Hot Keywords
Tumor Microenvironment Exosomes and Extracellular Vesicles Breast Cancer Metastasis Bone Metastasis Metastatic Renal Cell Carcinoma Lymph node metastasis Mesothelioma Hematological Malignancies Thyroid Cancer Liquid Biopsies Early Diagnosis Lung Cancer Brain Tumors Lymphoma Oncolytic Virus Cervical Cancer Cancer Stem Cells

Top
J Cancer Metastasis Treat 2022;8:38. 10.20517/2394-4722.2022.43 © The Author(s) 2022.
Open Access Review

Neoadjuvant treatment of pancreatic ductal adenocarcinoma: present and future

1Oncology Unit, Aretaieio University Hospital, National and Kapodistrian University of Athens, Athens 115 28, Greece.

2Radiation Oncology Unit, Aretaieio University Hospital, National and Kapodistrian University of Athens, Athens 115 28, Greece.

3Second Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Athens 115 28, Greece.

Correspondence to: Dr. Ioannis M. Koukourakis, MD, Oncology Unit, Aretaieio University Hospital, National and Kapodistrian University of Athens, V. Sophias 76, Athens 115 28, Greece. E-mail: koukourioannis@gmail.com

    This article belongs to the Special Issue Treatment of Pancreatic Cancer
    Views:35 | Downloads:45 | Cited:0 | Comments:0 | :0
    Academic Editors: Antonio Facciorusso, Palanisamy Nallasamy | Copy Editor: Fangling Lan | Production Editor: Fangling Lan

    © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

    Abstract

    Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with a poor prognosis. Effective treatment with acceptable outcomes is yet to be found, with chemo- and radioresistance comprising major impediments towards this goal. Although upfront surgery is the established therapeutic approach for resectable and borderline resectable disease, neoadjuvant treatment has recently monopolized the interest in clinical trials. This also applies to locally advanced pancreatic adenocarcinomas that could potentially be rendered operable. Chemotherapy and chemoradiotherapy are the most utilized therapeutic modalities in the neoadjuvant setting, while immunotherapy and targeting agents have been gaining significant attention. This critical review focuses on the clinical experience gained from retrospective and phase II/III randomized trials, reporting on the outcomes of neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Moreover, the ongoing trials, including those that involve immunotherapy and targeting agents, are summarized.

    INTRODUCTION

    Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most challenging malignancies due to the high mortality rates and the lack of effective treatment. According to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute of the United States of America, there were an estimated 60,430 new PDAC cases and 48,220 deaths in 2021[1]. Its increasing incidence has been attributed to numerous causative factors, including cigarette smoking, diabetes mellitus, obesity, alcohol consumption, pancreatitis, and a family history of pancreatic cancer[2]. Germline mutations concerning BRCA2, BRCA1, PALB2, ATM, CDKN2A, MSH2, MSH6, and TP53 have been shown to be present in up to 9.7% of PDAC cases. Somatic alterations in KRAS, TP53, CDKN2A, and SMAD4, on the other hand, are detected in nearly all of PDAC[3]. The best-studied mutations concern KRAS and are thought to be responsible for the progression of pancreatic intraepithelial neoplasia to PDAC by triggering metabolic, signaling, apoptotic, and homeostatic pathways[4]. Furthermore, BRCA1 and BRCA2 mutations, involved in the pathogenesis of breast and ovarian cancer, also characterize familial PDAC[5]. Therefore, meticulous monitoring of patients with a familial history of the aforementioned malignancies could allow early detection of a significant proportion of PDACs and, moreover, introduce early detection genetic tests.

    PDACs are usually classified as resectable (R-PDAC), borderline resectable (BR-PDAC), and unresectable-locally advanced (LA-PDAC)[6]. This classification reflects the different prognoses and therapeutic approaches applied. Although surgery is considered the backbone of therapy for R-PDAC and BR-PDAC, there has recently been a shift of focus towards neoadjuvant therapies in these two categories. Due to its extremely fast metastatic potential and subsequent unfavorable prognosis, it is believed that localized PDAC, in most cases, represents a metastatic disease in its early stages. In this context, neoadjuvant treatment could exhibit dual function. The first concerns the eradication of micrometastatic lesions and the increased probability of completion of systemic therapy, as a large proportion of patients are not fit to receive postoperative chemotherapy. The second one aims at recognizing diseases that will progress even during systemic therapy, thus suggesting a highly aggressive biological behavior. The subset of patients with PDAC bearing these adverse properties will avoid unnecessary surgical operations, which is often associated with a sharp decrease in the quality of life. Moreover, neoadjuvant chemotherapy or chemoradiotherapy (chemo-RT) could lead to tumor downstaging locally, facilitating surgery and a potential R0 resection[7-9]. The above rationale certainly applies to locally advanced disease, assumed inoperable at diagnosis, as preoperative chemotherapy and radiotherapy could down-stage the disease and allow a reappraisal of surgery.

    This review focuses on the clinical experience gained from retrospective and phase II/III randomized trials, reporting on the outcomes of neoadjuvant chemotherapy and chemo-RT for PDAC. Moreover, the currently ongoing trials, including those that involve immunotherapy and targeting agents, are summarized. The literature search was performed in the EMBASE and MEDLINE databases using the text words “pancreatic adenocarcinoma”, “neoadjuvant”, “chemotherapy”, “radiotherapy”, “immunotherapy”, “targeting agents”, and “surgery”. Phase II and III studies published between 1990 and April 2022 were retrieved. Ongoing phase II and III trials were identified on ClinicalTrials.gov.

    CHEMO- AND RADIORESISTANCE

    Chemoresistance is one of the most prominent challenges physicians have to face when treating different types of malignancies. As far as PDAC is concerned, genomic alterations, such as KRAS and SMAD4 mutations and TP53 inactivation, were originally believed to be the main drivers of the increased chemoresistance of PDAC. In a study by Yang et al., chemosensitivity to gemcitabine and cisplatin was increased in KRAS shRNA knockdown pancreatic cancer cells, suggesting that KRAS oncogene expression is linked with resistance to chemotherapeutic drugs[10]. Similarly, TP53 mutations of pancreatic cancer were associated with higher resistance to chemotherapy with gemcitabine[11]. Extensive research in the field, however, has supported that additional intracellular mechanisms and tumor microenvironment are equally important factors that reduce the efficacy of chemotherapy in pancreatic malignancies[12]. Altered expression of key enzymes involved in critical metabolic cellular pathways, such as aerobic glycolysis and glutamine metabolism, appears to induce a chemoresistant phenotype in pancreatic cancer cells[13]. Moreover, epigenetic mechanisms and especially target of methylation induced silencing 1 (TMS1) methylation are involved in acquired chemoresistance[14]. As far as the tumor microenvironment is concerned, PDAC is characterized by a dense extracellular matrix and fibroblastic stroma, which leads to decreased bioavailability of drugs in the tumor and, subsequently, diminished efficacy of the various chemotherapy regimens[15]. Pancreatic stellate cells and cancer-associated fibroblasts contribute to this chemoresistant phenotype through various mechanisms, including the production of components of the tumor stroma and the prevention of H2O2-induced apoptosis[12]. Finally, a study by Amit et al. demonstrated the inactivation of gemcitabine by tumor-associated macrophages, implying the potential role of the innate immune system in chemoresistance[16].

    Drug-specific resistance pathways may also be active in PDAC. Gemcitabine is one of the most used drugs - in combination with nab-paclitaxel - and as a deoxycytidine analog, it interferes with DNA synthesis. Suppression of the nucleoside transporter hENT1 gene or alterations of the function of deoxycytidine kinase and ribonucleoside reductase contribute to the resistance of pancreatic cancer cells to gemcitabine[17]. Overexpression of the dihydropyrimidine dehydrogenase and thymidylate synthase is involved in the resistance to gemcitabine and 5-FU[18]. Irinotecan is also a major drug for PDAC, used in the FOLFIRINOX [5-FU/leucovorin/irinotecan/oxaliplatin (FFX)] regimen. The activity of carboxyl-esterase-2 (CES2) in cancer cells is essential for the transformation of irinotecan to the SN-38 active derivative, and low expression of CES2 has been associated with poor prognosis in BR-PDAC[19]. Furthermore, DNA repair enzymes define the resistance of pancreatic cancer cells to platinum compounds and radiation; the excision repair cross-complementing proteins (ERCC) 1, 2, and 4 render cancer cells resistant to platinum agents, although a recent study failed to show any association between these enzymes and response to FFX chemotherapy[20]. Common resistance mechanisms to paclitaxel chemotherapy include taxane-metabolizing enzyme activity (e.g., CYP1 enzymes), overexpression of multidrug resistance proteins regulating the efflux of taxanes, tubulin gene mutations, and signaling molecules (POLO kinase, Bcl-2, and the ACT pathway)[21].

    Radioresistance is another impediment to the effective treatment of this extremely aggressive malignancy. PDAC is characterized by diffuse hypoxia throughout the tumor and its microenvironment[22]; thus, radiotherapy’s efficacy is quite limited. Moreover, pancreatic stellate cells, as mentioned above, inhibit H2O2-induced apoptosis, one of the main mechanisms through which radiotherapy elicits its cytotoxic properties[23]. Finally, cancer stem cells have been associated with increased radioresistance due to their enhanced ability of DNA repair and slow proliferation[24].

    NEOADJUVANT CHEMOTHERAPY FOR PDAC

    Monotherapy and older chemotherapy regimens for LA-PDAC

    LA-PDAC of the pancreatic head and body/tail is defined by tumor contact of more than 180° with the superior mesenteric artery (SMA) or celiac axis (CA). Body/tails tumors involving the aorta are also deemed inoperable. Finally, the inability to reconstruct the superior mesenteric vein (SMV) or portal vein (PV) due to tumor invasion or thrombus occlusion characterizes LA-PDAC[6].

