National guidelines for diagnosis and treatment of esophageal carcinoma 2022 in China (English version)

National Health Commission of the People’s Republic of China

Contents

1.Overview

2.Guidelines for diagnosis of esophageal cancer

2.1 Signs and symptoms

2.1.1 Clinical symptoms

2.1.2 Signs

2.2 Examinations

2.2.1 Imaging

2.2.2 Endoscopy

2.2.3 Other tests

2.3 Clinical diagnosis

2.4 Screening of high-risk group of esophageal cancer

2.5 Classification and staging of esophageal cancer

2.5.1 Segment of esophagus

2.5.2 Definition of esophagogastric junction (EGJ)

2.5.3 Endoscopic classification of superficial esophageal cancer and precancerous lesions

2.5.4 Classification of advanced esophageal cancer

2.5.5 Histological subtypes of esophageal cancer

2.5.6 International staging of esophageal carcinoma

2.5.7 UICC/AJCC regional lymph node stations (the 8th edition TNM staging system for esophageal cancer)

2.5.8 Japan esophageal society (JES) regional lymph node stations (the 11th edition staging system for esophageal cancer)

2.6 Nutritional assessment on patients with esophageal cancer

2.6.1 Nutritional risk screening

2.6.2 Nutritional assessment

3.Guidelines for treatment of esophageal cancer

3.1 Surgery

3.1.1 Principle of surgery

3.1.2 Guidelines for follow-up after surgery

3.2 Radiotherapy

3.2.1 Guidelines for radiotherapy

3.2.2 Dose

3.2.3 Normal tissue tolerance dose

3.2.4 Concurrent chemotherapy regimens and dosing

3.2.5 Assessment and follow-up after radiotherapy

3.3 Systemic therapy

3.3.1 Neoadjuvant chemotherapy

3.3.2 Adjuvant chemotherapy

3.3.3 Systemic therapy for recurrent/metastasized esophageal cancer

3.3.4 Assessment before systemic therapy

3.3.5 Regimens and dosing of systemic therapy

3.3.6 Prophylaxis and treatment of chemotherapy-associated complications

3.3.7 Follow-up after systemic therapy

3.4 Endoscopic therapy

3.4.1 Preoperative assessment of endoscopic treatment on early esophageal cancer

3.4.2 Principle of endoscopic therapy for early-stage esophageal carcinoma

3.4.3 Methods of endoscopic mucosal dissection

3.4.4 Complications and treatment of endoscopic therapy

3.4.5 Endoscopic treatment other than mucosal resection

3.4.6 Follow-up after endoscopic therapy

3.5 Pathological assessment

3.5.1 Source and fixation of specimens

3.5.2 Tissue dissection and gross description

3.5.3 Specimens from EMR/ESD

3.5.4 Specimens guidelines for radical resection

3.5.5 Pathological report

3.6 Comprehensive treatment model by stage

3.6.1 Stage 0/precancerous lesions

3.6.2 Stage I

3.6.3 Stage II

3.6.4 Stage III

3.6.5 Stage IVa,squamous cell carcinoma or adenocarcinoma

3.6.6 Stage IVb

3.7 Flowchart of treatment

3.8 Nutritional support

3.8.1 Indications for nutritional support

3.8.2 Requirements and pathways of nutritional support

3.8.3 Family nutrition support after discharge

3.9 Palliative therapy

3.9.1 Dysphagia

3.9.2 Complete obstruction

3.9.3 Upper gastrointestinal hemorrhage

1.Overview

Esophageal carcinoma is one of the most common malignant tumors worldwide.The Global Cancer Statistics 2020 estimated that there are 604,000 new cases and 544,000 cancer death of esophageal carcinoma globally.Despite the downtrend of its incidence and mortality in China,esophageal cancer is still one of the most threatening malignant tumors.According to the estimation of the prevalence of malignant tumors in China in 2015,the new cases of esophageal cancer in China were 246,000,with a crude incidence rate of 17.8/100,000,including 12.6/100,000 in the urban population and 24.6/100,000 in rural population while the crude death rate is 13.7/100,000 nationwide,including 10.0/100,000 in urban population and 18.4/100,000 in rural population.The incidence and death rate of esophageal cancer in China rank the 6th and the 4th in all malignancies,respectively. Significant regional differences were revealed in the incidence of esophageal cancer.High-prevalence areas are mainly located around the Taihang Mountain (e.g.provinces such as Henan,Hebei,Shanxi,and some areas of Shandong province such as Taian,Jining and Heze),Anhui province,the north of Jiangsu province,the south of Fujian province,Nanchong and Yanting of Sichuan province,and Shantou of Guangdong province.The incidence of esophageal cancer in China is more common in males and the rural population.Nevertheless,the incidence,especially for females,has been dropping since 2000.Squamous cell carcinoma is the most common histological type of esophageal cancer in China,and its incidence closely correlates with diet and lifestyle,such as long time very hot food and tea intake,smoking and alcohol.In addition,factors like certain mold/fungi contaminated food,charcoal or smoked food,water,soil constituent or environmental microbe may also contribute to the incidence of esophageal squamous cell carcinoma.

The advocation of a healthy lifestyle and dietary habits helps prevent the incidence of esophageal cancer.Screening for individuals with high-risk factors is essential to improve the early detection of esophageal cancer.The implementation of the strategy of early diagnosis and treatment on esophageal cancer by medical institutions at all levels helps improve the long-term survival and life quality of patients,while the standardized and multidiscipline diagnosis and treatment will further improve the prognosis of patients with locally advanced or late-stage esophageal cancer.The burden caused by esophageal cancer in our country will be fundamentally reduced only when the above medical measures are successfully implemented.Therefore,the development and implementation of guidelines for the diagnosis and treatment of esophageal cancer is necessary and requires the highest attention of medical practitioners of all specialties.

2.Guidelines for diagnosis of esophageal cancer

2.1 Signs and symptoms

2.1.1 Clinical symptoms

Typical symptoms of esophageal cancer include progressive dysphagia (difficulty in swallowing),sensation of foreign body,burning,food stagnation or feeling of fullness,with or without retrosternal pain,regurgitation,heartburn or ructus. The initial symptom usually presents with dysphagia when swallowing solid food. With the deterioration of symptoms,the patient may intake only semiliquid or liquid food,with or without regurgitation of chyme or mucus shortly after eating,yellow purulent sputum,fever,chest distress,dyspnea,vomiting,hematemesis,melena,chest/back pain,hoarseness or choking on drinking water.After several months with an increased risk of malnutrition due to dysphagia,the patient may present with emaciation,fatigue,weakness,hypodynamia and so on.

2.1.2 Signs

Patients with early-stage esophageal cancer usually have no specific signs.In the mid-to late-stage esophageal cancer,cervical or supraclavicular lymph node lesions are signs of lymph node metastasis; jaundice,hepatomegaly or hepatalgia indicates liver metastasis;restricted thoracic breathing,shallow and rapid respiration,full intercostal space,displacement of trachea to the unaffected side,weakening or disappearance of vocal fremitus suggests possible malignant pleural effusion;Increased tension of abdominal wall,weakened abdominal breathing,or moving dullness on percussion suggests malignant ascites and peritoneal metastasis; recent significant weight loss,thinning of skinfold thickness and scaphoid abdomen are signs of malnutrition or cachexia.

2.2 Examinations

2.2.1 Imaging

(1) Computed tomography (CT)

CT with intravenous and oral contrast enhancement is recommended.For thoracic esophageal cancer,a routine CT scan including the neck,chest and abdomen is recommended,while for esophagogastric junction carcinoma,the pelvic cavity should also be involved if necessary.CT with or without contrast and multidimension reconstructed images is utilized to assess the tumor location,depth of invasion and the relationship between the esophageal lesion and the surrounding structures,as well as the detection of regional lymph nodes or distant metastasis and the surrounding blood vessel invasion.If the contrast agent is contraindicated,(cervical)thoracic/upper abdominal CT without contrast,or cervical and abdominal ultrasound is recommended.

(2) Upper gastrointestinal series

Upper gastrointestinal series is used to evaluate the status of the primary tumor.It directly demonstrates the location and the size of the lesion.However,it is not accurate in the diagnosis of tumor invasion and cannot assess local lymph node metastasis.According to the operation guidelines,films should be acquired with at least 3 positions:anteroposterior,left anterior oblique and right anterior oblique positions.The fields should involve at least from the hypopharynx to the gastric pylorus.

(3) Magnetic resonance imaging (MRI)

MRI provides valuable complementary information on conditions that CT cannot determine,for example,the relationship between the primary esophageal lesion and trachea,bronchus or adventitia of the aorta.In addition,MRI is also of clinical value on the diagnosis of distant metastasis to the liver,brain,bones,etc.The utilization of MRI depends on the judgment of the doctor,however,for patients with metal implants or claustrophobia syndrome,MRI should be used with caution or is contraindicated.

(4)Positronemissiontomography-computed tomography (PET-CT)

PET-CT is utilized to assist diagnosis,staging before and after treatment,response evaluation,as well as important clinical decisions.A general PET-CT includes at least basis cranii and groin.The blood glucose needs to be controlled below 11.1 mmol/L (200 mg/dL) for patients with diabetes mellitus before the examination to avoid interfering with the quality of the image.We recommend repeating PETCT with the same scanner in the same medical center for re-staging after neoadjuvant therapy.The difference of18Ffluorodeoxyglucose (18F-FDG) dose should be within 20%of the radio activity,and the difference in resting time after the injection of tracer should be within 15 min.For pregnant females,the pros and cons of this test should be weighed for clinical decision-making against risks of fetal development.Lactating mothers should stop breastfeeding for more than 12 h after injection of18F-FDG.Claustrophobia is a relative contraindication.At present,there is no consensus on the threshold of the maximum standard uptake value in the diagnosis and efficacy evaluation.Therefore,the results of PET-CT should be interpreted in combination with the experience of the physician.

(5) Ultrasound

Ultrasound refers to the routine ultrasonography on the surface of the body.It is mainly utilized on evaluation of bilateral cervical/supraclavicular lymph nodes (N staging)and liver metastasis (M staging).Ultrasound guided percutaneous biopsy on suspected lesions can further help pathological diagnosis.The accuracy of above descripted cervical and abdominal/pelvic ultrasound staging examinations is correlated with the experience of the diagnostician,and is recommended for the high-volume medical centers.Furthermore,the ultrasonography can also detect and locate pleural effusion or ascites for patients with late-stage esophageal cancer.

2.2.2 Endoscopy

(1)Regular fiberoptic endoscopy

It is one of the necessary examinations for the clinical diagnosis of esophageal cancer which helps the gross classification of the primary lesions and biopsy for pathological diagnosis.Detailed endoscopic classification is presented in chapter of classification of esophageal carcinoma. For patients with complete or partial esophageal obstruction,the esophageal endoscope may not pass through to provide information on the tumor involvement of the distal part. Thus the upper gastrointestinal series or chest CT/MRI/PET-CT should also be taken into account for evaluation.

(2) Chromoendoscopy

The combination of narrow band imaging (NBI) and magnifying endoscopy may help differentiation of lesions from normal mucosa and assessment of tumor invasion by observation of esophageal intrapapillary capillary loops(IPCL) and microstructure of the mucosa.By directly observing the morphology of mucosal surface,the magnifying endoscopy can further differentiate benign and malignant lesions and infiltration depth of esophageal lesions according to the classification of IPCL.The confocal laser endomicroscopy (CLE) can magnify the tissue for 1,000 times to demonstrate the cellular and subcellular structures microcosmically,so as to achieve “optical biopsy” by histologically distinguishing lesions from nonlesions areas without real biopsy.The above special endoscopic techniques could be considered for medical centers with corresponding equipment.

(3) Endoscopic ultrasound (EUS)

EUS is important for staging because its capability of detecting the degree of invasion of the primary esophageal lesions.Moreover,EUS can be used to evaluate the status of lymph nodes surrounding the esophagus and celiac trunk.The EUS-guided fine-needle aspiration (EUS-FNA)can be utilized to achieve pathological diagnosis to confirm the N stage.EUS is contraindicated for patients with esophageal stricture that EUS cannot pass,or with suspected perforation.The application of EUS is also influenced by the experience of endoscopic doctors,and can be selected by the high-volume centers.

2.2.3 Other tests

(1) Currently,there are no specific tumor markers for diagnosis of esophageal cancer.Some tumor markers,like circulating tumor cells,circulating tumor DNA/RNA,epigenetic markers (DNA methylation,noncoding RNA,histone modifications,etc.),exosomes are still under development in laboratories or in pre-clinical researches.The tumor markers are not recommended for routine clinical practice unless for clinical trials.

(2) For patients with upper/middle esophageal cancer,when the image tests suspect trachea/bronchial membrane invasion,further bronchoscopy/endobronchial ultrasound(EBUS) is recommended.

