COLON and RECTAL CANCER
Colorectal cancer is a very common malignancy which will affect about 150,000 Americans this year. About 100,000 of these patients will have large bowel cancer and the remaining 50,000 will have rectal cancer.
About 50,000 of these patients will die. Colorectal cancer accounts for nearly 10% of all cancer deaths.
Risk Factors
The etiology of colon cancer is poorly understood. Risk factors include:
1. Age; this is probably the major risk factor. Colon cancer is usually diagnosed in patients over 50.
2. Genetic factors are also important, although most cases of colorectal cancer are sporadic rather than familial. Recently, several important genetic disorders have been identified that lead to a very increased risk of colon cancer. These are generally inherited in an autosomal dominant fashion. This means that it takes only one “bad gene” to markedly increase the risk of developing colon cancer. Unfortunately, 50% of the children of an affected parent will carry the “bad gene”.
One of these genetic defects is familial adenomatous polyposis. In this condition, there are numerous polyps throughout the colon and these are diagnosed at quite a young age. The second one is hereditary non-polyposis colorectal cancer. In this disorder, there are not nearly as many polyps, but those that occur are likely to become malignant. This condition is also called the Lynch Syndrome. The Lynch Syndrome is caused by mutations in mismatch repair genes. The Lynch Syndrome is characterized by diagnosis at a young age, usually between 40 and 50 years. Also, the patients may have endometrial, ovarian, stomach, small bowel or kidney cancer.
3. People who have a personal or family history of polyps or colorectal cancer are at increased risk of developing colon cancer. The risky polyps are those that are more than 1cm (about a half an inch) in size and those which are adenomatous, villous or tubulovillous.
Family history is quite important and multiple affected relatives are a warning sign that surveillance should begin probably no later than age 40 or 10 years earlier than the youngest colon cancer in the family. Genetic screening may be of benefit in these families.
4. Ulcerative colitis is a major risk factor for developing colorectal cancer and confers about a tenfold increased risk.
5. Alcohol consumption in excess, obesity and cigarette smoking all confer a modest but definite increase in risk.
Risk Reduction
Many patients ask how they can reduce their risk of colon cancer. The surest way to reduce ones risk of invasive colon cancer is a colonoscopy. During the colonoscopy polyps may be removed and any suspicious lesions may be biopsied.
Getting an elective colonoscopy at age 50 is a very important part of health maintenance for otherwise healthy people.
There are a number of studies that show that a diet high in fruits and vegetables is protective. It is probably wise to limit ones intake of red meat, although lean red meat probably confers very limited additional risk. The degree of protection that fiber offers is controversial and probably not major. There is some data to suggest that regular moderate physical activity is protective. Aspirin and non-steroidal anti-inflammatory agents may also offer some protection.
Symptoms
Symptoms of colorectal cancer include abdominal pain in 44% of patients, change in bowel habits in 43%, blood in the stools or dark stools in 40%, weakness in about 20%, Iron deficiency anemia in 10% and weight loss in about 5%. Symptoms can be of gradual onset or sudden such as when the tumor causes intestinal obstruction or perforation (a hole in the bowel wall). About 20% of patients will have disease already spread to the liver at the time of diagnosis. This will make them stage 4, and unfortunately, only very rarely curable. Patients who are not evidently metastatic beyond lymph nodes at presentation should be treated for cure.
Cancer can only be diagnosed by a biopsy and examination of the tissue under a microscope. Cancer can be suspected on the basis of symptoms, physical exam or x-ray tests, but actual proof positive depends on a tissue biopsy.
Staging
Once a cancer is diagnosed, the next step is staging. Staging just means asking where the tumor is.
Most patients are keenly interested in their stage. Staging is done during surgery and by x-ray studies.
The staging system depends on tumor size (T), number of nodes involved with tumor (N) and presence or absence of metastasis (tumor spread to other places such as liver or lung).
See table 1.
