I. Important updates.
1. FOLFOX, CapeOX as the preferred regimen for pT3-4, N0 or pT1-4, N1-2.
2. Perioperative chemotherapy will not exceed 6 months.
3. The following treatment options were added before surgical resection: chemotherapy (FOLFOX [preferred], CapeOX [preferred], 5-FU/LV, capecitabine) followed by chemoradiotherapy (capecitabine + RT [preferred],) infusion of 5-FU + RT [preferred, intravenous 5-FU/LV + RT].
4. FOLFOX+Cetuximab as a treatment option with the following caveat: Data on the treatment of potentially resectable liver metastatic disease remain controversial.
5. Test for RAS gene status, including KRAS exon 2 and non-exon 2, and NRAS, and also for BRAF gene status.
6. 12 lymph nodes may not be available in patients who respond to preoperative chemotherapy.
II. Overview
The incidence and mortality of colorectal cancer have been at the forefront of the disease and have been declining with the development of prevention strategies, early diagnosis, and better treatment modalities, but data show an increase in incidence in younger patients younger than 50 years of age and a potential 124.2% increase in the incidence of rectal cancer in 20-34 year olds by 2030, for unknown reasons. There is overlap between the NCCN guidelines for rectal cancer and those for colon cancer, particularly in the treatment of metastatic disease.
III. Risk assessment
IV. Staging
The seventh edition of the AJCC staging manual has made some adjustments to the staging of rectal cancer. t4 has been subdivided into t4a and t4b. n1 and n2 have been further subdivided to reflect the prognostic impact of the number of lymph nodes involved. Tumor deposits in the subplasma layer, mesentery, non-peritoneal pericolonic or perirectal tissues were defined as N1c, reflecting the prognostic impact of tumor deposits in the regional lymphatic drainage area.
V. Pathology
Pathologic staging is primarily delineated by surgical specimen examination. Some of the information to be recorded in detail includes: general description of the tumor and specimen, cancer grade, depth of penetration and extension to surrounding structures, assessment of tumor regional lymph nodes, number of positive regional lymph nodes, distant metastasis or non-regional lymph node involvement, proximal, distal and peri-annular margins, effect of neoadjuvant therapy, lymphovascular invasion, perineural invasion, and number of tumor deposits.
1. Margins
The seventh edition of the AJCC staging manual includes the following recommendations: surgeons should mark the deepest areas of tumor invasion in the specimen so that the pathologist can directly assess margin status; completeness of resection includes R0 resection, which is defined as complete tumor resection with negative margins, R1 incomplete tumor resection with microscopic margin involvement, and R2 resection, which is incomplete resection with visually visible residual tumor.
The circumferential cut margin (CRM) is an important pathological staging parameter in rectal cancer. For a colon completely surrounded by plasma membrane, the radical cut margin refers to the peritoneal margin, and the CRM is important for a colon or rectum that is not completely or only partially surrounded.
The CRM is the portion between the deepest part of the tumor infiltration and the nearest soft tissue outside the rectum (e.g., the retroperitoneal or inferior peritoneal surface of the tumor), or measured in mm from the lymph node margins, and is determined by evaluating the rectum and the outer rectal mesenteric margin specimen, which often requires marking the outermost superficial and slice-of-bread-like section specimens with ink. The committee considered a CRM of less than 1 mm from the transverse margin as positive.
The importance of pathologic evaluation of CRM in resected rectal tumor specimens is that CRM is a strong predictor of local recurrence and overall survival, including in neoadjuvant patients, and is an important consideration in determining postoperative treatment. If the tumor is only CRM positive in the lymph nodes, it should be documented because studies have shown that CRM positivity in the lymph nodes has a lower recurrence rate compared to CRM positivity in direct tumor extension.
