Among peritoneal surface malignancy settings, in patients with peritoneal metastases from gastric cancer integrated therapies have unfortunately to date have achieved modest results. Despite numerous series using combined cytoreductive surgery (CRS) with intraperitoneal hyperthermic chemotherapy (HIPEC) preoperative neoadjuvant therapy has proved indispensable to downstage disease and increase the number of patients scheduled for radical surgery. In choosing the ideal neoadjuvant therapy for these patients approaches differ widely among Asian and Western authors. Whereas Western series invariably use systemic chemotherapy (SC) variously integrated with biologic drugs, Asian researchers, especially Japanese, have for many years undertaken a therapeutic neoadjuvant approach foreseeing intraperitoneal normothermic chemotherapy combined with SC and prepared with oral fluoro according to a scheme known under the acronym neoadjuvant intraperitoneal and systemic chemotherapy (NIPS). These two strategies, also owing to their geographically distant locations, have been hard to compare and even when compared problems concerning patient selection have made the results difficult to interpret. Our randomized control study intends to select two homogeneous groups of patients and thus test the efficacy of the two neoadjuvant approaches. The underlying rationale is that, apart from tolerability and adverse effects, by using a more aggressive approach (NIPS) we can increase the percentage of patients likely to benefit from radical surgery. Our multicenter randomized control trial will enroll 184 patients with PMs from GC (92 in each arm) having homogenous clinical pathological characteristics related to PM extent and spread, who will undergo SC or NIPS.
Peritoneal metastases (PMs) are one of the most debilitating yet common metastatic forms in GC. The median OS for untreated patients is 3-6 months [Chan DY. J Gastrointest Surg 2017;21:425-33]. Although new molecular targeting and chemotherapeutic agents have improved the prognosis for patients with PMs from GC their outcome is still unsatisfactory and peritoneal spread remains the greatest barrier for a better prognosis of Stage IV GC. The first to describe conversion surgery for GC were Nakajima et al in 1997 and various approaches for GC with PMs have been reported especially from East Asia, mainly Japan [Nakajima T. Ann Surg Oncol 1997;4:203-208; Kitayama J Ann Gastroenterol Surg 2018;2:116-123] including neoadjuvant intraperitoneal chemotherapy combined with intravenous SC defined as NIPS. A key point in all studies including those reported by Western authors is the need for neoadjuvant chemotherapy in these patients to reduce PMs before CRS and convert the positive peritoneal liquid cytology to negative. And even though Western researchers do not use the term conversion surgery, to justify a CRS procedure even combined with HIPEC in patients with macroscopic PMs one needs to treat patients with a low PCI after NACT, without no evident progressive disease. On this topic, a further enlightening contribution comes from German researchers in a large case series who show that CRS in patients with a PCI more than 15 leads to a median 5 months survival whereas a PCI = 6 leads to 18 months survival [Rau B. Gastric Cancer 2020;23:11-22]. The same researchers underline that NSC (used by them in 74% of the cases) is an indisputable requirement to obtain reasonably significant results in patients properly selected to undergo CRS combined with HIPEC. The crucial point is therefore to identify the neoadjuvant treatment that will give the surgeon the information needed to select for CRS those patients most likely to benefit from surgery. On this point, Asian researchers¿ approaches differ, the first to use NIPS were the Western researchers who exclusively used intravenous NSC. An RCT conducted in recent years, compared the two procedures [Ishigami H. JCO 2018;36:1922-1929] and the arm receiving NIPS had longer, though not significantly longer outcome, than the arm receiving NSC alone. A further report from Ishigami et al. assesses their trial¿s value even better [Ishigami H. JCO 2019;37:167-168]. The first noteworthy point, which closely concerns our objective in this study, is that conversion surgery was allowed in 46% of the NIPS arm but in only 22% in the NSC arm. And the same study showed that CRS improved outcome in both groups. We therefore conclude that rather than being a mere end in itself, conversion surgery can improve outcome. Hence the more patients we bring to surgery the better will be their outcome. A final observation emerges from the data analyzed in the two groups, given that the NIPS arm (for whom no initial PCI was identified) included significantly more patients with severe ascites, a criteria that nevertheless should have penalized that arm. Another controversial point is that in the NIPS arm Ishigami used taxol also by systemic infusion whereas Yonemura originally proposed cisplatin [Yonemura Y. Cancers 2020; 12:116]. In the RCT we propose here, for the NIPS arm we follow Yonemura¿s original scheme associating cisplatin with taxol. Another point that differs from previously published schemes is that we gave NIPS cycles also as adjuvant therapy, to cover as far as possible recurrence in the peritoneum, the most frequent recurrence site in patients with PMs from GC. The decision to conduct an RCT testing the efficacy of NIPS as neoadjuvant therapy rather than the NSC conventionally tested by western researchers is especially meaningful because it would help publicize this method outside the far east.