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Immune Checkpoint Inhibitors: Podcast with Laura Petrillo


Immune Checkpoint Inhibitors.   They are revolutionary and transforming cancer care.  They shrink tumors and extend lives.  Plus they have a better side effect profile than traditional therapies for conditions like metastatic lung cancer, so when those with really poor performance status can't tolerate traditional chemotherapy, immune checkpoint inhibitors are an attractive option.  But should they be?

We talk on today's podcast with Laura Petrillo, a palliative medicine clinician and investigator at Massachusetts General Hospital and Harvard Medical School.  Laura was the first author of a paper published in Cancer titled "Performance Status and End-Of-Life Care Among Adults With Non-Small Cell Lung Cancer Receiving Immune Checkpoint Inhibitors."

In this study, Laura looked at 237 patients with advanced non-small cell lung cancer who initiated immune checkpoint inhibitors from 2015 to 2017.  She found that those with impaired performance status had significantly shorter survival after treatment with these medications that those with a bettter performance status.  They also receive immune checkpoint inhibitors near death more often than those with better performance status, and they found that those recieving immune checkpoint inhibitors near the end of life had lower hospice use and an increased risk of death in the hospital.

Along with how we should think about the findings of this study, we talk about common side effects of immune checkpoint inhitors that geriatricians and palliative care clinicians should know about, the cost of theses medications, and the differences with different types of cancer treatments like "targeted therapies".

by: @ewidera


  


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TRANSCRIPT

Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith in home quarantine ... well, I'm not actually in home quarantine. I guess I'm in ...

Eric: You are social distancing yourself.

Alex: I'm social distancing, I'm ... what do we call it? It's not lockdown.

Laura: Shelter in place.

Alex: Yeah, I'm in shelter in place, that's what I am.

Eric: And this is going to come out a little while from our recording - this is March 18 - we are still kind of in the middle of the pandemic. Hopefully going to prevent the surge, we'll see what happens when we actually get this published out, but we have a special guest with us today.

Alex: So we have Laura Petrillo, who is a Palliative Medicine Investigator at Massachusetts General Hospital and Harvard Medical School, and Laura's been on our podcast previously when she was at UCSF as a palliative care fellow, and then as a research fellow. Welcome back, Laura.

Laura: Thanks so much for having me guys, great to be here.

Eric: So we're going to be talking about a really important topic in both palliative care and in geriatrics. It's immune checkpoint inhibitors. We're going to learn a little bit about them, but importantly we're also going to talk about some of the outcomes that Laura has done some great research on with an article that was recently published in Cancer titled Performance Status in End of Life Care Amongst Adults with Non-Small Cell Lung Cancer Receiving These Immune Checkpoint Inhibitors. We'll have a link to the article on our show notes. But before we dive in the article, we always ask for a song request. You got a song request for Alex?

Laura: Yeah, actually. I was thinking about Radiohead, No Surprises.

Alex: Okay. And this is got the most depressing lyrics I have ever sung on the GeriPal Podcast. Can you share with us why you chose this song?

Laura: I mean, I think part of what we'll talk about eventually is just that it's helpful to know what's coming with any therapy that you embark on, and so one thing that I think hopefully this paper and other kind of real world evidence will start to show is that there are some unanticipated kind of risks, or burdens to treatment. And so, in any good kind of informed consent, risks/benefits conversation, there shouldn't be any surprises.

Alex: Ah, no surprises. Okay.

Laura: ... No surprises. Yeah. It was not quite as dark as the lyrics would sort of suggest.

Alex: Great. Here we go.

Alex: (singing)

Eric: I miss you in my office, Alex. I can't control your mix here.

Eric: I promise I won't actually insert the real Radiohead version. [laughter] So Laura, immune checkpoint inhibitors. How on earth did you get interested in this subject?

Laura: So, immunotherapy, which is just kind of the whole class of medications that use the immune system to fight cancer is a kind of new paradigm of cancer treatment, incredibly important, transforming the landscape for so many different types of cancer. And so just as a palliative care clinician, currently I mostly care for people who have cancer, and just seeing people live longer, have really different outcomes with immunotherapy than with traditional chemotherapy. And yet, sort of I also noticed that there were differences in some kind of end of life experiences that people were having and wanted to just see what we could see in the data, and explore a little bit about what is happening for people who are not typically represented in clinical trials.

