Chinese guidelines for diagnosis and treatment of pancreatic cancer 2018 (English version)

National Health Commission of the People’s Republic of China

Contents

1. Introduction

2. Diagnostic techniques and applications

2.1 Risk factors for pancreatic cancer

2.2 Clinical manifestations

2.3 Physical examination

2.4 Radiological examinations

2.4.1 Ultrosound

2.4.2 Computed tomography (CT)

2.4.3 Magnetic resonance imaging (MRI) and magnetic resonance cholangio-pancreatography (MRCP)

2.4.4 Positron emission tomography-CT (PET-CT)

2.4.5 Endoscopic ultrasonography

2.4.6 Role of ERCP in the diagnosis of pancreatic cancer

2.4.7 Cytology diagnosis via ERCP

2.4.8 ERCP combined with intraductal ultrasound (IDUS)

2.4.9 Bone scans

2.5 Blood immunologic and biochemical examinations

2.5.1 Blood biochemical examinations

2.5.2 Serum tumor markers tests

2.6 Histologic and cytological diagnosis

2.6.1 Cytological pathology diagnosis

2.6.2 Histopathology diagnosis of pancreatic cancer

2.6.3 Immunohistochemistry

2.6.4 Pathologic reports

2.7 Differential diagnosis of pancreatic cancer

2.7.1 Chronic pancreatitis

2.7.2 Carcinoma of ampulla

2.7.3 Pancreatic cystadenoma and cystadenocarcinoma

2.7.4 Choledocholithiasis

2.7.5 Other lesions of pancreas

3. Classification and staging of pancreatic cancer

3.1 Histologic classification of pancreatic cancer

3.2 Staging of pancreatic cancer (AJCC, the 8th edition)

3.2.1 Definition of T, N and M in pancreatic TNM staging

3.2.2 TNM staging for pancreatic cancer

4. Management of pancreatic cancer

4.1 Principles

4.2 Surgery

4.2.1 Principles of surgery

4.2.2 Preoperative biliary drainage

4.2.3 Indications for radical resection

4.2.4 Operation methods

4.2.5 Pancreatic anastomosis

4.2.6 Perioperative drug management

4.2.7 Management principles of postoperative complications

4.2.8 Surgical management of potentially resectable pancreatic cancer

4.2.9 Surgical management of locally advanced unresectable pancreatic cancer

4.3 Medical treatment

4.3.1 Chemotherapy effect for pancreatic cancer

4.3.2 Chemotherapy strategies for pancreatic cancer

4.4 Radiotherapy

4.4.1 Indications for pancreatic cancer radiotherapy

4.4.2 Radiotherapy techniques

4.4.3 Radiotherapy target area

4.4.4 Radiotherapy dose

4.4.5 Concurrent chemotherapy

4.4.6 Intraoperative radiotherapy

4.5 ERCP and related treatment

4.5.1 ERCP for preoperative biliary drainage in pancreatic cancer

4.5.2 Application of ERCP in unresectable pancreatic cancer

4.6 Interventional therapy

4.6.1 Principles of intervention therapy

4.6.2 Transarterial infusion chemotherapy

4.6.3 Ablation therapy

4.6.4 Interventional therapy for pancreatic cancer complications

4.7 Supportive care

4.7.1 Pain control

4.7.2 Nutritional status improvement

4.8 Traditional Chinese medicine treatment for pancreatic cancer

5. Diagnosis and treatment flowchart and follow-up

5.1 Diagnosis and treatment flowchart for pancreatic cancer

5.2 Follow-up

1. Introduction

Pancreatic ductal adenocarcinoma is one of the common pancreatic neoplasms, with extremely high malignancy.The latest statistical data from National Cancer Center of China showed that the incidence of pancreatic cancer had increased dramatically from 2000 to 2011. In 2015, the incidence of pancreatic cancer in China ranked ninth among malignant tumors, and the mortality rate was the sixth in malignant tumors.

Recently, with the development of radiology, endoscopy and pathology, the diagnosis of pancreatic cancer has been improved; with the development of new concept and technology of surgery (such as laparoscopy and robotics),locoregional therapy methods (such as stereotactic body radiation therapy, nanoknife ablation and radioactive particles implantation), and antitumor drugs [such as gemcitabine (GEM), nano albumin-bound paclitaxel, S-1,capecitabine, irinotecan, oxaliplatin and nimotuzumab],new opportunities and progress have been made for the management of pancreatic cancer.

For the standard treatment of pancreatic cancer in China, this clinical practice guidelines was made. However,not all the clinical scenarios were included.

2. Diagnostic techniques and applications

2.1 Risk factors for pancreatic cancer

The precise etiology for pancreatic cancer has never been elucidated, however, epidemiological investigation showed many risk factors. Nonhereditary factors included longterm smoking, old age, high-fat diet, high body mass index,chronic pancreatitis or concomitant diabetes. About 10%pancreatic cancer was hereditary, and these risk factors included hereditary pancreatitis, Peutz-Jeghers syndrome,familial malignant melanoma syndrome, and so on.CDKN2A, BRCA1/2 and PALB2 mutation have also been proved related to familial pancreatic cancer.

2.2 Clinical manifestations

Pancreatic cancer is a very malignant tumor and progresses rapidly, but its onset is occult and its early symptoms are atypical, and most patients are diagnosed at middle to late stage. The initial symptoms often depend on the location and extent of the tumor, for example, obstructive jaundice may occur in early pancreatic head cancer, however,jaundice generally does not occurred in early pancreatic body and tail tumors. Major clinical manifestations include:

(1) Abdominal discomfort or pain: It’s a common initial symptom. The majority of pancreatic cancer patients only presented with epigastric discomfort or dull pain, blunt pain and flatulence, which was often confused with symptoms of gastrointestinal and hepaticobiliary diseases. If there is an obstruction of pancreatic juice outlet, pain or discomfort may be aggravated after food intaking.Persistent severe abdominal pain may occur in the middle and late stage of tumor when invading the celiac plexus.

(2) Weight loss and fatigue: At the initial stage of the disease, 80%-90% of pancreatic cancer patients would experience wasting, fatigue and weight loss, which was related to lack of appetite, anxiety and tumor-induced debilitation.

(3) Alimentary symptoms: When the tumor blocks the lower portion of the common bile duct and pancreatic duct,bile and pancreatic fluid can not flow into the duodenum,then patients often present with dyspepsia. Impairment of pancreatic exocrine function may lead to diarrhea. When advanced pancreatic cancer invades the duodenum, it could lead to gastrointestinal obstruction or bleeding.

(4) Jaundice: It’s the primary clinical manifestation of pancreatic head cancer, and it’s related to the obstruction of bile duct outlet. It might be accompanied by skin itching, deep brown urine and clay stool.

(5) Other symptoms: Such as persistent or intermittent lowgrade fever and abnormal blood glucose, but generally without biliary tract infection.

2.3 Physical examination

(1) Weight loss: Most patients would experience cachexia at late stage.

(2) Jaundice: It often occurred in pancreatic head cancer,and it’s often caused by the obstruction of bile duct outlet.(3) Hepatomegaly: As a result of cholestasis or liver metastasis, the liver is hard, mostly painless, smooth or nodular.

(4) Enlarged gallbladder: A cystic, smooth and removable gallbladder without tenderness may be touched in some patients, known as Courvoisier sign, which is a characteristic of periampullary carcinoma.

(5) Abdominal lump: The abdominal mass can be touched at the late stage, and it’s mostly located in the upper abdomen, deep, nodular, hard and irremovable.

(6) Other signs: Such as supraclavicular lymph nodes enlargement, ascites, periumbilical nodes, or nodes in Douglas pouch in the late-stage pancreatic cancer patients.

2.4 Radiological examinations

To choose the optimal radiological techniques according to patient’s situation is the prerequisite for the accurate diagnosis of pancreatic lesions. The radiological examination should obey the basic rule which is entire(including the whole pancreas), dedicate (1-2 mm thin slice), dynamic (dynamic enhancement, regular follow-up)and three-dimensional (multiplanar reconstruction, to evaluate the relationship with neighboring tissues). The pre-treatment and post-treatment radiological examination flowcharts were shown in Appendix 1 (Figure A1) and Appendix 2 (Figure A2) in detail.

