Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams. In our last episode, we had this fantastic discussion with Dr. Lynn Schucter and Dr. David Porter about cancer therapeutics in the modern day. We really ran out of time as we were recording the podcast. To really get into some of the issues we wanted to discuss, I asked them to come back again so that we could sort of summarize what we talked about. This is complicated stuff for many of us, and it's good to hear it twice, but also finish up with some practical applications of the therapies we discussed, theoretically, in a clinical environment and what it means for our patients.

So, welcome back to Dr. Schucter. Dr. Schucter has enhanced Oncology immensely, both regionally and also nationally in her role as the Chief of the Division of Oncology at Penn and also the head of the American Society of Clinical Oncology. So Lynn, thanks again for coming.

Lynn Schucter, MD: Thank you so much for letting me join you tonight.

Host: And again, here is Dr. David Porter. Dr. Porter's a liquid oncologist. I'm going to be throwing him all my liquid oncology questions. I mean, that's lymphomas, leukemias, and so forth. He's the Director of the Center for Cell Therapy and Transplant and the President-Elect of the American Society of Transplantation and Cellular Therapy. David, thanks for coming.

David Porter, MD: Yeah. Thanks for having us back.

Host: Well, I just want to quickly add a little bit of summary from my perspective of last time. One of the key concepts that jumped out at me is specificity, that we are getting better about identifying the cancer and not harming the human. And that is a major thing. And we're doing that with, we discussed, molecular targeted therapy. And, you know, what also struck me as I sort of listened back through our first part one, was how much of this is immune based and how much of the success either involves, you know, monoclonal antibodies, which is of course immune system, but also specifically attacking cancers with therapies that either allow the immune system to do its job or enhancing it so that it can more specifically target cancer cells.

By the way, I just want to say, you know, I'm old enough to remember that we were still trying to figure out the best way to attack cancer. We thought angiogenesis, we could stop them from making new blood vessels. But it seems like at least in the last decade or so that we're really moving in and exploiting the immune system as a way of targeting cancer.

Lynn Schucter, MD: Right. And so, you've just described it very well. So at the same time, sort of two new approaches emerged. One is targeted therapy where we understand the genetic makeup of a cancer, the somatic mutations and figuring out then which drugs can target that mutation, so the specificity there, and understanding actually that some cancers share this information that a BRAF mutation could occur in melanoma and in colon cancer and in thyroid cancer. So, that's been interesting.

And then, at the same time, this new approach with immunotherapy. As we discussed, we thought there were many clues to using the immune system, but it really has only been in the last decade that understanding how to tweak it, the immune system really effectively would really kill cancer cells and, as you say, spare many of the usual side effects. So, it is a total sea change in terms of being more specific with our treatments, and that means way fewer side effects for our patients.

Host: So when we left off, we were talking about CAR T therapy, and that's where I felt like we got a little rushed at the end, David, because you were explaining something really cool, it's somewhat developed at Penn, and I'm just going to give a little bit of a layperson summary here of CAR T therapy. You are taking T-cells out of the patient. You are using gene therapy so you're integrating into the genetic structure of that T-cell the ability to make a new protein, an antigen receptor that then gets placed in the membrane of the T-cell that allows it to recognize the tumor as foreign or as something you want to attack, not necessarily foreign, depends on what the antigen is that you're attacking, right? And also has that ability to sort of tell the T-cell to attack. So, you know, in a way, you've gathered all these T-cells. You know, you train them to be hit men for a specific type of cell, and then you just set them loose in the body. And that's where we left off, David, right?

David Porter, MD: Yeah. I couldn't have explained it better myself. It's exactly right. You know, it has been known for many years, since probably the mid-1960s even that human immune cells could fight cancer. It was shown in the setting of bone marrow transplant even, that when you do a bone marrow transplant, you give a patient a new immune system and that donor's immune system is critically important to why bone marrow transplant works. And then, it took about 30 years to figure out it was the donor's T-cells that really were the main component, except it's very nonspecific. Yes, they can kill cancer cells, leukemia cells, but they can also damage other parts of the body in the setting of bone marrow transplant. We call that graft versus host disease, which is something, in fact, many in your audience may see as patients leave the care of their bone marrow transplant physician.

