Pancreatic Cancer: Updates in Pathogenesis and Therapies

Abstract

Despite the progress in pancreatic cancer (PC) chemo/radiotherapies, immunotherapies, and novel targeted therapies and the improvement in its peri-operative management policies, it still has a dismal catastrophic prognosis due to delayed detection, early neural and vascular invasions, early micro-metastatic spread, tumour heterogeneities, drug resistance either intrinsic or acquired, unique desmoplastic stroma, and tumour microenvironment (TME). Understanding tumour pathogenesis at the detailed genetic/epigenetic/metabolic/molecular levels as well as studying the tumour risk factors and its known precancerous lesions aggressively is required for getting a more successful therapy for this challenging tumour. For a better outcome of this catastrophic tumour, it should be diagnosed early and treated through multidisciplinary teams of surgeons, gastroenterologists/interventional upper endoscopists, medical/radiation oncologists, diagnostic/intervention radiologists, and pathologists at high-volume centres. Moreover, surgical resection with a negative margin (R0) is the only cure for it. In this chapter; we discuss the recently updated knowledge of PC pathogenesis, risk factors, and precancerous lesions as well as its different management tools (i.e. surgery, chemo/radiotherapies, immunotherapies, novel targeted therapies, local ablative therapies, etc.).

1. Introduction

Despite medical advances, pancreatic cancer (PC) is still a deadly challenging catastrophic tumour with a high mortality rate even after radical resection. It has a notable bad prognosis in comparison to the other malignant tumours due to its high malignant degree, gradual onset, typical symptoms defect, delayed discovery, difficult anatomical location, lower rate of curative resection, recurrence after resection, and high rate of chemo/radiotherapy resistance [1]. Globally; it is the 7th leading reason for cancer-related mortalities [2].

The most common cancer of the pancreas is pancreatic duct adenocarcinoma (PDAC) accounting for over 90% of cancers. Both the occurrence and progression of PDAC come from changes in some genes (i.e. KRAS oncogene mutational activation, inactivation of tumour suppressor genes (CDKN2A, TP53, and SMAD4), and/or mutations in other genes involved in the cell cycle and apoptosis). Also, it occurs due to some risk factors (i.e. tobacco smoking, alcohol, obesity, diabetes, chronic pancreatitis, etc.) as well as some precancerous lesions (i.e. pancreatic intraepithelial neoplasia [PanIN], intra-ductal papillary mucinous neoplasm [IPMN], mucinous cystic neoplasms [MCN], etc.) [1].

Besides PDAC, there are some other pathological types of PCs (e.g. Acinar cell carcinoma, small cell carcinoma, cystadenocarcinomas, pancreatoblastoma, pancreatic neuroendocrine tumours [PNET], etc.) [1].

Depending on the tumour stage, resectable cancers are treated by surgical resection followed by adjuvant therapy. On the other hand, borderline resectable tumours are treated by neoadjuvant therapy followed by surgical resection. However, for patients with locally advanced or distant metastatic PCs, FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin) and/or gemcitabine (a nucleotide analogue) plus albumin-bound paclitaxel (nab-paclitaxel) have been approved for use with high success [1, 3]. Lastly, future targeted therapies depending upon molecular pathways, tumour gene mutations and modulation of the tumour microenvironment (TME) are in progress under different phases of clinical trials [3].

2. Pathogenesis of PDAC

2.1 Genetics, molecular alterations, metabolic changes, and cancer pancreas

Understanding PDAC pathogenesis at the detailed genetic/epigenetic/metabolic/molecular levels as a tool to reach a more successful therapy for this challenging tumour remains an area of continuous aggressive research. The targeted molecular biology, whole exome sequencing studies, and genomic analyses showed that PDAC may occur due to mutational activation of some oncogenes/proto-oncogenes (i.e. KRAS, c-Myc, PAK4, MYB, HER2, etc.) and/or inactivation of some tumour suppressor genes (i.e. p16, TP53, SMAD4, CDKN2A, etc.), and/or mutations of DNA damage/repair (DDR) genes (i.e. ATM, BRCA1, BRCA2, PALB2, STK11, etc.), moreover, they can come from large chromosomal alterations (copy number alterations, chromosomal rearrangements, chromosomal instability from telomeres shortening, and clustered genomic rearrangements (chromothripsis)). Meanwhile; epigenetic DNA and histones alterations by methylation and acetylation respectively may be the leading causes of this catastrophic tumour [3].

The previous genetic alterations lead to changes in some signalling pathways (i.e. EGFR, TGFR, VEGF, IGF, Akt, NF-kB, Hedgehog, Wnt, Notch signalling, etc.) as well as other pathways (apoptosis and cell cycle pathways) causing PC progression [4]. So, those genetic alterations and changed signalling pathways became targets of the PC novel therapies (Figure 1).

Figure 1.

