Pancreatic cancer: clinical guidelines

List of Abbreviations

GI – gastrointestinal tract

CT – computed tomography

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

PET/CT — positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals and intravenous contrast enhancement

US – ultrasound examination

PTBD — percutaneous transhepatic cholangiodrainage

ECG – electrocardiography

ERCP — endoscopic retrograde cholangiopancreatography

MRCP – magnetic resonance cholangiopancreatography

Terms and Definitions

Pancreatic intraductal neoplasia (PanIN) – pancreatic intraductal neoplasia (PanIN)

Mucinous cystic neoplasms (MCN) – mucinous cystic neoplasm (MCN)

Intraductal papillary mucinous neoplasms (IPMNs) – intraductal papillary mucinous neoplasm (IPMN).

FOLFIRINOX – chemotherapy regimen – oxaliplatin**, irinotecan**, calcium folinate**, fluorouracil**, fluorouracil**

mFOLFIRINOX – chemotherapy regimen – oxaliplatin**, irinotecan**, calcium folinate**, fluorouracil**

GEMCAP – chemotherapy regimen – gemcitabine**, capecitabine**

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Pancreatic cancer is a malignant tumor originating from the pancreatic epithelium.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

In 10% of patients with pancreatic cancer, the development of the disease is associated with the presence of known hereditary syndromes. The most common are Peutz-Jeghers syndrome, Lynch syndrome, and hereditary breast and ovarian cancer syndrome associated with BRCA gene mutations [1]. In other patients, pancreatic cancer is sporadic. Risk factors for this pathology include vitamin D3 deficiency, alcohol abuse, chronic pancreatitis, diabetes mellitus, smoking, obesity, and low physical activity [2–4].

The pathogenesis of pancreatic cancer is divided into three consecutive stages. The tumor initiation stage consists of the occurrence of the first driver mutation. Clonal expansion and the metastasis stage represent the second and third stages in the pathogenesis of this disease, respectively [5]. However, accumulating evidence suggests that metastasis may not be the final stage of carcinogenesis [6]. Tumor cells acquire metastatic competence at relatively early stages of carcinogenesis and continue to evolve independently of the primary tumor in distant organs [7].

Precancerous conditions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), and mucinous cystic neoplasms (MCN). During the malignant transformation of the pancreatic epithelium, mutations in key genes accumulate. Most frequently, the initial event is a mutation in the KRAS gene. Subsequently, mutations appear in CDKN2A, TP53, SMAD4/DPC4 and BRCA2 genes, which drive the progression of precancerous lesions from low-grade dysplasia to invasive carcinoma. Stromal components and microRNAs play a significant role in tumor progression [8].

1.3 Epidemiology of the Disease or Condition

Ductal adenocarcinoma, along with its rarer microscopic variants, accounts for approximately 85–95% of all exocrine pancreatic neoplasms. Therefore, morbidity and mortality data for pancreatic cancer essentially reflect those for ductal adenocarcinoma.

In the structure of oncological morbidity among the population of Russia in 2021, pancreatic cancer accounted for 3.5% in men and 3.1% in women. In total, 13,845 new cases were diagnosed in 2021. The incidence rate of pancreatic cancer in Russia in 2021 was 6.8 per 100,000 population. The increase in pancreatic cancer incidence over the preceding 10 years was 15% [9,10]. The mean age of affected men is 65 years, and of women, 70 years.

Late diagnosis of this pathology remains unchanged in recent times: in 58% of cases, the disease is diagnosed at stage IV, i.e., in the presence of distant metastases. Stages I–II account for only 23% of detected cases. Consequently, one-year mortality reached 65%, which is one of the highest among all malignant neoplasms [10].

In the structure of cancer mortality in Russia in 2021, pancreatic cancer accounted for 6.6%, ranking 5th after lung, stomach, colon, and breast cancer. The mean age of individuals who died from pancreatic cancer was 65 years for men and 71 years for women.

The global epidemiological situation is generally similar. Age-standardized incidence rates in Europe and North America are 7.6–7.7 per 100,000 population. In the USA, pancreatic cancer mortality is projected to become the second leading cause of cancer death by 2030 [11].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of pancreas (C25):

C25.0 Head of pancreas

C25.1 Body of pancreas

C25.2 Tail of pancreas

C25.3 Pancreatic duct

C25.4 Islets of Langerhans

C25.7 Other parts of pancreas

C25.8 Overlapping lesion of pancreas

C25.9 Pancreas, unspecified

1.5 Classification of the disease or condition

1.5.1 International Histological Classification (International Classification of Diseases for Oncology (ICD-O) [199])

Benign and precancerous epithelial tumors

8441/0 Serous cystadenoma

8148/0 Low-grade glandular intraepithelial neoplasia

8148/2 High-grade glandular intraepithelial neoplasia

8453/0 Intraductal papillary mucinous neoplasm with low-grade dysplasia

8453/2 Intraductal papillary mucinous neoplasm with high-grade dysplasia

8455/2 Intraductal oncocytic papillary neoplasm

8503/2 Intraductal tubulopapillary neoplasm

8470/0 Mucinous cystic neoplasm with low-grade dysplasia

8470/2 Mucinous cystic neoplasm with high-grade dysplasia

Malignant epithelial tumors

8500/3 Ductal adenocarcinoma

8560/3 Adenosquamous carcinoma

8480/3 Colloid carcinoma

8490/3 Dyshesive carcinoma

8576/3 Hepatoid carcinoma

8510/3 Medullary carcinoma

8490/3 Squamous cell carcinoma

8014/3 Large cell carcinoma with rhabdoid phenotype

8020/3 Undifferentiated carcinoma

8035/3 Undifferentiated carcinoma with osteoclast-like giant cells

8550/3 Acinar cell carcinoma

8551/3 Acinar cell cystadenocarcinoma

8470/3 Intraductal papillary mucinous neoplasm with associated invasive carcinoma

8552/3 Mixed acinar-ductal carcinoma

8154/3 Mixed acinar-neuroendocrine carcinoma

8154/3 Mixed acinar-neuroendocrine-ductal carcinoma

8154/3 Mixed ductal-neuroendocrine carcinoma

8470/3 Mucinous cystic neoplasm with associated invasive carcinoma

8971/3 Pancreatoblastoma

8441/3 Serous cystadenocarcinoma

8452/3 Solid pseudopapillary neoplasm

1.5.2 Staging of the disease or condition (group of diseases or conditions)

TNM staging of pancreatic cancer (8th edition)

Primary tumor (T):

TX – primary tumor cannot be assessed,

Tis – carcinoma in situ,

T1 – tumor limited to the pancreas, 2 cm or less in greatest dimension,

T1a – tumor 0.5 cm or less in greatest dimension,

T1b – tumor greater than 0.5 cm but no more than 1 cm in greatest dimension,

T1c – tumor greater than 1 cm but no more than 2 cm in greatest dimension,

T2 – tumor greater than 2 cm but no more than 4 cm in greatest dimension,

T3 – tumor greater than 4 cm in greatest dimension,

T4 – tumor involves the celiac axis, superior mesenteric artery, or common hepatic artery, regardless of size.

Regional lymph nodes (N):

NX – regional lymph nodes cannot be assessed,

N0 – no regional lymph node metastasis,

N1 – metastases in 1–3 regional lymph nodes,

N2 – metastases in 4 or more regional lymph nodes.

Adequate postoperative staging requires morphological examination of at least 12 lymph nodes.

For tumors of the pancreatic head, regional lymph nodes include those along the common bile duct, common hepatic artery, portal vein, pyloric, infrapyloric, subpyloric, proximal mesenteric, celiac, anterior and posterior pancreatoduodenal, along the superior mesenteric vein and the right lateral wall of the superior mesenteric artery. For tumors of the body and tail of the pancreas, regional lymph nodes include those along the common hepatic artery, celiac trunk, splenic artery, splenic hilum, as well as retroperitoneal and lateral aortic lymph nodes.

There are fundamental discrepancies in the description of regional lymph nodes in the 8th edition of TNM between the AJCC and UICC versions. At the same time, there are no citations of studies on which the UICC based its classification of lateral aortic lymph nodes as regional. This information must be taken into account when formulating a patient treatment plan.

Distant metastasis (M):

M0 – no distant metastasis,

M1 – distant metastasis.

Table 1. Pancreatic cancer staging

1.6 Clinical presentation of the disease or condition

Carcinoma of the head of the pancreas most commonly presents with jaundice caused by biliary obstruction. However, in cancer of the body and tail of the pancreas, the initial symptoms are typically weight loss, abdominal pain, and elevated blood glucose. The nonspecific nature of the symptoms and their late onset in the course of the disease result in the majority of patients presenting with stage III–IV disease at initial diagnosis.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1) anamnesis data;

2) physical and instrumental examination findings;

3) pathomorphological examination data of biopsy (surgical) material.

2.1 Complaints and Anamnesis

Comment: gathering information on complaints and detailed history, including family history, is performed to identify factors that may influence treatment choices

2.2 Physical Examination

Comment: special attention should be paid to assessing general condition using the ECOG scale (Appendix G1), nutritional status, pain syndrome, body temperature, hemodynamics, skin and sclera color, enlargement of peripheral lymph nodes, and presence of ascites.

