Roundtable Discussion: Exploring Factors of a Patient With RR-DTC to Decide Appropriate Treatment

Steven I. Sherman, MD, FACE

Steven I. Sherman, MD, FACE, Naguib Samaan Distinguished professor in Endocrinology in the Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine at The University of Texas MD Anderson Cancer Center, moderated a Targeted Oncology Case-Based Roundtable event related to characteristic of patients with radioiodine-refractory differentiated thyroid (RR-DTC) and how to consider them when selecting treatment.

The group of experts was first asked how they define (RR-DTC), and what are the clinical and molecular features associated with response to radioiodine?

WANG: I don’t really have a lot of experience with thyroid cancer, but based on the case presented, after we do active radioiodine treatment, if a patient has the marker increase or pulmonary nodules like this patient, then I think that the patient has recurrence of disease. Whether this is radioiodine refractory, I would think so.

SHERMAN: There are several features about this case that fit with the contemporary definition of refractory disease. First of all, when she had her initial radioiodine scan, which was after a very high dose of therapy, this type of scan is typically done about 3 to 7 days after treatment. If she had radioiodine-sensitive disease, you would see it light up on the scan, so if her pulmonary metastases were radioiodine avid, it would have shown up on that posttreatment scan that’s done with 150 MCi. The first part of the definition would be a patient who has a scan that does not show uptake in any defined metastatic lesion. Even if there was a mixed picture where some lesions did take up iodine and others did not on that scan, the leading edge of the disease would define its characteristics. Disease that does not show up with radioiodine on that scan would define her case as refractory.

The second is, within just a few months of treatment, she had evidence of progression of disease. The American Thyroid Association [ATA] says that if a patient has progression within 12 months of radioiodine treatment, that’s essentially telling us, regardless of uptake, that this is a disease that’s going to grow, that is refractory to the treatment. She has 2 of the cardinal characteristics: lesions that didn’t show up at all on the radioiodine scan and new and progressing lesions within a year of therapy.

Now, there is some argument about some of the other characteristics, but those are really the 2 most common clinical features that define a patient as refractory. In terms of where this is most likely to be seen, RR-DTC tends to be more common in older patients and much less common in pediatric and young adult cases of the disease. That seems to have some correlation with genotype, and so tumors with BRAF mutations, which is the most common oncogene in papillary cancer, are ones that are also less likely to be radioactive iodine responsive, whereas those that have a RET fusion rearrangement are more likely to be radioiodine responsive.

SHERMAN: Overwhelmingly, three-quarters of you feel that you’re getting the patient at the right time, which is good to have that handoff be appropriate.

This is a patient with RR-DTC, with evidence of progression of her disease by imaging, as well as by tumor markers, but more importantly, by CT. But she has no symptoms from her disease at this point in time. She’s come to you for a consultation.

SHERMAN: Should this patient be started on systemic therapy, and why or why not?

CHALLAGALLA: She is asymptomatic, and the metastatic nodules are fairly small, meaning they’re less than 2 cm. If the growth potential is less than 20%, generally we observe and repeat CT scans or MRIs in 6 months or so.

SHERMAN: So smaller cells in the nodules, the fact that she’s asymptomatic, and perhaps the pace of change isn’t quite fast enough yet to warrant the therapy. Is that because the treatment is not going to be curative, that it’s a palliative intervention?

DASGUPTA: Isn’t that true for any metastatic disease, that treatment is palliative? From that argument, we should not treat any metastatic disease that is asymptomatic. I wouldn’t buy that argument. You know this is going to grow, so why wouldn’t I treat?

SHERMAN: That is a question about the trade-off between risk and benefit in an asymptomatic patient. Until recently, in the realm of thyroid cancer, the emphasis has been on palliating symptoms rather than trying to interfere with the disease process. With the caveat that when the disease is radioiodine responsive, it’s still curable. Historically, we’ve tried to [use] radioiodine aggressively because of that ability to cure the disease potentially.

Let’s assume that you’ve decided to go ahead and treat the patient. In part, the patient wants to be aggressive, does not want to allow the disease to keep growing, which, at this rate given the pace of change, I think this is a fairly significant rate of growth over just a few months.

SHERMAN: Are people here familiar with the guidelines on thyroid cancer from either the National Comprehensive Cancer Network [NCCN] or the ATA guidelines? And if so, do you use them in your practice?

DASGUPTA: I don’t see too many thyroid cases, but whenever I do, the first thing I do is go to NCCN guidelines. I definitely use that.

SHERMAN: One of the advantages of NCCN is that it is updated very promptly, whenever a new therapy or major new data come out. I think for the management of advanced disease, NCCN is a far more useful set of guidelines. For standard premetastatic therapy, the ATA guidelines, I think, are much more helpful than the NCCN.

SHERMAN: Do you find the differences between sorafenib [Nexavar] and lenvatinib [Lenvima] with regard to age and outcomes something that would affect your clinical decision-making? Does that influence your decision about whether to start therapy in an older patient?