2. Lymph nodes
The AJCC and CAP recommend evaluating 10-14 or 12-18 lymph nodes to accurately assess early colorectal cancer. The number of lymph nodes that can be detected is related to the patient’s age and gender, as well as the tumor grade and location. The number of acquired lymph nodes may decrease after neoadjuvant therapy and can be an indicator of effective response to treatment. Current studies on the detection of cancer cells in micrometastases or anterior lymph nodes are still controversial and are not used to make clinical decisions.
3. Treatment response
The AJCC manual and CAP guidelines require pathology reports to evaluate the effect of neoadjuvant therapy, or at least whether it is a radical treatment effect. A more optimal evaluation is to use a rating for tumor response: 0-3, with 0 being a complete response with no viable cells visible and 3 being a poor response with little or no tumor cell killing and a large number of tumor cells remaining.
4. Perineural invasion
Perineural invasion is associated with poor prognosis.
5. Extra-lymph node tumor deposition.
Extra-neural tumor deposits or satellite nodules are irregularly dispersed tumor deposits in the perirectal fat that are not continuous with the tumor margin and are not lymph node remnants, but are located within the lymphatic drainage area of the primary tumor and are not counted as lymph nodes. Most tumor deposits are considered to be lymphovascular invasion or perineural invasion. The number of extra-nodal tumor deposits should also be counted in pathology reports and is associated with decreased DFS and OS. Extracellular tumor deposits are classified as pN1c.
VI. The role of vitamin D in colorectal cancer.
vii. Clinical presentation and treatment of non-metastatic disease.
1. Treatment of polypoid carcinoma
Before making a decision to surgically remove an endoscopically resected adenomatous polyp or villous adenoma, the physician should review the pathology and communicate with the patient. Malignant rectal polyps are defined as invasion of the mucosal muscle layer straight to the submucosa (pT1). Polyps defined as carcinoma in situ do not penetrate to the submucosa and do not present with regional lymph node metastasis. The committee recommends that cancerous polyps be marked at colonoscopy or reoperated within 2 weeks if the surgeon deems it necessary.
For polyps (adenomas) with or without a tip, further surgery is not necessary if the polyp is completely resected and has good histologic features. Good histologic features include grade 1/2 lesions with no vascular lymphatic invasion and negative margins.
Patients with completely resected, single specimen, non-tipped polyps (pT1) with good histologic features and clean margins may be considered for observation, but it is important to know that the incidence of negative outcomes is significantly higher in these polyps than in multiple malignant polyps, with negative outcomes including residual, recurrence, mortality, and hematologic rather than lymph node metastases. Rectal surgery is also an option for these patients.
Rectal surgery is also recommended for polyps with poor histologic features, specimen destruction, or margins that cannot be evaluated. Poor histologic features of adenomas are grade 3 or 4, vascular lymphatic invasion, and positive resection margins. Such patients are at increased risk of lymph node involvement. There is no consensus definition of a positive margin; a positive margin for endoscopic excision of a polyp is defined as the presence of tumor within 1-2 mm of the transverse margin or the presence of tumor cells in the transverse margin of the thermal therapy.
Transanal or transabdominal resection is recommended for specimens with incomplete polyps or specimens whose margins cannot be evaluated. Transabdominal resection including lymph node dissection should be considered for those with adverse histologic features. Preoperative endoscopic ultrasound may provide additional information to guide the choice of surgical approach, although this method has limited accuracy in detecting residual tumor. All patients who have undergone polypectomy should be followed up.
2. Treatment of limited rectal cancer
Rectal cancer is defined as a cancerous lesion located within 12 cm of the anal verge on rigid rectal microscopy. Deciding on a treatment plan for a patient with rectal cancer is complex. In addition to determining the goal of surgical treatment for rectal cancer (curative or palliative), it is necessary to consider the functional changes caused by the treatment.
The possibility of maintaining or restoring normal bowel and anal function, as well as preserving urogenital function, needs to be considered. It is challenging to achieve both curative goals and minimal impact on quality of life in distal rectal cancer. The risk of pelvic recurrence is higher in rectal cancer than in colon cancer, and local recurrence is associated with poor prognosis. Special treatment should be performed with careful patient selection, sequential multi-modality treatment, and combined radiotherapy combined with surgery is recommended for selective patients.