2.3 Laboratory Diagnostics

• Patients with pancreatic cancer are recommended to undergo a complete blood count (CBC) with differential, general therapeutic blood chemistry tests, blood carcinoembryonic antigen (CEA) assay, blood carbohydrate antigen 19-9 (CA 19-9) assay, coagulogram (exploratory hemostasis assessment), and urinalysis to determine treatment strategy and for differential diagnosis of the disease [12–14].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: this scope of laboratory diagnostics is performed at the diagnostic stage and prior to treatment planning. During chemotherapy, the scope and frequency of laboratory tests are determined by clinical necessity [13]. For example, prior to the first course of chemotherapy, the maximum allowable age of a complete blood count is 14 days, and during chemotherapy – 5 days. The minimum panel of blood chemistry tests must include blood glucose, creatinine, total bilirubin, total protein, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) [15]. It should be remembered that CA 19-9 levels may be elevated in the presence of jaundice, cholangitis, or other inflammatory processes in the pancreatobiliary region; therefore, the assay for blood CA 19-9 tumor marker should be performed after biliary decompression (NLS A16.14.020 External biliary drainage, A16.14.020.005 Endosurgical percutaneous transhepatic biliary drainage, or A16.14.032 Biliary stenting), normalization of bilirubin levels, and resolution of inflammatory signs.

Comment: determining blood chromogranin A can be useful in cases of inconclusive pathomorphological findings regarding the histological type of a malignant tumor combined with a normal CA 19-9 level.

2.4 Instrumental Diagnostics

Comment: surgical intervention can be performed in some cases without morphological confirmation. The initiation of conservative treatment requires mandatory morphological verification due to the significant probability of false-positive results from instrumental imaging methods. The optimal approach for obtaining verification material is endoscopic ultrasonography (EUS) of the pancreatobiliary region (A04.14.003) and fine-needle aspiration biopsy of the pancreas. Core needle biopsy of the pancreas under EUS guidance (A04.14.003) provides additional material for immunohistochemical or molecular genetic testing, though it is a more complex and costly method. Biopsy must also be performed during diagnostic exploratory laparotomy (A16.30.006.002) or diagnostic laparoscopy (A16.30.079) in patients for whom radical surgery was planned without prior verification, but the process was deemed unresectable intraoperatively. A negative biopsy result in the presence of positive imaging findings is an indication for repeat procedures until diagnostically significant material is obtained. To save time and consumables during ultrasound-guided biopsy, it is recommended to implement rapid staining of cytologic slides and urgent assessment of the retrieved material for adequacy prior to routine pathomorphological examination of the pancreatic biopsy material.

In patients with resectable tumors (15–20% of all cases), a negative biopsy result should not delay or cancel surgical treatment if the treatment strategy is discussed at a multidisciplinary tumor board and the clinical diagnosis of pancreatic cancer is beyond doubt. At the same time, planning neoadjuvant therapy as the initial step for (borderline) resectable disease requires mandatory morphological verification.

• All patients with pancreatic cancer are recommended to undergo esophagogastroduodenoscopy (EGD) to assess the extent of tumor spread [20].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: EGD is a mandatory diagnostic method for patients with suspected pancreatic tumor. EGD allows visualization of duodenal invasion, assessment of the degree of duodenal tumor stenosis, and clarification of the localization and local tumor invasion of the organs and structures of the biliopancreatoduodenal zone.

• Patients with pancreatic cancer are recommended to undergo contrast-enhanced computed tomography (CT) of the abdominal and retroperitoneal cavities with intravenous bolus injection (A06.30.005.002), contrast-enhanced computed tomography of the thoracic cavity (A06.30.005.004), and contrast-enhanced computed tomography of the pelvic organs in women (A06.20.002.003) to assess the extent of the tumor process and for differential diagnosis of the disease [19,21,22].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: when performing abdominal CT with intravenous contrast enhancement, the mandatory use of automatic power injectors is required. The injection rate of contrast agents typically ranges from 2 to 5 mL/s, which can be considered quite sufficient to obtain informative results.

Manual administration of contrast agents during contrast-enhanced computed tomography of the abdominal and retroperitoneal cavities should be considered unacceptable, as it is impossible to obtain informative images of the studied organs in the required contrast phases, without the analysis of which correct diagnosis is generally impossible.

When calculating the main parameters of contrast-enhanced protocols, it is necessary to take into account the technical characteristics and design features of the computed tomography scanners used (in particular, tube rotation speed, tube current parameters, detector row width, etc.).

For a comprehensive analysis of the condition of abdominal organs, a 3- or 4-phase study must be used, including native, arterial, venous (or portal-venous), equilibrium (or delayed) phases. For each phase of the study, the scan start time from the moment of contrast injection (i.e., scan delay) is determined strictly individually, taking into account the preferred injection rate of X-ray contrast agents (usually 2–5 mL/s), their volume, the purpose of the study, and the technical parameters of the CT scanner. Modern computed tomography scanners use automatic techniques (such as "bolus-tracking", "sure start", and similar) to determine the scan delay.

The most common delay times are 20–30 seconds for the arterial phase (from the start of X-ray contrast agent injection), 50–70 seconds for the portal-venous phase, and 100–180 seconds for the equilibrium or delayed phase. Several authors in their studies also distinguish a pancreatic phase (or "late arterial phase") with a delay of 30–50 seconds (40–45 seconds) from the start of X-ray contrast agent injection.

The reference point (for starting the scan) can be the moment when the descending aorta lumen reaches an "enhancement" level of 100–120 HU, which usually occurs after 18–23 seconds. In this case, the scan delay from the specified reference point is: 5–6 seconds for the arterial phase, 19–22 seconds for the pancreatic phase, and 52–65 seconds for the portal-venous phase.

According to some authors, the delay time for the pancreatic phase was 22 seconds on 4–16-slice CT scanners and 24 seconds on 64-slice CT scanners (upon reaching an abdominal aorta enhancement level of 100 HU).

Significant variation in the discussed values is due to the hemodynamic characteristics of different patients, differences in the equipment used, and varying injection rates of X-ray contrast agents.

Only a thorough analysis of all intravenous contrast phases allows for a detailed evaluation of tumor enhancement characteristics, and in some cases, clarifies its nature, as well as determines the status of all key regional vascular trunks (in particular, the degree of their involvement in the tumor process or their-intactness).

Patients with suspected pancreatic lesions should undergo a standard examination of the entire abdominal region due to the high frequency of liver metastases.

The minimum scope of a CT report, in addition to describing the localization and size of the tumor mass, the features of its relationship with adjacent organs and structures, and the presence of enlarged lymph nodes (indicating their localization), must include a detailed assessment of its relationship (if any) with key regional vascular trunks, specifically: the celiac trunk and its main branches, the superior mesenteric artery (SMA) and superior mesenteric vein (SMV), the portal and splenic veins, namely:

• presence and extent of perivascular tumor infiltration,

• degree of vascular deformation (stenosis),

• where possible, the extent of intimate contact between the tumor and a given vessel (in the absence of intervening fat planes): less than half of its circumference (180°), greater than half of its circumference (180°), or the vessel enclosed within the tumor,

• presence or absence of thrombosis (tumor or blood thrombus) in the respective vessels,

It is necessary to describe the condition of the main pancreatic duct, intra- and extrahepatic bile ducts, and record the corresponding numerical values in case of their dilatation.

• Patients with pancreatic cancer are recommended to undergo contrast-enhanced magnetic resonance imaging (MRI) of the abdominal cavity (A05.30.005.001 Magnetic resonance imaging of the abdominal cavity with intravenous contrast enhancement, A05.30.005.002 Magnetic resonance imaging of the abdominal cavity with intravenous administration of a hepatotropic contrast agent) (± contrast-enhanced magnetic resonance imaging of the pelvic organs (A05.30.004.001)) with acquisition of images in the arterial, portal-venous, and delayed phases, as well as diffusion-weighted imaging as an alternative to MSCT in patients with allergies to iodine-containing X-ray contrast agents, when liver metastases are suspected but cannot be confirmed/excluded by other methods, as well as magnetic resonance cholangiopancreatography (MRCP) in the presence of obstructive jaundice requiring minimally invasive biliary drainage [19,21]

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: although pancreatic carcinomas can be well visualized on MRI, there is no evidence that MRI has diagnostic advantages over MSCT in terms of primary tumor staging [23–26]. However, MRI is capable of visualizing liver metastases with greater sensitivity and specificity, and is therefore recommended when liver metastases are suspected and their confirmation would alter treatment tactics [27,28]. MRCP allows evaluation of the nature of intra- and extrahepatic bile duct strictures, making subsequent endoscopic retrograde cholangiopancreatography (ERCP) optional.

• All patients with pancreatic cancer are recommended to undergo comprehensive ultrasound examination (US) of the abdominal cavity, retroperitoneal ultrasound, and comprehensive pelvic ultrasound (transvaginal and transabdominal) (A04.16.001, A04.30.003, A04.30.010) to assess the extent of the tumor process if CT or MRI cannot be performed [19,21].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: ultrasound is the simplest imaging method for detecting a pancreatic mass and evaluating other organs for metastases. However, this method is significantly inferior to CT in assessing vascular invasion, which is important when evaluating resectability. Ultrasound can be an alternative to CT in assessing treatment response in patients receiving palliative chemotherapy. Women are recommended to additionally undergo comprehensive pelvic ultrasound (transvaginal and transabdominal) (A04.30.010) due to the risk of metastasis to the uterine appendages.

• Patients with pancreatic cancer are recommended to undergo endoscopic ultrasonography of the pancreatobiliary zone if additional clarification of the degree of local tumor extension is needed and for biopsy guidance [21,29–31].

GCR BLOCE 1Grade of Recommendation B (Level of Evidence 1)

Comment: endoscopic ultrasonography of the pancreatobiliary zone is a highly sensitive method for assessing pancreatic tumor invasion into adjacent anatomical structures, including the duodenum, bile ducts, and major vessels [29]. In addition, endoscopic ultrasonography of the pancreatobiliary zone can serve as an imaging method during biopsy of the neoplasm [31] or celiac plexus neurolysis [30].

