To our knowledge, this is the third report of conversion surgery for advanced GC after nivolumab as third-line chemotherapy [3, 4].
Patients with para-aortic lymph node and peritoneal metastases are considered unresectable, and the survival of these patients is poor [5]. However, some studies showed the efficacy of conversion surgery for advanced GC [6,7,8]. Fukuchi et al. [7] reported that the presence of just one noncurative factor and R0 conversion resection were significant independent predictors of good overall survival. Kinoshita et al. [8] reported that the 3-year overall survival rate of patients with a single incurable factor was significantly longer than for patients with multiple factors. Our patient had a single incurable factor, para-aortic lymph-node metastasis, and because of the efficacy of nivolumab, we judged that complete resection was possible; therefore, we performed conversion surgery. As for the timing of conversion surgery, we did not reach a consensus; however, Zurleni et al. [1] stated that conversion surgery should be performed to render unresectable factors controllable until chemotherapy resistance. Based on this, the timing of the conversion surgery was reasonable.
Previously, third-line chemotherapy was not expected to resolve unresectable factors for advanced GC patients and most conversion surgeries. However, we succeeded in this regard in two cases of conversion surgery after nivolumab as third-line chemotherapy, including the current case. The second case was a 75-year-old man with advanced gastric antrum cancer with peritoneal metastasis. Peritoneal metastasis was resolved after 23 courses of nivolumab, and he successfully underwent distal gastrectomy with D1+ dissection (R0 resection). No lymph-node or peritoneal metastasis was observed in resected specimens [3]; thus, nivolumab demonstrated high efficacy. Namikawa et al. [9] noted that progression-free survival in advanced GC patients with immune-related adverse events (irAEs) was significantly longer than that of patients without irAEs (5.8 months vs. 1.2 months, respectively; P = 0.028). Matsuda et al. [10] showed that the absence of irAEs (hazard ratio (HR) = 9.54, 95% confidence interval (CI) 3.34–27.30 for yes vs. no) was associated with a poor prognosis in GC patients. Our two cases experienced unique adverse events of Grade 1 chylous ascites in the first case and Grade 1 rash and Grade 2 adrenal dysfunction in the second case. It is difficult to diagnose irAEs; however, unique phenomena appearing during nivolumab therapy may be an indication of therapeutic effect.
Certainly, we must discuss the validity of extended resection. Intraoperatively, the primary tumor was thought to have invaded the pancreas, spleen, and transverse colon. However, only a small histological section showed carcinoma (pT1b (SM)) (Figs. 3a, 4a), and other parts that were considered invasion in the gastric body were actually necrosis and fibrosis (Fig. 4b, c). Additionally, no carcinoma cells were observed in the pancreas histologically, and necrosis and fibrosis occupied a large area (Fig. 4d). The therapeutic effect was Grade 2b; however, it is difficult to distinguish carcinoma invasion or adhesion intraoperatively. Furthermore, peeling and dissection to remove the tumor are not recommended to achieve R0 resection; therefore, we were unable to avoid combined resection of the distal pancreas, spleen, and transverse colon. As a result, grade IIIa pancreatic fistula and anastomotic leakage occurred postoperatively. Complications after curative surgery have a negative impact on the prognosis of gastric cancer patients [11]. Kinoshita et al. [8] reported that 11% of patients who underwent conversion gastrectomy after combined docetaxel and cisplatin, and tegafur, gimeracil, and oteracil potassium therapy developed grade IIIa complications after surgery. Aside from neoadjuvant chemotherapy, several studies demonstrated that the number of resected organs is associated with poor prognosis [12,13,14]. However, Fabio et al. stated that it is not the number of resected organs but the completeness of resection that is the strongest prognostic factor [15]. Similarly, the risk factors for extended surgery are not clear, but extended conversion surgery requiring two or more organ resections should be carefully considered.
No signs of recurrence were observed 7 months after surgery. A consensus has not been established for cases in which the para-aortic lymph nodes have re-swollen; however, we will re-administer nivolumab. Surgery for para-aortic lymph nodes is difficult because of adhesion after postoperative inflammation, and complications other than resistance to nivolumab were not observed.