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Viegas, C.; Patrício, A.B.; Prata, J.; Fonseca, L.; Macedo, A.S.; Duarte, S.O.D.; Fonte, P. Treatment of Pancreatic Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/55468 (accessed on 03 July 2024).
Viegas C, Patrício AB, Prata J, Fonseca L, Macedo AS, Duarte SOD, et al. Treatment of Pancreatic Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/55468. Accessed July 03, 2024.
Viegas, Cláudia, Ana B. Patrício, João Prata, Leonor Fonseca, Ana S. Macedo, Sofia O. D. Duarte, Pedro Fonte. "Treatment of Pancreatic Cancer" Encyclopedia, https://encyclopedia.pub/entry/55468 (accessed July 03, 2024).
Viegas, C., Patrício, A.B., Prata, J., Fonseca, L., Macedo, A.S., Duarte, S.O.D., & Fonte, P. (2024, February 26). Treatment of Pancreatic Cancer. In Encyclopedia. https://encyclopedia.pub/entry/55468
Viegas, Cláudia, et al. "Treatment of Pancreatic Cancer." Encyclopedia. Web. 26 February, 2024.
Treatment of Pancreatic Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15092363

Pancreatic cancer represents one of the most lethal cancer types worldwide, with a 5-year survival rate of less than 5%. Due to the inability to diagnose it promptly and the lack of efficacy of existing treatments, research and development of innovative therapies and new diagnostics are crucial to increase the survival rate and decrease mortality.

pancreatic cancer tumors agents

1. Anatomophisiology of the Pancreas

The pancreas is an acinar tubular gland located in the retroperitoneal space, between the large curve of the stomach and the duodenum, arranged transversely in the upper wall of the abdomen. It has an elongated and flat structure, which measures approximately 15 cm in length and weighs 85–100 g [1][2].
This organ consists of the head, which is in contact with the duodenal loop and separated from the body of the pancreas through an isthmus, a restricted zone bounded by two cracks of the body, a slightly oblique part from below to and from right to left, disposed frontally to the aorta and the inferior vena cava, and of the tail, which is in contact with the spleen and is lined by the parietal peritoneum [3].
The pancreas is a gland with two functions: endocrine and exocrine. The exocrine pancreas secretes gastric enzymes into the digestive tract, which help in the food breakdown process. This fluid is a mixture of hydrochloric acid, gastric juice, and digestive enzymes such as trypsin, amylase, and lipase. Its role is to surround the partially processed food, known as the food bolus, and convert it into a substance called chyme. It reaches the duodenum through the Wirsung duct, which leads to the Vater ampule, and the Santorini duct, which flows 3 to 4 cm above. Pancreatic acini releases pancreatic juice to complete the process of chyme digestion in the duodenum. The main components of pancreatic juice are water, salts, bicarbonate, and various digestive enzymes. These components, namely the bicarbonate ions, are responsible for neutralizing the acid in the chyme and thus protecting the intestinal wall. In addition, this change creates a favorable environment for pancreatic enzymes to function properly [4].
The enzymes present in the pancreatic juice are:
  • Proteolytic enzymes, whose function is the digestion of proteins. They are divided into exopeptidases (such as carboxypeptidase), which act on the chemical bonds between amino acids, from a terminal end of the protein, and into endopeptidases (such as chymotrypsin and trypsin), which degrade proteins by cleaving chemical bonds between the amino acids of the protein molecule [2][5];
  • Glycolytic enzymes, or amylases, contribute to the digestion of carbohydrates and sugars. These enzymes hydrolyze the α-bonds in the starch chain, converting them into simple sugars (glucose and maltose). These sugars can then easily cross the intestinal mucosa and enter the bloodstream [2][6];
  • Lipolytic enzymes, or lipases, whose function is to digest lipids or fats. The lipases hydrolyze the fats, transforming them into glycerol-free fatty acids, easily assimilated by cells. In addition to this function, they also break down neutral fats or triglycerides into fatty acids and glycerin [2][3][4][5][6][7][8].