(1) Clinical assessment/staging
The initial evaluation of patients with rectal cancer provides important perioperative information for clinical staging of the disease. Clinical staging is used to guide treatment choices, including the propensity for surgery and surgical approach, whether perioperative radiotherapy is recommended, and the impact of clinical overstaging or understaging.
Thorough staging is required for patients whose initial presentation is suitable for surgical resection, including whole colonoscopy to assess concurrent lesions or other pathology and rigid proctoscopy to determine the location of the cancer (e.g., measuring the distance of the tumor from the anal verge). In addition other tests such as CEA, PS score status to determine surgical risk. Evaluation by imaging methods, such as endorectal ultrasound, allows preoperative assessment of the depth of tumor penetration and the presence of lymph node metastases.
More information on the extent of disease invasion and the occurrence of distant metastases can be clarified by preoperative CT. Endoscopic ultrasound or pelvic MRI, thoracic, abdominal, and pelvic CT are recommended for preoperative staging of rectal cancer; CT should be performed with intravenous and oral enhancement, and MRI enhancement may be considered if abdominal and pelvic CT are not adequate or enhanced CT is not appropriate.
The committee consensus is that PET scans do not need to be routinely used and that PET/CT, if performed, should not be used as a substitute for enhancement CT. PET/CT should only be used to evaluate results where the findings of enhancement CT are ambiguous or where the patient has a contraindication to intravenous contrast administration.
A study analyzing the accuracy of endoscopic ultrasound, MRI and CT for preoperative staging of rectal cancer confirmed that the sensitivity of endoscopic ultrasound and MRI for assessing the depth of tumor penetration into the muscularis was similar, that endoscopic ultrasound was more specific than MRI for assessing local tumor invasion, and that CT was not currently preferred for preoperative T-staging.
The sensitivity and specificity of lymph node involvement can only be assessed by CT and MRI for iliac, mesenteric, and retroperitoneal lymph nodes, and some studies have concluded that CT, MRI, and ultrasound are not the best evaluation methods.
Clinical staging also relies on histological examination of biopsy or local excisional specimens. Endoscopic biopsy specimens should be carefully evaluated pathologically looking for evidence of invasion of the mucosal muscle layer, and if resection of the rectum is being considered, an enterostomy specialist should be consulted early for better preoperative marking of the location and patient education.
(2) Assessment of treatment response
MRI, CT, or EUS are the most commonly used means of restaging after neoadjuvant therapy to plan surgical procedures, or in some patients, surgery or other treatment may not be necessary, and are effective in assessing T-staging and lymph node involvement. Functional MRI techniques can measure microcirculation, vascular permeability, and tissue cell density, which can help determine restaging in response to neoadjuvant chemotherapy.
(3) Surgical approach
The surgical approach is dependent on the location and extent of the disease and is primarily for the treatment of primary rectal cancer lesions. Modalities include local management such as polypectomy, transanal resection and transanal endoscopic microsurgery (TEM); invasive procedures include transabdominal resection combined with coloanal anastomosis.
(4) Transanal resection
Transanal resection is only suitable for selective T1 and N0 early stage cancers, less than 3 cm, moderately to highly differentiated, 8 cm from the anal verge, less than 30% of the rectal circumference, and without lymph node involvement, and can be performed transanally with guaranteed negative margins.
TEM facilitates transanal resection of small tumors if the lesion is completely within the rectum, and TEM is technically feasible for more proximal tumors. Both transanal resection and TEM include total resection of the vertical bowel wall to the perirectal fat. Negative deep incision margins (>3 mm) and mucosal margins need to be obtained to avoid tumor fragmentation.
The resected specimen should be marked before fixation and sent for examination by the pathologist. The advantages of local treatment are minimal complications, minimal mortality, and rapid postoperative recovery. More radical resection should be performed if there are adverse pathologic features such as positive margins, lymphovascular infiltration, poor differentiation, and invasion of the lower third of the submucosa.
