Treatment Update: Colorectal Cancer

Treatment for colorectal cancer often involves a combination of surgery and medication.

Surgery

In approximately 80 percent of patients diagnosed with colorectal cancer, the cancer is localized (has not spread to other parts of the body). In these cases, surgery is typically performed. The surgeon will remove the section of the colon or rectum that contains the tumor and will also remove nearby lymph nodes, which are small organs located throughout the body that remove waste and fluids and help fight infection. Removing the colon or rectal tumor and nearby lymph nodes enables a pathologist (a physician who examines laboratory samples of body tissue for diagnostic purposes) to more accurately determine the stage of the cancer.

Chemotherapy

When the tumor is located in the rectum, neoadjuvant (prior to surgery) chemotherapy is given to shrink the tumor, making the surgery an easier process and increasing its chances of success. Neoadjuvant chemotherapy is often given before or after radiation or chemoradiation.

After surgery, cancer cells that are not detectable by tests may still exist, so doctors may suggest adjuvant (after surgery) chemotherapy. The goal is to destroy any remaining tumor cells, decrease the chances of the cancer coming back and reduce the risk of tumor cells spreading to other parts of the body.

The neoadjuvant and adjuvant chemotherapies most often given in the treatment of colorectal cancer are:

• 5-Fluorouracil (Adrucil), also called 5-FU, is given intravenously (through a needle into a vein), often with the vitamin-like drug leucovorin (folinic acid) which helps it work more effectively.

• Capecitabine (Xeloda and others), taken in pill form, is changed by the body to 5-FU when it reaches the site of the tumor.

• Oxaliplatin (Eloxatin) is given intravenously in combination with 5-FU or capecitabine.

Colorectal cancer that has spread to other areas of the body (such as the liver or lungs) can be treated with oxaliplatin in combination with 5-FU or capecitabine. It can also be treated with irinotecan (Camptosar) in combination with 5-FU.

In 2015, the FDA approved Lonsurf, a pill that combines the chemotherapy trifluridine and tipiracil (an enzyme inhibitor that helps trifluridine work more effectively) for people with advanced colorectal cancer that is no longer responding to other therapies.

Targeted Therapy

Targeted therapies focus on specific molecules and cell mechanisms thought to be important for cancer cell survival and growth, taking advantage of what researchers have learned in recent years about how cancer cells grow. Targeted therapies are meant to spare healthy tissues and provide treatment against cancer cells that is more focused than chemotherapy.

• VEGF inhibitors. These treatments “starve” the tumor by blocking the action of VEGF (vascular endothelial growth factor), a protein released by tumors that contributes to blood vessel growth (angiogenesis). VEGF inhibitors bevacizumab (Avastin), ramucirumab (Cyramza) and ziv-aflibercept (Zaltrap) are given intravenously, typically along with chemotherapy such as oxaliplatin, irinotecan, 5-FU or capecitabine. VEGF inhibitors can help make chemotherapy drugs more effective.

• EGFR inhibitors. EGFR (epidermal growth factor receptor) is a protein often found in high amounts on the surface of cancer cells. The targeted therapies cetuximab (Erbitux) and panitumumab (Vectibix), given intravenously, are designed to block the action of EGFR, preventing cancer cells from growing into tumors. For patients with RAS wild-type tumors, an EGFR inhibitor is often given in combination with chemotherapy.

• Kinase inhibitor. Kinase proteins send important signals to the cell’s control center, including signals that promote cell growth. The kinase inhibitor regorafenib (Stivarga), taken in pill form, is designed to help stop the growth of tumors by blocking several kinase proteins. It is usually given in cases of advanced colorectal cancer that are no longer responding to other therapies.

• TRK inhibitors. There are two TRK inhibitors approved by the FDA for the treatment of solid tumors (including colorectal cancer tumors) that have the very rare NTRK gene fusion and have advanced following treatment or for which there is no other satisfactory treatment alternative. Larotrectinib (Vitrakvi) was approved in 2018 and entrectinib (Rozlytrek) was approved in 2019. Both of these drugs target a genetic driver of cancer rather than a specific type of tumor.

• HER2 inhibitors. About 4 percent of metastatic colorectal tumors have an abundance of human epidermal growth factor receptor 2 (HER2) receptor cells on their surface. These types of tumors are most often treated with trastuzumab (Herceptin), in combination with either pertuzumab (Perjeta) or lapatinib (Tykerb).

