Managing toxicities of treatment

Transcript

Igor Makhlin, MD [00:00:05]

Thanks so much, Caroline, and thank you, everybody. It’s such an honor to be here for this wonderful organization. It’s really just an incredible conference here. I recognize I’m the last presentation, and I will try to make it enjoyable.

Managing toxicities of therapy for metastatic breast cancer is such an important topic, and it gets more important every year because our therapies are continuing to expand. So I thought, this is such a relevant topic to talk about.

In thinking about how to plan this talk — because as our treatments are expanding, it’s great for patients, it’s great for the oncologist to be able to offer more treatments for patients — but of course that means there’s more to talk about, more toxicities. And I was thinking, should I just go through every new drug approval? Should I talk about every new side effect for every drug? And I do have like a 7-hour presentation ready to go. So if you guys are game, I am too.

But I thought, maybe we’ll try it a different way.

The first quarter of the talk, I want to go through major, overarching principles of how you can have discussions with your providers. And as you’re starting a new therapy, as you’re in your therapy journey, experiencing side effects, what should you be asking your provider team? That’s part number one.

There’s going to be a lot of mention of dose reduction throughout the talk as a strategy to manage toxicity. And I know that’s a loaded topic. It’s very common to have that question: Does that mean that the treatment’s not going to work if it’s at a lower dose? And it’s a very valid question. So I want to spend a couple of minutes going through how we even arrive at the right dose for the treatment, and try to open up that black box and make that conversation more approachable between you and your providers.

And then I thought I would take you into my clinic. I have seven patient examples of common side effects that have occurred. Unfortunately, there’s too many side effects to talk about, but I chose seven that are relatively common and that span across different therapies. So it’s not ultra specific to any one drug. It’s something that you can apply for the side effect.

Then we’ll end with some additional resources for getting support.

This illustration really gets at the crux of the question, of the issue, which is, in metastatic breast cancer, we have two very important goals. We want to, of course, have treatment that’s effective, but we also want to make sure quality of life is there and it’s maximized. Sometimes it’s a fine balance to strike. So how do we get there? That’s really the goal of it all.

As I was prepping for this talk and I was in clinic this past week, I thought I’d run this by a few of my own patients who I saw in clinic. I said to them, this is what I’m doing, this is what I’m talking about. And what comes to mind for you? When we were at a point where we were talking about a side effect or starting a new treatment, what comes to the surface for you? And these are just some quotes from patients.

“Kindness and compassion.” Looking for kindness and compassion from your providers, from your care team.

“Wanting to be listened to.”

“Faith and a great support system have been essential for my journey.”

“I don’t want the side effects to interrupt living my life.”

And I wonder how that resonates with you all in your own stories.

I’m generally allergic to infographics, I hate them, but this one I actually really liked. That’s because it does a great job painting a holistic picture of what ideal care should look like for any individual patient. To the left of the circle is the standard treatments that we have for metastatic breast cancer, mostly focusing on systemic therapies: immunotherapies, endocrine therapies, chemotherapies. But on the right-hand side of this circle is all of these additional supportive and integrative approaches and modalities that really can, that we should be talking about more. And I know I could be doing a better job of this. I think this highlights how much more we can be doing and talking about in the clinic. I’m so glad we have Dr. Mehta here today, he did a wonderful talk on bone mets. As an integrative care expert, I love that he’ll be up here on the stage to answer some of those questions as well.

Igor Makhlin, MD [00:04:57]

Let’s start with some general principles of symptom management. What are some components?

We have supportive care medications that we’ll talk about. These could be either prescribed or over the counter. We have lifestyle modifications. We’ll talk about some of those, like exercise. We have dose adjustments, which should be part of the conversation, whether or not it’s the right thing to do at the time, it should never be a wrong thing to ask.

Sometimes it takes switching to a different drug within the same class. If there are multiple brands, like for the aromatase inhibitors, we have three different aromatase inhibitors, and sometimes it just takes switching out the drug. They’re equally effective and different people respond better to different brands. But if all else fails, sometimes it’s just not the right drug, and we have to think about making a bigger switch.

When you’re starting a new treatment, this is what I think about in terms of what makes a good conversation. Of course you want to talk about what are the most common and likely side effects of the treatment you’re about to start. But you also definitely want to talk about the rare but life-threatening and serious side effects that you need to look out for. You need to know what the red flag symptoms are to be aware of. And that should definitely enter the conversation, especially the first time you’re hearing about this drug.

Another important question, this is not super common, but there are some drugs that we want to measure an enzyme or a blood marker for that drug that tells us how sensitive you’re going to be to metabolizing that drug. That’s really important because some drugs, if your body is a slow metabolizer, can be very toxic at the standard starting dose. We’ll touch on that in a little bit.

You’ll want to talk about the schedule and the dose of the therapy, of course, so you know how it’s given. Any at-home medications that should be prescribed to manage the side effects that you anticipate. Any side effects to consider logging, keeping a journal. For instance, with neuropathy, we want to hear, as providers, how fast is it coming, is it intermittent, is it constant, is it getting worse. That helps us work together to determine when we need to make a dose change.

Lastly, but not least, this is one of my favorite topics, is when my patients are going all over the world on amazing vacations — African safaris, hiking in the Alps — I want to be there with the patient, but I can’t. So it’s my job to just make it happen for them. You can always ask how flexible are we with the scheduling for major life events and trips.

When side effects arise, how do you have that conversation? You want to talk about any supportive meds at that time for that particular side effect that could help treat that side effect. Are there any lifestyle changes, dietary changes. If it’s diarrhea, should you be eating something different? Should you be avoiding certain triggers? When should we consider a dose adjustment? Is there a drug in the same class that we can switch out that might be a better fit, different side effect profile?

Speaking of dose adjustments, let’s move on to this next couple slides here.

How do we even get to the right dose? How do we get to the dose that you ultimately end up being prescribed? You would think that the starting dose is this really thoughtful, biologically effective dose that makes the most sense because that’s the dose that kills the most cancer cells, but that’s not really how it works most of the time.

You all probably are aware of the different phases of the clinical trials. The one that’s relevant to this discussion is the phase I trial, which is the trial that’s the first-in-human trials. So this is where the drug was effective in the lab, and now they’re moving it into the clinic, into the trial. Because it’s the first-in-human trial, we have to be extremely cautious. And the main priority of that trial is not to see how effective it is, but actually to understand how safe the dose is. What is the dose? How safe is the drug? What are the side effects? These are the priorities.

