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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
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