Eric: And could I ask you, when you embarked on this, what were you seeing kind of boots on the ground as far as any concerns or differences?

Laura: Yeah, so people who may be familiar with immune checkpoint inhibitors and immunotherapy from seeing it in the news, Jimmy Carter getting immunotherapy for his cancer and having a wonderful response, and others, and a lot of things in the media, just sort of these incredible stories of people having good responses to immunotherapy. But one of the phrases that was sort of bouncing around clinically was, "No one dies without immunotherapy," and that was because, in contrast to chemotherapy, which, cytotoxic chemotherapy, which can be so toxic with so many side effects at the end of life. When you're thinking about risk and benefits and kind of framing those conversations, there are these really clear tradeoffs between feeling worse with the hope of gaining some more time, versus focusing on quality of life, and I think that when these agents first started to come out with some incredibly hopeful outcomes for a subset of patients, and in certain types of cancers, there was the feeling that, oh, they're better tolerated.

Laura: They have a whole range of bananas side effects which we can talk about separately. But at the outset they seem like they're better tolerated in general, and so the feeling is kind of why not? If someone is otherwise either not able to to receive chemotherapy, they've already received chemotherapy, here's something that is kind of better tolerated. What is the harm in trying one of these potentially a miracle agents for someone who would otherwise be transitioning to hospice?

Laura: And so, immune checkpoint inhibitors are in sort of ... there are different indications across different cancer types. They're most widely used in melanoma, lung cancer, head and neck, renal cell cancer. There are a lot of ... they're a handful of cancers, but they're varying in terms of how successful they are. They're very successful in melanoma and lung cancer, they've been helpful and widely used. So when they were first approved for lung cancer though, they were approved in that second line setting, so previously treated patients, and I think that that affected that attitude about trying them prior to making a transition to comfort focused care.

Alex: Mm-hmm (affirmative). Can we, taking a step back, can you describe for our audience who, some of whom may have heard of immune checkpoint inhibitors or immunotherapy, some of whom may not. What is an immune checkpoint inhibitor in sort of really lay terms, and what are some examples of drug names they might be familiar with?

Laura: Absolutely. So, in general terms, the way that immunotherapy works is trying to get the immune system to be activated to fight cancer. And so, in general when the immune system sees any type of invader, like a bacteria or a virus, it's activated to recognize not self. But cancer cells typically sort of shut that off the same way that our own self cells shut that response off. And so, immune checkpoint inhibitors inhibit that inhibition of the immune system. So they say, "Immune system, come on over, attack the cancer cell," because that kind of little shield is no longer up to protect the cancer cells. So they sort of, they activate that ... they inhibit the pathway that is inhibiting the immune response. And so that is partly why we get those really crazy immune related adverse events, the kind of side effects of checkpoint inhibitors, because the immune system is activated in a nonspecific way, and then can ... not entirely nonspecific, but the immune system is activated and then can attack other tissues in the body.

Alex: Mm-hmm (affirmative).

Eric: Can you tell us some of the common side effects that we should kind of know about in both geriatrics and palliative care?

Laura: Yeah, absolutely. So, interestingly the most common side effects are very nonspecific. So they're fatigue, nausea. But then there are very important side effects like pneumonitis, which is inflammation in the lungs, obviously, and can cause serious respiratory problems; colitis, so attacking the gut cells and causing bloody diarrhea; and rash is common. But then there are these even more kind of toxic side effects like myocarditis, which can have a high fatality rate. So most of the fatalities from immune checkpoint inhibitors are from kind of some of the more severe immune related adverse events like myocarditis and pneumonitis. There are some other wild ones. There are neuro side effects that can attack the neuromuscular system, and so can cause side effects that can be paralyzing. And so there's, and transverse myelitis. I've seen a lot of kind of crazy things.

Laura: And basically any system in the immune system can be ... any system in the body, sorry, not in the immune system. Any system in the body can be attacked and cause side effects that sometimes will mimic known autoimmune diseases but sometimes are entirely new phenomena, and we're actively learning about them now kind of in real time with patients. There are some that were observed in clinical trials, but there are certainly more that are becoming more clear as they move into primetime.

