Cancer Pancreas: New Advances in Its Pathogenesis, Pathology and Management

#### **Chapter 4**

## Pancreatic Cancer: Updates in Pathogenesis and Therapies

*Emad Hamdy Gad*

#### **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 micrometastatic 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.).

**Keywords:** cancer treatment, pancreas, pathogenesis, therapy, pathology

#### **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**).

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].

*Pancreatic Cancer: Updates in Pathogenesis and Therapies DOI: http://dx.doi.org/10.5772/intechopen.112675*

#### **Figure 1.** *Pathogenesis of PDAC. Taken from Wood et al. [3].*

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].

Exosomes are small (30–100 nm) nano-scale extracellular vesicles with high stability, low immunogenicity, low cytotoxicity, and high membrane permeability

#### **Figure 2.** *Role of circRNAs in PC pathogenesis taken from Seimiya et al. [8].*

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.) [9–11].

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 [12–14].

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 multiplemole 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 [15–18].

#### **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

#### *Pancreatic Cancer: Updates in Pathogenesis and Therapies DOI: http://dx.doi.org/10.5772/intechopen.112675*

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, 19–23].

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 preclinical 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

#### **Figure 4.**

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

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].

#### **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

*Pancreatic Cancer: Updates in Pathogenesis and Therapies DOI: http://dx.doi.org/10.5772/intechopen.112675*

#### **Figure 5.**

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

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].

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 mucinproducing 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, 38–40].

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, 38–40].

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 downstaging 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].

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,

**Figure 6.** *A, B: Classic PD specimens (Author's operative work).*

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 nabpaclitaxel, 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

#### **Figure 7.**

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

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].

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, 52–55].

#### **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 ADPribose 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].

#### *Pancreatic Cancer: Updates in Pathogenesis and Therapies DOI: http://dx.doi.org/10.5772/intechopen.112675*

(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

**Figure 8.** *Immunotherapy and PC; taken from Jiang et al. [58].*

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**).

#### **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 [12–14, 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**


*Pancreatic Cancer: Updates in Pathogenesis and Therapies DOI: http://dx.doi.org/10.5772/intechopen.112675*


### **Author details**

Emad Hamdy Gad Hepatobiliary and Liver Transplantation Surgery Department, National Liver Institute, Menoufia University, Menoufia, Egypt

\*Address all correspondence to: emadgadsalemaa@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 5**

## Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening

*Abdullah Esmail, Mohamed Badheeb and Maen Abdelrahim*

#### **Abstract**

Pancreatic cancer (PC) is a highly fatal malignancy with a unique tumor microenvironment that limits the effectiveness of chemotherapeutics. PC develops from genetic mutations, cellular injury, and environmental exposure, progressing from precursor lesions to malignant neoplasms. This silent disease presents non-specific symptoms, including abdominal pain and painless jaundice. Serological and imaging evaluation aids in the diagnosis, with imaging modality selection dependent on cholestasis presence. The meticulous evaluation of vascular involvement and distant metastasis determines the tumor's resectability. Neoadjuvant therapy improves patient selection and limits micrometastases, while chemotherapy is the preferred treatment for unresectable cases. Early detection and personalized treatment are essential in improving PC's clinical outcomes.

**Keywords:** pancreatic cancer, tumorigenesis, screening, neoadjuvant therapy, pancreatic molecular profiling, pancreatic tumor microenvironment (TME)