Pathogenesis of PDAC. Taken from Wood et al. [3].

MicroRNAs (miRNAs) are double-stranded small non-coding RNA molecules regulating gene expression at mRNA levels either by their degradation or translational inhibition. They have a role in PC initiation, pathogenesis, progression, proliferation, invasion, migration, and metastasis by affecting oncogenes (i.e. KRAS), tumour suppressor genes (i.e. P53), and/or signalling pathways (i.e. Notch) [5]. So they became a target for miRNAs-based novel therapies of PC in the preclinical levels (e.g. miRNAs natural modulating agents [i.e. curcumin], synthetic oligonucleotides that destroy oncogenic miRNAs and/or synthetic tumour suppressive miRNAs) [6].

Long non-coding RNAs (lncRNA) such as HOTAIR are non-coding RNA molecules having lengths of more than 200 nucleotides with different cellular functions including transcriptional, post-transcriptional, and epigenetic regulation of gene expression. They have a critical role in PC progression by promoting proliferation, drug resistance, cell growth, migration, invasion, and metastasis. So, they will be a target for different therapies of PC soon [7].

Circular RNAs (CircRNAs) such as ciRS-7, circEIF6, etc. are single-stranded, non-coding covalently closed RNA molecules having a role in PC pathogenesis and progression by the followings: (1) Working as miRNAs decoys preventing them from binding to their target mRNAs leading to mRNAs stabilisation, perfect translation, and subsequently promoting tumour progression by proliferation, invasion, migration, metastasis, angiogenesis, augmenting chemotherapy resistance, and/or by inhibiting apoptosis. (2) Inhibiting post-translational modifications of proteins leads to protein stabilisation and tumour progression. (3) Acting as scaffolds for protein complexes leading to mRNA-protein complex formation enhancing mRNA expression and tumour progression. So, they will be a target for different therapies of PC soon (Figure 2) [7, 8].

Figure 2.

Role of circRNAs in PC pathogenesis taken from Seimiya et al. [8].

Exosomes are small (30–100 nm) nano-scale extracellular vesicles with high stability, low immunogenicity, low cytotoxicity, and high membrane permeability containing cellular constituents (i.e. DNA, RNA, proteins, and lipids). They are secreted by all cell types into the circulation to transport biological components to other cells and tissues regulating intercellular communication. The exosomes originating from PC cells have a role in cancer growth, promotion, and metastasis through the induction of fibronectin secretion and the resulting inhibition of metastatic tumour infiltration by macrophages and neutrophils. So, they became a target for the future therapies of PC, also, they can act as vectors/carriers for therapeutics/molecules transmission (drugs, miRNAs, circRNAs, lncRNA, small-interfering RNAs [siRNAs], etc.) [9, 10, 11].

By genomic (RNA-seq.) analysis, PDAC has been classified molecularly into the following four categories: (1) The squamous/quasi-mesenchymal/basal-like cancer; it is known by its high mesenchymal marker gene expression and by its worst prognosis when compared with the other categories, moreover, it is more sensitive to gemcitabine. (2) The pancreas progenitor/classical cancer is characterised by high epithelial marker gene expression and higher sensitivity to the EGFR inhibitors (erlotinib). (3) Immunogenic cancer is near to the pancreatic progenitor subtype but can be differentiated by the higher expression of the immune-related cell lines; furthermore, it has a higher sensitivity to immunotherapy, pembrolizumab. (4) The aberrantly differentiated endocrine-exocrine (ADEX)/exocrine-like cancer is characterised by a mixture of both endocrine and exocrine pancreatic cell lines [12, 13, 14].

PDAC may run in families (familial PC [families with at least two first-degree relatives with PDAC without observation of any other hereditary cancer syndromes]) and may be related to the following rare hereditary syndromes: (1) Hereditary pancreatitis with germ-line mutations in the cationic trypsinogen (PRSS1) gene, (2) Breast cancer susceptibility gene-1/2 (BRCA1/2) and PALB2 mutations, (3) Peutz–Jeghers syndrome due to mutations in the tumour suppressor gene STK11, (4) Familial atypical multiple-mole melanoma syndrome due to mutations in the tumour suppressor gene CDKN2A, (5) Hereditary non polyposis colon cancer (Lynch syndrome) due to mutation in mismatch repair (MMR) gene, (6) Familial adenomatous polyposis due to mutation of APC or MYTYH genes, (7) Ataxia telangiectasia due to mutation in the ataxia telangiectasia mutated (ATM) gene, (8) Li-Fraumeni syndrome Due to germ-line autosomal dominant mutation of TP53 gene, and (9) Werner’s syndrome due to absence of WRN gene function [15, 16, 17, 18].

