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My name's Miranda. I'm one of the team won working Khalid for the oncology content for minor bleep working with bonus to put this talk on tonight. Um Doctor Groom World is very kindly. Um Given this talk today, she's a consultant, medical oncologist working in the London Bart's Trust. Um Sorry again for the late start and apologies that we're going to have to um do the last couple of minutes again. I'm glad that you're here with us now. Thank you. Okay. Thank you, Miranda. So yes, as the Miranda said, my name is Tammy Grunewald. I'm a consultant medical oncologist currently working at Fox Health NHS Trust and I cheat, treat Gynie cancers and Melanoma. And I'm going to talk to you tonight about systemic anticancer therapies. So just uh as an introduction. So there are different modes of anticancer treatment. Um uh I'm going to talk about these four here which are systemic therapies. Um And but not forgetting that another major uh surgery and radiotherapy also make up part of our treatment paradigm for our patient's. So just as an overview, what am I going to talk about, I'm going to go through the different systemic anti cancer treatments. And that's going to be chemotherapy, targeted therapies, endocrine or hormonal therapies and immunotherapy. I'm going to talk about the toxicities and how they differ. And also I'm going to take you through some case studies of patient's that, that I have seen and also how these may relate to you in your jobs, which are not necessarily going to be oncology jobs, but as surgical or medical S H O S or junior doctors. So, first of all, I'm just going to do a brief introduction. How do we stage cancer? Because often staging of the cancer will help, will give us a guide of how to manage these patient's. So we use in the majority of solid tumors, we use a staging system called the TMM staging, which looks at the tumor essentially. How big the tumor is, does it penetrate through the wall of whatever organ it's affecting? Um has it then spread to the lymph nodes? Because nodal metastatic disease seems to be the first place where cancer spreads in the majority of patient's. Um and then does it have um is there any evidence of distance metastatic disease? And based on the TMM staging, we then are able to stage the cancer from stage one, which is early stage disease to stage four, which is disease with, which has metastasized outside of the primary side of the cancer. So, what are the goals of treatment? So we talk about goals of treatment in three ways. So the first one is curative treatment and that can be given in one of two ways. The first ways adjuvant therapy, which is generally given after a patient has had an operation for the cancer and there's no visible signs of cancer. And the goal of that treatment is to try and reduce the risk of the cancer coming back. And that's because some type of occasionally there are accounts of cells that have already metastasized, they're not visible on scans or left behind after, after treatment. And this is kind of an insurance policy to try and prevent the cancer from reading lapse. The other way that we give curative intent treatment is in the neoadjuvant setting, which means the patient has presented with, with a large primary tumor that is either not receptible or would, would, would require a very large operation. And we give some treatment in order to reduce the size or reduce the disease burden. And then, um to allow the surgeons to operate and get the cancer out fully following on from that. And generally after we've given either adjuvant or neo adjuvant treatment, and patients' have had either have had a good response in some cancers, we then go on to give some maintenance treatment and this tends to be lower doses of oral agents and most settings but occasionally intravenous. Um And the aim of these are either to prevent relapse again or to maintain disease control if we've managed to reduce the burden of disease, and then finally, we can give palliative chemotherapy or palliative systemic therapy. And the goal of that is not necessary to cure the cancer, but to prolong life. And especially if patient's are very symptomatic from their, from their disease or maintain the quality of life. And sometimes patient's can be on palliative treatment for, for months or even years. So how do we as oncologist, assess fitness for treatment? Um And what we need is really an objective way to do that and the way that we do that is echo performance safest and we have a grazing of 0 to 5, although five is dead. So we tend to use 0 to 4. And if you've, you've looked after oncology, patient's will often document what patient's performance status is. Uh Generally, we would offer systemic therapy to patient's with an echo of 0 to 2 in clinical trials. If you've ever read any clinical trials, the majority of patient's that uh allowed into clinical trials have got a performance status of 0 to 1. Um So the patient's do need to be fairly fit in order to tolerate into benefit from systemic treatment. So I'm first gonna talk a little bit about chemotherapy. Um chemotherapy is used in the most in most solid tumor's, um some cancers and more chemo sensitive than others. Um And we can give them either a single agents or often we give them as double its or even tripped at combinations of treatment. And they can be given either orally intravenously or subcutaneously depending on the formulation of the drug. Um So if you can think back to medical school, um mine was a very long time ago, think about our biology of the cell cycle. And essentially the way that chemotherapy works is