Recent data from a randomized phase-2 trial (NORPACT-1) [6] which compared upfront resection versus neoadjuvant treatment in resectable PDAC has shown that neoadjuvant chemotherapy did not improve overall survival. Nevertheless, there is still a discussion in those patients that anatomically are resectable but have signs of a biologically aggressive disease by elevated tumor marker, and how this could be a predictive marker of early relapse. In those patients anatomically resectable, it may be advisable to assimilate them under the current concept of biological borderline in those patients with elevated tumor markers.. To date, the ca 19 − 9 value is the only biochemical and/or imaging marker not included in the unresectability criteria (metastasis, encasement of the superior mesenteric artery or celiac trunk, unreconstructable involvement of the portal vein or superior mesenteric vein) that could tip the balance toward resectability or an attempt at neoadjuvant therapy with subsequent staging.
In our center, a value of 500 for the CA19-9 tumor marker is used to make a more appropriate selection of patients. Those with a higher value will undergo endoscopic drainage of the bile duct in case of compromise and a new assessment of the marker. In the event of a decrease in values, it is taken into account that the dilation of the bile duct was the cause of the exaggerated value of the tumor marker and they may be surgical candidates. In those patients who persist with borderline values, a staging exploratory laparoscopy can be considered that contemplates the evaluation of carcinomatosis or invasion of vascular structures not found in the preoperative studies.[2]
The tumor size did not show statistically significant differences between those who experienced early relapse and those who did not. However, in the previously published work by our center [7], it was defined as a prognostic factor in the multivariate analysis. This means that these results indicate no differences between the two groups, which does not imply that tumor size has no impact on prognosis. Imamura et al. presented their work in 2022, which, unlike our data, concluded that tumor size > 4 cm in the preoperative imaging study was a poor prognostic factor for early recurrence and that perioperative risk factors associated with disease-free survival adverse events were pathological lymphovascular invasion (HR, 4.31; p = 0.048) and non-hepatopancreatobiliary surgeon (HR, 5.9; p = 0.022). They did not objectify data about the value of the preoperative tumor marker for the early prediction of recurrence.[8]
In the following study presented by Tong et al, from the identified cohort of 184 patients, 172 patients were included for further analysis. 55 patients developed early liver metastases within 6 months after the operation. Univariate analysis showed that CA125 ≥ 30 IU/mL, tumor size ≥ 4 cm, poor tumor differentiation, and portal vein/superior mesenteric vein (PV/SMV) reconstruction were risk factors, and multivariate analysis showed that poor tumor differentiation and PV/SMV reconstruction were independent risk factors for early liver metastasis. The prognosis of liver metastasis was the worst among the different patterns of recurrence. Early liver metastasis indicates a poor prognosis in patients with PDAC.[9]
In a Scandinavian paper, Izumo et al. conclude that initial surgery is the standard treatment for resectable pancreatic ductal adenocarcinomas (R-PDAC); however, these tumors often recur. The recurrence rate was 74%, while the median time to recurrence was 1.2 years. On multivariate analysis, CA19-9 > 37 U/mL (HR: 1.99), tumor size > 2.6 cm (HR: 1.43), pathologic grade 3 (HR: 2.93), pathologic invasion of portal vein (HR: 1.48), LNM (HR: 1.79), and forgoing adjuvant chemotherapy (HR: 1.39) were risk factors for shorter disease-specific survival intervals. CA19-9 > 37 U/mL and tumor size > 2.6 cm were independent preoperative risk factors for early recurrence and poor outcome in patients with R-PDAC. This study, in agreement with the present one, agrees that both the low tumor marker CA19-9 and complete adjuvant treatment are the most determining factors for obtaining a late recurrence of the disease.[4]
Murata and Mizuno also agree that the serum CA19-9 level before surgery after preoperative chemoradiotherapy (CRT) was a strong predictor of early recurrence. [10]
One of the largest and most recent series on this subject is the one presented by Li, Yang and collaborators in 2021. Among 3,279 patients included, 1,234 (37.6%) experienced early recurrence (ER). They identified four preoperative risk factors for ER, including a larger maximum tumor diameter on computed tomography (CT), enlarged lymph nodes on CT, carbohydrate antigen (CA) 125 > 35 U/mL, and CA19-9 > 235 U. / milliliters. To date, it is one of the few works with the largest amount of sample size that made cut-off points in the values of the predictors, establishing a prediction model with the aforementioned variables.[11]
Analyzing the rest of the bibliography, we can see that this cut-off point for the tumor marker varies significantly between the different reference centers and there is no clear correlation in the cut-off value. The Japanese group of Imamura establishes a cutoff point of ca 19 − 9 of (> 52 U/mL) preoperative and (> 37 U/mL) postoperative. Values similar to those established by Hong et al. Considering as elevated a level of CA 19 − 9 greater than > 70 U/mL.[5].
We believe it is extremely important to emphasize that the concept of complete adjuvant treatment, regardless of the scheme used (folfirinox vs gemcitabine-capecitabine) showed better results than those patients who did not complete adjuvant treatment. These data from our population coincide with the Prodige 24 study, which highlights the importance of receiving full adjuvant therapy and is clearly favorable for late disease recurrences.