Treatment of rectal cancer

INTRODUCTION — The rectum is the section of the gastrointestinal system that connects the colon (large intestine) to the anus, where waste (fecal) matter passes out of the body (show figure 1). Like the colon, the rectum is part of the large intestine, and rectal and colon cancers are often referred to together as colorectal cancers. While the two conditions are part of the same disease process, the treatment of rectal cancer is different from colon cancer because of its unique anatomic location.

Like colon cancer, rectal cancer develops slowly over a period of years. Most cancers begin within a polyp, also called an adenoma. These are small growths of non-cancerous tissue that protrude from the lining of the large intestine. Over time, as these polyps grow, they can become cancerous and begin to invade the layers of tissue that form the wall of the rectum. At this point, they can spread to lymph nodes and to other organs such as the lung and liver, a process called metastasis.

RECTAL CANCER STAGING — Treatment and prognosis (outcome) depend upon the stage of the cancer. Staging of rectal cancer is based upon how far the cancer has penetrated into the wall of the rectum, whether the cancer has spread to lymph nodes located around the rectum, and whether the cancer has spread via the bloodstream to other organs (a situation called distant metastatic spread).

The initial evaluation of a rectal cancer usually involves a colonoscopy (a test in which a flexible tube with a camera is guided through the rectum and the rest of the colon). Abdominal and pelvic CT scans (specialized x-rays), and a chest x-ray are often recommended to look for evidence of cancer spread within the abdominal cavity and/or lungs. Other possible tests include a specialized rectal ultrasound or magnetic resonance imaging (MRI) scan.

The final stage of a rectal cancer is confirmed by the findings during surgery, which is the most accurate way to determine how far the tumor has spread.

There are two staging systems for rectal cancers: The TNM system (tumor, nodes, metastases) is most comonly used (show table 1) Less frequently, a modification of the Dukes system is used (show table 2)

A blood test for carcinoembryonic antigen (CEA, a substance produced by most colorectal cancers that circulates in the blood) should be obtained before a patient has his or her initial surgery. An elevated CEA level that does not return to a normal after surgery may be a sign of persistent disease and requires further evaluation.

RECTAL CANCER TREATMENT — The majority of rectal cancers are treated with a combination of surgery, radiation, and chemotherapy. Surgery alone may be curative for patients with stage I disease. For patients with stage II or III disease (see below), chemotherapy and radiation therapy are typically recommended following surgery (in which case, they are referered to as adjuvant therapy), or in some cases, before surgery (termed neoadjuvant therapy). Patients with stage IV (metastatic) rectal cancer are predominantly treated with chemotherapy, with or without surgery and radiation therapy. (See "Patient information: Treatment of metastatic colorectal cancer").

SURGERY — Regardless of the extent of the disease, surgery has an important role in treating rectal cancer. For patients with tumors that have not spread beyond the rectum ("localized disease"), surgery permits the removal of the cancerous part of the rectum and the associated lymph nodes, and the surgeon can examine the abdominal area directly for signs of cancer spread. Sometimes an operation to remove the cancerous tumor from the rectum is performed even in patients who have metastases (stage IV rectal cancer, show table 1). This is done to prevent bleeding and obstruction of the intestine, two problems that can be caused by an untreated enlarging rectal cancer.

Types of surgery — Surgical treatment for rectal cancer varies according to the extent of tumor involvement and the location of the cancer. For example, some rectal cancers are very small and limited to the surface of the rectal lining while others have grown through the entire rectal wall and are adherent (stuck) to nearby structures and organs, such as the abdominal or pelvic wall, the sacrum, the bladder, or the prostate gland. The extent of surgery that will be needed to remove these two tumors is very different.

In general, there are four types of operations: Transanal excision Low anterior resection (LAR) Abdominoperineal resection (APR) Pelvic exenteration

Most rectal cancers require an open surgical procedure, meaning that an incision is made through the abdominal wall to gain access to the lower intestine so the tumor can be removed (resected). However, some early tumors can be removed without an abdominal incision in a procedure called transanal excision.

