Resected pancreatic adenocarcinoma: An Asian institution's experience

Abstract Background Pancreatic adenocarcinoma (PDAC) is highly lethal. Surgery offers the only chance of cure, but 5‐year overall survival (OS) after surgical resection and adjuvant therapy remains dismal. Adjuvant trials were mostly conducted in the West enrolling fit patients. Applicability to a general population, especially Asia has not been described adequately. Aim We aimed to evaluate the clinical outcomes, prognostic factors of survival, pattern, and timing of recurrence after curative resection in an Asian institution. Methods and Results The clinicopathologic and survival outcomes of 165 PDAC patients who underwent curative resection between 1998 and 2013 were reviewed retrospectively. Median age at surgery was 62.0 years. 55.2% were male, and 73.3% had tumors involving the head of pancreas. The median OS of the entire cohort was 19.7 months. Median OS of patients who received adjuvant chemotherapy was 23.8 months. Negative predictors of survival include lymph node ratio (LNR) of >0.3 (HR = 3.36, P = .001), tumor site involving the body or tail of pancreas (HR = 1.59, P = .046), presence of perineural invasion (PNI) (HR = 2.36, P = .018) and poorly differentiated/undifferentiated tumor grade (HR = 1.86, P = .058). The median time to recurrence was 8.87 months, with 66.1% and 81.2% of patients developing recurrence at 12 months and 24 months respectively. The most common site of recurrence was the liver. Conclusion The survival of Asian patients with resected PDAC who received adjuvant chemotherapy is comparable to reported randomized trials. Clinical characteristics seem similar to Western patients. Hence, geographical locations may not be a necessary stratification factor in RCTs. Conversely, lymph node ratio and status of PNI ought to be incorporated.

section margin status. 7,8 The standard operation for tumors of the pancreatic head is a pancreaticoduodenectomy (Whipple procedure), whereas tumors of the body or tail can be resected using a distal pancreatectomy. 9 These procedures are associated with high operative mortality and morbidity. 9 Advancement in surgical technique and perioperative management of patients has led to a reduction in the morbidity and mortality associated with the above-mentioned surgeries. Moreover, with the improvement of imaging technique and the employment of a multidisciplinary team approach, better selection of suitable patients for surgery could be done. 10 Surgical outcomes at high-volume centers have been shown to be superior compared to outcomes at low-volume centers. In spite of that, many patients relapse at both local and distant sites after resection. Hence, adjuvant chemotherapy is crucial in the management of these patients as demonstrated in multiple randomized controlled trials (RCT). [11][12][13][14][15]17,18,38 Often, these trials stratify patients by geographical locations, resection margins, T-stage and lymph node status.
Adjuvant chemotherapy or chemoradiotherapy was conducted primarily in West enrolling fit patients with preserved organ functions and good performance status. Applicability to a general population especially in an Asian population has been inadequately described.
Pattern, timing, and predictors of recurrence after curative resection have been described primarily in Western populations.
We aimed to evaluate the clinical outcomes, prognostic factors of survival, pattern, and timing of recurrence after curative resection in an Asian institution.
We also compared the resected PDAC series from both Asian and Western populations.

| METHODS
Patients who underwent resection with curative intent in our center between 1998 and 2013 were identified from a retrospective database.
Patients eventually noted to have R2 resection or stage 4 disease were excluded. We collected clinicopathological and operative data of 165 patients. Follow-up and data collection extended to December 2015.
Following surgery, all specimens underwent histopathological review, and features such as histology subtype, pathological AJCC stage and grade, resection margin status, tumor size, LVI and PNI.

Resection margin involvement was defined according to the Royal
College of Pathologists guidelines, with microscopic evidence of tumor within 1 mm of a resection margin (RM) being classified as R1. 19 Laboratory parameters such as CA 19-9 and carcinoembryonic antigen (CEA) were measured preoperatively and postoperatively (patients without tests done within 3 months before or after the surgery was excluded from the analysis). The development of a hypointense mass in the resection site was considered as evidence of local recurrence. Similarly, detection of a new hypointense nodule/ mass in the liver, lung, or peritoneum was considered evidence of distant recurrence. No biopsies were performed in this series to confirm the diagnosis of recurrent cancer. If the CT findings were non-specific, a follow-up CT would be performed, and the date of recurrence will be taken as the date of the follow-up CT that demonstrate enlargement of the nodule or mass. Our study was approved by the Centralized Institutional Review Board of our institution.