(3) For patients with suspected enlarged lymph node surrounding trachea/bronchus,endobronchial ultrasoundguided transbronchial needle aspiration (EBUS-TBNA) is recommended for pathological diagnosis.

(4) Invasive tests under general anesthesia such as mediastinoscopy/video-assisted thoracic surgery/laparoscopic lymph node biopsy can be performed in highly selective patients after multidisciplinary discussion to assist in diagnosis and treatment decision.

2.3 Clinical diagnosis

Pathological diagnosis (golden standard) needs endoscopic biopsy.If the endoscopy is contraindicated,or pathological diagnosis cannot be established after repeated biopsy attempts,the upper gastrointestinal series,(cervical) chest(abdominal) CT with contrast,whole-body PET-CT or EUS/EBUS-guided needle biopsy should be all combined to assist diagnosis.For lymph node or distant metastasis suspected by imaging examinations,doctors should choose reasonable method of biopsy based on the comprehensive evaluation of medical conditions and operation risks.

The clinical staging tests should include (cervical)chest/abdominal (pelvic) CT with contrast,and if available,imaging examinations including ultrasound,EUS,PETCT,MRI,etc.Restaging after neoadjuvant therapy should be still based on the initial staging methods.Invasive biopsy could be implemented to reconfirm the suspected regional lymph node or distant metastasis after comprehensive consideration of medical conditions and operational risks.

2.4 Screening of high-risk group of esophageal cancer

High-risk group of esophageal cancer refers to people ≥40 years old,who live in areas with high incidence rate of esophageal cancer,or those with family history and risk factors of esophageal cancer (smoking,heavy intake of alcohol,squamous carcinoma of head and neck or respiratory tract,preferring very hot or pickled food,or with poor oral hygiene).For high-risk group of esophageal cancer,the recommended screening method is endoscopy with esophageal mucosa iodine solution staining.If no lesions are found,routinely follow-up with endoscopy is recommended.If superficial lesions are found,a biopsy should be taken to achieve pathological diagnosis.For lowgrade intraepithelial neoplasia/dysplasia,follow-up of every 3 years is recommended.If the pathological diagnosis is high-grade intraepithelial neoplasia/dysplasia without vascular invasion,endoscopic treatment should be considered.If the endoscopic manifestation seems more serious than pathological results,other endoscopy techniques (including magnifying endoscopy,NBI and staining etc.) are recommended for lesion evaluation and management decision-making.

For people ≥40 years old,with risk factors of esophageal cancer (achalasia,corrosive stenosis,tylosis and/or obesity),endoscopic esophageal mucosa iodine solution staining every 1-3 years is recommended.

For patients with known or newly detected Barrett’s esophagus,4-point biopsy (at least 8 biopsy samples) with an interval of 2 cm under endoscopy is recommended.If Los Angeles grade B,C,or D esophagitis is diagnosed,the patient should take the proton pump inhibitor regularly for 8-12 weeks,and then accept another endoscopy.In the absence of Barrett’s esophagus,endoscopic screening can be discontinued.For patients with pathologically diagnosed Barrett’s esophagus with dysplasia,endoscopy and biopsy every 3-5 years are recommended.If the pathological diagnosis is Barrett’s esophagus with low-grade endothelial neoplasia/dysplasia,endoscopic therapy or annual endoscopy with a 4-point biopsy every 1 cm is indicated.For patients with Barrett’s esophagus with high-grade endothelial neoplasia/dysplasia,endoscopic therapy or surgery is indicated.

2.5 Classification and staging of esophageal cancer

2.5.1 Segment of esophagus

(1) Cervical esophagus: Extending from hypopharynx to thoracic inlet (level of suprasternal notch).Adjacent to trachea,carotid sheath and spine.Usually 15-20 cm from the incisors in endoscopy.

(2) Upper segment of thoracic esophagus: Continuing from thoracic inlet to lower border of the azygos vein arch(superior to the level of hilum).Anteriorly surrounded by trachea,three branches of aorta and brachiocephalic veins.Posteriorly adjacent to spine.Usually 20-25 cm from the incisors in endoscopy.

(3) Middle segment of thoracic esophagus: Continuing from lower border of the azygos vein arch to lower border of the inferior pulmonary vein (between the superior and inferior level of hilum).It travels between left and right hilum anteriorly,adjacent to descending aorta on its left and to spine posteriorly.The right side of the esophagus is directly attached to the pleura.Usually 25-30 cm from the incisors in endoscopy.

(4) Lower segment of thoracic esophagus: Continuing from lower border of inferior pulmonary vein to esophagogastric junction (inferior to the level of hilum).Usually 30-40 cm from the incisors in endoscopy.

The location of the esophageal cancer is defined by the position of the epicenter of the tumor in the esophagus,which should be confirmed by combination of imaging tests and endoscopy.

2.5.2 Definition of esophagogastric junction (EGJ)

EGJ is the end of esophagus and beginning of the stomach.It locates around the level of cardia incisura or peritoneal reflection,or the inferior edge of the esophageal sphincter.It is not necessarily consistent with the histological squamocolumnar junction.Anatomically,EGJ includes the lower segment of thoracic esophagus,the border of esophagus and stomach,and 5 cm of proximal stomach.The clinical diagnosis and treatment of EGJ adenocarcinoma are usually based on Siewert classification:

Siewert type I: Adenocarcinoma of the lower esophagus with the epicenter located within 1-5 cm above the anatomic EGJ.

Siewert type II: True carcinoma of the cardia with the tumor epicenter within 1 cm above and 2 cm below the EGJ.

Siewert type III: Subcardial carcinoma with the tumor epicenter within 2-5 cm below the EGJ.

The staging of Siewert types I and II is as described in the staging for esophageal cancers.For Siewert type III or those tumor epicenter within 2 cm below the EGJ but not involves esophagus,the principle of gastric cancer staging should be followed.

2.5.3 Endoscopic classification of superficial esophageal cancer and precancerous lesions

The Chinese endoscopic classification includes concealed(congestive),eroded,plaque and papillary subtypes.The international endoscopic classification (Paris classification in 2005) includes: protruded (0-I),flat (0-II) and excavated(0-III) subtypes.The 0-I type includes pedunculated(0-Ip) and sessile (0-Is) subtypes.The intramucosal carcinoma usually presents as 0-IIb,0-IIa or 0-IIc type,with smooth or regular granular surface.The submucosal carcinoma often presents as 0-I or 0-III type,with irregular rough granular or rugged nodular surface(Appendix A).

Classification of invasion: The lesion limited in epithelium and without involving in basement membrane is described as M1 (high-grade endothelial neoplasia/severe dysplasia;Tis).The superficial esophageal cancer includes intramucosal carcinoma and submucosal carcinoma.The intramucosal carcinoma includes M2 (the lesion breaks through basement membrane and invades lamina propria mucosa,LPM) and M3 (the lesion invades into muscularis mucosa,MM) subtypes.According to the depth of invasion,the submucosal carcinoma is classified into SM1 (invading upper 1/3 of submucosa),SM2 (invading middle 1/3 of submucosa) and SM3 (invading lower 1/3 of submucosa).For the endoscopic dissected specimen of esophageal squamous carcinoma,200-μm thickness is the threshold between superficial and deep layer of submucosa.

2.5.4 Classification of advanced esophageal cancer

Medullary type: Featured by thickening of esophageal wall,with slope shape elevation of the margin.

Mushroom type: The margin of the tumor is elevated,with lip shape/mushroom-like extroversion.Superficial ulcers may be found on the surface of the tumor.

Ulceration type: Obvious ulceration located in the center of the lesion,usually companied with elevation of the margin.Constrictive type: Featured by constriction of the esophageal lumen.Patients usually complain obvious dysphagia.

Intraluminal type: The lesion is mushroom-like or polypoid,with or without thin pedicle.

2.5.5 Histological subtypes of esophageal cancer

According to the 2019 WHO classification of digestive neoplasm,the most common histological subtypes include squamous cell carcinoma,adenocarcinoma,neuroendocrine carcinoma,etc.Detailed information is described inAppendix B.

2.5.6 International staging of esophageal carcinoma

According to the 8th edition of Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) TNM staging system,the primary tumor(T),regional lymph node (N),distant metastasis (M) and histologic grade (G) are shown inAppendix C.

The AJCC prognostic staging group system includes clinical staging,pathological staging and post-neoadjuvant therapy histologic staging (Appendix C).

The above staging system applies to esophageal carcinoma,including squamous cell carcinoma,adenocarcinoma,adenosquamous carcinoma,undifferentiated carcinoma,neuroendocrine carcinoma,adenocarcinoma with neuroendocrine characteristics,etc.,but it does not apply to esophageal neuroendocrine tumor and nonepithelial tumor,such as lymphoma,sarcoma,gastrointestinal mesenchymoma and melanoma.

2.5.7 UICC/AJCC regional lymph node stations (the 8th edition TNM staging system for esophageal cancer)

1: [Right (1R) and left (1L)]: Lower cervical paratracheal between the supraclavicular paratracheal space and lung apex

2: [Right (2R) and left (2L)]: Upper paratracheal

2R: Between the intersection of the bottom of the brachiocephalic artery with the trachea and the lung apex

2L: Between the top of the aortic arch and the lung apex

4: [Right (4R) and left (4L)]: Lower paratracheal

4R: Between the intersection of the bottom of the brachiocephalic artery with the trachea and the superior border of the azygos vein

4L: Between top of the aortic arch and the carina

7: Subcarinal: inferior to the carina

8: [Upper (8U),middle (8M),and lower (8Lo)]: Thoracic paraesophageal

8U: From the lung apex to the tracheal bifurcation

8M: From the trachea bifurcation to the bottom of the inferior pulmonary vein

8Lo: From the bottom of the inferior pulmonary vein to the gastroesophageal junction

9: [Right (9R) and left (9L)]: Pulmonary ligament

9R: Within the right inferior pulmonary ligament

9L: Within the left inferior pulmonary ligament

15: Diaphragmatic: on the dome of the diaphragm or adjacent to or behind its crura

16: Paracardial: immediately adjacent to the gastroesophageal junction

17: Left gastric: along the left gastric artery

18: Common hepatic: immediately on the proximal (but not distal) common hepatic artery

19: Splenic artery: immediately on the proximal (but not distal) splenic artery

20: Celiac: at the base of the celiac artery

Cervical VI and VII regional lymph nodes refer to the lymph node substation standard of head and neck tumor.

2.5.8 Japan esophageal society (JES) regional lymph node stations (the 11th edition staging system for esophageal cancer)

The JES staging system of esophageal cancer is of significance for surgery and radiotherapy plan.It also has great value on treatment of patients with esophageal squamous cell carcinoma in China.JES regional lymph nodes stations:

(1) Cervical lymph nodes

No.100: Superficial cervical lymph nodes

No.100spf: Superficial cervical lymph nodes

No.100sm: Submandibular lymph nodes

No.100tr: Cervical pretracheal lymph nodes

No.100ac: Accessory nerve lymph nodes

No.101: Cervical paraesophageal lymph nodes

No.102: Deep cervical lymph nodes

No.102up: Upper deep cervical lymph nodes

No.102mid: Middle cervical lymph nodes

No.103: Peripharyngeal lymph nodes

No.104: Supraclavicular lymph nodes

(2) Thoracic lymph nodes

No.105: Upper thoracic paraesophageal lymph nodes

No.106: Thoracic paratracheal lymph nodes

No.106rec: Recurrent nerve lymph nodes

No.106recL: Left recurrent nerve lymph nodes

No.106recR: Right recurrent nerve lymph nodes

No.106pre: Pretracheal lymph nodes

No.106tb: Tracheobronchial lymph nodes

No.106tbL: Left tracheobronchial lymph nodes

No.106tbR: Right tracheobronchial lymph nodes

No.107: Subcarinal lymph nodes

No.108: Middle thoracic paraesophageal lymph nodes

No.109: Main bronchus lymph nodes

No.110: Lower thoracic paraesophageal lymph nodes

No.111: Supradiaphragmatic lymph nodes

No.112: Posterior mediastinal lymph nodes

No.112aoA: Anterior thoracic paraaortic lymph nodes

No.112aoP: Posterior thoracic paraaortic lymph nodes

No.112pul: Pulmonary ligament lymph nodes

No.113: Ligamentum arteriosum lymph nodes

No.114: Anterior mediastinal lymph nodes

(3) Abdominal lymph nodes

No.1: Right paracardial lymph nodes

No.2: Left paracardial lymph nodes

No.3a: Lesser curvature lymph nodes along the branches of the left gastric artery

No.3b: Lesser curvature lymph nodes along the 2nd branch and distal part of the right gastric artery

No.4sa: Left greater curvature lymph nodes along the short gastric arteries (perigastric area)

No.4sb: Left greater curvature lymph nodes along the left gastroepiploic artery (perigastric area)

No.4d: Right greater curvature lymph nodes along the 2nd branch and distal part of the right gastroepiploic artery

No.5: Suprapyloric lymph nodes

No.6: Infrapyloric lymph nodes

No.7: Left gastric artery lymph nodes

No.8a: Anterosuperior lymph nodes along the common hepatic artery

No.8p: Posterior lymph nodes along the common hepatic artery

No.9: Celiac artery lymph nodes

No.10: Splenic hilar lymph nodes

No.11p: Proximal splenic artery lymph nodes

No.11d: Distal splenic artery lymph nodes

No.12a: Hepatoduodenal ligament lymph nodes along the proper hepatic artery

No.12b: Hepatoduodenal ligament lymph nodes along the bile duct

No.12p: Hepatoduodenal ligament lymph nodes along the portal vein

No.13: Lymph nodes on the posterior surface of the pancreatic head

No.14v: Lymph nodes along the superior mesenteric vein

No.15: Lymph nodes along the middle colic vessels

No.16a1: Paraaortic lymph nodes in the diaphragmatic aortic hiatus

No.16a2: Paraaortic lymph nodes between the upper margin of the origin of the celiac trunk and the lower border of the left renal vein

No.16b1: Paraaortic lymph nodes between the lower border of the left renal vein and the upper border of the origin of the inferior mesenteric artery

No.16b2: Paraaortic lymph nodes between the upper border of the origin of the inferior mesenteric artery and the aortic bifurcation

No.17: Lymph nodes on the anterior surface of the pancreatic head

No.18: Lymph nodes along the inferior margin of the pancreas

No.19: Infradiaphragmatic lymph nodes

No.20: Paraesophageal lymph nodes in the diaphragmatic esophageal hiatus

2.6 Nutritional assessment on patients with esophageal cancer

Patient nutritional assessment is required at the initial stage of esophageal cancer diagnosis and treatment.It is also an important part of the comprehensive assessment at baseline.Nutritional assessment includes nutritional risk screening and nutritional assessment.

