by Dr. C.H. Weaver M.D. updated 3/2022
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 The average survival duration has improved from less than one year to over 3 years and 20% of patients now survive 5 years or longer as a result of the development of more effective systemic therapy.
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. Some individuals are only treated with precision cancer medicines or immunotherapy and can avoid chemotherapy all together. Because the caner has already spread outside the colon surgical removal of the primary cancer does not appear to improve survival.17 Individuals however with cancer that has metastasized to one or two sites may benefit from treatment with surgery or radiation directed to those sites.16,17 Treatment planning and 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 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)
- XELOX (Xeloda, Eloxatin, leucovorin)
- 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
According to results of the TRIBE 2 phase 3 clinical trial a strategy that begins treatment with FOLFOXIRI plus Avastin and reintroduces the same treatment after cancer progression is preferable to other chemotherapy regimens in patients with metastatic colorectal cancer.
In the TRIBE 2 clinical trial a total of 679 patients with previously untreated metastatic CRC were randomly assigned to receive treatment with FOLFOXIRI plus Avastin followed by reintroduction of the same regimen after cancer progression or treatment FOLFOX followed by FOLFIRI post-progression.
Overall patients treated with the FOLFOXIRI "program" survived 19.2 months without cancer progression compared to 16.4 months for those treated with FOLFOX followed by FOLFIRI. Overall survival was improved from 23 to 28 months on average. FOLFOXIRI treated patients experienced more side effects including diarrhea, low white blood cell counts and hypertension. Moreover, FOLFOXIRI treated patients were twice as likely to die from complications of treatment. There were 8 treatment-related deaths with FOLFOXIRI compared to 4 with FOLFOX6-FOLFIRI.
The study authors concluded that FOLFOXIRI plus Avastin followed by reintroduction of the same regimen after disease progression was a preferable therapeutic strategy to sequential administration of FOLFOX6-FOLFIRI in patients with metastatic CRC.26
These regimens all use Eloxatin chemotherapy and 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 this medication to no more than 3-4 cycles and patients should discuss this with their physician.
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.
Precision Cancer Medicine Treatment
Individuals with the following biomarkers may have their colon cancer treated differently using targeted precision cancer medicines.
Epidermal growth factor receptors (EGFR) occur in ~ 10% of colon cancers, are most commonly left sided and can be targeted with Erbitux® (cetuximab) and Vectibix (panitumumab) which are precision cancer medicine called monoclonal antibodies that work by binding to EGFR and when combined with chemotherapy can improve outcomes in patients that test positive for EGFR and do not have a RAS mutation.4,5,6
BRAFV600: Patients with mutant BRAF gene have historically had a poorer prognosis but their prognosis is significantly improved with the development of precision cancer medicines that target the V600E BRAF mutation. Treatment with a combination of precision medicines has been shown to double survival time for patients with recurrent cancer and doctors are now evaluating the use of these medications as initial therapy for BRAF positive colon cancer.3,21
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-High colon cancer can be more effectively treated with the precision cancer immunotherapy drugs called "checkpoint inhibitors." 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 (HER 2) targeted therapies can dramatically improve outcomes and all colo-rectal cancers should be tested for HER 2 at the time of diagnosis. This is important because patients over expressing HER2 do not benefit from treatment with the commonly used EGFR inhibitors and these medications should be avoided. Patients can benefit from treatment with one of several different precision cancer medicine combinations that target HER2 like Herceptin (trastuzumab), Tykerb (lapatinib) and Tucatinib.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.
Cancer driving mutations and biomarkers that can be used to develop new precision cancer medicines are being continuously identified and incorporated into genomic testing panels.
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 When it’s possible to completely surgically remove all liver metastases, surgery is a preferred treatment.
- One analyses has demonstrated that surgery for liver metastases that can be resected has produced long-term overall survival of nearly 50% at five years and nearly 30% at 10 years.16
- In some patients with inoperable liver metastases, an initial round of chemotherapy or neoadjuvant radiation therapy can be used to shrink the liver metastases enough so that surgery becomes possible.18
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 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.10,12-19
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.
Researchers reported the results of the OPTIMOX 2 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® 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 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.
Medications Commonly Used to Treat Recurrent Colon Cancer
- Xeloda (Capecitabine)
- Camptosar (Irinotecan)
- Eloxatin (Oxaliplatin)
- Avastin (Bevacizumab)
- Stivarga (Regorafenib)
- Lonsurf (TAS-102)
Erbitux is a monoclonal antibody that works by binding to the epidermal growth factor receptor (EGFR). EGFR is involved in cellular growth and replication, and by targeting EGFR, the spread of cancer can be reduced or delayed.