What CAR T-cells do is it takes those human T-cells and it reprograms them so that they specifically can attack something on a cancer cell, presumably any cell, in fact, it doesn't have to be a cancer cell. Just the way you say it, it genetically puts in a new gene. That's a chimeric antigen receptor. Remember, we said the term chimeric comes from that mythical beast in Greek mythology that's made of different parts. This gene, this protein has an external component. That's the antigen receptor, it's a fragment of an antibody, so you can design that to target whatever you want.

The most common scenario, the most effective one to date, is targeting CD19. It's on just about every B cell and B cell malignancy. Then, there's internal sequences in this synthetic protein that keep that chimeric antigen receptor stable in the T-cell membrane and internally our T-cell activation sequences. There's the CD3 zeta domain that tells the T-cell to become activated and a co-stimulatory domain. People, I'm sure, remember from immunology, you need signal 1 and signal 2. This molecule provides both. So, the T-cell can now recognize an antigen that you programmed in. When it does that, it has the sequences internally to activate the T-cell to co-stimulate the T-cell that allows it to start killing, it also allows it to start dividing. It can divide thousands of fold in the body and dramatically magnify whatever response can happen. So, not only does the T-cell kill, it continues to kill and continues to kill, and it can-- Carl June coined the term, these are serial killer cells because one cell can kill thousands of cancer cells.

Host: I have a question about the target. You mentioned that CD19 is on all B cells, and I don't want to go too far on the rabbit hole on this, but I'm curious, and it struck me twice when I listened to it, but CD19 is on all B cells. I mean, why don't all B cells continue to be killed as opposed to, you know, the lymphomatous ones?

David Porter, MD: Yeah. It's not a rabbit hole and the answer is they do. We talk about this as very specific therapy. In fact, it's nonspecific in that sense. CD19 is on just about every B cell malignancy, 90-95% of them, but it is also on normal B cells. So when CAR T-cells are effective, they develop B cell aplasia. And one of the concerning complications is hypogammaglobulinemia. Patients don't make antibodies because they have B cell aplasia and they're susceptible to infections.

In some cases, the CAR T-cells persist, and patients can have B cell aplasia for years and years. We know, however, from much of our experience with cancer therapies, that most patients can live relatively normal lives without B cells. We know how to manage that. We know how to care for those patients. We can give them intravenous immunoglobulin infusions to replete their antibodies that they don't make.

So in that respect, it is nonspecific and that is a complication of effective CAR T-cells. In some cases, the CAR T-cells go in though, and they do their thing. They kill the lymphoma, they do kill normal B cells. But then, the CAR T-cells can die off, they don't persist. Normal B cells can recover, and the cancer cells may never recover, and patients still may be cured and have normal B cell recovery, and both scenarios actually happen.

Host: So, the challenge, and we talked about this when we talked about solid tumors with this therapy moving forward is finding appropriate targets that you can design into that CAR, chimeric antigen receptor. And that, for instance, solid tumors, you said, David, it's difficult to find adequate targets or has been difficult to find adequate targets. And also, they tend to hide from the immune system, and certainly since you're using the immune system. And we left off with the point that if we took a checkpoint inhibitor, which helps to unmask the cell and sort of take away its shield from the immune system with one of these therapies that we may see some success with solid tumors as well.

David Porter, MD: It's certainly a really active area of investigation and there are numerous clinical trials trying to do just that with checkpoint inhibitors or other molecules, perhaps other cytokines that activate the T-cell when it otherwise couldn't be activated.

Host: So, somewhat of a variant on CAR T therapy that I read about was using tumor-infiltrating lymphocytes, right? So, these are you take a piece of the tumor out of the body. In the pathology, you find live T-cells. You then take those T-cells, you multiply them in the lab and they already are fighting the tumor. So, you just have to sort of increase the forces that are there, and then you infuse those back in. Lynn, that's an approach for solid tumors, right?

Lynn Schucter, MD: Right. And especially, it has been applied in melanoma. So, this work began at the National Cancer Institute with Dr. Steve Rosenberg. He developed this technology, TIL, which as you said, we do think the lymphocytes that are in the tumor do recognize the melanoma, they're there present in the tumor. And he really pioneered this approach where you take out the tumor, the tumor cells die, the melanoma cells die, you expand the lymphocytes. And then, you re-infuse them into the patients.

