National Health Commission guidelines for diagnosis and treatment of colorectal cancer 2023 in China (English version)

1. Overview

The incidence and mortality of colorectal cancer (CRC) in China have been on the rise. The Cancer Statistics Report of China in 2020 showed that the incidence and mortality of CRC ranked second and fifth among all malignant tumors, of which 555,000 new cases and 286,000 deaths. Among them, cities were much higher than rural areas, and the incidence of colon cancer had increased significantly. Most patients were already in the advanced stage at the time of diagnosis.

Screening can lead to a reduction in the incidence and mortality of CRC. The results of government-organized population-wide CRC screening in Tianjin, Shanghai, Zhejiang, and Guangzhou have also demonstrated the benefits of CRC screening. The currently recommended screening protocol for CRC is primarily a risk assessment and fecal occult blood test followed by colonoscopy if positive. In recent years, fecal DNA testing can further improve the effectiveness of fecal screening for CRC. Foreign experience also shows that direct application of colonoscopy once every 3−5 years in areas with more developed medical resources can also achieve better screening results.

The diagnosis and treatment of CRC may involve surgery, chemotherapy, radiotherapy, imaging evaluation, pathological evaluation and endoscopy, etc. Studies have shown that the model of multi-disciplinary team (MDT) can improve the diagnosis and treatment of CRC. In order to further standardize the diagnosis and treatment of CRC in China, improve the level of medical institutions, improve the prognosis of CRC patients, and ensure the quality and safety of medical treatment, this guideline is formulated.

2. Diagnosis

2.1. Clinical manifestations

Early CRC may have no obvious symptoms, and the following symptoms may occur when the disease develops to a certain extent:

(1) Changes in bowel habits;

(2) Changes in stool characteristics (thinning, bloody stools, mucus stools, etc);

(3) Abdominal pain or discomfort;

(4) Abdominal mass;

(5) Symptoms related to intestinal obstruction;

(6) Systemic symptoms: such as anemia, weight loss, fatigue, low fever, etc. Lumbosacral pain, jaundice, ascites may occur in advanced patients.

2.2. Disease history and family history

(1) The incidence of CRC may be related to the following diseases: ulcerative colitis, colorectal polyps, colorectal adenoma, Crohn’s disease, schistosomiasis, etc. The patient’s relevant disease history should be asked in detail.

(2) The incidence of hereditary CRC accounts for about 6% of the total incidence of CRC. Patients should be asked in detail about family history: Lynch syndrome, familial adenomatous polyposis (FAP), etc.

2.3. Physical examination

(1) General condition evaluation, nutritional status evaluation, superficial lymph nodes throughout the body, especially the inguinal and supraclavicular lymph nodes.

(2) Abdominal inspection and palpation to check for abdominal bulge, intestinal type, intestinal peristaltic wave and abdominal mass; abdominal percussion and auscultation to check for shifting dullness and abnormal bowel sounds.

(3) Digital rectal examination (DRE): For those with suspected CRC, a DRE must be routinely performed. The knee-chest or left-sided flexed knee position is recommended to clear the size, shape, texture, direction, range of intestinal wall circumference of the rectal tumor, the basal activity, the distance of the lower margin of the tumor from the anal margin and dentate line, the tumor’s invasion into the intestine, the relationship with the surrounding organs, and the presence of pelvic floor implants, while observing if there is blood on the finger stall.

(4) Vagino-recto-abdominal examination: For female patients with rectal cancer suspected of having tumors invading the vaginal wall, a vagino-recto-abdominal examination is recommended to clear the relationship between the mass and the posterior vaginal wall.

2.4. Clinical laboratory examinations

(1) Blood routine test: check for anemia.

(2) Urine routine test: test for hematuria, and combined with urinary imaging examination to understand whether the tumor invades the urinary system.

(3) Stool routine test: test for red blood cells and white blood cells.

(4) FOBT: has great value in the diagnosis of small amount of gastrointestinal bleeding.

(5) Test for blood biochemistry, blood electrolytes, liver and renal function.

(6) Peripheral blood carcinoma embryonic antigen (CEA) and carbohydrate antigen (CA)19-9 must be detected in patients with CRC at the time of diagnosis, before treatment, estimating curative effect and follow-up. Alpha fetoprotein (AFP) detection is recommended for patients with liver metastases. CA125 detection is recommended for patients with suspected peritoneal and ovarian metastases.

2.5. Endoscopy

Colonoscopy is recommended for all suspected CRC patients, except:

(1) Poor general conditions, difficult to tolerate;

(2) Acute peritonitis, intestinal perforation, extensive adhesion in abdominal cavity;

(3) Perianal or severe intestinal infection.

The endoscopic report must include: depth of view, size of the tumor, distance from the anal margin, morphology and extent of local infiltration. Pathological biopsies must be performed on suspicious lesions.

Since the colon may be wrinkled during examination, errors maybe exist in the distance between the distal side of the tumor and the anal margin in endoscopy. It is recommended to determine the lesion site with CT, MRI or barium enema.

2.6. Imaging

2.6.1. Common testing

(1) CT

1) Pre-processing and image reconstruction methods: CT plain and enhanced scans are recommended after cleansing the colon and having the patient drink 2,000 mL of water containing 2.5% mannitol to fill the bowel if clinically possible; injection of scopolamine is not routinely recommended to inhibit bowel motility; reconstruction including axial, sagittal, coronal and multi-angle is recommended.

2) CT is recommended for diagnosis of colon cancer, determination of clinical stage of colon cancer and distant metastasis of rectal cancer, evaluation of the effect of neoadjuvant or translational therapy for CRC and follow-up screening for local recurrence and distant metastasis.

I. CT-enhanced scans are recommended to determine clinical stage of colon cancer (cTNM) and non-regional lymph node metastases and distant metastases (cM) in rectal cancer; chest CT scan is recommended to determine lung metastases in CRC; CT-enhanced scans are recommended to determine local recurrence, lymph node metastases and distant metastases in CRC at follow-up.

II. CT-enhanced scans are recommended to evaluate the effect of neoadjuvant or translational therapy for primary colon cancer and CRC metastases.

III. In patients with contraindications to MRI, CT-enhanced scans are recommended to determine cTNM staging of rectal cancer, but CT is of limited value to determine extramural vascular invasion (EMVI), potential circumferential resection margin (CRM), and low perirectal complex.

IV. CT-enhanced scans are recommended to determine the nature of intramucosal or extrinsic compression lesions in the submucosal bowel wall as indicated by endoscopy; CT-enhanced scans are recommended for the differential diagnosis of tumors and tumor-like lesions similar to CRC, such as lymphomas, gastrointestinal mesenchymal tumors, metastases, and inflammatory pseudotumors.

(2) MRI

1) Pre-MRI management: Emptying the bowel before pelvic MRI scanning is recommended, overfilling the rectum is not routinely recommended, and injection of scopolamine to inhibit bowel motility is not routinely recommended.

2) MRI recommended imaging protocols: Non-fat-suppressed, high-resolution T2-weighted phase, including sagittal, perpendicular to the tumor axis and oblique imaging parallel to the tumor axis; diffusion-weighted imaging (DWI) axial imaging; additional imaging may include sagittal, coronal and axial enhanced scans.

3) Pelvic MRI is recommended to determine the cTNM stage of rectal cancer; upper abdominal MRI is recommended to diagnose liver metastases; pelvic MRI is recommended to evaluate the effect of neoadjuvant or translational therapy for primary rectal cancer and liver metastases, and to screen for local recurrence.

I. Pelvic MRI is recommended to determine cTNM stage, lateral lymph node metastasis, EMVI and potential CRM status before surgery, neoadjuvant or conversion therapy for rectal cancer; pelvic MRI is recommended to evaluate the effect of neoadjuvant or conversion therapy; pelvic MRI plain and enhanced scans are recommended to determine local recurrence of rectal cancer that cannot be confirmed by CT.

II. If the diagnosis cannot be confirmed on CT-enhanced scan, or if liver metastases are not visible on CT-enhanced scan after neoadjuvant therapy or conversion therapy, upper abdominal MRI scan and enhanced scan or, if necessary, enhanced MRI with a hepatocyte-specific contrast agent (e.g., Gd-EOB-DTPA) are recommended as further diagnostic methods.

III. CT enhancement scan cannot confirm the diagnosis of tumors and tumor-like lesions similar to rectal cancer; MRI plain scan and enhancement scan are recommended for further diagnosis.

(3) Ultrasound

Endorectal ultrasound is firstly recommended to determine the tumor stage of rectal cancer below T2, and CT and MRI are still recommended to diagnose lymph node metastasis (cN) and distant metastasis (cM).

When liver metastases are not shown on CT or MRI enhancement scans after neoadjuvant or conversion therapy, preoperative or intraoperative ultrasonography is recommended to assist in the diagnosis of metastases.

(4) PET/CT

¹⁸F-FDG PET/CT can be recommended as an alternative method for clinical staging of CRC and evaluation of treatment outcomes. ¹⁸F-FDG PET/CT can help detect or identify distant metastases that are missed or suspected by other imaging methods.

(5) X-ray

Gas-barium dual radiography is no longer recommended as a routine screening method for CRC.

2.6.2. Imaging strategies for special types of patients

(1) MRI scan protocol after neoadjuvant chemotherapy for rectal cancer

The first change in patients with rectal cancer after neoadjuvant chemotherapy is the reduction of tumor cell density rather than the reduction of tumor volume. Therefore, the role of functional imaging such as DWI and IVIM-DWI should be highlighted first. In addition, enhancement sequence can effectively identify the inflammatory response, fibrosis and cystic necrosis of tumor tissue after radiotherapy for rectal cancer, and can clearly show the extent of solid tumor components.

(2) Other tumor-like lesion scanning protocols

For colorectal neuroendocrine tumors, DWI and/or IVIM-DWI sequences can more accurately reflect the cell density and microcirculatory perfusion of the tumor; for colorectal mucinous adenocarcinoma, T2WI fat suppression sequences and enhancement sequences are recommended to effectively show the mucus lake within the tumor; for anal canal cancer, small FOV high-resolution oblique transverse axial T2WI sequences are recommended to show the depth of infiltration and the relationship between the anal canal cancer and the anal sphincter complex in high definition. DWI and IVIM-DWI combined with conventional T2WI sequences can effectively assess the efficacy of neoadjuvant chemotherapy for rectal cancer at an early stage and more accurately identify complete response after neoadjuvant therapy.

2.6.3. Recommended imaging methods for postoperative follow-up

Regular postoperative imaging plays an important role in cancer surveillance, and annual CT scans of the chest, abdomen, and pelvis are routinely recommended for the first 5 years after resection. For rectal cancer patients after surgery, rectal MRI follow-up is preferred if available; the initial recurrence rate of CRC is about 40%, and most of them will appear within 3 years, among which, pelvic recurrent CRC can be subdivided into anastomotic/perineal recurrence, anterior recurrence, posterior recurrence and lateral recurrence. PET-CT and/or MRI may still be required in some patients with suspected recurrent disease on clinical, colonoscopic and/or laboratory examination but with equivocal or normal previous imaging findings.

2.6.4. Imaging evaluation of clinical crucial issues in rectal cancer: MRI scanning and diagnosis of ultra-low rectal cancer

Rectal cancer with the lower edge of the tumor less than 2 cm from the dentate line or less than 5 cm from the anal margin is considered ultra-low rectal cancer. MRI scans should be performed with high-resolution T2WI oblique coronal imaging parallel to the anal canal to assess the relationship of the tumor to the sphincter complex. MRI is appropriate for assessing the safety of the distal total mesorectal excision (TME) plane. In the staging of ultra-low rectal cancer, the T1−T4 staging system used above the anorectal ring is inadequate. Assessment should be based on the radial extent of the tumor and the safety of the intersphincteric plane to guide surgical planning. As for the staging of ultra-low rectal cancer, there is a “1 to 4 level” staging system proposed by the MERCURY II study, and other studies suggest that the depth of anal canal invasion can also be used for evaluation. To date, there is no consensus on which evaluation or staging system to use. A significant number of imaging physicians and surgeons believe that using clear language to describe the relationship between the tumor and the internal sphincter, sphincter space, and external sphincter facilitates clear communication of important information. The diagnosis of M stage and EMVI refers to middle and upper rectal cancer.

2.6.5. MRI structural report of rectal cancer is recommended

The report template is shown in Table 1.

Table 1. MRI structural report of rectal cancer.

Name　　　 Sex　　　　　　 Age　　　　　　　Imaging number　　　　　　　Date of examination Test item　　　Rectal MRI　　　 Clinical diagnosis
MRI, magnetic resonance imaging; LN, lymph node; MRF, mesenteric fascia; EMVI, extramural vascular invasion of rectum.
T-staging of tumor
Lesion localization
Retroperitoneal fold		[　] Above the retroperitoneal fold and not involved [　] Below the retroperitoneal fold and not involved [　] Across the retroperitoneal fold and not involved [　] The retroperitoneal fold is involved
Location referring to the distance from lower margin of tumor to the margin of anus		[　] Upper rectal cancer: within 10−15 cm [　] Middle rectal cancer: within 5−10 cm [　] Lower rectal cancer: within 5 cm
Distance between the lower margin of tumor and the anal rectum ring (cm)
Size measurement
Mass type	Oblique axial position measurement: ___ mm × ___ mm				Sagittal position measurement (longitudinal diameter): ___ mm
Intestinal wall infiltration	The thickest intestinal wall measured at oblique axis: ___ mm				Sagittal position measurement (longitudinal diameter): ___ mm
Perimeter of lesions surrounding the intestine	<1/4 loop			1/4−1/2 loop	1/2−3/4 loop	3/4−1 loop
Description of T-staging with tumor invasion degree
	T1: Tumor invades submucosa
	T2: Tumor invades muscularis propria but does not penetrate it
	T3: Tumor invades through the outer membrane of the muscularis propria and reaches into perirectal mesenteric fat [　] ___ mm
	T3a: Tumor invades through muscularis <5 mm
	T3b: Tumor invades through muscularis for 5−10 mm
	T3c: Tumor invades through muscularis >10 mm
	T4a: Tumor penetrates the peritoneum or serous membrane (upper rectum)
	T4b: Tumor invades adjacent organs
Remark:
N-staging of lymph nodes (evaluation of lymph node margins, morphology and internal signal characteristics should be integrated)
[　] LN around the superior rectal artery			No. of suspicious lymph nodes:		Maximum short diameter:
[　] LN inside the mesenteric fascia			No. of suspicious lymph nodes:		Maximum short diameter:
[　] LN adjacent to the internal iliac vessels			No. of suspicious lymph nodes:		Maximum short diameter:
Lateral lymph node
[　] Obturator artery LN			No. of suspicious lymph nodes:		Maximum short diameter:
[　] Internal iliac vessels LN			No. of suspicious lymph nodes:		Maximum short diameter:
Remark:
M-staging
[　] Groin LN			No. of suspicious lymph nodes:		Maximum short diameter:
Remark:
MRF status			[　] Positive: front, back, left, right		Causes of MRF positive: tumor, lymph nodes, cancer nodules, positive EMVI
			[　] Negative
Remark:
EMVI			[　] Positive: front, back, left, right		Location: referring tumor location (upper, middle and lower segments)
			[　] Negative
Remark:
Other abnormal signs [　] suggest the possibility of mucinous adenocarcinoma
Diagnostic comments: mrT ___ N ___ M ___, MRF (　), EMVI (　).