2.4.1 Ultrosound

It’s simple, noninvasive and nonradioactive, and it’s an important examination methods for pancreatic cancer.

Conventional ultrasound can display the internal structure of pancreas, observe the obstruction of bile duct and the location of obstruction, and find out the cause of obstruction. Color Doppler ultrasound can help to determine whether the tumor has compressed or invaded the surrounding big vessels. Real-time contrast-enhanced ultrasound can reveal the hemodynamic changes of tumors,help to differentiate and diagnose tumors of different properties, and relying on the flexibility of real-time imaging and multi-section imaging, it has advantages in evaluating tumor microvascular perfusion and guiding interventional therapy.

The limitations of ultrasonography include small vision field, and interference by gastrointestinal tract gas and patient body shape, which makes it difficult to observe the pancreas completely, especially the tail of pancreas.

2.4.2 Computed tomography (CT)

With good spatial and temporal resolution, CT is the best noninvasive imaging method for pancreatic cancer, which is mainly used in the diagnosis, differential diagnosis and staging of pancreatic cancer. Plain scan can show the size and location of the lesion, but it cannot accurately diagnose pancreatic lesions and the relationship between the tumor and the surrounding structure is shown poorly. Threephase contrast-enhanced scan can better display the size,location, shape, internal structure and relationship with surrounding structures of the pancreatic tumor, and can accurately judge if there are liver metastases or enlarged lymph nodes. Various post-processing techniques of CT[including multiplanar reconstruction (MPR), maximum intensity projection (MIP), minimum intensity projection(MinP), shaded surface display (SSD), volume rendering technique (VRT)] can accurately provide information of pancreatic cancer itself, and of the relationship between the lesion and dilated pancreatic duct and its surrounding structures. Among them, MIP and MPR are the most commonly used post-processing techniques. In recent years, CT perfusion imaging technique is becoming more and more mature. It can reflect the blood flow and vascular characteristics of tumor quantitatively, in order to distinguish benign and malignant tumor, to evaluate the treatment response of tumor, and to predict the degree of malignancy and prognosis of tumor, etc.

2.4.3 Magnetic resonance imaging (MRI) and magnetic resonance cholangio-pancreatography (MRCP)

MRI is not the first choice for diagnosis of pancreatic cancer. It is a complementary method for CT when it’s difficult to diagnose the pancreatic lesions and it’s also the alternative to CT when the patient is allergic to CT contrast medium. MRCP and multi-phase enhanced scan have advantages in qualitative diagnosis and differential diagnosis of pancreatic cancer. It has been reported that MRI can be used to diagnose occult pancreatic head carcinoma using specific tissue contrast agents. MRI can also be used to monitor pancreatic cancer and predict the recurrence, vascular invasion and the invasiveness of pancreatic cancer, which could be a predictor of survival.MRCP can clearly display the panorama of the pancreaticobiliary system and help to judge the location of the lesion, thus helping to detect and differentiate the tumors around the ampulla. Compared to endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC), MRCP has the advantage of noninvasiveness. In addition, MR functional imaging can quantitatively reflect tumor metabolic information from a microscopic perspective,including diffusion-weighted imaging (DWI), perfusionweighted imaging (PWI) and magnetic resonance spectroscopy (MRS), which should be closely combined with conventional MR sequences to play a greater role in diagnosis, differential diagnosis and treatment response evaluation of pancreatic cancer.

2.4.4 Positron emission tomography-CT (PET-CT)

It could show the tumor metabolic activity and burden. It has obvious advantages in detecting extrapancreatic metastasis and evaluating systemic tumor load. It is not recommended as the routine radiological examination method for the diagnosis of pancreatic cancer and it has little efficacy in the diagnosis of small pancreatic cancer.PET-CT has an advantage in excluding and detecting distant metastatic lesions. It is recommended for patients with large primary lesions, suspected regional lymph node metastasis and significantly increased carbohydrate antigen 19-9 (CA19-9). During the follow-up after treatment of pancreatic cancer, PET-CT could differentiate between postoperative or post-radiotherapy change and local tumor recurrence. PET-CT could also help to diagnose and localize the recurrence and metastases when CA19-9 level is increased, but the conventional imaging was negative.Early monitoring of the response can be achieved by changes in tumor glucose metabolism in patients who are unable to be operated and receive chemoradiation, which could provide evidences for timely changes of treatment plan and adoption of more active treatment methods.

2.4.5 Endoscopic ultrasonography (EUS)

It could be used to improve the sensitivity and specifity of diagnosis of pancreatic cancer, especially the EUS-guided fine needle aspiration (EUS-FNA), which is the most accurate method for the localization and qualitative diagnosis of pancreatic cancer. In addition, EUS is also helpful in tumor staging.

(1) Early diagnosis: EUS is performed by inserting the probe into the stomach and duodenum, which are close to the pancreas. Because the endoscopic probe is close to the pancreas, the probe frequency is high, and the gastrointestinal gas interference is avoided, the sensitivity of the diagnosis of pancreatic diseases is greatly improved.Pancreatic cancer with a diameter less than 1 cm can be detected, which is of great value in the diagnosis of small pancreatic cancer.

(2) TNM staging: EUS can show the size of pancreatic cancer, whether the tumor invades peripheral blood vessels,common bile duct, duodenal wall, liver, or adrenal gland and whether there are metastatic lymph nodes, so it has a higher accuracy of TNM staging. EUS can provide more information than CT and MRI for patients who have highly suspected pancreatic lesions, which have not been found in the first imaging examination. EUS can also provide more information than CT and MRI for surrounding vascular invasion and lymph node metastases,and so it can be an important supplement to CT and MRU.

(3) EUS-guided intervention technology

1) EUS-FNA: EUS-FNA has a high accuracy in the diagnosis of pancreatic cancer and is the first choice for pathological diagnosis of pancreatic tumors. For most pancreatic tumors, EUS-FNA can provide enough tissue for pathological evaluation. It could be used in the following situations:

(a) To acquire the pathological diagnosis before chemoradiation.

(b) To repeat FNA if the first biopsy result was negative.

(c) To differentiate the diagnosis of pancreatic lesions.

(d) To confirm the diagnosis of potential metastases in unresectable patients.

2) Endoscopic ultrasound guided fine needle injection (EUSFNI): It’s a newly developed treatment technique based on EUS-FNA for middle- to late-stage patients, including oncolytic adenovirus injection, photodynamic treatment,radiofrequency ablation, physical treatment (hyperthermic or hypothermic) and radioactive particles implantation.

3) Endoscopic ultrasound guided biliary drainage (EUS-BD):

EUS provides accurate imaging and EUS-BD is less invasive than percutaneous transhepatic biliary drainage.EUS-BD is used in the following situations: routine ERCP failure; gastrointestinal obstruction or abnormality due to surgery (such as Whipple procedure, Billroth-II gastrojejunostomy, hepatojejunostomy and gastric bypass procedure); and congenital abnormality (parapapillary diverticulum).

4) EUS-guided pancreatic duct drainage: It’s used to alleviate abdominal pain induced by pancreatic duct obstruction due to high pressure of pancreatic duct and parenchyma, especially after ERCP failure.

5) For some patients with pancreatic tumors who cannot be surgically resected, it is feasible to block the celiac plexus under the guidance of EUS to relieve the pain and improve the quality of life of the patients.

6) EUS-guided gastrojejunostomy (EUS-GJ): Compared with duodenal stenting, EUS-GJ can prevent repeating duodenal stents due to previous stents being blocked or displaced by tumors. EUS-GJ can effectively alleviate obstruction in the long term by a minimally invasive method. Compared with the previous open gastrojejunostomy, this operation has the advantages of less trauma, shorter operation time, less pain and faster recovery, which fully reflects the advantage of endoscopic minimally invasive surgery.