Now, the challenge with TIL is they may be pretty good at manufacturing these cells, this product now, but you have to give it in combination with some chemotherapy and with other immune boosters. So because billions of cells are being infused, you have to sort of "make room" for those cells. So, patients actually, as part of the TIL therapy, go through almost like a mini bone marrow transplant. They're admitted to the hospital. They're in the hospital for about a month. They actually get chemo, fludarabine and Cytoxan, to really deplete their white blood cells and their platelets, and patients really become neutropenic, thrombocytopenic. And then, those TIL, the patient's own lymphocytes, thought to be smarter, and some studies modified in some way to make them even smarter, now there's room. But then, you also have to give that in conjunction with interleukin-2, which has a lot of side effects. So, that's a cytokine that has a capillary leak, low blood pressure.

So because, you know, Bethesda is not that far from Philadelphia where the National Cancer Institute is, we've been sending our patients from Penn to get the TIL protocol for more than two decades. And occasionally, this therapy would work incredibly well. One treatment, patients are really sick, but we've had patients who were refractory to all prior therapy and no signs of melanoma with one course of treatment. Now, they were taking really healthy patients. We would say you have to be an Olympic athlete and have metastatic melanoma to be able to tolerate this. But I'm not going to say fast forward because it's 20 years later, many clinical trials, many different approaches, this approach with TILs has been FDA approved for the treatment of metastatic melanoma patients. There are hurdles still, but it's a recent FDA approval. And for some patients, this is a really good approach.

So, we have a ways to go from this CAR T-cell approach, which is great specificity. Yes, we share side effects in terms of cytokines and managing these really complicated side effects. But it's really the first time that TILs have been approved in a solid tumor, and we really do think we're going to be able to build on this, understand how to manage the side effects, how to carefully select the patients. And David and his service who are so experienced in giving CAR T-cells, you know, our house staff who understand how to manage the side effects, how our nurse practitioners know how to manage the side effects of CAR T-cell, our inpatients at Penn are going to be managed by the same service. So, this is where our worlds overlap in such a beautiful way that we are really learning about how to manage these types of treatment now for solid tumor patients.

And, you know, the CAR T-cell approach and others like this, you know, being explored for brain tumors, for glioblastoma, David's really involved with those studies as well. So, we do see a real path here that cellular therapy, these are examples of cellular therapy are going to be effective in solid tumor, you know, both finding the right targets. We do think adding checkpoint inhibitors like PD-1 antibodies are going to help this. And, you know, now we're figuring out strategies to make it less toxic and more effective. But it's a long road, but we are really excited that it's here, FDA approved, and it'll be available for our patients very soon here at Penn.

Host: Before we leave immunotherapy, is there anything else more to say about it? I think you kind of just summarized where we're headed with this. Is there anything else on the horizon that you feel really excited about that maybe is not right ready for prime time, but is worthy of discussion?

Lynn Schucter, MD: Before I do that, let me just say medications like pembrolizumab (Keytruda), nivolumab, (Opdivo), you know, these are now approved in probably 50 different types of cancer. I mean, it's amazing how many cancer types, liquid tumors and solid, you know, some require certain target about PDL1 overexpression to be a candidate for these. Some don't require any test to see if it's appropriate to treat because the response rate is so high. I will say we use these first for metastatic stage IV disease, understand the side effects, understand the sometimes curing stage IV cancer, we talked about that before. But what we're seeing now is moving these into earlier and earlier stages of disease. So, you know, this was really just for stage IV, then for metastatic throughout the body, then it may be stage III, just lymph node involvement, and now earlier stages of disease.

And I guess one other point, we'll talk more about the side effects again and how we might collaborate, but what we are learning now too is we probably don't need to use as much as we've been using. So when we were starting immunotherapy, we gave it for a minimum of a year and some studies, three years. Because, you know, once the initial potential side effects occur, 20% of patients have side effects, you don't actually see late side effects very often. And so, this is a therapy that you could keep giving and keep giving.

We've had patients, you know, initial studies were on for five years. But there's some recent data that shows maybe two doses is enough, maybe one dose is enough. And, you know, specifically in melanoma, giving these combination of ipilimumab, a CTLA-4 antibody, with a PD-1 antibody, two cycles pre-op, if that patient has a complete pathologic response. We don't give any additional treatment, two cycles. So, our immunology colleagues have been telling us, you don't need to give so much of this. You don't need to give it for so long. T-cell exhaustion occurs. So when we see this now, complete pathological response, which is a very good predictor for outcome, we are understanding that we don't need to give so much. So, that's a big shift in how we're thinking about these medications.

