The present study investigated correlations between postoperative systemic inflammatory response and prognosis in advanced gastric cancer patients who underwent curative resection, using the maximum postoperative CRP level and WBC count during hospitalization after gastrectomy as markers of systemic inflammation. We found that CRPmax with a cut-off of 9.2 mg/dL was an independent prognostic factor, but WBCmax was not. Further, CRPmax affected OS and RFS independent of postoperative infectious complications. These results suggest that systemic inflammatory response as represented by CRPmax in the early phase after surgery induced by surgical stress and complications is associated with recurrence and survival in patients with stage II/III gastric cancer.
This study revealed CRPmax as an independent prognostic indicator for OS and RFS in patients with stage II/III gastric cancer who underwent curative resection. Consistent with our results, previous studies have demonstrated that postoperative systemic inflammatory response correlated with recurrence and poor prognosis in gastroenterological cancers including gastric cancer,[11, 12, 16] esophageal cancer,[17, 18] and colorectal cancer.[19] However, the optimal marker remains uncertain. Because the magnitude of surgical stress and postoperative complications can differ markedly among cancers, optimal markers and the respective cut-off values should be determined for each cancer. Okumura et al. revealed postoperative prolonged hyperthermia, defined as a maximum body temperature > 38°C for ≥4 days, as an independent prognostic factor for OS and RFS in patients with stage II/III gastric cancer.[11] However, whether postoperative prolonged hyperthermia affected survival independent of the occurrence of postoperative infectious complications was unclear because postoperative complications were strongly associated with prolonged hyperthermia in that study. We evaluated WBCmax and CRPmax as markers that are not only commonly used to estimate the magnitude of inflammation in postoperative management, but also simple and readily available in daily clinical practice. Consequently, we found that CRPmax was an independent prognostic factor for OS and RFS, but WBCmax was not. Similarly, Saito et al[12]. demonstrated that postoperative CRPmax (≥ 12 mg/dL) was an independent prognostic factor for RFS in advanced gastric cancer, although postoperative WBCmax was not. Further, this finding was validated in their subsequent large-scale multicenter study.[16] Postoperative CRPmax could provide a useful marker to predict prognosis in patients with stage II/III gastric cancer who undergo curative resection.
Interestingly, the high-CRPmax group in the present study was significantly associated with hematogenous metastasis as the pattern of recurrence. Similar to our result, Kurokawa et al. reported that liver metastasis, but not peritoneal or lymph node metastasis, was significantly more frequent in the high-CRPmax (≥ 12 mg/dL) group than in the low-CRPmax group. Although the exact mechanisms underlying this association between higher postoperative inflammation and hematogenous metastasis remain unclear, some potential explanations can be considered. First, host immunosuppressive influences such as impairment of cellular immunity caused by the surgical stress could negatively impact on circulating tumor cells (CTCs) and micro-metastatic cancer cells. Although natural killer cells and macrophages play important roles in eliminating CTCs and preventing the formation of metastases, both the cytotoxicity of natural killer cells and macrophage function are reportedly impaired in proportion to the extent and magnitude of surgery.[20, 21] Extraperitoneal tumor growth was demonstrated to be accelerated accompanied by suppressed natural killer cell cytotoxicity after surgery.[22] Second, systemic inflammation could accelerate the adhesion of CTCs to distant organs. E-selectin up-regulation, induced by inflammatory cells and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, has been shown to promote recruitment of CTCs to the vascular endothelium.[23–25] Third, growth factors and cytokines such as TNF-α, vascular endothelial growth factor and IL-6 induced by the inflammatory response could promote the proliferation and metastasis of residual cancer cells.[26] Thus, not only optimizing surgical procedures, but also immunomodulatory approaches and anti-inflammatory approaches in the perioperative period might improve oncological outcomes.
In the present study, postoperative infectious complications were not an independent prognostic factor for OS and RFS, despite significant associations with those outcomes in univariate analyses. Some studies have demonstrated that postoperative complications correlate with prognosis in gastric cancer patients,[4, 5] whereas others have not.[27, 28] This inconsistency may be attributable to differences in the definition and frequency of postoperative complications among studies. Moreover, most studies did not enter postoperative inflammatory responses (including surgical stress) into multivariate analyses for survival. Our findings suggest that systemic inflammatory response induced by not only postoperative complications, but also surgical stress is more important than the actual postoperative complications as a prognostic factor in patients with advanced gastric cancer.
In the present study, because the 71 patients with postoperative infectious complications included only three patients with high-CRPmax, we evaluated another cut-off value of CRPmax for patients with postoperative infectious complications. Consequently, patients with postoperative infectious complications and a high-CRPmax of > 26.2 mg/dL revealed poorer OS than those with low-CRPmax ≤26.2 mg/dL. This finding suggests that the magnitude of systemic inflammatory response caused by infection could affect OS. When postoperative infectious complications occur, early diagnosis and appropriate treatment for infectious complications may be important to reduce systemic inflammatory response and improve long-term outcomes in patients with stage II/III gastric cancer.
From Japan, some important surgical randomized controlled trials for advanced gastric cancer have been reported by the Japan Clinical Oncology Group (JCOG). The JCOG9501 study compared D2 lymphadenectomy alone with D2 lymphadenectomy plus para-aortic nodal dissection for advanced gastric cancer without clinical para-aortic lymph node metastasis.[29] The JCOG0110 study compared spleen preservation with splenectomy for advanced proximal gastric cancer not involving the greater curvature[30]. The JCOG1001 study compared non-bursectomy with bursectomy for advanced gastric cancer with cT3 (SS)-cT4b (SI).[31] However, none of these studies demonstrated the prognostic efficacy of extended surgery. One reason why extended surgery uniformly failed to improve survival may be that the negative impact on residual cancer cells of the systemic inflammatory response involved in surgical stress and postoperative complications may offset any positive impact of extended surgery. Furthermore, the JCOG9502 study compared an abdominal-transhiatal approach with a left thoracoabdominal approach for advanced gastric cancer with esophageal invasion of ≤3 cm revealed worse survival in the left thoracoabdominal approach group.[32] In the JCOG9502 study, the rate of postoperative complications was higher in the left thoracoabdominal approach group and surgical stress was obviously larger in that same group. The impact of postoperative systemic inflammatory response induced by surgical stress and postoperative complications on survival may warrant more attention from general surgeons.
This study has some potential limitations that should be considered when interpreting the results. First, this retrospective study was conducted at a single institution. Second, the present study showed heterogeneity in the adjuvant chemotherapy regimens, because the indications for and standard regimens of adjuvant chemotherapy had not been established until 2007, when the results of the ACTS-GC trial confirmed the efficacy of S-1 as adjuvant chemotherapy for stage II/III gastric cancer.[33] However, in the subgroup analysis with or without adjuvant chemotherapy, OS rates were significantly lower in the high-CRPmax group than in the low-CRPmax group. Prospective large-scale validation studies are needed to confirm our findings.