2.4.6 Role of ERCP in the diagnosis of pancreatic cancer

The most common ERCP manifestations of pancreatic cancer were proximal stenosis and distal dilatation of the main pancreatic duct: stenosis, interruption or displacement of the main pancreatic duct, uneven acinar shadow of the pancreatic parenchyma, retention of the contrast agent, filling defect of pancreatic juice contrast agent or displacement of branch pancreatic duct. Cancer of the head of the pancreas may show dilated double-duct sign when it compresses the main pancreatic duct and the common bile duct. ERCP cannot directly show tumors, it mainly makes the diagnosis of pancreatic cancer depending on the change of pancreatic duct and the morphology of the common bile duct, which has great value for the lower portion of the biliary duct and pancreatic duct obstruction or abnormal changes. In addition, pancreatic cancer also has some special ERCP signs, such as double-duct sign and soft rattan sign, which have specific diagnostic value for pancreatic cancer.

2.4.7 Cytology diagnosis via ERCP

The bile and pancreatic fluid was collected by ERCP intubation into the pancreaticobiliary duct and the cells were brushed or the tissues pinched in the pancreaticobiliary duct. Then the exfoliative cytology of pancreatic juice and bile or the pathological diagnosis was performed.Especially for the patients with obstructive jaundice who can not be operated on, the operation of biliary drainage and pathologic and cytological examinations can be completed simultaneously, which should be the first choice for the patients with obstructive jaundice without surgical indication. However, the sensitivity and specificity of biopsy and cytological brushing under ERCP are not satisfactory, and the effect needs to be further improved.

2.4.8 ERCP combined with intraductal ultrasound (IDUS)

IDUS under ERCP is a technique, which can obtain highresolution pancreaticobiliary duct images. The probe can do 360-degree scanning and can be easily inserted into the bile duct without duodenal papilla incision. IDUS can provide high-resolution images of the whole bile duct and its surrounding tissues in real time, which is superior to EUS in distinguishing benign and malignant bile duct stenosis. It has high sensitivity. When combined with pancreaticobiliary duct biopsy, IDUS can probe the lesion wall and biopsy location more accurately, making tissue acquisition more accurate, so as to improve the sensitivity of diagnosis.

2.4.9 Bone scans

Bone scans is the most widely used, cost-effective, and highly sensitive method for detection of malignant bone metastasis. Preoperative bone scans can be routinely performed in patients with pancreatic cancer who are highly suspected of bone metastasis

2.5 Blood immunologic and biochemical examinations

2.5.1 Blood biochemical examinations

No specific blood biochemical changes are detected at the early stage. Elevated serum ALT, AST, bile acids and bilirubin levels would be detected when pancreatic cancer invades liver and the bile duct is obstructed. At the late stage of the tumor, electrolyte disturbances and hypoalbuminemia may occur with cachexia. In addition, changes in blood glucose are also associated with the onset or progression of pancreatic cancer.

2.5.2 Serum tumor markers tests

The commonly used serum tumor markers clinically are CA19-9, carcinoembryonic antigen (CEA), and CA125, of which CA19-9 is the most common used one for pancreatic diagnosis, treatment response evaluation and recurrence surveillance. However, about 3%-7% of the pancreatic patients do not express CA19-9 for their special Lewis antigen negative blood type. Serum CA19-9 level would be falsely positive when bile duct is obstructed or infected,which can not indicate a tumor or a late-stage disease.Therefore, preoperative detection of CA19-9 levels is best performed after biliary tract decompression and when bilirubin level is normal.

2.6 Histologic and cytological diagnosis

2.6.1 Cytological pathology diagnosis

Cytological diagnosis of pancreatic cancer is composed by sampling techniques, slice preparation techniques and diagnosis reports.

The cell specimen sampling techniques: commonly used sampling techniques include: 1) Image (CT or ultrasound)-guided FNA; 2) EUS-FNA; 3) Intraoperative FNA; and 4)Cell brush of the pancreatic duct and the lower portion of common bile duct by ERCP.

Cell specimen preparation techniques: Cell specimen preparation techniques include routine smears, liquid-based slices and cell-block sections. Conventional smear is the most commonly used method of slice preparation. FNA or brushed cells are directly smeared on the glass, then wet dried and fixed by 95% alcohol. If the cystic fluid is acquired by FNA puncture, the liquid-based method will enrich the cells in the cystic fluid, thus obtaining a more abundant smear than the conventional smear. The main purpose of cell block preparation is to perform immunocytochemical staining. In addition, some small tissue structures can be restored in the slice of cell block, which is helpful for morphological diagnosis.

According to their own conditions and the nature of the lesion, each center chooses different methods of slice preparation, and it can help to improve the accuracy of diagnosis if the three methods are taken at the same time.Some centers can also carry out site assessment of cell samples if possible to improve the rate of sampling satisfaction.

Cytological diagnosis reports: The six-grade report system recommended by American Papanicolaou Society of Cytopathology was taken. In this report system cytopathology diagnosis was divided into the following six grades: Grade I, can not diagnosis; Grade II, no sign of malignancy; Grade III, untypical; Grade IVA, benign neoplasm; Grade IVB, neoplastic lesions, other; Grade V,suspected malignancy; Grade VI, malignancy. The most challenging diagnostic grading is “neoplastic lesions, other(IVB),” in which capsular coated cells of intraductal papillary mucinous neoplasms and mucinous cystic tumor can be mild, moderate, or even severe atypical. Cells with severe atypical changes are difficult to differentiate from adenocarcinoma cells. In addition, the diagnosis of some small round cell tumors, such as solid-pseudopapillary tumor, neuroendocrine tumor and acinar cell carcinoma often need to be detected by cell block immunocytochemistry.Cytological diagnosis details are shown in Appendix 3(Table A1).

2.6.2 Histopathology diagnosis of pancreatic cancer

(1) Pathological diagnosis criteria of pancreatic cancer:

Pancreatic carcinoma is diagnosed by histopathology and/or cytology of the biopsy tissue or resected specimen of the pancreatic lesion or the metastatic lesion.Pathological diagnosis should be combined with clinical evidences, including understanding the clinical manifestations and imaging findings of the patients thoroughly.

(2) Pathological diagnosis guidelines of pancreatic cancer: It is composed by specimen processing, specimen sampling,pathologic examination and pathologic report.

1) Key points of specimen processing

The surgeon should mark the location, type and number of the specimens on the pathological application sheet, and mark the surgical margins and important lesions with dye staining or suture.

The tumor specimen should be delivered completely to the pathology department for incision and fixation within 30 min after resection as far as possible.

Specimen should be fixed with 10% neutral formalin solution for 12-24 h.

2) Specimen sampling and examination

Specimen after pancreaticoduodenectomy: The tumor is opened perpendicular to the common bile duct from the duodenal papilla to the common bile duct with a probe, and the relationship between the tumor and the common bile duct and the duodenal wall is observed. The margins of stomach, pylorus, small intestine, pancreas and common bile duct are taken respectively. As to the tumor mass(including the deepest portion of infiltration and the relationship with surrounding tissues or organs), according to the tumor size, at least one block is taken per 1 cm;According to the color of each surface, areas of different texture should also be sampled.

Specimen after splenectomy and resection of the body and tail of the pancreas: The tumor mass is opened in the form of a leaf, and at least one block per 1 cm is taken according to the tumor size, including the pancreatic capsule, the pancreatic duct, the margin of the pancreas,the surrounding pancreas, the relationship between the pancreas and the spleen, and so on. All lymph nodes are sampled including peripancreatic lymph nodes and splenic hilar lymph nodes. Pancreatic tissues between tumors are required to be sampled if there are multiple tumors.

2.6.3 Immunohistochemistry

Commonly used immunohistochemical markers for differential diagnosis include vimentin, CK, EMA, CEA,CA19-9, CK19, CK7, CK20, MUC1, MUC4, CDX2, PR,CD10, syn, CgA, CD56, ACT, AAT, β-cantenin, and Ki-67. A reasonable combination of immunohistochemical markers should be used for differential diagnosis of pancreatic endocrine tumors and various types of pancreatic cancer.