Alex: And what are some of the common medications or drugs, names of these immune checkpoint inhibitors that our audience might be familiar with?

Laura: Yeah, absolutely. So, Pembrolizumab is one that's used commonly in lung cancer that we will talk about, often used in combination with platinum doublet chemotherapy. And then the Nivolumab is another one, Ipilimumab. So you might hear Ipi and Nivo. They have these cute little short named, Ipi, Nivo, Pembro.

Eric: That's great, because I never know how to actually pronounce these.

Laura: Yeah.

Alex: It ends in mab, that's the key.

Laura: It does, but that's not a ... that's not specific. There are others...

Alex: There are other drugs that end in mab that are not immune checkpoint inhibitors.

Laura: Yeah. Yeah. But the ones you'll see the most often are Nivolumab, Pembrolizumab, Ipilimumab, Atezolizumab, yeah. Those are some of them...

Alex: Those are the generic names. What are the, do you know the brand names for these just in case our audience may have heard of some of those?

Laura: ... Yeah. Yervoy, Opdivo, and Keytruda.

Alex: Keytruda.

Eric: Keytruda, the commercials for Keytruda.

Laura: Yeah, exactly.

Eric: I think all the mabs are monoclonal antibodies, and then-

Laura: That is true.

Eric: ... Yeah, and then you kind of go from there.

Laura: Yes. But not, I guess not all mabs are checkpoint inhibitors. So the checkpoint inhibitors are either the PD1 inhibitors, or CTLA4. So they're both working on that pathway that is helping the cancer hide from the immune system, or stopping the cancer from hiding from the immune system.

Alex: Mm-hmm (affirmative). That's great. Anything else by way of background that we should know about immune checkpoint inhibitors?

Laura: Yeah, I mean I think that the main thing to know is just that in settings like melanoma for example, they are just having such a drastic effect on survival. So metastatic melanoma, survival after a diagnosis would be kind of less than a year. Previously when we were sort of in the pre immunotherapy era ... there had been IL2, which actually also worked by affecting the immune system, but it was not very well tolerated so it wasn't used a lot. But, when immune checkpoint inhibitors came along, we now have patients living years. And for some oncologists will even use the word cure for people with metastatic melanoma. So it is-

Alex: Wow.

Laura: ... a huge difference, and it doesn't ... those kind of results don't happen for every patient who receives these drugs, but the hope of that kind of long-term, I use the word kind of durable response as opposed to cure because I think that we're still sort of learning. But there's just that hope that that will be the miracle drug. And I kind of, I'm on some Facebook groups of patients talking about these drugs and they're so excited and so thrilled with the kind of long-term response that they've had, and I've had plenty of patients, too, who just are living. They didn't expect to live to their daughter's high school graduation, and they're living to college graduation. And it's just, they don't even know ... that's just so incredible.

Laura: There's a huge amount of optimism, and I think that it is very much warranted, and these are really exciting drugs that are transforming the landscape, and combinations are coming out, and ways to make them even more effective, and other ways to use the immune system to fight cancer that are different kinds of immunotherapy that are ... the hype and enthusiasm, I think, is really, is warranted. I'm a believer, but I think that just from the supportive care point of view, there's a lot to understand, and there's also a lot to understand for kind of all adults, not just the ones who are in clinical trials. So that's why we set out to do this study.

Eric: Yeah. So, I mean it's a good segue to ... we're seeing a lot of people get this, even people with exceptionally poor performance status, and how do they actually respond to these new treatments? Do you want to tell us a little bit about kind of what you did in this study, kind of sum it up as far as who was included and kind of the methods of it?

