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Advanced Metastatic Colorectal CancerSpectrum Pharmaceuticals, Inc. An International Commercial-Stage Biotechnology Company

Colorectal cancer is cancer that starts in either the colon or the rectum. Colon cancer and rectal cancer have many features in common. The wall of the colon and rectum is made up of layers of tissues. Colorectal cancer starts in the inner layer and can grow through some or all of the other layers. The stage (extent of spread) of a cancer depends to a great degree on how deep the cancer goes into these layers.

Abnormal Growths in the Colon or Rectum

Cancer that starts in these different areas may cause different symptoms. But colon cancer and rectal cancer have many things in common. In most cases, colorectal cancers develop slowly over many years. We now know that most of these cancers start as a polyp -- a growth of tissue that starts in the lining and grows into the center of the colon or rectum. This tissue may or may not be cancer. A type of polyp known as an adenoma can become cancer. Removing a polyp early may keep it from becoming cancer.

Over 95% of colon and rectal cancers are adenocarcinomas. These are cancers that start in the cells that line the inside of the colon and rectum.

How Many People Get Colorectal Cancer?

The American Cancer Society's most recent estimates for colorectal cancer in the United States are for 2011:

  • About 101,340 new cases of colon cancer
  • About 39,870 new cases of rectal cancer
  • About 49,380 deaths from colorectal cancer

Not counting skin cancers, colorectal cancer is the third most common cancer found in men and women in this country. Overall, the lifetime risk of developing colorectal cancer is about 1 in 20.

The death rate from colorectal cancer has been going down for more than 20 years. One reason is that there are fewer cases. Thanks to colorectal cancer screening, polyps can be found and removed before they turn into cancer. And colorectal cancer can also be found earlier when it is easier to cure. Treatments have improved, too.

What Causes Colorectal Cancer?

While we do not know the exact cause of most colorectal cancers, there are certain known risk factors. A risk factor is something that affects a person's chance of getting a disease. Some risk factors, like smoking, can be controlled. Others, such as a person's age, can't be changed.

But risk factors don't tell us everything. Having a risk factor, or even several, does not mean that you will get the disease. And some people who get colorectal cancer may not have any known risk factors. Even if a person with colorectal cancer has a risk factor, it is often very hard to know what part that risk factor may have played in the development of the disease.

Researchers have found some risk factors that may increase a person's chance of getting polyps or colorectal cancer.

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Risk Factors You Cannot Change

Age

The chances of having colorectal cancer go up after age 50. More than 9 out of 10 people with colorectal cancer are older than 50.

Having had Polyps or Colorectal Cancer Before

Some types of polyps increase the risk of colorectal cancer, especially if they are large or if there are many of them. If you have had colorectal cancer (even if it has been completely removed), you are more likely to have new cancers start in other areas of your colon and rectum. The chances of this happening are greater if you had your first colorectal cancer when you were younger.

Having a History of Bowel Disease

Inflammatory bowel diseases, like ulcerative colitis and Crohn's disease, increase the risk of colon cancer. In these diseases, the colon is inflamed over a long time. If you have one of these diseases your doctor may want you to have colon screening testing more often. (These diseases are different than irritable bowel syndrome (IBS), which does not increase colorectal cancer risk.

Family History of Colorectal Cancer

If you have close relatives (parents, brothers/sisters, or children) who have had this cancer, your risk might be increased. This is especially true if the family member got the cancer at a younger age. People with a family history of colorectal cancer should talk to their doctors about when and how often to have screening tests.

Certain Family Syndromes

A syndrome is a group of symptoms. The 2 most common inherited syndromes linked with colorectal cancers are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC).

Familial adenomatous polyposis (FAP): FAP is caused by changes (mutations) a gene that a person inherits from his or her parents. About 1% of all colorectal cancers are due to FAP. People with FAP typically get hundreds or thousands of polyps in their colon and rectum, most often in their teens or as early adults. Cancer often starts in one or more of these polyps as early as age 20. By age 40, almost all people with this disorder will have cancer if surgery to remove the colon is not done.

If your doctor tells you that you have a condition that makes you or your family members more likely to get colorectal cancer, you will most likely need to begin colon cancer testing at a younger age, and you might want to think about genetic counseling.

Race or Ethnic Background

Some racial and ethnic groups such as African Americans and Jews of Eastern European descent (Ashkenazi Jews) have a higher colorectal cancer risk. Among Ashkenazi Jews, several gene mutations have been found that lead to an increased risk of colorectal cancer.

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Risk Factors Linked to Things You Do

Some lifestyle-related factors have been linked to colorectal cancer. In fact, the links between diet, weight, and exercise and colorectal cancer risk are some of the strongest for any type of cancer.

Certain Types of Diets

A diet that is high in red meats (beef, lamb, or liver) and processed meats (like hot dogs, bologna, and lunch meat) can increase your colorectal cancer risk. Cooking meats at very high heat (frying, broiling, or grilling) can create chemicals that might increase cancer risk.

Diets high in vegetables and fruits have been linked with a lower risk of colorectal cancer, but diets high in fiber do not seem to help.

