Colorectal cancer is the second leading cause of cancer deaths in the United States and the third leading cause of cancer deaths worldwide. Cancer of the large bowel, or colon and rectum—the last 4 to 6 feet (1 to 2 m) of the intestine—is a highly treatable and often curable disease when it is localized and diagnosed in its early stages. But when it spreads through the bowel wall to lymph nodes or nearby organs, the chances for cure are reduced.
Ten percent of all cancers in the United States involve either the colon or the rectum, which accounts for an overall lifetime risk for this cancer of 6 percent (one out of every seventeen Americans). An estimated 153,760 colorectal cancers will be diagnosed in 2007, 112,340 in the colon and 41,420 in the rectum. Colorectal cancer is the third most common cancer in both men and women and is second only to lung cancer as a cause of cancer deaths in the United States (accounting for 10 percent of all cancer deaths, with 55,170 deaths per year). Worldwide, approximately 1 million new cases of colorectal cancer are diagnosed each year.
These tumors may be common because about half the population over forty are thought to have clumps of tissues protruding from the inner layer (mucosa) of the colon or rectum. These mushroomlike growths are called polyps, and while most are benign, at least one type—adenomatous polyps—may be a precursor to cancer. About 90 percent of colorectal cancers are thought to arise from these polyps, and a person with a colorectal adenoma runs a threefold risk of developing colorectal cancer.
The rectum is the final 5 inches (12 cm) of the colon above the anus. However, while the colon and the rectum look similar and are connected to each other, there are major differences in the way colon and rectal tumors are treated.
Colorectal cancer is primarily a surgical disease; almost 50 percent of all patients can be cured with resection alone. In addition, long-term survival can be improved by using adjuvant chemotherapy in patients with colon cancer and chemoradiation in patients with cancer of the rectum. The chance for cure and the role of adjuvant therapy after resection is related to how far the tumor has invaded through the bowel wall and to whether or not it has spread to the nearby lymph nodes. For patients whose lymph nodes are invaded by cancer, tumor recurrence after surgery is a significant problem. Recurrent cancer is the ultimate cause of death in one-third of cases.
Types Most colorectal cancers develop in the glands of the inner lining, or mucosa, and are called adenocarcinomas. Other kinds of tumors, such as lymphomas, melanomas, squamous cell carcinomas, sarcomas, and carcinoids, occur much less frequently (less than 5 percent).
How It Spreads Colorectal cancer spreads directly from the mucosa, or inner lining, through the muscle wall of the bowel and into adjacent tissues. The tumor may metastasize through the lymphatic system to nearby lymph nodes, to the liver through the portal vein, and, less frequently, via the bloodstream to the bones or lungs.
What Causes It Environmental factors thought to contribute to the development of colorectal cancer include diet (high in saturated fat, low in fiber, and possibly low in calcium) and lack of exercise. It is most common in industrialized countries with high standards of living. It is becoming more common in Japan as consumption of fat increases. Recent data suggest that aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) may reduce colorectal cancer (possibly by reducing the incidence of colorectal adenomatous polyps). This has led to interest in using these agents to prevent colon cancer.
About 10 percent of all colorectal cancers can be attributed to an inherited cancer syndrome. One percent of colorectal cancers is related to an inherited condition called familial polyposis, in which multiple polyps begin to appear in childhood and adolescence. Given enough time, most affected individuals will develop cancer.
Several genetic factors linked to colorectal cancer have been found. Ras gene mutations, largely in the k-ras gene resulting from environmental causes rather than being passed on genetically, are found in half of all people with colorectal adenomas and cancers. The tumor-suppressor gene p53 on chromosome 17 seems to be inactivated in most cases. A second tumor-suppressor gene has been found on chromosome 18, and other genetic abnormalities have been found on chromosome 5. These may be important for tumor suppression. Once a colon cell has one of these chromosome changes, other “hits” to the cell may cause polyps and then cancers to develop. Defective mismatch repair genes, MLH1, MSH2, and MSH6, which are responsible for repairing errors that occur during DNA replication, are responsible for up to two-thirds of the inherited forms of colon cancer. When these genetic defects are identified in a patient with cancer, family members can be screened and tested to determine if they are at increased risk for the disease and are therefore in need of more intensive cancer screening.
Colon and rectal cancers
Risk Factors
At Significantly Higher Risk
•Advanced age. 90 percent of colorectal cancers occur in people over the age of fifty.
•Male sex. Men are more likely to develop colorectal cancer than women, although the disease remains common in women, too. The risk of cancer in a fifty-year-old man equals the risk in a sixty-year-old woman.
•Family history of colorectal cancer, especially among first-degree relatives. Patients with one affected first-degree relative have two to three times the risk of an average person.
•Inherited cancer syndromes, including
•hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome—patients in this group are also at increased risk for other tumors, such as adenocarcinomas of the ovary, endometrium, breast, and pancreas—and
•familial adenomatous polyposis (FAP)—affected patients develop hundreds of intestinal polyps as early as age ten, and almost all patients will go on to develop invasive colorectal cancer unless a prophylactic colectomy is performed.
•Personal history of benign polyps of the colon or rectum. Personal history of cancer of the ovary, endometrium, or breast is also a risk factor.
•Personal history of inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease). Patients with ulcerative colitis have a risk of colon cancer that is about five times the average. Cancer may also develop in the flat surface of the mucosa rather than in polyps.
•Personal history of pelvic radiation.
•Diets high in fat and low in fiber and calcium. Animal rather than vegetable fat is believed responsible. One study indicated that women who eat red meat (beef, lamb, and pork) daily have 2½ times the risk of those who eat red meat less than once a month. Those eating fish and chicken without the skin are at lesser risk.
•High consumption of charcoal-broiled foods; smoking; heavy alcohol consumption; and inadequate dietary intake of fruits and vegetables.
•Obesity and inactivity.
•African-Americans.
•Certain medical conditions, including non-insulin-dependent diabetes mellitus.
At Lower Than Average Risk
•Seventh-Day Adventists, lacto-vegetarians who do not drink alcohol or smoke, and Mormons, who abstain from alcohol, tobacco, coffee, and tea and eat meat in moderation.
•Mediterraneans.
•Hispanics.
•People that regularly use aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs).
•Regular intake of folic acid and calcium and hormone replacement in postmenopausal women may also be protective.
Screening
Death from colorectal cancer is highly preventable. Likely over 80 percent of colorectal cancers are preventable by use of screening tests. Screening has the capability of detecting precancerous polyps and removing them via a colonoscope before cancer ever occurs. Even if cancer does occur, colorectal cancer is highly curable in the early stages, and cancers detected at screening are much more likely to be in a curable stage. Several techniques for prevention/early detection are recommended and are widely available. These apply to the general population but are especially recommended for people at high risk (patients with first-degree relatives with colorectal cancer or other high-risk features). Several large studies have conclusively shown that screening decreases the mortality from colorectal cancer. However, only a minority of the population is undergoing regular colorectal cancer screening.
The American Cancer Society recommends that average-risk adults begin colorectal cancer screening at age fifty, with one of the following options: (1) annual fecal occult blood test (FOBT) or fecal immunochemical test (FIT); (2) flexible sigmoidoscopy every five years; (3) annual FOBT or FIT, plus flexible sigmoidoscopy every five years (this option is preferred over either procedure alone); (4) double-contrast barium enema (DCBE) every five years; (5) colonoscopy every ten years. Emerging data suggest that a special computerized tomography (CT) scan of the colon (CT colonography or virtual colonoscopy) may be an adequate or even superior replacement for the DCBE.
