Compassion and Compassionate Use, by David J. Einstein
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One oncologist provides his take on responding to "compassionate use" requests
TRANSCRIPT
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
[DR. LIDIA SCHAPIRA]
Welcome to JCO\'s Cancer Stories-- The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.
[GREG GUTHRIE]
"Compassion and Compassionate Use," by David J. Einstein. The email came down to this. This patient is running out of options, and he and his family are starting to think outside the box. Two months prior, the sender was my co-fellow. Now, after a blissful vacation month entirely unplugged from oncology, he and I were junior attending physicians, launched into the dual frontlines of inpatient and outpatient oncology.
He was staffing the consult service, I the inpatient oncology service, both of us simultaneously trying to keep our backburner outpatient clinics and research projects from boiling over. He was letting me know about my newest admission, a patient with advanced choriocarcinoma, which was ostensibly within my area of expertise of genitourinary cancers.
During years of residency training, we had learned to eyeball patients and differentiate sick from not sick-- or really, those who might be imminently dying from those who were OK for now. As oncology fellows, we recognized a new group-- the patients who seemed to be imminently dying on paper, but in person looked amazingly normal. The patient referred to in the email was such a patient-- an energetic engineer in his 50\'s, with a more than slight Boston accent, despite his years in California and Texas, and plenty of Red Sox gear to match.
On paper, he was in dire shape, with treatment-resistant advanced cancer and increasing toxicities of treatment. The patient and this family had taken on his disease with a battle mentality that works for some and makes others cringe. After multiple rounds of chemotherapy, resections, and radiation treatments failed to cure his disease, he moved on to the high-dose chemotherapy with autologous stem cell rescue that is the standard of care in this setting. If some chemotherapy is good, more is better.
However, he eventually exhausted his supply of stem cells, still without having achieved remission. Time to think outside the box, turning to his identical twin brother as a source of new stem cells. The patient proceeded to a last-ditch effort at high-dose chemotherapy, this time with syngeneic transplantation. It worked, for approximately three months.
Despite the most intensive efforts, his disease kept bouncing back. At this point, it was clear that chemotherapy would only transiently suppress his cancer, but not cure it. Meanwhile, his treatments left him with hearing loss severe enough to require hearing aids, poor kidney function, foot numbness, and bone marrow that, even on imaging, looked exhausted, plus prolonged cytopenias to prove it. What could be done?
This patient and his family had crossed the country in search of an outside the box treatment that might offer him the benefit that stand treatments had not. We are used to patients looking online for new diets and complementary medicines. We understand that this is a way to seek an active part in their care, when they otherwise feel like passive recipients.
The patient and his family had gone further, identifying a clinical trial available at our hospital that they desperately wanted to join. But the trial was in a different tumor type. And moreover, he would not be a candidate for any of the trial, given his accumulated treatment-related toxicities.
Undaunted, his sister found an online poster from our peer institution across the street, describing a novel compound used to treat a patient with his disease, with the resulting and seemingly miraculous remission. Again, we are accustomed to the patient who brings in the latest online research to an appointment. Sometimes it is not scientifically valid. Sometimes it is valid, but not applicable to the situation. And occasionally, it is both valid and applicable, and actually does result in a treatment change.
As I scrutinized the information the patient\'s sister provided, it actually seemed both possibly valid and applicable. I could find no obvious toxicity that precluded use of this drug. And yet, it was early in testing, far from full approval. "What about compassionate use?" the family asked.
Compassionate use was a term I had only heard spoken of dismissively. We oncologists prided ourselves on always being compassionate, whether we were administering therapies or stopping them. Treating outside of standard care without the structure of a research study is dangerous territory.
But this concept has a popular appeal. Who wouldn\'t want to try anything that could help in a desperate situation? Recently, proponents of so-called "right to try" legislation claimed that the Food and Drug Administration, or FDA, regulation was interfering with patients\' access to experimental therapies outside of trials. The FDA replied that they approved 99% of expanded access requests.
Indeed, compared with the regulatory hurdles I faced from my own institution, I discovered that the FDA was the smallest barrier of all. As I learned, creating a single-patient investigational new drug application for compassionate use was the ultimate in personalized medicine-- a clinical trial created for one person. In fact, it was a desperate hope thrown into the slow-moving and opaque gears of our clinical research regulation, only to be chewed into a million track changes documents and flurries of emails.
