Current trends in the diagnosis of pancreatic cancer
Současné trendy v diagnostice karcinomu pankreatu
Duktální adenokarcinom pankreatu (pancreatic ductal adenocarcinoma – PDAC) je obávanou malignitou s velice nízkým 5letým přežíváním i přes veškeré snahy o zdokonalení léčebných strategií. V současnosti je včasná detekce považována za nejúčinnější způsob, jak zlepšit přežití, jelikož pouze radikální resekce představuje kurativní potenciál. PDAC se dělí do čtyř kategorií podle rozsahu onemocnění: resekabilní, hraničně resekabilní, lokálně pokročilý a metastatický. Většina pacientů je bohužel diagnostikována s lokálně pokročilým nebo metastatickým onemocněním, a tím pádem není způsobilá pro kurativní resekci. To je dáno především absencí průvodních příznaků či jejich nevýrazností v době, kdy ještě onemocnění není lokálně pokročilé. Vhodná indikace a rychlá dostupnost adekvátních diagnostických nástrojů je nicméně rovněž kritickým bodem vzhledem k agresivní povaze onemocnění. Nákladově efektivní biomarker s vysokou specificitou a senzitivitou umožňující včasnou detekci PDAC bez potřeby pokročilých a invazivních metod stále chybí. Diagnostika tak zůstává závislá na radiologických metodách a endoskopické ultrasonografii. V naší přehledové práci shrnujeme nejnovější epidemiologická data, rizikové faktory, klinickou manifestaci a současné diagnostické trendy se zaměřením na sérové biomarkery a zobrazovací modality. Kromě toho popisujeme aktuální terapeutické postupy.
Klíčová slova:
duktální adenokarcinom pankreatu – pankreas – karcinom pankreatu – diagnostika karcinomu pankreatu – management karcinomu pankreatu – léčba karcinomu pankreatu
Authors:
Petr Vanek 1,2; Michal Eid 3; Robert Psar 2,4,5; Vincent Zoundjiekpon 1,2; Ondrej Urban 1,2; Lumír Kunovský 1,2,6,7
Authors place of work:
Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
2; Department of Hematology, Oncology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
3; Department of Radiology, University Hospital Olomouc, Olomouc, Czech Republic
4; Department of Radiology, Vitkovice Hospital, Ostrava, Czech Republic
5; Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
6; Department of Gastroenterology and Digestive Endoscopy, Masaryk Memorial Cancer Institute, Brno, Czech Republic
7; nd Department of Internal Medicine – Gastroenterology and Geriatrics, University Hospital Olomouc, Olomouc, Czech Republic
12
Published in the journal:
Vnitř Lék 2022; 68(6): 363-370
Category:
Hlavní téma
doi:
https://doi.org/10.36290/vnl.2022.076
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a dreaded malignancy with a dismal 5-year survival rate despite maximal efforts on optimizing treatment strategies. Currently, early detection is considered to be the most effective way to improve survival as radical resection is the only potential cure. PDAC is often divided into four categories based on the extent of disease: resectable, borderline resectable, locally advanced, and metastatic. Unfortunately, the majority of patients are diagnosed with locally advanced or metastatic disease, which renders them ineligible for curative resection. This is mainly due to the lack of or vague symptoms while the disease is still localized, although appropriate utilization and prompt availability of adequate diagnostic tools is also critical given the aggressive nature of the disease. A cost-effective biomarker with high specificity and sensitivity allowing early detection of PDAC without the need for advanced or invasive methods is still not available. This leaves the diagnosis dependent on radiodiagnostic methods or endoscopic ultrasound. Here we summarize the latest epidemiological data, risk factors, clinical manifestation, and current diagnostic trends and implications of PDAC focusing on serum biomarkers and imaging modalities. Additionally, up-to-date management and therapeutic algorithms are outlined.
Keywords:
pancreatic ductal adenocarcinoma – Pancreatic cancer – Pancreas – pancreatic cancer diagnosis – pancreatic cancer management – pancreatic cancer therapy
Introduction
Pancreatic cancer commonly refers to pancreatic ductal adenocarcinoma (PDAC), which represents the majority of malignant pancreatic neoplasms and has one of the worst prognosis among solid malignancies. Based on the GLOBOCAN 2020 estimates, it is the seventh leading cause of cancer-related death in both men and women worldwide with 496,000 new cases and mortality rate almost identical when accounting for 466,000 deaths (1). Incidence and mortality rates have been steadily rising in many countries, likely reflecting the increasing prevalence of obesity, diabetes, and alcohol consumption, although improvements in diagnostic and cancer registration practices may also be in play in some countries (1, 2). Rates are 4-fold to 5-fold higher in countries with high social-demographic indices, with the highest incidence rates in Europe, Northern America, and Australia/New Zealand (1). The time trend of malignant pancreatic neoplasms in the Czech Republic is demonstrated in Fig. 1 (3); in 2018 it was the seventh most frequently diagnosed malignancy with 2,332 new cases and the third most common cause of cancer mortality with 2,159 deaths, which ranked third in Europe (4). In the United States PDAC is currently the third leading cause of cancer death after lung cancer and colorectal cancer, and it is predicted to be the second deadliest cancer by 2030 (5, 6).