    The current establishment of FFX and GnP (gemcitabine/nab-paclitaxel) as preferred regimens for neoadjuvant treatment of LA-PDAC was preceded by a long period of clinical experimentation with older drugs and schedules. In 1997, a randomized trial by Burris et al. demonstrated moderately increased survival and improved pain palliation, achieved by gemcitabine alone over 5-FU[25]. The addition of cisplatin to gemcitabine has also been explored with conflicting results. Colucci et al. reported longer median time to disease progression when gemcitabine and cisplatin were combined vs. gemcitabine alone in patients with LA-PDAC or metastatic PDAC, while non-statistically significant better overall survival (OS) was observed[26]. On the contrary, 10 years later, the randomized phase III GIP-1 study showed that the combination of cisplatin and gemcitabine conferred no benefit[27]. A subset of LA-PDAC patients with BRCA mutations appear to be more sensitive to platinum drugs[28] and, as per the NCCN guidelines, gemcitabine-cisplatin is one of the two preferred first-line regimens for locally advanced disease alongside FFX for patients with known BRCA1/2 mutations[6]. An alternative regimen for advanced pancreatic cancer is erlotinib plus gemcitabine. Moore et al. reported that a statistically longer one-year OS can be achieved through these two drugs combined vs. gemcitabine monotherapy, although the benefit is small[29]. Another phase III trial published in 2009 compared gemcitabine monotherapy to gemcitabine plus capecitabine for the treatment of LA-PDAC and demonstrated significantly better response rates and progression-free survival (PFS), as well as a trend towards longer OS with the latter regimen[30]. Finally, a meta-analysis by Li et al. suggested that gemcitabine plus fluoropyrimidine drugs lead to improved OS in comparison to gemcitabine alone[31].

    Towards neoadjuvant FFX and GnP for LA-PDAC

    A phase II study by Conroy et al. introduced FFX in 2005 as an effective drug combination for the treatment of advanced pancreatic disease[32], further prompting the PRODIGE phase III trial that cemented the superiority of this regimen over gemcitabine monotherapy for metastatic PDAC as far as median OS (11.1 vs. 6.8 months), median PFS (6.4 vs. 3.3 months), and objective response rate (31.6% vs. 9.4%) are concerned[33]. These results have also been supported by a meta-analysis of 13 studies assessing the efficacy of FFX over gemcitabine alone with or without subsequent radiation or chemoradiation in LA-PDAC, which reported a median OS of 24.2 months when FFX was utilized vs. a 6-13 months OS achieved with gemcitabine[34]. In addition, FFX rendered LA-PDAC resectable in 76 out of 125 patients (60%) when analyzed retrospectively[35], thus exhibiting another potential benefit from its use. The effectiveness of GnP was originally addressed in a phase I/II study by Von Hoff et al.[36]. Two years later, the MPACT phase III trial, assigning patients with metastatic PDAC to either GnP or gemcitabine monotherapy, displayed longer median OS (8.5 vs. 6.7 months) and PFS (5.5 vs. 3.7 months) with the combined regimen and expanded the available and efficient chemotherapy drugs for this disease[37].

    Following the favorable results obtained in advanced and metastatic PDAC, FFX and GnP were evaluated in the neoadjuvant setting. A retrospective study comparing FFX and GnP as a preoperative regimen in LA- and BR-PDAC showed a survival benefit in patients who achieved pathological response and biochemical marker regression patterns. Both regimens, however, were equally effective, although a better tolerance of GnP should be considered when treating frail patients[38]. Another smaller retrospective study confirmed the equivalence of the two regimens[39]. Neoadjuvant GnP examined in the LAPACT phase II study provided a median OS of 18.8 months[40]. The NEOLAP-AIO-PAK-0113 randomized phase II trial, published in 2021, investigated whether induction chemotherapy with GnP followed by FFX could yield better outcomes than GnP alone[41]. Sequential induction chemotherapy was proven to confer similar results to the GnP regimen. Overall, applying multidrug induction chemotherapy could be a potential means to overcome the inherent chemoresistance of this malignancy [Table 1].

    Table 1

    Published phase II/III trials on neoadjuvant chemotherapy for PDAC

    Author (year)DiseaseType of studyNo ptsControl armNeoadjuvant chemotherapyNeoadjuvant chemo-RTMain findings
    LA-PDAC
    LAPACT; Philip (2020)[ 40]LA-PDACPhase II 107GnP followed by surgery or chemo-RT or GnPOptionalMedian PFS 10.9 months and median OS 18.8 months
    NEOLAP-AIO-PAK-0113; Kunzmann (2020)[41]LA-PDACPhase II (randomized)130No4 cycles of GnP
    2 cycles of GnP followed by 4 cycles of FFX
    NoSimilar results
    (HR 0.86, 95%CI: 0.55-1.36, P = 0.53)
    BR-PDAC
    Yoo (2017)[45]BR-PDACPhase II18NoFFXNoMedian survival 16.8 months
    ESPAC-5F; Ghaneh (2020)[46]BR-PDACPhase II (randomized, 4 arms)88Upfront surgery (group A)FFX (group B) or Gemcitabine/capecitabine (group C)50.4 Gy, 1.8 Gy/fraction
    Concurrent with capecitabine (group 4)
    Better 1-year survival in the neoadjuvant arms 77% vs. 40% (HR 0.27, 95%CI: 0.13-0.55, P < 0.001)
    NUPAT-01; Yamaguchi (2022)[47]BR-PDACPhase II (randomized)51NoA. FFX
    B. GnP
    NoOS is not significantly different between groups
    LA/BR-PDAC
    Lee (2012)[49]LA-PDAC
    BR-PDAC
    Phase I/II43NoGemcitabine and capecitabineNoMedian OS 23.1 months for patients that underwent surgery
    Reni (2018)[48]LA-PDAC
    BR-PDAC
    Phase II (randomized)54NoGemcitabine, nab-paclitaxel, cisplatin and capecitabine
    Nab-paclitaxel followed by gemcitabine
    No1-year PFS 58% (Arm A) vs. 39% (Arm B)
    18-month OS 69% (Arm A) vs. 54% (Arm B) (P = not significant)
    Saito (2018)[50]LA-PDAC
    BR-PDAC
    Phase II24NoGemcitabine, S-1, LVNoResection rate 60.9% (R0 76.5%)
    BR/R-PDAC
    Motoi (2013)[54]BR-PDAC
    R-PDAC
    Phase II36NoGemcitabine and S-1NoMedian OS 34.7 months in R0 resected patients
    R-PDAC
    Heinrich (2008)[52]R-PDACPhase II28NoGemcitabine and cisplatinNoMedian DFS 9.2 months and median OS 26.5 months
    O’Reilly (2014)[53]R-PDACPhase II38 NoGemcitabine and oxaliplatinNoResectability 71% and median OS 27.2 months
    Prep-02/JSAP05; Motoi (2019)[55]R-PDACPhase II/III364Upfront surgeryGemcitabine and S-1NoImproved median OS (36.7 vs. 26.6 months) ) (HR 0.72, 95%CI: 0.55-0.94, P = 0.015)
    NEPAFOX; Al-Batran (2021)[56]R-PDACPhase II/III40Upfront surgery followed by gemcitabineFFXNoImproved survival in the upfront surgery group (25.6 vs. 10.3 months) (HR 0.366, 95%CI: not reported, P = 0.0337)
    SWOG S1505; Sohal et al. (2020)[57]R-PDACPhase II (randomized)103NoFFX and GnP2-year OS improvement not statistically significant (41.6% and 48.8% with FFX and GnP, respectively)
    AIO-NEONAX; Ettrich et al. (2022)[59]R-PDACPhase II (randomized)127Upfront surgery followed by GnPGnP followed by surgery and adjuvant GNPNoLonger median OS in the perioperative chemotherapy arm (25.2 vs. 16.7 months) (HR, P value not reported)
    PAANACHE01-PRODIGE48; Schwarz et al. (20220)[60]R-PDACPhase II (randomized)146Upfront surgery A. FFX
    B. FOLFOX
    No1-year OS rates 84.1% in Arm A vs. 80.8% in the control arm (HR, P value not reported)

    There are no randomized phase III studies that have established either FFX or GnP in the neoadjuvant setting for LA-PDAC. The adoption of these regimens is mainly based on the superiority noted in trials on advanced and metastatic diseases. The choice between the two adopted regimens should be based on the expected tolerance. FFX is usually prescribed to patients with a performance status (PS) score of 0-1, while GnP has a moderately safer toxicity profile. Patients with poor PS are usually treated with gemcitabine monotherapy in a rather palliative setting, as they are unlikely to undergo surgery. In addition, gemcitabine plus cisplatin has been proven to be effective when BRCA1/2 or PALB2 mutations have been detected[6].

    BR-PDAC

    Briefly, BR-PDAC refers to tumors of the pancreatic head with direct contact with the common hepatic artery (CHA) without extension to CA or hepatic artery bifurcation. Encasement of SMA (pancreatic head tumors) and CA (body/tails tumors) should be less than 180°. Inferior vena cava (IVC) involvement and contact with the SMV or PV of more than 180° or vein thrombosis, the extent of which allows safe resection and reconstruction, also define BR-PDAC[6].

    A retrospective study in 2008 reported the effects of neoadjuvant treatment in a cohort of patients with BR-PDAC and suggested a potential survival benefit for patients who proceeded to surgical operation[42]. FFX and GnP have been compared in terms of efficacy for BR-PDAC[43]. Patients who received FFX had a greater probability of undergoing surgery and displayed longer PFS; however, there was no statistically significant difference in OS. A meta-analysis by Janssen et al. of 24 studies of patients with BR-PDAC who received neoadjuvant FFX concluded on the significant impact of this regimen on OS and R0 resection rates, underlining the importance of randomized studies that could confirm these results[44]. A small phase II study utilizing neoadjuvant FFX resulted in a median OS of 16.8 months[45]. The results of the ESPAC-5F four-arm randomized phase II trial, assessing resection rates when immediate surgery was compared to neoadjuvant chemotherapy with gemcitabine plus capecitabine or FFX or neoadjuvant chemoradiation, showed no difference between arms; a significantly longer one-year OS, however, was achieved with neoadjuvant treatment (77% vs. 40%)[46]. Finally, neoadjuvant FOLFIRINOX and GnP were assessed in the NUPAT-01 randomized phase II trial. OS did not differ significantly between groups, with three-year OS rates reaching an overall 54.7% and R0 resections rates achieved in 67.4% of patients[47].