Host: Incredibly interesting and cool. So, I wanted to dig into some specific examples, but I'm actually going to throw a curveball here. Lynn, from your broader perspective on solid tumors, I know melanoma has had dramatic advances. Are there any other areas, any other solid tumors that are really making a lot of progress, let's say renal cell, breast, colon, where these are really having a big impact?

Lynn Schucter, MD: Yes. I mean, all the tumors that you just mentioned, you know, we're applying these immunotherapies, but let me mention one other new approach that we didn't so much talk about. And that is the antibody drug conjugates. So, this is combining, so let's say we know the target let's take an example of breast cancer. So, everybody knows about HER2/neu. We measure HER2/neu expression on breast cancer. Primary care physicians are really familiar with Herceptin. That's been around for a long time, but now we are taking Herceptin, and conjugating it with a chemotherapy or a toxin. These are these antibody drug conjugates, ADCs. This is an explosion of new approaches. And so, these are being used very commonly in breast cancer with Herceptin as, you know, so in HER2-positive breast cancer, you know, either with a Taxol-like drug or similar, but a chemotherapy drug. Maybe people have heard of TDM1 and HER2 or Kadcyla. These are different HER2 receptance conjugated to chemotherapy.

Now, what's been really interesting is that we were only using Herceptin, say, for highly overexpressed HER2/neu, 2+, 3+ testing. But what we now know is 1+ positive HER2, using these antibody drug conjugates, it works for metastatic breast cancer. This was actually one of those standing ovations at ASCO two years ago when these results came out because it's a whole new class of women with metastatic breast cancer, HER2-low. You know, we're getting Herceptin very well tolerated when you combine it with chemotherapy target. Of course, there's more side effects, but it's really trying to bring specificity to monoclonal antibodies. And this ADC world exploded in drug development. So, this is true across so many different solid tumors, I'm sure in liquid oncology as well. I would just say for the primary care, this is like, "Watch this space." It's really exploding. And, you know, we're getting into more toxicities again. So, we're really trying to then figure out which patients really would benefit from these treatments and then sparing patients who aren't going to benefit and we don't want these patients to get those side effects.

Host: So, just to summarize what you just said in my terms and sort of put it in the context we've been talking about, HER2 was something that already was specific to breast cancer cells. So, you were able to target that and you already had a monoclonal antibody that you had developed that targeted that. And now, you just add a payload, as David had expressed in the previous podcast, that's now this drug that goes there and does its thing, and again, specificity in action, right?

So, David, in the liquid oncology environment, let me ask you first about CAR T therapy. Where does that fit in the lines of action? You know, and you had mentioned that CAR T therapy was sort of, you know, people had failed multiple other lines and they were sort of towards the end of options and then they were getting CAR T therapy. How has that changed?

David Porter, MD: Well, I think it's, you know, one of the many things that's changing dramatically. It is true in oncology therapies that just about any new therapy is tested in patients who are running out of options. And so, CAR T-cells when first tested 10, 14 years ago were for patients with multiply relapsed, far advanced refractory disease. The vast majority of patients destined to die of their disease without effective therapy. And many ended up being cured. And once you learn the efficacy and understand the toxicity and toxicity management and can determine where and when it's safe, it starts moving up in lines of therapy.

So in just the past couple of years, there have been at least two CAR T-cell products for lymphoma, for instance, FDA approved as second line, not third and fourth line. The CAR T-cells for myeloma were initially approved as fourth plus line therapy. And that means patients have had, you know, years of all kinds of treatment are now approved as second-line therapy. And the newest and most exciting clinical trials, in fact, are as initial front-line therapy. For selected patients, maybe with higher risk disease, you can predict that they're not going to do well with standard therapy. That's important in any of the diseases that CAR T-cells are applied to.

I must say one of the areas that I'm most excited seeing it move to earlier lines of therapy is in ALL, in pediatric ALL. The pediatric ALL is probably one of the greatest success stories in all of Oncology. It used to be uniformly fatal. Now, pediatricians cure 90% of these patients, but there's still kids who don't respond to standard therapies. They still die of leukemia. CAR T-cells have been dramatically effective for many of these patients with relapsed refractory disease. In fact, the first FDA indication for CAR T-cells was pediatric ALL.

