Preoperative predictors for early recurrence of resectable pancreatic cancer

Patients with pancreatic cancer have been reported to have a 5-year overall survival (OS) of approximately 5% [1]. Only 20% of patients with pancreatic cancer are candidates for potentially radical resection [2]. Surgical resection is associated with a median OS of 11 to 23 months and with a 5-year OS of about 20% [3, 4]. Furthermore, 60% of patients experience local and systemic relapse within the first 12 months after curative surgery [3]. Preoperative predictors of survival time after surgery have been reported as tumor size [3], preoperative lymph node metastasis [3], preoperative serum carbohydrate antigen (CA19-9) level [2, 3, 5], G3–G4 on pathological grading [2], duration of symptoms [2], and preoperative modified Glasgow Prognostic Score (mGPS) [6].

Moreover, some studies have suggested that minimally distant metastasis undetectable even by recent advanced diagnostic imaging might have existed at the time of surgery in patients with early recurrence [7, 8]. In fact, occult peritoneal or liver metastatic disease has been reported to be missed by CT in 4 to 15% of patients [3].

The National Comprehensive Cancer Network (NCCN) guidelines recommend surgical resection as the first choice for the treatment of RPC. However, some researchers found that median OS of patients with RPC was approximately 12 months after surgery alone [9]. Other researchers found that the median OS of patients with RPC was <2 years after surgery and adjuvant therapy [10, 11]. Furthermore, at least 25% of patients cannot receive adjuvant chemotherapy because of complications related to surgery [9]. One group of investigators found that the median OS in patients undergoing resection for RPC was 27 months using preoperative chemoradiation therapy, while the median OS was 17 months in patients receiving surgery alone (P = 0.004) [12]. However, no randomized controlled trials have been reported on the efficacy of neoadjuvant chemotherapy for RPC.

Although randomized controlled trials will give us the answer whether preoperative therapy is needed for all RPC, we think preoperative treatment is not needed for all RPC. If early recurrence of RPC can be predicted before performing surgery, we suppose that preoperative therapy should be selected prior to surgical resection for RPC patients.

The aim of this study was to identify preoperative predictors of early recurrence after curative resection for RPC. The results of this study could aid oncologists and surgeons in discriminating high-risk cases of RPC in which the cancer could recur within 1 year and selecting the patients who would benefit from preoperative therapy.

The present study indicated that the median OS of patients with RPC was 41.5 months, and 66.6% cases of patients with RPC experienced recurrence, including both recurrence within 1 year and recurrence beyond 1 year after surgery. The median OS of the recurrent cases among the RPC patients was 26.4 months, and the 5-year survival rate was 10%. Furthermore, the proportion of cases having recurrence within 1 year after curative resection for RPC was 35.6%, and the median OS was 14.2 months. These results suggest that even if the patients with RPC could be treated by curative surgery, more than half of them would experience recurrence, and their prognosis would be poor. Furthermore, independent risk factors for REC1 were histological grades G2–G4 and preoperative serum CA19-9 ≥ 529 U/mL. REC1 experienced recurrence in the pattern of more frequent distant metastasis, which might suggest that occult metastasis existed at the time of surgery. These results are crucial for the treatment strategy of RPC in the future.

The present study identified preoperative CA19-9 level ≥529 U/mL and histological grade G2-G4 as preoperative factors of recurrence within 1 year after curative resection for RPC. However, as it is usually difficult to diagnose the histological grade before surgery, the degree of differentiation is usually a post-resectional parameter. In fact, at our institution, the histological grade is not usually able to be diagnosed by endoscopic ultrasound (EUS)/fine needle aspiration (FNA) before surgery. Therefore, histological type cannot be considered as an appropriate preoperative factor. This suggests that the most appropriate preoperative independent factor is preoperative CA19-9 level ≥529 U/mL, excluding histological grade.

