Treatment of Stage IV of Colon Cancer
by Dr. C.H. Weaver M.D.
Colon cancer is classified as stage IV if the final evaluation following surgical removal of the cancer shows that the cancer has spread to distant locations in the body; this may include the liver, lungs, bones, distant lymph nodes or other sites. While it is commonly thought that patients diagnosed with stage IV colon cancer have few treatment options, certain patients can still be cured of their cancer, and others can derive significant benefit from additional treatment.
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. New combinations of chemotherapy drugs and the use of 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
For over 30 years the chemotherapy drug fluorouracil (5-FU) was the standard treatment for metastatic stage IV colon cancer. 5-FU 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.
More recently, 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 can be paired with Avastin® (bevacizumab) or Erbitux (cetuximab) to further improve survival to an average of 29 months.1
FOLFOXIRI + Avastin doubles the estimated 5-year overall survival rate when compared to FOLFIRI-Avastin.2
Precision Cancer Medicines
The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancer’s DNA that are driving that specific cancer. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. 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. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
By testing an individual’s colon cancer for specific unique 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 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.
- 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. Patients with MSI-H tumors may respond differently to certain treatment. It is important to test colon cancers for this trait because it can help determine if the colorectal cancer is related to an inherited family syndrome.
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.4,5,6
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
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 should ask their doctor about whether testing is appropriate.
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).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.
1 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)
2 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).
4 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.
5 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.
7 Alsina J, Choti MA. Liver-directed therapies in colorectal cancer. Seminars in Oncology. 2011;38:651-567.
8 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.
9 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.