Cytoreduction/HIPEC in Gastric Cancer: Who benefits, and when to consider it?

by Valerie Francescutti, MD, FRCSC
Assistant Professor of Oncology

and

Joseph Skitzki, MD, FACS
Assistant Professor of Oncology

Gastric adenocarcinoma commonly spreads through carcinomatosis or peritoneal metastases (PM). This was often discovered at the time of attempted curative gastric resection, given the poor ability of preoperative staging CT scans to detect the presence and extent of PM. In patients where visible PMs are absent, diagnostic laparoscopy with peritoneal lavage and cytology has been shown to be an effective method of noting free intraperitoneal tumor cells. This is also defined as M1 disease and is generally associated with T3 or T4 primary gastric cancers.

The overall mortality rate from gastric adenocarcinoma is high, with 60% of deaths associated with PM. For patients undergoing an R0 gastric resection, the recurrence rate with PM is estimated to be 30%. Despite the effectiveness of combination systemic chemotherapies given neoadjuvantly or adjuvantly, the peritoneum still represents a difficult site to treat, given the poor penetration of these agents and the propensity of gastric adenocarcinoma to recur in the peritoneum.

The current literature for the use of HIPEC for gastric PM has significant variation related to patient selection (gross PM vs. positive peritoneal cytology), treatment intent (palliative vs. attempt at curative treatment), surgical technique, intraperitoneal chemotherapy agent utilized, and systemic chemotherapy administered adjuvantly. A large meta-analysis of randomized clinical trials for gastric cancer patients with PM treated with HIPEC identified 20 trials, many representing Asian patients. A total of 2145 patients were evaluated, with overall three-year survival rate favoring the surgery and HIPEC combination group (OR 0.29). This did not hold true at five-year overall survival. Considering operative morbidity and mortality, this study indicated an increase in surgical morbidity for patients undergoing gastric resection and HIPEC compared with gastric resection alone (OR 1.82).

From the perspective of patient selection for cytoreduction and HIPEC, similar to other disease sites, the ability to completely cytoreduce a patient is important to consider, and thus patients with extensive PM are not candidates. In addition, unresectable location of PM, such as in the porta hepatis or extensive small bowel serosal PM, would make a patient a poor candidate for cytoreduction and HIPEC. Optimally, those with positive peritoneal cytology alone could benefit most. Patients who manifest hematogenous metastases, such as liver or distant nodal metastatic disease, are also unlikely to benefit. Careful clinical evaluation of the patient's performance and nutritional status are also key in ensuring good survival and surgical outcomes. In terms of timing, HIPEC would optimally be used at the time of gastric resection with lymphadenectomy to eradicate all macroscopic and microscopic tumor cells.

As large prospective randomized trials are lacking in Western patients, the GASTRICHIP trial is being undertaken in France. Over 300 patients will be randomized intraoperatively to receive gastric resection with or without HIPEC, with a primary outcome of five-year survival. Intraperitoneal oxaliplatin will be provided in a standardized fashion. In addition to survival outcomes, quality of life outcomes will also be evaluated. This study will assist in clarifying the role of HIPEC in gastric cancer.

References:

Bryan, R., Cruickshank, N., Needham, S., Moffitt, D., Young, J., Hallissey, M., & Fielding, J. 2001. Laparoscopic peritoneal lavage in staging gastric and oesophageal cancer. European Journal of Surgical Oncology, 27(3), 291.

Coccolini F, Cotte E, Glehen O, Lotti M, Poiasina E, Catena F, Yonemura Y, Ansaloni L. 2014. Intraperitoneal chemotherapy in advanced gastric cancer: meta-analysis of randomized trials. Eur J Surg Oncol. 40(1): 12-26.

Ribeiro, U., Gama-Rodrigues, J., Safatle-Ribeiro, A., Bitelman, B., Ibrahim, R., Ferreira, M., . . . Pinotti, H. 1998. Prognostic significance of intraperitoneal free cancer cells obtained by laparoscopic peritoneal lavage in patients with gastric cancer. Journal of Gastrointestinal Surgery, 2(3), 244.