2.6.1 Nutritional risk screening

Nutritional risk screening is a process of applying nutritional risk screening tools to determine whether a patient has a nutritionally-related risk that may affect clinical outcomes.At present,Nutritional Risk Screening 2002 (NRS2002) is commonly used in clinical practice.Patients should be screened for nutritional risk using NRS2002 within 24 h after admission by trained physicians,dietitians,pharmacists or nurses.Patients at risk of nutrition need plans of nutritional diagnosis and intervention;those without nutritional risk should be rescreened 7 d later.For patients planning to accept elective surgery,nutritional risk screening should be accomplished more than 10 d before surgery.NRS2002 includes three parts: score of impaired nutritional status,severity of disease and age (Appendix D).The overall score≥3 indicates “nutritional risk”,and thus a nutritional diagnosis and intervention plan needs to be developed.

2.6.2 Nutritional assessment

Nutritional assessment is a process for further understanding the nutritional status of patients at risk of nutrition. It consists of two parts: basic nutrition assessment and malnutrition assessment.

(1) Basic nutrition assessment: It is a nutrient management program that all patients at risk of nutrition need to accept.The assessment includes: nutrition-related history,dietary investigation,physical examination (height,weight,etc.),laboratory tests (liver and kidney function,blood glucose,lipids,electrolytes,acid-base balance,etc.).The above indicators are content of routine tests for all inpatients,and are also necessary for nutrition intervention plans,prescriptions and monitoring.

(2) Malnutrition assessment: It involves diagnosis and grading of malnutrition.We recommend malnutrition assessment in accordance with the consensus on criteria for the diagnosis of malnutrition initiated by global (nutrition)leaders.For patients with positive nutritional risk screen results,malnutrition can be diagnosed with at least 1 positive phenotypic indicator plus 1 positive etiological indicator (Appendix E).In addition,subjective global assessment (SGA) and patient-participated SGA may also be considered.

3.Guidelines for treatment of esophageal cancer

3.1 Surgery

Surgery is one of the main radical treatments for patients with esophageal carcinoma.Before 2000,left transthoracic esophagogastrostomy is the predominant approach for the surgical treatment of esophageal cancer in China.However,because of the blockade of the aortic arch that locates in the left thoracic cavity,as well as the limited triangle space superior to the aortic arch,the dissection of lower cervical and upper mediastinal lymph nodes may not complete. Therefore,the rate of cervical or upper mediastinal lymph nodes metastasis is as high as 30%-40%and the 5-year survival rate is about 30%-40% in recent 30 years for patients underwent left transthoracic esophagogastrostomy.With the progress of standardized treatment of esophageal cancer and the widely application of minimal invasive technique such as laparoscopy and VATS,more and more patients accepted right transthoracic esophagogastrostomy in recent years.Without the blockage of aortic arch,the thoracic lymph nodes are more likely thoroughly dissected.In China,most hospitals employ cervical lymph node dissection for selected patients.Comparing with left approach,thorough two-field (thoracic-abdominal) or three-field (cervicalthoracic-abdominal) lymph node dissection through right approach may help decrease the recurrence and metastasis of cervical and thoracic lymph nodes after surgery,and thus improving 5-year survival rate.Furthermore,the surgeryonly treatment model for locally advanced esophageal carcinoma has been replaced by surgery-centered multidisciplinary treatment which includes preoperative neoadjuvant and postoperative adjuvant therapy,involving chemotherapy,radiochemotherapy and immunotherapy.This section focuses only on the guidelines of surgical treatment.

3.1.1 Principle of surgery

(1) The resectability of esophageal carcinoma should be determined by experienced thoracic surgeons. The evaluation should also include surgical approach and lymph node dissection strategy to achieve radical resection on primary tumor and regional lymph nodes.

(2) The surgical treatment should be cautiously planned based on the comprehensive consideration of the status of esophageal carcinoma (including the involvement of esophageal cancer and clinical stage),patient’s comorbidities and the habits of the surgeon.

(3) Choice of surgical approach: Right transthoracic esophagogastrectomy is recommended for thoracic esophageal cancer.Left transthoracic esophagogastrectomy is also a choice for esophageal cancer located in mid-lower segment of thoracic esophagus without upper mediastinal lymph nodes metastasis.

(4) Choice of surgery procedure: The optional surgery procedures include: traditional open or video-assisted or robotic-assisted McKeown esophagogastrectomy (right thoracotomy followed by laparotomy and cervical anastomosis),Ivor Lewis esophagogastrectomy (laparotomy followed by right thoracotomy and anastomosis),Sweet esophagogastrectomy (left thoracotomy followed by stomach management through diaphragm and intrathoracic or cervical anastomosis),left thoracoabdominal incision plus cervical or intrathoracic anastomosis,combined with two-field (thoracic-abdominal) or three-field (cervicalthoracic-abdominal) lymph node dissection.For patients with stage cT1-2N0 esophageal cancer who are intolerant of thoracotomy,a variety of surgical procedures such as transhiatal inversion esophagectomy can be selected.For patients with esophogastric junction cancer,the selection of surgery method depends on the Siewert classification:Siewert type I refers to the esophageal surgery procedure;Siewert type III refers to gastric cancer surgery procedure.The surgery method for Siewert type II is still controversial.It is currently determined according to the habits and proficiency of thoracic gastrointestinal surgeons.

(5) Lymph node dissection: For patients with mid-lower thoracic esophageal cancer without suspected cervical lymph node metastasis,thorough thoracic and abdominal two-field dissection (routine thoracic and abdominal two fields plus upper mediastinal lymph node,especially lymph nodes around bilateral recurrent nerve chains);for patients with suspected cervical lymph node metastasis or upper thoracic cancer,cervical-thoracic-abdominal three-field lymph node dissection (bilateral lower cervical,bilateral supraclavicular and above described two-filed lymph nodes)is recommended.

(6) Substitutions and pathways: The most frequently selected substitutions for dissected esophagus are stomach,colon and jejunum. The need for microsurgical anastomosis of pedunculated vessels should be considered as appropriate. The esophageal bed,retrosternal or subcutaneous (anterior to the sternum) reconstruction is a choice of the pathway of substitution.

(7) The number of esophageal surgeries and the size of the professional team are one of the important factors relate to the perioperative complications and mortality of esophageal cancer. We recommend to implement esophagectomy in experienced large-volume centers or medical teams that have completed the standardized training.

3.1.2 Guidelines for follow-up after surgery

After esophagectomy,we recommend follow-up every 3 months in the first 2 years and every 6 months in the 3rd-5th year,and then annually in the following years.The follow-up examinations include neck/chest/abdomen CT or neck and abdomen ultrasound and laboratory tests.Imaging tests such as upper gastrointestinal series,PETCT,bone scan head MRI and endoscopy are optional according to the status of patients postoperatively.A biopsy may be performed as appropriate to confirm the diagnosis if suspected recurrences or metastatic lesions are found during follow-up.

3.2 Radiotherapy

Radiotherapy is a very important component of treatment on esophageal cancer that involving neoadjuvant,adjuvant,radical and palliative therapy.

For patients with cTis-2N1-3M0 or cT3-4aNanyM0 who are planning to accept surgery,neoadjuvant chemoradiotherapy is recommend to improve the rates of complete resection,pathological complete response and local tumor control,and thereby improving the long-term survival.For patients who are not tolerance to or refuse surgery,radical concurrent chemoradiotherapy is recommended.Postoperative adjuvant concurrent chemoradiotherapy may be considered based on the status of patients after pathologically confirmed uncompleted resection (R1 or R2 resection) and R0 resection but staged(y)pT4NanyM0.

For superficial esophageal carcinoma after endoscopic mucosal resection,if pathologically confirmed as stage T1b or T1a with vessel invasion,nerve involvement,poorly or undifferentiated,or non-R0 resection,esophagectomy is preferred.For patients who are not suitable for surgery after evaluation or refuse to accept surgery,adjuvant radiotherapy or concurrent chemoradiotherapy may be considered.For patients with unresectable cT4NanyM0 esophageal carcinoma (evaluated by surgeons) or those refuse surgery,radical concurrent chemoradiotherapy is recommended.

For patients with postoperative local recurrence,advanced esophageal cancer with obstruction,extensive lymph node metastasis,or with distant metastasis (lung,bone,brain,etc.) but have been assessed as disease stable or partial response after systemic pharmacotherapy,palliative radiation may be considered.

3.2.1 Guidelines for radiotherapy

(1) Techniques

We recommend intensity modulated radiation therapy(IMRT,preferred) or three-dimensional conformal radiation therapy.Many radiophysical researches have confirmed that these two types of radiotherapy are superior to two-dimensional radiotherapy on targeted area dose distribution,normal organ protection (especially heart and lung protection),and minimization of radiotherapy associated complications.

(2) CT simulation orientation

The patient is supine,with arms on the side of the trunk,or arms crossed and placed on the forehead.For cervical or upper segment of thoracic esophageal cancer,head-neckshoulders immobilization is recommended.For mid-lower segment of thoracic esophageal cancer or esophagogastric junction cancer,trunk immobilization is recommended.If not contraindicated,CT with contrast is recommended,with 0.5 cm slice thicknesses.

For lower segment of thoracic esophageal cancer,or esophagogastric junction cancer,or the targeted area involves left gastric artery/abdominal lymph nodes,in order to minimize the discrepancy of the irritation volume caused by gastric filling,the patients need to empty stomach 3-4 h before CT simulation orientation,and then orally take 200-300 mL semiliquid diets (e.g.,thick porridge,yogurt,etc.) right before the CT scan,or 15 min before each radiotherapy.

If the residuals of the stomach located in the mediastinum,the best way to orientation and radiotherapy is keeping the stomach empty.

(3) Definition of targeted area

1) Neoadjuvant concurrent radiotherapy or radical concurrent radiochemotherapy: The standard radiotherapy targeted area designation has not been established;therefore,it is recommended to outline neoadjuvant radiotherapy targeted area according to the design principles of radical radiotherapy target area.During the designation of targeted area after esophagectomy,the location of anastomosis should be taken into account to avoid to be involved.

Gross tumor volume (GTV) and gross tumor volumelymph node (GTVnd): The visible primary esophageal lesion (on pretreatment exams) is GTV.Confirmed or suspected metastasized lymph nodes are GTVnd.

Clinical target volume (CTV): (A) Cervical/upper thoracic esophageal cancer: the primary tumor (GTV) plus 3 cm expansion proximal and distal along the length of the esophagus,or GTVnd plus 0.5-1 cm expansion threedimensionally.CTV should also cover elective nodal regions such as mid-cervical,1 (lower cervical,supraclavicular),2,4,7 lymph node drainage regions.For cervical esophageal carcinoma,No.7 drainage area is selective.If the targeted areas are not adjacent,radiation for involved fields only should be considered,e.g.,upper thoracic esophageal cancer with abdominal lymph node metastasis.(B) Middle thoracic esophageal cancer: GTV plus 3 cm expansion proximal and distal along esophagus,or GTVnd plus 0.5-1 cm expansion three-dimensionally.It usually needs to cover 1,2,4,7 and part of 8 lymph node drainage regions.Due to the higher probability of metastasis to the abdominal lymph nodes in middle thoracic esophageal cancer,radiation to 15,16,17,and even 20 lymph node drainage regions of some patients need to be involved.(C) Lower thoracic esophageal cancer/Siewert type I or II EGJ cancer: GTV plus 3 cm expansion proximal and distal along esophagus and cardia,or GTVnd plus 0.5-1 cm expansion three-dimensionally.It usually needs to cover 7,8,15,16,17 and 20 lymph node drainage regions,even proximal part of 18 and 19 regions of some patients.If the targeted areas are not adjacent,radiation for involved fields only should be considered,e.g.,lower thoracic esophageal cancer and one lymph node drainage region metastasis.

