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Incidence and Mortality
It is difficult to separate epidemiological considerations of rectal cancer from those of colon cancer because epidemiological studies often consider colon and rectal cancer (i.e., colorectal cancer) together.
Worldwide, colorectal cancer is the third most common form of cancer. In 2012, there were an estimated 1.36 million new cases of colorectal cancer and 694,000 deaths.
Estimated new cases and deaths from rectal cancer in the United States in 2018:
Colorectal cancer affects men and women almost equally. Among all racial groups in the United States, African Americans have the highest sporadic colorectal cancer incidence and mortality rates.[3,4]
Anatomy of the lower gastrointestinal system.
The rectum is located within the pelvis, extending from the transitional mucosa of the anal dentate line to the sigmoid colon at the peritoneal reflection; by rigid sigmoidoscopy, the rectum measures between 10 cm and 15 cm from the anal verge. The location of a rectal tumor is usually indicated by the distance between the anal verge, dentate line, or anorectal ring and the lower edge of the tumor, with measurements differing depending on the use of a rigid or flexible endoscope or digital examination.
The distance of the tumor from the anal sphincter musculature has implications for the ability to perform sphincter-sparing surgery. The bony constraints of the pelvis limit surgical access to the rectum, which results in a lesser likelihood of attaining widely negative margins and a higher risk of local recurrence.
Increasing age is the most important risk factor for most cancers. Other risk factors for colorectal cancer include the following:
Evidence supports screening for rectal cancer as a part of routine care for all adults aged 50 years and older, especially for those with first-degree relatives with colorectal cancer, for the following reasons:
(Refer to the PDQ summary on Colorectal Cancer Screening for more information.)
Similar to colon cancer, symptoms of rectal cancer may include the following:
With the exception of obstructive symptoms, these symptoms do not necessarily correlate with the stage of disease or signify a particular diagnosis.
The initial clinical evaluation may include the following:
Physical examination may reveal a palpable mass and bright blood in the rectum. Adenopathy, hepatomegaly, or pulmonary signs may be present with metastatic disease. Laboratory examination may reveal iron-deficiency anemia and electrolyte and liver function abnormalities.
The prognosis of patients with rectal cancer is related to several factors, including the following:[6,20,21,22,23,24,25,26,27,28]
Only disease stage (designated by tumor [T], nodal status [N], and distant metastasis [M]) has been validated as a prognostic factor in multi-institutional prospective studies.[20,21,22,23,24,25] A major pooled analysis evaluating the impact of T and N stage and treatment on survival and relapse in patients with rectal cancer who are treated with adjuvant therapy has been published and confirms these findings.
A large number of studies have evaluated other clinical, pathologic, and molecular parameters.[32,33,34,35,36,37,38] As yet, none has been validated in multi-institutional prospective trials. For example, microsatellite instability–high, also associated with Lynch syndrome–related rectal cancer, was shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients with colorectal cancer who were 50 years old or younger at the time of diagnosis. In addition, gene expression profiling has been reported to be useful in predicting the response of rectal adenocarcinomas to preoperative chemoradiation therapy and in determining the prognosis of stages II and III rectal cancer after neoadjuvant 5-fluorouracil-based chemoradiation therapy.[40,41]
Racial and ethnic differences in overall survival (OS) after adjuvant therapy for rectal cancer have been observed, with shorter OS for blacks than for whites. Factors contributing to this disparity may include tumor position, type of surgical procedure, and presence of comorbid conditions.
Follow-up After Treatment
The primary goals of postoperative surveillance programs for rectal cancer are:
Routine, periodic studies following treatment for rectal cancer may lead to earlier identification and management of recurrent disease.[43,44,45,46,47] A statistically significant survival benefit has been demonstrated for more intensive follow-up protocols in two clinical trials. A meta-analysis that combined these two trials with four others reported a statistically significant improvement in survival for patients who were intensively followed.[43,48,49]
Guidelines for surveillance after initial treatment with curative intent for colorectal cancer vary between leading U.S. and European oncology societies, and optimal surveillance strategies remain uncertain.[50,51] Large, well-designed, prospective, multi-institutional, randomized studies are required to establish an evidence-based consensus for follow-up evaluation.
