Ep 204 Cancer Part 3: How do we treat it?

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Speaker 1: Throughout this series, we'll be discussing many aspects of cancer diagnosis and treatment, and we will be sharing several personal stories related to cancer. Some listeners might find this content upsetting. Please listen with Discretion.

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Speaker 2: Killer. My name is Amy and I'm a cancer survivor from Artira, New Zealand. My family has a history with a type of cancer called retna blastoma, which is a cancer of the eye. However, we can also track the history of how retna blastoma is treated in New Zealand, starting with my dad. He was diagnosed in nineteen fifty six with bilateral retina blastoma, meaning he had it in both eyes. They treated him with radium, which looking back on it obviously was not the most effective treatment. It didn't kill any of the cancer cells, but it also gave him mylodysplasia, a precursor to leukemia. In the end, he had both his eyes removed so that the cancer wouldn't spread. Diagnosed with bilateral retina blastomer in nineteen ninety four and was given radiotherapy. Radiotherapy was quite good at killing the cancer cells. However, it also altered the shape of my skull and gave me other numerous side effects which would Most of them were treated by either medication or surgery. In two thousand, my sister Meg was diagnosed with trilateral retina blastomer, meaning that she had the cancer in both of her eyes, but also a brain mass. She was treated with chemotherapy, which was still quite new at the time, and we thought that while at the time it was a very hard treatment, it was the best of the three. She had very limited side effects until she was seventeen. Now she was diagnosed with another form of cancer called osteosarcoma, not caused by the treatment, but a fairly common cancer to have with threatena blastomer as well, and she again was treated with chemotherapy. However, in the end she got chemo induced leukemia, which is a very aggressive and rare form of cancer caused by the thing that was meant to save her life. Unfortunately, she passed away six weeks later. So here I said, not being able to tell you if any treatment is amazing, but when you're faced with the alternative, you've got to go with what you've got.

00:02:41
Speaker 1: Thank you.

00:02:43
Speaker 3: Hi.

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Speaker 4: My name is Hallie and I currently work as a nurse in the United States. I've experienced in the operating room in your chronology and clinical trials. In each specialty, I've seen the effects of cancer in every aspect of one's life. It was only recently where I experience cancer more personally, as my dad was diagnosed in August of this year. I worked in oncology clinical trials from twenty twenty three to twenty twenty five. For many of these studies, patients were only considered after feeling a certain number of treatments. Essentially, they had to be sick enough but not too sick to qualify. For those patients who did consider being un study, I was amazed by the courage they had despite not knowing whether the treatment would ultimately heal or hurt them in the long run, they chose to proceed for the health of future patients who would inevitably come after them. In August twenty twenty five, my dad or received the diagnosis of stage two OR of pharyngeal HPV positive cancer at age fifty five. It was shocking, to say the least. My experience with clinical trials prepared me to educate my family on what was happening and what would likely eventually happen based on the data gathered by past clinical trial participants. This knowledge gave my dad the confidence to share about his experience in our community. Completed treatment in November and has his follow up PET in January, so fingers cross for clear scans. I learned a couple of important things throughout these experiences. One is that cancer treatment and its side effects can be brutal. An oncologist I worked with one said, the goal is to.

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Speaker 3: Treat the patient.

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Speaker 4: If treating the cancer gets in the way of that, we have to reevaluate the course of action. Number two is that cancer is not one size fits all. It can look like a chronic, slow growing disease and you can still live a very long, very happy, and very healthy life. It is not always destinance, even if the disease is advanced technology medicine has come so far. Number three is that cancer is so common understanding that it's not if it infiltrates your life, but when it infiltrates your life is very important. This is very scary, I admit, but very comforting knowing you are not alone and knowing there are healthcare workers there ready to fight the fight with you when the time comes to whether it's for you or a loved one.

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Speaker 1: Thank you all so so much for sharing your story with us. It truly means the world. Thank you to everyone who has written in it. These stories add such I mean, invaluable perspective on these stories of cancer and the experience with cancer, and we just re really, really really appreciate it.

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Speaker 5: Yeah, we do, thank you. We actually can't thank you enough for it. So thank you. And we have a lot more stories that we'll be sharing throughout this series and throughout this episode today. Truly, thank you so much to everyone who submitted. We wish that we could have included all of your stories. They all mean so much to us. Thank you, they do.

00:06:23
Speaker 1: Hi. I'm Aaron Welsh and I'm Erin Onmann Update and this is this podcast will kill You.

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Speaker 6: Welcome to episode three of.

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Speaker 1: Cancer, Cancer Cancer. It's been a journey so far.

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Speaker 5: I've learned a lot.

00:06:35
Speaker 1: Yes, same same. This is three of four total episodes on cancer. If you haven't listened to the first two, you should definitely go check them out because they'll add you don't have.

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Speaker 5: To, it's not like required, but there's a lot of context contests.

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Speaker 1: Yeah, we recommend, We do strongly recommend. Yeah, And it's just to give you a little bit of sneak peek if you haven't listened. Number one one is all about what is cancer clinically conceptually? How did we come by that knowledge throughout history? Episode two is about the evolution of cancer, the cellular basis of cancer, why makes a cancer sell a cancer cell?

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Speaker 5: Why do we get cancer, why do we get cancer?

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Speaker 1: Cancer, and animals, et cetera.

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Speaker 5: Today's episode is all about treatment, treatment, past, present, future.

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Speaker 1: Question back. That's I mean, I think that pretty much sums it up. Yeah. And then next week, our final episode of the series is all about sort of getting a sense of the current landscape of cancer around the world in the US, and then some of the other strategies that we can use to try to drive down these numbers through screening and prefection.

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Speaker 5: Yeah.

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Speaker 6: I love it.

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Speaker 5: It's going to be great, And we've covered a lot already. We have a lot more to cover. But as much as we have packed into this series, there is a lot that we have not been able to fit. Yeah, So we want everyone to know that. Number one, we have so many sources that everyone can read more about. Whatever your favorite aspect of the series has been, there's more reading for you, So check out our website to see the list of sources, and these are not the only cancer episodes that we are ever going to do. We kind of think of this as like laying a baseline so that in future episodes, as we explore individual cancers, everyone's on the same page.

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Speaker 1: To start with, so we like, oh, so, what's the difference between chemotherapy and surgery and radiation? You already have episode yeah, yeah, And as you'll hear throughout the series, as you've already heard, no two cancers or experiences with cancer are exactly alike. And so again, we just want to really express our gratitude to the first hand account providers for giving us kind of a snapshot or a sneak peek into just some of the myriad ways that cancer can affect our lives, can affect the lives of people who have been diagnosed with cancer, who are undergoing cancer treatment, who have become unexpected care givers, whose friends or loved ones are undergoing cancer treatment. It's this is like, this is so important, especially because you and I talk about cancer from a biological perspective. Right we're talking I mean a little bit of history, biology, evolution, but we're not talking about the experience as a cancer patient or somebody who has you know, a loved one with cancer, and so thank.

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Speaker 6: You, thank you.

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Speaker 5: We can't say thank you enough, like your first hand accounts, I think really make this series and make our podcast in general what it is.

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Speaker 6: So thank you, truly, truly.

00:09:32
Speaker 1: Okay, it iss a second to lust. I have an extra piece of yeah, I can just I'll do that business right now before we do the final piece.

00:09:43
Speaker 5: I'm excited, So tell us please sure.

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Speaker 1: Okay, So I wanted to shout out a couple episodes of Advances and Care, so you know, in this series, in this podcast will kill you. We're doing cancer from like a very big picture perspective, and so if you want to get some nitty gritty bits of information, there are a couple of episoddes of Advances and Care that I want to shout out.

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Speaker 7: This is the other podcast that a podcast I host, yeah, that features interviews with and also just like experiences with physicians and physicians scientists at New York Presbyterian.

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Speaker 1: And and so there are some just like such exciting research that's being done and it's so cool to hear about it like firsthand. So there's an episode episode thirty seven features doctor Magna Trevetti who's investigating chemotherapy induced peripheral neuropathy and how to better understand it, which is such a significant aspect of like side effects of chemotherapy, so really cool, important research. And then another one that's really recent. I believe it came out last week well you know it will come out in the future last week before after this episode. Yeah, and it highlights work done by doctor Scott Tagawa on the use of radiocen therapy in metastatic prostate cancer. Really cool stuff. I just didn't I didn't even know about it, and I was like, this is the future. Yeaheah, that's it's amazing. So anyway, you can find Advances and care wherever you get your podcasts.

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Speaker 5: Check it out, check it out. Okay, now for actually the last piece of business, it's quarantine Guarantee.

00:11:09
Speaker 1: Needs it's Plassy Berrita quarantine time exactly.

00:11:13
Speaker 5: We announced at the first episode of this series that we're not going to be putting alcohol in our quarantinies any more.

00:11:19
Speaker 1: Yeah, but it's a.

00:11:19
Speaker 5: Great name, so we're sticking with it. What are we drinking this week eron.

00:11:23
Speaker 1: The Crab, It's an Alpagato. Check out our social media to see me attempt to make it.

00:11:29
Speaker 5: Yeah, great, it'll be great. I think you'll be able to pull it off.