Planning target volume (PTV): Usually CTV plus 0.5 cm expansion three-dimensionally.For cervical or upper thoracic segment of esophageal cancer with head-neckshoulder immobilization,CTV plus 0.3 cm expansion is acceptable.

Planned gross tumor volume (PGTV) (when sequential or concurrent enhanced radiotherapy): GTV+GTVnd plus 0.5 cm expansion three-dimensionally.

2) Adjuvant radiotherapy/concurrent radiochemotherapy:the status of anastomosis should be involved for primary tumor that locates in cervical or upper thoracic segment,or the incision margin to tumor ≤3 cm.

GTV and GTVnd: After R1 or R2 resection,GTV includes residual primary tumor,anastomosis with positive margin,while GTVnd includes residual metastasized or suspected lymph nodes.

CTV: (A) Cervical/upper thoracic esophageal cancer:including GTV+GTVnd (if exists),anastomosis,1,2,4,7 lymph node drainage regions.For cervical esophageal carcinoma,No.7 drainage area is selective.If the tumor is T4b,the tumor bed should be involved.(B) Middle thoracic esophageal cancer: including GTV+GTVnd (if exists),1,2,4,7 and part of 8 lymph node drainage regions.No.15,16,17 and 20 drainage areas are selective according to the pathological results.If the tumor is T4b,the tumor bed should be involved.(C) Lower thoracic esophageal cancer/Siewert type I or II EGJ cancer: including GTV+GTVnd (if exists),1,2,4,7,8,15,16,17,20 lymph node drainage regions.If the tumor is T4b,the tumor bed should be involved.

PTV: usually CTV plus 0.5 cm expansion.For cervical or upper thoracic segment of esophageal cancer with headneck-shoulder immobilization,CTV plus 0.3 cm expansion is acceptable.

PGTV: (when sequential or concurrent enhanced radiotherapy): GTV+GTVnd plus 0.5 cm expansion.

3.2.2 Dose

(1) Neoadjuvant radiotherapy/concurrent radiochemotherapy: 95% PTV 40-50 Gy/1.8-2.0 Gy,once a day,5 times per week. If possible,concurrent enhanced radiotherapy can also be used.

(2) Adjuvant radiotherapy/concurrent radiochemotherapy:After R0 resection: 95% PTV 50-54 Gy/1.8-2.0 Gy,once a day,5 times per week.

After R1/R2 resection: 95% PTV 50 Gy/1.8-2.0 Gy,sequential radiotherapy 95% PGTV 10-14 Gy/1.8-2.0 Gy,once a day,5 times per week.If possible,concurrent enhanced radiotherapy can also be used.

(3) Radical radiotherapy/concurrent radiochemotherapy:

(A) 95% PTV 60 Gy/1.8-2.0 Gy,once a day,5 times per week.(B) 95% PTV 50 Gy/1.8-2.0 Gy,sequential radiotherapy 95% PGTV 10 Gy/1.8-2.0 Gy,once a day,5 times per week. If possible,concurrent enhanced radiotherapy can also be used.

Note: The dose of radical concurrent radiochemotherapy can be reduced to 50-54 Gy as appropriate.Sixty Gy is used in most Chinese hospitals.

3.2.3 Normal tissue tolerance dose

For patients planning to accept postoperative or preoperative radiotherapy,we recommend evaluating normal tissues by full prescribed dose (e.g.,95% PTV 60 Gy),and then performed at the actual prescribed dose,while determining the actual the normal tissue tolerance dose.

(1) Lung: average dose ＜14-16 Gy,V20≤28%,V30≤20%,Vng: average radiochemotherapy V20≤25%;The tolerance dose of the lungs should be as low as possible for patients who have accepted immunotherapy;

(2) Heart: V30＜40%,V40＜30%;

(3) Spinal cord (involved by radiation plan): Dmax≤45 Gy;

(4) Stomach: V40＜40%,Dmax≤55-60 Gy;

(5) Intestine: V40＜40%,Dmax≤55 Gy;

(6) Kidneys: V20＜30%;

(7) Liver: V30＜30%.

3.2.4 Concurrent chemotherapy regimens and dosing

(1) Paclitaxel and platinum

Paclitaxel 45-60 mg/m2IV on d 1;

Cisplatin 20-25 mg/m2IV on d 1 [or carboplatin (area under the concentration-time curve) AUC=2,IV,on d 1];Cycled weekly.

(2) Cisplatin and fluorouracil or capecitabine or tegafur

Fluoropyrimidine can be replaced by capecitabine or tegafur because of their better therapeutic effect,less side effects and availability for oral intake.

Cisplatin 30 mg/m2,IV on d 1;

Capecitabine 800 mg/m2,P.O.,Bid on d 1-5 (or tegafur 40-60 mg/m2,P.O.,Bid on d 1-5);

Cycled weekly.

(3) Paclitaxel and fluorouracil or capecitabine or tegafur

Paclitaxel 45-60 mg/m2,IV on d 1;

Capecitabine 625-825 mg/m2,P.O.,Bid on d 1-5 (or tegafur 40-60 mg/m2,P.O.,Bid on d 1-5);

Cycled weekly.

(4) Oxaliplatin and fluorouracil or capecitabine or tegafur (preferred for adenocarcinoma)

Oxaliplatin 85 mg/m2,IV on d 1,15,29;

Capecitabine 625 mg/m2,P.O.,Bid on d 1-5;or tegafur 40-60 mg/m2,P.O.,Bid on d 1-5;

Cycled weekly.

Please also seeAppendix Fon assessment of therapeutic effect.

3.2.5 Assessment and follow-up after radiotherapy

(1) Assessment after neoadjuvant radiotherapy: It is recommended to evaluate the therapeutic effect 1 month after the accomplishment of neoadjuvant radiotherapy.The examinations include CT with contrast (including neck,chest and abdomen) and laboratory tests like complete blood count (CBC),blood biochemistry,etc.The selective tests include upper gastrointestinal series,whole body PET-CT,bone scan and brain MRI.In order to achieve accurate clinical re-staging,invasive examinations like rebiopsy through esophageal endoscopy,re-biopsy of enlarged regional lymph nodes through endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA) or EUS-FNA should be considered.We recommend surgery 4-8 weeks after the accomplishment of radiotherapy.

(2) Follow-up after postoperative adjuvant radiotherapy:After the postoperative radiotherapy,we recommend follow-up of every 3 months for 2 years,and then 6 months for the following 3 years,and then annually.The routine tests include CT (include neck,chest and abdomen),and laboratory tests like CBC,blood biochemistry,etc.The selective tests include upper gastrointestinal series,whole body PET-CT,bone scan and brain MRI.If suspicious metastases of anastomotic,regional lymph nodes,or distal organs are found during follow-up,invasive tests like upper gastrointestinal endoscopy,fiber bronchoscopy,and EBUS-TBNA or EUS-FNA on enlarged regional lymph nodes may be considered as appropriate.

(3) Follow-up after radical radiotherapy: We recommend starting of follow-up in 1-2 months after the accomplishment of radical radiotherapy.Then continuing to follow up every 3 months for 2 years,and then 6 months for the following 3 years,and then annually.The routine tests include CT (include neck,chest and abdomen),and laboratory test likeCBC,blood biochemistry,etc.The selective tests include upper gastrointestinal series,whole body PET-CT,bone scan and brain MRI.If suspicious metastases of anastomotic,regional lymph nodes or distal organs are found during follow-ups,invasive tests like upper gastrointestinal endoscopy,fiber bronchoscopy,and EBUS-TBNA or EUS-FNA on enlarged regional lymph nodes may be considered as appropriate.

3.3 Systemic therapy

The symptoms of early-stage esophageal cancer are usually insidious,while most of the esophageal cancers are usually found in locally advanced or late stage.Therefore,chemotherapy is essential for the treatment of esophageal cancer to control the spread of the tumor.With the emergence of new drugs of molecular targeting therapy and immunotherapy in recent years,the role of systemic therapy is promising in the comprehensive treatment of esophageal cancer.

Currently,systemic therapy of esophageal cancer includes neoadjuvant chemotherapy and adjuvant chemotherapy for locally advanced patients,and chemotherapy,molecular targeting therapy and immunotherapy for latestage patients.

3.3.1 Neoadjuvant chemotherapy

The benefit of neoadjuvant chemotherapy includes possible down-staging of tumor,elimination of micro-metastasis and observation of tumor response to chemotherapy that may help to guide the postoperative treatment.Neoadjuvant chemotherapy may be considered for resectable locally advanced esophageal squamous cell carcinoma,including cTis-2N1-3M0 or cT3-4aNanyM0 cervical and thoracic esophageal cancer.We recommend perioperative or neoadjuvant chemotherapy for resectable locally advanced lower thoracic esophageal and esophogastric junction adenocarcinoma,including cTis-2N1-3M0 or cT3-4aNanyM0 or suspected cT4b EGJ adenocarcinoma.

3.3.2 Adjuvant chemotherapy

It is still controversial whether patients with esophageal squamous carcinoma should accept routine postoperative adjuvant chemotherapy. Adjuvant chemotherapy or radiochemotherapy may be considered for patients with risk factors (stage T4a or N1-3). Evidence on postoperative chemotherapy of lower thoracic esophageal and esophogastric junction adenocarcinoma originates from the researches on their perioperative chemotherapy.For patients who have accepted radical surgery after preoperative neoadjuvant chemotherapy,the same regimen of chemotherapy can be utilized after surgery.

For patients with esophageal and EGJ cancer (squamous cell carcinoma or adenocarcinoma) who have accepted neoadjuvant radiochemotherapy before surgery,1-year nivolumab improves disease-free survival (DFS) if pathological complete response was not achieved.Nivolumab will be the management strategy of recommendation for these patients after been approved by Chinese Food and Drug Administration (CFDA).Adjuvant chemotherapy usually starts 4 weeks after surgery.

3.3.3 Systemic therapy for recurrent/metastasized esophageal cancer

If tolerated,we recommend chemotherapy for all patients with metastasized esophageal cancer as initial treatment.If the disease progresses after systemic treatment,different regimens should be chosen. We also recommend chemotherapy for all patients with local recurrence or distant metastasis after radical treatment,if they can tolerate.

(1) First-line treatment

At present,immune checkpoint inhibitors combined with chemotherapy have become the standard of first-line treatment of late-stage esophageal cancer.For patients with late-stage esophageal and EGJ cancer (squamous cell carcinoma or adenocarcinoma),the first-line treatment can be combination of pembrolizumab and cisplatin+5-fluoropyrimidine. For patients with late-stage EGJ adenocarcinoma,the first-line treatment can be combination of nivolumab and oxaliplatin+fluorouracil.For patients with late-stage esophageal squamous cell carcinoma,the first-line treatment can be combination of camrelizumab and paclitaxel+cisplatin.

If immune checkpoint inhibitors are not suitable,chemotherapy only should be considered.Common chemotherapy regimens for late-stage esophageal squamous cell carcinoma include cisplatin+fluorouracil,paclitaxel+platinum,etc.The common chemotherapy regimen for late-stage EGJ adenocarcinoma is cisplatin or oxaliplatin+fluorouracil.For patients with good performance status,a three-drug combination of paclitaxel plus platinum and fluorouracil can also be considered for first-line therapy.In patients with HER-2-positive latestage EGJ adenocarcinoma,first-line therapy may be combined with trastuzumab on the basis of cisplatin+fluorouracil.

(2) Second-line and subsequent therapy

Immune checkpoint inhibitors have become an important treatment option for patients with late-stage esophageal cancer who have failed chemotherapy.For patients with late-stage esophageal squamous cell carcinoma who have failed first-line chemotherapy,camrelizumab or tislelizumab may be selected as second-line treatment.Tislelizumab could be the second-line treatment strategy of recommendation for patients with late-stage esophageal cancer or EGJ cancer after it is approved by CFDA.For patients with esophageal squamous cell carcinoma and PDL1 CPS≥10 who have failed first-line chemotherapy,pembrolizumab monotherapy may be the option of secondline therapy.For patients with EGJ adenocarcinoma who have failed at least second-line therapy,nivolumab could be a choice of third-line or subsequent treatment.

