Published online Jun 24, 2025. doi: 10.5306/wjco.v16.i6.105601
Revised: April 8, 2025
Accepted: May 13, 2025
Published online: June 24, 2025
Processing time: 141 Days and 13.6 Hours
Pancreatic ductal adenocarcinoma (PDAC) is characterized by high aggressiveness, poor prognosis, and unsatisfactory survival rates. The incidence of PDAC is increasing annually, and thus, the number of deaths due to PDAC is increasing worldwide. Modern imaging modalities, including multidetector computed to
Core Tip: Pancreatic ductal adenocarcinoma is an aggressive malignancy with a delayed diagnosis and poor prognosis. The newest diagnostic tools and proper management are crucial for determining survival. The current approach must be multidisciplinary and individualized. Surgical resection alone is not enough; it must be accompanied by other novel the
- Citation: Pavlidis ET, Galanis IN, Pavlidis TE. Updates in the diagnosis and management of ductal adenocarcinoma of the pancreas. World J Clin Oncol 2025; 16(6): 105601
- URL: https://www.wjgnet.com/2218-4333/full/v16/i6/105601.htm
- DOI: https://dx.doi.org/10.5306/wjco.v16.i6.105601
Pancreatic cancer is ductal adenocarcinoma (PDAC) in more than 90% of cases and is characterized by high aggressiveness, poor prognosis, and unsatisfactory survival rates posing considerable management challenges[1-4]. The median survival time is approximately 4 months for untreated patients with locally advanced or metastatic disease, and these patients account for up to 80% of cases. The incidence of PDAC is increasing annually, particularly in men, and, sub
The 5-year overall survival for all patients with PDAC fluctuates between 6% and 10%[9]; however, this rate may increase to 25% after curative surgical resection and adjuvant treatment[7,5]. In inoperable patients, treatment is limited to palliative treatment for symptom relief[8].
Early diagnosis and radical surgical excision offer a unique chance of long-term survival in patients with an otherwise poor prognosis. Unfortunately, at the time of diagnosis, only 10%-20% of patients are amenable to therapeutic operation[2]. Surgical resection is not recommended when distant metastasis is present; only palliative treatment and supportive care are indicated in inoperable cases[2]. In addition, surgery alone is insufficient instead of multimodal treatment to prevent micrometastasis[5,7].
A better understanding of the process of carcinogenesis, the tumor microenvironment, molecular alterations and gene mutations has led to novel treatment modalities. Adjuvant or even neoadjuvant systemic therapy, including che
On the basis of the high-grade malignancy of pancreatic cancer and the disappointing results of its management, this article highlights novel achievements and future research perspective efforts focused on achieving early diagnosis and proper management.
Modern imaging modalities for early accurate diagnosis include (in order of priority): (1) Three-phase contrast-enhanced multidetector computed tomography (CT) or novel photon-counting detector CT[13] and spectral CT for the detection of tumors, local or lymphatic spread, major vessel invasion and distant metastases; (2) Contrast-enhanced magnetic resonance imaging (MRI)-cholangiopancreatography for assessing local tumor conditions or distant metastases, preferably liver metastases and imaging of the common bile duct and pancreatic duct; (3) Endoscopic retrograde cholangiopancreatography (ERCP) for the diagnosis of pancreatic duct or common bile duct stenosis and stenting for palliative treatment in inoperable cases; (4) Positron emission tomography-CT for better staging and detection of small occult or obscure metastases not otherwise visible; and (5) Endoscopic ultrasound (EUS) in ambiguous cases and for obtaining tissue samples for biopsy or gene analysis[8,11].
Integrating recent advancements in artificial intelligence (AI)-assisted imaging and radiomics would provide a more up-to-date perspective[14]. Multiparametric MRI using artificial intelligence is a novel tool for evaluating intratumor characteristic findings that can accurately predict tumor biological behavior and prognosis[15] as well as the response to neoadjuvant treatment[16].