| Statistical analysis
Continuous variables were summarized using median and range.
Categorical variables were summarized using frequency and percentage. Overall survival (OS) was calculated as the time from surgery to death from all causes. Patients who were alive at last followup were censored at date of last follow-up. Median OS was estimated using the Kaplan-Meier method. Differences in survival curves were tested using the log-rank test. Univariable and multivariable analyses were performed using the Cox proportional hazards model. For multivariable analysis, variable selection was performed using a forward selection procedure. All variables, regardless of significance in univariable analysis, were entered as candidate variables in the forward selection procedure. Only variables with more than 10% missing data were excluded. The proportional hazards assumption was tested on the final multivariable model using a test based on Schoenfeld residuals. A P-value of less than .05 was taken as statistically significant in the univariable analyses. For the forward selection procedure, a P-value of less than .10 was used for addition of variables into the multivariable model.   Table 1. The most common site of recurrence was the liver (n = 58; 35.2%), followed by local recurrence (n = 39; 23.6%), distant lymph nodes (n = 31, 18.8%), peritoneum (n = 22, 13.3%), and lungs (n = 19; 11.5%).     Post-operative CA19-9

| Multivariable analysis of OS
Site of primary PNI LVI  There is also the randomized Phase 2 NEONAX trial (ClinicalTrials.gov Huebner et al showed that a LNR of ≥0.17 had poorer prognosis. 42 We found that a LNR ≥0.30 was associated with a poorer prognosis. Patients with LNR of 0, >0 to 0. disease could be further stratified based on the number of lymph nodes evaluated, with those with 11 or less LN examined having a poorer prognosis. 43 Another study showed that those with <12 TLN had a poorer prognosis, but this did not reach statistical significance. 44 In our study, however, we did not find that the TLN was a prognostic factor in patients with pN0 disease or in our entire cohort. While nodal status is incorporated as a stratification in a large proportion of randomized adjuvant trials in pancreatic cancer, 12,13,15,18 LNR could be a better stratification factor. LNR did not feature as a stratification factor in any of the randomized trials ( Table 4). The only randomized trial, which included LNR in its patients' clinic-pathological characteristics, was JASPAC-01 trial. 15 Tumor grade is a known prognostic factor found in many studies, including various RCTs. 5,6,11,14,18,22,26,27,30,48,49 ( Tables 3 and 4) Our study confirmed this finding. While Brennan et al found that tumors located at the head are associated with a worse prognosis, our results are contrary to this. 50 We found that patients with tumors at the body or tail had poorer prognosis. Multiple studies have suggested that the anatomical site is a prognostic factor; however, studies have been conflicting regarding which site is associated with a better prognosis. 51 56 The presence of PNI has been demonstrated as a negative prognostic factor in multiple studies. 5,6,26,30 (Table 3).
While the previously described factors are well described in the literature to be prognostic, the prognostic value of the resection margin remains controversial. 57 Margin status has been identified as prognostic factor in multiple studies. 58,59 However, other studies have demonstrated no relationship between the resection margin and OS. 60,61 Conflicting results have also been found for the posterior resection margin. 58,62 Our study found that resection margin status (R0 vs R1) and the posterior resection margin status (R0 vs R1) were not independently associated with OS in the multivariable analysis. There are numerous postulations for the conflicting results. First, the definition of microscopic margin positivity differs from study to study. 19,60 Second, there are wide variability in the way different centers handle and sample the resection tissue. 57 Third, the definition of the posterior margin is also not standardized in multiple studies. 57 Taking the above together, our study showed that our cohort had similar prognostic factors, recurrence patterns, and survival as other Western and Asian institutions. 5,6,10,[22][23][24][25][26][27][28][29][30] (Table 3) In the APACT trial which recruits both Western and Asian patients, country was used as a stratification factor. 17 Given the similarity in clinical characteristics in Western and Asian patients with PDAC, using country as a stratification factor may not be necessary. On the other hand, LNR and presence of PNI have consistently been found to be a significant prognostic factor in RCTs or large series from high-volume centres 5,6,11,14,16,18,22,26,27,30,48,49 (Tables 3 and 4) and should perhaps be used as a stratification factor instead.
Our study has several limitations. While we managed to demonstrate applicability of adjuvant therapy in a general Asian population consistent with what has been reported in RCT, all the patients in this cohort received single agent systemic therapy (gemcitabine or 5FU). A number of RCT has since been reported providing evidence for doublet and triplet combination therapies. 17,18 Future population-based studies are needed to clarify its applicability to a general population.
As this study is retrospective in nature, there may be recall bias. Furthermore, the study sample size is modest, perhaps explaining for lack of statistical significance in previously reported prognostic factors (eg, resection margins and presence of LVI). Finally, incomplete capture of variables may introduce bias in survival analysis.
In conclusion, the survival of Asian patients with resected PDAC who received adjuvant chemotherapy is comparable to reported randomized trials. Clinical characteristics of Asian patients with resected PDAC are similar to datasets described among patients from the West. Hence, geographical locations/country of origin may not be a necessary stratification factor in RCTs. Conversely, LNR and status of PNI ought to be incorporated.