The options of second-line therapy for late-stage EGJ adenocarcinoma include paclitaxel monotherapy,irinotecan monotherapy or docetaxel monotherapy.No standard second-line chemotherapy regimens for late-stage esophageal squamous cell carcinoma have been established.Therefore,if immune checkpoint inhibitors are not suitable,chemotherapy regimen for adenocarcinoma can be referred to in clinical practice.

In terms of targeted therapy,vidicetuzumab (disitamab vedotin) can be selected as third-line and subsequent treatment for late-stage HER-2 positive EGJ cancer.Antiangiogenic targeted drugs may also be a treatment option: apatinib could be an option of third-line and subsequent treatment for late-stage EGJ cancer;anlotinib or apatinib could be used as second-line and subsequent treatment for late-stage esophageal squamous cell carcinoma.

3.3.4 Assessment before systemic therapy

(1) Assessment of tumor

Pathological subtype needs to be confirmed by histological or cytological tests. History and physical (H&P)examination and imaging tests are needed to understand the location and fields of the tumor involved,the tendency of the disease development so as to determine the treatment target.Imaging assessment should be obtained before chemotherapy as baseline for outcome assessment after chemotherapy or long-term follow-up.

(2) Assessment of patients

Patients should be generally in good condition with Eastern Cooperative Oncology Group (ECOG)performance score (PS) 0-1 (Appendix G). CBC,hepatorenal function and EKG should be done within 1 week before chemotherapy. Chemotherapy can be considered if neutrophil ≥1.5×109/L,platelet ≥80×109/L,and HGB≥80 g/L.

(3) Assessment of concomitant diseases

Patients should have no serious complications,such as active digestive tract perforation/bleeding,gastrointestinal obstruction,pulmonary embolism or shock.If nonneoplastic fever occurs,the temperature needs to be below 38 °C.

Concomitant heart,lung or chronic diseases should be checked accordingly,e.g.,tests of myocardial enzymes,brain natriuretic peptide,dynamic electrocardiogram(Holter monitor),ultrasonic cardiogram,or pulmonary function.

3.3.5 Regimens and dosing of systemic therapy

(1) Neoadjuvant therapy

1) Fluorouracil,leucovorin,oxaliplatin and docetaxel(FLOT,preferred for adenocarcinoma)

Oxaliplatin 85 mg/m2,IV on d 1;

Docetaxel 50 mg/m2,IV on d 1;

Leucovorin 200 mg/m2,IV on d 1;

5-Fluorouracil 2,600 mg/m2,IV continuous infusion over 24 h on d 1;

Cycled biweekly,4 cycles before and another 4 cycles after surgery.

2) Fluorouracil and cisplatin (PF)

Regimen 1:

5-Fluorouracil 800 mg/m2,IV continuous infusion for 24 h daily on d 1-5;

Cisplatin 100 mg/m2,IV on d 1;

Cycled every 4 weeks,2-3 cycles before surgery,3-4 cycles after surgery (preferred for adenocarcinoma).

Regimen 2:

5-Fluorouracil 1,000 mg mg/m2,IV continuous infusion for 24 h daily on d 1-4;

Cisplatin 80 mg/m2,IV on d 1;

Cycled every 3 weeks,2 cycles before surgery.

Regimen 3:

5-Fluorouracil 800 mg/m2,IV continuous infusion for 24 h daily on d 1-5;

Cisplatin 80 mg/m2,IV on d 1;

Cycled every 3 weeks,2 cycles before surgery (preferred for squamous cell carcinoma).

3) Paclitaxel and cisplatin (TP,preferred for squamous cell carcinoma)

Regimen 1:

Paclitaxel 150 mg/m2,IV on d 1;

Cisplatin 50 mg/m2,IV on d 1;

Cycled every 2 weeks.

Regimen 2:

Paclitaxel 135 mg/m2,IV on d 1;

Cisplatin 70 mg/m2,IV on d 1;

Cycled every 3 weeks.

4) Docetaxel,cisplatin and fluorouracil (DCF,preferred for squamous cell carcinoma)

Docetaxel 70 mg/m2,IV on d 1;

Cisplatin 70 mg/m2,IV on d 1;

5-Fluorouracil 750 mg/m2,IV daily on d 1-5;

Cycled every 3 weeks.

(2) Adjuvant therapy

1) Nivolumab:

Nivolumab 240 mg,IV on d 1,cycled every 2 weeks for 16 weeks;and then nivolumab 480 mg,IV on d 1,cycled every 4 weeks.The treatment should no more than 1 year.(Note:Nivolumab will be the recommended adjuvant treatment option for patients with esophageal or EGJ cancer after it is approved by CFDA.)

2) Paclitaxel and cisplatin (TP,preferred for squamous cell carcinoma):

Paclitaxel 150 mg/m2,IV on d 1;

Cisplatin 50 mg/m2,IV on d 1;

Cycled every 2 weeks.

(3) First-line treatment for advanced stages

1) Fluorouracil and cisplatin (PF)5-Fluorouracil 750-1,000 mg/m2,IV continuous infusion for 24 h daily on d 1-4;

Cisplatin 70-100 mg/m2,IV for 4 h on d 1;

Cycled every 3-4 weeks.

2) Taxane and cisplatin (TP)

Regimen 1:

Paclitaxel 135-175 mg/m2,IV for 3 h on d 1;

Cisplatin 75 mg/m2,IV on d 1;

Cycled every 3 weeks.

Regimen 2:

Paclitaxel 90-150 mg/m2,IV for 3 h on d 1;

Cisplatin 50 mg/m2,IV on d 1;

Cycled every 2 weeks.

Regimen 3:

Albumin-bound paclitaxel (Abraxane) 125 mg/m2,IV on d 1 and d 8;

Cisplatin 75 mg/m2,IV on d 1;

Cycled every 3 weeks.

3) Oxaliplatin,fluorouracil and leucovorin (FLO,preferred for adenocarcinoma)

Oxaliplatin 85 mg/m2,IV for 2 h on d 1;

Leucovorin 200 mg/m2,IV for 2 h on d 1;

Then followed by 5-fluorouracil 2,600 mg/m2IV continuous infusion for 24 h on d 1;

Cycled every 2 weeks.

4) Docetaxel,cisplatin and 5-fluorouracil (modified DCF,preferred for adenocarcinoma)

Docetaxel 40 mg/m2IV for 1 h on d 1;

Cisplatin 40 mg/m2IV over 1-3 h on d 1;

5-Fluorouracil 2,000 mg/m2,IV continuous infusion for 48 h on d 1;

Cycled every 2 weeks.

5) Irinotecan and fluorouracil/leucovorin (preferred for adenocarcinoma)

Irinotecan 180 mg/m2IV for 30 min on d 1;

Leucovorin 400 mg/m2IV on d 1;

5-Fluorouracil 400 mg/m2IV on d 1;

Then 5-Fluorouracil 1,200 mg/m2IV continuous infusion for 24 h daily on d 1-2;

Cycled every 2 weeks.

6) Pembrolizumab,fluorouracil and cisplatin Pembrolizumab 200 mg,IV on d 1;

5-Fluorouracil 800 mg/m2,IV daily on d 1-5;

Cisplatin 800 mg/m2,IV on d 1;

Cycled every 3 weeks.

7) Nivolumab,fluorouracil and oxaliplatin (preferred for adenocarcinoma)

Regimen 1:

Nivolumab 360 mg,IV on d 1;

Capecitabine 1,000 mg/m2,P.O.,BID on d 1-14;

Oxaliplatin 130 mg/m2,IV on d 1;

Cycled every 3 weeks.

Regimen 2:

Nivolumab 240 mg,IV on d 1;

Oxaliplatin 85 mg/m2,IV on d 1;

Leucovorin 400 mg/m2,IV on d 1;

5-Fluorouracil 400 mg/m2,IV on d 1;

Then 5-fluorouracil 1,200 mg/m2IV continuous infusion for 24 h daily on d 1-2;

Cycled every 2 weeks.

8) Camrelizumab,paclitaxel and cisplatin (preferred for squamous cell carcinoma)

Camrelizumab 200 mg,IV on d 1;

Paclitaxel 175 mg/m2,IV on d 1;

Cisplatin 75 mg/m2,IV on d 1;

Cycled every 3 weeks.

(4) Second-line and subsequent treatment for advanced disease

1) Camrelizumab monotherapy: Camrelizumab 200 mg,IV on d 1,cycled every 2 weeks.

2) Pembrolizumab monotherapy: Pembrolizumab 200 mg,IV on d 1,cycled every 3 weeks.

3) Nivolumab monotherapy: Nivolumab 3 mg/kg,IV on d 1,cycled every 2 weeks.

(Note: At present,CFDA has only approved nivolumab for the third-line treatment of advanced or recurrent EGJ adenocarcinoma and gastric cancer,while its indication on second-line and subsequent treatment of advanced esophageal squamous cell carcinoma has not been approved.)

4) Tislelizumab monotherapy: Tislelizumab 200 mg IV on d 1,cycled every 3 weeks.(Note: Tislelizumab will be recommended for second-line treatment on advanced esophageal or EGJ cancer when it is approved by CFDA.)

5) Taxane monotherapy:

Regimen 1:

Paclitaxel 175 mg/m2,IV on d 1;

Cycled every 3 weeks.

Regimen 2:

Albumin-bound paclitaxel (abraxane) 100-150 mg/m2,IV on d 1 and d 8;

Cycled every 3 weeks.

Regimen 3:

Docetaxel 75-100 mg/m2,IV on d 1;

Cycled every 3 weeks.

6) Irinotecan monotherapy: Irinotecan 150-180 mg/m2,IV on d 1;

Cycled every 2 weeks.

7) Irinotecan and tegafur:

Irinotecan 160 mg/m2,IV on d 1;

Tegafur 40-60 mg P.O.,Bid on d 1-10;

Cycled every 2 weeks.

8) Apatinib (preferred for adenocarcinoma): Apatinib 250-500 mg P.O.continuously.

Assessment of therapeutic effects is shown inAppendix F.

3.3.6 Prophylaxis and treatment of chemotherapyassociated complications

Regular lab tests should be scheduled during chemotherapy based on the characteristics of different regimens.Supportive care should also be given if necessary.

Bone marrow suppression,gastrointestinal reactions and hepatorenal malfunction are the most common side effects of chemotherapy.The toxicity profiles of immunotherapy and targeted therapy drugs differ from those of chemotherapy and should be taken into account during treatment.

(1) Bone marrow suppression

CBC test once or twice per week is recommended after chemotherapy.The interval between two CBC tests can be different according to the regimen of chemotherapy and results of patients’ CBC test.Chemotherapy should be paused if grade 3-4 leukopenia or neutropenia occurs.Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor(GMCSF) should be given to these patients.The next cycle of chemotherapy may need to be delayed,or the dose of future chemotherapy may need to be adjusted.Interleukin-11 (IL-11) or recombinant human plateletin (TPO) should be given when platelet ＜50×109/L.If necessary,hemostatic agents should be considered.Prophylactic G-CSF or TPO may also be considered according to results of patients’CBC and regimen of the chemotherapy.

(2) Gastrointestinal reactions

Chemotherapy-associated nausea and vomiting: It usually occurs several hours or days after chemotherapy.Single or combined use of 5-HT3 receptor inhibitor,glucocorticoid and neurokinin-1 receptor inhibitor is an option for treatment. Combination of metoclopramide and diphenhydramine improves the effect of antiemetic,and helps control extrapyramidal symptoms.The disorder of water and electrolytes caused by serious vomiting needs to be closely monitored and corrected.

Loss of appetite: It is especially common in postoperative patients.Since the digestive system has been changed by surgery,nutrition support deserves more attention during chemotherapy.Oral nutrition supplements or appetite increasing agents,such as megestrol acetate,can be given.Enteral nutrition support can be given through placed gastric or jejunal nutrition tube.If necessary,parental nutrition support should be considered.

Diarrhea: Patients should avoid the intake of cold water and food rich in coarse fiber.Timely anti-diarrheic agents are needed.The chemotherapy should be paused if the diarrhea lasts more than 5 consecutive days or bloody diarrhea is observed,and dehydration and disorder of electrolytes need to be corrected.

(3) Malfunction of liver and kidneys

The history of hepatitis before chemotherapy is essential to know.We recommend hepatorenal function test once per cycle of chemotherapy.Once liver damage occurs,overall hepatic function assessment and liver-protecting agents should be given.For patients with renal insufficiency,the nephrotoxic agents are contraindicated.If the chemotherapy regimen includes nephrotoxic agents such as cisplatin,enough hydration should be given,and physicians should pay attention to the interactions of different agents.

(4) Neurotoxicity

Before the infusion of oxaliplatin,patients should be instructed not to touch any cold objects.Neurotrophic drugs should also be given.The chemotherapy should be stopped if serious neurotoxicity occurs.