I was rapidly assembling a trial protocol to use highly experimental therapy into patients whose disease was bound to cause suffocation or bleeding at any moment. It was a terrifying, anxiety-provoking situation for a physician, patient, and family alike. I felt caught between-- on the one side an eager and aggressive patient who wanted to sign anything, cover any cost, just to have a shot at a miracle, and on the other side, a process purposefully built to be as cautious as possible. I caught myself erupting in frustration, unfairly lashing out at the secretary who emailed me with Institutional Review Board, or IRB, edits on an informed consent form that the patient would never read.
Just as we were getting ready to sign this consent form, the patient\'s disease was making itself more plainly visible in the form of a bleeding superficial metastasis. Now, another regulatory catastrophe-- between the bleeding lesion and the need for radiation, he was ineligible for the trial because of the strictly-worded inclusion criteria used in the rigid old protocol. Time for yet another urgent amendment pleading for the IRB not to hold me to the rules that I myself had provided.
When, after months of work, the patient received a single dose of the study treatment, we all felt like we had climbed Everest. All along the way, I tried to frame this as a victory in and of itself, hoping he would die feeling he had tried everything. But he, of course, wanted to live, through sheer will and perseverance. And I\'ll admit, a small portion of me wanted to prove my doubts wrong, to be the junior attending daring enough to try something audacious and land a huge unconventional win.
It was not to be. After many tense clinic appointments and late-night calls during my drive home, our last conversations unfortunately occurred in the intensive care unit. With the rush of the high flu nasal cannula as background white noise, I told the patient that his disease was not even responding to the chemotherapy I had tried a week ago in an ultra last-ditch effort to get him back to the study drug.
I could not pull him back from the edge of that ultimate cliff. Although I had tried hard to have the appropriate discussions with the patient and his family on many occasions, trying to refocus their hopes on spending good time together, freedom from pain and breathlessness, and another day outside the infusion area and the oncology ward, I knew they felt I had failed them, that maybe pushing just a little harder would have made the difference.
One morning, I awoke to an email from the intensive care unit resident, letting me know that the patient had died that night. Thankfully, we had agreed that aggressive interventions in his dying moments would be even less effective than our chemotherapies. And instead, he had received much more effective supportive care. I let out a breath of simultaneous relief and regret.
I knew this moment had been coming, of course. I disagreed with my patient and his family about how to prepare for it. But my team and I had tried to make the patient and his family feel that every effort had been made on his behalf. I felt the failure, not in his inevitable death, but in never arriving at a moment of shared celebration for our combined efforts, when we could say together, even in that intensive care unit room, it was all worth it.
And when I went to contact his wife and sister, I never heard from them again. I certainly do not fault them for not returning my calls or emails during the midst of intense grief. Yet I never heard whether they felt that our compassionate use of a single dose of experimental treatment had helped or hurt. He went from being my all-consuming focus to a vanished spirit. And I had to wonder whether the family\'s silence gave me my answer.
The recent right to try legislation cleared the US Senate last year and the House of Representatives in March alone mostly partisan lines. Opponents, including representatives from the American Society of Clinical Oncology, as well as the American Cancer Society, pointed out the value of FDA oversight and the existing pathway for access to experimental therapies outside of clinical trials. Regardless of the fact that this legislation does not affect the institutional barriers I encountered, I do wonder whether it will inspire a growing number of desperate patients to exercise their right to try.
How should oncologists respond? Except in the cases of a drug that seems to have particularly exciting preclinical justification or early clinical data, I suspect most will advise their patients with advanced cancer to stick to more trodden territory, to try accepted anticancer therapies when they are judged to be reasonable and to switch to supportive care alone when the risk seems to outweigh the benefit, individualized to patient preferences. As we continue to chase progress in cancer, Wachter recently wrote, let\'s be sure that we don\'t rob dying patients of a smaller, more subtle miracle: a death with dignity and grace, relatively free from pain and discomfort. But there will always be the patients like mine: unsatisfied to do nothing, as much as we try to reinforce that intensive supportive care is far from nothing.
I recall the words of another oncologist who had seen the patient for a second opinion. These patients with refractory testicular cancer die with the chemo going in, chemotherapy, or perhaps increasingly, experimental drugs. If we are to routinely offer such patients access to experimental drugs outside of clinical trials, then we will need to address several issues in advance.