Transanal excision — The simplest type of surgery for rectal cancer is done without an abdominal incision by inserting instruments though the anal opening. This method can be used for removing large polyps and for removing tumors that are small and located relatively close to the anus (show figure 1). Most rectal tumors that can be succesfully treated in this way are stage I, and have a favorable appearance when they are examined under the microscope by the pathologist (ie, they are moderately-well or well differentiated rather than poorly differentiated). This means that the tissue forming the tumor is forming or beginning to form normal gland structures.

Superficial rectal cancers (T1, show table 1) are the most suitable for local excision, although selected patients with T2 tumors may be eligible for this approach as well.

When a rectal tumor is removed through a local excision, the tissue will be analyzed under the microscope to determine if further surgery is needed, and whether postoperative (adjuvant) therapy, which usually consists of a combination of radiation and chemotherapy, will or will not be recommended. These treatments are discussed below.

Low anterior resection — If an open approach is needed, the surgeon may be able to remove the tumor while leaving the anus intact if the tumor is located high enough in the rectum. This operation is called a low anterior resection (LAR) and requires an abdominal incision. LAR is used whenever possible in order to preserve rectal function. After removing cancerous tissue, the remaining colon is connected to the lower rectum, or in some cases, the upper anus, and the patient is able to have bowel movements in a normal fashion.

Sometimes, a temporary ileostomy or colostomy (in which the small intestine or colon is brought out to the skin of the abdominal wall allowing passage of the stool into an external bag) is necessary to allow the connected tissues to heal. After six to eight weeks, the ileostomy or colostomy is closed, an external bag is no longer needed to collect the stool, and the patient is able to have bowel movements in a normal fashion (from their anus).

During the LAR procedure, the surgeon will also remove all the lymph nodes (also called lymph glands) associated with the rectum. It is important to remove the lymph nodes when treating cancer because one way that cancer cells travel through the body is by using the lymphatic system. Lymph nodes contain special cells that trap cancer cells, and removing them helps to ensure that cancer cells from the primary tumor in the rectum are not able to spread beyond the lymph nodes. The tissue removed from the lymph nodes will also be examined to help determine whether further treatment is needed after surgery. A sufficient number of lymph nodes must be removed by the surgeon (typically at least 12) so that the pathologist can reliably determine whether nodal spread has occurred or not.

Abdominoperineal resection — Similar to the LAR, an abdominoperineal resection (APR) requires an abdominal incision and also requires an incision to remove the anus. This results in the need for a permanent colostomy (see "Life with a colostomy" below). The APR is used when tumors cannot be completely removed using LAR, most commonly because the tumor is too close to the anus. To remove enough surrounding tissue to ensure that the cancer is completely resected, the surgeon must remove the anus as well (show figure 2). During an APR, the lymph nodes in the vicinity of the rectum are removed, just as in the LAR.

Pelvic exenteration — If a cancer has invaded nearby organs, a more extensive operation may be needed. In this situation, it is often possible for the surgeon to remove a part of certain organs such as the bladder. If the function of these organs cannot be saved because of the extent of tumor involvement, the entire organ may need to be removed. Rarely, all of the tissues and organs within the pelvis (including the bladder, prostate [in men], and/or uterus [in women]), must be removed in order to successfully treat the cancer, a major operation called pelvic exenteration.

Most often, patients undergoing this procedure require a permanent colostomy. If the bladder is removed, the patient may also need a urostomy, an artificial opening on the front of the abdomen that allows urine to leave the body. Pelvic exenteration can cause a number of complications and may not result in a cure due to the widespread nature of the cancer.

For many patients with locally advanced rectal cancer, an alternative to pelvic exenteration is the administration of chemotherapy and radiation therapy before surgery. This can often shrink the tumor, allowing the surgeon to perform an LAR, an APR, or a more extensive operation, depending on how much cancer remains after chemotherapy and radiation therapy. This type of therapy is discussed in more detail below. (See "Preoperative (neoadjuvant) chemotherapy and radiation" below).