Carcinoembryonic antigen (CEA)
Measurement of CEA, a serum glycoprotein, is frequently used in the management and follow-up of patients with rectal cancer. A review of the use of this tumor marker for rectal cancer suggests the following:
In one Dutch retrospective study of total mesorectal excision for the treatment of rectal cancer, investigators found that the preoperative serum CEA level was normal in the majority of patients with rectal cancer, and yet, serum CEA levels rose by at least 50% in patients with recurrence. The authors concluded that serial, postoperative CEA testing cannot be discarded based on a normal preoperative serum CEA level in patients with rectal cancer.[52,53]
Other PDQ summaries containing information related to rectal cancer include the following:
Adenocarcinomas account for the vast majority of rectal tumors in the United States. Other histologic types account for an estimated 2% to 5% of colorectal tumors.
The World Health Organization classification of tumors of the colon and rectum includes the following:
Carcinoid (well-differentiated neuroendocrine neoplasm)
Intraepithelial neoplasia (dysplasia) associated with chronic inflammatory diseases
(Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Accurate staging provides crucial information about the location and size of the primary tumor in the rectum, and, if present, the size, number, and location of any metastases. Accurate initial staging can influence therapy by helping to determine the type of surgical intervention and the choice of neoadjuvant therapy to maximize the likelihood of resection with clear margins. In primary rectal cancer, pelvic imaging helps determine the following:[1,2,3,4,5,6,7]
Clinical evaluation and staging procedures may include the following:
In the tumor (T) staging of rectal carcinoma, several studies indicate that the accuracy of endorectal ultrasound ranges from 80% to 95% compared with 65% to 75% for CT and 75% to 85% for MRI. The accuracy in determining metastatic nodal involvement by endorectal ultrasound is approximately 70% to 75% compared with 55% to 65% for CT and 60% to 70% for MRI. In a meta-analysis of 84 studies, none of the three imaging modalities, including endorectal ultrasound, CT, and MRI, were found to be significantly superior to the others in staging nodal (N) status. Endorectal ultrasound using a rigid probe may be similarly accurate in T and N staging when compared with endorectal ultrasound using a flexible scope; however, a technically difficult endorectal ultrasound may give an inconclusive or inaccurate result for both T stage and N stage. In this case, further assessment by MRI or flexible endorectal ultrasound may be considered.[4,9]
In patients with rectal cancer, the circumferential resection margin is an important pathological staging parameter. Measured in millimeters, it is defined as the retroperitoneal or peritoneal adventitial soft-tissue margin closest to the deepest penetration of tumor.
AJCC Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define rectal cancer. The same classification is used for both clinical and pathologic staging. Treatment decisions are made with reference to the TNM classification system, rather than the older Dukes or Modified Astler-Coller classification schema.
Cancers staged using this staging system include adenocarcinomas, high-grade neuroendocrine carcinomas, and squamous carcinomas of the colon and rectum. Cancers not staged using this staging system include these histopathologic types of cancer: appendiceal carcinomas, anal carcinomas, well-differentiated neuroendocrine tumors (carcinoids). (Refer to the PDQ summaries on Anal Cancer Treatment and the Gastrointestinal Carcinoid Tumors Treatment for more information.)
Lymph node status
The AJCC and a National Cancer Institute-sponsored panel suggested that at least 10 to 14 lymph nodes be examined in radical colon and rectum resections in patients who did not receive neoadjuvant therapy. In cases in which a tumor is resected for palliation or in patients who have received preoperative radiation therapy, fewer lymph nodes may be present.[10,11,12] This takes into consideration that the number of lymph nodes examined is a reflection of both the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen.
Retrospective studies, such as Intergroup trial INT-0089 (EST-2288), have demonstrated that the number of lymph nodes examined during colon and rectal surgery may be associated with patient outcome.[13,14,15,16]
A new tumor-metastasis staging strategy for node-positive rectal cancer has been proposed.