Laura: Sure, absolutely. So, in clinical trials, as you know, they'll usually limit people who, limit participants to people who don't have a lot of comorbidities and who have good performance status, which is the oncology lingo for functional status, who just are not limited in their activities of daily living or in their amount of activity in any way. And so it's not an entirely representative population, particularly of previously treated patients with cancer. And so, and in our study we did kind of a real world study, and included all people who had received immune checkpoint inhibitors over a period of time, over about two years, and just looked at their survival outcome. So the length of time from the time that they received the checkpoint inhibitor. And then we also looked at some other kind of end of life healthcare utilization outcomes. We included people who had all types of, every performance status level, as opposed to the clinical trials, which are limited to performance status zero or one. Performance status for living people goes all the way up to four, and so usually people with worse performance status, performance status two, three, four, certainly four, but two, three even, are limited in receiving chemotherapy in general-

Alex: Can you remind us what performance status of two or three or four would look like?

Laura: ... Yeah, absolutely. So, performance status two is no longer working, up and about greater than 50% of the day. I mean, these are kind of how these things are graded, and they're clinically determined by the treating clinician, and there's huge kind of variability person to person, and between patients, and clinicians, and how they gauge performance status. And I would say in general, clinicians probably round down a bit with performance status levels to justify treating patients, but-

Alex: So round down meaning like closer to zero, end of the spectrum-

Laura: ... Giving people the benefit of the doubt.

Alex: Mm-hmm (affirmative).

Laura: And I think it's, I don't think, I definitely assign no ill will to that. It's kind of giving people the chance to get treatments.

Alex: So performance status of two, you're saying, would not be eligible for a clinical trial, and you just described that as somebody who's, if they are working, if they're working age, if they're ... they might not be working anymore.

Laura: They wouldn't-

Alex: Due to their illness, and they might still be getting up and about and taking care of themselves, doing their activities and day to day living, and-

Laura: Yeah...and it'd be no work activities, able to carry about light work. I'm sorry, no, the light work was one, and then two is self care but no work activities.

Eric: And for those who want to look at the ECOG, we'll put up a ECOG up on our website, too, so you can see the difference between one through four. Five is the simplest one, which is dead. I've never actually seen somebody code as a five, but I guess people do.

Laura: Yeah, it's not usually at the top of your mind ...

Eric: And you looked at the difference between performance status on the ECOG of zero one, versus greater than two, is that right?

Laura: Yeah, and we did subanalyses of ECOG two only, because there's a lot of interest in that particular group. I think that people feel less strongly about three or four, treating them. I think you can make a stronger case for kind of comfort focused measures in general, but PS2, in a place where you might be worried about giving chemo, but thinking about another drug that could be better tolerated, that's sort of ... you really want to think about risks and benefits carefully, and of course preferences, so.

Alex: Mm-hmm (affirmative). Two doesn't sound ... I mean, I'm just trying to convert these into patients I've seen or disability scales I'm more familiar with, so geriatric side of things, or a palliative performance scale, two doesn't actually sound all that disabled, quite frankly.

Laura: Right, and I think that working is a hard thing to use. There's plenty of reasons not to be working, but this is assuming that that activity and limitation is due to cancer and cancer symptoms.

Alex: Mm-hmm (affirmative).

Laura: But it is, it's the main thing that we, that oncologists use, and that is used in these clinical trials, so that's why we ... that was what we included. And we wanted to include this group that comprises a large portion of people who are, who have metastatic cancer, and who are being excluded, and who are receiving these drugs and kind of receiving counseling from their oncology team, potentially, about what their survival might be like. But that is kind of gleaned from a different group.

Alex: It looks like in your study you had 35% of patients at a performance status of two or greater.

Laura: Right.

Alex: Would not have been enrolled in a clinical trial.

Laura: Mm-hmm (affirmative). Exactly, yeah. Yeah.

Eric: ... And about five percent with an ECOG of three, and these people can ... are capable of limited self care, but mainly confined to bed or chair for more than 50% of their day. So about one in 20 are receiving this in your sample, so again, five percent.

Laura: Yeah, a small, small amount. And I think there is some survival bias present here, because you can think that people who kind of got through their first round of chemotherapy or first line or two of therapy, and who haven't made an option to kind of transition to comfort-focused care, there are certain people who would kind of make that transition prior to thinking about another line. So that is a consideration that there's a bit of survival bias in the previously treated group.

Eric: What did you find?

Laura: So, when we looked at survival according to performance status, one thing just ... one more kind of side note before we go there is just that it can be hard to tell the difference between kind of the prognostic and predictive significance of performance status or functional status generally. Because if you think, you take all comers who have these different levels of performance status and you follow their survival afterwards ... similar thing happens with age. People are just going to live less long. I mean these are predictive of ... these are independently predictive of survival, right?

