Current Treatment Strategies
How We Fight Cancer
A growing number of effective therapies are available to treat colorectal cancer. Traditional therapeutic regimes include surgery, radiotherapy and chemotherapy. For cancer that has metastasized, targeted therapy has been an additional option since 2004.
Surgery is standard for Stage I-through-III CRC, where the tumor is considered local. Often times, the surgeon removes not only the tumor but also the portion of the colon containing the tumor and the surrounding fat and lymph nodes.101 Typically the healthy sections of the colon or rectum are reconnected at the end of the surgery.102 If this is not possible, the surgeon will perform a colostomy,103 a procedure in which the colon is rerouted to an opening in the abdomen called a stoma.104 Colostomy is often a temporary procedure until the bowel fully heals.105 During the healing period, you can expect temporary diarrhea or constipation, which are common after surgery and can be alleviated with medication. Proper nutrition after surgery is important for healing and speeding recovery.106
Common side effects after surgery include:107
- Pain, which can be controlled with medication
- Problems eating solid food
- Bleeding or blood clots that can form in the legs
Radiation therapy kills cancer cells with high-energy rays. It may be used alone or in combination with other therapies to shrink tumors before surgery or to destroy any remaining cancer cells after chemotherapy.108 Radiation can also be used to reduce tumor size to make a patient more comfortable, even when the cancer cannot be removed.
There is a limit to the amount of radiation a body can receive without causing irreversible damage to health tissues. Your doctor will take into account any previous exposure you may have had to radiation in assessing your options.109
Side effects common to radiation therapy include:110
- Decrease in bowel-control
- Skin soreness
- Irritation in the bladder or rectum
- Sexual problems
Chemotherapy (commonly referred to as ‘chemo’) is the treatment of cancer through medicines or drugs that attack and kill cancer cells.111 It differs from surgery and radiation therapy112 in that it is a systemic therapy, which is a treatment that goes throughout the entire body. Most chemotherapeutic drugs are taken as a liquid injection into a vein, while others are taken as a pill. The drugs travel in the blood and attack cancer cells throughout the entire body.113
The development of new chemotherapies has been successful in that a larger percentage of patients are responding to these new therapies.114 There are many different types of chemotherapy drugs, and often, the drugs are used in combination to attack the cancer more aggressively. This is known as combination therapy, which can also reduce the likelihood that the cancer would become resistant to any single chemotherapeutic drug.115 Combination therapy may use non-chemo drugs such as targeted therapy, which is also a systemic therapy and consists of anti-EGFR and antiangiogenic therapies. Targeted therapy is explained further in this section.
Table 2 outlines systemic drugs used for colorectal cancer,116 which includes chemotherapy and targeted therapy.
Table 2. National Comprehensive Cancer Network (NCCN) recommended systemic therapies
Standard Chemotherapy Combinations117
FOLFOX is a combination of Oxaliplatin, Leucovorin and 5-FU. It is received through IV continuous infusion and is repeated every 2 weeks.
mFOLFOX is a modified combination of Oxaliplatin, Leucovorin and 5-FU. It is received through IV continuous infusion and is repeated every 2 weeks.
mFOLFOX + Bevacizumab is a combination of Oxaliplatin, Leucovorin, 5-FU and Bevacizumab. It is received through IV continuous infusion and is repeated every 2 weeks.
CapeOX is a combination of Oxaliplatin and Capecitabine. It is taken orally for 14 days and repeated every 3 weeks.
CapeOX+ Bevacizumab is a combination of Oxaliplatin and Capecitabine that is taken orally for 14 days, along with IV infusion of Bevacizumab for 1 day. It is repeated every 3 weeks.
FOLFIRI is a combination of Irinotecan, Leucovorin and 5-FU. It is received through IV and is repeated every 2 weeks.
FOLFIRI + Bevacizumab is a combination of Irinotecan, Leucovorin, 5-FU and Bevacizumab. It is received through IV and repeated every 2 weeks.
FOLFIRI + Ziv-aflibercept is a combination of Irinotecan, Leucovorin, 5-FU and Ziv-aflibercept. It is received through IV and repeated every 2 weeks.