About 4 percent will have a positive hidden-blood test (FOBT or FIT), and anywhere from 20 to 50 percent of these will be positive for polyps or cancer (10 percent will have cancer, and 20 to 30 percent will have adenomas). The likelihood that a single use of the test will be positive in a patient with a large polyp or cancer is only 20 to 40 percent. False negatives are high because colorectal cancers bleed intermittently and the test may be done between bleedings. The chance of a false negative test can be reduced by repeating the test regularly (every year or every other year). A false positive test is common, with only 5 to 10 percent of individuals with a positive test being found to have a cancer or very large polyp. The false positive rate can be reduced by not consuming red meat and avoiding foods high in vitamin C and iron—cantaloupe, broccoli, parsnips, cauliflower, mushrooms, potatoes, cucumbers, red radishes, and horseradish—for twenty-four hours before the test. Immunochemical tests for occult blood (FIT) have fewer false positive and negative results, but they are more expensive and not widely used. Many physicians take the opportunity to do a FOBT on stool obtained during a routine digital rectal exam. However, studies have shown that the likelihood of one-time testing identifying a colorectal cancer is very low. Therefore, while convenient, one sample, in-office FOBT is not recommended for colorectal cancer screening. Any one positive test (FOBT or FIT) should be followed up with a full colonoscopy.
The sigmoid colon and rectum should be examined with a flexible or rigid tube (sigmoidoscopy) every five years after age fifty. Alternatively, one can undergo a colonoscopy to examine the entire colon every ten years or a double-contrast barium enema every five years starting at the age of fifty. It takes about ten years for an adenomatous polyp to grow to the size where a cancerous change may occur. Both fecal occult blood tests and flexible sigmoidoscopy (combined with endoscopic or surgical removal of polyps) have been shown to substantially decrease colon cancer mortality in large studies. The National Polyp Study showed that colonoscopy and removal of polyps reduces the incidence of colorectal cancer by 76 to 90 percent. Measuring the level of the carcinoembryonic antigen (CEA) in the blood can sometimes detect an early recurrence after removal of a tumor, but it is not a good test for screening.
When the family history suggests the presence of a hereditary syndrome, genetic studies can be used to screen for people at high risk for developing colorectal cancer in selected cases. Other tests currently under investigation include stool DNA testing, but this test is not routinely recommended for screening at this time
Screening is costly but may be effective. Finding colorectal cancer before it invades tissues or spreads to lymph nodes will improve the cure rate. The American death rate from this cancer fell 5.5 percent from 1973 to 1985, but there are still 54,900 deaths per year.
Early Detection
Each person should be aware of the cancer early-detection guidelines that pertain to him or her. To understand the role of the cancer-related checkup, the American Cancer Society has adopted the following definitions: Screening is the search for disease in persons without symptoms. Once a person has had a positive screening test, or once signs or symptoms have been identified, further tests are considered diagnostic. Detection is the discovery of an abnormality in a person with or without symptoms. Diagnostic evaluation is the evaluation of a patient who has signs or symptoms suggestive of disease to determine the actual existence and nature of the disease.
American Cancer Society Colorectal Cancer Screening GuidelinesBeginning at age fifty, both men and women should follow one of these five testing schedules:• Yearly fecal occult blood test (FOBT)* or fecal immunochemical test (FIT)• Flexible sigmoidoscopy every five years• Yearly FOBT or FIT, plus flexible sigmoidoscopy every five years**• Double-contrast barium enema every five yearsPeople should talk to their doctors about starting colorectal cancer screening earlier and/or undergoing screening more often if they have any of the following colorectal cancer risk factors:• A personal history of colorectal cancer or adenomatous polyps• A strong family history of colorectal cancer or polyps (cancer or polyps in a first-degree relative [parent, sibling, or child] younger than sixty)• A personal history of chronic inflammatory bowel disease• A family history or genetic testing indicating the presence of a hereditary colorectal cancer syndrome (e.g., familial adenomatous polyposis or hereditary nonpolyposis colon cancer)*For FOBT, the take-home multiple sample method should be used.**The combination of yearly FOBT or FIT and flexible sigmoidoscopy every five years is preferred over either of these options alone. All positive tests should be followed up with colonoscopy.
Common Signs and Symptoms
Colon cancer symptoms depend on the location of the tumor. Cancers of the larger and more pliable right colon frequently bleed, causing anemia, but do not usually block the colon because the stool is still liquid in the right side of the colon. Cancers in the left colon may obstruct the bowel, causing a change in bowel habits (including diarrhea and constipation) and in stool size. There may be dark red rectal bleeding, or stools that are long and narrow.
Cancers in the rectum often cause an obstruction, causing a change in bowel habits (including constipation and a feeling that the bowel does not empty completely) and in the size of stools, which may also become long and narrow. There may also be rectal bleeding. Other symptoms include abdominal or pelvic pain, gas, bloating, vomiting, persistent constipation or diarrhea, weight loss, and weakness. Pain is a worrisome problem with rectal cancer, since it often means the tumor is growing into nerves.
Diagnosis
The evaluation of someone suspected of having colorectal cancer is variable but generally includes a physical examination, blood work, and radiographic imaging to assess the extent of disease.
Physical Examination
•General survey of the body.
•Digital rectal examination to feel for lumps.
•Abdominal exam to check for a mass or an enlarged liver (hepatomegaly).
•Exam to rule out enlarged lymph nodes over the left collarbone and in the groin (inguinal) area.
Blood and Other Tests
•Test for hidden blood in the stools (stool tests for bleeding may be negative in half of colorectal cancer cases).
•Complete blood count (CBC) to check for anemia.
•Blood chemistry tests to evaluate the liver enzymes (often elevated in the setting of liver metastases).
•Blood test for carcinoembryonic antigen (CEA), a serum tumor marker that may be elevated with primary or recurrent colorectal cancer. Very high levels of CEA may indicate more advanced disease. The CEA level should be measured before surgery and, if elevated, periodically (every three to six months) after surgery.
•Other laboratory tests may include creatinine (to assess kidney function), albumin (to assess nutritional status), and serum iron studies (to evaluate for the presence of blood loss/anemia).
Imaging
•Barium enema X-ray (also called a lower GI series)—often done in combination with a flexible sigmoidoscopy.
•Ultrasound of the abdomen—sometimes done to assess for disease outside the colon or rectum.
•Endorectal ultrasonography and/or pelvic MRI scan—often performed to assess for local extension or lymph node involvement in patients with rectal cancer. Ultrasound done via the rectum (endorectal) can accurately show tumor invasion and enlarged lymph nodes outside the rectum, but cannot indicate if enlarged lymph nodes actually contain metastatic tumor.
•Abdominal/pelvic computed tomography (CT) scan—to identify the extent of disease.
•Chest X-ray—to rule out lung metastases.
•PET (positron-emission tomography) scanning—can help identify possible tumor sites by measuring differences in sugar metabolism in different sites throughout the body. When a patient is suspected of having colorectal cancer, a PET scan can sometimes help differentiate between benign and malignant sites of disease. However, PET scans are not routinely performed in all patients. Instead, PET scans are more commonly used to identify occult metastases in patients previously treated for colorectal cancer in whom the CEA is elevated.
Endoscopy and BiopsyColonoscopic examination of the entire colon with a biopsy of any suspicious mass. A biopsy is important to confirm the diagnosis of colorectal cancer. While most colorectal cancers are adenocarcinomas, other tumor types occasionally occur in the bowel. An examination of the entire colon is important because multiple cancers or polyps occur in a minority of patients. The surgeon needs this information to assist planning for surgical resection. (Note that if a patient presents with a complete obstruction, then a double-contrast barium enema [or computed tomography colonography/virtual colonoscopy] should be done preoperatively if possible, and a complete colonoscopy should be performed three to six months after surgery to rule out additional polyps or primary tumors.)
Other Cystoscopy (or IVP, intravenous pyelogram)—sometimes required preoperatively in patients with rectal cancer to rule out involvement of the bladder.
