Therapeutic Options at Progression of mCRC


John Marshall, MD:For our case, if you remember, the patient had metastatic disease—lung, liver, primary is still in place, treated initially with FOLFOX-BEV. He probably then went to some maintenance therapy, had a nice initial response, and then 10 to 12 months later, starts to show signs of progression—some increasing shortness of breath, marker rising, new CT scan shows some progression. And so, now you’ve got to move into second-line therapy. I think all of us with oxaliplatin-based therapy frontline would move to irinotecan-based second-line, remembering that this patient has aKRASmutation. So, the question is, does one carry a biologic through to second-line? We have a mountain of evidence that VEGF inhibition through lines of therapy is positive. And so, in this case, the patient got irinotecan-based therapy with bevacizumab, continued through the frontline.

When we go from frontline to second-line, we have a lot of choices. One is we usually change from oxaliplatin to irinotecan, for example. Many people debate, “Do we keep the 5-FU going?” Most of us do. We would use FOLFIRI or even capecitabine. Irinotecan is doable. Where we differ around the world is the use of biologics in second-line. In the United States, we have 3 VEGF inhibitors approved in the second-line. Most of us continue on with bevacizumab through lines of therapy. You have the randomized clinical trial that supports that: the TML study, which supports a survival advantage by continuing bevacizumab through second-line. You already have a patient who’s tolerating the regimen. I never thought I would say this, but it’s actually the least expensive of the 3. Bevacizumab is a bargain relative to the other 2. So, I think most of us do bevacizumab beyond progression, in through the second-line, using that rationale. Europeans, other folks, feel like the impact of biologics in that setting is less strong based on the randomized trials, and so they choose to stop it. But if you look at our overall survivals, I believe it is that continuation that’s getting us to those 2 to 3 years’ overall survival.

So, our patient now has been getting FOLFIRI/bevacizumab—about 6-months of therapy—had an initial response, and then progressed again. There are new scans based on some symptoms. The patient has a little bit more abdominal distension, not feeling all that well, but still going to work. Now, they’re still slogging along doing what they’re doing. But on your imaging, you see some new early peritoneal carcinomatosis, which is never a good sign, and some progression of his disease. His performance status is about “1” now. Like I said, still going to work, still doing okay. And the question is, what do you do in third-line?

I think this is a really good candidate for regorafenib. I think the drug itself stabilizes cancers in about half of everybody who takes it, and about one-quarter of everybody who takes it is stable at 6 months or beyond. I think, because there’s not this traditional response seen with the drug, we feel like it has less value. But we don’t want to wait too long to use this drug. Many would be tempted to recycle the oxaliplatin in this patient. If he had it all the way at the beginning—it has been a year or so and now is coming back there—there’s not really any evidence that that brings a response rate to this patient either. So, I like the choice in this case of using regorafenib as a third-line choice in this patient.

When patients get to third-line with metastatic colon cancer, it’s a great place to do a hard stop and talk to our patients again. Remembering a couple of years ago, when we first started with this patient, we were all hope. We were all like, “Lots of drugs. We’re going to get a few years of survival out of this,” and now they’ve done that. They’ve gotten a couple of years of survival, and they’re at a different place. They understand where they are better. They understand that they’ve got a bad disease that’s probably not going to get better. They still want it to get better, but it’s probably not going to be cured. And so, they are valuing quality of life more. This is, to me, a really good hard stop with patients to say, “Alright, here’s where we’ve been, here’s where we are, here’s where our choices are going forward. What are your priorities? What’s important to you?”, and then setting out with a strategy.

This patient’s prognosis, untreated, is probably 6 months. So, fairly short from this point on. And what our overall goal here is to try and kick this down the road. Can we slow the progression? Can we add chunks of time to the overall survival that are meaningful with a good quality of life?

Transcript edited for clarity.

February 2013

  • A 53-year old Caucasian man presented to his gastroenterologist complaining of rectal bleeding and abdominal tenderness
  • PMH includes hypertension, well-controlled on a beta-blocker
  • Family history; mother died from breast cancer
  • He underwent colonoscopy with biopsy
    • Pathology results confirmed poorly-differentiated adenocarcinoma
    • Genetic testing was positive forKRASexon 2 codon 12 mutation
  • CT scan of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe.
  • Diagnosis: Adenocarcinoma of the colon; staging, T4N0M1
  • The patient was started on FOLFOX and bevacizumab, therapy is well-tolerated
  • The second follow-up scan showed a marked decrease in volume of the primary tumor, two of the liver lesions, and the lung lesion.

March 2014

  • The patient complains of intermittent shortness of breath but continues his normal activities
  • Imaging shows slow but steady progression in the plural lesion
  • Bevacizumab therapy was continued; the patient was also started on FOLFIRI
  • Follow-up imaging shows continued regression of the lung lesion; patient continues to tolerate therapy with management of gastrointestinal distress

February 2017

  • The patient complains of abdominal fullness, nausea, and constipation
  • He continues to work full-time but feels sluggish
  • MRI indicated diffuse metastatic disease in the peritoneum, consistent with carcinomatosis
  • The patient was started on regorafenib 80 mg, with a plan to gradually increase to 160 mg if tolerated
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