Effect of perioperative flurbiprofen axetil on long‐term survival of patients with esophageal carcinoma who underwent thoracoscopic esophagectomy: A retrospective study

Abstract Background and Objectives Nonsteroidal anti‐inflammatory drugs (NSAIDs) have an anti‐inflammatory response, but it remains unclear whether the perioperative use of flurbiprofen axetil can influence postoperative tumor recurrence and survival in esophageal carcinoma. We aimed to explore the effect of perioperative intravenous flurbiprofen axetil on recurrence‐free survival (RFS) and overall survival (OS) in patients with esophageal carcinoma who underwent thoracoscopic esophagectomy. Methods This retrospective study included patients who underwent surgery for esophageal carcinoma between December 2009 and May 2015 at the Department of Thoracic Surgery, Anhui Provincial Hospital. Patients were categorized into a non‐NSAIDs group (did not receive flurbiprofen axetil), single‐dose NSAIDs group (received a single dose of flurbiprofen axetil intravenously), and multiple‐dose NSAIDs group (received multiple doses of flurbiprofen). Results A total of 847 eligible patients were enrolled. Univariable and multivariable analyses revealed that the intraoperative use of flurbiprofen was associated with long‐term RFS (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.42–0.76, p = .001) and prolonged OS (HR: 0.49, 95% CI: 0.38–0.63, p = .001). Conclusions Perioperative flurbiprofen axetil therapy may be associated with prolonged RFS and OS in patients with esophageal carcinoma undergoing thoracoscopic esophagectomy.


