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The Latest Advancement in Pancreatic Ductal Adenocarcinoma Therapy: a Review Article for the Latest Guidelines and Novel Therapies

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The Latest Advancement in Pancreatic Ductal Adenocarcinoma Therapy: a Review Article for the Latest Guidelines and Novel Therapies biomedicines Review The Latest Advancement in Pancreatic Ductal Adenocarcinoma Therapy: A Review Article for the Latest Guidelines and Novel Therapies Marwa Elsayed 1 and Maen Abdelrahim 2,3,4,* 1 School of Medicine, University of Missouri Kansas City, 2301 Holmes, St. Kansas City, MO 64018, USA; [email protected] 2 Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA 3 Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA 4 Weill Cornell Medical College, Institute of Academic Medicine, Houston, TX 77030, USA * Correspondence: [email protected] Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the US, and it is expected to be the second leading cause of cancer deaths by 2030. The lack of effective early screening tests and alarming symptoms with early undetectable micro-metastasis at the time of presentation play a vital role in the high death rate from pancreatic cancer. In addition to this, the low mutation burden in pancreatic cancer, low immunological profile, dense tumorigenesis stroma, and decreased tumor sensitivity to cytotoxic drugs contribute to the low survival rates in PDAC patients. Despite breakthroughs in chemotherapeutic and immunotherapeutic drugs, pancreatic cancer remains one of the solid tumors that exhibit meager curative rates. Therefore, researchers Citation: Elsayed, M.; Abdelrahim, must dedicate more effort to understanding the pathology and immunological behavior of PDAC, M. The Latest Advancement in Pancreatic Ductal Adenocarcinoma in addition to properly utilizing more advanced screening modalities and new therapeutic agents. Therapy: A Review Article for the In our review, we focus mainly on the latest updates from clinical guidelines and novel therapies Latest Guidelines and Novel that have been recently investigated or are under investigation for PDAC. We used PubMed as a Therapies. Biomedicines 2021, 9, 389. search tool for finding original research articles addressing the latest developments in diagnosing https://doi.org/10.3390/ and treating PDAC. Additionally, we also used the clinical trials published on clinicaltrialsgov as biomedicines9040389 sources for our data. Academic Editor: Rossano Lattanzio Keywords: pancreatic ductal adenocarcinoma; pancreatic cancer; pancreatic cancer treatment; pan- creatic cancer novel therapy Received: 1 March 2021 Accepted: 27 March 2021 Published: 6 April 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in According to the CDC’s latest data, pancreatic ductal adenocarcinoma (PDAC) is published maps and institutional affil- the fourth leading cause of cancer deaths in the US [1], and it is expected to become the iations. second leading cause of cancer death by 2030 [2]. In addition to the late presentation of the disease and lack of early alarming symptoms, a large majority of patients with pancreatic cancer present with either locally advanced or metastatic disease upon diagnosis; all of these factors contribute to the projecting burden of death by PDAC [3]. Furthermore, PDAC patients have an average 5-year survival rate of 10% [4]. Moreover, the deep Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. location of the pancreas, aggressive nature of PDAC, and lack of reliable screening tests This article is an open access article make it very hard for a primary physicians to catch and diagnose the disease at earlier distributed under the terms and and more manageable stages. PDAC commonly occurs as a sequence of accumulating conditions of the Creative Commons genetic mutations in somatic cells, and less commonly, due to mutations in germline cells, Attribution (CC BY) license (https:// particularly the case in familial PDAC [5,6]. With the advantage of next-generation gene creativecommons.org/licenses/by/ sequencing, the PDAC pathophysiology is now better understood, and there is an emerging 4.0/). need for adding pathological classification to the current clinical and anatomical staging to Biomedicines 2021, 9, 389. https://doi.org/10.3390/biomedicines9040389 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 389 2 of 21 Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 22 formulate more personalized treatment plans [7,8]. Over the last decade, there has been PDAC pathophysiology is now better understood, and there is an emerging need for add- several breakthroughsing pathological in early screeningclassification modalities to the current and clinical cancer and therapeutics, anatomical particularly staging to formulate in the