2.6.4 Pathologic reports

The pathologic diagnosis report of pancreatic cancer is composed by gross specimen description, microscopic description, immunohistochemical staining results,pathologic diagnosis names, invasion areas (especially the relationship between the tumor and the common bile duct,duodenum and spleen. If the portal vein margin is involved,it should be reported), lymphatic and vascular tumor embolus, neural invasion, the invasion of pancreatic capsule, lymph node metastases and TNM staging. The gross specimen description is demonstrated in Appendix 4 and Appendix 5 in detail. In addition, the results of molecular pathology related to drug target detection,biological behavior evaluation and prognosis judgement are attached for clinical reference.

2.7 Differential diagnosis of pancreatic cancer

2.7.1 Chronic pancreatitis

(1) Chronic pancreatitis patients have a long history; serum amylase will increase when acute attack, but these patients seldom have jaundice.

(2) Abdominal CT showed irregular pancreatic contour,nodular bulge and heterogeneous pancreatic parenchyma.

(3) Abdominal plain scan and CT showed calcification in pancreas in patients with chronic pancreatitis.

(4) Elevated serum IgG4 level is the characteristic of autoimmune pancreatitis, which is one special type of chronic pancreatitis. In case of equivocal radiological diagnosis, pathologic biopsy is often needed.

2.7.2 Carcinoma of ampulla

(1) Intermittent jaundice might happen due to tumor necrosis and subsequent remission of bile duct obstruction.(2) Hypotonic duodenography might show “double contour sign” due to duodenal papilla filling defect and mucosal destruction.

(3) Ultrasound, CT, MRI and ERCP might reveal bile duct and pancreatic duct dilation, distant bile duct obstruction,“double duct sign” and ampulla occupation.

(4) Endoscopic ultrasound: As a new diagnostic technique,EUS is of special value to differentiate carcinoma of pancreas from carcinoma of ampulla, for it could catch sight of small lesions and detect the invasion depth and extent and peripheral enlarged lymph nodes, and so on.

2.7.3 Pancreatic cystadenoma and cystadenocarcinoma

Clinically pancreatic cystic neoplasms are rare, and more common in women. Radiologic examinations are important methods to differentiate them from pancreatic cancer, and the tumor marker CA19-9 is often normal. Ultrasound, CT and EUS could show intra-pancreatic cystic lesions with regular cavity, however, cystic degeneration with irregular cavity only happened after central necrosis of pancreatic cancer.

2.7.4 Choledocholithiasis

Patients with choledocholithiasis often have a long disease history of recurrence, and serum bilirubin level fluctuates greatly. Patients with acute cholangitis often experience the triad of abdominal pain, chills and fever and jaundice.

2.7.5 Other lesions of pancreas

They include pancreatic pseudocyst, insulinoma, solid pseudopapillary tumor, and so on. Clinically these lesions often grow slowly, and patients often have a long disease history and specific clinical manifestations, such as insulinoma with paroxysmal hypoglycemic symptoms and pancreatic pseudocyst with acute pancreatitis history. It’s not difficult to differentiate them from pancreatic cancer when combined with radiological examinations such as CT and definite biopsy pathology if necessary.

3. Classification and staging of pancreatic cancer

3.1 Histologic classification of pancreatic cancer

Referring to 2010 World Health Organization (WHO)histologic classification of pancreatic cancer (Appendix 6).

3.2 Staging of pancreatic cancer (AJCC, the 8th edition)

3.2.1 Definition of T, N and M in pancreatic TNM staging

(1) Primary tumor (pT)

pTx: Primary tumor cannot be assessed pT0: No evidence of primary tumor

pTis: Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia,intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.

pT1: The maximum diameter of tumor ≤2 cm

pT1a: The maximum diameter of tumor ≤0.5 cm

pT1b: The maximum diameter of tumor ≤1 cm, ＞0.5 cm

pT1c: The maximum diameter of tumor 1-2 cm

pT2: The maximum diameter of tumor ＞2 cm, ≤4 cm

pT3: The maximum diameter of tumor ＞4 cm

pT4: Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size.(2) Regional lymph nodes (pN)

pNx: Regional lymph nodes cannot be assessed.

pN0: No regional lymph node metastases

pN1: Metastases in one to three regional lymph nodes

pN2: Metastases in four or more regional lymph nodes

(3) Distant metastasis (pM)

pMx: Distant metastasis cannot be assessed.

pM0: No distant metastasis

pM1: Distant metastasis

3.2.2 TNM staging for pancreatic cancer (Table 1)

4. Management of pancreatic cancer

4.1 Principles

Multidisciplinary comprehensive diagnosis and treatment is the treatment basis of pancreatic cancer of any stage.According to physical condition, tumor location, invasion extent and clinical symptoms of different patients, it can be applied as a multi-disciplinary consultation model, and be planned to reasonably use existing diagnostic and therapeutic methods. It could acquire maximum cure and tumor control, reduce complications and improve the quality of life of patients. The management of pancreatic cancer includes surgery, radiotherapy, chemotherapy,intervention therapy and best supportive care. The performance status of patients who are going to receive chemoradiation should be evaluated according to Karnofsky score (Table A2 in Appendix 7) or Eastern Cooperative Oncology Group (ECOG) score (Table A3 in Appendix 8).

Table 1 TNM staging for pancreatic cancer (AJCC, the 8th edition)

4.2 Surgery

4.2.1 Principles of surgery

Surgical resection is the only effective method for patients with pancreatic cancer to get the chance of cure and longterm survival. However, more than 80% of pancreatic cancer patients do not have the chance to receive surgery for late stage diseases. Radical resection (R0) should be carried out as far as possible. The surgical margin is evaluated by “1 mm principle”, which means tumor free resection margin ≥1 mm is R0 resection, and margin＜1 mm is otherwise R1 resection. Before the patients receive treatment, they should complete the necessary radiological examinations, systemic assessment, and the multi-disciplinary consultation, which includes departments of radiological diagnosis, pathology,chemotherapy, radiotherapy and so on.

Evaluation of the tumor before surgical treatment is of great clinical significance. According to radiological manifestations, pancreatic cancer patients could be classified into three categories: resectable, potentially resectable and unresectable. Detailed management principles are made according to these three different categories. The major radiological evaluation criteria of resectability include: whether the tumor has distant metastasis, whether the superior mesenteric vein or portal vein is invaded, whether there is fat space around the celiac artery trunk, hepatic artery, superior mesenteric artery, etc.(Refer to Table A4 in Appendix 9 for detailed information).Standard surgical treatment is the best way to achieve a good prognosis. The following principles should be followed.

(1) Tumor-free principle: including no-touch principle, en bloc resection principle and occlusion of tumor blood supply principle.

(2) Adequate resection range: 1) standard pancreaticoduodenectomy: resection range includes 1/3-1/2 of the distal stomach, the whole common bile duct and gallbladder, resection margin at the left side of superior mesenteric vein/3 cm away from tumor, total duodenum and 15 cm of proximal jejunum. Adequate resection of fascia in front of the pancreas and retropanreatic soft tissue is mandated. Resection of the uncinate, tissue of regional lymphatic drainage area, regional nerve plexus, and loose connective tissue around large vessles is required; 2)standard distal pancreatectomy: Resection area includes the body and tail of pancreas, spleen, splenic artery and vein,regional lymphadenectomy, and sometimes includes the left Gerota fascia and partial mesocolon, but does not include the colon itself; and 3) standard total pancreatectomy: Resecton area includes pancreatic head,neck, body and tail, duodenum and the first part of jejunum, gallbladder and common bile duct, spleen and splenic artery and vein and regional lymphadenectomy, and sometimes includes the antrum and pylorus, the Gerota fascia and partial mesocolon, but does not include the colon itself.

(3) Safe resection margins: The following six margins for pancreaticoduodenectomy should be guaranteed:pancreatic (pancreatic neck) margin, common bile duct(common hepatic duct) margin, stomach margin,duodenum margin, retroperitoneal [which means superior mesenteric artery (SMA) and superior mesenteric artery(SMV) skeletonization] margin and other soft tissue margin(such as retropancreatic margin), of which pancreatic margin should be at least 3 cm away. For adequate margins,intraoperative frozen section of margins is advised.

