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: email@example.com
© 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.
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.
Pancreatic cancer, neoadjuvant treatment, chemotherapy, radiotherapy, surgery, immunotherapy
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. 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. 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. 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. Furthermore, BRCA1 and BRCA2 mutations, involved in the pathogenesis of breast and ovarian cancer, also characterize familial PDAC. 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). 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.
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. Similarly, TP53 mutations of pancreatic cancer were associated with higher resistance to chemotherapy with gemcitabine. 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. 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. Moreover, epigenetic mechanisms and especially target of methylation induced silencing 1 (TMS1) methylation are involved in acquired chemoresistance. 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. 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. 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.
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. Overexpression of the dihydropyrimidine dehydrogenase and thymidylate synthase is involved in the resistance to gemcitabine and 5-FU. 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. 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. 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).
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; 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. Finally, cancer stem cells have been associated with increased radioresistance due to their enhanced ability of DNA repair and slow proliferation.
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.
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. 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. On the contrary, 10 years later, the randomized phase III GIP-1 study showed that the combination of cisplatin and gemcitabine conferred no benefit. A subset of LA-PDAC patients with BRCA mutations appear to be more sensitive to platinum drugs 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. 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. 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. Finally, a meta-analysis by
A phase II study by Conroy et al. introduced FFX in 2005 as an effective drug combination for the treatment of advanced pancreatic disease, 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. 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. In addition, FFX rendered LA-PDAC resectable in 76 out of 125 patients (60%) when analyzed retrospectively, 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.. 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.
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. Another smaller retrospective study confirmed the equivalence of the two regimens. Neoadjuvant GnP examined in the LAPACT phase II study provided a median OS of 18.8 months. 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. 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].
Published phase II/III trials on neoadjuvant chemotherapy for PDAC
|Author (year)||Disease||Type of study||No pts||Control arm||Neoadjuvant chemotherapy||Neoadjuvant chemo-RT||Main findings|
|LAPACT; Philip (2020)[ 40]||LA-PDAC||Phase II||107||GnP followed by surgery or chemo-RT or GnP||Optional||Median PFS 10.9 months and median OS 18.8 months|
|NEOLAP-AIO-PAK-0113; Kunzmann ||LA-PDAC||Phase II (randomized)||130||No||4 cycles of GnP|
2 cycles of GnP followed by 4 cycles of FFX
(HR 0.86, 95%CI: 0.55-1.36, P = 0.53)
|Yoo (2017)||BR-PDAC||Phase II||18||No||FFX||No||Median survival 16.8 months|
|ESPAC-5F; Ghaneh (2020)||BR-PDAC||Phase II (randomized, 4 arms)||88||Upfront 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 ||BR-PDAC||Phase II (randomized)||51||No||A. FFX |
|No||OS is not significantly different between groups|
|Phase I/II||43||No||Gemcitabine and capecitabine||No||Median OS 23.1 months for patients that underwent surgery|
|Phase II (randomized)||54||No||Gemcitabine, nab-paclitaxel, cisplatin and capecitabine|
Nab-paclitaxel followed by gemcitabine
|No||1-year PFS 58% (Arm A) vs. 39% (Arm B)|
18-month OS 69% (Arm A) vs. 54% (Arm B) (P = not significant)
|Phase II||24||No||Gemcitabine, S-1, LV||No||Resection rate 60.9% (R0 76.5%)|
|Phase II||36||No||Gemcitabine and S-1||No||Median OS 34.7 months in R0 resected patients|
|Heinrich (2008)||R-PDAC||Phase II||28||No||Gemcitabine and cisplatin||No||Median DFS 9.2 months and median OS 26.5 months|
|O’Reilly (2014)||R-PDAC||Phase II||38||No||Gemcitabine and oxaliplatin||No||Resectability 71% and median OS 27.2 months|
|Prep-02/JSAP05; Motoi (2019)||R-PDAC||Phase II/III||364||Upfront surgery||Gemcitabine and S-1||No||Improved median OS (36.7 vs. 26.6 months) ) (HR 0.72, 95%CI: 0.55-0.94, P = 0.015)|
|NEPAFOX; Al-Batran ||R-PDAC||Phase II/III||40||Upfront surgery followed by gemcitabine||FFX||No||Improved 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)||R-PDAC||Phase II (randomized)||103||No||FFX and GnP||2-year OS improvement not statistically significant (41.6% and 48.8% with FFX and GnP, respectively)|
|AIO-NEONAX; Ettrich et al. ||R-PDAC||Phase II (randomized)||127||Upfront surgery followed by GnP||GnP followed by surgery and adjuvant GNP||No||Longer median OS in the perioperative chemotherapy arm (25.2 vs. 16.7 months) (HR, P value not reported)|
|PAANACHE01-PRODIGE48; Schwarz et al. (20220)||R-PDAC||Phase II (randomized)||146||Upfront surgery||A. FFX |
|No||1-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.
