Radiotherapy guidelines for rectal cancer in China (2020 Edition)

Rectal cancer is one of the most common malignant tumors. In China, rectal cancer has been the third most frequently diagnosed cancer and the fifth leading cause of cancer death, with changes of residents’ lifestyle factors and diets. The best treatment for rectal cancer depends on many factors. Multidisciplinary Treatment has become the basis for improving the therapeutic effect, in which radiology is increasingly necessary for treating patients with rectal cancer. For patients who have extensive, fixed, bulky tumors or obvious nodal disease, radiotherapy and chemotherapy combined with surgery has emerged as the standard of care. For patients with metastatic disease, the reasonable combination of local and systemic therapy might be an alternative. Improvements in imaging, pathological diagnosis and radiation techniques provide a solid foundation for promoting the level of clinical practice in rectal cancer. High‐quality magnetic resonance imaging distinguishing risk stratification, molecular markers predicting therapeutic effect and prognosis, magnetic resonance imaging in delineating target volumes drawn, intensity‐modulated radiation therapy, and image‐guides radiation therapy for precision treatment delivery are all being widely applied in multiple centers. Furthermore, as the role of targeted therapy and immune therapy has become increasingly prominent, the attempt of combined radiotherapy is also ongoing. In view of the characteristics and current situation of diagnosis and treatment of rectal cancer in China, the guidelines will present the basis and reference for combined treatment and standardized treatments. Meanwhile, there may be continuous new advances in clinical practice, and that will be a new basis to update the guidelines, directly benefiting all rectal cancer patients and facilitating discipline developments.


3.3
Imaging examination

Routine examination
For locally advanced rectal cancer, pelvic MRI is the preferred imaging method for clinical staging and risk factor stratification. 8 Computed tomography (CT) scan or contrast-enhanced scan of the chest, abdomen, and pelvis is used to search for possible pelvic or extrapelvic metastases. If the diagnosis of CT is questionable or the treatment decision needs to be changed, it is recommended that liver cell-specific contrast enhanced MRI be used to assess the liver metastasis of rectal cancer.
As the soft tissue resolution of CT scan is inferior to that of MRI, CT scan is not recommended as the preferred imaging method for clinical staging and risk factors stratification of locally advanced rectal cancer.
However, if patients have MRI contraindications, CT scan is an alternative and multiplanar reconstruction should be used.

Special inspection
1. Bone scan is the method for the diagnosis of malignant bone lesions.
2. PET/CT is not routinely indicated. For patients with metastatic diseases other than liver metastasis, or with local rectal tumor recurrence, PET/CT can be used for confirmation. 9,10

Clinical stage and risk stratification of rectal cancer assessed by medical imaging
The extent of the rectal cancer is measured from the most caudal aspect of the raised rolled edge of the tumor to the anal verge. 11,12 The broken line distance between the lower edge of a rectal tumor and the connecting line of the external anal sphincter is recommended by the Chinese Society of Clinical Oncology as the tumor localization standard. 13 High resolution pelvic MRI is suggested to detect extramural depth of rectal cancer invasion, metastatic lymph nodes, and extramural vascular invasion. Positive circumferential resection margin (CRM) is defined as tumor deposits, main tumor extension, extramural vascular invasion (EMVI), or suspicious lymph nodes lying within 1 mm of the mesorectal fascia. The structured report templates can improve the quality of MRI reporting for rectal cancer staging compared with free-text formats, and lead to higher risk satisfaction levels (see Appendix 1). 14 The items should include the extent of tumor, extramural depth of tumor invasion, lymph node, EMVI, and CRM. 15 If the short axial length of the pelvic sidewall lymph node is between 5 and10 mm, it can be defined as involvement suspected on MRI; it is defined as metastatic lymph nodes if the short axial length of the pelvic sidewall lymph node is ≥10 mm. 3.3.4 Response of rectal cancer to neoadjuvant chemoradiotherapy assessed by imaging Whether delayed surgery after radiotherapy for rectal cancer can improve the pathological complete remission rate and whether it increases the difficulty of surgery is still controversial. 16,17 It is recommended to perform MRI imaging evaluation 6-8 weeks after the end of radiotherapy for rectal cancer. It is suggested to deploy the structured report template in the evaluation of the response of rectal cancer, with assessment generally in the sixth to eighth week after neoadjuvant chemoradiotherapy. 18 Any changes regarding clinical stage and risk factors should be clarified in the report. The most important point is to show clinical complete response (CR). The common imaging modalities, such as EUS, MRI, and PET/CT, are helpful in diagnosing clinical CR. 19 If the clinical CR is detected, the strategy of watch and wait can be considered. 20

