Three-dimensional radiotherapy and intensity-modulated radiotherapy target delineation for rectal cancer

Rectal cancer is a common and high-incidence disease in China, which tends to occur in people
over the age of 40.
Most rectal cancers are sporadic and may also result from certain genetic disorders, but account for only about 5% of causes
.
It is a common tumor in Western countries, and the incidence in China is also increasing year by year, and its morbidity and mortality are among the
top ten.
The specific cause of sporadic rectal cancer is unknown, and it is mainly related
to genetic factors, environmental factors and lifestyle.

Symptoms of rectal cancer are usually not obvious and specific in the early stages, and common local symptoms as the tumor progresses include: changes in bowel habits, such as increased frequency of bowel movements, constipation, and changes in stool characteristics, such as irregular stools, loose stools, difficulty or blood in stools, pain or fall
.

Rectal cancer diagnosis

Based on the history and clinical presentation, the TNM staging evidence
of the tumor is accurately obtained by imaging studies such as physical examination, colonoscopy, abdominopelvic (non-contrast scan and contrast) MRI and CT, chest CT, or abdominal ultrasound to determine the extent of local lesion invasion, lymph node metastases, and distant metastases.

a) Physical examination: the focus is on digital rectal diagnosis, which is simple and easy to perform, which is a key examination method for early detection of rectal cancer, and can generally find rectal masses within 7~8 cm from the anus
.
If the tumor is located in the anterior wall of the rectum, male patients should clarify the relationship between the tumor and the prostate; Female patients should have vaginal bimanual examination to find out if the tumor has invaded the posterior vaginal wall
.
Digital examination should pay attention to the finger cuff for blood
staining.

b) Imaging diagnosis: rectal MRI can clearly show the adjacency of soft tissues and organs in the pelvis, and have a clearer judgment
on mesenteric fascial involvement, invasion, or pelvic lymph node metastasis.
Intrarectal ultrasound can distinguish local tumors involving the mucosa and submucosa from tumors
that infiltrate the muscularis propria or penetrate the muscular layer into the fat surrounding the rectum.
Intrarectal ultrasound can also help determine whether there are metastases
in the perirectal lymph nodes.
CT is useful in identifying distant metastases and identifying tumor-related complications (e.
g.
, perforation, fistula formation).

MRI of the liver is usually reserved for patients with suspicious but uncertain findings on CT scan, especially if
the liver disease burden needs to be better defined to determine the need for hepatectomy.

c) Pathological diagnosis: pathological tissue
can be obtained through colonoscopy.
Current factors used in clinical decision-making include the status of DNA mismatch repair (MMR) proteins and BRAF and RAS mutations
.

In addition to imaging, pathology, and molecular prognosis related to primary tumors, it is also necessary to conduct corresponding examinations and evaluations on the patient's age, general condition, comorbidities, nutritional status, blood biochemistry, blood routine, tumor markers, etc.
, to provide a basis for
treatment selection and prognosis judgment.

Staging of rectal cancer

Rectal cancer is staged using the 8th edition of AJCC
.

a) Primary tumor of rectal cancer (T):

Tx primary tumor cannot be evaluated;

T0 There is no evidence of the presence of a primary tumor;

Tis carcinoma in situ, intramucosal carcinoma (including those confined to the lamina propria without penetrating the muscular muscular layer of the mucosa);

T1 tumor invades the submucosal layer (penetrates the muscular muscular layer of the mucosa but does not enter the muscularis propria);

T2 tumors violate the muscularis propria;

T3 tumors penetrate the muscular lamina propria to the paracolorectal tissue;

T4 tumors penetrate the visceral peritoneum or directly invade adjacent organs or tissues;

T4a tumor penetrates the visceral peritoneum (including tumor intestinal perforation and continuous tumor invasion through the area of inflammation to the surface of the visceral peritoneum);

T4b tumors directly invade or adhere to adjacent organs or structures
.

b) Regional lymph nodes (N), clinical N(cN):

Nx regional lymph nodes could not be assessed;

