Given the high rate of distant relapse after surgical resection of PDAC, systemic therapy is essential for curative treatment. Phase III studies have shown the benefit of adjuvant chemotherapy in prolonging disease-free survival (DFS) and overall survival (OS) over surgery alone, with regimens including FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin), gemcitabine/capecitabine, and gemcitabine/nab-paclitaxel (G-NP) improving OS over gemcitabine alone (1–5). An important consideration is that patients enrolled in adjuvant therapy trials represent a highly selected group, having successfully recovered from surgery. Neoadjuvant chemotherapy has been driven by several ideas: (a) Treating occult metastatic disease early may improve outcomes. (b) Pancreatic surgery is morbid, and postoperative complications may delay or prevent adjuvant therapy. Delivering therapy before surgery ensures chemotherapy exposure. (c) Chemotherapy prior to surgery is better tolerated. (d) Neoadjuvant therapy allows for response assessment. (e) Patients with refractory disease may avoid non-therapeutic surgery. (f) Preoperative therapy provides observation time to manage comorbidities and optimize patient fitness for successful surgery recovery.

Remarkably, even though neoadjuvant therapy has been delivered for decades, there remains extremely limited level 1 data directly comparing neoadjuvant to adjuvant therapy. Most studies of “neoadjuvant therapy” have used perioperative chemotherapy rather than total neoadjuvant chemotherapy. Table 1 summarizes landmark studies utilizing perioperative chemotherapy for PDAC (6). Several conclusions can be drawn. Patients treated with perioperative chemotherapy on average receive a greater percentage of intended chemotherapy in the preoperative period rather than the adjuvant setting. Most studies incorporating neoadjuvant therapy also demonstrated a reduction in positive lymph nodes and found an improvement in rates of margin-negative (R0) resection, both prognostic factors for OS.

Recent landmark phase II/III neoadjuvant trials in localized pancreatic adenocarcinoma

Neoadjuvant therapy has many hypothesized advantages, but it poses multiple clinical challenges. These include the need for preoperative tissue diagnosis, preoperative biliary drainage in jaundiced patients, and venous access for chemotherapy. Monitoring patients during chemotherapy requires a coordinated multidisciplinary team to swiftly address treatment-related toxicity and biliary stent complications. Failure to address these issues may threaten patients’ candidacy for surgical resection. The NORPACT-1 phase II trial reported superior survival in patients undergoing pancreatectomy and adjuvant chemotherapy compared with intended 4 cycles of neoadjuvant FOLFIRINOX and adjuvant therapy (10). The study has faced numerous critiques, further emphasizing the need for level 1 data in this area. Two identically designed phase III trials comparing perioperative FOLFIRINOX (four cycles of neoadjuvant and two cycles of adjuvant therapy) are nearing full accrual in the United States (Alliance A021806) and Europe (PREOPANC-4) (Table 1). These studies will offer new insights into the value of these approaches for managing patients with resectable PDAC. Despite the results, given PDAC’s known inter- and intrapatient heterogeneity, many questions will remain — questions tracing back to our limited understanding of how systemic therapies impact PDAC biology. Major unanswered questions include:

Can we identify biomarkers to select patients who should receive neoadjuvant therapy versus undergoing upfront surgical resection? Often clinicians will select neoadjuvant therapy in those they judge to be at high risk for rapid relapse; however, specification of the prognostic factors predictive of rapid relapse remains imprecise. Molecular diagnostics such as circulating tumor DNA (ctDNA) are under active investigation to more precisely define radiographically occult disease. Early studies clearly suggest that detection of ctDNA prior to surgery and after neoadjuvant therapy are negative prognostic factors for resection. For example, data from the PANACHE01-PRODIGE48 trial demonstrated a median OS of 19.4 months in patients with a preoperative carbohydrate antigen 19-9 (CA19-9) level greater than 80 U/mL who also had detectable ctDNA and 30.2 months in the CA19-9–high or ctDNA+ group, and OS was not reached in the CA19-9–low or ctDNA– group (log-rank P = 0.0069) (11). Similarly, in a study of resected PDAC patients, the median relapse-free survival was 13 months for patients in whom postoperative ctDNA was positive versus 22 months for those with negative ctDNA (P = 0.003) (12). Such data suggest that we may be able to define parameters predictive of very poor outcomes from surgery; such patients would be ideal candidates for neoadjuvant therapy using novel therapeutic approaches, among them vaccine strategies discussed in the next section. However, low sensitivity and thus a poor negative predictive value severely limit the utility of ctDNA at present (13).