BOWEL FUNCTION AFTER SURGERY — Bowel function following rectal cancer surgery depends upon the specific operation that was performed and whether radiation therapy was also used (see below). Following a LAR, many patients experience initial difficulty with bowel control even if the anal sphincter (the valve that controls elimination of stool) has been preserved. You may feel a sense of bowel urgency and need to pass stool frequently. For most patients, bowel function improves over time, but it may not return to presurgery levels.

Patients in whom the connection between the colon and the anus was made very close to the anal opening have very little "rectal reservoir," or room, to store fecal matter before needing to move the bowels. These patients may have an increased frequency of bowel movements and some difficulty with evacuation (emptying the bowels). Sometimes a larger reservoir can be created out of the colon (colonic J Pouch) prior to connecting it to the lower rectum or anus. This provides more space to store fecal matter, and can result in better bowel function.

Life with a colostomy — Having a colostomy can alter a patient's body image, and this may be challenging, both physically and emotionally. However, with education and support about living with a colostomy, it is possible to lead an active life. A team effort that includes the colorectal surgeon, oncologist, and an enterostomal therapy (ET) nurse is vital to counsel and educate a patient and their family before surgery, and also in the care and rehabilitation following the procedure. The United Ostomy Associations of America is also a good source of information and support (www.uoaa.org).

CHEMOTHERAPY AND RADIATION — Chemotherapy and radiation therapy are recommended in addition to surgery for most patients with stage II or III rectal cancer. These treatments improve the likelihood of surviving the cancer. Even when all visible signs of cancer have been removed by the surgeon, between 20 and 50 percent of patients will have a recurrence of their cancer if it is treated with surgery alone.

One reason for this relatively high recurrence rate is that the area of the pelvis in which the rectum is located is a "tight space" and it is often difficult for the surgeon to remove a sufficient amount tissue around the tumor; this means that all of the cancer cells in the surrounding tissue may not be removed. In addition, tiny cancer cells may have "escaped" from the lymph nodes and spread to other organs. The combination of chemotherapy and radiation helps to reduce the chance of recurrence by targeting any remaining cancer cells.

There are two general ways to administer chemotherapy and radiation in patients who have rectal cancer:

Postoperative therapy — Postoperative (adjuvant) therapy is typically recommended for patients who have already undergone surgery. A commonly used treatment protocol (regimen) is as follows [1,2]: Two monthly courses of chemotherapy with the anticancer drug 5-fluorouracil (abbreviated 5-FU) given five days in a row, once per month. This is followed by: Radiation therapy over a five- or six-week period. During this time, a continuous intravenous infusion of 5-FU is administered. This approach requires that patients have a central venous access catheter (often termed a port) surgically inserted into one of the large blood vessels in the chest, and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is very small, battery-operated, and fits into a fanny pack that patients can wear around their waist to allow freedom of movement during therapy. Two further courses of chemotherapy with 5-FU given five days in a row, once per month.

For patients in whom ambulatory infusion pump therapy is not feasible, an alternative method of combining chemotherapy with radiation is to give one large dose (bolus) of 5-FU given into a vein in the arm for three days during the first and last weeks of radiation therapy. However, treatment-related toxic side effects may be greater with this approach [3]

Another increasingly popular alternative is to give a daily oral dose of the drug Xeloda (capecitabine). Although this regimen is more convenient for the patient, it has not yet been proven to be equivalent to therapy with infusional 5-FU.

Benefits — The use of combined chemotherapy and radiation after surgery reduces the risk of dying of rectal cancer by about 30 percent [4]. This benefit is relatively large, and as a result, adjuvant therapy with both chemotherapy and radiation is considered a standard approach in patients following rectal cancer surgery if the tumor involves the lymph nodes (stage III) or has grown through the entire bowel wall (stage II).

