by Dr. C.H. Weaver M.D. updated 4/2019
Colon cancer is classified as stage IV when the cancer has spread to distant locations in the body and cannot be primarily treated with surgery; this may include the liver, lungs, bones, distant lymph nodes or other sites.
Patients diagnosed with stage IV colon cancer have an increasing number of treatment options as a result of genomic testing and the development of precision cancer medicines. Some patients may be cured of their cancer, and others can derive significant long term survival benefit with appropriate sequencing of treatment based on their cancers genomic profile.(1) Patients should make sure they discuss the goal of treatment with their doctor - some patients can even avoid chemotherapy.
Patients with Stage IV colon cancer can be broadly divided into two groups:
- Those with widespread, metastatic cancer that cannot be treated with surgery (sometimes called unresectable cancer )
- Those with cancer that has metastasized to a single site
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.
The majority of patients diagnosed with stage IV colon cancer have unresectable or widespread disease. Careful sequencing of chemotherapy and precision cancer medicines continue to improve the outcomes for these patients.
This section covers the initial, also called first-line, treatment of Stage IV colon cancer. For information about the treatment of cancer that has recurred or progressed after initial treatment, visit Recurrent Colon Cancer.
Treatment of Metastatic Colon Cancer
Treatment of advanced colon cancer is best accomplished using chemotherapy and precision cancer medicines based on genomic-biomarker testing of the cancer. Some individuals are only treated with targeted therapies and can avoid chemotherapy all together. Treatment selection is based on
- Genomic biomarker testing
- Location of the primary cancer
- Patient preference
Fluorouracil chemotherapy (5-FU) has been the standard treatment for stage IV colon cancer and is typically administered with leucovorin (LV), a drug that is similar in structure and function to the essential vitamin folic acid. Leucovorin enhances the anticancer effects of fluorouracil by helping the chemotherapy drug bind to and stay inside the cell for a greater period of time, producing longer lasting anticancer effects.
The addition of other drugs to 5-FU/LV and an oral alternative has been found to provide additional benefit and standard chemotherapy treatment for advanced colon cancer now includes any of the following regimens.
- FOLFOX (LV/5-fluorouracil + Eloxatin (oxaliplatin)
- CAPEOX (Xeloda (capecitabine) + Eloxatin)
- FOLFIRI (LV/5-fluorouracil + Camptosar (irinotecan)
- FOLFOXIRI (LV/5-fluorouracil + Camptosar + Eloxatin)
FOLFOX AND FLOFIRI when paired with Avastin® (bevacizumab) is the standard initial treatment for most patients and improves survival particularly for the treatment of left sided colon cancers.
FOLFOXIRI + Avastin doubles the estimated 5-year overall survival rate when compared to FOLFIRI + Avastin.(2)
Eloxatin based chemotherapy regimens can be associated with significant side effects including diarrhea, fatigue and damage to the nerves (neuropathy). Many colon cancer experts are now limiting the use of the this medication to no more than 3-4 cycles and patients should discuss this with their physician.
Precision Cancer Medicines
By testing an individual’s colon cancer for specific unique genomic- biomarkers doctors can offer personalized treatment approach utilizing precision medicines.
Colorectal Cancer Biomarkers That can be Targeted
Not all colon cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing should be performed to test for certain genetic mutations or the proteins they produce on ALL patients because the results can help select treatments 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.
- 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”.
- 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.(3)
- 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 and patients with MSI-H tumors may respond differently to certain treatment.
- HER 2 is a protein involved in normal cell growth and well know as a target for treatment in breast cancer. Approximately 4% of colon cancers over-express (make too much of) the HER2 protein, and this over-expression contributes to cancer cell growth and survival. HER2 targeted therapies is HER2 + colon cancer can dramatically improved outcomes and all colo-rectal cancers should be tested for HER 2.
Targeting “Wild type” KRAS & RAS
Erbitux® (cetuximab) and Vectibix (panitumumab) precision cancer medicines called monoclonal antibodies that work 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.(4,5,6)
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.(3)
Maintenance therapy may improve survival for patients with metastatic colorectal cancer as compared with re-introduction of chemotherapy at the time of disease progression.(10) Maintenance therapy refers to therapy that is used following initial therapy, when a patient’s cancer is stable and not exhibiting signs of progression.
Researchers reported the results of the OPTIMOX2 clinical trial in which continuous maintenance therapy was evaluated among patients with metastatic colorectal cancer. This trial included 202 patients with metastatic colorectal cancer who were initially treated with Eloxatin® (oxaliplatin)-based chemotherapy. One group of patients was then treated with continuous maintenance chemotherapy (same as initial chemotherapy without Eloxatin to avoid neuropathy) while the other group was treated again once their disease progressed
- Progression-free survival was improved for patients treated with maintenance therapy and overall survival was improved from 19 to 26 months on average without significant side effects.
Treatment of Colon Cancer That Has Metastasized To a Single Site
Stage IV colon cancer commonly spreads to the liver or the lungs. Some patients who have cancer that has spread to a single area are candidates for surgery to remove the metastases.
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.(7)
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
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 advanced colon cancer being developed in clinical trials.
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 make sure their cancer undergoes genomic profiling. This can also be accomplished with blood testing using a "liquid biopsy" if tissue is not available.
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 over expresses the human epidermal growth factor receptor 2 (HER2).(8)
New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research.
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.(9) 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.
Next: Surgery for Colon Cancer
- Venook A, Niedzwiecki D, lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)
- Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group. J Clin Oncol. 33, 2015 (suppl 3; abstr 657).
- 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.
- 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.
- Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy. Journal of Clinical Oncology. 2010;28:3687-94.
- Maindrault-Goebel F, et al. Final Results of OPTIMOX2, a Large Randomized Phase II Study of Maintenance Therapy or Chemotherapy-Free (CFI) after FOLFOX in Patients with Metastatic Colorectal Cancer (MRC): A GERCOR Study. Proceedings from the 2007 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4013.