REDISCOVER guidelines for borderline-resectable and locally advanced pancreatic cancer: management algorithm, unanswered questions, and future perspectives

Resection and reconstruction of the superior mesenteric artery

The REDISCOVER guidelines recommend LA-PDAC resection in carefully selected patients. However, pancreatectomy with resection and reconstruction of the superior mesenteric artery (PRR-SMA) could not be recommended because of lack of consensus after the audience vote (72%). The majority of experts had agreed on PRR-SMA on the online Delphi rounds (88%).

There is no evidence that involvement of the superior mesenteric artery portends a worse prognosis when compared to the same degree of local tumor spread around the celiac trunk [25]. In fact, following neoadjuvant treatments, there is even no evidence that the prognosis of LA-PDAC is inferior to that of BR-PDAC, further reinforcing the concept of prognosis-based resectability [13, 25]. Most audience's concerns regarding PRR-SMA regarded the high level of technical difficulty of this procedure that typically leads to high rates of morbidity and mortality.

PRR-SMA is clearly a complex procedure, but postoperative outcomes are rapidly improving because of technical refinements and growing experience [20]. Two recent studies from China proposed the adoption of intestinal autotransplantation to overcome the challenges of PRR-SMA. Combining the data of these two studies, 46 PRR-SMAs were performed. Severe postoperative complications occurred in 17 patients (37%) and two patients died (4.3%) [23, 24]. In a recent Western study, 95 PRR-SMA were reported from a single center. In 91 and 32 patients, respectively, the superior mesenteric vein (96%) and the celiac trunk/hepatic artery (34%) were also resected. Upon completion of the learning curve (37 procedures) 3 of 58 patients died within 90 days (5.2%) [21]. These data favorably compare with the prohibitive mortality (11.8%) reported, only 10 years ago, for all types of pancreatectomy with arterial resection (11.8%), as well as, with a more recent systematic review on 70 PRR-SMA (20%) [26, 27].

Further experience with PRR-SMA should continue, beyond the REDISCOVER guidelines, only in centers with specific skills and experience. Data should be recorded in international registries, such as the REDISCOVER registry, or reported in prospective observational studies. Diffusion of PRR-SMA is unlikely to occur quickly, but denying resection solely because of lack of surgical experience should be carefully considered. While proficiency is progressively gained in relatively less complex procedures, consideration should be given to refer these patients to expert centers.

Management strategies for LA-PDAC patients fit for surgery unable to undergo multi-agent neoadjuvant chemotherapy

Most data concerning the survival advantage of neoadjuvant chemotherapy refer to multi-agent chemotherapy [28]. In a recent Scandinavian study approximately 20% of the patients with BR-PDAC and LA-PDAC could only receive best supportive care. FOLFIRINOX was delivered to only 50% of the patients while 15% received single-agent chemotherapy with gemcitabine. In the FOLFIRINOX group 53% of the patients suffered grade 3–5 adverse events and two of them died (1.9%) [13]. In an intention-to-treat study, 216 of 254 patients (85.0%) experienced FOLFIRINOX-related toxicity. Grade 3–4 toxicity was documented in 109 patients (42.9%), 100 patients required inpatient admission and management, while 73 patients (28.7%) required an emergency department admission. Poor tolerability (46.3%) was the main reason for not completing the 8 planned cycles of FOLFIRINOX [12]. The probability to receive multi-agent chemotherapy is mostly influenced by age and performance status. Only 10% of the patients aged 75 years or older can receive FOLFIRINOX and less than half of them complete the treatment [29]. More than half of patients receiving FOLFIRINOX require a biliary stent and almost a third of them requires additional endoscopic interventions for obstructed stents and/or cholangitis resulting in treatment delay and/or dose reduction. Overall, over 20% of the patients who are initiated on FOLFIRINOX fail to complete the number of planned cycles [12]. The possibility to receive FOLFIRINOX chemotherapy is not influenced by local tumor status [12, 29].

Therefore, it is clear that not all patients can receive multi-agent primary/neoadjuvant chemotherapy. Some of these patients, however, may be fit for surgery. The REDISCOVER guidelines acknowledged that upfront surgery may improve survival in BR-PDAC when multi-agent neoadjuvant chemotherapy cannot be delivered, but could not provide a similar recommendation for LA-PDAC. In these patients, efforts should be maximized to permit delivery of multi-agent neoadjuvant chemotherapy, failing which proceeding with resection does not appear to provide a clear oncological advantage.

