Toxicity Management with Checkpoint Inhibitor Therapy - Thomas Powles

July 1, 2019

Thomas Powles joins Charles Ryan discuss toxicity management and the most common toxicities you see in a bladder cancer population with checkpoint inhibitor therapy. Dr. Powles covers three main areas of toxicity management which include going twice as long once you've started immunosuppressants, starting steroids at a grade two toxicity, and the need to educate our patients to put them at the heart of managing their toxicity.


Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Read the Full Video Transcript

Charles Ryan: Hello from ASCO 2019. I'm joined by Dr. Thomas Powles from Barts, London, an expert on immunotherapy and bladder cancer among other things and I thought we could talk about toxicity management, which is a big issue around immunotherapies, not only in bladder cancer but in all areas where we're using checkpoint inhibitors.

Give us just a rundown of the most common toxicities you see in particular in a bladder cancer population with checkpoint inhibitor therapy.

Thomas Powles: It's quite difficult isn't it because as these new drugs have come into what I recall standard practice for pretty much all second-line therapy and PDL one positive frontline patients not eligible versus platinum-based therapy.

In bladder cancer, you look at that and say what effect does that have on the quality of life and I think quality of life has really gone up for patients and that's important because I think for doctors... immune therapy is new. It's more challenging, but of course, patients have never had chemotherapy before now and they just come. The choice between the two for them is quite easy.

And that's why in the original trials and the original enthusiasm, a lot of it was based around the toxicity being so much more attractive, because it's not unusual for bladder cancer patients to come in and say, "I don't want chemotherapy." Tend to be men that are in their sixties and seventies. A family member, a partner, had chemotherapy in the seventies, so this horrific experience and said, "I'm coming to the end of my life. I don't want that.

And that's not an unusual conversation but actually, the immune checkpoint inhibitors from a quality of life for the vast majority of patients are much better tolerated and that's a really important place to start because we got ourselves caught up a bit on toxicity management being more complex, and we'll talk about kidney cancer in a second, but actually when by you look at the quality of life of sunitinib versus nivolumab or ipilimumab you might say, "immune combination, that sounds dreadful and awful toxicity" but actually quality of life throughout is better for the immune combination. So a really important place to start with discussion is around the knowledge that for the majority of patients the toxicity is mild and significantly better than what we've seen with standard treatments.

So the question is, where do complications arise? And when we first... when I was first involved in these programs, the one thing that I noticed was that there wasn't a one size fits all model for toxicity associated with immune therapy, and that's a problem, because it means your textbooks and your bits and pieces are difficult to write and the guidelines are different. Last week I had a guy come in with really bad pemphigus.

Charles Ryan: From immunotherapy?

Thomas Powles: From immunotherapy. Really bad, and I had another patient with really bad hand-foot syndrome and they were on VEGF-TK plus immune therapy, and you thought "oh, it's the VEGF-TK." I said, "guess what?" Super smart, I stopped the VEGF-TK, I keep going with immune therapy, it gets worse and worse. It's not... it's immune therapy. So if you're seeing it, and it's unexpected, it's almost certainly the immune therapy and that means you need to be vigilant, firstly, and the second point is the patients need to be vigilant too.

And so the next point I want to make around this is that with chemotherapy, a grade one or a grade two diarrhea, you'd probably say. "take a few Imodium, see how you get on." With immune therapy, that would be unwise. You need to... and you can't just stop the immune therapy because it keeps going, so you actually need to reverse the process-

Charles Ryan: And oftentimes the toxicity's emerging late after the administration of the therapy.

Thomas Powles: Yeah. So the story's just a lot more complex and it's not coming every three weeks, measure the blood count, not point something, do, don't give, dose reduce. Those algorithms are easy... admit antibiotics or whatever. This is more difficult than that and it's more subtle, and so I think, clearly, there is a piece around experience. There's a huge piece around education and training. We've not done well, and the reason we've not done it well... I went to a... we did an experiment at my... we went to three of my A and E departments within our trust. We're a big hospital, three A and E departments, which is why our patient numbers are big and we went to the A and E doctors and said which one of these five is an immune-

Charles Ryan: This is the emergency department, we call it.

Thomas Powles: Yeah. Emergency department.

Charles Ryan: Okay, yeah. Just making sure everybody knows.

Thomas Powles: All it stands for is accident and emergency. A and E. So what we did is we went to the ED doctors and we asked them which one of these five drugs is an immune therapy drug. Let's say platinum was down there and-

Charles Ryan: Interesting. And? They didn't know.

Thomas Powles: 20% of ED doctors got this right, 20%. Then we asked them, "how do you treat side effects associated with this drug?" It was admit [inaudible 00:05:00] antibiotics, and you're going down completely the wrong route. There's no point in me... the knowledge that you and I have around... and our colleagues have around this... we're not the people at two in the morning... so it's not good. It's not good enough to say we'll educate ourselves. We have to educate the patients.

Charles Ryan: Yes. The patients have to go in and say, "I'm on immunotherapy. I'm having this skin reaction."

Thomas Powles: Yes. And this is how we treat... we have that and I know many people do and you need to have... we have hotline numbers at our hospital but this piece is really important because what we're noticing is... I'm sure you're the same... is when you intervene early, with immune reciprocity, and I'm not talking about specifics. I'm not going to talk about diarrhea and pneumonitis. You can read about those. What I'm talking about are the general concepts. Is when you have patients when you intervene early, you can normally keep going with the drug. If you intervene late, you'd require a high dose of IV whatever it might be and then infliximab. Inevitably, you need to stop the drug.

