DR CHEN: This is a 60-year-old woman who is a retired nurse. And she had initially presented with metastatic colon cancer in 2010. At the time of the diagnosis, she had a colon mass but she also had a very large pelvic mass. So she underwent surgery. That was a combination between our general surgeon as well as our GYN oncologist, and removed the colon mass and also removed the pelvic mass, and [she] was diagnosed with metastatic colon cancer.

DR LOVE: Was she symptomatic from the primary?

DR CHEN: She initially presented with abdominal distension, abdominal pain. And at the time of presentation before she had the surgery, it was not clear what was the primary disease.

DR LOVE: Just a word about patients: Quite a few of the patients in this survey had presented like this woman with metastatic disease, Randy — the decision between removing the primary and starting on systemic therapy. This lady sounds like she had some symptoms. She had a big mass. But in general, how do you think through which one to start with?

DR HECHT: This is something that we wrestle with all the time. And actually having the availability of presenting cases at a multidisciplinary board really is very helpful. And you said that there were the surgeons involved. Was this part of a formal — did you have a formal presentation, or is it more like you call someone up — we do both, because I think that having the radiologist there and going over the scans and all that sometimes can be very helpful.

DR LOVE: Can you just go through, though, how you make the decision?

DR HECHT: A lot of it really is by how the patient talks to you and the questions and how you feel. There was actually recently some more data that came out showing that, unlike in renal cell, where taking out the primary may have a number of different — and perhaps immunologic — it doesn’t seem to be the case.

Now the pendulum has swung back and forth a lot over the years. And at one time, the surgeons had convinced us that we should always take the primary out, because when they had to have — if it were an emergency surgery and someone became obstructed, and then they would say, “Well, they do much worse and they end up with ostomies.” And the problem was that two things happened. One was that our treatments became better, so patients were living longer and they were having tumor responses with modern chemotherapy and modern biological therapy. So it was not as much of a problem. If you look, the number of patients who needed emergent surgery was actually fairly low. So you were doing a lot of surgeries to help a few people.

The other thing that also happened, though it’s not used quite as much anymore, is that gastroenterologists were learning to put stents in, so patients didn’t necessarily need surgery, or as a bridge to surgery, so it wasn’t emergent surgery. The pendulum swung a little bit back as the surgery got better, because now, with laparoscopic surgery, the patients were really not — it was not as morbid. But for someone who has no — unless they’re bleeding or they’re obstructed, we don’t do that. It just delays the start of the treatment that they need.

DR LOVE: So this lady gets surgery. What was her situation postop? And when you evaluated, what were you thinking at that point?

DR CHEN: She actually did very well postoperatively.

DR LOVE: How much tumor did she have, residual tumor, either in the abdomen or elsewhere?

DR CHEN: Yes. She had very little residual tumor after the surgery.

DR LOVE: So there was nothing you had to measure.

DR CHEN: Yes. That’s correct, and I think the initial reason for going ahead with the surgery was, one, she was symptomatic. Second, it was unclear whether she had a gynecologic primary versus a colorectal primary.

DR LOVE: And they found that this was a, what, metastatic and lymphadenopathy, the big mass?

DR CHEN: Yes, That’s right.

DR LOVE: And they were able to remove it though?

DR CHEN: That’s right. They removed it.

DR HECHT: So she was NED? She had no evidence of disease after the surgery. So she had metastatic disease, but she was rendered to be completely tumor free?

DR CHEN: That’s correct.

DR HECHT: But it was metastatic retroperitoneal lymphadenopathy or something like that?

DR CHEN: A large pelvic mass.

DR HECHT: Was it ovarian, like a Krukenberg tumor?

DR CHEN: She actually did have metastasis to her ovary as well.

DR HECHT: But the primary was cecal?

DR CHEN: Yes.

DR HECHT: Okay.

DR LOVE: So what was the next step?

DR CHEN: The next step after she recovered from the surgery, then the question was whether to give her chemotherapy and what chemotherapy to give. So we did initially use a FOLFOX regimen, and a couple of months later added in bevacizumab for 6 months’ duration.

DR LOVE: And can you kind of fast forward, maybe get up to the point where she got the regorafenib, just go through what happened there? And then we’ll talk about it.

DR CHEN: Sure. So she was treated with FOLFOX/bevacizumab. And then afterwards she was on capecitabine/bevacizumab for maintenance.

DR LOVE: Could I just say that, 36 months?

DR CHEN: Yes, a long time. She had a long disease-free interval there.

