Treatment for colorectal cancer often involves a combination of surgery and medication. Currently there are 11 cancer drugs approved to treat colorectal cancer, two of which were recently approved by the U.S. Food and Drug Administration (FDA). Some of these are chemotherapy medications, while others are known as targeted treatments. (Unlike chemotherapy, targeted treatments are designed to spare healthy tissue in the hope of causing less severe side effects.)
The first step in treatment for colorectal cancer is often surgery to remove the section of the colon or rectum that contains the tumor, as well as nearby lymph nodes. (Lymph nodes are small organs located throughout the body that remove waste and fluids and help fight infection.) When a tumor is removed, doctors determine how likely it is that the cancer will return. In part, this depends on whether the tumor has passed through the wall of the colon or rectum or if tumor cells have spread to the lymph nodes. Once cancer cells reach the lymph nodes, they may spread to form new tumors in other parts of the body.
Chemotherapy given after surgery (and sometimes before surgery as well) can greatly reduce the chance of colorectal cancer spreading. For patients who have had surgery and whose cancer has not spread, the drugs used to reduce the chance of metastasis (spreading) are oxaliplatin (Eloxatin and others) and 5-fluorouracil (5-FU) or capecitabine (Xeloda and others). Capecitabine is a drug that the body turns into fluorouracil.
For people whose colorectal cancer has already spread to other areas of the body such as the liver or lungs, doctors often treat with chemotherapy alone. In some cases, surgery may also benefit patients with metastatic colorectal cancer, especially if chemotherapy has shrunk their tumors.
The medications used to treat metastatic colorectal cancer are 5-FU plus folinic acid (leucovorin) or levoleucovorin (Fusilev), capecitabine, oxaliplatin, and irinotecan (Camptosar and others). These drugs are combined in various ways to make them more effective. The most common drug combinations are called FOLFOX and FOLFIRI. Although the dosages and schedule vary, doctors give these treatments in cycles, each lasting two to four weeks. Treatment cycles are followed by a rest period to give the body time to recover from any side effects.
One newly approved oral chemotherapy drug is called Lonsurf, also known as TAS 102. Lonsurf is actually a combination of two drugs, trifluridine and tipiracil. Trifluridine is the active chemotherapy drug, but if a patient took that drug alone, the body would rapidly break it down, so it is combined with tipiracil to keep more of the drug available in the bloodstream to affect the tumor cell. Lonsurf is used for patients who have metastatic colorectal cancer and have received other standard therapies, including combination therapies, but still have disease progression. During clinical trials, Lonsurf was compared with placebo (no treatment), and some people clearly benefited and had stabilization of their disease. Lonsurf has expanded the range of treatment options for patients with metastatic colorectal cancer. Doctors are finding that using all of the standard drugs over time, in sequence, during the course of a patient’s diagnosis can give them the best outcomes in terms of extending survival and quality of life.
Targeted treatments focus on specific cell mechanisms thought to be important for the growth and survival of tumor cells. They work in different ways to destroy cancer cells.
Anti-angiogenesis drugs: Angiogenesis is the process of forming new blood vessels that nourish tissues. Drugs that block angiogenesis have been a target for therapy, because they make it impossible for tumors to grow. The three different anti-angiogenesis agents can be combined with chemotherapy to lead to longer overall survival. The most commonly used agent is bevacizumab (Avastin), followed by ziv-aflibercept (Zaltrap) and ramucirumab (Cyramza). The chemotherapy drugs that are typically combined with these anti-angiogenesis agents include oxaliplatin, irinotecan, 5-FU, and capecitabine.
Epidermal growth factor receptor (EGFR) inhibitors: Cetuximab (Erbitux) and panitumumab (Vectibix) block receptors that act as small antennas on the surface of colorectal cancer cells. When substances called epidermal growth factors attach to these receptors, they signal the cancer cells to grow and multiply. By blocking the receptors, these drugs prevent the growth factors from attaching and the cancer cells from growing into tumors.
Multi-kinase inhibitors: Regorafenib (Stivarga) targets kinase proteins, substances that send important signals to the cell’s control center. Some of the kinases help cells grow, while others help with angiogenesis. Regorafenib, which comes in pill form, is designed to help stop the growth of tumors by blocking these kinase proteins. This medication is used for people whose colorectal cancer has progressed after standard therapy. Regorafenib has the potential side effect of lowering blood counts, so patient’s blood cell levels have to be monitored carefully when using this treatment.
