**5. Adjuvant therapy in pancreatic adenocarcinoma**

**4. Resectability**

182 Advances in Pancreatic Cancer

static disease).

after a neoadjuvant treatment.

potential negative impact in survival.

recurrence rate very close to 100% [19, 20].

For patients with tumors that appear resectable during the baseline staging, based on tomography of the abdomen with pancreatic phase, which together represent probably only the 20% of all pancreatic cancers, surgery remains the only potentially curative treatment option [16, 17]. The conventional surgical procedure for pancreatic cancer of the head and or the uncinate process is the pancreaticoduodenectomy. Conventional pancreaticoduodenectomy (i.e., Whipple procedure) involves removal of the pancreatic head, duodenum, the first 15 cm of the jejunum, common bile duct, gallbladder, and a partial gastrectomy [18]. Many times, despite a good quality of the surgery and adequate adjuvant treatments, pancreatic cancer has recurrences that will not be able to be treated with a curative intention. Complete R0 resections have a high incidence of recurrence before 2 years after surgery [17], R1 and R2 resections will have a higher and faster incidence of recurrence and in general should not be considered as patients who underwent a curative surgery. Among patients who underwent an R0 surgery, 75% of them will have a recurrence due to microscopic metastatic disease that was undetectable at diagnosis, or due to resistance of locoregional residual tumor cells to adjuvant treatments that include adjuvant chemotherapy, adjuvant radiotherapy, or chemoradiation. Most of the patients who did not achieve a complete resection will relapse with a

At the time of taking decisions to define resectability of pancreatic tumors, a multidisciplinary approach, including surgeons who have expertise in pancreatic tumor resection, medical oncologists, radio- oncologists, and well-qualified radiologists should be mandatory. With the support of specialized radiologists and the rest of the team as well, surgeons will be able to define if the patients may undergo a surgery as an upfront treatment or if they are definitely unresectable (including locally advanced unresectable disease and meta-

A third group will be considered as "borderline" resectable patients. "Borderline resectable" definition is variable and somehow imprecise. As a global conception of this definition, we might consider that borderline pancreatic cancer involves those patients who, based on images and on oncological surgery team expertise, are not considered as unresectable but at the same time are not clearly resectable as an upfront treatment but could became resectable

Some reserve the term "borderline resectable" for cases where there is focal (less than one-half of the circumference) tumor abutment of the visceral arteries or short-segment occlusion of the superior mesenteric vein or portal vein confluence. Others suggest that venous narrowing without occlusion should be included in the definition of borderline resectable disease [21]. Due to that, the aim of surgery in pancreatic cancer is to achieve an RO resection to give the chance of a curative treatment; borderline resectable patients are the best candidates to be treated with neoadjuvant therapies, and most of the time they should not undergo surgery as a first treatment due to a higher risk of not achieving a complete resection resulting in a Until recently, gemcitabine chemotherapy was the standard of care as adjuvant treatment in complete resected pancreatic cancer patients [22]. The use of radiation therapy or chemoradiation has been controversial, without clear data to support its use among complete resected patients [23, 24]; however, there are groups that considered its use [25] mainly in the group of R1-resected patients and or among node-positive patients. It is important to remark that most of the recurrences will be distant metastasis and only a small percentage of patients will die due to local recurrence or due to local progression after resection; therefore, systemic treatments should always be considered unless a clear justification for local regional treatment has been made.

Since 2017, the standard of care for early stage, resectable pancreatic adenocarcinoma patients is surgery followed by adjuvant chemotherapy combination of gemcitabine plus capecitabine according to ESPAC-4 trial. The median overall survival for these patients in the gemcitabine plus capecitabine group was 28.0 months (95% CI, 23.5–31.5) compared with 25.5 months (22.7–27.9) in the gemcitabine group (hazard ratio (HR) 0.82 (95% CI, 0.68–0.98), p = 0.032). Reported results showed a positive impact for the adjuvant therapy in most of the clinical subgroups, including patients with R1 resection margins [26].

S-1 is an oral 5 FU prodrug that has been tested in several malignancies with good results but with a limited efficacy among Asian population. In the phase III JASPAC 01 trial, adjuvant chemotherapy with S-1 showed a 5-year overall survival rate of 43.6 versus 24.2% for gemcitabine (HR 0.60; P < 0.0001) and was relatively well tolerated [27]. These data support the use of S-1 as a new standard of care for adjuvant treatment among Japanese population that underwent surgery for pancreatic adenocarcinoma, but it should not be considered in non-Asiatic population due to the lack of existing data.

The use of adjuvant chemotherapy can be delayed or affected by postoperative complications but also by the appearance of early recurrences that can be found before systemic treatment starts or during early image control during adjuvant treatment. Prospective observational trials have shown that up to 38% of resected pancreatic cancer patients did not receive chemotherapy due to those reasons [28, 29]. Considering the bad prognosis of this disease, despite a complete resection when feasible, neoadjuvant treatments have been explored, which focused on improving those outcomes.