#### **1. Introduction**

Pancreatic cancer (PC) is used interchangeably to describe pancreatic ductal adenocarcinoma, the most common pancreatic malignancy and one of the most fatal cancers worldwide [1, 2]. To gain a better understanding of PC pathogenesis, it is crucial to comprehend the pancreatic tumor microenvironment (TME). The TME is uniquely characterized by a dense desmoplastic fibrotic stroma in which extracellular matrix proteins (e.g., collagens), along with tumor-derived immune cells (e.g., neutrophils, macrophages), host immune cells (e.g., T-cells), fibroblasts, and activated pancreatic stellate cells (PSCs), form a dense barrier that limits the efficacy of different chemotherapeutics. This renders PC a difficult-to-treat illness [3–6]. Indeed, the tumorigenesis of PC involves genetic mutations, cellular injury, and environmental exposure that permit the transition into precursor lesions, which further progress into malignant neoplasms [7]. For instance, a constitutively active KRAS allows persistent downstream signaling with substantial cellular proliferation, resulting in ductal metaplasia [8, 9]. However, this process requires the acquisition of further genetic mutations, such as Angiopoietin-like 4, that permit the progression into pancreatic intraepithelial neoplasia (PanINs) [10, 11]. Additionally, mutated TP53, CDKN2A, and SMAD4 accelerate PC growth and progression [12–15]. Moreover, various environmental factors are believed to contribute to PC tumorigenesis. Smoking has been shown to potentiate desmoplastic reactions by activating PSCs and the associated free radical injury [16]. Other contributing factors include obesity, primarily linked to its associated inflammatory status, which potentiates tumor progression [17, 18]. Furthermore, diabetes mellitus has been shown to over-activate PSCs, potentiating PC development [18]. Non-modifiable risk factors are also involved in PC development. Indeed, a higher incidence of PC was reported in patients of African American descent and patients with a family history of PC [19, 20]. Moreover, specific loci and familial cancer syndromes (e.g., hereditary non-polyposis colon cancer, familial atypical multiple mole melanoma syndromes) have been implicated in PC development [21]. Nonetheless, PC development is a multifactorial process, with various genetic and environmental factors contributing to its pathogenesis.

### **2. Clinical features of pancreatic cancer**

The presentation of PC may vary based on the tumor location and stage. It is generally a silent disease, and if symptoms do occur, they tend to be non-specific, often leading to alternative diagnoses [22, 23]. Although "silent jaundice" is a classical symptom, abdominal pain is more frequently reported in 60–80% of cases [24, 25]. Tumors located in the head of the pancreas (70% of cases) tend to present with jaundice earlier in the course of the illness, while those in the body or tail present with jaundice later, indicating hepatic metastasis instead of biliary obstruction [26].


**Table 1.**

*Brief summary of familial cancer syndromes associated with pancreatic cancer (PC).*

#### *Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening DOI: http://dx.doi.org/10.5772/intechopen.110887*

Other historical findings may include recent-onset diabetes, nausea or vomiting, anorexia, back pain, and weight loss.

In more advanced cases, pancreatic duct obstruction can result in symptoms of pancreatic failure, reported as post-prandial abdominal pain and steatorrhea. Fat malabsorption with associated vitamin deficiencies may also occur [24, 27–29]. Jaundice, hepatomegaly, and rarely epigastric mass may be noticed on examination [27]. Additionally, patients may experience recurrent venous stasis, resulting in splenomegaly with portal or splenic vein compression, ascites with inferior vena cava obstruction, and/or superficial thrombophlebitis (Trousseau's syndrome), palpable gallbladder (Courvoisier's sign), enlargement of the supraclavicular (Troisier's sign), or periumbilical (Sister Mary Joseph's node) lymph nodes may be observed [30–32]. Unfortunately, these findings are identified later in the course of the illness, indicating more advanced cases with poorer outcomes.

Clinicians should look for specific features of syndromes associated with PC, such as numerous atypical nevi in familial atypical multiple mole melanoma syndromes, mucocutaneous pigmentation in Peutz-Jeghers syndrome, and sebaceous tumors and cutaneous keratoacanthomas in patients with Lynch syndrome [33–35]. Syndromes associated with PC and their clinical features are summarized in **Table 1**.

