Rectal Cancer Treatment & Management

A multidisciplinary approach that includes surgery, medical oncology, and radiation oncology is required for optimal treatment of patients with rectal cancer. ^[43]  See the image below.

Determination of the optimal treatment plan for a patient with rectal cancer involves a complex decision-making process. Strong considerations should be given to the intent of surgery, possible functional outcome, and preservation of anal continence and genitourinary functions. The timing of surgical resection is dependent on the size, location, extent, and grade of the rectal carcinoma. The number of lymph nodes removed (12 or more; minimum, 10) at the time of surgery impacts staging accuracy and prognosis.

The first step involves achievement of cure, because the risk of pelvic recurrence is high in patients with rectal cancer and locally recurrent rectal cancer has a poor prognosis. Functional outcome of different treatment modalities involves restoration of bowel function with acceptable anal continence and preservation of genitourinary functions. Preservation of both anal and rectal reservoir function in treatment of rectal cancer is highly preferred by patients. Sphincter-saving procedures for rectal cancer are now considered the standard of care. ^[44]

Factors influencing sphincter and organ preservation in patients with rectal cancer can be described as follows ^[44] :

• Surgeon training
• Surgeon volume
• Use of neoadjuvant chemoradiotherapy

The following factors are associated with difficult sphincter preservation:

• Male sex
• Morbid obesity
• Preoperative incontinence
• Direct involvement of anal sphincter muscles with carcinoma
• Bulky tumors within 5 cm from the anal verge

Patients with the following may be candidates for local excision:

• Lesions located in low rectum (within 8-10 cm)
• Lesions occupying less than one third of the rectal circumference
• Mobile exophitic or polypoid lesions
• Lesions less than 3 cm in size
• T1 lesions
• Low-grade tumor (well or moderately differentiated)
• Negative nodal status (clinical and radiographic)

Disadvantages of abdominoperineal resection include the following:

• Need for permanent colostomy
• Significantly higher short-term morbidity and mortality
• Significantly higher long-term morbidities
• Higher rate of sexual and urinary dysfunction

Except for stage I rectal cancer, neoadjuvant and adjuvant chemotherapy and radiation therapy are standard aspects of treatment. Chemotherapy is with combination regimens, along with biologic agents in metastatic cases.

Because biologic therapy with programmed death 1 (PD-1) inhibitors has proved effective in metastatic rectal cancer that is mismatch repair deficient, Cercek et al conducted a prospective phase 2 study of the PD-1 inhibitor dostarlimab in 12 patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. Dostarlib was administered every 3 weeks for 6 months. All 12 patients had a clinical complete response, and none underwent chemoradiotherapy or surgery. During follow-up ranging from 6 to 25 months, no cases of progression or recurrence had been reported. ^[45]

To view a multidisciplinary tumor board case discussion, see Memorial Sloan Kettering e-Tumor Boards: Newly Diagnosed With Moderately Differentiated Rectal Adenocarcinoma.

Preoperative radiation therapy (RT) has many potential advantages, including the following:

• Tumor down-staging
• An increase in resectability, possibly permitting the use of a sphincter-sparing procedure
• A decrease in tumor viability, which may decrease the risk of local recurrence

A further advantage of preoperative RT is that radiation works better in well-oxygenated tissues. Postoperatively, tissues are relatively hypoxic as a result of surgery and may be more resistant to radiotherapy. In addition, if patients have postoperative complications, initiation of adjuvant therapy may be delayed.

Preoperative RT also minimizes the radiation exposure of small bowel loops due to pelvic displacement and adhesions following surgery. ^{[46, 47]} In a study of patients with locally advanced rectal cancer, a higher dose of radiation delivered using an endorectal boost increased major response in T3 tumors by 50% without increasing surgical complications or toxicity. ^[48]

The disadvantages of preoperative RT include the following:

• Delay in definitive resection
• Possible over-treatment of early-stage (stage I and II) rectal cancer
• Possible loss of accurate pathologic staging
• Increased postoperative complications and morbidity and mortality rates secondary to radiation injury

Preoperative RT decreases the risk of tumor recurrence in patients with stage II or III disease; however, this does not translate into a decrease in distant metastases or an increase in survival rate. Some recent reports cite an increase in survival; however, this is still the minority opinion.