(4) Lymphadenectomy: More than 15 lymph nodes should be obtained under standard lymph node dissection. For patients who received neoadjuvant therapy, the lymph nodes obtained could be less than 15. Routine extended retroperitoneal lymphadenectomy is not advised. Standard radical pancreatic cancer lymphadenectomy includes:

1) Standard range of lymph node dissection for pancreaticoduodenectomy for carcinoma of the head of pancreas: Suprapyloric and infrapyloric lymph nodes (No.5, 6), lymph nodes in front of common hepatic artery (No.8a), hepatoduodenal ligament lymph nodes (common hepatic duct, common bile duct and cystic duct lymph nodes, No.12b1, 12b2, 12c), lymph nodes on the posterior aspect of the superior and inferior portion of the head of the pancreas (No. 13a-b), lymph nodes on the right side of SMA (No. 14a-b) and lymph nodes on the anterior surface of the superior and inferior portion of the head of the pancreas (No. 17a-b).

2) Standard range of lymph node dissection for resection of carcinoma of body and tail of pancreas: Lymph nodes at the splenic hilum (No. 10), lymph nodes along the proximal and distal splenic artery (No. 11) and lymph nodes along the inferior margin of the pancreas (No. 18) should be resected with the specimen en bloc. Lymph nodes around the celiac artery (No. 9), partial lymph nodes along the superior mesenteric artery (No. 14) and abdominal periaortic lymph nodes (No. 16) are suggested to be resected when the tumor locates in the body of the pancreas.

4.2.2 Preoperative biliary drainage

(1) The aim of preoperative biliary drainage is to decompress the bile duct, to alleviate cholangitis, to ameliorate live function, to correct coagulation abnormality and lower operative mortality. However, the preoperative biliary drainage is not routinely recommended.

(2) It is recommended for patients with severe symptoms,fever, sepsis, and suppurative cholangitis.

(3) Biliary drainage could be accomplished by nasobiliary drainage or percutaneous transhepatic cholangial drainage(PTCD). Cholecystostomy is suggested only in hospitals that do not have the appropriate conditions.

(4) Operation could be performed when the bilirubin level has decreased at least 50%, and the liver function, the temperature and white blood cell (WBC) have become normal after 2 weeks of biliary drainage.

4.2.3 Indications for radical resection

(1) Age ＜75 years old, good performance status.

(2) Pancreatic cancer with clinical stage ≤II.

(3) No liver metastases, no ascites.

(4) It is found that the tumor is confined in the pancreas without portal vein and SMV invasion during intraoperative exploration.

(5) No distant dissemination or metastases.

4.2.4 Operation methods

(1) Pancreaticoduodenectomy for tumors in the head and neck of pancreas.

(2) Distal pancreatectomy plus splenectomy for tumors in the body and tail of pancreas.

(3) Total pancreatectomy for large tumors involved in the head, neck and body of the pancreas.

(4) As to the safety, the number of lymph nodes dissected and R0 resection rate, mini-invasive radical pancreatic cancer resection is comparable to open surgery. However,the oncologic benefit of mini-invasive surgery is undetermined, so it is only recommended to be performed in professional large pancreatic centers by experienced pancreatic surgeons.

4.2.5 Pancreatic anastomosis

The purpose of stump management after pancreatectomy is to prevent pancreatic leakage, and pancreaticojejunostomy is commonly used. A variety of pancreaticojejunostomy methods are now being performed by different surgeons,and the appropriate anastomosis should be taken to reduce the occurrence of pancreatic leakage.

4.2.6 Perioperative drug management

Patients undergoing major open surgery, regardless of their nutritional status, are recommended to take immune nutrition for 5-7 d before operation and to continue it until 7 d after the operation or when the patient could acquire more than 60% of nutrition needs by oral feeding.Immune-enhanced enteral nutrition should contain three substrates: ω-3 polyunsaturated fatty acid, arginine and nucleotides simultaneously. The effect of adding any one or two of the above three kinds of nutrients alone needs further studies. Oral enteral nutrition support is preferred.

Patients with moderate malnutrition who are going to receive major operations or patients with severe malnutrition are recommended to receive nutrition treatment for 1-2 weeks before surgery, even if the surgery is delayed.Patients who are not expected to acquire their nutritional needs through normal diet at least 7 d after operation and those who could not acquire 60% of the nutritional requirement by oral feeding for more than 1 week should be given postoperative nutrition treatment.

4.2.7 Management principles of postoperative complications

(1) Post-pancreatectomy hemorrhage (PPH): Acute PPH occurs in the first 24 h postoperatively, and delayed PPH occurs more than 24 h postoperatively. PPH includes extraluminal and intraluminal hemorrhage. PPH is graded into A, B and C according to International Study Group on Pancreatic Surgery (ISGPS) definition (referring to Table A5 in Appendix 10 for detailed information).

1) Extraluminal hemorrhage: Extraluminal hemorrhage is mainly caused by incomplete intraoperative hemostasis, the false hemostasis of the bleeding point under the condition of intraoperative hypotension, the shedding of the ligature,and the shedding of the electric coagulation scab.Coagulation defect is also the cause of extraluminal hemorrhage. The main prevention methods are strict hemostasis during operation, careful examination before abdominal closure, suture of important blood vessels and correction of coagulation defect before operation. Great attention should be paid to the extraluminal hemorrhage. A small amount of bleeding can be treated with drugs, blood transfusion and other conservative methods. However, a large amount of blood loss in a short time, resulting in hemorrhagic shock, should be operated as soon as possible to stop bleeding.

2) Intraluminal hemorrhage: Stress ulcer often occurs at least 3 d after operation. The prophylaxis of stress ulcer includes nutrition status correction and the reduction of the impact of surgery and anesthesia as far as possible.Stress ulcer is managed mainly by conservative methods,including hemostatic drugs, somatostatin, proton pump inhibitors, gastrointestinal decompression, 8% iced saline with norepinephrine injection via the stomach tube,hemostasis by gastroscopy and angiography embolization.If the conservative methods are invalid, relaparotomy can be considered.

(2) Postoperative pancreatic fistula (PPF): According to 2016 ISGPS criteria, a clinically relevant PPF is now redefined as a drain output of any measurable volume of fluid with an amylase level ＞3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the PPF. Consequently, the former “grade A PPF of 2005 definition” is now redefined and called a “biochemical leak,” because it has no clinical importance and is no longer referred to a true pancreatic fistula. Grade B pancreatic fistula is related to clinical practice and affects the postoperative process, including: continuous drainage for more than 3 weeks; clinical changes in the treatment of pancreatic fistula; percutaneous or endoscopic puncture and drainage; angiographic interventional therapy for hemorrhage; and signs of infection other than organ failure. Once single or multiple organ dysfunction occurs due to pancreatic fistula infection, the grade of pancreatic fistula is adjusted from B to C. The treatment of pancreatic fistula includes proper fasting, effective and adequate drainage, infection control, nutritional support, acid suppression and enzyme suppression. If there is abdominal bleeding, interventional embolization hemostasis could be considered. Surgical treatment is indicated for the pancreatic fistula with severe abdominal infection or massive bleeding.

(3) Delayed gastric emptying (DGE)

1) No consensus definition of DGE has been reached. The commonly used definition is as follows: nasogastric tube output ＞800 mL/d lasting for more than 10 d without gastric outlet obstruction, no water-electrolyte disorders or acid-base imbalance, no underlying diseases inducing gastroparesis, and no medication affecting the contaction of smooth muscles.

2) Diagnosis is made mainly by the disease history,symptoms, signs, alimentary tract contrast examination and gastroscope.

3) Management of DGE: Management of DGE includes adequate gastrointestinal decompression, active nutritional support, psychological suggestion, gastrointestinal prokinetic agents and treatment of underlying diseases and nutritional and metabolic disorders. Traditional Chinese Medicine might be helpful.