What is the optimal duration of neoadjuvant/adjuvant therapy? Typically, preoperative therapy duration is guided by patient tolerance and clinical measures of response, including radiographic response and CA19-9 when detectable. No prospective studies have addressed this question specifically, while retrospective studies suggest that longer durations of neoadjuvant therapy are associated with better outcomes. However, these findings are biased, as treatment-related toxicity or ineffectiveness usually causes therapy to stop. Our inability to accurately define clinical benefit from neoadjuvant therapy remains a large gap that is currently being addressed by molecular diagnostics and imaging strategies. The most straightforward approach uses PET scans to assess for clinical response. A Mayo Clinic group reported that PET responses were prognostic for improved outcomes after neoadjuvant therapy (14). Other approaches under investigation include radiomics and molecular diagnostics like ctDNA (15). Improving our ability to understand the clinical benefit of neoadjuvant therapy in real time will help us individualize treatment duration more precisely, improving survival and reducing treatment-related toxicity.

Recently, SWOG 1505 noted greater median dose density of both modified FOLFIRINOX (mFOLFIRINOX) and G-NP when received preoperatively versus postoperatively (mFOLFIRINOX preoperative 87.5% vs. postoperative 59.6%, P < 0.001; G-NP preoperative 77.3% vs. postoperative 51.7%, P < 0.001) (7). In this study, dose density received was associated with median survival (8). Similarly, a recent retrospective single-institution study of 225 patients who underwent pancreatectomy for stage I/II PDAC found that regardless of treatment sequence, completion of at least 67% of the recommended number of chemotherapy cycles was associated with improved OS (median OS, 34.5) compared with less than 67% of cycles (median OS, 17.9 months; HR, 0.39; 95% CI, 0.24–0.64) (9). However, neoadjuvant therapy was associated with a greater likelihood of receiving more than 67% of prescribed cycles of chemotherapy. An analysis of ESPAC-3 data demonstrated that completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor for survival after resection (16). A recent retrospective study examined the duration of adjuvant chemotherapy after preoperative FOLFIRINOX and found that adjuvant treatment improved survival (17). The effect was most pronounced in patients receiving less than 4 months of preoperative therapy, consistent with prior data suggesting that receipt of a minimum of two-thirds of prescribed therapy is beneficial.

Is it beneficial to switch neoadjuvant chemotherapy? For patients who receive perioperative therapy, a common clinical dilemma involves determining criteria for changing therapy either during the neoadjuvant component or in the adjuvant setting. There are prospective data to guide such decisions, but a recent meta-analysis of five retrospective studies involving 863 patients who underwent neoadjuvant therapy for localized PDAC found that 20% of patients underwent chemotherapy switching (18). Of these, 42% underwent curative-intent resection, and their survival was comparable to that of patients receiving first-line chemotherapy. Three phase II trials (NCT03322995, NCT04594772, and NCT04539808, ClinicalTrials.gov) are currently in progress in the United States evaluating chemotherapy switching for patients with potentially resectable PDAC. All are non-randomized phase II studies using FOLFIRINOX, each with slightly different criteria for switching to G-NP. While these studies will provide additional new data, ultimately only a randomized trial can definitively address the question of whether changing therapy in the neoadjuvant setting is of benefit, and unfortunately these studies’ relevance may be overrun by the emergence and integration of predictive biomarkers and more effective systemic therapies, namely KRAS inhibitors, as discussed in the next section.

How will our evolving understanding of PDAC biology and KRAS inhibitors change our approach to adjuvant/neoadjuvant therapy? Identifying basal and classical transcriptional subtypes of PDAC has led to studies on whether this biology predicts response or resistance to systemic therapies (19). Early data suggested that the basal subtype may be more resistant to FOLFIRINOX versus G-NP, with ongoing studies of biomarker-selected neoadjuvant therapy, including one using the Purity Independent Subtyping of Tumors (PurIST) classifier to differentiate basal versus classical subtypes (NCT0468331) (20). Recent preclinical data suggest that PDAC has distinct tumor-intrinsic kinomes related to basal and classical subtyping, which have implications for therapeutic response (21). For instance, basal-subtype tumors were more reliant on EGFR signaling and thus more responsive to EGFR inhibitors. Emerging data suggest that classical-subtype tumors may be more resistant to KRAS inhibition, a hypothesis that needs clinical testing (22). With pan-KRAS and KRASG12D-specific inhibitors entering late-phase trials for advanced disease, the next frontier will be their incorporation into the treatment of resectable disease. Given that response rates in chemorefractory advanced PDAC have ranged from 20% to 30% and disease control rates have approached 90%, it is hypothesized that KRAS inhibitors will markedly improve outcomes for resectable disease (23, 24). We need to understand whether there is a biological rationale for timing these therapies relative to surgical resection. Effective therapy prior to an operation could improve margin-negative surgery and reduce procedure-related tumor cell dissemination. Alternatively, reducing tumor cell burden via surgery may enhance the effectiveness of adjuvant KRAS inhibitors. Addressing such questions with preclinical studies is challenging, necessitating next-generation clinical trials that integrate these biomarkers to understand the place of these emerging therapies in managing patients with resectable PDAC, and that integrate them with cytotoxic regimens with proven, though modest, benefit.