ASCO: Intraperitoneal Chemotherapy May Boost Advanced Gastric Cancer Survival

By Crystal Phend
CHICAGO, 05 jun 2008-- Advanced gastric cancer penetrating the serosa membrane may respond well to intraperitoneal chemotherapy during surgery, Korean researchers found.Intraperitoneal plus intravenous chemotherapy increased the absolute rate of recurrence-free survival and overall survival about 10% at three and five years of follow-up compared with intravenous chemotherapy alone, reported Yoon-Koo Kang, M.D., Ph.D., of Asan Medical Center in Seoul, and colleagues at the American Society of Clinical Oncology meeting here.These randomized trial results "are very provocative" but not practice changing, commented David H. Ilson, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center in New York, who was a discussant for the study.
Confirmation is needed in a trial with fewer variables, he said. "The experimental arm in addition to adding intraperitoneal chemotherapy made several other modifications to the chemotherapy." The researchers suggested that the primary reason for the survival and recurrence advantages to their regimen was the use of intraperitoneal chemotherapy and the early start of chemotherapy.
Their results showed no link between dose of doxifluridine administered and overall or recurrence-free survival. A prior trial showed no benefit from adding cisplatin (Platinol) and prolonged doxifluridine (the oral prodrug of 5-fluorouracil [Adrucil]) in curatively resected advanced gastric cancer, Dr. Kang noted.
Dr. Ilson agreed that intraperitoneal chemotherapy was likely a major contributor. Peritoneal recurrence is common after gastric resection, but administering cytotoxic drugs directly to the peritoneum increases exposure 10- to 100-fold, he said.
Intraperitoneal chemotherapy is a standard of care for ovarian cancer but rarely used in gastric cancer, Dr. Ilson said. U.S. oncologists typically use 5-fluorouracil and radiation as adjuvant treatment for gastric cancer, he said.
On the basis of a Spanish study showing improved disease-free and overall survival with intravenous mitomycin-C (Mutamycin) plus short-term oral fluoropyrimidine chemotherapy, the researchers tested an even more aggressive approach in the randomized AMC 0101 study.
Compared with the control treatment, the experimental regimen added:
A course of 100 mg of intraperitoneal chemotherapy during surgery.
Earlier initiation of mitocycin-C (15 mg/m2 on day one after surgery versus 20 mg/m2 three to six weeks after surgery).
Six months of cisplatin at a dose of 60 mg/m2 on day one every four weeks.
Twelve versus three months of doxifluridine at a dose of 460 to 600 mg/m2 per day.
The study included 521 patients with completely resected, histologically proven, nonmetastatic gastric adenocarcinoma and gross serosa involvement.
After a median 3.5 years of follow-up, 229 progression or death events had occurred.
For the primary endpoint, the experimental strategy improved the rate of recurrence-free survival by about 10% at both three (60.2% versus 50.0%, hazard ratio 0.695, P=0.006) and five years (50.5% versus 43.8%).
Subgroup analyses showed a similar pattern of benefit with the exception of patients without total resection and those with stage IV disease, for whom results were equivocal.
The recurrence rate was significantly reduced overall with the experimental regimen (P=0.02), and tended to be lower for both peritoneal and distant recurrence.
Overall survival likewise was significantly improved with the more aggressive regimen by about an absolute 10% at three (71.2% versus 59.6%, HR 0.710, P=0.02) and five years (56.2% versus 47.0%).
The experimental regimen caused substantially more grade 3-4 neutropenia than seen with the control treatment (34.2% versus 11.6%). Higher-grade anemia and vomiting were also more common with the peritoneal chemotherapy-containing regimen.
However, intraperitoneal chemotherapy administered during surgery did not increase surgical complications.
"Gastric cancer is an area where we've had very little progress," Dr. Ilson concluded. "The currently available standards of care have limited benefit and we clearly need to look for other ways to improve outcome."
Dr. Kang disclosed no conflicts of interest. Dr. Ilson reported receiving research funding from sanofi-aventis, Genentech, and Bristol-Myers Squibb/Imclone.
Primary source: American Society of Clinical Oncology meetingSource reference:Kang Y-K, et al "Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer: A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short- term doxifluridine (Mf) (AMC 0101) (NCT00296322)" ASCO meeting 2008; Abstract LBA4511.