2.2 The TME and its related factors in the pathogenesis of cancer pancreas

The PDAC TME is composed mainly of pancreatic stellate cells (PSC), immune cells, inflammatory cells, endothelial cells, extracellular matrix (ECM), neuronal cells. Also, soluble proteins like growth factors and cytokines have a main role in cancer pathogenesis, progression, and chemo-resistance through the followings: (1) The tumour has a dense desmoplastic stroma (comes mainly from PSC) with accumulation of a large amount of ECM (i.e. collagens, elastins, hyaluronan, etc.) leading to isolation of the tumour mass, severe hypoxia, and hypo-perfusion preventing drugs and immune cells from reaching the tumour cells; moreover activated PSCs promote cancer cell growth, proliferation, and invasion; (2) Immune cell changes (i.e. abundance of cells like myeloid-derived suppressor cells, tumour-associated macrophages (TAMs), and tumour-associated neutrophils and depletion of others like dendritic cells and anticancer T cells) promote immunosuppressive microenvironment preventing immune-mediated targeting of the tumour; (3) The cancer associated fibroblasts (CAF) have a role through metabolic support of the tumour, immune modulation of its microenvironment, promotion of cancer cell growth, survival, and invasion, and drug resistance; (4) Inflammatory process components (i.e. cytokines like TNF-α, IL-6, interferon-γ, and free radicals) have a role in PC promotion and progression. So, modulation of this TME became the target of many novel targeted therapies of PDAC in different recent clinical trials (Figures 1 and 3) [2, 3, 14, 19, 20, 21, 22, 23].

Figure 3.

The effect of PDAC TME on cancer pathogenesis and progression taken from Deng et al. [14].

The developmental shift of PDAC cells from the epithelial to the mesenchymal or fibroblastoid phenotype epithelial mesenchymal transmission (EMT) is considered a vital step in the progression of the primary tumours to the invasive/metastatic/drug-resistant ones. It is a developmental process characterised by the degradation of the adherens and tight junctions of the epithelial cells to be converted to highly mobile and invasive mesenchymal cells. Molecularly, it is associated with decreasing levels of E-cadherin and conversely increasing levels of N-cadherin. In addition, it is associated with different signalling pathways of PC progression (i.e. Notch.), and with pancreatic cancer stem cell (PCSC) induction. This EMT enables cells to invade the surrounding tissues, the circulation, and finally to disseminate to distant sites [12, 24].

Due to their self-renewing and differentiation capabilities, PCSCs have a role in PC initiating and progression through tumour growth, invasion, metastasis, recurrence, and chemo/radio-resistance. They are regulated by different signalling pathways (i.e. Notch, Hedgehog, Wnt, etc.) and their chemo/radio-resistance comes from DNA repair capacity, increased DNA damage tolerance, tumour EMT, and higher levels of detoxification enzymes, epigenetic modifications, quiescence, and interaction with TME components. So, they became the target of many therapies of PC in the pre-clinical and clinical models [25].

The microbiota (i.e. bacteria, fungi, viruses, protozoa, etc.) normally inhabit human bodies mainly gastrointestinal tracts (GITs). They can be found also in oral cavities and different tissues like the pancreas playing an essential role in keeping body homeostasis; however; the microbiota imbalance (dysbiosis), and their combined genetic material (microbiome), have a major role in initiation and progression of tumours like PDAC by gene mutation, changing the TME immunity, altering tumour metabolism, promoting tumour inflammatory responses, and by promoting drug resistance (Figure 4). They can be detected by real-time quantitative polymerase chain reaction (qPCR) that can be confirmed by fluorescence in situ hybridization and immunohistochemistry and finally specified by amplified rRNA sequencing. Moreover, they became a target of novel therapies for PC in different clinical trials [26].

Figure 4.

Microbiota imbalance (dysbiosis) in PDAC; taken from Li et al. [26].

2.3 Risk factors of cancer pancreas

Several factors are increasing the risk of PDAC (Figure 1). One of these factors is cigarette smoking which promotes cancer development by DNA damage as well as by inflammation and fibrosis [27]. Similarly, diabetes mellitus either new-onset diabetes or long-standing one as well as obesity increase the risk of cancer pancreas through altered metabolic pathways, higher levels of adipocytokines, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase, changed gut microbiota, increased PCSCs, increased EMT, and inflammation [9, 28].

The other factors related to PDAC occurrence are older age, male gender, processed meat, chemicals like asbestos, chronic pancreatitis, heavy alcohol consumption, and infections like hepatitis B virus, Helicobacter pylori, and human immunodeficiency virus infections [3, 29, 30].

On the other hand, patients with allergies (i.e. asthma, nasal allergies, hay fevers, etc.) have a lower risk of PC occurrence due to their active immune system [2]. Similarly, a diet with high fruit, vegetables, and folate reduces the risk of its occurrence [29].