First, federal and local regulatory burdens will have to be substantially lower. We will need to simplify the process of writing a protocol, obtaining a IRB approval, and amending the protocol as clinical circumstances evolve. As a word of advice, oncologists embarking on such a process should be careful about recycling protocols written for standard trials. In particular, because these protocols are designed around a specific patient, the inclusion and exclusion criteria should be minimal.
Second, directors of clinical trial programs will have to decide whether their operations are capable of diverting resources from standard trials to these urgent and unfunded projects. Finally and most importantly, individual clinicians will have to develop strong end-of-life communication skills to help frame a shared decision-making process properly. And they may even have to make especially difficult decisions about when to exercise a right to deny such requests.
I hope that all of my patients will feel that I have treated them compassionately and with the tools best suited to their situation, whether or not this includes compassionate use of unproven therapies. And I hope that my patient did indeed feel that we left no stone unturned and that he felt some small satisfaction in this.
[DR. LIDIA SCHAPIRA]
Welcome to Cancer Stories. I\'m Lidia Schapira, editorial consultant for the Journal of Clinical Oncology\'s Art of Oncology, and the host for this podcast. My guest today is Dr. David Einstein, a medical oncologist at Beth Israel Deaconess Medical Center in Boston and an instructor at Harvard Medical School. Dr. Einstein is the author of "Compassion and Compassionate Use."
David, welcome to our program.
[DR. DAVID EINSTEIN]
Well, thanks so much for having me. It\'s a real honor.
[DR. LIDIA SCHAPIRA]
It\'s terrific to have you. Tell me a little bit about your writing. Have you always been a writer?
[DR. DAVID EINSTEIN]
Yeah, actually this goes back to my intern year, oddly enough, when I was signing out a patient to the night float intern. And I was telling the story of what had happened that day. And the night float intern told me, wow, that\'s a really interesting story. And that was the first time I had ever thought of translating what I did on a daily basis onto paper. And that was a very moving experience, which I\'m happy to share, as well.
But that sort of got me started about reflecting on patients and key moments in my medical practice. And now, all these years later, and being a first-year attending, I\'m on a similar learning curve. And I wanted to, again, take an opportunity to step back and reflect on what it was that I was doing.
[DR. LIDIA SCHAPIRA]
And can you tell the listeners a little bit of what that reflecting process is like for you?
[DR. DAVID EINSTEIN]
Yeah. So I think that, a lot of times, these things seem to pop up at unexpected times, so on the commute home or the shower in the morning. And it\'s sort of these nagging thoughts that just keep coming into your head. And eventually, they\'ve been bouncing around for long enough that you feel the need to actually put that down on paper and reflect on what it is that your mind\'s trying to work out.
[DR. LIDIA SCHAPIRA]
And do you have a writing group, or is this pretty much a solitary activity for you?
[DR. DAVID EINSTEIN]
I\'d say fairly solitary. But oftentimes, it\'s sparked by discussions with colleagues. And then also, once I\'ve actually put something down on paper, I very much solicit colleagues\' input, just as I would for any kind of difficult medical case or difficult psychosocial case. And so on everything that I\'ve written, I\'ve always tried to circulate it among a couple of trusted colleagues for their input, as well.
[DR. LIDIA SCHAPIRA]
And so if this was, perhaps, sparked by a difficult clinical scenario, can you tell us a little bit about what made this particular case so challenging and difficult for you?
[DR. DAVID EINSTEIN]
Yeah. I think that, early on in elementary school, we\'re sort of taught that stories are conflict and resolution. And the really unique thing about this situation was that there were a variety of conflicts and really very little resolution. And that, I think, was what made it keep recurring in my mind as something that I really felt the need to reflect on.
[DR. LIDIA SCHAPIRA]
Tell us a little bit about this patient and how you were drawn in in his very desperate fight and his wish to have a shot at a miracle.
[DR. DAVID EINSTEIN]
Yeah, so again, this was early on in my attending career. So you\'ve got all sorts of your own anxieties anyway about staffing an inpatient service and keeping an outpatient clinic going and starting up research projects. And as I\'m starting, I hear from my colleague about this very sick gentleman. But I go in to meet him, and he looks like an ordinary guy off the street. And it was sort of hard to reconcile those two things at first.