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TABLE 1 Tumor – Node – Metastasis (TNM) Staging system for colon and rectal cancer |
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Primary tumor (T)
Tx – Primary tumor cannot be assessed Tis – Carcinoma in situ T1 – Tumor invades submucosa (inner most lining of colon) T2 – Tumor invades muscularis propria ( into the muscle) T3 – Tumor invades through the muscularis propria into the subserosa (gets outside the colon) T4- Tumor invades other organs or structures, or perforates
Regional lymph nodes (N)
Nx – Regional lymph nodes cannot be assessed N0 – No regional lymph node metastasis N1 – Metastasis in one to three regional lymph nodes N2 – Metastasis in four or more regional lymph nodes
Distant Metastasis (M)
Mx – Presence or absence of distant disease cannot be determined M0 – No distant metastasis detected M1 – Distant metastasis detected
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Survival depends most upon stage; but several other factors are important. These include the overall health of the patient; i.e. he/she must be fit enough for surgery and for chemotherapy or radiation (if needed).
Other features of the cancer which have prognostic significance include grade, location and histologic subtype. As would be expected, patients with high-grade tumors fare less well than those with low-grade tumors. For stage II and III cancers, histologic subtype also plays a role with signet ring cancers being associated within a 36% 5-year survival, adenocarcinoma with a 60% survival and mucinous adenocarcinoma with a 58% survival.
In general, an improved 5-year survival is associated with right colon cancers (70%) when compared to left sided lesions (64%).
Survival by stage for both colon and rectal cancer is shown below.
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TABLE 2 Five-Year Cancer Specific Survival Rate for Colon Cancer Cases Diagnosed in 2002 |
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Stage |
National |
RMC |
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I |
93% |
100% |
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IIA-IIB |
83% |
68%* |
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IIA-C |
60% |
59% |
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IV |
8% |
0%* |
*Not statistically significant
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Stage |
National Five-Year Survival for rectal cancer cases diagnosed in 2002 |
RMC Five-Year Survival for rectal cancer cases diagnosed in 2002 |
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I |
81% |
83% |
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IIA-IIB |
61% |
56% |
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IIIA-C |
52% |
40%* |
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IV |
7% |
0%* |
*Not statistically significant
Our 5-year survival compares favorably with national survival rates.
Colon Cancer versus Rectal Cancer
Colon cancer and rectal cancer have different treatments and different metastatic patterns. Hence, we will discuss each separately.
Colon Cancer
Stage I
Stage I colon cancer is usually adequately treated with surgery.
Stage II
Stage II colon cancer is also treated with surgery; a minority of patients will also receive chemotherapy. Indications for chemotherapy include
- The lesion has caused perforation (a hole in the bowel wall)
- There are malignant attachments to adjacent organs
- A large poorly differentiated tumor
Our Cancer Center is very excited to be one of only three hospitals in the state of Alabama which participated in Protocol ECOG 5202 (http://www.cancer.gov/clinical trials/ECOG-E5202) in which a stage II patient’s risk of failure was determined by testing for 18LOH (chromosome 18 loss of heterozygosity) and MSS (microsatellite stability).
Loss of heterozygosity means the loss of normal function of a tumor suppressor gene located on chromosome 18.
Microsatellites are short repeat sequences of DNA. These regions are sometimes miscopied during cell division.
Several gene products are responsible for repairing errors that occur during DNA replication.
If genetic damage is not repaired, tumors are likely to occur. Sometimes the repair problem occurs sporadically (i.e. by “bad luck”) and sometimes the repair problem is inherited.
Both 18 LOH and MSS are determined on paraffin blocks of the patient’s tumor. Patients who fell in a high-risk group based on these findings were given chemotherapy with or without Avastin (a drug which targets new blood vessel growth). It is hoped that results of this study will prove that we are able to determine which patients are at high risk for failure and that we have effective therapy for high-risk stage II colon cancer patients. The study has accrued sufficient patients; results are eagerly anticipated.
Stage III
Any patient who has lymph nodes involved by tumor should be considered for adjuvant chemotherapy.
A better idea of a patient’s risk can be obtained from going to Adjuvant Online. This tool is not accessible to patients, but is accessible to your doctor.