Staging
The stage of colorectal cancer reflects whether the cancer has remained within the bowel or has spread to other sites. As with all cancers, defining the exact stage of disease is an important step toward identifying the appropriate therapy.
A number of different staging systems for colorectal cancer have been employed over the past century. The original system developed by Dr. Dukes in 1932 has been modified several times. Since 1985, a staging system based on the tumor/nodes/metastasis (TNM) classification has been used. This staging system corresponds to the Dukes classification scheme but is thought to be more informative. The 1990 National Cancer Institute Consensus Panel recommended using the TNM system to identify people at high risk for recurrence because it incorporates the tumor size and degree of invasion, as well as the number of lymph nodes involved. The TNM staging system is described in more detail in the next section and was recently modified to subclassify traditional Stage II and III patients into distinct prognostic groups.
Treatment Overview
Colorectal cancers are primarily treated surgically, resulting in cures in 50 to 60 percent of patients. The type and extent of surgical resection are determined by the precise location of the tumor. In addition to surgery, depending on the stage of the tumor, adjuvant chemotherapy for colon cancers and chemoradiation therapy for rectal cancers increase survival. In patients with metastatic colorectal cancer, chemotherapy extends survival, radiation is used to palliate symptoms, and the utility of several new biologically based agents (targeting specific properties of cancer cells or tumors in general) has been established.
The approach to treatment is different in patients with rectal cancer compared to patients with colon cancer. This relates to the location of the rectum in the pelvis and the fact that the rectum lacks the covering layer present in the colon (the serosa), both of which factors contribute to a higher rate of local recurrence. Most researchers believe that adjuvant radiotherapy alone decreases the risk of local recurrence in patients with rectal cancer without improving survival. In contrast, combined radiotherapy and chemotherapy increases the disease-free survival in patients with rectal cancer more than radiation alone and improves long-term survival as well. The prognosis of rectal cancer depends on how far the tumor has penetrated through the bowel wall or into adjacent structures and on whether the cancer has spread to local lymph nodes. After surgery alone in node-negative patients with rectal cancer, local recurrence is 5 to 10 percent for Stage I patients and 25 to 30 percent for patients with Stage II disease.
Recent studies indicate that the number of local lymph nodes involved is important. When one to four nodes are involved, survival is significantly better than if more than four nodes are involved.
Additional poor prognostic factors for both colon and rectal cancers include
•penetration through the bowel wall,
•perforation or obstruction,
•high histologic grade under the microscope,
•mucinous (colloid) histologic subtype,
•invasion of the blood vessels, lymphatics, or nerves under the microscope, and
•high DNA content or aneuploidy.
Several features suggest an unfavorable outcome in patients with rectal cancer:
•Fixed, nonmobile tumor or invasion of or adherence to other parts of the pelvis or adjacent tissues.
•Deep ulceration.
•The tumor penetrates through the bowel wall or encircles the rectal wall.
•The radial margin is positive after resection.
•The tumor is larger than 2½ inches (6 cm).
Other features portend a poor prognosis in patients with colon cancer:
•Involvement of abdominal nodes.
•Involvement of adjacent organs.
•The level of carcinoembryonic antigen (CEA) in the blood is high before surgery.
Thus, the prognosis (chance of recovery) in a given patient depends on multiple factors, including the stage of the tumor, whether the cancer has blocked or created a hole in the colon or rectum, the blood levels of carcinoembryonic antigen before treatment begins, whether the cancer has recurred, and the patient’s general health. In each case, all of these factors are integrated to determine the final treatment plan.
ColonSurgery Tumors of the colon should be removed whenever practical in an effort to prevent complications such as blockage of the bowel and bleeding from developing. Because of the potential problems related to leaving the primary tumor in place, surgery should even be considered in patients with metastatic disease. However, recent advances in the treatments available for patients with distant spread have reduced the imperative to remove the primary tumor in asymptomatic individuals.
The standard operation is designed to remove the affected portion of the bowel along with the entire lymph node drainage. This requires removing the vessels that supply blood to a considerable portion of the bowel, so most of the time about one-third to one-half of the colon is removed even if the tumor itself is relatively small. After removal of the cancer and a length of normal tissue on either side of the tumor, the remaining sections of the colon are reconnected (anastomosis). Recent data suggest that in some cases, a laparoscopically assisted (minimally invasive) colectomy may be an acceptable alternative to an open surgery for colon cancer when performed by a qualified surgeon. A laparoscopically assisted procedure should not be considered in the setting of acute obstruction or perforation, rectal or transverse colon tumor, prohibitive abdominal adhesions, or locally advanced disease.
Sometimes reconnecting the bowel is not possible after tumor resection because there is too much stool or contamination in the area. This occurs most commonly in patients who have tumors in the left side of the colon and who presented with a partial or complete obstruction. These patients receive a temporary colostomy, which can be reversed as soon as six to ten weeks later (see this post, “Living with an Ostomy”).
Local excision may be used for the removal of polyps in most cases.
Radiation Therapy Radiation therapy has a limited role in the treatment of colon cancer. In selected cases, radiotherapy may help reduce local recurrences. Palliative radiation is primarily used for localized metastatic tumors.
Chemotherapy More than 50 percent of patients with colon cancer have tumors that penetrate the serosa (T3) or have positive lymph nodes (N1–3). Interest in adjuvant therapy stems from the fact that roughly 20 to 25 percent of those with Stage II disease and 50 percent of those with Stage III cancer have recurrences if treated with surgery alone.
Adjuvant therapy is controversial in patients with Stage II disease, as randomized clinical trials have failed to establish a clear benefit. While routinely offered to individuals perceived to be at relatively high risk for recurrence, participation in clinical trials should be encouraged for patients with Stage II disease. In contrast, adjuvant chemotherapy is of proven value in patients with Stage III colon cancer (positive lymph nodes), decreasing both the risk of recurrence and death. Fluorouracil (5-FU)–based chemotherapy (often in combination with oxaliplatin [Eloxatin]) has emerged as the standard therapy in this setting and is generally given for a total of six months. While it has no direct antitumor activity, leucovorin (LV) is often added to 5-FU–based chemotherapy because it increases the activity of 5-FU. Clinical trials exploring additional regimens are ongoing.
Patients with metastatic disease limited to the liver, pelvis, or lungs should be evaluated for resection. In general, metastatic colon cancer is incurable unless resected completely, in which case the five-year survival approaches 30 percent. For decades, 5-FU combined with leucovorin was the mainstay of therapy for patients with unresectable metastatic disease in spite of limited response rates (15 to 20 percent) and the lack of a significant impact on survival.
The results of several recent studies have changed our approach to the treatment of patients with advanced disease. Infusional 5-FU is better tolerated than bolus 5-FU and is somewhat more efficacious. Capecitabine (Xeloda), an oral 5-FU prodrug, is associated with continuous infusion-type pharmacokinetics and is likely to replace infusional 5-FU in the future. Treatment is associated with less diarrhea and bone marrow suppression than bolus 5-FU, but palmar-plantar-erythrodysesthesia is more common (hand-foot syndrome) and consists of pain, redness, and rash involving the hands and feet. Furthermore, the addition of irinotecan (Camptosar, CPT-11), oxaliplatin, and/or bevacizumab (Avastin; an antiangiogenic agent) increases the chance of tumor shrinkage (response rate) and prolongs overall survival compared to 5-FU/leucovorin alone. Combination chemotherapy is associated with increased toxicity, however, and the optimal drug sequence and regimens have not yet been defined. Thus, the current approach to the treatment of patients with advanced disease involves individualizing therapy after integrating symptoms (e.g., from primary tumor versus metastases), other medical conditions, and patient/physician preference. Participation in clinical trials should be encouraged.
Depending on the choice of agent in the first-line setting, oxaliplatin or irinotecan can be used in patients with 5-FU–refractory disease. Biologically based agents like the antiangiogenic agent bevacizumab and the epidermal growth factor inhibitors cetuximab (Erbitux) and panitumumab (Vectibix), also play a role in the treatment of patients with chemotherapy-refractory disease.