Laura: So doing that on its own, just saying that the survival ... what we found, ultimately, was that they live less long. Punchline, they live less long, and I can give you the numbers in a second. But it's ... what I think we need to do is know what we were unable to do, which would've been great to do, but we are unable to do, because of the way that this is a retrospective cohort study, is be able to say among people who had an ECOG performance status of two, if they had a checkpoint inhibitor versus didn't have a checkpoint inhibitor, how long would they live? And that would give us some kind of predictive significance, insight into the predictive value of that, of the performance status in this outcome. But, we don't have that ability. We didn't do a randomized trial. We did a retrospective study. So, we know that it has prognostic significance to have a worse performance status.

Laura: And so what we found was that among people with a performance status of zero or one, the median overall survival, so if you took the curve of patients, the middle of that curve was 14.3 months in the performance status zero one group, and in the performance status two or greater group it was four and a half months. So really different. If you look at the Kaplan Meier curves, it just is a really different shape, drops off a lot more steeply from the PS2 or greater group.

Alex: Mm-hmm (affirmative). So I guess the point here is that checkpoint inhibitors are not some miracle drug for patients who are, have some degree of disability and non-small cell lung cancer.

Laura: So I think that one thing to just keep in mind is we don't know what would've happened. We don't have the counterfactual what would've happened with these patients if they hadn't received it, and we also, the median overall survival is the median, and so there are going to ... there are some patients who lived awhile. And I think that one thing that is, another thing that's important to note, there's so many kind of caveats and backgrounds to give here, but for some of the checkpoint inhibitors, there are even ... for all checkpoint inhibitors, whether or not checkpoint inhibitors will be successful at least in lung cancer can be predicted somewhat by the presence of the receptor, so PDL1, the receptor for these, that indicates that these drugs, that the tumor might be sensitive. And so that predated, or this study kind of predated the widespread use of the PDL1 test. So, it may be that there's a subgroup that does well here that might be indicated by having the presence of PDL1, and it may be that without these, people did worse.

Laura: So, what we can say clearly is that people with worse performance status don't exactly do as well as the people with performance status zero or one. So you can't just extrapolate those clinical trial results when you're having a conversation with an adult with functional impairment.

Alex: Mm-hmm (affirmative).

Eric: Well I'm going to push you, Laura. Having done this study and getting the results that you have, does it inform what we should do maybe differently in either geriatrics or palliative care when we're caring for individuals who may be thinking about starting these medications, or are on them?

Laura: So I think we need to move to the second part of the findings, because I think that that is an important piece to inform that conversation.

Laura: So, part of what I was curious about for my clinical experience was if proceeding with this idea of no one dies without a checkpoint inhibitor, does that ... is there an opportunity cost in terms of the conversations that people are having about end of life, their preparation for end of life, how they're kind of receiving their care, and whether they've made transitions in how that care is being delivered. And so we looked at the ... we first looked at kind of the proportion of patients who were receiving checkpoint inhibitors very close to the end of life, because just with the precedent of kind of chemotherapy in the last two weeks of life and in the last month of life being a real indicator of kind of how utilization of healthcare at the end of life, we know that that correlates with increased death in the hospital, increased hospitalization, decreased kind of hospice and comfort-focused care. So we looked to see if the same was true here, if people who got checkpoint inhibitors close to the end of life also had differences in the end of life are that they received, if this sort of hail Mary approach to kind of end of life treatment forestalls any of that type of care that we ... not every person believes that that's the optimal type of care. But if it did, in general, delay that type of end of life care.

Laura: And we did. We found that patients were kind of less likely to receive hospice care, that they were more likely to die in the hospital, and they were more likely to have been hospitalized in the last month of life than people who didn't receive checkpoint inhibitors in the last month of life. So it was similar to chemotherapy, something that affected the end of life outcome. And I mean I think that you can ... it makes sense. It's logical. People are receiving checkpoint inhibitors, they may have one of these crazy side effects, or you might have heightened suspicion for one of those side effects, and so something that might be the symptom of cancer progressing, or just a cancer related symptom, might in a time where we're trying to understand and learn more about these immune-related adverse events might prompt admission to a greater degree. So people were hospitalized more often. They in fact did experience these side effects, and I think that that was the reason for some of these hospitalizations and just, the other thing to know is that it takes a little while to have a response. You have to kind of get the immune system going, and for people whose cancer was on a timeline to be close to the end of life, and you don't necessarily have that time for the effect to work.