And he always traveled as a group. He had this whole support team that had been with him through everything. So his wife was always bedside. She was a high school sweetheart. And his sister was always bedside, and she was actually a biotech lawyer. And he was an engineer.
And I think, especially between the lawyer and the engineer, they had a very go-getter attitude. They did their own research. They came up with treatment plans. They really were extremely thoughtful people, and also, in a sense, very aggressive people to have pushed through everything that he had already been through even before I met him.
[DR. LIDIA SCHAPIRA]
And that resonated with you, as well, right, the idea that, here is somebody who has done all of this research and put in this incredible effort. And then what happened?
[DR. DAVID EINSTEIN]
Right. So it\'s not so dissimilar from what we as physicians do, and I very much respected their efforts. They came to us, clearly, after all standard treatments, and even some non-standard treatments, had not gotten the hoped for result of a cure. And that\'s one of the things that makes testis cancer so difficult, of course, is that, we aim for cure so much of the time. And those times where we fail or the disease overwhelms us, that\'s that much harder to prepare for.
And so I started looking over other palliative chemotherapy regimens and the toxicities and the relative benefits and response rates of all of these. And the more I thought about it, the more I thought, what is this a bridge to? What am I trying to get out of any of this?
And with them, I started to explore the ideas of targeted therapy, which we\'ve heard so much about, and immune therapies, which he had actually already tried. And we got to that point where I was saying, there is no treatment, no matter how efficacious, that\'s going to work with what I see in front of me, with all these toxicities. And they processed that.
But they came back, and after doing a little more research, came up with this case report from just across the street, about a patient with a similar disease getting some long-term response out of an experimental drug, which had completed Phase 1 testing. And so they said, how do we get this? And I looked through the traditional routes of trying to get him on trial or trying to get exceptions. And the more I looked, the more I ran into roadblocks.
And eventually, they asked me about this compassionate use concept, which I had heard only vaguely about, and certainly no personal experience with that. And as I started asking around among my colleagues, I found out that, really, very few people have much experience with this, other than one other at our institution. And so it really was sort of reinventing the wheel, as far as treatment protocol.
[DR. LIDIA SCHAPIRA]
It sounds like this gentlemen, if we are to sort of give a title to this scenario, is one of those, as you say, engaging people who is a fighter, but for whom death is really not an option. Am I right in saying that, that they just would not have that conversation with you? They were really searching for something that could be done, an action solution to this problem.
[DR. DAVID EINSTEIN]
Right. They were very intelligent people. They knew that he was in a dire situation. I try to use the word death and dying in my conversations to be as clear as possible. And they weren\'t able to process that and talk about that. But it was very clear that this was not the kind of patient who would feel comfortable going home and focusing on symptoms.
And in a sense, there wasn\'t much to focus on, until the end really came. Because with these diseases, they just progress so rapidly. And so for him, he very clearly was on the side of, I would rather die in a hospital with treatment toxicity, even if none of that stuff helped me, rather than-- if you can\'t tell me that any of these treatments are going to help, then I\'d rather not be here. Which I would say a good 3/4 of my patients are a little bit more in the latter camp.
And there\'s a point at which everyone sort of feels like, let\'s do whatever is in our power to work on the symptoms of your disease and stop assaulting you with therapies that might not help and could certainly hurt. He was very clearly on the polar opposite end of that spectrum. And for him, I think, a little bit of his engineering personality, it was important to think up a new way of treating this disease, and to go for that incredibly slim shot of a long-term remission, however slim that might be.
[DR. LIDIA SCHAPIRA]
That\'s so interesting. So you bring in his profession as an engineer. He was probably a problem-solver. And as you say, at the moment you met, he didn\'t have symptoms, really, to palliate. And he was as prepared as he could be for what was likely going to come next. But you use the word \'compassion\' in your title, and I want to bring you back to this a little bit.
What did you feel in the role as his physician? And I wonder if, as thoughtful as you are in your approach to your patient, if you wondered, if he had a long-term relationship, perhaps, with another physician along the way, or how could you give him what he needed, even if it wasn\'t exactly what he wanted?