(4) Other complications: including abdominal infection,bile leakage, chyle leakage and late postoperative complications.

4.2.8 Surgical management of potentially resectable pancreatic cancer Patients with potentially resectable tumors often achieve low R0 resection rate, and the best treatment strategy has been controversial. Neoadjuvant therapy (chemotherapy, or chemoradiation, or induction chemotherapy followed by concurrent chemoradiation) is advocated for patients who might benefit from it after multidisciplinary discussion to downstage the tumor, and then surgical resection is performed. If R0 resection is accomplished when combined with portal vein/SMV resection for patients who received neoadjuvant therapy followed by tumor resection,comparable survival benefit as primarily resectable patients could be achieved. However, the survival benefit of pancreatic cancer resection combined with arterial resection is controversial, and it still needs to be evaluated by large prospective data. In view of the lack of high-level evidence-based medicine evidences at present, borderline resectable pancreatic cancer (BRPC) patients are recommended to participate in clinical trials. The surgical exploration could be carried on directly on the patient’s request by himself. Palliative R2 resection is not recommended for this group of patients, except for exceptional cases such as operative hemostasis to save lives.

4.2.9 Surgical management of locally advanced unresectable pancreatic cancer

For these patients, active treatment is still possible to obtain good therapeutic effects. For patients whose life expectancy is ≥3 months do not experience duodenal obstruction temporarily, prophylactic gastrojejunostomy could be performed if indicated clinically. Choledochojejunostomy or hepaticojejunostomy could be performed for patients with unresectable tumors and biliary obstruction or expected biliary obstruction. In patients with duodenal obstruction, gastrojejunostomy could be performed if the expected survival time is more than 3 months. Intraopetative radiotherapy and irreversible electroporation(nanoknife ablation) could also be taken to improve local tumor control rate and relieve pain. Patients should receive postoperative chemotherapy ± radiotherapy.

4.3 Medical treatment

4.3.1 Chemotherapy effect for pancreatic cancer

Effect of chemotherapy for pancreatic cancer is limited. In recent years, a large number of clinical studies on medical treatment of pancreatic cancer have been carried out at home and abroad. Chemotherapy could not only prolong the survival of patients, but also relieve the pain and improve quality of life.

(1) GEM-based chemotherapy

1) GEM monotherapy: It was reported on JCO that GEM was used to treat advanced pancreatic cancer in 1997. The clinical benefit rate was 23.3%. The median survival time(mOS) was 5.7 months. The 1-year survival rate was 18%,which was significantly better than that of 5-FU.Nowadays, GEM monotherapy has become the standard chemotherapy regimen for advanced pancreatic cancer.

2) GEM-based combination therapy: In 2013, a phase Ⅲclinical study (MPACT) showed that compared with GEM monotherapy, the median overall survival was significantly prolonged by the combination of albumin bound paclitaxel(Nab-P) with GEM (8.5 months vs. 6.7 months, P＜0.01).GEM combined with Nab-P has become the first choice for advanced pancreatic cancer patients of good performance status.

Recent studies of GEM versus GEM combined with S-1 in the treatment of advanced pancreatic cancer showed that the combination therapy significantly prolonged survival.So the regimen of GEM combined with S-1 was recommended as one of the first-line treatment options.

(2) 5-FU-based chemotherapy

Before 1996, fluorouracil was the first-line treatment for advanced pancreatic cancer. In the combination chemotherapy regimens based on fluorouracil, the PRODIGE study compared the efficacy and safety of FOLFIRINOX (5-FU + calcium folinate + irinotecan +oxaliplatin) regimen with that of GEM monotherapy in the treatment of metastatic pancreatic cancer. The results showed that FOLFIRINOX significantly prolonged the overall survival and progression free survival compared with GEM, however, the toxicity of FOLFIRINOX regimen was greater than that of GEM. So, FOLFIRINOX regimen was recommended for the treatment of locally advanced or advanced pancreatic cancer patients in good physical condition. In 2013, the GEST study conducted in Japan and Taiwan, China explored the first-line therapeutic efficacy of S-1 in advanced pancreatic cancer. The results showed that the efficacy of S-1 was not inferior to that of GEM, and it was well tolerated. S-1 has become one of the standard drugs for advanced pancreatic cancer.

(3) Molecular target therapy

The results of the comparative study of erlotinib combined with GEM and GEM monotherapy showed that the combination therapy had significant survival benefits compared with GEM, however, the survival benefit was very limited.

4.3.2 Chemotherapy strategies for pancreatic cancer

Chemotherapy strategies mainly include postoperative adjuvant chemotherapy, neoadjuvant chemotherapy,palliative chemotherapy for patients with locally advanced disease or with distant metastasis.(1) Resectable pancreatic cancer After radical resection, all the pancreatic cancer patients should be treated with adjuvant chemotherapy. GEM or fluorouracil monotherapy is recommended as the adjuvant chemotherapy regimen. Combination chemotherapy is recommended for patients with good physical fitness. The commonly used regimens are shown in Table 2. For patients with fast recovery of physical condition after operation, the initiation of adjuvant chemotherapy could be as early as possible within 8 weeks after operation, and the course of treatment would be 6 cycles or more.

Neoadjuvant chemotherapy is recommended for resectable pancreatic cancer patients with high-risk factors,such as: 1) High serum CA19-9 level; 2) Large primary pancreatic tumor; 3) Extensive lymph node metastases; and 4) Severe weight loss and extreme pain. Patients with resectable pancreatic cancer undergoing radical operation after neoadjuvant chemotherapy without evidence of recurrence or metastasis are advised to continue adjuvantchemotherapy after multidisciplinary team (MDT)evaluation. For the adjuvant chemotherapy regimen, it is recommended to refer to the response of neoadjuvant chemotherapy or the results of clinical researches.

Table 2 Commonly used regimens and detailed protocols of adjuvant chemotherapy for pancreatic cancer after radical resection

(2) BRPC

Treatment strategies for patients with BRPC are not supported by large-scale clinical studies, so it is recommended that clinical studies be carried out. It is recommended that preoperative neoadjuvant therapy should be carried out in BRPC patients with good performance status, and that additional adjuvant chemotherapy should be decided after MDT evaluation.For the adjuvant chemotherapy regimen, it is recommended to refer to the response of neoadjuvant chemotherapy or the results of clinical researches. The commonly used protocols are detailed in Table 3.

(3) Unresectable locally advanced or distant metastatic pancreatic cancer

1) First-line medical treatment

The treatment effect for unresectable locally advanced or distant metastatic pancreatic cancer is unsatisfactory generally. It is recommended that clinical studies be carried out. It is recommended that the first-line chemotherapy regimens for unresectable locally advanced or distant metastatic pancreatic cancer patients should be chosen based on physical fitness (Table 4).2) Second-line treatment

Patients who experienced disease progression after firstline chemotherapy could choose non-overlapping drugs as second-line chemotherapy regimens based on used drugs,patient’s comorbidity and side effects. If GEM is used in the first-line chemotherapy, 5-FU + calcium folinate +liposome irinotecan (not listed in China), FOLFIRI,FOLFIRINOX, FOLFOX, CapOX, capecitabine monotherapy and pembrolizumab (limited to microsatellite instablility patients, not listed in China) could be chosen in the second-line treatment.

Whether the patients with pancreatic cancer should continue chemotherapy after the failure of the first- and second-line chemotherapy is still controversial, and there is no definite chemotherapy regimen. It is suggested that clinical research be carried out. The WHO criteria and RECIST criteria (refer to Appendix 11 and Appendix 12 in detail) could be adopted to evaluate the chemotherapy response.