Immunotherapy is a type of cancer treatment that uses the body’s immune system to fight cancer. This is a very promising new field that has grown recently across all different kinds of cancer, and several new immunologic drugs have been approved by the FDA for treatment of some cancers. The challenge with immunotherapies in this field is that most people with colorectal cancer do not appear to have immunosensitive tumors, meaning that their cancer does not respond to immunologic treatment. One of the great current challenges in research is figuring out how to make more colorectal cancers more immunogenic (responsive to immunotherapy).
Personalizing Treatment: The Role of Genetic Mutations
Each tumor has its own biological makeup, based on the genes found in its cells. An important area of cancer research is understanding the biology of tumors and their genes. With this information, doctors can learn whether a particular tumor is likely to respond to a particular treatment. That helps doctors choose the right treatment for each person’s tumor. This approach—known as precision medicine or personalized medicine—is much more effective than using the same treatment for everyone, since some treatments don’t work for certain types of tumors.
To better understand what type of tumor a patient has, doctors look for tumor “markers” in the cell’s genes. Markers can predict whether a given treatment will be effective against a tumor or whether there is a high risk of the tumor coming back.
A key group of tumor markers that have been found in colorectal cancer are called KRAS, NRAS, and HRAS—known all together as the RAS genes. Forty percent of people with colorectal cancer have a mutation (change) in a RAS gene. Through clinical trials, researchers have learned that these patients do not benefit from treatment with the EGFR inhibitors cetuximab and panitumumab. However, they do benefit from chemotherapy.
The other 60 percent of people with colorectal cancer have no RAS mutation. People with this unchanged form of RAS are said to have the RAS wild-type gene. These patients do tend to benefit from treatment with EGFR inhibitors.
Knowing whether you have a RAS mutation or the RAS wildtype gene is important to your health care team in deciding the best treatment for your specific type of cancer. Because people with RAS mutations will not benefit from EGFR inhibitors, they can use other treatments that will be more helpful to them—or consider taking part in clinical trials.
Another area of current research is a mutation in the BRAF gene. Just like with RAS, the majority of patients with BRAF mutations do not respond to EGFR inhibitors. Through clinical trials, we have learned that there are certain drugs that may be able to block this BRAF gene, so that patients with this mutation can respond to EGFR inhibitors as well as people who don’t have the mutation. The drugs that are being studied for BRAF mutations have not yet been approved by the FDA, but this is a very active area of research, and new therapies may become available in the near future.
About 4 percent of metastatic colorectal cancers have a genetic trait known as a microsatellite instability (MSI), causing these tumors to have very large numbers of genetic mutations. Early clinical trials have shown that having a cancer with an MSI-H makes a patient more likely to benefit from immunotherapy. Ongoing clinical trials are further investigating this concept, which we hope will lead to FDA approval for use of immunotherapeutic drugs for people with MSI-High metastatic colorectal cancer. Researchers are also actively trying to find ways to stimulate the immune system in other patients with metastatic colorectal cancer who do not have an MSI.
Because tumor markers and genetic traits are such an important step on the road toward personalized medicine, researchers conduct many clinical trials on them. They are looking for new treatments that will work for people with RAS and BRAF mutations, MSI, and other genetic characteristics. They are also continuing to study people without these genetic traits to learn more about the medicines that will benefit them most.
To effectively treat any cancer, doctors must be able to give patients their full dose of medications, on schedule. But side effects of chemotherapy and targeted treatments can interfere with treatment. That is why it is so important to prevent side effects, or to treat them promptly if they do develop. If you are experiencing any side effects, you can and should seek help. If your doctor doesn’t ask you about side effects, be sure to bring them up.
Here Is a List of Common Side Effects and Ways They Can Be Prevented and Managed:
Nausea and vomiting are common side effects of nearly all chemotherapy treatments. However, there are many excellent anti-nausea medications that, if taken before the nausea and the vomiting really take hold, can stop the process and allow patients to tolerate the treatment much better. Doctors may prescribe ondansetron (Zofran and others), granisetron, and dolasetron (Anzemet). The steroid dexamethasone is also sometimes used, as is aprepitant (Emend).