• Patients with pancreatic cancer are recommended to undergo retrograde cholangiopancreatography (ERCP) in the presence of obstructive jaundice requiring common bile duct stenting [19,21].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: due to the complexity and probability of complications, this method is currently most frequently used for common bile duct stenting in obstructive jaundice (A16.14.032 Biliary duct stenting). The technique is preferred as ERCP, and direct opacification of the pancreatic ductal system should be performed strictly according to indications and exclusively using non-ionic radiocontrast agents, since high-osmolar ionic radiocontrast agents cause destruction of the duct lining epithelium and lead to spasm, impaired secretion outflow, and acute pancreatitis of varying severity. ERCP allows for the acquisition of biopsy (surgical) material for pathomorphological examination.

• Patients with pancreatic cancer are recommended to undergo positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement (PET/CT) when metastatic disease cannot be ruled out by other imaging methods [12,32].

LoR CLE 3Level of Recommendation C (Level of Evidence 3)

Comment: the addition of PET/CT to standard imaging modalities increases the sensitivity of distant metastasis detection from 57% to 87%. In selected cases with suspected distant metastases (e.g., high CA 19-9 levels or large primary tumor size) where confirmation would alter treatment strategy (e.g., avoiding surgery), PET/CT is recommended. However, PET/CT is NOT a replacement for protocol-based CT in assessing primary resectability when deciding on the feasibility of radical surgery.

• Patients with pancreatic cancer are recommended to undergo whole-body bone scintigraphy if skeletal muscle/bone metastasis is suspected [33].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• Patients with pancreatic cancer are recommended to undergo diagnostic laparoscopy (A16.30.079) when peritoneal dissemination of the tumor is suspected or when morphological verification of the diagnosis is not possible by other methods [19,21].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: besides enabling tissue acquisition for morphological tumor verification, diagnostic laparoscopy may be useful in patients at high risk of metastatic disease, such as those with CA 19-9 levels > 500 IU/mL or regional lymph node metastasis[34].

• Patients with pancreatic cancer are recommended to undergo contrast-enhanced brain MRI or contrast-enhanced brain CT if brain metastasis is suspected [35,36].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

• Patients with pancreatic cancer are recommended to undergo electrocardiography (ECG) (recording of the electrical activity of the heart's conduction system) to refine the treatment strategy [37–39].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

2.5 Other Procedures

• All patients scheduled for or already receiving systemic therapy for pancreatic cancer are recommended to undergo germline molecular genetic testing for BRCA1, BRCA2 mutations in blood (A27.05.040) and molecular genetic testing for mutations in the PALB2 gene [40,41].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comment: considering the >5% frequency of mutations in BRCA1, BRCA2, and PALB2 genes, as well as the significant impact of these mutations on chemotherapy regimen selection, testing for these mutations is advisable for all patients who are candidates for medical treatment.

Due to the high frequency of monoallelic somatic mutations with low predictive value regarding drug sensitivity, germline mutation testing is optimal. If tumor tissue is tested for these mutations, the report should indicate whether the inactivating mutation is monoallelic or biallelic.

Given the extremely low sensitivity of existing PCR-based test systems, next-generation sequencing (NGS) should be preferred. If sequencing is not feasible, the laboratory should use a PCR-based test system approved for detecting pancreatic cancer mutations, as this is associated with the highest likelihood of detecting a BRCA2 mutation [42].

• All patients scheduled for or already receiving systemic treatment for metastatic pancreatic cancer are recommended to undergo molecular genetic testing for KRAS mutations in biopsy (surgical) material (specifying the exact mutation locus) and microsatellite instability (MSI) testing in biopsy (surgical) material by PCR.

Comment: about 80–90% of pancreatic carcinomas harbor KRAS mutations, indicating a minimal chance of identifying a therapeutically actionable biomarker. Conversely, the absence of a KRAS mutation indicates the feasibility of further testing for other therapeutically significant biomarkers, such as BRAF alterations, EGFR mutations, ALK, NTRK, ROS1 translocations, NRG1 gene fusions, and HER2/neu overexpression/amplification [43,44].

Detection of the MSI phenotype in the tumor occurs in less than 1% of cases and is independent of KRAS status [45]. The probability of identifying an MSI-H phenotype is significantly higher in the presence of monoallelic BRCA mutations or CHEK1 mutations [46]. It should be noted that a genetically proven Lynch syndrome does not obligatorily imply the presence of MSI-H in pancreatic carcinoma. Tumor tissue from all patients with Lynch syndrome must be tested for the MSI phenotype.

• Patients with pancreatic cancer are recommended to undergo pathomorphological examination of pancreatic biopsy (surgical) material (including immunohistochemical methods) to determine prognosis and subsequent treatment strategy [19,21].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: it is recommended to reflect the following parameters in the pathological anatomy report:

1) distance from the resection margin to the tumor;

2) tumor size;

3) histological type of the tumor;

4) tumor differentiation grade;

5) indication of the total number of examined and affected lymph nodes;

6) presence of involvement of the resection margins (the following are examined: the resection margin in the area adjacent to the superior mesenteric artery [uncinate process margin], posterior surface, venous resection margin, pancreatic resection margin, common bile duct resection margin, anterior surface of the pancreas);

7) presence of lymphovascular, extra- and intrapancreatic perineural invasion (a negative result must also be stated);

8) presence of invasion into the duodenal wall and the intrapancreatic part of the common bile duct;

9) presence of invasion into the portal vein wall and/or superior mesenteric vein wall in case of their resection (indicating the depth);

10) degree of tumor regression in case of preoperative therapy [8, 47].

Currently, there are many grading systems for assessing therapeutic response after neoadjuvant chemotherapy, including The College of American Pathologists (CAP), MD Anderson (MDA), Evans’ criteria, The Japanese Society (JPS), and Area of residual tumor (ART). The most convenient and reproducible is the CAP grading system (version Panc.Exo_4.2.0.2.REL_CAPC), according to which the therapeutic effect is assessed as follows (see Appendix G3):

- Score 0 – no viable cancer cells, complete therapeutic response;

- Score 1 – single cells or rare small groups of residual adenocarcinoma, marked therapeutic response;

- Score 2 – residual cancer with evident tumor regression, with both single cells and groups of adenocarcinoma cells present, partial therapeutic response;

- Score 3 – extensive residual cancer with no evidence of therapeutic response [48].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The prescribing and use of medications specified in the clinical guideline are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescribing and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition. Deviations from the instructions must be justified by the clinical situation and confirmed by a decision of the medical commission of the medical organization. Changing chemotherapy regimens or altering drug doses within a regimen does not necessarily require a formal oncological multidisciplinary team (MDT) meeting and may be determined by the attending physician.

3.1 Surgical Treatment

• In patients with resectable stage I-III pancreatic cancer (T_1-3N_0-1M₀), combined treatment including surgery and adjuvant chemotherapy is recommended [49–54].

GCR BLOCE 2Grade of Recommendation B (Level of Evidence 2)

Comment: for resectable pancreatic cancer (see Table 2), surgical treatment is recommended as the first step. An alternative option, primarily relevant in clinical situations that meet the radiological criteria for resectability but exhibit high-risk features for metastatic disease (e.g., CA 19-9 level >500 U/mL, regional lymph node metastasis [with distant metastasis ruled out by diagnostic laparoscopy or PET/CT]), is perioperative chemotherapy consisting of 2-4 months before surgery and 2-4 months after surgery (6 months of therapy in total, Table 4).

• In patients with borderline resectable and unresectable pancreatic cancer (T_3-4N_0-1M₀), preoperative and induction chemotherapy are recommended, respectively, followed by referral to high-volume centers with extensive experience in treating this disease for a reassessment of resectability [55].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: Morphological verification is mandatory before initiating medical therapy. Preoperative and induction chemotherapy regimens are presented in Table 4. Preferred regimens (in the absence of contraindications) are FOLFIRINOX or combinations of #gemcitabine** and #paclitaxel + albumin. In patients with BRCA or PALB2 gene mutations, the optimal approach is FOLFIRINOX or a combination of #gemcitabine** with platinum compounds. Initiating treatment with chemotherapy entails the need for tumor biopsy for morphological verification of the diagnosis and biliary drainage procedures [56,57]. The duration of induction chemotherapy for borderline resectable and unresectable disease is 12-18 weeks. If the disease remains unresectable and there is no disease progression after completion of 16-18 weeks of induction chemotherapy, it is recommended to either continue the previously initiated treatment regimen (if well tolerated) or administer maintenance chemotherapy (e.g., fluoropyrimidine monotherapy if the patient previously received FOLFIRINOX). There is no evidence favoring either strategy at the time these guidelines were formulated. The recommended total duration of chemotherapy, including the induction and maintenance phases, should be at least 6 months. Continuing chemotherapy for more than 6 months (e.g., until tumor progression) is also a viable option given the lack of clinical trials investigating the optimal duration of chemotherapy in this patient group. The decision to continue chemotherapy until progression according to RECIST 1.1 criteria (see Appendix G2) should be made taking into account treatment efficacy dynamics and tolerability.

Pancreatic cancer resectability criteria are detailed in Table 2.

Table 2. Assessment of resectability for non-metastatic pancreatic cancer [58]

• If, during surgery for pancreatic head cancer, the disease is deemed unresectable and there is a risk of impending intestinal obstruction and/or obstructive jaundice, it is recommended to perform bypass anastomoses to prevent obstructive jaundice and gastrostasis [19,21].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• In patients with severe comorbidities and non-metastatic pancreatic cancer that preclude surgical intervention, it is recommended to perform palliative medical treatment and minimally invasive procedures (e.g., percutaneous transhepatic cholangiography PTHC [A16.14.006.002 Ultrasound-guided percutaneous transhepatic cholecystostomy, cholecystocholangiostomy], biliary stenting [common bile duct, A16.14.032], duodenal stenting [A16.15.022 Pancreatic tumor stenting] for the relief of jaundice or high small bowel obstruction, as well as supportive care) [19,21].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: the decision that surgery is unfeasible can only be made by a multidisciplinary tumor board involving specialists in various modalities of antitumor treatment (surgery, systemic therapy, radiotherapy) with the invitation of a general practitioner and an anesthesiologist-resuscitologist.