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.
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. FFX and GnP have been compared in terms of efficacy for BR-PDAC. 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. A small phase II study utilizing neoadjuvant FFX resulted in a median OS of 16.8 months. 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%). 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.
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. 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.
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.
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.
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). 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. 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. 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.
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. Although randomized trials are not available, phase II trials have provided encouraging results, with a two-year survival of around 50%[68-70].
Upfront surgery of presumed operable PDACs results in high rates (up to 60%) of incomplete excisions. The postoperative survival of patients with involved surgical margins is significantly worse. 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. 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. 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. 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. 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, 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. 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%.
Published phase II/III trials on neoadjuvant chemo-RT for PDAC
|Author (year)||Disease||Type of study||No pts||Control arm||Neoadjuvant chemotherapy||Neoadjuvant chemo-RT||Main findings|
|Sherman (2015)||LA-PDAC||Phase II||45||No||Gemcitabine, capecitabine and docetaxel||50.4 Gy, 1.8 Gy/fraction|
Concurrent capecitabine and gemcitabine
|1-year OS: 71%|
|Eguchi (2018)||LA-PDAC||Phase II||34||No||No||40-54 Gy, 2-1.8 Gy/fraction|
Concurrent gemcitabine/S1 followed by chemotherapy
Median OS for operated patients 3.63 years
|CONKO-007; Fietkau et al. (2022)||LA-PDAC||Phase III||525||No||FFX (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|
|Kim (2013)||R/BR/LA-PDAC||Phase II||68||No||No||30 Gy, 2 Gy/fraction|
Concurrent gemcitabine and oxaliplatin
|Resectability 63% (R0 84%)|
Median OS 27.1 months for operated patients
|Chakraborty (2014)||BR-PDAC||Phase II||13||No||Induction chemotherapy followed by chemo-RT||50 Gy, 2.5 Gy/fraction|
Median survival 13 months
|Katz (2016)||BR-PDAC||Phase II||22||No||FFX||50.4 Gy, 1.8 Gy/fraction|
Median OS 21.7 months
|Fiore (2017)||BR/LA-PDAC||Phase II||41||No||Gemcitabine and oxaliplatin||54 Gy, 1.8 Gy/fraction|
|Median OS 19.2 months|
|Murphy (2018)||BR-PDAC||Phase II||48||No||FFX before chemo-RT||25 Gy, 5 Gy/fraction or|
54 Gy, 1.8 Gy/fraction
R0 surgery 97%
2-year PFS 43% (all pts)
2-year PFS 72% (operated pts)
|Jang (2018)||BR-PDAC||Phase III||50||Upfront surgery||No||54 Gy, 1.8 Gy/fraction|
|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||BR-PDAC||Ongoing Phase III (4 arms)||88||Upfront 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||BR-PDAC||Phase II (randomized)||126||No||FFX (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)|
|Phase II||57||No||No||30 Gy, 3 Gy/fraction|
Concurrent with S-1
|2-year OS 83% in patients with resectable, and 58% in borderline resectable tumors|
|PREOPANC; Vesteijne ||BR-PDAC|
|Phase III||246||Upfront surgery||No||36 Gy, 2.4 Gy/fraction|
|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)|
|Talamonti ||R-PDAC||Phase II||20||No||No||36 Gy, 2.4 Gy/fraction|
Concurrently with seven weekly infusions of gemcitabine
R0 margins 95%
Lack of lymph node involvement 65%
|Evans (2008)||R-PDAC||Phase II||86||No||No||30 Gy, 3 Gy/fraction|
Concurrently with seven weekly infusions of gemcitabine
R0 margins 89%
Median survival 34 months in operated patients vs. 7 months in inoperable
|Turrini (2009)||R-PDAC||Phase II||102||No||No||45 Gy, 1.8 Gy/fraction|
Concurrently with 5-FU/Cisplatin
Ro margins 92%
Lack of lymph node involvement 76%
|Varadhachary (2008)||R-PDAC||Phase II||79||No||No||45 Gy, 1.8 Gy/fraction|
Concurrently with four bi-weekly infusions of gemcitabine and cisplatin
Median survival 31 months
|Golcher (2015)||R-PDAC||Phase II (randomized)||66||Upfront surgery||No||50.4 Gy, 1.8 Gy/fraction|
Concurrently with four weekly cycles of gemcitabine and cisplatin
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. 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. 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).
