Treating Stage IV Right-Sided CRC Beyond Progression

Bassel F. El-Rayes, MD:Nowadays, the majority of patients who receive up-front therapy with combination chemotherapy plus a targeted drug do have either response or stable disease. Very, very few patients have primary refractory disease and progression on frontline therapy. This is very good news for our patients. They can expect a good outcome from frontline therapy.

Unfortunately, as we keep patients on combination chemotherapy for a prolonged period of time, side effects become more prevalent. Therefore, around 4 to 6 months into treatment, the side effects become more prevalent and the disease control becomes less of an issue. It is an accepted strategy to try and decrease the chemotherapy to enhance the balance between benefit and toxicity. Usually the drug that you would remove at that point in the program would be oxaliplatin or irinotecan. Especially with oxaliplatin, because of the cumulative neuropathy, it is advisable not to continue the oxaliplatin until progression and rather to stop after 4 to 6 months and then start maintenance.

Maintenance regimens could include capecitabine alone or capecitabine plus bevacizumab or a 5-FU [fluorouracil] regimen plus bevacizumab. Any of those options would be reasonable. In my practice, I tend to use capecitabine plus bevacizumab because I feel the data that support prolonged disease control with that regimen are slightly better. In addition, I feel the capecitabine offers patients an oral option, which also has an impact on their quality of life.

As we see in this patient, many patients unfortunately do progress while on frontline therapy. On the average, the time to progression is around 9 to 11 months. And at the time of progression, there are several options that could be entertained. Those options would depend on the sidedness of the tumor and the mutational panel. In our specific patient, given this patient has disease in the ascending colon, I would prefer to continue with the bevacizumab into the second-line setting, continuing the 5-FU into the second-line setting, and then exchange the oxaliplatin to irinotecan so the patient would be on FOLFIRI [folinic acid, fluorouracil, and irinotecan]/bevacizumab in the second-line setting, reserving the EGFR inhibitor for later lines of therapy.

In my practice, I reserve EGFR inhibitors for later lines of therapy, like the third line and beyond. In patients who haveRASwild-type and tumors on the right side of the colon, I usually would prefer using bevacizumab in the first line and second line and keep the EGFR option for later on.

The future for colorectal cancer [CRC] is going to be us looking at a more personalized approach for patients. Personalizing the approach will depend on molecular profiling as well as better imaging and better staging. With better imaging and better staging, we will be able to select the patients who benefit from metastasectomy. With molecular profiling, we will be able to select subgroups of patients that benefit from specific therapies.

We are already entering this age, because now we select an EGFR inhibitor based on aRASmutation and sidedness. We have specific therapy forBRAF-mutated colon cancer, which is evolving. And we have specific therapy for patients who have MSI [microsatellite instability]—high tumors, and specific therapy for patients who haveNTRKmutations. This list is going to expand and grow. I think next will be specific therapy for patients who have overexpression ofHER2/neu. And as this list expands and grows, we’re going to be able to tailor therapy more to the patient’s needs and select therapy that has a bigger impact, although it’s applicable for smaller subgroups of patient but has a bigger impact on those small subgroups.

Transcript edited for clarity.

Case: A 75-Year-Old ManWithRight-Sided mCRC

Initial presentation

• A 75-year-old Caucasian man presented to his PCP with rectal bleeding, fatigue, weight loss, and constipation

Clinical workup

• Colonoscopy: fungating mass in the ascending colon
• Biopsy: invasive, poorly differentiated adenocarcinoma
• Imaging: CT scan of the chest/abdomen/pelvis showed multiple small liver lesions including a 3-cm mass in right lobe
• Molecular testing on tissue biopsy:
  • KRAS, RAS, andBRAFWT
  • Microsatellite-stable
• ECOG PS 1

Treatment

• Patient underwent a diverting colostomy without complication
• He was started on FOLFOX and bevacizumab
• Follow up imaging at 3, 6, and 9 months showed a partial response
• He was continued on bevacizumab and underwent capecitabine maintenance
• Imaging at 12 months showed 2 new liver lesions (1.2 cm and 3.4 cm)