00:11:33
Speaker 1: We'll see. I could try. I could try. Also, check out our website This podcast will kill You dot com for lots of cool things, transcripts, contact us, form first hand account form stuff like that.

00:11:43
Speaker 5: Yeah, check it out, merch, Patreon, et cetera. A rate review, subscribe. We're on YouTube.

00:11:49
Speaker 1: Should we done? Let's take a quick break and then get into it. Get into it, okay.

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Speaker 8: On October twentieth, twenty twenty four, I crossed the finish line at the Amsterdam Marathon, qualifying for both the Chicago and Boston marathons. Six weeks later, I found a lump in my armpit, and two days after Christmas, I got the call I had breast cancer. Looking back, I missed the warning signs. In August, I noticed a small cyst under my right nipple. I'd had cysts before, so I ignored it, waiting for it to go away. Later, my nipple started a flatten. That's a symptom I didn't recognize, and I still didn't act. But when I found that lump, I called my doctor. The diagnosis stage two HR positive hurtuo negative invasive doctal carcinoma, the most common type of breast cancer, except I'm a man, and that made it rare. My initial treatment plan was the standard chemotherapy followed by surgery and radiation, but as a patient, I wanted to understand my options. The search for a second opinion led me to the Dana Farber Cancer Institute in Boston and their program for breast cancer in men. There, I joined the Ethyn clinical trial, which replaced chemotherapy with endocrine therapy to study the efficacy of various drug combinations, specifically for men. I became Ethan participant number nine, and that decision gave me clarity, direction, and purpose. I wasn't just benefiting from the research. I became the research. It turned my breast cancer nightmare into an adventure, and it gave me something else too. It gave me the chance to live a normal life. During treatment. Over the next nineteen weeks, I was treated with a combination of medications, an aromatase inhibitor, gonatal suppression, and a CDK four to six inhibitor, and I kept running, even completing four marathons during treatment. That's something I would not have been able to do if I'd been on chemotherapy. My doctor's reactions were priceless when I told him about the race, as I'd run since our last visit. In June, I had a successful mestectomy and removal of six lymph nodes, and that was followed by radiation. As soon as I was cleared, I jumped back into marathon training. I had Chicago coming up in October and New York City in November, where I had a charity bid for the Breast Cancer Research Foundation. That's the organization that funded the Ethink clinical trial, and I'm all set to run Boston this April. Breast cancer and men is rare, roughly one percent of all breast cancer cases. Most men don't even know they can get it and wait too long to be checked. Awareness in male specific research is needed to save these men's lives like it's saving mine.

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Speaker 9: My name is Yalla, Europe and in September twenty twenty two, I was forty one years old and I was diagnosed with stage three colon cancer. I had surgery to remove the cancer and two very large ovariansysts, and my ovaries as well, and after that I did rounds of chemo and was told to consider myself cured. I would go in for a CT scan every year as a follow up, and the first year everything looked great, but in late twenty twenty four the scan was showing some irregularities that needed additional scans, which led to a pet CT scan, and that came back with the result that my original colon cancer had metastasized to the top of my vagina and was spreading in my pelvis. In March twenty twenty five, I went in to have massive surgery to remove my bladder, my uterus, my rectum, some of my intestines, and appendix, and I woke up from surgery with a eurostomy and a colostomy. I still have yet to accept either of these, and the eurostomy has been difficult to deal with since we've discovered that I also have diabetes incibitus, which is a very bad combination with a eurostomy. As I was recovering from surgery, I had a new CC scan for my lungs, which showed lots of nodules that they weren't able to diagnose at that point. These nodules turn out to be the original colon cancer that has metastasized to my lungs. This means that my cancer is now incurable and I am going to die from this At some point.

00:16:45
Speaker 1: Last week, we looked at cancer through an evolutionary lens. Rather than seeing cancer as solely the enemy in an unrelenting war, we asked a different question, what does it mean to be a cancer cell? And why does it exist in the first place. That perspective shift allowed us to explore new ways to approach cancer treatment, not just by fighting evolution, but by working with it, and it helped us to better understand why many standard therapies may show initial promise but then stop working for an individual. Over the past century and a half, cancer therapy has undergone a profound transformation, like truly hard to wrap your head around.

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Speaker 5: Just how profound, even in the last like ten years, Yes, amazing, right, yeah.

00:17:33
Speaker 1: But for most of human history, cancer was rarely treated and never cured. Wow, right, Like that alone is monumental, and in part it's because it remained such a mystery to scientists and physicians. Treatment developments in the twentieth century inspired initial hope that a cure for cancer, for all cancer was possible. After all, if we can put a man on the moon, why couldn't we cure cancer. The answer is actually fairly straightforward. Besides the nature of cancer itself, which we learned about in episode one and episode two, the moon landing was guided by decades of foundational basic research, whereas cancer research up through the nineteen seventies had been centrally focused on treatment development without fully understanding the nature of cancer itself.

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Speaker 5: They're like underpinnings of that biology.

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Speaker 1: Yeah, that makes the genetics driving cancer, the different mutation, yeah, all these different pathways. And in fact, some early chemotherapy researchers actually disdained funding for basic research, seeing it as less urgent than devising treatments for the patients who were dying in front of them, and they had seen dying over and over again. And you know, I think my initial reaction was, like, basic research is the backbone to everything. It is how we understand the world. Is you need basic research for application, bottom line. But I also do understand that frustration and that perspective and that patients because you know, if you think about it, these clinical oncologists were for years watching and their patients die in front of them, extremely limited in their ability to do anything to save their patients or even just lessen their pain.

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Speaker 5: And it is true that there are so many medicines that we use that we don't fully understand the mechanisms of how exactly they're working. And they do a really good job, and so why do we need to do I can understand totally. I don't feel it, but I understand that absolutely absolutely.

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Speaker 1: I think that another aspect of this is that cancer, because of their limited ability to do anything, it challenges your role, your identity as healer.

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Speaker 8: Yeah.

00:19:40
Speaker 1: If you go into medicine to save lives and your face with this thing that is not letting you do that, and it's like, what, I need to do something about this? Yeah, right. But as the decades went on, and as many new treatments failed to live up to initial expectations, it grew increasingly clear that if we wanted to understand why treatments failed or to devise improved treatments, basic research was absolutely necessary. So today I'm going to tell the story of the three main treatment modalities that emerged over this period. Prior to the extensive incorporation of basic research. And these are not the only ways that we treat cancer. I know that you're going to take us through many other really exciting therapies, but their development of these three has profoundly shaped the way that we think about cancer and how we continue our search for better therapies. Part one surgery. From the earliest descriptions of cancer until the last years of the nineteenth century, the very last years, surgery represented the primary, if not the only, method of cancer therapy that showed any degree of success, but its popularity was uneven, and this is for good reason. Consider this eighteenth century so seventeen hundred's description of mastectomies. This is pre anesthesias, pre aniseptic technique.

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Speaker 5: I'm just like remembering the butchering art and like, yes, not good.

00:21:04
Speaker 1: It's that's his understatement. Yeah, quote, many females can stand the operation with the greatest courage and without hardly moaning at all. Others, however, make such a clamor that they may dishearten even the most undaunted surgeon and hinder the operation. To perform the operation, the surgeon should be steadfast and not allow himself to become discomforted by the cries of the patient end quote.

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Speaker 6: Oh Man oh Man, oh Man, oh Man, oh Man.

00:21:32
Speaker 1: Yeah. So, rather than submitting themselves to that ordeal, many patients and physicians turned towards systemic treatments, which typically included a toxic chemical such as mercury, lead, or arsenic, which were our first chemotherapies. In a sense, wow, you know, chemical cures or chemical treatments definitely not cures. When anesthesia and antiseptic technique came on the scene in eighteen forty six and eighteen sixty seven, respectively, surgery transformed into a science. Surgeons could measure their progress. They could assess what worked and what didn't work, And as more and more cancer patients went under the knife and lived to tell about it, surgeons noticed that while many people recovered completely, in many more the cancer recurred, it came back. The regrowth seemed concentrated on the margins of the original surgery. It was like tiny seeds of invisible cancer had just been left behind to then continue to grow. The answers to this problem seemed straightforward, right, like just cut away more during the initial surgery. With that, radical surgery was born, Okay, Surgeons in the late nineteenth and early twentieth centuries pushed the metaphoric and literal borders of excision as far as they could, and most major solid tumors became fair game, even those that had previously been seen as too deep or too risky to attempt removal. Breast cancer, which had challenged every physician that attempted to treat it, became an early target of this radical approach, with many surgeons, notably William Halstead, advocating for wider and wider margins, first to the axillary lymph nodes, so the ones in your armpit were removed, then muscle, then maybe even bone. The question became how much could we remove while still preserving life? Wow, radical mistectomies may preserve life if you survived the initial surgery itself and the recovery period, but at what cost to quality of life?

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Speaker 3: Right?

00:23:35
Speaker 1: That didn't seem to rank too highly for advocates of the radical approach, many of which who viewed a more conservative surgical approach as a quote unquote mistaken kindness. That's what it was often caused, because it was.

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Speaker 5: Like, I think you're being kind, but you're just leaving cancer cancer behind.