(5) Anaphylaxis

Prophylactic glucocorticoids,H2receptor inhibitor or diphenhydramine may decrease the possibility of anaphylaxis.If the regimen of chemotherapy includes agents with high possibility of anaphylaxis,patients should be closely monitored in the first 2 h after infusion of the agent.The infusion should be stopped immediately once anaphylaxis occurs.The emergent treatment includes epinephrine,glucocorticoids,oxygen inhalation and vasopressors.

(6) Immune-related adverse reactions

The immune checkpoint inhibitors may induce immunerelated adverse reactions.For patients with history of autoimmune diseases,the treatment decision should be made cautiously.All patients accepting immune checkpoint inhibitor treatment should be closely monitored.It is recommended to monitor CBC,hepatorenal function,myocardial enzymes,and thyroid function for these patients during the whole treatment.If non-specific symptoms like fatigue occur,test of adrenocorticotrophin

(ACTH) and cortisol should be considered.If symptoms like tachypnea,productive cough,fever,chest pain and hemoptysis occur,chest image test should be considered.If immune-related adverse reactions are diagnosed,immune checkpoint inhibitors should be suspended or permanently discontinued depending on severity of the reactions,and treatment for adverse reactions should be followed.Serious adverse reactions such as immune-related pneumonitis or myocarditis can rapidly become fatal and should deserve more attention.If necessary,immunosuppressive therapy such as glucocorticoids should be used quickly and aggressively.

(7) Common adverse reactions of apatinib

The most common adverse reactions of apatinb include albuminuria,leukopenia/neutropenia,hypertension,handfoot syndrome,transaminase elevation,etc. During treatment with apatinib,blood pressure should be monitored and regular CBC,hepatorenal function,and urine tests should be conducted.If necessary,the drug should be discontinued and treatment on the adverse reactions should be given.

3.3.7 Follow-up after systemic therapy

(1) For patients with resectable esophageal cancer who accept neoadjuvant chemotherapy,therapeutic effect should be assessed in time.We recommend H&P before every cycle of chemotherapy,and imaging tests after 2-3 cycles of chemotherapy.If results of above tests indicate progress of disease,chemotherapy should be discontinued and the resectability of the tumor should be reassessed.For resectable lesions,patients should accept surgery in time.

(2) For patients underwent radical surgery who accept adjuvant chemotherapy,we recommend imaging tests after the accomplishment of scheduled chemotherapy because no standard indicators of observation are available.If the patient is asystematic and the disease is stable,we recommend follow-up of every 3-6 months for first 2 years,and then 6-12 months for the following 3 years,and then annually since then.The routine tests include H&P,imaging tests,CBC,blood biochemistry or endoscopy,if necessary.

(3) For patients with metastasized esophageal cancer who accept palliative chemotherapy,we recommend imaging tests after scheduled chemotherapy end because of short median duration of remission.If the patient is asystematic and the disease is stable,we recommend follow-up of every 2 months.The routine tests include H&P,imaging tests,CBC,blood biochemistry or endoscopy,if necessary.

3.4 Endoscopic therapy

3.4.1 Preoperative assessment of endoscopic treatment on early esophageal cancer

Endoscopic mucosal resection (EMR) is recommended for early esophageal cancer without lymph node metastasis.For patients the depth of invasion was pathologically diagnosed as SM2 or SM3,even without clinically suspected lymph node metastasis,surgery is still the preferred treatment. Therefore,the preoperative assessment of invasion and extent of tumor,and involvement of lymph nodes are essential for selection of reasonable treatment and prognosis prediction.The extent of the lesion is mainly assessed by chromoendoscopy and digital chromoendoscopy,while the depth of the lesion is mainly assessed by endoscopic ultrasound,squamous epithelial IPCL classification and endoscopic feature of the lesion. However,the uniform standard is still not established,and the technique and experience of the operator can easily influence the outcome.The golden standard is still pathology after EMR.

3.4.2 Principle of endoscopic therapy for early-stage esophageal carcinoma

Comparing with traditional radical surgery,endoscopic mucosal dissection for early esophageal cancer/precancerous lesion has similar prognosis,less surgical trauma and complications,faster recovery and less expenses.The endoscopic mucosal dissection is advantageous as it takes into account both clinical diagnosis and treatment and may improve the quality of life by preserving esophagus.It is recommended for patients with cTis-1aN0M0 esophageal cancer,including high-grade dysplasia,esophageal cancer limited in epithelium (M1) or lamina propria mucosa (M2),and lesions invading into muscularis mucosa (M3) or superficial submucosa (SM1) but without vascular/nerve invasion or enlarged regional lymph nodes around the esophagus.If the lesion extends more than 3/4 cycle of the esophagus,the endoscopic treatment is not recommended for those who are at high risk of postoperative stenosis after evaluation by experienced endoscopists.

3.4.3 Methods of endoscopic mucosal dissection

Endoscopic mucosal dissection mainly includes EMR,multi-band mucosectomy (MBM) and endoscopic submucosal dissection (ESD).

(1) EMR

EMR is endoscopicen blocdissection or part by part dissection of mucosal lesions.It is a method for diagnosis and treatment of superficial esophageal tumors.It includes techniques like EMR with a cap (EMRC),EMR with ligation (EMRL) and endoscopy piecemeal mucosal resection (EPMR),which is established on basis of traditional submucosal injection-lifting-dissection method.Different EMR techniques share similar mechanisms that separate submucosa and muscularis propria by submucosal injection,and then dissect regional lifted mucosal lesions by different methods.

EMRC aspirates lesions by a transparent cap on top of the endoscope,and then dissects the lesion.It is easy to operate with less complications,however the range of resectable mucosa is limited by the size of the cap.EMRL ligates the lesion to block the blood flow first,and then dissects the lesion after the formation of sub-pedicle.EMRL has clear field and less bleeding.EPMR is employed for big lesions that cannot be completely dissected by single traditional EMR.This technique dissects the lesion part by part and is suitable for large flat lesion ＞2 cm.However,the part-by-part dissected specimen can hardly be jointed together to evaluate the outcome of dissection,and easily leads to residual lesions or recurrence.

(2) MBM

MBM is a modified multi-mucosa dissection technique on basis of esophageal varices ligator.The main process includes marking,capped dissection and treatment of the wound.Compared with EMR,MBM obviously shortens the operation time as submucosal injection is not needed.In addition,MBM is effective,safe,easy to operate and inexpensive.The endoscopic physician should follow the standard operation process to avoid residual of the lesion.

(3) ESD

ESD is a method to completely dissect the diseased mucosa and submucosa for lesions of various location,size and depth of invasion.In ESD,the tissue between mucosa and muscularis propria is separated by a special electric scalpel after submucosa injection.The whole procedure includes 5 steps: 1) marking the lesion;2) submucosal injection to lift the lesion;3) partial or circled dissection of the mucosa;4)submucosal decollement to completely separate the mucosa and propria muscularis,and then completely remove the lesion once for all;and 5) treatment of the wound:including treating the vessels of the wound and check-up of the lesion margin.The classical ESD has been modified to channel mucosal decollement (mark-injection-distal opening-proximal dissection-establishment of the channeldissect from both sides).This technique can also be utilized to treat esophageal lesions with large areas.

3.4.4 Complications and treatment of endoscopic therapy

Although it is a minimal invasive treatment,endoscopic dissection can still lead to complications because of the influence of equipment,technique,experience of the operator and patients’ status. The most common complications are bleeding,perforation,postoperative esophageal stenosis and infection.

(1) Bleeding

Intraoperative bleeding refers to the local wound bleeding that needs hemostatic therapy (electrocoagulation or hemostatic clips); delayed postoperative bleeding presenting with hematemesis and melena in 30 d after the operation,and hemoglobin dropping more than 20 g/L.Bleeding in EMR is associated with the size of the lesion.Lesions ＞2 cm greatly increase the risk of intraoperative and postoperative bleeding.Intraoperative bleeding occurs more in hybrid electric dissection,while postoperative bleeding occurs more in coagulation current dissection.The possibility of ESD-associated bleeding may be influenced by the location,size,type and adhesion of the lesion,layer of the dissection,distribution of vessels,and experience of the operator.

(2) Perforation

The risk of intraoperative perforation is higher in ESD than in EMR.It can usually be noticed in time during operation.Postoperative perforation should be considered if physical examinations find subcutaneous emphysema around front chest or neck and face,or chest X-ray/CT reveals mediastinal air. The perforation in ESD is associated with experience of the operator,location and extent of the lesion,and the existence of ulcer besides the lesion.Utilization of CO2gas during operation and prophylactic clipping of damaged muscular layer help decrease the incidence of perforation while exposure of wounded muscular layer may increase the possibility of perforation.Massive gas accumulation in the digestive tract may cause break of the small muscular layer wound to form perforation.Therefore,the gas in the digestive tract should be exhausted promptly during the operation. Strict adherence to indications of endoscopic dissection,sufficient submucosal injection,and suitable equipment may also help prevent perforation.

(3) Esophageal stenosis

It refers to the stenosis of the esophageal lumen after endoscopic dissection that needs endoscopic treatment.This kind of stenosis usually occurs in 1 month after operation and presents with various degree of dysphagia.The extent,depth of invasion of the lesion,and circumferential ratio and longitudinal length of the wound are common risk factors of postoperative esophageal stenosis.More than 3/4 circle of esophageal lesion dissection increases the incidence of stenosis after endoscopic dissection to 88%-100%.

3.4.5 Endoscopic treatment other than mucosal resection

(1) Radiofrequency ablation (RFA)

RFA utilizes the heat effect of electromagnetic wave to lead dehydration and coagulation necrosis of the tumor,so as to achieve the goal of treatment.The depth of the therapy can be controlled around 1,000 μ m to decrease incidence of peroration and postoperative stenosis.It can be utilized for patients with multiple,long lesions,or early esophageal cancer or precancerous lesions that involve full circumference of esophagus but intolerant to or refuse surgery.

(2) Photodynamic therapy (PDT),argon plasma coagulation (APC),laser therapy,thermal probe therapy and cryotherapy

These techniques can be utilized solely or in combination with endoscopic resection.PDT utilizes special laser to provoke the selectively gathered photosensitizer around the tumor to produce singlet oxygen that leads to tumor necrosis through complex physics,chemical and immune mechanism.It can be used on the treatment of large,multiple early lesions.The physicians should take care of the complications such as photosensitive reaction and postoperative perforation. APC is a non-contact thermocoagulation method. It can effectively treat precancerous lesions of esophagus while the indication on treatment of early esophageal cancer should be strictly controlled. The non-resection treatment causes the destruction of lesions and cannot get tissue specimens for precise pathological assessment.In addition,whether the tumor is completely removed also cannot be assessed.Close follow-up is needed,and long-term therapeutic outcome still needs further confirmation. Patients with contraindications of esophageal mucosal dissection or ablation can consider these techniques.

3.4.6 Follow-up after endoscopic therapy

The follow-up of esophageal precancerous lesions and early esophageal cancer after endoscopic resection should be at postoperative 3,6 and 12 months,and then annual endoscopy if no recurrence occurs. The follow-up requirement for patients with mild dysplastic hyperplasia is every 3 years,and for patients with moderate dysplastic hyperplasia is once a year.Combination of staining and/or magnifying endoscopy during follow-up is needed.For esophageal mucosal lesions,the wound after endoscopic resection should be carefully observed.Staining or NBI may be utilized if necessary.Endoscopic re-treatment helps decrease recurrence rate if remnant lesions are found.The remnant or recurrent mucosal lesions can usually be completely removed endoscopically.Further surgery or radiochemotherapy can be added to patients with failed endoscopic treatment.Biopsy and pathological assessment should be done if positive or suspected lesions are found.In addition,imaging tests related to diagnosis of esophageal carcinoma should not be ignored,and physicians should be alert about multiple primary esophageal squamous cell carcinoma and second primary cancer (e.g.,head and neck squamous cell carcinoma,gastric cancer,etc.).

3.5 Pathological assessment

3.5.1 Source and fixation of specimens

(1) Source of specimens

Source of specimens includes: specimens from endoscopic biopsy,EMR/ESD and radical surgery resection.

(2) Fixation of specimens

Fixation of specimens should be timely and sufficient.Neutral buffer formalin fixative solution (10%) should be utilized as soon as possible (best immediately after the specimen is acquired;the surgical dissected specimen should be fixated in 30 min).The volume of the fixative solution should be more than 10 times than that of specimens.The fixation time is 6-72 h.

Specimens from endoscopic biopsy: after the separation of the specimen,endoscopy physician or his/her assistant should obtain the tissue from the biopsy forceps and unbend the specimen on his/her finger.Place the unbend mucosa on the surface of a piece of small filter paper,and then place it into the fixative solution immediately.

Specimens from EMR/ESD: the endoscopy physician should unbend the specimen with the surface of the mucosa faced up,and then fix the specimen on cork board (or foam board) by fine-steel needles.The specimen should be fixed without folds or excessive traction (which may cause deformation of specimens) should be avoided.The specimen should be immersed completely into the fixative solution after the distal and proximal margins have been marked respectively.