Limitations of transanal resection include the lack of pathologic staging of the involved lymph nodes and evidence that lymph node micrometastases are common in early rectal lesions and unlikely to be identified by rectal endoscopic ultrasound. This may explain the higher incidence of local recurrence with local resection. Therefore, local resection of T1N0 rectal cancer needs to be carefully selected, with careful examination of the resection specimen and transabdominal resection if T2 disease or high-risk features are identified.
(5) Transabdominal resection
Patients who do not meet the requirements for local surgery should undergo transabdominal resection. Anus-preserving surgery with preservation of sphincter function is the preferred treatment option, but not achieved in all cases. Preoperative radiotherapy may reduce the size of the tumor, making sphincter preservation possible in some cases initially due to a large mass.
Transabdominal resection is recommended for TME. TME consists of a total resection of the rectal mesentery, including associated vascular and lymph node structures, adipose tissue, and rectal mesenteric fascia, by means of sharp separation and preservation of the autonomic nerve.
The lymphatic drainage area is influenced by the location of the rectal tumor, with more distal tumors draining upward and laterally and more proximal tumors draining upward only. the TME approach radically removes the lymphatic reflux area from the tumor above, and the committee does not recommend extended lymph node dissection unless these lymph nodes appear clinically suspicious for involvement. TME followed by coloanal anastomosis should be performed if anal function is preserved and distal clearance is complete.
In the upper and middle rectum, the LAR of TME can be extended to 4-5 cm below the distal inferior border of the tumor before colorectal anastomosis, which is a treatment option. If anastomosis is not possible, a colostomy is required. A wider TME facilitates adequate lymph node dissection to increase the possibility of a negative circumferential margin.
If the tumor directly invades the anal sphincter or levator muscle, a combination of APR and TME is required. APR involves removal of the entire rectosigmoid, rectal and perianal mesentery, rectal mesentery, and perianal soft tissue, a procedure that necessarily requires a colonic fistula.
Evaluation of the surgical specimen after TME is important and includes a general assessment of appearance, integrity, and CRM, which the committee defines as a positive CRM when the tumor is within 1 mm of the incisional margin. the quality of the rectal mesenteric specimen can be assessed by referring to the Dutch Rectal Cancer Trial scores.
(6) Laparoscopic resection
The data on laparoscopic treatment of rectal cancer are scarce. For the time being, laparoscopic surgery for rectal cancer is more suitable for clinical trials.
(7) Adjuvant and neoadjuvant treatment of resectable non-metastatic disease
Neoadjuvant and adjuvant treatment for stage II or III rectal cancer includes regional treatment due to its high risk of local recurrence. Risk factors include proximity to pelvic wall structures and organ locations, lack of plasma membrane envelope, and technical difficulties in obtaining wider surgical margins. In contrast, adjuvant treatment of colon cancer places more emphasis on prevention of distant metastases, as colon cancer is characterized by a lower risk of local recurrence.
Although radiation therapy reduces the rate of local recurrence in rectal cancer, it also increases toxicity. For some patients with low risk of recurrence surgery and adjuvant chemotherapy may be sufficient, such patients are proximal T3N0M0 rectal cancer. However, staging is often inadequate in clinical practice, so guidelines recommend that patients should still be treated with preoperative radiotherapy.
Combination treatment modalities include surgery, combined radiotherapy, and chemotherapy, and are recommended for patients with stage II or III rectal cancer. The guidelines for perioperative pelvic RT recommend two treatment sequences: preoperative radiotherapy and postoperative chemotherapy; and chemotherapy, radiotherapy, and then surgery. The duration of perioperative treatment, including chemotherapy and radiotherapy, should not exceed 6 months.
①For preoperative or postoperative radiotherapy, the committee recommends preoperative radiotherapy for stage II or III patients. Postoperative radiotherapy is recommended for stage I rectal cancer with up-staging after pathologic evaluation. The postoperative radiotherapy regimen is usually a sandwich regimen, with chemotherapy used before and after combination radiotherapy, typically a 5-FU-containing chemotherapy regimen.