Given that, there’s different ways to run these phase I trials, but I want to just show you the archetype of how this is done. This is an example of what we call a dose escalation trial. Every little circle is a participant in the trial. They typically start out with these really small cohorts of participants, usually three. They start at a very low dose, and they track side effects. What we’re looking for is something called a dose-limiting toxicity, which is basically any toxicity that is so toxic that we can’t push the dose any further. And typically the lowest dose is not going to get there.

Igor Makhlin, MD [00:10:16]

The first three participants do okay with side effects. They move on to the next cohort at the higher dose. That cohort does well, they move on to the next one. They keep pushing the dose higher until somebody gets a dose-limiting toxicity. At that point, depending on how many, they either stop there or they expand the cohort to see if it’s going to persist or if it was just a one-off. Ultimately what happens is they push the dose until it’s just too toxic, and then they back down one level and that’s the dose.

That doesn’t necessarily mean that the lower dose is ineffective, that’s just not what the trials are set up to test. This is not the only way. As trials evolve and become more nuanced, hopefully there’s going to be, I can’t even imagine how AI is going to impact this, but this is how it’s been done for years and years. And so I just want you to understand that because when we’re talking about a dose reduction, it doesn’t automatically imply that it’s going to be less effective.

The other thing I wanted to mention is how side effects are graded or assessed in trials. Because how they’re graded in trials is how they’re then transferred over. Once the drug gets approved, there’s a whole prescribing label that we as clinicians look at when we’re determining whether we need to make a dose adjustment for any particular side effect. In the trials, this is called the CTCAE, and it’s essentially a grading system that standardizes across any trial for any side effect. There’s a whole glossary, you can access it online. Anything you could think of. Low blood cells, diarrhea, nausea, vomiting, anything has its own grading system from 0, which is when the side effect isn’t there, all the way to grade 5, which we never want to get to, when somebody died from the side effect.

Here’s an example for diarrhea. This is how they grade diarrhea. Grade 1, you have less than four stools per day, that’s increased over your baseline, and it just goes higher and higher. Grade 3 is at least seven stools above baseline, or hospitalization. Grade 4 is life threatening.

This is from the label for Verzenio or abemaciclib. Some patients here know about Verzenio and the potential for diarrhea. I’m seeing some nods. It’s a common conversation that we have. And if you look at the label, what the label is telling us is for grade 1, that’s one to three diarrheal episodes per day above baseline, no dose adjustment necessary. You get up to recurrent grade 2 or grade 3, that’s when they’re talking about reducing the dose.

What does that mean practically? It means that if you just follow the label, with no further conversation, you’re only really adjusting the dose if there’s consistently four or more diarrheal episodes per day above baseline. But is that the same for everybody? If you’re having three episodes of diarrhea every day and you work a job and that’s just not compatible with your daily life, does that mean that we don’t consider a dose adjustment?

The other thing is we don’t have a trial or data for every single drug, for every single dose adjustment. It just hasn’t been done. But here’s an example keeping with the Verzenio theme. This was from the early-stage breast cancer setting where Verzenio was approved for high risk, early-stage breast cancer. In the trial, it turns out that many patients had to dose reduce, probably for diarrhea. There’s other side effects too, but that’s the main one.

Once the drug hit the market and went into the real world, it was clear that this was happening all over the place, and we were having trouble maintaining patients at the standard dose. There was all this concern about are we doing our patients a disservice by dose adjusting too early. So they went back to the large 5,000+ patient clinical trial, and they went back and looked at outcomes by dose reduction. So patients who didn’t have a dose reduction, patients who did and how much.

The point of those curves is you don’t need to know anything about this graph other than observing that the curves are overlapping. It’s telling you there was no difference in outcome. So the goal was to stay on the drug, whatever the dose was that was compatible with staying on the drug.

Igor Makhlin, MD [00:14:50]

With that, I want to move on to some cases. I thought I would start case one with a case for dose reduction just to keep it moving on this theme.

This is a 62-year-old woman with metastatic, ER-positive, HER2-negative breast cancer who presented to me for second opinion. She was on adjuvant anastrozole treatment until 2019 when she had recurrence of the breast cancer to the bones. Genomic testing at the time was negative, and she began standard-of-care fulvestrant with palbociclib.

She did well for 4 years on this regimen until she had progression and switched over to abemaciclib as second line. She again had progression in the bones about 6 months later. At that point was switched to a drug called capecitabine, or you might know it as Xeloda. She was initially started on 2,000 milligrams, twice daily for 14 days on, 7 days off. Twelve weeks later, she gets a follow-up PET scan and she has a complete response, which is great. However, she started enduring worsening skin changes in the palms and soles of her feet, and this is what they look like.

This is called hand-foot syndrome. It’s one of the most common side effects of this drug. It’s pretty unique to this drug, actually. And what you see is, obviously there’s redness of the skin, there’s inflammation, there’s pain, there’s peeling. It can become hard to walk. And so what do we do now?

Capecitabine is approved for several different cancers. It’s not unique to metastatic breast cancer, but the dose for metastatic breast cancer has been 1,250 m/m², so it’s dosed to the body surface area, in twice daily doses for 14 days on, 7 days off. Now with the average BSA, the body surface area, for an adult woman that basically gets us to just over four tablets, twice daily, for 14 days on, 7 off. And for anybody who’s had Xeloda, that’s a lot.

Over the years there has been the question of can we get that dose lower. This is one of the few examples that I’m aware of where there was this very elegant and complex mathematical modeling that showed that capecitabine given 7 days on and once you get to 7 days, that’s really the peak effect of cell kill. Once you go past 7 days it doesn’t necessarily add much more.

This was a randomized trial comparing fixed dose 1,500 milligrams, twice daily, for 7 on, 7 off, versus the standard dosing I just mentioned in patients with metastatic breast cancer. And what they found was there was no difference in effectiveness between the two regimens. But take a look at the difference in frequencies of high-grade diarrhea, hand-foot syndrome, and mouth ulcer. So you can see this was much better tolerated.

