Kundranda and participants examine first-line and subsequent therapies in CRC

In a focused oncology case-based roundtable, Madappa Kundranda, MD, PhD, and attendees discussed the case of a patient with recently diagnosed unresectable colorectal cancer.

PARIK: I think my biggest concern would be the neurotoxicity of oxaliplatin; the recurrence time is not so great. I almost suspect the oxaliplatin didn’t work at all. I would add an organic product to this diet to try and maximize the initial response.

KUNDRANDA: I think that’s certainly why most [use]. The 6 month rule that we typically use… in terms of platinum sensitivity, most of that rule comes from our ovarian cancer patients.

In this case, with someone who has had such a short disease-free interval and has never been exposed to irinotecan, that’s certainly very reasonable. [As is] adding a biological to that. the importance of NGS in the initial treatment of biological agents…when you think of NGS, I think we all do. Some of the labs automatically react to at least microsatellite instability [MSI] tests, and I saw it. Some of our labs tend to do a larger panel, as we’ve seen, which is the expanded KRAS panel, as well as MSI testing.

Generally, when you have a patient with a new diagnosis of metastatic colon cancer or rectal cancer, do you normally get one of the full NGS panels or do you get more of the limited panels [panel], NTRK mergers, krasMSI and HER2 now because of the treatment options we have in this subset of patients?

KAHN: I find it easier to do everything at once in 1 frame. For example, with FoundationOne [testing]you can get it all [simultaneously] and it’s much easier than ordering individually.

KUNDRANDA: Anyone else have a different approach? Because before we had cases where we only got a limited panel; once the patient progresses to first line and second line, that’s when they would get the fullest panel. Or does everyone go for the full panel up front?

SOUTH : I agree with Dr. Kahn. I also get the whole full panel, with a kras mutation panel, sent to the front. All the fabric is no problem, such as the amount of fabric [the way we run into] lung cancer issues when we do piecemeal testing. But in this case it is not really a problem, but it is still more convenient to collect all the information at the beginning of treatment.

KUNDRANDA: I agree. That’s one of the changes we’ve seen across the board, as fabrics become the problem. When I do a liver biopsy to get tissue for molecular profiling, now I just call it “molecular profiling” – I don’t need the whole panel of all the CD tests done…. It is worth doing this in advance for a multitude of reasons.

One is obviously finding the best option for those patients, but also making sure that if you have to retest those patients—[for] a clinical trial or similar – you already have tissue in the bank and you haven’t depleted it. It’s been helpful with colon cancer, and I think most cancers, trying to do that right off the bat.

KUNDRANDA: Most of us would look at that and say that would be a patient that you would absolutely change your treatment for, because that patient has radiological progression and that makes it a lot easier. You also have clinical progression.

The question becomes—and [I’ve] encounter this a multitude of times, or if you have questionable clinical progression; radiologically, things are stable; and you have a biochemical progression – what do you generally do in this context?

Do you change treatment or continue with the same agent, knowing full well that the biochemical progression could probably be delayed compared to the radiological progression? How comfortable is everyone with changing treatment based on biochemical progression?

YO: carcinoembryonic antigen [CEA] cheats on me every time. It’s worrying to see a continued increase, but there were a few times where I continued to scan and saw [almost] no measurable change.

Often I have a discussion with a heavily treated patient, so usually I go with the CT scan and the measurable changes in the disease, and I tend to do a biopsy and confirm.

KUNDRANDA: I completely agree. This is where we’ve all been burned: when the patient becomes anxious because they track their ACE from 6.9 ng/mL to 7.1 ng/mL, then drop to 6.8 ng/mL, then back at 7.2 ng/mL.

The patient thinks that [is] progressive [disease]. I see this in my clinic at least once a week. But you also have the real biochemical progression where you see a CEA going from 40 ng/mL to 80 ng/mL; but radiologically the patient is stable, perhaps a questionable clinical course.

The only exception… where I changed treatment is when I have biochemical progression with absolute clinical progression – there is weight loss, there is new pain that I cannot explain for any other raison…

Most of these patients have progression. Even in these patients, if you wait the extra 3 or 4 weeks and restore them, they will have radiological progression.

PARIK: Are there a number [or percentage increase of CEA] do you use to determine progress?

KUNDRANDA: No. Unfortunately, it depends on their baseline. Some of these patients are non-secretors or they are only minimal secretors. I’ve had patients with a CEA of 1000 ng/mL who are doing well; I’ve had patients with a CEA of 25 ng/mL who crashed and burned. CEA by itself does not give us an idea in terms of disease burden or rate of progression, although trends are useful.