Management of LA-PDAC patients fit for surgery exhibiting elevated serum Ca 19.9 levels post-neoadjuvant oncology treatments

The probability of radical resection is predicted by the Ca 19.9 level, which carries clear prognostic implications in PDAC [30, 31]. Ca 19.9 levels of > 500 kU/L are a biologic factor associated with borderline resectability [9]. Long-term survival following resection is predicted by both a decrease in Ca 19.9 of ≥ 50% and a normalization of Ca 19.9 in response to neoadjuvant oncology therapies [32, 33]. Depending on pretreatment levels, between 66 and 22% of patients achieve normalization of Ca 19.9 levels [32]. The best indicators to anticipate favorable survival are a baseline level of Ca 19.9 < 80 kU/L and a response to treatment of ≥ 85% [33, 34]. Predicting post-resection outcomes is further improved by Ca 19.9 dynamics during oncology treatments [35].

However, following neoadjuvant oncology therapies, Ca 19.9 level does not decrease or rises in approximately 10% of patients [33]. Some of these patients are fit for surgery, have no evidence of distant metastasis, and harbor a potentially resectable tumor. If “high” Ca 19.9 levels persist following chemotherapy switch, the surgeon is faced with the difficult dilemma of denying resection based only on Ca 19.9 levels. In these patients, according to oncology guidelines, the most sensible course of action is radiation treatment [15, 19]. However, the REDISCOVER guidelines recommended resection for BR-PDAC with stable/rising Ca 19.9 levels but denied this possibility for LA-PDAC. Considering LA-PDAC and BR-PDAC share the same biology, once again, technical complexity and higher operative risk were the main reasons to deny resection in LA-PDAC in the absence of favorable Ca 19.9 response.

Optimal number of chemotherapy cycles pre-surgery

There is no agreement about the ideal number of cycles of chemotherapy before resection. The 2024 NCCN guidelines recommend ≥ 2 to 6 cycles of gemcitabine plus cisplatin in BRAC mutated patients, and ≥ 4 to 6 cycles of all the other chemotherapy regimens (namely, FOLFIRINOX, m FOLFIRINOX, NALIRIFOX, and gemcitabine plus albumin-bound paclitaxel) [15]. The 2023 ESMO guidelines do not recommend a specific number of cycles [19]. A recent, phase 2, randomized and controlled trial employed 8 cycles of mFOLFIRINOX as a neoadjuvant chemotherapy regimen for BR-PDAC and found that this regimen was superior to 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy or hypofractionated image-guided radiotherapy [36]. The ESPAC5 trial compared different short-course neoadjuvant oncology regimens (gemcitabine plus capecitabine: two cycles; FOLFIRINOX: four cycles; and capecitabine-based chemoradiotherapy: capecitabine 830 mg/m2 twice a day orally over the 5.5 weeks of radiotherapy) versus upfront surgery in BR-PDAC. Neoadjuvant chemotherapy (either gemcitabine plus capecitabine or FOLFIRINOX) had the best survival compared with upfront surgery [37].

An international cohort study of 520 patients evaluated adjuvant chemotherapy in patients with resected pancreatic cancer after at least 2 cycles of neoadjuvant FOLFIRINOX treatment (47% resectable PDAC; 40% BR-PDAC; 10% LA-PDAC; 3% stage unknown). The median number of neoadjuvant FOLFIRINOX cycles was 6 for patients who received adjuvant therapy and for those who did not [38]. In a recent systematic review and meta-analysis, the median number of FOLFIRINOX cycles administered to with LA-PDAC ranged from 4.9 to 11.5. The number of FOLFIRINOX cycles did not influence the rate of surgical resection and R0 resection [39]. In a similar study on BR-PDAC the median number of FOLFIRINOX cycles was ranged from 4 to 9. The median number of chemotherapy cycles did not affect overall survival [40].

In a systematic review and meta-analysis on neoadjuvant gemcitabine plus nab-paclitaxel in BR-PDAC and LA-PDAC, the median number of chemotherapy cycles ranged from 2 to 8 [41]. In a single-center retrospective study the median number of neoadjuvant gemcitabine plus nab-paclitaxel for BR-PDAC was 3 (range 1–10) [42]. In the recent NORPACT-2 trial, the number of neoadjuvant chemotherapy cycles was 4 for FOLFIRINOX and 2 for gemcitabine plus nab-paclitaxel [13].