it most drugs will target some point in the cell cycle. Essentially. What chemotherapy does is it tries to kill rapidly dividing cells, which are what counts are cells are. Um So if you can have a look, this is just a more in depth diagram of how cells divide. And um various different chemotherapy agents will act on different parts of the cell cycle and try and prevent the and and and cause cancer cell death or cell growth. So some, so for example, taxanes will inhibit uh micro tubal function. Um and then there's anti phono drugs and lots of different drugs will work in different ways. But essentially they have a similar mechanism of Axion. And because chemotherapy targets rapidly dividing cells, it's not only cancer cells that they kill, but they can affect other cells. And so there are quite a lot of potential toxicities from chemotherapy as we can see in this diagram here. Um some of them are acute toxicities, toxicities that we see immediately or within a few days of starting chemotherapy. And there are some that are later toxicities that we do have to warn patient's of such as, you know, nerve damage, neuropathy, which can be long term, long term cardiac damage and potentially they can also cause second malignancies. And it's really important to have a good idea of what these potential side effects are in order to obtain informed consent when you're consenting someone to go ahead with chemotherapy. The other thing that we have to think about also is that there are some toxicities and that can be life threatening and I'll talk a little bit about one of those a bit later. Um And these are things that you need to be aware of because if you're in the emergency department, admitting someone with the potential chemotherapy side effect is important just to have a bit of an idea of what sort of side effects we might see. So how do we grade toxicity? Again, it's it's very useful to have an objective way of grading are toxicities. And that, and we use the National Cancer Industries common terminology criteria for adverts events. And that way if different medical professionals are seeing the patient's on different days, um you can actually establish how severe the toxicity was and is it getting better? Um And how do you manage these toxicities? So most trusts um will have either in a uh an acute oncology service and most trust will also have some guidelines of how to manage the most common toxicities that we see for. Keep from chemotherapy and these are an example of some of the guidelines that we use in bars health. And we have a fantastic acute oncology service, which is a nurse at service Monday to Friday, which is also supported by a consultant oncologist three times a week. There's also 24 hour oncology support available. So either a chemotherapy hotline, which is man's by one of our chemotherapy nurses where patients can call and get advice 24 hours a day, as well as a registrar and a consultant on call if you need advice out of hours. Um and very importantly, um when we see patients in clinic and we can sentence for chemotherapy, we have to get written informed consent that before starting any treatment, we talked to them a clinic about the potential side effects if we give them nominee mcmillian information sheet about the regimen that we're recommending and then we get them to sign a consent form. Um There are standards just chemotherapy trust consent forms, but more and more moving towards these um cr UK consent forms which are standardized consent forms. And actually, this is an example of one for just any sort of systemic county cancer treatment. But if you go on to the CR UK website, you'll actually find that most of the regimens have their own consent form that we're trying to use in our clinics now. So I'm just gonna finish this chemotherapy section with a case study of a patient that I recently saw in one of my cute Oncology Ward rounds and she was a 74 year old female with past medical history of hypertension, high cholesterol's of tinnitus and unprovoked devi. A few years ago, she was on some anti hypertensives, um, some anti cholesterol medication and also an antidepressant and had no known drug allergies. Um, family history had a blood cancer. Her mother had bladder cancer at age of 83 she had a performance status of one. Um And so she presented in February of this year with a self detected left breast mass. She had some imaging which showed which confirmed a single breast mass with also a pathological looking axillary node and a biopsy confirmed a great too invasive ductal cost her breast which was hormone receptor positive. So that's what the er and the pr means of eastern and progesterone receptor positive and also was her two positive. So that's another biomarker that we look at in um breast cancer. We'll talk a bit about biomarkers. Later, she had staging scans to try and in order to determine what stage she was and these were thankfully negative with no evidence of MS static disease. And this was a patient who was planned for new adjuvant chemotherapy because she had a large breast mass. She had some exhilarate, an auxiliary inflow that it was involved. And so she started her neoadjuvant chemotherapy on the third of April on the 14th of April. She called our chemotherapy hot hotline and told the nurses that she was federal with a temperature of 38 degrees. She was feeling unwell. She had a sore mouth and she was also vomiting and she was sent to her local a any and where she was seen in a full septic, too extreme with went off and she was given intravenous antibiotics for presumed neutropenic fever but no clear source of infection. And when her blood