4.4 Radiotherapy

Radiotherapy is important for pancreatic cancer throughout the whole stages. Resectable localized pancreatic cancer patients, who are intolerant of or reject surgery, are advised to take radical precision radiotherapy, which is a new option to provide long-term survival for this group of patients. Borderline resectable patients can receive highdose radiotherapy or chemoradiation directly, and resectability is then evaluated according to the treatment response. Chemoradiation is the first choice in the treatment for locally advanced pancreatic cancer. For pancreatic cancer patients with oligometastasis (limited number of metastatic foci and limited organs), irradiation of the primary tumor and metastases can be used to relieve obstruction, compression or pain and improve local control of tumors. The role of postoperative radiotherapy for pancreatic cancer is still controversial. For pancreatic cancer patients with local residual disease or positive margin, postoperative concurrent chemoradiation can make up for the inadequacy of the operation. Intensitymodulated radiotherapy (IMRT) such as volume rotation intensity modulated radiotherapy (VMAT) and spiral tomography intensity modulated radiotherapy (TOMO)and stereotactic radiotherapy (SBRT) based on multi-line beams (X-ray or γ -ray) focusing are increasingly used in the treatment of pancreatic cancer. The dose pattern of radiotherapy has gradually changed to high-dose and lowfractionation (large fraction radiotherapy) pattern, and local control rate, pain relief rate and survival rate have been improved.

Table 3 Commonly used regimens and detailed protocols of neoadjuvant chemotherapy for pancreatic cancer

4.4.1 Indications for pancreatic cancer radiotherapy

(1) Resectable pancreatic cancer

For resectable pancreatic cancer patients who refuse surgical treatment or are unable to tolerate surgical treatment for medical reasons, it is recommended to receive high-dose, low-fractionation radiotherapy or SBRT.

Table 4 First-line chemotherapy regimens for unresectable locally advanced or distant metastatic pancreatic patients

(2) BRPC

Patients with BRPC can be treated with high-dose, lowfractionation radiotherapy or SBRT directly to improve R0 resection rate, which is helpful to improve survival of patients.

(3) Locally advanced pancreatic cancer

In the case of locally advanced pancreatic cancer, it is recommended to receive high-dose, low-fractionation IMRT or SBRT combined with chemotherapy, which could result in better prognosis than conventional radiotherapy could.

(4) Oligometastatic pancreatic cancer

For metastatic pancreatic cancer patients with good systemic therapy response or relatively slow tumor progression, both the primary and metastatic tumors could be treated with high-dose radiotherapy, and the local control rate could be transformed into survival prolongation.

(5) Recurrent pancreatic cancer

For recurrent pancreatic cancer patients after resection or other local treatments such as radiofrequency ablation, the risk of radiotherapy is higher than that of primary treatment patients, because of previous treatment injury and gastrointestinal diversion, which is not conducive to development.

(6) Postoperative adjuvant radiotherapy

Postoperative adjuvant radiotherapy is controversial and lacks high-level evidence-based medicine evidences.Compared with chemotherapy alone, conventional radiotherapy combined with chemotherapy can reduce the local recurrence rate.

4.4.2 Radiotherapy techniques

SBRT and IMRT techniques, including VMAT and TOMO, have better dose distribution conformability and focus than three-dimensional conformal radiotherapy does.Combined with the simultaneous integrated boost dose mode in target or target area, the irradiation dose of pancreatic tumor could be increased without increasing the radiation dose of normal tissues. It is very important to carry out accurate radiotherapy for pancreatic cancer, to refine all aspects of radiotherapy, to improve the accuracy of target drawing, and to reduce the error of positioning and the disturbance of respiratory movement and other factors.

4.4.3 Radiotherapy target area

For unresected lesions, it is recommended to irradiate the primary pancreatic tumor or the recurrent lesion and metastatic lymph nodes, but excluding the regional lymph node drainage area.

The volume of the target area for postoperative radiotherapy should be determined based on the preoperative CT scan or the silver clip placed during the operation, and should include the primary tumor bed and the regional high-risk lymph node area.

4.4.4 Radiotherapy dose

Increasing the dose of radiotherapy is one of the key factors to improve the local control rate of pancreatic cancer. The dose mode should be determined according to the equipment technology. The dose of 40-70 Gy/5-20 f can be selected, and the higher the biological effective dose(BED) is, the higher the local control rate is. The premise is to ensure that gastrointestinal radiation injury is avoided or reduced. The common total dose is 45-54 Gy, and the single dose is 1.8-2.0 Gy.

4.4.5 Concurrent chemotherapy

GEM or fluorouracil (5-FU continuous intravenous infusion, or capecitabine, or S-1) monotherapy or GEM or fluorouracil based multidrug regimens, are preferred for concurrent chemotherapy.

4.4.6 Intraoperative radiotherapy

Intraoperative radiotherapy is usually performed as planned or when the tumor is found unresectable during laparotomy or if the margin of the tumor is close or positive during the operation. It is suggested that the intraoperative electron irradiation dose should be 15-20 Gy, and the external beam radiotherapy (within 1 month after operation) should be supplemented with 30 Gy/10 f or 40 Gy/20 f.

4.5 ERCP and related treatment

Diagnostic ERCP is not recommended as the first choice for the diagnosis of pancreaticobiliary diseases, however, it is more commonly used in the diagnosis by cholangiopancreatography in the course of therapeutic ERCP. The flowchart of ERCP diagnosis and treatment for pancreatic cancer is shown in Appendix 13 (Figure A3).

4.5.1 ERCP for preoperative biliary drainage in pancreatic cancer

Cholestasis caused by the bile duct stricture due to the pancreatic cancer compression can theoretically increase the morbidity after operation and lead to high mortality and disability rate. Preoperative biliary drainage can also improve the synthetic function of liver, improve the clearance of endogenous toxins and ameliorate the mucosal function of digestive tract, thus contributing to the safe operation. However, preoperative biliary drainage in patients with resectable pancreatic cancer should be carefully considered. The results of randomized controlled trials have shown that, within the range of acceptable jaundice (serum bilirubin ≤250 μmol/L), the postoperative effect of the direct operation group was better than that of the preoperative biliary stent group. Therefore, preoperative biliary drainage should be strictly indicated. The indications of preoperative biliary drainage include:

(1) Patients with fever, septicemia, obvious cholangitis and other symptoms that should be improved before operation;(2) Patients with severe symptoms, itching and suppurative cholangitis; (3) Patients whose operations were delayed due to various reasons; and (4) Patients who should receive preoperative chemoradiation.

Nasobiliary drainage tubes, or removable biliary stents are preferred for biliary drainage; however, non-removable bare metal stents should be avoided.

4.5.2 Application of ERCP in unresectable pancreatic cancer

Primarily, more than 80% of pancreatic cancer patients are not indicated to undergo radical surgery because of local invasion or distant metastasis, so palliative treatment of pancreatic cancer patients is especially important, and its goal is to alleviate symptoms and improve the quality of life. Seventy percent to 80% of patients with advanced pancreatic cancer would experience biliary obstruction, so the main purpose of palliative treatment for these patients is to decompress the bile duct. Compared with PTCD,although endoscopic bile duct drainage has the risk of intubation failure and pancreatitis, the chance of successful drainage is greater, the location of stent is more accurate,and the risk of bleeding and bile leakage is less than that of percutaneous transhepatic bile duct drainage. The overall morbidity is lower than that of PTCD. In general, ERCP is recommended as the first choice for palliative biliary drainage. PTCD is only considered when ERCP is not available, or when the operation fails or when the endoscopic treatment is ineffective. Based on the analysis of efficacy and cost-effectiveness, the plastic biliary stents are recommended for patients whose life expectancy is less than 3 months, and metallic biliary stents for those whose life expectancy are at least 3 months. The nasobiliary drainage tube may be used if necessary before stent implantation.

4.6 Interventional therapy

The interventional therapy of pancreatic cancer mainly includes: interventional therapy for pancreatic cancer and pancreatic cancer metastasis and the treatment of pancreatic cancer related complications. The main treatment methods include transarterial infusion chemotherapy, ablation therapy, PTCD, biliary stent implantation, intestinal stent implantation, and embolization for hemorrhage.

4.6.1 Principles of intervention therapy

(1) The digital subtraction angiography machine is the prerequisite. Indications and contraindications of intervention therapy should be strictly applied, and standardization and individualized treatment should be emphasized.