  • Nucleases enzyme, that promote the digestion of nucleic acids. Ribonuclease cleaves RNA molecules in the sugar ribose and the nitrogenous bases adenine, cytosine, guanine, and uracil, while the deoxyribonuclease digests the DNA molecules in the sugar deoxyribose and the nitrogen bases cytosine, adenine, guanine, and thymine. There are enzymes of two types (α and β) that catalyze the hydrolysis of the phosphodiester bonds [2][9].
The endocrine pancreas plays a pivotal role in maintaining blood glucose balance. It is essential to regulate glucose levels in the bloodstream to ensure a consistent and steady supply of glucose to cells. Elevated levels of glucose can cause damage to the kidneys, eyes, and other tissues. So, the pancreas secretes two antagonistic hormones that control this homeostasis: glucagon and insulin [10]. Glucagon is produced by α-cells and accumulates within the secretory granules from which it is released by exocytosis at the time of hypoglycemia. In the liver, hepatocytes recognize this through a specific receptor. This recognition triggers a series of phosphorylation reactions that activate the enzymes responsible for glycogen breakdown and glucose synthesis, leading to an increased release of glucose into the bloodstream. Glucagon hormone also stimulates the fat tissue to transform triglycerides into glucose. Finally, this hormone promotes amino acid uptake and active phagocytosis mechanism, along with others [11].
In contrast to glucagon, insulin functions to reduce blood glucose levels after food consumption by facilitating the uptake of glucose by the liver, muscles, and adipose tissues. Insulin is produced in β-cells, and when there is a peak of glucose in the blood, insulin is released to the systemic circulation, increasing the glucose uptake by cells by binding to the membrane receptor tyrosine kinase. This receptor activates the exocytosis of the GLUT4 transporter molecule’s specific glucose tolerance. When the extracellular concentration of glucose is reduced, GLUT2 is transported back into the cell by endocytosis and stored in vesicles for later use [9][12].
Insulin also stimulates the intracellular use of glucose and facilitates its transformation into glycogen (in the liver or muscles) or into triglycerides (adipose tissue) in a process named glycolysis. In addition, insulin stimulates lipid metabolism, favoring the passage of free fatty acids from plasma to adipocytes, which convert them into triglycerides, reducing the mobilization of fats and inhibiting their oxidative dissolution. It also acts on the metabolism of proteins, facilitating the transport of amino acids to cells [2][12][13].
Insulin secretion is mediated by glycemia through a negative feedback mechanism. β cells are overly sensitive to blood glucose levels, so by massively flowing through the membrane, it causes a series of biochemical reactions that end with the depolarization of cells. By activating a system of microtubules and microfilaments, the flow of Ca2+ ions promotes the excretion of this hormone [2][14].
The pancreatic functions are controlled by the autonomic nervous system (ANS) and the endocrine hormone system. The ANS is constituted by sympathetic and parasympathetic innervation. The sympathetic innervation acts in situations of stress, fear, emergency, or excitation, while the parasympathetic innervation acts in the opposite situations, namely during rest and digestion. The sympathetic innervation acts by stimulating the α cells of the pancreas to secrete glucagon into the bloodstream, which in turn stimulates the liver to initialize glycogen cleavage into small glucose molecules. Subsequently, glucose is released into the bloodstream and reaches the cardiac and skeletal muscles. The pancreas β cells are also activated by the sympathetic innervation to reduce the secretion of glucose and insulin, which counteracts the effect. The parasympathetic innervation, opposing the sympathetic innervation, stimulates the release of insulin and pancreatic secretions [15].
Secretin and cholecystokinin (CCK) are the two hormones secreted by the endocrine system to regulate digestive function. Secretin and CCK are produced by the cells of the duodenum lining. The former is produced to respond to the arrival of the chyme, and it induces the secretion of bicarbonate and water by the pancreas while it also inhibits the formation of gastrin by the stomach. Gastrin is produced in response to the presence of proteins and fats in the chyme. Once released, it circulates through the bloodstream and binds to pancreatic acini. This binding stimulates these cells to produce and release pancreatic secretions rich in digestive enzymes. These enzymes then help break down protein molecules into peptides and convert lipid molecules into soluble microdroplets, facilitating their absorption by intestinal cells [16][17].

