotherapy with the modified FOLFOX6 regimen, the addition of preoperative arterial chemotherapy reduced the 5-year estimated risks of disease-free survival events by 40%, of liver metastases by 61%, and of death by 41% in the trial population overall, according to data reported at the annual Gastrointestinal Cancers Symposium cosponsored by the AGA Institute, the American Society of Clinical Oncology, ASTRO, and the Society of Surgical Oncology. But stratified analyses showed that these benefits were significant only among the patients with stage III disease.
Dr. Jianmin Xu
“Preoperative hepatic and regional arterial chemotherapy had no effect on colorectal cancer surgery or postoperative morbidity,” commented lead investigator Jianmin Xu, an oncologist at the Zhongshan Hospital, Fudan University, in Shanghai. This therapy “is safe and feasible and can reduce liver metastasis and improve disease-free survival and overall survival, especially for the stage III patients.”
“Dr. Xu’s study was a positive study, but we have no description of the catheter problems or the number of patients who could be treated,” commented invited discussant Dr. Nancy E. Kemeny of Memorial Sloan-Kettering Cancer Center, New York. Additionally, outcomes in the control group fell short of those seen in patients treated with FOLFOX historically.
Despite accumulating evidence of benefit, the procedure is not yet ready for incorporation into routine care, according to Dr. Kemeny. “Since we don’t have a lot of information about the problems with the catheters or other problems like that, we need a larger, international study. I think one should be done because if you can prevent recurrences right away, which is what this study is suggesting, then that’s very good for these patients. We have ways of dealing with this afterwards, but it would be nice to prevent it right way. So given the fact that we already have five studies suggesting some benefit with this type of treatment, we should move into a large randomized study,” she recommended.
A session attendee noted that although colon cancer most commonly recurs in the liver, rectal cancer most commonly recurs in the pelvis. “Therefore, chemoradiotherapy is the standard of care now [for rectal cancer]. So infusional arterial chemotherapy should be used in patients with colon cancer, I think,” he said.
The patients with rectal cancer received radiation therapy after surgery if needed, Dr. Xu replied. “In the future, we will do subgroup analyses for colon cancer and for rectal cancer,” he added.
Dr. Nancy E. Kemeny
In the trial, patients from five hospitals in China were randomized to immediate curative primary surgery or to hepatic and regional arterial chemotherapy – floxuridine (FUDR), mitomycin C, and oxaliplatin delivered to both the main tumor-supplying artery and to the common hepatic artery – followed by curative primary surgery a week later. All patients received the same adjuvant therapy.
In the intention-to-treat population, estimated 5-year disease-free survival, the trial’s primary endpoint, was 75% with preoperative arterial chemotherapy versus 61% without it (hazard ratio, 0.60; P less than .001), reported Dr. Xu, who disclosed no relevant conflicts of interest. Subgroup analyses indicated that the benefit was significant in patients with stage III disease (68% vs. 51%; HR, 0.62; P = .017) but showed only a trend in patients with stage II disease (84% vs. 74%; HR, 0.64; P = .068).
Patients in the arterial chemotherapy group also were less likely to develop liver metastases (8% vs. 18%; HR, 0.39; P less than .001) and had better overall survival (81% vs. 72%, HR, 0.59; P = .003). But subgroup analyses again showed that benefit was significant only in the stage III patients.
Efficacy findings were similar in the trial’s eligible population, which excluded patients who were found to have pathologic stage I or IV disease at surgery and patients who developed metastases within 6 months of surgery.A total of 25% of patients in the arterial chemotherapy group experienced grade 3 toxicity from the procedure. However, the rate of postoperative complications did not differ significantly between the arterial chemotherapy and control groups.