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Are You Overdosing Your Patients?
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Released: November 13, 2024

John Marshall
John Marshall, MD
Catch Up On All Episodes of Oncology Unscripted

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Are You Overdosing Your Patients?

Welcome [00:00:05]

John Marshall, MD: Hey, everybody, John Marshall with Oncology Unscripted, even though I've got a little bit of a script right here, but don't tell anybody. Today, we're going to talk all about dosing of medicine, and do we have it right or not, particularly with some of our newer cancer medicines. And I'm going to really drill down on a couple that I know a lot about that I hope you will use in your own practice, quite honestly, and make your life a little easier, and, more importantly, your patient's life a little easier. 

Science Snapshot [00:00:34]

From a science perspective, I just came across, really yesterday, in the New England Journal, an article that that piqued my interest. Because it only went very nicely with the theme of our episode today, but around dosing, but really value in terms of what's it worth to get a little bit more survival.

And this was a study as a metastatic lung cancer study in the New England Journal of Medicine. I've got an actual copy of it. Right there. There it is. And this is by Cho et al. It's a very important study. It's the MARIPOSA study. You all know about it. It's amivantamab, there you go, plus lazertinib, which is, I guess, like Lazarus from the New Testament, maybe, maybe not. But this is in patients with EGFR-mutated non-small cell lung cancer, and, of course, the current standard of care is osimertinib. A relatively easy medicine to take has some side effects. The doublet wins in the end of the day, by a small amount, and that's with both PFS and trending towards OS. But I went to the toxicity table because do we have the doses of these medicines correct? And so maybe that's reflected in tox, and I'll come back to this in a little bit, but you know, there's not equal toxicity at all. In fact, the doublet therapy has essentially double the amount of grade three toxicity, and the investigators are fairly bold in saying, however, the incidents of grade four, which is almost dead, and five, dead, or discontinued treatment, were similar between the two groups. So now we've elevated it. Don't pay attention to grade three toxicity, we know that's going to be different here, let's look at dead and almost dead grade four and five and see if that's different. And it really struck me when I looked at the deltas on the advantages, the clinical outcomes, and the deltas on the toxicity that, is this really worth it? Should this become a new standard of care? New England Journal usually doesn't print things that it doesn't think are at least at risk for being the new standard of care. So, those folks out there who take care of lung cancer are going to have to figure out if this really reflects a new change and is that worth it.

Are You Overdosing Your Patients? [00:03:02]

And really why I picked that paper, it's important, but, to me, it's all about dose. And I think we are overdosing people. I am old enough to remember that when chemotherapy was the thing that we needed to get to what we call the maximum tolerated dose. And this was how much could you give you all know what this means. How much could you give without bumping the patient off, because the principle was that more was better.

I want to reflect on this a little bit because we learned pretty clearly in some cancers, that was true, germ cell cancer, some leukemias, maybe adjuvant breast cancer, but that dose intensity mattered in those diseases. But let's look at adjuvant breast cancer, because when I was a junior faculty member here, we were doing bone marrow transplants in the adjuvant setting for stage two and three breast cancers. So, we were doing marrow ablative, myeloablative therapies because more was better. And if you know that story, you know that the people who were leading some of those papers out of South Africa ended up committing fraud. Their results were fraudulent, and many, many women were exposed to bone marrow transplants because of their data suggesting it might be helpful, when in fact it was not. So, more was not better in that scenario.

And the other place that I was living at the time, again, 20, 30 years ago, was the advent of capecitabine. Simple drug. You use it a lot in your practice, I am sure, but what dose and schedule do you use? Do you remember, were you around when the actual dose studies were done? Back in the day, we would not only do something called maximum tolerated dose, we would then have a supplemental study of recommended phase two dosing. And very often that meant a randomized clinical trial of different doses and schedules of the medicine looking for both toxicity and efficacy to see which one works the best. Yep, they did that with capecitabine back in the day. And they looked at continuous dosing, right? Just giving it continuously at a certain dose. They looked at 2 weeks on 1 week off with leucovorin. Two weeks on, one week off, without leucovorin. Those two doses were a little different. And guess what? All three had exactly the same outcome in terms of response rate and progression free survival. All of that, exactly the same. The continuous dosing had the lowest toxicity. But guess what? We picked the one that used the most capecitabine pills. Not leucovorin, you could use fewer pills if you threw a little leucovorin in, but this was just capecitabine at what we now know as its dose, two weeks on, one week off. That sold the most pills, not because of benefit, but because dose intensity at the time mattered. And we are still clinging on to that dose and schedule. Many, many people are, whether it's a XELOX regimen or just capecitabine or maintenance capecitabine, but it's not correct.

