The Rationale for FOLFOX and Bevacizumab in mCRC

Wells Messersmith, MD:In July of 2016, which is about 10 months later, that’s fairly typical for first-line chemotherapy in terms of what’s called progression-free survival—so, surviving without it getting worse. The patient complains of increasing fatigue. A CT scan is obtained and that shows 3 new liver lesions plus growth in one of the other lesions. So, clearly, at this point, this patient is not resectable, not curable. You’re on a palliative paradigm, and, again, it’s 10 months after you’ve started the FOLFIRI. And if you look across multiple trials, that 10-month mark is very, very common for progression-free survival, so a very typical situation.

And so, now the question is, what do we do next? If the patient got FOLFIRI and bevacizumab first-line, we’ll usually switch to a FOLFOX-based regimen or CapeOx, or capecitabine and oxaliplatin. If the patient received FOLFOX or CapeOx first-line, we’ll then switch to FOLFIRI. So, basically, the cytotoxic backbone is switched depending on what you used in the first-line setting. Secondly, what do you do about the biologic? The evidence is that you can do one of several things. You could use bevacizumab again and that’s through the TML trial, which showed a 20% reduction in death by continuing bevacizumab in the second-line setting. You could use ziv-aflibercept, which, per the VELOUR trial, was also shown to have a roughly 20% reduction. And you could also use ramucirumab.

All of these are approved in the second-line setting. All of them have a hazard ratio of approximately 0.80, so a very incremental, small survival benefit, but statistically significant. We can argue about the economics of that and what all that means in terms of these modest survival benefits, but they all have a role in that setting. So, in this case, this patient was given FOLFOX and bevacizumab, which is a completely reasonable thing to do in this setting. And as I said, you could choose the other biologics as well.

The rationale for using FOLFOX and bevacizumab is basically based on 2 studies. One is the Tournigand, which showed that if you start with A, you go to B and if you start with B, you go to A in terms of cytotoxic regimen. If you start with FOLFOX, then you go to FOLFIRI. You start with FOLFIRI, then you go to FOLFOX. So, that’s the cytotoxic backbone story. And then the biologic story, you can use 3 choices, all of which have level-one evidence: continuing bevacizumab for the TML trial, switching to ziv-aflibercept for the VELOUR trial, and switching to ramucirumab. So, any of those would be reasonable options in this case.

The factors when deciding therapy are several. The first is, again, what are the goals of therapy? Many patients after 10 months of chemotherapy, they’re tired. They want to discuss what the goals are here, what’s their quality of life because we’re not curing patients. It’s, by definition, palliative, and I can’t tell you how many second opinions I’ve seen when I’ve said to the patient, “What’s the goal of this? It sounds like you’re having a tough time. You’re in bed a lot. You’re not having a good quality of life. What is your goal?” And they can’t answer the question. Some of them say, “Well, the goal is to cure.” You know if they have widespread cancer, that’s not going to happen. And so, being very clear with what the goals of therapy are, I think, is very important.

Secondly, and this gets back to the goals, what’s the toxicity going to be? For instance, if a patient has preexisting neuropathy, you might be careful about using oxaliplatin in the second-line setting. If they had terrible side effects from 5-FU, you might be thinking about other choices there. So, this is where therapy becomes more and more personalized based on how the patient is doing. I’ve had patients after 10 months of chemotherapy, they look great and they really want to keep going. And I’ve had patients who just look horrible at that point. So, the goals of therapy, how the patient is doing, and, again, options. You have lots of options. If you look at the NCCN guidelines, there are pages and pages of these algorithms because there are different options that you can use.

The rationale for continuing bevacizumab beyond progression is based on the TML study, that’s treatment through multiple lines. And that was a study that basically randomized patients in the second-line setting between either continuing bevacizumab or stopping it, and it showed a survival benefit with a hazard ratio of roughly 0.8. The same hazard ratio was obtained by switching to ziv-aflibercept or ramucirumab. So, again, you have those 3 choices in the second-line setting, and you can make arguments back-and-forth in terms of which one you choose, and I think most oncologists choose what they’re comfortable with and what they’ve had good experience with.

Transcript edited for clarity.

September 2015

• A 71-year-old Caucasian male presented with severe left lower quadrant pain
  • He sought medical treatment after experiencing bloody diarrhea
• PMH: hypertension, managed with benazepril
• He is active and can perform daily activities without restrictions
• Laboratory findings: remarkable for CEA, 6.0 ng/mL
• Colonoscopy showed a mass in the descending colon which was biopsied
  • Pathological findings: Moderately differentiated adenocarcinoma
• NGS mutation testing results wereNRAS, KRAS, HRAS, HER2,andBRAFwild-type
  • Microsatellite stable
• CT of the chest, abdominal, and pelvis showed an 8-cm mass in the sigmoid colon
  • a 2-cm mass in the right lobe of the liver, and a 5-cm in the left lobe adjacent to the left hepatic vein
  • Impression: metastatic disease, borderline resectable
• Treatment was initiated with FOLFIRI + bevacizumab
• Imaging at 3 and 6 months showed decreased size of the liver nodules, but was not resectable

July 2016

• The patient complained of increased fatigue, requiring the need for frequent rest
• CT scan showed increasing size of the liver nodule (3 cm) and appearance of 3 new small liver lesions (<2 cm)
• He began therapy with FOLFOX + bevacizumab

February 2017

• The patient reported weight loss, increasing fatigue, and shortness of breath
• CT scan revealed progressive disease with no improvement in the primary and metastatic lesion size and/or number
• A new pulmonary nodule was seen in the right lung
• He was switched to irinotecan + cetuximab
• PET/CT at 3 months showed stable disease
• At 6 months, he reported moderate improvement in fatigue