When you have metastatic colorectal cancer, your doctor may talk about first-line, second-line, and third-line treatments. These terms describe the order treatments are tried: first-line is the initial approach, second-line comes next if the first doesn't work, and third-line is another option if the cancer continues to grow.
It's normal to worry if your first treatment doesn't work – but don't lose hope. Other options are available. In this guide, you'll learn how to know if your treatment is working and what you can do next.
| Line of treatment | Examples |
| First-line | FOLFOX, FOLFIRI, CAPOX, FOLFOXIRI, target therapy (e.g., bevacizumab), immunotherapy |
| Second-line | FOLFIRI (if FOLFOX or CAPOX was first), change targeted therapy or immunotherapy, clinical trials |
| Third-line | Trifluridine and tipiracil (Lonsurf), regorafenib (Stivarga), fruquintinib (Fruzaqla), clinical trials, liver-directed therapy, palliative radiation |
How to Know When Treatment Isn't Working
There are several ways to know whether the first treatment for your metastatic colorectal cancer is not working or isn't a good fit, says Mohammed Najeeb Al Hallak, MD, MS, an oncologist at Barbara Ann Karmanos Cancer Institute in Detroit.
Your symptoms don't improve. "I check on symptoms that were there before starting chemo," says Al Hallak. For colorectal cancer, this may include belly pain, weight loss, or low appetite.
"Ideally, patients should see some improvement two to three weeks after their first dose," says Al Hallak. If your symptoms don't improve or get worse, it may be a sign that your cancer is not responding to the first-line treatment.
You need more pain medication. Al Hallak notes, "When a patient tells me at their second visit that they are using pain medicine less, I know they're responding to treatment." The opposite – needing more pain medicine – can be a sign the treatment isn't working.
Tests don't improve. Carcinoembryonic antigen (CEA) and circulating tumor DNA (ctDNA) tests are checked. "Most of the time, you will see CEA at least start to stabilize after the first dose," says Al Hallak. "By the second dose, it should start to go down." If treatment is working, your ctDNA level should go down too.
First-Line Metastatic Colorectal Cancer Treatment Options
Most people start with chemotherapy combinations, sometimes paired with a targeted therapy or immunotherapy.
Chemotherapy Drug Combinations
- FOLFOX
- Folinic acid (also called leucovorin, calcium folinate, or FA)
- Fluorouracil (also known as 5FU)
- Oxaliplatin
Fluorouracil and oxaliplatin are chemotherapy drugs that destroy cancer cells, while folinic acid helps fluorouracil work better.
- FOLFIRI
- Folinic acid (Wellcovorin)
- Fluorouracil (Adrucil)
- Irinotecan (Camptosar)
Fluorouracil and irinotecan destroy cancer cells, while folinic acid helps fluorouracil work better.
- CAPOX
- Capecitabine (Xeloda)
- Oxaliplatin (Eloxatin)
Capecitabine and oxaliplatin are both chemotherapy drugs.
- FOLFOXIRI
- Folinic acid
- Fluorouracil
- Oxaliplatin
- Irinotecan
While it may be more effective than two-drug combinations, doctors carefully assess a patient's overall fitness before recommending this treatment because it is very intensive, says Al Hallak.
Targeted Therapy
Targeted therapy reduces the growth and spread of cancer cells by targeting proteins in or on cancer cells. Examples include bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix). Your doctor may recommend adding targeted therapy to chemotherapy. But not all patients benefit from these drugs, says Al Hallak. Their effectiveness depends on where the tumor is located in the colon (left or right side) and on specific genetic mutations in the cancer.
Immunotherapy
Immunotherapy helps the body's immune system target cancer cells. Immune checkpoint inhibitors such as nivolumab (Opdivo) and pembrolizumab (Keytruda) are often used to treat tumors that have gene changes involving mismatch repair genes or a high level of microsatellite instability.
Second-Line Metastatic Colorectal Cancer Treatment Options
If first-line treatment isn't working, your doctor may suggest one of the following.
Switching chemotherapy. If your first-line treatment was FOLFOX or CAPOX (oxaliplatin-based treatments), your doctor may suggest switching to an irinotecan-based treatment like FOLFIRI.
Changing targeted therapy or immunotherapy. Your doctor may suggest using a different therapy, if appropriate, based on the tumor location and genetic mutations.
Clinical trials. Clinical trials may be a way to get access to new treatments that are not yet widely available. Your doctor will check to see if there is a clinical trial you can take part in.
Third-Line Metastatic Colorectal Cancer Treatment Options
Even if second-line treatment doesn't work, you still have several options.
Chemotherapy pills. Your doctor may suggest a combination pill called trifluridine and tipiracil (Lonsurf). Trifluridine kills cancer cells. Tipiracil helps trifluridine to be effective. Lonsurf is often combined with bevacizumab to improve outcomes, says Al Hallak.
Targeted therapy. Other options to stop tumor growth include targeted therapies such as fruquintinib (Fruzaqla) or regorafenib (Stivarga).
Clinical trials. Clinical trials are another option to consider in third-line treatment. Al Hallak recommends looking into trials early, while you are still feeling well enough to qualify. One trial that is currently recruiting participants is testing the combination of fruquintinib with electromagnetic waves to treat metastatic colorectal cancer (NCT07130903).
Liver-directed therapy. If cancer has spread to your liver, treatments like Y-90 radioembolization can help control liver tumors while you continue other therapy.
Palliative radiation. Radiation can ease pain from cancer in bones or other areas. Reducing pain may improve your strength and open doors to more treatment options.
Takeaways
Treatment for metastatic colorectal cancer is done in steps: first-line, second-line, and third-line. Doctors track your symptoms, and they use blood tests and scans to see if treatment is working. Options include chemotherapy, targeted therapy, immunotherapy, clinical trials, liver-directed therapy, and palliative care. Eating well, staying active, and addressing mental health can improve outcomes.
FAQs
How do doctors decide which treatment is right for me?
Before starting treatment for metastatic colorectal cancer, doctors usually run genetic testing on your tumor tissue and a blood sample. This looks for changes, called mutations, in the cancer's DNA. The results help your doctor choose the treatment plan most likely to work for you.
Could other medicines be adding to my symptoms?
It’s important to tell your doctor about any other medicines you are taking. Pain medicines like opioids can cause constipation, which may worsen belly pain, says Al Hallak.
What else can I do, besides treatment, to have the best possible outcome?
Al Hallak encourages patients to focus on healthy, balanced eating rather than restrictive diets that cut out entire food groups, such as sugar. Your body needs a mix of protein, fats, and carbohydrates to stay strong during treatment. Your doctor may also recommend exercise programs designed specifically for cancer patients, like the CAPABLE program. Research shows that regular exercise improves survival in colon cancer. Mental health matters too. "Be honest with your doctor if you're struggling," Al Hallak says. "We can refer you to a specialist. Every institution has someone to help you cope."
Show Sources
Photo Credit: iStock/Getty Images
SOURCES:
Mohammed Najeeb Al Hallak, MD, MS, oncologist, Barbara Ann Karmanos Cancer Institute, Detroit.
Barbara Ann Karmanos Cancer Institute: "CAPABLE Study Registration."
The New England Journal of Medicine: "Structured Exercise after Adjuvant Chemotherapy for Colon Cancer."
Cancer Research UK: "FOLFOX," "FOLFIRI," "CAPOX," "FOLFOXIRI."
ClinicalTrials.gov: "Amplitude-Modulated Radiofrequency Electromagnetic Fields (AM RF EMF) in Combination With Fruquintinib in Refractory Metastatic Colorectal Cancer."
