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Stage IV-Metastatic Colon Cancer

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.



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.




9 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.

10 Alsina J, Choti MA. Liver-directed therapies in colorectal cancer. Seminars in Oncology. 2011;38:651-567.

11 American Cancer Society. Colorectal Cancer Facts & Figures 2017-2019. Atlanta: American Cancer Society, 2017.

12 Cho M, Gong J and Fakih M.The state of regional therapy in the management of metastatic colorectal cancer to the liver. Expert Review of Anticancer Therapy, 2016; 16(2): 229–245.

13 van Hazel GA, Heinemann V, Sharma NK et al. SIRFLOX: Randomized Phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2016; 34: 1723–1731.

14 Kennedy AS, Ball D, Cohen SJ et al.Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for 90Y resin microspheres. Journal of Gastrointestinal Oncology. 2015; 6: 134–142.

15 SIR-Spheres® microspheres (Yttrium-90 Microspheres) Product Information. Available at:

16 Wei A, Greig P, Grant D, et al. Survival After Hepatic Resection for Colorectal Metastases: A 10-Year Experience. Annals of Surgical Oncology. 2006; 13:668-676.

17 Portier G, Elias D, Bouche O, et al. Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial. Journal of Clinical Oncology. 2006; 24: 4976-4982.

18 Capussotti L, Muratore A, Mulas MM, Massucco P, Aglietta M. Neoadjuvant Chemotherapy and Resection for Initially Irresectable Colorectal Liver Metastases. British Journal of Surgery. 2006;93:1001-1006.

19 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.

20 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.

21 J Clin Oncol. 2019 March 20. Epub ahead of print).

22 Grothey A, Sobrero AF, Siena S et al. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Paper presented at: 2012 Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA. Abstract LBA385.

23 FDA approves new treatment for advanced colorectal cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at:

24 Argiles G, et al. Abstract O-026. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.

25 Lancet Oncol. 2019 Jun 28. Epub ahead of publication

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