Colon Cancer Treatment by Stage
Stage 0
TNM Tis (tumor or carcinoma in situ), N0, M0
This is a very early cancer that is found only in the innermost lining of the colon; it has not spread below the limiting membrane of the first layer of colon tissue (mucosa).
Standard Treatment Local excision of the tumor or polyp is sometimes sufficient. Standard surgery, however, involves removing the tumor along with at least 2 inches (5 cm) of normal colon on either side of the tumor site, and the nearby lymph nodes and veins. Because of the way blood is supplied to the colon, it is usually necessary to remove either the entire right side or the entire left side of the colon. This decreases the chance for local recurrence and increases the safety of the operation.
Five-Year Survival 95 percent
Stage I (Dukes’ A, B1)
TNM T1–2, N0, M0
The cancer has spread beyond the innermost tissue layer of the colon to the middle layers; it is confined to the lining or muscular wall of the colon and has not yet spread anywhere else.
Standard Treatment This stage is highly curable. Radical surgery is the primary treatment and results in a high cure rate. No adjuvant therapy is warranted for this stage because of the low risk for recurrence.
Five-Year Survival 90 to 95 percent
Stage II (Dukes’ B2, B3)
TNM T3–4, N0, M0 (IIA and IIB)
The cancer has spread through the muscular wall of the intestine (T3, N0 [IIA]) and possibly extended to adjacent organs and/or through the peritoneum (T4, N0 [IIB]), but has not spread to lymph nodes. (Note that at least twelve lymph nodes should be examined to establish node-negative disease according to the American Joint Committee on Cancer and a National Cancer Institute–sponsored panel.)
Standard Treatment Surgical removal of the primary tumor, with or without adjuvant chemotherapy, is standard. Adjuvant therapy is controversial in patients with Stage II colon cancer (i.e., no lymphatic spread). On average, there is a 20 to 25 percent chance of recurrence in these patients (a range of 15 to 30 percent in recent studies). Randomized trials have failed to establish a consistent benefit (the improvement in disease-free survival at five years is thought to be less than 5 percent). As a result, 5-FU–based adjuvant chemotherapy is not routinely recommended outside of a clinical trial in the absence of high-risk features. In every patient, the potential benefit of chemotherapy needs to be weighed against the potential for toxicity (including a 0.5 to 1.0 percent risk of treatment-related death).
Note that some patients with Stage II colon cancer are at relatively high risk for recurrence and may be particularly likely to benefit from adjuvant chemotherapy (although this has not been proven in randomized controlled trials). Potential high-risk features include complete obstruction or perforation (e.g., five-year survival 60 to 70 percent), invasion of adjacent organs, inadequate lymph node sampling, and poorly differentiated histology.
A number of molecular markers also hold promise in predicting the outcome of patients with Stage II disease. Patients with tumors containing loss of heterozygosity at chromosome 18q may be at a greater risk of recurrence. In contrast, patients with tumors associated with evidence for microsatellite instability may have a relatively good outcome. While not yet routinely incorporated into practice, the utility of such tumor-associated molecular markers for guiding therapy in patients with Stage II disease is currently under investigation. Participation in clinical trials is encouraged.
Five-Year Survival 70 to 85 percent (lower if the tumor invades adjacent organs or causes complete obstruction or perforation)
Investigational
•Clinical trials of chemotherapy, radiation therapy, and/or biological therapy after surgery
•Adjuvant chemotherapy with capecitabine (Xeloda)-based regimens
•Adjuvant therapy incorporating the antiangiogenic agent bevacizumab (Avastin) or epidermal growth factor inhibitors (e.g., cetuximab [Erbitux] and panitumumab [Vectibix])
•Postoperative local radiation therapy (may help control tumors that have perforated or spread to tissues adjacent to the colon)
•Identification of molecular markers with prognostic significance
Stage III (Dukes’ C)
TNM Any T, N1–2, M0 (IIIA, IIIB, and IIIC)
The cancer has spread outside the intestine to one or more lymph nodes near the bowel. N1 is three or fewer lymph nodes involved. N2 is four or more lymph nodes involved.
The cancer is Stage IIIA if it invades the lining or muscular wall of the bowel (T1/T2) and up to three lymph nodes are involved (N1). The cancer is considered Stage IIIB if the tumor has invaded through the bowel wall or to nearby tissues (T3), or involves adjacent organs and/or is through the peritoneum (T4), and up to three lymph nodes are involved (N1). The cancer is considered Stage IIIC, regardless of how much it extends through the bowel wall, if four or more lymph nodes are involved (any T, N2).
Standard Treatment All patients with Stage III colon cancer should be considered for adjuvant chemotherapy, as only about 50 percent of patients are cured by surgical resection alone. Treatment with adjuvant 5-FU/leucovorin (LV) chemotherapy improves the five-year survival to 65 percent. Thus, the standard treatment is removal of a wide section of the colon and rejoining the remaining ends (creating an anastomosis), followed by six months of 5-FU–based adjuvant chemotherapy. Recent findings suggest that the addition of oxaliplatin (Eloxatin) improves three-year disease-free survival (77.8 percent versus 72.9 percent, a statistically significant difference) based on pooled data from patients with resected Stage II and III colon cancer compared to treatment with 5-FU/LV alone (the incremental benefit was statistically significant in Stage III, but not Stage II, patients). Final data related to overall five-year survival are still pending. The addition of oxaliplatin was associated with increased toxicity (low white blood cell counts and peripheral neuropathy). Nevertheless, oxaliplatin + 5-FU + LV (FOLFOX) was approved by the FDA for the treatment of Stage III colon cancer in 2005; the regimen has since become a standard option for patients who are candidates for combination chemotherapy. For patients with Stage III colon cancer in whom treatment with only 5-FU and leucovorin is planned, capecitabine (Xeloda) (an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-FU) is an equivalent alternative. In the absence of residual disease, radiation therapy has no current standard role in the treatment of patients with completely resected colon cancer. Participation in clinical trials is also appropriate.
Five-Year Survival 50 percent overall with surgery alone (a range of 25 to 60 percent depending on the extent to which the tumor penetrates the bowel wall and the number of lymph nodes involved); 40 to 60 percent when the tumor is within the bowel wall (T1–2, Dukes’ C1); 20 to 40 percent when the tumor extends through the bowel wall (T3, Dukes’ C2); 30 percent or less when adjacent structures are involved (T4, Dukes’ C3). These data do not reflect adjuvant therapy programs.
The 1990 NCI Consensus Conference used positive lymph nodes for determining prognosis. If one to four nodes are positive, the five-year survival is 55 to 60 percent in the absence of adjuvant chemotherapy. When five or more nodes are positive, only 33 percent will be cured with surgery alone. Adjuvant chemotherapy should improve all of the old prognostic figures.
Investigational Eligible patients should be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens, radiation, or biological therapy alone or in combination.
•Adjuvant chemotherapy with capecitabine (Xeloda)-based combination chemotherapy regimens
•Adjuvant therapy incorporating the antiangiogenic agent bevacizumab (Avastin) or epidermal growth factor inhibitors (e.g., cetuximab [Erbitux] and panitumumab [Vectibix])
•Postoperative local radiation therapy (may help control tumors that have perforated or spread to tissues adjacent to the colon)
•Identification of molecular markers with prognostic significance
Stage IV (Dukes’ D)
TNM Any T, any N, M1
Patients with Stage IV disease have cancer that has spread beyond the colon to distant sites or organs, possibly including the liver or lungs.