Because of the absence of specific symptoms, the majority of PDAC are diagnosed late with poor prognosis, as most patients have advanced and incurable disease at detection (7). The 5-year survival rate for metastatic disease is 3.0%, rising to 14.4% for regional and 41.6% for localized disease (8). The dismal prognosis is also due to the aggressive nature of the tumor and its resistance to chemotherapy and radiotherapy (9–11). Compared to other malignancies, there has been little improvement in the survival rate of patients with PDAC in recent decades, and radical surgical resection of localized disease remains the only curative approach (12–14).
Screening with detection of asymptomatic stages of PDAC and its precursors has been proposed to improve results. At present, however, guidelines recommend against unselected screening for PDAC in asymptomatic adults, concluding that the potential benefits do not outweigh the potential harms, and such approach is reserved for high-risk individuals (15, 16). Given the lack of highly sensitive and specific diagnostic biomarkers, the diagnosis is currently dependent on advanced imaging modalities; sometimes it requires preoperative tissue acquisition.
The purpose of this review is to summarize the current diagnostic approach to PDAC in the general population, reviewing clinical presentation, relevant conventional and investigational biomarkers, and imaging modalities with complementary methods. Additionally, current management options are outlined.
Risk factors
The lifetime risk of developing PDAC is approximately 1.5% in the general population (8). Modifiable risk factors include dietary habits, obesity, type 2 diabetes mellitus (DM), excess alcohol consumption, and tobacco use. Among lifestyle risk factors, cigarette smoking has the strongest association with PDAC (17, 18). Estimates suggest that smokers are approximately twice as likely to develop PDAC compared with their non-smoker counterparts (19). Obesity, defined by body mass index (BMI) ≥30 kg/m2, carries an increased likelihood of developing PDAC compared to individuals with normal range BMI (hazard ratio of 1.15–1.53) (20). DM has been correlated with development of PDAC (pooled relative risk of 2.1), although PDAC itself is a risk factor for developing DM (19, 21, 22). Diets heavy on processed meat, high-fructose beverages, and saturated fat are associated with obesity, type 2 DM, and PDAC (23). Furthermore, fatty infiltration of the pancreas has been correlated with development of pancreatic intraepithelial neoplasias, precursors to PDAC (24).
Non-modifiable risk factors include age, sex, area, and genetic susceptibility. Most cases of PDAC are sporadic, but 10-15% are estimated to be attributable to inherited risk factors (16, 25, 26). Several genetic susceptibility syndromes that are associated with an increased risk of developing PDAC have been identified, particularly Peutz-Jeghers syndrome, familial atypical multiple mole and melanoma syndrome, hereditary breast and ovary cancer syndrome, Lynch syndrome, ataxia- telangiectasia, and hereditary pancreatitis (27), although a detailed overview of these is beyond the scope of this review. The risk of developing PDAC increases further with age; median is 65 years (4). However, a recent US study evaluating trends in cancer occurrence among young adults showed a disproportionate rise in the incidence of various obesity- related malignancies, including PDAC, among individuals 25–49 years old (23). This observation may be related to increasing rates of obesity and type 2 DM (28). The incidence of PDAC is overall higher in men; this gap is even more pronounced in developed countries (29).
Clinical presentation
In current practice, the diagnosis PDAC is frequently delayed, as symptoms are often few, if any, and vague. Consistent with this fact, only a minority of patients diagnosed with PDAC present with resectable disease. Most patients (85–90%) present with either locally advanced (unresectable) or metastatic disease (30). Those who do develop symptoms usually have non-specific complaints: epigastric or back pain, nausea, bloating, abdominal fullness, or change in stool consistency, all that can be often understandably attributed to alternative, benign causes, and thus can stall the diagnostic process (19, 31, 32).
The clinical features that occur with the highest frequency at the time of diagnosis include abdominal pain (40–60%), abnormal liver function tests (~50%), jaundice (~30%), new-onset DM (13–20%), dyspepsia (~20%), nausea or vomiting (~16%), back pain (~12%), and weight loss (~10%) (19, 33). Symptoms also depend on the location of the tumor within the pancreas. Most tumors (60–70%) arise from the head or neck of the pancreas and are more likely to present with biliary obstruction leading to painless jaundice. In contrast, tumors of the pancreatic body tend to invade adjacent vascular structures and are more likely to cause back pain on presentation; tail tumors can often grow unimpeded due to fewer anatomical neighbors (19). Malignant obstruction of the main pancreatic duct (MPD) can result in symptoms of pancreatic enzyme insufficiency (diarrhea, flatulence, steatorrhea, and postprandial abdominal pain) and occasionally in acute pancreatitis (19, 34).
Importantly, pancreatogenic (type 3c) DM has recently become a major topic. It refers to diabetes associated with disease of the exocrine part of the pancreas and is most often caused by chronic pancreatitis, but it can also be a paraneoplastic manifestation of PDAC. Moreover, it could fit the early diagnosis concept based on the patient‘s metabolic profile. Sharma et al. reported that an increase in fasting blood glucose levels may precede the diagnosis of PDAC by up to 3 years (35). Furthermore, Sah et al. described 3 distinct phases prior the diagnosis of PDAC based on metabolic and soft tissue changes: phase 1 (30–18 months; hyperglycemia) characterized by isolated hyperglycemia, phase 2 (18–6 months; pre-cachexia) with hyperglycemia and decreases in serum lipids, body weight, and subcutaneous abdominal fat, and phase 3 (6-0 months; cachexia) including loss of visceral fat with sarcopenia (36).