did come back, her white cell count was not point, not too with neutrophils of zero and she was commenced on GCSF to try and boost her white cell count and was on board spectrum antibiotics. So, February neutropenia is something that we all need to be aware of. Um and this is you will encounter this wherever you work and it's an important toxicity um that we need to recognize and treat fairly quickly. And the reason for that is if we don't treat it quick, then it can be potentially life threatening. Um It's one of the most common and most serious and can be a very serious complication of chemotherapy. And really the thing, if you're gonna remember one thing from tonight's talk that if you suspect a patient has a neutropenic fever, then you need to initiate antibiotics really from within an hour of them hitting the emergency department. And so what we say and what the trust guidelines also say is that even you don't need to wait for blood test to come back. You send off a septic screen and you give them some antibiotics and every trust will have the guidelines of what antibiotics to give these patient's and pet. We also give patient's a little card to say they're having chemotherapy in the at risk of neutropenic fever. So that's chemo. I might just continue and then we can have questions at the end, I think just, just in the interest of time if that's okay, but if you do have any burning questions and have to be interrupted. So the next treatment that I'm going to talk about is targeted therapy. Um So Hannah Han and Weinberg in 2011 gave this lovely doc you uh this lovely picture of the hallmarks of cancer. So what drives cancer to grow? And there's lots of things that drive cancer to grow, which means there's lots of things that we can potentially target to stop them growing. Um More recently, um we've got many more treatments that have come out but and not necessarily chemotherapy agents, but they're more targeted therapies. And that's because we've, we've got more personalized medicine where we've got patient's who come in with signs and symptoms of cancer or with the cancer. And then we have a look at the cancer and we want to try and understand what makes these cancers grow. So, in some of these patient's drug, something, you know, something X will be causing it to grow in others? Something why would be causing it to grow? And can we target that in order to prevent their cancer from growing? But it wouldn't necessarily work in somebody else who's got a different sort of cancer. Um So there's looking at this hallmarks of cancer, there are a lot of proteins, um genes that can be targeted as you can see here. Um in order to prevent the cancer from growing, and we do have some drugs to target this. For example, E G F R P three kinase inhibitors, Mtor inhibitors be rough inhibitors um that we use in some solid tumor's. So how do targeted therapies work? So if you can see here without electrically, we've got all of these different proteins that cause um cell proliferation, cell growth, self survival um and ultimately metastases. And if we block any of these at certain points in their pathway, that will be that will stop that cell growth and proliferation. So essentially targeted therapies will act on these specific molecular targets and their designs to interact with these targets and stop cancer cell growth rather than actually killing themselves themselves. So we've got a number of different sorts of targeted therapies. We can kind of split them into small molecule compounds. On one of COVID antibodies, small molecule compounds are typically developed for targets with inside the cell and they're, they're small so they can enter the cells quite easily. Whereas monoclonal antibodies are generally quite large and contents the cells. So they use for targets that are outside the cells on the cell's surface. What are the differences between the two? So the small molecule inhibitors which often end with the nib uh generally oral agents. Um and as I mentioned before, their targets can be within the cell and they're expensive but not that expensive. They can defuse quite easily but and can also potentially inhibit multiple different targets. But the more targets that you're inhibiting, the higher the side effect that the more side effects you may get with these drugs. Um they tend to bind and inhibit um kinase ear's monoclonal antibodies, which tend to end with a map a generally intravenous. They target self service, um proteins only and are very expensive. They don't diffuse far from the blood vessels. They tend to block a single target or block receptors. So this is just an example aside that highlights the number of different drugs that we have. And there certainly is not all of the medications that we have. But over the years, as you can see kind of 2001, there were one but in the, in the, you know, the last decade or last 15 years, also, we've had a number of different new targeted agents that have come about. And these are some examples of some monoclonal antibodies that are used in solid tumors as well. I think at your stage in training we wouldn't expect you to know what drugs that we use. But I think it's, um, it's important for you to know the effects of the drugs and the different classes of drugs that we, that we use. So what toxicities do we see with the different targeted therapies? And the answer is that, that they can evolve multiple organs. Um We say that, that these drugs are generally better tolerated than chemotherapy, but that's not always the case. Um But what we do see with these drugs, particularly with the oral targeted therapies that if someone does get a