Cyramza™ (ramucirumab) is as a monoclonal antibody that works by blocking the growth of new blood vessels to the cancer, essentially starving it of nutrients.
Vectibix® (panitumumab) is a monoclonal antibody targeted against the EGFR pathway. Vectibix appears to benefit only those patients whose cancers do not contain a mutation in a gene known as KRAS. KRAS mutations occur in an estimated 40-50% of metastatic colorectal cancers and can be identified by testing a sample of tumor tissue.
The U.S. Food and Drug Administration (FDA) approved Stivarga® (regorafenib) for the treatment of patients with metastatic colorectal cancer that has progressed following previous treatment because Stivarga was demonstrated to delay cancer progression and prolong survival.22,23 Stivarga is a multi-kinase inhibitor that targets multiple biological pathways involved in cancer development and is an important addition to the portfolio of treatments that can be sequenced to provide the best outcomes in colo-rectal cancer. Additional studies published in 2019 have provided guidance on how to optimally dose Stivarga to achieve the highest quality of life. These studies suggest that Stivarga should be initially administered at a lower dose and then gradually increased or escalated to an optimal dose. This strategy helps avoid unnecessary side effects and improve quality of life.24,25
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 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.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack colon cancer cells with specific abnormalities, leaving normal cells largely unharmed. Development of precision medicines are for the treatment of colon cancer is ongoing and these novel medicines are first utilized patients with recurrent cancers and once proven effective they become available through clinical trials for treatment of earlier stage disease. All patients need to make sure their cancer undergoes genomic profiling. This can also be accomplished with a tissue sample and in blood using a "liquid biopsy" if tissue is not available.
COLOMATE: Using a Liquid Biopsy in CRC to Select a Molecularly Targeted Therapy.
The primary objectives of the COLOMATE trial are “to perform blood-based genomic profiling on patients with treatment-refractory metastatic colorectal cancer to facilitate access to specific targeted treatments based on the molecular profiles of their cancers. Patients with specific cancer driving genomic alterations such as RAS/BRAF wild-type, HER2-amplified, FGFR-altered, and RAS-mutated, abnormalities will be eligible to be treated with precision cancer medicines in development that target these mutations. Genetic Testing in Screening Patients With Metastatic or Unresectable Colon or Rectal Cancer for a COLOMATE Trial
- TKI-Checkpoint Inhibitor Combinations
Combination of Stivarga with a checkpoint inhibitor could help overcome immunotherapy resistance and improve outcomes. Targeted oral tyrosine kinase inhibitors (TKIs) such as Stivarga (regorafenib) have an established role in third-line treatment of metastatic colorectal cancer, combining a TKI with checkpoint inhibitor immunotherapy appears promising based on clinical study results presented at the Congress.
In an initial study Stivarga and the checkpoint inhibitor Opdivo (nivolumab) were evaluated in heavily pretreated patients with mCRC and advanced gastric cancer. Despite patients having failed an average of three prior lines of therapy 38% responded to the TKI-Checkpoint Inhibitor combination.26
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. 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.
- 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.
- FDA Approves First-Line Use of Vectibix® (Panitumumab) Plus FOLFOX for Patients with Wild-Type KRAS Metastatic Colorectal Cancer
- FDA approves first cancer treatment for any solid tumor with a specific genetic feature
- FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer
- 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.
- Alsina J, Choti MA. Liver-directed therapies in colorectal cancer. Seminars in Oncology. 2011;38:651-567.
- American Cancer Society. Colorectal Cancer Facts & Figures 2017-2019. Atlanta: American Cancer Society, 2017.
- 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.
- 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.
- 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.
- SIR-Spheres® microspheres (Yttrium-90 Microspheres) Product Information. Available at: com/us/clinicians/package-insert/.
- 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.
- 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.
- 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.
- 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.
- J Clin Oncol. 2019 March 20. Epub ahead of print).
- 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.
- FDA approves new treatment for advanced colorectal cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at: fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321271.htm
- Argiles G, et al. Abstract O-026. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.
- Lancet Oncol. 2019 Jun 28. Epub ahead of publication.
- Lancet Oncol. 2020 Mar 9. Epub ahead of print.
ImClone Systems, Inc. Erbitux® Phase III Study Meets Primary Endpoint in First-Line Treatment of Metastatic Colorectal Cancer. Available at: =. Accessed January 2007.
Tabernero J, Cohn AL, Obermannova R, et al. RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp). 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 512.