#### **3. Diagnosis of pancreatic cancer**

The clinical presentation of PC is neither specific nor sensitive for establishing a diagnosis; therefore, suspected cases typically require serological and imaging testing. Liver function tests, including serum aminotransferase, bilirubin, and alkaline phosphatase, should be performed in all patients. The selection of subsequent testing primarily depends on the presence of jaundice or obstructive laboratory features (e.g., elevated direct bilirubin). In such cases, transabdominal ultrasound (TAUS) provides excellent sensitivity in detecting masses in the head of the pancreas and visualizing biliary tract patency or dilatation (**Figure 1**) [42, 43].

For anicteric patients who present with epigastric pain or other worrisome symptoms, such as weight loss, anorexia, or post-prandial flatulence, an abdominal computed tomography (CT) scan should be performed, which provides higher sensitivity in detecting lesions in the body and tail of the pancreas. In addition, a CT scan can be used initially, rather than TAUS, in cases of acute pancreatitis, as bowel gases may obscure the visualization of the biliary tract and the pancreas [44, 45]. If initial imaging is positive, further evaluation using a multi-phase contrast-enhanced, helical abdominal CT scan (i.e., pancreatic protocol) is the preferred option, accurate characterization of the pancreatic mass and resectability evaluation [46–48].

In cases where initial imaging (i.e., TAUS or CT scan) is negative, no further testing is required unless there is a strong suspicion that pancreatic cancer is the culprit of patient symptoms. In such cases, patients may undergo endoscopic retrograde cholangiopancreatography (ERCP), which allows for direct visualization of the biliary tract and pancreatic duct, tissue sampling for histopathological examination, and therapeutic decompression through stent insertion in selected cases. Alternatively, magnetic resonance cholangiopancreatography (MRCP) can be used in patients who are not qualified to undergo ERCP due to bowel obstruction or cases when ERCP fails to provide an informative visualization of the biliary tract [49–51]. When these modalities are negative, no further testing is required unless pancreatic cancer is

#### **Figure 1.**

*Simplified algorithm for pancreatic cancer diagnosis. \* Pancreatic protocol to assess the resectability of the tumor.*

strongly suspected. In such cases, endoscopic ultrasound (EUS) may be sought to to assess further the presence of any pathologies, which should be sampled through fine needle aspiration (FNA). More recently, contrast-enhances EUS appeared to be a more feasible approach for tissue sampling in such cases [43, 52–54].

*Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening DOI: http://dx.doi.org/10.5772/intechopen.110887*

Tumor, node, metastasis (TNM) system by the American Joint Committee on Cancer manual is a widely-accepted staging system that aids in the assignment of patients based on the resectability of PC. Additionally, it provides prognostic information based on the stage; for instance, patients in stage Ia had an overall 5-years survival of 39% compared to 11% in stage III [48, 49]. Nevertheless, a four-grouped classification system is used by many clinicians, which classifies PC based on resectability into; resectable, borderline resectability, locally advanced, and metastatic PC [50]. Regardless of the system used, the ultimate goal is to determine the suitable patient for curative resection.

#### **4. Screening of pancreatic cancer**

Early diagnosis of PC has been shown to improve overall survival. Nevertheless, the low incidence of PC discourages the implementation of nationwide screening modalities due to the high risk of false positive cases that may undergo unnecessary invasive testing. Furthermore, there are currently no guidelines regarding the optimal screening for PC [55–58]. Therefore, patients should be selected cautiously and counseled regarding their risks, the benefits and harms of the test, and the probable outcomes of their testing.

Given the rarity of PC, a targeted screening approach may be the most suitable option. Initially, the identification of high-risk patients based on National Comprehensive Cancer Network (NCCN) recommendations [59] is primarily made on the basis of specific associated genetic mutations or syndromes to select the most appropriate age for screening initiation, as summarized in **Table 2**.