00:23:52
Speaker 1: Exactly. Amid the early twentieth century hype surrounding radical mystectomies, a few dissenting voices began to be heard. Their question was simple, is that kindness always mistaken? As it turns out, no, the push towards radical mistectomies was initially spurred on by observations of tumor recurrence, and it was reinforced by armchair logic. It just seemed to make sense, right, You're like, of course we want to cut more. Of course we want to cut more. So it wasn't supported by statistical things, at least initially that approach, the beginning of that approach, And to be fair, the state of breast cancer diagnosis during the late eighteen hundreds was nothing like it is today. There was no screening, so very early stages were unlikely to be detected, and diagnosis often followed clinical symptoms. So by the time that you actually went to the doctor to address something, you were like.

00:24:46
Speaker 6: It's already pretty far in fast. Yeah.

00:24:48
Speaker 1: So for example, in one case report, Halstea describes an eight centimeter breast tumor as small. Oh wow, So that is kind of like just shifting our perspective in what breast cancer Now.

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Speaker 5: We're talking about like a matter of millimeters that you see on a mammogram that you would never be able to feel.

00:25:06
Speaker 1: Right, Yeah, but eight centimeters being small? Wow, And the data backing up this approach is not entirely convincing, at least not for all cases. Three or five year survival rates very drastically depending on how advanced the cancer was. Staging was an emerging tool at this time, and it left some people to question radical therapy as the universal approach that we should use for everything. So, for localized, slow growing tumors, a more a radical approach resulted in greater tissue loss and disability than a more conservative surgery, which would have likely led to the same outcome. Right, You didn't need to cut out as much as much because this was slow growing and wasn't going to cause those problems down the line. But for those with more advanced cancer, radical mistectomies seemed unlikely to remove all cancero is tissue. It had already spread. Its not going to be any size, right, and so it led one surge. And to conclude, quote radical mistectomies, greater trauma is not justified by greater cure rates. End quote. We can make this surgery more and more painful, but it's not going to actually increase survival. But if a tumor was small at the time of surgery and aggressive and had not spread, yeah, a radical mistectomy might have been the way to go, might be the way to go. There was no one right answer. And again this like highlights this theme as cancer of cancer being incredibly unique and requiring a personalized approach. But despite the mostly unconvincing data and support of radical mistectomies and the robust opposition to it, this approach dominated surgical treatment for breast cancer until the nineteen seventies or so wow. Yeah, and in the nineteen eighties also, But like it did fade over time. But then this was sort of more of the turning point where like a more balanced and personalized approach became you know what to do? So and there were there were many things that changed this. The first was pushback from feminist groups who demanded that physicians consider the patient in these major treatment decisions. And the second was a large scale study published in the nineteen eighties that compared survival, remission, and morbidity between radical and non radical approaches that showed no difference in survival and remission, but greater morbidity with radical mistectomies. And then the third thing was that there were better advancements in cancer diagnosis, so like via x X ray and CT scans, and then also treatment like radiation and chemotherapy had come onto the scene, right, and so it was like, we can we can do do other things than a radical approach. Yeah. And so while for this surgical section I focused mostly on breast cancer, surgery was an integral and often the only treatment for many types of cancers throughout the late eighteen hundreds, and a radical approach was justified in some cases more than others. Today, surgery remains a cornerstone of cancer treatment, along with radiation and chemotherapy. Part two radiation, Okay, doing these in chronologically.

00:28:09
Speaker 5: I love this.

00:28:10
Speaker 1: Yeah. In the eighteen nineties, around the same time that Halstead was spreading the word about radical mistectomies, two massive breakthroughs by three scientists were about to change the world forever. Like not an exaggeration. The first William Ropkin's discovery of X rays in November eighteen ninety five, and the second Marie Sklodowska Curie and Pierre Curie's discovery of radium and polonium in eighteen ninety eight. It's amazing to me how those two things happened with just in a few.

00:28:42
Speaker 6: Years, a couple of years apart, I know.

00:28:44
Speaker 1: Yes, And within a few years of these discoveries, physicians were utilizing radiation as a treatment for cancer, really, which is probably like the fastest turnaround time between initial discovery and application for anything ever.

00:29:00
Speaker 6: Wild.

00:29:00
Speaker 5: They were just like everything, Wow, this thing, you could kill things with it.

00:29:05
Speaker 1: That's exactly what it was, Okay, yeah, yeah. And these were not like the kinds of scientific discoveries like I feel like we're so used on the podcast being like and then somebody discovered this and then they were a discovered in this obscure journal right rais and years later Yeah. No, It just instantly excited the broader scientific and medical community, and there were there was no shortage of people who were willing to work on X rays and radium. Wow, yep. And it didn't take long for these new radiation scientists to notice strange rashes after exposure to radiation, strange side effects, things like your hair would fall out, you would get these swollen skin, some kind of rash would emerge rather than evoking alarm. That alarm would come later. This led people to wonder whether radiation could be used to kill a harmful tissue or cells like cancerous tumors or bacteria. There's some controversy over who should hold the rightful title of first radiation therapist, which shows just how popular radiation therapy was in the early years, like right after its discovery. But from my reading, the front runner appeared. There are like multiple papers on this. The front runner appears to be a French physician, Victor Despines. Okay if that's I don't know how you say his name, despig nes t do it? Yeah, we were talking about it. Despine's inspiration came from early reports demonstrating the bacteriocytal effects of X rays. Guinea pigs inoculated with tuberculosis and then subsequently radiated did not develop the disease. Okay, okay, So if you think back to the first episode in this series, cancer was commonly thought to be caused by pathogens around this time, so operating under this assumption in July of eighteen ninety six, let me just remind you that X.

00:31:00
Speaker 2: Ray in.

00:31:03
Speaker 5: Ninety five wow, Wow than a year yep.

00:31:07
Speaker 1: Despines used X rays to treat a fifty two year old patient of his who had stomach cancer. He traced the outline of the tumor to track progress. At the end of treatment, Despines claimed improvement, not cure, but his conclusions have since been called into question. Whether he had success or not he probably didn't, whether his scientific reasoning was sound It wasn't. Definitely wasn't. Victor Despin's was likely the first person to apply radiation to a patient with the intention of shrinking a cancerous tumor. How interesting isn't that not Emil grub Grub who was often claimed even by me, I was like, wait a second, I didn't think it was this. I thought it was this other guy who did it, and I went back to our radiation notes from years ago, and no, Well, his story has been discarded because the first time he wrote about it was not at the time, but like thirty something years later he was like, oh, yeah, that was me.

00:32:08
Speaker 6: I was the first.

00:32:09
Speaker 1: I did it because I had this idea. Okay, there's no like, no it yeah, okay, so it doesn't matter. I like the reason I find this so interesting, This debate over priority is because it shows just how excited people were about radiation. There were so many, many different things at the time. Yeah, radiation, I mean it was it felt magical. It was science made magic, right. It allowed you to peer inside the body without using a knife, It made things glow in the dark, It emitted heat, It killed bacteria. What couldn't this precious substance do. Over the late eighteen hundreds and early nineteen hundreds, lab based empirical science had established itself as the standard for developing and testing new treatments, So there was this increasing pressure to demonstrate the efficacy and safety to a lesser degree of a drug before administering it. Okay, For some physicians, this was an unwelcome affront that challenged or undermined the traditional role of doctor as healer. Like what are you doing?

00:33:13
Speaker 8: Right?

00:33:14
Speaker 1: If treatments were being developed and tested by scientists in labs and then given to physicians to administer, didn't that just make physicians glorified drug dispensers. What were they actually doing then, if they weren't testing out therapies on their patients?

00:33:29
Speaker 5: So interesting, Aaron.

00:33:30
Speaker 1: Yeah, I mean also painting with a broadbrush et cetera. But I do think that there was initial pushback against this the science in medicine and like using statistics rather than experience. Okay, you know, an individual experience. Yeah. And so with radiation, physicians were not content to just sit around and wait for the scientists to figure it out. They were going to forge ahead.

00:33:53
Speaker 7: With radiation therapy regardless, regardless, they're like, we got this.

00:33:57
Speaker 1: Yeah. And because radiation was accessible to physicians, and this is reflected in early case reports, so most experiments with radiation therapy were carried out by physicians in private practice rather than those in academia or public institutions. Yeah. And because no one could yet explain how it worked, it added to the quote unquote professional mystery of medical practice, reinforcing this boundary between physician and patient. And to be fair, these physicians weren't drawn to radiation therapy solely because it lent them this aura of like expertise or wanted to help that they wanted to help their patients. They were sold on the hope that radiation promised. Many patients who received radiation therapy truly underwent a transformation. Their pain lessened, their tumors shrink disfiguring rashes disappeared, and not just when it came to cancer, but like all sorts of ailments where radiation was used. With radiation therapy, physicians could take action, especially in cases that previously had appeared beyond their help ability. Gradually, as case reports of radiation therapy accumulated, guidelines were created, like how much radiation to administer, how often, how long that sort of thing, what types of different yeah, and hazards were recognized. Radiation, it seemed, could not only shrink tumors, but cause them, like with radical surgery. Initial enthusiasm for radiation therapy gave way to tempered expectations. It's the same thing over and over again. But combining these two therapies improved outcomes. But by the nineteen thirties, those outcomes had largely plateaued. It was like, we've kind of reached our point.