2.6.6. CT structural report of colon cancer can be used

The report template is shown in Table 2.

Table 2. CT structure report of colon cancer.

Name　　　　　　　　　 Sex　　　　　　　 Age　　　　　　Image number　　　　　　　Date of examination Inspection item　　　　　Colon CT　　　　　Clinical diagnosis
CT, computed tomography; RSM, retroperitoneal surgical margin; EVMI, extramural vascular invasion.
Tumor location
Left colon	[　]		Right colon	[　]
Cecum	[　]
Ascending colon	[　]
Hepatic flexure of colon	[　]
Transverse colon	[　]
Splenic flexure of colon	[　]
Descending colon	[　]
Sigmoid colon	[　]
Size measurement
Mass type		Size of mass: _____ mm × _____ mm
Intestinal wall infiltration		The thickest layer of tumor: _____ mm
RSM (only applicable to the ascending/descending segment)				[　]
Tumor staging
Invasion to submucosa (T1)				[　]
Tumor invades the muscularis propria but does not penetrate into the muscularis propria (T2)				[　]
Tumor breaks through muscularis propria (T3) <5 mm				[　]
Tumor breaks through muscularis propria (T3) ≥5 mm				[　]
Tumor invades beyond peritoneal coverage (T4a)				[　]
Invasion of adjacent organs (T4b)				[　]
Lymph node
No. of suspected positive lymph nodes in the region _____ Maximum short diameter _____
No. of suspected positive retroperitoneal lymph node _____ Maximum short diameter _____
EMVI				[　]
Distant metastases
Liver metastases
Lung metastases 　　　　　　　　Left lung　　　　　　 [　]　　　　　　 Right lung				[　]
Peritoneal implant metastases				[　]
Other metastatic lesions				[　]
Other abnormal signs
Tumor perforation				[　]
Intestinal obstruction				[　]
Diagnostic comments: ctT ___ N ___ M, EMVI (　).

For cases with suspected liver metastases in abdominal examination, CT and MRI structural reports for liver metastases can be used. The report templates are shown in Table 3 and Table 4.

Table 3. CT structure report of hepatic metastatic tumor.

1. Fatty liver: Yes [　] No [　]
CT, computed tomography; LN, lymph node, MRI, magnetic resonance imaging.
2. Number of liver metastatic tumors: 1−3 [　] 4−7 [　] 8 or more [　]
3. Size of hepatic metastatic tumor: The largest lesion _____ mm is located in _____ segment
4. Distribution of lesions:
Caudate	S1 [　]
Left lobe	S2 [　]		S3 [　]			S4 [　]
Right lobe	S5 [　]		S6 [　]			S7 [　]		S8 [　]
5. Relationship with important blood vessels:
Right portal vein	Trunk	Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
	Branch	Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
Left portal vein	Trunk	Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
	Branch	Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
Right hepatic vein		Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
Middle hepatic vein		Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
Left hepatic vein		Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
Inferior vena cava		Not shown [　]		Shift [　]			Next to [　]		Well-defined [　]
6. Hilar lymph nodes: Yes [　] No [　]
Size of the largest LN _____ mm × _____ mm
7. Origin of vascular variation:
Left hepatic artery	Arteria hepatica propria [　]				Left gastric artery [　]
Right hepatic artery	Arteria hepatica propria [　]				Superior mesenteric artery [　]
Common hepatic artery	Celiac trunk [　]				Superior mesenteric artery [　]				Abdominal aorta [　]
8. Uncertain transfer lesion: Yes [　] No [　]
9. Location distribution of uncertain transfer lesion:
Caudate	S1 [　]
Left lobe	S2 [　]		S3 [　]			S4 [　]
Right lobe	S5 [　]		S6 [　]			S7 [　]		S8 [　]
Suggestions: For the lesions less than 10 mm according to CT results, it is recommended that indeterminate metastatic lesions in other cases should be included and further evaluation by hepatic contrast-enhanced MRI should be done except for those with typical metastatic tumor manifestations.
10. Others

Table 4. MRI structure report of hepatic metastatic tumor^*.

1. No. of liver metastatic tumors: 1−3 [　] 4−7 [　] 8 or more [　]
*, only applicable to cases with hepatic metastasis considered by abdominal contrast-enhanced MRI. Not applicable for patients with liver metastasis after treatment. MRI, magnetic resonance imaging; LN, lymph node; CT, computed tomography.
2. Size of hepatic metastatic tumor: The largest lesion _____ mm is located in _____ segment
3. Distribution of lesions:
Caudate	S1 [　]
Left lobe	S2 [　]				S3 [　]			S4 [　]
Right lobe	S5 [　]				S6 [　]			S7 [　]				S8 [　]
4. Relationship with important blood vessels:
Right portal vein			Trunk		Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
			Branch		Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
Left portal vein			Trunk		Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
			Branch		Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
Right hepatic vein					Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
Middle hepatic vein					Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
Left hepatic vein					Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
Inferior vena cava					Not shown [　]		Shift [　]			Next to [　]				Well-defined [　]
5. Hilar lymph nodes: Yes [　] No [　]
Size of the largest LN _____ mm × _____ mm
6. Origin of vascular variation:
Left hepatic artery				Arteria hepatica propria [　]					Left gastric artery [　]
Right hepatic artery				Arteria hepatica propria [　]					Superior mesenteric artery [　]
Common hepatic artery				Celiac trunk [　]					Superior mesenteric artery [　]						Abdominal aorta [　]
7. Uncertain transfer lesions: Yes [　] No [　]
8. Location distribution of uncertain transfer lesions:
Caudate		S1 [　]
Left lobe		S2 [　]				S3 [　]					S4 [　]
Right lobe		S5 [　]				S6 [　]					S7 [　]			S8 [　]
Suggestions: For the lesions less than 10 mm shown by CT results, it is recommended that indeterminate metastatic lesions should be classified and further evaluation by hepatic contrast-enhanced MRI should be done, except for those with typical metastatic tumor features
9. Others

2.7. Histopathological examination

The pathological biopsy report is the basis for the treatment of CRC. Patients diagnosed as invasive carcinoma of CRC by biopsy require standard therapy. Biopsy pathology should try to clarify whether there is submucosal infiltration. In cases of high-grade intraepithelial neoplasia or intramucosal carcinoma, a multidisciplinary discussion is recommended for proper diagnosis and treatment by integrating other clinical information, including the tumor size and invasion depth as evaluated by endoscopy or imaging, whether there is suspicious lymph node metastasis, etc. When low rectal tumors may involve anal preservation decisions, the pathologist is advised to note in the report whether the biopsy tissue has reached the “canceration” level. It is recommended to detect KRAS, NRAS and BRAF gene mutations in patients with clinically diagnosed recurrence or metastatic colorectal cancer (mCRC) to guide tumor targeted therapy. It is recommended that patients with early-stage CRC be evaluated for prognosis and risk of recurrence by testing for KRAS, NRAS, and BRAF gene mutations. It is recommended to perform mismatch repair (MMR) protein expression or microsatellite instability (MSI) detection for all CRC patients for the screening of Lynch Syndrome, prognostic stratification and guided immunotherapy, etc. MMR-deficient (dMMR) tumors with MLH1 deletion should be tested for BRAF mutant molecules and/or MLH1 methylation to assess the risk of Lynch syndrome. Conditional units can be combined with clinical needs to carry out the detection of HER2 and NTRK indicators.

2.8. Open surgery or laparoscopic exploration

In the following cases, it is recommended to perform laparotomy or laparoscopic exploration:

(1) After various diagnostic methods, the diagnosis is still not clear and the colorectal tumor is highly suspected.

(2) Intestinal obstruction occurs and conservative treatment is not effective.

(3) Suspected bowel perforation.

(4) Massive hemorrhage of the lower gastrointestinal tract ineffective with conservative treatment.

3. Specimen collection and pathological evaluation

3.1. Specimen fixation criteria

(1) Fixative: 10% neutral buffered formalin fixative without heavy metals is recommended.

(2) Amount of fixative: ≥5−10 times the volume of the fixed specimen.

(3) Fixed temperature: normal room temperature.

(4) Fixated duration: the specimen should be dissected and fixed as soon as possible, and the time from isolation to fixation should not exceed 30 min. Surgical specimens must be standardized cut open and fixed. It is recommended that the pathologist should perform the dissection and fixation of the specimens.

Endoscopic specimens or biopsy specimens is recommended: in 6−48 h.

Surgical specimen: in 12−48 h.

3.2. Specimen collection requirements

3.2.1. Biopsy specimens

(1) Check the number of clinical specimens to be submitted and all specimens must be taken for biopsy.

(2) To avoid loss, wrap specimens in gauze or soft permeable paper.

(3) Each wax block was embedded with no more than 5 biopsy specimens and adjusted according to the size of the tissue (No more than 3 biopsy specimens per wax block is preferred).

3.2.2. Endoscopic resection specimens

(1) Specimen fixation is recommended to be normalized by clinicians: After the biopsy specimen is isolated, the endoscopist should attach the base surface of the biopsy mucosal tissue to the filter paper in time, and immediately immerse it in the fixative. After the mucosal resection under endoscopy in vitro, the endoscopist unfolds the specimen, and fix the mucosa upward with a pin to the cork or foam board, mark the lateral margins of mouth and anus, and turn the mucosa downward into the fixating solution. For the resected polyps, place the pedunculated polyps directly into the fixator, and mark the resection margin before putting the sessile polyps into the fixator.

(2) It is recommended to record the size and morphological features of the specimen or the tumor lesion along with the distance from each orientation to the resection margin.

(3) Sampling of resected polyp specimens: Firstly, clarify the resection margin of the polyp, the presence or absence of the peduncle, and the diameter of the peduncle, it is recommended to apply ink to the resection margin of the peduncle (pedunculated polyps) and cauterize the resection margin (sessile polyps). During the sampling, it should be taken into account that the resection margin and the infiltration of pedunculated polyps can be evaluated objectively and correctly.

It is suggested to take the material as follows: The sessile polyps are well taken in parallel from the base center of the resection margin to the left and right sides (Figure 1). For polyps with peduncle resection margin >2 mm in diameter, cut the specimen perpendicular to the plane of the peduncle resection margin slightly deviating from the center of the peduncle resection margin. Then parallel to this section, take all specimens at intervals of 2−3 mm (Figure 2); When the diameter of the peduncle resection margin is no more than 2 mm, sampling all specimens at intervals of 2−3 mm perpendicular to the plane of the resection margin, so that the pedunculated section serves as a separate wax block (Figure 3). It is recommended to take all materials in the same embedding direction. Record the orientation corresponding to the tissue block.

Figure 1.

Sampling of sessile polyps. Cut in parallel with the base of the resection margin as the center, and take all materials to the left and right sides. The direction of the arrow is the embedding direction recommended.

Figure 2.

Sampling of pedunculated polyps with broad base (>2 mm). Sampling specimens at intervals of 2−3 mm perpendicular to the plane of the peduncle resection margin. The direction of the arrow is the embedding direction recommended.

Figure 3.

Sampling of pedunculated polyps with narrow base (≤2 mm). Sampling specimens at intervals of 2−3 mm perpendicular to the plane of the peduncle resection margin. The direction of the arrow is the embedding direction recommended.

(4) Sampling of specimens from endoscopic mucosal resection and mucosal dissection: assessment of the resection margin is particularly critical because the mass is generally close to the resection margin. It is suggested to mark the basal and lateral margins with different pigments, so that we can locate the resection margin and evaluate the tumor resection margin when observing. Cut the specimen in parallel at intervals of 2−3 mm (Figure 4). The specimens with clinical special marks can be adjusted appropriately: divide them into tissue blocks of appropriate size, collect and embed all in the same direction (The last tissue strip should be reversely embedded with the other tissue strips, ensuring that the most sides of the tissue strip cut surface are embedded downward).

Figure 4.

Sampling of specimens from endoscopic mucosal resection and mucosal dissection. Cut the specimen in parallel at intervals of 2−3 mm, all taken and embedded in the same direction.

3.2.3. Surgical specimens

(1) General examination and recording: Describe and record the general characteristics of the intestinal tube and tumor, along with the distance from the tumor to the bilateral and radial (circumferential) resection margins. Ink is recommended to mark the radial (circumferential) resection margin of the serous area corresponding to the tumor so as to accurately assess the depth of tumor infiltration and distance from the resection margin. Lymph node sampling should be grouped according to the direction of lymphatic drainage. It is recommended that clinicians group the lymph nodes for examination (pathologists cannot distinguish lymph node groups in vitro).

(2) Sampling

1) Cut open the intestinal tube along the long axis of the intestinal wall and fully excise the tumor specimen perpendicular to the intestinal wall. Sampling tumor tissues according to size, depth of infiltration, texture and color separately. Take one more full-layer tumor and intestinal wall tissue in the deepest part to evaluate the deepest degree of tumor invasion. Observe the serous membrane involvement carefully. When the tumor approaches or invades the serous membrane, take the area of serous membrane suspected, so as to judge accurately the serous membrane involvement under microscope. Cut tissues that can show the relationship between tumor and adjacent mucosa.

2) Excise the distal and proximal surgical margins. It is recommended to cut the mesangial/circumferential margins (The soft tissue closest to the cancer, all areas not covered by peritoneum). For cases with suspected positive mesenteric/circumferential margins, it is recommended that the surgeon cut the part marked with ink, and manage to distinguish marks for different resection margins.

3) If the specimen contains ileocecal, anal canal or anus, it should be taken from ileocecal flap, dentate line and anal margin. If the tumor invades the above sites, the tissue block which fully shows the degree of lesion should be cut. Routine sampling appendix.

4) Complete mesorectum excision is required for radical resection of middle and low rectal cancer. Pathologist are advised to conduct systematic examination and evaluation on the surgical specimens, including the integrity of the mesentery membrane and existence/absence of tumor invasion to the circumferential margin. Pathologic examination is the most intuitive method to evaluate the integrity of mesorectum.

5) Lymph nodes: Embed all the lymph nodes detected. Large lymph nodes would be dissected and then embedded. At least 12 lymph nodes should be detected in radical specimens without neoadjuvant treatment.