Laura: So you never really know when you see a patient in front of you how long they have, but functional status is one of our best clues, right? So you think we've got some patients who have kind of worsened functional status, and they may be close to the end of life, and it's not totally benign necessarily to give them a checkpoint inhibitor only in the sense that it might delay some of the kind of transitions in care that would help people to have those ... avoid burdensome end of life interventions and have care that's more focused on quality of life at the end of life.

Alex: Mm-hmm (affirmative). How expensive are these?

Laura: Expensive. Yeah.

Alex: Yeah. We're talking-

Laura: Tens of thousands of dollars.

Alex: ... tens of thousands of dollars...

Laura: Yeah.

Alex: And typically given as an infusion once every ...

Laura: Every two to three weeks.

Alex: Two to three weeks, yeah. So incredibly expensive medications. It'd be hard for a hospice to justify paying for one of these medications because it would cost them so much money it would mean they had to make tradeoffs in terms of other services that they could provide for patients.

Laura: Yeah, and I think there are other settings where ... my general interest is kind of novel cancer therapies and kind of supportive care and palliative care for them, and particularly helping people sort of understand the risks and benefits, and to understand their prognosis in the studying of these. So I think a lot about targeted therapies as well, and people who have cancer that's kind of addicted to an oncogene, and in those settings actually, some of the oral targeted therapies can be actually really palliating, and kind of the idea of continuing them into hospice makes so much sense.

Alex: And those are pennies, like morphine. Those are really cheap.

Laura: No, they're expensive too, but I actually see a different case for those because actually continuing them even beyond progression can be palliating, and can alleviate symptoms, whereas here you're kind of going for this ... it's like a gamble. There's not a guarantee that you're going to have a response. You have maybe, I don't know, 20 or 40% chance of having a response at all, and then if you do, it's hope for this kind of long-term response. And so the thought had been, give it a shot, see if it works. I mean, there are very incredible stories of people coming into the hospital. One of our oncologists has a story about a person coming in with kind of metastatic melanoma with leptomeningeal disease, and getting a dose or two of checkpoint inhibitors and walking out.

Alex: Wow.

Laura: I mean there's just ... really incredibly, kind of rising from the dead sort of stories about these drugs, and I think that if, particularly if clinicians have seen them, they're really hesitant to withhold anything like that. Patients have heard about it in the news, and they're interested in it as well. I mean, I think that ... I totally understand where the interest comes from, but I think that what is important is to have full knowledge of these potential kind of tradeoffs between the potential benefit, giving that roll of the dice to see if you have that effect versus kind of what other things could be moving towards preparing for end of life.

Alex: I have two more questions. The first is, you mentioned targeted therapies and distinguished them from immunotherapy, immune checkpoint inhibitors. Could you just give us sort of a lay understanding of what targeted therapies are, and how that's different from immunotherapy?

Laura: Yeah. Sometimes, and this is a caveat because there's so much lingo. Sometimes people will say that immunotherapy and immune checkpoint inhibitors are targeted, which is very confusing because they are targeting the PD1 pathway, and the kind of immunoresponse, but in general targeted therapy seems to be used more for drugs that specifically target overexpressed oncogenes, or oncogenes that are driving cancer growth. So examples would be kind of BRAF and melanoma, or EGFR, [inaudible 00:33:09] and other oncogenes in lung cancer. So this is where there's just a clear gene that has been mutated or copy number kind of increased, or rearranged, so that they are, that gene is really driving the tumor growth. And then the drugs that target that just shut it down, so they work in a different way. They're really specific, and that's why they're called targeted. They're really specific for their target, and they do have side effects, although kind of ... particularly in lung cancer is what I'm most familiar with. Some of the newer generation are better tolerated. But they just, they're oral drugs, they ... still expensive, still fancy, and it's just, it's different.

Laura: Immunotherapy, the class of immunotherapy includes immune checkpoint inhibitors, but also includes things like card key therapy, and TILs, tumor infiltrating lymphocytes. So there's just a different class of cancer treatment.

Alex: Mm-hmm (affirmative).

Eric: Laura, can I ask you, one last question from my end, I think Alex said he had one more question. Now you did this in an academic medical center, I can only guess which one, which probably also had a lot of access to palliative care for these folks.

Laura: Yes.

Eric: Do you suspect that maybe if you went into other ... again, it's so hard because it's a very specific type of academic medical center that a lot of people go to from other places, do you suspect if you looked elsewhere you'd either see worse numbers as far as hospice use and those types of things? Or better numbers? How should we think about generalizability of your foundings that you saw here?

Laura: It's a great question. So one thing that sort of tips off what our end of life experience is like here is just the hospice rate. I mean there was just, compared to the national average, we had a really high rate of just hospice referral in general here.

Eric: I'm shocked. Really high.

Laura: Really high. Really, really high. We do have a lot of palliative care here, and a lot of outpatient palliative care, early integrated.

Alex: Early integrated.

Eric: 71% of all of the patients received hospice services. 68 for those with performance status between zero one, and 55 for greater than two. Or, 75% for greater than two. So really not ...

Laura: Yeah. And yet we saw differences. So I mean, I think that they're ... and there wasn't really differences in, I couldn't look at receipt of palliative care, actually, because we have so many palliative care studies here that people were getting palliative care through other studies, so it wasn't necessary that they were referred by their clinicians independently, so I couldn't look at that as a factor in some of these end of life outcomes necessarily. I did look at clinician behavior, because that is one of the hugely impactful things for a hospice referral. But no, I mean I think that certainly the performance status findings, I think, are relevant in different places, just thinking about, just have pause when you're thinking about counseling a patient who has a functional status limitation. In recommending or at least feeling like there's limited harm because they're better tolerated, just thinking about the range of potential drawbacks I think would be important.

Laura: And then in terms of the end of life outcomes, I think that there is likely to be similar patterns of higher utilization given the kind of side effects, the just difference in overall mode of care, the insurance issue. I think the insurance thing is kind of one of the clearest things that probably drove this kind of needing to continue with kind of our standard gear of medical care when somebody is not on hospice, if you're receiving these type of drugs, which would land someone in the hospital with any type of change in their symptoms. So, I think that all of those things are likely happening elsewhere. And I'll just say too, we presented this work at the ASCO Supportive Care Symposium last year, and so many people came up and were kind of taking pictures and sending it to their colleagues being like, "Oh, yeah. I have seen this, I've been worried about this, I've been thinking about, I want to be able to talk with people. I know that it's different." They've seen that their patients are not necessarily mimicking the clinical trials, and they're making differences in the kind of end of life care they're receiving. So that was pretty validating, just to know that at least anecdotally people felt like they had a shared experience.

Eric: Alex did you have a last question?

Alex: No, that was my last question about the implications for clinical discussions. That's great.

Eric: Well, Laura, I want to thank you for joining us today.

Laura: Thanks so much for having me.

Eric: I really appreciate it, again, given everything that's going on here. How about we end with a little bit more of that depressing song, Alex?

Laura: The depressing song gives it away, right? We've been able to talk about a non-Covid topic for this amount of time...

Alex: It's true that at least at this time the majority of patients were taken care of. In fact, all of the patients are, palliative care service do not have Covid. That may change over time, and may have changed by the time this podcast comes out. But, we'll go back to this song that has the lyric, "I'll take a quiet life, a handshake of carbon monoxide." [laughter] ...think of just how grim that lyric is.

Alex: (singing)

Laura: Very nice.

Eric: Laura, a very big thank you for joining us today, it's always great to see your face and hear you. Alex, it's good to see you greater than six feet away. And to all of our listeners, thank you for joining us today, and a big thank you to Archstone Foundation.

Alex: Thank you Laura.

Laura: Thanks guys, great to see you.

Eric: Bye everybody.

Laura: Take care.

Alex: Bye.



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