mCRC: Frontline Therapy and Multidisciplinary Approach

Wells Messersmith, MD:The choice of FOLFIRI and bevacizumab in this case is completely defensible. FOLFIRI is a standard first-line regimen, and bevacizumab is also standardly used and it’s FDA-approved for the first-line setting within infusional regimens such as FOLFIRI. So, this is a very standard option. And if you look at NCCN guidelines and ASCO guidelines, you’re going to see the theme is choice. There are a lot of choices that someone can do. And, in fact, you might notice the last big trial in the United States allowed what’s called dealer’s choice cytotoxic backbone. So, people got so sick of fighting over FOLFIRI versus FOLFOX. One person liked this, one person liked that. They got so sick of it that they said, “You know what, this is going to be dealer’s choice. You can choose whatever cytotoxic backbone you want, then the study is just going to randomize against bevacizumab and cetuximab, the biologic.”

So, a lot of people are very passionate about this. You’ll find people who strongly believe in FOLFIRI, the idea being it doesn’t have a cumulative neurotoxicity like oxaliplatin has in FOLFOX. Other people strongly argue for FOLFOX because you keep your hair and some argue you don’t get as much diarrhea. So, the side effect profiles differ from one to the other. Also, irinotecan and FOLFIRI can have more drug interactions, so you have to be on the lookout for that. But, in general, I think of them as fairly interchangeable.

The only thing with this case that I would consider, however, is note that the patient is borderline unresectable. What that means is that at this point, there are 2 lesions. You can’t cut them out, but if we’re able to shrink them, we might be able to and that often happens in patients. If you’re able to get it off the middle hepatic vein, for instance, maybe there’s going to be enough of a future liver remnant that you now can do surgery. So, that is an important consideration, and the difference between FOLFIRI and FOLFOX in that situation is that there really aren’t any data to support using FOLFIRI after liver resection. And there are some data to use FOLFOX after a liver resection. So, if you’re going to be thinking about surgery, although it’s controversial, the trial is not a slam dunk by any means, but it was a much smaller underpowered trial. But what data are there would support FOLFOX, so you might choose that in a patient who’s borderline resectable.

The second thing, just to point out, is the METHEP-2 trial. That trial randomized people to just the standard doublet, if you will, of FOLFOX or FOLFIRI to FOLFOXIRI—in other words, going with the kitchen sink: 5-FU, irinotecan, and oxaliplatin. And there actually was a survival benefit in a high resection rate. Now, are you going to do that in a 71-year-old? You’re going to have to think about that because that regimen has a lot of toxicity. But in this case, I would say FOLFIRI/bevacizumab is totally reasonable. Some people might choose FOLFOX because of the data as an adjuvant therapy. So, if this patient went to surgery, you would use it afterwards, for instance. And some people might choose FOLFOXIRI because of the evidence in the METHEP-2 trial showing that you have a better shrinkage rate, higher resection rates, and there was a survival benefit. Although that was a small trial and it’s just 1 study.

A multidisciplinary approach to determine resectability is critical. It really can’t be overstated for several reasons. First of all, you need to be clear with the patient what the goals of therapy are. If the goals of therapy are palliative and the patient doesn’t have any symptoms to palliate, there would be no reason to use a multi-agent toxic regimen in the patient. Whereas if you could shrink the tumor and save the patient’s life, both you and the patient are willing to have a much higher tolerance for toxicity because it might save their life. So, have that multidisciplinary conversation with the liver surgeon and ask, “Is this resectable or not? What do you need me to do to make it resectable?”—and also have that conversation with the patient. There are some patients who say, “Look, I’m too old for this. I don’t want liver surgery no matter what you do. I’m not interested.” So, you really have to clarify with your surgeon and with your patient what the goals of therapy are.

The second issue is that, remember, chemotherapy can be toxic to the liver. And I’ve had a number of cases where patients were resectable from the get-go, they got 2 years of chemotherapy, now they have severe liver damage, fatty liver disease—chemotherapy-associated steatohepatitis it has been called—and now we can’t do surgery because their liver is so unhealthy from all the chemotherapy. So, you’ve missed a chance of cure by not having a multidisciplinary approach.

The other issue is if you have a small lesion and you shrink it too much, the surgeon won’t be able to see it. So, you need to be very clear with your surgeon as to the timing of scans, because if there’s a small lesion that might disappear, you might do a little bit of an earlier scan and have that patient taken to surgery sooner. Because if the surgeon can’t cut out a lesion and it’s not in an anatomic location that they can just take out the whole lobe, then things become very difficult. So, that is really critical, I think, from the get-go to make sure that surgery has laid eyes on the CT scan, possibly laid eyes on the patient, and that everyone is onboard with the same plan.

At our center, we have a multidisciplinary clinic, which many centers have, where we review patients as a group and then the surgeon, the medical oncologist, and, if needed, the radiation oncologist see the patient at once, so that the entire plan for the next year is laid out and agreed upon with the patient, the family, and all the physicians. And that way you have that multidisciplinary approach right from the get-go.

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