Fever and infections can result when chemotherapy causes the level of white blood cells to drop, making it harder for the body to fight infection. That is why even a low-grade fever should be reported to your doctor, to make sure that your blood counts are normal. If the counts are low and you have a fever, antibiotics can be given to fight an existing infection. In addition, to raise the level of these blood cells to prevent infection from happening at all, doctors sometimes prescribe medications such as filgrastim (Neupogen) or pegfilgrastim (Neulasta).
Anemia, caused by a lowered level of red blood cells, often occurs in patients with colorectal cancer who develop blood in the stool. Fatigue (an extreme tiredness that isn’t usually eased by sleep) is the main symptom of anemia. Depending on the cause, anemia treatment may include eating more iron-rich foods such as dark green, leafy vegetables; sweet potatoes; beans; meat and fish; or enriched bread, cereal or pasta. Ask your health care team which foods would be best for you. In some cases, doctors treat anemia with iron supplements, blood transfusions, or drugs that help the body to make more red blood cells.
Blood clots may affect some cancer patients. This serious side effect occurs when a solid mass of blood cells forms and lodges in a blood vessel or in the heart. Blood thinners such as warfarin (Coumadin and others) and drugs called lowmolecular- weight heparins (LMWHs) effectively treat blood clots. For patients in the hospital who have had cancer surgery, doctors also use a mechanical cuff to prevent blood clots. One cuff is placed on each leg and gently squeezes every few minutes to help keep blood flowing.
Mucositis (sores inside the mouth and on the lining of the throat and digestive tract) can result from radiation treatments and from some types of chemotherapy. The sores inside the mouth may resemble canker sores. Mucositis can be a serious problem because it can cause pain and infections, making it difficult to eat, drink, and swallow. Once treatment ends, mouth sores do disappear. But before they fade, it’s important to work closely with your health care team to manage this side effect with good oral care and prescription products such as Gelclair or “miracle mouthwash” (sometimes called “magic mouthwash”).
Skin rash and other skin and nail conditions often result from the use of targeted treatments such as cetuximab and panitumumab. The skin rash may look almost like acne, but the cause is not oiliness but dryness. The skin becomes very dry and irritated. These symptoms are often a sign that these drugs are working; nevertheless, if you are taking an EGFR inhibitor and the skin side effects are bothersome, it is important to talk to your doctor about possible treatments. Rashes can often be treated or even prevented with antibiotics or certain creams.
Neuropathy (nerve damage) from chemotherapy such as oxaliplatin can lead to numbness or tingling in the hands and feet. One type of neuropathy is called transient, meaning it happens right after treatment. Transient neuropathy causes coldness, and it can affect the throat as well. To manage this, patients can keep their food at lukewarm temperature, and they may keep a pair of gloves by the refrigerator to reduce the discomfort from the cold until the neuropathy goes away. A second kind of neuropathy can develop over time, and it can even start after you are finished taking a drug. Gabapentin (Neurontin and others) is often used to relieve the pain of neuropathy. A lot of research is being done in this area.
Talk with your doctor if you are interested in getting into a clinical trial studying neuropathy. In the meantime, avoid drinking alcohol, which can damage nerves. Try wearing sneakers or shoes with “rocker bottoms” that allow the feet to roll while walking. These can relieve some of the pressure on the soles of the feet. Use hand tools, kitchen utensils, and even toothbrushes and pens with wider grips that make them easier to hold. It’s very important to talk with your doctor about nerve symptoms you experience so that he or she can adjust the dose or stop oxaliplatin if needed.
Pain can greatly affect your quality of life—your daily activities, eating habits, ability to get a good night’s sleep, and even your outlook and how you interact with others. Controlling different types of pain may require different approaches, which is why it is so important for members of your health care team to understand the type of pain you are experiencing. There are many excellent medications that can be used to help manage pain. It is important that you do not try to suffer through the pain without medication. Cancer pain can be strong, and sometimes strong medications are needed to help manage it. Your health care team can also help with the side effects of certain pain medications, such as constipation (defined as fewer than three bowel movements a week).