Fine needle aspiration (FNA) or fine-needle tissue biopsy (FNB) during EUS or under imaging guidance and positive cytology of aspirated pancreatic juice with the aid of ERCP safely establish the preoperative diagnosis[8]. The use of novel needles for EUS-FNB ensures that the diagnostic accuracy of core tissue biopsy exceeds 95%, thus replacing mostly traditional EUS-FNA[17].
The most reliable tumor marker that is used worldwide for early preoperative detection, early recurrence assessment, and prognosis prediction is carbohydrate antigen (CA 19-9) when its levels exceed 400 U/mL[3,5,8,18,19]. It is particularly useful for the early diagnosis of pancreatic cancer in patients with chronic pancreatitis and diabetes mellitus[20].
Liquid biopsy detection of tumor DNA, tumor parts or cancer cells can contribute to early diagnosis, therapeutic efficacy monitoring and follow-up[3]. The use of extracellular vesicles (EVs, particularly exosomes) as biomarkers of treatment efficacy increases liquid biopsy accuracy[21]. EVs and circulating tumor DNA (ctDNA) are novel emerging diagnostic tools, and they have the potential to change the management of malignant tumors by possible replacement of tissue biopsy. The diagnostic accuracy of these methods has been further enhanced by novel PCR and next-generation sequencing digital applications[22]. Perspective combination biomarker strategies, such as ctDNA with CA 19-9 or miRNAs, would provide additional value[14].
Histologic confirmation, not only the suspicion of pancreatic adenocarcinoma, is necessary before any surgical intervention or chemotherapy treatment. In cases of negative or unclear preoperative cancer histologic confirmation, it is better to wait for outcomes of liquid biopsy or the other newer molecular tests described herein before proceeding[23,24].
EUS-guided tissue acquisition is a novel valuable modality for the confirmation of PDAC, and its genomic profile evaluation can be used to plan accurate management[23].
In any case, early diagnosis remains challenging despite progress in liquid biopsy, miRNA analysis[25], genomic analysis[26,27], metastasis-associated protein analysis[7] and the identification of circulating cancer-derived exosomes[18]. However, there are difficulties and questions regarding the use of ctDNA liquid biopsy as a biomarker, which can be used to detect primary tumors early in ambiguous cases and determine the strong possibility for a high risk of metastases. Circulating DNA may originate from necrotic or apoptotic cells at primary or metastatic sites. In addition, the circulating cell-free fraction of DNA can be found under normal conditions, including injuries, exercise, inflammation and sepsis[26].
Several genetic and epigenetic changes have been identified that could be used as novel diagnostic biomarkers or promising therapeutic targets[28,29]. The most common gene mutations include those in the KRAS gene and its al
A scheme of the diagnostic approach for PDAC is shown in Figure 1A.
For the staging of PDAC, the American Joint Committee on Cancer 8th edition has been used[34], as shown in Tables 1 and 2. It is important in determining the management plan as well as survival; 5-year overall survival fluctuates between 3% for stage IV patients with distant metastases and 83.7% for early-stage IA patients[35]. In addition, an international consensus has defined the criteria for local borderline resectable cases of PDAD[36], as shown in Figure 1B.
| T | Greatest dimension (cm) |
| Tis | In situ |
| T1 | ≤ 2 |
| T1a | ≤ 0.5 |
| T1b | > 0.5 and < 1 |
| T1c | 1-2 |
| T2 | > 2 and ≤ 4 |
| T3 | > 4 |
| T4 | Involvement of celiac axis, superior mesenteric artery, and/or common hepatic artery |
| Stage | Parameters |
| 0 | Tis, N0, M0 |
| I | |
| Ia | T1, N0, M0 |
| Ib | T2, N0, M0 |
| II | |
| IIa | T3, N0, M0 |
| IIb | T1-T3, N1, M0 |
| III | Any T, N2, M0 or T4, any N, M0 |
| IV | Any T, any N, M1 |
PDAC is inoperable or unresectable in 80%-90% of cases because of locally advanced tumors or distant metastasis, including liver (50%) and peritoneal seeding (30%); in addition, there is overall lymph node involvement of 70%, either local or distant. Cancer is characterized as borderline resectable when it is in close proximity (part of major blood vessels or even invasion), indicating the need for neoadjuvant treatment[36]. The cancer is considered resectable when it is located in the pancreas or just around it[2,5,7,34]. The cornerstone of managing patients with resectable disease is curative surgical resection, followed by adjuvant treatment[5]. However, surgery alone is insufficient, and multimodal treatment is needed. The novel promising therapeutic modalities are immunotherapy and vaccination, gene-targeted therapy and biological agents that inhibit angiogenesis since the biology of pancreatic cancer is the factor that most strongly affects the outcome[7,9,37].
