Dr. Shannon Westin and her guest, Dr. Patrick Stone, discuss the article, Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial, recently published in JCO.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts and research published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for JCO and a Gynecologic Oncologist by trade. I am thrilled today to present Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial. This manuscript is a dual publication in the Journal of Clinical Oncology and presentation at the European Association of Palliative Care Congress here on May 17, 2024.

And to review this incredible research with us will be Professor Patrick Stone, the Head of Department of Marie Curie Palliative Care Research Department, Division of Psychiatry at University College London. Welcome, Dr. Stone.

Dr. Patrick Stone: Thank you very much. Thank you.

Shannon Westin: Let's get right to it, we'll level set. Can you speak a bit about the definition of cancer-related fatigue and how common it is in people with advanced cancer?

Dr. Patrick Stone: Sure. I think fatigue is a difficult thing to nail down really and define it clearly, and there are lots of definitions out there. In many ways, the simplest definition is the EAPC, the European Association of Palliative Care's definition of just a subjective sensation of weakness, feeling tired, and exhaustion. The reality is that that symptom is very common in the general population. And so if you really want to get a handle on it, I think a good way to do it is to think about taking an operational definition and say, "Look, if fatigue is normally distributed approximately in the general population, then we should consider severe fatigue or pathological fatigue could be defined as fatigue that is worse than 95% of the general population. And if you think that definition, then prevalence of fatigue in patients with newly diagnosed breast or prostate cancer, for instance, is around 15%, so three times as common as the most severe fatigue in the general population. If you come to patients with newly diagnosed non-small cell lung cancer, it's up to about 50%. And if you come to my area, which is palliative care and you go to a hospice and you ask people to complete a fatigue questionnaire, 78-80% of people complain of fatigue that is more severe than 95% of the general population. So that I think gives us a good handle on sort of the severity of this problem in cancer patients and how it progresses as disease progresses.

Shannon Westin: I love this because I think we always struggle with exactly how to nail down the definition and exactly how to treat it. So I think that it's a really nice transition to existing treatment options for this issue and exactly how they might work.

Dr. Patrick Stone: The first thing to say is in medicine if you can find a cause then you give a treatment directed at the cause and obviously that applies to fatigue as well. So the first thing is to do a thorough assessment of your patient, and if you can find an easily remediable cause such as anemia, hypocalcemia, or hypomagnesemia, or maybe other things like depression, which might manifest as fatigue, then you should try and give a treatment directed at that cause. But, for many patients, there won't be a single clearly identifiable cause you can target.

And then people use more broad spectrum approaches if you like. The most well-studied I think is exercise. And exercise, there have been lots of randomized controlled trials in different types of exercise and it's a well attested treatment, which I think has good evidence of effectiveness, certainly in patients who are on treatment and in disease-free survivors. There is less evidence in advanced cancer because the trials are fewer. I would still say that there's moderate quality evidence that exercise is effective in advanced cancer.

The other group of treatments, broadly speaking, would be psychological therapies, cognitive behavioral therapy and psychoeducational approaches, mindfulness based stress reduction, that sort of thing. And again, in earlier stage disease and in patients on treatment and in survivors, there's more quality evidence that that sort of approach can help, if not alleviate fatigue, allow people to cope better with fatigue. But the evidence in advanced cancer is weaker than for exercise. So I think the evidence for the effectiveness of those psychological therapies is not so strong.

And then you come on to pharmacological therapies and there have been lots of trials of different agents. I won't list them all because most of them are negative and don't show any benefit. A few things which perhaps still show promise from previous trials, there have been, for instance, a few trials looking at ginseng as a herbal therapy. One very good quality trial showed benefit. Although another trial in advanced cancer didn't replicate that finding, so that ginseng is out there. Steroids, widely used in advanced cancer for general relief of many symptoms like fatigue, lack of energy, low moods, appetite. But although widely used, surprisingly little hard evidence or effectiveness, specifically for fatigue, but one relatively recent, well conducted randomized control trial, provides us with some firm evidence, also, that dexamethasone can help in the short term in advanced cancer patients. It obviously wouldn't be a recommended treatment longer term because of its side effects.

And then we really come on to the crux of this study which is probably the most widely studied single agent beyond that, is methylphenidate, which is a psychostimulant agent, raises central dopamine catecholamine levels in the brain. And there's probably a thousand or so randomized control trials sort of being conducted looking at that prior to prize of this study that we're talking about.

Shannon Westin: I would love to hear a summary of the data that were pre-existing in this study. So how well does methylphenidate seem to work, or what were the conflicting results that were seen prior?