    Other chemotherapy regimens have been applied in phase II trials for BR/LA-PDAC. A randomized phase II study on a four-drug combination (gemcitabine, nab-paclitaxel, cisplatin and capecitabine) vs. sequential nab-paclitaxel and gemcitabine suggested improved OS in the multidrug arm[48]. Two additional phase II studies[49,50] on gemcitabine with capecitabine or S-1 are also mentioned in Table 1, which summarizes published phase II/III trials on neoadjuvant chemotherapy for PDAC.

    R-PDAC

    Although R-PDAC has not been clearly defined, it is commonly accepted that it should not abut or encase the regional vascular structures, namely SMA, CHA, and CA. It is undetermined whether the involvement of SMV and PV contributes to the resectability of this tumor; in the event of contact between tumor and SMV, it should be limited to less than 180° without disrupting the venous contour in all respects[6].

    Due to the lack of sufficient evidence from clinical trials and studies supporting the superiority of neoadjuvant therapy over upfront surgery, the latter is considered as a standard-of-care treatment in resectable tumors despite the high postoperative morbidity rates. Nevertheless, neoadjuvant treatment has gradually gained ground recently, thanks to some favorable results from completed trials. In a pilot study, no benefit in OS and disease-free survival (DFS) was demonstrated in patients who received neoadjuvant chemotherapy with gemcitabine and oral S-1 over patients who underwent surgical resection[51]. Heinrich et al. conducted a prospective phase II trial comparing neoadjuvant chemotherapy with gemcitabine and cisplatin to the resection-first option and reported an OS of 26.5 vs. 19.1 months, respectively, and a similar DFS between the two arms (9.2 vs. 9 months)[52]. O’Reilly et al. proved in a phase II, single-arm trial that neoadjuvant gemcitabine and oxaliplatin may offer surprisingly long OS (27.2 months) and DFS (30.6 months)[53]. Similarly, neoadjuvant gemcitabine and S-1 offered a median OS of 34.7 in R0 patients[54]. The most promising results were published in the PREP-02/JSAP05 phase II/III randomized trial, which showed that neoadjuvant chemotherapy (gemcitabine and S-1) has a statistically significant superiority in OS (36.7 vs. 26.6 months in the upfront surgery group)[55]. Al-Batran et al. reported a phase II/III randomized study (NEPAFOX trial) comparing upfront surgery with adjuvant gemcitabine-based chemotherapy (Arm A) to perioperative FFX (Arm B). The results, however, were disappointing; median OS was 25.68 (Arm A) vs. 10.03 (Arm B) months, respectively, while median PFS was also lower among patients who received neoadjuvant chemotherapy[56]. In 2020, the SWOG S1505 phase II trial demonstrated that neither neoadjuvant FFX nor GnP for R-PDAC was associated with a statistically significant improvement in two-year OS when compared to the a priori threshold of 40% (41.6% and 48.8% with FFX and GnP, respectively)[57]. Surgical results from the same trial display an 85% R0 resection rate in patients who underwent surgery (95%), while complete or significant pathologic response with systemic treatment was achieved in 33% of patients[58]. The final results of the NEONAX randomized phase II trial comparing neoadjuvant GnP (followed by surgery and adjuvant GnP) with upfront surgery followed by adjuvant GnP for patients with R-PDAC were published[59]. Perioperative GnP was associated with a longer median OS (25.2 vs. 16.7 months). The authors suggested that this difference in OS could be attributed to more patients receiving chemotherapy preoperatively and fewer patients proceeding to adjuvant chemotherapy in the upfront surgery arm. Similar to the NEONAX trial, the efficacy of neoadjuvant FOLFIRINOX for patients with R-PDAC was investigated in the PANACHE01-PRODIGE48 randomized phase II study[60]; one-year OS rates were 84.1% and 80.8% for patients who received neoadjuvant chemotherapy with FOLFIRINOX and upfront surgery, respectively, indicating that preoperative treatment for R-PDAC is a sound option and demands further investigation. The above trials are summarized in Table 1.

    NEOADJUVANT CHEMO-RT FOR PDAC

    Experience from definitive chemo-RT for LA-PDAC

    Several randomized trials provided evidence that the addition of chemo-RT to chemotherapy is beneficial for patients with LA-PDAC. In 2011, a randomized trial conducted by ECOG reported 74 patients with LA-PDAC who received gemcitabine with or without local radiotherapy (total dose 50.4 Gy and 1.8 Gy/fraction)[61]. The quality of life achieved was similar in both groups, while a significantly improved OS (median 11.1 vs. 9.2 months) in the chemo-RT arm was noted. Five years later, the LAP07 randomized trial on 442 patients was published[62]. Patients were randomized to receive gemcitabine with or without erlotinib, followed by a second randomization of patients without disease progression at four months. In this latter phase of the trial, 133 patients received chemo-RT (54 Gy conventionally fractionated RT with capecitabine). After a median follow-up of 36.7 months, the median OS was similar in all groups. However, the rate of locoregional progression in the chemo-RT group was significantly lower than the one recorded for the chemotherapy group (32% vs. 46%). Chemo-RT was well tolerated, as no increase of grade 3-4 toxicities was recorded. Only 6% of the patients recruited in the trial had surgery after chemo-RT.

    Low total dose conventionally fractionated photon RT, which applies a low dose per fraction, seems to be ineffective at suppressing the growth or eradicating PDAC, which is well-known to be radio- and chemoresistant[63,64]. Large radiotherapy fractions, the application of which has become feasible with modern radiotherapy techniques including stereotactic approaches, may be more potent against radioresistant PDAC cells. A study from the MD Anderson Cancer Center recruited a total of 200 patients in a dose escalation radiotherapy protocol using intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to deliver a biologically effective dose of 50-70 Gy concurrently with capecitabine[65]. Patients receiving a dose above 70 Gy had a significantly better OS (median 17.8 vs. 15 months) and estimated two-year survival rates (36% vs. 19%). The locoregional relapse-free survival was almost doubled (10.2 vs. 6.2 months). Using biomarkers, the isolation of the group of patients with a high tendency to develop metastasis could exclude them from radiotherapy and eventually help to identify a subgroup that would benefit from the locoregional control offered by RT[66].

    Densely ionizing radiation, produced by proton and heavy-ion linear accelerators, also has potential advantages. However, these rely on the superior dose distribution and the consequent sparing of normal tissues, as well as on the specific radiobiology of this type of radiation that kills cancer cells ignoring the hypoxic tumor microenvironment and the repair capacity of single DNA strand breaks[67]. Although randomized trials are not available, phase II trials have provided encouraging results, with a two-year survival of around 50%[68-70].

    Neoadjuvant chemo-RT for LA/BR-PDAC

    Upfront surgery of presumed operable PDACs results in high rates (up to 60%) of incomplete excisions[46]. The postoperative survival of patients with involved surgical margins is significantly worse[71]. Based on the favorable outcome of patients with rectal cancer receiving neoadjuvant chemo-RT, the hypothesis that neoadjuvant chemo-RT could also be beneficial in pancreatic cancer is sound. An analysis of 6936 patients with PDAC, collected from the National Cancer Database, identified 3185 patients who were treated with neoadjuvant chemo-RT and 3751 with neoadjuvant chemotherapy[72]. Negative resection margins were more frequent in the chemo-RT group (86.1% vs. 80%), but postoperative mortality rates were higher (6.4% vs. 3.6%). There was no survival benefit detected between the two groups.

    Several retrospective studies with a relatively low number of patients have reported high resectability rates in LA/BR-PDAC treated with FFX with or without radiotherapy[8]. In 2014, a study by Kharofa et al. suggested that induction chemotherapy followed by chemo-RT (total dose 50.4 Gy and 1.8 Gy/fraction with gemcitabine or capecitabine) results in 70% resectability with negative margins in 98% of cases[73]. The study comprised 39 patients with borderline resectability and 30 resectable cases. The local failure at two years was impressively low (9%), and 23% of operated patients were alive without disease at the time of analysis (median follow-up of 47 months). Another retrospective study by Katz et al. included 129 patients with BR-PDAC treated with gemcitabine-based chemo-RT[74]. Resectability was obtained in 66% of patients (95% R0 resection), and the median OS reached 33 months. In 2022, a report by Hill et al. analyzed 198 patients[75], 76 of whom had received neoadjuvant chemotherapy and 122 chemo-RT with stereotactic body radiation therapy (SBRT) technique. SBRT offered significantly higher complete resectability rates (92% vs. 70%) and negative node histopathology (59% vs. 42%). Of interest, a pathologic complete response (pCR) rate of 7% was recorded. However, there was no survival benefit from SBRT (two-year OS rate of 50.4%).

    Nevertheless, phase II and a small number of phase III trials have provided encouraging results in LA/BR-PDAC[46,73-85], as shown in Table 2. In 2018, a phase II study from the Massachusetts General Hospital reported 48 patients with BR-PDAC who were treated with eight cycles of FFX[82]. Patients who achieved resolution of the vascular involvement (56%) were further treated with hypofractionated accelerated proton radiotherapy (5 Gy × 5 fractions) with capecitabine, while the rest of the patients received long course chemo-RT (total dose 50.4 Gy and 1.8 Gy/fraction) with capecitabine or 5-FU. Tumor resection was feasible in 32/48 patients, with R0 resection obtained in 97% of cases. The overall two-year PFS rate was 43%, while the median PFS for operated patients reached 48.6 months. The two-year OS rate for this latter group of patients was 72%.