00:35:39
Speaker 5: We've come as far as we can with this these technologies.

00:35:42
Speaker 1: Yeah, Part three chemotherapy. All right, So, this quote from a nineteen thirty seven article in Fortune magazine sums up the state of cancer therapy at the time. Quote. The startling fact is that no new principle of treatment, whether for cure, or prevention has been introduced, the methods of treatment have become more efficient and more humane. Crude surgery without anesthesia or as acepsis has been replaced by modern painless surgery with its exquisite technical refinement. Biting caustics that ate into the flesh of past generations of cancer patients have been obsoleste by radiation with X ray and radium. But the fact remains that the cancer cure still includes only two principles, the removal and destruction of disease tissue. No other means have been proved end quote nineteen seventeen thirty seven. Okay, the stagnation in cancer treatments was not due to a lack of will or need. As medicine made headway against infectious diseases, cancer rose to prominence as a leading cause of disability and death in many countries around the world, but the funding landscape for medical research lagged behind the shifting trends in mortality, and cancer had ranked consistently low on the priority list for a number of years. That Fortune article that I just quoted from was not alone in raising the alarm on the limited success for existing cancer therapies and the dismal funding allocated for cancer research. This outcry, which is just like so many people were like, we demand something change, We demand that you pay attention to this. It led to Congress passing a bill to create the National Cancer Institute in nineteen thirty seven. Okay, yeah, and things were nineteen thirty seven were on the eve of World War two. Essentially things slowed down to focus on wartime efforts for basically until the war ended. Yeah, but within a few years after the war's end, chemotherapy, the era of modern chemotherapy began. The first major clue came out of the ashes of World War not number two, but number one. So while just one among many atrocities committed during the Great War, mustard gas was a nightmare brought to life. Okay, yeah, we should do an episode on this.

00:38:04
Speaker 5: I know it's been on our list for a really long time, has Yeah.

00:38:08
Speaker 1: Mustard gas is a toxic gas that leaves you asphyxiated burns. It killed tens of thousands of soldiers and left physical and psychological scars on many more. Physicians studying the long term effects of mustard gas during World War One found anemia to be a common outcome. It was like the gas had depleted the bone marrow. I know little you know, yeah, you know where this is going. Little hint there, little hint. And this observation may have been lost to history in World War One if an awful tragedy hadn't happened. During the Second World War. In December of nineteen forty three, German planes bombed American ships in an Italian harbor, and one of these ships contained like seventy tons of mustard gas. And I don't think mustard gas was really extensively used or used at all during World War Two, but I think it was like a it was like going just a case. Yeah. When the ship was bombed, of course, all that mustard gas went out into the harbor, went into the like the surrounding town, and thousands of people in the area were impacted. Many died, and physicians who were working on the patients who were affected again noted this bone marrow depletion and lymph node degradation that was brought on by the gas. So this caught the interest of two researchers who were studying lymphoma, and they were like, what is going on in lymphoma where the lymph bone marrow seemed to be affected. Is it possible that nitrogen mustards, these compounds in nitrogen gas could be used to produce the same effect in our patients? Could it like attack the malignant white blood cells that are produced by the bone marrow? Sure enough? Yeah? Wow the tumor shrink.

00:39:53
Speaker 6: Wow.

00:39:54
Speaker 1: Yeah.

00:39:55
Speaker 5: So they were like, we'll use mustard gas to treat patients.

00:39:59
Speaker 7: Basically, Okay, it wasn't precisely mustard right, right, but something similar.

00:40:03
Speaker 1: Yeah, the same sort of like logic that was like, how do we do this?

00:40:06
Speaker 3: Yeah?

00:40:07
Speaker 1: Yeah wow, And they had to delay their publication until after the war ended, but when the paper finally came out in nineteen forty six, it inspired real hope that cancer could be treated with chemicals.

00:40:22
Speaker 6: Wow, akachmemotherapy.

00:40:25
Speaker 1: And this was a concept that had been introduced decades earlier but not really demonstrated clinically. I was like, we're going to try arsic, We're going to try all these things, right, all.

00:40:33
Speaker 5: These super toxic things, but that just weren't specific enough or weren't whatever enough.

00:40:40
Speaker 3: Yeah.

00:40:40
Speaker 6: Interesting.

00:40:41
Speaker 1: Yeah. Unfortunately, the remissions that were induced by nitrogen gases were short lived, but it did spur on researchers to investigate other compounds. It was like finally, kind of like just getting your foot in.

00:40:54
Speaker 5: The door, right, Like this concept has merit. Yeah, let's find others, find other things.

00:40:59
Speaker 1: And one of the researchers who was excited about this was has a name you might recognize, Sidney.

00:41:05
Speaker 5: Farber Farber Institute, Dana Farbert Institute. Yeah, it's like where is it in my brain?

00:41:12
Speaker 3: Yeah?

00:41:14
Speaker 5: I know?

00:41:14
Speaker 1: It was good?

00:41:15
Speaker 5: Yeah, okay.

00:41:16
Speaker 1: So Farber was trained in pediatric pathology, but he found himself intrigued by childhood leukemia, which was a devastating disease that doctors were completely helpless to treat me at that time. And leukemia was fairly unique among cancers then because it could be quantified. You could count your patient's blood cells to see how they were doing.

00:41:37
Speaker 5: Oh interesting, okay, whereas we didn't have markers as much for others.

00:41:41
Speaker 1: You can't have as many markers, or it was like more amorphous, like what does it mean to have a growth in this tumor at that right?

00:41:47
Speaker 3: Right? Right?

00:41:47
Speaker 1: And so this made this made leukemia an appealing target for Farber because it meant that you could measure how well a certain treatment was working. If you see your patient's cells go down drop, then maybe that's a good exact or better right. But and so in the late nineteen forties, Farber came across some work done by Lucy Wills. Do you remember this name?

00:42:08
Speaker 5: No, but tell me you know.

00:42:10
Speaker 1: The same, because we've done an episode follate oh our full eate episode?

00:42:14
Speaker 8: Yeah?

00:42:15
Speaker 1: Yes, yes, Okay. So she was the physician who discovered that marmite, specifically the folate in marmite.

00:42:21
Speaker 6: Forgot about marmite.

00:42:23
Speaker 1: I know, I can never forget about marmite, but that marmite could help treat anemia by prompting the body to produce normal blood cells. Right, And so Farber thought that maybe if I administer folate to my leukemia patients, that will prompt their bone marrow to produce normal reds, normal red blood cells. But instead it actually seemed to speed up the leukemia process. It was not good. It was more white blood cells. Okay, not good. And so he was like, okay, we're going to stop this trial. What's going on here? Maybe it's not that the like the bone marrow doesn't seem unable to produce cells. Maybe I just needed to get it to stop making cells completely. And that's the problem. So instead of giving folate, which would encourage cell production, what if I gave something that was like anti fold that like stopped yeah, cell production.

00:43:13
Speaker 6: Huh.

00:43:14
Speaker 1: That's what he did, Okay, And what happened were the first chemotherapy induced to leukemia remissions in history. Wow, which I mean, I just like it must have been astonishing. Yeah, to see that we've talked about this, this kind of thing that happened before, like with the first insulin administered, the first antibiotics administer Just like this sudden switch that destiny is not firm.

00:43:39
Speaker 6: Everything is now changed.

00:43:40
Speaker 1: Yeah, yeah, Wow. And these remissions, the news of these remissions had a similar energizing effect on the world of cancer medicine as did those ones induced by nitrogen mustards. There now seemed to be no doubt that chemotherapy held the key to the cancer treatment puzzle, and in a sense, it did. The only problem was that cancer kept changing the locks.

00:44:04
Speaker 6: Yeah.

00:44:05
Speaker 1: Within a few months, Farber's first patient, three year old Robert Sandler, showed signs of recurrence. His leukemia stopped responding to the drug, and he died in nineteen forty nine. This pattern a new chemotherapy drug or combination of drugs shows initial promise, recurrence happens, and then resistance develops. Is both familiar and heartbreaking, but it also demonstrates progress, right, like how many more months did Robert have with his family that he wouldn't have gotten otherwise? Progress was incremental for early chemotherapy research, but that extra time was precious, and as the nineteen fifties melted into the nineteen sixties, that extra time grew and grew. For certain cancers. The first cures were reported during this period, choreo carcinomas, and they were met with initial disbelief, like it kind of like you know, chemotherapies which showed such initial hope, but then and were quickly like, okay, this is not a temporary solution. Temporary solution. Then to have these like full cures were like this's just going to come.

00:45:08
Speaker 5: Back, right, I don't want to get my hopes too high.

00:45:11
Speaker 1: Yes, yeah, but those were largely the exception.

00:45:17
Speaker 8: Right.

00:45:17
Speaker 1: Overall results tended to be mixed. There was you know, your you're you were given more time, That time was not guaranteed, and it was often filled with horrible side effects, right, and and so there were there was a lot of kind of like this this general air, this general aura of disappointment mixed with hope, like constantly, just like these cycles of disappointment and hope, disappointment and hope for both physicians and the clinical on colleges working on this, as well as people with cancer and their families. Yeah. And there was a sense too that like, the more aggressive the chemo, the better. We need to push our patients' bodies to the acts, to the absolute maximum.