And that’s our current new dose that we’re doing. Actually we’ve been doing this for quite a bit, ever since I was in fellowship. This is how I learned about the dosing, at Penn. It’s just the data was published this past year.

She was recommended to reduce the dose to 1,500, twice daily; 7 on, 7 off. She was also recommended to initiate topical diclofenac gel twice daily. Diclofenac gel is also known as Voltaren gel. Are you all familiar with Voltaren gel? Some shakes, some nods. You can get it over the counter. It’s basically a topical NSAID, like topical Motrin, but it’s in a cream form. The benefit is you’re not absorbing it all throughout your body. So it helps locally.

[Diclofenac gel] was originally approved for arthritis, but it was shown to potentially have efficacy in reducing the inflammation in the skin, which causes hand-foot syndrome. This was a randomized trial for patients who were starting capecitabine testing this topical diclofenac gel twice daily for 12 weeks versus placebo, because the standard is to do nothing — that’s why this is a placebo.

What they found was that the rate of hand-foot syndrome was significantly lower in those patients who were taking the diclofenac gel. There were fewer dose reductions and fewer discontinuations.

This is something that I tend to recommend patients consider starting even prophylactically, but at least for sure if there’s any hint of developing hand-foot syndrome, definitely something to consider.

For this patient, her skin did improve significantly, as did her energy levels with the lower dose and with the diclofenac gel. And she continues to do well.

Igor Makhlin, MD [00:19:49]

The summary for capecitabine here is that newer dosing guidelines recommend 1,500 mg, flat dose not to your body surface area — 7 on, 7 off. If you’re on Xeloda currently and you’re on a more pronounced dosing regimen and you’re having trouble with it, it’s something you can talk about with your provider.

We know from the trial there’s similar efficacy, improved quality of life, and we just talked about the topical diclofenac gel, which you should be aware of.

The other thing is the general recommendation is to stay moisturized throughout the day, and one particular hand cream — I’m not officially endorsing this, I’m just bringing what patients are constantly telling me — they love the Working Hands cream. They love that. But basically any moisturizer that you can keep the skin nice, especially in the wintertime when it’s quite dry, is helpful. To reiterate, I’m not like employed by Working Hands. I don’t make anything, I’m just passing along the message from my patients.

The additional point here is, remember I talked about that the blood marker that you can have for certain drugs that test the metabolism for that drug. This is one of the two cases, or situations, where it’s relevant. So this drug capecitabine is metabolized by an enzyme called DPYD. It’s too late in the day for me to pronounce the full word for you, but DPYD is what it’s called. And you want to make sure you check it before you start the drug.

This is an enzyme that, if you measure the enzyme across the population, some proportion of people will have a full normal genotype for this enzyme — what we call the way that the enzyme is programmed in our body. But others will have a sort of intermediate metabolic rate, and others will even a very slow rate.

The recommendation is, if you’re tested for this enzyme and you have a very slow metabolism, it’s not even recommended to start the drug period. Because it could be too toxic. But if you’re in that intermediate category, the recommendation is to start it at half the dose.

All right, moving on to case number two, we’re going to talk about fatigue. A 65-year-old woman presents for routine follow-up prior to her regularly scheduled infusion with trastuzumab deruxtecan, also known as T-DXd for short, or Enhertu. And this is for ER-negative, HER2-positive metastatic breast cancer.

She began therapy in April 2024 after progression of disease in the liver and achieved a complete response on subsequent PET scans. She’s been receiving the standard therapy dose at 5.4 milligrams per kilogram. She’s reporting minimal nausea, having normal bowel movements, but has been noticing increasing fatigue over the past 2 months.

She now has limiting fatigue for the first 2 weeks of the cycle. It’s a 3-week cycle. And only in that last week is she really getting back to baseline. On further discussion, she gets 8 hours of sleep nightly and takes 2- to 3-hour naps each day. She has been more sedentary due to fatigue. She did have thyroid studies checked just to make sure that wasn’t contributing, and it wasn’t. She does maintain a balanced diet, and she’s interested in any complementary therapies that might help with her fatigue.

Fatigue is extremely common. It’s defined as the sensation of weakness or tiredness, either physically, cognitively, or emotionally. And it’s really important to remember it’s any of those domains. It’s not just physical. It is probably the most common side effect across all treatments that we encounter. It can be cumulative in intensity and interfere with daily functioning and significantly impact the overall quality of life.

Any time there’s major fatigue, we always should be having the conversation, is this the right dose for you. There may be conversation about stimulants like methylphenidate. Largely, the trials have not been great for those stimulants, so they’re often not recommended as first-line. They mostly don’t do a great job helping with fatigue and have their own bevy of side effects.

There are mind-body interventions such as Qigong, which has shown intriguing improvements in fatigue and in these early pilot studies. Qigong, if you’re not aware of it, is this ancient Chinese practice. Tai chi is a form of Qigong. It’s both mind and body, it’s very meditative, it’s slow and deliberate movements. In prepping for this talk, I did a 10 minute YouTube session of Qigong, and it was pretty great. It works your balance, it works your strength, and you feel better after doing it. So I highly recommend trying it.

Igor Makhlin, MD [00:25:01]

But I do want to bring out two important studies that we can think about in additional supportive care for fatigue. The first is this really interesting trial that was published in Nature Medicine last year, testing a supervised, structured exercise program for patients with metastatic breast cancer. Essentially what they did was they enrolled close to 400 participants with metastatic breast cancer of any type. And they randomized participants into one of two cohorts, or categories.

The first cohort was standard of care. Now, standard of care in this trial was defined as they were given a pamphlet with useful information about what kind of exercises can be helpful, but there was no oversight. It was really just, here’s the pamphlet, do your thing. The other cohort was a structured, supervised exercise program. It was over 9 months, two 1-hour weekly sessions. In the last 3 months of the trial, participants were given an opportunity to continue it but do it on their own.

What you can see here is that the purple line is the exercise group and the black line is the control group. In both overall quality of life and in physical fatigue, the exercise cohort did much better. What this tells us is even if you’re feeling fatigued, doing regular exercise will help you feel stronger and improve your fatigue. And we have that from randomized level data.