An example follows below. In this example a 60-year-old female patient with one to three positive nodes and otherwise good health has 36 chances in 100 of recurrence without treatment. Her risk decreases to 16 chances in 100 with treatment. Your doctor can substitute your age, overall health, depth of tumor invasion, grade and number of positive nodes.
Knowing your risk of recurrent cancer and your risk of dying from other conditions, such as heart disease, will give you the data that you need to make an informed decision regarding adjuvant therapy.
The most widely used adjuvant therapy consists of three drugs; 5FU, Leucovorin and Oxaliplatin. These combinations are generally called FOLFOX4 or FOLFOX6.
Sometimes just 5FU and Leucovorin are used. This is usually used in people with multiple other health problems or people with severe peripheral neuropathy (damaged nerves in arms and legs usually from poorly controlled diabetes).
The FOLFOX treatment is given for 46 hours every other week for 12 doses and is discussed in the chemotherapy section.
Rectal Cancer
Rectal cancer affects about 50,000 Americans each year and differs from colon cancer in that the rectum is a relatively fixed structure; i.e. it does not move much – as opposed to the colon which moves freely through the abdominal cavity. Because of this, the rectum is a good target for radiation. Also, rectal cancers are more likely to spread to surrounding local structures and to the lungs rather than to liver as colon cancer usually does.
Staging
The staging system is the same as for colon cancer - see table 1.
Staging is done without surgery and is based on physical exam, scans and an endorectal ultrasound. An endorectal ultrasound uses a rectal probe to visualize surrounding lymph nodes.
Survival
Survival depends on stage as shown below and is shown in table 2.
Treatment
Stage I tumors can be treated by surgery. Higher stage tumors ( stage II and III) should receive preoperative chemotherapy and concurrent (at the same time) radiation.
After a 4-6 week rest, surgery is performed. Several advantages exist for preoperative treatment – these include:
1. The tumor may be downstaged, increasing the chances that a colostomy can be avoided.
2. Rectal tissue that is exposed to radiation is removed at the time of surgery.
Post surgery chemotherapy – usually FOLFOX – is generally given (see chemotherapy section).
Stage 4 patients are best treated with chemotherapy; surgery is also used if the lesion is causing significant obstruction.
Chemotherapy
Stage III and some stage II colon cancer patients and stage II and III rectal cancer patients usually receive postoperative adjuvant treatment.
The most widely used adjuvant therapy consists of three drugs; 5FU, Leucovorin and Oxaliplatin. These combinations are generally called FOLFOX4 or FOLFOX6.
Sometimes just 5FU and Leucovorin are used. This combination is usually used in people with multiple other health problems or people with severe peripheral neuropathy (damaged nerves in arms and legs usually from poorly controlled diabetes).
In order to receive 5FU, the patient must have a Mediport. A Mediport is a little box under the skin with a tubing that leads to a major blood vessel. This is inserted by your surgeon and is an outpatient procedure. The Mediport is then connected via tubing to a pump (about the size of a paperback book) and the 5FU is infused over 46 hours at home every other week.
The FOLFOX treatment is given for 46 hours every other week for 12 doses.
You come into the office and Mediport is accessed (needle put in it). Blood count is determined. You see the doctor and if everything “checks out” you proceed to the chemotherapy room. There a specially trained chemotherapy certified nurse administers the leucovorin, oxaliplatin and the 5fu is carried home in the pump. Day 2, you receive just 5fu and leucovorin. 5fu is carried home in your pump. On day 3 the pump is removed.
This is called one cycle. 12 cycles are recommended, one every other week.
Metastatic Disease
About one in five patients have metastatic (disease spread to distant sites) at the time of diagnosis; other patients will develop tumor recurrence after what was hoped to be curative treatment. In general, stage IV patients are treated for palliation (longer and better quality of life) rather than for cure. A fortunate few can have resection or radiofrequency ablation of a single or a few lung or liver mets with curative intent.
