Neurologic Complications of Conventional Chemotherapy and Radiation Therapy (Neuro-oncology December 2023)

Educational Objectives

The goal of this program is to improve management of neurologic complications of conventional cancer treatments. After hearing and assimilating this program, the clinician will be better able to:

1. Assess the severity of adverse effects of chemotherapy.
2. Identify risk factors for, and measures that may be protective against, development of chemotherapy-induced peripheral neuropathy.
3. Prescribe effective pharmacologic treatment of peripheral neuropathy associated with chemotherapy.

Summary

Neurologic Complications of Conventional Chemotherapy and Radiation Therapy (Neuro-oncology December 2023)

Dr Weathers: This is Dr Allison Weathers with Continuum Audio. Today, I’m interviewing Dr Jennie Taylor on neurologic complications of conventional chemotherapy and radiation therapy, which is part of an issue on neuro-oncology. Dr ­Taylor is an Associate Professor of Neurology and Neurological Surgery at University of California, San Francisco, in San Francisco, California. Dr Taylor, thank you so much for being with me today to talk about such a really wide-ranging and really important topic. And I was struck immediately by how incredibly accurate, actually, the very first line of the abstract of your article is — that neurologic complications are both common and among the most feared outcomes of cancer treatments. And that made me immediately think of the first question I had to ask you. So, why is the frequency increasing? And given that the complications of cancer treatments are so broad in general — they affect so many aspects of the body, so many things are involved — why are the neurologic ones, in particular, so feared?

Dr Taylor: Thank you, Dr Weathers, for the opportunity to talk about this subject matter. And I think that neurologic complications are becoming more common and continue to be a feared outcome because patients with cancer are living longer — there’s increasing survival. And I think immunotherapy is a very good example, which is discussed in a different article within the Continuum. And I certainly reference the listeners back to that article of really good example of how patients with previously metastatic disease — who would have been terminal within a few years, even within the last decade — are living longer and longer. However, I think there continues to be this worry from patients, as they enter into their survivorship aspect of their illness, of the long-term effects of all of the treatment that they’ve undergone. And I think that the neurologic complications, in particular, are something that can be really impactful, and I think very difficult to study, as is true for so many neurologic complications of so many medications. And I think while there’s an increasing number of people who are surviving, we’re seeing delayed impacts of these neurologic complications. I think there’s pain components, as it relates to peripheral nerve injury. And I think “brain fog” and “chemo fog,” as something that lingers amongst many survivors with multiple different types of treatments, is something that continues to be poorly understood in its mechanisms, preventions, and treatments. And so, I think it’s something that worries patients a lot as they go through treatment and start on treatment, and even after treatment is over — and what is going to get better and what may stick around.

Dr Weathers: So, it’s interesting, I think you really spoke to, in your response, how much — and it makes so much sense — about why the patients are concerned about the potential neurologic complications of treatments. And they’re so well known — especially, as you mentioned, the brain fog and the neuropathy. It’s funny, when I read the line, I was struck by how much, frankly, we as providers are fearful of the neurologic complications and having to address them, which I think is true. And hopefully, it’s not just me. Why do you think these are feared by us as neurologists?

Dr Taylor: I think that is an important highlight. I think it’s not just feared by the neurologists; I think it’s also feared by the oncologists and the radiation oncologists, and the village of providers who are caring for these patients. I think the underlying rationale is pretty similar for patients. I think understanding the why and the mechanisms of injury (and therefore, how to be preventative), and how the natural trajectory may change during recovery from the cancer therapy during survivorship. There is, I think, a lack of evidence for therapeutic interventions, for preventative interventions. And so, both during the course of the treatment itself, I think the neurologists are very worried about how these side effects are graded, how they influence the patient — who hopefully, of course, is benefiting from this treatment — but how it influences dosing and timing, duration of potentially life-saving treatments. But also, as the neurologists being beholden on looking for signs or indications of irreversible damage that could potentially cause more morbidity for patients who are surviving. And then I think the flip side of that, from the oncologist’s perspective, is trying to figure out how to manage some of these toxicities, anticipate these toxicities, both during the course of treatment and after the course of treatment, again with potentially life-saving medication. So, I think this article really highlights that synergy of the importance of neurologists being engaged in this patient population, not only for metastatic disease, of course, but because of these neurologic complications of cancer as it relates to their therapies. And that partnership is really critically important with the neurologists, the oncologists, and again, even the radiation oncologists.