[DR. DAVID EINSTEIN]
Mm-hmm, yeah. It\'s really tough coming in at that kind of position, of course. He had a very, very solid relationship with this previous oncologist in a different state, also at a tertiary care academic center. So he was very used to working with that individual and had that trust built up. I\'m meeting him, of course, in the worst possible scenario, when he\'s already gone through everything that we would normally try and even some more off-the-beaten-path treatments.
So it\'s definitely difficult to meet somebody in that position, to gain trust, to build a rapport, to have a long-term relationship to work off of, before you start launching into really difficult end-of-life decision-making, and all the particulars of trying to do what we did, which involves a myriad of details and logistics. And so communicating all of those things, we really had to have this incredibly intense time together to start working on all these things as a shared group.
And I think, all along, I felt that I really wanted to emphasize that we were all on the same team. I didn\'t want him feeling like he had come to me, and that I was in any way shooting down his dreams or not offering anything, from an oncology standpoint. And so time and time again, I really emphasized the fact that, whatever my recommendations are, let\'s make it about what makes sense for you and what makes sense for your disease, that our common enemy here is the cancer. And that whatever happens, that needs to be the focus.
So the focus should not be on the details so much, as how those details get us to the big picture plan. So I think that I really identified with this urge to research and his urge to come up with novel mechanisms. That\'s what we do as oncologists all the time.
But I also had a little bit of trouble getting to understand a guy who was so clearly focused on being in hospital and receiving treatments, even in the situation where I think most of us would feel very uncomfortable with that idea. And so building that understanding took longer, and I think, ultimately, led to a little bit of misunderstanding as things went on.
[DR. LIDIA SCHAPIRA]
As we about the end, first of all, it sounds like, for you, this felt like climbing Everest. And that\'s what you say in your essay, and that you certainly were deeply engaged in an active relationship. And then the treatment doesn\'t work, and he dies. He dies, fortunately, without an aggressive attempt at resuscitation. But then the end leaves you, I think, with a bit of a sour taste, in that there is no final parting with the family or expression of gratitude. Tell us a little bit about how you felt about that and how you\'ve managed to think about it, with a little bit more time.
[DR. DAVID EINSTEIN]
Yeah, so all along this process, there were really just so many hurdles, quite a large team that I was working with. And a lot of people expressing doubts and frustrations of their own about how much work this was and how quickly it all had to happen. So I pushed through those things as much as I could.
And I explained everything that was going on behind the scenes to the patient and his family. And I wanted them not to bend over backwards and thank us for all these efforts. I think it was much more important that he just feel like he had some degree of control and understanding of the situation in an otherwise very out of control situation.
So as we got to the end, we had some, obviously, very serious conversations in the ICU and, ultimately, worked on how to plan for his survivors and how to treat symptoms at the end. And we had such an incredibly intense relationship this entire time, where we were constantly in phone and email touch about all of these hurdles that we worked through together. And when you get that email in the morning, saying your patient died overnight, of course, I rushed into the hospital, tried to see if anyone\'s still around. But by that point, everyone had gone home.
And I was actually never able to make contact with them again. I usually like to give a family a couple of days, of course, since it\'s such an intense time. And I did my best to reach out and leave it very open-ended, that I would love to talk if it made any sense to them, but certainly no pressure. But really what I wanted to reconnect with them about was this incredibly intense experience and how they perceived that that might have helped or not helped him feel like he had been well cared for at the end of his illness.
And it\'s very odd, as the physician, to go from an intense relationship to 0 relationship. And it makes it, I think, a little bit tougher as you go forward to say, was I doing right by this patient? What should I learn for the next experience?
[DR. LIDIA SCHAPIRA]
David, that was of a beautiful summary. And I\'m sorry we need to end it there. We could go on talking so much longer. Thank you for sending the essay. That was Dr. David Einstein, sharing his thoughts on his essay, "Compassion and Compassionate Use."
Join me next time for another conversation about the art of oncology. Until next time, thank you for listening to this JCO\'s Cancer Stories-- The Art of Oncology podcast. If you enjoyed what you heard today, don\'t forget to give us a rating or review on Apple Podcasts, or wherever you listen.
While you\'re there, be sure to subscribe so you never miss an episode of JCO\'s Cancer Stories-- The Art of Oncology podcast. This is just one of many of ASCO\'s podcasts. You can find all of the shows at podcast.asco.org.
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