Best Practices in Managing Side Effects Associated With Renal Cell Carcinoma Treatment

Zita Lim

With the advent of tyrosine kinase inhibitor (TKI)/immunotherapy (IO) combination therapies and the overlapping toxicities that they may carry, such as diarrhea, how do you differentiate which agent is causing the toxicity? And how do you approach treating those side effects?

Emily Lemke

I think diarrhea is one of the toughest side effects because we know it obviously can be caused by the IO or the TKI. So this is where I really lean on the half-life idea. Immunotherapy's half-life is significantly longer than that of TKIs. So if the patient has questionable grade 3/4 diarrhea, I have them stop their TKI right away, especially if they're on axitinib/pembrolizumab. And their diarrhea should resolve within a day or so based on the TKI half-life. But if it doesn't stop, then we investigate further with some stool studies and inflammatory markers, such as lactoferrin. If the diarrhea is exceptionally severe, I admit patients for either IV steroids and/or a colonoscopy. But timing is really important and how quickly or not things resolve after stopping medications.

I also think there's a volume side of this too, where, in full-blown immune-mediated colitis, patients are going to be having 10 to 12 stools a day, if not more. Whereas with TKI diarrhea, you can get to that point, but usually you start out with maybe three or four stools a day to begin with, and that's usually when I'm hoping patients are calling me to intervene. I certainly counsel these patients on these differences. I think patient education can be one of the most important tools we have on these dual combinations. I educate patients to call me for anything that seems wrong, because with some of the IO side effects, we don't know what we don't know.

And the other aspect that's nice with the scheduling of pembrolizumab/axitinib is that you are seeing these patients on a pretty regular basis, as compared to patients who might be on just a TKI and eventually get to an every-12-week follow-up schedule, hopefully you can catch these toxicities early.

But diarrhea is always a tough one. It’s one of the main side effects we deal with, with all of the renal cell carcinoma therapies. What is your go-to treatment when you've already exhausted loperamide as a tool for TKI-induced diarrhea?

Zita Lim

In those patients, we typically employ Lomotil, sometimes alternating with the loperamide. There have been situations where we have also even had to add other treatments, such as colestipol or even tincture of opium in the rare patient. You may also need to consider dose interruptions and reductions.

How do you employ treatment breaks for patients on TKIs?

Emily Lemke

I think treatment breaks are a really important tool for patients on TKIs, and practitioners need to be comfortable with this approach. Depending on what TKI you’re using and what kind of half-life it has, those factors help me determine how many days of a treatment break to give patients. So, for example, we were talking about diarrhea. If diarrhea is not improving with the over-the-counters or Lomotil, then that's when I stop the TKI, usually for 4 or 5 days, and then if the diarrhea resolves completely, I might have the patient restart the TKI at the same or a lower dose.

It's really important for patients to understand that it is better for them to take treatment breaks every 5 or 6 weeks to reset their system so they can continue to tolerate these therapies long term than to never take a treatment break and risk the toxicities becoming so severe that they are unable to tolerate the therapy altogether. I tell every patient when we're starting these therapies to expect a treatment break at some point, and that if they can't tolerate a certain dose, we will find a sweet spot for them, which is possible with all of these regimens.

Another strategy I use a lot is taking weekend breaks, where patients take the therapy at full dose or even a reduced dose Monday through Friday, and then they take the weekends off. Even just that 2-day break really allows them to stay on the therapy and tolerate it much, much better.

It's easy to rechallenge these patients if they've had significant diarrhea, or hand-foot syndrome on TKIs after it's resolved. But with immunotherapy, that can be a little bit more controversial. Do you ever have patients stop an IO for a grade 3/4 toxicity and then consider restarting it, or do you change the therapy altogether?

Zita Lim

I think we have to approach each toxicity individually. There are some toxicities such as thyroiditis, or even adrenal insufficiency, which we anticipate that patients may develop, especially those receiving the doublet immunotherapy combination, and that we can easily manage. We catch them, we treat them, we replace either patients’ thyroid levels or their cortisol, and we can continue treating them on their immune therapy.