6) As for surgical specimens of rectal cancer after neoadjuvant treatment, the changes of the original tumor site should be observed and recorded. If the mass is obvious still, take it according to the routine sampling. If the tumor is small or there is no obvious tumor with the naked eye, the original tumor should be taken altogether on the basis of the colonoscopy description before treatment.

(3) Size of specimen recommended: no more than 2.0 cm × 1.5 cm × 0.3 cm.

3.3. Principles of post-sampling specimen process and retention time

(1) Preservation of the remaining specimens. The remaining tissue should be stored in the standard fixative solution, and the sufficient amount of fixation and formaldehyde concentration should be maintained at all times to avoid tissue decay caused by the dry-up of specimen or decrease in quantity or concentration of fixed solution; in order to prepare materials whenever needed in line with observation and diagnosis through microscope; or to review the general specimen or supplement the materials when receiving clinical feedback after the pathological report is issued.

(2) Retention time for remaining specimens. It is suggested that 2 weeks after the issuance of the pathological diagnosis report, the hospital can handle it in accordance with the relevant regulations, when no clinical feedback information has been received, and no cases such as requesting a review due to the disagreement of the consultation opinions of the external hospital have occurred.

(3) Retain fresh tissue at low temperatures for further study use if permitting.

3.4. Pathological types

3.4.1. Early-stage (pT1) CRC

Cancer cells penetrate the muscularis mucosae of colorectum and infiltrate into the submucosa, but do not involve the muscularis propria, known as early CRC (pT1). Carcinoma with severe dysplasia of the epithelium and no penetration of the muscularis mucosa is called high-grade intraepithelial neoplasia or dysplasia, conceptually including intramucosal carcinoma confined to the mucosal layer but with membrane propria infiltration. For more accurate clinical guidance, it is recommended to identify and report intramucosal carcinoma

The submucosal infiltration depth of early CRC should be measured and graded for local resection specimens under endoscope or by transanal operation. For flat lesions, when the depth of submucosal infiltration is ≤1,000 μm.

It is a shallow submucosal infiltration, which is an indication of endoscopic therapy. When the depth of submucosal infiltration is greater than 1,000 μm, it is deep submucosal infiltration, and other factors as well as clinical conditions need to be considered of weather to perform surgical operation to expand the resection range.

When the muscularis mucosae is clear, the depth of infiltration is measured from the lower edge of the muscularis mucosae to the deepest infiltration. When the muscularis mucosae disappear completely and there is an interstitial reaction around the gland, the depth of submucosal infiltration is measured from the surface. Pedicular lesions are divided into head invasion and stalk invasion, with the line between tumor and non-tumor junctions on both sides as the baseline (Figure 5), and infiltration above baseline as head invasion (which can include non-tumor mucosa). Head infiltration is equivalent to submucosal shallow infiltration (≤1,000 μm). Infiltration below baseline is considered pedicular infiltration, equivalent to submucosal infiltration (>1,000 μm).

Figure 5.

For pedunculated lesions, the line at the junction of adenoma and normal mucosa is taken as the baseline, the infiltration above the baseline is regarded as head infiltration, and the infiltration below the baseline is regarded as pedunculated infiltration.

3.4.2. General types of advanced CRC

(1) Bulge type: Anyone whose tumor protrudes into the intestinal cavity belongs to this type.

(2) Ulcer type: This type is found in those with deep ulcerations or penetrating the muscularis.

(3) Type of infiltration: The tumor infiltrates into the whole layers of the intestinal wall, thickening the local intestinal wall, but there is no obvious ulcer or bulge on the surface.

3.4.3. Histological type

Refer to World Health Organization (WHO) classification of digestive system tumors (5th edition) published in 2019. The proportion of common adenocarcinoma containing specific histological types such as mucinous adenocarcinoma or signet ring cell carcinoma should be noted.

(1) Adenocarcinoma, non-special type;

(2) Serrated adenocarcinoma;

(3) Adenomatoid adenoma;

(4) Micropapillary adenocarcinoma;

(5) Mucinous adenocarcinoma;

(6) Low adhesion carcinoma;

(7) Signet ring cell carcinoma;

(8) Medullary carcinoma;

(9) Adenosquamous carcinoma;

(10) Undifferentiated carcinoma, non-special type;

(11) Carcinoma with sarcomatoid composition.

3.4.4. Histological grade

Colorectal adenocarcinoma (common type) can be divided into 4 grades according to the proportion of glandular duct formation: highly differentiated (>95% glandular duct formation), moderately differentiated (50%−95% glandular duct formation), poorly differentiated (0−49% glandular duct formation), and undifferentiated (no glandular duct formation, mucogenesis, neuroendocrine, squamous or sarcomatoid differentiation). Colorectal adenocarcinomas can also be divided into low-grade (high-medium differentiation) and high-grade (low-differentiation) according to WHO classification of digestive system tumors (5th edition) published in 2019, and the grading is indicated according to the poorest differentiated component. Tumor budding and poorly differentiated clusters of tumor cells at the aggressive front should not be included in the classification and should be reported separately.

3.5. Contents of pathological report

3.5.1. Contents and requirements of pathological reports for biopsy specimens

(1) Basic information of patients and inspection information.

(2) Report the grade for intraepithelial neoplasia (dysplasia). For the diagnosis of low rectal tumor with high-grade intraepithelial neoplasia, it is suggested that the pathologist note in the report whether the biopsy tissue has reached the degree of “canceration”, because this may involve clinical treatment decision.

(3) Distinguish the histological type in cases of invasive carcinoma.

(4) When identified as CRC, the detection of MMR protein (MLH1, PMS2, MSH2, MSH6) expression is recommended. For unresectable CRC, K-ras, N-ras genes, BRAF gene mutations must be detected. Other relevant molecular markers can be detected according to clinical needs.

Clinicians should understand the limitations of biopsy specimens. If the biopsy pathology cannot fully determine the presence of submucosal infiltration, it is diagnosed as high-level intraepithelial neoplasia. Then the tumor body may be invasive cancer.

3.5.2. Contents and requirements of pathological reports for endoscopic resection specimens

(1) Basic information of patients and inspection information.

(2) Size of the sample or tumor.

(3) Grading of intraepithelial neoplasia (dysplasia).

(4) In the case of invasive carcinoma that penetrates the muscularis mucosae into the submucosal layer, histological classification, grade, depth of submucosal invasion, vascular invasion, nerve invasion, horizontal and vertical resection margins should be reported. It is recommended to reported MMR protein (MLH1, MSH2, MSH6, PMS2) expression and tumor budding grade.

If the cancer has the 3th or the 4th grade differentiation, deep submucosal infiltration, vascular invasion, positive basal resection margin high grade of tumor budding and other high-risk factors, clinicians need to take re-surgery into consideration. If the distance between tumor and resection margin is less than 1 mm, and adenoma/low grade dysplasia can be seen on the horizontal margin, the margin is considered as negative, but need to be marked.

3.5.3. Contents and requirements of pathological reports for surgical specimens

(1) Basic information of patients and inspection information.

(2) General condition: tumor size, general type, depth of infiltration with the naked eye, presence/absence of perforation, distance from tumor to both sides of resection margin, integrity of the mesenterium in total mesorectal excision surgery.

(3) Degree of tumor differentiation (tumor classification, grade).

(4) The depth of tumor invasion (pT stage) (pT stage or ypT is determined by the viable tumor cells, while acellular mucus lake in specimens after neoadjuvant treatment are not considered to be residues tumor).

(5) Tumor budding is closely related to vascular invasion, nerve invasion and immune score, and is an important indicator to judge prognosis and evaluate the efficacy of adjuvant therapy. It is recommended to report tumor budding grade. Tumor budding is a cluster of tumor cells less than 5 cells located at the leading edge of tumor infiltration. The total number and grade of buds should be reported from the densest area (hot spot) at 20 times visual field. The grade criteria are shown in Table 5.

Table 5. Grade for tumor budding.

Grade	Total No. of buds (hot spot measuring 0.785 mm2, visual field of 20 times)
Low	0−4
Intermediate	5−9
High	10 or more

(6) Detect the number of lymph nodes and the number of positive lymph nodes, as well as tumor deposit (TD) (pN stage) outside the lymph nodes. The latter refers to the solid deposit of cancer cells that are not connected with the primary tumor in the perienteric adipose tissue. Cancer cell deposition but no residual lymph node can be seen through microscope. When there is no lymph node metastasis, but there are TDs, it is reported as pN1c stage, and the number of TD should be reported; when lymph node metastasis exists, the pN stage is based on the number of positive lymph nodes, without considering cancer deposit, but the number of TD should also be presented in the pathological report.

(7) Status of the proximal and distal resection margins.

(8) It is recommended to report the condition of the mesangial/circumferential margin (if the tumor is close to the resection margin, the distance between the tumor and the resection margin should be measured and reported under a microscope, and it is reported as positive resection margin when the distance between tumor and resection margin is less than 1 mm).

(9) Tumor response grade (TRG), used to assess the efficacy of preoperative neoadjuvant therapy, as shown in Table 6.

Table 6. Tumor regression grade (TRG).

Grade	Level of regression	Degree description
Level 0	Complete response	No residual cancer cells
Level 1	Near complete response	Single cells/small groups of cancer cells remaining
Level 2	Partial response	Significant tumor regression with residual cancer cells more than single cells or groups of cells
Level 3	Poor or no response	Extensive residual cancer cells with no significant tumor regression

(10) Vascular invasion (V stands for blood vessels, V1 for microscopic blood vessel infiltration, V2 for blood vessel infiltration with the naked eye, and L for lymphatic vessel). It is recommended to distinguish blood vessel from lymphatic vessel infiltration and venous invasion as much as possible.

(11) Nerve bundle invasion.

(12) MMR protein (MLH1, PMS2, MSH2, MSH6) expression/microsatellite instability. Further optional testing for BRAF gene mutation status and MLH1 methylation status based on immunohistochemical testing is recommended, and patients with results suggesting possible Lynch syndrome should undergo genetic counseling and mismatch repair gene mutation testing. In case of abnormal expression of MMR protein (partial deletion of expression, cytoplasmic expression), multiplex fluorescence polymerase chain reaction (PCR) coupled with capillary electrophoresis is recommended to further clarify the microsatellite status.

(13) KRAS, NRAS, BRAF gene status must be tested, and HER2 status and NTRK can be tested when determined as relapsed or metastatic CRC. Without surgical resection specimens, they can be measured from biopsy specimens. Detection of KRAS, NRAS, and BRAF gene mutations is recommended for early-stage CRC to assess prognosis and recurrence risk.

A complete pathological report is based on a detailed pathological diagnostic application form filled by the clinician, with detailed surgical findings, results of related clinical auxiliary examination, and clearly marked lymph nodes. The mutual communication, trust and cooperation between clinicians and pathologists are the basis for establishing correct staging and guiding clinical treatment. The templates of pathological report of endoscopic resection specimens and surgical specimens are shown in Tables 7,8, and the anatomic staging and prognostic groups are shown in Table 9.

Table 7. Structural report of colorectal endoscopic resection specimens^*.

Name　　　　　　　　　　Sex　　　　　　　 Age　　　　　　　Pathology number Medical record number 　　　　　　　　　　　Inspection site
*, For complete polyp or mucosal/intestinal wall excision specimens only.
Specimen size	Maximum diameter: ____ cm; Other two diameters: ____ cm × ____ cm
Polyp size	Maximum diameter: ____ cm; Other two diameters: ____ cm × ____ cm
Polyp structure	□ Peduncle length ____ cm, diameter ____ cm □ Broad base
Type of polyp	□ Tubular adenoma □ Villous adenoma □ Tubulovillous adenoma □ Traditional serrated adenoma □ Sessile serrated lesions □ Hamartoma-like polyps □ Other
High-level intraepithelial neoplasia	□ None □ Yes □ Inherent membrane invasion (intramucosal carcinoma)
Invasive carcinoma (carcinoma infiltrating submucosa)	□ None □ Yes
Size of invasive cancer	Maximum diameter: ____ cm Other two diameters: ____ cm × ____ cm
Histological classification	□ Adenocarcinoma, non-special type □ Serrated adenocarcinoma □ Adenoma-like adenocarcinoma □ Micropapillary carcinoma □ Mucinous adenocarcinoma □ Poorly cohesive carcinoma □ Signet ring cell carcinoma □ Medullary carcinoma □ Adenosquamous carcinoma □ Undifferentiated carcinoma, non-special type □ Carcinoma with sarcomatoid component
Histological grade	□ Uncertain □ Low level (well/moderately differentiated) □ High level (poorly differentiated, undifferentiated)
Tumor invasion (deepest point)	□ Membrane propria □ Muscularis mucosae □ Submucosal layer (≤1,000 μm infiltration) □ Submucosal layer (>1,000 μm infiltration) □ Muscularis propria
Deep resection margin (pedunculated resection margin)	□ Cannot be assessed □ Non-invasive cancer, invasive cancer distance from resection margin: ____ mm □ Invasive cancer involvement
Mucosal resection margin	□ Cannot be assessed □ No intradermal tumor and dysplasia □ Adenoma (low-grade intraepithelial neoplasia/dysplasia) visible □ High-grade intraepithelial neoplasia/dysplasia or intramucosal carcinoma □ Invasive cancer involvement
Tumor budding	□ Low (0−4/20 times if visual field) □ Medium (5−9/20 times of visual field) □ High (10 or more/20 times of visual field) □ Cannot be assessed
Vascular invasion	□ Invisible □ Microvascular invasion □ Lymphatic invasion □ Venous invasion □ Uncertain
Immunohistochemistry of mismatch repair protein	MLH1 (　) PMS2 (　) MSH2 (　) MSH6 (　) □ Not applicable

Table 8. Structural report of surgical resection specimens of colorectum.