00:46:04
Speaker 2: War.

00:46:04
Speaker 1: We're fighting a war. And this is this like this is when the concept of maximum tolerable dose was introduced, where it's like how much can we administer without killing the patient? Right now? Oh God, is this idea? And then also like chemotherapy, the same with radiation can lead to more cancer causing effects, or can can lead to higher cancer risk later on just because you're causing such right.

00:46:28
Speaker 6: You're just damaging cells cells, Yeah, yeah, yeah.

00:46:33
Speaker 1: The cancer treatment world seemed pretty singularly focused on chemotherapy for decades. Much of the billions in cancer funding went towards finding new combos or compounds, and this was driven in part by Farber's partnership with activist and philanthropist Mary Lasker, which led to a huge increase in cancer awareness as well as funding. Together, they turned cancer into a political and social issue, which was a much needed transformation. Their approach was guided by the belief that with enough resources we could brute force our way into a cure for all cancer, and unfortunately that cure failed to materialize. Funding for research, no matter how vast, was still a finite resource. An incremental progress in chemotherapy was made at the cost of investment in basic research or development of other treatment modalities. Eventually, as chemotherapy research plateaued, other treatments emerged in the nineteen eighties and the nineteen nineties, informed by our growing understanding of the cellular mechanisms of cancer, which I'm excited to hear you talk about, and today there exists a broad array of cancer therapies that allow oncologists to design a personalized treatment plan for their patients. We still don't have a magic bullet for cancer for all cancer, and we likely never will, at least it's hard to imagine that we will based on the way that cancer works in our bodies. But the clinical transformation that cancer has undergone in the past century and a half. It really makes me optimistic for the future. There is no denying that chemotherapy was revolutionary and it remains a cornerstone of cancer treatment today. But I have to admit that there are parts of it history, at least, that I really struggle with the belief that you can task force cancer while disregarding the importance of basic research and the commercialization both historically and today of drug development that discourages looking outside the box that makes new treatments prohibitably expensive for people. The concept of in network, I mean, which.

00:48:41
Speaker 5: Is I know, this is like a US it's so American thing, it's so disgusting, it is.

00:48:48
Speaker 1: Inhumane.

00:48:48
Speaker 6: Yes, it is, yep.

00:48:51
Speaker 1: And there are parts of the story too that I feel like are reminiscent of the quote unquote mistaken kindness, of the age of radical surgery, where it's like, no, we need to use the most aggressive treatment possible. There And in the nineteen sixties and nineteen seventies, when palliative care was kind of introduced as this concept, there was a lot of pushback from clinical oncologists who are like, that's giving up. We don't want to give up. We want to fight, we want our patients to fight. We want our we want us to fight without actually like maybe considering talking.

00:49:24
Speaker 5: With the people and finding out what's happening in your life and what your goals are and what your hopes and dreams are, and how this diagnosis and treatment has affected your life.

00:49:33
Speaker 1: Yeah. Yeah, I mean I think that there's a lot of just like we talked about in the beginning part of this episode, there's a lot of push pull on like what it means to be a physician and a healer and what does that look, you know, healer versus physician? What is it? Yeah, that's a philosophical question.

00:49:49
Speaker 5: Well I might talk more about it, Okay, not really, not directly, but.

00:49:54
Speaker 1: Yeah, there are also parts that sound, you know, too much like a forward march of pro progress by prescient rebels. Right, Like these people fought against even though their data showed that they weren't getting anywhere, they continued to fight against it. And I'm like that, I don't know if that's the strength necessarily, Like they happen to be right about this, but there are many more people in history that were wrong right, and they weren't entirely right anyway. Yeah, and that's just also the way that we tell science stories. I think that's an issue with that. There's also I think in a lot of these stories there's a lack of accounting for the human cost and unfulfilled promises that were brought on by all therapies during this time. I mean, we owe so much to early patients, not just of chemotherapy, but of surgery and radiation and every person who has ever participated in a clinical trial ever. It's incredible.

00:50:47
Speaker 5: Is it is so selfless and it is so beautiful that someone is willing to know this might not help me, but it will help someone else down the line.

00:50:57
Speaker 1: Yes, yeah, Yeah, that's one of the parts that I find inspiring. And I also find, you know, Farber's passion and vision inspiring. There are parts that are uplifting, like those whose lives who have that have been extended or saved by chemotherapy, And there are parts that are thought provoking, like where do we go from here? Yeah? Where do we go from here? Cancer treatment, though it has dominated the research scene for decades, is just one way to approach this problem of multicellularity. What if we could minimize our use of aggressive therapy or even better, avoid treatments entirely. That's what I'll be talking about next week. How can we incorporate screening and prevention into our picture of cancer?

00:51:45
Speaker 5: Oh, I'm really excited about that.

00:51:48
Speaker 1: But for now, I'll turn it over to you, Aaron, to tell me how these different types of cancer treatment work.

00:51:54
Speaker 6: Let me bring us up to speed.

00:51:55
Speaker 1: Please.

00:52:10
Speaker 6: Hi.

00:52:11
Speaker 3: My name is doctor Longwyn and I'm an obgaan physician. In November of twenty twenty, I felt a small lump in my right breast. I wasn't too worried about it, but as I was due for a mammogram, I had my colleague ordered as a diagnostic. Within three weeks, the mammogram quickly led to a breast biopsy, and two days after my son's sixth birthday, my breast radiologist friend and colleague told me I had cancer. It was in the middle of a work day and she was so so very kind to me. I walked to a private spot behind the hospital and called my husband with the news. Then I pulled myself together and finished seeing patients in the office. I consider myself lucky. I caught it early and had a lumpectomy a month after my diagnosis. Four days after surgery, I walked back into my hospital. I got my second COVID booster. A month after that, I was back at work and continue to work when I had my weak of radiation treatment. I will be five years with no evidence of disease soon, and at that time I will be able to stop taking tamoxifen. It's been a journey. Medically induced menopause is no joke, but I am so grateful to my friends, family, and colleagues who have been nothing but supportive. In my field, I'm the referring physician to the breast surgeon and oncologist. I didn't like being on the other side of it, but I know firsthand now that my patients are extremely well taken care of. Thanks for letting me share my story. I know that this may come as a surprise to many of my long term patients who might hear this, but I'm okay with that. Doctors are human beings too, and cancer doesn't care. Get your mammograms, peraps, mirrors, and colonoscopy's done. It can save your life.

00:53:49
Speaker 10: Hello. My name is Jasmine and this is my experience with cancer. To start, I'm going to tell you about my grandfather. My grandfather was a prankster and a jokester, locked on his grandkids in trouble for jokes he started. He was an amateur mixologist, always trying and making something new. He was always outside and loved to meet new people. One of the first signs that something was wrong came from their friends he had made. They noticed that he was rapidly losing weight without seeming to try. This led to a trip to the doctors. On April sixteenth, twenty twenty four, my grandfather was diagnosed with stage four pancreatic cancer. Shortly after this diagnosis, his children dropped everything and went to Florida to be with him and my grandmother. One thing we all wondered about was how this was missed for so long. He had regular visits with the doctor and seemed to be in good health. They quickly realized how sneaky cancer can be. We learned that pancreatic cancer as often misdiagnosed as diabetes, which my grandfather had. We also learned that pancreatic cancer has a very poor prognosis, and my grandfather was only given a couple of months to live. In my grandfather's usual fashion, he made a joke and fought.

00:55:03
Speaker 1: Back the time.

00:55:05
Speaker 10: My grandparents are coming back to their home state in Missouri. His doctor was making plans for the next year, maybe more. We were all astatic. Unfortunately, in July he got a very bad infection that had him in the hospital for days. By the time they managed to clear it, his strength was gone. He was never able to resume his treatments. On November ninth, twenty twenty four, early in the morning, surrounded by family and his loving wife, he passed away. One thing that sucks with cancer is to memories. It steals. Seeing my grandfather as a shadow of his former self hurt beyond belief. He was also only half a year away from my wedding because of cancer. I never got to show my grandfather and my wedding dress. Because of cancer, he never got to meet his third great grandchild, he was born two weeks later. This soul journey husband a roller coaster from despair to hope to say goodbye one last time. I can only hope to see you again one day. Thank you for listening to my story.

00:56:37
Speaker 5: I don't think I'm going to tell you how these work. Necessarily, that's fine in detail, but what I do want to do I mean in part because it would be way too much to try and deep dive on Oh, I know, like all of this.

00:56:51
Speaker 1: Give me the broad strokes.

00:56:52
Speaker 5: I will, thanks, And I want to kind of walk us through some context on like how we use the tools that you walked us through, because those are still the three, how do we use them today? How is that different than how we use them historically? And then what are some of the biggest new technologies that have now become a mainstay and a like integral part of our cancer treatment. But they're new within the last like ten fifteen years, and yet now they are like the standard of care. So that's what we're gonna do. Okay, okay, great. So I talked in the very first episode of the series about how we stage cancers, and the staging of cancers is a really important part of this initial process in deciding how that treatment is going to progress and what treatments are going to be recommended. Knowing where this cancer came from, what kind of tissue, how far it has spread, all of this has to be taken into consideration to plan your particular cancer treatment.

00:57:52
Speaker 1: Camera.