Standard Treatment
Surgical Options Cancer at this stage is not usually curable, but removal of a large section of the colon and reconnection of the bowel is still considered so complications such as obstruction, bleeding, and bowel perforation can be avoided. Tumors that are blocking the colon may be surgically bypassed (diverting colostomy), leaving the tumor in place. Importantly, recent advances in the treatments available for patients with distant spread have reduced the imperative to remove the primary tumor in asymptomatic individuals.
The liver is the most common site of metastases in colorectal cancer. As such, 80 percent of colon cancer patients ultimately die of liver failure. If the metastases are resectable, surgical removal of the metastases can cure 20 to 30 percent of patients. The prognosis is better if there are fewer lesions—one lesion is better than three—and there is no survival benefit unless all lesions are removed. Noncurative surgery has the same prognosis as no surgery at all. In selected cases, both the colon cancer and the liver metastases (if there are three or fewer) can be removed at the same surgery. For selected patients with unresectable disease isolated to the liver, ablative therapies such as cryotherapy and radiofrequency ablation represent alternatives to resection, although their long-term benefits have not been clearly defined. In addition, use of preoperative chemotherapy to convert initially unresectable liver metastases to tumors that can be removed surgically should be considered; the long-term outcome of such patients appears to approach that of patients with initially resectable disease. Resection should also be considered in rare cases of isolated lung or pelvic metastases, as up to 25 percent of patients may be cured if all tumors can be removed.
The risk of recurrence after resection of liver metastases may be reduced if 5-FUDR chemotherapy (floxuridine) is delivered by infusion pump through the main hepatic artery after surgical resection of all known liver metastases (see this post, “What Happens in Surgery”). Clinical trials are ongoing, however, and the precise role of adjuvant systemic or liver-directed chemotherapy after liver resection remains ill-defined.
Chemotherapy For decades, 5-FU (+/– leucovorin) has been the mainstay of therapy for patients with unresectable metastatic disease in spite of limited response rates and the lack of a significant impact on survival (a median survival of around twelve months). Capecitabine (Xeloda), an oral 5-FU prodrug, is associated with continuous infusion-type pharmacokinetics and is likely to replace infusional 5-FU in the future. Treatment is associated with less diarrhea and bone marrow suppression than bolus 5-FU, but palmar-plantar-erythrodysesthesia (hand-foot syndrome) is more common and consists of pain, redness, and rash involving the hands and feet. Recent studies suggest that the addition of irinotecan (Camptosar, CPT-11; a topoisomerase-1 inhibitor) or oxaliplatin (Eloxatin; a DNA-damaging agent) to 5-FU–based chemotherapy increases the response rate in previously untreated patients (35 to 50 percent). Furthermore, the addition of oxaliplatin and irinotecan to our armamentarium has translated into a dramatic improvement in the median of survival of patients with metastatic colorectal cancer (now eighteen to twenty-one months). The data suggest that the order in which patients receive specific agents may be less important than the availability of all three drugs (e.g., irinotecan, oxaliplatin, and a fluoropyrimidine [5-FU or capecitabine]). As such, second-line therapy has become routine but varies depending on the patient’s prior treatment. In general, therapy must be individualized according to comorbidities, performance status, and kidney and liver function.
Targeted Agents Recent results suggest that the addition of agents designed to block tumor blood vessel growth (angiogenesis) or growth factor signaling (e.g., the epidermal growth factor receptor (EGFR) inhibitor) may enhance the activity of chemotherapy alone in Stage IV disease. There is an expanding body of evidence suggesting that tumors need to grow new blood vessels (angiogenesis) in order to grow and metastasize. This information has translated into an entirely new approach to the treatment of cancer, in which surrounding normal cells are the target of the therapy as opposed to the tumor cells themselves. A number of approaches are in development and more than twenty agents are already being tested in clinical trials (see this post “Antiangiogenesis”).
Bevacizumab (Avastin), a humanized monoclonal antibody directed against the angiogenesis regulator vascular endothelial growth factor (VEGF), has been shown to enhance the activity of chemotherapy for metastatic colorectal cancer (and was approved for use in this setting in 2004). Unlike traditional cytotoxic agents, the use of bevacizumab is associated with hypertension, proteinuria, arterial thromboembolic events, bleeding, and gastrointestinal perforations. Cetuximab (Erbitux), a chimeric antibody targeting the epidermal growth factor receptor, is indicated in combination with irinotecan (Camptosar, CPT-11)–based therapy for patients refractory to irinotecan-based chemotherapy (roughly 20 percent response rate) or as single-agent therapy for patients intolerant to irinotecan (10 percent response rate). The main side effect of an EGFR inhibitor like cetuximab is an acneiform rash. Panitumumab (Vectibix), another recently approved EGFR inhibitor, is associated with an 8 percent response rate as a single agent in patients with chemotherapy-refractory disease. Its relative efficacy compared to cetuximab is unknown. Both cetuximab and panitumumab have been and are being explored as components of first-line treatment, in combination with chemotherapy and/or bevacizumab (Avastin), but neither of these EGFR inhibitors is specifically approved for this setting at this time.
Hepatic Arterial Therapy Treatment of unresectable liver metastases with intraarterial chemotherapy (floxuridine [5-FUDR]) by an infusion pump or a hepatic artery catheter is associated with a response rate of over 50 percent, although a definitive increase in survival has not been shown. While convenient and generally well tolerated, liver-directed chemotherapy requires that a pump (connected to the hepatic artery) be placed surgically. Treatment-related toxicity can be seen, including liver toxicity, scarring of the bile duct (biliary sclerosis), gastritis, diarrhea, and pain, requiring dose reductions in 40 to 50 percent of patient. 5-FUDR intra-arterial therapy may also benefit patients who have failed systemic treatment with 5-FU. Approximately 30 percent of these patients will respond to liver-directed therapy, although a clear increase in survival has not been shown. The utility of this approach after failure of or in combination with a modern irinotecan (Camptosar, CPT-11)– or oxaliplatin (Eloxatin)-based chemotherapy regimen is under investigation.
Radiation Radiation therapy may be given to help control tumor-associated symptoms and may be given in combination with continuous-infusion 5-FU. Radiation is most frequently used to control bony metastases or recurrent disease in the pelvis.
Individualizing Care Patients with metastatic disease should be considered for clinical trials with novel agents and/or combinations. Since chemotherapy for metastatic colorectal cancer is not curative, however, one needs to compare the potential risks and benefits in every individual case. Some patients are not optimal candidates for systemic chemotherapy due to personal preference or debilitation from concomitant medical illness, the cancer itself, or the development of treatment-related toxicity. In these patients, supportive care may be the best option. Alternatively, treatment with infusional 5-FU (with or without bevacizumab [Avastin]) or single-agent capecitabine (Xeloda), or an EGFR inhibitor may be feasible.
Five-Year Survival Less than 10 percent, rising to 20 to 30 percent if liver or lung metastases can be removed surgically
Investigational
•Adjuvant therapy after resection of metastatic disease.
•Preoperative (neoadjuvant) chemotherapy prior to resection of metastatic disease.
•Clinical trials are constantly being designed to develop better ways of delivering known chemotherapeutic agents (in an attempt to enhance efficacy and decrease toxicity) alone or in combination with other drugs, radiation, or surgery. In addition, novel chemotherapeutic agents continue to be developed and tested in the clinic. The most exciting new treatment strategies, however, are based on fundamental advances in our understanding of the molecular mechanisms underlying the development of colorectal cancer. While primarily being studied in the setting of advanced disease, many of these strategies may have the greatest promise in the adjuvant setting, when all obvious disease has been removed.
Treatment Follow-Up
After definitive treatment for a primary colon cancer (or curative resection of a metastatic site), patients should be followed regularly for evidence of recurrent disease. The interval between appointments generally increases after two years, but regular visits continue for five years.
•History and physical examination every three to four months for two years, then every six months.
•Obtaining a chest X-ray every twelve months for five years should be considered.