Diagnostic approach
It is not possible to reliably diagnose a patient with PDAC based on symptoms and signs alone. Awareness of risk factors may lead to an earlier and more aggressive evaluation in patients who present with symptoms suspicious for the disease. Traditional methods of diagnosing PDAC include serum tumor markers, imaging methods, and endoscopic ultrasound (EUS) with or without biopsy. The employment of multiple diagnostic modalities can help to detect PDAC in the early stage and thus improve survival. An overview of the diagnostic work-up of a suspected pancreatic mass is outlined in Fig. 2 (37, 38).
Laboratory testing
The only routinely used serological marker in the diagnosis of PDAC is carbohydrate antigen (CA) 19-9. Nevertheless, the sensitivity and specificity of CA 19-9 in the diagnosis of early PDAC are not high, which limits its clinical application. The marker maintains a sensitivity of 79–81% and specificity of 82–90% for the diagnosis of PDAC in symptomatic patients (19, 39), and its elevation signifies advanced disease and poor prognosis (40–42). However, as PDAC is usually asymptomatic at the early stage, the positive predictive value of CA 19-9 is only 0.9% in this setting (43, 44). Furthermore, the elevation of CA 19-9 can also be caused by other conditions, including benign diseases (pancreatitis, cirrhosis, biliary obstruction, and acute cholangitis) (45–47) and different malignancies (colorectal, gastric, and uterine cancers) (38). Moreover, CA 19-9 is not expressed in some individuals with a specific genotype, and only 65% of patients with resectable PDAC have elevated serum levels (40, 48). Due to all these reasons, CA 19-9 is not recommended for routine screening, although its value as a screening tool is being revisited (49). Serial measurements of CA 19-9 have a role in monitoring disease response to systemic treatment in the neoadjuvant or metastatic setting (50–53). Elevated preoperative CA 19-9 may also help identify patients whose surgeries are less likely to result in an R0 (margin-negative) resection and can predict long-term survival after resection (19, 39, 54).
Carcinoembryonic antigen (CEA) and CA 125 are nonspecific markers that might be elevated in patients with PDAC as well. According to reports in the literature, the combination of serum CA 19-9 with CA 125 increased sensitivity, and the combination of CA 19-9 with CEA increased specificity compared to CA 19-9 alone (55, 56).
In recent years, novel blood-based biomarkers for early diagnosis and prognostic stratification have made progress. Studies have confirmed that abnormally expressed serum non-coding microRNAs (miRNAs) have certain significance in the diagnosis of early-stage PDAC, or even in precancerous pancreatic lesions (44, 57). The diagnostic value of microRNAs was shown to be higher than that of conventional serum markers (58), and there is evidence that the combination of miRNAs and CA 19-9 is more accurate (59, 60). Moreover, miRNA expression profiles may distinguish between malignant and benign lesions of the pancreas (61), and they may be used for the prediction of chemoresistance and facilitate personalized treatment planning (44, 62). Another emerging strategy are so-called “liquid biopsies” that can capture tumor-associated components, such as circulating tumor DNA, extracellular vesicles, and circulating tumor cells. It has been reported that circulating tumor cells can be detected in the peripheral blood of 40%–100% of pancreatic cancer patients, which may be used for the diagnosis of early PDAC (63). These novel methods seem very promising, although further studies are needed to verify the results and validity of these strategies in clinical practice.
Imaging methods
Abdominal ultrasound (US) is a non-invasive, broadly available, and easily feasible technique that is usually the first imaging method used in suspected pathology of the pancreatobiliary tract (64). The disadvantage of abdominal US is its low specificity, expert dependence, and also the dependence on the patient‘s body habitus (64). According to various authors, the sensitivity of US in PDAC detection ranges from 48%–98% (64, 65). In a Japanese multicenter study involving early-stage pancreatic cancers, dilatation of the MPD was the most common abnormality on US in up to 75% patients (66).
Computed tomography (CT) has a crucial role in diagnosis, staging, and planning or monitoring the treatment of patients with PDAC (64, 67). Currently, a biphasic pancreatic protocol with submillimeter section thickness and standard use of multiplanar reconstructions are recommended (64, 67). It involves both intravenous contrast with a high iodine content (at a rate of 3–5 ml/s) and ingestion of water as a neutral oral contrast (64). The pancreatic phase should be performed after 40–50 seconds and the portal phase after 65–70 seconds following intravenous contrast application. Three-dimensional (3D) images are convenient for assessing tumor-vessel relationships, especially before planned surgery (64).
Based on the extent of disease, PDAC is divided into one of four categories: resectable (Fig. 3), borderline resectable, locally advanced (Fig. 4), and metastatic (Fig. 5). Due to the gradual improvement of CT imaging technology, the sensitivity of CT for detection and evaluation of PDAC resectability has increased from 76% to 95% and 73% to 83%, respectively (67). CT is accurate for determination of unresectable disease with sensitivity of up to 91% and specificity of 100% (64).
