Case 2: Sidedness in mCRC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Shubham Pant, MD:Richard, you talked about resection, but will this retrospective data change how you treat metastatic cancer? Would you resect the primary tumor on the right side based on this data?

Richard Kim, MD:Well, that’s retrospective data. It’s very hypothesis generating. We all know that as standard practice, for a patient who is symptomatic, is bleeding, or has near obstruction, we would take out the primary tumors for a clinical benefit. I think that’s clear. But in patients who are asymptomatic, whether you would take out the primary tumor or not, there has been conflicting data—mostly retrospective. The standard practice, at least at our institution, in patients who are asymptomatic, is not to take out the primary tumor.

Now, this data is very intriguing. The right-sided tumor patients tend to do poorly anyway, so taking out their primary tumor may make a difference. But based on that, I don’t think we can change the standard of care. As you know, there is a trial going on in Europe right now. This is a randomized trial of chemotherapy plus or minus surgical resection upfront. That randomized study will tell us, once and for all, what the right answer is. Based on the retrospective data I just presented, I will probably not take the patient to surgery upfront.

Shubham Pant, MD:Now we come to the big question: sidedness. In this day and age, with fancy next-generation sequencing and everything else, does sidedness make a difference? Mike, if somebody comes in with a left-side tumor, what do you talk to them about? Let’s say they don’t have any mutations. They’reHER2-negative. They are microsatellite stable. There is noBRAForKRASmutation. What are your current recommendations?

Michael Morse, MD:First, we want to make sure that we’re all on the same page, in terms of sidedness, in what we’re really talking about. The data are strongest when you talk about the left side splenic flexure, all the way through the sigmoid colon. And for the right-sided cases, most of the data [are] for the ascending colon. The data for the transverse colon are often lumped in with the right-sided data, based more on embryologic considerations. Obviously we’d like to know the biologic explanation for the sidedness, and obviously there are molecular differences in the tumors on the left and right sides. We will hopefully be able to use that information to make decisions in the future. Right now, what we have is just for clinical observation. The prognosis for the tumors on the left side is better than those on the right side. At least for right-sided tumors, there’s a big differential in response with anti-EGFR therapy.

In terms of counseling somebody regarding therapy, I think it’s easy for the right-sided tumors because there is such a clear difference. The NCCN [National Comprehensive Cancer Network] guidelines recognize that if you’re going to use anti-EGFR therapy, at least in the first line, it should be used only in people who have left-sided primary tumors. Whether or not you would choose an anti-EGFR therapy or bevacizumab for a left-sided tumor is still an open question, and again, it’s reflected in the NCCN guidelines. They don’t specify one or the other. I think you can see that there is a small difference between anti-EGFR therapy and bevacizumab in left-sided tumors, but it is a very small difference. As Richard pointed out, there are concerns about tolerability of the different regimens. You really have to discuss this with a person before making a blanket decision about what you’re going to treat them with.

Shubham Pant, MD:That’s a great point. So the first point is tolerability, right? What can it do? Are there other comorbidities that you would take into consideration for treating a patient? Let’s say they were like this patient—a healthy, fit, 35-year-old with no mutations. Richard, what would you do if they came to you with a right-sided tumor?

Richard Kim, MD:I think it is pretty straightforward. In young patients who have a right-sided tumor that isRASwild type, the data clearly show that the anti-EGFR drug is not as effective as anti-VEGF therapy. So for a right-sided tumor, I would probably use either FOLFOX [folinic acid, fluorouracil (5-FU), and oxaliplatin] or FOLFIRI [folinic acid, fluorouracil, and irinotecan] plus bevacizumab. That would be my choice for someone with a right-sided tumor.

For patients with left-sided tumors, once again, depending on which trial you look at, if you look at the FIRE-3 study, the benefit of the EGFR drug is about 8 months’ difference. In the CALGB 80405 study, the benefit is a little less. If you look at the ESMO [European Society for Medical Oncology] guidelines—it’s a different country, obviously—for left-sidedRASwild-type disease, the recommendation is to use the EGFR drug. They don’t even put the VEGF drug on there.

The NCCN guidelines sort of give you a choice. And so it’s a discussion to have with the patient. Personally, putting somebody on EGFR therapy for a long time is very tough on the patient. You see the rash, the paronychia that occurs. That’s probably the only reason I would stay away from it. But I would have a discussion with the patient. I would talk about the possible survival benefit and the potential toxicity that he or she may get from the EGFR drug. So I would say in the first-line of therapy for a left-sided tumor, it’s fifty-fifty in terms of what I would do. It all depends on the discussion with the patient.

Shubham Pant, MD:So what you are saying is that the Americans differ from the Europeans? The Americans don’t think you should use it for right-sided tumors, right? And the Europeans suggest to definitely use the anti-EGFR therapy for left-sided tumors, just to be clear. It’s actually very interesting. They’re not exactly the same, but they’re similar, in a way, in what they’re recommending.

Richard Kim, MD:In the first line, it’s sort of dry, in terms of not using anti-EGFR therapy for a right-sided tumor. The question is, what about in the second- and third-line settings? If you haveRASwild-type disease in a right-sided tumor and you give FOLFIRI or FOLFOX plus bevacizumab and you progress on it, we understand that. But then what do you do?

Shubham Pant, MD:Mike, what do you do in that case?

Michael Morse, MD:Well, I’d like to see more data. There are some data for later-line therapy. Even there, I think they question whether there is activity, which means there is a real biologic explanation for this. As more data come out, it may be the case that we find that right-sided tumors do not respond to anti-EGFR therapy. However, currently, because there are inadequate data to answer that and because we have only so many drugs to treat people with, we will inevitably offer them anti-EGFR therapy, even for a right-sided tumor.

Richard Kim, MD:I agree with that. There are some data in the second line for anti-EGFR therapy. It might not work for right-sided tumors. In the third line, there may be a slight overall survival benefit. It’s unclear. Therefore, I would not use it. I would use this as my last resource. If out of options, if this is a right-sided tumor and I have nothing to offer, and if there are no trials, that is when I would use it. But as you said, I would be very hesitant to use it in the first- or second-line setting. So that would be the last resource of treatment.

Transcript edited for clarity.