•Complete blood count and liver function tests every three to four months for two years, then every six months.
•Blood CEA level every three to four months for two years, then every six months. The CEA level may rise before other clinical, X-ray, or laboratory tests are suggestive of tumor recurrence. If the CEA rises above normal, about one-third of patients may have a recurrent tumor that can be totally removed with surgery and so may be cured.
•CT scans of the abdomen and pelvis if a patient’s symptoms, physical examination, or laboratory studies suggest recurrent disease (alternatively, surveillance CT scans every six to twelve months in patients with resected Stage II-IV colon cancer should be considered).
•Colonoscopy every one to three years depending on whether or not additional polyps are discovered.
Recurrent Colon Cancer
Cancer may recur in the colon or any part of the body, including the liver and lungs.
Treatment for recurrent colon cancer is essentially the same as for Stage IV, although therapy also depends on the site of the recurrence.
•Resection should be considered if there is only one area of recurrence such as the liver or lung.
•Occasionally, the cancer will come back at the site of the original colon surgery (anastomotic recurrence), where sections of the bowel have been sewn together. These local suture-line recurrences can be removed surgically with a reasonable chance for cure.
•Chemotherapy with single drugs (10 to 20 percent response rate), combinations (30 to 45 percent response rate), and investigational drugs have been used for palliation. The specific chemotherapy employed depends on the time interval between prior adjuvant therapy and tumor recurrence. Tumors that recur within one year of adjuvant chemotherapy are generally considered 5-FU–resistant. In contrast, 5-FU–based chemotherapy is often used as first-line therapy in chemo-naive patients or patients whose tumors recur more than one year after adjuvant therapy.
RectumSurgery Surgery is the primary treatment for rectal cancer and results in cure in approximately 45 percent of all patients. The prognosis of rectal cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. Preoperative clinical staging plays a critical role in determining which patients are candidates for local excision rather than a more extensive surgery and which patients may benefit from preoperative chemotherapy and radiation therapy in an attempt to maximize the chance of a curative resection.
State-of-the-art treatment for localized rectal cancer involves removing the tumor, at least 3/4 inch (2 cm) of normal tissue on either side of it, and the regional lymph nodes. The precise surgical procedure performed depends on the size and location of the tumor. In general, a major limitation of surgery for the treatment of rectal cancer is the inability to obtain wide radial margins because of the presence of the bony pelvis. As a result, several different operations are considered when a patient presents with rectal cancer. Most frequently, the surgeon does an excision via the anus (transanal excision), a low-anterior resection (LAR) of the involved portion of bowel allowing preservation of the sphincter (coloanal anastomosis), or an abdominoperineal resection (APR) of the entire rectum and sphincter, resulting in permanent colostomy placement. A key principle underlying the transabdominal approaches to removing rectal cancers (LAR and APR, coloanal anastomosis) is incorporation of a total mesorectal excision, whereby the tissue surrounding the rectum is also removed, thus decreasing the chance of incomplete resection. Furthermore, unlike in transanal excisions, the draining lymph nodes are removed during transabdominal resections of rectal cancers. The final treatment plan also takes into account the relative merits of chemotherapy and radiation and depends on the clinical stage of the tumor, its location in the rectum, and what percentage of the circumference of the rectum is involved.
Most rectal tumors can be resected without impairing sphincter function (transanal resection or LAR). Noninvasive tumors that appear to be confined to the top layers of the rectal lining (mucosa and submucosa) can sometimes be treated with endocavitary radiation or removed from below, entering through the anus and using a cold probe (cryotherapy), electrofulguration, or simple excision without removing part of the bowel. Transanal excision can also be considered in the setting of an invasive cancer, but only if it is small (less that 11/4 inches [3 cm]), well-differentiated, and without evidence of involvement of the local lymph nodes or adjacent structures. If the margins are negative and there is no evidence of gross pelvic disease after local excision, adjuvant pelvic radiation is often employed to reduce the risk of local recurrence as an alternative to an APR.
Cancers in the upper part of the rectum, close to where it connects to the sigmoid colon, are removed by a low-anterior resection. The remaining colon is attached to the anus (coloanal anastomosis), thus allowing preservation of sphincter function. Very low lying rectal tumors (within 2 to 2½ inches [5 to 6 cm] of the anus), however, require removal of the entire rectum and anus, leaving the patient with a permanent colostomy (abdominoperineal resection) (see this post “Living with an Ostomy”).
In some patients with a tumor that is low in the rectum, radiation given before the operation may reduce the size of the tumor, allowing it to be removed while still leaving enough bowel below the tumor site for the surgeon to sew the bowel back together. This will spare the rectum and the sphincter muscle, thereby avoiding the need for a colostomy in up to 85 percent of patients with rectal cancer. Since the type of operation performed affects the risk of local recurrence, a sphincter-sparing procedure should be pursued only if a curative resection (with negative margins) can be achieved. About 10 to 15 percent of patients have a late local recurrence of cancer in the pelvis, particularly when sphincter-preserving operations have been used for low-lying tumors.
Adjuvant Radiation Therapy Because of an increased tendency for first failure in locoregional sites, the impact of perioperative irradiation is greater in rectal cancer than in colon cancer. Radiation given before or after surgery decreases local failure, although most clinical trials have failed to show a significant impact on survival with radiation therapy alone.
Placing the radiation source inside the rectum (intraluminal radiation therapy) may result in a high cure rate in some cases, such as a small, well-differentiated tumor above the sphincter. This may preserve the sphincter.
Combined Modality Therapy In contrast to treatment with radiation alone, 5-FU–based chemotherapy combined with radiation is associated with a decrease in locoregional failures and a small increase in survival. Furthermore, protracted continuous infusion is superior to bolus infusion (daily injections of chemotherapy for several days in a row) of 5-FU in combination with radiation therapy and has become the standard of care in patients receiving chemoradiation. The use of capecitabine (Xeloda) instead of infusional 5-FU is an area of intense interest.
Stage I (Dukes’ A, B1, and Tis, T1–2) tumors have a high cure rate with definitive surgery alone, and there is no need for adjuvant chemotherapy for these stages, unless the patient had a T2 lesion treated with transanal excision (the risk of local recurrence is 25 percent without radiation). Stage II and III tumors (Dukes’ B2, C, and T3–4, N1–2) are characterized by penetration of the tumor through the bowel wall and/or spread into lymph nodes at the time of diagnosis. Because of the relatively poor prognosis and high risk of local recurrence, patients with Stage II and III tumors of the mid to low rectum should be considered for adjuvant chemoradiation using 5-FU–based chemotherapy plus radiation. This has historically involved 5-FU plus radiation, sandwiched between 5-FU–based chemotherapy.. Cancers that develop high in the rectum (above the peritoneal reflection) behave and are treated like colon cancers, and radiation is not usually used. The relative importance of chemotherapy and radiation is an area of intense interest in the face of evolving surgical techniques. Similarly, extrapolating from colon cancer, the use of capecitabine and/or oxaliplatin (Eloxatin) in the treatment of rectal cancer is the focus of several ongoing clinical trials.
Neoadjuvant Therapy The optimal timing of adjuvant therapy for rectal cancer is controversial. Neoadjuvant therapy (delivered before surgical resection) harbors the promise of preoperative tumor regression, leading to a higher chance of curative resection and a sphincter-sparing procedure. On the other hand, neoadjuvant therapy can be associated with toxicity and resultant delays in a potentially curative resection. In addition, by definition, neoadjuvant therapy limits our ability to accurately stage the cancer at surgery. Consequently, we may overtreat patients who receive neoadjuvant therapy, since the exact stage at presentation can’t be determined.