N0 No regional lymph node metastases;

N1 1~3 regional lymph node metastases (tumor in lymph nodes≥0.
2 mm) or any number of tumor implants and all lymph nodes are negative;

N1a 1 regional lymph node metastasis;

N1b 2~3 regional lymph node metastases;

N1c has no regional lymph node metastases, but there is tumor implantation
.
Subserosal, mesentery, non-peritoneal covering colon/rectal tissue with tumor deposit (TD), no regional lymph node metastasis;

N2 Regional lymph node metastases of 4 or more;

N2A 4~6 regional lymph node metastasis;

N2B regional lymph node metastases
of 7 or more.

c) Distant transfer (M)

M0 No distant transfers;

M1 has distant metastases;

M1a metastases to a single site or organ without peritoneal metastases;

M1b metastases to two or more sites or organs without peritoneal metastases;

M1c peritoneal metastases or peritoneal metastases with metastases
to other sites or organs.

d) Clinical prognosis staging

Phase 0 TisN0M0;

Phase I T1-2 N0 M0;

Phase II T3-4 N0 M0;

Phase IIA T3N0M0;

Phase IIB T4aN0M0;

IIC stage T4bN0M0;

Phase III T any N1-2M0;

Phase IIIA T1-2N1M0, T1N2aM0;

IIIB stage T3-4aN1M0, T2-3N2aM0, T1-2N2bM0;

IIIC stage T4aN2aM0, T3-4aN2bM0, T4bN1-2M0;

IVA stage T any N any M1a;

IVB stage T any N any M1b;

IVC phase T any N any M1c
.

Principles of rectal cancer treatment

For patients with early-stage rectal cancer (T1-2N0M0), radical surgery is the standard of care
.
However, in patients undergoing local resection, further treatment depends on postoperative pathologic outcomes: with pT1 invasive tumors with good prognostic factors (high and high school differentiation, no lymphovascular invasion or no perineural invasion, no mucin production, negative margins), endoscopic monitoring after local therapy is sufficient; For pT1 lesions with adverse prognostic factors, or even pT2 lesions, curative surgery is the standard approach
.

The indications for neoadjuvant radiotherapy are mainly for stage II.
/III.
low-grade rectal cancer: the recommended interval of 5~12 weeks after the end of long-term concurrent chemoradiotherapy to undergo radical surgery; Short-course radiation therapy combined with immediate radical surgery (surgery within 1 week of completion of radiotherapy) is recommended for surgically resectable stage T3 rectal cancer
.
The short-course radiotherapy/concurrent chemoradiotherapy combined with neoadjuvant chemotherapy mode is recommended for stage II/III rectal cancer
with high-risk recurrence factors.
Adjuvant radiotherapy is mainly recommended for patients with rectal cancer who have not undergone neoadjuvant radiotherapy, have a postoperative pathological stage II.
/III.
, and are at high risk of recurrence
.

In patients with concomitant metastatic disease, treatment must be individualized to confirm whether the metastases are potentially resectable and whether the primary tumor is symptomatic
.
There is no consensus on the best treatment, but systemic chemotherapy is the cornerstone of treatment for stage IV patients and results in a significant improvement
in survival.

Patients with low rectal cancer with a strong desire to preserve the anus may be advised to undergo chemoradiotherapy first, and if the tumor is sensitive to chemoradiotherapy and achieves complete clinical remission, a treatment strategy
of waiting for observation can be considered.
For local recurrence of rectal lesions and difficulty in resection, local radiotherapy can be considered to convert them into resectable lesions and then undergo surgical resection
without previous radiotherapy.

Indications for radiotherapy

Referring to the NCCN Clinical Practice Guidelines for Rectal Cancer V1.
2021 (level 1 evidence), the indications for radiation therapy are as follows:

a) Clinically diagnosed stage II/III rectal cancer, preoperative radiotherapy (chemotherapy) is planned;

b) Pathological diagnosis of stage II/III rectal cancer, postoperative radiotherapy (chemotherapy) therapy (those who have not received radiotherapy and chemotherapy before surgery);

c) distant metastases (M1) rectal cancer but indications for pelvic radiotherapy;

d) adenocarcinoma or squamous cell carcinoma primary in the canal is excluded from this Code;

e) This specification does not cover rectal cancer
that recurs in the pelvis after rectal cancer surgery.