Name　　　　　　　　　Sex　　　　　 　　Age　　　　　　　Pathology number Medical record number 　　　　　　　　　　Inspection site
American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) Colorectal Cancer TNM Staging System (8th Edition, 2017) Primary tumor (T) 　Tx　Primary tumor cannot be evaluated 　T0　No evidence of primary tumor 　Tis　Carcinoma in situ: intramucosal carcinoma (invades lamina propria, but without penetrating the muscularis mucosae) 　T1　Tumor invades submucosa 　T2　Tumor invades muscularis propria 　T3　Tumor invades through muscularis propria into pericolorectal tissues 　T4　Tumor invades the visceral peritoneum or invades/adheres to adjacent organs or structures 　　T4a　Tumor penetrates the visceral peritoneum (including tumor perforation of the gross intestine and continuous infiltration of 　　the tumor through the inflammatory region) 　　T4b　Tumor directly invades or adheres to adjacent organs or structures Regional lymph nodes (N) 　Nx　Regional lymph node invaluable 　N0　No regional lymph node metastasis 　N1　Metastasis in 1−3 regional lymph nodes (intra-node tumors ≥0.2 mm) or any number of tumor deposits and no metastasis of 　all identifiable lymph nodes 　　N1a Metastasis in 1 regional lymph node 　　N1b　Metastasis in 2−3 regional lymph node 　　N1c　There is no regional lymph node metastasis, but there are tumor deposits in the following areas: Subserous, mesenteric 　　or pericolic/rectal mesenteric tissue without peritoneum coverage 　N2　Metastasis in 4 or more regional lymph nodes 　　N2a　Metastasis in 4−6 regional lymph nodes 　　N2b　Metastasis in 7 or more regional lymph nodes Metastasis (M) 　M0　No distant metastasis 　M1　Metastasis confined to one or more distant sites or organs, or peritoneal metastasis confirmed 　　M1a　Metastasis in one site or organ without peritoneal metastasis 　　M1b　Metastasis in two or more sites or organs without peritoneal metastasis 　　M1c　Metastasis only in the peritoneal surface or along with other sites or organs
Specimen size	Length: _____ cm Circumference: _____ cm
Tumor location	To the proximal end _____ cm, to the distal end _____ cm
General type	□ Bulge type □ Ulcer type □ Invasive type
Tumor size	Maximum diameter: _____ cm Other two diameters: _____ cm × _____ cm
Perforation of tumor	□ Visible □ Invisible □ Uncertain
Histological classification	□ Adenocarcinoma, non-special type □ Serrated adenocarcinoma □ Adenoma-like adenocarcinoma □ Micropapillary carcinoma □ Mucinous adenocarcinoma □ Poorly cohesive carcinoma □ Signet ring cell carcinoma □ Medullary carcinoma □ Adenosquamous carcinoma □ Undifferentiated carcinoma, non-special type □ Carcinoma with sarcomatoid component
Histological grade	□ Uncertain □ Low level (well/moderately differentiated) □ High level (poorly differentiated, undifferentiated)
Tumor invasion (deepest point)	□ Cannot be assessed □ No evidence of primary tumor □ No membrane propria infiltration □ Intramucosal carcinoma, invasion of the membrane propria/muscularis mucosae □ Tumor invades submucosal layer □ Tumor invades the muscularis propria □ Tumor penetrates the muscularis propria to subserosal adipose tissue or pericolic/perirectal soft tissue □ Tumor penetrates the visceral peritoneum (serous membrane) (including tumor perforation of the gross intestine and continuous infiltration of the tumor through the inflammatory region) □ Adhesion of tumor to other organs or structures: □ Tumors directly invade nearby structures:
Proximal resection margin	□ Cannot be assessed □ No intradermal tumor and dysplasia □ Adenoma (low-grade intraepithelial neoplasia/dysplasia) □ High-grade intraepithelial neoplasia/dysplasia or intramucosal carcinoma □ Invasive cancer involvement
Distal resection margin	□ Cannot be assessed □ No intradermal tumor and dysplasia □ Adenoma (low-grade intraepithelial neoplasia/dysplasia) □ High-grade intraepithelial neoplasia/dysplasia or intramucosal carcinoma □ Invasive cancer involvement
Circumferential (radial) or mesangial margin	□ Inapplicable □ Cannot be assessed □ Non-invasive cancer □ Invasive carcinoma (distance between tumor and resection margin less than 1 mm)
Therapeutic effects (for cancer after neoadjuvant treatment)	□ No pre-treatment □ Therapeutic effect □ No residual tumor (grade 0, complete response) □ Moderate response (grade 1, minor residual tumor) □ Minimal response (grade 2) □ No certain response (grade 3, poor response) □ Uncertain
Tumor budding	□ Low (visual field of 0−4/20 times) □ Medium (visual field of 5−9/20 times) □ High (visual field of 10 or more/20 times) □ Cannot be assessed
Vascular invasion	□ Invisible □ Microvascular invasion □ Lymphatic invasion □ Venous invasion □ Uncertain
Nerve invasion	□ Invisible □ Visible □ Uncertain
Lymph node	□ No lymph nodes submitted or no lymph nodes found □ No. of lymph nodes examined _____ □ No. of lymph nodes involved _____
Extranodal tumor deposits	□ Invisible □ Visible (Number: _____) □ Uncertain
Immunohistochemistry of mismatch repair protein	MLH1 (　) PMS2 (　) MSH2 (　) MSH6 (　)
Pathological stage	□ m (multiple primary tumors) □ r (relapse) □ y (after neoadjuvant treatment) T ___ N ___ M ___

Table 9. Anatomical staging/prognosis group.

Stage	T	N	M
cTNM is the clinical stage, and pTNM is the pathological stage; prefix y is used for tumor stage after neoadjuvant (preoperative) treatment (e.g. ypTNM). The stage for patients with complete pathological response is ypT0N0M0, which may be similar to stage 0. The prefixe r is used in patients who relapse after a tumor-free interval gained by treatment (rTNM).
0	Tis	N0	M0
I	T1	N0	M0
	T2	N0	M0
IIA	T3	N0	M0
IIB	T4a	N0	M0
IIC	T4b	N0	M0
IIIA	T1−2	N1/N1c	M0
	T1	N2a	M0
IIIB	T3−4a	N1/N1c	M0
	T2−3	N2a	M0
	T1−2	N2b	M0
IIIC	T4a	N2a	M0
	T3−4a	N2b	M0
	T4b	N1−2	M0
IVA	Any T	Any N	M1a
IVB	Any T	Any N	M1b
IVC	Any T	Any N	M1c

4. Surgical treatment

4.1. Standards for surgical treatment of colon cancer

4.1.1. Principles of surgical treatment of colon cancer

(1) Thorough abdominal exploration from far to near is required. Liver, gastrointestinal tract, uterus and appendages, peritoneum, greater omentum related mesentery, major paravascular lymph nodes and tumor adjacent organs must be explored and recorded.

(2) Routine extensive excision of intestine, dissection of regional lymph nodes and en bloc resection are recommended, and routine dissection of more than two stations of lymph nodes is recommended.

(3) Sharp dissection technology is recommended.

(4) It is recommended to follow the principle of tumor-free surgery.

(5) For tumor that has lost the chance of radical surgery, if the patient has no bleeding, obstruction, perforation symptoms or symptoms caused by compression of adjacent organs, the need for resection of the primary lesion is determined based on multidisciplinary team (MDT) evaluation.

(6) For the colon neoplasm whose clinical diagnosis is highly suspicious of malignant tumor and whose pathological biopsy report indicates high-grade intraepithelial neoplasia, if patients can tolerate surgery, surgical exploration is recommended.

4.1.2. Treatment of early colon cancer cT1N0M0

Endoscopic resection, local excision or colectomy is recommended. For superficial (SM1) submucosal invasion, endoscopic resection may be considered. Before making the decision, relevant information such as tumor size, depth of invasion and degree of tumor differentiation should be carefully evaluated. If endoscopic resection is performed, endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) resection is feasible. For the tumor which is pathologically confirmed as T1 after local excision, if it is removed completely with negative resection margins (including the base of the tumor) and favorable histologic features which indicate a good prognosis (such as well-differentiated, no vascular invasion), surgical resection is not recommended, no matter the tumor is sessile or pedunculated.

Additional bowel segment resection plus regional lymph node dissection is recommended if there are 1) histological features with poor prognosis, such as poorly differentiated carcinoma (hypo-differentiated carcinoma, undifferentiated carcinoma, signet-ring cell carcinoma, mucinous adenocarcinoma, etc.), with vascular infiltration; 2) non-complete resection with fragmented specimens and unassessable resection margins; 3) submucosal infiltration depth ≥1,000 μm; 4) positive resection margin (tumor present within 1 mm from the resection margin or tumor cells visible at the resection margin of the electric knife); and 5) tumor budding G2/G3.

If endoscopic resection or local excision is performed, the following requirements must be met:

(1) Tumor size <3 cm;

(2) The perimeter of the lesion surrounding the intestine is less than 30%;

(3) Resection margin distance to tumor ≥1 mm;

(4) Mobile, not fixed;

(5) Only for stage T1 tumors;

(6) High-moderate differentiation;

(7) No sign of lymph node metastasis by pre-treatment imaging examination.

(8) Tumor budding G1.

Note: Locally resected specimens must be flattened and fixed by the surgeon. The specimens must be marked and then sent for pathologic examination.

4.1.3. T2−4, N0−2, M0 colon cancer

(1) The preferred surgical methods are colectomy of the corresponding colon segment with dissection of regional lymph nodes. Regional lymph node dissection must include paracolic lymph nodes, mesenteric lymph nodes at central or root of the mesentery. It is recommended to mark the lymph nodes at root of the mesentery and send them for pathologic examination; if lymph nodes and deposits beyond the scope of dissection are suspected to have metastasis, complete resection is recommended. The incomplete resection is considered as palliative resection.

(2) For FAP, total colorectal resection plus ileal pouch anastomosis or total colorectal resection with end-to-end ileorectal anastomosis are recommended (the anastomosis is recommended to be located within 7 cm from the anal verge to facilitate future follow-up). In case of canceration, the appropriate surgical procedure will be performed according to the site of cancer. Selection between total colorectal resection or segmental resection combined with follow-up by colonoscopy should be made on the basis of adequate communication with patients with Lynch syndrome, according to the site of cancer, distribution of lesions, patient’s age and wishes.

(3) For the tumor that invades adjacent tissues or organs, multi-visceral resection is recommended. Colon cancer staged as cT4 by preoperative imaging examination can be treated with colectomy after preoperative chemotherapy or chemoradiotherapy (CRT) on the premise of MDT discussion.

(4) Laparoscopic-assisted colectomy is recommended to be conducted by surgeons experienced in laparoscopy as appropriate.

(5) For resectable colon cancer that has caused intestinal obstruction, it is recommended to conduct the I-stage resection and anastomosis, or the I-stage resection with a proximal end colostomy and closure of the distal stump, or the I-stage resection and anastomosis with a proximal prophylactic stoma, or the II-stage resection after the colostomy, or limited resection after the stent implantation. If the locally advanced tumor cannot be resected, the palliative treatment including surgery is recommended, such as proximal end colostomy, bypass surgery, stent implantation, and catheter placement for the intestinal obstruction, etc.

(6) Robot-assisted colon cancer resection can be carried out in centers where conditions permit, and procedures such as NOSES surgery can be carried out under conditions of strict mastery of indications.

4.2. Standards for surgical treatment of rectal cancer

The principle of abdominal exploration for rectal cancer surgery is the same as that for colon cancer.

4.2.1. Local excision of cT1N0M0 rectal cancer

The treatment principle of early rectal cancer (cT1N0M0) is the same as that of early colon cancer.

Transanal (non-laparoscopic and non-endoscopic) resection of early rectal cancer (cT1N0M0) must meet the following requirements:

(1) Tumor size <3 cm;

(2) The perimeter of the lesion surrounding the intestine is less than 30%;

(3) Resection margin distance to tumor >3 mm;

(4) Mobile, not fixed;

(5) Within 8 cm from the anal verge;

(6) Only for stage T1 tumors;

(7) No lymphovascular invasion (LVI) or perineural invasion (PNI);

(8) High-moderate differentiation;

(9) No sign of lymph node metastasis on pre-treatment imaging examination.

(10) The conditions permit to perform full-thickness resection.

Note: With the introduction of TEM and TAMIS surgical techniques, the distance from the anal verge for transanal local excision of rectal tumors can be expanded and extended. Locally resected specimens must be flattened and fixed by the surgeon. The specimens must be marked and then sent for pathologic examination.

4.2.2. cT2−4, N0−2, M0 rectal cancer

Radical surgery is recommended. Low anterior resection (LAR) is recommended for middle or upper rectal cancer; abdominoperineal resection or sphincter preserving surgery (under careful selection) is recommended for lower rectal cancer. Resection of middle or lower rectal cancer must follow the principle of total mesorectal excision (TME), and the mesorectum should be dissected sharply if possible. Try to confirm the negative circumferential resection margin (CRM). For the suspected positive CRM, follow-up treatment should be added. Make sure the distance from distal resection margin of rectum wall to tumor is 1−2 cm, and the distance from the distal resection margin of the mesorectum to tumor is more than or equal to 5 cm or the whole mesorectum is resected. Intraoperative fast frozen-section biopsy should be performed to determine whether there are residual tumor cells on the resection margin if necessary. On the premise of radical cure of tumor, try to preserve anal sphincter function, urinary and sexual function. The principles of treatment are as follows:

(1) Excise the primary tumor and ensure adequate surgical margins. The distal resection margin should be at least 2 cm away from the distal end of the tumor. If the distal resection margin of distal rectal cancer (<5 cm from the anus) is 1−2 cm from the tumor, intraoperative fast frozen-section biopsy is recommended to confirm that the resection margin is negative. Make sure the distal resection margin of the mesorectum is ≥5 cm or the whole mesorectum is resected.

(2) Resect the lymphatic and adipose tissue in the mesorectum and if there is clear imaging evidence of high suspicion of lateral lymph node metastasis, it is recommended to perform lateral lymph node dissection.

(3) Try to preserve pelvic autonomic nerve.

(4) For locally advanced middle or upper rectal cancer staged as cT3−4 and/or N+ by preoperative imaging examination, preoperative CRT or preoperative chemotherapy is recommended. The interval between preoperative CRT and surgery is shown in the CRT section.

(5) For the tumor that invades adjacent tissues or organs, multi-visceral resection is recommended.

(6) For the rectal neoplasm with ineffective conservative treatment complicated by intestinal obstruction, bleeding, or perforation which is clinically highly suspicious of malignancy without pathological diagnosis, exploratory laparotomy is recommended if the patient can tolerate surgery.

(7) For resectable rectal cancer that has caused intestinal obstruction, it is recommended to conduct I-stage resection and anastomosis, or I-stage resection and anastomosis plus proximal prophylactic stoma, or Hartmann surgery, or II-stage resection after colostomy, or limited resection after stent implantation to relieve obstruction. Intraoperative intestine lavage is recommended before I-stage resection and anastomosis. If the risk of anastomotic leakage is estimated to be high, Hartmann surgery or I-stage resection and anastomosis as well as preventive colostomy are recommended.

(8) If the locally advanced tumor cannot be resected or patient cannot tolerate surgery, it is recommended to conduct palliative treatment including interventional therapy or radiotherapy for uncontrollable bleeding and pain, and proximal double barrel colostomy or stent implantation for intestinal obstruction and supportive treatment.

(9) If there is a clear residual tumor during the surgery, it is recommended to place metal surgical clips as a marker for subsequent radiotherapy.

(10) Laparoscopic-assisted radical resection for rectal cancer is recommended to be conducted by surgeons experienced in laparoscopy as appropriate.

(11) Robotic-assisted rectal cancer resection can be performed in centers where conditions permit, and procedures such as transanal minimally invasive surgery (TAMIS) and NOSES surgery can be performed under conditions of strict mastery of indications.