Various serological markers and liquid biopsies have been extensively studied; however, only Carbohydrate Antigen 19-9 (CA19-9) has gained approval from the Food and Drug Administration (FDA). Carcinoembryonic antigen (CEA), which is classically elevated in colorectal cancer, appears to have some diagnostic utility for detecting cancer but has lower specificity compared to CA19-9. The use of multiple biomarkers together provides higher cumulative sensitivity and specificity. For instance, CA19-9, CEA, CA125, and CA242 together had 90.4% and 93.8% sensitivity and specificity, respectively, substantially higher than any single marker [60–62]. More recently, liquid biopsies have gained tremendous interest as an alternative non-invasive method to detect PC. Mainly, circulating tumor DNA (ctDNA) and circulating tumor


#### **Table 2.**

*Screening age recommendations for high-risk patient groups.*


#### **Table 3.**

*Different pancreatic cancer screening methods, their usefulness, and limitations.*

cells (CTCs) are among the most promising. However, they are not readily available in many healthcare settings and have variable diagnostic accuracy [63–65]. **Table 3** summarizes different screening methods, their usefulness, and limitations.

Little is known regarding the best approach to screening for PC. Nevertheless, a comprehensive evaluation with cautious patient selection and integrative serological and imaging testing may be the most appropriate approach.

#### **5. Management of pancreatic cancer**

The management of PC is multidisciplinary. The tumor resectability should be evaluated initially with a multi-phase contrast-enhanced, helical chest and abdominopelvic CT scans. The tumor is considered resectable when confined to the pancreas with no metastasis or vascular encasement, such as the superior mesenteric artery/ vein, celiac trunk, or common hepatic artery. Conversely, the presence of hepatic, peritoneal, or extra-abdominal metastasis renders the tumor unresectable [89, 90]. Nevertheless, in selective cases, the NCCN considers PC to be borderline unresectable. Examples of such cases include head of pancreas cancer that directly contacts the inferior vena cava, hepatic artery with no extension to the bifurcation, or tail/ body PC with a celiac axis of 180 degrees or less [59]. For resectable PC that involves the head of the pancreas, the Whipple procedure is performed, including pancreatic head, duodenum, proximal jejunum, common bile duct, gall bladder, and a portion of the stomach resection (i.e., pancreaticoduodenectomy) [91, 92]. In contrast, distal pancreatectomy is typically performed in PC of the body/tail, which occasionally may include splenectomy [93]. Biliary drainage has been classically performed preoperatively in patients with obstructive jaundice. However, the clinical benefits of this approach are controversial; therefore, it should be reserved for patients with severe hyperbilirubinemia, protracted itching, or cholangitis [94–96].

Neoadjuvant therapy has been found to outperform initial surgical resection for PC in providing a more precise patient selection and possibly limiting micrometastases linked to PC recurrence even after surgical resection. In addition, lower marginpositive resections were observed with the use of neoadjuvant therapy [97–99]. However, there are currently no established guidelines regarding optimal chemotherapy. The FOLFIRINOX protocol and a combination of gemcitabine plus nab-paclitaxel have been used, but there is no sufficient evidence to support the superiority of each approach [100]. Thus, we recommend a multidisciplinary team evaluation that takes into account the patient's preferences, institutional experience, and cost-effectiveness when selecting the chemotherapeutic agents.

Metastatic and locally advanced PC are generally considered unresectable, and chemotherapy is the preferred approach for such cases. Although there is no consensus available for the preferred regimen, FOLFIRINOX or Gemcitabine-based protocols may be used. Different clinical trials have demonstrated the efficacy of each approach. However, FOLFIRINOX has shown a longer overall survival compared to Gemcitabine [101–105]. Patients who fail one protocol may be considered for the other after assessing their performance status. Additionally, patients should be reevaluated for possible resection following chemotherapy, as tumor downstaging may permit resection.

