Treatments for Colorectal Cancer: A Guide by Dr. Laura Porter

  Today I want to talk about the mechanisms of action of various treatments for colorectal cancer.  There are three different categories of systemic or drug treatment. Chemotherapy This treatment uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.  It also kills normal cells which is the reason for the side effects associated with chemotherapy.  Most chemotherapy targets cells that are fast growing which includes cancer cells, and surface or exposed cells such as skin, hair, nails and the GI tract. The main chemotherapy agents used are

• 5-FU, fluorouracil: FDA approved in 1962, it works by inhibiting DNA synthesis resulting in cell death, it is classified as an antimetabolite.
• Leucovorin: Counteracts the toxic effects of 5-FU, 'rescuing' the patient while permitting the 5-FU to inhibit DNA synthesis and prolong its activity
• Xeloda, capecitabine: FDA approved in 2001, it is another antimetabolite that is an oral medication which is selectively activated by tumor cells to process as 5-FU.
• Eloxatin, oxaliplatin: FDA approved in 2002, it is a platinum drug that targets fast dividing cells causing DNA damage which results in cell death.
• Camptosar, irinotecan: FDA approved in 1996, it blocks an enzyme in cells needed for cell division and growth, resulting in DNA breaks and cell death.
• Lonsurf, TAS-102: FDA approved in 2015, it is an oral medication that works like 5-FU by inhibiting DNA synthesis. The interaction of the components in TAS-102 may work against tumor cells that are resistant to 5-FU.

Targeted Therapy Targeted therapy, or biologics, are a type of treatment that uses drugs or other substances to identify and attack specific types of cancer cells with less harm to normal cells.  They are currently only used in patients with metastatic or stage IV colorectal cancer.

• Avastin, bevacizumab: FDA approved in 2004, it blocks the growth of new blood vessels thereby starving the tumor and causing cell death.
• Erbitux, cetuximab: FDA approved in 2004, it is a mouse/human monoclonal antibody that targets the EGFR (epidermal growth factor receptor), leading ultimately to increased cell death as well as reduced reproduction of tumor cells and blood vessels. It is only given to people that are KRAS wild-type.
• Vectibix, panitumumab: FDA approved in 2006, it is similar in action to Erbitux but it is a fully human monoclonal antibody.
• Stivarga, regorafenib: FDA in approved 2012, it is an oral medication that is similar in action to Avastin. It inhibits VEGF 2 and 3 and receptors that are involved in tumor cell growth and new blood vessel production.
• ZALTRAP, ziv-afilbrecept: FDA approved in 2012, is a human monoclonal antibody that is similar to Avastin. It works by inhibiting both human vascular endothelial growth factor receptors 1 (VEGFR1) and 2 (VEGFR2). Disruption of the binding of VEGFs to their cell receptors may result in the inhibition of tumor blood vessel growth, metastasis, and possible tumor regression.
• Cyramza, ramicurumab: FDA approved in 2014, it is a fully human monoclonal antibody directed against VEGFR-2 by blocking the growth of blood vessels to the tumor.

Immunotherapy Immunotherapy or immuno-oncology is a type of biological therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. Immunotherapy is currently only FDA approved in those with metastatic colorectal cancer who are MSI-H, or microsatellite instable. This means the tumor has a higher number of genetic mutations which make it more visible to the immune system. Clinical trials are being done in those that are MSS, or microsatellite stable, who have tumors that have less mutations.

• Keytruda, pembrolizumab: FDA approved in 2017 for MSI-H colorectal cancer, it is a humanized monoclonal antibody directed against PD-1 which is a protein present in immune cells called T-cells. T-cells keep the body’s immune system from reacting. This immunotherapy prevents the tumor from evading the patient’s immune system.
• Opdivo, nivolumab: FDA approved in 2018 for use with or without ipilumumab in MSI-H colorectal cancer, it is a fully human monoclonal antibody directed against programmed death-1 (PD-1, PCD-1). This results in the activation of T-cells and immune responses against tumor cells or pathogens.
• Yervoy, ipilumumab: FDA approved in 2018 for use with or without nivolumab in MSI-H colorectal cancer, it is a recombinant human monoclonal antibody directed against the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). This leads to a cytotoxic T-lymphocyte (CTL) mediated immune response against cancer cells.

I hope this has been helpful in understanding the differences in systemic treatment for colorectal cancer.     In 2003 Laura D. Porter MD was 43 years old and in her second year of her Pediatric Residency, when she was diagnosed with Stage IV Colon Cancer.  She had two recurrences in her ovary and liver and then in her pancreas and abdominal lymph nodes.  In May 2006 she became cancer free after many medical interventions.  It was during this time that she became involved with patient advocacy.  In 2005 she started attending online chats and found that her medical knowledge was an asset for those going through cancer treatment. She currently serves as an advocate/volunteer on over ten committees. Everything she does is with those affected by cancer in mind. Would this be of benefit to them, is this important for them to know?