Neoadjuvant therapy in pancreatic cancer: what is the true oncological benefit?

Curative R0 resection remains the only chance for long-term survival in PCa [22, 23]; however, approximately half of the resections are microscopically incomplete and two-thirds of initially R0-diagnosed patients will develop local recurrence [24]. Despite the prognostic relevance of the pathological resection rate, a standard definition for R0 resection is still lacking, which leads to high variability on R0 resection rates that range between 15% and 92% [1, 24‐26]. After the introduction of a standardized pathology protocol consisting of axial slicing technique, multicolor margin staining and extended sampling, and a circumferential resection margin (CRM) > 1 mm, the R1 rate significantly increased from 14 to 76% in a retrospective study carried out by Esposito et al. [27, 28]. These observations indicate that resection margin involvement is a common finding in PCa which is often underestimated due to the lack of a standardized pathological examination of all relevant margins [28] and insinuated the need to increase surgical radicality in other to obtain wider resection margins and higher R0 rates. In line with these results, a retrospective study with 360 patients revealed similar local recurrence rates of R0- and R1-staged PCa patients suggesting the widespread presence of undiagnosed microscopic residual disease. Further intercontinental discrepancy is reported on the definition of R0 status, which is 0-mm tumor distance from resection margin in the USA and > 1 mm in Europe and Australia [1, 24, 27, 29, 30]. In our recent meta-analysis assessing the importance of the resection status in PCa, we demonstrated that even with standardized pathology protocols, resection margin’s prognostic validity may be primarily confined to pancreatic head tumors [24].

Pancreatic surgeons are continuously developing new strategies to increase surgical radicality and improve R0 resection rates [4]. The feasibility of portomesenteric venous resection has been widely demonstrated. In contrast, extended arterial involvement remains a controversial issue in the management of PCa. Although tumor encasement of the superior mesenteric artery, common hepatic artery, or celiac artery defines local irresectability according to current guidelines, advances in the field of pancreatic surgery have turned the focus on redefining strategies that allow more radical approaches involving the resection and reconstruction of major peripancreatic arteries, to achieve R0 resection in patients without distant metastasis [4, 31].

In the first meta-analysis evaluating AR in patients undergoing pancreatectomy for PCa, AR was discouraged as standard of care and was associated with remarkably higher perioperative morbidity (OR = 2.17) and mortality (OR = 5.04) and poor survival (OR = 0.50) [4]. Conversely, in a recent study, Del Chiaro et al. demonstrated the feasibility and safety of AR in pancreatectomy, which was accompanied by increased survival compared with palliative procedures and showed no difference in postoperative mortality and morbidity, even though it was associated with longer operation time and higher blood loss [31, 32]. Consistent with these results, Sonohara et al. demonstrated that PCa patients with AR had marginally higher recurrence-free survival and longer overall survival without a significant increase in the incidence of severe postoperative complications [33]. Current studies evaluating celiac artery resection also showed that these procedures can be performed safely and with an encouraging median survival [32, 34]. Further analyses suggested the improvement to be a consequence of newly developed and more effective chemotherapeutical regimens used in neoadjuvant settings. The increasing use of neoTx has notably increased the rate of R0 resections in patients with initially suspected arterial infiltration [35] and has led to significantly higher survival 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]. Therefore, neoTx appears to provide an additional benefit to AR in patients with BR and LA PCa undergoing extended pancreatectomy by decreasing tumor burden and arterial invasion [33, 38]. In the case of adequate therapeutic response and good performance status, resectability should be re-assesed via surgical exploration, as cross-sectional images often fail to identify the extent of the remaining viable tumor. Combining AR with pancreatectomy in these cases increases the feasibility of R0 resection, which is still the only option to achieve long-term survival [39]. Here, neoTx should be performed rather than upfront surgery. Clinical trials analyzing the superiority of combined chemotherapeutical regimes and radical surgical resections are still needed and ongoing [4, 40‐42].

Cancer immunotherapy has demonstrated remarkable therapeutic efficacy in many solid malignancies [43]. Due to low tumor mutational burden and the presence of a highly immunosuppressive TME, immunotherapies have consistently failed to elicit the expected outcomes in PCa [44]. This limitation may be circumvented by the application of immunotherapy in a neoadjuvant setting, with the primary tumor serving as an antigen source for in situ T cell priming that may unleash a more potent antitumoral immune response compared with adjuvant approaches [45]. Current neoTx in PCa mostly relies on classical chemotherapy regimens such as FOLFIRINOX and does not make use of immune-based and molecular-targeted therapies. Surprisingly, we observed an immunological shift toward more cytotoxic inflammation in the 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.

Ongoing trials on PCa are now focusing on combinatorial approaches exploiting the ability of cancer vaccines to promote T cell recruitment followed by the subsequent activation of cytotoxic cells by checkpoint inhibitors (ICIs) or immunomodulatory agents [48]. The inhibition of T cell checkpoints such as T lymphocyte protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) has shown enormous promise in a number of cancer types [49, 50] by unleashing tumor-specific cytotoxic T cells that already reside in TME before treatment [51]. So far, none of these antagonists has proven effective in PCa [48]. However, the combination of a CD40 agonist with nab-paclitaxel plus gemcitabine resulted in partial response in 4 of 21 patients with PCa, and a clinical trial for its use as a neoadjuvant is underway (NCT02588443). Adoptive immunotherapy involves the injection of tumor reactive immune cells into patients and has increasingly gained attention over the past years. Although the first clinical trials with chimeric antigen receptor (CAR) T cells or tumor-pulsed dendritic cells in advanced PCa have shown promise [48], adoptive approaches have yet not been tested in neoadjuvant settings in PCa. The number of clinical trials evaluating the use of neoadjuvant immunotherapy is limited compared with its use within palliative approaches (Table 1).

In low mutational tumors such as PCa, neoTx may be particularly beneficial to potentiate the antitumor immune response compared with adjuvant approaches, as the tumor epithelium itself remains an essential source for the release of tumor antigens and cross-priming of tumor-directed T cell responses. This important reservoir for induction of tumor-directed immune responses is no longer available after tumor resection [52]. Liu et al. administrated various combination immunotherapies in either neoadjuvant or adjuvant setting and discovered that regardless of the type of immunotherapy used, neoadjuvant approaches were superior to adjuvant treatments in primary breast tumors [53]. 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].