    Table 2

    Published phase II/III trials on neoadjuvant chemo-RT for PDAC

    Author (year)DiseaseType of studyNo ptsControl armNeoadjuvant chemotherapyNeoadjuvant chemo-RTMain findings
    LA-PDAC
    Sherman (2015)[76]LA-PDAC Phase II45NoGemcitabine, capecitabine and docetaxel50.4 Gy, 1.8 Gy/fraction
    Concurrent capecitabine and gemcitabine
    1-year OS: 71%
    Eguchi (2018)[77]LA-PDACPhase II34NoNo40-54 Gy, 2-1.8 Gy/fraction
    Concurrent gemcitabine/S1 followed by chemotherapy
    Resectability 15%
    Median OS for operated patients 3.63 years
    CONKO-007; Fietkau et al. (2022)[88]LA-PDACPhase III525NoFFX (Group A)FFX followed by chemo-RT (50.4 Gy, 1.8 Gy/fraction with concurrent gemcitabine) (Group B)Higher R0 resections rates in the chemo-RT arm. Median PFS (HR 0.919, 95%CI: 0.702-1.203, P = 0.54) and OS (HR 0.964, 95%CI: 0.760-1225, P = 0.766) not significantly different between the two arms
    BR-PDAC
    Kim (2013)[78]R/BR/LA-PDACPhase II68NoNo30 Gy, 2 Gy/fraction
    Concurrent gemcitabine and oxaliplatin
    Resectability 63% (R0 84%)
    Median OS 27.1 months for operated patients
    Chakraborty (2014)[79]
    BR-PDACPhase II 13NoInduction chemotherapy followed by chemo-RT50 Gy, 2.5 Gy/fraction
    Concurrent capecitabine
    Resectability 38.4%
    Median survival 13 months
    Katz (2016)[80]BR-PDACPhase II 22NoFFX50.4 Gy, 1.8 Gy/fraction
    Concurrent capecitabine
    pCR 13%
    Median OS 21.7 months
    Fiore (2017)[81]BR/LA-PDACPhase II41NoGemcitabine and oxaliplatin54 Gy, 1.8 Gy/fraction
    Concurrent gemcitabine
    Median OS 19.2 months
    Murphy (2018)[82]BR-PDACPhase II 48NoFFX before chemo-RT25 Gy, 5 Gy/fraction or
    54 Gy, 1.8 Gy/fraction
    Concurrent capecitabine
    Resectability 66.6%
    R0 surgery 97%
    2-year PFS 43% (all pts)
    2-year PFS 72% (operated pts)
    Jang (2018)[83]BR-PDACPhase III
    50Upfront surgeryNo54 Gy, 1.8 Gy/fraction
    Concurrent gemcitabine
    Higher resectability in the chemo-RT arm (51.8% vs. 26.1%) (P = 0.004)
    Better 2-year OS (30.7% vs. 26.1%) (HR 1.495, 95%CI: 0.66-3.36, P = 0.028)
    ESPAC-5F; Ghaneh 2020[46]BR-PDACOngoing Phase III (4 arms)
    88Upfront surgery (group A)FFX (group B) or Gemcitabine/capecitabine (group C)50.4 Gy, 1.8 Gy/fraction
    Concurrent capecitabine (group D)
    Better 1-year survival in the neoadjuvant arms 77% vs. 40% (HR 0.27, 95%CI: 0.13-0.55, P < 0.001)
    A021501; Katz et al. 2021[84]BR-PDACPhase II (randomized)126NoFFX (Group A)FFX followed by SBRT (33-40 Gy in 5 fractions) or hypofractionated image-guided RT (25 Gy, 5 Gy/fraction) (Group B)Chemo-RT did not improve median OS (31 months Group A vs. 17.1 Group B) (95%CI: 22.2-NE and 12.8-24.4 for Group A and B, respectively) (HR, P value not reported)
    BR/R-PDAC
    Okano (2017)[85]BR-PDAC
    R-PDAC
    Phase II57NoNo30 Gy, 3 Gy/fraction
    Concurrent with S-1
    2-year OS 83% in patients with resectable, and 58% in borderline resectable tumors
    PREOPANC; Vesteijne (2022)[87]BR-PDAC
    R-PDAC
    Phase III
    246Upfront surgeryNo36 Gy, 2.4 Gy/fraction
    Concurrent gemcitabine
    Better 5-year OS in the chemo-RT arm (20.5% vs. 6.5%) (HR 0.73, 95%CI: 0.56 to 0.96; P = 0.025)
    R-PDAC
    Talamonti (2006)[89]R-PDACPhase II20NoNo36 Gy, 2.4 Gy/fraction
    Concurrently with seven weekly infusions of gemcitabine
    Resectability 85%
    R0 margins 95%
    Lack of lymph node involvement 65%
    Evans (2008)[90]R-PDACPhase II86NoNo30 Gy, 3 Gy/fraction
    Concurrently with seven weekly infusions of gemcitabine
    Resectability 85%
    R0 margins 89%
    Median survival 34 months in operated patients vs. 7 months in inoperable
    Turrini (2009)[91]R-PDACPhase II102NoNo45 Gy, 1.8 Gy/fraction
    Concurrently with 5-FU/Cisplatin
    Resectability 74%
    Ro margins 92%
    pCR 13%
    Lack of lymph node involvement 76%
    Varadhachary (2008)[92]R-PDACPhase II79NoNo45 Gy, 1.8 Gy/fraction
    Concurrently with four bi-weekly infusions of gemcitabine and cisplatin
    Resectability 65.8%
    Median survival 31 months
    Golcher (2015)[93]R-PDACPhase II (randomized)66Upfront surgeryNo50.4 Gy, 1.8 Gy/fraction
    Concurrently with four weekly cycles of gemcitabine and cisplatin
    Good tolerance
    No difference between groups

    A Korean study published in the same year enrolled 50 patients with BR-PDAC to receive preoperative chemo-RT with gemcitabine vs. upfront surgery and adjuvant chemo-RT[83]. The resectability rates were significantly higher in patients receiving neoadjuvant chemo-RT (51.8% vs. 26.1%) and the two-year OS rate was significantly better in the neoadjuvant arm (40.7% vs. 26.1%).

    Early results of the ESPAC-5F multicenter randomized phase II trial were reported at the 2020 ASCO congress[46]. Patients with BR-PDAC were recruited in a four-arm study (upfront surgery vs. neoadjuvant gemcitabine/capecitabine vs. neoadjuvant FFX vs. neoadjuvant chemo-RT). An early analysis of 88 patients showed a benefit in the neoadjuvant arms in terms of one-year survival rate (77% vs. 40%). There are no data available on the role of RT yet. In contrast, the A021501 randomized phase II trial did not demonstrate a survival benefit in patients with BR-PDAC who received SBRT or hypofractionated RT after neoadjuvant mFOLFIRINOX when compared to patients that received mFOLFIRINOX alone (median OS 29.8 vs. 17.1 months for the chemotherapy alone and chemotherapy plus RT arms, respectively)[84].

    The PREOPANC randomized trial, published in 2020, included 246 patients who were treated with preoperative chemo-RT vs.upfront surgery[86]. Patients had BR/R-PDAC and were randomized to receive upfront surgery vs. neoadjuvant chemo-RT with gemcitabine, followed by surgery and postoperative gemcitabine chemotherapy. The R0 resection rates were better in the RT group (71% vs. 40%). The DFS and locoregional control were also improved in the RT arm, while a benefit in survival was also noted (median OS 35.2 vs. 19.8 months). Long-term results of the PREOPANC study were published in 2022, and the five-year OS rate was significantly better in the chemo-RT arm (20.5% vs. 6.5%), despite the rather small 1.4 months difference in median survival (15.7 vs. 14.3 months in the chemo-RT and upfront surgery arms, respectively)[87]. Moreover, the first results of a randomized phase III trial (CONKO-007) comparing induction chemotherapy (GnP or FOLFIRINOX) followed by additional chemotherapy cycles or chemo-RT (RT + gemcitabine) for patients with advanced PDAC were reported in the 2022 ASCO Annual Meeting I. Although patients in the chemo-RT arm were linked with higher R0 resection rates and pathologic complete responses, PFS and OS did not differ significantly between the two groups[88].

    Neoadjuvant chemo-RT for R-PDAC

    Neoadjuvant chemo-RT for R-PDAC has also been under investigation [Table 2]. A small early phase II study on 20 patients treated with chemo-RT with seven weekly infusions of gemcitabine showed 85% resectability rates (94% R0 margins) and absence of nodal involvement in 65% of specimens (five specimens with minimal residual disease)[89]. In 2008, Evans et al. reported a study on 86 patients with R-PDAC who received preoperative gemcitabine chemotherapy (seven weekly infusions) and radiotherapy (30 Gy in 10 fractions)[90]. Tumor resectability was obtained in 85% of patients, with a median OS of 34 months, compared to seven months for patients who were assumed inoperable. In 89% of operated patients, the histological margins were negative. Another relatively large phase II trial by Turrini et al. involved 101 patients with R-PDAC who were treated with neoadjuvant chemo-RT (total dose 45 Gy and 1.8 Gy/fraction) with cisplatin and 5-FU[91]. Overall, 26 out of 101 patients progressed during neoadjuvant therapy, while the remaining underwent surgery (92% R0 resections). Complete pathological responses were achieved in 13% of specimens, and a lack of nodal involvement was observed in 76% of patients. Varadhachary et al. reported 79 patients treated with chemo-RT with gemcitabine and cisplatin[92]. In total, 52 out of 79 (70%) underwent surgery, and their median survival was 31 months.

    More recent phase II studies continue to provide encouraging results from neoadjuvant chemo-RT. A study from Japan recruited 57 patients (33 resectable tumors)[85], treated with hypofractionated RT (total dose 30 Gy and 3 Gy/fraction) and S-1 chemotherapy. The two-year OS was 83% in resectable tumors and 58% in tumors with borderline resectability. In 2015, the first ever randomized phase II trial (University of Erlangen) was published[93]. Although this was terminated prematurely due to low recruitment rates, 66 patients were analyzed. Patients were randomized to receive primary surgery or neoadjuvant chemo-RT (total dose 50.4 Gy and 1.8 Gy/fraction) with four weekly cycles of gemcitabine and cisplatin. The study confirmed good tolerance, but there was no difference in terms of efficacy.

    NEOADJUVANT TARGETED THERAPIES FOR PDAC

    PDAC is a tumor with extensive activation of multiple growth and metastasis-related molecular pathways. Overall, four major pathways are active. The KRAS gene is frequently mutated, which leads to the overactivation of the RAF-MEK-ERK and PI3K-AKT/mTOR pathways[94]. Furthermore, mutations of the EGFR gene are common in PDAC. The EGFR pathway also intersects with the insulin growth factor IFG-1 pathway, both promoting growth and migration properties of the cancer cells[95,96]. Angiogenic pathways involving VEGF secretion and VEGF-receptor overexpression by the neo-vasculature also characterize a subgroup of PDACs[97]. In addition, the hepatocyte growth factor receptor (Met) pathway regulates cancer cell interactions with the tumor stroma and cancer-associated fibroblasts, promoting stromatogenesis, invasion, and metastasis[98]. Finally, a subgroup of patients with BRCA1/2 mutations suffer from DNA repair deficiency, which is a potential target for the development of molecular therapy[99].