Clinical diagnosis
Patients with the aforementioned symptoms (e.g., hematochezia, stool frequency, and stool deformation), and patients in line with one of the following clinical situations, should be highly suspected of rectal cancer.
1. Masses are found at DRE. The mass is hard, brittle, and easy to bleed on touch; rectal stenosis and fixation when palpating in the late stage.
2. Pelvic CT, MRI, and PET/CT examinations can reveal a rectal mass, thickening and stenosis of the rectal wall, or high uptake of fluorodeoxyglucose by PET/CT. 3. Colonoscopy is recommended. Early lesions present with local mucosal erosion, ulcers, nodules, and polypoid masses. In the middle stage, there is a cauliflower-like tumor or concave ulcer surface.
The surface of the tumor is dirty, the texture is stiff, and it is bleeds easily when touched. In the late stage, it can show rectal stenosis.
It needs to be emphasized that clinical diagnosis of rectal cancer should be further confirmed by histopathological examination.

Laparotomy or laparoscopic exploration
If the diagnosis is still not definite and rectal tumors are highly sus-

Histopathological examination
4.3.1 Biopsy specimens 1. All biopsy tissues should be taken, and it is recommended that they should be embedded in at least two wax blocks for immunohistochemical and molecular pathological detection.
2. Pathological report content should involve histological classifica-  3. If IMRT is used, then treatment plan verification is mandatory.

Management of low rectal cancer with difficulty in preservation of the anal sphincter
Image-guided radiation therapy is recommended to collect relevant imaging information during treatment, to determine the treatment target area and reduce positioning errors.
4. Intraoperative radiotherapy, brachytherapy, or external irradiation techniques can be used for local intensive treatment.

Positioning technical specifications
CT simulation of 3D-CRT and IMRT techniques.
1. Empty the bladder and rectum 1 h before CT simulation, then drink 600-800 mL water, which contains 20 mL iodine contrast agent to visualize the small intestine, and hold back the bladder to reduce the irradiated volume of the small intestine 40 ; repeat this process, but stop drinking iodine contrast agent for every fraction of radiotherapy. accurately. 41 PET/CT simulation is not recommended for routine applications due to its low tissue resolution and high cost.

2-D radiotherapy simulation. See 2-D irradiation.
Target definition and delineation 2-D irradiation. Preoperative or postoperative radiotherapy for rectal cancer must include the primary tumor or tumor bed, lymphatic drainage areas, and a high-risk recurrence area. It is usually recommended to use isocentric three-field irradiation technology, con-sisting of one "posterior field" and two "lateral fields". Two "lateral fields" should be adjusted with 30 • wedge-shaped plates. For reference boundaries of two-dimensional irradiation see Table 1. The irradiation field must be determined by referring to the tumor condition, surgical records and pathology, and so forth. The dose ratio of one "posterior" and two "lateral" fields is 2:1: The same as "Posterior fields" The same as "Posterior fields" Posterior 1/3-1/2 of femoral head

Half of sacrum
Notes: Caudal boundary for post-"Dixon" operation: caudal of obturator. Caudal boundary for post-"Miles" operation: perineal scar.