2. Pancreatic Cancer

Pancreatic cancer ranks among the principal causes of cancer-related mortality, characterized by a reduced 5-year survival rate. The disease starts without any precise early signs or symptoms, and its expression will vary depending on the position of the tumor inside the organ. Around 50% of patients have icterus, which is more frequently observed when the tumor is in the head of the pancreas as a result of the blocking of the adjacent biliary system [18].
In addition, pancreatic cancer may manifest with other symptoms, including abdominal discomfort, nausea, and weight loss. When tumors spread to other organs, duodenal obstruction, gastrointestinal bleeding, and pancreatic duct obstruction can lead to steatorrhea. Early manifestations of the disease have been associated with hyperglycemia and diabetes mellitus. Advanced pancreatic cancer may present with ascites, pain, impaired liver function, hyperglycemia, anemia, and depression. These various symptoms further contribute to the complexity of diagnosing and managing pancreatic cancer [19][20].
Certain risk factors for pancreatic cancer, such as smoking habits, can be modified, while others remain unclear scientifically. Factors like diets rich in red and processed meats and low in fruits and vegetables, physical inactivity, and coffee consumption have been associated with pancreatic cancer. Recent studies have demonstrated an association between alcohol overuse and pancreatic cancer. This association is probably mediated through alcohol involvement in the development of chronic pancreatitis and cirrhosis, which are established risk factors for this particular cancer type. However, factors like age, family history, and type II diabetes are non-modifiable risk factors. Pancreatic cancer is more prevalent in individuals over 45 years of age, with males having a slightly higher risk than females. Additionally, African Americans are more vulnerable to pancreatic cancer than Caucasians. However, the reason behind the higher occurrence of type II diabetic individuals is still unknown. So, understanding and managing these risk factors can contribute to better preventive strategies for pancreatic cancer [18]. However, the presence of one or several risk factors characteristic of a pathology does not ensure the development of the disease [21]. Approximately 5% to 10% of pancreatic cancer patients have a family history of the disease. People having the BRCA2 mutation, known for increased risk of breast and ovarian cancer, are now identified as having higher susceptibility to pancreatic adenocarcinoma. Besides BRCA2, other genes with variants associated with elevated pancreatic cancer risk include BRCA1, MLH1, MSH2, PRSS1 (linked to familial pancreatitis), STK11, PALB2, ATM, CDKN2A, APC, MSH6, and PMS2 [2][19][20].
About 80% of cases of pancreatic cancer develop in the exocrine portion of the pancreas, and around 75% of cancers in the exocrine pancreas are situated within the head, 15 to 20% in the body, and only 5 to 10% in the tail [22][23]. Pancreatic cancer situated in the exocrine portion is predominantly diagnosed as ductal adenocarcinoma, accounting for approximately 95% of cases [24][25]. These primarily originate from the pancreatic ducts and, less commonly, from acinar cells (acinar cell carcinoma). Acinar cell carcinoma is distinguished by prominent acinar cell differentiation, cytoplasmic granules, and a prominent single nucleus [26]. Pancreatic cancer is the result of hereditary mutations in cancer-related genes, including oncogenes, tumor suppressor genes, cell cycle genes, genes involved in apoptosis, and genome maintenance genes. Additionally, cell turnover, telomerase shortening, and genomic instability can contribute to the transformation of pancreatic epithelial cells into tumor cells [2][27].
Pancreatic intraepithelial neoplasm (PanIN) is usually located in the small pancreatic duct and is divided into 3 groups by epithelial atypia, PanIN-1 (minimum atypia), which also has 2 subgroups (i.e., PanIN-1A (flat type) and PanIN-1B (papillary type)), PanIN-2 and PanIN-3 (limited atypia). This type of neoplasm is associated with invasive carcinoma and chronic pancreatitis, and HER-2/neu expression is 82% in PanIN 1A, 86% in PanIN 1B, and 92% in PanIN-2 [28]. Pancreatic cysts are common, some of which are curable precursors of a possible ductal adenocarcinoma. Within these neoplasms, researchers first have the intraductal papillary mucinous, located in the exocrine pancreas. This type of lesion is defined by non-invasive productions of papillary mucin and arises in the larger pancreatic ducts. Because of their large size, they easily have been detected in imaging tests, and the evolution to more invasive cancer can be prevented [2][24][25][29][30].
