Neoadjuvant Therapy Is Promising for Locally Advanced Gastric Cancer

NEW YORK-A new regimen combining intravenous (IV) cisplatin (Platinol) and irinotecan (CPT-11, Camptosar) given before surgery and intraperitoneal (IP) floxuridine (FUDR)/cisplatin after surgery produced promising responses in locally advanced gastric cancer. Howard Hochster, MD, of New York University School of Medicine, presented these findings at the 6th University of Texas M. D. Anderson Cancer Center Investigators' Workshop. Irinotecan/cisplatin induction chemotherapy (Figure 1) was of interest because previous studies showed neoadjuvant therapy can be delivered in this setting and can induce tumor downstaging, improve "R0" resectability rates, and identify patients with subclinical metastases. The IP adjuvant approach is attractive for preventing local recurrence because it provides direct treatment at high-risk sites, produces higher drug concentrations, provides longer contact between the drug and the tumor cell, and allows for treatment of liver metastases caused by portal absorption. "The background for this trial is that the majority of phase III trials have shown no significant survival benefit," Dr. Hochster said. "The Intergroup 0116 study was the first large phase III trial to show survival benefit with adjuvant chemoradiation, and only patients with curative 'R0' resections were eligible. Three-year disease-free survival was 48% vs 31%, and median survival was 36 vs 27 months, for a 35% risk reduction in survival." Acceptable Toxicity Endpoints for the NYU study of 34 patients with biopsy-proven locally advanced gastric cancer were response (pretreatment clinical vs postoperative pathologic), disease-free survival (including analysis of sites of recurrence), and overall survival. Ability to deliver the planned dose is often an issue in this type of trial. A total of 86% received the planned dose of irinotecan (600 mg/m²), and 78% received the planned dose of cisplatin (200 mg/m²). "These patients were somewhat malnourished and presented a treatment challenge to begin with, but we did manage to get in approximately 80% of both drugs as planned," reported Dr. Hochster. Nearly all of the 32 evaluable patients had some type of grade 3/4 hematologic toxicity after induction chemotherapy. Thirteen patients had grade 3 neutropenia, and three patients had grade 4 neutropenia, but there were only four cases of grade 3/4 febrile neutropenia. Catheter complications were a problem in 24 patients. They included one case of peritonitis, one instance in which the catheter broke, and one infection at the port site. A total of 29 patients underwent surgical resection, and 25 had complete clearing with a negative surgical margin (R0). The median number of lymph nodes removed was 28. During the 30 days after surgery, 2 patients died, and 10 patients had complications, including three reoperations, one anastomotic leak, four cardiac or respiratory problems, and five wound problems. The median postoperative length of stay was 9 days. Pathologic Response There were 1 pathologic complete response (CR) to induction chemotherapy; 18 partial responses (PR), many of which were microscopic residual disease; 6 cases of stable disease (SD); and 7 cases of disease progression. Dr. Hochster concluded that irinotecan- based neoadjuvant therapy and postoperative IP therapy could be delivered safely and with acceptable toxicity in this patient population. No increase in surgical morbidity was seen in the postchemotherapy gastric resections, and 85% of patients achieved an R0 curative resection. "Pathologic response was a bit disappointing to us," Dr. Hochster admitted. "We saw evidence of downstaging, mostly of the primary tumor, in over 50% of patients, but most patients still had microscopic nodal involvement."

Sixteen patients remain with no evidence of disease at a median follow- up of 15.9 months, three patients are alive with disease, and three died of other causes. The main sites of recurrence have been intra-abdominal, including the liver (five patients) and distant metastases (five patients). There have been no local recurrences. Mean overall survival is 37.5 months, at a mean follow-up of 28 months in surviving patients. "Preliminary survival data are encouraging, and at present, median survival is comparable to that in the treatment arm of INT 0116," Dr. Hochster said. Longer follow-up is needed to determine the ultimate impact. This study raises two specific questions: First, should neoadjuvant therapy be used routinely in the treatment of patients with gastric cancer? Second, would results with IP therapy equal those of radiotherapy in the adjuvant setting? Further study is required to answer these questions, Dr. Hochster concluded.