Dr Weathers: I think that’s a really excellent point about how important that teamwork is. And I realized as I was looking at my next question, in some ways, that it actually answers my previous one in that these are a little bit — they invoke fear because, in some ways, they are so broad. So, in addition to being common, they’re just really broad in scope, the ­neurologic complications of cancer treatments. They can be acute or delayed — they can occur years and years after exposure. They can affect pretty much every part of the nervous system. And then they can also range from very mild to even fatal. And oftentimes, to make it even more complicated, they can be really challenging to distinguish from the effects of the cancer themselves. So how do you even start to tackle a topic that’s this broad? What is your approach to the classification of the neurologic complications of cancer?

Dr Taylor: I think you hit the nail on the head — it’s certainly a very broad topic. It hits all of the highlights of all of us who go through neurology training — the central nervous system, the peripheral nervous system — you know, acute effects, delayed effects. I think that the CTCAE, which is Common Terminology Criteria for Adverse Events, particularly is relevant in this context of cancer therapy. And so, these CTCAE, I know is something in neurology that I didn’t necessarily learn that much about. But in the cancer worlds, this is a very standardized way of trying to tackle these very broad and potentially very impactful topics. This is by no means isolated to the nervous system. It certainly encompasses laboratory values, and myelosuppression, and lots of cancer-directed therapies. But I think it is very helpful in the immediate piece of trying to work with the oncologists and navigating these neurologic complications during treatment. It’s very helpful to grade the impact of these adverse events, I think, particularly as it relates to neurologic disease. And so, for the most part, the CTCAE is graded on a scale of grade 1, which is fairly mild, all the way up to grade 5, which is death. And in the oncology world, often this grade 3, which is really implicated in the course of treatment of impacting activities of daily living for patients — so, weakness, pain, fatigue. You know, these are things that are sort of graded on this scale, with often that grade 3 being something that can be indicative of maybe doing something a bit different with how the medication is being managed — either increasing supportive medications for pain control, dose reductions, breaks in treatment, longer duration between therapies. So, I think that’s been a helpful way of trying to break this down into bite-size approaches. I think, for a lot of cytotoxic agents that we sort of traditionally think about when we think about neuropathy, for example, I believe that we know a lot of this information now. So, these are drugs that have been given probably to millions of patients around the world at this point, and so the trajectory of the symptoms for peripheral neuropathy, for example, is very mapped out with some of these older, traditional types of cytotoxic agents. And I think we’re able to learn and take some of that trajectory and apply it a bit more to newer drugs, newer therapies. I think there’s a thought that targeted agents and tyrosine kinase receptor inhibitors and oral pills, that these are all less toxic for patients. And I think -I think that’s a bit of a misconception. I think these are often drugs that are given over longer periods of time for patients, more continuously, and have maybe a very different set of toxicities, and the delayed impact may be a little less clear. And then again, I think the cognitive aspects of any cancer-directed therapy, even hormone therapy for something like breast cancer or prostate cancer, are things that we don’t necessarily have immense understanding of risk factors, of, again, prevention and treatment. Those are often, I believe, the aspects of this care that are a bit more daunting, I think, particularly for oncologists, and again, more really important focus with the neurologists’ input and partnership. And so, I think this sort of CTCAE way of trying to define things in a bit of a clear way, you know, sort of, “if you can name it, you can tame it” type of idea. And then also grading things to try to understand how impactful these are for patients to standardize, and then therefore, react in a systematized way, can be very helpful in thinking about sort of the acute, subacute, and delayed effects of these treatments.