The conventional therapy for pediatric ALL, for any ALL, is multi-agent chemotherapy, four, six drug combinations of chemotherapy for a year or two years, followed by long-term maintenance. These are kids who are supposed to be in school. They're supposed to be doing athletics, and they're going in every month or every week for chemotherapy. There are incredible long-term side effects. Imagine you could apply a one-and-done therapy like CAR T-cells. You collect their immune cells, you make the CAR T-cells, you give them to them and can cure them with one episode of care and spare them that long-term two years in and out of chemotherapy. Those clinical trials are now ongoing as initial therapy in just about any disease. And I think that's one of the many exciting things that we're seeing with all kinds of cell and immunotherapies.

Host: I think we all know a child who's had ALL. My son, I think two of his fellow students had ALL. So, it's a common thing. And again, you know, as you said, a very successful area of Oncology, but not without its downsides, right? How about monoclonal antibody drug conjugates, like Lynn was describing in the liquid oncology environment, or things that aren't sort of cell-based?

David Porter, MD: Well, of course, Lynn hit it right on target to go with the theme of our discussion. Those antibody drug conjugates are very important, exciting, old and new therapies in the hematologic malignancies as well, particularly against B cell malignancies, antibody drug conjugates for tumors. There's also novel targeted therapies with radioactive conjugates. They're used to treat certain kinds of leukemia. They have been used in the setting of bone marrow transplant when you want to target, say, radiation only to the bone marrow cells and not to the rest of the body. So, you can use antibody radiation conjugates just like you can antibody drug conjugates. And it really is a rapidly growing, exciting field.

Host: Are you doing less bone marrow transplants than in the past, or are we still needing to do those?

David Porter, MD: We're still needing to do them. One would think with all of these new therapies, there would be fewer and fewer transplants. I've spent my entire career as a bone marrow transplant physician, and I will say that the vast majority of people I know have a goal of trying to put yourself out of business, right? We wish that there were better, safer therapies. It seems like we are doing more and more. It's in part because we're diagnosing more people with cancer. People are living longer, they are living healthier with cancer, so more patients are fit to be able to go through a bone marrow transplant.

I also think we've made tremendous progress in the field of transplant where it's gotten safer and more practical. When I first started, the definition of too old was about 50 or 55. We now routinely transplant patients well into their 70s, certainly mid-70s if not older on occasion. So, the disease indications have expanded, but the patient population has expanded dramatically. Previously, there was nothing for those patients. You just said, "I'm sorry, you're too old, you can't do it." Now, there are potentially curative options. So, we are still doing many transplants, fortunately or unfortunately.

Host: And those are in the leukemia environment as well for leukemias and then multiple myeloma, I assume.

David Porter, MD: No, there are different kinds. There's the autologous transplant where the patient uses their own cells, or allogeneic where they have a donor. The most common indications are things like multiple myeloma or non-Hodgkin's lymphoma for an autologous or self-transplant. The donor transplants, our most common indications are things like AML, acute myelogenous leukemia, or myelodysplasia, ALL, certainly in kids, some in adults. I will tell you the most common indication for an allogeneic or donor bone marrow transplant used to be CML, chronic myelogenous leukemia. I think we mentioned last time we talked that I think this explosion of targeted therapy started with the development of imatinib or Gleevec. BCR-ABL tyrosine kinase inhibitor was FDA approved, I think, in 2000 or around there. We now rarely do bone marrow transplant for CML, for instance. That has just had a dramatic impact. It's gone from the most common indication to a very, very unusual indication just to show you how these targeted therapies impact that world as well.

Host: Well, David, I want to ask you about lymphoma, because we see lymphoma. I have a patient who's actively being treated for lymphoma right now. You know, I remember from my training, high-grade lymphomas were more curable, because they were more aggressive and was more responsive to cytotoxic chemotherapy, but it could kill you sooner if you didn't treat them. Low-grade lymphomas, smoldered for years, but were harder to cure. And then, our intermediate were somewhere in between those two extremes. Has that changed?

David Porter, MD: It really has not. There are the low-grade lymphomas exactly as you remember. They often smolder at times, maybe don't even need treatment. The adage fits very well. If it's not broken, don't fix it. They are generally thought of as incurable with standard types of chemotherapy. I pick those words very carefully when I talk to patients because they're not incurable. They're incurable with our typical kinds of chemotherapy that we treat lymphoma with, and even antibody therapy. And there's pretty good data that treating many of these diseases earlier doesn't result in any better outcome than treating them later. And since any of these treatments can have side effects, you can wait to treat them until they need to be treated. If it's not broken, don't fix it.