According to the tumor location, the surgical operation includes a. proximal pancreatoduodenectomy with standard lymphadenectomy, including the lymph nodes right to the superior mesenteric artery along with soft tissue around the pancreas, b. retrograde or antegrade distal pancreatectomy with or without spleen preservation or c. even total pancreatectomy[2,38-40]. Among the three types of pancreatectomy, R1 resection (infiltrated resection margins) results in microscopic residual tissue and accounts for 17%-19% of all cases[40]. Radical antegrade modular pancreatosplenectomy is preferable to standard retrograde pancreatosplenectomy for body and tail location, ensuring better lymph node clearance[38]. Vein resection without reconstruction has been proposed for locally advanced disease, increasing the resectability rate[41].
The number of retrieved lymph nodes is a reliable and auspicious prognostic indicator when the number of retrieved nodes is above 12 and without infiltration[42]. Nevertheless, infiltrated resection margins are often found by histopathological assessment, which indicates that systemic therapy is either adjuvant or neoadjuvant[43].
Laparoscopic or robotic pancreatectomy is an evolutionary surgical intervention in the current era of minimally invasive surgery with satisfactory short- and long-term outcomes. Compared with open pancreatectomy, robotic pancreatectomy has a longer duration, results in less blood loss, and is associated with shorter postoperative pain and hospital stays; it has similar rate of pancreatic fistulas but with lower clinical significance, more accurate resection margins (R0 resection) and lymph node clearance, and comparable survival rates[44].
The preferred first-line chemotherapy scheme is FOLFIRINOX, which includes a combination of leucovorin (folinic acid), 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine plus nab-paclitaxel for advanced metastatic disease in well-performing patients. Gemcitabine alone can be used in frail patients[45]. Additionally, modifications of FOLFIRINOX have sometimes been used, i.e., without irinotecan FOLFOX (folinic acid, 5FU and oxaliplatin) or without oxaliplatin FOLFIRI (folinic acid, 5FU and irinotecan)[2,46,47].
As a first-line chemotherapy for inoperable PDAC, FOLFIRINOX has better clinical efficacy than does gemcitabine plus nab-paclitaxel, with median progression-free survival of 6.5 months vs 5.3 months and median overall survival of 12.3 months vs 10.34 months[48].
Cytotoxic chemotherapy is the main option for systemic treatment of metastatic disease[1]. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) and GEMNABP (gemcitabine and nab-paclitaxel)[49] are increasingly used for metastatic disease with satisfactory outcomes[1,50]. However, chemoresistance is a major setback in pancreatic cancer, as in other solid tumors, though it can be overcome by precise targeting of malignant cells[43]. Certepetide is a novel antineoplastic drug that regulates the cell microenvironment and may be useful in inoperable advanced cases[51].
Novel stereotactic body radiation therapy and MRI-guided radiotherapy, adjuvant or neoadjuvant, have limited the side effects of radiation, providing accurate targeting and increased effectiveness, thus resulting in tumor shrinkage, restriction and local control; additionally, palliative radiotherapy results in pain relief in advanced cases[2,30,52].