The management of rectal cancer varies somewhat from that of colon cancer because of the increased risk of local recurrence and a poorer overall prognosis. Differences include surgical technique, the use of radiation therapy, and the method of chemotherapy administration. In addition to determining the intent of rectal cancer surgery (i.e., curative or palliative), it is important to consider therapeutic issues related to the maintenance or restoration of normal anal sphincter, genitourinary function, and sexual function.[1,2]
The approach to the management of rectal cancer is multimodal and involves a multidisciplinary team of cancer specialists with expertise in gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology.
Primary Surgical Therapy
The primary treatment for patients with rectal cancer is surgical resection of the primary tumor. The surgical approach to treatment varies according to the following:
Types of surgical resection include the following:[1,2,3]
Polypectomy alone may be used in certain instances (T1) in which polyps with invasive cancer can be completely resected with clear margins and have favorable histologic features.[4,5]
Local excision of clinical T1 tumors is an acceptable surgical technique for appropriately selected patients. For all other tumors, a mesorectal excision is the treatment of choice. Very select patients with T2 tumors may be candidates for local excision. Local failure rates in the range of 4% to 8% after rectal resection with appropriate mesorectal excision (total mesorectal excision for low/middle rectal tumors and mesorectal excision at least 5 cm below the tumor for high rectal tumors) have been reported.[6,7,8,9,10]
For patients with advanced cancers of the mid- to upper rectum, low-anterior resection followed by the creation of a colorectal anastomosis may be the treatment of choice. For locally advanced rectal cancers for which radical resection is indicated, however, total mesorectal excision with autonomic nerve preservation techniques via low-anterior resection is preferable to abdominoperineal resection.[1,2]
The low incidence of local relapse after meticulous mesorectal excision has led some investigators to question the routine use of adjuvant radiation therapy. Because of an increased tendency for first failure in locoregional sites only, the impact of perioperative radiation therapy is greater in rectal cancer than in colon cancer.
Preoperative chemoradiation therapy
Neoadjuvant therapy for rectal cancer, using preoperative chemoradiation therapy, is the preferred treatment option for patients with stages II and III disease. However, postoperative chemoradiation therapy for patients with stage II or III rectal cancer remains an acceptable option.[Level of evidence: 1iA]
Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3–T4 or node-positive disease (stages II/III), based on the results of several studies:
Multiple phase II and III studies examined the benefits of preoperative chemoradiation therapy, which include the following:
Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[15,16,17,18,19,20,21,22] However, preoperative radiation therapy is associated with increased complications compared with surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[23,24,25,26]
(Refer to the Preoperative chemoradiation therapy section in the Stages II and III Rectal Cancer section of this summary for more information about these studies.)
Postoperative chemoradiation therapy
Preoperative chemoradiation therapy is the current standard of care for stages II and III rectal cancer. However, before 1990, the following studies noted an increase in both disease-free survival (DFS) and overall survival (OS) with the use of postoperative combined-modality therapy:
Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems.
Fluorouracil (5-FU): The following studies examined optimal delivery methods for adjuvant 5-FU:
(Refer to the Stages II and III Rectal Cancer section of this summary for detailed information about these study results.)
Acceptable postoperative chemoradiation therapy for patients with stage II or III rectal cancer not enrolled in clinical trials includes continuous-infusion 5-FU during 45 Gy to 55 Gy pelvic radiation and four cycles of adjuvant maintenance chemotherapy with bolus 5-FU with or without modulation with leucovorin (LV).
Findings from the NSABP-R-01 trial compared surgery alone with surgery followed by chemotherapy or radiation therapy. Subsequently, the NSABP-R-02 study, addressed whether adding postoperative radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[Level of evidence: 1iiA]
In the NSABP-R-02 study, the addition of radiation therapy significantly reduced local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02) but failed to demonstrate a significant survival benefit. Radiation therapy appeared to improve survival among patients younger than 60 years and among patients who underwent abdominoperineal resection.
While this trial has initiated discussion in the oncologic community about the proper role of postoperative radiation therapy, omission of radiation therapy seems premature because of the serious complications of locoregional recurrence.