#### **List of abbreviation**


*Pancreatic Cancer – Updates in Pathogenesis, Diagnosis and Therapies*


### **Author details**

Abdullah Esmail1 \*, Mohamed Badheeb2 and Maen Abdelrahim1,3,4\*

1 Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, USA

2 Internal Medicine Department, College of Medicine, Hadhramout University, Mukalla, Yemen

3 Weill Cornell Medical College, New York, NY, USA

4 Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX, USA

\*Address all correspondence to: aesmail@houstonmethodist.org and mabdelrahim@houstonmethodist.org

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening DOI: http://dx.doi.org/10.5772/intechopen.110887*

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#### **Chapter 6**

## Surgical Options to Mitigate the Consequences of Pancreatic Anastomosis Leak after Pancreaticoduodenectomy

*Azize Saroglu and Alexander Julianov*

#### **Abstract**

Pancreaticoduodenectomy is still the only treatment option that offers a chance to cure patients with pancreatic cancer and malignant periampullary tumors. Pancreaticojejunal anastomosis is the preferred method of reconstruction after pancreaticoduodenectomy. However, because of the high incidence of anastomotic leak and subsequent severe consequences, pancreaticojejunal anastomosis still remains the Achilles' heel of the operation. Several technical modifications of pancreaticojejunal anastomosis exist, but none completely eliminates anastomotic leak, postoperative pancreatic fistula, or severe complications. Therefore, considerable efforts have been made to study and develop surgical options that can mitigate the severity and avoid fatal consequences of postoperative pancreatic fistula. This chapter presents and discusses some of the existing and emerging surgical strategies devoted to mitigating the catastrophic consequences of pancreatic anastomotic leaks.

**Keywords:** pancreaticoduodenectomy, anastomotic leak, pancreatic fistula, pancreaticojejunostomy, pancreatic cancer, falciform ligament, transanastomotic external stent, coronary stent

#### **1. Introduction**

Pancreaticoduodenectomy (PD) is still the only treatment option that offers a chance to cure patients with pancreatic cancer and malignant periampullary tumors. Regarding the constantly growing incidence of pancreatic ductal adenocarcinoma [1, 2], the demand for PD worldwide is expected to increase as well. Pioneer surgeons such as Codivilla in 1898 and Kausch in 1909 performed the first pancreatic head resections without pancreatic anastomosis [3, 4]. Whipple also performed his first PD without reconstruction of pancreatico-enteric continuity [5], but in his subsequent 36 pancreatic head resections reconstructed the drainage of the pancreatic duct by pancreaticojejunal anastomosis (PJA), which is now the preferred method to reestablish pancreatic ductal drainage.

Currently, PD remains a complex and risky surgical intervention, requiring substantial surgeon experience despite advances in surgical techniques and technology [6, 7]. With the refinement of the surgical technique of PD, the main problems with intraoperative bleeding and early postoperative mortality were gradually resolved, and a series of more than a hundred consecutive operations with no postoperative mortality were published for the first time in the 90s from the leading centers [8, 9]. However, compared to other abdominal operations, the complication rate of PD is still high, mainly due to PJA leak and subsequent severe consequences that remain the Achilles' heel of the operation. It becomes obvious that searching for a no-leak PJA technique is unrealistic, and it is considered that an individual surgeon's mastery of a specific anastomotic technique, in conjunction with a large personal experience, is likely to be the best predictor of a low PJA leak rate [10–12].

### **2. Surgical techniques to mitigate the consequences of PJA leak**

The main problem of a leaked PJA comes from the extravasation of pancreatic enzyme-rich juice into the perianastomotic region, which can cause severe morbidity due to the development of intra-abdominal abscesses leading to sepsis or pseudoaneurysms leading to severe hemorrhage and even mortality. Surgical techniques devoted to mitigating the fatal consequences of PJA leak aim to control/reduce pancreatic juice extravasation into the abdomen or to prevent the contact of dissected peripancreatic vascular structures with leaked pancreatic enzymes, decreasing the incidence and grade of postoperative pancreatic fistula (POPF) (**Figure 1**).

