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Page 2 of 16 Sugarbaker. J Cancer Metastasis Treat 2018;4:7 I http://dx.doi.org/10.20517/2394-4722.2017.67

INTRODUCTION
[1,2]
Gastric cancer is the fourth most common cancer in the world with a 5-year survival rate of 25% . In
follow-up, a large percentage of gastric cancer patients will develop peritoneal dissemination (up to 40%)
[3-5]
which results in a less than 5% 5-year survival rate . In primary gastric cancer, peritoneal metastases are
[6]
a common finding present in 5%-20% of patients undergoing gastrectomy . The peritoneum is the most
[7]
common location of first recurrence in about half of patients . Although the standard of care for treatment
of primary gastric cancer involves surgery, intravenous chemotherapy and radiotherapy, specific treatments
for peritoneal metastases are poorly defined. Possible treatments include neoadjuvant systemic chemotherapy
(NAC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), cytoreductive surgery (CRS) and
perioperative chemotherapy which may include hyperthermic intraperitoneal chemotherapy (HIPEC) and/
[8]
or early postoperative intraperitoneal chemotherapy (EPIC) . CRS and HIPEC/EPIC is already considered
standard of care for selected patients with appendiceal peritoneal metastases, peritoneal mesothelioma,
and a limited extent of peritoneal metastases from colorectal carcinomatosis [9-11] . For gastric cancer with
peritoneal metastases, current treatment recommendations remain controversial. The following is an attempt
to summarize the role and efficacy of NAC, NIPS, CRS and HIPEC and/or EPIC as prevention or treatment
for peritoneal metastases of gastric cancer.

PREVENTION OF PERITONEAL METASTASES USING PERIOPERATIVE INTRAPERITONEAL
CHEMOTHERAPY
Surgical treatment failure with resection site and intraabdominal tumors are the most common sites of first
recurrence in gastric cancer after potentially curative resection [12-14] . Regardless of neoadjuvant chemotherapy
[15]
or postoperative adjuvant treatment, this local-regional progression occurs . The peritoneal surfaces and
liver remain the major sites of recurrence with a reduced local progression when extended lymphadenectomy
as compared to limited surgery is used [16-18] .

Although confined to the abdomen, peritoneal seeding has an adverse impact on survival [19-22] . Sources of
recurrence after curative resection are (1) spontaneous spreading from the primary tumor; and (2) surgical
trauma causing scattering of cancer cells during the surgical procedure. If serosal surface invasion has
occurred within the primary tumor, then spontaneous dissemination is more common and patients are
frequently found to have viable intraperitoneal cancer cells (positive cytology) [19,21-23] . Tumor cells can also
seed the intraabdominal cavity during surgery according to the tumor cell entrapment hypothesis [Figure 1].
During cancer resection, there is transection of lymphatic channels, close margins of resection, and tumor-
[24]
contaminated blood spillage. Marutsuka et al. identified free cancer cells in peritoneal lavage samples
in patients’ initial cytology negative approximately 70 min after dissection of lymph node metastases.
[25]
Takebayashi et al. showed that gastrectomy spilled viable cancer cells into the peritoneal space in 24 of
[26]
57 patients. They concluded that surgery induces peritoneal metastases. Arita et al. determined that large
amounts of intraoperative hemorrhage increased the risk of peritoneal recurrence. This may support the
contention that cancer cells are present in large numbers within blood lost from the gastric cancer specimen.
These iatrogenically disseminated tumor cells adhere spontaneously within minutes and vascularization is
facilitated by fibrin entrapment and the wound healing process. Cytokines, such as growth factors important
for wound healing, may also propel tumor progression. The tumor cell entrapment hypothesis explains part
of the pathogenesis of resection site and distant peritoneal metastases. It is the theoretical basis for adjuvant
[27]
perioperative intraperitoneal chemotherapy .
Perioperative timing of intraperitoneal chemotherapy
The tumor cell entrapment hypothesis suggests that intraperitoneal chemotherapy must be administered
perioperatively in order to access the tumor cells prior to entrapment within fibrin and conversion into
cancer implants within adhesive scar tissue. If intraperitoneal chemotherapy is delayed until after the
formation of adhesive scars, it will have uneven distribution and lack direct contact with viable cancer cells.