5. Medical treatment

General principles of medical drug treatment: the purpose of treatment must be defined, and it must belong to preoperative treatment/postoperative adjuvant treatment or palliative treatment; the imaging baseline evaluation must be conducted before systemic treatment, and the detection of relevant molecular markers is recommended. It is recommended to detect K-ras and N-ras gene mutations in patients with clinically diagnosed recurrent or mCRC in order to guide tumor targeted therapy. The evaluation of BRAF^V600E mutation status should be carried out simultaneously during Ras detection, so as to stratify the prognosis and guide the clinical treatment. It is recommended to detect the expression of MMR or MSI in all patients with CRC for Lynch syndrome screening, prognosis stratification and immunotherapy guidance. In order to evaluate the risk of Lynch syndrome, BRAF^V600E mutation and/or MLH1 methylation should be performed in dMMR tumors with MLH1 deficiency. It is recommended to perform HER2 immunohistochemistry for those units that are qualified. In the course of treatment, we must evaluate the curative effect and side effects in time, and adjust the treatment target, drug and dosage according to the patient’s condition and physical strength score under the guidance of MDT. Pay attention to improve the quality of life of patients and treatment of complications, including pain, nutrition, mental and psychological needs.

5.1. Preoperative treatment of CRC

5.1.1. New adjuvant therapy for rectal cancer

The purpose of neoadjuvant therapy is to reduce local recurrence, improve the resection rate, improve the rate of anus preservation and prolong the disease-free survival (DFS) of patients. It is recommended that neoadjuvant chemoradiotherapy (nCRT), neoadjuvant chemotherapy or neoadjuvant immunotherapy is applicable to rectal cancer with MRI assessment less than 12 cm from anus.

(1) It is recommended to perform MMR or MSI testing before preoperative treatment of rectal cancer. If the result is pMMR or MSS, neoadjuvant radiotherapy based on fluorouracil-based drugs is recommended. If it is dMMR or MSI-H, as foreign studies have shown a high response rate to PD-1 monoclonal antibody, the decision of neoadjuvant immunotherapy can be considered under the guidance of MDT.

(2) Patients with T1−2N0M0 or contraindications of radiochemotherapy are recommended to surgical treatment directly, and new adjuvant therapy is not recommended. For those who have difficulties in preserving the anal sphincter and have a strong desire to preserve the anus, radiotherapy should be administered after full communication with the patients (see 6. Radiotherapy for CRC for specific indications for radiotherapy), and then decide whether to operate according to the efficacy assessment.

(3) In principle, preoperative nCRT is recommended for T3 and/or N+ patients with resectable rectal cancer (see radiotherapy section for specific radiotherapy indications); after MDT discussion, neoadjuvant chemotherapy alone can also be considered, and then combined radiotherapy can be determined according to the efficacy evaluation.

(4) Patients with T4 or local advanced unresectable rectal cancer must receive preoperative radiochemotherapy. After treatment, resectability must be reevaluated, and the feasibility of surgery must be discussed by MDT.

In nCRT, capecitabine alone or continuous infusion of 5-fluorocrail (5-FU) or 5-FU/leucovorin (LV) or capecitabine in combination with irinotecan is recommended as the first choice, and chemotherapy is carried out simultaneously during long-term radiotherapy. Please refer to 6. Radiotherapy for CRC.

(5) For patients who are not suitable for radiotherapy, it is recommended to decide whether to use neoadjuvant chemotherapy alone under the discussion of MDT.

5.1.2. Preoperative treatment of T4b colon cancer

(1) For the initial local non-resectable T4b colon cancer with pMMR or MSS, chemotherapy or chemotherapy combined with targeted therapy is recommended (see Preoperative treatment of CRC liver metastases for specific regimens). If necessary, under the discussion of MDT, decide whether to add local radiotherapy. In case of dMMR or MSI-H, it is recommended to decide whether to use immunotherapy under MDT discussion.

(2) For the initial local resectable T4b colon cancer, it is recommended to decide whether to receive preoperative medication or direct surgery under the discussion of MDT.

5.1.3. Preoperative treatment of liver and/or lung metastasis of CRC

CRC patients with liver and/or lung metastasis, metastasis is resectable or potentially resectable, please refer to the relevant sections for details. Preoperative chemotherapy or chemotherapy combined with targeted drug therapy is recommended under the discussion of MDT. Targeted drugs include cetuximab (recommended for K-ras, N-ras, BRAF genes wild-type patients), or combination of bevacizumab. Capeox (capecitabine + oxaliplatin), or FOLFOX (oxaliplatin + fluorouracil + hydrofolate), or FOLFIRI (irinotecan + fluorouracil + hydrofolate), or FOLFOXIRI (oxaliplatin + irinotecan + fluorouracil + hydrofolate) was recommended as the chemotherapy plan. It is suggested that the time limit of treatment is 2−3 months.

After treatment, it is necessary to reevaluate and consider the feasibility of local destructive treatment, including surgery, radiofrequency ablation and stereotactic radiotherapy.

5.2. Adjuvant treatment of CRC

The adjuvant therapy should be determined according to the primary site, pathological stage, molecular markers and postoperative recovery. It is recommended that adjuvant chemotherapy should be started about 4 weeks after operation (the patients with poor constitution should be prolonged appropriately), and the time limit of chemotherapy should be 3−6 months. During the treatment, we should adjust the dosage and/or shorten the chemotherapy cycle according to the patients’ physical condition, drug toxicity, postoperative TN stage and patients’ wishes. Adjuvant therapy is not recommended in patients with contraindications of radiotherapy and chemotherapy.

(1) Adjuvant therapy is not recommended for stage I (T1−2N0M0) CRC.

(2) Adjuvant chemotherapy for stage II colon cancer

For stage II colon cancer, we should confirm whether there are the following high-risk factors: poor histological differentiation (grade III or IV), normal MMR, microsatellite stability (MSS), T4, vascular lymphatic infiltration, preoperative intestinal obstruction/intestinal perforation, insufficient lymph nodes (less than 12) detected in specimens, nerve invasion, positive or undeterminable resection margin.

1) If there is no high-risk factor, follow-up observation or single drug like fluorouracil chemotherapy is recommended.

2) If there are high-risk factors, adjuvant chemotherapy is recommended. Capeox or FOLFOX, based on oxaliplatin, or 5-FU/LV or capecitabine as a single drug, are recommended for chemotherapy. The treatment time is 3−6 months.

3) If the tumor tissue is mismatched repair defect (dMMR) or high-level microsatellite instability (MSI-H), postoperative adjuvant chemotherapy is not recommended.

(3) For stage II rectal cancer, please refer to 6. Radiotherapy for CRC.

(4) Adjuvant chemotherapy for stage III CRC

Adjuvant chemotherapy is recommended for patients with stage III CRC. Capeox, FOLFOX or capecitabine, 5-FU/LV is recommended for chemotherapy. For low-risk patients (T1−3N1), 3-month regimen with CapeOx can also be considered as adjuvant chemotherapy.

(5) Adjuvant radiotherapy and chemotherapy for rectal cancer

Rectal cancer which is T3−4 or N1−2 with distance to anal margin less than 12 cm is recommended to use preoperative neoadjuvant radiochemotherapy. If neoadjuvant radiotherapy is not performed before operation, the adjuvant radiotherapy and chemotherapy will be determined according to the postoperative pathological conditions, among which fluorouracil based chemotherapy is recommended. Please refer to 6. Radiotherapy for CRC.

(6) Drugs that are not recommended.

(7) At present, irinotecan, tegafur, letetrexed and targeted drugs are not recommended in adjuvant chemotherapy.

5.3. Systemic treatment of recurrent/metastatic CRC

At present, 5-FU/LV, irinotecan, oxaliplatin, capecitabine, tripyridine and letetrexed are used in the treatment of advanced or metastatic CRC. Targeted drugs include cetuximab (recommended for K-ras, N-ras, BRAF genes wild-type patients), bevacizumab, regofinib, and furquitinib. Immune checkpoint inhibitors include PD-1 monoclonal antibody or PD-L1 monoclonal antibody.

(1) Detection of K-ras, N-ras, BRAF genes and microsatellite status is recommended before treatment.

(2) Combined chemotherapy should be the first-line and second-line treatment for patients with mCRC who can tolerate chemotherapy. The following chemotherapy regimens are recommended: FOLFOX/FOLFIRI ± cetuximab (recommended for K-ras, N-ras, BRAF genes wild-type patients), CapeOX/FOLFOX/FOLFIRI/ ± bevacizumab. The first-line treatment of FOLFOXIRI ± bevacizumab can also be considered for patients with large tumor burden, poor prognosis or need of transformation treatment, if the general situation allows. FOLFOXIRI + cetuximab can also be considered in the treatment of K-ras, N-ras, BRAF genes wild-type patients who need transformation.

(3) The prognosis of right colon cancer (from ileocecal to splenic curvature) is worse than that of left colon cancer and rectum (from splenic curvature to rectum). For K-ras, N-ras, BRAF genes wild-type patients, the first-line treatment of right colon cancer in the anti-vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab) combined chemotherapy is better than the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (cetuximab) combined chemotherapy, while in the left colon cancer and rectal cancer in the anti EGFR monoclonal antibody combined chemotherapy is better than the anti VEGF monoclonal antibody combined chemotherapy.

(4) Patients with three or more lines of treatment are recommended to take regofinib or furquitinib or to participate in clinical trials, or to consider tripyrimidine. We can adjust the initial dose of regofinib in the first cycle treatment according to the patient’s condition and physical condition. For the patients who did not choose the targeted drugs in the first and second-line treatment, cetuximab ± irinotecan (recommended for K-ras, N-ras, BRAF genes wild type) can also be considered.

(5) For the first-line patients receiving oxaliplatin, if the second-line treatment is chemotherapy plus bevacizumab, FOLFIRI or improved irinotecan plus capecitabine are recommended. For patients who cannot tolerate combined chemotherapy, 5-FU/LV or capecitabine single drug ± target drug is recommended. Letetrexed should be considered in patients with advanced CRC who are not suitable for 5-FU/LV.

(6) Patients with stable disease but no chance of R0 operation after 4−6 months of palliative treatment may be considered for maintenance treatment (such as 5-FU/LV or capecitabine single drug or combination of targeted treatment or suspension of systemic treatment with low toxicity), so as to reduce the toxicity of combined chemotherapy.

(7) For BRAF^V600E mutation patients, if the general condition is good, the first-line treatment of FOLFOXIRI + bevacizumab can be considered.

(8) For the patients with dMMR or MSI-H, PD-1 monoclonal antibody therapy in first line is recommended. If not treated with PD-1 monoclonal antibody in first line, PD-1/PD-L1 monoclonal antibody therapy is recommended in second line or above.

(9) For the patients who carry an NTRK fusion variant, NTRK inhibitor therapy is recommended after failure of standard therapy.

(10) If the general condition or organ function of late patients with advanced CRC is poor, the best supportive treatment is recommended.

(11) If the metastasis is limited to the liver or/and lung, refer to 7. Treatment for liver metastases and 8. Treatment for lung metastases.

(12) For patients with local recurrence of CRC after surgery, it is recommended to conduct multidisciplinary evaluation to determine whether there is a chance to resect, radiotherapy or radiofrequency ablation and other local treatment, so as to achieve the state without tumor evidence. If it is only suitable for systemic therapy, the above principles of drug treatment for advanced patients should be adopted.

5.4. Other treatments

On the premise that the above conventional treatment is not applicable, the patients in the advanced stage can choose local treatment, such as interventional treatment, tumor injection, physical treatment or Traditional Chinese Medicine treatment.

5.5. Best support treatment

The best supportive treatment should run through the whole process of patients’ treatment, and it is suggested that multidisciplinary comprehensive treatment. The best supportive treatment recommendations cover the following:

(1) Pain management: Accurately perfect pain assessment, comprehensive and reasonable measures to treat pain, recommended according to the principle of three-step pain treatment, actively prevent and deal with adverse reactions of painkillers, and pay attention to etiology treatment. Pay attention to the pain education and psychosocial support of patients and their families, and strengthen communication and follow-up.

(2) Nutritional support: It is suggested to assess the nutritional status regularly, give appropriate nutritional support and advocate enteral nutrition support.

(3) Psychological intervention: It is suggested that oncology psychiatrists should provide psychological intervention and necessary psychotropic drug intervention in the areas where conditions permit.

5.6. Latest progress in diagnosis and treatment of CRC

5.6.1. Latest technology

Next generation sequencing (NGS): NGS can perform high-throughput genetic testing for tumor tissues and body fluids (e.g. blood, malignant ascites, pleural effusion, etc.) at one time. NGS testing can help CRC patients find rare variants and understand drug resistance mechanisms after drug treatment. It is recommended to conduct NGS at qualified genetic testing institutions to find suitable clinical studies or drug treatments. In addition, circulating tumor DNA (ctDNA) based on peripheral blood has also shown some clinical value in recent years. In mCRC, ctDNA dynamic monitoring has significance in assessing drug efficacy and prognosis; in stage II−III CRC, ctDNA is used to assess postoperative minimal residual disease (MRD) status, thus providing more reference for the development of adjuvant treatment strategies. It is encouraged for patients to participate in clinical studies related to ctDNA testing.

5.6.2. Latest drug development

(1) Clinical studies

Clinical trials have the potential to provide additional benefits to patients based on existing standard treatments. Given that there are still many limitations in the efficacy of current standard drug therapy, it is recommended that patients be encouraged to participate in clinical trials corresponding to their disease on a voluntary basis.

(2) Special genetic variants

For CRC with special molecular types such as BRAF^V600E, HER2 amplification, KRASG12C, POLE/POLD1 non-synonymous mutations, foreign studies have shown that the corresponding drug therapy has certain efficacy. Such patients are firstly recommended to participate in clinical studies corresponding to them, and they can also be considered to try treatment for specific targets under the guidance of experienced medical oncologists.

6. Radiotherapy for CRC

6.1. Indications for radiotherapy for CRC

The main modes of radiotherapy or CRT for rectal cancer are neoadjuvant/adjuvant therapy, radical therapy, conversion therapy and palliative therapy.

Neoadjuvant radiotherapy indication is mainly for stage II−III mid-low rectal cancer (from the anus <12 cm), including long-course concurrent CRT or short-course radiotherapy (SCRT) combined with chemotherapy. For stage II−III rectal cancer with high-risk recurrence factors, or for those who need to increase tumor regression or pursue Watch & Wait (W&W) strategy to preserve the anal sphincter, CRT or short-course radiotherapy combined with consolidation chemotherapy is recommended, or total neoadjuvant therapy (TNT) modality can also be used. For stage II−III rectal cancer with low to moderate risk and low tumor burden, and surgically resectable stage T3 rectal cancer diagnosed by MRI or ultrasound endoscopy, radical surgery can be received at an interval of 5−12 weeks after long-course radiochemotherapy, or radical surgery can be received within 1 week after completion of short-course radiotherapy (short-course radiotherapy followed by immediate radical surgery), or radical surgery can be performed 8 weeks after consolidation chemotherapy. Adjuvant radiotherapy is mainly recommended for rectal cancer who have not received nCRT and have postoperative pathological stage II−III and are at high risk of local recurrence. Patients who need preoperative or postoperative radiotherapy should be recommended to hospitals with radiotherapy equipment and conditions for radiotherapy.