• In patients with a tumor located in the head of the pancreas, it is recommended to perform a (gastro)pancreatoduodenectomy (A16.15.010 Pancreatoduodenectomy) [21,49].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comment: standard lymph node dissection (A16.06.007 Retroperitoneal lymphadenectomy) involves the removal of the following lymph nodes: suprapyloric and infrapyloric lymph nodes, lymph nodes along the hepatic artery and celiac trunk with its branches, lymph nodes along the common bile duct, lymph nodes around the cystic duct, retropancreatic lymph nodes, lymph nodes along the inferior margin of the pancreatic head, lymph nodes along the right semi-circumference of the superior mesenteric artery, and lymph nodes along the superior margin of the pancreatic head. In the absence of major vascular invasion and given sufficient surgical experience, the procedure may be performed via a laparoscopic approach.

• In patients with carcinoma located in the body or tail of the pancreas, it is recommended to perform distal subtotal pancreatectomy (A16.15.009.002 Distal pancreatectomy with splenectomy), including the removal of the body, tail of the pancreas, and the spleen [21,50].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comment: if technically feasible and with sufficient experience of the oncologic surgeon, the procedure may be performed via a laparoscopic approach. It is recommended to remove the following lymph node groups: splenic hilum lymph nodes, lymph nodes along the splenic artery, lymph nodes along the inferior border of the pancreas, along the common hepatic artery and celiac trunk, located along the left semi-circumference of the superior mesenteric artery, and middle colic lymph nodes along the corresponding artery.

Appleby procedure (A16.15.009 Pancreatic resection) is only possible in specialized centers with specialists experienced in such interventions, against the background of stabilization or a partial clinical response to preoperative therapy.

• In patients with carcinoma involving all parts of the pancreas, it is recommended to perform a total pancreatectomy (A16.15.011 Total duodenopancreatectomy) to increase patient survival [21,59].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

• In pancreatic cancer patients without medical contraindications, systemic antimicrobial prophylaxis is recommended during surgery to prevent infectious complications [60].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comment: the choice of systemic antimicrobial agents should be determined by the attending physician for each individual patient, taking into account their characteristics

• In patients with pancreatic cancer after surgical intervention in the absence of medical contraindications, enzyme replacement therapy is recommended, as well as blood glucose monitoring and correction [61–63]

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2)

Comment: the incidence of enzymatic insufficiency ranges from 36-100% after pancreatic resection. Therapy for enzymatic insufficiency is recommended for all patients postoperatively in the absence of contraindications and should aim at its correction even without laboratory confirmation of the diagnosis. The starting dose of enzyme replacement therapy (ERT) includes 40,000-50,000 IU of pancreatin** with meals and 25,000 IU with snacks. Subsequently, the dose of the drug may be adjusted on an individual basis. Most often, the required lipase dose after total pancreatectomy (A16.15.011 Total duodenopancreatectomy) is significantly higher than the initial dose specified. More detailed information on ERT is presented in section 3.3.

Secondary glucose metabolism disorder associated with pancreatic cancer is termed pancreatogenic diabetes mellitus (type 3c). This complication is associated with a risk of progression and an unfavorable prognosis, increases the risk of toxicity from medical treatment, and requires management by an endocrinologist.

3.2 Conservative treatment

3.2.1 Perioperative and adjuvant therapy

• In patients with pancreatic cancer, antitumor drug therapy is recommended in accordance with the general principles outlined in the "Practical Guidelines for General Aspects of Antitumor Drug Therapy" of the Russian Society of Clinical Oncology [13].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

• In patients with borderline resectable pancreatic cancer (T_3-4N_0-1M₀), preoperative chemotherapy is recommended followed by an assessment of the results; in the absence of negative dynamics, surgery is recommended [64].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: chemotherapy is the main method of preoperative therapy. Chemotherapy regimens are similar to those outlined for the treatment of metastatic cancer (Table 4). Preferred regimens (in the absence of contraindications) are FOLFIRINOX or combinations of #gemcitabine** and #paclitaxel + albumin. If patients have mutations in the BRCA or PALB2 genes, the optimal approach is to use the FOLFIRINOX combination or a combination of #gemcitabine** with platinum compounds. When choosing a chemotherapy regimen, the following data should be considered: the patient's general condition, age, presence of complications from the tumor process, and serious comorbid conditions. The duration of preoperative chemotherapy is 12-18 weeks.

• In patients older than 70 years, a comprehensive geriatric assessment (mycarg.org) is recommended to understand the risks of grade 3-5 complications when using drug combinations and the need for dose adjustments, which will improve the quality of life of these patients and the continuity of ongoing treatment [65].

GCR BLOCE 1Grade of Recommendation B (Level of Evidence 1)

• In patients with unresectable pancreatic cancer (T_3-4N_0-1M₀), induction therapy is recommended followed by a reassessment of resectability [64,66–68].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comment: chemotherapy is the main method of induction therapy. Chemotherapy regimens are similar to those outlined for the treatment of metastatic cancer (Table 4). Preferred regimens (in the absence of contraindications) are FOLFIRINOX or combinations of #gemcitabine** and #paclitaxel + albumin. If patients have mutations in the BRCA or PALB2 genes, the optimal approach is to use the FOLFIRINOX combination or a combination of #gemcitabine** with platinum compounds. When choosing a chemotherapy regimen, the following data should be considered: the patient's general condition, age, presence of complications from the tumor process, and serious comorbid conditions.

The duration of induction chemotherapy ranges from 12 to 24 weeks. If the unresectable process persists and there is no disease progression after the end of induction chemotherapy, it is recommended to either continue the previously initiated chemotherapy regimen (if well tolerated) or administer maintenance chemotherapy (e.g., #fluorouracil**/#capecitabine** monotherapy if the patient previously received FOLFIRINOX). There is no evidence of the superiority of either approach.

The recommended total duration of chemotherapy, including induction and maintenance phases, should be at least 6 months. Administering chemotherapy for more than 6 months (e.g., until tumor progression) is also a justified option due to the lack of clinical studies addressing the optimal duration of chemotherapy in this patient group. The decision to continue chemotherapy until progression according to RECIST 1.1 criteria (see Appendix G2) should be made taking into account the response dynamics and the tolerability of this treatment.

The role of radiation therapy as part of induction therapy for pancreatic cancer has not been definitively established. Published randomized trials do not support its use in either borderline resectable (ALLIANCE A021501, ESPAC-5f trials) or unresectable cancer (LAP 07, CONKO-007 trials). Currently, the use of radiation therapy for these indications is not recommended outside of clinical trials [57,69–71].

• Following resection of stage I-III pancreatic carcinoma (T_1-3N_0-1M₀), adjuvant chemotherapy is recommended to be initiated within 3 months in all pancreatic cancer patients in the absence of contraindications to achieve remission [72].

GCR ALEL 1Grade of Recommendation A (Level of Evidence 1)

Comment: treatment should be initiated within 3 months after surgery, optimally between 4 and 8 weeks postoperatively. If the patient's condition after surgery does not allow chemotherapy to be started within 3 months, a later start of adjuvant therapy is still advisable, although less effective [73]. If surgical treatment is performed without preoperative chemotherapy, the duration of adjuvant chemotherapy is 6 months [74].

Before starting chemotherapy, it is advisable to perform an examination (evaluation of the chest and abdominal cavities with IV contrast, as well as CA 19-9) to ensure there is no disease progression. The preferred adjuvant chemotherapy regimen is mFOLFOXINOF... wait, mFOLFIRINOX, in case of contraindications to its use – the GEMCAP combination, and if that is not feasible – monotherapy with #gemcitabine** or #fluorouracil**/#capecitabine** (Table 3) [72,74–76].

Table 3. Adjuvant chemotherapy regimens for pancreatic cancer

¹ mFOLFIRINOX has the highest efficacy, but is recommended only for patients with an ECOG performance status of 0-1 (Appendix G1), without severe surgical complications and comorbidities. For the prevention of febrile neutropenia when using the mFOLFIRINOX regimen, primary prophylaxis of neutropenia with filgrastim** at a dose of 5 mcg/kg subcutaneously 24 hours after the completion of chemotherapy until neutrophil counts recover, or pegfilgrastim** at 6 mg subcutaneously once, or empegfilgrastim** at 7.5 mg subcutaneously once 24 hours after the end of each chemotherapy course, may be prescribed. Alternatively, secondary prophylaxis of neutropenia is acceptable, considering that neutropenia is not always a dose-limiting toxicity and in some cases dose reduction of drugs is more appropriate [58,81].

² Despite initially reduced doses of mFOLFIRINOX in adjuvant therapy, the high toxicity of the regimen in frail patients after surgical treatment in some cases requires initial regimen modification or dose reduction during treatment if unmanageable toxicity develops. The minimum drug doses are 120 mg/m² for irinotecan, 60 mg/m² for oxaliplatin, and 1800 mg/m² for fluorouracil. Modification of calcium folinate to reduce toxicity is not provided.

³ In patients who cannot receive mFOLFIRINOX adjuvant chemotherapy, the GEMCAP regimen is preferred.