3D-CRT and IMRT.
1. Target volume definition before operation GTV: gross tumors refer to endoscopy, MRI, and pelvic CT imaging information.
GTVnd: metastatic lymph nodes and tumor deposits of lymphatic drainage area, include the mesorectum, the presacral, the common iliac, the internal iliac, the obturator, and the external iliac.
Clinical target volume (CTV): it is typically defined as the high-risk lymph nodes and the recurrence region. It is recommended to distinguish different high-risk areas according to the following Table 1, cT4 invading an anterior organ or structure** *** *For both mesorectal fascia (-) and N0 based on accurate imaging, the cranial border of clinical target volume may be lowered at the level of the bifurcation of superior rectal artery or at the S1-S2 interspace. **The external iliac lymph area may be included when T4b tumors invade anterior organs or structures, but except levator ani muscle infiltration or T4a. ***Ischiorectal fossa should be included when ischiorectal fossa, external anal sphincter, or levator ani muscles are infiltrated. Clinical target volume is suggested to include the infiltrated part of the ischiorectal fossa (gross tumor volume extended 1 cm) and the unaffected contralateral ischiorectal fossa may not be included. ****Inguinal lymph area is not routinely irradiated for prophylactic purpose when tumors invade the anal canal/levator ani muscle/ischiorectal fossa/seminal vesicle gland/prostate/bladder/uterus. If the skin around the anus or the lower one-third of the vagina is invaded, prophylactic irradiation of inguinal lymph area should be considered.

Target volume definition after operation
CTV: CTV is suggested to include the tumor bed, anastomose (Dixon), perineal scar (Miles), lymphatic drainage area, and high-risk recurrence area. It is recommended to include the corresponding subareas according to the following Table 2 Neoadjuvant radiotherapy.

Short-course radiotherapy
The commonly used fractionation is 25 Gy in five fractions. It is recommended to conduct surgery within 1 week after radiotherapy. This scheme is mainly performed when it is unnecessary to obtain an obvious downstage or R0 resection through neoadjuvant radiotherapy. 37 It is also performed in locally advanced rectal cancer with serious distant metastases, for controlling local lesions before systemic chemotherapy and targeted therapy.
Surgery is recommended to be conducted at 6-12 weeks after radiotherapy. This scheme is suitable for nearly all rectal cancer patients in need of neoadjuvant radiotherapy. 37 Neoadjuvant CRT. Long-course radiotherapy is more frequently used.
There are different modes to combine radiotherapy and chemotherapy: (i) standard concurrent CRT; (ii) induction chemotherapy + concurrent CRT; (iii) concurrent CRT + consolidated chemotherapy; (iv) induction chemotherapy + concurrent CRT + consolidated chemotherapy (also called "sandwich: mode 45 ); and (v) total neoadjuvant therapy mode. 46,47 Certainly, short-course radiotherapy could also be feasible. Neoadjuvant chemotherapy is often followed 1-2 weeks after short-course radiotherapy. 38 Radical CRT. Radical CRT is mainly carried out in patients unsuitable or unwilling to receive surgery. Radiation dose and fractionation depend on therapeutic effects after neoadjuvant CRT.
1. When a cCR is obtained, a "watch and wait" strategy could be applied, instead of a boost irradiation. 19 2. When a cCR is not obtained, a boost irradiation could be considered, according to the interval between two courses of radiotherapy, irradiated doses of normal organs, and so forth. 48 3. In patients treated with long-course neoadjuvant radiotherapy, the dose of a boost irradiation is recommended as 10-20 Gy in 5-10 fractions (external beam radiotherapy) or 5 Gy (brachytherapy), to make the total dose be 60-70 Gy. [48][49][50] Palliative radiotherapy. Palliative radiotherapy is often performed in patients who are unsuitable for chemotherapy or surgery, due to their advanced age or systemic diseases. Radiation doses, fractionation, and techniques depend on clinical stages and therapeutic aims.

