Medically reviewed by Dr. C.H. Weaver M.D. updated 5/2019
When colon cancer has returned following an initial treatment with surgery, radiation therapy, and/or chemotherapy or has stopped responding to treatment, it is said to be recurrent or relapsed.
Patients with recurrent colon cancer can be broadly divided into two groups:
- Those with recurrent cancer that can be surgically removed with the goal of cure.
- Those with more widespread cancer.
Colon cancer may spread (metastasize) to the liver, lung, or other locations. When the site of metastasis is a single organ, such as the liver, and the cancer is confined to a single defined area within the organ, patients may benefit from local treatment directed at that single metastasis.
Most patients with recurrent colon cancer have previously been treated and the recurrent cancer may be resistant to whatever regimen the patient has already taken. Testing for specific genomic abnormalities of an individuals cancer is essential to determine optimal treatment for recurrent disease. Many patients survive for years after developing recurrent cancer as a result on precision cancer medicines being developed to target the specific genomic abnormalities. In addition participation in a clinical trial if available should be considered.(1,2,3)
Precision Cancer Medicines
Genomic testing of an individual’s colon cancer for specific unique biomarkers allows doctors to select specific precision medicines. Individuals not previously tested should undergo genomic testing of the cancer tissue to determine whether newer precision cancer medicines are a treatment option. If its not possible to test the specific area of recurrence useful genomic information can still be obtained using a "liquid biopsy" to look for genomic abnormalities in the blood.
The purpose of precision cancer medicine is to define the genomic alterations in the cancer’s DNA that are driving that specific cancer. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Not all colon cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing is performed to test for certain genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack specific colon cancer cells with specific genetic mutations.
- EGFR: The epidermal growth factor receptor (EGFR) is involved in cellular growth and replication. Some colon cancers produce too much EGFR and this leads to more rapid growth of the cancer. Some medicines specifically target EGFR and the spread of cancer can be reduced or delayed.(4,5)
- The RAS Genes: KRAS and NRAS are a family of proteins found in cells that when mutated promote cancer cell growth. An estimated 40–50% of colorectal cancers contain these genes. Some colon cancer treatments don’t work if the RAS gene is abnormal. If cancer has a KRAS or NRAS mutation drugs that inhibit cancer cell growth and survival by targeting a protein known as the EGFR are ineffective. Cancers lacking these genetic mutations are referred to as “wild type”.(1,2)
- BRAF: BRAF is also a gene that signals cells to divide. Patients with mutant BRAF genes generally have a poorer prognosis (chance of survival and worse side effects) but may benefit from treatment with a precision cancer medicine.(6)
- PIK3CA: While somewhat new, a growing number of clinicians are testing for mutant PIK3CA genes; particularly in patients who have early-stage colorectal cancer. There is some suggestion that aspirin use may help decrease the risk of recurrent colorectal cancer in patients with early stage disease and PIK3CA mutation.
- Microsatellite Instability High (MSI-H) MSI-H is a DNA abnormality found in about 15% of colon cancers. It is most often found in tumors associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-H is what “happens” when the genes that regulate DNA function don’t work correctly. These DNA regulating genes, known as Mismatch Repair Genes (MMR), work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable. A high frequency of instability is called MSI-H. Patients with MSI-H cancers appear to respond better to immunotherapy than chemotherapy.(8,9)
Targeting “Wild type” KRAS & RAS
Erbitux® (cetuximab) and Vectibix (panitumumab) are a type of precision cancer medicine called a monoclonal antibody that works by binding to EGFR which is involved in cellular growth and replication,. By targeting EGFR the spread of cancer can be reduced or delayed. Both Vectibix and Erbitux can be combined with chemotherapy to improve outcomes in patients that test positive for EGFR and do not have a RAS mutations.(4,5,7)
Targeting BRAF and EGFR Doubles Progression-free Survival in Metastatic Colorectal Cancer
Zelboraf (vemurafenib) is a novel precision cancer medicine that only works in patients whose cancer has a V600E BRAF mutation. Five to 10 percent of colorectal cancer patients carry a very specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF protein that stimulates cancer growth. The addition of Zelboraf to treatment with Erbitux in patients with metastatic colorectal cancer that have a BRAF V600E mutation has been shown to double survival time without cancer progression.(6)
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells. A diagnostic test to measure the level of PD-L1 is available.(8,9)
PD-1: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by certain immune cells. Drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.
Keytruda (pembrolizumab) and Opdivo (nivolumab) belong to a new class of medicines called “checkpoint inhibitors” and both have significant anti-cancer activity in advanced colorectal cancer patients with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) abnormalities.(8,9)
Other targeted treatments have emerged to match a person’s genetic makeup or a tumor’s genetic profile. As a result, all patients should undergo molecular testing.