The decision to use neoadjuvant therapy is based on preoperative staging with ultrasound, CT, and MRI, techniques that are relatively imprecise. However, pathological staging, from the surgical resection specimen, remains the gold standard. Since neoadjuvant therapy has the potential to “downstage” the tumor by changing the histopathological findings, it can be impossible to know the true stage at diagnosis based on a sample collected intraoperatively after neoadjuvant therapy (in 15 to 25 percent of cases, there is evidence for a complete response—i.e., no residual tumor seen in the operative sample). Thus, because the true initial stage is unknown, patients treated with neoadjuvant chemoradiation typically receive 5-FU–based chemotherapy after surgical resection regardless of the pathological findings at surgery. For patients with bulky tumors or tumors adherent to local structures (e.g., vagina, bladder, or pelvic sidewall), neoadjuvant therapy is routine. It is also frequently recommended for Stage II and III disease characterized by tethering and circumferential involvement. In addition, long-term bowel function may be superior after neoadjuvant chemoradiation compared to postoperative treatment, hence a trend toward preoperative treatment in any patient with evidence for probable T3–4 or lymph node–positive disease.
In general, as in the adjuvant setting, cancers that develop very high in the rectum (near the junction with the colon) behave and are treated like colon cancers. As such, the role of neoadjuvant radiation is very limited in this setting.
Palliation As with metastatic colon cancer, resection should always be considered in patients with metastatic rectal cancer, as there is the potential for long-term cure in up to 30 percent of patients with resectable liver or lung metastases. In general, patients with advanced rectal cancer are treated in the same way as patients with metastatic colon cancer; recent advances in treatment options using combination chemotherapy and biologically based agents have led to significant improvements in overall survival.
Pelvic radiation therapy (with or without 5-FU chemotherapy) may be used for palliation of symptoms or to prevent a local recurrence in patients who were not previously irradiated.
Laser therapy may be a very effective way to relieve an obstruction or control localized bleeding.
Rectal Cancer Treatment by Stage
Stage 0 (Dukes’ A)
TNM Tis (tumor or carcinoma in situ), NO, MO
This superficial, noninvasive carcinoma in situ is a very early cancer that has not spread below the mucosa (first layer of rectal tissue).
Standard Treatment Because of its superficial nature, limited rather than radical surgery, as well as other procedures, may be used. Surgery may involve cutting out only the tumor itself (enucleation) or the tumor and a small wedge of tissue.
Other options include electrocoagulation and external or internal (inside the rectum) radiation therapy for rectal sphincter preservation.
Five-Year Survival Over 95 percent
Stage I (Dukes’ B1)
TNM T1–2, NO, MO
Stage I rectal cancers are confined to the lining or muscular wall of the rectum and have not yet spread outside the rectum. In T1–2 tumors, the cancer is limited to the bowel wall.
Standard Treatment Surgery will generally result in a cure. There is a 5 to 10 percent chance of a local recurrence with this stage of cancer. When the tumor is in the upper rectum, a wide margin of tissue may be removed and the bowel reconnected (low-anterior resection [LAR]). When the tumor is near the anus, an abdominoperineal resection (APR) and colostomy is the standard treatment.
Local transanal resection (i.e., removal of the tumor via the anus with no abdominal incision) can be done in selected patients with small (less that 1½ inches [4 cm]), well- to moderately differentiated tumors that are mobile, completely resectable, noncircumferential, and without evidence for involvement of local lymph nodes or adjacent structures. Adjuvant pelvic radiation is often employed to reduce the risk of local recurrence (especially for T2 lesions, which have a more than 20 percent chance of lymph node involvement and require adjuvant chemoradiation or a more extensive surgical resection). Tumors excised transanally and found to have high-risk features like positive margins, lymphovascular invasion, and/or poor differentiation require additional, definitive surgery (and postoperative chemoradiation therapy, depending on the surgical staging).
Radiation inside the bowel (intraluminal) may be used in selected patients. This technique requires special equipment and experience, but the results are equivalent to surgery and can preserve the sphincter muscle.
Five-Year Survival 85 to 95 percent
Investigational
•Use of oral 5-FU prodrugs and/or oxaliplatin (Eloxatin) in combination with radiation
•Novel surgical techniques
Stage II (Dukes’ B2, B3)
TNM T3–4, N0, M0
A Stage II cancer has penetrated all layers of the bowel wall with or without extension to adjacent tissues (uterus, ovaries, or prostate), but has not spread to lymph nodes. T3 tumors extend through the bowel wall; T4 tumors involve adjacent structures such as the uterus, ovaries, bladder, and prostate.
Standard Treatment Stage II rectal cancer is highly treatable and often curable. There are several options for treatment:
•Wide surgical excision with abdominoperineal resection or low-anterior resection followed by adjuvant chemoradiation therapy.
•Bulky tumors or tumors near the anus are generally treated with preoperative (neoadjuvant) chemoradiation followed by surgical resection in an attempt to preserve sphincter function. In addition, long-term bowel function may be superior after neoadjuvant chemoradiation compared to postoperative treatment, hence a trend toward preoperative treatment in any patient with evidence for probable T3–4 or lymph node–positive disease. Since accurate pathological staging is difficult after neoadjuvant therapy, most patients also receive additional 5-FU–based chemotherapy postoperatively.
Five-Year Survival 30 to 70 percent (50 to 70 percent for T3, N0; 30 percent for T4, N0)
Investigational
•Neoadjuvant hyperfractionated radiotherapy.
•Radiation during surgery (intraoperative radiation therapy) is being evaluated for locally advanced disease.
•Identification of molecular markers with prognostic significance.
•A novel stapling device to join the ends of the bowel may allow the surgeon to perform a low-anterior resection in some patients with low rectal cancers (sphincter-sparing).
•Laparoscopic surgery and other novel surgical techniques.
•Studies exploring the relative contributions of systemic chemotherapy and chemoradiation in the treatment of patients with completely resected rectal cancer (margins negative).
•Use of oxaliplatin (Eloxatin), irinotecan (Camptosar, CPT-11), and/or oral fluoropyrimidines (capecitabine [Xeloda]), alone or in combination with radiation, in the adjuvant or neoadjuvant setting.
•Use of biologically based therapies such as bevacizumab (Avastin) and EGFR inhibitors in the adjuvant or neoadjuvant setting.
•Studies exploring the optimal timing of resection after neoadjuvant chemoradiation.
Stage III (Dukes’ C1, 2, 3)
TNM Any T, N1–2, M0
The cancer has spread within or outside the rectum and one or more lymph nodes are involved. N1 means that up to three lymph nodes are involved; N2 means that four or more lymph nodes are positive.
Standard Treatment The number of lymph nodes that are involved has prognostic significance in rectal cancer. Overall, there is a 50 percent chance of recurrence with this stage of disease. The 1990 Consensus Conference on Colon and Rectal Cancer noted that if one to four lymph nodes are positive, 55 to 60 percent of patients will be cured with surgery alone; if five or more nodes are positive, only 33 percent will be cured with surgery alone. Based on these data, adjuvant/neoadjuvant chemoradiation and adjuvant 5-FU–based chemotherapy is standard for this stage of disease.
Standard treatment for rectal cancer involves surgical resection plus adjuvant chemotherapy and radiation. Chemoradiation may be given either pre- or postoperatively. There is a trend to treat patients with fixed or bulky tumors with neoadjuvant (preoperative) chemoradiation. For tumors near the anus, chemoradiation therapy followed by surgery may allow the sphincter function to be preserved. In general, patients with rectal cancer involving the lymph nodes are also offered several additional cycles of 5-FU–based chemotherapy after recovering from surgery and radiation.
Removal of rectal cancer near the anus requires an APR and permanent colostomy. In contrast, tumors in the upper rectum can often be resected without compromising sphincter function (LAR); the proximal bowel is reconnected to the anus (coloanal anastomosis). When adjacent organs are involved, removal of the pelvic organs (pelvic exenteration) may be necessary to completely remove all of the cancer.
