Dr Orenstein details how he manages quality of life for patients with advanced renal cell carcinoma.
Toni Choueiri, MD: Well, Dr. Orenstein, logistically, in a minute or two, how do you manage adjusting the dose in the schedule, both for IO [immune-oncology] as well as for TKI [tyrosine kinase inhibitors]?
Moshe Orenstein, MD, MA: That's a great question, because this comes up practically. Especially when we're talking about IO TKI [immune-oncology tyrosine kinase inhibitors] combinations, we know that there is a certain chronicity of toxicity for patients who are taking daily TKIs. We're familiar with the hand-foot syndrome, the diarrhea, the potential mouth sores, etc. First, I would say that I always start patients, or as a general rule I start patients with the doses that were used in the clinical trials, acknowledging and telling patients upfront that there's a reasonable chance that we will have to either change the dose or the schedule. I think the first thing that's important, regardless of the combination, is to set expectations with the patient that we're going to try for that response, we're going to try for that durable peak response, we're going to try at a dose that may lead to some toxicity in the short term, and then we're going to manage things over the chronic as almost like a chronic disease as opposed to an acutely lethal cancer. The number one is to set the expectation, understanding that there will be changes over time. And then it really depends; for the IO agent, I generally leave patients on it at the prescribed dose, with the exception of an immune-related adverse event, where if it's really severe that they need steroids, we have to think twice about re-initiating the IO agent. And I want to focus on the TKI [tyrosine kinase inhibitors], because I think that's where a little bit more nuances come into play. And what I do in terms of changing the dosing and the scheduling is I try to take into consideration what the half-life of the TKI is. A drug like cabozantinib, where the half-life is 90-plus hours, and it's going to take a while, I might be more inclined just to lower that patient's dose as opposed to giving the patient a break, because a break to resolve toxicity might need to be a week-plus. When it comes to a TKI [tyrosine kinase inhibitors] like axitinib, where the half-life is about four hours or so, I might leave the patient on the standard dose and then take a couple of days off, have some resolution of the toxicity, and then resume. So, again, first, it's about setting the expectation; the IO [immune-oncology], I generally leave on continuously. And from the TKI perspective, it's taking into consideration the half-life or resolution and using that as the springboard to decide whether to lower a dose or whether to give intermittent few day breaks.
Toni Choueiri, MD: We have a question actually from the audience for you, Dr. Orenstein: how frequent, in your experience, is anemia in a patient with intact renal tumor while going through an ipi-nivo [ipilimumab/nivolumab] treatment? There's someone, kidney in place, they get ipi-nivo [ipilimumab/nivolumab], the tumor is there. 47-year-old healthy male; do you see a lot of anemia here?
Moshe Orenstein, MD, MA: I'm more likely to see anemia at disease presentation. I see it less likely with treatment with immunotherapy. In fact, in some ways, when treating the patient if they're starting to feel better, and the QoL is improved ipi-nivo, often that is reflected in the improvement in the hemoglobin as well. I would say I don't generally see it as a toxicity; obviously, there are those immune-related adverse events that cause some degree of bone marrow suppression and you can have anemia. But, in general, I don't see a lot of that in my practice.
Toni Choueiri, MD: Perfect. Let me move on to Dr. Braun here. In your experience, Dr. Braun, how much you end up with those reduction and interruption? And could it impact efficacy when you re-escalate sometimes? What's your experience?
David A. Braun, MD, PhD: Yeah, absolutely. I think Dr. Orenstein gave a really nice and comprehensive overview. Part of it is about expectation-setting. I tend to do the same thing, and I think there's data to support this; starting at the dose typically used in the clinical trial. There are always exceptions, and you have to individualize care for each patient. But, in general, starting at that standard dose, but also knowing that many, many patients have to dose de-escalate, and to set that expectation, that is not a failure. That is not something's gone wrong if you have to lower the dose of something; that's often par for the course. I think part of it is sort of that expectation-setting. And then, similarly, I think with dose reductions and dose interruptions, it's patient-specific and depends, I think Dr. Orenstein mentioned very nicely how it depends on the drug itself, and the pharmacokinetics of the drug and how long it's in the system. I think, in my experience, a little bit on the patient as well, there's sometimes different sort of patterns of toxicity. Sometimes patients have this sort of build-up effect, and this for the TKIs, specifically, where they're okay at the beginning, but after being on the TKI [tyrosine kinase inhibitors] for some amount of time, things sort of build up and up and up, and they need a little bit of a reset, a little bit of a break from therapy. And that's different from kind of an ongoing and continuous type of toxicity that really warrants more of a dose reduction. I think both the pharmacokinetics and also the sort of patient-specific side effects sort of both play a role here. In terms of impacting efficacy, again, I think it's really important to emphasize that it is not a failure, and not a not a wrong thing, and not necessarily going to impact it and really be a detriment to efficacy to decrease the dose, I think it's always good to maximize the amount of matter of medicine, that patient can be on that's tolerable, but the key word there is tolerable, and they should be able to live their lives. And it's all about finding that balance for each patient.
Toni Choueiri, MD: This is great. But going back to that great case, let's say, we don't talk a lot about neoadjuvant, but do you ever treat patient systemically first before nephrectomy? That's an audience question. And let's say that the patient has a resectable disease or non-metastatic disease. Have you had cases where you needed to do systemic treatment?
David A. Braun, MD, PhD: That's a really sort of astute audience member. I totally agree. I think for this particular patient with IMDC [International Metastatic RCC Database Consortium] poor risk disease with a declining performance status, I actually would be really hesitant to do an upfront cytoreductive nephrectomy. I think there's maybe very specific cases; it's a palliative nephrectomy, because there's a lot of pain, or intractable hematuria that I consider it. But in general, for this sort of patient, I think upfront systemic therapy is actually probably the right answer, because this is a patient at high risk of clinical deterioration, who, if they get a cytoreductive nephrectomy, they might actually not even be able to make it the first line. And so, I would say, for me, at least, for patients like this would be more the rule than the exception to start with systemic therapy.
Toni Choueiri, MD: And I agree with you, I think there has been some cases; I actually have a patient, I had more than one, but currently a patient I am treating that has a single kidney. The other kidney doesn’t work at birth and tumor, the patient would be on dialysis, it was a large tumor. The patient get the VEGF IO [vascular endothelial growth factor immune-oncology], and on the first scan, he had a partial response, still not completely prone to have a partial nephrectomy, but close enough. We are continuing the VEGF IO [vascular endothelial growth factor immune-oncology] here. The goal is for more shrinkage, and the patient could have a partial nephrectomy. I'm not sure we're going to be near normal or normal kidney function, but at least move forward, try to cure the patient, preserve some kidney function, rather have them on dialysis. But these are very uncommon, and you all know that.
This transcript has been edited for quality.