⁴ In case of a shortage of calcium folinate, it is possible to reduce the dose of this drug in regimens with infusion or bolus administration of fluorouracil to a fixed dose of 50 mg per day, or to exclude it from treatment altogether without a significant impact on treatment efficacy and tolerability.

In cases of positive resection margins (R1), chemotherapy regimens remain the same, although the benefit of the GEMCAP regimen in R1 status is questionable.

The role of adjuvant radiotherapy is currently being evaluated in prospective randomized trials. Its routine use is NOT recommended even with positive resection margins (R1) or confirmed regional lymph node metastases (pN1-2).

Comment: if preoperative chemotherapy is administered for 6 months followed by surgery, postoperative follow-up without adjuvant therapy is recommended. If the duration of preoperative chemotherapy was less than 6 months, adjuvant chemotherapy is recommended so that the total duration of chemotherapy is 6 months. In this case, it is recommended to administer the adjuvant phase of chemotherapy using the same antineoplastic agents that were used before surgery. However, given the higher risk of unmanageable toxicity after surgery compared to the preoperative phase, drug doses from the preoperative regimen should be adapted according to the patient's postoperative condition.

Unsatisfactory tolerability of chemotherapy may be the basis for premature discontinuation of therapy.

3.2.2 Therapy for metastatic pancreatic cancer

• In patients with metastatic pancreatic cancer, it is recommended to use systemic chemotherapy to control disease symptoms and increase overall survival [82–85].

GCR BLOC 1Grade of Recommendation B (Level of Evidence 1)

Comment: recommended first-line chemotherapy regimens for pancreatic cancer are summarized in Table 4. With any chemotherapy regimen, treatment is recommended to continue until disease progression according to RECIST 1.1 criteria (see Appendix G2) or until unacceptable toxicity that persists despite dose reductions.

Table 4. First-line chemotherapy for pancreatic cancer

¹ For the prevention of febrile neutropenia when using the FOLFIRINOX regimen, primary prophylaxis of neutropenia with filgrastim** at a dose of 5 mcg/kg subcutaneously 24 hours after completion of chemotherapy until neutrophil recovery, or pegfilgrastim** at 6 mg subcutaneously once, or empegfilgrastim** at 7.5 mg subcutaneously once 24 hours after the end of each chemotherapy course may be prescribed. Alternatively, secondary prophylaxis of neutropenia is acceptable, considering that neutropenia is not always a dose-limiting toxicity [58,81].

² In case of a shortage of calcium folinate, it is possible to reduce the dose of this drug in regimens with infusion or bolus administration of fluorouracil to a fixed dose of 50 mg per day, or to exclude it from treatment altogether without a significant impact on treatment efficacy and tolerability.

The choice of regimen for metastatic pancreatic cancer depends primarily on the patient's condition. In case of a satisfactory general condition with an ECOG score of 0–1 (Appendix G1), normal liver and kidney function, and the absence of severe complications of the tumor process and concomitant diseases, the use of FOLFIRINOX or #gemcitabine** + #paclitaxel + albumin regimens is recommended. For individual patients with extensive tumor spread and related symptoms (ECOG performance status 2), the combination of #gemcitabine** and #paclitaxel+albumin may be recommended if tumor response is expected to alleviate disease symptoms [82,85,86].

If the above criteria are not met, single-agent gemcitabine chemotherapy is recommended** [83]. Chemotherapy is not recommended for severely debilitated patients; in this case, only supportive care should be provided [19].

The combination of gemcitabine** and erlotinib** is not recommended for pancreatic cancer due to a clinically insignificant increase in overall survival in an unselected population with substantially greater toxicity [82,92].

The addition of fluoropyrimidines to gemcitabine** does not increase survival in locally advanced and metastatic cancer and is not recommended for clinical practice.

The addition of platinum-based drugs to gemcitabine** does not increase survival in locally advanced and metastatic cancer and is not recommended for clinical practice in the absence of BRCA or PALB2 mutations.

The significant toxicity of the FOLFIRINOX regimen justifies upfront modification of this regimen, which may include one or more of the following options [82]:

• primary prophylaxis of neutropenia with a colony-stimulating factor;

• dose reduction of bolus (to up to 320 mg/m² or complete omission) and infusion (to up to 2000 mg/m²) administration of #fluorouracil**;

• dose reduction of #irinotecan** (to up to 150 mg/m²);

• dose reduction of #oxaliplatin** (to up to 65 mg/m2).

Also, after 8 courses of FOLFIRINOX chemotherapy, switching to maintenance therapy with #fluorouracil**/#capecitabine** or the FOLFIRI regimen until progression is possible. In this case, rechallenge with FOLFIRINOX should be considered as an option for second-line therapy after progression [93].

• In patients with metastatic pancreatic cancer and pathogenic germline BRCA mutations who have not progressed after at least 16 weeks of first-line platinum-based chemotherapy, it is recommended to consider either continuing chemotherapy (including as maintenance chemotherapy) or switching to maintenance therapy with olaparib** until disease progression or unacceptable toxicity [91].

GCR CLEL 2Grade of Recommendation C (Level of Evidence 2)

Comment: A randomized clinical trial demonstrated a progression-free survival benefit with maintenance therapy using olaparib** tablets at a dose of 300 mg twice daily until disease progression or unacceptable toxicity compared with placebo in patients with metastatic pancreatic cancer and pathogenic germline BRCA mutations who had not progressed after at least 16 weeks of first-line platinum-based chemotherapy. A later transition to olaparib maintenance therapy is permissible, including in cases where clinical benefit or stable disease is maintained with fluoropyrimidine- or FOLFIRI-based maintenance chemotherapy. Treatment with olaparib must be initiated no later than 8 weeks from the date of the last chemotherapy cycle. To date, olaparib** has not demonstrated an overall survival benefit compared with placebo maintenance [91].

The use of olaparib** not as maintenance therapy, but as a standalone treatment, is not recommended due to low clinical efficacy.

• In the event of progression following adjuvant chemotherapy and/or first-line chemotherapy, all patients with pancreatic cancer in satisfactory general condition are recommended to receive second-line chemotherapy to control disease symptoms and extend overall survival [94,95].

GCR BLOCE 3Grade of Recommendation B (Level of Evidence 3)

Comment: Second-line chemotherapy may be recommended for patients in satisfactory condition (ECOG status 0–1) and selected patients with moderate condition (ECOG status 2) (Appendix G1) related to tumor dissemination, provided that the expected response to chemotherapy can improve the general condition. Patients with a severely compromised general condition (ECOG status 3–4) should receive supportive care only. If progression develops more than 6 months after the discontinuation of prior chemotherapy, reinitiation of the same chemotherapy regimen is advisable. Otherwise, initiating alternative chemotherapy agents is recommended. However, when other drug treatment options are exhausted, reintroduction of previously used antineoplastic agents may be considered if disease progression was not previously documented during that therapy or at the first response assessment after its completion. Recommended second-line chemotherapy regimens for pancreatic cancer are summarized in Table 5 [89,96–99].

Table 5. Second-line chemotherapy for pancreatic cancer

¹ In case of calcium folinate shortage, the dose of this drug in regimens with continuous infusion or bolus administration of fluorouracil may be reduced to a fixed dose of 50 mg daily or omitted entirely without significantly affecting treatment efficacy and tolerability.

In cases of cachexia, prescribing #megestrol acetate [141,142] at a dose of 320–480 mg orally once daily and/or olanzapine at a dose of 2.5 mg orally once daily is advisable, with the duration determined on an individual basis. There are no data supporting the use of third-line chemotherapy. The decision to use third-line chemotherapy is made individually.

If rare molecular alterations are identified, such as BRAF or EGFR mutations, ALK, NTRK, or ROS1 translocations, or HER2/neu overexpression/amplification in the absence of KRAS mutations, personalized therapy targeting these signaling pathways may be used in second- and later-line settings.

• In patients with an isolated locoregional recurrence following surgical treatment, as well as continued growth of a primary unresectable tumor after chemotherapy in the absence of distant metastases, it is recommended to consider either surgical treatment (in the scope of pancreatic re-resection or remnant pancreatectomy), chemoradiotherapy, or 3–4 months of chemotherapy followed by stereotactic body radiation therapy [143,144].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: chemoradiotherapy or 3–4 months of chemotherapy followed by stereotactic body radiation therapy (A07.14.001.003 Stereotactic external beam radiation therapy for pancreatic tumors using neutron, proton, and heavy ion beams; A07.30.009.001 Conformal external beam radiation therapy, including IMRT, IGRT, VMAT, stereotactic) is advisable. Irradiation is delivered to a total cumulative dose (TCD) of 54.4 Gy in 28 fractions combined with #capecitabine** at a dose of 830 mg/m² twice daily orally every day on radiation therapy days. When using stereotactic body radiation therapy, it is recommended to deliver 3 fractions to a TCD of 30–45 Gy or 5 fractions to a TCD of 25–45 Gy. The target volume includes the primary tumor with involved lymph nodes or the tumor recurrence.

3.3 Management of complications of the tumor process and antitumor treatment

• Performance of a biliodigestive procedure (A16.14.006.002 Ultrasound-guided percutaneous transhepatic cholecystostomy, cholecystocholangiostomy; A16.14.032 Biliary duct stenting) in patients with obstructive jaundice is recommended as the first step to prepare for radical surgery in the presence of cholestasis complications, such as active cholangitis, a total bilirubin level greater than 250 µmol/L, or when urgent (5-7 days) surgical treatment is not feasible [99,145].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: patients with obstructive jaundice require biliodigestive interventions (A16.14.006.002 Ultrasound-guided percutaneous transhepatic cholecystostomy, cholecystocholangiostomy; A16.14.032 Biliary duct stenting) if treatment is planned to begin with a conservative phase. Hyperbilirubinemia does not significantly increase the risk of major postoperative complications, while biliary decompression procedures significantly and often unjustifiably delay radical surgical treatment. Minimally invasive biliary drainage is recommended via an antegrade approach (percutaneous transhepatic interventions, A16.14.006.002 Ultrasound-guided percutaneous transhepatic cholecystostomy, cholecystocholangiostomy) or retrograde approach (endoscopic interventions, A16.14.032 Biliary duct stenting). Open biliodigestive interventions (A16.14.027 Hepatoduodenostomy) are indicated only when minimally invasive biliary drainage is ineffective or impossible; bypass anastomoses that could be used during reconstruction in the second stage of radical surgery should be used (e.g., hepaticojejunostomy; use of a "long" intestinal loop; antecolic placement of the jejunal loop, etc.)