Lack of Exercise

Getting more exercise may help reduce your risk. Being very overweight (or obese) increases a person's risk of having and dying from colorectal cancer.

Smoking

Most people know that smoking causes lung cancer, but long-time smokers are more likely than non-smokers to get colorectal cancer. Smoking also increases the risk of many other cancers.

Alcohol Use

Heavy use of alcohol has been linked to colorectal cancer. Men should limit their use to no more than 2 drinks a day and women no more than one.

Type 2 Diabetes

People with type 2 diabetes have an increased chance of getting colorectal cancer. They also tend to have a worse outlook (prognosis).

The American Cancer Society and several other medical organizations recommend earlier testing for people with increased colorectal cancer risk. These recommendations differ from those for people at average risk. For more information, talk with your doctor.

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About Treatment

The 4 main types of treatment for colorectal cancer are:

  • Surgery
  • Radiation therapy
  • Chemotherapy ("chemo")
  • Targeted therapies (like monoclonal antibodies)

Depending on the stage of your cancer, 2 or more types of treatment may be used at the same time, or used one after the other.Take your time and think about all of your treatment choices. You may want to get a second opinion. This can give you more information and help you feel better about the treatment plan you choose. Your chances of having a good outcome are highest in the hands of a medical team that has experience in treating colorectal cancer.

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Surgery

The types of surgery used to treat colon and rectal cancers differ slightly so they are described separately.

Colon Surgery

Surgery is often the main treatment for earlier stage colon cancer. The surgery is called a colectomy or a segmental resection. Usually the cancer and a piece of normal colon on either side of the cancer (as well as nearby lymph nodes) are removed. The 2 ends of the colon are then sewn back together. For colon cancer, a colostomy (an opening on the belly for getting rid of body wastes) is not usually needed, although sometimes a short-term colostomy may be done to let the colon heal.

Most often, surgery is done through a cut (incision) in the belly (abdomen), but for some earlier stage cancers a different approach might be an option. In laparoscopic-assisted colectomy, instead of one long incision in the abdomen, the surgeon makes several small ones. Special long instruments are put into these small openings and used to remove part of the colon and lymph nodes. This method seems to be about as likely to cure the cancer as the standard approach for earlier stage cancers, and patients usually recover faster than they do after the usual operations. But the surgery calls for special skill. If you are thinking about laparoscopic surgery, be sure to look for a skilled surgeon who has done a lot of these operations.

Some very early colon cancers (stage 0 and some early stage I tumors) or polyps can be removed using a colonoscope (the same thin, flexible scope used to do a colonoscopy). When this is done, the surgeon does not have to cut into the abdomen. Early stage cancers that are only on the surface of the colon lining can be removed along with a small amount of nearby tissue. For a polypectomy, the cancer is cut out across the base of the polyp's stalk, the area that looks like the stem of a mushroom.

Rectal Surgery

Surgery is usually the main treatment for rectal cancer, although radiation and chemo will often be given before or after surgery. There are several types of surgery for rectal cancer.

Operations (such as polypectomy, local excision, and local transanal resection) can be done with instruments placed into the anus, without having to cut through the skin. One of these methods might be used to remove stage I cancers that are fairly small and not too far from the anus.

For some stage I, and most stage II or III rectal cancers, other types of surgery may be done. These are described here:

Low anterior resection: This approach is used for cancers near the upper part of the rectum, close to where it connects with the colon. The surgeon makes the cut in the belly. Then he removes the cancer and a small amount of normal tissue on either side of the cancer, along with nearby lymph nodes and a large amount of fatty and fibrous tissue around the rectum. The anus is not affected. After the surgery, the colon is reattached to the anus and waste leaves the body in the usual way.

Proctectomy with colo-anal anastomosis: For some stage I and most stage II and III rectal cancers in the middle and lower third of the rectum, the entire rectum and the colon attached to the anus will need to be removed. This is called a colo-anal anastomosis (anastomosis means "connection"). This is a harder operation to do. For a short time, an ostomy (an opening on the belly for getting rid of body wastes) is needed to allow healing after surgery. A second operation is done later to close the ostomy opening.

Abdominoperineal (AP) resection: For cancers in the lower part of the rectum, close to its outer connection to the anus, an abdominoperineal (AP) resection is done. For this the surgeon makes a cut in the belly (abdomen), and another in the area around the anus. Because the anus is removed, a colostomy is needed. A colostomy is an opening of the colon in the front of the abdomen. It is used as a way for the body to get rid of solid body waste (feces or stool). The usual hospital stay for an AP resection is 4 to 7 days, depending on your overall health.

Pelvic exenteration: If the rectal cancer is growing into nearby organs, more extensive surgery is needed. In a pelvic exenteration the surgeon removes the rectum as well as nearby organs such as the bladder, prostate, or uterus if the cancer has spread to these organs. A colostomy is needed after this operation. If the bladder is removed, a urostomy (an opening to collect urine) is also needed.

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Radiation Treatment for Colon and Rectal Cancer

Radiation treatment is the use of high-energy rays (such as x-rays) to kill cancer cells or shrink tumors. The radiation may come from outside the body (external radiation) or from radioactive materials put right in the tumor (brachytherapy or internal or implant radiation).

