Treating Stage 4 Colorectal Cancer

Following your colorectal cancer diagnosis, your team of doctors will begin to advise you on the treatment options that are available and which are most suitable for your diagnosis. Depending on your stage, cancer/tumor type and genetics, some treatments may be more or less effective than others, and having a better understanding of what to expect can help you make more informed decisions.

In this series of articles, we cover the treatment that you may be recommended based on the cancer stage when you are diagnosed. We hope this helps you keep a positive mindset while preparing for the next phase of your journey with cancer.

This article will outline and explain the available and likely treatments for stage 4 colorectal cancer.

Stage 4 colorectal cancer, based on the American Joint Committee on Cancer (AJCC) TNM system, is an advanced cancer that has spread from the colon to other organs in the body. Typically, the liver is the primary site of metastasis, but it can also affect other areas, including the lungs, peritoneum (abdominal cavity lining), distant lymph nodes, or in rare cases, the brain.

Treatment for stage 4 colorectal cancer has to be considered on a case-by-case basis, as the degree of metastasis, how large the tumors are and where they are located will impact the types of treatment that are applicable.

When surgery is possible

For stage 4 colorectal cancer, it's crucial to understand the surgery's goal, whether it's curative or aimed at symptom control.

Unfortunately, the curative potential of surgery in most cases is limited. However, if there are isolated small metastatic lesions in the peritoneum, liver or lungs that can be surgically removed along with the primary colon cancer, surgery may extend survival. This involves the removal of the cancerous colon segment, nearby lymph nodes and the metastatic areas.

Post-surgery, chemotherapy is often administered, while ablation, embolization and radiation therapy may be considered for liver metastases.

When surgery is not possible

In cases where metastatic lesions are too extensive for surgical removal, neoadjuvant chemotherapy may be administered to shrink tumors before attempting surgery. Post-surgery, further chemotherapy may be warranted.

When surgery cannot cure the cancer due to widespread metastasis, chemotherapy becomes the primary treatment. Surgery may still be necessary if the cancer obstructs the colon. A stent — a small, expandable metal mesh coil — can sometimes be placed via a colonoscopy to maintain the colon's patency, reducing the need for surgery. In other cases, procedures like colectomy or diverting colostomy may be considered.

Most stage 4 patients receive chemotherapy and/or targeted therapies. The choice depends on previous treatments and overall health. Appropriate treatment regimens are determined through biomarker tests for the following:

• Mutations in KRAS, NRAS, BRAF genes
• Amplification of HER2
• DNA mismatch repair (MMR) deficiency

KRAS (Kirsten rat sarcoma)

Colorectal cancer cases bearing the KRAS mutation are resistant to certain targeted therapy drugs such as cetuximab and panitumumab. In one clinical trial, a KRAS protein inhibitor known as adagrasib displayed anti-tumor activity in metastatic colorectal cancer patients when used as monotherapy or in combination with cetuximab. However, as of December 2022, adagrasib has been FDA-approved only for use with non-small cell lung cancer (NSCLC).

NRAS (Neuroblastoma RAS viral oncogene homolog)

Presently, there aren’t any FDA-approved drugs that target NRAS directly. As such, NRAS-positive colorectal cancer patients are typically treated with chemotherapy combinations such as FOLFOX, FOLFIRI and CAPEOX in combination with VEGF inhibitor bevacizumab.

BRAF (proto-oncogene B-raf)

The current standard treatment for metastatic colorectal cancer bearing BRAF mutations is FOLFOXIRI with VEGF inhibitor bevacizumab. More recently, FDA has approved in 2021 the use of BRAF inhibitor encorafenib with the use of cetuximab to treat metastatic colorectal cancer harboring a BRAF V600E mutation.

HER2 (Human Epidermal Growth Factor Receptor 2)

In early 2023, FDA granted accelerated approval for the use of tucatinib and trastuzumab to treat people with late-stage HER2-positive colorectal cancer. Both drugs inhibit the HER2 protein that is produced in excessive amounts when the HER2 gene is amplified, but through different ways. Tucatinib is a kinase inhibitor while trastuzumab is a monoclonal antibody that binds to the HER2 receptor.

Another drug, trastuzumab deruxtecan is also used to target HER2-positive cancer cells. It is a conjugate of two parts: one part consists of a monoclonal antibody with the same amino acid sequence as trastuzumab, and another part is made of deruxtecan, a topoisomerase I inhibitor. The binding of the antibody to the HER2 receptors of tumor cells triggers internalization of the drug complex that subsequently causes DNA damage and eventually programmed cell death, or apoptosis.

If a regimen loses effectiveness, alternatives are explored. Targeted therapies are an option for those with specific genetic or protein alterations. High microsatellite instability or MMR gene changes may lead to immunotherapy with drugs like pembrolizumab or nivolumab.

DNA mismatch repair (MMR) deficiency

Testing for DNA mismatch repair deficiency in colorectal cancer patients is crucial in determining effective treatment plans. Most colorectal cancer cases cannot be treated with immunotherapy, but a subgroup of patients who bear tumors with DNA mismatch repair deficiency or high microsatellite instability (MSI) can.

At present, the following immunotherapy drugs (immune checkpoint inhibitors) are available for use in treatment of colorectal cancer:

• Dostarlimab
• Ipilimumab
• Pembrolizumab

Treating liver metastases

For liver tumors, ablation, embolization or radiation may be presented as options. Ablation is the use of heat to destroy tumors, while embolization involves reducing blood flow to the tumor by injecting substances into an artery in the liver.

Chemoembolization, a combination of chemotherapy and embolization, may also be used; the blood supplied to liver cancer cells typically come via the hepatic artery. In chemoembolization, chemotherapy drugs can be delivered directly to the tumors via injections into the hepatic artery, before introducing an embolic agent to stem blood flow to the tumor.

Radiation therapy may be used in combination with ablation (radio frequency ablation or RFA) and embolization (radioembolization) as minimally invasive ways to treat unresectable liver metastases.

Palliative care focuses on relieving the symptoms and reducing the physical and mental stress that the cancer exerts on your body. Ultimately, the goal of it is to improve your quality of life.

At late stage colorectal cancer, it is common for the tumors to grow so large that it begins to obstruct the lumen of your colon. It may also grow into and press against other organs, which can cause pain. Different therapies, including chemotherapy and radiation therapy can help alleviate colon cancer symptoms such as pain, and may temporarily shrink tumors in advanced stages to reduce blockage. However, it's unlikely to cure the cancer without intervention from other treatments.

It is also important to remember that your treatment plan may be different from another patient’s, and so following the advice of your cancer care team is crucial. Undergoing treatment for stage 4 colorectal cancer can be physically and emotionally demanding, and having a strong support system can alleviate your emotional stress and help with other tasks that may become too physically taxing.