Dr. Patrick Stone: I think the rationale for this study was that it was the perfect background to justify another randomized controlled trial, which there have been– Well, I can't remember exactly how many there were in existence before my trial started, but when I last looked, there were 10 studies, 10 randomized controlled trials in cancer patients. Most of those trials have been neutral. They've shown no benefit over placebo, so most of the individual trials are negative. But meta-analyses always tend to show a positive result. So when you count the trials together, it gets you over the finishing line and you can see a positive benefit. But individually, the trials were quite heterogeneous, they're quite different. There were only four trials prior to the publication of this one that were done specifically in advanced cancer patients. One of them was published only a couple of years ago while my study was going on. And of those four trials, three of those have also been neutral, not showing a benefit over placebo. One study involving 28 patients and using a PRN as required dosing schedule showed some benefit. But the other studies with a total of about 330 odd patients have been neutral.

Shannon Westin: I think that brings us to a great transition, just to talk a little bit about the design and objectives of your current study.

Dr. Patrick Stone: Well, what we wanted to do was take the best bits, if you like, of the previous studies, and try to give ourselves the best chance of finding a clinically meaningful improvement in fatigue in patients with advanced cancer. And I was focusing on advanced cancer, principally because I'm a specialist in palliative medicine. That's the group of patients I'm most working with, whereas a lot of the studies have involved mixed groups of cancer patients or patient's disease-free or on treatment. But we looked at patients who were under the care of palliative care services, with incurable cancer, with a prognosis estimated to be less than a year or around a year.

We wanted to try to get the dose of the medication up to a good level because some of the other studies which have shown benefit have got up to quite high levels of methylphenidate, approximating to about 40 to 60 milligrams of methylphenidate a day or equivalent. And we wanted to give the drug in an individually titrated dose because that would reflect the way it is used in clinical practice. You would adjust the dose like you might with morphine for pain relief. You would expect to adjust the dose of this medication up to get a therapeutic benefit. So we had this titration period where we adjusted the dose of the drug every week. We reviewed whether patients were feeling better, worse, or the same. We asked about side effects. And on the basis of the response to those questions, we either went up with the drug or kept the dose the same, or, if necessary, would come down. The primary endpoint was designed to be fatigue after six weeks of dose titration, plus or minus a window of two weeks, accepting the fact that we might miss a few patients at the six-week mark, for whatever reason. So we had a little window around that. That's what we were looking to do.

Shannon Westin: And why did you choose the six-week time point?

Dr. Patrick Stone: Well, there was no obvious time point to choose. One of the biggest positive studies previously was by Lower and colleagues back in 2009, and they had found their maximum benefit at around four weeks, or it took rather four weeks to reach the maximum benefit. So we wanted to give the patients in our trial every chance of demonstrating the benefit, and they'd also escalated the doses in their study up to above 40 milligrams or equivalent. And so we wanted to go up as high as we could, and we didn't feel that if we were adjusting the dose every week, that we could get up to a sufficiently high dose in any shorter time span. So six weeks sort of fitted, allowing us to titrate the dose up to a maximum of 60 milligrams a day, which is where we wanted to get up to.

Shannon Westin: And what about a little bit more detail on the population you included, and maybe give us a sense of how well you think that represents your general population affected by fatigue in the setting of advanced cancer?

Dr. Patrick Stone: We recruited patients from hospices, so that's inpatient palliative care units in the UK, but also from hospital palliative care services, from oncology outpatient services as well, oncology patients who are under the care of palliative care services, and we also recruited from some community palliative care services. So we had quite a good spread of settings, and all of our patients had advanced incurable cancer under the care of palliative care services. But I would say, I think by the nature of doing this randomized controlled trial, inevitably we ended up with quite a selected population, just because of the inclusion and the exclusion criteria that we had to apply. And the regulators were quite clear about who we shouldn't be putting on the drugs. And I think by the time you've excluded all the potential adverse consequences of using methylphenidate, we probably have ended up with a group of patients who were relatively fit compared to the general run-of-the-mill palliative care population, I would say. So I think that that is a limitation with regards to the generalizability of our result.

Shannon Westin: How did you measure fatigue in this study? What was the mechanism for that objective?

Dr. Patrick Stone: It's a subjective rating scale. We use a very well-established and well-validated measurement instrument. It's the Functional Assessment of Chronic Illness Therapy FACIT-F which is the fatigue subscale of their anemia subscale, which is a 13-item questionnaire, very well validated and widely used in lots of previous studies. Higher scores represent better quality of life and, therefore, lower levels of fatigue. So that's the scale that we used.

Shannon Westin: Got it. So let's get to it. How well did methylphenidate work to impact fatigue compared to placebo? And were there any groups that seemed to have a bigger impact?