Neoadjuvant treatment, including chemotherapy, radiotherapy[53] or a combination, has been used in borderline operable or locally advanced cases[9,54]. Although neoadjuvant therapy can offer potential benefits, such as reducing tumor size, addressing micrometastases early, and improving surgical outcomes, its universal application in all operable cases remains a topic of debate. Neoadjuvant treatment with gemcitabine plus S-1 (tegafur, a precursor of 5-fluorouracil; gimeracil, an inhibitor of 5-fluorouracil; and oteracil, a limiting agent of 5-fluorouracil toxicity) has beneficial effects[55]. Neoadjuvant chemotherapy can improve the outcome of locally advanced disease by tumor downstaging and gene profile alteration[31], despite the resulting immune suppression[56] and the existing controversy[8]. Additionally, a positive response to neoadjuvant treatment may predict a favorable outcome of potential subsequent surgical in
Gene therapy against the involved genes and novel vaccines have been used with encouraging results[31,60,61]. Vaccines that stimulate the immune system have provided preliminary hopeful outcomes[62]. The combination of herpes virus vaccines with PD-1 antibodies increases therapeutic efficacy[63].
Targeting the KRAS gene mutation, which is found in more than 90% of pancreatic cancers[4,33], may have beneficial effects. High levels of KRAS G12C gene mutations that occur at codon 12 activate the cycle of malignant cells and promote tumor growth, proliferation, invasion and spreading, resulting in a poor prognosis[1,5,64,65]. Similarly, patients with the KRAS G12D and G12V gene mutations had poor progression in contrast to those with the KRAS wild type, whereas those with the KRAS G12R gene mutation had better progression. In these patients, FOLFIRINOX had a better effect than gemcitabine[66].
For anti-KRAS G12C gene mutations, which are found in few cases, the drugs sotoracib or adagrasib have been used in patients with inoperable PDAC. They have modest survival benefits that can be increased by the addition of epidermal growth factor receptor inhibitors, i.e., erlotinib, gefitinib, cetuximab, and necitumuma[1,65,66]. Both drugs were recently approved by the FDA, but resistance to these drugs may occur. However, their combination with son of sevenless homolog 1 inhibitors (lapatinib-afatinib) increases treatment effectiveness[67]. For the Pan-RAS inhibitor RMC-(94)6236, initial results from ongoing studies have been reported[30]. For other gene mutations beyond those of the KRAS gene[68], the following promising therapies have been used: (1) BRAF V600E gene (dablafenib plus trametinib); (2) NTRK gene (larotrectinib or entrectinib); (3) RET gene (selpercatinib); and (4) BRACA1,2 gene (PARP inhibitors, i.e., olaparib, niraparib, rucaparib, and talazoparib, which have the disadvantage of developing resistance frequently limiting their use) and NRG1 gene (zenocutuzumab)[1,30,33]. There are ongoing trials, such as the NCI-MATCH trial, which uses next-generation genetic tests, and the POLO study, which is a phase III clinical trial, evaluating the effectiveness of the PARP inhibitor olaparib in BRCA1/2 metastatic PDAC. Olaparib was associated with increased progression-free survival (7.4 months vs 3.8 months in patients without treatment)[33].
The tumor microenvironment plays a pivotal role in planning management[51,69].
Immunotherapy targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has been used in many cancers, but pancreatic cancer has a lower response rate[70]. Pembrolizumad against PD-1 is the only drug approved by United States Food and Drug Administration (FDA) for advanced pancreatic cancer, but durvalumab, which targets PD-L1, has been used in clinical trials[9]. The limited success of immune checkpoint inhibitors in treating PDAC may be improved by emerging strategies, such as targeting the tumor microenvironment (extracellular matrix, immune cells, mesenchymal cells, tumor cells and fibroblasts), which can efficiently direct immunotherapy[69].
Recent advancements in immune checkpoint inhibitors, personalized vaccines, and CAR-T-cell therapies have revealed the important role of the continuing safety and efficacy of immunotherapy as a therapeutic choice for adjuvant or even frontline treatment[2,68]. Among its other applications, immunotherapy is a unique alternative for patients in advanced inoperable stages who have minimal or no response to other treatments[62].