Dr Weathers: I think that makes a lot of sense. And it’s a really good approach to kind of help organize, which we said can be a really overwhelmingly broad topic. So now that we have that kind of system in our head, I want to move now from the really broad discussion to spending a few minutes returning to something you mentioned earlier on — the more specific toxicity of chemotherapy-induced peripheral neuropathy. As you point out in the article, CIPN can not only limit treatment acutely, but also becomes a really critical survivorship issue due to its impact on morbidity, especially in breast and colon cancer survivors. How has the diagnosis of CIPN evolved over the last decade or so? And, in particular, you mentioned prevention a few times — can CIPN be prevented? And in general, what are some of the key points our listeners should be aware of as they think about this diagnosis?

Dr Taylor: Yeah, again, I think with more traditional taxane-based therapies, vinca alkaloids, proteasome inhibitors, I think there’s a wealth of understanding of typical different trajectories that are nuanced, maybe, for different types of these particular drugs. So, with this concept of coasting with certain platinum-based therapies being something that’s sort of very well known, and therefore you can kind of anticipate things with patients and provide some reassurance and guidance on how patients may manage or experience that. Because that also often means that symptoms can be exacerbated and get worse over the first three months, even after treatment is completed. So, I think some of this diagnosis has been very helpful. As is true for so many peripheral neuropathies, I think chemotherapy-induced peripheral neuropathy can often be a difficult diagnosis to make and can often be very clinically based, as opposed to electrophysiologically based. And I think it depends, of course, on what the drugs are that the patient is experiencing. And back to that sort of CTCAE — there’s sort of good ways to help grade this — and using that threshold of impact of activities of daily living to kind of understand if something needs to be readjusted. I think there are some risk factors that probably warrant extra education for certain populations as you’re entering in, and not to say that drugs that are more likely to cause CIPN — chemotherapy-induced peripheral neuropathy — that they should be avoided in these populations, but I think maybe proceeding with caution and a lot of education for patients and families. And so, I think that includes things where peripheral neuropathy is likely to be a problem anyways. For example, poorly controlled diabetes, advanced age, any pre-existing neuropathy, Charcot-Marie-Tooth. So I think there are some particular populations where everyone’s red flags are very much up. I think, outside of that, prevention for this particular toxicity, I think, has been looked at with a couple of large phase 3 studies. And while things seems sort of encouraging, the most level of evidence is still kind of in the 2C level, maybe a bit into 3C level — so not super high-level evidence. And I think this probably is just reflective, again, of that sort of lack of real clear understanding of how these complications impact different people. And there are some examples of cryotherapy. Vitamin D deficiency is thought to maybe be a risk factor with CIPN. Exercise and functional training has shown to potentially be helpful in prevention, and compression therapy. So those are discussed in the article, and I think that those are relatively low-risk, potentially high (or at least medium) -impact preventative agents. And so, I think that that’s certainly something that should be explored and discussed with patients, particularly who may be at higher risk and may be using medications that potentially are where we see this complication more often. It’s often true — it’s a recurring theme throughout the article — and really hammered this home to me even as a neuro-oncologist that, you know, a lot of these toxicities are exacerbated when you’re combining them together. So, when you’re combining multiple drugs — which is sort of self-explanatory — but when you’re combining multiple drugs together that each, individually, have a relatively low risk of CIPN, then these things will get exacerbated and amplified when you merge them. So, I think there are some preventative measures that are, again, relatively low risk that might be worth discussing with patients.

Dr Weathers: That is really promising to hear. Both, one, the increased awareness around some of the risk factors, and how we can counsel our patients, as well as some of the preventative measures, especially exercise and things like that. Have there been any advances in terms of treatment of chemotherapy-induced peripheral neuropathy?