• In patients with obstructive jaundice, it is recommended to perform biliodigestive interventions (A16.14.006.002 Ultrasound-guided percutaneous transhepatic cholecystostomy, cholecystocholangiostomy; A16.14.032 Biliary duct stenting) for biliary drainage if treatment is planned to begin with conservative therapy [146].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comment: it is recommended to perform minimally invasive biliary drainage via an antegrade (percutaneous transhepatic interventions, A16.14.006.002 Ultrasound-guided percutaneous transhepatic cholecystostomy, cholecystocholangiostomy) or retrograde (endoscopic interventions, A16.14.032) approach. In case of stenting (A16.14.032 Biliary duct stenting), self-expanding metal stents should be preferred. Plastic stents carry increased risks of migration and obstruction, which increases the risk of life-threatening complications, especially during chemotherapy. Their use is acceptable when the expected life expectancy is less than 3 months. Open biliodigestive interventions (A16.14.022 Hepaticojejunostomy) are indicated only when minimally invasive biliary drainage is ineffective or not feasible.

• In patients with gastric outlet or duodenal obstruction caused by compression and/or tumor infiltration of the pylorus or duodenum, it is recommended to urgently resolve this complication via stenting (A16.15.022 Stenting for pancreatic tumors) or formation of bypass anastomoses (A16.17.017 Creation of a small bowel bypass anastomosis) if treatment is planned to begin with a conservative phase [146,147].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

• In patients with severe pain syndrome and the impossibility of radical surgery, it is recommended to prescribe adequate analgesics, perform celiac plexus block (A22.24.004 Radiofrequency ablation of peripheral nerves, plexuses, autonomic ganglia) or palliative radiotherapy (A07.14.001.003 Stereotactic external beam radiation therapy for pancreatic tumors using neutron, proton, and heavy ion beams, A07.30.009 Conformal external beam radiotherapy) to reduce pain severity [12,21,148–150].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: celiac plexus block (A22.24.004 Radiofrequency ablation of peripheral nerves, plexuses, autonomic ganglia) is performed percutaneously or endoscopically. Alternatively, radiotherapy may be used for analgesic purposes (A07.14.001.003 Stereotactic external beam radiation therapy for pancreatic tumors using neutron, proton, and heavy ion beams, A07.30.009 Conformal external beam radiotherapy). A course of stereotactic radiotherapy (fraction dose 5-6 Gy, 5 times a week, total dose 25-30 Gy, depending on the irradiation volume of surrounding critical organs, taking into account their tolerance, A07.14.001.003 Stereotactic external beam radiation therapy for pancreatic tumors using neutron, proton, and heavy ion beams) or a course of conformal radiotherapy (A07.30.009 Conformal external beam radiotherapy) in a hypofractionated regimen (fraction dose 3-4 Gy, 5 times a week, total dose 30-28 Gy, respectively) can be administered. Verification of the calculated treatment plan must precede the start of the course of irradiation when using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (RapidArc). The patient should also receive analgesics that provide reliable relief of the pain syndrome.

Comment: the majority of patients show signs of nutritional deficiency, manifested as significant weight loss, cachexia, and sarcopenia. One of the causes of this complication that needs to be corrected is exocrine pancreatic insufficiency. According to meta-analyses, the frequency of enzyme deficiency is 44% in patients with unresected pancreas and 36-100% after surgery [63]. The clinical picture of enzyme deficiency has no specific symptoms and includes weight loss, diarrhea, abdominal pain/discomfort, anemia, electrolyte disturbances, etc. Diagnosis of enzyme deficiency does not always yield an accurate result. The direct method—assessing pancreatic juice output into the duodenum—is invasive and labor-intensive, which is why it is rarely used in practice. Indirect tests are used, for example, fecal elastase-1 testing (A09.19.010 Determination of pancreatic elastase-1 activity in stool) and measurement of biochemical markers (e.g., albumin [A09.05.011 Determination of blood albumin level], pre-albumin, magnesium [A09.05.127 Determination of total serum magnesium level], retinol-binding proteins, vitamins A, D [A09.05.221 Determination of 1,25-OH vitamin D level in blood], E) [62]. Measurement of the stool fat absorption coefficient and the radioisotope breath test are not available for routine testing. The fecal elastase-1 test (A09.19.010 Determination of pancreatic elastase-1 activity in stool) is used only to confirm the diagnosis of enzyme deficiency, but is not suitable for assessing its dynamics during enzyme replacement therapy.

Therapy for enzymatic insufficiency is indicated for all patients after surgery or in the absence of pancreatic resection if clinical signs of enzymatic insufficiency are present, and it should aim at its correction even without laboratory confirmation of the diagnosis. The starting dose of enzyme replacement therapy (ERT) includes 40,000–50,000 IU of pancreatin** during main meals and 25,000 IU during snacks. Subsequently, the drug dose may be adjusted on an individual basis. Most frequently, the required dose of pancreatin** after total pancreatectomy is significantly higher than the specified initial dose. Meta-analysis data indicate a worsening of the overall prognosis in patients who refuse ERT[63].

• In patients with pancreatic cancer, if hyperglycemia is detected, an examination (consultation) by an endocrinologist is recommended to correct blood glucose levels [151].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: secondary glucose metabolism disorder in pancreatic cancer is called pancreatogenic diabetes mellitus (type 3c). This complication is associated with a risk of progression, poor prognosis, increases the toxicity risks of medical treatment, and requires management by an endocrinologist [151].

• When treating ascites in patients, it is recommended to perform paracentesis (A16.30.007 Peritoneal drainage) and use diuretics to control the symptoms of this complication [152,153].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• In patients with pancreatic cancer, supportive and symptomatic therapy is recommended to improve quality of life and tolerability of antitumor treatment [154].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment:

The principles of treatment and prevention of nausea and vomiting in patients with pancreatic cancer comply with the guidelines set forth in the "Practical Guidelines for the Prevention and Treatment of Nausea and Prevention in Cancer Patients" [155].

The principles of treatment and prevention of bone complications in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Use of Osteomodifying Agents for the Prevention and Treatment of Bone Pathology in Malignant Neoplasms" [156].

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia" [157].

The principles of prevention and treatment of hepatotoxicity in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Clinical Guidelines for the Management of Antitumor Therapy-Induced Hepatotoxicity" [158].

The principles of prevention and treatment of cardiovascular complications in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Management of Cardiovascular Toxicity of Antitumor Drug Therapy" [159].

The principles of prevention and treatment of dermatological complications in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Medical Treatment of Dermatological Reactions in Patients Receiving Antitumor Drug Therapy" [160].

The principles of nutritional support in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for Nutritional Support in Cancer Patients" [161].

The principles of prevention and treatment of nephrotoxicity in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Management of Antitumor Drug-Induced Nephrotoxicity" [162].

The principles of prevention and treatment of thromboembolic complications in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" [163].

The principles of prevention and treatment of drug extravasation consequences in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Guidelines for the Management of Antitumor Drug Extravasation Sequelae" [164].

The principles of prevention and treatment of immune-mediated adverse events in patients with pancreatic cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Management of Immune-Mediated Adverse Events" [165].

Diet therapy

Comment: malnutrition, cachexia, and sarcopenia reduce quality of life and are poor prognostic factors. A balanced diet, calorie calculation, and prescription of specialized sip-feeding formulas are important aspects of a multidisciplinary approach to patient care. Additional information is available in the RUSSCO Practical Guidelines for the Treatment of Anorexia-Cachexia Syndrome in Cancer Patients [167].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• During prehabilitation, patients with pancreatic cancer are recommended to undergo exercise therapy (physiotherapy exercises), psychological and nutritional support, and patient education [166,168–172].

GRC BLOE 3Grade of Recommendation — B (Level of Evidence – 3)

Comments: a comprehensive prehabilitation program—including home-based exercise therapy (moderate-intensity physical activity combining both aerobic and anaerobic exercises), nutritional counseling, and counseling by a medical psychologist to overcome anxiety and depression (starting 28 days before surgery and continuing for 8 weeks postoperatively)—significantly improves postoperative quality of life. Psychological prehabilitation involving stress-coping techniques (relaxation techniques, positive mindset training) for 40–60 minutes 6 days a week, starting 5 days before surgery and continuing for 30 days postoperatively, significantly improves quality of life.

Comments: the use of incentive spirometry, elevation of the head of the bed, early initiation of breathing exercises, and early patient activation help prevent postoperative pulmonary congestion [173].

To prevent muscle mass loss, pulmonary and thrombotic complications, bed rest is indicated for 2 hours before surgery and no more than 6 hours after. Breathing exercises begin immediately after the patient regains consciousness following surgery. The patient is taught postoperative breathing exercise techniques prior to surgery. After surgical treatment, diaphragmatic breathing is recommended, as it improves lymph circulation and ventilates the lower lobes of the lungs, which typically do not inflate sufficiently during thoracic breathing.