To assess resectability of the lesion, it is necessary to assess potential infiltration of the superior mesenteric artery, coeliac axis and its branches, portal vein, and superior mesenteric vein. Three degrees of vascular contact with the tumor are evaluated, i.e., no contact, abutment (≤180°), or encasement (>180°), on the basis of which it is possible to predict resectability (64, 68). The disadvantage of CT in determining local resectability of PDAC is the existence of interobserver variability among evaluators, even among experienced radiologists (69). In addition to the tumor-vessel contact, the size of the tumor itself also predicts resectability. Significantly more positive resection margins are described in tumors measuring >4 cm than in tumors measuring <2 cm on CT (70). Thrombosis, vascular deformation, and collateral vessel development are other features increasing the likelihood of vascular invasion (68, 71).
The anatomical (radiological) definition of borderline PDAC is not fully uniform. It is generally described as a locally advanced tumor without distant metastases that affects the mesentericoportal veins or potentially resectable arteries (68, 72, 73). In addition to the anatomical definition, it is necessary to evaluate the risk of distant metastases, CA 19-9 levels, and the patient‘s performance status or comorbidities (68, 73).
PDAC typically becomes hypodense on postcontrast CT. However, in 5–14% it can be directly indistinguishable, i.e, isodense compared to the surrounding parenchyma (74). EUS with fine-needle tissue acquisition can confirm these isodense tumors with a sensitivity of 90.5% (75). As an early predictor of a malignant tumor before development of a focal pancreatic lesion on CT, a novel feature may be suggestive – the ”K sign”. It is a localized narrowing of the pancreatic parenchyma on an axial CT scan resembling the shape of the letter K (76). Advances in the use of artificial intelligence also represent a great potential, offering new opportunities not only for the detection but also for the classification of pancreatic lesions (67).
Magnetic resonance (MR) imaging of the pancreas along with MR cholangiopancreatography (MRCP) allow for accurate detection of early PDAC by facilitating morphological analysis of pancreatic ductal changes (64). A recent study found that incipient MPD stenosis on pre‑ -diagnostic MRCP can be detected 26–49 months prior to pancreatic tumor detection on any of the imaging methods (CT, MR, or EUS) (77). The advantages of MR include the ability to identify isodense tumors or tumors within a hypertrophic pancreatic head, distinguish neoplasm from mass-forming pancreatitis, and also to detect small liver metastases unrecognized on CT (64, 73). Its sensitivity and specificity in assessing vascular invasion is comparable to CT (73). Nonetheless, MR imaging might not be routinely done in some centers due to its lower availability and higher costs compared to CT. Therefore, MR is not currently used as the primary imaging method in PDAC (64).
Positron emission tomography (PET)/CT is not routinely indicated in the diagnostic evaluation of PDAC, but it should be considered in patients with a high risk for occult metastatic disease, such as those with CA 19-9 concentrations out of proportion to their suspected stage (19).
Endoscopy
The role of endoscopic retrograde cholangiopancreatography (ERCP) in patients with suspected PDAC has evolved into a mainly therapeutic modality for patients with biliary obstruction requiring placement of a biliary stent. However, routine preoperative decompression for obstructive malignant jaundice should not be performed in patients who are eligible for resection; it has not been proven to be beneficial in regard to patient outcome, and there is evidence for increased postoperative complications (78). Strict indication criteria should thus apply, e.g., concurrent acute cholangitis.
EUS is considered the most sensitive method for detecting early pancreatic neoplasms (79). The median sensitivity of EUS for the detection of pancreatic tumors across 22 studies was 94% (80). Importantly, it has a very high negative predictive value (81, 82). This is valuable for clinicians as it indicates that EUS can also exclude pancreatic cancer. In patients with PDAC it is frequently used as a complementary staging tool to evaluate regional lymph nodes, define the degree of tumor-vascular involvement, or secure a definitive cytologic or histologic diagnosis (77, 83).
EUS-guided fine-needle biopsy (preferred over fine-needle aspiration) is the most favorable modality for obtaining tissue specimens from the pancreas (Fig. 6). However, preoperative tissue diagnosis may not be needed in surgical candidates with potentially resectable pancreatic lesions that are highly suspected of malignancy. While a positive sample can confirm the diagnosis, benign findings don’t exclude the presence of malignancy. Once PDAC is suspected on initial imaging, the next step is generally a staging evaluation to establish disease extent and resectability rather than biopsy. A preoperative biopsy may be recommended if a diagnosis of chronic or autoimmune pancreatitis is suspected and differential diagnosis yields difficulties.
Therapy
Radical resection is the only potential curative approach in patients with PDAC. Neoadjuvant or adjuvant chemotherapy/chemoradiotherapy may improve disease-free survival and overall survival (OS) (84, 85). However, resection with curative intent is feasible only in 10%–20% of patients. Unfortunately, in these resected patients, positive resection margins are observed in the majority of cases. Thus, neoadjuvant chemotherapy or chemoradiotherapy is the standard of care in border-line resectable and locally advanced unresectable tumors. Chemotherapeutic intensive regimen with 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) results in a significantly better secondary resection rate and OS (85, 86).
In resectable PDAC, the current standard of care is resection followed by adjuvant chemotherapy or chemoradiotherapy. However, neoadjuvant therapy can be also considered in this setting, especially if risk factors are present, e.g., large primary tumors, enlarged lymph nodes, high baseline CA 19-9 levels, significant weight loss, or severe pain. Chemotherapeutic protocols for neoadjuvant and adjuvant treatment are interchangeable and are based on FOLFIRINOX regimen or gemcitabine/nab-paclitaxel combination (87).