Patients with low rectal cancer who have a strong desire to preserve their anus may be recommended to undergo nCRT first. If the tumor is sensitive to CRT and achieves clinical complete response (cCR), the treatment strategy of W&W may be considered (see 6.1.5 W&W strategy for details); Radical surgery is recommended if cCR is not achieved. For recurrent or metastatic rectal cancer who have the chance of radical resection, if the rectal lesion is local but difficult to resection, and not receiving radiotherapy before, local radiotherapy can be considered to transform it into surgically resectable lesion; The indications of palliative radiotherapy for rectal cancer are local recurrence and/or distant metastasis tumor, or some patients who cannot tolerate surgery, and cannot be cured by radiotherapy and combined therapy. Postoperative radiotherapy may also be considered after palliative resection of colon cancer and labeling.

6.1.1. Radiotherapy for stage I rectal cancer

Those who have difficulties in preserving the anal sphincter during surgery for stage I rectal cancer and those who have a strong will to preserve anus, should undergo radiotherapy after full communication with the patients, and then choose W&W strategy or surgery according to the efficacy assessed by MDT. Radical surgery is recommended for patients with high-risk factors after local resection of stage I rectal cancer (see 4. Surgical treatment for details). If further radical surgery cannot be performed for some reasons, or if further combined abdominoperineal resection is needed for low rectal cancer and the patient has a strong desire to preserve anus, concurrent CRT followed by W&W strategy is feasible.

6.1.2. nCRT for stage II−III rectal cancer

The clinical diagnosis was stage II−III rectal cancer, and rectal MRI was the first choice for local examination (see 2. Diagnosis for details). If the patient cannot receive MRI, rectal ultrasonography is recommended. Stratified treatment based on the location of the tumor in the rectum and the risk of recurrence suggested by MRI is recommended, as shown in Table 10. Preoperative neoadjuvant radiochemotherapy is recommended, instead of postoperative radiotherapy.

Table 10. Neoadjuvant chemoradiotherapy stratification treatment recommendations for stage II−III rectal cancer.

Risk stratification for recurrence of stage II−III rectal cancer	Treatments	Recommended level
TME, total mesorectal excision; MRF, mesorectal fascia; EMVI, extramural vascular invasion; CRT, long-course concurrent chemoradiotherapy; SCRT, short-course radiotherapy.
Low-risk group, meeting all the following criteria: 　cT3a/b if middle or high 　cN0/high cN1 　MRF (−) 　EMVI (−)	Direct TME surgery; surgical quality evaluation of TME; postoperative adjuvant therapy is determined by postoperative pathology	Recommended
	If high quality TME surgery is not assured, preoperative CRT + delayed surgery/SCRT + immediate surgery should be performed	Recommended
Middle-risk group, MRF (−) and meeting any or more of the following criteria: 　cT3c/d low, levators clear 　cN1−2 (not extranodal) 　EMVI (−)	Preoperative CRT + delayed surgery/SCRT + immediate surgery	Recommended
High-risk group, MRF (−) and meeting one or more of the following criteria: 　cT3c/d or very low, levators clear 　cN1−2 (extranodal) 　EMVI (+)	Preoperative CRT/SCRT sequential chemotherapy + delayed surgery	Recommended
Extremely high-risk group, meeting one or more of the following criteria; 　MRF (+) 　cT4 　The elevator ani muscle is invaded 　Lateral lymph node (+)	Preoperative CRT/SCRT sequential chemotherapy + delayed surgery/Sequential neoadjuvant chemotherapy + CRT + delayed surgery/TNT	Recommended
Elderly patients with infirmity or severe complications who cannot tolerate CRT	SCRT + delayed surgery	Recommended
Patients who have difficulty in preservation of the anal sphincter and have a strong desire to maintain sphincter function	Concurrent chemoradiation + sequential chemotherapy/SCRT + sequential chemotherapy + surgery/ watch and wait determined by therapeutic effect	Recommended

6.1.3. Neoadjuvant immunotherapy

For dMMR/MSI-H rectal cancer, after sufficient communication with the patients, PD-1/PD-L1 immune checkpoint inhibitor treatment can be performed, and the decision to undergo radiotherapy, chemotherapy, and surgery is based on the efficacy evaluation. For pMMR/MSS rectal cancer, multiple prospective phase I−II studies at home and abroad have shown that radiotherapy combined with PD-1/PD-L1 inhibitors can increase tumor regression and pCR/cCR rate. For pMMR/MSS rectal cancer patients who meet the indications for neoadjuvant therapy, it is recommend to participate in clinical studies that combine radiotherapy with immunotherapy.

6.1.4. Adjuvant CRT for rectal cancer

For patients with rectal cancer with preoperative diagnosis of stage I or not receiving neoadjuvant CRT for various reasons and postoperative pathological diagnosis of stage II−III, stratified treatment was recommended according to TME surgical quality, CRM status and distance from the tumor to the anal margin, as shown in Table 11.

Table 11. Adjuvant chemoradiotherapy stratification treatment recommendations for stage II−III rectal cancer.

Risk stratification for recurrence of stage II−III rectal cancer	Treatments	Recommended level
TME, total mesorectal excision; CRM, circumferential resection margin; MRF, mesorectal fascia.
Meeting any of the following criteria: 　T3−4N0 low; 　CRM+; 　pN+; 　Tumor deposits (TDs) 　Nerve invasion + poor quality of TME operation/mesenteric 　defects/the quality of TME operation could not be evaluated	Postoperative concurrent chemoradiotherapy	Recommended
Meeting all the following criteria: 　T3−4aN0 if middle or high; 　CRM−; 　pN0;	Postoperative concurrent chemoradiotherapy	Not suggested
Nerve invasion−; 　Good quality of TME operation/smooth and intact mesentery

6.1.5. W&W strategy

For low advanced rectal cancer (cT1N0, cT2N0, cT3−4 or N+) with difficulty in preserving the anal sphincter, preoperative concurrent CRT is recommended if the patient has a strong desire to preserve the anus. The combination sequence of radiotherapy followed by consolidation chemotherapy is recommended, which is conducive to achieving higher tumor regression rates and organ preservation rates. If cCR is obtained after nCRT, the W&W strategy can be adopted. The evaluation time of cCR is recommended to be 8−12 weeks after concurrent nCRT, and extended to 16−24 weeks for those who received consolidation chemotherapy or TNT regimen during interval, as appropriate. And it is recommended to follow up every 2−3 months for 2 years, and the frequency of further follow-up is referred to postoperative patients. cCR evaluation items are strongly recommended to include DRE, colonoscopy and rectal MRI, all of which must meet the cCR evaluation criteria, as shown in Table 12.

Table 12. cCR criteria.

Evaluation item	cCR criteria
cCR, clinical complete response; MRI, magnetic resonance imaging; T2WI, T2 weighted imaging; ADC, apparent diffusion coefficient; DWI, diffusion weighted imaging.
Digital rectal examination	No clear mass was observed, and the intestinal wall was soft
Endoscopy	No clear residual tumor was observed, and only leukoplakia and/or telangiectasia could be seen in the original tumor area
Pelvic cavity MRI	T2WI showed no clear tumor signal and no suspicious lymph nodes in the tumor bed area; No tumor hyperintensity and no hypointensity in the ADC map with DWI b values between 800−1,000

6.1.6. Stage IV rectal cancer

For concurrent metastatic rectal cancer, both local treatment for the primary tumor and systemic treatment for distant metastases are necessary and should be discussed under the framework of MDT to arrange the order of local and systemic treatment according to the degree of health threat, resectability, and risk of recurrence of the primary foci and metastases. Systemic treatment and local treatment such as radiotherapy of the primary tumor or surgical resection should be used. For heterochronic metastatic rectal cancer, it is recommended for MDT discussion to decide whether local destructive treatment (including surgery, radiofrequency ablation, stereotactic radiotherapy, etc.) or palliative radiotherapy will be performed for metastatic lesions.

6.1.7. Locally recurrent rectal cancer

For locally recurrent rectal cancer, if they have not received pelvic radiotherapy before, preoperative concurrent CRT is recommended. After CRT, the patient should be reevaluated and strive for surgical resection; If the patient has received pelvic radiotherapy before, the high risk of second-course radiotherapy should be carefully evaluated, and it is recommended to determine the treatment plan by MDT.

6.2. Guidelines of radiotherapy for rectal cancer

Hospitals can choose suitable radiotherapy technology according to their different radiotherapy equipments, and three-dimensional conformal or intensity modulated radiation therapy (IMRT) technology is recommended. Qualified hospitals can consider the application of volumetric rotational intensity modulation technology, which can optimize dose distribution while significantly shorten the treatment time and reduce the patient’s displacement error during treatment. Intraoperative radiotherapy, intracavitary irradiation or external irradiation may be applied for local dosing. Radioactive seed implantation therapy is not routinely recommended.

6.2.1. Three-dimensional and intensity modulated radiotherapy localization

(1) Preparation before localization: It is recommended to drink 800−1,000 mL of water after emptying the bladder 1 h before positioning to make the bladder full and empty the stool.

(2) Body position and body film fixation: Supine position or prone position can be adopted, and thermoplastic body film fixation.

(3) Simulated CT: The range of CT scan is recommended, the upper boundary is from the level of the 2−3rd lumbar vertebra, the lower boundary is to the upper 1/3 segment of the femur, and the thickness is 5 mm. Patients who are not allergic should have an enhanced venography scan to clearly show the tumor and blood vessels. For those who have received preoperative radiotherapy, it is recommended that qualified medical centers apply MRI localization CT/MRI fusion simultaneously to help clarify the tumor range so as to more accurately delineate the target area.

6.2.2. Definition of exposure range and target volume

Gross target volume (GTV) refers to gross tumor determined by clinical examination, including GTVp (rectal primary tumors and EMVI of the intestinal wall) and GTVnd (positive lymph nodes). Clinical target volume (CTV) includes GTV, the region with high risk of recurrence of the primary tumor and the region with lymphatic drainage, which must be irradiated. Planned target volume (PTV) is formed by CTV outward expansion, including CTV itself, and covers uncertain factors such as organ movement and daily positioning during irradiation.

(1) The regions with high risk of recurrence of primary tumor include tumor/tumor bed, mesorectal region and presacral region. Radiation fields are recommended to include tumor/tumor beds and safety margins of ≥1−2 cm.

(2) The region with lymphatic drainage includes the mesorectal region, the iliac endovascular lymphatic drainage region and the obturator lymphatic drainage region. For the clear presence of lymph node metastasis in the external iliac vessel lymphatic drainage region, irradiation of the lymphatic drainage region of the external iliac vessels is recommended. When T4 tumors invade the anterior structure, the lymphatic drainage region of the external iliac vessels can be irradiated (not included when only the levator ani muscle is invaded).

(3) For patients with tumors and/or residues, pelvic irradiation plus additional irradiation to high-risk recurrence areas should be given by simultaneous additional radiotherapy (SIB-IMRT) or pelvic irradiation followed by additional irradiation with local field shrinkage. Meanwhile, the dose of irradiation to the intestine should be carefully considered.

(4) Definition of organ at risk: Pelvic small intestine, colon, bladder, bilateral femoral head, male and female genitalia, male urethral bulb, and female perineum are organs at risk in the preoperative/postoperative radiotherapy area of rectal cancer, it is recommended to delineate and define the dose and volume of exposure. Attention should be paid to communicating with patients about the impact of radiotherapy on fertility and sexual function. It is recommended that patients with reproductive needs seek reproductive medicine consultation.

(5) Radiotherapy for recurrent pelvic lesions: If there is no previous history of radiotherapy, radiotherapy for recurrent tumor and high-risk recurrence region is recommended, and local dose radiotherapy for tumor can be considered. If so, radiotherapy should be decided according to the situation. If radiotherapy is performed, it mainly targets the gross tumor and a safe boundary of ≥1−2 cm, and can consider including adjacent high-risk areas. The recommended dose segmentation for re-irradiation therapy is described later.

(6) Radical radiotherapy for early rectal cancer: Due to its small invasion range and low incidence of lymph node metastasis, it is advisable to appropriately reduce the preventive radiation range on the basis of including the safe margin of the tumor ≥1−2 cm, the mesorectal area, and the presacral area.

(7) The specific target region was delineated and the definition of organ at risk was referred to the professional books on radiotherapy.

6.2.3. Radiotherapy dose and segmentation pattern

There must be a clear definition of radiation dose whether using techniques such as IMRT or three-dimensional conformal radiotherapy. The volume dose definition method must be applied.

Preoperative neoadjuvant radiotherapy segmentation mode: There are mainly two kinds of dose segmentation modes in preoperative neoadjuvant radiotherapy. 1) SCRT mode, 5 Gy × 5 radiotherapy is recommended for primary tumors and high-risk region. Surgery can be performed within one week after short-course radiotherapy or after sequential chemotherapy. Short-course radiotherapy combined with sequential chemotherapy has a good effect on tumor regression and has little impact on the systemic treatment time, making it suitable for locally advanced rectal cancer patients with medium to high risk; Short-course radiotherapy combined with sequential chemotherapy can be considered for patients with middle and low rectal cancer with difficulty in preserving anal sphincter in surgery and strong desire to preserve anus. The SCRT segmentation model combined with immediate TME surgery is not suitable for patients with rectal cancer who are MRF positive or T4 (i.e., LARC which cannot be initially resected at R0 or cannot be resected). This mode is mainly applicable to locally advanced rectal cancer patients with low to medium risk and low tumor burden, and must be preceded by a MDT discussion and adequate communication with the surgeon (The connection between radiotherapy and operation time); 2) Long-course CRT mode, it is recommended to irradiate the primary tumor and high-risk area with DT 45.0−50.4 Gy, 1.8−2.0 Gy each time, for a total of 25−28 times. The long-course CRT mode of 5-Fu or capecitabine monotherapy or capecitabine combined with irinotecan during radiotherapy is mainly suitable for patients with stage II−III rectal cancer, which is conducive to full tumor regression. Long-course CRT can also be carried out for patients with difficulty in preserving anal sphincter in stage I middle and low rectal cancer surgery who have a strong desire to preserve anus, so as to strive for W&W strategy after cCR. At present, there have been prospective Phase II studies both domestically and internationally showing that early to mid-stage (T1−T3bN0M0) rectal cancer can achieve high CR rates and organ retention rates by combining radiotherapy and chemotherapy with local resection, or by adding local doses of radiotherapy (including internal and external irradiation). Patients with early to mid-stage low rectal cancer can also consider joining corresponding clinical studies; 3) If preoperative radiotherapy adopts other dose segmentation methods, effective biological dose (BED) must be ≥30 Gy; and 4) For patients with lateral lymph node metastasis, it is recommended to choose whether to perform surgical dissection based on the condition of lateral lymph node regression after neoadjuvant radiotherapy; If lateral lymph node dissection cannot be performed due to various reasons, and there is currently no high-level evidence-based medical evidence to support it, additional radiation therapy may be considered for metastatic lateral lymph nodes during neoadjuvant radiochemotherapy.