The other supportive care strategy, which has interesting and randomized level data is this study looking at Wisconsin ginseng. Now ginseng comes from all over the world, but this study in particular looked at Wisconsin ginseng. It also enrolled roughly 400 participants into one of two cohorts. The entry criteria was there had to be pre-existing fatigue for at least 1 month prior to enrollment. And they were randomized to either standard of care, no ginseng. I think it was like rice powder was the placebo capsule. And then the intervention arm was Wisconsin ginseng dosed at about 1,000 mg, twice daily.

What they showed was, in a multi-dimensional, multi-point fatigue scale. At the 4-week mark, there was a trend towards improved fatigue, but at the 8-week mark there was a statistically significant improvement in the fatigue scale. I’m not saying this is a slam-dunk approach for every patient, but it’s certainly worth considering.

To summarize fatigue: It’s very common in patients undergoing cancer chemotherapies or other systemic therapies. I should also mention fatigue is multifactorial. It’s not always necessarily from the treatments. There can be inflammatory molecules or cytokines, we call them, in the body as a result of the cancer, as well as the cognitive and emotional components. It’s a very complex interplay there.

We know that exercise combats fatigue based on randomized level data. And we also saw some randomized data for supporting Wisconsin ginseng, with the caveat that with any supplement — and Dr. Mehta, when he joins me on stage, if there’s questions about this —whether it’s an over-the-counter at Giant or pharmacy of choice versus a prescription, you always have to make sure with your treating team that it doesn’t interact with your medications. Because even if it’s a supplement that you can get over the counter, if you’re ingesting it and it interacts with your organs and the medications, I consider that a medicine, whether it’s FDA regulated or not. So you always want to double check with your treatment team.

And then dose reductions can be very helpful in mitigating fatigue.

Alright, so case three is nausea.

A 56-year-old woman with ER-positive, HER2-low metastatic breast cancer presents for cycle two of T-DXd, Enhertu. She’s been tolerating it overall pretty well, but has had significant nausea for the first 4 days, including three episodes of vomiting. But otherwise good energy, no shortness of breath or cough, doing great, just the nausea.

Let’s talk about nausea. It’s very, very common. Another one of those very common side effects, particularly common with T-DXd. Something we’ve learned over time as we started using the drug from its introduction back in 2019. We know that across trials that tested the drug, 75% of patients report some level of nausea and 45% of patients report some level of vomiting.

Igor Makhlin, MD [00:30:09]

Nausea can be managed preventatively and reactively, for any breakthrough nausea.

Some other common chemotherapies with high frequency nausea can be AC — which we don’t routinely give in metastatic breast cancer but in select cases can be done — carboplatin and sacituzumab govitecan, otherwise known as Trodelvy.

Let’s think about the toolkit. We’ve come a long way over the past few decades with nausea management. A patient of mine in clinic was telling me the other day when they had their first breast cancer treated they had to pay like a thousand dollars for one tablet of Zofran. But we’ve come so far.

If you’re getting infusional therapy, there’s a whole list of categories of pre-meds that we can use, and the extent of how much we use depends on how likely the medicine, the chemo, is to cause nausea. The categories we have available to us are called the 5-HT3 or serotonin receptor antagonists, commonly known as Zofran. There’s a longer-acting version of Zofran called palonosetron. But basically that’s one category.

Dexamethasone can do many things, but relevant to this, dexamethasone is a great anti-nausea medicine. So that can be given as a pre-med.

A relatively newer class of drugs called NK1 receptor antagonists. The drug is fosaprepitant, the trade name is Emend, if that rings a bell.

And then olanzapine, otherwise known as Zyprexa. It’s an antipsychotic, but at the doses we give it for nausea it can be very effective as a pre-med for nausea and can be offered as a post med as well.

Speaking of post meds, depending on the likelihood of severity for nausea, we can give dexamethasone for a few days after the infusion, and we can also give olanzapine at bedtime, it just depends on how long that nausea pattern is for any particular person. We can customize that.

For breakthrough nausea, you should always have something prescribed for you at home. I like sublingual ondansetron, or Zofran. The sublingual is nice because if you’re taking it for breakthrough nausea, you’re already possibly vomiting. So if you’re not confident you can even hold down the anti-nausea medicine, the sublingual just disintegrates or dissolves under your tongue. Faster absorption, more effective. The other drug is Compazine, or prochlorperazine.

There’s another category called anticipatory nausea. I’m not sure if you’ve heard about this one, but for those who have had a really bad experience in the infusion chair and now, even before you get to clinic, you’re already associating that feeling of nausea. You’re getting nauseous just thinking about coming to clinic. My patients get nauseous coming to see me all the time. But you can actually take lorazepam, or Ativan, which has been shown to help with anticipatory nausea.

And then finally, ginger is something you can prepare or eat raw ,or you can prepare it as a tea. That can be just another level of support for nausea.

To summarize for nausea, you want to ask your care team about your list of pre-meds and just know that there’s flexibility, there’s room to go up or go down depending on how much nausea you’re having. I’ve had patients on T-DXd have no nausea, and we took away the steroid because it was causing other side effects. It really should be tailored to your experience.

If nausea does develop, you want to consider adding those additional therapies that we talked about. The olanzapine at bedtime can be really helpful, and as a bonus it can help with sleep as well.

Now if you’ve tried everything and you’re still refractory to nausea, time to talk about a dose reduction, which can be very helpful and effective.

All right, onto case four.

We have our 56-year-old patient, we just talked about. Her nausea is much better controlled after adding the Emend and olanzapine at bedtime. But 10 weeks later she presents with a new mild cough that lasted 5 days. She’s had no recent sick contacts, no shortness of breath. A CT scan is done and shows some inflammatory changes in the lungs that are concerning for pneumonitis. The trastuzumab, the T-DXd, is discontinued, and she initiates prednisone, 60 milligrams. A repeat CT is done in a month and shows resolution of the changes in the lungs. And she’s feeling better.

Igor Makhlin, MD [00:35:09]

Let’s talk about pneumonitis or interstitial lung disease (ILD).

Have you all heard of pneumonitis? Show of hands? Perfect, I’m loving that because it really is so important to be aware of.

Pneumonitis can be caused from a number of different therapies, not just T-DXd. It can be caused by certain chemotherapies like gemcitabine and paclitaxel. It can be caused by immunotherapies like pembrolizumab. It can be caused by the CDK 4/6 inhibitors — black box warning, low risk, but it can happen with palbociclib, ribociclib, and abemaciclib.