#### **Figure 1.**

*International Study Group of Pancreatic Surgery (ISGPS) grading of postoperative pancreatic fistula (modified by [13]).*

*Surgical Options to Mitigate the Consequences of Pancreatic Anastomosis Leak… DOI: http://dx.doi.org/10.5772/intechopen.109524*

#### **2.1 Transanastomotic external pancreatic duct stent**

The goal of transanastomotic external stenting is to control pancreatic juice leakage by diverting the pancreatic secretion through the PJA outside the body by exteriorization of the stent from the jejunal lumen through a Witzel tunnel (**Figure 2**).

From a technical standpoint, we performed duct-to-mucosa PJA in two layers and opened the jejunum corresponding to the pancreatic duct after completion of the external layer of the posterior row sutures of the anastomosis. The posterior ductto-mucosa sutures are then easily placed, and the chosen transanastomotic stent is introduced through a small opening in the jejunal limb at a distance of approximately 10 cm from the PJA. We left the uncut and used at least one of the tied posterior row duct-to-mucosa sutures to secure the stent in the desired position. The PJA is completed then, and the stent is secured at a second point in the Witzel tunnel. It is also important to note that some measures have to be taken in order to divert or reduce the flow of the pancreatic juice in the operative field after transection of the gland, as it might cause intraperitoneal saponification around the pancreas due to pancreatic lipase-induced lipolysis, and has been shown to negatively impact anastomotic healing [14]. As a preventive measure, we temporarily placed the external stent in the remnant pancreatic duct (**Figure 3**) and/or covered the cut surface of the pancreas with gauze.

The use of transanastomotic external stents after PD has been a matter of debate and controversy due to conflicting results published from single-institution retrospective and/or nonrandomized studies. However, initial randomized trials on the subject clearly demonstrated the ability of the technique to reduce morbidity and the incidence of clinically relevant PJA leaks, especially in patients at high risk of developing POPF [15–17]. Further research and high-quality evidence from systematic reviews and meta-analyses have confirmed the efficacy of transanastomotic external stents in reducing the incidence and grade of POPF in both randomized and nonrandomized settings [18–21]. The largest systematic review to date with meta-analysis of the POPF-related mortality rate includes 60,739 patients and undoubtedly confirmed that external transanastomotic stents decreased the POPF-related mortality rate [22].

The main problems with the use of external stents are stent malfunction and/ or migration. Stent migration can be prevented by securing the stent at least at two

#### **Figure 2.**

*Pancreaticoduodenectomy. Transanastomotic stent placement. (A) Positioning the stent after completion of the posterior row sutures of the PJA. (B) Stent covered by anterior, first row, and duct-to-mucosa sutures. (C) Exteriorization of the stent from the jejunal lumen [original photograph].*

#### **Figure 3.**

*Pancreaticoduodenectomy. Stent (arrow) is placed in the pancreatic duct immediately after transection of the gland to divert the pancreatic juice from the operative field during the resection [original photograph].*

points: at the anastomosis and at the Witzel tunnel, and by leaving the ample length of the stent between the Witzel tunnel and abdominal wall to compensate for the tension of the fixation point at the anastomosis in a case of abdominal distension during the postoperative period. Malfunction of nondisplaced stents is rare and is a result of clotting (which can be resolved by stent irrigation) or of use of a stent with just 1–2 distal openings that could impact the pancreatic duct if positioned too distally from the PJA. To prevent the latter, additional holes can be made in the stent tube to secure drainage of the duct close to the PJA. However, we consider that even the displaced from the pancreatic duct external stent can still be beneficial by reducing the intraluminal pressure of the jejunal limb in cases of PJA leak.