Table 8 describes the chemotherapy regimens used to treat rectal cancer.
The acute side effects of pelvic radiation therapy for rectal cancer are mainly the result of gastrointestinal toxicity, are self-limiting, and usually resolve within 4 to 6 weeks of completing treatment.
Of greater concern is the potential for late morbidity after rectal cancer treatment. Patients who undergo aggressive surgical procedures for rectal cancer can have chronic symptoms, particularly if there is impairment of the anal sphincter. Patients treated with radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than do patients who undergo surgical resection alone.[24,32,33,34,35,36,37]
An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction than do patients who undergo surgical resection alone. A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with radiation therapy.
Improved radiation therapy planning and techniques may minimize these acute and late treatment-related complications. These techniques include the following:[39,40,41,42,43]
In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy × five daily treatments) followed by surgery one week later, rather than the long-course chemoradiation approach used in the United States. One reason for this difference is the concern in the United States for heightened late effects when high radiation doses per fraction are given.
A Polish study randomly assigned 316 patients to preoperative long-course chemoradiation therapy (50.4 Gy in 28 daily fractions with 5-FU/LV) or short-course preoperative radiation therapy (25 Gy in 5 fractions). Although the primary endpoint was sphincter preservation, late toxicity was not statistically significantly different between the two treatment approaches (7% long course vs. 10% short course). Of note, data on anal sphincter and sexual function were not reported, and toxicity was physician determined, not patient reported.
Ongoing clinical trials comparing preoperative and postoperative adjuvant chemoradiation therapy should further clarify the impact of either approach on bowel function and other important quality-of-life issues (e.g., sphincter preservation) in addition to the more conventional endpoints of DFS and OS.
Standard Treatment Options for Stage 0 Rectal Cancer
Stage 0 rectal cancer or carcinoma in situ is the most superficial of all rectal lesions and is limited to the mucosa without invasion of the lamina propria.
Standard treatment options for stage 0 rectal cancer include the following:
Polypectomy or surgery
Local excision or simple polypectomy may be indicated for stage 0 rectal cancer tumors. Because of its localized nature at presentation, stage 0 rectal cancer has a high cure rate. For large lesions not amenable to local excision, full-thickness rectal resection by the transanal or transcoccygeal route may be performed.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Standard Treatment Options for Stage I Rectal Cancer
Stage I tumors extend beneath the mucosa into the submucosa (T1) or into, but not through, the bowel muscle wall (T2). Because of its localized nature at presentation, stage I rectal cancer has a high cure rate.
Standard treatment options for stage I rectal cancer include the following:
Surgery with or without chemoradiation therapy
There are three potential options for surgical resection in stage I rectal cancer:
Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement about 20% of the time. Patients may want to consider additional therapy, such as radiation therapy and chemotherapy, or wide surgical resection of the rectum. Patients with poor histologic features or positive margins after local excision may consider low-anterior resection or abdominoperineal resection and postoperative treatment as dictated by full surgical staging.
For patients with T1 and T2 tumors, no randomized trials are available to compare local excision with or without postoperative chemoradiation therapy to wide surgical resection (low-anterior resection and abdominoperineal resection).
Standard Treatment Options for Stages II and III Rectal Cancer
Standard treatment options for stages II and III rectal cancer include the following:
Total mesorectal excision with either low anterior resection or abdominoperineal resection is usually performed for stages II and III rectal cancer before or after chemoradiation therapy.
Retrospective studies have demonstrated that some patients with pathological T3, N0 disease treated with surgery and no additional therapy have a very low risk of local and systemic recurrence.
Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3 or T4 or node-positive disease, based on the results of several studies.
Evidence (preoperative chemoradiation therapy):
Short-course preoperative radiation therapy followed by surgery and chemotherapy
The use of short-course radiation therapy before surgery has been a standard approach in parts of Europe and Australia.
Evidence (short-course preoperative radiation therapy):
Subsequently, the Polish Rectal Trial and the Trans-Tasman Radiation Oncology Group (TROG) compared short-course preoperative radiation therapy with the standard long-course preoperative chemoradiation therapy administered with 5-FU.