(2) Interventional therapy mainly applies to the following situations:

1) Locally advanced unresectable pancreatic cancer evaluated by radiological examinations; 2) Unresectable pancreatic cancer for other reasons; 3) The infusion chemotherapy as a special form of neoadjuvant chemotherapy for pancreatic cancer; 4) Postoperative prophylactic infusion chemotherapy or adjuvant chemotherapy; 5)Pancreatic cancer with hepatic metastasis; and 6) Control of pancreatic cancer complications, such as pain,hemorrhage, digestive tract obstruction and obstructive jaundice.

4.6.2 Transarterial infusion chemotherapy

(1) Infusion chemotherapy for pancreatic cancer: When the catheter is placed selectively in the celiac artery and the superior mesenteric artery, arteriography is then performed. If the tumor blood supply vessels are identified,the location, size, number and supply artery of the tumor are determined, then transarterial infusion chemotherapy is performed after the catheter is superselectively inserted into the tumor supply vessels. If there is no clear tumor blood supply artery, the target vessel should be determined according to the tumor location, invasion area and blood supply showed by radiological examinations. In principle,the tumors of the head and neck of the pancreas are infused via the gastroduodenal artery, and the tumors of the body and tail of the pancreas are mostly infused via the celiac artery, superior mesenteric artery or splenic artery.

(2) Infusional chemoembolization for hepatic metastasis of pancreatic cancer: If the pancreatic cancer patient is accompanied with liver metastasis, he/she should be treated with hepatic artery infusion chemotherapy or/and embolization at the same time.

(3) Drugs commonly used for infusion chemotherapy:Commonly used drugs include GEM, fluorouracil,adriamycin (epirubicin), platinum (cisplatin and new chemotherapeutic agents such as lobaplatin), and these drugs could be used alone or in combination. The dosage is determined according to the body surface area, liver and kidney function and routine blood test results of the patients.

4.6.3 Ablation therapy

The operator must undergo strict training and has sufficient practice accumulation. Before treatment, the patient’s general condition, tumor status (size, location,number, etc.) should be comprehensively evaluated, and the relationship between the tumor and adjacent organs should be noted. Finally, the appropriate puncture pathway and ablation range should be planned. The selection of appropriate imaging guidance techniques (ultrasound, CT or MRI) and ablation techniques (e.g. irreversible electroporation) is emphasized.

The range of ablation should include at least 5 mm paracancerous tissue in order to completely necrotize the tumor. It is suggested that the ablation area should be expanded appropriately for the tumors with unclear boundary and irregular shape when the condition of adjacent tissues and structures allows.

4.6.4 Interventional therapy for pancreatic cancer complications

(1) Interventional therapy for jaundice: 65%-75% of pancreatic cancer patients are accompanied with biliary obstruction. Percutaneous transhepatic biliary stent and PTCD could effectively reduce bilirubin levels, alleviate itching and other symptoms and prevent other complications such as cholecystitis, which provide opportunities for surgery and chemotherapy.

(2) Interventional therapy for the digestive tract obstruction: 5%-10% of the pancreatic cancer patients will have gastrointestinal obstruction symptoms such as the gastric outlet obstruction and the duodenal obstruction.The digestive tract stent implantation can relieve early satiety, nausea, postprandial vomiting, weight loss and other discomfort, and improve the quality of life of the patients.

(3) Interventional therapy for hemorrhage: For patients with bleeding of the pancreatic tumor or the metastatic tumors or with postoperative hemorrhage, if the conservative treatment is ineffective, embolization could be considered. The location of bleeding is determined by interventional angiography, and then embolization of bleeding vessels could be performed to stop bleeding.

4.7 Supportive care

The purpose of the supportive care is to prevent or alleviate the pain and improve the quality of life.

4.7.1 Pain control

The pain due to tumor invasion is a major symptom in most patients with pancreatic cancer. The main causes of pancreatic cancer pain include direct infiltration of pancreatic cancer to the peripheral nerves, inflammation of nerves around pancreas, increase of capsule tension caused by pancreatic mass and increase of pancreatic duct pressure caused by pancreatic head mass. The pain treatment is based on the analgesics, and it often requires the combination of surgery, intervention, nerve block,chemotherapy, radiotherapy, and psychology to choose the best pain control method. First of all, it is necessary to identify the reason of pain, and surgical treatment is often needed for non-cancerous pain caused by emergency situations such as the digestive tract obstruction or perforation. Analgesic therapy should follow the WHO“three step analgesic ladder” principle. Patients with mild pain could take indomethacin, paracetamol, aspirin and other non-opioid drugs. Patients with moderate pain could be treated with weak opioid drugs such as codeine, and acetaminophen/codeine and ibuprofen/codeine are commonly used 3-4 times per day. Severe pain should be treated with oral morphine in time. It is necessary to determine the degree of cancer pain, according to which patients are prescribed adequate oral opioid painkillers on time. Intramuscular injection of pethidine only should be avoided. The adverse effects of oral analgesics such as nausea, vomiting, constipation, dizziness and headache should be taken into care.

4.7.2 Nutritional status improvement

Routine nutrition screening and evaluation is necessary for pancreatic cancer patients, if there is a nutritional risk or malnutrition, active nutritional support should be given to prevent or delay the development of cancer cachexia. It is suggested that the total calories of 25-30 kcal/kg and protein of 1.2-1.5 g/kg should be supplied and adjusted according to the changes of nutritional and metabolic status of patients. If there are complications, the calories can be increased to 30-35 kcal/kg. Common nutritional support methods include nutrition education, enteral nutrition, and parenteral nutrition. It is recommended to follow the principle of “five steps for malnutrition” for nutritional support. Patients with anorexia or dyspepsia could take medroxyprogesterone or medroxyprogesterone with trypsin tablets to improve appetite and promote digestion.

4.8 Traditional Chinese medicine treatment for pancreatic cancer

Traditional Chinese medicine can promote the recovery of body function after pancreatic cancer surgery, reduce the toxic reactions of radiotherapy, chemotherapy and targeted therapy, relieve the symptoms of patients, improve the quality of life of patients, and may prolong the survival. As one of the important treatment methods for pancreatic cancer, it can be used alone or in combination with other anti-tumor drugs.

China Food and Drug Administration has approved a variety of modern traditional Chinese medicine preparations for the treatment of pancreatic cancer.However, these drugs have been on the market for many years. Early experimental and clinical studies are relatively weak, and there is still a lack of high-level evidences to fully support them. It needs to be actively studied in depth.

In addition to these listed proprietary traditional Chinese drugs, abiding by the principle of dialectical treatment of traditional Chinese medicine, the traditional Chinese medicine compound treatment is one of the most commonly used methods. It might reduce tumor-related complications, improve the quality of life and prolong the survival of patients.

5. Diagnosis and treatment flowchart and follow-up

5.1 Diagnosis and treatment flowchart for pancreatic cancer

Refer to Figure A4 in Appendix 14 for detailed information.

5.2 Follow-up

The main purpose of follow-up is to find metastasis and recurrence, which can be potentially treated radically, and to find tumor recurrence or the second primary cancer as early as possible, and then to manage them in time to improve the overall survival and the quality of life of the patients. It is recommended that the patients who underwent pancreatic cancer resection should be followed up once every 3 months in the first year, once every 3-6 months in the 2nd and 3rd year, and once every 6 months thereafter. The examination items during follow-up include routine blood test, biochemical test, serum tumor markers such as CA19-9, CA125, and CEA, ultrasound, X-ray, thin slice chest CT scan, upper abdominal contrast enhanced CT and so on. The follow-up period is at least 5 years.Liver MRI or bone scan is suggested to be performed for patients suspected of liver metastasis or bone metastasis.Patients with advanced disease or distant metastasis should be followed up at least once every 2-3 months. The examination items during follow-up include routine blood test, biochemical test, serum tumor markers such as CA19-9, CA125, and CEA, chest CT, upper abdominal contrast enhanced CT and PET-CT if necessary. The aim of follow-up is to evaluate the nutritional status and tumor progression of patients and then to adjust the comprehensive treatment regimen in time.