Specimens from radical dissection: disclosing the esophageal wall alongside the opposite side of the tumor.With the mucosa faced up,fixing the specimen on cork board (or foam board) covered with gauge by pins.Then prone the mucosa and then immerse the specimen into the fixative solution as soon as possible (in 30 min after separation of the specimen).

3.5.2 Tissue dissection and gross description

(1) Verification

Before tissue dissection,basic information should be verified (i.e.,name,submitting department,bed ID,admission number and type of the specimen,etc.).

(2) Specimens from biopsy

1) Gross inspection and recording: describing the size and number of the submitted tissue.

2) Tissue dissection: All the submitted mucosa should be dissected.The mucosa should be kept in folded filter paper to secure no loss.Eosin should be added to help the specimen be recognized by technicians during embedding and dissection.Specimens with different sizes should be placed in different dehydration boxes to avoid missing or over-cut of the small tissue.The unfolded flat mucosa should be embedded vertically (the mucosa is perpendicular to the bottom of the embedding box).One paraffin block should include no more than 3 parallel,vertically embedded slices (since most of the precancerous lesions and early esophageal cancer are flat,and the diagnosis of these lesions needs to understand the ratio of the dysplastic cells that invaded to the squamous epithelial layers,and whether the propria lamina mucosa is involved.The requirement on the clarity of the tissue layers is strict.The above-described methods of unfolding and embedding can secure the layers of the tissue be presented clearly,which are essential for the accurate diagnosis of early esophageal cancer and precancerous lesions).The margin of the paraffin block that does not contain tissues should be removed by knife.We recommend 6-8 consecutive tissue slices on every glass sheet for observation.

3.5.3 Specimens from EMR/ESD

(1) Gross inspection and record

The size of the specimens (length × width × thickness)needs to be measured and recorded.The length and width of the esophagus and stomach should be measured respectively for esophagogastric junction specimens.Other features that need to be recorded include color of the mucosa,existed visible lesions,shape of the lesions,obvious bumps or depressions,erosion or ulcers,size of the lesions(length × width × thickness),gross type,and distance between the lesion and margin of the specimens (at least the distance between the lesion and the nearest margin of the mucosa should be recorded).The dissected multi-block specimens should be reconstructed before fixation by the surgeon on basis of endoscopic outline of the lesion/outline of iodine unstained area (esophageal squamous epithelial lesions).Before the treatment of complex specimens,communication between surgeons and pathologists,or sketch map on extension and reconstruction of the specimen provided by the surgeon is recommended.

(2) Tissue dissection

All the specimens should be selected.Iodine solution is preferred (taking the specimen out of fixative solution and washing it at least 30 min before iodine staining) for identification of the lesion (unstained area) and the nearest margin.The specimen should be cut vertically to the nearest margin.To locate the margin and assess its condition,the margin of the mucosa and the base need to be marked by prepared Chinese ink or carbon ink (different colors can be utilized to mark distal and proximal margin for differentiation,if possible). The esophagogastric junction specimen should be cut from proximal distal end to demonstrate the relationship between the tumor and the esophagogastric junction.All specimens should be cut parallelly every 2-3 mm.If the specimen is too large,the method of cutting should be modified by dividing one slice into multiple slices,marked with a,b,c,etc.respectively.Embedding vertically on same direction (embedding the first and the last cut slices.If there are any endoscopic lesions are detected,re-embedding after 180° turning,to secure all the margins surrounding the specimen can be observed),and recording the order/location of the embedded specimen.Recording the corresponding location of the tissue block (well-marked picture or sketch map is recommended).We recommend writing numbers and cut the multiple dissected specimens,regardless of the condition of the margin.

3.5.4 Specimens guidelines for radical resection

(1) Gross inspection and record

Recording the length of the dissected esophagus,stomach(if included),and visible or invisible esophagogastric junction.The location of the tumor (based on the description of surgery and endoscopy): cervical esophagus,upper segment of thoracic esophagus,middle segment of thoracic esophagus,lower segment of thoracic esophagus,and esophagogastric junction.Recording the distance between the lesion and the distal or proximal end,the gross type (including description of the appearance),size,color of the slice,quality,depth of invasion of the tumor,and whether the esophagogastric junction is involved(relationship between tumor and esophagogastric junction:tumors completely locate in esophagus without involvement of esophagogastric junction;the center of the tumor locates in the distal esophagus involving the esophagogastric junction;the center of the tumor locates in esophagogastric junction;the center of the tumor locates in the proximal stomach,involving esophagogastric junction).If the esophagogastric junction is involved,distance between center of the tumor and esophagogastric junction should be recorded.Siewert classification is recommended for esophagogastric junction adenocarcinoma.

(2) Tissue dissection

If necessary,iodine solution should be utilized (taking the specimen out of fixative solution and washing it at least 30 min before iodine staining) for identification of the lesion(unstained area) and the nearest margin.One strip of the esophagus cutting from proximal to distal ends (passing center of the tumor) should be embedded (including tumor,paraneoplastic mucosa and both distal and proximal margins).The corresponding location of the tissue block should be recorded (well-marked picture or sketch map is preferred).Longitudinal cutting is recommended while transverse cutting is acceptable if the tumor locates far away from both margins.The submitted margin in the stapler should be all cut for observation.The place where the tumor invaded the deepest,and the suspected involved circumferential resection margin deserves more attention.Prepared Chinese ink or carbon black ink is recommended to mark the circumferential resection margin.For early esophageal cancer,or specimens of radical surgery after neoadjuvant therapy with inconspicuous tumor,all the suspected lesions and tumor beds should be cut.Areas with eroded,rough mucosa or unstained by iodine,nodules in esophageal or gastric wall,and tissues of esophagogastric junction should be dissected respectively. Submitted grouped lymph nodes should be all embedded and dissected. The submitted adjacent organs,such as mediastinal pleura,lung or diaphragm,should be checked and dissected.It is recommended that the size of dissected tissues should be no more than 2.0 cm × 1.5 cm × 0.3 cm.More than 15 lymph nodes should be harvested from patients without neoadjuvant therapy undergoing standard two-or three-field lymph node dissection.

3.5.5 Pathological report

The pathological report of esophageal cancer should include all the contents associated with patients’ treatment and prognosis,i.e.,source of the specimen,location of the tumor,gross classification,size and number of the specimen,histological type,subtype and grade,depth of invasion,vessels and nerve invasion,spread or metastasis in the wall,status of the surrounding mucosa,lymph node metastasis and status of circumference/both proximal and distal margins.Finally,(y)pTNM staging should be noted.

(1) Gross description

Gross description includes source of the specimen,location,gross classification,size (three dimensional measurement of the tumor size should be measured) and number of the tumors.

(2) Primary tumor

Histological type,subtype and grade (Appendix B),depth of invasion [propria lamina mucosa,mucosal muscularis,submucosal,superficial muscularis,deep muscularis,fibrous membranes or surrounding tissues or organs.For cancer invades into submucosa,if the specimen is acquired from endoscopic resection,the depth (μm) of the submucosal invasion should be measured and differentiation between SM1 (depth of submucosal invasion ＜200 μ m) and SM2(depth of submucosal invasion ＞200 μm) is recommended.If the specimen is acquired from radical surgery,differentiation among SM1 (upper 1/3 of submucosa),SM2(middle 1/3 of submucosa) and SM3 (lower 1/3 of submucosa) is recommended],margin (side margin and basement margin for endoscopic specimens; distal,proximal and circumferential margins for radical surgical specimens) (The status of the margins needs to be reported,such as invasive carcinoma,intraepithelial neoplasia/dysplasia,Barrett esophagus,or Barrett esophagus accompanied with intraepithelial neoplasia/dysplasia;distance from the tumor to the margins should be noted;0,＜0.1 cm and ≥0.1 cm system are recommended to report the distance from tumor to the circumferential margin),vessel invasion (especially for endoscopic resected specimens. If vessel invasion is suspected,immunohistochemical CD31,D2-40 tests are recommended for confirmation of vessel invasion,while EVG staining is recommended for diagnosis of venous invasion),nerve invasion and metastasis in the wall.

(3) Paracancerous tissues

Intraepithelial neoplasm/dysplasia and its grade,Barrett esophagus,existence of esophagitis,gastritis,and their types.

(4) Lymph node metastasis

Number of lymph nodes metastasis/total submitted lymph nodes number.The number of the lymph nodes with capsule invasion should be reported.

(5) Response of treatment (after neoadjuvant therapy)

Pathological assessment (Appendix H) should be applied to the specimen from patients underwent neoadjuvant therapy according to the standard of College of American Pathologists (CAP) and ratio of residual tumor cells(Mandard,Becker tumor regression grade,and tumor regression grading of esophageal carcinoma of the Japanese Society of Esophageal Diseases can be referred).

(6) Other accompanied diseases should also be reported.

(7) PD-L1 CPS score.For patients with esophageal squamous cell carcinoma planning to accept PD-1 inhibitor,the PD-L1 CPS score should be assessed in cancer tissues.PD-L1 (Dako22C3) kit has been approved as companion diagnostics of pembrolizumab treatment for esophageal squamous cell carcinoma.CPS≥10 is considered as positive. Immunohistochemistry on HER2 and mismatch repair protein (MLH1,PMS2,MSH2,MSH6)and/or MSI tests should be done for esophagogastric junction adenocarcinoma.

(8) Important history should also be addressed (i.e.,history of tumor and neoadjuvant therapy).

(9) (y)pTNM staging.

3.6 Comprehensive treatment model by stage

UICC/AJCC staging (8th edition) is adopted in the following description.

3.6.1 Stage 0/precancerous lesions

For low-grade intraepithelial neoplasia,regular follow-up is recommended while endoscopic radiofrequency ablation is also accepted.Endoscopic resection (EMR/ESD/MBM) is recommended for high-grade intraepithelial neoplasia,and endoscopic radiofrequency ablation and cryotherapy can also be selected according to clinical conditions.Surgical treatment may also be considered in patients who may have refractory stenosis after ESD due to excessively long lesions or lesions extent ＞3/4 circumference.

3.6.2 Stage I

ESD or EMR is the preferred treatment for T1a lesions.If refractory stenosis may occur after ESD because the lesion is too long or extent ＞3/4 circumference,or lymph node metastasis is suspected,surgery is recommended.Surgery is the preferred treatment for stage I lesions of T1b or later.If the patient refuses to accept surgery,or with cardiopulmonary malfunction,endoscopic ESD plus postoperative radiotherapy is the choice.Postoperative adjuvant therapy usually does not be needed for completely resected(R0 resection) stage I esophageal cancer.

3.6.3 Stage II

(1) Esophageal squamous cell carcinoma

cT2N0M0: Surgery is the preferred treatment.

cT2N0M0 and cT3N0M0: Combination of neoadjuvant therapy and surgery is recommended.

(2) Esophageal adenocarcinoma

cT2N0M0: Surgery is the preferred treatment.

cT1N1M0: Combination of neoadjuvant therapy and surgery is recommended.

If the patient refuses to accept surgery,or with cardiopulmonary malfunction,radical radiochemotherapy should be considered. Neoadjuvant therapy includes preoperative chemotherapy or concurrent radiochemotherapy.

3.6.4 Stage III

Combination of neoadjuvant therapy and surgery is recommended for treatment of both esophageal squamous cell carcinoma and adenocarcinoma.If the patient refuses to accept surgery,or with cardiopulmonary malfunction,radical radiochemotherapy should be considered.For stage III patients unsuitable for surgery,current standard treatment is concurrent radiochemotherapy.

3.6.5 Stage IVa,squamous cell carcinoma or adenocarcinoma

Combination of neoadjuvant therapy and surgery is recommended for treatment of T4a.If the patient refuses to accept surgery,or with cardiopulmonary malfunction,radical radiochemotherapy should be considered.Radical radiochemotherapy or chemotherapy is recommended for treatment of T4b (tumor invades important organs like vertebral body,trachea,aorta or heart).

3.6.6 Stage IVb

The main treatment is systemic therapy and palliative treatment.If the performance status of the patient is good,systemic therapy is recommended.If patients cannot tolerate the above treatment,palliative and supportive care are the main treatment.The destination of the treatment is to prolong life and improve life quality.Palliative treatment includes endoscopic treatment (esophageal dilation,stent,etc.),pain relieving,symptomatic treatment and nutrition support.

3.7 Flowchart of treatment

Figures 1-8show the treatment process of esophageal carcinoma.

Figure 1 Primary treatment options for medically fit patients.cTis-cT1a needs to be confirmed by pathological tests after endoscopic mucosal dissection.If refractory stenosis may occur after ESD due to the lesion is too long or involves 3/4 circumference,surgery is recommended.ESD,endoscopic submucosal dissection.

