Preoperative treatments in borderline resectable and locally advanced pancreatic cancer: Current evidence and new perspectives

Pancreatic cancer (PC) represents the seventh most common cause of death worldwide, the fourth in the most developed countries (Siegel et al., 2022, Sung et al., 2021). Most cases present with metastatic spread at diagnosis and the 5-year survival rate still doesn’t exceed 10 %. Surgery is the only curative treatment available for pancreatic ductal adenocarcinoma (PDAC) but only 15–20 % of patients present a resectable disease at diagnosis (Khorana et al., 2016) and most of non-metastatic cases are not amenable to receive upfront surgery, mainly due to vascular involvement.

A precise radiological assessment of cancer local extension plays a key role for adequate treatment planning. The concept of borderline resectable pancreatic cancer (BRPC) was firstly introduced (Varadhachary et al., 2006) as an intermediate entity between upfront resectable pancreatic cancer (RPC) and locally advanced pancreatic cancer (LAPC). Since then, this definition has been slightly modified, with some degree of discordance among the various classification systems and without a univocal definition of surgical resectability (Callery et al., 2009, Tempero et al., 2014, Pancreatic adenocarcinoma,). Most recent NCCN guidelines (Pancreatic adenocarcinoma) define BRPC a disease in which the tumour contact with the superior mesenteric vein or portal vein is either > 180° or ≤ 180° with vein contour irregularity or thrombosis, still with feasible complete resection and vein reconstruction. It is also considered BRPC with a limited arterial involvement: ≤ 180° with the celiac axis (CA) (or >180° without involving the aorta and with intact and uninvolved gastroduodenal artery); ≤ 180° with the superior mesenteric artery; contact with the common hepatic artery without involving the CA or hepatic artery bifurcation. Other cases of vascular involvement by non-metastatic pancreatic adenocarcinoma are defined as LAPC.

The lack of consensus has led to considerable variance in clinical practice among the different cancer centres, especially when deciding if patients are candidates for a preoperative treatment (Wittel et al., 2019, Kirkegård et al., 2019). Moreover, these diversities represent another element of difficulty in forming homogeneous populations for dedicated clinical trials and to produce new evidence (Gilbert et al., 2017), considering that BRPC and LAPC patients have been often included in the same clinical trials. The heterogeneous definition of BRPC has been complicated even more by other classifications which consider not only the anatomical extension of the disease but also biological characteristics and patients’ clinical conditions (Denbo and Fleming, 2016, Isaji et al., 2018, Kang and Kim, 2021). Various ‘high-risk’ characteristics for metastatic disease are reported in literature, such as high Ca19.9 levels (various levels reported, i.e., >500 IU/mL) with a normal bilirubin level, involvement of regional lymph nodes, indeterminate liver lesions, systemic inflammatory response (i.e., neutrophil-lymphocyte ratio, C-reactive protein-albumin ratio).

In this tangled setting, neoadjuvant therapy has a dual purpose: increasing R0 resections in cases with a complex anatomy and selecting patients with a biologically aggressive disease who wouldn’t benefit from an upfront surgical resection, in order to prevent futility from an extremely invasive procedure (Lopez, 2014, Toesca et al., 2018). Margin-negative resection (R0) represents an important prognostic factor and several studies have proven that neoadjuvant therapy allows to reach high R0 resection rates (up to 90 % of patients who are offered surgery), with low rates of lymph nodes involvement (Janssen et al., 2019, Cloyd et al., 2020a). Moreover, preoperative treatment permits both an improved locoregional control (Hue et al., 2021) and an early exposure to systemic chemotherapy (CT), potentially addressing occult distant metastases. This point is even more important considering that a remarkable quota of patients won’t be able to receive adjuvant therapy after surgery due to postoperative complications/prolonged recovery (reported in up to 53 % of patients and that can prevent postoperative therapy in at least 25 % of cases) and/or deterioration of performance status (PS), especially considering that patients undergoing pancreatic surgery are increasingly older and with more comorbidities (Mayo et al., 2012, Ducreux, 2015, Wu et al., 2014, Merkow et al., 2014). A ‘total neoadjuvant’ approach (Tomasello et al., 2021, Kim et al., 2021) could lower the high attrition rate of patients undergoing a perioperative regimen. Additionally, the use of a neoadjuvant therapy allows to reassess treatment response (Evans et al., 2015, Heger et al., 2020, Cloyd et al., 2020b), possibly even with mid-treatment restaging in case of a sequential combination regimen, with a potential redirection of subsequent management (Alva-Ruiz et al., 2021). Finally, patients undergoing neoadjuvant treatment are associated with fewer post-pancreatectomy complications, such as pancreatic fistula, infections, postoperative procedural interventions (Krell et al., 2021). All these considerations on the advantages of preoperative therapy are even more valid for LAPC, in which a preoperative ‘conversion’ treatment is mandatory in trying to reach resectability criteria. Neoadjuvant strategies present several pros which promote their widespread usage in non-metastatic PC; however, also some cons must be mentioned, in particular regarding the absence of predictive biomarkers of response to systemic therapies. Moreover, the use of neoadjuvant CT could represent an overtreatment in several patients who may benefit from radical surgery only, especially in RPC, in which data on neoadjuvant strategies are still poor.

Primary systemic therapy is now the standard of care for both BRPC and LAPC. However, literature data are still controversial regarding the therapeutic strategies. CT, chemoradiation (CRT) or a combination of both are all considered as valid options and no regimen has been proven as clearly superior to the others (Tang et al., 2021). Discussions also regard the type, dose and duration of the various CT regimens, the technique, dose and fractionation of locoregional treatments and the ideal sequence of multimodal strategies. No robust data from randomized controlled trials comparing the different approaches are available. In this unsettled debate on preoperative treatment in non-metastatic PC, our objective is to focus on the regimens currently in use and relative literature data, to report international trials that compare the available therapeutic options or explore the introduction of new pharmacological agents, and to analyse possible new scenarios in microenvironment evaluation before and after neoadjuvant therapies or in patients’ selection at a molecular level.

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