• During chemotherapy, it is recommended to perform a set of exercise therapy (A19.30.007 Physiotherapy exercises using a training device), relaxation techniques including diaphragmatic breathing and progressive muscle relaxation, and consider prescribing a course of medical massage (A21.01.001 General medical massage) to improve the patient's general condition [174,175].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comments: the scope and intensity of exercise therapy are tailored individually based on the degree of fatigue (mild, moderate, severe). As the general condition improves, exercise therapy intensity may be increased. A combination of aerobic and resistance training is recommended.

5. Prevention and Dispensary Observation

• Patients with pancreatic cancer are recommended to undergo follow-up monitoring (dispensary observation) after treatment completion in accordance with the regulations for dispensary observation of adults with oncological diseases [176].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: dispensary observation implies follow-up visits (examination, consultation) with an oncologist and evaluations every 3 months for the first year, every 6 months for the second year, and annually thereafter for life [177]. There is no evidence that active post-treatment monitoring and early detection of disease recurrence increase overall survival. Therefore, gathering patient complaints and performing regular physical examinations is acceptable. However, rapid clinical deterioration during disease progression limits the prospects of utilizing modern chemotherapy regimens. Thus, optimal patient visits are every 12 weeks for the first two years, and every 6 months thereafter, to perform the following evaluations:

- Comprehensive ultrasound of the abdominal organs, ultrasound of the retroperitoneal space (A04.16.001, A04.30.003) of the abdominal organs (comprehensive), or computed tomography of the abdominal and retroperitoneal organs with intravenous bolus contrast enhancement (A06.30.005.002), or MRI of the abdominal organs with intravenous contrast enhancement (A05.30.005.001),

- Comprehensive pelvic ultrasound (transvaginal and transabdominal) for women,

- Targeted chest X-ray,

- Blood carcinoembryonic antigen (CEA) testing, blood carbohydrate antigen 19-9 (CA 19-9) testing if their levels were elevated at the pre-treatment stage, as well as a complete blood count and general clinical blood chemistry panel to assess liver and kidney function [178].

• For the prevention of pancreatic cancer, screening of the healthy population at high risk for pancreatic cancer is recommended [179–181].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: Pancreatic cancer screening studies are in the early stages. However, early metastasis and high patient mortality even after radical surgical treatment at early stages require the introduction of a pancreatic cancer early detection program in high-risk groups. Studies conducted have made it possible to define high-risk groups for pancreatic cancer: the presence of STK11 or CDKN2A mutations, or BRCA 1/2, ATM, PALB2, or Lynch syndrome mutations, provided there is at least one first- or second-degree relative who has suffered from pancreatic cancer. The high-risk group also includes cases of familial pancreatic cancer without an identified risk mutation: these are family members with at least two cases of pancreatic cancer including one first-degree relative [179, 182].

For patients with STK11 mutations, screening is recommended to begin at age 30–35; with CDKN2A mutations, starting at age 40 or 10 years younger than the youngest case of cancer in the family. Screening in other risk groups begins at age 50 or 10 years younger than the earliest case of pancreatic cancer in the family [181].

Screening methods include performing endoscopic ultrasonography (A04.14.003 Endosonography of the pancreatobiliary zone) and/or MRCP (A05.15.002 Magnetic resonance cholangiopancreatography) on an annual basis. Screening intervals may be shorter based on individual characteristics and suspicious findings. Patients must be informed of the risks of screening associated with the detection and subsequent surgical treatment of lesions that, upon histological examination, will not feature elements of high-grade dysplasia or cancer. Although the proportion of such surgeries reaches 47%, pancreatic cancer screening in the selected population has nonetheless demonstrated cost-effectiveness [183, 184]. Expert communities believe that the potential benefits of screening outweigh the risks [180].

6. Organization of Medical Care

Medical care, with the exception of medical care within clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Public Health Protection in the Russian Federation", is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized federal executive body;

2) in accordance with the procedure for providing care in the profile "oncology" (Order of the Ministry of Health of the Russian Federation No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to the Adult Population with Oncological Diseases", which is mandatory for execution on the territory of the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

A medical care standard is developed on the basis of these clinical guidelines, approved and endorsed in accordance with this article in the manner established by the authorized federal executive body, and includes averaged indicators of the frequency of delivery and multiplicity of application:

1) of medical services included in the nomenclature of medical services;

2) of medicinal products registered in the territory of the Russian Federation (with indication of average doses) in accordance with the instructions for medical use and the pharmacotherapeutic group according to the Anatomical Therapeutic Chemical classification recommended by the World Health Organization;

3) of medical devices implanted into the human body;

4) of blood components;

5) of types of clinical nutrition, including specialized clinical nutrition products;

6) of other items based on the characteristics of the disease (condition).

The prescription and use of medicinal products, medical devices, and specialized clinical nutrition products not included in the corresponding medical care standard or not provided for by the corresponding clinical guideline are permitted in the presence of medical indications (individual intolerance, life-threatening conditions) by decision of the medical commission.

Primary specialized health care is provided by an oncologist at an outpatient oncology care center, or in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (oncology hospital) and includes measures for the prevention, diagnosis, treatment of oncological diseases, and medical rehabilitation.

An oncologist at an outpatient oncology care center, or in the absence of such a center, an oncologist at a primary oncology office or the outpatient department of an oncological dispensary (oncology hospital) within one day from the date of establishing a preliminary diagnosis of a malignant neoplasm organizes the collection of biological material for cytological examination and/or biopsy (surgical) material and its referral to the pathologoanatomical bureau (department) in accordance with the rules for conducting pathologoanatomical examinations and/or to a clinical diagnostic laboratory (department, division) in accordance with the rules for conducting laboratory examinations, and also organizes other diagnostic examinations necessary to establish the diagnosis, including the spread of the oncological process and the stage of the disease.

In the event of the impossibility of collecting biopsy (surgical) material or conducting other diagnostic examinations in the medical organization where the outpatient oncology care center (primary oncology office) is organized, the patient is referred by the oncologist to an oncological dispensary (oncology hospital) or a medical organization providing medical care to patients with oncological diseases.

The timelines for diagnostic instrumental and laboratory examinations, including pathologoanatomical examinations, in case of suspected oncological diseases must not exceed the timelines established in the program of state guarantees for free medical care to citizens, approved by the Government of the Russian Federation.

Emergency medical care is provided in accordance with Order of the Ministry of Health of the Russian Federation No. 388n dated June 20, 2013, "On Approval of the Procedure for Providing Emergency, Including Specialized Emergency, Medical Care".

Emergency medical care is provided by paramedic emergency teams, physician emergency teams in emergency or urgent form outside a medical organization, as well as in outpatient and inpatient settings for conditions requiring urgent medical intervention.

The oncologist of the outpatient oncology care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive body, to clarify the diagnosis (in case of the impossibility of establishing the diagnosis, including the spread of the oncological process and the stage of the disease), determine treatment tactics, and also in the presence of medical indications for providing specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care for citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for high-tech medical care, referral to a medical organization providing high-tech medical care is carried out in accordance with the procedure for organizing the provision of high-tech medical care using the Unified State Health Information System.

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:

- digital images obtained from pathomorphological studies, sent to the fourth-group pathologoanatomical bureau (department) (reference center) via information interaction, including the use of telemedicine technologies for remote interaction between medical personnel;

- digital images obtained from diagnostic radiology methods, sent to the remote diagnostic radiology consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical personnel;

- of biopsy (surgical) material for re-examination of pathomorphological, immunohistochemical, and molecular genetic studies: to the pathologoanatomical bureau (department) of the fourth group (reference center), as well as to molecular genetic laboratories for conducting molecular genetic studies.

Treatment tactics are determined by a medical board (consilium) of physicians, including oncologists, a radiation oncologist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for the treatment of malignant neoplasms, systemic antineoplastic therapy, and radiation therapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians if necessary.

When changing the treatment method, holding an oncology multidisciplinary team meeting is mandatory.

The decision of the oncology multidisciplinary team is drawn up in a paper-based protocol, legibly hand-written or typed and signed by the participants of the meeting, or in the form of an electronic document signed using an enhanced qualified electronic signature of the meeting participants.

The decision of the oncology multidisciplinary team, drawn up as a protocol, is entered into the patient's medical documentation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, public associations, and other non-profit organizations operating in the field of health protection.

Indications for hospitalization in a round-the-clock or day hospital of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a multidisciplinary team of oncologists and radiotherapists, with the involvement of other specialist physicians as necessary.

Hospitalization is indicated:

1) when it is necessary to perform complex interventional diagnostic medical interventions requiring subsequent monitoring in a 24-hour or day hospital setting;

2) if there are indications for specialized antitumor treatment (surgical intervention, radiation therapy, including contact, external beam radiation therapy and other types of radiation therapy, drug therapy, etc.) requiring monitoring in an inpatient or day-inpatient setting;

3) if there are complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form.

An indication for discharging a patient from a medical organization is the completion of a course of treatment, or one of the stages of providing specialized, including high-tech, medical care in an inpatient or day-inpatient setting, provided there are no treatment complications requiring drug correction or medical interventions in an inpatient setting.

7. Additional Information

7.1 Factors influencing the outcome of pancreatic ductal adenocarcinoma

Treatment outcomes for pancreatic cancer are improving. The proportion of long-term survivors is increasing not only due to improved treatment approaches in patients with non-metastatic disease [77], but also due to more successful treatment of metastatic cancer [77,185].

Factors influencing disease outcome are quite numerous and include the patient's general condition, comorbid pathology, the extent of the tumor process, and the presence of complications from the tumor process. Biomarkers capable of predicting the tumor's propensity for rapid metastasis and the efficacy of chemotherapy are actively being studied [186, p. 4,187,188].