Capecitabine is taken orally for 14 days and is repeated every 3 weeks.
Capecitabine + Bevacizumab is a combination of taking Capecitabine orally for 14 days and Bevacizumab IV infusion for 1 day. This combination is repeated every 3 weeks.
Regorafenib is taken orally for 21 days and repeated every 28 days.
Chemotherapy can also be used for neoadjuvant therapy in order to shrink the tumor before surgery, facilitating the procedure, and it can be used after surgery to attack any cancer cells that might remain. Your doctor will work with you in deciding which drug, or combination of drugs, would be best for you depending on the type and stage of your cancer, and whether surgery will be involved.
Side Effects of Chemotherapy
Chemotherapy is accompanied by side effects because, as the drugs kill cancer cells, they can also affect healthy cells. Common side effects include:117
- Hair loss
- Nausea and vomiting
- Mouth, gum and throat problems
- Nerve and muscle problems
Introduction to Targeted Therapies
Beginning in 2004, new treatments were developed called “Targeted Therapies,” which are designed to attack specific cell pathways used by cancers to survive and grow. These new treatments capitalize on advances in our understanding of the molecular basis of cancer and are improving our ability to treat metastatic colorectal cancer.
By interfering with these pathways, several benefits can be achieved:
- Cancer cells are unable to grow and commit a type of suicide, also called apoptosis
- Blood vessels that grow and feed cancer cells are halted, called antiangiogenesis
- Tissue around the cancer, known as the tumor microenvironment, can maintain a more normal structure.
Together, these new types of therapies represent a revolution in cancer treatment that offers new options and new hope for patients with mCRC.
If you have mCRC, the type of targeted cancer therapy you may receive depends on many factors, including the specific targets identified in your tumor. In this way, targeted cancer therapies are designed to be more selective for cancer cells than normal cells, which may lead to fewer side effects than chemotherapy drugs.119
Targeted cancer therapies are being studied for use alone, in combination with other targeted therapies, or with different forms of chemotherapy to treat mCRC.
Targeted Therapy: Antiangiogenic Treatments
In 2004, the U.S. Food and Drug Administration (FDA) began to approve antiangiogenic therapies for the treatment of cancer. These treatments work by targeting the growth of abnormal blood vessels that feed tumors and have revolutionized cancer treatment. Initially, antiangiogenic therapies targeted the specific proteins vascular endothelial growth factor (VEGF), but now the latest therapies target multiple growth factors and pathways. Today, there are three types of antiangiogenic therapies for treating metastatic colorectal cancer—antibody, fusion protein, and tyrosine kinase inhibitor—that are available in three lines of therapy.
Bevacizumab (Avastin®) is an antibody drug that binds to and neutralizes a protein called VEGF-A. It is effective as first-line treatment for mCRC and is used in combination with chemotherapy. The drug is also approved as part of second line treatment in combination with chemotherapy. Patients receive bevacizumab as an intravenous infusion every two weeks and can be scheduled on the same day that chemotherapy is given. Patients may continue bevacizumab even after stopping chemotherapy, as long as the disease is controlled and side effects are manageable.
Bevacizumab was approved in 2004 as first-line therapy for mCRC, based on the results of the randomized, placebo-controlled, double blind clinical trial called AVF 2107. This trial enrolled more than 800 patients and found that bevacizumab plus chemotherapy improved median overall survival compared to those treated with chemotherapy alone.
In 2006, bevacizumab was approved for treatment in the second-line setting of mCRC, in combination with FOLFOX chemotherapy, based on the results of the 829 patient clinical trial called E3200. Bevacizumab was approved in 2013, based on the results of the ML18147 clinical trial which enrolled 820 patients, as a treatment in second-line use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapies, depending on prior treatment.
Ziv-aflibercept (Zaltrap®) is a type of targeted drug known as a fusion protein. This drug is designed to target multiple growth factors involved in cancer and angiogenesis, specifically proteins called VEGF-A, VEGF-B and a related protein called placental growth factor (PlGF). Ziv-aflibercept is approved for use as treatment in second-line therapy in combination with chemotherapy (FOLFIRI) for mCRC. Patients typically receive ziv-aflibercept every two weeks through an intravenous infusion with chemotherapy. Treatment continues as long as the disease does not progress and side effects are manageable.