The point is you need to understand the warning signs to recognize it and alert your care team. I’m going to hammer that home a few times.

The pathophysiology is poorly understood at this point. We still don’t really know for any particular drug why it’s happening. But we know that there’s certainly an inflammatory component to this response in the lungs, which causes inflammatory damage, which can lead to shortness of breath and cough.

For patients who get T-Dxd, across trials the overall rate of developing pneumonitis is about 10% to 13%, but only about 1% to 2% of those are severe pneumonitis that requires hospitalization. Most can be managed as an outpatient, but it can be fatal if it’s not brought to attention. So it’s really, super important to be aware and to notify your care team.

What are the warning signs? If you’re on one of these drugs and you develop new shortness of breath that’s progressively worsening, for instance, from exertion, worsening, progressing to rest. Definitely need to know if there’s a new cough, which is often dry cough. Need to know about that. If there’s new fevers, need to know about that. Fevers can be caused by a number of different situations. It can be caused by the drug, it can be caused by the cancer, it’s called tumor fever. It can be caused by an infection or a blood clot. Either way, if a fever’s happening, you need to let your team know.

What’s going to be done is a high resolution CT scan, which takes really thin slices. It’s more high-res than a basic CT scan that that you might normally get. And it looks for evidence of inflammatory changes, which show up as these sort of cloudy findings on either side. It could be on one side of the lung or it could be both sides.

How do we manage it? It really depends on if you’re having symptoms or not. If you’re having no symptoms, this is just routinely picked up on your routine staging scans. This is called grade 1. And this is the only time that we can reconsider trying the drug again after we’ve gotten you through it. And in that case the T-DXd is held for up to 4 weeks. You can consider adding steroids. It’s not mandated in grade 1 where there’s no symptoms. But depending on the level of those cloudy findings, we can add steroids. Then you want to repeat that scan in about 4 weeks and make sure that it’s resolved. And if it has, you can rechallenge.

But if there are symptoms, and I’m talking if there’s a mild cough, with radiographic evidence of pneumonitis, we’re done with T-DXd because — this may change in the future — but right now we just don’t have the data to say it’s safe to restart, and the risk is too high.

In those cases we want to add high dose steroids like our patient got in the vignette. We want to consider hospitalization depending on the severity of symptoms. If the shortness of breath is getting pretty severe, that’s the time to go into the hospital because the tempo and the pace of this can progress pretty rapidly, and you need to be in a controlled medical environment where interventions can happen quickly. We often consult pulmonary to help with management.

To summarize, for pneumonitis: It’s an inflammatory reaction in the lungs. It can be picked up on routine scans without symptoms, or it can cause shortness of breath and/or dry cough. And the management is, it’s always stopping the drug but whether it’s temporary or not depends on if the symptoms were there or not, and starting steroids.

It can be life threatening, so it’s really crucial to reach out to your team as soon as you have symptoms.

Igor Makhlin, MD [00:39:50]

All right, so case number five is low white blood counts.

Now we have a 45-year-old woman who was recently diagnosed with ER-positive, HER2-negative metastatic breast cancer to the bones, who started ribociclib, letrozole, and leuprolide, for ovarian suppression.

With these CDK 4/6 inhibitors, we typically check blood counts every 2 weeks for the first 2 months because we know that the white blood cells can drop. Day 14 of cycle one, they’ve come down a little bit, they look great. Cycle two, day one. Now we’re seeing a bit more of a drop. The white count is 2.3, the neutrophil count is 1.1. Do we need to reduce the dose? What are we doing with these white counts?

Leukopenia, or low white blood cell counts. is quite common with certain therapies. With chemotherapy, it can happen and with the CDK 4/6 inhibitors it’s particularly common. Now, white blood cells, if you look at your CBC, the complete blood cell count, the white blood cell is the umbrella term. Because we have many different types of white blood cells, and the WBC number is that composite number. But what we care about mostly is the neutrophils, which are the bacteria fighting cells that are there to fight infection. And so we want to monitor those because when they get too low, depending on the situation, that can put you at high risk for infection.

For the CDK 4/6 inhibitors, it’s particularly common, especially with palbociclib and ribociclib, less so with abemaciclib. There we have the diarrhea to worry about, but here it’s not as bad with the white blood cells. Interestingly it’s actually considered an on-target effect. The CDK4 and the CDK 4/6 is present in white blood cells and we’re blocking that protein. So if you see the white count coming down, that’s an on-target effect of the drug. It’s almost like a biomarker that the drug is acting. And interestingly, based on data published by some of my colleagues at Penn, we’ve actually seen that those who have a drop in their white blood cell counts tend to actually do better on these drugs.

Unlike chemotherapy, so chemotherapy lowers your white blood cells by attacking the stem cells, which are making white blood cells. And that’s a different story, right? Because there you’re actually losing white blood cells, and you’re less able to fight off an infection. But with the CDK 4/6 inhibitors, you’re not killing those cells, you’re just sort of putting them to sleep for a little bit. And you can still mount a response to the infection if it arises. If you look at the rates of low neutrophils in the major trials, you can see up to 80% of patients will drop their white count and up to 60% of patients will have high grade drops in their white count. But if you look at the rates of severe infection, depending on the trial, you look at, I’m quoting here from the original palbociclib trial, 0% severe infection rate. Our goal, typically, is to keep it above 1.0, or 1,000 depending on how the report reads it. But basically we want it to be above 1.0.

We know that from some studies done with these CDK 4/6 inhibitors. We want to consider though, if they’re getting persistently far below 1.0, that’s when I tend to want to reduce the dose because even though the rates of high grade infection are low, we want to be on the safer side. It’s OK to dose reduce if the white blood cells are significantly lower.

And we don’t use growth factors here, by the way. We don’t use growth factors like Neulasta with CDK 4/6 inhibitors where they can be used with chemo.

Now the other thing with neutropenia, or low neutrophils, is we can often see mouth ulcers arise when the neutrophils are quite low. They tend to come down when the neutrophils come down. They tend to go away when the neutrophils come up. And of course they can be painful and irritating, so what can we do about it?