The PREOPANC randomized trial, published in 2020, included 246 patients who were treated with preoperative chemo-RT vs.upfront surgery. 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). 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.
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). 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). 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. 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. 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), 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. 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.
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. 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. 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. 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.
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. 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. Promising results have also been published regarding the concurrent administration of trametinib with pembrolizumab and RT in locally recurrent PDAC. 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. A phase III trial comparing gemcitabine with or without erlotinib showed prolongation of the PFS. 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. 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.
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. 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. 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. 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
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. 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. 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
Ongoing trials on neoadjuvant chemotherapy for PDAC
|ClinicalTrials.gov identifier||Country||Disease||Type of study||Control arm||Experimental arm||Primary endpoint||Status|
|NCT03941093||USA||LA-PDAC||Phase III||Neoadjuvant GnP or FFX followed by surgery||Neoadjuvant GnP or FFX and Pamrevlumab anti-CTGF MoAb followed by surgery||OS and resectablity||Recruiting|
|USA||LA-PDAC||Phase III||Neoadjuvant GnP||Tumor Treating Fields (TTFields -Alternated electric tumor treating fields) and GnP||OS||Recruiting|
|China||LA-PDAC||Phase II/III||Irreversible electroporation (IRE) followed by gemcitabine starting on day 7 after IRE treatment||Gemcitabine infusion over 30 minutes following percutaneous IRE||OS||Completed|
|France||LA-PDAC||Phase II||Neoadjuvant gemcitabine||Intratumoral injection of CYL-02 plus neoadjuvant chemotherapy with gemcitabine followed by gemcitabine alone||PFS||Active, not recruiting|
|Phase III||Neoadjuvant FFX||Neoadjuvant GnP||OS||Recruiting|
|NCT01521702||France||R-PDAC||Phase III||Surgery||Neoadjuvant gemcitabine and Oxaliplatin followed by surgery||PFS||Recruiting|
|NCT02172976||Germany||R-PDAC||Phase II/III||Surgery followed by adjuvant gemcitabine||Neoadjuvant and adjuvant FFX||Median OS||Completed|
|NCT03750669||China||R-PDAC||Phase II||None||Sequential GnP and FFX before surgery||DFS||Recruiting|
|NCT04927780 (PREOPANC-3)||Netherlands||R-PDAC||Phase III||Upfront surgery followed by adjuvant FFX||Neoadjuvant FFX followed by surgery and adjuvant FFX||OS||Recruiting|
|NCT04340141||USA||R-PDAC||Phase III||Upfront surgery followed by adjuvant FFX||Neoadjuvant and adjuvant FFX||OS||Recruiting|
|Italy||R-PDAC||Phase II||Upfront surgery followed by adjuvant gemcitabine||Neoadjuvant cisplatin, epirubicin and gemcitabine||Event free survival|
|NCT02030860||USA||R-PDAC||Phase I||Neoadjuvant GnP||Neoadjuvant GnP and paricalcitol||Adverse events||Completed|
|NCT05268692||Japan||R-PDAC||Phase II/III||Neoadjuvant GnP||Neoadjuvant gemcitabine/S-1||OS|
(NorPACT) - 1
|Denmark, Finland, Norway, Sweden||R-PDAC||Phase II/III||Surgery followed by adjuvant FOFLIRINOX||Neoadjuvant FFX followed by surgery and adjuvant FFX||OS||Active, not recruiting|
Ongoing trials on neoadjuvant chemo-RT for PDAC
|ClinicalTrials.gov identifier||Country||Disease||Type of study||Control arm||Experimental arm||Primary endpoint||Status|
|NCT01458717||Korea||BR-PDAC||Phase II/III||Upfront surgery followed by chemo-RT with gemcitabine and maintenance gemcitabine chemotherapy||Neoadjuvant chemo-RT with gemcitabine followed by surgery and maintenance gemcitabine chemotherapy||2-year survival rate||Completed 2018|
|France||BR-PDAC||Phase II||Neoadjuvant FFX followed by surgery and adjuvant gemcitabine or 5FU/LV||Neoadjuvant FFX followed by chemo-RT with capecitabine, surgery and adjuvant gemcitabine or 5FU/LV||Resectability (R0 rates)||Recruiting|
|NCT03777462||China||BR-PDAC||Phase II||Neoadjuvant GnP followed by surgery||A Neoadjuvant GnP chemotherapy and SBRT followed by surgery|
B Neoadjuvant S-1/nab-paclitaxel chemotherapy and SBRT followed by surgery
|Trial NL7094 (NTR7292) (PREOPANC-2)||Netherlands||BR-PDAC||Phase III||Neoadjuvant gemcitabine-based chemo-RT followed by surgery and adjuvant gemcitabine||Neoadjuvant chemotherapy with FFX followed by surgery||OS||Completed|
|NCT02839343||USA||BR-PDAC||Phase II||Neoadjuvant 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
|OS||Active, not recruiting|
|NCT00335543||Germany - Austria||R-PDAC||Phase II||Surgery alone||Neoadjuvant chemo-RT with cisplatin and gemcitabine||OS||Completed|
Connective tissue growth factor (CTGF) promotes the growth of fibroblasts and angiogenesis. 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. 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).