    Targeting agents against KRAS and downstream pathways have mainly focused on RAF and MEK inhibitors. Direct inhibition of KRAS with pharmacological agents is problematic for several reasons[100]. Trametinib, a MEK inhibitor, has some potential in the treatment of PDAC, as a randomized phase II study showed benefit in combination with gemcitabine, with a longer duration of response[101]. Promising results have also been published regarding the concurrent administration of trametinib with pembrolizumab and RT in locally recurrent PDAC[102]. Moreover, the combination of trametinib with the autophagy inhibitor chloroquine is being assessed in an ongoing trial for advanced PDAC (NCT03825289), but there are no trials in the neoadjuvant setting. AKT inhibition with the MK-2206 agent has shown activity in PDAC, and two clinical studies have been completed in advanced and metastatic disease (NCT01658943, NCT01783171).

    Anti-EGFR therapies have been tested against PDAC. Randomized phase III trials on the combination of cetuximab monoclonal antibody (MoAb) with different gemcitabine, irinotecan, and cisplatin combinations failed to improve the survival of patients with metastatic disease[103]. A phase III trial comparing gemcitabine with or without erlotinib showed prolongation of the PFS[29]. The GEMCAD 10-03 phase II trial published in 2018 combining neoadjuvant gemcitabine and erlotinib with RT in R-PDAC provided encouraging results, suggesting further trials should be conducted with neoadjuvant erlotinib[104]. Moreover, a recent phase I/II trial showed benefit in terms of OS when combining the IGF-1R antagonist with gemcitabine and erlotinib in advanced disease, suggesting a potential value in the neoadjuvant setting[105].

    Specific anti-VEGF or anti-VEGF-receptor agents, e.g., bevacizumab and ramucirumab, respectively, have not shown any efficacy in combination with chemotherapy for PDAC[106]. Broad spectrum multitarget tyrosine kinase inhibitors (MTKIs), e.g., sunitinib, sorafenib, imatinib, and axitinib, have displayed limited activity in PDAC[107,108] . In a phase III trial, axitinib failed to show a benefit in combination with gemcitabine in advanced PDAC[109]. Recent experimental data suggest that MTKIs may remodel the PDAC microenvironment, enhancing the efficacy of immunotherapy, which may lead to trials combining MTKIs with immune checkpoint inhibitors[110]. In the neoadjuvant setting, the NCT00557492 trial examining the combination of RT with bevacizumab and gemcitabine before surgery has been completed; there are no available results yet.

    Targeting the intense desmoplastic activity of PDAC is another interesting area of research. Saridegib (IPI-926), an inhibitor of the Sonic Hedgehog pathway involved in fibroblastic proliferation, has been tested in a phase I trial together with FFX in advanced PDAC[111]. Hyaluronan depletion through the administration of pegylated hyaluronidase (PEGPH20) is also of therapeutic relevance in PDAC. A randomized trial combining PEGPH20 with GnP did not, however, improve the survival of patients with metastatic PDAC[112]. In fact, the SWOG S1313 trial showed detrimental effects[113].

    In patients with BRCA mutations, DNA repair is compromised. In this subgroup of patients, poly(ADP-ribose) polymerase (PARP) compensates for the missing repair activity of BRCA. PARP inhibitors, such as olaparib, improve the survival of PDAC patients with BRCA mutations, administrated either as monotherapy or in combination with gemcitabine[114]. The POLO trial randomized patients whose disease had not progressed after platinum-based chemotherapy to maintenance olaparib or placebo; the results, although not statistically significant, displayed a trend towards longer time to subsequent chemotherapy and overall survival with olaparib treatment[115]. The ongoing APOLLO trial (NCT04858334), sponsored by the NCI, is investigating olaparib’s role as a postoperative monotherapy regimen in R-PDAC, but there are no trials at the neoadjuvant level. Niraparib is also under investigation in the treatment of PDAC (NCT03553004).

    Losartan is an angiotensin II receptor blocker, mostly used to treat hypertension. It was also utilized in the neoadjuvant setting as a targeting agent for LA-PDAC treatment in a single-arm phase II study by Murphy et al.[116]; neoadjuvant FFX combined with losartan followed by either short or long course chemo-RT was prescribed in patients with unresectable PDAC. Surgery was performed in 86% of patients, while R0 resection was achieved in 69% of them. In the subgroup of patients who underwent surgery, median PFS and OS were longer when compared to the overall median PFS and OS (21.3 and 33 months vs. 17.5 and 31.4 months, respectively). Losartan, together with FFX, SBRT, and nivolumab, is also under investigation in a phase II trial for LA-PDAC (NCT03563248).

    ONGOING TRIALS ON NEOADJUVANT CHEMOTHERAPY AND CHEMO-RT

    There are several ongoing phase II and III trials for PDAC, examining both chemotherapy [Table 3] and chemo-RT [Table 4] in the neoadjuvant setting. Selected trials are presented in this section.

    Table 3

    Ongoing trials on neoadjuvant chemotherapy for PDAC

    ClinicalTrials.gov identifierCountryDiseaseType of studyControl armExperimental armPrimary endpointStatus
    LA-PDAC
    NCT03941093USA LA-PDACPhase IIINeoadjuvant GnP or FFX followed by surgeryNeoadjuvant GnP or FFX and Pamrevlumab anti-CTGF MoAb followed by surgeryOS and resectablityRecruiting
    NCT03377491
    (PANOVA-3)
    USALA-PDACPhase IIINeoadjuvant GnPTumor Treating Fields (TTFields -Alternated electric tumor treating fields) and GnP
    OSRecruiting
    NCT03673137
    (Y2018-ZD-001)
    ChinaLA-PDACPhase II/IIIIrreversible electroporation (IRE) followed by gemcitabine starting on day 7 after IRE treatmentGemcitabine infusion over 30 minutes following percutaneous IREOSCompleted
    NCT02806687
    (THERGAP-02)
    France LA-PDACPhase IINeoadjuvant gemcitabineIntratumoral injection of CYL-02 plus neoadjuvant chemotherapy with gemcitabine followed by gemcitabine alonePFSActive, not recruiting
    LA/BR-PDAC
    NCT04617821ChinaLA-PDAC
    BR-PDAC
    Phase IIINeoadjuvant FFXNeoadjuvant GnPOSRecruiting
    R-PDAC
    NCT01521702FranceR-PDACPhase IIISurgeryNeoadjuvant gemcitabine and Oxaliplatin followed by surgeryPFSRecruiting
    NCT02172976GermanyR-PDACPhase II/IIISurgery followed by adjuvant gemcitabineNeoadjuvant and adjuvant FFXMedian OSCompleted
    NCT03750669ChinaR-PDACPhase IINoneSequential GnP and FFX before surgeryDFSRecruiting
    NCT04927780 (PREOPANC-3)NetherlandsR-PDACPhase IIIUpfront surgery followed by adjuvant FFXNeoadjuvant FFX followed by surgery and adjuvant FFXOSRecruiting
    NCT04340141USAR-PDACPhase IIIUpfront surgery followed by adjuvant FFXNeoadjuvant and adjuvant FFXOSRecruiting
    NCT01150630
    (PACT-15)
    ItalyR-PDACPhase IIUpfront surgery followed by adjuvant gemcitabineNeoadjuvant cisplatin, epirubicin and gemcitabine Event free survival
    NCT02030860USAR-PDACPhase I Neoadjuvant GnP Neoadjuvant GnP and paricalcitolAdverse eventsCompleted
    NCT05268692JapanR-PDACPhase II/IIINeoadjuvant GnPNeoadjuvant gemcitabine/S-1OS
    NCT02919787
    (NorPACT) - 1
    Denmark, Finland, Norway, SwedenR-PDACPhase II/IIISurgery followed by adjuvant FOFLIRINOXNeoadjuvant FFX followed by surgery and adjuvant FFXOSActive, not recruiting
    Table 4

    Ongoing trials on neoadjuvant chemo-RT for PDAC

    ClinicalTrials.gov identifierCountryDiseaseType of studyControl armExperimental armPrimary endpointStatus
    BR-PDAC
    NCT01458717KoreaBR-PDACPhase II/IIIUpfront surgery followed by chemo-RT with gemcitabine and maintenance gemcitabine chemotherapyNeoadjuvant chemo-RT with gemcitabine followed by surgery and maintenance gemcitabine chemotherapy2-year survival rateCompleted 2018
    NCT02676349
    (PANDAS-PRODIGE 44)
    FranceBR-PDACPhase IINeoadjuvant FFX followed by surgery and adjuvant gemcitabine or 5FU/LVNeoadjuvant FFX followed by chemo-RT with capecitabine, surgery and adjuvant gemcitabine or 5FU/LVResectability (R0 rates)Recruiting
    NCT03777462ChinaBR-PDACPhase IINeoadjuvant GnP followed by surgeryA Neoadjuvant GnP chemotherapy and SBRT followed by surgery
    B Neoadjuvant S-1/nab-paclitaxel chemotherapy and SBRT followed by surgery
    OSRecruiting
    Trial NL7094 (NTR7292) (PREOPANC-2)NetherlandsBR-PDACPhase IIINeoadjuvant gemcitabine-based chemo-RT followed by surgery and adjuvant gemcitabineNeoadjuvant chemotherapy with FFX followed by surgeryOSCompleted
    NCT02839343USABR-PDACPhase IINeoadjuvant chemotherapy with FFX followed by surgery and adjuvant chemotherapy with FOLFOX
    Neoadjuvant chemotherapy with FFX followed by hypofractionated RT followed by surgery and adjuvant chemotherapy with FOLFOX
    OSActive, not recruiting
    R-PDAC
    NCT00335543Germany - AustriaR-PDACPhase IISurgery aloneNeoadjuvant chemo-RT with cisplatin and gemcitabineOSCompleted

    LA-PDAC

    Connective tissue growth factor (CTGF) promotes the growth of fibroblasts and angiogenesis[117]. The NCT03941093 phase III trial is examining the addition of an anti-CTGF MoAb to the standard FFX or GnP neoadjuvant chemotherapy, aiming at OS. Alternating electric fields have a direct inhibitory effect on tumor growth[118]. In this context, the PANOVA-3 (NCT03377491) phase III trial is actively recruiting patients to assess the effects of GnP plus alternated electric tumor treating field (TTFields), provided by an externally applied device, on OS. The Y2018-ZD-001 (NCT03673137) phase II/III trial incorporates irreversible electroporation to chemotherapy with gemcitabine, which could potentially enhance the bioavailability of drugs. Gene therapy is also being explored in the THERGAP-02 (NCT02806687) phase II trial, which randomizes patients to gemcitabine alone or gemcitabine plus intratumoral injection of CYL-02 (plasmid gene therapy).