Dr Taylor: Yes, I think the Table 3 in the article kind of runs through some examples — which is certainly not meant to be an exhaustive list — but some options of pharmacologic and then nonpharmacologic concepts that have been put into place that have shown, at least sort of, again, moderate-level evidence. I think that duloxetine is sort of the medication that’s demonstrated in large, randomized studies to reduce high rates of pain. And so, I think that’s often the medication, particularly as it relates to platinum-based therapy (though it probably extends for other chemotherapy agents as well), potentially would be helpful. So, I think duloxetine, even starting at a relatively low dose and potentially titrating up — always, of course, making sure that any medication that’s started while the patient is actively on chemotherapy needs to sort of be, quote-unquote, “cleared” with the oncologist to be sure that there’s no drug-drug interactions, or that there’s potentially unintended consequences. Often these patients may be feeling a bit fragile, and so “starting low and going slow,” as often is our mantra, would be potentially helpful. I think other medications, venlafaxine, tricyclic antidepressants, antiepileptics, of course, such as gabapentin or pregabalin, are also relatively low evidence but may be appropriate to try in patients, certainly, that have significant morbidity from these symptoms. For patients who are experiencing more of a small-fiber neuropathy, menthol cream (topical menthol cream) may potentially be helpful. And then there are some other topical agents that are kind of discussed in that Table 3 — capsaicin creams. Generally speaking, occasionally tramadol and opioids may be necessary for very significant pain. And then there are, again, sort of nonpharmacologic interventions — exercise, functional training — again, similarly, for prevention, potentially also helpful in treatment. And then things like acupuncture, neurofeedback, cognitive behavioral therapy. So, again, pretty low risk. But I think physical therapy can be really helpful for these patients, not only because their recovery may be true — it may be that the neuropathy improves — but there may also be some lingering permanency in that things may not all the way recover. And so, being sure that falls are being prevented and that patients and caregivers understand kind of how to navigate that world of — either with small-fiber neuropathies or even large-fiber sensory neuropathies — just to minimize worsening other morbidities, especially during the survivorship.

Dr Weathers: I’m glad we spent a few minutes doing a deep dive, because to your point, I think this is really one that has such a huge impact on overall quality of life in survivors, and really deserves a lot of advocacy and continued research. And to pivot now and kind of focus on another, actually, area with also a kind of really similar impact in a lot of ways on survivors as well, is that of the neurologic complications of radiotherapy. As you highlight in the article, even with the advancements in the field of oncology, including immunotherapies and biologics, radiotherapy remains a mainstay of cancer treatment. And as survivors are living longer, the potential long-term complications are even greater. So, I’m going to go back to the question I posed to you earlier about your approach to tackling a topic that’s this broad, as it seems to apply here as well. What are the broad categories that should be considered when you think about the complications of radiotherapy? And how has our understanding of radiation toxicity evolved? Are there any advancements that you’re particularly excited or hopeful about?