Five-Year Survival 30 to 70 percent (depending on the number of lymph nodes involved and the extent of invasion through the bowel wall)
Investigational See Stage II Rectal Cancer.
Stage IV (Dukes’ D)
TNM Any T, any N, M1
The cancer has spread outside the rectum to distant areas, including organs such as the liver and lungs. The approach to treatment in patients with metastatic rectal cancer is very similar to that of patients with advanced colon cancer (see Stage IV colon cancer).
Standard Treatment Treatment is basically directed toward palliation, although there can be long-term disease-free survival if isolated metastases in the liver or lung can be removed.
Surgical Options Even in the setting of metastatic disease, palliative resection of the primary tumor should be considered in order to treat or prevent complications such as pain, obstruction, and bleeding. In addition to systemic chemotherapy, radiation is an option for treatment of local disease that can’t be removed. The relative benefits need to be compared to the potential impact on quality of life in the face of incurable distant disease. In some cases, obstructing tumors may be bypassed instead of removed (diverting colostomy).
Resection of isolated liver, ovary, or lung metastases should be entertained and can lead to a long-term cure in roughly 25 to 30 percent of patients. Liver metastases can be removed or ablated at the same time the primary rectal cancer is resected in selected cases.
Chemotherapy See Stage IV colon cancer.
Five-Year Survival 5 percent, rising to 20 to 30 percent if liver or lung metastases can be removed surgically
Investigational See Stage IV colon cancer.
Treatment Follow-Up
Rectal cancer has a much higher rate of local recurrence than colon cancer. Close follow-up may lead to the earlier diagnosis of recurrent disease and improved treatment. After definitive treatment for rectal cancer, patients should be followed regularly for evidence of recurrent disease. The interval between appointments gradually increases after two years, but regularly scheduled visits should continue for at least five years.
•History and physical examination every three to four months initially.
•Obtaining a chest X-ray every six to twelve months for five years should be considered. Isolated lung metastases are much more likely to occur in patients with rectal cancer than in patients with colon cancer.
•Complete blood count and liver function tests every three months.
•Blood CEA level every three to four months, since the CEA level may rise before other clinical, X-ray, or laboratory tests are suggestive of tumor recurrence. If the CEA rises above normal, about one-third of patients may have a recurrent tumor that can be totally removed with surgery and so may be cured.
•CT scans of the abdomen and pelvis if a patient’s symptoms, physical examination, or laboratory studies suggest recurrent disease (surveillance CT scans every six to twelve months in the case of Stage II rectal cancer or greater should be considered).
•Colonoscopy every one to three years depending on whether or not additional polyps are discovered.
Recurrent Rectal Cancer
Rectal cancer can recur locally or often in the liver or lungs, and it is important to determine if the recurrence is only local or metastatic. Treatment depends on the site of recurrence as defined by physical and X-ray examinations and scans.
•Local recurrence in the rectum or isolated metastases to the liver or lung can sometimes be surgically removed, possibly leading to a cure or significantly prolonged survival.
•Patients who develop recurrent disease more than six months after completion of adjuvant chemotherapy are often treated with the same 5-FU–based regimen again. Recurrent disease that occurs less than six months after adjuvant therapy is generally considered chemotherapy-resistant and an alternative regimen is employed.
Standard Treatment Removal of isolated lung or liver metastases may be done in selected cases. The five-year survival rate for patients with solitary metastases exceeds 20 percent. The chances for cure are improved when there are only two or three metastases to be removed. Noncurative removal provides no benefits to patients who have no symptoms, since survival is not affected.
Both palliative radiation therapy and palliative chemotherapy may be given for recurrent disease (see Stage IV colon cancer).
Investigational See Stage IV colon cancer.
The Most Important Questions You Can Ask If You Have Colorectal Cancer
•What is the stage of my cancer?
•What is my prognosis?
•Do I need surgery? How extensive does my surgery need to be? Will I need a colostomy? Will it be permanent?
•Will I need adjuvant or neoadjuvant chemotherapy?
•Do I need radiation? Should it be delivered before or after surgery? Will it be combined with chemotherapy?
•Will adjuvant chemotherapy or radiation increase my chance of being cured?
•What treatment-related side effects am I likely to experience?
•Will there be any long-term side effects from my treatment (surgery, chemotherapy, or radiation)?
•Are my children or other relatives at higher risk for colorectal cancer?
•How will I know if I am cured? What kind of follow-up will you be doing after my therapy?
•How are chemotherapy, surgery, and radiation used in the setting of metastatic disease? What are the goals of therapy?
•What clinical trials might be appropriate?
•What will happen if I don’t have the suggested treatment?
Summary: Treatment of Colorectal Cancer1. Stage I Colon and Rectal Cancer
No adjuvant therapy is warranted, since there is a low risk of recurrence (except in the setting of a transanal excision for T2, N0 rectal cancer).
2. Stage II Colon Cancer
Specific adjuvant therapy cannot be recommended routinely for low-risk tumors outside a clinical trial. Patients whose tumors have poor prognostic features are often considered candidates for adjuvant chemotherapy. All patients should consider enrollment in a clinical trial.
3. Stage III Colon Cancer
There is a high risk for recurrence, and treatment with 5-FU–based chemotherapy is recommended (alone or in combination with oxaliplatin [Eloxatin]). Capecitabine (Xeloda) is an acceptable alternative to 5-FU/LV alone. Enrollment in clinical trials is encouraged.
4. Stages II and III Rectal Cancer
Adjuvant or neoadjuvant radiotherapy and chemotherapy (chemoradiation) is recommended to improve local control and survival. Systemic 5-FU–based chemotherapy (outside the context of radiation) is also recommended. Enrollment in clinical trials is encouraged.
5. Stage IV Colorectal Cancer
Resection of metastatic deposits can be curative in selected cases. In the absence of resectable disease, treatment with palliative chemotherapy with or without bevacizumab (Avastin) should be considered. Use of an EGFR inhibitor should be considered in patients with chemotherapy-refractory disease. Participation in clinical trials is appropriate. Radiation is used to control local symptoms (e.g., those related to pelvic disease or bone metastases). Because of the potential problems related to leaving the primary tumor in place (including bleeding, obstruction, and perforation), resection of the affected segment of bowel should be considered even in patients with metastatic disease. The relative benefits need to be weighed against the potential impact on quality of life in the face of incurable distant disease. In some cases, obstructing tumors may be bypassed instead of removed (diverting colostomy).
A Prevention Program for Colorectal CancerSeven Steps to Lowering Your Risk of Colorectal CancerGet regular colorectal cancer screening tests beginning at age fifty. If you have a personal or family history of colorectal cancer or colorectal polyps, or a personal history of another cancer or inflammatory bowel disease, talk to your health care provider about earlier screening tests. Based on the available data, many health care providers consider colonoscopy the preferred screening test because of its accuracy in detecting polyps and its ability to remove polyps before cancer occurs.Eat a diet rich in fruits and vegetables and whole grains from breads, cereals, nuts, and beans. Include sources of calcium such as low-fat milk products. Although the data on adding fiber supplements to the diet to prevent colon cancer or polyps has been disappointing, there remains suggestive data that dietary fiber may be protective over the long term.Eat a diet low in red or prepared meats and fat.Eat foods containing folate such as leafy green vegetables.If you use alcohol, drink only in moderation. Alcohol and tobacco in combination are linked to colorectal cancer and other gastrointestinal cancers.If you use tobacco, quit. If you don’t use tobacco, don’t start.Exercise for at least twenty minutes, three to four days each week. Moderate exercise such as walking, gardening, and climbing steps may help you reduce your risk.Additional Points to Discuss with Your Health Care ProviderConsider supplements of vitamins and minerals such as folate and calcium, which may regulate the growth rate of the cells that line the colon.Consider the use of daily aspirin, especially if you have already had polyps or colorectal cancer.
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