| INTRODUCTION
Esophageal carcinoma, the fourth most common malignancy in China, 1 is characterized by a high degree of locoregional recurrence, distant metastases, and poor overall survival (OS). 2,3 Being the sixth most common cause of cancer-related mortalities, it accounts for an estimated 400,000 cases (4.9%) of death worldwide. 1 Reportedly, approximately 80% of new cases occur in less-developed regions of the world, out of which about 60% of them occur in China. 4 Among the two dominant histologic subtypes (esophageal adenocarcinoma and esophageal squamous cell carcinoma [ESCC]), 5 ESCC remains the main subtype with approximately 90% of cases occurring in the Asia-Pacific region, including China. 6 China presents a high incidence of esophageal carcinoma, especially in rural regions. Furthermore, higher incidence rates of ESCC have been reported in different provinces of China, including Hebei, Henan, Fujian, and Chongqing, followed by Xinjiang, Jiangsu, Shanxi, Gansu, and Anhui, 7 with recognized hotspots in Linxian (Henan province) and Cinxian county, and near Taihang Mountains. 8,9 The profound heterogeneity of etiological risk factors underlying esophageal carcinoma is particularly compelling. Despite its rapidly progressive course, the involvement of modifiable risk factors in conjunction with late-stage presentation highlights the scope for better management of the disease. 10 Several decades of extensive research in the high-risk areas of China have provided novels insights on the epidemiology, etiology, early detection, 11 and management of this disease. [12][13][14][15][16][17] However, despite recent advances in the diagnosis and treatment of this neoplastic condition, failure of chemotherapy and radiotherapy leads to tumor recurrence and poor prognosis. This could be mainly due to its aggressive nature and the limited efficiency of treatment modalities. 18 Currently, esophagectomy is the mainstay of treatment for patients with resectable esophageal carcinoma, although distant control and complete resection rate continue to remain a challenge. 19,20 Nevertheless, the overall 5-year survival rate after esophagectomy remains about 21% in China. 21 This dismal result could be attributed to recurrence after resection of the primary tumor. Locoregional recurrences or/and distant organ metastases were found in approximately 50% of patients within 2-3 years of surgery. [22][23][24] The recurrence patterns following esophagectomy have been wellstudied. 22,24,25 Factors such as histologic tumor depth invasion, 22,24 local-regional lymph node metastases, 24 and intramural metastasis 25 have been shown to predict tumor recurrence. Of note, recent improvements in perioperative management have reduced postoperative mortality to acceptable levels. However, the perioperative period is highly vulnerable to the development of metastases, including the accelerated growth of micrometastatic disease and increased formation of new metastatic foci. 26 Several factors, including profound depression of antitumoral cellular immunity, may contribute to this phenomenon. 27 In addition, during the perioperative period per se, the immune function of patients could be influenced by the anesthesia management; volatile anesthetics and opioids might worsen the immunosuppression and thereby exacerbate long-term outcome, while local anesthetics and nonsteroidal anti-inflammatory drugs (NSAIDs) might diminish the immunosuppression and exert beneficial effects. [28][29][30] Moreover, the perioperative use of βadrenoceptor antagonists, NSAIDs, intravenous anesthetics, and antithrombotic agents has been linked with improved survival outcomes in patients with neoplasms. 27,31 Furthermore, NSAIDs have been shown to minimize postoperative opioid consumption and further aid the strengthening of the cell-mediated immune competence. 32 Collectively, these findings indicate that perioperative management is crucial as it may contribute to the long-term outcome of patients after surgery. Still, the degree of pain after thoracic surgery is very high. [33][34][35] In the absence of standardized treatment, acute pain will turn into chronic pain in more than 30% of the patients, [36][37][38] affecting the patient's quality of life and cooperation.
Hence, analgesia must be used, but carefully and keeping oncological safety in mind.
A previous retrospective study in 327 women who underwent mastectomy for breast cancer demonstrated that the intraoperative administration of ketorolac (NSAID) significantly reduces the risk of breast cancer relapse compared with other analgesics (sufentanil, ketamine, and clonidine). 27 Furthermore, another recent study showed that the perioperative use of dexamethasone with/without flurbiprofen axetil is associated with longer survival in patients who underwent surgery for non-small-cell lung carcinoma (NSCLC). 27 Flurbiprofen axetil, an injectable prodrug of flurbiprofen, 39 is a nonselective cyclooxygenase inhibitor used as an NSAID. 40,41 It is widely used for postoperative pain relief. 42 A study by Tedore et al. 43 showed that flurbiprofen exerts its analgesic effect by inhibiting prostaglandin (PG) synthesis. Nevertheless, the effect of perioperative use of NSAIDs, especially flurbiprofen, on the long-term survival of patients with ESCC still remains elusive. Furthermore, it is unclear whether the perioperative use of flurbiprofen has an impact on the postoperative recurrence after surgery for esophageal cancer.
Therefore, in view of the above and the association between flurbiprofen and long-term survival is uncertain, this study aimed to investigate the effect of perioperative intravenous flurbiprofen axetil on recurrence-free survival (RFS) and OS in Chinese patients with esophageal carcinoma who underwent thoracoscopic esophagectomy.

| Groups and NSAID administration
Since not all doctors at the authors' center use flurbiprofen for analgesia during the perioperative period, some patients did not re-

| Endpoints
The primary endpoint of this study is RFS and OS. RFS was defined as the time (in months) from the date of surgery until the first recurrence or death due to oncological cause, whichever occurred first. OS was defined as the time from the date of surgery until death due to any cause. Recurrence was defined as clinical evidence of local recurrence or metastases on radiological examination.

| Follow-up
The survival data of all patients were collected by telephonic interview using a structured questionnaire, including short-term comorbidity information, such as gastrointestinal distress, cardiovascular events, and respiratory complications. Postsurgery, patients were followed tri-monthly for the first 2 years, then twice a year for 3 years, and annually thereafter. Patients were censored if they were lost in follow-up or remained disease-free at the end of follow-up.

