Metastatic Colorectal Cancer: What Now?

This page is for people with colorectal cancer that has spread (metastatic), and for their families. It covers the tumor tests that shape treatment, the main drug choices, when surgery is still possible, and when to get help fast.

Metastatic colorectal cancer is no longer treated as one disease. Before the first-line regimen (the first treatment plan) is picked, the tumor tissue should be tested for four things. If any are missing, say so out loud at your next visit.

Mismatch repair status. This is reported as MMR (mismatch repair) protein staining, or as MSI (microsatellite instability) testing. A tumor that is dMMR (mismatch repair deficient) or MSI-high can be treated with immunotherapy, drugs that help the immune system attack cancer. NCI says about 4 percent of stage IV colorectal cancers are dMMR or MSI-high.

RAS. This covers two genes, KRAS and NRAS. It decides whether two antibody drugs, cetuximab and panitumumab, can be used at all.

BRAF V600E. This is one specific change in the BRAF gene. NCI says it is found in about 10 percent of metastatic colorectal cancers and is a sign of a poorer outlook. It also opens up a specific drug pair.

HER2. Less common. The FDA has given accelerated approval to tucatinib with trastuzumab for HER2-positive, RAS wild-type cancer that has grown after standard chemo. HER2 can also open up trials.

Ask when your results are expected, and whether any treatment can start while you wait.

KEYNOTE-177 was a trial in 307 people. All had untreated MSI-high or dMMR metastatic colorectal cancer. Half got pembrolizumab by infusion every 3 weeks. Half got standard chemo.

Median progression-free survival was 16.5 months with pembrolizumab and 8.2 months with chemo. This is the time by which half the people in each group had seen their cancer grow. The hazard ratio was 0.60, which means the risk of the cancer growing was lower with pembrolizumab. The response rate (tumors shrinking) was 43.8 percent versus 33.3 percent. Responses also lasted longer: the median was not reached with pembrolizumab, against 10.6 months with chemo. Final overall survival results, so far shared only as a meeting abstract, were a median not reached with pembrolizumab and 36.7 months with chemo.

So one immune drug kept the cancer in check longer than chemo in the first line. It applies to a small share of these cancers, so the test result matters a lot.

First-line chemo is usually FOLFOX or FOLFIRI. Both include 5-FU and leucovorin. FOLFOX adds oxaliplatin. FOLFIRI adds irinotecan. One antibody is then added on top.

If RAS is wild type, meaning no change was found, cetuximab or panitumumab can be added. Both block EGFR. That is the switch sitting just above RAS in the chain.

If RAS is mutated, the chain is already switched on below that point, so blocking EGFR is not expected to help. It can even do harm. In the PRIME trial, people with KRAS-changed tumors who got panitumumab with FOLFOX had shorter progression-free survival (7.3 months) than those who got FOLFOX alone (8.8 months).

For RAS-mutated disease, the usual partner is bevacizumab instead. It blocks VEGF, the signal tumors use to grow blood vessels.

The BEACON trial enrolled 665 people with this change who had already had one or two regimens. One arm got encorafenib tablets by mouth daily, plus binimetinib, plus cetuximab. Cetuximab was given by vein, a larger loading infusion first and then a smaller one weekly, both worked out from body size.

Encorafenib and binimetinib are tablets you would take at home. If this combination is offered to you, follow the amounts on your own prescription rather than the trial's.

Median overall survival (the time by which half the people in the group had died) was 9.0 months in that arm. It was 5.4 months in the control arm, which got FOLFIRI or irinotecan with cetuximab. The hazard ratio was 0.52.

In updated results, median overall survival was 9.3 months with either the two-drug or the three-drug version, and 5.9 months in the control arm. Based on these data, the FDA approved the two-drug version, encorafenib with cetuximab, for this cancer after earlier treatment.

NCI says about 4 percent of colorectal cancers carry the KRAS G12C variant. Sotorasib and adagrasib target it directly. In colorectal cancer they are paired with an anti-EGFR antibody such as panitumumab, because blocking KRAS alone can let the EGFR signal switch back on.

This part gets missed. Colorectal cancer that has spread only to the liver, and sometimes only to the lung, can still be removed with the aim of cure. NCI says surgery cures 25 to 40 percent of carefully selected people whose liver or lung spread can be removed.

When liver spread is cut out with a clear margin, meaning no cancer at the cut edge, 5-year survival was 25 to 40 percent in mostly nonrandomized studies. Some people have too much liver disease to operate on at first. NCI says chemo can occasionally shrink it enough for surgery to become possible.

Radiofrequency ablation (using heat to destroy tumors) is another route for limited liver disease. A needle probe burns small tumors. NCI reports major complications in about 2 percent, and deaths in under 1 percent.

So the early question is not only which chemo. It is also this: is there any path to surgery, and who is the liver surgeon reading my scans? That belongs at a tumor board, not to one clinician alone.

Four drugs get used early: a 5-FU type drug, oxaliplatin, irinotecan, and bevacizumab. After those, options continue. In the RECOURSE trial, trifluridine-tipiracil, an oral pill pair, gave a median overall survival of 7.1 months. Placebo gave 5.3 months. Most people in that trial had already had four or more prior lines.

Ask where a trial fits before you run out of standard options. Many trials have entry rules about general health and organ function, so it helps to ask early.

In SEER data, about 23 percent of colorectal cancers are found only after spread to a distant site. For those, 5-year relative survival is 16.9 percent. Overall 5-year relative survival is 65.4 percent. For cancer still confined to the bowel, it is 91.3 percent. All of these come from the group diagnosed between 2016 and 2022, which is the most recent SEER has released. These national figures pool everyone, including people treated before current biomarker-guided care. They do not describe one person.

• Call 911 or go to an emergency department if you have belly pain with vomiting and no gas or stool passing. This can mean a blocked bowel. Go too if you are vomiting blood, passing black tarry stools, or bleeding heavily from the back passage. New shortness of breath or chest pain, or a swollen sore calf, needs the same urgency, because these can be signs of a blood clot. Do not drive yourself.
• Call your care team without delay, at any hour, if you have a fever of 100.4°F (38°C) or higher while on chemo. This one does not belong on the same-day list. Chemo knocks down the white cells that fight infection, and CDC treats a fever during chemotherapy as a medical emergency. Cannot reach them fast? Go to an emergency department and tell the staff you are on chemo.
• Call your care team right away if you have new yellow eyes or skin, or dark urine with pale stools. If you are on immunotherapy such as pembrolizumab, MedlinePlus says to call right away for diarrhea, blood or mucus in your stool, or severe belly pain.
• Call your care team right away if you are on oxaliplatin and you stumble or lose your balance, or find it hard to write or do up buttons.
• Call your care team the same day if you are passing much narrower stools, your belly is bloating, or belly pain keeps building without the emergency signs above.
• Tell your care team soon if numbness or tingling in your hands and feet is bad or does not go away, or you have a rash and cracked skin on your hands and feet.

Colon Cancer Treatment by Stage, MSI-H Colorectal Cancer, KRAS G12C in Colorectal Cancer, What Metastatic Cancer Means, and Clinical Trials.

• https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq
• https://www.cancer.gov/types/colorectal/patient/colon-treatment-pdq
• https://seer.cancer.gov/statfacts/html/colorect.html
• https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
• https://medlineplus.gov/druginfo/meds/a614048.html
• https://medlineplus.gov/druginfo/meds/a607035.html
• https://www.cdc.gov/cancer-preventing-infections/patients/fever.html