Taken together, these studies demonstrate that short-course preoperative radiation therapy and long-course preoperative chemoradiation therapy are both reasonable treatment strategies for patients with stage II or III rectal adenocarcinoma.
Progress in the development of postoperative treatment regimens relates to the integration of systemic chemotherapy and radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and 5-FU-based chemotherapy for stages II and III rectal cancer was established by a series of prospective, randomized clinical trials, including the following:[9,10,11][Level of evidence: 1iiA]
These studies demonstrated an increase in DFS interval and OS when radiation therapy was combined with chemotherapy after surgical resection. After the publication in 1990 of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference recommended postoperative combined-modality treatment for patients with stages II and III rectal carcinoma. Since that time, preoperative chemoradiation therapy has become the standard of care, although postoperative chemoradiation therapy is still an acceptable alternative. (Refer to the Preoperative chemoradiation therapy section of this summary for more information.)
Additional evidence (postoperative chemoradiation therapy):
Many academic oncologists suggest that LV/5-FU/oxaliplatin (FOLFOX) be considered the standard for adjuvant chemotherapy in rectal cancer. However, there are no data about rectal cancer to support this consideration. FOLFOX has become the standard arm in the latest Intergroup study evaluating adjuvant chemotherapy in rectal cancer. An Eastern Cooperative Oncology Group trial (ECOG-E5202 [NCT00217737]) randomly assigned patients with stage II or III rectal cancer who received preoperative or postoperative chemoradiation therapy to receive 6 months of FOLFOX with or without bevacizumab, but this trial closed because of poor accrual; no efficacy data are available.
Preoperative oxaliplatin with chemoradiation therapy
Oxaliplatin has also been shown to have radiosensitizing properties in preclinical models. Phase II studies that combined oxaliplatin with fluoropyrimidine-based chemoradiation therapy have reported pathologic complete response rates ranging from 14% to 30%.[18,19,20,21,22] Data from multiple studies have demonstrated a correlation between rates of pathologic complete response and endpoints including distant metastasis-free survival, DFS, and OS.[23,24,25]
There is no current role for off-trial use of concurrent oxaliplatin and radiation therapy in the treatment of patients with rectal cancer.
Evidence (preoperative oxaliplatin with chemoradiation therapy):
The primary objective of this study is locoregional disease control.[Level of evidence: 1iiD] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following:
Postoperative oxaliplatin-containing regimens
On the basis of results of several studies, oxaliplatin as a radiation sensitizer does not appear to add any benefit in terms of primary tumor response, and it has been associated with increased acute treatment-related toxicity. The question of whether oxaliplatin should be added to adjuvant 5-FU/LV for postoperative management of stages II and III rectal cancer is an ongoing debate. There are no randomized phase III studies to support the use of oxaliplatin for the adjuvant treatment of rectal cancer. However, the addition of oxaliplatin to 5-FU/LV for the adjuvant treatment of colon cancer is now considered standard care.
Evidence (postoperative oxaliplatin):
It is unclear whether the results of these colon cancer trials can be applied to the management of patients with rectal cancer. There are no randomized phase III studies to support the routine practice of administering FOLFOX as adjuvant therapy to patients with rectal cancer.
Primary chemoradiation therapy followed by intensive surveillance for complete clinical responders
Since the advent of preoperative chemoradiation therapy in rectal cancer, the standard approach has been to recommend definitive surgical resection by either abdominoperineal resection or laparoscopic-assisted resection. In most series, after long-course chemoradiation therapy, 10% to 20% of patients will have a complete clinical response in which there is no sign of persistent cancer by imaging, rectal exam, or direct visualization during sigmoidoscopy. It was a long-held belief that most patients who did not undergo surgery for personal or medical reasons would experience a local and/or systemic recurrence. However, it became clear that patients with a pathologic complete response to preoperative chemoradiation therapy followed by definitive surgery had a better DFS than did patients who did not have a pathologic clinical response.