    BR-PDAC

    A Chinese phase III trial is focusing on standard regimens (FFX vs. GnP) (NCT04617821), with OS as the primary endpoint. PREOPANC-2 (NL7094) is a randomized phase III study consisting of two arms: (1) neoadjuvant gemcitabine-based chemo-RT followed by surgery plus adjuvant gemcitabine chemotherapy; and (2) neoadjuvant chemotherapy with eight cycles of FFX followed by surgery. Recruitment has been completed. Neoadjuvant FFX followed by chemo-RT or hypofractionated irradiation vs. neoadjuvant chemotherapy alone with FFX is also under investigation (NCT02839343).

    R-PDAC

    We expect the preliminary results of the NorPACT-1 (NCT02919787) study, which compares immediate surgery to preoperative chemotherapy using FFX, and the NEOPAC (NCT01521702) trial, which examines neoadjuvant chemotherapy with gemcitabine and oxaliplatin vs. upfront surgery. In addition, the SWOG S1505 (NCT02562716) trial is currently comparing neoadjuvant modified FFX to neoadjuvant GnP to determine which regimen leads to better OS. Moreover, the European NCT00335543 phase II trial compares surgery alone to neoadjuvant chemo-RT with cisplatin and gemcitabine.

    NEOADJUVANT IMMUNOTHERAPY FOR PDAC

    In the last decade, immunotherapy with immune checkpoint inhibitors has revolutionized the clinical practice of oncology in the majority of human carcinomas. A striking exception is PDAC. In a review by Henriksen et al. of 24 identified studies on the treatment of metastatic PDAC with ipilimumab and anti-PD-1/PD-L1 MoAbs with or without chemotherapy, the response rates were disappointing, and the median survival did not exceed six months[119]. The poor response to immunotherapy is related to the immunosuppressive tumor microenvironment, low percentage of PDACs with mismatch repair deficiency, high expression of arginase and IDO that promote immunological tolerance, and infiltration of the tumor stroma by regulatory T cells and myeloid cells[120].

    Struggling to uncover the immuno-resistance of advanced PDAC, it is unlikely to expect the launch of neoadjuvant immunotherapy trials. A small randomized trial on preoperative administration of IL-2 did not show any benefit[121]. However, encouraging results were reported in a subsequent study on 30 patients, suggesting an improvement in PFS and OS[122]. A recent analysis identified 526 patients in the National Cancer Database who received neoadjuvant (408) or adjuvant immunotherapy (118)[123]; patients treated with neoadjuvant immunotherapy had longer survival. A phase I trial on the preoperative administration of the CD40 agonist MoAb selicrelumab demonstrated significant changes in the tumor microenvironment with less fibrosis, fewer M2-type macrophages, and increased presence of mature dendritic cells compared to cases that had received chemo-RT[124]. Furthermore, the combination of an anti-CD40 MoAb with nab-paclitaxel is under investigation in a phase I trial (NCT02588443). In 2022, the results of maintenance vaccination with the OSE2101 vaccine after induction chemotherapy with FOLFIRINOX for patients with advanced pancreatic cancer were reported; OSE2101 conferred a 12-month OS rate of 40% (vs. 44% in patients who continued treatment with FOLFIRINOX) and was not associated with grade 3 or higher toxicities[125]. Ongoing trials on neoadjuvant immunotherapy are shown in Table 5.

    Table 5

    Ongoing trials on neoadjuvant immunotherapy for PDAC

    ClinicalTrials.gov identifierCountryDiseaseStudy typeTreatmentPrimary endpointStatus
    LA-PDAC
    NCT01959672USALA-PDAC with
    High serum CA125 levels
    Phase IIGemcitabine/5-FU/leucovorin every 3 weeks plus Oregovomab anti-CA125 and nelfinavir mesylate (protease inhibitor). SBRT starts on week 11. Assessment of resectabilityResponse and resectability ratesCompleted (has results)
    NCT04327986USALA-PDACPhase I/IIDose escalation of M9241 (IL-12 immunocytokine) with M7824 (bi-functional anti-PD-L1 and anti-TGFβ ΜοΑb), with or without SBRTSafety, dose finding efficacyCompleted
    NCT02446093USALA-PDACPhase I/IIAglatimagene besadenovec (oncolytic adenoviral vector), valacyclovir and chemo-RT followed by surgery. Control arm: chemo-RT and SurgeryResectability safetyRecruiting
    NCT03767582USALA-PDACPhase I/IINivolumab and CCR2/CCR5 dual antagonist with or without GVAX and SBRTSurvival pathological responsesRecruiting
    NCT03563248USALA-PDACPhase IIFFX and SBRT with or without Losartan (inhibitor of angiotensin) with or without Nivolumab, followed by surgeryR0 resections survivalRecruiting
    NCT02648282USALA-PDACPhase IICyclophosphamide plus GVAX plus Pembrolizumab plus SBRTDMFSActive, not recruiting
    LA/BR-PDAC
    NCT03983057ChinaLA-PDAC
    BR-PDAC
    Phase IIFFX vs. FFX and anti-PD1 MoAbPFSRecruiting
    BR-PDAC
    NCT03970252USABR-PDACPhase IINivolumab and FFXPathological responseRecruiting
    BR/R-PDAC
    NCT02305186USABR-PDAC
    R-PDAC
    Phase I/IIPembrolizumab and chemo-RT (capecitabine + 50.4 Gy, 1.8 Gy/fraction) vs. chemo-RTSafety immunopathology studyRecruiting
    NCT04940286USABR-PDAC
    R-PDAC
    Phase IIDurvalumab, oleclumab (anti-CD73 ectonucleotidase), GnP followed by surgeryPathological response safetyRecruiting
    R-PDAC
    NCT03727880USAR-PDACPhase IIPembrolizumab and Defactinib vs. Pembrolizumab before surgeryPathological responsesRecruiting
    NCT02588443USAR-PDACPhase IRO70097890 (anti-CD40) with or without GnP before surgeryAdverse eventCompleted
    NCT00727441USAR-PDACPhase IIA GVAX vaccination followed by surgery. Postoperative vaccination, chemo-RT with gemcitabine and 5-FU
    B Low dose cyclophosphamide, GVAX vaccination followed by surgery. Postoperative vaccination, chemo-RT with gemcitabine and 5-FU
    Safety and OSCompleted 2020
    NCT02451982USA R-PDACPhase IIA GVAX vaccine with CY followed by surgery and chemo-RT
    B Same as A plus Nivolumab followed by surgery and chemo-RT
    C Same as B plus urelumab followed by surgery and chemo-RT
    D BMS-986253 and Nivolumab the surgery and chemo-RT
    Pathologic response and intra-tumoral immunological response evaluationRecruiting

    FURTHER TREATMENT APPROACHES

    It is important to underline that, alongside the ongoing trials assessing the efficacy of combined treatment modalities for PDAC, new strategies are also being tested in the neoadjuvant setting. Most notably, adoptive therapy incorporates alternation between treatments according to patient tolerance and tumor response. The NeoOPTIMIZE (NCT04539808) and NCT03322995 phase II trials are focusing on the early adoption of different chemotherapy regimens or chemoradiation when the initial drug combination is associated with increased toxicity or poor clinical response. Moreover, tumor subtype-based therapy is another approach under evaluation. In the NCT04683315 phase II trial, RNA expression profiling is being used to categorize PDAC as either basal or classical. Patients with the molecular basal and classical tumor subtypes will receive GnP and FFX, respectively, and treatment response will be assessed. GATA6 expression is another biomarker which could potentially impact treatment choice (NCT04472910). Finally, circulating tumor DNA (ctDNA) is also under investigation as an early marker of tumor response or resistance to neoadjuvant chemotherapy (NCT04616131).

    CONCLUSIONS

    The results from retrospective studies and phase II/III randomized trials on the neoadjuvant treatment of PDAC are quite encouraging. Ongoing phase III trials investigating chemotherapy, chemo-RT, immunotherapy, targeting agents and their combinations will shed more light on the advantages of this rising clinical practice and potentially herald a new era in the treatment algorithm of non-metastatic PDAC.

    DECLARATIONS

    Authors’ contributions

    Performed search of literature, analysis of data, writing of the first draft of the study and final approval of the manuscript: Koukourakis IM, Desse D, Papadimitriou M

    Made substantial contributions to conception and design of the study, interpretation, writing of the study and final approval of the manuscript: Papadimitriou C, Konstadoulakis M, Zygogianni A

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    None.

    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.

    Copyright

    © The Author(s) 2022.

    References

    • 1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021;71:7-33.

      DOIPubMed
    • 2. Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol 2015;44:186-98.

      DOIPubMed
    • 3. Lee MS, Pant S. Personalizing medicine with germline and somatic sequencing in advanced pancreatic cancer: current treatments and novel opportunities. Am Soc Clin Oncol Educ Book 2021;41:1-13.

      DOIPubMed
    • 4. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020;17:153-68.

      DOIPubMed
    • 5. Llach J, Carballal S, Moreira L. Familial pancreatic cancer: current perspectives. Cancer Manag Res 2020;12:743-58.

      DOIPubMed PMC
    • 6. National Comprehensive Cancer Network (NCCN). Pancreatic adenocarcinoma guidelines. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455 [Last accessed on 14 September 2022].

    • 7. Fathi A, Christians KK, George B, et al. Neoadjuvant therapy for localized pancreatic cancer: guiding principles. J Gastrointest Oncol 2015;6:418-29.

      DOIPubMed PMC
    • 8. Oba A, Ho F, Bao QR, Al-Musawi MH, Schulick RD, Del Chiaro M. Neoadjuvant treatment in pancreatic cancer. Front Oncol 2020;10:245.

      DOIPubMed PMC
    • 9. Leal AD, Messersmith WA, Lieu CH. Neoadjuvant treatment of localized pancreatic adenocarcinoma. J Gastrointest Oncol 2021;12:2461-74.