Metastatic disease is an indication for palliative chemotherapy. This approach can prolong survival, decrease tumor-related symptoms, and preserve quality of life. For patients with a good performance status, intensive FOLFIRINOX regimen or gemcitabine/nab-paclitaxel combination are the standard of care, whereas gemcitabine or 5-fluorouracil alone are preferred for unfit patients (88).
Currently, target therapy is still limited in PDAC and is feasible in only a minority of metastatic patients. Olaparib is a specific inhibitor of Poly (ADP-ribose) polymerase. In patients with germline BRCA1 or BRCA2 mutations who didn’t progress on chemotherapy with platinum derivatives, olaparib results in a statistically-significant prolonged median progression-free survival (89). An immune checkpoint inhibitor pembrolizumab is already approved for patients who harbor high microsatellite instability, DNA mismatch repair deficiency, or high tumor mutational burden (90). NTRK inhibitors lacotrectinib and entrectinib may be considered among patients with PDAC harbouring NTRK fusion (87).
Conclusion
Pancreatic cancer remains one of the deadliest malignancies with dismal prognosis and limited options for effective therapy. It presents vaguely and heterogeneously, and the grim reality is that most patients have advanced or metastatic disease at diagnosis. In regards to the attempts at early detection of PDAC without the need for advanced or invasive methods, a discovery of a cost-effective biomarker with high specificity and sensitivity has currently been a goal of many researchers. Nonetheless, an effective screening tool is still not available. Contrastenhanced CT using a dual phase pancreatic protocol remains the mainstay method for diagnosing PDAC and determining its resectability. EUS is an increasingly used adjunctive staging method that also allows for tissue diagnosis when necessary. Additionally, conscious indication of pancreatic imaging using MR may improve diagnostic rates in selected groups of patients.
CORRESPONDING AUTHOR:
assoc. prof. Lumir Kunovsky, M.D., Ph.D.
2ndDepartment of Internal Medicine – Gastroenterology and Geriatrics University Hospital Olomouc,
Faculty of Medicine and Dentistry, Palacky University Olomouc,
I. P. Pavlova 6, 779 00 Olomouc, Czech Republic
Cit. zkr: Vnitř Lék. 2022;68(6):363-370
Článek přijat redakcí: 15. 4. 2022
Článek přijat po recenzích: 3. 6. 2022
Zdroje
1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71(3):209-249. doi: 10.3322/caac.21660.
2. Arnold M, Abnet CC, Neale RE, et al. Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology 2020; 159(1):335-349.e15. doi: 10.1053/j.gastro.2020.02.068.
3. Dusek L, Muzik J, Kubasek M, et al. Epidemiology of Malignant Tumours in the Czech Republic. [online]. 2022. [cit. 2022-2-26]. Available at: http://www.svod.cz.
4. Ústav zdravotnických informací a statistiky České republiky. Novotvary 2018 ČR. [online]. 2022. [cit. 2022-02-26]. Available at: https://www.uzis.cz/res/f/008352/novotvary2018.pdf.
5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70(1):7-30. doi: 10.3322/caac.21590.
6. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74(11):2913-21. doi: 10.1158/0008-5472.CAN-14-0155.
7. Huang L, Jansen L, Balavarca Y, et al. Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut 2019; 68:130–9. doi:10.1136/ gutjnl-2017-314828.
8. National Cancer Institute. Cancer Stat Facts: Pancreatic Cancer. [online]. 2021. [cit. 2021-08- 29]. Available at: https://seer.cancer.gov/statfacts/html/pancreas.html.
9. Hernandez YG, Lucas AL. MicroRNA in pancreatic ductal adenocarcinoma and its precursor lesions. World J Gastrointest Oncol 2016; 8(1): 18-29. doi: http://dx.doi.org/10.4251/ wjgo.v8.i1.18
10. Falasca M, Kim M, Casari I. Pancreatic cancer: Current research and future directions. Biochim Biophys Acta 2016; 1865(2):123-32. doi: 10.1016/j.bbcan.2016.01.001.
11. Gharibi A, Adamian Y, Kelber JA. Cellular and molecular aspects of pancreatic cancer. Acta Histochem 2016; 118(3):305-16. doi: 10.1016/j.acthis.2016.01.009.
12. Zhang X, Shi S, Zhang B, et al. Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes. Am J Cancer Res 2018; 8(3):332-353.
13. Ryska M. Karcinom pankreatu – současný efektivní diagnostický a terapeutický postup. Cas Lek Ces 2016; 155:38–43.
14. Aslanian HR, Lee JH, Canto MI. AGA Clinical Practice Update on Pancreas Cancer Screening in High-Risk Individuals: Expert Review. Gastroenterology 2020; 159(1):358-362. doi: 10.1053/j.gastro.2020.03.088.
15. Owens DK, Davidson KW, Krist AH, et al. Screening for pancreatic cancer: US preventive services Task force reaffirmation recommendation statement. JAMA 2019; 322:438–44. doi:10.1001/jama.2019.10232.
16. Goggins M, Overbeek KA, Brand R, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020; 69(1):7-17. doi: 10.1136/gutjnl-2019-319352.
17. Bosetti C, Lucenteforte E, Silverman DT, et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol 2012; 23(7):1880-8. doi: 10.1093/annonc/mdr541.
18. Iodice S, Gandini S, Maisonneuve P, Lowenfels AB. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg 2008; 393(4):535-45. doi: 10.1007/ s00423-007-0266-2.
19. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet 2020; 395(10242):2008- 2020. doi: 10.1016/S0140-6736(20)30974-0.
20. Stolzenberg-Solomon RZ, Schairer C, Moore S, et al. Lifetime adiposity and risk of pancreatic cancer in the NIH-AARP Diet and Health Study cohort. Am J Clin Nutr 2013; 98(4):1057-65. doi: 10.3945/ajcn.113.058123.
21. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995;273(20):1605-9.
22. Andersen DK, Korc M, Petersen GM, Eibl G, et al. Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer. Diabetes 2017; 66(5):1103-1110. doi: 10.2337/db16-1477.
23. Sung H, Siegel RL, Rosenberg PS, Jemal A. Emerging cancer trends among young adults in the USA: analysis of a population-based cancer registry. Lancet Public Health 2019; 4(3):e137-e147. doi: 10.1016/S2468-2667(18)30267-6.
24. Rebours V, Gaujoux S, d‘Assignies G, et al. Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN). Clin Cancer Res 2015; 21(15):3522-8. doi: 10.1158/1078-0432.CCR-14-2385.
25. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004; 64(7):2634-8. doi: 10.1158/0008-5472.can-03-3823.
26. Schneider R, Slater EP, Sina M, et al. German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer 2011; 10(2):323-30. doi: 10.1007/ s10689-010-9414-x.
27. Vanek P, Slodicka P, Zoundjiekpon V. Pancreatic cancer screening: ready for prime time?. Gastroent Hepatol 2021; 75(5):390-398. doi: 10.48095/ccgh2021390.
28. Park W, Chawla A, O‘Reilly EM. Pancreatic Cancer: A Review. JAMA 2021; 326(9):851-862. doi: 10.1001/jama.2021.13027.
29. McGuigan A, Kelly P, Turkington RC, et al. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018; 24(43):4846–4861. doi:10.3748/wjg.v24.i43.4846
30. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021; 71(1):7- 33. doi: 10.3322/caac.21654.
31. Macdonald S, Macleod U, Campbell NC, et al. Systematic review of factors influencing patient and practitioner delay in diagnosis of upper gastrointestinal cancer. Br J Cancer 2006; 94(9):1272-80. doi: 10.1038/sj.bjc.6603089.
32. Walter FM, Mills K, Mendonça SC, et al. Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study. Lancet Gastroenterol Hepatol 2016; 1(4):298-306. doi: 10.1016/S2468-1253(16)30079-6.
33. Schmidt-Hansen M, Berendse S, Hamilton W. Symptoms of Pancreatic Cancer in Primary Care: A Systematic Review. Pancreas 2016; 45(6):814-8. doi: 10.1097/MPA.0000000000000527.
34. Kunovsky L, Dite P, Jabandziev P, et al. Causes of Exocrine Pancreatic Insufficiency Other Than Chronic Pancreatitis. J Clin Med 2021; 10(24):5779. doi: 10.3390/jcm10245779.
35. Sharma A, Smyrk TC, Levy MJ, et al. Fasting blood glucose levels provide estimate of duration and progression of pancreatic cancer before diagnosis. Gastroenterology 2018; 155(2): 490–500. doi: 10.1053/j.gastro.2018.04.025.
36. Sah RP, Sharma A, Nagpal S, et al. Phases of metabolic and soft tissue changes in months preceding a diagnosis of pancreatic ductal adenocarcinoma. Gastroenterology 2019; 156(6): 1742–1752. doi: 10.1053/j.gastro.2019.01.039.
37. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 Suppl 5:v56-68. doi: 10.1093/annonc/mdv295.
38. Lang J, Kunovsky L, Kala Z, Trna J. Risk factors of pancreatic cancer and their possible uses in diagnostics. Neoplasma 2021; 68(2):227-239. doi: 10.4149/neo_2020_200706N699.
39. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol 2012; 3(2):105-19. doi: 10.3978/j.issn.2078-6891.2011.021.
40. Kaur S, Baine MJ, Jain M, et al. Early diagnosis of pancreatic cancer: Challenges and new developments. Biomark Med 2012; 6(5): 597–612. doi:10.2217/bmm.12.69.
41. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006; 24(33):5313-27. doi: 10.1200/ JCO.2006.08.2644.
42. Kunovsky L, Tesarikova P, Kala Z, et al. The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterol Hepatol 2018; 2018:5389820. doi: 10.1155/2018/5389820.
43. Kim JE, Lee KT, Lee JK, et al. Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. J Gastroenterol Hepatol 2004; 19(2):182-6. doi: 10.1111/j.1440-1746.2004.03219.x.
44. Eid M, Karousi P, Kunovsky L, et al. The Role of Circulating MicroRNAs in Patients with Early- Stage Pancreatic Adenocarcinoma. Biomedicines 2021; 9(10):1468. doi: 10.3390/biomedicines9101468.
45. Kau SY, Shyr YM, Su CH, et al. Diagnostic and prognostic values of CA 19-9 and CEA in periampullary cancers. J Am Coll Surg 1999; 188(4):415-20. doi: 10.1016/s1072-7515(98)00326-3.
46. Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007; 33(3):266- 70. doi: 10.1016/j.ejso.2006.10.004.
47. Mann DV, Edwards R, Ho S, et al. Elevated tumour marker CA19-9: clinical interpretation and influence of obstructive jaundice. Eur J Surg Oncol 2000; 26(5):474-9. doi: 10.1053/ ejso.1999.0925.