Secondly, mucosal cystic neoplasms (MCNs) are well-defined tumors with mucin-producing cysts and septation with distinctive ovarian-like stroma without communication with the ductal system. It is usually a single lesion consisting of a thick fibrous wall. This type of neoplasm can be invasive and non-invasive. Non-invasive MCNs are subdivided into MCNs with low-grade dysplasia, moderate dysplasia, or high-grade dysplasia [25][31]. Thirdly, there is the serous cystadenoma SCAs, in which the cysts are mostly benign and slow-growing, coated by non-mucinous epithelium. Finally, solid pseudopapillary neoplasia is exceedingly rare. This type of lesion usually has a favorable prognosis, although it is mostly malignant [2][24][32][33][34].
Endocrine or neuroendocrine tumors (NETs) are relatively rare, accounting for less than 5% of all pancreatic cancers. These tumors can be either benign or malignant, and at the microscopic level, their appearance may be similar, making them challenging to identify. Malignancy is typically diagnosed when it metastasizes to other organs. Diverse types of NETs exist:
  • Functional NETs: Approximately 50% of neuroendocrine tumors produce hormones that are released into the bloodstream, leading to the onset of symptoms (for example, gastrinomas, insulinomas, glucagonomas, somatostatinomas, VIPomas—vasoactive intestinal peptides, and the PPomas—pancreatic polypeptides).
  • Non-functional NETs: This type of tumor typically does not produce hormones in levels high enough to cause noticeable symptoms, which makes them more likely to develop into cancer as they remain asymptomatic for a longer period.
  • Carcinoid tumors: This type of tumor does not often originate in the pancreas, as they are more commonly found in other parts of the digestive system. These tumors typically produce serotonin (5-HT) or its precursor, 5-hydroxytryptophan (5-HTP).
  • Pancreatoblastomas: This is an uncommon solid cell neoplasm, and their exact locations are not yet well characterized. These tumors comprise multiple cellular components, including the acinar component [2][35][36][37].
The American Joint Committee on Cancer has developed a tumor-nodule-metastasis classification system for the assessment of pancreatic cancer stage and type. The evaluation parameters include tumor size and its association with blood vessel involvement, leading to tumor characterization as TX to T4. The extent of lymph node involvement determines nodal classification from NX to N1. The presence or absence of identifiable metastases in distant organs defines the metastatic category as M0 or M1, respectively [18].
Improvements in the expertise of the pathogenesis of pancreatic cancer have been increasing in the last decade, thus contributing to the development of more effective diagnostic methods and therapies. Numerous subsets of genes have been identified to undergo activation or deactivation during pancreatic cancer progression. Activation of oncogenes (point mutation and amplification) and inactivation of tumor suppressor genes initiate the development of pancreatic cancer. Despite the complexity of all the genetic changes mentioned earlier, they collectively constitute a fundamental set of processes crucial for comprehending pancreatic cancer [25][38][39]. Pancreatic cancer is caused by somatic mutations, genetic alternations, and the germ line. There are sixteen identified mutated oncogenes, including KRAS, TP53, CDKNA2A, SMAD4, MLL3, TGFBR2, ARID1A, SF3B1, EPC1, ARID2, ATM, ZIM2, MAP2K4, NALCN, SLC16A4, MAGEA6 [24][27][32].
The KRAS oncogene frequently undergoes mutation, mainly at codon 12 and occasionally at codons 61 and 13, leading to alterations in 90% of pancreatic cancer cells, with 20% of these affecting the entire body. This mutated oncogene exerts negative effects on cell survival and functions, including cell differentiation and proliferation [33]. A mutation in KRAS induces the development of ductal precancerous formations and triggers hyperplastic multifocal focus in the pancreatic duct. Additionally, it can activate multiple signaling pathways, such as the P13K-AKT pathway, which impacts cell survival and mobility; the MEK and ERK1/2 pathway, affecting angiogenesis, cell proliferation, cellular apoptosis, cancer cell migration, and cell cycle regulation; the notch pathway, influencing cell proliferation, cell differentiation, and cellular apoptosis; and the Hedgehog pathway, contributing to metastasis. Furthermore, the activation of STAT3 has been identified in pancreatic cancer patients, and inhibitors targeting this oncogene are already being utilized in the treatment of this cancer [2][40].