In sum, preoperative RT may be effective in improving local control in localized rectal cancer but is only of marginal benefit in attainment of improved overall survival; it does not diminish the need for permanent colostomies, and it may increase the incidence of postoperative surgical infections; it also does not decrease the incidence of long-term effects on rectal and sexual function. ^[49] The authors recommend preoperative chemoradiation therapy in patients with large bulky cancers and with obvious nodal involvement. ^[46]

A study by Cassidy et al found that elimination of neoadjuvant radiation therapy for select patients with stage II and III rectal adenocarcinoma is associated with worse overall survival. In their review of 21,707 patients with clinical T2N1 (cT2N1), cT3N0, or cT3N1 rectal cancers in the National Cancer Data Base, the 5‐year actuarial overall survival rate was 75% for patients who received neoadjuvant chemoradiotherapy versus 67.2% for those who received neoadjuvant multiagent chemotherapy (P < 0.01). ^[50]

Neoadjuvant long-course RT plus radiation sensitization with a fluoropyrimidine (eg, capecitabine, fluorouracil), followed by a treatment break of approximately 8 weeks before surgical excision and concluding with adjuvant chemotherapy, has been a standard of care in rectal cancer. Other options for neoadjuvant treatment include the following ^{[1, 43]} :

• Short-course RT
• Chemotherapy (eg, with FOLFOX [leucovorin calcium (folinic acid), fluorouracil, oxaliplatin] or CapeOX [capecitabine plus oxaliplatin])
• Short-course RT followed by chemotherapy

The randomized RAPIDO trial found that at 3-year follow-up, patients receiving short-course RT (5x5 Gy), then chemotherapy with CapeOX or FOLFOX4 followed by total mesorectal excision (TME) had a disease-related treatment failure rate of 23.7%, compared with 30.4% in patients who received neoadjuvant capecitabine-based chemoradiotherapy followed by TME and optional adjuvant chemotherapy. ^[51]  

For locally advanced rectal cancer, a newer standard of care is total neoadjuvant therapy (TNT), which consists of induction chemotherapy (eg, with CapeOX or modified FOLFOX6 [mFOLFOX6]) followed by chemoradiation therapy and then TME. In a retrospective cohort analysis of patients with locally advanced (T3/4 or node-positive) rectal cancer, the cohort that received TNT (n = 308) had higher rates of complete response and were more likely to have temporary ileostomy reversed within 15 weeks of proctectomy, compared with the cohort that received the standard regimen of neoadjuvant chemoradiation therapy, surgery, and planned adjuvant chemotherapy (n = 320). ^[52]

The local transanal excision of rectal cancer is reserved for early-stage cancers in a select group of patients. The lesions amenable for local excision are small (< 3 cm in size), occupying less than a third of a circumference of the rectum, preferably exophytic/polypoid, superficial and mobile (T1 and T2 lesions), low-grade tumors (well or moderately differentiated) that are located in low in the rectum (within 8 cm of the anal verge). There should also be no palpable or radiologic evidence of enlarged mesenteric lymph nodes. The likelihood of lymph node involvement in this type of lesion ranges from 0-12%. ^{[44, 53]}

A study by Peng et al found that local excision in early-stage rectal cancer may result in high local recurrence rates. The authors recommend limiting the use of this procedure to highly selected groups of patients, specifically those with a tumor size of 2.5 cm or smaller. ^[54]

Local excision is increasingly used to treat stage I rectal cancers despite its inferiority to total mesorectal excision, which is the current standard of care. In a study of all rectal cancer patients in the National Cancer Data Base from 1998 through 2010, researchers found that local excision was used to treat 46.5% of the patients with T1 tumors and 16.8% of those with T2 tumors. For patients with T1 cancer, local excision rates increased from 39.8% in 1998 to 62.0% in 2010. For patients with T2 cancers, rates increased from 12.2% to 21.4%. ^{[55, 19]}

Preoperative endorectal ultrasound should be performed. If nodes are identified as suggestive of cancer, do not perform transanal excision. The lesion is excised with the full thickness of the rectal wall, leaving a 1-cm margin of normal tissue. The defect is usually closed; however, some surgeons leave it open. Unfavorable pathologic features such as positive resection margins, lymphovascular invasion, lymph node metastasis, perineural invasions, and recurrent lesion at follow-up evaluations mandate salvage resection. Usually, an abdominal perineal resection or proctosigmoidectomy with coloanal anastomosis is performed as a salvage resection following failure of local excision. ^[53]

The advantages of local excision include rapid recovery, minimal effect on sphincter function, and relatively low perioperative morbidity and mortality. Recovery is usually rapid. The 5-year survival rate after transanal excision ranges from 65-100% (these figures include some patients with T2 lesions). The local recurrence rate ranges from 0-40%. Patients with lesions that display unfavorable histologic features but are excised completely may be treated with adjuvant radiation therapy.

Cancer recurrence following transanal excision of early rectal cancer has been studied by Weiser et al. ^[56] Failures due to transanal excision are mostly advanced local disease and are not uniformly salvageable with radical pelvic excision. These patients may require extended pelvic dissection with en bloc resection of adjacent pelvic organs such as the pelvic side wall with autonomic nerves, coccyx, prostate, seminal vesicle, bladder, vagina, ureter, ovary, and uterus. The long-term outcome in patients with recurrent rectal carcinoma who undergo radical resection is less favorable than expected, relative to the early stage of their initial rectal carcinoma. ^[56]

In summary, the treatment of T1 and T2 rectal cancers continues to be challenging. Local excision is associated with higher rate of recurrence, especially in T2 lesions. Ultimately, 15-20% of patients may experience recurrence. When local recurrence is detected, patients usually have advanced disease, requiring extensive pelvic excisions. Therefore, strict selection criteria are essential when considering local excision. All patients should be informed of the risk of local recurrence and the lower cure rates associated with recurrence. ^{[44, 56, 57]}

This radiotherapy method differs from external-beam radiation therapy in that a larger dose of radiation can be delivered to a smaller area over a shorter period. Selection criteria for this procedure are similar to those for transanal excision. The lesion can be as far as 10 cm from the anal verge and no larger than 3 cm. Endocavitary radiation is delivered via a special proctoscope and is performed in an operating room with sedation. The patient can be discharged on the same day.

A total of 6 applications of high-dose (20 to 30 Gy), low-voltage radiation (50kV) is given over the course of 6 weeks. Each radiotherapy session produces a rapid shrinkage of the rectal cancer lesion. An additional booster dose can be given to the tumor bed. The overall survival rate is 83%, although the local recurrence rate is as high as 30%. ^[53]

Transanal endoscopic microsurgery is another form of local excision that uses a special operating proctoscope that distends the rectum with insufflated carbon dioxide and allows the passage of dissecting instruments. This method can be used on lesions located higher in the rectum and even in the distal sigmoid colon. Transanal endoscopic microsurgery has not come into wide use yet because of a significant learning curve and a lack of availability.

Procedures are described that use the traditional open technique. All of these procedures, except the perineal portions, can also be performed using laparoscopic techniques, with excellent results. Laparoscopic surgery offers the advantages of faster recovery time and less pain, compared with open surgery. The nuances of the laparoscopic technique used are beyond the scope of this discussion.

A study by Li et al found that laparoscopic and open surgery for middle and lower rectal cancer are associated with similar long-term outcomes. The study shows the value of technical experience when performing laparoscopic surgery and encourages the use of this surgery by experienced teams. ^[58]

Long-term results from the UK Medical Research Council trial of laparoscopically assisted versus open surgery for colorectal cancer showed no differences between groups in overall or disease-free survival or recurrence rates. ^[59]  

In an international randomized, open-label trial (COlorectal cancer, Laparoscopic or Open Resection II [COLOR II]) involving 1044 patients with localized solitary rectal cancer located within 15 cm from the anal verge, comparison of the locoregional recurrence rate at 3 years showed no significant differences between the laparoscopic and open-surgery groups (5% in both). Disease-free-survival (74.8% and 70.8%, respectively), overall survival (86.7% and 83.6%), and rate of complications also showed no significant differences. ^[60]

Low anterior resection (LAR)

LAR is generally performed for lesions in the middle and upper third of the rectum and, occasionally, for lesions in the lower third. Because this is a major operation, patients who undergo LAR should be in good health. They should not have any preexisting sphincter problems or evidence of extensive local disease in the pelvis.

Patients will not have a permanent colostomy but should be informed that a temporary colostomy or ileostomy may be necessary. They also must be willing to accept the possibility of slightly less-than-perfect continence after surgery, although this is not usually a major problem.

Other possible disturbances in function include transient urinary dysfunction secondary to weakening of the detrusor muscle. This occurs in 3-15% of patients. Sexual dysfunction is more prominent and includes retrograde ejaculation and impotence. In the past, this has occurred in 5-70% of men, but more recent reports indicate that the current incidence is lower. ^[46]

The operation entails full mobilization of the rectum, sigmoid colon, and, usually, the splenic flexure. Mobilization of the rectum requires a technique called total mesorectal excision (TME). TME involves sharp dissection in the avascular plane that is created by the envelope that separates the entire mesorectum from the surrounding structures. This includes the anterior peritoneal reflection and Denonvilliers fascia anteriorly and preserves the inferior hypogastric plexus posteriorly and laterally. TME is performed under direct visualization. Mesorectal spread can occur by direct tumor spread, tumor extension into lymph nodes, or perineural invasion of tumor. ^{[38, 57, 46]}

TME yields a lower local recurrence rate (4%) than transanal excision (20%), but it is associated with a higher rate of anastomotic leak (11%). For this reason, TME may not be necessary for lesions in the upper third of the rectum. The distal resection margin varies depending on the site of the lesion. A 2-cm margin distal to the lesion must be achieved. For the tumors of the distal rectum, less than 5 cm from the anal verge, the minimally accepted distal margin is 1 cm in the fresh specimen. Distal intra-mural spread beyond 1 cm occurs rarely. Distal spread beyond 1 cm is associated with aggressive tumor behavior or advanced tumor stage. ^[38]

The procedure is performed with the patient in the modified lithotomy position with the buttocks slightly over the edge of the operating table to allow easy access to the rectum. ^[57]   A circular stapling device is used to create the anastomosis. A double-stapled technique is performed. This entails transection of the rectum distal to the tumor from within the abdomen using a linear stapling device. The proximal resection margin is divided with a purse-string device.

After sizing the lumen, the detached anvil of the circular stapler is inserted into the proximal margin and secured with the purse-string suture. The circular stapler is inserted carefully into the rectum, and the central shaft is projected through or near the linear staple line. Then, the anvil is engaged with the central shaft, and, after completely closing the circular stapler, the device is fired. Two rings of staples create the anastomosis, and a circular rim or donut of tissue from the proximal and distal margins is removed with the stapling device.

According to a study by Maurer et al, the introduction of TME has resulted in an impressive reduction of local recurrence rates. TME appears to have improved survival in patients without systemic disease. ^[61]

The anastomotic leak rate with this technique ranges from 3-11% for middle-third and upper-third anastomosis to 20% for lower-third anastomosis. For this reason, some surgeons choose to protect the lower-third anastomosis by creating a temporary diverting stoma. This is especially important when patients have received preoperative radiation therapy. The rate of stenosis is approximately 5-20%. A hand-sewn anastomosis may be performed; if preferred, the anastomosis is performed as a single-layer technique. The leak and stenosis rates are the same.

In R0 resection, the inferior mesenteric artery (IMA) should be excised at its origin, but this rule is not mandated by available supportive evidence. Patients with non–en-bloc resection, positive radial margins, positive proximal and distal margin, residual lymph node disease, and incomplete preoperative and intra-operative staging would not be considered to have complete resection of cancer (R0 resection). ^[38] Patients with R1 and R2 resection are considered to have an incomplete resection for cure. Incomplete R1 and R2 resection does not change the TNM stage but affects the curability. ^[38]

In a 2012 multicenter, randomized controlled trial, mesorectal excision with lateral lymph node dissection was associated with a significantly longer operation time and significantly greater blood loss than mesorectal excision alone. ^[62]

A study by Han et al analyzing factors that might be predictive of pathologic complete response (pCR) in patients with stage II and III rectal cancer undergoing TME after preoperative chemoradiation indentified high tumor location and low carcinoembryonic antigen (CEA) level after chemoradiation therapy as independent predictive factors for pCR. ^[63]

Colo-anal anastomosis (CAA)

Very distal rectal cancers that are located just above the sphincter occasionally can be resected without the need for a permanent colostomy. The procedure is as already described; however, the pelvic dissection is carried down to below the level of the levator ani muscles from within the abdomen. A straight-tube coloanal anastomosis (CAA) can be performed using the double-stapled technique, or a hand-sewn anastomosis can be performed transanally. ^[46]

The functional results of this procedure have been poor in some patients, who experience increased frequency and urgency of bowel movements, as well as some incontinence to flatus and stool. An alternative to the straight-tube CAA is creation of a colonic J pouch. The pouch is created by folding a loop of colon on itself in the shape of a J. A linear stapling or cutting device is inserted into the apex of the J, and the stapler creates an outer staple line while dividing the inner septum. The J-pouch anal anastomosis can be stapled or hand sewn.

An alternative to doing the entire dissection from within the abdomen is to begin the operation with the patient in the prone jackknife position. The perineal portion of this procedure involves an intersphincteric dissection via the anus up to the level of the levator ani muscles. After the perineal portion is complete, the patient is turned to the modified lithotomy position and the abdominal portion is performed. Either a straight-tube or colonic J-pouch anal anastomosis can be created; however, both must be hand sewn. ^[46]

The advantages of the J pouch include decreased frequency and urgency of bowel movements because of the increased capacity of the pouch. A temporary diverting stoma is performed routinely with any coloanal anastomosis.

Laparoscopic Rectal Resections

The first laparoscopic colectomy study was published in 1991 by Jacobs et al. It included 20 cases, mostly right and sigmoid colectomies but only one low anterior rectal resection and one abdominal perineal resection. ^[64] In the succeeding decades, minimally invasive rectal procedures, including radical proctectomy, became a well-accepted practice for rectal cancers. Compared with open resection, laparoscopic proctectomy is associated with earlier return of bowel function and faster overall recovery. However, operating room time, and laparoscopic resections should be performed by experienced surgeons.

In 2012, Trastulli et al compared open and laparoscopic rectal resection for cancer in a meta-analysis of nine randomized clinical trials that included1544 patients. In the study, patients who underwent laparoscopic rectal resection experienced shorter hospital stay; earlier return of bowel function; reduced intraoperative blood loss; and less postoperative bleeding, late intestinal adhesion obstruction, and late morbidity. Intra-operative and late oncological outcomes were similar in the two groups. ^[65]  

The COLOR-II trial, a European multi-center, randomized phase III noninferiority study, concluded that in the hands of skilled surgeons, the safety, resection margins, and completeness of rectal resection are similar with laparoscopic and open proctectomy. In both the laparoscopic group (n=739) and the open proctectomy group (n=364), 10% of patients had positive circumferential margins (< 2 mm). Morbidity and mortality within 20 days after surgery were similar in both groups. The laparoscopic surgery group had less blood loss, earlier return of bowel function, and shorter duration of hospital stay, but laparoscopic surgeries took longer. ^[66]  

However, another multi-center randomized trial (ACOSOG Z6051), conducted in patients with stage II and III rectal cancer in the United States and Canada, failed to support the noninferiority of laparoscopic resection for rectal cancer. A successful rectal resection—defined as a tumor-free circumferential radial margin larger than 1 mm and complete total mesorectal resection—was identified in 81.7% of 220 laparoscopic rectal resection cases and 86.9% of 222 open resection cases, which did not meet the study's criterion for noninferiority. Conversion from laparoscopic resection to open rectal resection occurred in 11% of the patients. Operative time was significantly longer for laparoscopic procedures than for open proctectomy. ^[67]  

Abdominal Perineal Resection (APR)

APR is performed in patients with lower-third rectal cancers. APR should be performed in patients in whom negative margin resection (see Table 2, below) will result in loss of anal sphincter function. This includes patients with involvement of the sphincters, preexisting significant sphincter dysfunction, or pelvic fixation, and sometimes is a matter of patient preference.

Table 2. Acceptable Minimal Distal and Proximal Resectional Margins for Rectal Cancer. ^{[38, 68]} (Open Table in a new window)

A 2-team approach is often used, with the patient in modified lithotomy position. The abdominal team mobilizes the colon and rectum, transects the colon proximally, and creates an end-sigmoid colostomy. The perineal team begins by closing the anus with a purse-string suture and making a generous elliptical incision. The incision is carried through the fat using electrocautery. The inferior rectal vessels are ligated and the anococcygeal ligament is divided. The dissection plane continues posteriorly, anterior to the coccyx to the level of the levator ani muscles.

Then, the surgeon breaks through the muscles and retrieves the specimen that has been placed in the pelvis. The specimen is brought out through the posterior opening, and the anterior dissection is continued carefully. Care must be taken to avoid the prostatic capsule in the male and the vagina in the female (unless posterior vaginectomy was planned). The specimen is removed through the perineum, and the wound is irrigated copiously. A closed-suction drain is left in place, and the perineal wound is closed in layers, using absorbable sutures. During this time, the abdominal team closes the pelvic peritoneum (this is not mandatory), closes the abdomen, and matures the colostomy. ^[46]

In patients who have rectal cancer with adjacent organ invasion, en bloc resection should be performed in order to not compromise cure. This situation is encountered in 15% of rectal cancer patients. The urinary bladder is the organ most commonly involved in locally advanced rectal carcinoma. Extended, en bloc resection may involve partial or complete cystectomy. ^{[38, 46]}  In women, rectal carcinoma also commonly invades the uterus, adnexa, and posterior vaginal wall.

Treatment of colorectal cancer with liver metastasis

Chemotherapeutic regimens for liver metastasis including systemic and intrahepatic administration have only had limited benefit. Systemic chemotherapy had 18-28% response rates. However, one meta-analysis found that carefully selected patients with metastatic colorectal cancer may benefit from preoperative chemotherapy with curative intent. ^[69]

It is well accepted that liver resections in selected patients are beneficial. Overall, 5-year survival rates following surgical resection of liver metastasis vary from 20-40%. A study by Dhir et al found that among patients undergoing hepatic resection for colorectal metastasis, a negative margin of 1 cm or more had a survival advantage. ^[70]

Although radical resection of rectum is the mainstay of therapy, surgery alone has a high recurrence rates. The local recurrence rate for rectal cancers treated with surgery alone is 30-50%. Rectal adenocarcinomas are sensitive to ionizing radiation. Radiation therapy can be delivered preoperatively, intraoperatively, or postoperatively and with or without chemotherapy.

Tumor stage, grade, number of lymph node metastases, lymphovascular involvement, signet cell appearance, achievement of negative radial margins, and distance from the radial margin are important prognostic indicators of local and distant recurrences. Low anterior (LAR) or abdominal-perineal resection (APR) in conjunctions with total mesorectal excision (TME) should be performed for optimal surgical therapy.

A study by Margalit et al found that patients older than 75 years had difficulty tolerating combined modality chemotherapy to treat rectal cancer. They required early termination of treatment, treatment interruptions, and/or dose reductions. ^[71]

Intraoperative radiation therapy

Intraoperative radiation therapy is recommended in patients with large, bulky, fixed, unresectable cancers. The direct delivery of high-dose radiotherapy is believed to improve local disease control. Intraoperative radiation therapy requires specialized, expensive operating room equipment, limiting its use.

Adjuvant radiation therapy

The advantages of postoperative radiation therapy include immediate definitive resection and accurate pathologic staging information before beginning ionizing radiation. The disadvantages of postoperative radiation therapy include possible delay in adjuvant radiation therapy if postoperative complications ensue; no effect on tumor cell spread at the time of surgery; and the decreased effect of radiation in tissues with surgically-induced hypoxia. Published randomized trials suggest that preoperative or postoperative radiation therapy appears to have a significant impact on local recurrence but does not increase survival rates. ^[46]

Adjuvant chemotherapy

Chemotherapy options for rectal cancer have greatly expanded in recent years, but the efficacy of chemotherapy remains incomplete and its toxicities remain substantial. Combination therapy with use of as many drugs as possible is needed for maximal effect against rectal cancer. ^[1] See Table 3, below.

Table 3. Common Chemotherapeutic Regimens for Colon and Rectal Cancer (Open Table in a new window)

The most useful chemotherapeutic agent for colorectal carcinoma is 5-fluorouracil (5-FU), an antimetabolite. Fluorouracil is a fluorinated pyrimidine, which blocks the formation of thymidylic acid and DNA synthesis. Clinically, it offers good radiosensitization without severe side effects, although diarrhea can be dose limiting and, if severe, life-threatening. 5-FU has been used in conjunction with radiation (combined modality) therapy before surgery (neoadjuvant), as well as after surgery.

Stage I (T1-2, N0, M0) rectal cancer patients do not require adjuvant therapy due to their high cure rate with surgical resection. High-risk patients, including those with poorly differentiated tumor histology and those with lymphovascular invasion, should be considered for adjuvant chemotherapy and radiotherapy.

National Comprehensive Cancer Network (NCCN) guidelines recommend FOLFOX (folinic acid [leucovorin], 5-FU, and oxaliplatin) or CapeOx (capecitabine plus oxaliplatin) as reasonable for patients with high-risk or intermediate-risk stage II disease; however, FOLFOX is not indicated for good- or average-risk stage II rectal cancer. ^[1] FOLFOX is associated with neuropathy, and one long-term study confirmed that although overall neurotoxicity did not significantly increase after a median of 7 years, rates of specific neurotoxicity (numbness and tingling of the hands and feet) remained elevated. ^[72]

Use of FOLFOX or FOLFIRI (folinic acid, 5-FU, and irinotecan) is recommended in treatment of patients with stage III or IV disease.

The US Food and Drug Administration (FDA) has approved trifluridine/tipiracil (Lonsurf), as monotherapy and in combination with bevacizumab, for metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–vascular endothelial growth factor (VEGF) biological therapy; and, if RAS wild-type, an anti–endothelial growth factor receptor (EGFR) therapy. Trifluridine is a nucleoside analog that inhibits cell proliferation by incorporating into DNA and interering with DNA synthesis; tipiracil inhibits the metabolism of trifluridine.

Efficacy and safety for trifluridine/tipiracil monotherapy were evaluated in the phase III RECOURSE trial, an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer. Patients had received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with KRAS wild-type tumors—cetuximab or panitumumab. Median overall survival was 7.1 months with trifluridine/tipiracil vs 5.3 months with placebo (P < 0.001). The progression-free survival was 2 months with trifluridine/tipiracil vs 1.7 months with placebo. ^[73]

Approval for combination therapy with bevacizumab was based on the results from the phase III SUNLIGHT trial, in which 246 patients received either trifluridine/tipiracil plus bevacizumab (combination group) or trifluridine/tipiracil alone (FTD–TPI group). The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD–TPI group (P < 0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD–TPI group (P< 0.001). ^[74]

Biologic therapy

Cetuximab, a recombinant humanized monoclonal antibody that binds specifically to the epithelial growth factor receptor (EGFR), is recommended as part of combination therapy (eg, with FOLFOX or FOLFIRI) for unresectable metastatic rectal cancer. ^[1] Cetuximab should not be used in patients with the KRAS mutation. ^[75] In addition, a study by Maughan et al found that cetuximab added to oxaliplatin-based chemotherapy has no confirmed benefit in patients with advanced colorectal cancer. ^[76]

In randomized phase III studies, panitumumab, a monoclonal antibody for EGFR, combined with FOLFOX4 or FOLFIRI significantly improved progression-free survival when compared with FOLFOX4 or FOLFIRI alone in patients with metastatic colorectal cancer and wild-type KRAS status. ^{[77, 78]}

Simkens et al found that patients with a high body mass index (BMI) had better overall survival on chemotherapy regimens than those with a low BMI. This effect was not seen in patients receiving chemotherapy and targeted therapy; the authors suggest that a possible decreased efficacy of bevacizumab in obese patients may account for the discrepancy. ^[79]

A study by Boisen et al in patients with metastatic colorectal cancer reported significantly better outcomes with first-line CapeOx plus bevacizumab in patients whose primary tumors originated in the rectum and sigmoid colon. For patients treated with CapeOx only, no association between primary tumor location and outcome was found. ^[80]

Pembrolizumab, a monoclonal antibody to programmed cell death–1 protein (PD-1), gained accelerated approval from the US Food and Drug Administration (FDA) in 2017 for unresectable or metastatic colorectal cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. In 2020, the FDA extended the indications for pembrolizumab to include first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. ^[81]

In January 2023, the FDA granted accelerated approval of tucatinib (a tyrosine kinase inhibitor for HER2) in combination with trastuzumab (an anti-HER2 monoclonal antibody) for treatment of RAS wild-type HER2-positive unresectable or metastatic colorectal cancer in patients who progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Approval was based on results from the open-label, multicenter MOUNTAINEER study (n=84), in which tucatinib in combination with trastuzumab yielded an overall response rate of 35% (3.6% complete response; 35% partial response), with a median duration of response of 12.4 months. ^[82]

Fruquintinib (Fruzaqla), a selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, was approved by the FDA in November 2023 for adults with metastatic colorectal cancer who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

Approval was based on results of the FRESCO and FRESCO-2 trials. ^{[83, 84]} Overall survival (OS) was the major efficacy outcome in both trials. In FRESCO-2, median OS was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group (hazard ratio [HR] 0.66, P < 0.0001). ^[84] In FRESCO, median OS was 9.3 months and 6.6 months, respectively (HR 0.65, P < 0.001). ^[83]

Statins

Preclinical and epidemiologic studies have suggested that statins may have antineoplastic properties. Nevertheless, a study by Ng et al found that statin use during and after adjuvant chemotherapy did not result in improved disease-free survival, recurrence-free survival, or overall survival in patients with stage III colon cancer. ^[85]

Adjuvant chemoradiation therapy

Patients with locally advanced rectal cancer (T3-4, N0, M0 or any T, N1-2, M0) should receive primary chemotherapy and radiotherapy. The combination of preoperative radiation therapy and chemotherapy with fluorouracil improves local control, distant spread, and survival. The basis of this improvement is believed to be the activity of fluorouracil as a radiosensitizer. Surgical resection can be done 4 to 10 weeks after completion of chemotherapy and radiotherapy.

A meta-analysis of neoadjuvant long-course chemoradiotherapy followed by total mesorectal excision for locally advanced rectal cancer concluded that waiting for a minimum of 8 weeks from the end of chemoradiotherapy to surgical excision increases pathological complete response (pCR) and downstaging rates, and improves recurrence-free survival without compromising surgical morbidity. With longer intervals, the odds ratio (OR) for pCR was 1.41 (95% confidence interval [CI] 1.30-1.52; P <   0.001) and the OR for tumor downstaging was 1.18 (95% CI 1.05-1.32; P = 0.004). The increased rate of pCR translated to reduced distant metastasis and overall recurrence but not local recurrence. ^[86]

A study by Ebert et al of colorectal cancer genetics and treatment found a link between hypermethylation of transcription factor AP-2 epsilon (TFAP2E) and clinical nonresponsiveness to chemotherapy in colorectal cancer. ^[87]

Radioembolization

The FDA has approved yttrium-90 resin microspheres (SIR-Spheres) for the treatment of unresectable metastatic liver tumors from primary colorectal cancer in combination with adjuvant intra-hepatic artery chemotherapy with floxuridine.

A prospective, multicenter, randomized phase III study by Hendlisz et al compared the addition of yttrium-90 resin to a treatment regimen of fluorouracil 300 mg/m² IV infusion (days 1-14 every 8 wk) with fluorouracil IV alone. Yttrium-90 was injected intra-arterially into the hepatic artery. The addition of radioembolization with yttrium-90 significantly improved time to liver progression and median time to tumor progression. ^[88]  

However, improvement in liver disease control has not translated to a benefit in overall survival. Three multicenter randomized, phase III trials—FOXFIRE, SIRFLOX, and FOXFIRE-Global—have evaluated the efficacy of combining first-line chemotherapy with selective internal radiotherapy  using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. A combined analysis of those trials found that overall survival was not significantly different in patients who received FOLFOX chemotherapy plus selective internal radiotherapy (n=554) compared with those who received FOLFOX only (n=549). ^[89]

Response to treatment indicator

A retrospective study conducted by Santiago and colleagues found the split scar sign was a simple morphologic pattern visible on restaging magnetic resonance (MR) high-resolution T2-weighted imaging (T2-WI) which, although not sensitive, is very specific for the identification of sustained complete responders after neoadjuvant therapy in rectal cancer. The split scar sign consists of an area of low signal on the inner wall of the rectum at the site of the tumor, corresponding to fibrosis of the submucosa, with a layer of intermediate signal intensity, representing the muscularis propria, immediately deeper in the wall of the rectum. In tumors that have breached the muscularis propria, there may also be an outermost layer of low-signal perirectal fibrosis.

Because the split scar sign is visible on high-resolution T2-weighted MR imaging, it does not require any changes to standard protocol.  At first restaging pelvic MR imaging (mean: 9.1 weeks after the end of radiotherapy), the split scar sign identified patients who sustained a complete response with very high specificity (0.97) and positive predictive value (0.93-0.94).  The split scar sign has the potential to improve patient selection for "watch-and-wait" after neoadjuvant therapy in rectal cancer. ^[90]

In a prospective cohort study that included 1575 healthcare professionals with stage I to III colorectal cancer, Song et al found that rates of colorectal cancer (CRC)–specific mortality and overall mortality were lower in patients who had higher intake of dietary fiber, especially from cereals. Survival rates were higher in patients who increased their fiber intake after diagnosis from levels before diagnosis, and in patients reporting higher intake of whole grains. ^{[91, 92]}

After multivariable adjustment, each 5 g increment in daily fiber intake was associated with a 22% decrease in CRC-specific mortality and a 14% decrease in all-cause mortality. In patients who increased their fiber intake after diagnosis, each 5 g increase in daily fiber intake was associated with 18% lower CRC-specific mortality. The relationship between fiber intake after diagnosis and CRC-specific mortality  reached a maximum at approximately 24 g/d, beyond which no further mortality reduction was found. ^{[91, 92]}

Evaluation of the source of fiber showed that cereal fiber was associated with lower CRC-specific mortality (33% per 5-g/d increment) and all-cause mortality (22%); vegetable fiber was associated with 17% lower all-cause mortality but not with significantly lower CRC-specific; no association was found for fruit fiber. Whole grain intake was associated with lower CRC-specific mortality (28% decrease in risk per 20-g/day increment), although this beneficial association fell to 23% after adjusting for fiber intake. ^{[91, 92]}

US Multi-Society Task Force on Colorectal Cancer guidelines recommend local surveillance with flexible sigmoidoscopy or endoscopic ultrasound (EUS) every 3−6 mo for the first 2−3 y after surgery in patients at increased risk for local recurrence. ^[93] This includes the following:

• Patients with localized rectal cancer who have undergone surgery without total mesorectal excision
• Patients who have undergone transanal local excision (ie, transanal excision or transanal endoscopic microsurgery) or endoscopic submucosal dissection
• Patients with locally advanced rectal cancer who did not receive neoadjuvant chemoradiation and then surgery using total mesorectal excision techniques

The task force also advises that all patients who have undergone curative resection of rectal cancer should receive their first surveillance colonoscopy 1 y after surgery (or 1 y after clearing perioperative colonoscopy).

The National Comprehensive Cancer Network recommends the following surveillance measures ^[1] :

• History and physical examination every 3–6 mo for 2 y, then every 6 mo for a total of 5 y
• Carcinoembryonic antigen (CEA) assays every 3–6 mo for 2 y, then every 6 mo for a total of 5 y for T2 or greater lesions
• Chest/abdominal/pelvic CT:  every 6–12 mo for a total of 5 y for stage II and III; every 3–6 mo for 2 y, then every 6–12 mo for a total of 5 y for stage IV
• Colonoscopy in 1 y; if no preoperative colonoscopy was performed, due to obstructing lesion, colonoscopy in 3–6 mo; if advanced adenoma is found, repeat in 1 y; if no advanced adenoma, repeat in 3 y, then every 5 y
• Proctoscopy (with EUS or MRI) every 3–6 mo for the first 2 y, then every 6 mo for a total of 5 y (for patients treated with transanal excision only)
• PET-CT scan is not routinely recommended