Preoperative (neoadjuvant) chemotherapy and radiation — Although often given after surgery, chemotherapy and radiation may be offered to a patient prior to the rectal operation, most commonly if the tumor is large or located low in the rectum. This is called neoadjuvant chemoradiotherapy. The purpose of such an approach is to try to shrink the tumor before the operation is performed.

Research indicates that, compared to the postoperative approach, neoadjuvant chemoradiotherapy provides better local control of the tumor, a twofold higher chance of avoiding a permanent colostomy, and fewer side effects of radiation, with no detrimental impact on survival [5].

The administration of chemotherapy in addition to radiation therapy is critical to the success of the approach. As in the postoperative setting (described above), the most common approach for preoperative chemotherapy and radiation is the administration of continuous intravenous 5-FU with an ambulatory infusion pump during the radiation.

An increasingly popular alternative to infusional 5-FU during radiation is to give a daily dose of oral Xeloda during radiation therapy, largely because it is more convenient for the patient. Although guidelines from the National Comprehensive Cancer Network (NCCN) endorse this approach as an acceptable alternative to infusional 5-FU, no study has shown that long-term outcomes are equivalent. Studies are underway to help answer this question.

Patients who undergo neoadjuvant chemotherapy and radiation therapy should receive an additional six months of chemotherapy alone after surgery. There are several reasonable options, including: Single agent 5-FU alone, given intravenously daily for five days every four weeks Oral therapy with the drug capecitabine (Xeloda®) A combination of 5-FU and leucovorin (with both drugs given once weekly for six of every eight weks) The addition of a third drug (oxaliplatin) to 5-FU and leucovorin (a regimen that is abbreviated FOLFOX)

Side effects — Both radiation and chemotherapy can cause side effects, particularly when used together.

Chemotherapy — The most common side effects with 5-FU are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. When 5-FU is given continuously, it can cause "hand-foot syndrome", which causes soreness, redness and peeling of the skin of the palms and soles of the feet. Supplemental vitamin B6 (also called pyridoxine) may provide benefit in this situation.

Orally active 5-FU derivatives like Xeloda® share the same side effects as intravenous 5-FU, although diarrhea and mucositis is less common with Xeloda® while hand-foot syndrome is somewhat more common.

Most patients tolerate chemotherapy reasonably well and many are able to continue working during treatment, often with a reduced schedule of hours due to fatigue. Hair loss is an uncommon side effect of the chemotherapy drugs used for rectal cancer.

Combined chemotherapy and radiation — Possible side effects of 5-FU and radiation include diarrhea, irritation or inflammation of intestinal tissue leading to a sense of bowel urgency, bleeding and discomfort in passing stool, and skin irritation around the anus.

PROGNOSIS — Each patient with cancer is different, and it is impossible to predict what to expect in the future. Both before and after cancer treatment, it is important to discuss ongoing management, lifestyle changes, and future treatment options.

Prognosis generally depends upon the stage of the cancer at the time that it is removed. Cancer that is identified and treated early has the best prognosis. The likelihood of dying is greater with increasingly advanced cancer. The average five year survival by stage is approximately [6]: Stage I — 66 to 78 percent Stage II — 55 to 62 percent Stage III — 31 to 42 percent

FOLLOW-UP AFTER TREATMENT — The term surveillance refers to the follow-up testing after surgery for colon cancer that is performed to detect a cancer recurrence or a new colorectal cancer. The following are recommendations for posttreatment surveillance (show table 3) [7]. Patients should see their clinician every three to six months for the first three years and then yearly thereafter. A medical history is done to determine if there have been signs or symptoms suggestive of a cancer recurrence. The physical examination should include a rectal examination for patients who have undergone low anterior resection. A blood test for carcinoembryonic antigen (CEA, a substance produced by most colon cancers that circulates in the blood) should be obtained every one to three months in patients with stage II and III disease for at least the first three years after primary resection. An increase in the CEA may be the first sign of a recurrence of the cancer. This is true even if preoperative CEA levels were normal.