② Possible advantages for combined radiotherapy include local radiotherapy sensitization, systemic control of disease, preoperative radiotherapy to increase the possibility of preserving the anal sphincter and pathologic complete response. The main chemotherapeutic agent used in radiotherapy is 5-FU. the committee recommends capecitabine as an alternative to 5-FU, does not recommend oxaliplatin for neoadjuvant radiotherapy, and does not recommend bevacizumab, cetuximab, panitumumab, or irinotecan for combined radiotherapy.
(iii) Possible advantages of induction chemotherapy include early prevention and removal of micrometastases, higher pathologic response rates, minimization of ileostomy time, ease of resection, improved tolerability, and increased rates of completion of chemotherapy. Therefore induction chemotherapy is used as an acceptable option in the 2015 version.
④ For preoperative neoadjuvant chemotherapy only no neoadjuvant radiotherapy may reduce the toxic effects of radiotherapy.
⑤ Multiple radiation fields should include the tumor, the tumor bed and surrounding 2-5 cm margins, presacral and internal iliac lymph nodes, and for T4 tumors invading anterior structures, also include external iliac lymph nodes, and for tumors invading the distal anal canal, consider including inguinal lymph nodes. The recommended dose is 45-50Gy in 25-28 sessions. Techniques and positioning that reduce the dose of small bowel radiotherapy are encouraged, and intensity-modulated radiotherapy (IMRT) is used only for clinical trials or for re-radiotherapy of recurrent disease.
Cooperation in preoperative treatment, surgery and adjuvant chemotherapy is important. For patients treated with preoperative radiotherapy, the committee recommends an interval of 5-12 weeks after completion of full dose radiotherapy before surgery to facilitate recovery. While longer intervals may increase the rate of complete pathologic remission, it is not clear if there is a clinical benefit. If longer intervals are clinically indicated, they do not result in increased blood loss, operative time consumption, or positive margin rates.
(6) Short-course radiotherapy has the same local control and OS compared with conventional radiotherapy and may be a treatment option.
(7) Response to neoadjuvant therapy is associated with long-term outcome, distant metastasis, and local recurrence. Patients whose tumors have been downgraded to yT1-2 after neoadjuvant therapy are more likely to benefit from postoperative adjuvant therapy, and adjuvant therapy should be administered to these patients.
The Committee does not support a wait-and-see approach for those who achieve complete remission with neoadjuvant therapy.
⑨ All patients with stage II or III rectal cancer who have completed neoadjuvant radiotherapy and surgery and who have not received preoperative neoadjuvant chemotherapy should receive adjuvant chemotherapy. The committee recommends FOLFOX or CapeOX regimen preferably, FLOX, 5-FU/LV capecitabine may also be applied.
(8) Treatment recommendations for T1 or T2 patients
Lymph node negative T1 lesions can be resected either transabdominally or transanally. If local excisional pathologic evaluation reveals poor differentiation, positive margins, invasion of the lower third of the submucosa, lymphovascular invasion, or re-staging of T2, re-excision should be performed transabdominally. High-risk patients who cannot undergo reoperation need to be treated with sandwich-mode chemotherapy, radiotherapy, and chemotherapy to reduce treatment deficits, as the lymph node status of such patients is unknown.
Lymph node-negative T2 lesions should undergo transabdominal resection because the local recurrence rate can be 11%-45% with local resection alone. No further treatment is required for pT1-2, N0, M0 after transabdominal resection, and if pT3, N0, M0 or lymph nodes are positive, sandwich modality therapy is required, including one cycle of adjuvant chemotherapy with 5-FU/LV, FOLFOX or capecitabine ± oxaliplatin, followed by 5-FU/RT or capecitabine/RT, and finally 5-FU/LV, FOLFOX or capecitabine ± oxaliplatin.