QURASHI: No, if I can use and treat, I will go ahead and treat.

SHERMAN: I think that that’s now a change, because at an earlier time, those of us primarily focusing with patients with thyroid cancer were a bit reluctant to start older patients because of concern about their tolerance and whether they would benefit as much. The longer-term analyses from the phase 3 SELECT trial [NCT01321554] is suggesting just the opposite, that the older patients are the ones who benefit the most from the treatments.¹

QURASHI: Is there any sort of biologic rationale as to why older patients have this benefit? What’s the thought on that?

SHERMAN: I’m not sure about the benefit, but age is more important as a prognostic factor in DTC than it is in almost any other solid tumor. I believe it’s the only solid tumor where it figures into the American Joint Committee on Cancer staging whether patients [receive a diagnosis] before or after age 55. Whether this is a function of the immune system, whether there are biologic differences— there’s some evidence that BRAF mutations tend to be more common in older individuals, so there may be some genotypic differences. Older patients may also have TERT promoter mutations more commonly to go along with those BRAF changes. Those may relate to the underlying aggressiveness of the disease, but why an antiangiogenic therapy like lenvatinib is more effective in the older population is less clear. It could also be that it’s just the underlying risk for mortality. Disease-related mortality is so much higher in the older population that we tend to see more events in that group, and therefore, it’s easier to see the benefit of treatment in those who are at higher risk for mortality.

HUANG: In the SELECT trial, was there any sense of how many of those patients had RET mutations, BRAF mutations, or things like that?

SHERMAN: BRAF mutation was what was most common, and surprisingly, the patients with BRAF mutations did just as well as those who did not.² The response to lenvatinib was pretty similar. What was surprising—but the same thing was seen in the DECISION trial [NCT00984282] as well—is that in the placebo arm of both studies, the patients who had BRAF mutations tended to do better on placebo than those who did not have BRAF mutations.^2,3 That flies in the underlying general sense of prognosis with BRAF mutations.

The explanation’s been thought to be that the patients who did not have BRAF mutations must’ve had multiple other mutations that added up, eventually leading to aggressive, progressive refractory disease. All it took was a BRAF mutation to be eligible for this trial, whereas, if the patient didn’t have a BRAF mutation, they were going to need a whole lot of other things going wrong with their cancer to get to this point; that is the leading thought process to it.

SHERMAN: The rationale to keep in mind is, these drugs are toxic. They have significant AEs, and they certainly have significant cost, up over $10,000 a month, and so that’s also part of the trade-off. It’s very important that we monitor patients proactively for AEs and, in particular, asymptomatic AEs like severe hypertension. We have all our patients monitoring their blood pressure at home and sending us in blood pressure logs, week after week, especially as they get started on the drug.

SHERMAN: How do you approach the management of things that are symptomatic, like diarrhea or proteinuria?

CHALLAGALLA: Because we do have experience with lenvatinib in other cancers, none of these have been too major of an issue, except fatigue.

WANG: Weight loss is also another AE that is hard to manage.

SHERMAN: It is, especially with chronic therapy. Appetite stimulants, nutritional supplements, and focusing on the weight loss early on are very important. With the diarrhea, we start patients out with Imodium [loperamide], but we sometimes have to add Lomotil [diphenoxylate/ atropine]. Sometimes we have to add tincture of opium. It can be problematic.

We also need to monitor for proteinuria. If it’s very high, we need to get them off drug. Mild proteinuria can often be managed with angiotensin converting enzyme inhibitors or angiotensin-receptor blockers, as these patients generally are also hypertensive, and so we might manage the proteinuria that way. But it’s important to have a regular monitoring program to look for these AEs.

SOLANKI: Has there been any correlation with the hypertension and response?

SHERMAN: There’s been some, especially in the lenvatinib data, clearly suggesting that targeting the vasculature is not just the mechanism of toxicity but the mechanism of effectiveness of the drug.

SOLANKI: Do you have any criteria for lenvatinib in eligible patients?

SHERMAN: Yes. The contraindications are relative, so for patients who are on blood thinners, we’re a little bit more reluctant. Certainly, patients who’ve had neck irradiation are at much higher risk for fistula formation; using a potent antiangiogenic like lenvatinib, that’s one of our most common, nearly absolute contraindications to therapy. Patients who have encasement of the carotids are also ones we tend to steer away from antiangiogenics like lenvatinib if we can. If they have brain metastases, we will typically irradiate those before they get started on an antiangiogenic. [Also, if they have had] stroke or a myocardial infarction recently. We do screening brain MRIs in our patients, usually before starting lenvatinib.

_References:

_{1. Brose MS, Worden FP, Newbold KL, Guo M, Hurria A. Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial. J Clin Oncol. 2017;35(23):2692-2699. doi:10.1200/JCO.2016.71.6472}

_{2. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine- refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470}

_{3. Brose MS, Nutting CM, Jarzab B, et al; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-328. doi:10.1016/S0140-6736(14)60421-9}