~Colorectal Cancer, Part 3 - Treatment

Treatment of Colorectal Cancer

The choice of treatment for colorectal cancer depends largely on the stage of the patient's cancer. Possible treatments include surgery, anticancer drugs (chemotherapy), radiation, biological therapy, supplementation, and diet modification. Surgery and radiation therapy are considered local treatments. They focus on eliminating the cancer from a limited or local area, such as the colon or rectum and regional lymph nodes. Chemotherapy, biological or immunotherapy, supplementation, and diet modification are considered systemic therapy. In systemic therapy, the entire body is treated in order to eradicate any cancer cells that may have spread from the colorectal tumor to other areas of the body.

Local Treatments

Surgery

Surgery is the most common and usually the first treatment for patients who have colorectal cancer. The classic surgical procedure for colon cancer is an anterior resection that employs a "no touch" isolation technique. First the surgeon explores the abdomen to determine whether the tumor is resectable. Resection involves removal of the section of the bowel containing the tumor. Resection is performed segmentally (e.g., right or left hemicolectomy) with end-to-end anastomosis (the loose ends are connected to each other).

In some cases, the patient will require a colostomy. A colostomy may be required because it is necessary to remove a large amount of the intestine and the loose ends cannot be reattached, or colostomy may be necessary if the resection needs to be completed at a later date. A colostomy involves rerouting waste products from the colon through an opening in the abdominal wall called a stoma instead of passing them through the colon to the rectum where wastes are typically expelled from the body. The fecal waste is then collected in a bag and discarded. A colostomy may be temporary, or if the surgery is very extensive, it may be permanent.

Total colonic resection is performed for patients with familial polyposis and multiple colonic polyps. Although the drug sulindac (a COX inhibitor) appears to influence the morphological appearance of polyps in patients with familial adenomatous polyposis and induces apparent regression, it does not influence the progression of polyps toward a malignant pattern.

There are several forms of surgical treatment used for rectal cancer that do not involve cutting into the abdomen:
  • Electrofulgeration: the use of electricity to destroy tumors
  • Local excision: the removal of (cutting) a layer of the rectum that contains cancer
  • Local full-thickness resection: the removal of (cutting) cancer from all layers of the rectum
Any form of surgery can have side effects. In many cases, surgery for colorectal cancer will involve a large incision in the abdomen. The healing process for such major surgery can be very involved. The patient may experience postsurgical pain, weakness, fatigue, loss of appetite, and other effects for which medications and treatments may be prescribed. Depending upon factors such as age, general state of health, type of surgery, and extent of cancer, side effects and recovery time will vary considerably. Alterations in diet may be necessary during the recovery process due to the major changes made to the digestive tract. Chemotherapy, radiation therapy, biological therapy, supplementation, and diet modification either individually or in various combinations may be used after surgery (refer to the Cancer Surgery protocol for more specific information, including the type of postoperative analgesic to request).

Radiation Therapy

Radiation therapy (also known as radiotherapy) is considered a local treatment for colorectal cancer that uses targeted, high-energy x-rays to impede cancer cells' ability to grow and divide. The aim of radiation therapy is to aim the rays at the parts of the body where cancerous tumors were found to kill the cancer cells, while minimizing damage to healthy tissue. Radiation therapy is usually used postoperatively to eliminate any cancer that might have been missed.

Side effects of radiation include fatigue, localized hair loss, changes to appearance of skin, and digestive problems. Medicines and other treatments can reduce the intensity of the side effects. As with other cancer treatments, the incidence of side effects varies with patient health and the exact nature of the treatment.

For more information regarding radiation therapy please see the Cancer Radiation Therapy protocol.

Adjuvant Treatment

The goal of an adjuvant treatment is to systemically eliminate any cancer cells or micrometastases that may have spread from the primary tumor site to other parts of the body as well as to eliminate any microscopic cancer cells that may remain in the colorectal area. It is called systemic therapy because the entire system of the body is treated.

Several types of systemic treatments are usually used for early stage colorectal cancer: chemotherapy, biological or immunotherapy, supplementation, and diet modification. These therapies are referred to as adjuvant, meaning "in addition to," because they are used with surgery and radiation.

Chemotherapy

Chemotherapy uses drugs that can be taken in pill form or injected intravenously to kill cancer cells. Sometimes, a combination of the two is used. However, IV drugs must be given in a hospital or physician's office. Depending on the drugs used, chemotherapy is administered once or twice a month for 3-6 months. Sometimes the range might be extended to 7 or 8 months. Chemotherapy usually begins 4-6 weeks after the final surgery and is administered in a combination of two to three drugs that have been found to be the most effective.