Figure 2 Management of locally advanced esophageal carcinoma.＊,For cervical esophageal cancer,concurrent radiochemotherapy is recommended;multidisciplinary comprehensive therapy including surgery is also acceptable.＊＊,If tumor invades organs like heart,vertebral body,trachea,aorta,etc,systemic therapy is recommended.

Figure 3 Surgical outcomes and management for squamous cell carcinoma (Patients have NOT received preoperative treatment).

Figure 4 Surgical outcomes and management for squamous cell carcinoma (Patients HAVE received preoperative treatment).＊,Chinese Food and Drug Administration has not approved indications for postoperative adjuvant therapy of esophageal cancer with Nivolumab.Therefore,it can be used for clinical practice after approval.

Figure 5 Surgical outcomes and management for esophageal adenocarcinoma (Patients have NOT received preoperative treatment).

Figure 6 Surgical outcomes and management for esophageal adenocarcinoma (Patients HAVE received preoperative treatment).＊,Chinese Food and Drug Administration has not approved the indication for postoperative adjuvant therapy of esophageal cancer with nivolumab.Therefore,it can be used for clinical practice after approval.

Figure 7 Follow-up/surveillance after esophageal adenocarcinoma treatment (Any histological type).H&P,history &physical examination;CT,computed tomography;MRI,magnetic resonance imaging;GI,gastrointestinal.

Figure 8 Management for unresectable locally advanced,locally recurrent or metastatic esophageal cancer.ECOG,Eastern Cooperative Oncology Group.

3.8 Nutritional support

For patients at risk of nutrition,the nutritional support plan should be developed in time.Nutritional support refers to the method of providing appropriate nutrients for patients who cannot eat through the enteral or parenteral route,including nutritional supplementation,nutritional support and nutritional therapy.There are three ways of support: oral nutrition supplementation,enteral and parenteral nutrition support. Standardized nutritional support should include elements such as the start-up time of nutritional support,pathway selection,nutritional support goals,nutrient selection,and monitoring plan.Surgical procedures for esophageal cancer involve reconstruction of the upper gastrointestinal tract,decreased or loss of gastric acid secretion.Therefore,these patients have special requirements for postoperative nutritional support.

3.8.1 Indications for nutritional support

(1) Weight loss ＞10% in 6 months prior to assessment;

(2) Body mass index (BMI) ＜18.5 kg/m2;

(3) NRS2002 score ≥5;

(4) SGA grade C.

3.8.2 Requirements and pathways of nutritional support

Intensive diets and oral nutritional supplementation are sufficient for most patients with esophageal cancer at risk of nutrition.For patients with an NRS2002 score ≥5 or severe malnutrition whose goal of nutritional support cannot be achieved by oral nutrients only,the enteral nutrition-tube feeding,supplemental parenteral nutrition,or even whole parenteral nutrition should be given to improve the patients’ nutritional status before treatment and the adaptability to stress after treatment.

When formulating a nutritional support plan for cancer patients,the use of indirect calorimetry is recommended to measure the energy consumption individually to guide the energy supply.By this way,the energy intake could be as close as possible to patient’s energy consumption,so as to maintain energy balance and avoid excessive or insufficient intake.If the actual energy expenditure cannot be measured directly to guide the nutrient supply,the weight formula can be used to estimate the energy requirement,which is provided at 25-30 kcal/(kg·d).The recommended protein supplement should be ＞1.2 g/(kg·d) and can be increased to 2.0 g/(kg·d) with normal renal function.

Currently,there is no sufficient evidence to show the advantages of surgical modalities in improving nutritional status and management,and the impact of surgical modalities depends on the experience of the surgeon.The gastrointestinal pathway is preferred for postoperative nutritional support,with tube feeding and/or oral administration.If the tube was placed intraoperatively,enteral nutrition can be initiated within 24 h of surgery.The enteral nutrition infusions begin at a low rate and increase gradually to the daily target volume depending on the patient’s tolerance.In patients with postoperative anastomotic fistula,an individualized nutritional support program should be formulated according to the severity of the fistula,the performance status and nutritional needs of the patient.Enteral nutrition support of any pathway or combined parenteral nutrition support should be considered.

3.8.3 Family nutrition support after discharge

Patients with esophageal cancer still need regular nutrition assessment after discharge. Nutritional support is recommended for those with persistent severe malnutrition. Dietary guidance combined with oral nutritional supplement is preferred for discharged patients.The placed nutrition tube can be retained at the time of discharge for the need of family enteral nutrition support.Family nutrition support should be implemented and continuously improved under the guidance of an experienced nutritional support team (including physicians,dietitians,pharmacists and nurses).

3.9 Palliative therapy

Palliative therapy is also called best supportive care.It is a multi-dimensional comprehensive management for symptom relief and improvement in quality of life.A multimodality interdisciplinary approach is especially needed.

3.9.1 Dysphagia

Dysphagia often arises due to obstruction,or is associated with esophageal cancer-leaded dysmotility.At present,no standardized scoring scale on severity of swallowing impairment in China is available for clinical practice.The transnasal tube or gastrostomy/jejunostomy catheterization for temporary nutritional support may be considered.For patients with dysphagia who are not candidates for curative surgery,esophageal stent can be considered after multidisciplinary counselling.

3.9.2 Complete obstruction

The goal of palliative care in patients with complete obstruction of the upper gastrointestinal tract is to maintain the daily nutritional intake.The preferred nutritional support pathway is upper gastrointestinal bypass(gastrostomy/jejunostomy catheterization).Based on this method,experienced endoscopic centers may consider esophageal endoscopic balloon dilation,covered stent placement after ablation therapy,or chemoradiotherapy.

3.9.3 Upper gastrointestinal hemorrhage

Once symptoms of upper gastrointestinal bleeding such as hematemesis and melaena occur,it indicates that the esophageal cancer is on the verge of terminal stage,and the primary tumor rupture or secondary esophageal-aortic fistula occurs.Treatment such as endoscopy,intervention,or surgery may be considered as appropriate depending on the medical conditions and the patient’s status.Server anemia and hemorrhagic shock should be prevented by close monitoring of hemoglobin levels,and management with hemostatic and acid suppressing drugs.

Working group members

Group leader:Lyuhua Wang

Associate group leaders:Jinming Yu,Zhentao Yu,Yin Li

Group members:Jun Wang,Guiqi Wang,Feng Wang,Zhen Wang,Xin Wang,Junfeng Liu,Yongkun Sun,Zhigang Li,Yong Li,Keneng Chen,Xinming Zhao,Shuoyan Liu,Hongjing Jiang,Jianjun Qin,Jing Huang,Xiaozheng Kang,Yongtao Han,Zhouguang Hui,Jianhua Fu,Lijie Tan,Liyan Xue

Translation group members

Nan WuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Yuan FengKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Appendix A

Paris classification is recommended for early/superficial esophageal carcinoma (same as Japanese gross classification of early/superficial esophageal carcinoma,that is,Type 0):

1.Protruded (0-I): including pedunculated (0-Ip) and sessile (0-Is) subtypes;

2.Flat (0-II): including elevated (0-IIa),flat (0-IIb) and depressed (0-IIc) subtypes.According to the elevation/depression proportion,lesions with both superficial elevation and depression are classified into 0-IIc+IIa and 0-IIa+IIc subtypes;

3.Excavated (0-III): Lesions with both excavation and superficial excavation are classified into 0-IIc+III and 0-III+IIc subtypes according to the proportion of excavation and superficial excavation.

Appendix B

Table A1 WHO classification of esophageal carcinomas (referring to the 2019 WHO classification of tumors of the digestive system)

Appendix C

Table A2 TNM staging of esophageal carcinoma (UICC/AJCC 8th edition,2017)

Table A3 Clinical TNM staging of squamous cell carcinoma and adenocarcinoma of esophagus (cTNM)

Table A4 Pathological TNM staging of squamous cell carcinoma and adenocarcinoma of esophagus (pTNM)

Note:

1.HGD,high-grade dysplasia.

2.Number of harvested regional lymph nodes should be more than 15 to achieve accurate staging.

3.Location (primary cancer site) is defined by position of the tumor epicenter (divided into upper,middle and lower segment of esophagus.Upper esophagus=cervical esophagus+upper thoracic esophagus;middle esophagus=middle thoracic esophagus;lower esophagus=lower thoracic esophagus+abdominal esophagus).

4.Tumors invading esophagogastric junction (EGJ),or with a midpoint in the esophagus side of EGJ,or within the proximal 2 cm of the stomach side (Siewert types I and II) are classified as esophageal cancer for staging purposes;Tumors with a midpoint in the stomach more than 2 cm distal to the EGJ (Siewert type III) are staged using the gastric cancer staging system.

5.Basal cell-like squamous cell carcinoma,spindle cell squamous cell carcinoma,small cell carcinoma,large cell neuroendocrine carcinoma and undifferentiated carcinoma are staged as poorly differentiated squamous cell carcinoma.Mixed carcinomas with squamous cell carcinoma components (e.g.adenosquamous carcinoma) or histologically unidentified carcinoma are staged as squamous cell carcinoma.

6.Neuroendocrine tumors (NETs) of the esophagus are rare,and their staging is based on the TNM staging of gastrointestinal neuroendocrine tumors.

7.This staging system is not suitable for non-epithelial tumors such as lymphoma,sarcoma,gastrointestinal stromal tumor and melanoma.

8.At present,there are two major TNM staging systems for esophageal cancer in the world.The Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system considers supraclavicular lymph node metastasis as M1 and the lymph nodes around celiac trunk are still regional lymph nodes.However,the Japanese Esophageal Society (JES) consider the supraclavicular lymph nodes are still regional lymph nodes of thoracic esophageal carcinoma while the celiac lymph nodes are not.

Table A5 Pathological TNM staging (ypTNM) after neoadjuvant therapy for esophageal cancer

Appendix D

Table A6 Nutritional risk screening 2002

Appendix E

Table A7 GLIM criteria

Appendix F Response evaluation criteria for radiotherapy and chemotherapy

1.WHO response evaluation criteria for solid tumors (1981)

Complete response (CR),disappearance of all lesions for at least 1 month.

Partial response (PR),the product of the two largest perpendicular diameters of the tumor had deceased by ＞50%,no progression of other lesions,for at least 1 month.

Stable disease (SD),the product of the two largest perpendicular diameters of the tumor had deceased by ≤50%,increased by≤25%,for at least 1 month.

Progressive disease (PD),the product of the two largest perpendicular diameters of the tumor had increased by ＞25%.

2.RECIST response evaluation criteria (2000)

2.1 Evaluation of target lesions

Complete response (CR),disappearance of all target lesions.

Partial response (PR),at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Progression disease (PD),at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Stable disease (SD),neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

2.2 Evaluation of non-target lesions

Complete response (CR),disappearance of all non-target lesions and normalization of tumor marker level.

Non-complete response/stable disease (IR/SD),persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Progression disease (PD),appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

3.Evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence.In general the patient’s best response assignment will depend on the achievement of both measurement and confirmation criteria.

Appendix G

Table A8 Karnofsky scoring (KPS,percentage)

Table A9 Zubrod-ECOG-WHO score (ZPS,five-grade system)

Appendix H Pathological response assessment after neoadjuvant therapy

Pathological regression after preoperative neoadjuvant chemotherapy/radiotherapy significantly correlates with prognosis.

Table A10 Pathological response criteria following neoadjuvant therapy according to CAP/NCCN guidelines

Appendix I Terms and definitions (applicable for the guidelines)

1.Esophageal cancer

Cancer arises from esophageal epithelium ranging from the beginning of esophagus continuing from hypopharynx to the esophagogastric junction.It mainly includes two types: esophageal squamous cell carcinoma and esophageal adenocarcinoma,and other rare types of malignancies.

1.1 Squamous cell carcinoma of esophagus

A malignant epithelial cell tumor originating from esophageal epithelium with squamous cell differentiation.

1.2 Adenocarcinoma of the esophagus

A malignant epithelial cell tumor mainly originating from adenoid differentiated Barrett mucosa of the lower 1/3 esophagus,occasionally originating from the ectopic gastric mucosa of the upper esophagus,or the proper glands of the esophagus.

2.Barrett esophagus

The squamous epithelium of the lower segment of esophagus is replaced by single columnar epithelium.

3.Precancerous diseases and precancerous lesions of the esophagus

Precancerous diseases include chronic esophagitis,Barrett’s esophagitis,esophageal leukoplakia,esophageal diverticula,esophageal achalasia,esophageal casts,reflux esophagitis and benign esophageal stricture.

Precancerous lesions are characterized by different levels of atypical squamous cells in esophageal squamous epithelium.According to depth of the lesion invasion,they include low grade intraepithelial neoplasia/dysplasia (confined to upper onehalf of the squamous epithelium) and high-grade intraepithelial neoplasia/dysplasia (tumor invasion exceeds lower one-half of esophageal squamous epithelium,known as carcinoma in situ formerly).