DR LOVE: So she gets FOLFOX/bev, Randy, then gets capecitabine/bev as maintenance, which I think is interesting.

DR HECHT: But she had no evidence of disease when you were doing all of this?

DR LOVE: When you started, right.

DR HECHT: It was kind of an adjuvanty —

DR LOVE: Stage IV NED.

DR HECHT: Yes.

DR CHEN: Right. That’s right.

DR LOVE: But she did great, so she went three and a half years.

DR HECHT: I’m sorry. Did you say the MSI status for her? Just for the right-sided tumor —

DR CHEN: Yes. She was MSI stable.

DR HECHT: Oh, MSS. Okay.

DR CHEN: She was KRAS mutant and BRAF wild type.

DR HECHT: Which goes — because they’re mutually exclusive.

DR CHEN: Yes.

DR HECHT: So did well.

DR CHEN: She did well. And then she had progressive disease and was treated with FOLFIRI/bev.

DR LOVE: Where was the disease progression?

DR CHEN: She did have liver progression when she had disease progression.

DR HECHT: Interesting.

DR LOVE: What was next?

DR CHEN: We did have to dose reduce on the FOLFIRI regimen. I think she had abdominal discomfort, diarrhea. And then after that, when she progressed, because she was KRAS-mutant, we could not use anti-EGFR therapy. So we did treat her briefly with a course of aflibercept as well as irinotecan.

DR LOVE: I thought that was really interesting.

DR CHEN: But I think we discussed at that time whether to use that versus going ahead with the regorafenib.

DR LOVE: Could I just ask, how did she do on the irinotecan/aflibercept? It says you had some issues related to dose, you had to modify.

DR CHEN: Right. I think it was she had more fatigue. She was having a lot of intermittent abdominal discomfort, asthenia.

DR LOVE: So maybe, Randy, you can comment on her course. This lady has now gotten, if you include the maintenance, 4 different bevacizumab — or, I should say, chemo/angiogenic combinations. FOLFOX/bev with cape/bev maintenance, FOLFIRI/bev, common choice, irinotecan/aflibercept. Interesting. What do you usually do? I mean that first part of it is pretty common, but once you get beyond FOLFIRI/bev as second line in the mutated patient?

DR HECHT: I think you actually bring up 2 interesting points. One, is aflibercept any different than bevacizumab? And my personal feeling is probably not, and so I don’t think that you really add an awful lot at this point, compared to bevacizumab.

The second but linked question is, does it make sense to continue an antiangiogenic therapy? And that’s some of the work that we had done actually a while ago. And there’s actually preclinical data that there are all sorts of proangiogenic resistance mechanisms that get upregulated. And then you have an antiangiogenic. And I don’t think there’s a huge difference from aflibercept or ramucirumab — they’re hitting different parts of the VEGF pathway — or bevacizumab. And that, when you take it away, in some ways we’re kind of alluding to prostate cancer, that even in patients who progress with hormonal therapies, maybe it’s better to continue someone on — or HER2, that’s done, though the data is fairly weak. And so I can’t say that it’s wrong to do it.

Regorafenib is an antiangiogenic therapy. And so it at least gets that and may do something else. So my own personal bias is that I would not have done — but I can’t say that it’s wrong — but I would probably not have done the irinotecan plus aflibercept, if only because I don’t think it would have added. She had just progressed on FOLFIRI plus bevacizumab. Now, maybe it’s still better to have some antiangiogenic in, whether it’s regorafenib or whether it’s aflibercept, or not.

I think what, Neil, you were pointing out, there’s been some questions about toxicity perhaps with that combination. Aflibercept’s not used very much.

DR LOVE: It was like myelosuppression or something.

DR HECHT: It was GI toxicity.

DR LOVE: With aflibercept.

DR HECHT: Though, once again, there were differences. There were cross-trial comparisons. And aflibercept has not really caught on for a number of different reasons. One, there was this hint, maybe, of more GI toxicity. It was also priced poorly, so that was also a reason, and there was a New York Times editorial, which probably doesn’t help.

DR LOVE: Len Saltz.

DR HECHT: Exactly, with Len saying that they were not putting it on formulary —

DR LOVE: At Memorial. Right.

DR HECHT: — at Memorial Sloan Kettering.

Metastatic wild-type nonsquamous non-small cell lung cancer (NSCLC)

Metastatic colorectal cancer (mCRC)

Metastatic epithelial ovarian cancer (OC)