Delineation of organs at risk and dose constraints
The organs at risk for rectal cancer radiotherapy mainly include the small bowel, colon, bladder, femoral heads, perineum, and other unspecified tissues. 51,52 Considering the problems that may be

Recommended constraints Maximum constraints
Perineum. Defined as the skin and adipose tissue of the penis, scrotum, and pubic symphysis in men, and the skin and adipose tissue of the clitoris, labia, and minor symphysis in women.

Recommended constraints Maximum constraints
Unspecified tissues. It is defined as the upper limit of L5 below, referring to all the normal tissues except PTV and organs at risk mentioned above. The upper constraints of this tissue shall not exceed 105% of the prescribed dose. That is, the radiotherapy treatment plan should avoid the generation of dose hot spots in other undefined normal tissues.

Radiotherapy plan design
Preparation before planning 1. Inspection before planning: Check coordinate origin (user origin) and reference mark points.

Plan design
Adding auxiliary structures before optimization.

Structure name Purpose
Ring 1 (the pink area in Figure 1) Increase CI Ring 2 (the orange area in Figure 1) Increase CI B-P (the blue area in Figure 1) Control low-dose CI = TVPV2 ÷ (TV × PV),TVPV represents the volume of the PTV wrapped by the prescription dose, the TV represents the volume of the PTV, and the PV represents the total volume wrapped by the prescription dose. Larger CI values indicate the better conformity of the target.
1. Field setting: IMRT plan for rectal cancer generally uses five to seven fields according to the size and complexity of the target area. The angle distribution of the field can be divided equally or patients can be treated in the prone position, avoiding 180 • and focusing the beam on the back, so as to better protect the small intestine. 55 The schematic diagram of the field is shown in Figure 3.

Parameter optimization:
The optimization conditions suggest that the dose-volume physical optimization parameters should be combined with the generalized equivalent uniform dose biological optimization parameters. When the basic plan optimization is completed, select "using the current plan as the intermediate dose for optimization" to optimize again.

Plan evaluation:
(1) Dose distribution evaluation: view the dose distribution layer by layer, sketch or automatically generate the dose structure for the high-dose area (hot spot) and the low-dose area (cold point) in the target, and then iteratively optimize the dose distribution, as shown in Figure 3-1, 3-2, 3-3.

Field setting:
Two arcs are generally recommended for rectal cancer, because double arcs have stronger modulation ability than a single arc, which can improve the uniformity and conformability of the target, and the dose control ability of the target and organs is better. The schematic diagram of the field is shown in Figure 5. 3. Plan evaluation: (1) Dose distribution evaluation: The dose distribution is shown in (2) DVH: The dose volume histogram is shown in Figure 9. The radiation dose of each organ and target is evaluated in detail according to the DVH diagram to ensure that the corresponding prescription dose is obtained in the target and to control the dose gradient of the target as far as possible. Compared with IMRT, VMAT has stronger modulation ability 56,57 and produces a better target dose distribution while protecting the organs. 35 In addition, it can also shorten treatment time, accelerate dose delivery, and reduce the discomfort caused by patients' staying in a fixed position for a long time, thus avoiding the dose offset due to involuntary movement brought about by patients' discomfort. However, the disadvantage is that it has to take a long time to optimize its rotational intensity modulation, which can be somewhat cumbersome. Therefore, it is suggested that conditional treatment institutions should choose VMAT as one of the radiotherapy planning methods for rectal cancer.

Recommendation of preoperative radiotherapy and operation interval
The immediate operation mode of short-course (5 × 5) was within 1-2 weeks after radiotherapy, whereas the delayed operation mode was within 6-8 weeks. Surgical treatment is recommended 5-12 weeks after long-course CRT.

Treatment of pulmonary metastases
Surgery for pulmonary metastases in rectal cancer can be performed based on imaging diagnosis without histopathological diagnosis or the evidence of percutaneous needle biopsy. However, under certain conditions, such as atypical image features of pulmonary metastases, the metastases should be confirmed by histopathology or close observation. Local therapies for pulmonary metastases in rectal cancer include local surgery, RFA, and SBRT.