However, numerous studies demonstrate that the primary factor influencing outcome is adequately prescribed and administered treatment [74,94,95]. Therefore, unjustified refusal of treatment, even in advanced stages, is considered unacceptable.

7.2 Characteristics of rare histological subtypes of exocrine pancreatic neoplasms

Solid pseudopapillary neoplasms account for less than 1% of all pancreatic tumors, occurring predominantly in young women (in 90% of cases) at a mean age of 20 years. While previously classified as tumors of uncertain malignant potential, they are currently regarded as low-grade malignant tumors [189–191].

The tumors have an indolent course. The prognosis is favorable. Distant metastases are detected in ≈8% of cases. Treatment is predominantly surgical, including cases with distant metastases. The recurrence rate is less than 5%. Adjuvant therapy is generally not used.

No chemotherapy protocols have been developed for patients with unresectable metastases, and published case reports indicate low immediate efficacy of chemotherapy, although the indolent course provides prolonged stabilization. These tumors frequently express sex hormone receptors, and endocrine therapy with tamoxifen or aromatase inhibitors combined with ovarian suppression may be considered if necessary [189–191].

Acinar cell carcinomas and mixed acinar-endocrine carcinomas have a more favorable course compared to ductal carcinomas. General principles of treatment do not differ from those for pancreatic ductal adenocarcinoma. Mixed acinar-endocrine carcinomas are also treated according to the principles of exocrine cancer treatment.

At the molecular level, KRAS mutations are rare in these tumors. Among molecular alterations deserving attention, BRAF alterations should be highlighted. Although BRAF mutations are uncommon, BRAF or RAF1 rearrangements (e.g., SND1-BRAF fusions) are identified in 23% of cases, making these tumors potentially sensitive to MEK inhibitor therapy. Analysis of small studies also shows a higher frequency of BRCA gene mutations and MSI-H in acinar cell carcinomas of the pancreas [140,192–194].

Intraductal papillary mucinous neoplasm associated with invasive adenocarcinoma and mucinous cystic neoplasm associated with invasive adenocarcinoma are a group of tumors arising from the malignant transformation of benign cystic neoplasms. Their prognosis is determined by the biology of the malignant component and the extent of the disease. Accumulated experience does not allow for a specific treatment algorithm. Therefore, it is recommended to follow the same guidelines established for classic ductal adenocarcinoma [195–197].

Serous cystadenocarcinoma develops from a benign precursor and has a more favorable prognosis, despite the capacity to metastasize. The indolent course makes surgery the primary treatment method even in the presence of distant metastases [198,199].

Pancreatoblastoma is an extremely rare tumor occurring in childhood. About 15 cases of pancreatoblastoma diagnosed in adult patients have been published worldwide, the majority of whom died shortly thereafter. The principles of surgical treatment, (neo)adjuvant therapy, and treatment of disseminated disease should follow clinical guidelines for children [200,201].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Pokataev I.A., MD, Head of the Chemotherapy Service, City Clinical Oncology Hospital No. 1 of the Moscow Healthcare Department, Moscow

Alieva S.B., MD, Leading Researcher, Department of Radiological Research, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Galkin V.N., Chief Physician, S.S. Yudin City Clinical Hospital of the Moscow Healthcare Department, Moscow

Gevorkyan T.G., Deputy Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Gladkov O.A., Professor, MD, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine, Chelyabinsk

Zagainov V.E., MD, Chief Specialist in Surgery, Head of the Department of Surgical Diseases, Nizhny Novgorod State Medical Academy, Privolzhsky District Medical Center of the FMBA of Russia (PDMC), Nizhny Novgorod

Karachun A.M., MD, Head of the Department of Abdominal Oncology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

Karmazanovsky G.G., Academician of the RAS, MD, Professor, Head of the Department of Radiology and Magnetic Resonance Imaging with Ultrasound Diagnostics Room, A.V. Vishnevsky National Medical Research Center of Surgery of the Russian Ministry of Health

Komarov Yu.I., PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

Kriger A.G., MD, Professor, Chief Researcher, Russian Scientific Center of Roentgenoradiology of the Russian Ministry of Health, Moscow

Kudashkin N.E., PhD, Senior Researcher, Oncology Department of Surgical Methods of Treatment No. 7 for Hepatopancreatobiliary Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Kuchin D.M., PhD, Oncologist, Privolzhsky District Medical Center of the FMBA of Russia (PDMC), Nizhny Novgorod

Lebedev K.K., PhD, Oncologist, Department of Abdominal Oncology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health;

Lukyanchenko A.B., MD, Leading Researcher, X-ray Diagnostics Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow

Lyadov V.K., MD, Head of Oncology Department No. 4, S.S. Yudin City Clinical Hospital of the Moscow Healthcare Department, Moscow

Malikhova O.A., MD, Professor of the Department of Oncology and Palliative Medicine, RMCPPE, Head of the Endoscopy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow

Moroz E.A., Senior Researcher, Department of Pathology, Division of Morphological and Molecular Genetic Diagnostics of Tumors N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow

Obukhova O.A., PhD, Head of the Medical Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Patyutko Yu.I., MD, Professor, Leading Researcher, Surgical Department No. 7 for Liver and Pancreatic Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Podluzhny D.V., PhD, Head of Surgical Department No. 7 for Liver and Pancreatic Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Tkachenko E.V., PhD, Head of the Short-Term Chemotherapy Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

Tryakin A.A., MD, Head of Oncology Department of Drug Treatment (Chemotherapy) No. 2, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Tulin P.E., PhD, Senior Researcher, Positron Emission Tomography Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Fadeeva N.V., PhD, Head of the Anti-Tumor Drug Therapy Department, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine, Chief Freelance Chemotherapist of the Ministry of Health of the Chelyabinsk Region

Fedyanin M.Yu., MD, DSc, Head of the Chemotherapy Department, Moscow Multidisciplinary Clinical Center "Kommunarka", Senior Researcher at the Oncology Department of Drug Treatment (Chemotherapy) No. 2, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health

Yurichev I.N., PhD, Endoscopist, Lapino-1 Clinical Hospital "Mother and Child", Moscow Region

Nevolskikh A.A., MD, DSc, Deputy Director for Therapeutic Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Ivanov S.A., Professor of the RAS, MD, DSc, Director of the A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Khaylova Zh.V., PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Chernykh M.V., PhD, Deputy Director for Radiological Treatment Methods, Research Institute of Clinical Oncology, Head of the Radiotherapy Department, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

Oncologists;

Surgeons;

Radiologists;

Radiologists;

Medical geneticists;

Medical students, residents, and postgraduate students.

Methods used for evidence collection/selection: electronic database searches; analysis of current scientific developments on the problem of RB in Russia and abroad; synthesis of the practical experience of Russian and international specialists.

Table P1 – Scale for assessing the levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table P2 – Scale for assessing the levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table P3 – Scale for assessing the levels of recommendation persuasiveness (LRP) for prevention, diagnosis, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Methods used for formulating recommendations: expert consensus.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review

• Internal expert review

Description of the guideline validation method:

The draft of these recommendations was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care pediatric oncologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a practical tool for daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and peer review: The draft recommendations were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Updates to clinical guidelines: updating is carried out at least once every three years, taking into account new information on the diagnosis and management of patients with pancreatic cancer. The decision to update is made by the Ministry of Health of the Russian Federation based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicines, medical devices, and the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Appendix A3. Reference Materials

Current instructions for medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Diagram 1. Flowchart of diagnosis and treatment of a patient with pancreatic cancer

Appendix C. Patient Information

Information for patients on the diagnosis, treatment, and prevention of pancreatic cancer is available on the pages of professional patient communities, for example: http://www.russcpa.ru/patsientam/

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. WHO/ECOG performance status scale [202]

Russian title: WHO Patient Performance Status Scale/ECOG

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS)

Source (official developer website, publication with validation): https://ecog-acrin.org/resources/ecog-performance-status

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655

Type: rating scale

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Contents:

Key (interpretation): provided within the scale itself

Appendix G2. Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Russian title: Criteria for evaluating tumor response to chemotherapy (RECIST 1.1)

Original title: Response evaluation criteria in solid tumors 1.1

Source (official developer website, validation publication):

Original publication: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-247

Type: rating scale

Purpose: evaluation of response to chemotherapy

The content, key, and template in Russian are presented in methodological recommendations No. 46 of the Scientific and Practical Center for Medical Radiology of the Moscow Healthcare Department and are available on the website http://medradiology.moscow/d/1364488/d/no46_2018_recist_11.pdf [203]. This document is the property of the Moscow Healthcare Department and is not subject to reproduction and distribution without appropriate permission.

Appendix G3. Criteria for assessing the therapeutic effect of preoperative therapy in surgical specimens

Russian title: Criteria for assessing the therapeutic effect of preoperative therapy in surgical specimens

Original title: Protocol for the Examination of Specimens From Patients With Carcinoma of the Pancreas (version Panc.Exo_4.2.0.2.REL_CAPC)[48]

Source (official website of developers, publication with validation): Burgart LJ, Shi C, Adsay NV, et al. Protocol for the Examination of Specimens From Patients With Carcinoma of the Pancreas 2020. Available at: https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates.

Type: rating scale

Purpose: assessment of pathomorphological response to preoperative treatment

Contents:

- Score 0 – adenocarcinoma cells are absent, complete therapeutic effect;

- Score 1 – single cells and groups of residual adenocarcinoma cells are present, pronounced therapeutic effect;

- Score 2 – residual tumor with signs of regression is detected, with the presence of both single cells and groups of adenocarcinoma cells, partial therapeutic effect;

- Score 3 – residual tumor without signs of therapeutic response

Key (interpretation), explanations: provided in the scale itself