The CEA level can help to detect recurrences that might be amenable to further curative surgery. Thus, periodic CEA levels may not be necessary in patients who would not be able to undergo resection for a recurrent cancer. All patients with rectal cancer should undergo a complete colonoscopy either before surgical resection or within a few months after resection. This will exclude polyps and other cancers that may be present in other areas of the colon. (See "Patient information: Colonoscopy").

An additional screening colonoscopy is recommended one year later to evaluate for polyps or new cancers [8]. If none are detected, the next colonoscopy is recommended in three years, and then every five years thereafter. Any symptoms or laboratory values that suggest recurrence require immediate colonoscopy. For patients who have had an abdominopelvic resection, colonoscopy is performed through the colostomy. For patients who have undergone low anterior resection for rectal cancer, flexible sigmoidoscopy (scope examination of just the lower part of the intestine) is recommended every six months for five years for patients who have not received pelvic radiation therapy. Flexible sigmoidoscopy is not needed for patients who have received pelvic radiation therapy. (See "Patient information: Flexible sigmoidoscopy"). The 2005 American Society of Clinical Oncology guidelines suggest that patients with stage II or III should have an annual CT scan of the chest and abdomen for three years. If radiation was not administered, an annual pelvic CT scan is also recommended for the first three years after treatment [7]. As with the CEA levels (see above), CT scans are used to detect recurrences that might be treatable with further surgery. Thus, periodic CT scanning may not be necessary in patients who would not be able to undergo surgery for a recurrent cancer.

If the CEA becomes elevated or the patient develops symptoms that are worrisome (eg, abdominal pain, bloating, inability to pass stools), an abdominal CT is recommended to determine if there are metastases.

The following tests are not necessary for routine surveillance: Testing for microscopic amounts of blood in the stool (guiac or stool cards) Liver function tests (a panel of blood tests) Complete blood count (a blood test) Yearly chest x-ray

OPTIONS FOR RECURRENT CANCER — If a rectal cancer recurs in the area of the rectum, the best therapy is determined by several factors, including what treatments were used previously and where the new cancer is located. Treatment options are similar to those for primary tumors, and include surgery, chemotherapy, radiation therapy.

The treatment of patients with advanced rectal cancer depends upon the extent and location of the tumor involvement. Although the majority of patients cannot be cured by any therapy, some patients with limited involvement may be cured by further surgery. In other cases, chemotherapy is the best option. (See "Patient information: Treatment of metastatic colorectal cancer").

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


IMPLICATIONS FOR THE FAMILY — A diagnosis of rectal cancer can be devastating for the patient and also for their family. The best way to cope with all of these issues varies from person to person and among families. Do not underestimate the importance of good support; it is something that each patient should discuss with their healthcare team.

An important issue for close relatives (siblings, parents, or children) of a person with colorectal cancer is the risk of developing colon cancer themselves. This also applies to family of persons with specific types of polyps, called adenomatous polyps.

Relatives should understand the following information: People who have one first-degree relative (parent, brother, sister, or child) with colorectal cancer or adenomatous polyps at a young age (before the age of 60 years), or two first-degree relatives diagnosed at any age should begin colon cancer screening earlier, typically at age 40, or 10 years younger than the earliest diagnosis in their family, whichever comes first, and screening should be repeated every 5 years. (See "Patient information: Screening for colon cancer"). People who have one first-degree relative (parent, brother, sister, or child) who has experienced colorectal cancer or an adenomatous polyps at age 60 or later should begin screening at age 40, and screening should be repeated as for average risk people. People with a second-degree relative (grandparent, aunt, or uncle) or third-degree relative (great-grandparent or cousin) with colorectal cancer are screened as average-risk people.

Some conditions (such as hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis) are associated with an even higher risk of colonic polyps or cancer in family members, and require more aggressive screening for family members. Patients and their family should discuss these issues with a healthcare provider who is experienced in these areas.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute

1-800-4-CANCER
(www.cancer.gov)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
The American Gastroenterological Association

(www.gastro.org)
The American College of Gastroenterology

(www.acg.gi.org)


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