Several single-institution studies have challenged this standard of care by demonstrating that most patients with complete clinical response will be cured of rectal cancer without surgery and that many patients who experience a local recurrence can be treated with surgical resection (abdominoperineal resection or laparoscopic-assisted resection) at the time of their recurrence.[34,35,36,37] These institutional series were hampered by their small size and inherent selection bias.
Evidence (primary chemoradiation therapy followed by intensive surveillance for complete clinical responders):
Patients managed by watch and wait underwent a more intensive follow-up protocol consisting of outpatient digital rectal examination; MRI (every 4–6 months in the first 2 years); examination under anesthesia or endoscopy; computed tomography scan of the chest, abdomen, and pelvis; and at least two carcinoembryonic antigen measurements in the first 2 years. The optimal follow-up has not been determined.
For patients who have a complete clinical response to therapy, it is reasonable to consider a watch-and-wait approach with intensive surveillance instead of immediate surgical resection.
Treatment of patients with advanced or recurrent rectal cancer depends on the location of the disease.
Metastatic and Recurrent Rectal Cancer
Standard treatment options for stage IV and recurrent rectal cancer include the following:
Surgery with or without chemotherapy or radiation therapy
For patients with locally recurrent, liver-only, or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment. Patients with limited pulmonary metastasis, and patients with both pulmonary and hepatic metastasis, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[2,3,4,5] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.
Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone after an initial, attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival.[7,8]
The use of induction chemoradiation therapy for previously nonirradiated patients with locally advanced pelvic recurrence (pelvic side-wall, sacral, and/or adjacent organ involvement) may increase resectability and allow for sphincter preservation.[9,10] Intraoperative radiation therapy in patients who underwent previous external-beam radiation therapy may improve local control in patients with locally recurrent disease, with acceptable morbidity.
First-line chemotherapy and targeted therapy
The following are active U.S. Food and Drug Administration (FDA)-approved drugs that are used alone and in combination with other drugs for patients with metastatic colorectal cancer:
When 5-FU was the only active chemotherapy drug, trials in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[12,13] and improved survival and quality of life in patients who received chemotherapy versus best supportive care.[14,15,16] Several trials have analyzed the activity and toxic effects of various 5-FU/LV regimens using different doses and administration schedules and showed essentially equivalent results with a median survival time in the approximately 12-month range.
Irinotecan and oxaliplatin
Three randomized studies in patients with metastatic colorectal cancer demonstrated improved response rates, progression-free survival (PFS), and overall survival (OS) when irinotecan or oxaliplatin was combined with 5-FU/LV.[18,19,20]
Evidence (irinotecan vs. oxaliplatin):
Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer. However, when using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[Level of evidence: 1iiDiii]
Before the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU/LV.[25,26][Level of evidence: 1iiA]
Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated capcitabine/oxaliplatin (CAPOX) versus 5-FU/oxaliplatin regimens (FUOX or FUFOX).[27,28]
Evidence (oxaliplatin vs. capecitabine):
When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a 5-FU/oxaliplatin regimen.
Bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer. There are currently no completed randomized controlled studies evaluating whether continued use of bevacizumab in second-line or third-line treatment after progressing on a first-line bevacizumab regimen extends survival.
Cetuximab is a partially humanized monoclonal antibody against EGFR. Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.
The comparisons between arms A and B and arms A and C were analyzed and published separately.[37,38]
Aflibercept is a novel anti-VEGF molecule and has been evaluated as a component of second-line therapy in patients with metastatic colorectal cancer.
Ramucirumab is a fully humanized monoclonal antibody that binds to vascular endothelial growth factor receptor-2 (VEGFR-2).
Panitumumab is a fully humanized antibody against the EGFR. The FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy. In clinical trials, panitumumab demonstrated efficacy as a single agent or in combination therapy, which was consistent with the effects on PFS and OS with cetuximab. There appears to be a consistent class effect.