      DOIPubMed PMC
    • 10. Yang K, Li Y, Lian G, et al. KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer. Int J Cancer 2018;142:2323-34.

      DOIPubMed
    • 11. Fiorini C, Cordani M, Padroni C, Blandino G, Di Agostino S, Donadelli M. Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim Biophys Acta 2015;1853:89-100.

      DOIPubMed
    • 12. Swayden M, Iovanna J, Soubeyran P. Pancreatic cancer chemo-resistance is driven by tumor phenotype rather than tumor genotype. Heliyon 2018;4:e01055.

      DOIPubMed PMC
    • 13. Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: impact of altered energy metabolism. Crit Rev Oncol Hematol 2017;114:139-52.

      DOIPubMed
    • 14. Ramachandran K, Miller H, Gordian E, Rocha-Lima C, Singal R. Methylation-mediated silencing of TMS1 in pancreatic cancer and its potential contribution to chemosensitivity. Anticancer Res 2010;30:3919-25.

      PubMed
    • 15. Weniger M, Honselmann KC, Liss AS. The Extracellular matrix and pancreatic cancer: a complex relationship. Cancers (Basel) 2018;10:316.

      DOIPubMed PMC
    • 16. Amit M, Gil Z. Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase. Oncoimmunology 2013;2:e27231.

      DOIPubMed PMC
    • 17. Nakano Y, Tanno S, Koizumi K, et al. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br J Cancer 2007;96:457-63.

      DOIPubMed PMC
    • 18. Komori S, Osada S, Mori R, et al. Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer. Pancreas 2010;39:1284-92.

      DOIPubMed
    • 19. Capello M, Lee M, Wang H, et al. Carboxylesterase 2 as a Determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma. J Natl Cancer Inst 2015;107:djv132.

      DOIPubMed PMC
    • 20. Tezuka S, Ueno M, Kobayashi S, et al. Predictive value of ERCC1, ERCC2, ERCC4, and glutathione S-Transferase Pi expression for the efficacy and safety of FOLFIRINOX in patients with unresectable pancreatic cancer. Am J Cancer Res 2018;8:2096-105.

      PubMed PMC
    • 21. Maloney SM, Hoover CA, Morejon-Lasso LV, Prosperi JR. Mechanisms of taxane resistance. Cancers (Basel) 2020;12:3323.

      DOIPubMed PMC
    • 22. Shah VM, Sheppard BC, Sears RC, Alani AW. Hypoxia: friend or foe for drug delivery in pancreatic cancer. Cancer Lett 2020;492:63-70.

      DOIPubMed PMC
    • 23. Moir JA, Mann J, White SA. The role of pancreatic stellate cells in pancreatic cancer. Surg Oncol 2015;24:232-8.

      DOIPubMed
    • 24. Arnold CR, Mangesius J, Skvortsova II, Ganswindt U. The role of cancer stem cells in radiation resistance. Front Oncol 2020;10:164.

      DOIPubMed PMC
    • 25. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13.

      DOIPubMed
    • 26. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 2002;94:902-10.

      PubMed
    • 27. Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 2010;28:1645-51.

      DOIPubMed
    • 28. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 2014;111:1132-8.

      DOIPubMed PMC
    • 29. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-6.

      DOIPubMed
    • 30. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009;27:5513-8.

      DOIPubMed
    • 31. Li Q, Yan H, Liu W, Zhen H, Yang Y, Cao B. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomized controlled trials. PLoS One 2014;9:e104346.

      DOIPubMed PMC
    • 32. Conroy T, Paillot B, François E, et al. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study. J Clin Oncol 2005;23:1228-36.

      DOIPubMed
    • 33. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.

      DOIPubMed
    • 34. Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016;17:801-10.

      DOIPubMed PMC
    • 35. Hackert T, Sachsenmaier M, Hinz U, et al. Locally advanced pancreatic cancer: neoadjuvant therapy with folfirinox results in resectability in 60% of the patients. Ann Surg 2016;264:457-63.

      DOIPubMed
    • 36. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:4548-54.

      DOIPubMed PMC
    • 37. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703.

      DOIPubMed PMC
    • 38. Macedo FI, Ryon E, Maithel SK, et al. Survival outcomes associated with clinical and pathological response following neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel chemotherapy in resected pancreatic cancer. Ann Surg 2019;270:400-13.

      DOIPubMed
    • 39. Arima S, Kawahira M, Shimokawa M, et al. Gemcitabine plus nab-paclitaxel versus FOLFIRINOX in locally advanced, unresectable pancreatic cancer: a multicenter observational study (NAPOLEON study). Pancreas 2021;50:957-64.

      DOIPubMed
    • 40. Philip PA, Lacy J, Portales F, et al. Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study. Lancet Gastroenterol Hepatol 2020;5:285-94.

      DOIPubMed
    • 41. Kunzmann V, Siveke JT, Algül H, et al. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2021;6:128-38.

      DOIPubMed
    • 42. Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg 2008;206:833-46; discussion 846.

      DOIPubMed PMC
    • 43. Chapman BC, Gleisner A, Rigg D, et al. Perioperative and survival outcomes following neoadjuvant FOLFIRINOX versus gemcitabine abraxane in patients with pancreatic adenocarcinoma. JOP 2018;19:75-85.

      PubMed PMC
    • 44. Janssen QP, Buettner S, Suker M, et al. Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis. J Natl Cancer Inst 2019;111:782-94.

      DOIPubMed PMC
    • 45. Yoo C, Kang J, Kim KP, et al. Efficacy and safety of neoadjuvant FOLFIRINOX for borderline resectable pancreatic adenocarcinoma: improved efficacy compared with gemcitabine-based regimen. Oncotarget 2017;8:46337-47.

      DOIPubMed PMC
    • 46. Ghaneh P, Palmer DH, Cicconi S, et al. ESPAC-5F: four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. JCO 2020;38:4505-4505.

    • 47. Yamaguchi J, Yokoyama Y, Fujii T, et al. Results of a phase II study on the use of neoadjuvant chemotherapy (FOLFIRINOX or GEM/nab-PTX) for borderline-resectable pancreatic cancer (NUPAT-01). Ann Surg 2022;275:1043-9.

      DOIPubMed
    • 48. Reni M, Zanon S, Balzano G, et al. A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma. Eur J Cancer 2018;102:95-102.

      DOIPubMed
    • 49. Lee JL, Kim SC, Kim JH, et al. Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma. Surgery 2012;152:851-62.

      DOIPubMed
    • 50. Saito K, Isayama H, Sakamoto Y, et al. A phase II trial of gemcitabine, S-1 and LV combination (GSL) neoadjuvant chemotherapy for patients with borderline resectable and locally advanced pancreatic cancer. Med Oncol 2018;35:100.

      DOIPubMed
    • 51. Tajima H, Ohta T, Kitagawa H, et al. Pilot study of neoadjuvant chemotherapy with gemcitabine and oral S-1 for resectable pancreatic cancer. Exp Ther Med 2012;3:787-92.

      DOIPubMed PMC
    • 52. Heinrich S, Schäfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg 2008;248:1014-22.

      DOIPubMed
    • 53. OʼReilly EM, Perelshteyn A, Jarnagin WR, et al. A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann Surg 2014;260:142-8.

      DOIPubMed PMC
    • 54. Motoi F, Ishida K, Fujishima F, et al. Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial. Ann Surg Oncol 2013;20:3794-801.

      DOIPubMed
    • 55. Motoi F, Kosuge T, Ueno H, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol 2019;49:190-4.

      DOIPubMed
    • 56. Al-batran S, Reichart A, Bankstahl US, et al. Randomized multicenter phase II/III study with adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: the NEPAFOX trial. JCO 2021;39:406-406.

    • 57. Sohal D, Duong MT, Ahmad SA, et al. SWOG S1505: results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). JCO 2020;38:4504-4504.

    • 58. Ahmad SA, Duong M, Sohal DPS, et al. Surgical outcome results from SWOG S1505: a randomized clinical trial of mFOLFIRINOX versus gemcitabine/nab-paclitaxel for perioperative treatment of resectable pancreatic ductal adenocarcinoma. Ann Surg 2020;272:481-6.

      DOIPubMed PMC
    • 59. Ettrich TJ, Uhl W, Kornmann M, et al. Perioperative or adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: updated final results of the randomized phase II AIO-NEONAX trial. JCO 2022;40:4133-4133.

      DOIPubMed PMC
    • 60. Schwarz L, Bachet J, Meurisse A, et al. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy: a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). JCO 2022;40:4134-4134.

      DOI
    • 61. Loehrer PJ Sr, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105-12.

      DOIPubMed PMC
    • 62. Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016;315:1844-53.

      DOIPubMed
    • 63. Seshacharyulu P, Baine MJ, Souchek JJ, et al. Biological determinants of radioresistance and their remediation in pancreatic cancer. Biochim Biophys Acta Rev Cancer 2017;1868:69-92.

      DOIPubMed PMC
    • 64. Zeng S, Pöttler M, Lan B, Grützmann R, Pilarsky C, Yang H. Chemoresistance in pancreatic cancer. Int J Mol Sci 2019;20:4504.

      DOIPubMed PMC
    • 65. Krishnan S, Chadha AS, Suh Y, et al. Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation. Int J Radiat Oncol Biol Phys 2016;94:755-65.

      DOIPubMed PMC
    • 66. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13.

      DOIPubMed PMC
    • 67. Loeffler JS, Durante M. Charged particle therapy-optimization, challenges and future directions. Nat Rev Clin Oncol 2013;10:411-24.

      DOIPubMed
    • 68. Hiroshima Y, Fukumitsu N, Saito T, et al. Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer. Radiother Oncol 2019;136:37-43.

      DOIPubMed
    • 69. Maemura K, Mataki Y, Kurahara H, et al. Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology 2017;17:833-8.

      DOIPubMed
    • 70. Shinoto M, Terashima K, Suefuji H, et al. A single institutional experience of combined carbon-ion radiotherapy and chemotherapy for unresectable locally advanced pancreatic cancer. Radiother Oncol 2018;129:333-9.

      DOIPubMed
    • 71. Ghaneh P, Kleeff J, Halloran CM, et al. The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma. Ann Surg 2019;269:520-9.