Dr Taylor: Absolutely. I think our radiation oncology colleagues are genius physicists, and as they get more creative in understanding the areas that are truly vulnerable in the brain and may really impact long-term toxicity, I think there’s increasing more ways — proton therapy being a good example, hippocampal-sparing radiation for whole brain — I think there’s a lot of very creative ways. And again, back to your advocacy point, I think patients and caregivers of patients who have undergone whole-brain radiation therapy really are left with a lot of significant cognitive impairments. And so, I think, because of that, there’s the clear benefit of using memantine. And again, hippocampal-sparing for whole-brain radiation, I think, has been driven by these actual cognitive, neurologic, neuropsychological outcomes — not survivorship or necessarily brain failure or metastatic disease, but I think an actual cognitive outcome. And I think that those studies, which have all come out within the last five to ten years, have really revolutionized how we’re thinking about that balance, that survivorship, and mitigating risk while obviously, of course, continuing to control the cancer. And I think, though the CTCAE I think is helpful when it comes to these radiotherapy consequences, I think it’s a little bit different. I think, while you’re in radiation, you kind of have to go through radiation. And I think the aftermath of radiation — of these acute, subacute, and delayed effects — are pretty universal, whether it’s the brain, whether it’s the spinal cord, or even the plexus and peripheral nerves. I think that paradigm of when to look for different radiologic findings, neurologic symptoms, and then management, I think are very different sort of during the acute phase, that subacute phase, and the delayed phase. I think the acute phase is often really highlighted by the fatigue that patients experience. And so, of course, when patients are fatigued, you know, neurologic symptoms, or any symptom, potentially is just going to be more bothersome or be a bit worse. And so, I think managing fatigue for whole-brain radiation is certainly something that is important, or even for partial-brain radiation — I think it’s also important. We certainly see fatigue even for patients who undergo stereotactic radiosurgery. And so, any sort of version of radiotherapy I think is often impacted, sort of, by fatigue. I think there are ways to help mitigate it. And the physics of this, I think, have been fleshed out for several decades. The more radiation that’s given in a more concentrated dose — so, large areas of high radiation concentration — are going to be more acutely toxic than fractionating the radiation into some sort of balance of the normal brain (which is going to obviously be caught in the crossfire of radiation) to allow it to heal and adjust and recover if you fraction out things over the course of potentially several weeks. So, sort of the 3 Gy per day fraction is kind of a general thought. If you’re using radiation that’s higher than 3 Gy over a relatively large area, per day, you’re going to be ending up with more toxicity than if you fractionate it to less than 3 Gy. I think there’s instances, such as stereotactic radiosurgery, where you’re using very precise, very small targets, and using very high doses, where obviously the physics of that are a bit different. I think the early delayed phase is really something we see a lot in neuro-oncology — this concept of pseudoprogression. And for those of us who treat a lot of (or anyone who’s cared for) glioblastoma patients, this is something that we really see very robustly, often within the first three months. To your point you mentioned previously, it can be incredibly difficult to distinguish these radiologic, very robust neurologic symptoms, from, really, tumor progression. And often a surgery is needed, or additional therapy, such as anti-VEGF therapy with bevacizumab, to help manage all of this brain edema. I think, over the course of the last decade-plus, we’ve really understood this phenomenon much better, and allowed us to continue on certain treatments that we think are helpful for the patients while managing these sorts of radiologic and neurologic symptoms of pseudoprogression, but not necessarily pivoting to new therapy. And I think that that’s really also the experience in neuro-oncology of treating glioblastoma patients is then also translated. As more and more brain metastases are often treated with high doses of radiation focally (stereotactic radiosurgery, as opposed to whole-brain radiation), this sort of concept of everything looking worse for a while and then calming down has, I think, informed our oncology and radiation oncology community as a whole, even outside primary brain tumors. And then I think the biggest worry, of course, for most patients who go through radiotherapy, is the delayed effects — so, those cognitive, long-term cognitive effects, which are often something that we see, you know, six months, a year — short-term memory issues, you know, difficulty getting back to work for patients. And so, I think this is where things like memantine, hippocampal-sparing radiotherapy, has really been additively beneficial.

Dr Weathers: I think there are some really key points for our listeners to keep in mind, especially thinking about exactly, again, what phase are the patients in as they think about their approach. So, even though it is very broad, that’s a really good way to organize and not get overwhelmed by the broadness. Thinking about, again, the long-term complications, are there any other long-term complications that our listeners should keep in mind when thinking about the complications of radiotherapy?