After surgery, radiation can kill small areas of cancer that may be missed during surgery. If the size or place of a tumor makes it hard to take it out, radiation may be used before surgery to shrink the tumor. Radiation can also be used to ease symptoms of advanced cancer, such as intestinal blockage, bleeding, or pain.

The main use for radiation treatment in people with colon cancer is when the cancer has attached to an internal organ or the lining of the belly (abdomen). If this happens, the doctor can't be sure that all the cancer has been removed, and radiation is used to kill the cancer cells left behind after surgery. Radiation is seldom used to treat metastatic colon cancer.

For rectal cancer, radiation is often given either before or after surgery to help prevent the cancer from coming back in the place where it started.

External-beam radiation therapy: In this treatment, radiation is focused on the cancer from a machine outside the body. This is the type most often used for people with colon or rectal cancer. Treatments are given 5 days a week for many weeks. Each treatment lasts only a few minutes, but the setup time -- getting you into place for treatment -- usually takes longer.

A different approach may be used for some cases of rectal cancer with small tumors. A small device can be put into the anus to deliver the radiation. This way the radiation reaches the rectum without passing through the skin and other tissues of the abdomen. This means it is less likely to damage nearby tissues and cause side effects.

Brachytherapy (internal radiation therapy): In this method, small pellets or seeds of radioactive material are placed next to or right into the cancer. The radiation travels only a short distance, limiting the effects on nearby healthy tissues. This method is sometimes used in treating people with rectal cancer, particularly sick or older people who would not be able to go through surgery.

Some patients who have a lot of spread to the liver but little or no spread to other distant parts of the body may get treatment with infusion through the artery that goes to the liver. The doctor injects tiny glass "beads" that are coated with a radioactive atom (yttrium-90). These beads block some of the small blood vessels that feed the tumors and their radioactivity helps kill the cancer cells.

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Chemotherapy

Chemotherapy (chemo) is the use of drugs to fight cancer. The drugs may be put into a vein or given by mouth. These drugs enter the bloodstream and spread throughout the body, making this treatment useful for cancers that have spread to distant organs.

Chemo is sometimes used before surgery to try to shrink the cancer and make surgery easier. It may also be given after surgery because it can increase the survival rate for patients with some stages of colorectal cancer. Chemo can also help relieve symptoms of advanced cancer and help people live longer.

In some cases, chemo drugs can be put into an artery leading to the part of the body with the tumor. This approach is called regional chemotherapy. Since the drugs go straight to the cancer cells, there may be fewer side effects. Regional chemotherapy is sometimes used for colon cancer that has spread to the liver.

Spectrum markets a drug called FUSILEV (levoleucovorin) for injection. FUSILEV is used in combination with a chemotherapy drug called 5-fluorouracil (5-FU) for the palliative treatment of advanced metastatic colorectal cancer.

FUSILEV enhances the toxicity of 5-FU by increasing 5-FU induced inhibition of thymidylate synthase, an enzyme important in DNA repair and replication.

The most common side effects that have been observed in patients with advanced colorectal cancer receiving FUSILEV in combination with 5-FU were diarrhea, nausea and stomatitis. FUSILEV enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of FUSILEV and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination.

Please talk with your doctor about all possible side effects with FUSILEV.

Please see the FUSILEV website at www.fusilev.com for full prescribing and complete safety information.

INDICATIONS AND USAGE

FUSILEV is a folate analog indicated for:
Rescue after high-dose methotrexate therapy in osteosarcoma.
Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.
Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

LIMITATIONS OF USE

FUSILEV is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

IMPORTANT SAFETY INFORMATION

Contraindications
FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Warnings and Precautions
Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute
FUSILEV enhances the toxicity of fluorouracil.
Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study.

Adverse Reactions
Allergic reactions were reported in patients receiving FUSILEV.
Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high dose methotrexate therapy.
The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Fusilev in combination with 5-FU were diarrhea, nausea and stomatitis.

Drug Interactions
FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

Reporting of Suspected Adverse Reactions
You are encouraged to report side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see the FUSILEV (levoleucovorin) for injection full prescribing information for complete safety information.

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Targeted Therapies

Targeted therapies are drugs that attack the parts of cancer cells that make them different from normal cells. These targeted drugs work differently from standard chemo drugs. They often have different (and less severe) side effects. At this time, they are most often used either along with chemo or by themselves if chemo is no longer working.

Some of these are man-made proteins called monoclonal antibodies that have been approved for use, along with chemo, to treat colorectal cancer.

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More Treatment Information

For more details on treatment options -- including some that may not be addressed in this document -- the National Comprehensive Cancer Network (NCCN) and the National Cancer Institute (NCI) are good sources of information. The NCCN, made up of experts from many of the nation's leading cancer centers, develops cancer treatment guidelines for doctors to use when treating patients. Those are available on the NCCN Web site (www.nccn.org).

The U.S. National Cancer Institute's website (http://www.cancer.gov) provides accurate, up-to-date information about many types of cancer, information about clinical trials, resources for people dealing with cancer, and information for researchers and health professionals.

Source: The Web site of the American Cancer Society (http://www.cancer.org)

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