Anti-EGFR antibody versus anti-VEGF antibody with first-line chemotherapy
In the management of patients with stage IV colorectal cancer, it is unknown whether patients with KRAS wild-type cancer should receive an anti-EGFR antibody with chemotherapy or an anti-VEGF antibody with chemotherapy. Two studies attempted to answer this question.[46,47]
Evidence (anti-EGFR antibody vs. anti-VEGF antibody with first-line chemotherapy):
On the basis of these two studies, no apparent significant difference is evident about starting treatment with chemotherapy/bevacizumab or chemotherapy/cetuximab in patients with KRAS wild-type metastatic colorectal cancer. However, in patients with KRAS wild-type cancer, administration of an anti-EGFR antibody at some point in the course of management improves OS.
Regorafenib is an inhibitor of multiple tyrosine kinase pathways including VEGF. In September 2012, the FDA granted approval for the use of regorafenib in patients who had progressed on previous therapy.
TAS-102 (Lonsurf) is an orally administered combination of a thymidine-based nucleic acid analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine, in its triphosphate form, inhibits thymidylate synthase; therefore, trifluridine, in this form, has an anti-tumor effect. Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase, which actively degrades trifluridine. The combination of trifluridine and tipiracil allows for adequate plasma levels of trifluridine.
TAS-102 was approved by the FDA for the treatment of metastatic colorectal cancer patients based on the results of the RECOURSE trial.
Approximately 4% of patients with stage IV colorectal cancer will have tumors that are microsatellite unstable; this designation is also known as microsatellite-high (MSI-H). The MSI-H phenotype is associated with germline defects in the MLH1, MSH2, MSH6, or PMS2 genes, and is the primary phenotype observed in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Patients can also have the MSI-H phenotype because one of these genes was silenced via a process called DNA methylation. Testing for microsatellite instability can be done with molecular genetic tests, which look for microsatellite instability in the tumor tissue or with immunohistochemistry, which looks for the loss of mismatch repair proteins.
In May 2017, the FDA granted approval for using pembrolizumab, a programmed cell death protein 1 (PD-1) antibody, in patients with microsatellite unstable tumors.
Second-line chemotherapy with irinotecan in patients treated with 5-FU/LV as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[53,54,55,56]
Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU/LV to bolus and infusional 5-FU/LV, single-agent oxaliplatin, or FOLFOX4. The median TTP for FOLFOX4 versus 5-FU/LV was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[Level of evidence: 1iiDiii]
Palliative radiation therapy,[11,56] chemotherapy,[13,58,59,60,61,62,63] and chemoradiation therapy [64,65] may be indicated. Palliative, endoscopically-placed stents may be used to relieve obstruction.
Treatment of Liver Metastasis
Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metachronous hepatic metastasis after resection of the primary tumor.[67,68,69] Although only a small proportion of patients with liver metastasis are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy administration provide a number of treatment options. These include the following:
Hepatic metastasis may be considered to be resectable based on the following factors:[70,71,72,73,74,75,55,76,77,78,79,80,81,82]
For patients with hepatic metastasis that is considered to be resectable, a negative margin resection has been associated with 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the North Central Cancer Treatment Group trial NCCTG-934653 (NCT00002575).[83,84,85,86,87][Level of evidence: 3iiiDiv] Improved surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of neoadjuvant chemotherapy.
Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.
Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[89,90,91,92,93,94,95] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.
The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain.
Evidence (adjuvant chemotherapy):
Additional studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone would provide results similar to hepatic intra-arterial therapy plus systemic treatment.
Intra-arterial chemotherapy after liver resection
Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.[78,98,99,100,101,102] Controversy regarding the efficacy of regional chemotherapy was the basis of a large multicenter phase III trial (Leuk-9481) (NCT00002716) of hepatic arterial infusion versus systemic chemotherapy. The use of combination intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation.
Increased local toxic effects after hepatic infusional therapy are seen, including liver function abnormalities and fatal biliary sclerosis.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Stage Information for Rectal Cancer
Updated staging information for 2017 (cited American Joint Committee on Cancer as reference 11).
Stages II and III Rectal Cancer Treatment
Editorial changes were made to this section.
Stage IV and Recurrent Rectal Cancer Treatment
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of rectal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Rectal Cancer Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Rectal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/colorectal/hp/rectal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389402]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2018-08-17
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