Deciding on Upfront Treatment for mCRC

John Marshall, MD:This is a really interesting case where most of his cancer is actually in his liver. He’s got this lung lesion; he’s got a primary there as well. And we do have new techniques around liver-directed therapies that are increasingly used, increasingly popular. We know we have a PFS advantage, but we’re still waiting on the overall survival advantage. So, the question is, who’s a good candidate for that? Well, this guy’s on the border. He had a fairly large lung lesion, his primary is still in place, but if he has a really good response—this is one of those patients that 4 to 6 months into treatment, I’m thinking about sending him to surgery—remove the primary. Nowadays, that’s laparoscopically done; you have to hold the chemotherapy around it. There’s evidence that says maybe removing primaries is a good idea, and you get it out of the way. It’s done. And then you’re dealing with this isolated lung lesion in the liver metastases. It wouldn’t be crazy to do liver-directed therapy at that point, although that might be a card I would hold until later. So, we are increasingly aggressive with surgical and local therapies when patients have oligometastatic disease and these kinds of patterns.

Whenever I see a brand new patient with metastatic colon cancer, I ask a question that actually is a question that throws them off, but I ask them anyway. I ask, “What do you do for fun?” and they, like, freak out. They don’t have any fun, but they think about it a minute and then I get a really interesting look into their lives with that answer. It tells me about their hobbies, it tells me about how they really enjoy their time, what they do with it. And what I’m really doing there is trying to get a sense of what side effects to avoid. Because if I’ve got oxaliplatin, then I’ve got this cumulative neuropathy.

So, I’ve got a guy right now who really likes to play guitar. He’s a 70-year-old guy. He plays in this band, and you wouldn’t think it when you see the guy, but he likes his guitar. And so, I’m going to avoid oxaliplatin in this guy for a long as I can. Others, particularly in these younger folks, are raising kids. They are driving all over the place, they are busy at work, and they don’t have time for a 2-day infusion. So, these are people that I’m already steering over to capecitabine as their form of 5-FU. When you find out more about your patients, you can decide between oxaliplatin/irinotecan and pump 5-FU/capecitabine.

We have been ignoring data for 15 years. Trial after trial has shown that left-sided colon cancers behave better than right-sided colon cancers, but we ignored it because we really didn’t know what to do with that. It didn’t influence our treatments, it didn’t change anything. It really wasn’t until Alan Venook went back to 80405—this big randomized clinical trial—reviewed every single chart himself and determined whether the patient had a left-sided or right-sided colon cancer. And then, he not only confirmed that left-sided colon cancers did much better than right-sided colon cancers, but he transformed our practice in showing that right-sided colon cancers, even those that haveRASwild-type,BRAFwild-type—so the ones that are molecularly profiled appropriately—failed to benefit from EGFR therapy, and this made no sense to us. It still makes no sense to us. We thought we had the enriching molecular profile, but it turns out just being over here means that it won’t work as well.

So, this is further narrowing the patient in frontline who should get EGFR therapy. It really is thatRASwild-type,BRAFwild-type, left-sided colon cancer where you would use EGFR frontline. Other studies have reconfirmed this, so this is not just the 80405 trial. It has not made it to the NCCN guidelines with a little asterisk that says “Right versus left.” I’m always nagging our doctors in our practice to make sure you put in the rightICD10code—and there’s a right one and a left one. Everybody says it doesn’t matter. And I’m like, “Now it matters. I want you to know, we have to know which side it is.” And so, when you characterize a colon cancer patient now, you need to knowRASstatus, you need to know MSI, and you need to know sidedness.

Whenever we set out on patients, we decide which regimens they should get. And as I said before, it’s either oxaliplatin-based, irinotecan-based, or both. There’s FOLFIRINOX with bevacizumab in the frontline. That’s generally reserved for the higher tumor burden, theBRAF-mutated tumor. So, in this case, I would say you’re between an irinotecan-based regimen and an oxaliplatin-based regimen.

Most of us in the United States use oxaliplatin-based frontline therapy. I think that’s tradition. We’re used to it. One of the things we’ve learned early on is that you can only give so much of it because of the cumulative neuropathy. So, most of us are pretty good at backing it off at a certain point. The one really strong note is if you start with oxaliplatin-based therapy frontline, you cannot get to 12 cycles. Don’t do it. There’s nothing magic about 12 cycles of the drug. Six to 8 is plenty and then back off to your maintenance approach.

I know a lot of doctors who favor irinotecan frontline because they don’t have to worry about that; they can just keep giving it as long as they want. I think that’s a perfectly legitimate choice. My bias toward an oxaliplatin-frontline regimen, quote honestly, is that almost all clinical trials in the second-line use irinotecan. And so, as soon as I give irinotecan frontline, those patients are now ineligible for second-line clinical trials. Maybe not the best rationale for that, but that’s why I do it. The second is that with oxaliplatin, you don’t really lose your hair. These are newly diagnosed patients, and the last thing they want—they’re getting a Mediport, they’re going through all of this—is to be losing their hair. I know how miserable that is. So, we try to put that off until later and use the irinotecan second-line.

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