      PubMed
    • 72. Oba A, Wu YHA, Colborn KL, et al. Comparing neoadjuvant chemotherapy with or without radiation therapy for pancreatic ductal adenocarcinoma: National Cancer Database cohort analysis. Br J Surg 2022;109:450-4.

      DOIPubMed
    • 73. Kharofa J, Tsai S, Kelly T, et al. Neoadjuvant chemoradiation with IMRT in resectable and borderline resectable pancreatic cancer. Radiother Oncol 2014;113:41-6.

      DOIPubMed PMC
    • 74. Katz MH, Fleming JB, Bhosale P, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer 2012;118:5749-56.

      DOIPubMed
    • 75. Hill CS, Rosati LM, Hu C, et al. Neoadjuvant stereotactic body radiotherapy after upfront chemotherapy improves pathologic outcomes compared with chemotherapy alone for patients with borderline resectable or locally advanced pancreatic adenocarcinoma without increasing perioperative toxicity. Ann Surg Oncol 2022;29:2456-68.

      DOIPubMed PMC
    • 76. Sherman WH, Chu K, Chabot J, et al. Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma. Cancer 2015;121:673-80.

      DOIPubMed
    • 77. Eguchi H, Yamada D, Iwagami Y, et al. Prolonged neoadjuvant therapy for locally advanced pancreatic cancer. Dig Surg 2018;35:70-6.

      DOIPubMed
    • 78. Kim EJ, Ben-Josef E, Herman JM, et al. A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. Cancer 2013;119:2692-700.

      DOIPubMed PMC
    • 79. Chakraborty S, Morris MM, Bauer TW, et al. Accelerated fraction radiotherapy with capecitabine as neoadjuvant therapy for borderline resectable pancreatic cancer. Gastrointest Cancer Res 2014;7:15-22.

      PubMed PMC
    • 80. Katz MH, Shi Q, Ahmad SA, et al. Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: alliance for clinical trials in oncology trial A021101. JAMA Surg 2016;151:e161137.

      DOIPubMed PMC
    • 81. Fiore M, Ramella S, Valeri S, et al. Phase II study of induction chemotherapy followed by chemoradiotherapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer. Sci Rep 2017;7:45845.

      DOIPubMed PMC
    • 82. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol 2018;4:963-9.

      DOIPubMed PMC
    • 83. Jang JY, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg 2018;268:215-22.

      DOIPubMed
    • 84. Katz MHG, Shi Q, Meyers JP, et al. Alliance A021501: preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. JCO 2021;39:377-377.

    • 85. Okano K, Suto H, Oshima M, et al. A prospective phase II Trial of neoadjuvant S-1 with concurrent hypofractionated radiotherapy in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma. Ann Surg Oncol 2017;24:2777-84.

      DOIPubMed
    • 86. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC trial. J Clin Oncol 2020;38:1763-73.

      DOIPubMed PMC
    • 87. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the dutch randomized PREOPANC trial. J Clin Oncol 2022;40:1220-30.

      DOIPubMed
    • 88. Fietkau R, Ghadimi M, Grützmann R, et al. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial. JCO 2022;40:4008-4008.

      DOIPubMed
    • 89. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 2006;13:150-8.

      DOIPubMed
    • 90. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008;26:3496-502.

      DOIPubMed
    • 91. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single institution experience. Oncology 2009;76:413-9.

      DOIPubMed
    • 92. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008;26:3487-95.

      DOIPubMed
    • 93. Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol 2015;191:7-16.

      DOIPubMed PMC
    • 94. Luo J. KRAS mutation in pancreatic cancer. Semin Oncol 2021;48:10-8.

      DOIPubMed PMC
    • 95. Troiani T, Martinelli E, Capasso A, et al. Targeting EGFR in pancreatic cancer treatment. Curr Drug Targets 2012;13:802-10.

      DOIPubMed
    • 96. Mutgan AC, Besikcioglu HE, Wang S, Friess H, Ceyhan GO, Demir IE. Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. Mol Cancer 2018;17:66.

      DOIPubMed PMC
    • 97. Annese T, Tamma R, Ruggieri S, Ribatti D. Angiogenesis in pancreatic cancer: pre-clinical and clinical studies. Cancers (Basel) 2019;11:381.

      DOIPubMed PMC
    • 98. Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol 2020;17:487-505.

      DOIPubMed PMC
    • 99. Crowley F, Park W, O’Reilly EM. Targeting DNA damage repair pathways in pancreas cancer. Cancer Metastasis Rev 2021;40:891-908.

      DOIPubMed PMC
    • 100. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell 2014;25:272-81.

      DOIPubMed
    • 101. Infante JR, Somer BG, Park JO, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer 2014;50:2072-81.

      DOIPubMed
    • 102. Zhu X, Cao Y, Liu W, et al. Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial. Lancet Oncol 2022;23:e105-15.

      DOIPubMed
    • 103. Forster T, Huettner FJ, Springfeld C, et al. Cetuximab in pancreatic cancer therapy: a systematic review and meta-analysis. Oncology 2020;98:53-60.

      DOIPubMed
    • 104. Maurel J, Sánchez-Cabús S, Laquente B, et al. Outcomes after neoadjuvant treatment with gemcitabine and erlotinib followed by gemcitabine-erlotinib and radiotherapy for resectable pancreatic cancer (GEMCAD 10-03 trial). Cancer Chemother Pharmacol 2018;82:935-43.

      DOIPubMed
    • 105. Abdel-Wahab R, Varadhachary GR, Bhosale PR, et al. Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma. J Hematol Oncol 2018;11:71.

      DOIPubMed PMC
    • 106. Sahai V, Saif MW, Kalyan A, et al. A phase I/II open-label multicenter single-arm study of FABLOx (Metronomic 5-fluorouracil Plus. nab ;5:35-42.

      DOIPubMed PMC
    • 107. Cascinu S, Berardi R, Sobrero A, et al. Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: a GISCAD randomized phase II study. Dig Liver Dis 2014;46:182-6.

      DOIPubMed PMC
    • 108. Reni M, Cereda S, Milella M, et al. Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial. Eur J Cancer 2013;49:3609-15.

      DOIPubMed
    • 109. Ioka T, Okusaka T, Ohkawa S, et al. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial. Jpn J Clin Oncol 2015;45:439-48.

      DOIPubMed PMC
    • 110. Falcomatà C, Bärthel S, Widholz SA, et al. Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. Nat Cancer 2022;3:318-36.

      DOIPubMed PMC
    • 111. Ko AH, LoConte N, Tempero MA, et al. A phase I Study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas 2016;45:370-5.

      DOIPubMed PMC
    • 112. Van Cutsem E, Tempero MA, Sigal D, et al. Randomized phase III Trial of pegvorhyaluronidase Alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J Clin Oncol 2020;38:3185-94.

      DOIPubMed PMC
    • 113. Ramanathan RK, McDonough SL, Philip PA, et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX Alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol 2019;37:1062-9.

      DOIPubMed PMC
    • 114. Rubinson D, Wolpin BM, Warsofsky IS, et al. Durable clinical benefit from PARP inhibition in a platinum-sensitive, BRCA2-mutated pancreatic cancer patient after earlier progression on placebo treatment on the POLO trial: a case report. J Gastrointest Oncol 2021;12:3133-40.

      DOIPubMed PMC
    • 115. Kindler HL, Hammel P, Reni M, et al. Overall survival results from the POLO trial: a phase iii study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol 2022:JCO2101604.

      DOIPubMed
    • 116. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX in Combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol 2019;5:1020-7.

      DOIPubMed PMC
    • 117. Chen Z, Zhang N, Chu HY, et al. Connective tissue growth factor: from molecular understandings to drug discovery. Front Cell Dev Biol 2020;8:593269.

      DOIPubMed PMC
    • 118. Carrieri FA, Smack C, Siddiqui I, Kleinberg LR, Tran PT. Tumor treating fields: at the crossroads between physics and biology for cancer treatment. Front Oncol 2020;10:575992.

      DOIPubMed PMC
    • 119. Henriksen A, Dyhl-Polk A, Chen I, Nielsen D. Checkpoint inhibitors in pancreatic cancer. Cancer Treat Rev 2019;78:17-30.

      DOIPubMed
    • 120. Leinwand J, Miller G. Regulation and modulation of antitumor immunity in pancreatic cancer. Nat Immunol 2020;21:1152-9.

      DOIPubMed
    • 121. Angelini C, Bovo G, Muselli P, et al. Preoperative interleukin-2 immunotherapy in pancreatic cancer: preliminary results. Hepatogastroenterology 2006;53:141-4.

      PubMed
    • 122. Caprotti R, Brivio F, Fumagalli L, et al. Free-from-progression period and overall short preoperative immunotherapy with IL-2 increases the survival of pancreatic cancer patients treated with macroscopically radical surgery. Anticancer Res 2008;28:1951-4.

      PubMed
    • 123. Amin S, Baine M, Meza J, Lin C. The impact of neoadjuvant and adjuvant immunotherapy on the survival of pancreatic cancer patients: a retrospective analysis. BMC Cancer 2020;20:538.

      DOIPubMed PMC
    • 124. Byrne KT, Betts CB, Mick R, et al. Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. Clin Cancer Res 2021;27:4574-86.

      DOIPubMed PMC
    • 125. Hilmi M, Mitry E, Turpin A, et al. A randomized, non-comparative, phase II study of maintenance OSE2101 vaccine alone or in combination with nivolumab (nivo) or FOLFIRI after induction with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): first interim results of the TEDOPAM GERCOR D17-01 PRODIGE 63 STUDY. JCO 2022;40:4148-4148.

      DOI

    Cite This Article

    Koukourakis IM, Desse D, Papadimitriou M, Konstadoulakis M, Zygogianni A, Papadimitriou C. Neoadjuvant treatment of pancreatic ductal adenocarcinoma: present and future. J Cancer Metastasis Treat 2022;8:38. http://dx.doi.org/10.20517/2394-4722.2022.43

    Views
    35
    Downloads
    45
    Citations
     0
    Comments
    0

    0

    Comments

    Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.

    Article Access Statistics

    • Viewed: 35
    • Downloaded: 45
    • Cited: Crossref0

    Share This Article

    See Updates

    © 2016-2022 OAE Publishing Inc., except certain content provided by third parties