Treatment Options 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 organs). Surgery is most often the first step in treating localized colorectal cancer. 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

The purpose of “neoadjuvant” (prior to surgery) chemotherapy is to shrink the tumor, making the surgery an easier process and increasing its chances of success. Neoadjuvant chemotherapy is sometimes given in combination with radiation.

After surgery, cancer cells that are not detectable by tests may still exist, so doctors often 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 which 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 zivaflibercept (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, they are 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.

  • TRK inhibitor. There are two TRK inhibitors approved by the FDA for the treatment of solid tumors (including colorectal cancer tumors) that have an NTRK gene fusion and have advanced following treatment or for which there is no other satisfactory treatment alternative. Larotrectinib (Vitrakvi) was approved in November 2018 and entrectinib (Rozlytrek) as approved in August 2019. Both of these drugs are “agnostic” in that they 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).

In April 2019, the FDA approved the kinase inhibitor encorafenib (Braftovi) in combination with the EGFR inhibitor cetuximab for the treatment of BRAF-mutated metastatic colorectal cancer.

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, were granted accelerated approval by the FDA for people with metastatic colorectal cancer that has progressed after chemotherapy and that 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 July 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.

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, then 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.

Personalizing treatment: the role of genetic mutations

Each tumor has its own biological makeup, based on the genes found in its cells. The genes in tumor cells are different from genes in healthy cells. An important area of cancer research is understanding this biology. With this information, it’s possible for doctors to know whether a particular tumor is likely to respond to a specific therapy, allowing for the best possible treatment approach. This is known as precision (or personalized) medicine.

To better understand the biological makeup of a person’s tumor, doctors look for changes in genes within the tumor that may serve as “markers.” Markers can predict whether a given treatment will be effective against a tumor and the risk of the tumor recurring (the cancer returning).

Following are tumor markers and genetic changes that can be identified in colorectal cancer.

RAS

A key group of tumor markers that have been found in colorectal cancer consists of changes in KRAS and NRAS—known collectively 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 people do not benefit from treatment with the EGFR inhibitors cetuximab and panitumumab (see “Targeted Therapy” section). However, the presence of these genetic alterations does not affect response to chemotherapy.

The other 60 percent of people with colorectal cancer have no RAS mutation. These people are said to have the RAS “wild-type” gene. These individuals have a higher likelihood of benefiting from treatment with EGFR inhibitors.

BRAF

As with RAS mutations, the majority of patients with mutations in the BRAF gene do not respond to EGFR inhibitors. Clinical trials have shown there are certain drugs that can block this BRAF gene, which may allow patients with this mutation to respond to treatment with EGFR inhibitors. This is an active area of research, and combination therapies that block the BRAF gene are now available.

MSI-H

About 4 percent of metastatic colorectal cancers (cancers that have spread to other parts of the body) have a genetic trait known as high microsatellite instability (MSI-H), which causes these tumors to have a large number of genetic mutations. There are three drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of this type of tumor (see “Immunotherapy” section). Additional treatment approaches are being studied in clinical trials.

NTRK Fusions

A genetic abnormality can cause the neurotrophic receptor tyrosine kinase (NRTK) gene in a cancer cell to become connected (fused) to another unrelated gene. When this occurs, it causes uncontrolled “signaling” of tropomyosin receptor kinase (TRK) proteins that can lead to tumor growth. A TRK inhibitor has been approved by the FDA for the treatment of people with colorectal cancer that exhibits this genetic abnormality (see “Targeted Therapy” section).

 

 

Information provided by CancerCare.

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