• Combination therapies

  • The kinase inhibitor encorafenib (Braftovi), in combination with the EGFR inhibitor cetuximab, is approved for the treatment of BRAF-mutated metastatic colorectal cancer that has been treated with at least one prior therapy. It is also approved for the second-line treatment of metastatic colorectal cancer that has a BRAF V600E mutation.

  • In January 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for RAS wild-type HER2-positive unresectable (inoperable) or metastatic colorectal cancer that has progressed following treatment with chemotherapy.

Immunotherapy

Our immune system works constantly to keep us healthy. It recognizes and fights against danger, such as infections, viruses and growing cancer cells. In general terms, immunotherapy uses our own immune system as a treatment against cancer.

In 2017, the immunotherapy drugs pembrolizumab (Keytruda) and nivolumab (Opdivo), known as PD-1 inhibitors or immune checkpoint inhibitors, were granted accelerated approval by the FDA for people with metastatic colorectal cancer that has progressed after chemotherapy and has one of two specific genetic features (MSI-H or DNA mismatch repair deficiency), both of which can prevent DNA within cells from repairing itself.

In 2018, the FDA approved nivolumab in combination with the immunotherapy ipilimumab (Yervoy) for the treatment of people with previously-treated metastatic colorectal cancer that is positive for either MSI-H or DNA mismatch repair deficiency.

In June 2020, the FDA approved pembrolizumab for the first-line treatment of people with unresectable (inoperable) or metastatic colorectal cancer that is positive for either MSI-H or DNA mismatch repair deficiency.

Immunotherapy continues to be a key area of research in the treatment of metastatic colorectal cancer, including:

• Vaccines. Vaccines that boost the immune system have the potential to treat colorectal cancer or prevent it from recurring after treatment. A number of vaccines are being studied in clinical trials. One vaccine approach involves removing a person’s own immune system cells from their blood, altering them with a substance that provides instructions to attack cancer cells and injecting them back into the person’s body.

• Immune checkpoint inhibitors. Tumor cells often have “immune checkpoint” molecules that act as a shield, allowing the cancer to evade an attack by the immune system. Immune checkpoint inhibitors are drugs designed to remove the shield and allow the immune system to attack the cancer cells.

• Combining immunotherapy and targeted therapy. PD-1 is a molecular “brake” that prevents the body’s immune system from attacking tumors. Combining PD-1 inhibitors with targeted or other therapies that activate immune cells may stimulate the immune system to attack cancer cells.

All cancer treatments can cause side effects. It’s important that you report any side effects that you experience to your health care team so they can help you manage them. Report them right away—don’t wait for your next appointment. Doing so will improve your quality of life and allow you to maintain your treatment plan. It’s important to remember that not all patients experience all side effects, and patients may experience side effects not listed here.

Side Effects of Chemotherapy

The side effects of chemotherapy depend on the type and dose of drugs given and the length of time they are used, and can include:

• Fatigue
• Nausea or vomiting
• Diarrhea
• Hair loss
• Increased risk of infection (from having too few white blood cells)
• Easy bruising or bleeding (from having a low platelet count)
• Changes in memory or thinking
• Peripheral neuropathy (numbness or tingling in hands and feet)

Side Effects of Targeted Therapy

Targeted therapy doesn’t have the same effect on the body as do chemotherapy drugs, but can still cause side effects. Side effects of targeted therapies can include diarrhea, liver problems (such as hepatitis and elevated liver enzymes), nerve damage, rash, high blood pressure and problems with blood clotting and wound healing.

Side Effects of Immunotherapy

Immunotherapy travels through the bloodstream, helping to prompt an immune response. Because it can trigger an attack on healthy cells as well as cancer cells, certain side effects may be experienced, including fatigue, decreased appetite and digestive tract symptoms (including colitis). The management of these potential side effects is discussed in the next section of this booklet. Immunotherapy can also affect the thyroid, skin, lungs, liver, pancreas, adrenal glands and kidneys.

General Side Effects

Some side effects may occur across treatment approaches. This section provides tips and guidance on how to manage these side effects should they occur.