The CA19-9 tumor antigen was initially described by Koprowski et al. as a colorectal cancer marker [16] and is currently the most clinically useful marker of pancreatic cancer. Furthermore, CA19-9 is reliable as a possible prognostic marker for tumor resectability, recurrence, and survival [12, 17]. Berger et al. reported a longer median survival and greater percentage of patients surviving to 5 years among patients with either normal or undetectable preoperative levels of CA19-9 compared with patients having elevated levels [18]. Other investigators found that a postoperative decrease in CA19-9 and a postoperative CA19-9 value <200 U/mL were both significant predictors of survival in patients with pancreatic adenocarcinoma [4, 19]. Humphris et al. reported that normalization of CA19-9 within 6 months of resection was a prognostic factor [20]. On the other hand, it has been reported that only the preoperative CA19-9 level was associated with the prognosis or resectability of patients. Nakao et al. reported that the only preoperative predictor of survival time after surgery is a preoperative CA19-9 value ≥2000 U/mL [5]. Furthermore, other investigators have found that elevated preoperative CA19-9 levels were significantly associated with tumor unresectability, although the reported cutoff levels ranged from 100 to 350 U/mL [21‐28]. In the present study, the AUC of the cutoff point of the CA19-9 value was 0.6815, and so it is difficult to say whether this AUC is the optimal value. Henceforth, the optimal cutoff value of CA19-9 should be evaluated by collecting a larger number of cases. Additionally, Turrini et al. suggested that the preoperative serum CA19-9 level by itself should not preclude surgery in patients who have undergone preoperative staging [29]. These investigators noted that even patients with very high values of preoperative CA19-9 may normalize their serum CA19-9 levels and have an overall survival equivalent to patients with normal preoperative serum CA19-9 levels. In the current study, we found that the group with higher CA 19-9 values tended to have poorer median OS. It is possible that preoperative serum CA19-9 level is associated with prognosis. But, careful evaluation is needed to determine whether the prognosis of this patient group was based on only the preoperative serum CA19-9 level.

We additionally examined the patterns of recurrence of RPC. The patients who experienced recurrence within 1 year had a greater amount of distant metastasis than local recurrence. These results might suggest that patients with early recurrence after curative surgery had minimally distant metastasis that was not detected via imaging modalities at the time of surgery, and their lesions did not visibly appear until after surgery.

Furthermore, we examined the recurrence patterns of each group stratified according to the combination of preoperative serum CA19-9 level and tumor size. The patients whose preoperative CA19-9 level was high despite smaller tumor diameter tended to have the poorest survival. From this result, it might also be speculated that patients whose preoperative CA19-9 level was high despite small tumor size had minimally distant metastasis before or at the time of surgery. It should be kept in mind that RPC patients with high preoperative serum CA19-9 levels have potentially distant metastasis. In particular, the possibility exists that patients whose preoperative CA19-9 level is high despite smaller tumor diameter have distant metastasis. Additionally, from the results of the present study, an appropriate cutoff value of preoperative serum CA19-9 value might be approximately 500 U/mL.

Chemotherapy for pancreatic cancer has recently been developed. A previous study reported that the median OS was 11.1 months after treatment with FOLFIRINOX for metastatic pancreatic cancer [30] and was 8.5 months after treatment with nab-paclitaxel plus gemcitabine [31]. The median OS of locally advanced pancreatic cancer is 24 months after first-line FOLFIRINOX with about 1/4 being resectable after this therapy [32]. Another study found that neoadjuvant chemotherapy contributed to high resection rates of local advanced pancreatic cancer [17]. Considering those reports, one option may be to administer preoperative chemotherapy for RPC patients who have high preoperative serum CA19-9 values, intending to exclude those patients who have the potential for early recurrence after surgery and to control minimally distant metastasis in those patients. It has recently been reported that staging laparoscopy in patients with local advanced pancreatic ductal adenocarcinoma is effective for selecting patients with occult distant organ metastasis [33]. To perform staging laparoscope for RPC patients having high preoperative CA19-9 values may make better patient selection for preoperative therapy.

In this study, we mainly focused on preoperative therapy. But, postoperative adjuvant therapy after curative resection has been showed to improve survival [34]. CONKO-001 showed treatment with gemcitabine for 6 months after complete resection of pancreatic cancer significant increased disease-free survival (DFS) and OS compared with observation alone. ESPAC-3 showed no significant difference in survival between adjuvant 5-fluorouracil/folinic acid and adjuvant gemcitabine. But, about 15% of patients may develop overt metastatic disease during postoperative recovery period; therefore, early initiation of adjuvant chemotherapy within 20 days after surgery has been shown to improve DFS and OS [35, 36]. These reports may indicate we should perform combination of preoperative therapy and postoperative early adjuvant therapy for RPC cases with CA19-9 ≥ 529. RCT trial (PREOPANC trial) as to preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer is conducted at the moment; the results will lead our studies to further directions [37].

The limitations of the present study were as follows. This was a retrospective study conducted at a single institution, and the sample size was small. Approximately 5–10% of the general population was Lewis antigen A- and B-negative, which meant that they did not synthesize CA19-9 antigen and would not have elevated levels, even with pancreatic cancer. In the present series, the data related to Lewis antigens A and B could not be included.

Preoperative serum CA19-9 level ≥529 U/mL and histological grades G2–G4 were independent predictive factors for identifying recurrence within 1 year after pancreatectomy for RPC. Furthermore, REC1 had more frequent distant metastasis than non-REC1, which suggested that patients experiencing recurrence within 1 year had minimally distant metastasis. This might indicate the possibility that patients with high preoperative serum CA19-9 values and have potential distant metastasis despite suffering from RPC, especially, with small tumor, should receive combination of preoperative therapy and postoperative early therapy.