MiRNAs are also implicated in the progression of pancreatic tumors and have incredibly important oncogenic functions. Between the 1000 existent miRNAs, pancreatic cancer functions are regulated by miRNA-196a, miRNA-190, miRNA-186, miRNA-200b, miRNA-15b, miRNA-95, miRNA-21, miRNA-155, miRNA -221 and miRNA-222 [41].
Tumor suppressor genes have the function of protecting the cell cycle or promoting apoptosis of tumor cells. The TP53, also known as the p53 protein, is encoded by a tumor suppressor gene and performs a key role in G2-M phase progression, regulating the G1-S checkpoint of the cell cycle. The expression of the TP53 gene and the action of its protein are activated by cellular stress signals: nutritional and oxidative stress from reactive oxygen species (ROS), hypoxia, activation of oncogenes, and DNA damage. Thus, it induces apoptosis, regulates senescence, repairs DNA, and alters cellular metabolism if errors occur. A mutation in its gene by missense conjugation mutations with loss of the remaining allele results in the inactivation of this protein. This phenomenon is typically observed in approximately 75% of cases of ductal adenocarcinoma. The loss of function of this protein enables cell survival and division despite DNA damage, leading to the accumulation of additional anomalies [2][25][42].
Mutations and deletions in DPC4 (deleted in pancreatic carcinoma, locus 4), LKB1 (liver kinase B1), and INK4a (inhibitor of kinase 4a) are identified in 95% of pancreatic cancer cases. Additionally, the deletion of MKK4 (mitogen-activated protein kinase 4) is observed in patients with pancreatic cancer. Interestingly, DPC4 triggers metastases despite its absence in pancreatic cancer cells. Furthermore, the mutation of the LKB1 gene is linked to Peutz-Jeghers syndrome, which is associated with an increased risk of pancreatic cancer [27].
Besides the physical examination, imaging tests are conducted to investigate suspected cancerous areas, assess the tumor localization or metastasis status, analyze treatment efficacy and progress, and monitor for cancer recurrence after treatment. Among the imaging tests, computed tomography allows detailed cross-sectional images to be obtained after the injection of intravenous (IV) contrast and is commonly used in the diagnosis of pancreatic cancer. A biopsy is performed using endoscopic ultrasound to guide the needle to the specific site. Although computed tomography can also be applied, it is not as usual [27][43].
Another imaging test that can examine the pancreatic ducts is called cholangiopancreatography. Its objective is to assess whether the ducts are obstructed, narrowed, or dilated due to the presence of a tumor. Somatostatin receptor scintigraphy can be particularly useful for detecting pancreatic NETs. Positron emission tomography (PET) involves injecting a slightly radioactive form of sugar with an affinity for cancer cells. A specialized camera is used to create an image of areas with radioactivity in the body. This imaging test is sometimes employed to investigate the spread of exocrine pancreatic cancer. However, since NETs grow slowly, they may not appear well in PET examinations [2][44].
Lastly, another imaging test for pancreatic cancer detection is angiography, a test that evaluates blood vessels. This detection technique consists of injecting a contrast dye into an artery to set out the blood vessels, followed by an X-ray, allowing one to visualize if the blood flow in a precise region is blocked or compressed by the existence of a tumor. It also allows checking if pancreatic cancer has increased through the wall of specific blood vessels [44].