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).
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.
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. 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.
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. However, encouraging results were reported in a subsequent study on 30 patients, suggesting an improvement in PFS and OS. A recent analysis identified 526 patients in the National Cancer Database who received neoadjuvant (408) or adjuvant immunotherapy (118); 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. 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. Ongoing trials on neoadjuvant immunotherapy are shown in Table 5.
Ongoing trials on neoadjuvant immunotherapy for PDAC
|ClinicalTrials.gov identifier||Country||Disease||Study type||Treatment||Primary endpoint||Status|
High serum CA125 levels
|Phase II||Gemcitabine/5-FU/leucovorin every 3 weeks plus Oregovomab anti-CA125 and nelfinavir mesylate (protease inhibitor). SBRT starts on week 11. Assessment of resectability||Response and resectability rates||Completed (has results)|
|NCT04327986||USA||LA-PDAC||Phase I/II||Dose escalation of M9241 (IL-12 immunocytokine) with M7824 (bi-functional anti-PD-L1 and anti-TGFβ ΜοΑb), with or without SBRT||Safety, dose finding efficacy||Completed|
|NCT02446093||USA||LA-PDAC||Phase I/II||Aglatimagene besadenovec (oncolytic adenoviral vector), valacyclovir and chemo-RT followed by surgery. Control arm: chemo-RT and Surgery||Resectability safety||Recruiting|
|NCT03767582||USA||LA-PDAC||Phase I/II||Nivolumab and CCR2/CCR5 dual antagonist with or without GVAX and SBRT||Survival pathological responses||Recruiting|
|NCT03563248||USA||LA-PDAC||Phase II||FFX and SBRT with or without Losartan (inhibitor of angiotensin) with or without Nivolumab, followed by surgery||R0 resections survival||Recruiting|
|NCT02648282||USA||LA-PDAC||Phase II||Cyclophosphamide plus GVAX plus Pembrolizumab plus SBRT||DMFS||Active, not recruiting|
|Phase II||FFX vs. FFX and anti-PD1 MoAb||PFS||Recruiting|
|NCT03970252||USA||BR-PDAC||Phase II||Nivolumab and FFX||Pathological response||Recruiting|
|Phase I/II||Pembrolizumab and chemo-RT (capecitabine + 50.4 Gy, 1.8 Gy/fraction) vs. chemo-RT||Safety immunopathology study||Recruiting|
|Phase II||Durvalumab, oleclumab (anti-CD73 ectonucleotidase), GnP followed by surgery||Pathological response safety||Recruiting|
|NCT03727880||USA||R-PDAC||Phase II||Pembrolizumab and Defactinib vs. Pembrolizumab before surgery||Pathological responses||Recruiting|
|NCT02588443||USA||R-PDAC||Phase I||RO70097890 (anti-CD40) with or without GnP before surgery||Adverse event||Completed|
|NCT00727441||USA||R-PDAC||Phase II||A 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 OS||Completed 2020|
|NCT02451982||USA||R-PDAC||Phase II||A 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 evaluation||Recruiting|
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).
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.
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 AAvailability 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
© The Author(s) 2022.
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