2.4 The precancerous lesions of PDAC as well as its pathology

The invasive PDAC may arise from some curable resectable precancerous lesions; the most common of them is PanIN. These are less than 5 mm microscopic neoplasms involving the pancreatic ducts. However, a less common larger precancerous macro cystic lesion that involves the ducts and is also the IPMN [31]. Lastly, MCN is the least common lesion. They do not involve the ductal system and have a characteristic ovarian-type stroma. They are more common in women and involve the pancreatic body and/or tail [32].

Morphologically, the previous precancerous lesions are sorted into low-grade and high-grade ones based on cytological and architectural atypia. The low-grade lesions have mild to moderate cytologic atypia and basally oriented nuclei. On the other hand, the high-grade ones have severe cytologic atypia, loss of nuclear polarity and marked architectural alterations [31, 33]. Regarding PanIN, their progression from normal epithelium to low-grade PanIN 1, 2 then to high-grade PanIN 3, and lastly to invasive PDAC is related to specific genetic alterations (i.e. early [KRAS mutation, telomere shortening], intermediate [p16/CDKN2A loss], and late [mutations of DPC4/SMAD4, TP53, BRCA2]). Moreover, the invasive PDAC is mostly associated with high-grade lesions (PanIN 3, and high-grade dysplasia of cystic lesions) (Figure 5) [16].

Figure 5.

Genetic progression of PanIN to invasive PDAC; taken from Kumari [16].

Regarding the pathology of PDACs, macroscopically, they are seen as fairly demarcated firm white-yellow masses with atrophic fibrotic neighbouring non-neoplastic pancreatic tissue; moreover, obstructive dilation of pancreatic ducts may be seen. On the other hand, the invasive tumour is characterised microscopically by mucin-producing glands elicited in a dense desmoplastic stroma with haphazard glandular arrangement, nuclear pleomorphism, glandular luminal necrosis, perineural, and lymphovascular invasions; moreover, they vary microscopically from well-differentiated duct forming carcinomas to poorly-differentiated carcinomas with glandular differentiation demonstrable only on immunolabelling [34, 35].

3. Treatment of PDAC

Despite the recent developments in diagnosis, surgery, radio/chemotherapy, immune therapy as well as targeted therapies of PDAC, it still has a very poor prognosis due to delayed detection, early micro-metastatic spread, drug resistance either intrinsic or acquired, unique desmoplastic stroma and TME, and tumour heterogeneities [36]. The 5-year survival rate after PC diagnosis may reach only 5–11%. However, for the very early diagnosed ones, it may rise to 85% and horribly; for the locally advanced or the metastatic ones, it may become less than 3% [1, 8, 16, 37]. For a better outcome of this catastrophic tumour, it should be diagnosed early and treated through multidisciplinary teams of surgeons, gastroenterologists/interventional upper endoscopists, medical/radiation oncologists, diagnostic/intervention radiologists, and pathologists at high-volume centres. Moreover, surgical resection with a negative margin (R0) is the only cure for it. However, resection is associated with high morbidity and mortality, so, meticulous preoperative assessment and preparation are required for better outcomes after resection (i.e. biliary drainage and nutritional support if required) [3, 29, 38, 39, 40].

Despite less than 20% of patients having resectable tumours at presentation [41], this aggressive tumour can be classified into resectable, borderline resectable, locally advanced, and distant metastatic. We will discuss the treatment options of those different types of PC as well as the different novel therapies for this catastrophic tumour.

3.1 The resectable tumour

The resectable tumour that lacks distant metastases, has no abnormal LNs away from the surgical basin and has no vascular invasion (No tumour–artery interface [celiac axis, superior mesenteric artery (SMA), or common hepatic artery (CHA)], >180-degree tumour–vein interface [superior mesenteric/portal veins (SMV/PV)]) is managed through surgical (open, laparoscopic, or robotic) removal of the affected pancreatic region (i.e. pancreaticoduodenectomy, distal pancreatectomy+splenectomy, and whole pancreatectomy+splenectomy for cancers of head, body/tail and whole gland respectively) as well as standard/extended lymphadenectomy (NB: ≤15 LNs should be excised) followed by adjuvant chemo/radiotherapy for improving long-term outcomes. However, neoadjuvant therapy before resection may be used in this group of patients especially patients with markedly elevated CA19-9, huge primary tumours and huge regional lymph nodes for assessing the benefit of surgery and for improving its outcome. Moreover, preoperative biliary drainage should be avoided in this group of patients due to its related drawbacks except in neoadjuvant therapy patients, as well as cholangitis and/or high bilirubin (>15 mg/dL) patients [3, 29, 38, 39, 40].

The previous management is prescribed with good patient performance status (PS) (based on Eastern Co-operative Oncology Group [ECOG]) with no major comorbidities; however, if the PS is poor, the patients with resectable non-operable PC are managed by single-agent chemotherapy (i.e. gemcitabine, 5-FU, etc.) or supportive symptomatic treatment [42].