They are potentially curative. We've known for years that bone marrow transplant can cure even low-grade lymphomas when chemotherapy can't, but they are dangerous and risky. They are still today associated with a 10-20% treatment- related mortality rate having nothing to do with lymphoma. But I also believe we certainly have enough data now that CAR T-cells can cure low-grade lymphomas for those patients who need it when they don't respond well, when they need treatment and standard therapies aren't working.

The intermediate grade or high grade lymphomas are, as you say, potentially curable with multi-agent chemotherapy. We now talk about chemoimmunotherapy. We rarely give chemotherapy without a monoclonal antibody as part of the treatment regimen. The regimens are getting better, more patients are entering remission, more are being cured with chemotherapy. There are still people where chemotherapy doesn't work. Those patients are incurable, again, with standard types of therapy and can be cured with things like bone marrow transplant, peripheral blood stem cell transplants, and now even CAR T-cells. So, the ability to approach these patients has really expanded dramatically.

Host: A common smoldering malignancy I see is CLL, which is obviously most common in older patients, and can go for years just smoldering along in asymptomatic state, but we're starting to use the therapies we've talked about for that now, right?

David Porter, MD: Absolutely. CLL is very much like the low-grade lymphomas. It is a smoldering hematologic malignancy that we use the term chronic to mean lasts a long time, doesn't grow quickly. And there are patients who have had CLL for 10, 20 years and never needed treatment. There is a very, very long list of treatments that gets longer and longer every year that are incredibly potent, powerful, and effective for CLL. But again, the standard therapies are not curative. The good news is the majority of patients don't need to be cured. They can be monitored. And as you say, you have patients with CLL. This is a disease that in many cases can be monitored by a primary care physician and see an oncologist on occasion or when things aren't working smoothly. But there are still patients when the standard therapies don't work who need something else that can be a dangerous, aggressive malignancy. About 10% of patients will have what's called a Richter's transformation. The slow-growing chronic CLL can transform into a very aggressive lymphoma that can be imminently life-threatening, that needs more intensive therapy. And again, these are situations where modalities like stem cell or bone marrow transplant historically had been the only potentially effective therapy, but at enormously high risk, and now very amenable potentially to CAR T-cell therapy in any of those scenarios.

Host: That's very exciting. Okay. So, I don't want to go too far. I realized as I was sitting here, there was one other set of diseases that we see quite commonly in primary care that I think is in your area, David, and that is the myeloproliferative disorders. CML is a myeloproliferative disorder, we've talked a lot about CLL. But we see polycythemia vera, we see essential thrombocytosis, not so much the myelofibrosis and others, but those are JAK2, right? So, they all have a common mutation, right? And we have a therapy for that.

David Porter, MD: Yes. So, it is, again, one of the exciting successes of understanding the biology of these diseases. the molecular pathology, if you will, there are JAK2 inhibitors that are oral medications that are readily available and FDA approved, the most common one being a drug, ruxolitinib and now iterations on that. These are situations where the targeted therapies can treat very often side effects and various complications. Though are not curative, they can control the disease. In some cases, they control it for many months until more definitive therapy can be given. In some cases, they can control the disease for several, if not many years, but it is an example of targeted therapies that have been developed once you understood the biology of the disease.

Host: So, I have on my agenda to talk about the future, but we've really covered, I think, a lot of that ground already. I do want to circle back to some of the traditional stuff, which is still around, taking out tumors early with surgery, doing radiation therapy, and then, you know, just classical cytotoxic chemotherapy, which I think we've talked about as being integrated into some of these lines of therapy already.

And then, you had talked about for surgery, that oftentimes you're, you're working with the surgeons, the oncologist is working closely with the surgeons. You're often doing neoadjuvant chemo before operating. And you had mentioned that actually exposes the cells to the immune system in a way that allows them to be more sensitive before the surgery when there's a, I guess, a larger bulk of tumor. But how is surgery changing in all of this? I guess that's a very broad question, but how is that environment changing?

Lynn Schucter, MD: Yeah, I think surgery has changed quite a bit in the sense of we understand that, again, less is more. And so, the techniques and what's involved with the surgery, it's not functionally affecting patients. It's a much smaller surgery. So if you think about how we treat breast cancer, I mean, the extremes of going from radical mastectomy to now lumpectomy, but even those techniques of breast conservation and how to do the right amount of surgery, you know, with the right margins, that is just so advanced and there's new techniques. Maybe you've had Sunil Singhal on maybe about this tumor glow, but you know, the idea is also trying to understand what's the right amount, but not too much and identifying where is that edge of normal to abnormal.