Postoperative adjuvant CRT dose: For patients at stage II−III who did not receive radiotherapy before surgery, it is recommended to give DT 45.0−50.4 Gy to tumor bed and high-risk area after surgery, 1.8−2.0 Gy each time, a total of 25−28 times. 5-FU or capecitabine chemotherapy was given simultaneously during radiotherapy. For patients with residual tumor or positive resection margin, secondary surgery is recommended. If the second operation cannot be performed or the patient refuses the second operation, it is suggested to add the radiation dose DT 10−20 Gy to the local shrinking field after the total pelvic irradiation. The method of synchronous dosage is not recommended when the intestinal tube is in the target area. And the intestinal exposure dose must be considered, especially the small intestine/colon dose in the radiation field (Dmax ≤50−55 Gy, V45 ≤65 cc, V40 ≤100 cc, V35 ≤180 cc).

Re-irradiation dose for pelvic recurrence: Lacking high-level evidence-based medical evidence, hyperfractionated radiotherapy can be used to reduce late reaction toxicity, with a dose of 1.2−1.5 Gy each time and twice per day; Or 1.8 Gy each time, once a day; Total dose 30−40 Gy; The main purpose is to improve the resection rate, increase local tumor control, and alleviate symptoms. There is a lack of consensus on the limit of normal tissue exposure in re-irradiation therapy, and the application of IMRT can be considered to minimize intestinal exposure dose.

6.2.4. Recommended interval between neoadjuvant radiotherapy and surgery

The interval between neoadjuvant radiotherapy and surgery is different depending on the course of neoadjuvant radiotherapy: 1 week after SCRT (5 Gy × 5) (SCRT + immediate surgery mode) or 6−8 weeks after SCRT (SCRT + delayed surgery mode).

Surgery is recommended at 5−12 weeks after LCRT.

In recent years, multiple randomized controlled studies have shown that chemotherapy during interval can increase tumor regression and reduce recurrence and metastasis. For stage II−III rectal cancer with high-risk recurrence factors, or those who need to increase tumor regression or strive for the W&W strategy to preserve the anal sphincter, radiochemotherapy or short-course radiotherapy combined with consolidation chemotherapy, or TNT mode is recommended, and the interval is extended to 16−24 weeks as appropriate.

6.3. Principle of combined CRT for rectal cancer

6.3.1. Concurrent chemotherapy regimen

(1) Fluorouracil monotherapy or capecitabine combined with irinotecan is recommended for concurrent chemotherapy during long-course radiotherapy, and there are four specific types: 1) Capecitabine 825 mg/m², Bid, 5 d a week, oral medication on radiotherapy days is recommended; 2) 5-FU 225 mg/(m²·d), continuous intravenous infusion during radiotherapy, 24 h a day, 5−7 d a week; 3) 5-FU 400 mg/(m²·d) + LV 20 mg/(m²·d), d 1−d 4, intravenous infusion during the 1st and 5th week of radiotherapy; and 4) Joint plan: Capecitabine 625 mg/m², Bid, 5 d a week, orally administered on radiotherapy days; UGT1A1 genotyping is used to guide the dosage of irinotecan. The recommended dosage of irinotecan for patients with UGT1A1*1*1 (genotype 6/6) and UGT1A1*1*28 (genotype 6/7) genotyping was 80 mg/m², once a week; 65 mg/m², once a week, respectively.

(2) It is not recommended to add bevacizumab, cetuximab, panizumab and other targeted drugs into preoperative CRT for rectal cancer.

(3) Concurrent chemotherapy and targeted therapy drugs are not recommended for SCRT.

6.3.2. Adding chemotherapy during interval between concurrent CRT or brachytherapy and surgery

For LARC, especially in patients with pretherapeutic assessment of MRF positive or T4b or lateral lymph node metastasis, sequential chemotherapy can be performed after long-course concurrent CRT or short-course radiotherapy to increase the degree of tumor regression, followed by surgery. FOLFOX, CapeOx or capecitabine monotherapy can be selected as chemotherapy regimens, and 2−6 cycles of chemotherapy are recommended in the interval.

6.3.3. Sequence of postoperative adjuvant CRT and adjuvant chemotherapy

For patients who need additional pelvic radiotherapy after radical resection of stage II−III rectal cancer, it is recommended to first concurrent CRT followed by adjuvant chemotherapy, or to first 1−2 cycles of adjuvant chemotherapy, concurrent CRT followed by adjuvant chemotherapy. For patients with negative resection margins and pN2, the prior adjuvant chemotherapy followed by concurrent CRT can also be considered.

6.4. Radiotherapy for mCRC

Radiotherapy for mCRC is recommended to be discussed by MDT, and finally the most reasonable treatment plan is determined according to the following aspects: 1) The size, number and location of metastasis; 2) The patient’s situation of receiving other treatments; 3) The functional state of the metastatic organ, such as the liver; and 4) The controlling condition in other tumor sites. The primary benefit of radiotherapy for mCRC is the reduction of local symptoms and the radical treatment of a small or isolated number of lesions. Radiotherapy is more secure and minimally invasive compared to surgical procedures and interventions. Stereotactic body radiation therapy (SBRT), alternatively referred to as stereotactic ablative radiotherapy (SABR), can attain equivalent prognoses to surgery when the BED >100 Gy. SBRT is predominantly advised when tumors are in proximity to the heart or principal vasculature.

7. Treatment for liver metastases

7.1. CRC with initially radical resectable liver metastases

7.1.1. Definition

Synchronous liver metastases are defined as liver metastases detected at or before diagnosis of the primary tumor. Metachronous liver metastases are considered to be those detected after radical resection of the primary CRC.

7.1.2. Patients with liver metastases are all recommended to receive multidisciplinary therapy

(1) Neoadjuvant chemotherapy

1) CRC is diagnosed with initially radical resectable liver metastases: Preoperative chemotherapy is recommended when there is no bleeding, obstruction or perforation in the primary lesion, and liver metastasis has high-risk factors of recurrence after resection. The chemotherapy regimens are referred to medical treatment section.

2) Radical resectable liver metastases after radical resection of CRC: Preoperative chemotherapy can be used for patients who have not received chemotherapy after primary tumor resection, or who have completed chemotherapy 12 months ago and have high-risk factors of liver metastases recurrence after resection. The chemotherapy regimens are referred to medical treatment section; Patients who had received chemotherapy within 12 months before the detection of liver metastases can have direct resection for liver metastases.

(2) For patients who have no evidence of disease (NED) after liver metastases resection, it is recommended to decide whether to receive postoperative adjuvant chemotherapy after MDT discussion according to preoperative treatment and postoperative pathology.

7.1.3. Local treatment

(1) Indications of surgery for liver metastasis

1) Primary CRC can be or has been removed radically.

2) The remnant liver still has adequate function after liver metastases resection.

3) The general condition of patients who have no extrahepatic metastasis or only pulmonary nodular lesions allow.

(2) Contraindication of surgery for liver metastasis

1) Primary CRC cannot be removed radically.

2) There are unresectable extrahepatic metastatic lesions.

3) The residual liver volume after surgery is expected to be insufficient.

4) The general condition of patients does not tolerate surgery.

(3) Surgical treatment

1) If the synchronous liver metastasis is allowed to get a radical resection, synchronous resection of primary CRC and liver metastasis is recommended.

2) The synchronous liver metastasis which could not satisfy the condition of simultaneous resection of primary lesions and liver metastases after preoperative evaluation: a) Surgical resection of the primary lesions was performed firstly, and the resection of the metastatic lesions can be delayed within 3 months after the resection of primary lesions; and b) Simultaneous resection of primary tumors and liver metastases is not recommended for emergency surgery.

3) Liver metastasis occurred after radical resection of CRCs. Previously, primary lesions got a radical resection without recurrence of the primary tumor. For these patients whose liver metastases can be completely resected and the volume of hepatectomy is <70% (without cirrhosis), surgical resection of liver metastases should be performed.

4) If the metastatic lesions which recurred after excision of liver metastases have reached the operating conditions, liver metastases can be excised twice, three times or even many times.

(4) Operation method

1) Preservation of at least one of the three hepatic veins after resection of hepatic metastases. Making sure the hepatic residue volume ≥40% for synchronous resection, or ≥30% for metachronous hepatectomy. Surgical resection of metastatic lesions should conform to the R0 principle, and the resection margin >1 mm at least.

2) If the liver metastasis is limited to the left or right half of the liver and there is no liver cirrhosis, regular hemi-hepatectomy is feasible.

3) Intraoperative ultrasound or contrast-enhanced ultrasound is recommended to be used during the operation, which is helpful to find the liver metastasis lesion that may be difficult to be diagnosed by imaging examination before operation.

4) Selective portal vein embolization (PVE) or portal vein ligation (PVL) can increase the compensation of the remaining liver after hepatectomy and increase the possibility of surgical resection.

5) Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) can shortly increase the volume of residual liver to get more chances of stage II hepatectomy, but the complications and mortality of the complex operation are higher than traditional hepatectomy.

(5) Ablation treatment: Radiofrequency ablation is also one of the methods to eradicate liver metastases. However, the local recurrence rate is higher than other therapies. In general, radiofrequency ablation can be performed for metastatic lesions with a residual diameter of <3 cm, and up to 3 liver metastases can be ablated during a single treatment session. Combined radiofrequency ablation is also recommended for metastatic lesions with a residual diameter of <3 cm if the estimated residual liver volume is too small during the hepatectomy. The indication of microwave ablation is similar to radiofrequency ablation. Due to the microwave can avoid the limitation of tissue drying carbonization, higher temperature and larger ablation zone can be shortly produced inside the tumor, and the necrosis of tumor cells may be more complete.

(6) SBRT: SBRT is one of the optional radical treatments for liver metastasis. It is a non-invasive, well-tolerated and effective treatment and can give high precision and high dose irradiation to the lesion. Indications of liver metastases for SBRT:

1) The primary lesion was under control, and the patients are generally in good condition with expected survival ≥3 months;

2) The normal liver size >700 mL;

3) Child-Pugh grading A or B.

It is recommended that for most liver metastases, especially those with diameter ≤3 cm, BED should be ≥100 Gy on the premise of safety. SBRT is not suitable for liver metastasis which is close proximity to vital organs such as small intestine, stomach, duodenum and kidney. It is not recommended to carry out SBRT in hospitals and units without image-guided technology or respiratory control technology.

7.2. Potentially resectable liver metastases treatment

Treatment plans must be developed through MDT discussions. It is recommended to re-evaluate after systemic targeted chemotherapy or other treatments. If the lesions convert to resectable liver metastasis, it can be treated as resectable treatment plans. If the lesions still cannot be resectable, refer to the content of chemotherapy for recurrent/metastatic CRC in the section of 5. Medical treatment.

7.3. Unresectable liver metastases treatment

7.3.1. Treatment of primary lesions

(1) When there is no bleeding, obstruction or perforation in the primary CRC, systemic chemotherapy can be performed, or the primary lesions can be excised first, followed by further treatment. (Note: it is still controversial whether primary tumor resection is necessary in CRC patients with primary lesions without bleeding, obstruction, or perforation accompanied by persistent unresectable liver/lung metastasis.)

(2) When the primary lesions of CRC have bleeding, obstruction or perforation, it should be removed first and followed by systemic chemotherapy. After treatment, the patient should be evaluated to determine the next course of treatment every 6−8 weeks.

7.3.2. Radiofrequency ablation

It is recommended to consider radiofrequency ablation in the following situations: 1) Patients with resectable liver metastases who are generally inappropriate or unwilling to receive surgical treatment; 2) If the residual liver volume is too small after hepatectomy, large liver metastases can be resected first, and then remaining metastatic lesions with the diameter <3 cm can be treated with radiofrequency ablation.

7.3.3. Radiotherapy

For unresectable liver metastases, radiotherapy can be considered if systemic chemotherapy, hepatic arterial infusion chemotherapy, or radiofrequency ablation are ineffective.

8. Treatment for lung metastases

General guidelines of treatment: because the number, site, size, primary tumor, extrapulmonary metastases, and genotype of lung metastases all affect prognosis and treatment decisions. Comprehensive therapy should be conducted under the discussion of MDT. Therapeutic approaches include systemic therapy, radical local therapy (e.g., R0 surgical resection, SBRT and ablation therapy), and local palliative treatment. MDT discussion should combine the patient’s clinical characteristics with accessibility to medical resources to determine treatment goals and thereby formulate a rational and orderly comprehensive treatment strategy.

8.1. Resectable lung metastases treatment

8.1.1. Neoadjuvant and adjuvant therapy

See 7. Treatment for liver metastases. However, there is a controversy about the need for chemotherapy after resection of lung metastases.

8.1.2. Local treatment

Imaging diagnosis can be used as the basis for surgery, without the need for evidence of histopathology and percutaneous needle biopsy. When imaging findings indicate that metastatic lesions are atypical or other conditions require, the metastatic lesions should be confirmed by histopathology or close observation.

(1) Indications of surgery

1) The primary lesion must be removed radically (R0).

2) Resection of lung metastases is not recommended if there are unresectable extrapulmonary lesions.

3) Adequate function must be maintained after pneumonectomy.

4) Fractional resection may be considered in some patients.

5) There are resectable metastatic lesions outside the lung, which can be treated at the same time or different stages.

(2) Surgery timing

The timing of resection of lung metastases should be determined by MDT.

1) Immediate surgery: it can avoid resectable lesions developing into unresectable lesions, or tumor spreading.

2) Delayed surgery: since multiple lung metastases are common, the observation period of 3 months can be reserved for single micro nodule, which may avoid repetitive surgery.

3) For patients who can tolerate simultaneous excision of lung and liver metastases, simultaneous hepatectomy and pneumonectomy are feasible. For patients who cannot tolerate simultaneous resection, it is suggested to resect the liver first and then the lung.

(3) Surgery methods

Wedge resection was the most common method, followed by segmental resection, lobectomy and pneumonectomy. Nanometer laser excision is suitable for patients with multiple sites or deep metastases.

Lung metastasis has a high recurrence rate. If the recurrent lesion can be resected, patients with appropriate conditions can have secondary or even multiple resection, which can effectively prolong patient’s survival time.