00:57:52
Speaker 5: Yeah, so I'm going to go through the three that you had gone through I think I have them in a different order of this, and then we'll move on to like immunotherapies and some of the newer things. So surgery, surgery, surgery is very often still a part of cancer treatment. It is totally going to depend on the tumor if there is a tumor at all. Obviously, for blood cancers not going to have a surgery, sue. It's going to depend on where exactly that's located, how far it has spread. But for a very large proportion of cancers, a surgery that removes that entire tumor and aims to remove a margin of healthy tissue. And that's what when we hear in your pathology report you get it says, oh, it had.

00:58:40
Speaker 6: Clear margin margins.

00:58:42
Speaker 5: That means that all of the surrounding tissue did not have cancerous tissue. So if it didn't have clear margins, it means that tumor is all the way to the edge of the tissue that we got, which means we think we might have had everything behind. If it's all the way to the margins. If you have clean margins, it means we didn't leave anything behind.

00:58:59
Speaker 1: So what would it say if your report did not say, clean margins, what would it say.

00:59:03
Speaker 5: It might say that it like there was cancer's tissue to the periphery or including the margins or something like that.

00:59:08
Speaker 6: Okay, so that would be not good, got it?

00:59:12
Speaker 5: And so yeah, that is the point, and so that is the goal of any kind of surgery usually is to remove all of the tumor and then some portion of healthy, non cancerous tissue all the way around the tumor. How exactly we're going to do that, what kinds of surgery is going to happen, how much tissue that's going to be all depends on the cancer. And there's probably a lot that I could have gotten into on the incredible surgical advancement so many there are so many incredible surgical techniques that have been developed in the last few years decades, both in terms of understanding how much tissue needs to be removed. Do we need to do radical mastectomies very often not like you said, lumpectomies often have similar morbidity and well better morbidity and similar survival and recurrence rates. But also there's been so much advancement in things like minimally invasive surgeries, in the use of robotic surgery surgery, which has allowed for surgery to be a part of cancer treatment where before it couldn't be. If you think of trying to do surgery in a place that's very small and has a lot of really important anatomical structures, like in our head and neck, a lot of time surgery wasn't an option in those areas because they're so small, because there's so much important tissue there. But now, with the advancement of minimally invasive and robotic techniques, you might be able to have a surgery which could significantly improve your outcomes. So there have been incredible That's all I'm going to say about surgery. It's like, sorry, I'm not doing it justice to all of you surgeons out there, but you do incredible work.

01:00:45
Speaker 1: Oh my gosh, I mean it is. It is like it was reading that quote from nineteen thirty seven where it's like we have the most technologically advanced surgery and I'm like you did then you have no idea idea what's coming well, and like.

01:00:57
Speaker 5: The advancements in plastic surgery and like you know, reconstructions and things like, it's it's amazing and incredible. So like shout out to surgeons everywhere. I feel like I probably don't shout the whoop woop to you, uh, and so that so surgery is a really important part of many, many types of cancer treatment. Yes, chemotherapy is the other big time mainstay, and chemotherapy comes in a lot of different varieties these days. But the way that they all work mechanistically is that they kill cancer cells, and they do this by being cytotoxic broadly, meaning toxic two cells broadly. The goal with all chemotherapies is that they are targeting mostly rapidly dividing cells, right, because we know from our cancer biology and like basic science research, that cancer cells are continuously dividing. That's one of their big hallmarks. And so by targeting these rapidly dividing cells, we are mostly targeting cancer cells. So some of these chemotherapies might work by disrupting DNA replication, right. Some of them might work by disrupting what's called microtubule formation, which is like how your cells have to arrange the DNA as they divide, So some might target that, some of them might There's lots of different specific ways that each chemotherapy drug might interact with those rapidly dividing cells, but across the board that's what they're targeting, which means that while they target cancer cells, they are also affecting all of our rapidly dividing cells, like our hair follicles, like our GI tract, like our bone marrow, like our skin cells, and so that can cause a really really wide range of very significant side effects. We can see things like mylosuppression, which is what we saw in those first chemotherapy drugs you were talking about, which means your bone marrow is suppressed, which might be a good thing in certain treatments, but also might be a very negative side effect where you have significant anemia and now you have no immune system to fight off other opportunistic infections and things like that. They all cause things like fatigue and weakness. They're going to have a lot of gastrointestinal side effects, nausea, vomiting, potentially diarrhea, all kinds of things, your hair falling out. This is a common side effect of many, many different chemotherapy treatments. There's also a lot that can affect certain cells in our body, like, for example, our heart cells, because they accumulate in some of our tissues, and so you have to be very careful with the dosage that you're given across your entire lifetime, yep. And so all of this again has to be taken into consideration in your specific cancer yep.

01:03:49
Speaker 6: Right.

01:03:51
Speaker 5: One of the things that I think is probably new and different in how we use chemotherapy today compared to how we maybe used to use it in the past, is that there is of a very distinct decision on when to use chemotherapy, and so we might use different types of chemotherapy with different intentions at different points in someone's cancer journey. So we sometimes might use chemotherapy before surgery, and this is called neoadjuvant or sometimes pery operative, depending on the exact timing of when you give that. But the goal might be to shrink that tumor before we go in to try and remove it with surgery, right right. Other times we might use it after surgery, so adjuvant chemotherapy, and that means like, in addition to this surgery you're removal of most of the cancer tissues, We're going to also do chemotherapy to kind of kill anything that might be left behind or anything that's more broadly systemic or something like that. And these are not mutually exclusive. You might have one regimen for before and one regimen for after surgery, and you're using these in combination, so that's chemotherapy. Then we still have radiation, and I think it's very interesting to think about how I mean it's both old and not old.

01:05:05
Speaker 6: I guess radiation.

01:05:07
Speaker 1: It's old in the history of cancer therapy, but it's not old in a history.

01:05:11
Speaker 6: Of med science.

01:05:12
Speaker 5: Yeah, but even radiation therapy has come a very very long way.

01:05:17
Speaker 1: So targeted, yeah, instead of just like let's have X rays entire shoe store.

01:05:24
Speaker 6: Yeah, oh gosh.

01:05:26
Speaker 5: But especially with advancements I think in things like interventional radiology another shout out to interventional radiologist. Everywhere we can deliver radiation now to much more targeted areas. And sometimes this might still be external radiation. And so there's different techniques that you know, have different names. There's like stereotactic and sometimes it's called radiosurgery, even though a lot of times there's no surgery involved, there's no cutting open of anything. I don't know. Sometimes it's called radiotherapy, sometimes it's called radio surgery.

01:05:57
Speaker 1: What does surgery mean as a term? What's the room?

01:06:00
Speaker 6: And that's a you question.

01:06:03
Speaker 5: But these kinds of techniques in general that use external radiation usually use now very advanced imaging, so MRIs or ct scance or something in combination with radiation to deliver that radiation to very specific areas of your body. And that's to minimize the effect on all of your surrounding healthy tissues. And so sometimes what we'll see, and I think people who maybe have been familiar with someone who's had like a head and neck cancer or something like that, or a brain cancer, you might have to have made these very specialized masks that hold your head in a very very specific position and that's made only for you so that that radiation can be delivered to one specific area to target only that tumor and none of the surrounding tissue.

01:06:51
Speaker 1: Also, you should look up radio liken therapy because it's very exciting.

01:06:55
Speaker 6: Love it.

01:06:56
Speaker 5: And so how we deliver that, whether it's external or weather. There's something called break etherrapy, which is where you have radioactive material. So rather than external like beam radiation, you have radioactive material that's either put on something like a wire or a little seed they call it, and that might be placed inside or very close to a tumor. It might be left there for the long term, it might be there only during the course of a procedure. Again, this is where things like interventional radiology can really play a huge role in targeting tumors that are even deep inside the body, which is incredible. And we have other techniques now besides just radiation that I think kind of fall into this kind of procedural category where we might use heat or electricity or even ice freezing in one of theodomia episodisodes. Yeah, so we can do that cryotherapy directly to tumors. They use this for things like liver some liver cancers or liver tumors and things like that. Why, Okay, it's easy to access, that's one of the paysons. Yeah, and livers have really good blood supply, so then like the surrounding tissue is still going to have good blood supply, I think is part of it. It's also just a very commonplace that you get tumors, so yeah, things like that. So we've come a really long way in our use of radiation, and radiation still has very significant side effects, especially we use it a lot in you know, either anal or rectal cancers, and like the after effects of radiation on the surrounding tissue can be very severe in the long term. So it's still not, by any means a perfect system.

01:08:41
Speaker 1: No, I think. I think this is something that, like chemotherapy in general, comes up as a what will what will we look back on in the future and go.

01:08:51
Speaker 5: Whoa, whoa, this is what we did.

01:08:53
Speaker 1: This is what we did. I mean, and again, like, this is the like people are. It's not like people are working on this as a torture device. No, people physicians worked on this because they wanted to help their patients, save patients anticipated in this because they wanted to have their own lives extended or the lives of other future cancer patients.

01:09:11
Speaker 6: Like it's yeah, yeah, it's it is.

01:09:14
Speaker 1: But I agree, I know, I know, it's really it's complicated.

01:09:17
Speaker 6: It really is.