So, I just would say, our surgeons would say, that it's largely outpatient surgery. It's much, more specific and targeted. Occasionally, it's even with local anesthesia and not general anesthesia, depending upon the circumstances. It's so important that we work with our surgeons in terms of accurate staging. And so, of course, they're involved with removing the primary tumor, but it is this multidisciplinary approach of understanding. You know, has it traveled to lymph nodes? I'm sure you've touched on this topic of sentinel lymph node mapping, which is such a great technique to find microscopic regional lymph node involvement. And that really has evolved to so many of the solid tumors.

And then, it's incredibly uncommon now for our surgeons to do completion lymph node dissections, where we take out eight or 10 lymph nodes. And those complications of lymphedema, which is so challenging, especially in the leg and in the arm. So, our surgeons are, you know, more and more expert on not such big surgeries, just really doesn't affect function. And I would say a big focus is also decreased complications of surgery. They're so in tune to decreasing risk of bleeding, clotting complications, infections.

And then, we work really closely again with our radiation oncologist. I mean, they've understood the long-term consequences of radiation to normal tissue. You've seen that in practice that our patients, it's amazing, not amazing in a good way, but how much tissue changes over time. Like somebody who's had a neck dissection, radiation therapy to the neck, you see 15 or 20 years later how changed the anatomy is, the carotid artery risks, like understanding delayed toxicities of these treatments. So, same advances with the specificity of radiation therapy, giving less, giving shorter courses. It used to be six or eight weeks in breast cancer. Now, it's much, much shorter courses of treatment. I'm sure you've touched on proton therapy, which is really a great way to decrease the risk of toxicity to normal tissue.

So, all that we've described on the specificity of systemic treatment is certainly happening in radiation oncology and surgery. And, you know, we touched on this concept of neoadjuvant, so we're understanding more and more what's the right sequence. So, is surgery the right first step? Is immunotherapy the right first step? You know, I do have to say about just the multidisciplinary nature of how we deliver cancer care at Penn. I have to say, I think this is one of the most amazing distinguishing features. You know, there are tumor boards for every certain type of cancer. So actually, in GI cancers, they have five tumor boards a week, different parts of the body. And, you know, with surgeons, they're meeting at 7:00 a.m. But the multidisciplinary nature of cancer care is also actually a remarkable advance in how we work together and figure out the right order.

And then also, in the follow up phase, do people really need to see all of us. We really want to simplify the patient's followup as well, so we work together also in that way so that patients are not coming to see all of us all the time when we are curing more and more patients. But this multidisciplinary nature gets back to this specificity and the right amount of treatment, the right sequence, and partnering together on the best care. Really important.

Host: What I'm noticing in my practice is that a lot of these cancers that I, you know, really feared in many ways, I'm just seeing becoming more chronic diseases as you're applying different modalities at different times of their course of disease. And people are just living longer, you know, and keeping at it. So, it's terrific. And you can see it in primary care, you can see these folks coming back and you're like, "Wow, you had metastatic breast cancer 12 years ago. And here you are, you're working and you're coming in and I'm talking to you about smoking cessation," you know?

Lynn Schucter, MD: Thank you for doing that.

Host: Yeah. These are the good things to happen. Well, I've now left us with only a few minutes. I'm glad we did two sessions because clearly I had a lot of questions. Let's just focus on the primary care physician a little bit. I mean, we see our role, I think, in early detection, and so we focus on this quite a bit. Lynn, I make sure all my patients are seeing a dermatologist if I'm not doing a full skin exam. But I want to get to this issue of survivorship a little bit because these folks are coming back to us. And, you know, I have a patient who's on pembroluzimab. And I have a patient who's had CAR T therapy and is coming in to see me. And you had touched on it just now then when you said that the patients are not coming back all to see you or to see everybody. They're seeing one identifiable individual and then follow it forward. But, you know, I guess, maybe I'll ask both of you, David, we can start with you. After somebody's had CAR T therapy and they come back to me, is there something I should know about?

David Porter, MD: Yeah. And it's a really good point because the only way that enough people are going to get access to all of these therapies are if people who maybe don't live near the major academic institutions can go back to their primary care physician and their primary caregivers. What should you know about? The couple of really important things that we make sure to educate our partners on are things that we touched on like hypogammaglobulinemia. Many of these patients end up with B cell aplasia that has real implications to things like giving them vaccines or monitoring them for infection, responses to vaccines and also for repletion. Some of these patients may benefit from IV Immunoglobulin repletion, and that is something that can happen with a primary care physician in addition to the vaccine therapy, et cetera.