Besides imaging tests, it is of utmost importance to perform blood tests for an early cancer diagnosis to determine the most effective treatment. Diverse types of blood tests are performed depending on where the pancreatic cancer is located. For example, for a tumor located in the exocrine part, the hepatic function test, which measures bilirubin levels, is performed. Moreover, for the premature finding and diagnosis of this type of cancer, several tumor markers should also be analyzed in the bloodstream. In this sense, CA 19-9 carbohydrate antigen and the carcinoembryonic antigen (CEA) are the most frequent markers analyzed being approved by the Food and Drug Administration (FDA) for that purpose. However, the American Society of Clinical Oncology does not recommend it in a diagnostic phase since these tumor markers have low sensitivity specificity and can also be found in high levels in people due to other reasons besides pancreatic cancer [45][46].
In the case of pancreatic neuroendocrine tumors, blood tests are conducted to analyze pancreatic hormone levels, namely insulin, gastrin, glucagon, somatostatin, pancreatic polypeptide, and vasoactive intestinal peptide. Furthermore, the levels of chromogranin A (CgA) and glucose and c-peptide (for insulinomas) may also be evaluated [47].
In carcinoid tumors, a blood test can be executed to detect the presence of serotonin, which is produced by many of these tumors. Additionally, urine analysis can evaluate serotonin and related chemicals, such as 5-HIAA and 5-HTP. Although the methods mentioned above may indicate the presence of pancreatic cancer, the only definitive way to confirm it is through a biopsy. This procedure involves obtaining a small tissue sample from the tumor and examining it under a microscope. Biopsies can be performed percutaneously (through the skin), endoscopically (endoscopic), or through surgery (surgical), with the latter being less common [2][27].

3. Conventional Treatment of Pancreatic Cancer

Systemic chemotherapy is employed to alleviate symptoms and enhance the survival rate of cancer patients. However, pancreatic cancer tumors exhibit a significant resistance to chemotherapy. Response rates are below 20% for various chemotherapeutic agents, including antimetabolites, alkylating agents, antibiotics, and anthracyclines, whether used individually or in combination therapy [48].
GEM, a pyrimidine antagonist, has shown promising results. This drug substituted 5-fluorouracil as a first-line treatment for metastatic pancreatic cancer due to better overall survival time and greater clinical improvements by alleviating usual symptoms such as pain, functional impairment, and weight loss. But, despite all these results, GEM only increases life expectancy by an average of 6 weeks, ranging from 4.5 to 6 months [49][50].
Nowadays, GEM is used both in monotherapy and combination therapy with other chemotherapeutic agents, namely, fluorouracil, pemetrexed, irinotecan, exatecan, cisplatin, oxaliplatin, paclitaxel, and docetaxel [48]. A phase III clinical trial revealed that by adding oxaliplatin to GEM, there was an increment in the response rate and progression-free survival, providing clinical benefits, although it still failed to improve the survival rate. Another example was the addition of erlotinib to GEM, which increased the 1-year survival rate in comparison to treatment by GEM alone [51][52].
In 2011, FOLFIRONOX, a mixture of 5-FU, leucovorin/folinic acid, oxaliplatin, and irinotecan, revealed a superior survival rate in patients with pancreatic cancer, compared to GEM as the sole agent, which led to the use of this drug as therapy of choice in this type of cancer. Nevertheless, the toxicity profile of the drug was not insignificant, showing an elevated risk of myelosuppression, fatigue, vomiting, diarrhea, and thrombocytopenia. Despite the improvement in overall survival rate, it remained low, highlighting the need for more effective treatments in the management of pancreatic cancer [48][53].®
Radiotherapy is frequently consumed in combination with systemic chemotherapy, as it does not provide significant benefits when used alone after pancreatic cancer surgery. However, a randomized phase III study demonstrated that patients derived greater benefits from the combination of chemotherapy and radiotherapy compared to chemotherapy alone in isolation [54][55].
Radiotherapy offers significant benefits in terms of local control and can improve the resectability rate after downstaging. However, it does not lead to notable improvements in mean survival rates for patients with non-resectable pancreatic cancer. The introduction of a novel and specific technique known as stereotactic radiotherapy, which delivers targeted radiation doses to tumors using imaging guidance, has shown some improvements in survival outcomes. Nevertheless, the overall survival rate for pancreatic cancer patients remains unsatisfactory, and there are concerns about the associated treatment toxicity. Further studies are necessary to determine the role of radiotherapy in resectable pancreatic tumors [56].