Three-dimensional radiotherapy and intensity-modulated radiotherapy targets

Target definition

Referring to the RTOG Delineation Guide, targets are defined as follows:

a) GTV: rectal tumors including colonoscopy and rectal MRI/pelvic CT, invasion of extrarectal vessels;

b) GTVnd: includes mesenteric area, presacral area, intrailiac, obturator metastatic lymph nodes and carcinoma nodules on rectal MRI/pelvic CT (grade 2A evidence);

c) CTVp: specifically CTV of the primary lesion, including a range of 2 cm extension in the cephalopodal direction of the primary lesion (2A level evidence);

For T4b invasion of the prostate/seminal vesicles, CTVp should also include an expanded range of 1~2 cm (2A evidence).

For T4b invasion of uterus/vagina/bladder, CTVp should include the invaded uterus/vagina/bladder and expand the range of 1~2 cm, and consider the above organ dynamics and deformations, and give appropriate expansion to form an internal irradiation target (2A level evidence).

CTVp should include the entire bladder/vagina/ipsilateral scia-rectal fossa in patients with T4b and rectorectal fistula and invasion of the sciatorectal fossa through the external sphincter
.

d) CTV: specifically refers to high-risk lymph node drainage areas and high-risk recurrence areas
.
Subdivisions of CTV:

1) Pelvic presacral region (PS): The anterior region
of the sacrum.

2) Mesentery area (M): consists of
the entire mesenteric area and the mesenteric fascia.

3) Lateral cervical lymph node area (LLN P).

4) obturator lymph nodes area (LLN A).

5) Extrasacral lymphatic drainage area (EI).

6) inguinal lymph nodes area (IN).

7) Ischiorectal fossa (IRF).

8) Anal sphincter complex (SC).

Considering the difference in the degree of bladder fullness during radiotherapy, CTV is recommended to be placed 1~1.
5 cm
in the bladder direction.

e) PTV: CTVp and CTV left and right, ventral and dorsal direction expansion 0.
7~1.
0 cm, head and foot direction expansion 1 cm, excluding skin, three-dimensional expansion
is recommended.

GTV and GTVnd outline definitions

a) GTV (red) positions the MR image by contrasting, and completes the sketching of the GTV at the CT positioning image (Figure 1).

Figure 1 Example of GTV profiling for rectal cancer

b) GTVnd (pink): Metastatic lymph nodes are clearly displayed in diagnostic magnetic resonance or localization magnetic resonance images, which can refer to and assist in completing the delineation of GTVnd in CT positioning images (Figure 2-Figure 4).

Figure 2 Example of lymph node delineation in the mesenteric region of rectal cancer prone position

Figure 3 Example of lymph node delineation in the presuprasral region of rectal cancer

Fig.
4 Example of lymph node delineation in the prone lymphatic drainage area of rectal cancer

CTV and PTV outline definitions

The delineation of CTV is individualized according to the patient's condition, especially the stage and location of the tumor, as detailed in the table below
.

Recommendations for CTV delineation based on T/N stage and location of rectal cancer (level 2B evidence)

