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The use of postoperative intraperitoneal chemotherapy has been evaluated based on the pharmacokinetic advantage of intraperitoneal chemotherapy and the finding that many patients relapse in the peritoneum after surgical resection. A variety of phase II and III trials have been performed.
Building on early promising results from phase II trials, several phase III studies have evaluated the role of intraoperative or postoperative intraperitoneal therapy in patients undergoing potentially curative surgery. In an early study by Dixon and colleagues, patients were randomly assigned to surgery alone or to surgery followed by intraperitoneal thiotepa.137 No significant difference in survival was seen between the two groups. In a more recent study, Sautner and associates examined the use of postoperative intraperitoneal cisplatin compared with surgery alone in a group of 67 patients.164 Although the primary lesion was resected in each case, 21% of the individuals had localized peritoneal carcinomatosis. No survival benefit was seen for the treated patients.
In a phase III trial from Japan, 113 patients were randomly assigned to surgery alone or intraoperative mitomycin C at the time of surgery.165 For patients who underwent curative surgery, intraperitoneal therapy led to a significant improvement in 2- and 3-year OS. No difference in survival was seen for patients with macroscopic peritoneal carcinomatosis. In a separate trial from Japan, 88 patients with peritoneal cytology-positive lavage fluid, but without macroscopic peritoneal metastases, were randomly assigned in the operating room to surgery alone, surgery plus intraoperative peritoneal chemotherapy, or a combination of surgery, intraoperative peritoneal therapy, and “extensive intraoperative peritoneal lavage.”166 The 5-year OS was 43.8% for the extensive intraoperative peritoneal lavage group, compared with 4.6% for those receiving only intraoperative chemotherapy and 0% for those receiving only surgery.
In a single-institution phase III trial from Korea, 248 patients with clinical stage II or III gastric cancer were randomly assigned to surgery alone or to receive intraperitoneal mitomycin C on day 1 and intraperitoneal 5-FU on days 2 to 5.167 Overall, 110 of the 248 patients had either stage I or stage IV disease. When 5-year OS was calculated for the entire group, benefit to adjuvant therapy was seen (P = 0.0278). In a subset analysis, however, the benefit was limited to patients with stage III or IV disease.
Given the small size of most trials of adjuvant intraperitoneal therapy, a meta-analysis was performed.168 Ten of the 13 trials included in the meta-analysis were deemed to be of “fair” quality and 3 to be of “poor” quality. With these recognized limitations, the use of hyperthermic intraoperative intraperitoneal chemotherapy was associated with an improved OS.
Preoperative Systemic and Postoperative Intraperitoneal Chemotherapy
Other investigators have examined the usefulness of combining preoperative chemotherapy and postoperative treatment with intraperitoneal chemotherapy in view of the high peritoneal failure rate following resection of gastric cancer. Initial attempts to use intraperitoneal chemotherapy alone in the adjuvant setting did not show benefit.164,165,167,169-172
Kelsen and associates studied 56 patients with high-risk (clinical stage T3–4) gastric cancer as determined by EUS.171 Patients received three cycles of neoadjuvant FAMTX. Following surgery, patients were treated with intraperitoneal 5-FU and cisplatin along with infusional 5-FU for three cycles. Fifty (89%) patients were explored and 34 (61%) resected for cure. When the initial EUS result was compared to the final pathological staging, 51% of these patients were downstaged. No complete pathological responses were observed, and the median survival was 15.3 months.
Crookes and colleagues updated their promising results with a somewhat similar trial design.169 Fifty-nine patients with potentially resectable cancer received two cycles of 5-FU, leucovorin, and cisplatin preoperatively, and two cycles of intraperitoneal 5-FUDR and cisplatin were given postoperatively to resected patients. Ninety-five percent of the patients underwent exploration, and 68% had a curative resection. The rate of pathological CR was only 9%, but the median survival is estimated to be an impressive 52 months.
In a more recent phase II trial, 32 evaluable patients with locally advanced but potentially resectable stomach cancer received two cycles of systemic cisplatin and irinotecan.172 Twenty-nine patients were able to undergo surgery, and 25 had an R0 resection. Patients with resection subsequently received two cycles of intraperitoneal FUDR and cisplatin. Preoperative chemotherapy led to downstaging in 50% of the patients. With a median follow-up of 28 months, 10 (31%) were alive without relapse, 4 (13%) were alive with relapse, and the remainder had died from either disease (41%) or other causes (16%). Of the 25 patients with an R0 resection, none had a local relapse. A phase III trial of this approach has not yet been reported.
Summary of Intraperitoneal Chemotherapy
The use of intraperitoneal therapy in the adjuvant setting remains investigational and requires further evaluation. Until further appropriately designed, prospective clinical trials show clear benefit to this approach, the use of intraperitoneal therapy should be restricted to controlled clinical trials.