A Phase II Trial of Cytoreduction, Gastrectomy, and Hyperthermic Intraperitoneal Perfusion with Chemotherapy for Patients with Gastric Cancer and Carcinomatosis or Positive Cytology.

BACKGROUND: Current national guidelines do not include hyperthermic intraperitoneal chemoperfusion (HIPEC) as treatment for gastric cancer, and there are no completed clinical trials of cytoreduction, gastrectomy, and HIPEC from the US. METHODS: Patients with gastric adenocarcinoma and positive peritoneal cytology or carcinomatosis who had completed systemic chemotherapy and laparoscopic HIPEC underwent cytoreduction, gastrectomy, and HIPEC with 30 mg mitomycin C and 200 mg cisplatin. The primary endpoint was overall survival (OS), with a secondary endpoint of postoperative complications (NCT02891447). RESULTS: We enrolled 20 patients from September 2016 to March 2019. Six patients had positive cytology only and 14 had carcinomatosis. All patients were treated with systemic chemotherapy with a median of eight cycles (range 5-11 cycles) and at least one laparoscopic HIPEC. The median peritoneal carcinomatosis index at cytoreduction/gastrectomy/HIPEC was 2 (range 0-13). After surgery, the 90-day morbidity and mortality rates were 70% and 0%, respectively. Median length of hospital stay was 13 days (range 7-23 days); median follow-up was 33.5 months; median OS from the date of diagnosis of metastatic disease was 24.2 months; and median OS from the date of cytoreduction, gastrectomy, and HIPEC was 16.1 months. 1-, 2-, and 3-year OS rates from the diagnosis of metastatic disease were 90%, 50%, and 28%, respectively. CONCLUSIONS: Survival rates for patients with gastric adenocarcinoma and peritoneal disease treated with cytoreduction, gastrectomy, and HIPEC are encouraging; our early results are similar to those of recent prospective registry studies. Multi-institutional and cooperative group trials should be supported to confirm survival and safety outcomes.

Phase I Trial of Hyperthermic Intraperitoneal Chemoperfusion (HIPEC) with Cisplatin, Mitomycin, and Paclitaxel in Patients with Gastric Adenocarcinoma and Associated Carcinomatosis or Positive Cytology.

BACKGROUND: The purpose of this phase I trial is to evaluate the safety and toxicity of laparoscopic hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC), combining mitomycin, cisplatin, and paclitaxel for patients with gastric cancer metastatic to the peritoneum. PATIENTS AND METHODS: A Bayesian optimal interval design was used to prospectively identify the safety and tolerability of escalating doses of paclitaxel in combination with flat doses of mitomycin (30 mg) and cisplatin (200 mg) during laparoscopic HIPEC. The primary objective is to define the maximum tolerated dose. Secondary endpoints include surgical complications and overall survival (OS). RESULTS: A total of 27 patients were treated between 11/2017 and 11/2018. No dose-limiting toxicities were observed. Treatment-related grade 1-2 toxicities were leukopenia (11%), oral dysesthesia (4%), arthralgia (4%), and diarrhea (4%). Treatment-related grade 3-4 toxicities included leukopenia (4%) and neutropenia (4%). The maximum dose for paclitaxel was 60 mg/m2. Rates of Clavien-Dindo surgical complications were grade I 96% (all electrolyte deficiencies requiring replacement), II 4%, III 0%, IV 0%, and V 4%. The median follow-up time was 15 months. One- and 2-year OS rates from date of metastatic disease were 73.9% and 58.1%, respectively. CONCLUSIONS: Laparoscopic HIPEC with mitomycin, cisplatin, and paclitaxel may be safely used at intraperitoneal doses of 30 mg, 200 mg, and 60 mg/m2, respectively. Although electrolyte abnormalities were common, systemic toxicity was low. Survival rates were promising, supporting further research into intraperitoneal therapy for stage IV gastric cancer.

Laparoscopic Hyperthermic Intraperitoneal Chemotherapy is Safe for Patients with Peritoneal Metastases from Gastric Cancer and May Lead to Gastrectomy.