Brain metastases
The treatment of rectal cancer brain metastasis includes surgical resection, stereotactic radiotherapy, and whole brain radiotherapy. The treatment plan is based on the number and location of brain metastases, whether there are extracranial metastases, and the general condition of the patient. 63

Bone metastasis
The principle of rectal cancer bone metastasis treatment is to add rea- For unresectable liver metastases, conversion therapy could be tried, and if the liver metastases could be reduced to resectable disease, surgery should be performed as soon as possible.

Liver metastases
The indications of SBRT for liver metastases are as follows (3A evidence): 1. The number of liver metastases up to three, the maximum diameter of liver metastasis ≤5 cm; 2. The primary lesions were controllable, and there was no extrahepatic metastases or with small extrahepatic metastases.
3. The expected survival time is ≥3 months; 4. The liver has not received radiotherapy and the volume of normal liver tissue >700 mL; 5. The general condition of the patient is good, the level of serum liver enzyme is normal or <200% of the upper limit of normal value; the blood coagulation function is normal; Child-Pugh grade is A or B.
It is recommended that for most liver metastases, especially those with diameter ≤3 cm, the effective biological dose should be ≥100 Gy on the premise of safety. 65 SBRT is not suitable for liver metastasis, which is closely adjacent to important organs, such as the small intestine, stomach, duodenum, and kidney.
It is not recommended to carry out SBRT for liver metastasis in hospitals without image guidance or respiratory control technology.

Lung metastases
The indications of SBRT for lung metastases are as follows (3B evidence): 1. The number of lung metastases is one to three; the maximum number of small lesions is no more than five; and the maximum diameter is ≤5 cm. 66 2. The distribution of lung metastasis is relatively limited, and it is the best in the same side of the lung; the peripheral lung metastases are more suitable for SBRT.
3. The primary lesion was under control, and no extrapulmonary metastasis or extrapulmonary metastasis was controlled.
4. The general condition of the patient is good and the lung function is normal.

Expected survival time is ≥6 months.
It is recommended that the BED ≥100 Gy on the premise of safety. It is recommended that different techniques be used to limit or track the motion of lung metastasis, and the exact location of lung metastasis can be confirmed by image guidance system before each SBRT. It is not recommended to carry out SBRT for lung metastasis in hospitals without image guidance or respiratory control technology.

Brain metastases
Stereotactic radiotherapy for brain metastases from rectal cancer includes stereotactic radiosurgery, fractionated stereotactic radiotherapy, and hypofractionated stereotactic radiotherapy.
It is recommended that fractionated stereotactic radiotherapy is used for large lesions (usually with its diameter >3 cm), with a single dose of 3.5-4 Gy and a total dose of 52.5-60 Gy.
For huge lesions, the mode of segmented radiotherapy can be used.
After giving 40 • 50 Gy, rest for 1-2 months, and then replenish the volume after the tumor shrinks.

Spinal metastases
The indications of SBRT for spinal metastases: up to two vertebral bodies are involved , and there is a distance of 3-5 mm between the metastatic tumor and spinal cord.
At present, the main segmentation modes are single segmentation and multiple segmentation. The single segmentation has a relatively low local control rate, but a relatively high recurrence rate.

Ablation and radiofrequency therapy
The most studied techniques for metastatic colorectal cancer (mCRC) in the lungs and liver are RFA, microwave ablation, I-125 brachytherapy ablation therapy, and cryoablation in China.
Lung metastases from CRC: The local ablation therapy was suitable for up to three metastatic sites and lesion size <3 cm. Simultaneous treatment is not recommended in left and right lung lesions.
Liver metastases from CRC: The local ablation therapy was suitable for up to five metastatic sites and lesion size <3 cm. A treatment option is up to the lesions' location, size, number, and doctor's experience.