HER2-Positive Colorectal Cancer
The HER2 receptor is a protein that is normally found on the surface of several different types of cells in the body. The HER2 receptors span into the cell, and are involved in a biologic pathway that is involved in cellular replication. Sometimes, a mutation within a gene that is responsible for the HER2 receptor becomes mutated, and too many receptors are produced. This, in turn, results in cells that divide and spread without their normal biologic controls.
Cancer cells that have too many HER2 receptors are referred to as HER2-positive. Fortunately, targeted agents have been developed that bind to different sites within the HER2 pathway, resulting in decreased cell division and spread.
Two of these agents are trastuzumab and lapatinib. The two agents bind along the HER pathway at different points, both producing anti-cancer effects. Both agents are approved for the treatment of HER2-positive breast cancer. The treatment combination consisting of Herceptin (trastuzumab) plus Tykerb (lapatinib) provides significant anti-cancer activity in colorectal cancer that overexpresses the human epidermal growth factor receptor 2 (HER2).(11)
Treatment of Colon Cancer that Has Metastasized to a Single Site
Stage IV colon cancer commonly spreads to the liver or the lungs. When metastases are limited to a single organ, treatment of that organ may improve outcomes:
Treatment of the Liver: When it’s possible to completely surgically remove all liver metastases, surgery is the preferred treatment. Although surgery offers some patients the chance for a cure, a majority of patients with liver metastases are not candidates for surgery because of the size or location of their tumors or their general health. Some of these patients may become candidates for surgery if initial treatment with chemotherapy shrinks the tumors sufficiently. If the tumors continue to be impossible to remove surgically, other liver-directed therapies may be considered. These other therapies include radiofrequency ablation (use of heat to kill cancer cells), cryotherapy (use of cold to kill cancer cells), delivery of chemotherapy directly to the liver, and radiation therapy. Relatively little information is available from clinical trials about the risks and benefits of these other approaches, but they may benefit selected patients.(10)
Treatment of Older Individuals
A large percentage of patients with advanced colorectal cancer are 65 years or older. Because elderly patients commonly have concurrent illnesses or other medical difficulties that are perceived to exacerbate the side effects of chemotherapy, elderly patients are often treated with reduced doses of chemotherapy. Clinical studies have shown, however, that elderly patients get the same benefit from chemotherapy treatment as younger patients.
While a dose reduction or delay may sometimes be necessary, it may also compromise the optimal treatment of some patients. All patients over 65 should be closely monitored for toxic side effects of chemotherapy, especially during their initial chemotherapy administration cycle.
Strategies to Improve Treatment of Recurrent Colon Cancer
The progress that has been made in the treatment of colon cancer has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of colon cancer.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. New precision medicines are being developed for the treatment of colon cancer and patients should ask their doctor about whether testing is appropriate.
New Approaches to Treating Liver Metastases: Researchers continue to explore news ways to treat cancer that has spread to the liver. One approach that is being evaluated is radioembolization This strategy uses radioactive microspheres (small spheres containing radioactive material). The small spheres are injected into vasculature of the liver, where they tend to get lodged in the vasculature responsible for providing blood and nourishment to the cancer cells. While lodged in place, the radioactive substance spontaneously emits radiation to the surrounding cancerous area while minimizing radiation exposure to the healthy portions of the liver.(2) Researchers are also exploring alternatives to radiofrequency ablation for the destruction of liver tumors, as well as new approaches to delivering chemotherapy to the liver.
Phase I clinical trials: New chemotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anticancer activity in patients.
- Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine. 2008;359:1757-65.
- Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26:1626-1634.
- Colucci G, Gebbia V, Paoletti G, et al. Phase III Randomized Trial of FOLFIRI Versus FOLFOX4 in the Treatment of Advanced Colorectal Cancer: A Multicenter Study of the Gruppo Oncologico Dell’Italia Meridionale. Journal of Clinical Oncology. 2005;(23)22:4866-4875.
- Cunningham D, Humblet Y, Siena S, et al. Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer. New England Journal of Medicine 2004;351:337-345.
- Hriesik C, Ramanathan R, Hughes S. Update for Surgeons: recent and noteworthy changes in therapeutic regimens for cancer of the colon and rectum. Journal of the American College of Surgeons2007; 205: 468-478.
- Alsina J, Choti MA. Liver-directed therapies in colorectal cancer. Seminars in Oncology. 2011;38:651-567.
- Reference: Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncology. Published online April 20, 2016.