(4) Radiofrequency ablation

For lung metastases with small size (maximum diameter <3 cm) and far from the large vessels, radiofrequency ablation shows a good local control rate (about 90%).

(5) SBRT

The indication of SBRT for lung metastases:

1) The primary lesion was under control and the patients are generally in good condition with expected survival ≥3 months;

2) It will be optimal if the distribution of lung metastases was relatively limited and on one side;

3) Lung have enough function to tolerate radiotherapy.

It is recommended that BED ≥100 Gy on the premise of safety. It is recommended to use different techniques to limit or track the mobility of lung metastases, and to verify the exact location of lung metastases through an image-guided system before each SBRT. SBRT is not recommended in hospitals and units without image-guided or respiratory control techniques.

8.2. Unresectable lung metastases treatment

Refer to the 7. Treatment for liver metastases.

9. Treatment of other metastases

9.1. Treatment of peritoneal metastases

In general, peritoneal metastases have a poor prognosis and are mainly treated with systemic therapy (specific drug options refers to 5.3 Systemic treatment of recurrent/metastatic CRC). According to the patient’s tumor load, ascites fluid condition, and physical score, the following local treatments can be considered in experienced tumor center under the guidance of MDT: 1) cytoreductive surgery (CRS): total resection of the peritoneum (before the parietal peritoneum, left and right side peritoneum, pelvic peritoneum, diaphragmatic peritoneal complete resection, liver round ligament, sickle ligaments, greater omentum and lesser omentum resection, and intestinal surface, mesenteric, remove and burn the tumor of visceral peritoneum), multi-visceral resection (stomach, small intestine, colorectal, part of the pancreas, spleen, gallbladder, liver, uterus, ovaries, kidney, ureter, etc.), etc; and 2) hyperthermia intraperitoneal chemotherapy (HIPEC): open or closed intraperitoneal hyperthermia chemotherapy with or without CRS is recommended.

9.2. Ovarian metastases

Ovarian metastasis can occur in female patients with colorectal tumors and can be divided into synchronous and metachronous ovarian metastasis, depending on the timing of diagnosis. Synchronous ovarian metastasis requires differentiation from primary ovarian cancer, especially when CA125 and HE4 significantly increase. Metachronous ovarian metastasis is more common within 2 years after treatment of CRC and is indicated by an increase in CA19-9 and CEA. Imaging examinations show enlarged ovaries or clear-boundary ovarian masses usually on both sides.

CRC ovarian metastasis is often non-symptomatic, rapidly progressing, and poorly responsive to chemotherapy. Bilateral ovariectomy followed by postoperative systemic treatment is recommended. If ovarian metastasis is accompanied by other metastases, tumor cell reduction HIPEC can be considered.

9.3. Brain metastases

The brain metastatic incidence was 0.6% to 3.2%, and it can be devided into brain parenchyma metastasis and leptomeningeal metastasis. The prognosis of leptomeningeal metastasis is even worse. Surgery and radiotherapy remain the main treatments for brain metastases. Chemotherapy alone is not recommended, as chemotherapy does not prolong the overall survival of patients with brain metastases. Surgery can alleviate the intracranial hypertension and neurological dysfunction caused by space-occupying lesions and peritumoral edema, and the surgery can also confirm the pathological diagnosis. Surgical resection followed by whole brain radiotherapy (WBRT) is recommended for patients with single brain metastasis lesion and well-controlled extracranial tumors. Radiotherapy regimen can also be WBRT combined with stereotactic radiosurgery (SRS).

For patients with brain multi-metastases and systemic tumor under controlled, if the operation does not cause new neurological dysfunction, it can be considered to surgically resect the tumor with space occupying lesion effect.

In addition to the treatment of the tumor itself, glucocorticoid is recommended to alleviate the space-occupying lesion effect and the symptoms of intracranial hypertension caused by secondary brain edema. Antiepileptic treatment is necessary for patients with secondary epilepsy, but prophylactic treatment is not recommended for patients without epilepsy.

9.4. Bone metastases

The purpose of the bone metastases treatment is to prevent or treat pathological fractures and relieve nerve compression, which can alleviate the symptoms and improve patients’ quality of life. Comprehensive treatment should be used for bone metastases, including surgery, radiotherapy, bisphosphonates or denosumab monoclonal antibody, systematic treatment of primary disease (chemotherapy, molecular targeting therapy, etc.), pain relief therapy, nutritional support therapy.

As the treatment plan is directly affected by pathological type of the tumor, CT-guided biopsy is recommended for patients with long-term inactive primary tumor. For patients with a malignant multi-metastases tumors history and finding new spinal lesions appear at this time, pathological biopsies should also be performed if the time permits, because it is not uncommon that the second-time pathological result or classification is inconsistent with the first-time. Direct surgery can be performed for patients with progressive or acute symptoms.

After evaluating the patients’ survival, the Mirels score system, spinal SINS score system and the degree of nerve compression should be used to determine whether there were surgical indications. The aim of the operation on long bone metastasis is to prevent the occurrence of pathological fracture or restore the continuity of pathological fracture: closed intramedullary nail technique can be used for those without serious cortical destruction; for those with extensive destruction, the tumor should be clearly cut and removed, then bone cement should be filled in and internal fixation should be applied; tumor joint replacement can be performed if the tumor affects the joint function. The purpose of spinal bone metastasis is to relieve pain, protect neurological function, maintain or reconstruct spinal stability. A small number of patients may be cured by extensive resection. Vertebroplasty can be performed for patients with pathological spinal fracture if the patient has intact posterior wall of vertebral body and exclude the nerve compression: percutaneous pedicle screw fixation can be used for defection of vertebral body posterior wall; separation of spinal tumor can be performed if there are symptoms of spinal cord compression; The en bloc resection can be used for patients with isolated metastatic spinal tumor whose estimated survival time is more than 12 months.

10. Treatment of local recurrence in rectal cancer

10.1. Classification

At present, the following methods are recommended for the classification of local recurrence: According to the anatomical site in pelvis, it can be divided into central type (including anastomotic stoma, mesorectum, soft tissue around the rectum, perineum after abdominoperineal resection), anterior type (infiltration into the urogenital system including the bladder, vagina, uterus, seminal vesicle, and prostate), posterior type (invasion into the sacrum, anterior sacral fascia), and lateral type (infiltration into the soft tissue of pelvic wall or bony pelvis).

10.2. Treatment principles

Multidisciplinary assessment based on condition of patients and lesions: comprehensive treatment of primary surgery in combination with perioperative CRT is recommended to the initial resectable patients; CRT and/or systemic treatment is recommended to the initial unresectable patients, and the surgical resectability should be assessed after treatment.

10.3. Surgical treatment

(1) Assessment of resectability

Preoperative assessment for the possibility of radical resection of recurrent lesions is neccessary. Whether preoperative CRT can be used depends on the extension of recurrance. The resectability of lesions should be verified according to the results of surgical exploration, and fast frozen pathology should be used if necessary. Unresectable local relapsed focus includes:

1) Extensive pelvic lateral wall invasion;

2) External iliac blood vessels involvement;

3) Greater sciatic notch and sciatic nerve invasion;

4) The second sacrum level and above invasion.

(2) Surgical principle

1) It is recommended that a specialist in colorectal surgery should choose proper surgical plan in combination with preoperative CRT, intraoperative radiotherapy, and adjuvant radiotherapy and chemotherapy according to the specific conditions of patients and lesions.

2) If necessary, it is recommended to formulate surgical plans with physicians in urology, orthopedics, vascular surgery, obstetrics and gynecology.

3) Surgical exploration must be from far to near and pay attention to exclude distant metastases.

4) Must follow the principle of en bloc resection and try to achieve R0 resection.

5) Pay attention to protect the ureter (discretionarily place the ureteral stent before surgery) and the urethra.

(3) Surgical methods of resectable lesions

The surgical methods include LAR, APR, Hartmann surgery and pelvic cavity dissection, etc.

1) Central type: APR is recommended to guarantee R0 resection; LAR can be considered in patients who have received anus-preserving operation if the lesion is limited. Transperineal or transsacral resection can be considered if the recurrent vulvar lesion is limited after APR.

2) Anterior type: If patients can tolerate surgery, the resection of invasive organs should be considered, and then posterior half-pelvic dissection or total pelvic organectomy may be performed.

3) Lateral type: Involved ureter, internal iliac blood vessels and piriformis should be resected.

4) Posterior type: Invaded sacrum was resected by combined abdominosacral resection. The incision of the perineum can be covered with omentum or primary suture. Use myocutaneous flaps or biomaterial patches if necessary. For some patients with recurrent large tumor after low APR, abdominal perineal re-incision combined with radical resection can be considered. If necessary, partial sacrum can be removed for larger surgical visual field.

10.4. Principle of radiotherapy

Preoperative concurrent CRT (try to obtain the pathology of the recurrent lesion before radiotherapy) is recommended to the patients who have never received pelvic cavity radiotherapy, and then the surgery can be considered. For the patients who have local resectable lesions, surgery should be considered first, and then whether postoperative radiotherapy/chemotherapy will be considered. Patients who have received pelvic cavity radiotherapy in principle no longer receive radiotherapy. It is recommended that the most reasonable treatment plan can be formulated through MDT discussion.

10.5. Principle of medical treatment

Perioperative medical treatment plan depends on previous chemotherapy history for initial resectable patients. For unresectable recurrent patients, radiotherapy and/or systemic treatment should be decided under MDT discussion. After treatment, the resectability should be reevaluated through MDT discussion.

11. Rehabilitation treatment of colostomy

11.1. Personnel, tasks, architecture

Qualified hospitals are recommended to be equipped with enterostmal therapists (specialist nurses). The duties of an enterostmal therapist include preoperative and postoperative care of all ostomies (enterostomy, gastrostomy, urostomy, tracheostomy, etc), treatment of complex wounds, care of incontinence, setting up ostomy specialist outpatient clinic, liaison with patients and other professionals and ostomy merchants, organizing ostomy fraternities and conducting ostomy visitor activities.

11.2. Preoperative psychotherapy

It is recommended to fully explain the relevant diagnosis, surgery and nursing knowledge to patients, so that patients can accept the facts of the disease and have a comprehensive understanding of what is about to happen.

11.3. Preoperative ostomy location

It is recommended that the site of ostomy should be selected by physicians, enterostmal therapists, family members and patients before operation.

(1) Requirements: patients can see by themselves, convenient for nursing, have enough paste area, and there is no discomfort when the ostomy equipment is affixed to the ostomy skin.

(2) The common locations of enterostomy are shown in Figure 6.

Figure 6.

Common locations of enterostomy.

11.4. Postoperative nursing of enterostomy

(1) After operation, we should pay attention to observe the blood supply of ostomy and whether there is retraction or not.

(2) The standard for the selection of ostomy products should be light, transparent, odorproof, leak-proof and protect the surrounding skin, and suitable for patients to wear.

(3) Keep the skin around the enterostomy clean and dry. Patients who take antibiotics, immunosuppressants and hormones for a long time should pay special attention to fungal infection at the enterostomy site.

12. Follow-up

Regular follow-up is recommended after the treatment of CRC.

(1) Medical history, physical examination and CEA, CA19-9 surveillance, once every 3 months for 2 years, then once every 6 months for a total of 5 years, once a year after 5 years.

(2) Chest/abdominal/pelvic CT or MRI once every half a year for 2 years, and then once a year for 5 years.

(3) Enteroscopy within 1 year after operation, and if there is any abnormality, it should be reexamined within 1 year. If there is no polyp, it should be reexamined within 3 years, and then once every 5 years, resection of colorectal adenoma is recommended in follow-up examination. If the total colon examination is not completed by colonoscopy before operation, it is recommended that enteroscopy should be performed 3−6 months after operation.

(4) PET-CT is not a routine recommended examination. For patients with existing or suspected recurrence and distant metastasis, PET-CT examination can be considered to exclude recurrence and metastasis of CRC.

Working group members

Principal consultant: Yan Sun

Consultant: Shu Zheng, Desen Wan

General group leader: Jin Gu, Jianping Wang

Surgery Group

Group leader: Sanjun Cai, Jin Gu, Jianping Wang, Xishan Wang, Suzhan Zhang

Task group members (listed alphabetically by last name):

Gong Chen, Kefeng Ding, Xuedong Fang, Baoqing Jia, Dalu Kong, Ping Lan, Haiping Pei, Zhizhong Pan, Guiyu Wang, Guiying Wang, Zhenning Wang, Ziqiang Wang, Yi Xiao, Jianmin Xu, Zhongfa Xu, Jin Yan, Yingjiang Ye, Zhongtao Zhang, Ren Zhao

Secretary: Lei Lian, Qian Liu, Yifan Peng

Medicine Group

Group leader: Jin Li, Lin Shen, Ruihua Xu

Task group members (listed alphabetically by last name):

Yi Ba, Chunmei Bai, Li Bai, Yanhong Deng, Jian Li, Tianshu Liu, Yunpeng Liu, Hongming Pan, Min Tao, Jianming Xu, Xianglin Yuan, Ying Yuan, Yanqiao Zhang, Aiping Zhou

Secretary: Feng Wang, Xicheng Wang

Radiotherapy Group

Group leader: Jing Jin, Zhen Zhang

Task group members (listed alphabetically by last name):

Yuanhong Gao, Yongheng Li, Shixin Liu, Weihu Wang, Renben Wang, Junxin Wu, Jinbo Yue, Hongyan Zhang, Li Zhu, Yuan Zhu

Secretary: Yuan Tang, Fan Xia

Pathology Group

Group leader: Zhiyong Liang

Task group members (listed alphabetically by last name):

Mulan Jin, Li Liang, Weiqi Sheng, Yan Sun, Weicheng Xue, Shuangmei Zou

Secretary: Weixun Zhou

Imaging Group

Group leader: Yingshi Sun

Task group members (listed alphabetically by last name):

Jiangning Dong, Yi Wang, Tao Yu, Xiaoyan Zhang, Zhiyang Zhou

Secretary: Ruijia Sun, Juan Wang

Secretary Group

Group leader: Qian Liu, Yifan Peng, Xicheng Wang

Task group members (listed alphabetically by last name):

Lei Lian, Ruijia Sun, Yuan Tang, Feng Wang, Juan Wang, Weixun Zhou

Translation Group

Group leader: Jin Gu, Yong Yang

Task group members (listed alphabetically by last name):

Zhaoya Gao, Haopeng Hong, Dandan Huang, An Huang, Jingyi Shi, Zhuang Sun, Jingxuan Xu

Correspondence to: Prof. Jin Gu. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Haidian District, Beijing 100142, China; Peking-Tsinghua Center for Life Science, Peking University International Cancer Center, Haidian District, Beijing 100142, China; Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Shijingshan District, Beijing 100144, China. Email: zlgujin@126.com.