Colon cancer is classified as stage IV or metastatic 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
Initial – First Line Treatment of Metastatic Colon Cancer
Treatment of advanced colon cancer may consist of chemotherapy, precision cancer medicines, and immunotherapy or some combination that is often determined by genomic – biomarker testing of the cancer.
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.
The addition of other drugs to 5-FU/LV and an oral alternative has been found to provide additional benefit to 5-FU alone and standard chemotherapy treatment for advanced colon cancer now includes any of the following regimens for individuals that do not have a cancer driving mutation or targetable biomarker.
- FOLFOX (LV/5-fluorouracil + Eloxatin (oxaliplatin)
- CAPEOX (Xeloda (capecitabine) + Eloxatin)
- FOLFIRI (LV/5-fluorouracil + Camptosar (irinotecan)
- FOLFOXIRI (LV/5-fluorouracil + Camptosar + Eloxatin)
These treatment regimens typically paired with Avastin® (bevacizumab) are the standard initial treatment for most patients and improve survival particularly for the treatment of left sided colon cancers. FOLFOXIRI + Avastin has been estimated to double the 5-year overall survival rate when compared to FOLFIRI + Avastin.2
Colon Cancer Mutations Targeted by Precision Cancer Medicines
Genetic Mutations: 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 genetic mutations or the proteins they produce on ALL patients. By testing an individual’s colon cancer for specific unique genomic- biomarkers doctors can offer a personalized treatment approach utilizing precision medicines. Colon cancer mutations are being identified and new medicines developed to target these mutations on an ongoing basis.
Individuals with the following biomarkers may have their colon cancer treated differently using targeted precision cancer medicines – other biomarkers are being identified on an ongoing basis.
Epidermal growth factor receptor (EGFR) occurs in ~ 10% of colon cancers.4,5,6
BRAFV600: Patients with mutant BRAF genes generally have a poorer prognosis but may benefit from treatment with precision cancer medicines.3,21
Microsatellite Instability High (MSI-H): MSI-H is a DNA abnormality found in about 15% of colon cancers.Keytruda, and Opdivo have both been demonstrated to improve treatment of individuals with MSI-High disease.7,8
HER 2: Human epidermal growth factor receptor 2 (HER2) targeted therapies can dramatically improve outcomes HER2 + colon cancers and all colo-rectal cancers should be tested for HER 2.9
NTRK:neurotrophic tropomyosin receptor kinases (NTRKs genes, which encode for TRKs can become abnormally fused to other genes, resulting in growth signals that can lead to cancer and be targeted with specific medications.
Treatment of Colon Cancer That Has Metastasized to a Single Site
Many individuals with CRC involving the liver or other sites erroneously conclude that they have no treatment options other than systemic therapy. Stage IV colon cancer commonly spreads to the liver or the lungs and patients who have cancer that has spread to one or two treatable sites are candidates for additional local treatment directed at the metastases.11,12 Clinical trials have demonstrated that the combination of systemic therapy and surgery for liver metastases further improves treatment outcomes.16,17,18 When it’s possible to completely surgically remove all liver metastases, surgery is a 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.
If the tumors cannot be removed surgically there are several other therapeutic options for the treatment of liver metastases, and isolated areas of cancer in other organs. The type of directed therapy used is determined by the size of the cancer, the number of metastases, and the location of the cancer within the liver or other organs.
The use of minimally invasive techniques such as ablation, embolization, and radioembolization allows the delivery of radiation therapy or chemotherapy directly to the liver tumor(s). Other therapies include radiofrequency ablation (RFA) which uses heat to kill cancer cells, cryotherapy (use of cold to kill cancer cells), delivery of chemotherapy directly to the liver, and radiation.10,12,13,14,15,16,17,18,19
SIR-Spheres Y-90 resin microspheres are a medical device used in an interventional radiology procedure known as selective internal radiation therapy (SIRT), or radioembolization, which targets high doses of radiation directly to liver tumors. The treatment consists of tens of millions of radioactive Y-90 coated resin particles, each no bigger in diameter than a human hair. SIR-Spheres Y-90 are injected into the hepatic artery, which is the main blood supply to the liver via a catheter inserted into the femoral artery through an incision in the groin. The Y-90 resin microspheres become lodged in the smaller blood vessels that surround cancer in the liver, where they deliver a high dose of radiation to the cancer, while sparing healthy liver tissue.13,15
Patients need to understand that many advanced treatment options are only be available at cancer centers specializing in the treatment of colon and rectal cancers and patients should consider getting an opinion at one of these centers.
Maintenance Therapy
Maintenance therapy may improve survival for patients with metastatic colorectal cancer as compared with re-introduction of chemotherapy at the time of disease progression.20 Maintenance therapy refers to therapy that is used following initial systemic therapy, when a patient’s cancer is stable and not exhibiting signs of progression.
Treatment of Recurrent Metastatic Colon Cancer
When colon cancer has returned following 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 isolated recurrence of cancer that can be surgically removed or treated with a directed therapy with the goal of cure.
- Those with more widespread cancer.
Most patients with recurrent colon cancer have previously been treated and the recurrent cancer has typically become resistant to whatever treatment regimen was initially used. Testing for specific genomic abnormalities of an individual cancer is essential to determine optimal treatment for recurrent disease. Many patients survive for years after developing recurrent cancer as a result of precision cancer medicines being developed to target the specific genomic abnormalities. In addition, participation in a clinical trial if available should be considered.
Many individuals will not have a specific mutation identified that can be targeted. Treatment of these individuals consists of chemotherapy medications not previously used or participation in a clinical trial.22,23,24,25
Medications Commonly Used to Treat Recurrent Colon Cancer
- 5-Flourouracil
- Xeloda (Capecitabine)
- Camptosar (Irinotecan)
- Eloxatin (Oxaliplatin)
- Avastin (Bevacizumab)
- Erbitux (Cetuximab)
- Cyramza (Ramucirumab
- Vectibix (Panitumumab)
- Stivarga (Regorafenib)
- Lonsurf (TAS-102)
Strategies to Improve Treatment
The major research focus in advanced colon cancer is the identification of additional cancer driving mutations as targets for precision cancer medicines and the development of immunotherapy treatment strategies.
References
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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).
3 http://abstracts.asco.org/199/AbstView_199_194502.html
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7 https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm
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