Because the aging society is imminent in many countries, reliable prognostic factors for elderly patients with cancer are needed to provide optimal treatment strategies. The present study evaluated the prognostic impacts of WBC and CRP as markers of the preoperative inflammatory status and postoperative inflammatory response caused by surgical stress and infectious complications, which are most commonly used in daily perioperative management, in 193 elderly patients with gastric cancer. We found that high pre-CRP and high WBCmax after radical gastrectomy were independent prognostic factors for OS. Furthermore, PIS as a combined prognostic index based on pre-CRP and WBCmax provided superior prognostic value than either pre-CRP or WBCmax alone. Our results suggested that perioperative inflammatory status is strongly associated with long-term outcomes after curative resection in elderly patients with gastric cancer.
In the present study, pre-CRP was an independent prognostic factor for OS in the elderly patients with gastric cancer. Consistent with our results, previous studies have demonstrated that preoperative elevated CRP is associated with worse long-term outcomes in various malignancies, including gastric cancer [4, 5, 15]. However, the exact mechanisms underlying the association between high pre-CRP and worse prognosis have not yet been clarified. CRP is a well-known acute-phase protein mainly secreted by hepatocytes in response to inflammation caused by tissue damage and infection [16]. Several studies have reported that higher levels of CRP are associated with increased risks of all-cause mortality in the general population [17–19], suggesting that higher levels of inflammatory status could worsen prognosis in humans. In cancer patients, preoperative CRP level could be elevated by tumor progression, and previous studies have revealed that high levels of CRP were associated with advanced disease in various types of cancer [20]. Consistent with previous studies, our results demonstrated that high pre-CRP tended to be associated with advanced tumor stage, although no statistical significance was found (Table 3). In the present study, multivariate analysis revealed pre-CRP and pathological stage as independent prognostic factors for OS, suggesting that pre-CRP may reflect the malignant aggressiveness of the tumor itself independent of pathological stage.
High postoperative WBCmax and CRPmax could be mainly caused by postoperative infectious complications and surgical stress. Recent studies have revealed that postoperative inflammatory response is involved in tumor recurrence and worsened prognosis in various types of cancer [8, 21, 22]. Two plausible explanations for the association between postoperative inflammatory response and worse prognosis are considered. One is that the cytokines and growth factors induced by the inflammatory response may promote the proliferation and metastasis of residual cancer cells; the other is that an elevated systemic inflammatory status may lead to worsened general condition and host immunosuppression resulting in a compromised immune response to residual cancer cells. In the present study, WBCmax, but not CRPmax, was an independent prognostic factor for OS in elderly patients with gastric cancer. Inconsistent with our results, Saito et al. and Kuroda et al. reported CRPmax, but not WBCmax, as an independent prognostic factor for RFS and OS in advanced gastric cancer [22, 23]. We have previously revealed WBCmax, but not CRPmax, as an independent prognostic factor for OS in stage I thoracic esophageal squamous cell carcinoma [7]. Such findings suggest that the potential prognostic inflammation markers identified may vary between study populations, although higher postoperative inflammatory response is associated with worse prognosis. Reducing surgical stress and proper perioperative management to prevent complications may be essential strategies for improving long-term outcomes in elderly patients who undergo curative gastrectomy.
In the present study, subgroup analysis according to the presence of infectious complications revealed that OS was significantly worse in the high-WBCmax group among patients without infectious complications, while no significant difference was seen among patients with infectious complications. This suggested that a greater degree of surgical stress has a negative impact on long-term outcomes in elderly patients with gastric cancer. Furthermore, another subgroup analysis according to age revealed OS as significantly worse in the high-WBCmax group among patients ≥ 80 years of age, while no significant difference was seen among patients < 80 years of age, suggesting that postoperative inflammatory response has a greater impact on prognosis in patients ≥80 years of age than in patients < 80 years of age. These findings indicate that decreasing surgical stress and prevention of infectious complications are important challenges to tackle for improving survival, particularly in very elderly patients who undergo curative gastrectomy.
We found that the PIS consisting of pre-CRP and WBCmax showed a higher AUC for OS than either pre-CRP or WBCmax alone and provided an independent prognostic factor in elderly patients with gastric cancer. A few studies have explored the prognostic impact of perioperative inflammatory status. Yamamoto et al. revealed that a combined index using pre-CRP and CRPmax was more useful for predicting disease-specific survival than either pre-CRP or CRPmax alone in colorectal cancer patients [10]. Lu et al. showed that the group with high values for both pre-CRP and CRPmax displayed the worst recurrence-free survival among gastric cancer patients [11]. Although those studies used CRPmax as a postoperative inflammation marker, higher perioperative inflammatory status was suggested to be associated with worse prognosis. Thus, our findings suggested that PIS, which represents perioperative inflammatory status, provides a reliable predictive indicator for OS, and has potential to help surgeons offer effective, individualized treatment.
Anti-inflammatory agents might have potential as candidates for perioperative adjuvant treatment for higher inflammatory status patients. For example, some antidiabetic drugs such as metformin and sitagliptin are known to have anti-inflammatory properties, and have been reported to significantly decrease CRP levels [24]. Statins are a group of medicines that can lower the serum cholesterol level, but also have anti-inflammatory properties, and statin therapy was reported to reduce CRP level at 30 days [25]. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and cyclooxygenase 2 inhibitors have been reported to prevent primary and secondary cancers in some large epidemiological studies, and to inhibit proliferation and promote apoptosis in a variety of tumor cells [26]. Further clinical studies are needed to implement anti-inflammatory agents for patients with high perioperative inflammatory status.
The present study has some limitations that warrant consideration. First, this was a retrospective study conducted at a single institution, which might have resulted in some selection biases. In addition, the sample size was relatively small because participants were limited to elderly patients. Second, the extent of lymphadenectomy and adjuvant chemotherapy were determined based on the subjective decisions of the attending physician in consideration of the patient’s general condition, rather than any objective indicators. In the present study, although the extent of lymphadenectomy tended to be lower compared with younger patients, no regional lymph node recurrences were observed. Within these limitations, the present study demonstrated that high pre-CRP and high WBCmax after radical gastrectomy were independent prognostic factors for OS, and PIS offered superior predictive value for OS in elderly patients with gastric cancer. Large-scale prospective studies are needed to validate our results.