Now there is some data out there suggesting that if you stop the drug and the response goes on... no one wants patients to come into harm's way. No one's looking for grade three toxicity. So number one, patient education is absolutely crucial and then number two that's important is this thing around early intervention. I do this and some people hate it and I'm not suggesting that anyone else should do it, but at our institution, we have education sessions for patients, so when you're starting immune therapy you have an education session. They tend to be nurse-led. They would then get that nurse's telephone number and he or she would be a contact. They have a hotline number they can call too, so that's a hospital or doctor number that they can phone up. They have a card with a... and then we also print off the immune therapy guidelines for the patients, so when they have toxicity guidelines and the pitch up, they then will have them with them. So if you go and eat at a pub or whatever, you've got the guidelines. They've got those with them too.

And the last bit we do, which I think is controversial, is we send patients home with some steroids. And we-

Charles Ryan: All patients, from day one?

Thomas Powles: Yeah. So you say, "you don't need to take these, and you shouldn't take them, and when you need to take them, then you seek medical advice." But if you've got grade... in the middle of the night you've grade... you've got two diarrhea or you've got a [inaudible 00:07:32], you start this. Why not start it... you don't... when they come into hospital we... I guess we'd wait for their blood tests to come back, maybe, but we're not doing colonoscopies, we're not waiting for results to come back, we intervene early, and then if necessary, it turns out not to be a big deal, we stop them the next day, but the danger is you sit on this for three days, having had a phone call where they said, "get some steroids." "I wasn't able to on a Saturday" or whatever it might be, and then it sort of escalates and I do think that's a problem.

So that's our broad principle in the way we look at things. The second thing that I was keen to talk about around this issue was around escalation. So what's serious, what's significant, what's the role of drugs like infliximab, mycophenolate, when do you switch to IV steroids, how long do you keep going for. And again, there are guidelines that are available. As a rule, grade three toxicity tends to be moving towards intravenous type treatment. When you're grade two, when mild toxicity on oral tablets, when that escalates, so a transaminitis going from a grade two to a grade three, if things are getting worse or... strictly speaking, as soon as you start oral steroid, everything should start going in the right direction pretty quickly, and if it's not doing that... you know, I've had people up the dose of oral steroids. I'm not a great believer in that, so if you're thinking about that, you should be switching.

Charles Ryan: So just to be clear, at about a grade two toxicity you'll start oral steroids?

Thomas Powles: Yes, so let's say diarrhea three times a day.

Charles Ryan: Right. Oral steroids. If it goes up to grade three on the steroids, you admit them for IV steroids?

Thomas Powles: Yes.

Charles Ryan: And then what?

Thomas Powles: So then the question is whether you should be admitting IV steroids and adding in infliximab, and we're not currently doing that, so we would first try the IV steroids and then if that was unsuccessful over a 48 hour period, no longer than that... again, if you're not getting it in control, at that point you're bringing in the infliximab. What I think is happening a bit, Chuck, and what worries me a little bit, and around the same principle around the emergency... your emergency department issue, our education's not great around there. I'm not convinced our education is great about escalation.

So patients often go home for the week of steroids. The patients then think everything's fine, because they've been given the treatment, so they don't need to tell the doctor anymore, because it's going to get better eventually, and so they go home, and then five days later, you find out they're in the emergency department in some hospital down the road, which is doing the best they can, poor knowledge, understandably. I know nothing about orthopedic surgery, and they're on antibiotics, and they're on growth factor... bits and pieces and the steroids have been stopped because of the infection. And so that worries me too. And again, this is only five or ten percent of patients getting into harm's way, but what's really important is that I think it does make a difference around early intervention. I think from a doctor's perspective when things go wrong, you remember that, and we think, "well, are there ways of dealing with that?" And then, of course, the obvious way.

So actually, I'm really worried about these drugs, and so that's why I think to be very proactive, patient education, putting the patients at the heart of managing their toxicity, escalating very quickly when you're not in control and then the last piece that I wanted to talk about, and then I'll stop, is about de-escalation and when you stop.

Some of the melanoma doctors, melanoma people, would give me checkpoint inhibitors before, us mortal bladder doctors, and we... the education from them was... they said, "Tom, go twice as long as you would think with the steroids. If you're thinking of stopping, just go a few more days. Give it an extra week, whatever it might be. Taper down," because particularly with transaminitis and diarrhea, they'll just bounce back, and then when they bounce back, my impression is you really start back from base one. So you give them four weeks of treatment, you got it back under control, all well... stop, and then suddenly you're back on another four weeks of treatment. You're better off going for a week past normalization. So I tell people to be patient with steroids and go for a little bit longer, taper the doses down and then stop slowly, and the data on efficacy suggests that there isn't a big problem there.

Charles Ryan: Good. Interesting. So that's really good advice. Go twice as long as you think once you've started immunosuppressants, steroids or infliximab.

Thomas Powles: Yeah, it's not twice as long as the whole course, but you know-

Charles Ryan: Right. No, no, no, but if you think you're done, you're probably not. That's the key point, key point number one. Key point number two is, start steroids at a grade two toxicity. Don't wait for things to get worse and escalate from there to IV steroids and potentially infliximab. And then the other key point that you've said a few ways now is, it's really, we need to educate our patients to know what's going to happen, for the patients to actually understand that the doctors they may see in the emergency department or in the urgent care clinics may not know anything about these drugs and while they can look them up, they will not have that sort of intuition or that sense of urgency that we may already have. So this was really practical advice for those of us out there who are treating these patients. I think that almost every oncologist now is getting pretty close to having a good amount of experience with immunotherapies because if they treat a lot of different cancers, there's a lot of different indications.

So thank you for your time and advice and it's always a pleasure to talk to you.

Thomas Powles: Great.

Charles Ryan: Thank you, Tom.

Thomas Powles: Thank you.