Abstract
BackgroundNeoadjuvant therapies (neoTx) have revolutionized the treatment of borderline resectable (BR) and locally advanced (LA) pancreatic cancer (PCa) by significantly increasing the rate of R0 resections, which remains the only curative strategy for these patients. However, there is still room for improvement of neoTx in PCa.PurposeHere, we aimed to critically analyze the benefits of neoTx in LA and BR PCa and its potential use on patients with resectable PCa. We also explored the feasibility of arterial resection (AR) to increase surgical radicality and the incorporation of immunotherapy to optimize neoadjuvant approaches in PCa.ConclusionFor early stage, i.e., resectable, PCa, there is not enough scientific evidence for routinely recommending neoTx. For LA and BR PCa, optimization of neoadjuvant therapy necessitates more sophisticated complex surgical resections, machine learning and radiomic approaches, integration of immunotherapy due to the high antigen load, standardized histopathological assessment, and improved multidisciplinary communication.
Highlights
The introduction of neoTx has led to a remarkable increase in the rate of surgical resections in pancreatic cancer (PCa) patients with locally advanced (LA) or borderline resectable (BR) tumors, which were initially deemed inoperable at the time of diagnosis
We observed an immunological shift toward more cytotoxic inflammation in the tumor microenvironment (TME) of PCa after conventional neoTx. This was mainly due to the depletion of immunosuppressive cells like regulatory T cells (Treg cells) [46] and myeloid-derived suppressor cells (MDSCs) [45, 47]. These results suggested that neoTx is able to prime the TME and potentiate the effect of immunotherapy by boosting the local antitumor immune response in PCa
NeoTx leads to an immunologic shift toward a more effective antitumor immune response in the pancreatic TME, which recently provided impetus for studying the possibility of combining neoTx with immunotherapy in patients with PCa
Summary
The introduction of neoTx has led to a remarkable increase in the rate of surgical resections in PCa patients with LA or BR tumors, which were initially deemed inoperable at the time of diagnosis. R randomized, Non-R non randomized, LA locally advanced, NR not resectable, M metastatic, Re resectable, PR partial response, CR complete response, pCR pathological complete response, pRR pathological response rate, DCR disease control rate, AE adverse events, CAR T cells chimeric antigen receptor modified T cells, IRE irreversible electroporation, PFS progression-free survival, OS overall survival, RECIST response evaluation criteria in solid tumors, SoC standard of care, CTx chemotherapy, ATx adjuvant therapy, DHT delayed hypersensibility, CTCAE common terminology criteria for adverse events, ECG electrocardiogram, PFS progression-free survival, MTD maximum tolerated dose, STBR stereotactic body radiation, ORR objective response rate, RP2D recommended phase 2 dose, RDE recommended dose for expansion, DCR disease control rate, TIL tumor-infiltrating lymphocytes, DLT dose-limiting toxicity rates (78.8%) compared with patients who underwent upfront surgery (26.7%) [36] In line with these results, Bachellier et al reported remarkably prolonged survival in neoadjuvantly treated patients (23 months) compared with upfront resected PCa patients (13.7 months) after extended pancreatectomies involving AR [37]. In line with these observations, Brooks et al demonstrated that only the combination of neoadjuvantly applied gemcitabine and a PD-1 inhibitor, but not adjuvant treatment, effectively suppressed local tumor recurrence and improved survival in a transgenic mouse model of PCa [52]
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