There’s a number of things you can use daily. Baking soda and salt water rinses, very easy to do, put together. You can do that daily even as a preventative measure. You can also use different lidocaine-based solutions that you can sort of swish and swallow or swish and spit. That mostly numbs the area but doesn’t really treat the ulcers. What’s worked really well in my practice is using oral dexamethasone mouth rinse, which has been proven, especially for certain drugs. There’s a drug that has been still available, hasn’t been given as frequently nowadays, everolimus, which used to cause a lot of mouth ulcers, and the oral steroid rinse really, really dropped the frequency of ulcers with the use of the dexamethasone.

Alright, that’s the low white blood cell case. Now we have two more to go.

Igor Makhlin, MD [00:45:10]

Case six is a 45-year-old woman with ER-positive, HER2-negative metastatic breast cancer, who recently began abemaciclib along with letrozole and leuprolide for first-line treatment. Shortly after starting, she developed several episodes of diarrhea. You knew it was coming, I mentioned it a few times. They’re loose, watery stools, and she’s describing four stools per day, mostly brought on by food. She’s also getting these stomach spasms with the diarrhea.

She’s a physician, and the diarrhea is very disruptive to a busy clinic day where she’s in and out with patients.

Talking about diarrhea, it’s a very common side effect of certain systemic therapies in breast cancer. But it also can be caused by chemotherapies, targeted therapies, immunotherapy. Really any therapy could potentially cause diarrhea. And it’s always important to make sure we we’re considering other causes at the first onset. Always want to make sure there’s no infection going on like C.diff. And for therapies at high risk for diarrhea, you want to have some at-home meds ready to go just in case.

Loperamide, or Imodium, is our go-to. It’s our first line. It actually comes with abemaciclib in the kit, because they’re ready for it. They learned their lesson. I hope they’re not listening right now. It’s a great drug.

Loperamide is frequently first-line antidiarrheal. It tends to work really well. We tend to start out by giving two capsules for the first diarrheal episode. And then you can follow it after every diarrheal episode you can give another capsule, or two milligrams.

If that’s not working, we have other drugs at our disposal. Lomotil is another drug. This is a prescription medication your provider can write for you. That often does help if Imodium is not helping. But again, dose modification may be necessary if those are not helpful as well.

For our patient, remember her diarrhea was brought on by meals. So the suggestion was why not try a dose of Imodium before the meal? And that seemed to do the trick. It really terminated the diarrheal episodes. The other considerations that we think about for diarrhea in addition to medications could be dietary changes. You might want to consider avoiding fatty foods or acidic foods that can really irritate the GI lining.

Then for the stomach spasms that our patient had, this is another common symptom that can come with diarrhea. Dicyclomine, or Bentyl, often works really well for a really spasmodic type of pain in the stomach.

OK, last case. This is another really common situation in the clinic, joint pain. Here a 63-year-old woman with metastatic ER-positive, HER2-negative breast cancer just began therapy with ribociclib and letrozole. On follow-up she notes she’s developed significant joint stiffness, particularly when getting up from a seated position and after long periods of inactivity as well as some mild swelling in her fingers. The joint pains, which includes her knees, her hips, her wrists. They’re really impacting her daily functioning.

This is part of the umbrella of something called AI-induced musculoskeletal symptoms or AIMSS. AI is aromatase inhibitor. Letrozole is an aromatase inhibitor, and this is really a constellation of possible effects from these drugs. It’s very common.

The frequencies that have been reported vary, but up to 75% of patients can develop this. It typically presents with joint stiffness, and in my experience, and really what’s been reported out there, it tends to be like an inflammatory type of joint pain. The most common way that patients describe it to me is I get really stiff after waking up. I’ve got to really stretch and move after getting out of bed, or if I’m sitting at the desk for a while, I get really stiff and I have to move and, and stretch those joints out.

Interestingly, there are other effects from within AIMSS that we just clearly don’t do a good enough job asking about because this can cause carpal tunnel syndrome, it can cause trigger finger, fatigue, reduced grip strength. I’ve had conversations where the patient is telling me she’s doing great, minimal joint pain, it’s fine. And then I ask, well have you ever had trigger finger? And she says, oh actually I developed that 2 months ago, but I thought that was completely unrelated to the letrozole.

This can all happen and it all stems from the underlying pathology here, which is that the drop in estrogen levels can lead to an increase in inflammatory markers called cytokines at the joint spaces, which leads to inflammatory irritation of the joint spaces. For instance with trigger finger, that inflammation over time can lead to those little nodules that can develop along the sheath, which can then make it really hard to bend your finger. It’s all kind of related to that pathology.

Igor Makhlin, MD [00:50:21]

We also know that drop in estrogen levels can affect pain sensitivity. And so that coupled with the inflammatory effects in the joint spaces really is what can cause this.

How do we manage AIMSS?

The primary recommendation here is movement. That can be exercise with aerobic or strength training. Daily stretching is super important. Yoga. Patients who have tried yoga, this is anecdotal, but it’s also been studied in trial settings. These are small cohort type of studies. But yoga, because of its effects on the joints and the muscles and the movement, has really been shown to be helpful with joint pains, with arthralgias, or joint pains.

Qigong, another one. I told you about Qigong before, it can be very helpful here. Acupuncture has actually been tested in randomized studies. I heard Dr. Mehta talk about acupuncture, and we can talk about that some more. But it’s been studied in a randomized trial where patients were separated into real acupuncture, sham acupuncture with needles that weren’t doing anything, and wait list control. The three groups were compared, and real acupuncture did show improvements in joint pain. So another really interesting and supportive additional approach that you can think about.

You can also consider taking a short holiday, 2 to 4 weeks, maybe a bit much in the metastatic setting. So you can consider like a week and then switching to a different AI because it really can be just the brand that you’re on may not be agreeing with you. But certainly you can switch. Like if you’re on letrozole you can switch to exemestane, which is very different chemically it’s different even though it’s doing the same thing ultimately.

They’re all equally effective. That’s the point I’m trying to make, is they’re equally effective. So there shouldn’t be concern about are you going to lose efficacy, it’s really about which one works best for you.

There’s also some data on Omega-3 fatty acids, which are anti-inflammatory and can also potentially help with joint pains. And then for carpal tunnel syndrome you can consider using a night time splint, steroid injections. If that doesn’t work or help, you can consider carpal tunnel release surgery.

