CRC: Rationale for Systemic Therapy and Maintenance

Tanios Bekaii-Saab, MD:When we look at the study, CALGB 80405, and we look at the left versus right, overall, the left-sided tumors do better than the right-sided tumors. When we start breaking down those arms by exposure to cetuximab versus bevacizumab, on the right side, the cetuximab arm does terrible. And we know that these EGFR inhibitors, now across multiple studies, don’t have a role, or much of a role, in the first 2 lines—maybe now 3 lines with the REVERCE data of therapy before—so we go to bevacizumab and regorafenib before we get to an EGFR inhibitor.

Now on the left side, the data look a little bit different. It may favor somewhat the EGFR inhibitor, cetuximab, chemotherapy plus cetuximab, as long as the patient is RAS wild-type, BRAF wild-type, and I would even throw in HER2-nonamplified patients.

Now, the difference between the 2 arms was not that wide—meaning that the option of bevacizumab in the first line on the left-sided tumor that’s RAS wild-type remains an option to be discussed versus cetuximab or EGFR inhibitor. The difference between the 2 is not great enough, in my viewpoint, to essentially tilt it completely 1 way or the other.

In all frankness, there are a lot of limitations to interpreting a lot of these studies. The left side versus the right side is relying mostly on retrospective analysis and primarily on negative trials—5F3 was a negative trial; CALGB 80405 was also a negative trial. So, making a lot of assumptions from these studies when the differences are small in some subsets is certainly questionable. Overall, I think that on the right side, it’s clear because you can’t even make up that delta. On the left side, that delta is a little smaller—quite smaller—and so I think the discussion with the patient will have to include a discussion about toxicities, a discussion about potential risks and benefits, and limitations to interpret the data from these studies.

One of the most important aspects of how we treat patients with colon cancer today is to think about it as a marathon and not a sprint. We want to make sure that our patients stay in good health, their quality of life is preserved so we can, at multiple points, expose them to treatment that would essentially lead to cure a tumor response and have a maintenance phase that will allow them essentially to have a much-improved quality of life throughout their treatment, which is now for most patients lasting years and years and years. For some patients, we’re talking about between 5 and 10 years, and for a few, more than 10 years.

So, we really have to plan right. I think data after data after data from CAIRO, from OPTIMOX, FOLFIRI studies on and off—you name it, every study suggests the same thing: that beyond 3 to 4 months of exposure to FOLFOX and perhaps FOLFIRI, FOLFOX or CAPOX have the most data; FOLFIRI—just a couple of small studies that align with what we do with oxaliplatin. What we’ve learned from that cumulative evidence is that patients get 3 to 4 months of FOLFOX or FOLFIRI. After that, they can go on capecitabine plus bevacizumab.

Capecitabine would be given at a low dose continuously. In my clinic, I try to skip the weekend—Saturday or Sunday. Patients in the United States tend to have less tolerance for capecitabine than the European patients, and these studies were performed primarily in Europe. As such, what we find is that patients will have extreme difficulties going on a daily basis. And so, I go for 5 days, give them 2 days off—Saturday and Sunday, typically, to make it easy for them to remember—a lower dose, 625 mg/m²twice a day. That’s with the capecitabine. And then the bevacizumab: 7 1/2 mg/kg every 3 weeks. So, again, they don’t have to come into the infusion center except every 3 weeks.

And that optimizes, I think, the outcome for those patients and continues to preserve their quality of life. A lot of the toxicities that occur from these various chemotherapies are not just limited to direct toxicities that we see typically in the first 3, 4 cycles, which are cumulative toxicities. They get fatigued— their organs get fatigued; their livers get fatty. In fact, if we expose them—to continuously hammer with this aggressive chemotherapy—oftentimes some patients will have fatty liver, and some patients can end up with liver cirrhosis. With oxaliplatin, we can end up with splenomegaly, neurotoxicity. So, there are implications to our treatments, and that’s why I think the best approach is that we give chemotherapy for 3 to 4 months—FOLFOX or FOLFIRI—and then plus bevacizumab, and that’s followed by capecitabine and the bevacizumab maintenance.

Transcript edited for clarity.

Metastatic Colorectal Cancer Originating on the Left Side

October 2016

• A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction
  • PMH: atrial fibrillation, moderately controlled on a beta- blocker; patient is also on warfarin
  • CEA elevated; 23.3 ng/mL
• Pathology:
  • Undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 were involved
  • Molecular testing:RASandBRAFwild-type, microsatellite stable
• Imaging with PET/CT showed multiple lung lesions bilaterally, three measuring approximately 3.0 cm
• Diagnosis: grade 3 colorectal adenocarcinoma, stage T4N2M1
• The patient preferred to avoid rash and received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions
• The patient was continued on bevacizumab maintenance

August 2017

• The patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed marked progression in two of the lung lesions and development of 3 small liver lesions
• The patient was switched to FOLFIRI and cetuximab; her heart rhythm was closely monitored and remained stable
• Follow-up imaging at 2 months and 4 months showed stable disease in the lung and liver lesions; her symptoms improved
• At 4 months, the patient complained of severe fatigue and was changed to maintenance therapy

January 2018

• At 5 months, the patient reports reappearance of symptoms and states she requires frequent rest because of fatigue
• CEA, 89.8 ng/mL
• CT shows progressive disease in the lung and presence of several small boney lesions
• The patient is motivated to try another therapy