The upper limit of CTV mainly involves the upper limit of the prepelvic sacral area (PS) and the intrailiac lymphatic drainage area (LLN P), and the upper limit of PS recommends the use of sacral cape; The upper limit of LLN P is recommended to choose a sacro cape without missing metastatic lymph nodes to reduce irradiation
to the intestine.
For preoperative radiotherapy for high rectal cancer, the lower limit of the mesenteric area (M) is recommended to include 3~5 cm below the lower edge of the tumor, and it is not necessary to cover all the mesentery rectum (except for lymph node metastasis); Preoperative radiotherapy for middle and lower rectal cancer, including the entire mesenteric area
.
Whether clinically the contralateral lymph nodes (LLN P, LLN A) are metastasized, its diagnostic accuracy is not high; Confirmation of lateral lymph node metastases should be based
on the multidisciplinary opinion of the specific medical center.
Expert opinion on whether to prophylactic irradiation to the inguinal lymphatic drainage area (IN) is unanimous, and the general rule of thumb is that prophylactic irradiation IN is recommended for patients with a large tumor burden and high regional lymph node metastasis, and with simultaneous invasion of the skin around the anus or the lower 1/3 of the vagina; In tumors with early T stage, especially in the presence of N0, even if the tumor invades the skin around the anus or the lower 1/3 of the vagina, prophylactic exposure to IN
may be considered.
In cases where the sciatorectal fossa (IRF) is not affected, IRF should be irradiated with caution with preoperative radiotherapy to reduce surgical complications; Even if the tumor invades the IRF, only the invaded part needs to be irradiated, not the entire IRF
.

CTV and CTVp extension to PTV data should be based on their own experience, or refer to the recommendations of RTOG, three-dimensional expansion in the ventral and dorsal direction of 0.
7~1.
0 cm, cephalopod expansion 1 cm, excluding skin (grade 2B evidence).

CTV sketch demonstration

a) Anterior sacral area: divided into the pre-abdominal sacral area and the pelvic presacral area

Pre-abdominal sacral area-PS S (cyan) (figure 5), border:

Upper bound: bifurcation of the abdominal aorta is at least 0.
5 cm above the left and right common iliac arteries or metastatic lymph nodes within that area;

Nether: Sacro Point;

anterior boundary: 1 cm anterior to the lumbar vertebrae, 1.
0 cm anterior to the common iliac vessel;

Posterior boundary: anterior edge of the lumbar spine;

Outside: 0.
7~1.
0 cm
lateral to the common iliac vessel.

Perosacral presacral area-PS (light blue) (figure 6), border:

Upper bound: bifurcation of the common iliac artery into the medial and external iliac arteries/sacral cape;

Lower bound: levator ani muscle inserted into the external sphincter/perirectal mesangial adipose tissue disappears, equivalent to the level of the coccygeal tip;

anterior border: 1.
0 cm anterior to lumbar vertebrae; 1 cm anterior to the sacrum coccyx / posterior edge of the mesenteric fascia;

Posterior border: anterior edge of lumbar vertebrae/anterior edge of sacrum coccyx;

Outside: Sacroiliac joint/inner edge
of iliac muscle.

Figure 5 Example of CTV delineation of the anterior abdominal region of rectal cancer

Figure 6 Example of CTV delineation of the pelvic presacral region of rectal cancer

b) Mesorectal area-M (dark green) (Figure 7), border:

Upper bound: the submesenteric artery bifurcation is the junction of the sigmoid colic artery and the superior rectal artery/rectal B;

Lower bound: where levator ani muscle is inserted into the external sphincter/where the mesangial adipose tissue around the rectum disappears;

Supraprocal: the anterior edge of the superior rectal artery is expanded by 0.
7 cm;

Anterior middle / inferior: mesenteric fascia, posterior border of anterior pelvic organs;

Posterior boundary: anterior limit of the pelvic anterior sacral area;

Externally: laterally, medial side of the lateral iliac lymph node area;

Outside: mesenteric fascia, medial side of the lateral lymph node area;

Outside: medial edge
of levator ani.

Figure 7 Example CTV delineation of the mesenteric area of rectal cancer

c) Intrailiac lymphatic drainage zone - LLN P (yellow) (Figure 8) border:

Upper bound: bifurcation of the common iliac artery is the internal and external iliac arteries;

Lower bound: levator ani muscle insertion into the external sphincter/pelvic floor;

On the anterior boundary: extravascular 0.
7 cm;

In the anterior boundary: virtual coronal plane of ureteral entry into the bladder, posterior to the upper segment of the external iliac vessels;

Below the anterior boundary: posterior edge of the obturator internal muscle;

posterior border: lateral border of sacroiliac joint;

On the inner boundary: 0.
7 cm perivascular (above the mesentery), without avoiding normal anatomy;

Middle / inferior inner boundary: mesenteric fascia, pelvic organs;

Externally: iliopsoas, pelvis;

External middle/inferior: the medial margin
of the pelvic wall muscles (piriformis and internal obturator).