PRASAD: Sometimes the only thing [changing] is the rate of increase in CEA, maybe in a week or 2, if it doubles, it can be [progression]. Sometimes patients become symptomatic, with more pain and possibly ascites, and sometimes CT scans don’t show peritoneal carcinomatosis so well. In these cases, we may need to plan for a change in treatment if we think they are progressing despite treatment.

KUNDRANDA: This is a very good point because this is where your clinical progression comes into play. Combining clinical progression with biochemical progression makes a difference.

KUNDRANDA: A majority opted for irinotecan with an anti-EGFR inhibitor. [Others said] to re-challenge the patient because the patient was [on] capecitabine and bevacizumab. Will you re-challenge the patient with FOLFIRI or will you re-challenge the patient with FOLFOXIRI with bevacizumab?

That was the question because the patient had this progression after about 10 months. It is certainly reasonable. But, bearing in mind that the patient has residual neuropathy, continuing platinum therapy will be a poor return on investment. With irinotecan/anti-EGFR, the question is whether you would use an anti-EGFR as part of a BRAF mutation? I think we have enough data to indicate that if the patient has a BRAF mutation, use of an anti-EGFR is unlikely to be beneficial. If anything, it could be detrimental. In this scenario, revert to re-provoking the patient with FOLFIRI plus bevacizumab [Avastin] would be reasonable. Moving from processing to TAS-102 [trifluridine-tipiracil (Lonsurf)] with or without bevacizumab… is [a good] way to do so for a multitude of reasons, at least based on the data we have. Use regorafenib [Stivarga] would also be reasonable. Those would be the 3 options at this point.

KUNDRANDA: In a patient who took FOLFOXIRI for [a while] and had toxicities and is now on capecitabine plus bevacizumab, would it be possible to change treatment to something less myelosuppressive? Or at this point would you say getting more for your money in the context of getting more for cytotoxic reduction is the way to approach this?

MUKHERJEE: We learned how to manage neutropenic infections. I think neurotoxicity is the one that gives us the most problems.

KUNDRANDA: Absoutely. If you have a patient [and]in this case, resume FOLFIRI/bevacizumab, would you start with a dose reduction in these patients?

MUKHERJEE: It depends on the level of toxicity. If a patient has a fair burden of neurological toxicity, yes I would. If the patient is fine, I would start and see how it goes, then scale it down as needed.

KUNDRANDA: If you end up having myelosuppression – let’s just say mostly neutropenia, and the rest is more or less manageable – as far as growth factor support goes [authorized]are you experiencing difficulties… in a patient who has undergone dose reductions?

Did you complete the challenge to get either Neulasta [pegfilgrastim] or Neupogen [filgrastim] in these patients if you experience myelosuppression, whether you reduce the dose or not?

PARIK: No, it’s approved.

KUNDRANDA: I’ve had issues where the patient has an absolute neutrophil count of 900 and I still can’t get [growth factor support]. I think it’s probably an insurance issue, but…isn’t that a problem you’ve had in general?

PARIK: There is insurance we have that will require a fever with it. Fever is easy to document.

With the availability of TAS-102 and the data available, are you still using regorafenib?

KUNDRANDA: When you think about the survival benefit between TAS-102 and regorafenib, they are comparable. I don’t think most practices use TAS-102 alone, and we don’t have a direct comparison between TAS-102 and regorafenib.

Do any of you typically use TAS-102 alone, or have you had any issues getting bevacizumab approved with TAS-102?

YO: Insurance declined 2 times because they said the patient had progressed on bevacizumab, so why do you have to use it again?

They just go and get FDA approvals, and there’s no approval. This is not strongly suggested by National Comprehensive Cancer Network guidelines.

KUNDRANDA: I did not encounter this problem.

KUNDRANDA: Do any of you know what data we have on fruquintinib [Elunate], which is an oral anti-VEGF? the [trial] started outside China [NCT02314819]. Fruquintinib is an oral anti-VEGF agent, affects the VEGF1, VEGF2 and VEGF3 pathways. The survival data was impressive. Overall survival was approximately 9 months in these refractory patients.1

However, the caveat of this study was the fact that… in the Chinese patient population, none of them were exposed to an anti-VEGF. I have to take this with a grain of salt thinking about it, as it was fruquintinib versus placebo in these patients. We currently have a study [of fruquintinib] which is open on several sites, and we should have some of the data very soon.

More than likely, this would be another agent we’d have the refractory tuning for and definitely something I think is worth mentioning, although we don’t have the data yet.

REFERENCE

1. Li J, Qin S, Xu RH, et al. Effect of fruquintinib versus placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855

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