#### **2.2 Transanastomotic internal pancreatic duct stent**

The internal transanastomotic stent seems theoretically superior to the external stent, as it eliminates the exteriorized part of the drain. However, the results of numerous randomized trials, systematic reviews, and meta-analyses failed to prove the benefit of internal PJA stents versus no-stent in terms of the incidence and severity of POPF, morbidity, and mortality after PD [18, 19, 21–25]. The use of internal stents is associated with a high rate of stent migration, and, contrary to an external stent, the malfunction of an internal stent in place cannot be assessed.

As the theoretical benefits of internal PJA stents cannot be neglected, recent research has focused on the options to find/develop an internal stent that can be safely positioned and secured in place, especially in a patient with a soft pancreas and very small duct size, in whom the use of an external stent is impractical because of the very narrow lumen of the fitting stent or even impossible. To overcome these limitations in patients with a small pancreatic duct size that cannot fit the external stent, since November 2016 we started to use as an internal PJA stent a commercially available, covered, and balloon-expandable coronary artery stent (**Figure 4**).

*Surgical Options to Mitigate the Consequences of Pancreatic Anastomosis Leak… DOI: http://dx.doi.org/10.5772/intechopen.109524*

#### **Figure 4.**

*Pancreaticoduodenectomy. Postoperative computed tomography showing pancreaticojejunal anastomosis with covered coronary artery stent (arrow) in place [original photograph].*

We positioned the stent using the over-the-wire technique after completion of the posterior row sutures of the PJA. Briefly, the jejunal limb was punctured at a chosen point opposite the transected pancreatic duct with the needle passing through both the lateral and medial bowel walls. A guidewire was inserted through the needle into the pancreatic duct. The coronary artery stent is positioned under intraoperative ultrasound guidance over the wire in the anastomosis and the pancreatic duct and expanded enough to be self-impacted in the duct. Anastomosis was then completed using anterior row sutures. A similar use of an uncovered coronary artery stent with positioning under X-ray guidance was recently reported by Huscher et al. [26], and the use of biodegradable stents in 10 patients was reported by Sulieman et al. [27]. Although the use of expandable internal PJA stents is still in its infancy, the initial results of their use are promising in terms of reducing the clinically relevant POPF rate and major morbidity with no stent-related complications [26, 27].

#### **2.3 Peripancreatic vessel wrap**

Irrespective of the anastomotic technique and use of transanastomotic stents, the risk of high-grade POPF is not negligible, especially for International Study Group of Pancreatic Surgery (ISGPS) grade C-D anastomoses (**Figure 5**).

The most dramatic and life-threatening complication of PJA leak is grade C POPF with severe postoperative hemorrhage caused by erosion of a major peripancreatic vessel from the leaked pancreatic juice and accompanying local infection. Different surgical options can be used to wrap the peripancreatic vessels in an attempt to prevent contact with aggressive leakage content in the case of POPF, thus preventing vessel erosion and severe hemorrhage. For this purpose, we routinely use the teres/ falciform ligament of the liver (**Figure 6**), which is carefully preserved and tailored during laparotomy at the beginning of the surgery. Alternatively, omental or peritoneal patches can be used to protect the vessels in the case of a sacrificed or small teres


#### **Figure 5.**

*Clinically relevant postoperative pancreatic fistula (POPF) rates for ISGPS A-D grades of pancreaticojejunal anastomoses (modified by [28]).*

#### **Figure 6.**

*Pancreaticoduodenectomy. (A–C) Wrapping the retroperitoneal vessels with the teres/falciform ligament flap [original photograph].*

ligament. The chosen wrap is carefully positioned to cover the major arteries and veins and secured in place with nonabsorbable sutures. From the above options for the protection of divided or skeletonized vessels, the use of a teres/falciform ligament has become the most frequently applied technique due to evidence for its effectiveness in published case series [29–33], systematic reviews [34–36], and a recent randomized clinical trial [37].