Figure 8 Example of CTV delineation of the intrailiac lymphatic drainage area of rectal cancer

d) Obturator lymphatic drainage zone - LLN A (purple) (Figure 9) border:

Upper bound: femoral apex;

Lower bound: obturator artery exits the pelvic level;

In the anterior boundary: posterior wall of external iliac vessels;

Inferior boundary: when the external iliac vessels leave the pelvis or anterior edge of the obturator artery;

posterior border: posterior border of the internal obturator muscles or anterior edge of the internal iliac lymph node area;

Inner boundary: mesenteric fascia, pelvic organs;

External: medial border
of the obturator internal muscle.

Figure 9 Example CTV delineation of obturator lymphatic drainage area in rectal cancer

e) Extrailiac lymphatic drainage zone-EI (off-white) (Figure 10) border:

Upper bound: bifurcation of the common iliac artery is the internal and external iliac arteries;

Lower boundary: where the deep iliac artery intersects with the external iliac artery or where the top of the acetabulum joins the suprapubic ramus;

Anterior border: 0.
7 cm anterior to blood vessel, anterolateral iliopsoas muscle 1.
5 cm;

posterior boundary: posterior edge of the external iliac vein;

Inner boundary: 0.
7 cm inside the vessel, avoiding pelvic organs;

Outside: iliopsoas.

Figure 10 Example of CTV delineation of extrailiac lymphatic drainage area in rectal cancer

f) Inguinal lymphatic drainage zone-IN (yellow-brown) (figure 11) border:

Upper bound: where the deep iliac vein intersects with the external iliac artery or where the top of the acetabulum joins the suprapubic branch;

Lower bound: where the great saphenous vein joins the femoral vein/lower edge of the sciatic tuberosity;

Anterior border: at least 2 cm forward around the inguinal vessels, including all visible lymph nodes;

posterior boundary: femoral triangle surrounded by the iliopsoas, pubic muscles, and adductor longus;

Inner boundary: at least 1~2 cm around the inguinal vessels, including all visible lymph nodes;

External: Smith muscle or medial border
of iliasopsoas.

Figure 11 Example of CTV delineation of inguinal lymphatic drainage area of rectal cancer

g) Sciatorectal fossa - IRF (sky blue) (fig.
12) boundary:

Upper bound: where the inferior pudendal artery leaves the pelvic cavity;

Nether: virtual bevel of the lower edge of the sphincter complex and the ischial tuberosity;

Anterior boundary: enclosed by the internal obturator muscle and the external sphincter;

Posterior boundary: middle/upper: gluteus medius; Bottom: Virtual wiring of the inner edge of the gluteus maximus;

Inner boundary: external sphincter;

External: upper / middle: obturator internal muscle; Bottom: ischial tuberosity, gluteus maximus
.

h) sphincter complex-SC (orange) (figure 13) border:

Upper bound: where the levator ani muscle is inserted into the external sphincter/rectal canal junction;

Nether: margin in the relaxation position;

Anterior, posterior, inside, external: surrounded by
the external sphincter.

Figure 12 Example of CTV delineation of sciatorectal fossa for rectal cancer

Figure 13 Example CTV delineation of sphincter complex for rectal cancer

i) Collection of high-risk recurrence areas (CT layer 0.
5 cm thick, prone position) (figure 14).

The table below shows the colors
of high-risk relapse zones.

Table Color of high-risk recurrence areas of rectal cancer

Fig.
14 Collection of high-risk recurrence areas of rectal cancer

Source: National Cancer Center/National Center for Quality Control