mCRC: Considerations for Localized Therapy and Maintenance

Wells Messersmith, MD:The issue of liver-directed therapy is a complex question that has been settled recently—not completely, but a lot of helpful information came from the SIRFLOX and FOXFIRE trials. In those studies, patients with advanced unresectable colorectal cancer with liver predominant disease—meaning most of the bulk of the tumor was in the liver—are randomized to either have embolization with radio spheres or not. What they found was that although it improved what’s called hepatic progression-free survival—meaning the disease didn’t get worse in the liver for a bit longer—unfortunately, it had no effect on overall survival.

In an unplanned subgroup analysis, they did show that right-sided tumors seemed to have more benefit, but that really isn’t enough to affect our treatment recommendations. And, of course, this patient has a left-sided tumor, so in this case, we would not use liver-directed therapy.

The toxicities of FOLFOX and bevacizumab are usually fairly mild. Obviously, it depends patient to patient, and oftentimes we try to see that patient back after the first week to get a sense of how they’re going to do. You’ll have patients who will have a horrible allergic reaction the first day, and you’re basically never able to use that regimen again. And you’ll have other patients who just sail through and really have no problem.

The key thing that I warn patients about is cold sensitivity, which is from the neuropathy—the nerve damage from oxaliplatin—and that manifests itself in a couple different ways. The first is that if they touch a cold object, like eat ice cream or drink a cold drink or pick up an ice cube, it creates a very uncomfortable feeling in the fingertips or on their throats, and that’s because of that cold sensitivity. Many patients will have that last for a few hours. Some will have it last for a few days. The other thing I also warn them about is what I and many people call first bite syndrome, which is that the first bite in the morning can be quite uncomfortable in the jaw if they bite something hard. So, we just warn them about that so they’re just aware of it, basically.

And then, finally, over time in a cumulative fashion, it gets a little bit worse with each dose. Patients can have numbness and tingling. Even when walking across a cold linoleum floor, for instance, people can get a little uncomfortable feeling. Now, if somebody has a preexisting neuropathy, it can be a problem with balance because proprioception—that sense of where your joints are when you’re not actually looking at them—can be affected. And so, you really have to be careful you’re not causing falls and having people stumble or have other problems.

The 5-FU can cause diarrhea and mouth sores and also a rash on the hands and feet, so that’s something we certainly check for. And then in terms of the high blood pressure, there’s a lot interest in that, and, frankly, people are so concerned about it that they wouldn’t use the drug. But in general, that’s really easily manageable, and so sometimes we have to increase the dose of the existing antihypertensive drug.

Of course, one of the key things that I always do is try to make sure my patient’s blood pressure is checked at home. Because when they’re coming to clinic, they’re going to get chemotherapy for the first time; they’re nervous, it was a pain to park, etc, etc. They’re hyped up, and blood pressure can tend to go up when they’re in clinic with us. But oftentimes if you actually check it at home, it’s fine. So, that’s something that can be monitored over time. The same with protein in the urine. We check for that and monitor it, but we don’t have to wait for that to come back before starting therapy, and we’ll just monitor that in a more chronic fashion through treatment.

The idea of a maintenance therapy is to continue some type of chemotherapy and try to hold things steady and keep the cancer from growing without having to continue all the drugs. In this case, for maintenance therapy for colorectal cancer where you’ve started someone on FOLFOX and bevacizumab, there are 3 different options, really. One would be to do nothing. But there are multiple trials including CAIRO3 and AIO 0207, which seemed to show that if you stop everything, you lose survival. And the idea there is that the tumor can sprout up and grow very quickly if you’re not getting some type of therapy.

Then the question comes, OK, let’s say we decide we’re going to maintain with something, what should that be? And most trials have used both 5-FU either in the form of infusional 5-FU or capecitabine plus bevacizumab. And in that case, most of the trials seem to indicate that as long as you continue those, you don’t really seem to lose survival, as opposed to keeping all the chemotherapy going.

Some of the trials also included a bevacizumab alone arm. And in those cases, there was a trend that it wasn’t as good as 5-FU and bevacizumab, but most of the time, it wasn’t statistically significant. I would say most of the oncologists who I talk to tend to use 5-FU and bevacizumab, either infusional 5-FU or capecitabine. But if the patient’s having a lot of toxicities or problems from 5-FU, it wouldn’t be unreasonable to do a maintenance regimen, which is the bevacizumab.

And the other key thing is that you’re stopping the oxaliplatin, so that’s going to help control that neuropathy, so it doesn’t get worse and worse. Because one of the things about oxaliplatin neuropathy—that anyone who uses these drugs is liable to tell you—is that after you stop oxaliplatin, it actually gets worse for up to a month. And so, if somebody’s already having trouble buttoning buttons or writing their name or typing, that can be a big problem.

It’s interesting—there’s actually a study looking at using software to analyze typing patterns to try to pick up neuropathy prior to it becoming clinically significant. It will be interesting to follow those studies and see what they can come up with.

Transcript edited for clarity.

Progression of Left-Sided mCRC

February 2016

• A 66-year-old man reported with constipation, bloating, abdominal pain and weight loss of 12 pounds in 2 months
• PMH: mild hypertension, well-controlled on CCB
• Lab evaluation: Grade 2 anemia (Hb 9.2 g/dL)
• Colonoscopy revealed a7-cm mass in sigmoid colon
• CEA, 80 ng/mL
• The patient underwent sigmoid colectomy
• Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue;
  • Biopsy: 7of 12 resected nodes positive
  • Molecular testing:KRASmutation in codon 12 of exon 2; microsatellite stable
• CT scan showed several lesions in both lobes of the liver, measuring up to 17 mm in diameter, and 3 small lesions (<6 mm) in the left lower pulmonary lobe
• Diagnosis: Stage 4 colorectal cancer
• The patient received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• The patient was continued on bevacizumab maintenance

February 2017

• One year after starting therapy, the patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed progression in three of the liver lesions and one lesion in the right pulmonary lobe
• The patient was started on FOLFIRI and continued bevacizumab

January 2018

• Eleven months later, CEA level rose significantly
• Follow-up CT showed progressive disease in the lung and liver
• The patient is interested in knowing his options at this stage