Metastatic Colorectal Cancer: What to Ask

Cetuximab and panitumumab block a receptor called EGFR. They only work if the pathway below that receptor is normal.

NCI is explicit. Tumors with KRAS variants are not sensitive to cetuximab. Adding cetuximab helps survival in colon cancers that lack a KRAS variant.

There is a warning attached. NCI notes that people with KRAS-altered tumors may do worse when cetuximab is added to chemotherapy containing bevacizumab.

So RAS testing is standard before anyone reaches for those drugs, and it is worth asking for by name. It is rarely the only test run. Most centres now look at a wider panel at the same time: BRAF, mismatch repair or MSI, HER2, and sometimes NTRK and other fusions. Which side of the colon the tumour started on also feeds into the choice. Ask what panel was sent and what came back.

NCI lists targeted therapy with encorafenib and cetuximab for patients with a BRAF V600E change.

That combination is not a replacement for chemotherapy everywhere in the course of treatment. Where it sits — first line, or after chemotherapy has been tried — depends on how you are, how fast the disease is moving, and what your oncologist judges. Ask whether your tumour was tested, and if the change is there, where in the plan this combination would come.

About 4% of stage IV colorectal cancers are mismatch repair deficient, also written dMMR or MSI-high.

NCI explains that this can be tested by looking for lost mismatch repair proteins. Since 2015 it has also predicted response to checkpoint drugs.

Pembrolizumab was approved in 2020 for untreated metastatic dMMR or MSI-high colorectal cancer. If you are in that group, the first treatment may not be chemotherapy at all.

MSI-high is also the main pattern seen in Lynch syndrome. A positive result matters to your relatives.

NCI treats liver-only disease as a distinct situation.

Its list includes chemotherapy before surgery to shrink the tumor, surgery to remove part of the liver, and radiofrequency ablation or cryosurgery for people who cannot have surgery.

Ask for a liver surgeon to look at your scans early. Waiting until chemotherapy finishes can close a door.

• Has my tumor been tested for KRAS and NRAS variants, and what did they show?
• Is there a BRAF V600E change, and does encorafenib with cetuximab apply?
• Is my tumor mismatch repair deficient or MSI-high?
• If it is, should immunotherapy come before chemotherapy?
• My spread is liver only. Can a liver surgeon review my scans now?
• Which chemotherapy backbone are you choosing, and would bevacizumab be added?
• How will you monitor my hands and feet on oxaliplatin, and what would make you change the dose or pause it?

This is one of the clearest trade-offs in colorectal cancer.

The clearest figures come from the pooled IDEA analysis NCI cites, which studied stage III disease after surgery rather than metastatic disease. Nerve damage of grade 2 or worse affected 16.6% of people given 3 months of FOLFOX, against 47.7% given 6 months. With CAPOX the figures were 14.2% and 44.9%. The length of treatment, not the drug alone, drove the difference.

Those figures come from adjuvant treatment after surgery for stage III disease, where the course has a planned end date. Metastatic treatment does not work that way, and you should not use them to set your own stopping point. What they do show is that the nerve damage builds with the total amount given. So ask, before you start, how your hands and feet will be checked, how you should report changes, and what would prompt a dose change or a break. That conversation belongs at the beginning, not after your fingers go numb.

• Call your cancer team at once if you measure 100.4°F (38°C) or higher, or get shaking chills, at any point while you are on chemotherapy. Fluorouracil-based chemotherapy dips your white cells between cycles, and CDC treats a fever during chemotherapy as a medical emergency. Ring them day or night. If you cannot reach them quickly, go to an emergency department and say at the desk that you are having chemotherapy. Go to an emergency department too if you have severe cramping belly pain with vomiting and no gas or stool passing, which can mean the bowel is blocked, for sudden severe belly pain with a hard, tender abdomen, for heavy rectal bleeding with dizziness or fainting, or for a rash with wheezing, throat tightness or faintness during a cetuximab or panitumumab infusion.
• Call your care team the same day if diarrhea will not stop or you cannot keep fluids down, which matters most on irinotecan. Call for new yellowing of the eyes or skin, and for a new cough, chest pain or breathlessness while you are on immunotherapy.
• Call your care team within a day or two if numbness or tingling in your hands or feet is new or getting worse, or if cold drinks make your throat feel tight. Both point to oxaliplatin nerve damage, and the dose can be changed. Do the same for an acne-like rash that is spreading or sore, for mouth sores that stop you eating, and for home blood pressure readings running high on bevacizumab.

Related: Cancer Staging, Biomarker Testing, Clinical Trial vs Standard Treatment, and Palliative Care.

• NCI PDQ - Colon Cancer Treatment (Patient Version)
• NCI PDQ - Colon Cancer Treatment (Health Professional Version)
• NCI PDQ - Rectal Cancer Treatment (Patient Version)
• NCI PDQ - Gastrointestinal Complications (Health Professional Version)
• NCI - Infection and Neutropenia During Cancer Treatment
• CDC - Watch Out for Fever (Preventing Infections in Cancer Patients)