3.2 The borderline resectable tumours

In patients with borderline resectable tumours (i.e. tumours that lack distant metastases, have no abnormal LNs away from the surgical basin, tumours with reconstructable invasion of SMV/PV or > 180-degree encasement of SMA); the treatment starts by the neoadjuvant chemo-radiation therapy aiming at down-staging of the tumour before resection and improving margin-negative resection rates, followed by surgical resection±intra-operative electron radiation therapy. In this category of patients, relief of biliary obstruction by plastic stenting before the neoadjuvant therapy should be done, furthermore, intraoperative venous reconstructions can be performed when needed with acceptable outcomes, and the adjuvant therapy can be given postoperatively. On the other hand, in patients with poor PS, the management will be palliative single-agent chemotherapy or supportive care [3, 29, 40, 43].

3.3 The surgical procedures

Classic pancreatoduodenectomy (PD), pylorus-preserving PD, radical PD, standard PD, extended PD, distal pancreatectomy, and total pancreatectomy are known procedures for resection of PDAC [43, 44].

Classic PD involves the excision of the pancreatic head, gallbladder, bile duct, duodenum, and gastric antrum [45]. A wide Kocher manoeuvre is performed, and the gastrocolic ligament is divided, the pancreatic neck is then dissected off the SMV. The porta hepatis dissection starts by exposing the CHA, and then identification and ligation of the gastroduodenal and right gastric arteries are performed. Then the PV is dissected off the pancreatic neck. Cholecystectomy as well as division of the common hepatic duct is then performed. The gastric antrum as well as the proximal 10 cm of jejunum is then resected. The pancreatic neck is then transected. Then the pancreatic head and uncinate process are dissected from the SMV/PV. (NB: some centres perform ‘SMA-first’ approaches to decrease blood loss and assess for R0 resection.) The soft tissue along the right lateral aspect of the SMA should be excised to prevent local recurrence. The resected specimen is removed as a single mass (en bloc resection) as shown in Figure 6. Then reconstruction starts with the pancreaticojejunostomy in the form of a retro colic end-to-side duct-to-mucosa anastomosis using interrupted sutures ± pancreatic stenting. Then, hepaticojejunostomy is performed distal to the previous anastomosis in a single layer of posterior continuous, and anterior interrupted sutures. Then finally, ante colic, end-to-side two layers gastrojejunostomy anastomosis is done around 50 cm from the hepaticojejunostomy anastomosis [43, 44].

Figure 6.

A, B: Classic PD specimens (Author’s operative work).

In pylorus-preserving PD, the duodenum is divided distal to the pylorus taking care to preserve the gastroepiploic arcade. It maintains the integrity of the stomach and improves patients’ quality of life. However, the radical PD operation is performed when there is no tissue plane between the tumour and SMV/PV by venous resection and reconstruction [43, 44].

In the PD procedure, the extent of the associated lymphadenectomy differs (standard vs. extended). In standard lymphadenectomy (standard PD), the resection involves gastric/pyloric nodes, anterior/posterior pancreaticoduodenal nodes, nodes to the right of the hepatoduodenal ligament/anterior to the CHA, and the ones to the right of the SMA. On the other hand, in extended lymphadenectomy (extended PD), the nodal excision includes nodes to the left/right of the hepatoduodenal ligament, common/proper hepatic arteries nodes, celiac axis nodes, all SMA nodes, and nodes in the anterolateral aspect of the aorta/the inferior vena cava. Moreover, the extended PD may be accompanied by the so-called total mesopancreas excision (TMPE) (i.e. a retropancreatic area, extending from pancreatic head, neck, and uncinated process to the aorto-caval groove, composed of loose areolar and adipose tissues, nerves, lymphatic as well as capillaries). The extended PD, radical PD, as well as TMPE, are all performed to reach R0 resection and to decrease recurrence [43, 44, 46]. Meanwhile, PD operations should be performed at high-volume centres (<10 surgeries/year) to get better survival due to experienced surgical/perioperative care at those high-volume centres [35, 47].

Distal pancreatectomy + splenectomy are performed for tumours of the pancreatic body/tail. The operation can be done through the left-to-right or right-to-left pancreatosplenectomy approaches with consideration of celiac axis nodal excision. However, total pancreatectomy is whole pancreas resection for tumours of the whole pancreas without liver or peritoneal metastases; it should be done in patients with strictly controlled clinical indications due to its multiple metabolic drawbacks [43, 44].