context ofmore gastrointestinal personalized treatment malignancies; plans [7,8]. however, Over thesethe last have decade, not there matched has been the several increment in bothbreakthroughs incidence and in mortalityearly screening rates ofmodalities PDAC. Therefore,and cancer findingtherapeutics, new strategiesparticularly in the and therapeuticcontext agents toof gastrointestinal improve the outcomes malignancies; and ho survivalwever, ofthese PDAC have isnot an matched urgent need.the increment in both incidence and mortality rates of PDAC. Therefore, finding new strategies and ther- 2. Treatment of PDACapeutic agents to improve the outcomes and survival of PDAC is an urgent need. The only curative therapy for PDAC is surgical excision [9]; however, only 10–20% of patients are found2. Treatment to be eligible of PDAC for resection at the time of diagnosis. More than 50% of patients are foundThe to only have curative metastatic therapy disease for PDAC at the is surgical first presentation excision [9]; [however,10]. To date,only 10–20% treatment approachesof patients for patients are found with to be PDAC eligible depend for resection on the at clinical the time and of anatomicaldiagnosis. More stage than 50% of the disease [11of]. patients Notably, are a found great to deal have of metastatic ongoing diseas studiese at arethe first relying presentation on the molecular [10]. To date, treat- ment approaches for patients with PDAC depend on the clinical and anatomical stage of pathology of PDAC to identify individualized, tailored plans for PDAC patients [12–14]. the disease [11]. Notably, a great deal of ongoing studies are relying on the molecular The initial workup process of PDAC aims to confirm the diagnosis and to look for evidence pathology of PDAC to identify individualized, tailored plans for PDAC patients [12–14]. of distant metastasisThe initial [15, 16workup]. Using process imaging of PDAC modalities, aims to confirm non-metastatic the diagnosis PDAC and canto look be for evi- classified into resectable,dence of distant borderline metastasis resectable, [15,16]. Using and locallyimaging advanced modalities, PDACnon-metastatic based onPDAC can the involvementbe of classified the surrounding into resectable, arterial borderline (superior resectable, mesenteric and artery,locally commonadvanced hepaticPDAC based on artery, and celiacthe axis) involvement and venous of the (superior surrounding mesenteric arterial vein (superior or portal mesenteric vein) structures, artery, common and hepatic other nearby organsartery, and and lymph celiac nodesaxis) and [17 ,venous18]. According (superior tomesenteric the National vein or Comprehensive portal vein) structures, Cancer Networkand (NCCN) other nearby guidelines organs published and lymph in 2017,nodes certain[17,18]. criteriaAccording should to the be National applied Compre- to obtain eligibilityhensive for surgicalCancer Network resection; (NCCN) the main guidelines goal is published to involve in 2017, as many certain patients criteria as should be possible under theapplied umbrella to obtain of surgicaleligibility treatment for surgical [19 resection;]. The treatment the main outcomegoal is to andinvolve the as many median overall survivalpatients as depends possible in under the first the umbrella place on of the su stagergical oftreatment the PDAC, [19]. The as mentioned treatment outcome in Figure1. and the median overall survival depends in the first place on the stage of the PDAC, as mentioned in Figure 1. PDAC non- metastatic metastatic with borderline resectable without resectable palliative palliative locally advanced chemotherap y chemotherapy Upfront Resection NAT followed NAT CRT OS: 11 OS: <4 by Resection surgery Adjuvant Adjuvant Under Chemotherap Chemoradiothera investigatio Resection Resection OS: 13 y py n OS: 22-54 OS: 16 OS: 24 OS: 16 Figure 1.Figure The outcomes 1. The outcomes of different of treatment different strategies treatment in strategies PDAC. OS: in overall PDAC. survival OS: overall (measured survival in months); (measured NAT: in neo- adjuvant chemotherapy. months); NAT: neoadjuvant chemotherapy. 2.1. Resectable PDAC The criteria for resectability are summarized in Table1 based on the latest recommen- dations from the NCCN, and AHPBA/SSO/SSAT Consensus (Americas HepatoPancreato- Biomedicines 2021, 9, 389 3 of 21 Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract) [19,20]. Despite the remarkable development of surgical options and procedures for pancreatic cancer resection [9], a large number of patients will develop local recurrence or distant metastasis, which supports the theory of non-evident micro-metastases at the time of surgical resection [21,22]. This fact has prompted medical researchers to investigate the role of
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