BACKGROUND: Laparoscopic hyperthermic intraperitoneal chemotherapy (LS-HIPEC) is a novel strategy for patients with gastric adenocarcinoma (GA) metastatic to the peritoneum. We evaluated the safety profile of LS-HIPEC for patients with positive peritoneal cytology (PPC) or carcinomatosis from GA. METHODS: Outcomes were reviewed of patients with stage IV GA with peritoneal involvement who received LS-HIPEC from June 2014 to January 2017. LS-HIPEC included a 60-minute perfusion of mitomycin-C (30 mg) and cisplatin (200 mg) with inflow temperatures of 41-42 °C and outflow temperatures of 39-40 °C. RESULTS: A total of 71 LS-HIPEC procedures were performed in 44 patients. At diagnosis, 68% (n = 30) had carcinomatosis and 32% (n = 14) had isolated PPC. Three patients (7%) underwent LS-HIPEC for intractable ascites. All patients initially received systemic chemotherapy, and 20 patients (45%) received pre-procedural chemoradiotherapy. The median number of LS-HIPEC procedures performed per patient was one (range 1-5 procedures). There were no conversions to laparotomy, two outflow catheter obstructions, and one major (Clavien-Dindo grade III) surgical complication within 30 days. A total of seven postoperative adverse hematologic events (> CTCAE 2) were observed in five patients (11%), without any major renal or gastrointestinal adverse events within 30 days. The median overall length of hospital stay after LS-HIPEC was 2 (range 2-11) days. Eleven patients (25%) underwent secondary gastrectomy following resolution of peritoneal cytology. CONCLUSIONS: Laparoscopic HIPEC is a safe procedure and may be repeated in patients with peritoneal metastases from gastric cancer. Future studies are required to determine the optimal HIPEC regimen and timing relative to systemic therapy to best minimize morbidity.

Lessons learned from a phase II clinical trial of laparoscopic HIPEC for gastric cancer.

BACKGROUND: Over the last two decades, intraperitoneal chemotherapy has been found to have activity for select subgroups of patients with carcinomatosis from colon, ovarian, appendiceal, and recently, gastric origins. However, there is little data to support an aggressive surgical approach of cytoreduction (debulking) and hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC) for patients with gastric cancer and positive cytology or carcinomatosis. The morbidity and mortality rates of cytoreduction and HIPEC, in combination with gastrectomy, are significant and the survival rates of this approach may not extend beyond that of treatment with systemic chemotherapy. The objective of this clinical trial, therefore, was to perform HIPEC in a neoadjuvant fashion via a minimally invasive approach without cytoreduction for patients with gastric cancer and positive cytology or low volume carcinomatosis. Patients found to have resolution of all extra-gastric disease are then candidates for gastrectomy. METHODS: Patients with gastric and gastroesophageal adenocarcinoma and positive peritoneal cytology or radiologically-occult carcinomatosis that have completed treatment with systemic chemotherapy were offered participation in the study. RESULTS: We have performed 38 laparoscopic HIPEC procedures in 19 patients. Laparoscopic HIPEC consists of Mitomycin C 30 mg and Cisplatin 200 mg in 3-7 L of infusate circulated using an extracorporeal circulation device at a flow rate of 700-1500 mL/minute for 60 min. The Laparoscopic HIPEC procedure may be performed up to five times. In this video, we sought to present the surgical technique refined during our development and completion of this Phase II clinical trial (NCT02092298). CONCLUSION: The purpose of this presentation is to (1) demonstrate the technique of laparoscopic HIPEC and (2) review the surgical lessons learned from performing multiple HIPEC procedures prior to attempted gastrectomy.

Phase II Trial of Laparoscopic Hyperthermic Intraperitoneal Chemoperfusion for Peritoneal Carcinomatosis or Positive Peritoneal Cytology in Patients with Gastric Adenocarcinoma.

PURPOSE: The aim of this phase II study was to perform neoadjuvant hyperthermic intraperitoneal chemoperfusion (HIPEC) via a minimally invasive approach without cytoreduction for patients with gastric cancer and positive peritoneal cytology or low-volume peritoneal carcinomatosis. METHODS: Patients with gastric or gastroesophageal adenocarcinoma and positive peritoneal cytology or radiologically occult peritoneal carcinomatosis after systemic chemotherapy received laparoscopic HIPEC with mitomycin C 30 mg and cisplatin 200 mg. Patients whose peritoneal disease resolved were offered gastrectomy. The primary endpoint was overall survival (OS), with secondary endpoints of HIPEC complications and gastrectomy rate. RESULTS: We enrolled 19 patients (6 with positive peritoneal cytology only and 13 with peritoneal carcinomatosis) and treated them with 38 laparoscopic HIPEC procedures. Patients had received a median of 8 cycles (range 3-12) of systemic chemotherapy prior to enrollment. Fourteen patients were also treated with chemoradiotherapy before or between cycles of HIPEC. The complication rate for HIPEC was 11% (4 of 38 procedures), the 30-day mortality rate was 0%, and the median length of hospital stay after HIPEC was 3 days (range 2-6). Five patients went on to receive gastrectomy. The median follow-up was 18.9 months, the median OS from the date of diagnosis of metastatic disease was 30.2 months, and the median OS from the first laparoscopic HIPEC was 20.3 months. CONCLUSIONS: Laparoscopic HIPEC was well tolerated, and an encouraging number of patients demonstrated an absence of peritoneal disease after HIPEC and were able to undergo gastrectomy. Comparative studies will be required to clarify survival benefits.

Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy.

BACKGROUND: The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN: The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS: Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age ≥ 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS: Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS.