Rectal Cancer Treatment & Management

The surgical definition of the rectum differs from the anatomical definition; surgeons define the rectum as starting at the level of the sacral promontory, while anatomists define the rectum as starting at the level of the 3^rd sacral vertebra. Therefore, the measured length of the rectum varies from 12 cm to 15 cm. The rectum is different than the rest of the colon, in that the outer layer is made of longitudinal muscle. The rectum contains 3 folds, namely valves of Houston. The superior (10 cm to 12 cm) and inferior (4 cm to 7 cm) folds are located on the left side and middle fold (8 cm to 10 cm) is located at the right side.

National Comprehensive Cancer Network guidelines define rectal cancer as cancer located within 12 cm of the anal verge by rigid proctoscopy. This definition was developed by the Dutch Colorectal Cancer Group study, which found that the risk of recurrence of rectal cancer depends on the location of the cancer. Univariate sub-group analyses showed that the treatment effect for surgery alone vs preoperative radiotherapy plus surgery was not significant in patients whose cancer (TNM stage I to IV) was located between 10.1 cm and 15 cm from the anal verge.^[22]

Determination of optimal treatment plan for patients 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 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.^[23]

Factors influencing sphincter and organ preservation in patients with rectal cancer can be described as follows:^[23]

Factors influencing sphincter preservation

• Surgeon training
• Surgeon volume
• Neoadjuvant chemoradiotherapy

Factors 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

Patient selection 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 APR

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

Patient-related, tumor-related, treatment-, and surgeon-related factors influence the ability to restore intestinal continuity in patients with rectal cancer.

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%.^{[23, 24]}

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 only using this procedure in highly selective groups of patients, specifically those with a tumor size of 2.5 cm or smaller.^[25]

Preoperative ERUS 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.^[24]

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.^[26] 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.^[26]

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 lower cure rates associated with recurrence.^{[26, 23, 27]}

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 application of high-dose (20Gy 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 as high as 30%.^[24]

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. 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.^[28]

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 recent reports indicate that the current incidence is lower.^[29]

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.^{[19, 29, 27]}

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.^[19]

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.^[27] (See the table below.) 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 rate. TME appears to have improved survival in patients without systemic disease.^[30]

Table 2. Acceptable Minimal Distal and Proximal Resectional Margins for Rectal Cancer.^[19] (Open Table in a new window)

The anastomotic leak rate with this technique ranges from 3-11% for middle-third and upper-third anastomosis and 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).^[19] 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.^[19]

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.^[29]

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.^[29]

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.

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 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.

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.^[29]

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. Rectal carcinoma most commonly invades the uterus, adnexa, posterior vaginal wall, and bladder. The urinary bladder is the organ most commonly involved in locally advanced rectal carcinoma. Extended, en bloc resection may involve partial or complete cystectomy.^{[19, 29]}

Inadequate sampling of lymph nodes may reflect non-oncologic resection or inadequate inspection of pathologic specimens. The use of more extended pelvic lymphadenectomy has been studied for rectal cancer. Extended lymphadenectomy involves removal of all lymph nodes along the internal iliac and common iliac arteries. This procedure has been associated with significantly higher sexual and urinary dysfunction without any additional benefit in local recurrence especially in patients with adjuvant radiotherapy.^[21]

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. 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.^[31]

A multidisciplinary approach that includes colorectal surgery, medical oncology, and radiation oncology is required for optimal treatment of patients with rectal cancer. 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.

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 metastasis, 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.

Adjuvant radiation therapy

Preoperative radiation therapy has many potential advantages, including tumor down-staging; an increase in resectability, possibly permitting the use of a sphincter-sparing procedure; and a decrease in tumor viability, which may decrease the risk of local recurrence. Preoperative radiation therapy works better in well-oxygenated tissues prior to surgery. Postoperatively, tissues are relatively hypoxic as a result of surgery and may be more resistant to radiotherapy. If patients have postoperative complications, there may be delay in initiating adjuvant therapy. Preoperative radiation therapy also minimizes the radiation exposure of small bowel loops due to pelvic displacement and adhesions following surgery.^{[29, 32]}

The disadvantages of preoperative radiation therapy include delay in definitive resection, possible loss of accurate pathologic staging, possible over-treatment of early-stage (stage I and II) rectal cancer, and increased postoperative complications and morbidity and mortality rates secondary to radiation injury. Preoperative radiation therapy 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 radiotherapy 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.^[33] The authors recommend preoperative chemoradiation therapy in patients with large bulky cancers and with obvious nodal involvement.^[29]

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 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.^[29]

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.^[34]

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 chemotherapy

Chemotherapy options for colon and 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.

The most useful chemotherapeutic agent for colorectal carcinoma is 5-fluorouracil (5-FU), an antimetabolite. The prodrug, 2-deoxy-5-floxuridine (5-FUDR), is rapidly converted to 5-FU and is used for metastatic liver disease by continuous intrahepatic infusion. 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 (T_1-2, 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. The new NCCN guidelines recommend combination therapy with infusional fluorouracil, folinic acid, and oxaliplatin (FOLFOX) 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.^{[35, 36]}

Patients with locally advanced rectal cancer (T_3-4, N₀, M₀ or T_any, N_1-2, 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.

Use of FOLFOX or the combination of folinic acid, fluorouracil, and irinotecan (FOLFIRI) is recommended in treatment of patients with stage III or IV disease. Cetuximab should not be used in patients with the KRAS mutation.^[37] A study by Maughan et al also found that cetuximab added to oxaliplatin-based chemotherapy has no confirmed benefit in patients with advanced colorectal cancer.^[38]

In recent randomized phase III studies, panitumumab, a monoclonal antibody for EGFR, combined with FOLFOX4 (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improved progression-free survival when compared to FOLFOX4 or FOLFIRI alone in patients with metastatic colorectal cancer and wild-type KRAS status.^{[39, 40]}

Table 3. Colorectal Chemotherapeutic Regimens (Open Table in a new window)

Adjuvant chemoradiation therapy

In patients with r stage II and III resectable rectal cancer, preoperative chemoradiation enhances the pathological response and improves local control; however, it does not improve either disease-free or overall survival.^[41]

Radioembolization

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 q8wk) with fluorouracil IV alone. Yytrium-90 was injected intra-arterially into the hepatic artery. Findings showed that the addition of radioembolization with yytrium-90 significantly improved time to liver progression and median time to tumor progression.^[42]