Dr Taylor: Yeah, I think vascular complications (your delayed vascular complications) are something, again — as we see people living longer and longer after radiotherapy, either for primary brain tumor patients or even metastatic disease — that we see these long-term ischemic events or hemorrhagic events. And again, I think that the neurologists are going to sort of come into play. And often, managing that, you’re looking at secondary stroke prevention for those patients. You know, it’s always so hard to care for patients who have done so well and had such good tumor control, only to have, years, decades later, potentially even fatal complications, hemorrhagic complications, or really significant ischemic events that really can impact the patient’s sort of survivorship. I think minimizing the amount of brain that gets exposed, obviously, making sure patients’ blood pressure and vascular health, avoiding smoking — you know, the things that vascular neurologists are so wonderful for advocating — I think are also true for cancer survivors. I think “SMART syndrome” is certainly something that I would like the listeners to just remember. So, SMART is stroke-like migraine attacks after radiation therapy. And I think this is something that, again, is not very well understood but I think has very much an — a sort of neurologic manifestation. Often, these patients not necessarily have migraine attacks, but actually seizures. There’s often very clear radiologic abnormalities of restricted diffusion, enhancement, cortical FLAIR abnormalities that we often see. And this, of course, needs to be within the area of high-dose radiation. Again, it can be very difficult to be totally confident that this is not a recurrent tumor in the brain. And it probably has some sort of vascular underpinning, though again, the mechanisms of this are not necessarily well fleshed out. Certainly, management of antiepileptics with seizures is important, and discussing any secondary stroke preventions for patients. But often this is self-resolving. It can recur, which I think is important to remember, and so patients may need longer-term antiepileptic therapy. But I think this is always something to kind of be on the lookout for with cancer patients whom you’re seeing in the emergency room or in the inpatient setting, because they often kind of get very sick, very quickly. And it really is more neurologic and radiologic, but it’s really a neurologic management issue. And I think it’s — it’s a bit unique and something that neurologists should probably be aware of, and that’s discussed in the article as well.

Dr Weathers: Definitely an important one to keep in mind. I’ve seen it a few times over the years, and it’s always definitely something to have to kind of remember, you know, and keep an eye out for, because if you don’t remember, you don’t remember to ask the right questions about the history and it can be easily missed. So, I think that is a great reminder, as well as remembering the long-term vascular complications. Thank you for those reminders, as well as, overall, for this great discussion — for taking the time to speak with me about this, again, critically important topic. On that note, any final thoughts you would like to share with our listeners? Other take-home points that they should make sure to remember?

Dr Taylor: Thank you so much, Dr Weathers, again, for the opportunity to discuss this article. And I think, just for advocacy of partnership with your oncology colleagues and your radiation oncology colleagues, I think that these neurologic complications are something that patients, while they’re in treatment and after treatment, are really worried about and their caregivers are really worried about. And I think the neurologist is very uniquely poised to provide some guidance, reassurance, and management, long-term, and I think really provide immense value to their oncology, radiation oncology colleagues. And I think while there are some of these complications that we do understand a bit, and we kind of know some risk factors as well as some strategies for management, I think there’s a lot that we don’t know. I think there’s a lot of opportunity for ongoing research and understanding something that is really very highly impactful for so many cancer survivors (for whom we hope, of course, there’s more and more over time), not only as they’re going through their illness but as survivors. And so, again, I thank you so much for the opportunity to really highlight the importance of the neurologist’s role in treating cancer patients.

Dr Weathers: Well, thank you.

The material presented in Continuum Audio has been made available by the AAN for educational purposes only and is not intended to represent the only method or procedure for the medical situations discussed but rather to present an approach, view, statement, or opinion of the speaker(s), which may be helpful to others who face similar situations. Opinions expressed by the speakers are not necessarily those of the AAN, its affiliates, or the publisher. The AAN, its affiliates, and the publisher disclaim any liability to any party for the accuracy, completeness, efficacy, or availability of the material contained in this program (including drug dosages) or for any damages arising out of the use or nonuse of any of the material contained in this program.

Readings

Taylor JW. Neurologic complications of conventional chemotherapy and radiation therapy. Continuum (Minneap Minn) 2023;29(6, Neuro-oncology).

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr Taylor has received research support from Mount Sinai University and the University of Colorado. Dr Taylor has received publishing royalties from a publication relating to health care. The institution of Dr Taylor has received research support from AbbVie, Inc., Agios Pharmaceutical, Inc., Bristol-Myers Squibb, and Navio Theragnostics, Inc.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Taylor reports no disclosure.

To view disclosures of planning committee members with relevant financial relationships, visit: legacy.audio-digest.org/continuumaudio/committee. All other members of the planning committee report nothing to disclose.

Acknowledgements

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