But what about other adverse events? Then we need to ask ourselves what are the toxicities, and to what the extent are they affecting the patient. There are some rare but potentially highly morbid toxicities that we have encountered such as myositis, myocarditis, or myasthenia gravis, which sometimes have a tendency to overlap. In those situations, we do not rechallenge them because unfortunately, we've lost patients to these toxicities, so we just try to get them through the toxicity.

Other toxicities like colitis and pneumonitis, however, are more challenging. If you catch them early, you may be able to resume IO therapy if the adverse event is treated. We also have other treatments that we sometimes will employ—different immunomodulators, such as infliximab or vedolizumab.

Emily Lemke

Yeah, I don’t think there's a one-size-fits-all approach for the patients who end up needing the biologics. I personally haven't rechallenged patients who have needed infliximab or vedolizumab—not to say that it can't be done. And I think there's a group of these patients who have these grade 3/4 toxicities who actually have some durable responses.

What's your opinion on grade 3/4 toxicity and its impact on response rates?

Zita Lim

We have seen patients who had severe toxicities and then we had to discontinue their therapy. Initially, we just follow them and allow them to recover from their toxicity. And then we scan them to see whether their response to IO therapy continues. So it's reassuring to me and to patients to know that you can be treated with steroids or immunomodulators and still have a response to therapy. I think that's a common concern that patients have and a reason they may not want to divulge to you that they're having toxicities: They're afraid that you'll give them steroids and that it may reduce their response.           

How do you manage taste changes for patients receiving TKIs?

Emily Lemke

This is one of the hardest side effects to manage because it's not debilitating enough that you want to stop treatment altogether, but it's so annoying for patients. I have a couple of nontraditional approaches. I tell patients about mberry, which amplifies the sweet taste buds on your tongue, and I tell them they can pop one before they eat to try and try to get everything they can out of the food they're eating.

I also had one patient actually tell me that Lemonheads were their saving grace when it came to just those metallic kind of tastes, and they would just always have a little box in their pocket, and pop one every couple hours. That's a super low-cost, low-risk way to try and manage these taste changes.

And then there's zinc sulfate, which can help mitigate the specifically metallic taste that a lot of patients get on these therapies. I haven't seen that work super well, but it's usually listed in practice guidelines on managing taste changes.

Zita Lim

We can also refer patients to a nutritionist to see how they can amplify their calorie intake. We sometimes will consider therapeutics such as Marinol (tetrahydrocannabinol), especially for patients on TKIs who can have drastic weight loss.

Another unique side effect I find with TKIs is hand-foot syndrome. Do you have any pearls for helping patients through that toxicity?

Emily Lemke

Hand-foot syndrome is a toxicity that sometimes does necessitate treatment breaks and dose reductions, just because it can significantly impact quality of life and increase risk for infection. Before dose reductions, I usually have patients try using certain creams, like Udderly Smooth or even Regenecare Wound Care Gel, which is a compound available at most pharmacies. But then when those approaches don't work, I turn to treatment breaks.

Hypertension is another common TKI side effect we see on a regular basis. How do you manage that?

Zita Lim

I think there's no right or wrong answer, but I'm of the school of thought that if you break it, you buy it. So I feel like if I induce the hypertension, it's up to me to try to manage it, especially if the patient doesn't already have a cardiologist.

I find that the hypertension that patients develop on these TKIs is much more abrupt than what we see with essential hypertension, where you start with diet and exercise modifications, followed by the addition of hydrochlorothiazide. TKI-associated hypertension tends to be refractory to those approaches. Not that they should not be employed, but certainly, you may have to be more aggressive in your management.

Typically, if patients’ kidney function and potassium level are normal, I like to start them with an ACE inhibitor. Once we have maximized the ACE inhibitor dose, I will add a different class, such as a calcium channel blocker, like an extended-released nifedipine, or a beta blocker and even hydralazine. I personally try to avoid clonidine, because I don't like the rebound hypertension that patients can develop. But if you're not comfortable treating the hypertension yourself, you should refer the patient to a cardiologist, or even a nephrologist to let them help you.