The committee recommended a total duration of perioperative treatment of approximately 6 months. Those with pathologic evidence of pT3, N0, M0 and negative cut margins and favorable prognostic features should be treated with first-line resection; the benefit of RT is likely to be small and chemotherapy alone should be considered.
(9) Recommendations for treatment of T3 or T4, lymph node involvement, local unresectable or patient intolerant of resection
The treatment sequence for patients with T3-4, N0 or any T, N1-2 or locally unresectable or intolerant of surgery has two options: chemoradiotherapy, followed by resection if resectable, and then chemotherapy; and chemotherapy, followed by radiotherapy, followed by resection if resectable.
5-FU/RT or capecitabine/RT is the preferred regimen; FOLFOX or CapeOX is the preferred chemotherapy regimen; preoperative therapy should be considered prior to resection unless contraindicated. The committee recommends that poor response to treatment is not a necessary consequence of unresectability and that surgical exploration is appropriate. Transabdominal resection should be performed 5-12 weeks after the end of neoadjuvant therapy, with a total of approximately 6 months of perioperative treatment; if surgery is not appropriate after initial therapy, systemic therapy should be instituted, at which point FOLFOXIRI is acceptable.
T3, N0 or any T, N1-2 surgery can be first-line treatment for patients for whom radiotherapy is not appropriate. Pathologic stage p T1-2, N0, M0 after transabdominal resection requires only observation; pathologic stage p T3, N0, M0 or p T1-3, N1-2, M0 is treated with a sandwich regimen for approximately 6 months; pathologic proximal T3, N0, M0 with negative margins and good prognostic features have less benefit from RT after transabdominal surgical resection and may be considered for chemotherapy alone.
For unresectable tumors, the radiation dose should be higher than 54 Gy and limited to 45 Gy for the small bowel. for T4 tumors or recurrent cancer or those with very close or positive margins, intraoperative RT (IORT) facilitates resection, which involves direct intraoperative exposure of the tumor to RT. if IORT cannot be performed, 10-20 Gy or brachytherapy should be considered.
VIII. Principles of treatment for metastatic disease
ix. Treatment of locally recurrent disease
Local recurrence of rectal cancer is characterized by pelvic or anastomotic recurrence. Potentially resectable isolated pelvic or anastomotic recurrences are usually treated by resection followed by adjuvant radiotherapy or perioperative radiotherapy and combined 5-FU infusion. iORT or brachytherapy should be considered at the time of resection. imrt can be used for re-irradiated patients. Chemotherapy is given for unresectable lesions, and radiotherapy is added or subtracted as tolerated by the patient. Block removal therapy is not recommended.
X. Post-treatment monitoring
XI. Summary
The NCCN committee believes that multidisciplinary collaboration is important in the treatment of rectal cancer; adequate pathologic evaluation, with at least 12 lymph nodes if possible; transanal resection is an option for early stage patients with negative endoscopic ultrasound or MRI confirmed lymph nodes who meet the criteria; transabdominal resection is indicated for the remaining rectal cancers; perioperative radiotherapy and chemotherapy are the preferred treatment strategies for most patients with suspected or confirmed T3-4 or patients with regional lymph node involvement.
Recommended postoperative surveillance procedures include CEA, chest, abdominal, and pelvic CT, and colonoscopy. Those with local recurrence should be considered for resection and receive chemotherapy and radiotherapy. If resection is not possible, chemotherapy and, if appropriate, radiotherapy will be administered. Patients with pulmonary and hepatic metastases should be considered for surgical resection if complete resection is possible. Perioperative chemotherapy and radiotherapy are used for concurrent metastases, and perioperative chemotherapy is used for non-concurrent metastases.
Continuous therapy is recommended for patients with diffuse unresectable metastatic disease. Principles to consider when initiating therapy include pre-planned strategies when changing therapy. Initial therapy selection is based on the patient’s ability to tolerate strong therapy. Stronger initial therapies include FOLFOX, FOLFIRI, CapeOX, and FOLFOXIRI, with the addition of biologic agents.