3.4 The neoadjuvant and adjuvant therapies

As mentioned before; neoadjuvant therapy is given to some patients with resectable tumours for chemosensitivity testing, better patient selection for surgery (no surgery if the disease progresses under neoadjuvant therapy), disease control, higher rate of R0 resection, tumour down-staging, post-surgical pancreatic leakage reduction, and improving postoperative survival outcomes. Also, it is given to borderline resectable cases for obtaining higher R0 resection rate, tumour down-sizing, and for improving post-resection survival rates [48]. Three to six cycles of neoadjuvant therapy can be given and the regimen differs according to the patient’s PS, treatment response, etc. It may be FOLFIRINOX, gemcitabine plus nab-paclitaxel, 5-FU, gemcitabine, capecitabine, or combinations of the previous drugs± radiotherapy [39, 48].

On the other hand, six cycles of adjuvant therapy are recommended to be given within 4–12 weeks of surgery for decreasing postoperative recurrence and improving post-operative disease-free survival and overall survival rates. The proper regimen of adjuvant treatments varies according to many factors (i.e. patient’s PS, treatment response, toxicities, etc.). FOLFIRINOX is the recommended adjuvant therapy in fit patients by various recent groups (i.e. European Society for Medical Oncology [ESMO], National Comprehensive Cancer Network [NCCN], and American Society of Clinical Oncology [ASCO] groups); however, drugs like gemcitabine plus nab-paclitaxel, 5-FU, gemcitabine, capecitabine, or combinations of them± radiotherapy can be given also [39, 48]. In addition, the radiotherapy may be in the form of photon radiotherapy or particle radiotherapy (proton or carbon ion radiotherapies); moreover, it can be given as external beam radiation therapy, brachytherapy, targeted three-dimensional conformal radiation therapy (3D-CRT), MR-guided radiotherapy and/or super gamma knife stereotactic conformal radiotherapy [3, 44].

3.5 E-the locally advanced/distant metastatic tumour

According to the recent European and American guidelines, the treatment of the locally advanced pancreatic cancer (LAPC) (i.e. non-reconstructable invasion of SMV/PV and/or < 180-degree encasement of SMA and/or tumour invading the first jejunal branch of the SMA without distant metastases) and the distant metastatic cancer is as follow: In patients with good PS, the first line treatment is FOLFIRINOX or gemcitabine plus nab-paclitaxel. However, the second line treatment is the alternative combination of the previous therapies (i.e. FOLFIRONOX treated patients are given gemcitabine plus nab-paclitaxel or gemcitabine (if nab-paclitaxel is not available) as a second line therapy while gemcitabine plus nab-paclitaxel treated patients take 5-FU+ nano liposomal irinotecan however, if nano liposomal irinotecan is not available, they take 5-FU+ irinotecan or 5-FU+ oxaliplatin as a second line) (Figure 7) [48]. The previous chemotherapeutics can be given as systemic IV therapy, and as transcatheter arterial infusion therapy; moreover, in the future, they can be given through exosomal transport or nanotechnology by combining them with nanoparticles (i.e. liposomes, micelles, iron nanoparticles, gold nanoparticle, etc.) [10, 36]. On the other hand, patients with poor PS are given single-agent chemotherapy (e.g. gemcitabine or 5-FU) or supportive symptomatic treatment (Figure 7) [3, 44, 48].

Figure 7.

Algorithm for first- and second-line chemotherapies in advanced PC; taken from Lambert et al. [48].

The previous palliative therapies of locally advanced/distant metastatic tumours should be combined with the following palliative therapies: (1) For biliary obstruction, surgical hepaticojejunostomy or endoscopic self-expanding metal stents are good options; (2) For gastric outlet obstruction, gastrojejunostomy and metal stenting are good options for patients with longer and shorter life expectancy respectively; (3) Intractable pancreatic pain is managed by percutaneous/endoscopic/surgical celiac plexus block; (4) Malnutrition can be managed by nutritional support. (NB: in some locally advanced non-metastatic cases, neoadjuvant therapy can be given then reassessment then curative surgery can be performed [conversion surgery]) [49].

Nanotechnologies are updated technologies developed to improve physicochemical properties (i.e. post administration solubility and circulation times) of the anticancer drugs (e.g. gemcitabine) to improve their efficacy and to decrease their resistance. Nanoparticles can act as PC drug carriers that increase drug absorption, permeability, circulation time, and tumour penetration. Also, they can decrease drug degradation, metabolism, and toxic side effects. They are promising future therapies for PC. Albumin-bound paclitaxel, liposomes, micelles, iron nanoparticles, and gold nanoparticles are examples of those nanoparticles [50, 51].

3.6 The loco-regional targeted therapies

The loco-regional targeted therapies performed either intraoperatively (open or laparoscopic), percutaneously, or as endoscopic ultrasound (EUS)-guided tools, have promising results in managing LAPC. These loco-regional therapies can be divided into thermal ablative therapies such as microwave ablation, radiofrequency ablation, cryo-ablation, and high intensity focused ultrasound ablative therapy, and non-thermal therapies like irreversible electroporation, and photodynamic therapies. Meanwhile, there are other EUS-guided therapies of LAPC such as radioactive seed implantation (brachytherapy; iodine-125), locally targeted radiotherapy, fine needle injection of chemotherapeutics (e.g. Gemcitabine, topical anti-KRAS therapy, etc.), biliary drainage (choledochoduodenostomy, hepaticogastrostomy, stenting, and gallbladder drainage), gastroenterostomy, celiac neurolysis, etc. [44, 52, 53, 54, 55].