The above mentioned management options are shown schematically in Figure 1C.
By incorporating all the relevant information mentioned throughout the manuscript, the predictive factors for favorable prognosis are summarized in Table 3.
| Number | Factor |
| 1 | Stage T1-T2 |
| 2 | Without metastases beyond the pancreas |
| 3 | Curative surgical resection |
| 4 | R0 resection without infiltration of resection margins |
| 5 | G1 (high) cell differentiation or even G2 (moderate); G3 (poor) provides worse outcomes |
| 6 | Absence of lymph node infiltration |
| 7 | Retrieved lymph nodes > 12 |
| 8 | Absence of perineural invasion |
| 9 | Neoadjuvant systemic treatment in borderline resectable cases, at least |
| 10 | Novel adjuvant systemic treatment |
| 11 | Absence of early recurrence |
| 12 | Without malnutrition and sarcopenia |
| 13 | Multimodality treatment |
The best prognosis is related to G1 (high) cell differentiation, followed by G2 (moderate) and G3 (poor) cell differentiation, which results in worse outcomes[35].
Perineural invasion and excruciating pain predict recurrence and a dismal prognosis. Targeting neural invasion with therapeutic biological agents, unless pain is relieved, may restrict tumor progression[71].
A large very recent multicenter trial (GARIBALDI) from Italy including 402 patients with PDAC without metastases who underwent a. surgery (36.6%), including only surgery (3%) and adjuvant chemotherapy (91.8%), b. neoadjuvant chemotherapy and surgery (14.2%) and c. only chemotherapy (49.3%), reported that, during a follow-up period of 57.6 months, 300 deaths (74.6%) occurred[72].
The management options for pancreatic cancer must be multidisciplinary. Modern adjuvant treatment after curative resection has increased the median overall survival from 18.6 months to 38.3 months[2].
In addition to their diagnostic role as PDAC biomarkers, circulating exosomes in liquid biopsy may be used as vehicles for drug delivery, providing targeted treatment against the growth of cancer cells in PDAC and other cancers[18].
Local ablation of the tumor by radiofrequency (RFA), microwaves, irreversible electroporation or electrochemotherapy has been applied in patients who are unfit for surgery or after failed chemotherapy in advanced disease. RFA, along with immunotherapy, constitutes a novel approach[73].
Nanoparticles have been used for the delivery and accurate distribution of chemotherapy, immunotherapy drugs and imaging materials (radiotracers) precisely within tumors[74].
Many studies have focused on novel radiomic methods, including machine learning and artificial intelligence, which could be valuable in early diagnosis, prognosis prediction and management strategic planning[2,75].
The standard adjuvant treatments approved by the FDA include chemotherapy with FOLFIRINOX and its modifications, gemcitabine, nab-paclitaxel, targeting KRAS gene mutation and immunotherapy with pembrolizumad. The other mentioned treatments are novel promising treatments awaiting FDA approval (gene therapies, vaccines and immunotherapy with durvalumab) or further validation through more consistent clinical experience (circulating exosomes and nanoparticles)[1,18,30,33,74].
Future challenging perspectives are anticipated to be based on the evolution of artificial intelligence. This innovation would be capable of analyzing enormous amounts of data regarding precise genomic assessment involved in cancer cell development and accurate selection of responsible gene targeting. The latter could manage the existing gap of resistance to treatment; additionally, it may reduce the high cost of novel oncological drugs, which is a current barrier along with their uncertain effectiveness. AI could be used to validate novel biomarkers for early diagnosis, including genomics and radiomics, or for determining accurate individualized combination immunotherapy, chemotherapy and targeted therapy.
Pancreatic cancer has a poor prognosis. When radical therapeutic surgery is performed whenever possible, multimodal and personalized treatments are necessary for modern management. Novel chemotherapy, radiotherapy, targeted therapy and immunotherapy may improve survival and patient quality of life. Further research efforts at the molecular level are needed to prevent the growth, invasion, and spread of cancer cells. Machine learning and artificial intelligence are promising novel modalities.
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