Recurrent disease may be heralded by a rising CEA. About 80% of patients who have an active colon cancer spread beyond the lymph nodes will have an elevated CEA. If the CEA is elevated it can be used to track the activity of the colon cancer. The CEA is determined by a blood test.
Treatment of metastatic colon cancer largely involves chemotherapy. Commonly used drugs are 5-FU, Leucovorin, Oxaliplatin, Camptosar (Irinotecan), Erbitux (Cetuximab) and Avastin.
What drug combinations are used depends on whether you have previously had any of the drugs in the adjuvant setting or metastatic setting and your overall physical condition.
If you have not had FOLFOX or have had it more than 12 months previously, these drugs may be an option for you. Another good choice is FOLFIRI – the combination of 5FU, Leucovorin and Camptosar. Avastin may be added to either drug combination. In order to grow, tumors must have a blood supply which they get by use of a protein called VEGF (vascular endothelial growth factor). Avastin is an antibody which “mops up” VEGF and thus interferes with the tumor’s blood supply. Erbitux (Cetuximab) is an excellent drug for those patients whose tumor is not KRAS mutated. Cetuximab is an antibody to EGFR (epidermal growth factor receptor) which is located on the cell surface. KRAS is a protein that acts as an “on/off” switch. KRAS status is determined on your stored tumor tissue.
Side Effects
Leucovorin is a special vitamin whose purpose is to potentiate (make stronger) 5FU. No side effects are expected.
5FU (5 Fluorouracil) is a generally well tolerated drug. Nausea is unusual. A few patients may experience diarrhea, mucositis (sore mouth) or hand-foot syndrome (red and tender feet and hands). Hair loss does not occur and count suppression is uncommon.
Oxaliplatin can cause suppression (lowering) of white cells, platelets and red cells. Suppression of white cells can increase the odds of infection; low platelets may increase bleeding, while a decrease in red cell count (anemia) can cause weakness. These problems resolve when the drug is held. Usually no hair loss occurs.
Cold intolerance can be a problem for several days after each treatment. This means that you may experience numbness or tingling if you get cold outside or grab something cold from the refrigerator. This cold intolerance extends to drinking cold liquids. The sensation that results can be quite unpleasant.
The one potentially major side effect is peripheral neuropathy (damage to nerves in the arms and legs). This neuropathy is manifested by numbness and tingling and sometimes pain starting in the feet and subsequently spreading to the fingers. Should this side effect occur, your doctor will likely modify the dose or omit Oxaliplatin until the side effect has resolved. Be sure you let your doctor know if you experience this.
Continuation of Oxaliplatin beyond mild to moderate toxicity may be irreversible and may be a major problem. The toxicity from Oxaliplatin is cumulative, i.e. – the more you get the more likely this side effect.
Camptosar is given over 90 minutes and is often combined with 5FU and Leucovorin. This drug causes minimal nausea, some count suppression and diarrhea. The diarrhea can be a problem – be sure to discuss management with your nurse. Call the office if simple measures such as diet, Imodium AD or Lomotil do not improve the problem. Also, call us if you think you may be getting dehydrated. Camptosar can be used for long periods of time in patients who tolerate it well – there does not appear to be cumulative toxicity.
Avastin is a drug that targets blood vessels. A tumor must develop a blood supply if it is to grow. This drug interferes with this process. Avastin does not cause nausea, blood count suppression or hair loss. Side effects are few, but when they occur can be serious. These include hypertension, protein in the urine, blood clots in arteries, hemoptysis (coughing up blood) and intestinal perforation (hole in the colon). Hypertension may require medication. The protein in the urine generally resolves when Avastin is held. A stroke or MI may cause permanent damage. Surgery is required to fix a perforation.
Erbitux has one major side effect, rash. The rash, which is troublesome for many patients, can be treated with antibiotics and creams. It usually improves after about three months. Diarrhea can occur and is controllable with Imodium AD or Lomotil.
There have been major advances in the treatment of stage 4 colon cancer. Median survival is now approaching 22 months for patients who receive aggressive treatment.
Ask questions. Be involved in your care. Fighting cancer requires a commitment from you and from your doctor.