3.7 Updated novel therapies

Some novel therapies can be given to specific groups of patients. These are: (1) Patients with BRCA1/2 mutations are given platinum-based therapy or poly ADP-ribose polymerase (PARP) inhibitors (i.e. niraparib and olaparib); the drugs that promote cancer cell DNA damage or prevent its repair respectively causing cell cycle arrest and apoptosis [56]. Regarding platinum-based therapy, cisplatin has shown clinical benefits in different retrospective and prospective studies [3]. Moreover, Olaparib was approved by FDA in 2019 as a maintenance therapy for PC patients who responded to first-line cisplatin therapy as it increased their progression-free survival [56]. (2) PDAC with microsatellite instability (MSI)/MMR deficiency may respond to the immune therapy, pembrolizumab, which is an immune checkpoint inhibitor (anti-PD1 [programmed cell death protein-1]); it acts by preventing of binding of PD-1 to PD-L1 (programmed death ligand-1), this prevention leads to increased proliferation of the antitumour antigen-specific T cells as well as increased innate immunity to the tumour [3, 57]. Pembrolizumab is more effective in MSI-high tumours than MSI-low tumours, so it has been combined with chemotherapy, radiotherapy, and other immunotherapies in different clinical trials to increase its effect in MSI-low PDACs; an example of those trials is the COMBAT trial (NCT02826486) that concluded that the combination of pembrolizumab and CXCR4 antagonist with chemotherapy may improve tumour response to chemotherapy [3].

3.8 Immunotherapy under different phases of clinical trials (phases I, II, and III trials) with promising results that will have a main role in the future of PC therapy

(1) Immunotherapy targeting TME (i.e. Pegylated recombinant human hyaluronidase [PEG-PH20], in a phase Ib trial performed on stage IV PC patients, after they were given a combination of PEGPH20 and gemcitabine; the overall survival [OS] in high hyaluronic acid [HA] patients was higher than that in low HA patients) [58] (2) Immune checkpoint inhibitors like ipilimumab (immune checkpoint inhibitor, monoclonal antibody against CTLA-4, in a phase Ib trial when ipilimumab was given with GVAX [granulocyte macrophage colony-stimulating factor [GM-CSF vaccine]], the OS was longer than that observed when ipilimumab was given alone in advanced metastatic PC patients) [58]; moreover, there several ongoing clinical studies of Ipilimumab either as a monotherapy or as a combined medication with other immune checkpoint inhibitors, vaccines, chemotherapies, and/or tyrosine kinase inhibitors [59]. (3) Vaccines such as GVAX (it showed favourable results when given as combination therapy with different chemo-radiation therapies either in resectable or metastatic PCs in some clinical trials of phases I and II) [59]; mutant RAS peptide vaccine (in a Phase I/II study, the 10-year survival reached 20% after treatment with mutant RAS vaccine) [58]; Telomerase peptide vaccine (GV1001, despite showing promising results in a phase I/II trial of PC patients, it made no significant survival benefit when added to chemotherapy in other advanced PC phase III studies) [58, 59]; algenpantucel-L (an allogenic vaccine formed of αGal-expressing engineered PDAC cell lines; in a phase II study of PC patients, it showed promising results regarding disease-free survival [DFS] and OS when added to standard adjuvant chemotherapy) [59, 60]; K-Ras peptide vaccine (K-Ras mutated gene product; it showed promising results in phases I/II clinical trials when given alone or in combination with GVAX vaccine) [59]; Mucin-1 vaccine (it showed favourable outcomes in different phases I/II trials of PC patients) [59], VEGFR2 peptide vaccine (VEGFR2–169; it showed good results in a phase I trial of advanced PC when added to gemcitabine therapy) [59], Antigastrin vaccine (G17DT, it showed promising results when given either alone or in combination with other chemotherapies in different clinical trials of advanced PC populations) [59]; and lastly; dendritic cell (DC) vaccine (it showed acceptable results when given to PC patients in some trials) [59]. (4) Oncolytic viruses like ONYX-015 (adenovirus, in phase I/II trial of PC patients, its combination with gemcitabine was feasible and well-tolerated despite poor response) [58]; herpes simplex virus (HSV) (HF10, when it was given to six patients in a phase I trial, three were stable, one was in regression, and two were in progression) [58]; and Pelareorep (reovirus, it showed promising high viral replication in tumour cells and acceptable tolerance when combined with gemcitabine in a phase II study, also, it showed promising results and good safety when combined with chemotherapy and pembrolizumab in a phase Ib study) [60]. (5) Adoptive T-cell therapy (Chimeric antigen receptor [CAR]-T cell therapy, in phase I clinical study of patients with chemotherapy-refractory metastatic PC, the safety and efficacy of CAR-T- meso cells were promising) [58]. (6) Immunomodulatory agents like CD40 agonist antibodies (a tumour necrosis factor α receptor expressed on macrophages, B cells, and dendritic cells; in phase I clinical trial of advanced PC patients treated with both CD40 agonists and gemcitabine; the treatment was tolerable with promising results) [58]; JAK-STAT signalling pathway inhibitor (ruxolitinib, in phase II clinical trial of patients with metastatic PC who were treated with both ruxolitinib and capecitabine, the OS was significantly longer than that was observed in those patients treated with capecitabine alone) [58]; and CCR2 inhibitor (a chemokine receptor 2 inhibitors, PF-04136309, it showed favourable results when given with FOLFIRINOX in a phase Ib clinical trial of PC patients) [59]. 7-Monoclonal antibodies such as cetuximab (monoclonal antibodies against EGFR, when cetuximab was given with gemcitabine in a phase III study of the PC population; unfortunately, it did not show benefit) [61]; bevacizumab (monoclonal antibody against VEGFR, it also did not show benefit when combined with gemcitabine in a phase III study of PC patients) [61]; and MVT-5873 (monoclonal antibody against CA19.9, it showed promising results regarding safety, tolerability, and reduction of CA19.9 levels during the treatment course) [61] (Figure 8).