Although the exact schedule depends on the specific drugs used, drugs may be given day 1 of a 3-week cycle or there may be a period of a week or two on the drugs, followed by a period of about 2 weeks off the drugs. It is believed that this cycling allows the body a chance to rest and recover between treatments. An entire course of chemotherapy lasts about 4-6 months, again depending on the drugs used. Unfortunately, these drugs have many side effects that can damage or destroy healthy tissues throughout the body. Some of these tissues and the side effects associated with them include:
  • Lining of digestive tract: nausea, vomiting, diarrhea, poor appetite, mouth sores
  • Hair roots: loss of hair
  • Blood cells: anemia (weakening of red blood cells' ability to carry oxygen), reduced blood clotting ability, and reduced immune (disease fighting) response
One problem with conventional chemotherapy dosing regimens is that while they allow the body a chance to rest and recover, this rest period may also enable the cancer a chance to grow new blood vessels and possibly mutate into a type that is chemotherapy resistant. Some studies indicate that a more scientific approach would be to lower the dose of conventional cytotoxic agents, reschedule their application, and combine chemotherapy drugs with agents designed to interfere with cancer's various growth pathways (signal transduction pathways) and inhibit the production of blood vessels (Holland 2000).

This lower-dose approach, known as metronomic dosing, uses a dosing schedule as often as every day. An amount as low as 25% of the maximum tolerated dose (MTD), in combination with various signal transduction (growth) pathway inhibitors, targets the endo-thelial cells making up the blood vessels and microvessels feeding the tumor. Endothelial cells then die with much less chemotherapy than conventional cancer cells, and the side effects to healthy tissue and the patient in general are dramatically reduced (Hanahan et al. 2000).

Biological or Immunotherapy

This form of therapy involves using drugs to boost the body's natural immune response (ability to fight disease). Examples of these drugs are interferon and monoclonal antibodies. They work with the body's immune system to block the growth of cancer cells. Biological therapy can be used on its own or in conjunction with other therapies.

Immunotherapy can result in side effects that are reminiscent of the flu: fever, aches, weakness, fatigue, and chills. Patients may also experience skin problems such as easy bruising or rashes, as well as diarrhea and nausea.

Cimetidine (Tagamet)

The drug cimetidine (brand name Tagamet) is sold over the counter and as a prescription medication. It has historically been used to reduce stomach acid production.

In 1988 a prospective, randomized, placebo-controlled study investigated the effect of cimetidine on the survival of 181 patients with gastric cancer. They were given either cimetidine at a dose of 400 mg twice daily or placebo for 2 years or until death. The study found that those given cimetidine had a significantly prolonged survival rate particularly in patients with more serious (Stages II and IV) disease ( Tonnesen et al. 198 8). Many hypotheses were offered to explain this phenomenon. Since cimetidine is a histamine receptor antagonist, it was suggested that the actions were mediated by this mechanism.

Cimetidine is a competitive inhibitor of the histamine receptors on the cells of the stomach that secrete acid. It binds to these receptors, called H2 receptors, and does not allow histamine to bind. Histamine is responsible for signaling these cells to secrete acid. If cimetidine is present, the cells do not get the signal to produce acid, thus reducing the pH of the stomach.

Histamine is one of the compounds the body secretes to inhibit an immune response. Histamine can be released in the tumor environment and act to suppress the immune response that the body may mount an attack on a tumor. In 1972, it was discovered that T suppressor cells, which are part of the regulatory arm of the immune system, express receptors for histamine on their surface (Melmon et al. 1972). T suppressor cells have been demonstrated to accelerate the growth of tumors. It was also demonstrated that histamine was capable of suppressing the immune response by activating these T suppressor cells (Rocklin et al. 1979). Many tumors, particularly colorectal cancers, secrete histamine resulting in elevated histamine levels within the tumor. Also, histamine is often secreted in response to surgical resection of colorectal cancers and significant immunosuppression ensues from this and other factors.

Several studies have shown that the administration of H2 antagonists inhibits this immune suppression (Hansbrough et al. 1986; Adams 1994; Adams et al. 1993). During surgery, some cancer cells may be released into the bloodstream and a suppressed immune system may contribute to their ability to escape immune surveillance and establish metastatic lesions. If the immune system is suppressed, these cells stand a better chance of becoming tumors. Cimetidine seems to inhibit this suppression, enabling the immune system to build up a more effective response to the tumor so the cancer can be attacked by the immune system. This may be one of the mechanisms through which cimetidine works; however, other H2-blockers (ranitidine for example) that are stronger than cimetidine do not demonstrate this effect to the same degree as cimetidine.

