Treatment of Stage IV- Metastatic or Recurrent Colon Cancer

Genomic testing dictates how precision cancer medicines, chemotherapy & surgery are used to treat advanced colon cancer

by Dr. C.H. Weaver M.D. updated 7/2019

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. Some individuals are only treated with precision cancer medicines or immunotherapy and can avoid chemotherapy all together. Individuals with cancer that has metastasized to one or two sites may also be treated with surgery or radiation directed to those sites. 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)
  • CAPEOX (Xeloda (capecitabine) + Eloxatin)
  • FOLFIRI (LV/5-fluorouracil + Camptosar (irinotecan)
  • FOLFOXIRI (LV/5-fluorouracil + Camptosar + Eloxatin)

These treatment regimens sometimes 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)

All these regimens are Eloxatin based chemotherapy regimens 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 the 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. Learn more here...

Precision Cancer Medicine Treatment

Individuals with the following biomarkers may have their colon cancer treated differently using targeted precision cancer medicines.

Epidermal growth factor receptor (EGFR) occurs in ~ 10% of colon cancers, is most commonly left sided and can be targeted with Erbitux® (cetuximab) and Vectibix (panitumumab) - precision cancer medicine called monoclonal antibodies that works 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 genes generally have a poorer prognosis but may benefit from treatment with precision cancer medicines.

  • Targeting BRAF with Zelboraf (vemurafenib) a novel precision cancer medicine that only works in patients whose cancer has a V600E BRAF mutation has been shown to double survival time without cancer progression.
  • Bravtovi™ + Mektovi® targeting the hard to treat BRAFV600E-mutation is also effective and other treatment regimens targeting BRAFV600 are being evaluated in clinical trials. (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 (HER2) targeted therapies can dramatically improved outcomes HER2 + colon cancers and all colo-rectal cancers should be tested for HER 2. Herceptin (trastuzumab) plus Tykerb (lapatinib) provides significant anti-cancer activity in colorectal cancer that over expresses HER2.(9)

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 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.(10,12-19)

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.

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 the following groups:

  • Those with an isolated recurrence of cancer that can be surgically removed or treated with a directed therapy with the goal of cure.
  • Those with widespread cancer and an identifiable genomic or biomarker target can be treated with a precision cancer medicine.
  • Those with widespread cancer and no genomic or biomarker target are treated with chemotherapy.

Precision Cancer Medicines

Testing for specific genomic abnormalities of an individuals cancer is essential to determine optimal treatment for recurrent disease and should be performed on ALL patients with recurrent cancer if it has not previously been performed. 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. If it's not possible to test the specific area of recurrence useful genomic information can still be obtained using a "liquid biopsy" to look for genomic abnormalities in the blood.

Many patients survive for years after developing recurrent cancer as a result of precision cancer medicines being developed to target the specific genomic abnormalities. Patients with an identifiable genomic or biomarker target can be treated with precision medicines outlined above.

Systemic Chemotherapy Treatment

Most patients with recurrent colon cancer that have previously been treated with a systemic therapy have become resistant to whatever treatment regimen was initially used. Individuals who do not have a specific mutation identified that can be targeted are typically treated with chemotherapy medications not previously used or should consider participation in a clinical trial.

For individuals with a recurrence following chemotherapy treatment for early stage disease treated several years previously, treatment with a FOLFOX/FOLFIRI type regimen outlined at the beginning of this article can be used.

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)

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 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.

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.

References

  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).
  3. http://abstracts.asco.org/199/AbstView_199_194502.html
  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.
  6. http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-newsArticle&ID=1934128
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  8. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569366.htm
  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: com/us/clinicians/package-insert/.
  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).
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  25. Lancet Oncol. 2019 Jun 28. Epub ahead of print
  26. Fukuoaka S et al. abstract 2522.
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