How Does Dr Marshall Dose Capecitabine? [00:06:29]

The correct way to give capecitabine by John Marshall. Fixed dosing, never use the small pills, only use 500 milligram pills, size up your patient. Do an estimate of creatinine, clearance, because this is a renally cleared drug. Most patients I start at 1500 milligrams, three pills in the morning, after breakfast, 1500 after dinner. Monday through Friday, because you know what if radiation doesn't work on the weekend neither does chemotherapy, every week. Okay, so if you're a two-week one-week offer, you're giving it 14 days every three weeks. My way, I'm actually giving it 15 days every three weeks. And because you give that little weekend off, the hand foot syndrome is less, it doesn't build up nearly as much. Are you given the right dose? If somebody comes back in within a month or two and starts to have some hand foot syndrome, if it's mild, you're probably at the right dose. If there's no toxicity, you think about increasing it. If there's a lot of toxicity, you need to decrease it. We all are pretty clear on that. Some of us like to decrease it by pill count and keep the continuous dosing. Others like to do one week on, one week off as a modification. One little trick to know that you're giving the right amount, check your patient's MCV. If they've been on capecitabine for, I don't know, a couple months, you'll notice that MCV will be going up because that's the antifolate effect that you're seeing. You got your own little built-in micro-biomarker in your CBC of every patient that you're giving capecitabine. So, I'm telling you, switch out to this dosing and you can give your ox every two weeks or every three weeks. I'll leave that up to you. That's another matter altogether.

Consider Dose-Escalating Regorafenib [00:08:15]

Tony Saab taught us how to use regorafenib, Stivarga. Because we knew that if we gave full doses, 160 milligrams daily, it was too much, too spicy. Lots of patients said, forget it. I'm not taking that drug ever again. Tony showed that if you started lower at 80 and then inched it up, and then inched it up, you did a lot better

Should We Rethink TKI and Immunotherapy Dosing? [00:08:35]

Now, what's the right dose of a tyrosine kinase inhibitor? The studies are done with maximum tolerated dose. Give as much as you can give. More is better. Use that in the clinical trial. But more and more, we are seeing that you don't need to give that much. But are we comfortable in dose-reducing? Are we okay with saying, all right, I'll just cut the dose back because Marshall said it's okay. No, we're not. Because we don't want to regret that it was our dose that maybe it didn't work. So, we're feeling compelled to give the dose. Even the insurance companies are mandating that we give the dose that is in the package insert. When, for a lot, maybe most, of these TKIs, we don't need to give nearly that much.

I believe the same is true for immunotherapy. Because let's face it those patients whom we stop for IO toxicities, you know, they seem to be doing okay. So maybe we don't need to do nearly the duration or as often. If the way the drugs work is the way they say they work, then you wouldn't need to have it continuously exposed all the time to patients. So, we're probably overdosing TKIs all the time, and we're probably overdosing immunotherapy.

What Schedule Does Dr Marshall Use for Trifluridine/Tipiracil? [00:09:57]

 Another colon cancer drug that I think is important to understand is Lonsurf dosing, trifluridine/tipiracil. What a crazy regimen that was. So, five days on, two days off, five days on, two weeks off. It takes forever just to coach the patient on what to take, and there are two pill sizes and all of that, and myelosuppression is the big side effect of that regimen. We just looked at that and said, that's crazy, just give it every other week. So we still stick with our Monday through Friday because it's easier for patients to remember. And instead of two weeks in a row, we give it every other week. And believe it or not, that is essentially solved a lot of the cumulative suppression, myelosuppression, the nausea, all of that stuff that you see with that drug by getting away from the package insert. dose reducing, maybe a little using only one pill size, again, to get your optimum dose and schedule.

So, we need to understand better how to dose these medicines. The problem is, we don't use them that often, many of them, so we're dependent upon looking stuff up, and what the package insert, and what the insurance company, what the guidelines say. We all don't have a person who's an expert on speed dial that you can say, well, what would you do if you were giving this patient this treatment? So, we clearly need an improved resource for all of us to understand what the correct dose is that we need to use day in and day out to optimize our patients, both benefit but also toxicity, so that we know that we are doing the best job possible.

Up Next: A Candid Conversation with Dr Mark Ratain on Drug Dosing [00:11:37]

And, so, to that end, I have invited not only a lifelong, career long friend and mentor, but really what I think is maybe the world's expert in this space. And that's Dr Mark Ratain from the University of Chicago. He cares passionately about this and is actually doing something about it. So, listen to this interview with Mark Ratain, MD.

Learn more by watching:
Candid Conversations With the Experts: Dose Matters with Dr Mark Ratain

MedBuzz: Monopoly Concerns with Oncology Acquisitions: Should We Be Worried? 

This transcript has been lightly edited for clarity.