Managing Digestive Tract Symptoms

Nausea and vomiting

• Avoid food with strong odors, as well as overly sweet, greasy, fried or highly seasoned food.
• Nibble on dry crackers or toast. These bland foods are easy on the stomach.
• Having something in your stomach when you take medication may help ease nausea.
• Do not lay down after eating.

Diarrhea

• Drink plenty of water. Ask your doctor about using drinks such as Gatorade which provide electrolytes. Electrolytes are body salts that must stay in balance for cells to work properly.
• Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary. If the diarrhea is bad enough that you need medicine, discuss it with your doctor or nurse.
• Choose fiber-dense foods such as whole grains, fruits and vegetables, all of which help form stools.
• Avoid food high in refined sugar and those sweetened with sugar alcohols such as sorbitol and mannitol.

Managing Loss of appetite

• Eating small meals throughout the day is an easy way to take in more protein and calories, which will help maintain your weight. Try to include protein in every meal.
• To keep from feeling full early, avoid liquids with meals or take only small sips (unless you need liquids to help swallow). Drink most of your liquids between meals.
• Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, ice cream, granola bars, liquid nutritional supplements, puddings, nuts, canned tuna or trail mix.
• If you are struggling to maintain your appetite, talk to your health care team about whether appetite-building medication could be right for you.

Managing Fatigue

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects of many cancer treatments. If you are taking a medication, your doctor may lower the dose of the drug, as long as it does not make the treatment less effective. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you.

There are a number of other tips for reducing fatigue:

• Take several short naps or breaks during the day.
• Take short walks or do some light exercise, if possible.
• Try easier or shorter versions of the activities you enjoy.
• Ask your family or friends to help you with tasks you find difficult or tiring.
• Save your energy for things you find most important.

Fatigue can be a symptom of other illnesses, such as anemia, diabetes, thyroid problems, heart disease, rheumatoid arthritis and depression. So be sure to ask your doctor if he or she thinks any of these conditions may be contributing to your fatigue.

Managing Pain

To help your doctor prescribe the best medication, it’s useful to give an accurate report of your pain. Keep a journal that includes information on:

• Where the pain occurs
• When the pain occurs
• How long it lasts
• How strong it is on a scale of 1 to 10, with 1 being the least amount of pain and 10 the most intense
• What makes the pain feel better and what makes it feel more intense

There are a number of options for pain relief, including prescription and over-the-counter medications. It’s important to talk to a member of your health care team before taking any over-the- counter medication to determine if they are safe and will not interfere with your treatments.

Q: I heard about there being differences between left-side tumors and right-side tumors. What does that mean?

A: There are biological differences in tumors depending on their location within the colon. Metastatic colorectal cancer tumors originating from the left side of the colon (the descending colon, sigmoid colon and rectum) are associated with better outcomes than tumors originating from the right side of the colon (the cecum and ascending colon). These differences will likely be the subject of increased focus in the coming years as researchers seek to more deeply understand the difference in treatment options and outcomes based on the location of the tumor.

Q: I was recently diagnosed with colorectal cancer and will soon have surgery. Will I definitely need to have a colostomy as part of the surgical process?

A: A colostomy is a procedure which diverts a portion of the colon to a small opening—called a stoma—in the wall of the abdomen. The stoma is attached to a pouch, which collects stools as they exit the body. Depending on the extent of your surgery, the need for a temporary or permanent colostomy is possible, or even likely. However, there are options that may be available to you, which you should discuss with your surgeon or another member of your health care team.

If you do require a colostomy, there is support available to help you adjust to the change in your daily routine. It can be valuable to speak with an oncology social worker at CancerCare. Consulting with an enterostomal therapy nurse (who specializes in ostomy care and rehabilitation) and/or joining a local support group can also be very helpful.

Q: I have been diagnosed with colorectal cancer, and I’m concerned about my children’s risk of getting the disease. What screenings or tests are recommended for them?

A: Typically, it is recommended that children undergo their first colonoscopy when they are ten years younger than their parent was at the time of their colorectal cancer diagnosis. It is also important to know whether you have an inherited condition, such as Lynch syndrome, which increases the risk of colorectal cancer. If your colorectal cancer is possibly inherited, your children should talk to their physician about genetic screening, in addition to undergoing colonoscopies at the recommended intervals.