| Comparison analyses of RFS and OS between controls and the groups that received flurbiprofen
The intraoperative administration of flurbiprofen, either as a single dose or multiple doses, was found to be associated with long-term RFS and OS (p < .001) (Figure 2A,B). Four factors that were identified by univariable analyses were included in the multivariable Cox

| Comparison analyses of RFS and OS between single-dose NSAID group and multiple-dose NSAID group
Interestingly, there was no significant difference between the RFS of patients who received a single dose of flurbiprofen and that of those who received multiple doses ( Figure 2C). Similarly, the frequency of flurbiprofen dosage was not found to influence the OS in these patients ( Figure 2D). Three factors that were identified by univariable analyses were included in the multi-  One of the most prominent prognostic factors affecting the treatment of esophageal cancer is lymph node metastasis. 44 The presence and number of metastatic lymph nodes governing the lymph node status have been shown to be independent predictors for long-term survival. 40,45,46 Lymph node metastasis has been shown to be associated with poor survival, 47 whereby an increasing number of metastatic lymph nodes predicted a progressively poor prognosis. 48 Reportedly, the 5-year survival rate for patients with lymph node metastasis is quite low. On average, patients with a single lymph node metastasis showed a significantly longer survival compared with those having two or more lymph node metastases. 49 Similarly, a study by Zhang et al. 50   Staging in esophageal cancer depends on the depth of tumor invasion, involvement of regional lymph nodes, and the presence or absence of metastasis. 51 In this study, we showed that the tumor stage could have a significant impact on both the OS and RFS of patients who did not receive a perioperative intravenous infusion of flurbiprofen axetil.
Emerging evidence suggests that the perioperative timeframe is a crucial facilitator of metastatic progression, with several Substantive clinical and epidemiological evidence indicates that the increase in the levels of proinflammatory mediators, such as cytokines, chemokines, and PGs in solid tumors, has become a major risk factor for cancer development. 54 A review of the literature reveals that PGs, especially prostaglandin E2 (PGE 2 ), produced by COX-2 (a member of the cyclooxygenase enzyme family), promote neoplastic progression. 55 The role of COX-2 in carcinogenesis, especially in cell proliferation, apoptosis inhibition, angiogenesis, invasiveness, and immunosuppression, has been well-studied. 56 Furthermore, the overexpression of COX-2 was found to be significantly associated with the depth of invasion, lymph node metastasis, distant metastasis, and TNM stage in esophageal cancer. 57 Moreover, a number of the study suggested that COX-2 overexpression was associated with a poor prognosis. 58 64 In addition, the expression of PD-L1 (ligand for PD-1) has been linked with rapid cancer progression, higher recurrence rates, and worse survival. 63 Corroborating the results of this study, these findings collectively indicate that perioperative flurbiprofen therapy may modify the immunecheckpoint expression and limit long-term cancer recurrence, thus improving the OS rates in patients undergoing esophagectomy for esophageal carcinoma.
Expectedly, in this study, multivariable analyses showed age to be independently associated with poorer survival in patients who did not receive perioperative flurbiprofen. After adjustment for the potential confounder (age), the association between perioperative flurbiprofen administration and the lower risk of cancer recurrence and prolonged survival remained significant. Advanced age is associated with poor outcomes following esophageal resection. 65 Moreover, advanced age is considered a relative contraindication for flurbiprofen (and other NSAIDs) and consequently prompts a decreased usage of flurbiprofen in elderly patients. Therefore, the perioperative use of flurbiprofen in elderly patients with esophageal cancer after surgical resection can improve survival, but dose control and potential risk monitoring are essential.
In addition to the significant findings revealed by this study, there are some limitations currently study. Despite accessing highquality electronic health record databases and considering all-known variables that could affect the outcome in our statistical analyses, a series of potential uncontrolled and unrecognized biases, such as selection bias, diagnostic bias, and bias in follow-up, which may confound the results were inevitable due to the inherent nature of this observational retrospective study. Furthermore, the singlecenter study design may limit the generalizability of the findings in this study. Moreover, the follow-up data regarding patients' neoadjuvant chemotherapy, adjuvant radiation, or other adjuvant therapies were unavailable, which might influence the study's endpoint. Third, study groups received either a single equivalent dose of intravenous flurbiprofen preoperatively or multiple doses of flurbiprofen with 100 mg both preoperatively and postoperatively (twice a day for 2 days). As the treatment was uniform, concerning the individual difference, individualized dosage regimens based on the patient's status and the tumor nature need to be considered to minimize the potential bias.

| CONCLUSIONS
In summary, this study demonstrated significant associations be-