01:09:18
Speaker 5: So those are the kind of big three that we still use today. But there's a lot more ways now that we have to help treat and prevent recurrence of cancers going forward. So yeah, I mentioned therapy. Well let's get there. Okay, one short thing before we go, immunotherapy. Here we go.

01:09:40
Speaker 6: Ready.

01:09:41
Speaker 5: The only thing I wanted to mention aside from immunotherapy before I dig deep into that is that for some cancers we test for and I mentioned this in I think the last episode, for some cancers we might test for things like hormone receptors. So we know for some prostate cancers, for some breast cancers, these might be very hormone sensitive. And so for some people, part of their treatment might include hormone blockers, and this might be to halt the growth and also to prevent recurrence of cancers, you know, kind of maybe towards the end of a therapy or in some cases, like throughout the entire course of their cancer treatment. And so that's a very relatively I mean, hormones have been around forever, but I mean.

01:10:19
Speaker 1: The kind of the conceptual design of hormone therapy has been around since probably like the nineteen thirty something like that, when hormones were like becoming a thing. Yeah, the height of endocrinology, or at least like the beginning excitement around it. Yeah, but I don't think, like, I'm actually not sure when it became more of a routine or standard of care for certain cancers.

01:10:40
Speaker 5: Probably depends on when they figured out that these cancers were sensitive to hormones for their growth but you are right that I think that one of the biggest ways that we've changed in how we target cancers today is the advent of immunotherapy. So I want to talk a little bit about what that means because it's a very broad category, and depending I think on who you talk to, they might be more generous in what counts as immunotherapy, and I'm going to be very generous in what we count as immunotherapy, okay, And that means anything that is targeting the immune system with the goal of using the immune system to help target our cancers.

01:11:17
Speaker 1: Like, hey, he's over there, right.

01:11:19
Speaker 5: And so that might be in a relatively passive way. Passive doesn't quite work, but that's correct, actually, and that might be something like monoclonal antibodies. So monoclonal antibodies are things that we use very commonly now for a lot of different types of cancers. And these are antibodies that we give to a person that target specific cell receptors on their particular cancer in order to help our immune system recognize them. The reason I say passive is because it's like the antibodies are doing the flagging.

01:11:52
Speaker 1: Yeah, you're not telling the immune system is not like you're not going, come on, come on, come on, do this.

01:11:56
Speaker 6: It's like it's just.

01:11:57
Speaker 5: Putting these flags on yeah them. So that's an amazing way that we have found for a lot of different types of cancers. We have monoclone antibodies for breast cancers, for chematologic cancers, for a lot of different for blood cancers, for a lot of different types of cancers. But even you could think of a bone marrow transplant as a type of immunotherapy. A bone marrow transplant is wiping out the cancero bone marrow and replacing it with a new bone marrow. That is immunotherapy. All of this is leveraging our body's own immune system. Because cancers are incredibly good at evading this, they can manipulate a lot of our typical defenses. So the aim of a lot of the newest forms of immunotherapy is to reactivate a lot of the immune responses that are turned off or altered in some way or another during cancer. For some cancers can identify very specific receptors, for example, like her too New, which a lot of people may have heard of in breast cancer. It's not only in breast cancer, it's also in gastric cancers and things. But that's a specific receptor that is present on some cancers that we have an antibody that can target, and that can boost our immune systems response to targeting that cancer.

01:13:20
Speaker 6: Yeah.

01:13:21
Speaker 5: So by identifying those kinds of receptors that we might be able to target, we can help our own immune system recognize those cells as being damaged or as being cancerous and eliminating those cells. So monoclonal antibodies are one. There's another type of immunotherapy that is very very common now that's really quite new, like in the last I think probably ten or fifteen years, and these are called checkpoint inhibitors. Yes, yes, and these basically help to again turn back on a mechanism that cancer cells usually turn off. Ancer cells turn off this ability for our normal T cells to recognize cancer as cancer. So checkpoint inhibitors turn that back on and make our T cells go, oh wait a second, wait I see this, and you're not right?

01:14:14
Speaker 1: Yeah, how could I have missed this?

01:14:16
Speaker 6: Exactly?

01:14:17
Speaker 5: Exactly, And so those are very incredible. And we have a number of different checkpoint inhibitors that target different checkpoints, as it were, because different ones might be turned on and off in different types of cancers. Another very very exciting, super new kind of area of immunotherapy that has shown a special promise and has the most like approved treatments for blood cancers like leukemia's and lymphomas and myelomas is something called car T cell therapy.

01:14:45
Speaker 1: I know car T cell therapy.

01:14:48
Speaker 5: This is very exciting, too detailed for me to like go dig deep on, but it basically involves engineering your own T cells, So taking out immune cells from your body, led cells from your own body, adding things to them, putting them back in your body with these specific types of receptors on them that target your specific cancer.

01:15:12
Speaker 1: Basically saying, let's engineer these cells to become, you know, cancer detectors.

01:15:17
Speaker 5: Cancer detectors in a way that they aren't right now. And what's really fascinating is that they've been able to do this. And again I've got some papers if you want to dig really deep on the mechanisms here, because it is really fascinating. But they're able to do this in a way that also helps sort of jump over several hoops that our immune system usually has to jump through, so that you don't have to convince everyone in your immune system to get on board through.

01:15:42
Speaker 1: That red tape exactly get right to the cancer.

01:15:45
Speaker 6: Just get right to the cancer.

01:15:46
Speaker 5: So that's very incredible, and there's a lot of interest in being able to use these type of therapy for solid tumors as well. So far as far as I know, we don't have any therapies that are cart you sell for those yet, but I do think that that's one of the big ones on the horizon.

01:16:00
Speaker 6: And I could be wrong about that.

01:16:01
Speaker 5: I might have just missed some super new research, but it's very like immunotherapy in general broadly, and all of these specific types of immunotherapy, and I'm sure I'm missing some really are incredible in that they recognize this knowledge of basic cell biology and the basic cancer biology of how they are evading our immune system and are looking for ways to use our own immune system get it back online the way that it ought to be right. So I think that that's really incredible, and they show so much promise.

01:16:33
Speaker 1: Well, and I think it's just like thinking about the millennia of evolution, thinking about like last week's episode, and how cancer cells have to overcome have to evolve so many different mutations, so many different ways to then evade the immune system, proliferate all these different things. Yeah, our immune system does an incredible job of usually preventing that from happening in the first place, exactly. And so if we can just like be like, you know what, we have a really great cancer detector and cancer eliminator here, Let's just give it.

01:17:06
Speaker 5: A little bit of a boost, right, Let's leverage what we've already got in a way. And sometimes, very often these immunotherapies might be used in combination with chemotherapy and they might actually help to improve chemotherapy outcomes or mitigate some of the resistance that we see to chemotherapy. So, as one example, if a chemotherapy drug is inducing DNA damage, and that's the main thing that it's doing, is damaging the DNA, but the tumor cells that are there have these mechanisms that resist our immune system's ability to detect damaged DNA, where the tumor itself is like it doesn't matter how much you damage me, I'm still going to proliferate. Then immunotherapy might be able to help make those damage cells more.

01:17:50
Speaker 6: Visible to the immune system.

01:17:53
Speaker 5: So they kind of can work in tandem and in conjunction like that, which I think is pretty incredible. There are a number of papers from less than twenty years ago, ten, fifteen years ago, twenty eleven, and twenty sixteen. I found a few that are all about immunotherapy that say, this is the beginning of the end of cancer. We've done it. We've done it, and.

01:18:16
Speaker 1: It's not that, sorry, haven't we learned this lesson?

01:18:19
Speaker 6: I know.

01:18:20
Speaker 5: It's not that the hype isn't warranted, because again, immunotherapistess have shown and have made incredible bounds. They have made it so that some cancers that used to have absolutely no treatment can now be put completely into remission, if not cured in some cases, because of immunotherapies. So it's not that the hype isn't warranted. But for every promising aspect of these therapies, there are also side effects. There are also unforeseen consequences, and very often the reality that we see is that the successes in early or pre clinical trials don't always replicate on a big scale, and cancers still evolve and adapt even to our best immunotherapy efforts. Not everybody is going to respond to them. Not everyone is going to respond in exactly the same way. And so it really is that in all of the papers now about like what is the future of oncology, in the future of you know, cancer treatment, it is this idea that you had said, Aaron, of personalized or precision medicine, precision medicine and for cancer therapy. What that means is that no to cancer treatments might be exactly the same. We have to find a combination of medicines, of immunotherapy, of chemotherapy, hormone therapy, surgery and radiation and whatever we come up with in the future to treat your specific cancer and adapt that treatment to your cancer as it goes.

01:19:50
Speaker 6: Yeah, and you mentioned Aaron.