The approval of ziv-aflibercept in 2012 was based on the results of a randomized, double-blind, placebo-controlled clinical trial called VELOUR. This trial studied 1226 patients with mCRC whose disease progressed during or within 6 months of receiving chemotherapy or chemotherapy plus bevacizumab. The study found a significant improvement in median overall survival if patients were treated with ziv-aflibercept combined with the FOLFIRI chemotherapy, compared to those who received chemotherapy alone.
Regorafenib (Stivarga®), a targeted therapy that comes in pill form, is a tyrosine kinase inhibitor (TKI). This kind of treatment is designed to target cancer cells and the blood vessels feeding them by interfering with chemical signals or pathways inside abnormal cells. Regorafenib targets the signaling of multiple growth factors involved in tumor angiogenesis, including VEGF receptors, Fibroblast Growth Factor (FGF) receptors, Platelet-Derived Growth Factor (PDGF) receptors, and the angiopoietin receptor TIE-2. Additional targets of regorafenib include RAF, BRAF, RET and KIT. Regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy. Regorafenib is taken once daily, typically on a 28 day cycle, with 21 days on therapy followed by a 7 day rest period.
Regorafenib was approved in 2012 based on the results of the randomized, double-blind, placebo-controlled CORRECT trial, which enrolled 760 patients with mCRC previously treated with multiple lines of therapies. The results showed a significant improvement in median overall survival among patients treated with regorafenib versus those who received placebo.
The epidermal growth factor receptor (EGFR) is a molecule identified on cancer cells that contributes to tumor development and growth. In about 80% of malignant CRC tumors, EGFR signaling plays a role in the progression of the disease. EGF also can cause angiogenesis. Anti-EGFR treatment targets this receptor to interrupt its signaling and, thus, hinder tumor development.
There are two anti-EGFR targeted agents approved for mCRC: cetuximab (Erbitux®) and panitumumab (Vectibix®).
Cetuximab is a targeted therapy used with chemotherapy for first line treatment of patients who have KRAS mutation-negative (wild-type), EGFR-expressing mCRC.120 It is also used as a single agent in patients who have failed previous chemotherapies.
Panitumumab is used as a single agent for treating patients with EGFR-expressing mCRC who have experienced progression of their disease while or after taking a chemotherapy regimen.121
KRAS (pronounced kay-rass) is a gene that helps doctors customize therapy for patients with mCRC. KRAS tests determine the target therapies for which you may be eligible. The drugs cetuximab and panitumumab are ineffective in tumors that carry mutations of the KRAS gene. Roughly 40% of colorectal cancers have KRAS mutations while the non-mutated KRAS gene (also known as “wild type”) is found in the remaining 60%. Identifying KRAS mutation status avoids unnecessary expenses and toxicities from anti-EGFR inhibitors, which are ineffective in KRAS mutated colorectal cancers.
Most targeted therapies have side effects that are generally milder and better tolerated than chemotherapy. Nonetheless, they still produce side effects that must be carefully monitored and managed.
Side-effects common to antiangiogenic agents include:
- Elevated blood pressure (hypertension)
- Excess protein in the urine
- Bleeding and coagulation problems, delayed wound healing, gastrointestinal perforation, and, very rarely, life-threatening hemorrhages
Some side effects that can occur with EGFR targeted treatments include: 123
- Skin rash
- Low blood pressure
- Breathing problems
There are many ongoing clinical studies to find predictive biomarkers (molecular characteristics of a tumor that can help inform decisions about a patient’s treatment148) that will identify the colorectal patients who will best respond to antiangiogenic therapies.
Duration of Treatments
There are ongoing studies investigating the optimum sequence combinations and duration of the various chemotherapies and targeted treatments.
Such developments hold significant promise for providing each patient with the most effective treatment, greatly improving patient outcomes.