Figure 8.

Immunotherapy and PC; taken from Jiang et al. [58].

3.9 Other therapies that are probable promising future therapies

(1) Metabolic therapies like atorvastatin and metformin. (2) Antifibrotics like halofuginone. (3) Gene therapy like CYL-02. (4) Cell Cycle Check Point Inhibitors like abemaciclib and palbociclib. (5) Notch pathway inhibitor like Demcizumab. (6) Hedgehog signalling pathway inhibitor like vismodegib. (7) TGF-ß pathway inhibitor like trabedersen. (8) Therapeutic microbiota like MS-20. (9) M-TOR inhibitor like everolimus. (10) EGFR inhibitors (erlotinib). (11) Phytochemicals like curcumin. (12) Agents targeting KRAS mutant cancers like exosome-delivered KRAS siRNA (exosome) and anti-KRAS T cell transfer [12, 13, 14, 39, 49, 62, 63].

4. Conclusion

Despite the advance in the field of PC therapies (e.g. chemo/radio/immune/targeted therapies) and the well-developed peri-operative management policies for it during recent years, it still has a catastrophic poor prognosis due to its delayed detection, early neural/vascular invasions, early micro-metastatic spread, tumour heterogeneities, drug resistance either intrinsic or acquired, unique desmoplastic stroma and TME. It is fundamental to understand and make aggressive studies and researches about its pathogenesis at the different genetic/epigenetic/metabolic/molecular levels as well as to study its risk factors and its known precancerous lesions for getting a more successful therapy for it. Meanwhile, for reaching surgical R0 resection and a better outcome for this dismal challenging tumour, it should be diagnosed early and treated through multidisciplinary teams of surgeons, gastroenterologists/interventional upper endoscopists, medical/radiation oncologists, diagnostic/intervention radiologists, pathologists at high-volume centres.

Abbreviations

PDAC	pancreatic duct adenocarcinoma
PanIN	pancreatic intraepithelial neoplasia
IPMN	intra-ductal papillary mucinous neoplasm
MCN	mucinous cystic neoplasms
TME	tumour microenvironment
PC/s	pancreatic cancer/s
miRNAs	microRNAs
lncRNA	long non-coding RNAs
circRNAs	circular RNAs
siRNAs	small-interfering RNAs
BRCA	breast cancer susceptibility gene
MMR	mismatch repair gene
ATM	ataxia telangiectasia mutated gene
PSC	pancreatic stellate cells
ECM	extracellular matrix
TAMs	tumour-associated macrophages
CAF	cancer associated fibroblasts
EMT	epithelial to the mesenchymal
PCSC	pancreatic cancer stem cells
SMA	superior mesenteric artery
CHA	common hepatic artery
SMV/PV	superior mesenteric/portal veins
PS	performance status
ECOG	Eastern Co-operative Oncology Group
PD	pancreatoduodenectomy
SMV	superior mesenteric veins
PV	portal vein
TMPE	total mesopancreas excision
ESMO	European Society for Medical Oncology
NCCN	National Comprehensive Cancer Network
ASCO	American Society of Clinical Oncology
LAPC	locally advanced pancreatic cancer
EUS	endoscopic ultrasound
PARP	poly ADP-ribose polymerase
MSI	microsatellite instability