Going to a dermatologist isn't just specific to melanoma. Patients with a lot of these B cell malignancies are at higher risk for skin cancers and have to go to their dermatologist. There are long-term side effects. Fatigue, patients take a long time to recover. I think, you know, to me, the hardest part is communication. We're all too busy, right? And we have a hard time finding the time to communicate and get on the phone and educate each other, what you're seeing, what we're seeing. But being able to educate each other about what's happening with the patient is really important.

And I think the other point I really want to make is that not everything is cancer. So while you can't expect the primary care physician to understand the nuances of a really rare therapy like CAR T-cells, which still is somewhat rare, patients have a lot of symptoms, and too often we find they attribute everything to their cancer, and sometimes their care team attributes everything, "Well, they had leukemia. They had lymphoma. They had melanoma. It must be their cancer," they still become hypothyroid. They still have other medical issues. And so, I think it's important that the Oncology team, the CAR T-cell team, whatever works with the primary care physician, to not make assumptions about many of these long-term symptoms and work together to not just attribute everything to their past therapies.

Host: We see that a lot. Yeah, like any trauma, like any traumatic event in many ways, it gets attributed back. Lynn, you were going to say something.

Lynn Schucter, MD: Yeah. And I would add that, especially with the immunotherapy with PD-1 antibodies, there are side effects that occur acutely that we know about. I mean, really any organ can be affected, but we commonly obviously see colitis and arthritis and hepatitis and skin rashes. But it's the endocrinopathies that often they can be missed by the oncologist, frankly. We have a way of labs that we order routinely. But, you know, we have seen patients with, hypophysitis, new type 1 diabetes, obviously thyroid dysfunction. And our working with the primary care physicians in the emergency room, that's just so helpful here. And, you know, these are sometimes unexpected, and I want to say that we have to stay humble that even now, a decade later, we still don't understand all the toxicities.

Melanoma can happen in young people and old people basically. But I've had a 25-year-old guy and he calls me on the weekend that it's summer and he's not sweating. He's playing basketball, he's not sweating. I'm like, "Okay." But, you know, I just sort of don't exactly blow him off, but I was like, "Okay, I don't think it's related," but this really persists, and he's hot. And it actually was an autoimmune reaction to the sweat glands. We brought him in, they biopsied it, and this is a known thing, and he couldn't sweat. But I recently gave somebody ipi plus nivo one cycle and they have myasthenia gravis. So, people go to the emergency room and say, "I'm on chemo." But of course, they're not on chemotherapy, they're on immunotherapy. People are worried about infection and they give him antibiotics. So, I would just say this is so complicated. Yes, we're having a major impact on cancer, but we are really revving up the immune system, and we don't completely understand it and it's hard to turn it off. Patients who never had rheumatoid arthritis then and now they're on Remicade forever.

So, I just would say we have to be humble. We have to partner together and we don't always see it. And so, as David said, this communication with you is essential. And to the beginning of the conversation, our patients do come to you for advice. They do want to know, "Should I do this treatment? Should I stay on it? My oncologist says I could stop? What do you think? Should I even take this treatment? Should I?" And, you know, we are giving these therapies to people in their 70s, in their 80s, even in their 90s. And this is where these conversations about real benefit, like real benefit, you know, what are the real risks and understanding that with all of us communicating is it's so essential. So essential. We really value the work you do in this team, and we couldn't do it without you, without all our primary care colleagues.

Host: I think that's a good place to end. This has been terrific. And I really appreciate you spending two hours with us to go over all of this. And because, you know, we're in our environments, and maybe to David's point, we will recognize somebody that could get a therapy that they're not being offered in the hinterlands, if you will, and get them down to you guys so that we make sure they are getting the cutting-edge therapy. That's a major, value, I hope, of this podcast. So thank you, Lynn. Thank you, David, for joining us.

Lynn Schucter, MD: Thank you.

David Porter, MD: Thank you, Kendal. That was fun.

Host: And with that, we will end the Penn Primary Care Podcast. Please join us again next time.

disclaimer: Please note that this podcast is for educational purposes only. For specific questions, please contact your physician. And if an emergency, please call 911 or go to the nearest emergency department.