Somatostatin and its analogs, peptide hormones, can act as inhibitors of tumor cell growth by triggering signal transduction, which negatively controls cell growth, or through downregulation of tumor growth [57]. Szende et al. provided evidence that somatostatin can trigger tumor regression through a cell death program mechanism [58]. However, somatostatin monotherapy does not offer therapeutic benefits in the treatment of pancreatic cancer. Ebert et al. demonstrated that the use of a somatostatin analog called octreotide at a high dose resulted in a median survival of 6 months for patients with advanced pancreatic cancer, whereas the low dose only achieved half of that survival time [59][60].
Besides somatostatin and its analogs, estrogens can be potential candidates for the treatment of pancreatic cancer, given the presence of estrogen receptors in pancreatic carcinomas. Rosenberg et al. described that patients receiving a combined regimen of octreotide and tamoxifen exhibited a significant average survival benefit of 12 months as compared to those undergoing monotherapy [61][62].
The use of leuprolide (Lupron), a luteinizing hormone agonist, by itself or combined with somatostatin, demonstrated in vitro and in vivo activity in hamsters with pancreatic cancer. Zaniboni et al. performed a phase II clinical trial evaluating the leuprolide-tamoxifen combination, but the results were disappointing, achieving only a mean survival of 5 months. In short, the impact of hormone therapy on this type of cancer is quite limited [63][64][65]. The application of this therapy has been increasing, particularly in pancreatic cancer. The microenvironmental immunosuppressive tumor in pancreatic cancer plays a crucial role in disease progression and is linked to the limited effectiveness of conventional therapies. Typically, the microenvironment in pancreatic cancer comprises a fibrotic stroma with significant stromal density, acting as a barrier that hinders the delivery of cytotoxic drugs and limits the access of T cells to tumor cells [66][67]. Furthermore, the extensive infiltration of myeloid cells, including macrophages and immature/suppressor myelogenous cells derived from myeloid cell derivatives (MDSCs), accumulated during the progression of pancreatic cancer can induce T cell dysfunction. Consequently, depleting macrophages or MDSCs enhances the infiltration and activation of CD8 T cells, thereby improving the immune response against tumor cells [67][68].+
According to Zhang et al. myeloid cells play a crucial role at various stages of pancreatic carcinogenesis, and thus, depleting myeloid cells during the development of pancreatic cancer can hinder tumor formation [68]. In their study, they also found that myeloid cells act as regulators of immune checkpoint ligand PD-L1 expression in tumor cells through the activation of epidermal growth factor/mitogen-activated protein kinase signaling. PD-L1 is an immune-inhibitory molecule that suppresses T-cell activation, contributing to tumor progression. Consequently, inhibiting MAPK can enhance tumor susceptibility to PD-1/PD-L1 blockade, presenting a potential new therapeutic strategy for treating pancreatic cancer [67][68].
Lastly, the other option for the management of pancreatic cancer is surgery. Nowadays, there are two types of surgery for pancreatic cancer: a potentially curative surgery, which is performed when diagnostic test results show that removal of the entire tumor is possible, and palliative surgery, which can be executed if diagnostic tests show that the tumor is already too metastasized to be fully removed, only being performed to alleviate symptoms or to prevent future complications such as blockage of the bile duct or intestine.
However, since most pancreatic cancers are only diagnosed at stage IV, since there are no noticeable symptoms in the first stages, and metastases already exist, resection surgery is not usually performed [48].
Besides the adverse effects, conventional therapies are constrained by delivery problems, compromising their efficacy. Thus, it is important to optimize a delivery strategy for therapeutic agents, namely using nanotechnologies. These allow the transport of therapeutics selectively into tumor tissue, minimizing toxicity in healthy tissues and reducing collateral events and resistance related to the immune system [69].

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Subjects: Oncology
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Cláudia Viegas
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Ana B. Patrício
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João Prata
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Leonor Fonseca
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Ana S. Macedo
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Sofia O. D. Duarte
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Pedro Fonte
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