In addition, many tumors are infiltrated with lymphocytes as a part of the immune response. These tumor infiltrating lymphocytes (TIL) are a good prognostic indicator because they are part of the body's immune response to the tumor (Harrison et al. 1994). With more TIL present, the body is better capable of attacking and eliminating the tumor. Administration of cimetidine significantly elevated the proportion of colorectal cancers with TIL, probably by inhibiting the suppressive function of histamine (Morris et al. 1995). In addition to the presence of TIL, the ability of peripheral lymphocytes to kill tumor cells is associated with enhanced disease free survival (Uchida 1993). In 1994, a study was performed that demonstrated that just 7 days of treatment with cimetidine (5 days preoperative and 2 days postoperative) decreased the 3-year mortality rate from 41% to 7% in colorectal cancer patients. As evidenced, postoperative administration of cimetidine may enhance the function of these cells as well.

Further, it has been postulated that cimetidine might exert an effect on the ability of cancer cells to metastasize. Cells circulating in the blood must have a mechanism by which they can stop circulating, bind to the cells in the area of interest, and perform their various functions. For a lymphocyte, this means that it has the ability to travel to a site of infection or a wound and stop there to perform its immunological functions. Similarly, for a cancer cell to bind and proliferate in an area, it must first adhere to the inside of a blood vessel.

One of the adhesion molecules that is present on blood vessel cells is called E-selectin. Several types of cancer cells use the carbohydrate groups called Lewis antigens (Lewis X and Lewis A.4) that are found on their surface to bind to E-selectin. It has been discovered that cimetidine inhibits the expression of E-selectin (ELAM-1) and inhibits cancer cell adhesion, and cancer cells that are in the bloodstream cannot bind to the cells of blood vessels and establish a metastatic tumor. Instead they are eventually eliminated. This would obviously lead to a much better outcome for the patient. Indeed, patients with aggressive colon cancer (Duke's Grade C) had a remarkable 84.6% 10-year survival rate when treated with cimetidine for 1 year after surgery compared to a 23.1% 10-year survival rate for patients that were not treated with cimetidine as an adjuvant therapy (Matsumoto et al. 2002).

After this discovery was made, one researcher went back to look at the Lewis antigen expression in tumors that were resected from patients that had been treated with cimetidine. When the tumors were analyzed for Lewis antigen expression, those patients who had tumors with the Lewis antigen and were treated with cimetidine had an average survival rate of 90.7% compared to 33.7% for those that were not treated with cimetidine. For those patients whose tumors did not express the Lewis antigens, there was no significant difference between cimetidine treated and untreated. However, approximately 70% of the tumors in this study did express the Lewis antigen (Matsumoto et al. 2002).

Research has also demonstrated that cimetidine used in conjunction with chemotherapy can significantly improve survival rates. For example, the outcome of Matsumoto's study, which was conducted through the collaboration of 15 institutions in Japan, revealed very promising findings. From 1990-1992, 64 patients were enrolled in a study to examine the effects of cimetidine. Patients were treated for 1 year after primary tumor removal with a chemotherapy drug called 5-FU (5-fluorouracil) and cimetidine or 5-FU by itself. The patients were given either 200 mg of 5-FU with 800 mg of oral cimetidine or 200 mg of 5-FU alone daily for 12 consecutive months. The patients were followed for 10 years, and the results are truly remarkable. Overall, the 10-year survival rate for the cimetidine treated group was 84.6%, while the group that received 5-FU alone was 49.8% (Matsumoto et al. 2002).

The beneficial effects of cimetidine in the treatment of colon cancer are well-documented. These effects probably arise from the multiple actions of cimetidine as an H2 receptor antagonist, an immunomodulator, and an inhibitor of adhesion molecule expression. The FDA, however, has not approved these indications for use in cancer treatment. This means that colorectal cancer patients should discuss the use of cimetidine with their oncologist. While cimetidine can be purchased over the counter, if it is physician prescribed, it may be covered by insurance.

The proven mechanisms of action of cimetidine suggest that it would significantly alter the ability of certain colon cancers to grow and metastasize. Additional studies will verify how effective cimetidine is on its own in improving long-term survival in colon cancer patients.

Treatment of Pain

In colorectal cancer, as well as in other cancers, the growth of tumors can result in abnormal levels of pressure on nerves. Therefore, pain is a major concern for patients.

Cancer treatments can result in pain reduction when the reduction of the tumor relieves pressure on the nerves. The doctor can prescribe pain relief medications that can be successful singly or in combination. The most common side effects of pain medications are fatigue and constipation. Rest and laxatives can moderate these.

In cases when pain medication alone is not enough to make the patient comfortable, the treatment team may decide on treatments that affect the nerves directly. These include alcohol injection in a nerve to inhibit pain response and surgically severing nerves to prevent transmission of pain impulses. Refer to the Cancer Surgery protocol to learn why morphine should be avoided except to alleviate pain in hospice-type settings.

Continued . . .


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