01:19:52
Speaker 5: This idea of adaptive therapy, and there's a lot of really strong preclinical evidence for this idea of adaptive therapy basically not aiming for cure but just sort of keeping things as they are. And it's not something that's used widely. It's mostly all in clinical or pre clinical research at this point. But I think that this concept is so fascinating but requires a complete paradigm shift in how we think about cancer, how we are measuring success in cancer treatments, and how we conceptualize cancer. Period one percent, right, absolutely, And I think that this is a really important framework because, like we've said so many times by this point, like some cancers we can cure, most cancers we cannot. But often when we go into an oncologist office, that is still the hope. And it is not necessarily clear that a therapy the goal might not even be curative treatment, but whether that goal is communicated clearly to the people undergoing it and their families may or may not actually happen. And you know, we do have palliative care and palliative therapies that are often used, and I have so much love for palliative care and pallative care physitions, but I think that they are seen as a last resort for many. They are seen as giving up. There's often kind of clashes, unfortunately, between oncologists and palliative care physicians in what their goals are. Whether the goal is you know, reducing the cancer, or whether the goal is the patient's goals and their families goals and what you want out of your life and.

01:21:46
Speaker 6: Things like that.

01:21:47
Speaker 5: And so I think that these ideas of using therapies with different goals in mind, it has to come a really long way before we're kind of there.

01:21:57
Speaker 1: It does, and I think that like part of the the challenge with it is the way that cancer treatments. And again i'll throw Nixon under the bus, I don't really care. Yeah, but this idea of like war on cancer, we throw enough money at this problem, we will come up with a solution, and then that fail to deliver on that promise, on that all of these money spent. That money was not ill spent at all. No, the problem was the messaging in the first place, and saying there is going to be this thing, and so then when that thing doesn't materialize, there's disappointment and there's a loss of faith really sometimes in the scientific and medical community because what was promise has not been delivered without seeing what actually has been delivered, which is incredible. And so this reframing of cancer as this unavoidable consequence of multicellularity, or this consequence of multicellularity maybe not entirely unavoidable, but this thing that maybe is cure the goal? What is the right goal? How do we measure success? All of these different things are not have not really had a seat at the table when it comes to the war on cancer exactly, and so I think that has been that has contributed so much as well to the fear surrounding it.

01:23:11
Speaker 3: Yeah.

01:23:11
Speaker 5: Yeah, I think one of our listeners actually wrote in, and I really love the way that he framed this idea, because he was saying that all of these analogies saying that we have to fight cancer, that it's this battle. This imagery implies that if you've lost, it's because you didn't fight hard enough.

01:23:28
Speaker 1: Are winners and losers, and you didn't fight exactly.

01:23:31
Speaker 5: And so I'm going to quote him and thank you so much for sending this email. He said, quote, cancer is not something that you fight, it's something you endure. And I think that that's just so powerful because it's true for so so many people. You know, despite how much progress we have made, and I don't want to understate how much progress we have made, right, there are also still huge disparities in cancer treatment on so many different.

01:23:58
Speaker 1: Levels, so much levels.

01:24:00
Speaker 5: On one level, not all cancers get the same amount of research funding, so not all cancers are as well understood. So we have these new paradigm shifting treatments like car T cell therapy for some cancers, and others, we have nothing new under the sun. And for cancers where new or exciting or very promising treatments still exist, these are not universally available by any means. So where you live in the world, where you live in this country in the United States, whether you live in a big city like Boston where you have your pick of cancer treatment centers, or if you live in a state that has no access to clinical oncology or in academic medical center in this country, what insurance provider you have, and whether or not they are willing to cover any of your treatments or what is recommended. Your race, your education, life level, your socioeconomic status. All of these things affect your access to treatment and have affected the outcomes that we see in cancer treatments and cancer mortality. And this has led to really huge disparities in especially cancer mortality, but as well as like diagnosis, which contributes to mortality exactly exactly. We'll talk more about that next week. But what we see in the US is that black Americans and Americans who live in rural areas, and Americans with lower education levels or lower socioeconomic status, which often go hand in hand, have significantly higher mortality rates across almost all cancers. And we'll talk in a lot more detail about that later. So I think it's true what you said already, Aaron, and what actually Lindsay Fitzharris said in our book Club episode that like, are we going to look back on cancer treatments how we do it today in thirty or fifty years and say, WHOA, I can't believe that we did these things. And at the same time, the way that we treat cancer today is drastically different than how we treated it ten, even twenty, even five years ago for some cancers. So it's really, it's really really incredible how much progress has been made. And this has been made because of funding for basic research. This has been made because of funding for clinical trials, and right now that funding has been cut in the US hugely, hugely, nearly four billion dollars so far in cuts to the National Institutes of Health and NSF, including over seven hundred and ninety million dollars from the National Cancer Institute alone. And what is so scary is that the therapies that we have today came from research that was done five, ten, fifteen, twenty years ago.

01:26:54
Speaker 1: There's a time lag to all of this.

01:26:57
Speaker 5: So we will not know the impacts of all of the cuts that we have seen to basic research and clinical research that has happened this year and last year, for the next five or ten years, but there will be impacts.

01:27:12
Speaker 1: It's investment, Like, there is no other way to look at this. Funding for basic research, funding for clinical trials, funding for any kind of scientific medical research is investment, investment in our future. And the fact that that's being cut, I mean, yeah, what more can we say that hasn't been said. It's shortsighted, It is ridiculous. It shows a complete lack of understanding of the way that the world works and how each individual person has benefited directly from basic research.

01:27:44
Speaker 5: Yes, so a huge thank you to everyone who has ever participated in clinical trials, in any kind of research trials, all of you who are working on research, who are doing that research like it. It cannot be overstated how impactful that is and will be.

01:28:03
Speaker 6: And thank you. That's all.

01:28:05
Speaker 1: Yeah. I had a little note here too that was like thinking about the history of treatment and how far we've come, and how many people have been involved in that, in the fundraising for it and the raising awareness of it, in the participating in clinical trials, and the being willing to organize a clinical trial. Everyone who has been support staff the pis everything takes.

01:28:25
Speaker 5: So many people. Yes, and it is so valuable. And hopefully this will change and it will continue to be valued as it is in other countries and things like that. But I have a lot of interesting articles. If people want to read more about what we anticipate, some of those impacts might be Yes, so that's cancer treatment today, answer.

01:28:47
Speaker 1: Treatment A survey of the existing treatments.

01:28:50
Speaker 6: Yes, that was great, thanks, Yeah, sources.

01:28:55
Speaker 5: Yeah, yeah, people want to read more. I want a lot more, a lot.

01:29:01
Speaker 1: Yes, let's see again. I'll shout out The Emperor of All Maladies. Great story about the by Siddartha Mukherjee. Great story about the history of different cancer therapies, but especially chemotherapy is the main focus there to learn more about the history of surgery Wild and post in well, Okay, wild at All from twenty fifteen called the title The Evolution of Cancer Surgery in Future Perspective by Hater from nineteen ninety eight. The Clinic as Laboratory The case of Radiation Therapy nineteen eighteen ninety six to nineteen twenty Really interesting about this transitional shift between evidence supported research and how that kind of flew in the face of experience supportive decisions. Then by Galmarini at all from twenty twelve, cancer Chemotherapy a Critical Analysis of its sixty years of history.

01:29:54
Speaker 5: Okay, I have quite a lot of papers for this one, including a lot of fis on different types of cancer. So if you're interested in like breast cancer treatments today, colon cancer treatments today, I have a lot of papers that you could look at those details, but some broader ones I mentioned. There was one from twenty eleven by Melman at all in Nature called Cancer Immunotherapy Comes of Age, which is really interesting read. I have one on car T cell therapy from Patel at all twenty twenty five that's called from Concept to Cure the Evolution of car T cell Therapy that goes into a lot more detail on what exactly that is. I have a couple other papers on adaptive therapy and things, but I also just want to give a shout out to to These are not peer reviewed. These are articles that were written by Nature staff members, but they're about kind of trying to forecast what some of the impacts of these funding cuts might be. Because we can't know right now, and so these are kind of interesting papers that you could take a look at. They're just sort of articles. They're not, again, not peer reviewed, but they're interesting. And again I got a long list here, so go to our website. This podcast would kill you dot com to see all of this is from this episode and every single one of them one.

01:31:03
Speaker 1: So we've read so many papers. Thank you again so much to the providers of our first hand accounts. Yeah, it means the world, it really does.

01:31:12
Speaker 6: Thank you.

01:31:14
Speaker 5: Also, thank you to John and Brett, our respective husbands, for all of your help and letting us talk your ear off about this. I also want to shout out my friend Julia, who is a palliative care physician and she let me talk in her ear for a long time about my feelings about all of this. So thank you Julia.

01:31:31
Speaker 1: Thank you, Juliah. Thank you to Bloodmobile, who provides the music for each episode, this episode and all of our episodes. Wow, I haven't said that in a while.

01:31:39
Speaker 6: In that way since a week from week today.

01:31:42
Speaker 5: Thank you to everyone in the exactly right studios but we're recording this today. Thank you to Tom and Leanna and Pete and everyone who's here today, Jessica and Corey everyone.

01:31:55
Speaker 1: Yes, thank you, thank you, and thank you to you listeners. You make us, make you make this happen. You thank you for listening, participating in this podcast in some way.

01:32:05
Speaker 6: We really appreciate it.

01:32:06
Speaker 1: How do we not do this better at this point?

01:32:09
Speaker 6: Listen, We're trying.

01:32:10
Speaker 1: We're trying. Thank you. Patrons. Also, your support means everything. Yes, thank you, thank you. Until next time, wash your hands.

01:32:18
Speaker 6: Stealthy Animals

01:32:25
Speaker 3: A