It is evident that we lack clarity regarding the ideal number of chemotherapy cycles to administer before surgery in patients with BR-PDAC and LA-PDAC. Moreover, the influence of dose reductions and the extent of dose reduction on the identification of suitable surgical candidates remains uncertain. There is an urgent need for further research to address these critical questions.

Comparative efficacy of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC

Primary chemotherapy is typically favored in LA-PDAC due to its ability to achieve systemic disease control and potentially induce downstaging of the primary tumor. However, it may not adequately address local disease control in all patients.

Primary chemoradiotherapy combines the cytotoxic effects of chemotherapy with the locoregional control provided by radiotherapy. In theory, it should be beneficial for LA-PDAC where achieving local disease control is a priority. Studies evaluating primary chemoradiotherapy in LA-PDAC have shown promising results in terms of local tumor response, downstaging, and achieving negative surgical margins. However, chemoradiotherapy does not seem to improve overall survival. A meta-analysis of 5 randomized controlled trials revealed that chemoradiotherapy did not confer a survival advantage compared to chemotherapy alone but increased the rates of grade 3 to 4 adverse events [43, 44].

Some patients receive primary chemotherapy followed by consolidation radiotherapy. Although these patients are not initially considered surgical candidates, some of them may eventually undergo surgery due to stable disease and good clinical conditions. However, surgery in these patients is technically more complex due to the consolidation of radiotherapy effects into retroperitoneal scarring tissue. Whenever possible, radiotherapy should be used for neoadjuvant purposes.

The choice of oncological treatment in LA-PDAC is often based on the practices and preferences of individual institutions. Therefore, defining the optimal treatment pathway is a key research objective.

Appropriate timing for surgical resection post-neoadjuvant/primary chemoradiotherapy

The optimal timing for surgical resection in patients with BR-PDAC or LA-PDAC following neoadjuvant or primary chemoradiotherapy is still a topic of debate and ongoing research.

A study demonstrated that prolonging the interval between completion of chemoradiotherapy and surgery, with continued chemotherapy, for up to 20 weeks was linked with several benefits. These included an enhanced pathologic response and an extended median overall survival [45].

However, despite these findings, consensus has yet to be reached regarding the precise timeframe for surgery after chemoradiotherapy in these patient populations. Consequently, determining the optimal timing for surgical intervention after chemoradiotherapy remains a significant research objective.

Role of ablation therapies

Different ablation techniques have been developed and proposed especially for LA-PDAC. Non-thermal ablation techniques include irreversible electroporation, stereotactic body radiation, photodynamic therapy, and brachytherapy. Thermal ablation therapies include high-intensity focused ultra-sound, cryoablation, radiofrequency ablation, microwave ablation, and laser-induced thermotherapy. Irreversible electroporation holds significant promise; however, to date, all of these approaches are still considered investigational and lack an established role in the management of BR-PDAC and LA-PDAC [46, 47].

Management of patients with oligometastasis and LA-PDAC

PDAC often exhibits early metastatic dissemination. Initially, metastases may be microscopic and undetectable. Once metastases become visible, regardless of their number, the disease is considered systemic, and treatment typically revolves around chemotherapy.

The concept of oligometastasis has emerged as a result of recent advancements in oncology. In this scenario, the number and sites of metastases are limited making localized cancer treatments of potential benefit. Examples include liver metastases from colorectal cancer, lung metastases from various primary tumors, and adrenal metastases from lung cancer [48]. However, a clear definition specifying the maximum number of metastases qualifying as oligometastasis is lacking.

In PDAC, metastases are primarily found in the liver, peritoneum, or lungs. Lung metastases may exhibit a less aggressive biological behavior. Resection of isolated lung metastases in PDAC is already considered a treatment option for carefully selected patients [49]. In the abdomen, the concept of oligometastasis primarily pertains to liver metastases. Generally, in patients who demonstrate a robust response to chemotherapy over 8–9 months and exhibit no signs of tumor progression shortly after discontinuing chemotherapy, resection of liver metastases alongside the primary tumor is being considered for carefully selected individuals [50].

In LA-PDAC, the concept of oligometastasis has not been extensively explored, likely due to concerns regarding the complexity of surgery. Furthermore, when metastases were initially occult, distinguishing between synchronous metastases that responded to treatment and metastases that developed despite oncology treatments can be challenging.

Future studies should endeavor to establish a clear definition of oligometastasis in PDAC and elucidate its prognostic implications and treatment options, particularly for LA-PDAC.