#### **2.4 Prophylactic abdominal drainage**

Historically, abdominal drains are routinely placed at the time of pancreatic resection to allow postoperative evacuation of intra-abdominal secretions, lymphatic fluid, blood, bile, and pancreatic juice. Theoretically, the use of drains should reduce the incidence of intra-abdominal collections and the need for re-intervention after PD. However, the routine use of prophylactic abdominal drains after PD has been questioned in the past decade and remains a matter of debate and controversy [38–41]. Further randomized clinical trials on the subject also reported conflicting results and did not resolve this issue. The PANDRA trial concluded that clinically important POPF was significantly reduced in patients without drainage, although there was no

*Surgical Options to Mitigate the Consequences of Pancreatic Anastomosis Leak… DOI: http://dx.doi.org/10.5772/intechopen.109524*

significant difference in overall morbidity [38]. However, the next randomized trial was prematurely closed because patients without prophylactic intraperitoneal drainage had a higher mortality rate than those with drainage [39]. Subsequent systematic reviews and meta-analyses also reported that patients without prophylactic drainage after PD had a higher mortality rate despite a similar or lower rate of overall major complications and readmissions [40, 41]. Regarding the above data, although the use of prophylactic abdominal drains in PD is associated with a higher rate of POPF compared to no drain abandoning, its routine use is not justified. Moreover, there is still room for research, and not well-studied options, to achieve more benefits from prophylactic drains to reduce the incidence and grade of clinically relevant POPF after PD. For this purpose, a few groups have reported promising results with prophylactic saline irrigation around a PJA after PD and around the pancreatic stump after distal pancreatectomy [42–44].

We routinely place prophylactic drains parallel to the upper and lower borders of the remnant pancreas, passing the drains to the right, beneath the PJA, and hepaticojejunostomy. In the case of a biochemical leak, we started intermittent drain irrigation (2–3 times daily with 20–30 ml saline solution per drain with no suction) to dilute the aggressive content of the subclinical leak. In our experience, this strategy was always effective in controlling the leak and maintaining the drain patent.

#### **3. Conclusion**

The constant evolution of pancreatic surgery makes PD a widespread intervention, which is now performed routinely even outside specialized centers. Although there are several reports of reduced intra-abdominal complications and mortality, POPF remains the most common unavoidable and life-threatening complication of PD. It becomes obvious that no single measure could be effective enough to eliminate POPF or to reduce its severity to the level of clinically irrelevant postoperative events. However, the combined use of the existing and emerging surgical strategies proved to mitigate the catastrophic consequences of pancreatic anastomosis leak and might be more successful in attempts to achieve this goal.

Based on available clinical evidence, we routinely used a combination of the above-mentioned surgical measures (transanastomotic drain plus vessel wrap plus abdominal drains) in more than a hundred pancreatic resections. Our postoperative protocol included daily measurement of drain fluid amylase levels and prompt start of drain irrigation in a case of biochemical leak, as mentioned above. We proceeded with irrigation of the drain until normalization of the drain fluid amylase (less than 3× the upper limit of normal serum amylase), but no longer after the second postoperative week. A systemic antibiotic is started if the patient develops a clinically apparent PJA leak, body temperature >37.5°C, or had prior chemotherapy. The biochemical leak rate was 17% and the ISGPS grade B POPF rate was 11%, with no POPF-related mortality. Notably, none of the patients in this series developed ISGPS grade C POPF nor required image-guided intervention or reoperation. Although none of the surgical techniques can completely eliminate the occurrence of PJA leak after PD, the simultaneous use of measures proven to reduce the risk and/or severity of POPF can effectively mitigate the catastrophic consequences of pancreatic anastomosis leak and should be implemented in PD management protocols.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Abbreviations**


### **Author details**

Azize Saroglu\* and Alexander Julianov Trakia Hospital, Stara Zagora, Bulgaria

\*Address all correspondence to: azize\_saroglu@hotmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Surgical Options to Mitigate the Consequences of Pancreatic Anastomosis Leak… DOI: http://dx.doi.org/10.5772/intechopen.109524*

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Section 4