Dr. Patrick Stone: Well, the bottom line, of course, is that at six weeks, plus or minus two weeks, there was no statistically significant benefit for methylphenidate over placebo. There was a two-point improvement in fatigue scores, but it wasn't statistically significant. And two points on the FACIT-F did not reach our predetermined five-point difference that we regarded as representing a minimally clinically important difference. We looked at lots of secondary fatigue endpoints. We measured fatigue every week over the whole course of the study. And actually, at weeks 2, 3, 4, 5, and 6, there was indeed a statistically, nominally statistically significant difference in fatigue scores. But I really would not want anybody to read anything over much into that finding because it was not a pre-stated hypothesis of our study. It wasn't a pre-stated endpoint, it was a secondary outcome. And moreover, even if this was regarded as a statistically significant finding, and as I say, it was only nominally statistically significant finding, the magnitude of the change was still not sufficiently large that I think it would want to influence your clinical decision making.

With other groups just to say, we did look specifically at whether patients with the most severe fatigue would experience benefit over and above other patients, because in a previous study, that looked at modafinil, an agent that promotes vigilance, although the overall finding was neutral in a subgroup of patients with the most severe fatigue, modafinil seemed to work. So we thought we better check in this study whether patients with the most severe fatigue had a differential benefit. But we found no such effect. We found no difference in patients who were on or off treatment or indeed among the patients who scored highest with the depression subscale on the hospital anxiety and depression scale. None of these subgroups showed any benefit over placebo.

Shannon Westin: How did patients tolerate methylphenidate? Was it tolerable?

Dr. Patrick Stone: That was the thing I think that I was most relieved about. I am a cautious and anxious investigator, and the last thing I wanted to do was to put palliative care patients at risk by giving them a drug which might cause some harm. So I was very relieved when we analyzed the results to confirm that methylphenidate was very well tolerated. There was no real pattern of evidence for any increase in adverse effects over placebo. In fact, when we looked at just people who self-reported severe adverse effects, we found a higher rate in the placebo group than in the methylphenidate group in fact. And in terms of serious adverse events, there were 25 serious adverse events in both groups, so there was, again, no pattern that suggested methylphenidate was causing harm. So, yes, it was well tolerated, but did not result in a clinically important improvement in fatigue.

Shannon Westin: Were you surprised by the results?

Dr. Patrick Stone: I honestly went into this with an open mind. I didn't come in with a real fixed agenda that I want to prove that this thing works. In fact, although methylphenidate was being used by some of my colleagues around the country and I know it's used by some colleagues internationally, personally I was not using it because I didn't feel the evidence was strong enough to justify using it. So I was waiting for the results of my own trial before making my decision. And I don't plan now to be using it on the basis of the results of the study.

Shannon Westin: Sounds pretty definitive. It's always frustrating, and I know our patients, when we tell them to exercise when they're exhausted, they're like, "Are you kidding me?" Right? So it would be wonderful if there is like the perfect pill that we can give them. It's certainly disappointing. What do you think we should be exploring next for the resolution of fatigue in this patient population?

Dr. Patrick Stone: Well, I think one thing. Going back to your very first question to me about defining fatigue, I think one problem is we don't really have a mechanistic understanding of what we're talking about here necessarily with cancer related fatigue. And it's a bit of an umbrella term, I suspect, for a lot of different things, and may have a common endpoint in terms of the symptom. But maybe if we could better define, if you like, for want of a better word, the phenotype of fatigue, it may be that we could actually target a treatment in certain subgroups of patients that may be of more benefit. So maybe some greater basic science pinpointing what is causing fatigue, so that we can design the treatments, rather than just try repurposing existing drugs on the off chance that they work. And the other thing is okay, maybe we can't pinpoint a particular cause, we think it's multi factorial. If we think it's multifactorial, then perhaps we ought to be using a multimodal treatment approach and maybe it's actually exercise, psychological therapies, and diet, plus or minus a drug, and that's the approach if we can't pinpoint a specific cause.

Shannon Westin: I love the idea of incorporating the translational work to really try to understand the etiology better and then use something more targeted. It's that version of precision medicine but for palliative care as well. I really like that.

Well, this has been awesome. Thank you so much, Dr. Stone. I think that your insight is so much appreciated, and thank you for putting together this definitive work to help us treat our patients better every day. I really appreciate the time you took.

Dr. Patrick Stone: Thank you very much.

Shannon Westin: You're so welcome.

And thank you to our listeners. This has been methylphenidate versus placebo for treating fatigue in people with advanced cancer, randomized, double-blind, multicenter, placebo-controlled clinical trial. And again, this is a dual publication in the JCO as well as a presentation at the European Association of Palliative Care Congress on 5/17/24. And we are so thrilled that you could join JCO After Hours and we hope you will check out our other offerings wherever you get your podcasts. Have an awesome day.

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Methylphenidate for Fatigue in Advanced Cancer

Journal of Clinical Oncology (JCO) Podcast

Methylphenidate for Fatigue in Advanced Cancer