Metastatic Colorectal Cancer: What Now?

Metastatic colorectal cancer is no longer treated as one disease. Before a first-line regimen 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 or MSI-high responds to immunotherapy. Most colorectal cancers do not.

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. It carries a worse outlook. It also unlocks a specific drug pair.

HER2. Less common. It opens targeted options and trials.

Results usually take one to three weeks. Chemo can often start while they are pending. The antibody choice waits.

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. The hazard ratio was 0.60. The response rate was 43.8 percent versus 33.3 percent. Responses also lasted far longer.

That is a rare finding. One immune drug beat a chemo combination 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. Blocking EGFR does nothing. It can do worse than nothing. In trials, people with RAS-altered tumors who got an anti-EGFR antibody with FOLFOX had shorter progression-free survival than those who did not. Few tests in cancer care draw a line this sharp.

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

BRAF V600E tumors do poorly on standard chemo. 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 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.

The FDA approved the two-drug version, encorafenib with cetuximab. The three-drug version did not add enough to be worth the extra side effects.

About 4 percent of colorectal cancers carry the KRAS G12C variant. Sotorasib and adagrasib target it directly. In colorectal cancer, unlike lung cancer, these drugs work better when paired with an anti-EGFR antibody such as panitumumab. Blocking KRAS alone lets 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.

When liver spread is cut out with a clear margin, meaning no cancer at the cut edge, 5-year survival runs 25 to 40 percent. Some people have too much liver disease to operate on at first. If chemo shrinks it enough, surgery becomes possible. Their 5-year survival is close to that of people who could be operated on from the start.

Radiofrequency ablation is another route for limited liver disease. A needle probe burns small tumors. Major complications run about 2 percent, and deaths 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. Trials tend to require decent organ function and stamina. Both fall over time.

In SEER data, about 23 percent of colorectal cancers are found only after spread to a distant site. Overall 5-year relative survival is 65.4 percent. For cancer still confined to the bowel, it is 91.3 percent. All three 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 a swollen sore calf, needs the same urgency. Clots are more common in this cancer.
• 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 the same day if you have new yellow eyes or skin, or dark urine with pale stools. If you are on immunotherapy for MSI-high disease, call the same day for several watery stools a day, or blood or mucus in your stool.
• Call your care team within a day or two if you are passing much narrower stools, your belly is bloating, or belly pain keeps building without the emergency signs above. Do the same for numbness or tingling in your hands and feet on oxaliplatin, or for 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