48. Goggins M. Molecular markers of early pancreatic cancer. J Clin Oncol. 2005 Jul 10;23(20):4524-31. doi: 10.1200/JCO.2005.19.711.
49. Fahrmann JF, Schmidt CM, Mao X, et al. Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection. Gastroenterology 2021; 160(4):1373-1383.e6. doi: 10.1053/j.gastro.2020.11.052.
50. Bauer TM, El-Rayes BF, Li X, et al. Carbohydrate antigen 19-9 is a prognostic and predictive biomarker in patients with advanced pancreatic cancer who receive gemcitabine-containing chemotherapy: a pooled analysis of 6 prospective trials. Cancer 2013; 119(2):285-92. doi: 10.1002/cncr.27734.
51. Tzeng CW, Balachandran A, Ahmad M, et al. Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer. HPB (Oxford) 2014; 16(5):430-8. doi: 10.1111/hpb.12154.
52. Wong D, Ko AH, Hwang J, et al. Serum CA19-9 decline compared to radiographic response as a surrogate for clinical outcomes in patients with metastatic pancreatic cancer receiving chemotherapy. Pancreas 2008; 37(3):269-74. doi: 10.1097/MPA.0b013e31816d8185.
53. Pelzer U, Hilbig A, Sinn M, et al. Value of carbohydrate antigen 19-9 in predicting response and therapy control in patients with metastatic pancreatic cancer undergoing first-line therapy. Front Oncol 2013; 3:155. doi: 10.3389/fonc.2013.00155.
54. Hartwig W, Strobel O, Hinz U, et al. CA19-9 in potentially resectable pancreatic cancer: perspective to adjust surgical and perioperative therapy. Ann Surg Oncol 2013; 20(7):2188- 96. doi: 10.1245/s10434-012-2809-1.
55. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016; 388(10039):73–85. doi:10.1016/s0140-6736(16)00141-0
56. Zhao Z, Liu W. Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment. Technol Cancer Res Treat 2020; 19. doi: 10.1177/1533033820962117.
57. Rawat M, Kadian K, Gupta Y, et al. MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential. Genes (Basel) 2019; 10(10):752. doi: 10.3390/genes10100752.
58. Johansen JS, Calatayud D, Albieri V, et al. The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer. Int J Cancer 2016; 139(10):2312-24. doi: 10.1002/ijc.30291.
59. Liu J, Gao J, Du Y, et al. Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer. Int J Cancer 2012; 131(3):683–691. doi:10.1002/ijc.26422
60. Schultz NA, Dehlendorff C, Jensen BV, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 2014; 311(4):392–404, doi:10.1001/jama.2013.284664
61. Shams R, Saberi S, Zali M, et al. Identification of potential microRNA panels for pancreatic cancer diagnosis using microarray datasets and bioinformatics methods. Sci Rep 2020; 10(1):7559. doi: 10.1038/s41598-020-64569-1.
62. Iwagami Y, Eguchi H, Nagano H, et al. miR-320c regulates gemcitabine-resistance in pancreatic cancer via SMARCC1. Br J Cancer 2013; 109(2):502-11. doi: 10.1038/bjc.2013.320.
63. Martini V, Timme-Bronsert S, Fichtner-Feigl S, et al. Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers 2019; 11(11). doi:10.3390/cancers11111659.
64. Zhang L, Sanagapalli S, Stoita A. Challenges in diagnosis of pancreatic cancer. World J Gastroenterol 2018; 24(19):2047-2060. doi: 10.3748/wjg.v24.i19.2047.
65. Okaniwa S. How Does Ultrasound Manage Pancreatic Diseases? Ultrasound Findings and Scanning Maneuvers. Gut Liver 2020; 14(1):37-46. doi: 10.5009/gnl18567.
66. Kanno A, Masamune A, Hanada K, et al. Multicenter study of early pancreatic cancer in Japan. Pancreatology 2018; 18(1):61-67. doi: 10.1016/j.pan.2017.11.007.
67. Chu LC, Park S, Kawamoto S, et al. Pancreatic Cancer Imaging: A New Look at an Old Problem. Curr Probl Diagn Radiol 2021; 50(4):540-550. doi: 10.1067/j.cpradiol.2020.08.002.
68. Jutric Z, Melstrom LG. New Treatment Options and Management Considerations in Borderline Resectable Pancreatic Cancer. Oncology (Williston Park) 2017; 31(6):443-52.
69. Joo I, Lee JM, Lee ES, et al. Preoperative CT Classification of the Resectability of Pancreatic Cancer: Interobserver Agreement. Radiology 2019; 293(2):343-349. doi: 10.1148/radiol. 2019190422.
70. Hong SB, Lee SS, Kim JH, et al. Pancreatic Cancer CT: Prediction of Resectability according to NCCN Criteria. Radiology 2018; 289(3):710-718. doi: 10.1148/radiol.2018180628.
71. Shen YN, Bai XL, Li GG, Liang TB. Review of radiological classifications of pancreatic cancer with peripancreatic vessel invasion: are new grading criteria required? Cancer Imaging 2017; 17(1):14. doi: 10.1186/s40644-017-0115-7.