5.7.1
Principles of treatment Evaluate the conditions of patients and lesions. For patients with resectable or potentially resectable recurrence, strive for surgical resection of recurrence, in combination with preoperative or postoperative radiotherapy and chemotherapy, intraoperative radiotherapy, and so forth. 67 Comprehensive treatment of radiotherapy and chemotherapy is recommended for unresectable patients.

Preoperative evaluation
According to the scope of recurrence, the resectability should be evaluated to decide whether to use preoperative chemoradiotherapy.

Surgical methods
The mode of operation is recommended according to the classification of local recurrence.

Principles of radiotherapy
For patients who have not received pelvic radiotherapy before, concurrent preoperative chemoradiotherapy is recommended (if it is possible, confirm the pathological diagnosis of recurrent lesions before treatment). For patients with resectable local lesions, surgical resection can also be received first, and then decide whether to receive postoperative chemoradiotherapy. Capecitabine is recommended for concurrent chemoradiotherapy. For patients who have previously received pelvic radiotherapy, radiotherapy is no longer performed in principle, and no clear consensus has been made on the use of re-irradiation. A multidisciplinary team evaluation is recommended to make a reasonable treatment plan. The treatment effect of surgical patients after neoadjuvant radiotherapy was significantly better than that of non-operative patients. 68 Irradiation scope and dose 3-D conformal or intensity modulated radiotherapy is recommended.

PREVENTION AND TREATMENT OF RADIOTHERAPY COMPLICATIONS
The most common complications of pelvic radiotherapy for rectal cancer occur in the hematopoietic system, digestive system, and genitourinary system.

6.1
Hematopoietic system If there is no obvious improvement after active treatment, radiotherapy should be suspended and the radiotherapy plan should be modified if necessary.
2. Late complications are difficult to treat and often occur at 3-6 months after the end of radiotherapy, including chronic radiation proctitis, bleeding, rectal or anal stricture, and pain.

Urogenital system
Radiation cystitis is common. The early reactions are urethritis, cystitis, and painful urination. Most of the symptoms are mild. After drinking more water, if necessary, one is quickly relieved or healed with hormone therapy. The long-term complications are mainly hemorrhagic cystitis, bladder contracture, urethral stricture, and obesity contracture. Some patients have sexual dysfunction after radiotherapy, which is related to the damage of blood vessels and nerves caused by radiotherapy and surgery.

EVALUATION OF THERAPEUTIC EFFECTS
The evaluation of therapeutic efficacy of rectal cancer is divided into two parts, namely, preoperative and postoperative evaluation. The evaluation methods mainly include the following examinations: DRE, CT examination (chest/whole abdomen/pelvic enhanced CT scan is recommended), ultrasound, proctoscopy, MRI, and PET-CT.

Evaluation of the therapeutic effect of preoperative radiotherapy (chemotherapy)
DRE, proctoscopy, and MR examination are mainly used to evaluate the preoperative therapeutic effects of patients. Relevant results can assist to formulate appropriate surgical strategies, select the expected surgical type, and decide whether it is suitable for the "watch and wait" strategy. Generally, the evaluation of therapeutic effect is performed 12 weeks after the initiation of radiotherapy (chemotherapy).

Evaluation of the postoperative therapeutic effect
See follow up in Section 8.

FOLLOW UP
A post-treatment surveillance program should be recommended for patients with rectal cancer as their following treatment. During the surveillance, the recurrence and metastasis of cancer should be closely monitored; the resolution of acute toxicities, long-term effects of treatment, possible late sequelae of treatment, and their impacts on patients' function should be carefully observed. 70 The recommended surveillance program is as follows.  T4b Tumor directly invades* or adheres** to adjacent organs or structures N-Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 One to three regional lymph nodes are positive (tumor or lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative N1a One regional lymph node is positive N1b Two or three regional lymph nodes are positive N1c No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues N2 Four or more regional lymph nodes are positive N2a Four to six regional lymph nodes are positive N2b Seven or more regional lymph nodes are positive