I want to end with some resources that you can look towards for additional support. I’ll start with, has anybody here heard of Living Beyond Breast Cancer? It’s a wonderful organization. I heard from Caroline earlier that 60% of attendees today are first-time attendees, and that’s amazing. I hope you’re having a great conference today. Such a wealth of resources here. And what a great community for you all to join in community here to learn about metastatic breast cancer. So that’s Living Beyond Breast Cancer.

Unite for Her is another really excellent program that I refer patients to. For those who haven’t heard about it, it’s really incredible. They partner with different services around the area. This is for patients who are in Pennsylvania, New Jersey, and Delaware. And with metastatic breast cancer, lifelong renewable program. Every 6 months you get this passport where you get access to acupuncture, reiki therapy, oncologic massage, counseling, nutrition. It’s just a wealth of resources. So I absolutely encourage everybody here to sign up.

They’re national now? Oh, excellent! They’re national. Sorry about that. Anybody listening virtually can also sign up as well.

I did have one extra slide. I just want to also say another super important resource is your care team. Right? Along with your family, your friends, your personal support system, your care team should be your support. And that’s not just your oncologist, it’s not just the nurse practitioner or the PA that work with you. It’s the infusion nurses who are pros at managing how the infusions happen. It’s the infusion nurses, it’s your social workers who are there for counseling and for financial resources. It’s the oncology pharmacists who are there to work with us hand-in-hand and help us understand is that supplement that you’re considering safe to take with the medicines that we’re prescribing. It takes a village nowadays for this incredibly complex cancer.

And I’ll end it there. Thank you so much, everybody.

Caroline Koffke, RN, BSN, OCN [00:55:00]

Thank you so much Dr. Makhlin. We very much appreciate it. You are a wealth of knowledge, and it is incredibly apparent that you take managing toxicities of your patients incredibly seriously.

I have a question for both of you to start, and then I know Casey and Joanne have some wonderful questions as well.

Obviously you are both very in tune with your patients and, Dr. Makhlin, you brought up a great point, which is you bring up dose reductions, you bring up the possibility of changing things for your patients very, very early. I am assuming that not every oncologist does that. So for some of our people here watching, either in person or livestream, what suggestions would you both give them to start having these conversations with their own provider at home?

Igor Makhlin, MD [00:55:50]

I think just starting with an open-ended question, if you’re talking about the range of options for how to deal with the management. It doesn’t have to be the obvious answer, but just starting out by saying, Are there different doses for this drug? What does the label say? What would the label say for the severity of the side effect I’m having, which is guided by dose reduction?

I would start with a very open-ended question and just go from there.

Pallav Mehta, MD [00:56:19]

Yeah, I would agree. I think patients have taught me a lot over the years in terms of dosing. I used to be really kind of strict in the numbers based on the clinical trial data, but Verzenio is a good example. That’s a drug that is, for many of our patients, sometimes difficult to tolerate. And reducing the dose was something that I was nervous about, originally. Now we have data to show a lower dose is just as effective.

I think I would rather, if a treatment is working, and I think that’s the important point. If something is working, and we can work with the patient to try and maneuver the dosing, within reason, then we really should. And sometimes it just requires, Dr. Makhlin mentioned a holiday. Sometimes a short time off of a drug, sometimes just lowering it and then coming back up. The body does handle these things better the second time around, sometimes.

Casey Liening [00:57:21]

we got a lot of questions on pneumonitis. So to combine a number of them, I’m going to break it down into two parts. How can you scan for pneumonitis? When should you scan for it? And how long does it typically take to show up in a patient?

Igor Makhlin, MD [00:57:45]

Great questions. How frequently should you scan? You’re going to be getting, as per routine, standard staging scans. And Dr. Mehta did a great job talking about the different types of scans that we do most commonly, either CTs or the PET CTs, which both include a CT of the chest. And so there is no standard guideline for how often we should be scanning.

In the trials, they were more aggressive. They were doing initially scans every 6 weeks. I think in the real world, that’s probably not practical. I think in practice, if you were to ask 10 different oncologists, the practice varies. I tend to scan every 3 months, as per the routine when we’re doing our updated scans. And then, of course, if there’s any suggestion of symptoms, we absolutely do scan.

Pallav Mehta, MD [00:58:35]

Agreed. He said it all.

Joanne Bursich [00:58:39]

A couple questions on acupuncture.

Is acupuncture safe if you’ve had lymph nodes removed or if you have a port, or if you have lymphedema issues? And then are there specialized acupuncturist specializing in oncology patients or just general?

Pallav Mehta, MD [00:58:55]

Yeah, I can take that.

I don’t know the specific additional training acupuncturists can get. I believe there is something recently where there’s an additional training that can be done for cancer just because it’s such a widely used modality in cancer.

But in terms of safety, I think the first point is you do want to go to an acupuncturist that is an acupuncturist. I know it sounds obvious, but there’s a lot of fly-by-night places out there claiming, the sham acupuncture. When I first heard that term, I had the same reaction everyone else did, which is sham acupuncture? How do you stick needles in? But there’s folks doing things. I’ve had patients who’ve gotten to people who they’ve had bleeding. So I do worry, particularly in women who had an axillary dissection and radiation to the axilla, even if they don’t have clinical lymphedema, there can be sometimes lymphedema that’s a little more subclinical. So I worry about needles in that area, but my understanding is from speaking with acupuncturists, that that’s just one part of the body. There’s other areas of parasympathetic nervous system activation, which I think is the mechanism behind its benefit, that can be done.

Caroline Koffke, RN, BSN, OCN [01:00:12]

Thank you. I have a question.

Diarrhea, we’ve talked about it a lot. Why is it so common for so many of these drugs to have diarrhea as a side effect?

Igor Makhlin, MD [01:01:24]

That’s a great question. The mechanism varies depending on the type of treatment. So with chemotherapy, there’s direct cytotoxic injury to the lining of the GI tract, which can lead to diarrhea. And different chemotherapies have different mechanisms for how they damage the cells. There can be DNA damage, there can be damage interrupting the replication of the cells. So with chemotherapy, I think it’s a little bit more straightforward that we’re getting injury to the GI lining.

With other therapies, like abemaciclib for instance, I actually think it’s not well understood how it causes diarrhea. Then of course with immunotherapies you can have autoimmune diarrhea, or colitis, where you have an autoimmune attack against the colon, the lining of the colon leading to diarrhea and pain.