72. Pietryga JA, Morgan DE. Imaging preoperatively for pancreatic adenocarcinoma. J Gastrointest Oncol 2015; 6(4):343-57. doi: 10.3978/j.issn.2078-6891.2015.024.
73. Elbanna KY, Jang HJ, Kim TK. Imaging diagnosis and staging of pancreatic ductal adenocarcinoma: a comprehensive review. Insights Imaging 2020; 11(1):58. doi: 10.1186/s13244- 020-00861-y.
74. Blouhos K, Boulas KA, Tsalis K, Hatzigeorgiadis A. The isoattenuating pancreatic adenocarcinoma: Review of the literature and critical analysis. Surg Oncol 2015; 24(4):322-8. doi: 10.1016/j.suronc.2015.09.006.
75. Psar R, Urban O, Cerna M, et al. Improvement of the Diagnosis of Isoattenuating Pancreatic Carcinomas by Defining their Characteristics on Contrast Enhanced Computed Tomography and Endosonography with Fine-Needle Aspiration (EUS-FNA). Diagnostics (Basel) 2021; 11(5):776. doi: 10.3390/diagnostics11050776.
76. Kobashi Y, Uchiyama M, Matsui J. The „K-Sign“-A Novel CT Finding Suggestive before the Appearance of Pancreatic Cancer. Cancers (Basel) 2021; 13(16):4222. doi: 10.3390/cancers13164222.
77. Yamao K, Tsurusaki M, Takashima K, et al. Analysis of Progression Time in Pancreatic Cancer including Carcinoma In Situ Based on Magnetic Resonance Cholangiopancreatography Findings. Diagnostics (Basel) 2021; 11(10):1858. doi: 10.3390/diagnostics11101858.
78. Scheufele F, Schorn S, Demir IE, et al. Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: A meta-analysis of current literature. Surgery 2017; 161(4):939-950. doi: 10.1016/j.surg.2016.11.001.
79. DeWitt J, Devereaux B, Chriswell M, et al. Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer. Ann Intern Med 2004; 141(10):753-63. doi: 10.7326/0003-4819-141-10-200411160-00006.
80. Kitano M, Yoshida T, Itonaga M, et al. Impact of endoscopic ultrasonography on diagnosis of pancreatic cancer. J Gastroenterol 2019; 54(1):19-32. doi: 10.1007/s00535-018-1519-2.
81. Săftoiu A, Vilmann P. Role of endoscopic ultrasound in the diagnosis and staging of pancreatic cancer. J Clin Ultrasound 2009; 37(1):1-17. doi: 10.1002/jcu.20534.
82. Klapman JB, Chang KJ, Lee JG, Nguyen P. Negative predictive value of endoscopic ultrasound in a large series of patients with a clinical suspicion of pancreatic cancer. Am J Gastroenterol 2005; 100(12):2658-61. doi: 10.1111/j.1572-0241.2005.00315.x.
83. Puli SR, Singh S, Hagedorn CH, et al. Diagnostic accuracy of EUS for vascular invasion in pancreatic and periampullary cancers: a meta-analysis and systematic review. Gastrointest Endosc 2007; 65(6):788-97. doi: 10.1016/j.gie.2006.08.028.
84. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018; 379(25):2395-2406. doi: 10.1056/NEJMoa1809775.
85. Versteijne E, Suker M, Groothuis K, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol 2020; 38(16):1763-1773. doi: 10.1200/JCO.19.02274.
86. Hackert T, Sachsenmaier M, Hinz U, et al. Locally Advanced Pancreatic Cancer: Neoadjuvant Therapy With Folfirinox Results in Resectability in 60% of the Patients. Ann Surg 2016; 264(3):457-463. doi:10.1097/SLA.0000000000001850.
87. Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19(4):439-457. doi:10.6004/jnccn.2021.0017.
88. Gränsmark E, Bågenholm Bylin N, Blomstrand H, et al. Real World Evidence on Second- Line Palliative Chemotherapy in Advanced Pancreatic Cancer. Front Oncol 2020; 10:1176. doi:10.3389/fonc.2020.01176.
89. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019; 381(4):317-327. doi:10.1056/NEJMoa1903387.
90. Leroux C, Konstantinidou G. Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology. Cancers (Basel) 2021; 13(4):799. doi:10.3390/cancers13040799.
Štítky
Diabetologie Endokrinologie Interní lékařstvíČlánek vyšel v časopise
Vnitřní lékařství
![Číslo 6](https://www.prolekare.cz/media/cache/resolve/journal_issue/media/image_pdf/ceea22d6ef98e2cd1aaa29d6e0ef82c0.jpg)
2022 Číslo 6
- Není statin jako statin aneb praktický přehled rozdílů jednotlivých molekul
- Pregabalin je účinné léčivo s příznivým bezpečnostním profilem pro pacienty s neuropatickou bolestí
- Moje zkušenosti s Magnosolvem podávaným pacientům jako profylaxe migrény a u pacientů s diagnostikovanou spazmofilní tetanií i při normomagnezémii - MUDr. Dana Pecharová, neurolog
- Dávkování a správná titrace dávky pregabalinu
- Magnosolv a jeho využití v neurologii
Nejčtenější v tomto čísle
- Early gastric cancer
- Current trends in the diagnosis of pancreatic cancer
- Comprehensive approach to a patient with arterial hypertension and dyslipidemia
- SGLT-2 inhibition a useful tool in the treatment of heart failure with reduced and preserved ejection fraction