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Sugarbaker. J Cancer Metastasis Treat 2018;4:7 I http://dx.doi.org/10.20517/2394-4722.2017.67 Page 11 of 16

with a median survival of 18.0 vs.17.4 months, respectively. If patients did not receive an operation, median
survival was similar for primary and recurrent disease as well, 9.6 vs. 8.2 months, respectively.

Another effort to use neoadjuvant intraperitoneal chemotherapy to control peritoneal metastases prior
[59]
to gastrectomy was presented by Kitayama et al. . They used a combination of intraperitoneal and
intravenous paclitaxel along with S-1. Repeated laparoscopy was performed to assess response and
gastrectomy was used selectively on patients who showed shrinkage of their peritoneal nodules as well as
negative peritoneal cytology at a repeat laparoscopy. After a median number of chemotherapy cycles of 5,
gastrectomy was performed in 34 of the 64 patients. Sixty-five percent of these patients had an R0 resection.
Median survival time and 1-year overall survival of the gastrectomized patients was 26.4 months and 82%,
respectively. Those 30 patients who did not receive gastrectomy had a median survival of 12.1 months
[59]
and a 26% 1-year survival. Kitayama et al. concluded that salvage gastrectomy after intravenous and
intraperitoneal paclitaxel was promising even for patients with gastric cancer and peritoneal metastases with
ascites.

[60]
Fujiwara et al. reported on 18 patients with primary gastric cancer and peritoneal metastases treated with
NIPS. After combined intraperitoneal and systemic chemotherapy, 14 patients showed negative peritoneal
cytology and no macroscopic peritoneal metastases. The median survival time of his entire group was 24.6
months and there was no treatment-related mortality.

Neoadjuvant systemic chemotherapy vs. NIPS to date
Clinical trials comparing the beneficial effects of systemic chemotherapy using modern regimens versus
NIPS chemotherapy have not occurred. No doubt, in both treatments, those patients who have a resolution
of their peritoneal metastases and then go on to have a successful R0 gastrectomy have a superior outcome.
[61]
Al-Batran et al. used neoadjuvant systemic chemotherapy followed by surgical resection in patients with
limited metastatic gastric or gastroesophageal junction cancer. A small number (4 of 60, 6.7%) had peritoneal
metastases as an isolated site of metastatic disease. Nevertheless, the strategy of neoadjuvant systemic
chemotherapy prior to resection of all clinical evidence of disease was similar to the NIPS strategy. In their
arm B, 36 of 60 (60%) of patients proceeded to surgery. Overall survival of the patients who proceeded to
surgery was 31.3 months and 15.9 months for the other patients. These results are similar to the benefits of
NIPS followed by cytoreductive surgery. Comparative studies at some time in the future are indicated.

Adverse events from NIPS and cytoreductive surgery
The adverse events related to combined therapies NIPS, cytoreductive surgery and then HIPEC may be
less than that anticipated for a complex treatment that requires up to 6 months for completion. Problems
with the intraperitoneal port are much less than in prior reports of long-term intraperitoneal chemotherapy
[62]
for ovarian cancer . In this report there were many catheter-related complications, most of which were
caused by the extensive peritoneal adhesions. The intraperitoneal ports were placed after a major surgical
intervention and only 42% of patients completed all 6 cycles of intraperitoneal chemotherapy. In contrast,
catheter-related complications were rare in patients having NIPES because the ports were placed prior to any
surgical intervention. Adverse effects grade 3 and 4 were reported in 9% of patients in the multi-institutional
[63]
study reported by Yonemura et al. in 2012. All of these side effects were from chemotherapy and not
catheter-related.

[58]
In the 194 patients reported by Canbay et al. in 2014, the most common chemotherapy-related grade 3
or 4 adverse events were bone marrow suppression and diarrhea. Bone marrow suppression occurred after
3 courses in 3 patients, after 5 courses in 3 patients, and after 6 courses in 4 patients. Less common adverse
events were port site infection (n = 2) and renal failure (n = 1).

Prior reports of extensive cytoreductive surgery plus HIPEC following multiple cycles of intraoperative
[64]
chemotherapy showed an increased morbidity primarily a result of fistula . In the multi-institution report