Pallav Mehta, MD [01:01:21]

Yeah, I would agree. When you think about chemo, in patients who get chemotherapy, and I was talking with someone earlier today about this. When patients get chemotherapy and then get some of these other drugs, we do see a higher incidence of diarrhea in them, with the obvious theory being that because chemo is damaging the lining, they’re called mucosal toxins, they damage mucosa. Mucosa is not just in the gut, mucosa is in your eyes and nose and bladder. So if the mucosa is damaged and then you get drugs that interact with different receptors in that lining, you’re going to get more diarrhea.

I think there’s some interesting work going on now about something called the microbiome, which people have heard the term. It’s kind of the world of bacteria in our gut and how that may influence toxicities, and interestingly, the benefits of certain treatments like immunotherapy, like some of the oral drugs. So stay tuned on that.

Casey Liening [01:02:26]

Yes, I’m going to do my best to summarize the question that I saw but can’t find. It was on lowering dosages.

Someone had asked, the efficacy of lowering the dose, obviously, does that hurt the efficacy of the drug? And then is there evidence to suggest that if you take a break, can you potentially get a longer run with that specific treatment?

Pallav Mehta, MD [01:02:58]

I can start. There is a therapeutic window, we call it, for these drugs. It’s not like if you get a hundred percent benefit, I’m going to make up a number, a hundred milligrams, you get a hundred percent benefit, you’re going to get 10% benefit at 10 milligrams. You probably will get no benefit at 10 milligrams. So there is a window. Now what that therapeutic window is, we sometimes do figure out through clinical trials, the phase I trials, we figure out safety.

But what you realize is, in clinical practice, that if a treatment is working and the toxicity is the reason that a patient might have to stop, I do tend to be more creative about dosing. That’s what you want to speak with your oncologist about is if something is working, and there’s a toxicity, then you can take time off these drugs. And generally, with short amounts of time, you’re not damaging the response.

The point about if you start and stop, would you achieve a better response? Generally the answer to that is no. I think in in the prostate cancer world there was some work on estrogen therapies and that approach, but in breast cancer that just hasn’t really panned out.

Igor Makhlin, MD [00:01:04:17]

Yeah, and I think the big picture here is that in metastatic breast cancer, the goal is to stay on treatment as long as it’s working. And because it’s, theoretically, an indefinite treatment, if it’s working, we want to keep it going.

I know that this is a trite phrase, but we often say it’s like a marathon, and if the dose that you’re on is causing a level of misery. It really is individualized to your experience, and we have to work together to find a dose that makes life worth living.

Joanne Bursich [01:05:01]

Does dose reduction help with brain fog?

Pallav Mehta, MD [01:05:07]

Brain fog is complicated. What does it really mean? We colloquially use the term chemo brain. There’s been work on chemo brain to figure out it’s not a cognitive dysfunction for most people. There certainly doesn’t seem to be a progression to dementia necessarily, but it depends on what it’s coming from. I think a lot of the things we sometimes blame, particularly in women, in younger women, that we blame on things like chemotherapy are the hormonal impact.

I think we underestimate the hormonal impact of some of these treatments. For most younger women, either we put them into menopause, we change their hormonal status and that has a real impact on their ability to think clearly.

But one of the things we’ve realized, there was some studies done recently on this, that you’re not forgetting, it’s not a memory problem or a cognition problem, it’s a focus, concentration, and attention problem. So when you can’t focus and concentrate — my wife asks me to get five things from the grocery store, I remember three, maybe, because I’m not focusing. But that’s the idea. It’s this scatterbrained, some of it is anxiety because you’re so much in your head that you’re thinking about that it manifests in this quote cognitive, or chemo brain, thing. But dose reductions don’t change that.

Caroline Koffke, RN, BSN, OCN [01:06:29]

Very helpful. I’ve asked most of the docs here today, so I’d like to ask both of you as well.

You have shared a plethora of resources, and I know as Jean mentioned earlier, these slides, the presentations, they will be available for you to look at again. Because I think that’s a super helpful way to retain kind of an information overload of this wealth of knowledge that you both have provided with us today.

What, if anything, what are your go-to resources that you share with your patients in order to make sure that they have trusted sources, especially for symptom management? Because it can be a scary place out there on the internet.

Igor Makhlin, MD [01:07:03]

I just realized there was also one more slide that for some reason didn’t make it up there, but there’s this entity called the NCCN, the National Comprehensive Cancer Network. And they not only publish the guidelines, the consensus-based guidelines for us as oncologists to follow, but they also publish a wealth of information for patients.

There’s essentially a companion guideline for every cancer and for supportive care in patient material. You can access it for free. I think that’s a great resource, and I’m sorry it wasn’t up there on the slide. But you can google NCCN patient resources and it’ll come right up.

Pallav Mehta, MD [01:07:45]

Since you mentioned a free one, I’ll mention one that you would have to pay for, but maybe there’s some grants available for this.

There’s a website that your institution may have access to. It’s called UpToDate. I’ve used it for, boy, 20 years. They have an entire section for patients. And it’s so well written, and it is up to date. I mean, they really do update everything for us and for patients. So it’s a really great resource. There’s a cost there, there’s a monthly fee. But I think it’s a wonderful resource for the management of any medical issue, not just cancer. From an integrative health standpoint, I think the Society of Integrative Oncology probably has the best evidence-based information around integrative and cancer medicine.

Igor Makhlin, MD [01:08:37]

And just one more that popped into my head, and I sometimes we’ll print these guides out for patients is, if you want to write this down, it’s OncoLink. It’s a Penn resource, but it’s probably available. And they basically have an OncoLink for every treatment that you might be getting, which is what to expect, whether it’s side effects, information, resources. And then I’ll often print out a bone health after cancer resource, which talks about vitamin D supplementation, calcium, like what Dr. Mehta talked about. So OncoLink is another great free resource.

Caroline Koffke, RN, BSN, OCN [01:09:11]

Thank you. I know finding trusted information right now is paramount. And Dr. Mehta you also did a phenomenal job of opening my eyes to resources like physical therapists, massage therapists who have the extra training and the certification that shows this is someone I can trust.

Thank you both for sharing those trusted resources. It’s so, so important. And thank you both for your time today. I feel like I learned so much from both of you and we just really, really appreciate you being here with us. So a big round of applause for both of them.