side effect and we either stop the treatment or just delay it for a while and give them a break. Those side effects do tend to go away and then sometimes we can either start at the same dose or a lower dose to try and reduce the risk of those side effects coming back. Um And that they can cause kind of target specific toxicities as well depending on what, what we're targeting. So I'm just going to give you a bit of an example about how Melanoma has changed over the years because I treat Melanomas. And also that this is a, this is a cancer that we can give either immunotherapy too or targeted therapy to in the 50% of patient's that have a mutation that is targeted ble. And again, as you can see back in the, in the nineties and early two thousands, we didn't have very effective treatment for Melanoma. And now in the, in the, in the 2020 s era, plus, we've got lots of different treatments and actually chemotherapy doesn't really play a role in this cancer anymore. Um So I'm just going to give you an example of a case study of one of our patient's who I met in clinic last year. He was a 67 year old gentleman with a significant past medical history of alcoholic cirrhosis and actually had had an admission to the hospital earlier in the year with decomp instated liver disease. Um, he has a history of scheme of heart disease with um our cars infarction in 2015, also had some COPD and hypertension and was on a number of different medications. However, although he had a significant past medical history, his performance status was zero. So in July of this, of last year, he presented with a pigmented lesion on his right chest, which was excised and it was, it was noted to be a very large and very thick superficial spreading melanoma. Um He went on to have a wide local excision and sent from know biopsy to show and he had one lymph node involved. So he had his final stage was stage three C melanoma. So high risk melanoma for relapse. And also when we looked under the microscope and we said from molecular testing, he was noted to have a B reputation which is seen in about 50% of patient's with Melanoma who was then referred to our clinic for a discussion and consideration of a German treatment to try and reduce the risk of the cancer coming back in the future. So he actually had an option of either having targeted therapy because he had to be a reputation or immunotherapy, which we can give to all patients with high risk melanoma. And in the adjuvant setting in discussion with his hepatologist, we decided that actually um targeted therapy was probably the way to go because there was a risk of long term toxicities, particularly liver damage with immune checkpoint inhibitors. Whereas with targeted therapies, when we stop the drug, the side effects tend to disappear and they don't tend to be long term. So following cycle, one of treatment, he presented with a skin rash which is very commonly seen with, with, with the tyrosine kinase inhibitors or targeted therapies that we use, which improve just with topical treatment. Although if they are very bad, sometimes we don't need to give steroids. But following cycle to, we noted that his, his, his liver function was starting to go off and he had some deterioration, his synthetic liver functions, his album and had dropped his iron are, was going up his papers with drops and there was a rise in his A L T. And at that 0.1 discussion with the patient and with his hepatologist, we decide to stop adjuvant treatment because at this stage, the risks of treatment outweighed the benefits. However, if he does relapse or, or his cancer does come back and metastasize in the future, we'll have to reassess the situation because obviously the benefits of treatment at that stage might outweigh the risks. So these are just some of the things that we have to think about in the clinic. So it's not just about the treatments that we give, but we do have to look at the hot the patient as a whole. So the next sort of targeted agents that we use predominantly in bow counselors and I use a lot of ovarian counts of the anti angiogenic six. And so how they work essentially, um in order for something to grow, it needs a blood supply and when um tumor's have a blood supply that goes to it and it causes angiogenesis and essentially, it, it allows the bloods that the tumor to, to grow. But these blood vessels are generally abnormal. Um And, and so veg F is one of the targets that we target to try and prevent new blood vessels from forming. Um Again, there's a number of different targets that we can use in order to prevent angiogenesis. Um and some of these oral agents. And, but this is um um is the one that I use quite a not which is an intravenous agent that's given once every three weeks. Um It's normally um started in combination with chemotherapy um and then continued on as maintenance treatment as we discussed before and I use it a lot of ovarian cancer. Um So the toxicities from anti budget of therapy tend to differ from that of chemotherapy due to its mechanism and actions and the main things that we have to be aware of that they can cause high BP, they can cause leaking a protein from your urine. Um There's a risk of bleeding or hemorrhage due to abnormal blood vessels. There is a risk of fistulas or abscess formation and, and a small risk of gastrointestinal perforation. And there's also a high risk of thromboembolic events which which patient's with cancer already at a high risk of and they can impair wound healing. So, if patient's are going for any large surgical procedures, then we need to hold the treatment for at least 4 to 6 weeks before and 4 to 6 weeks after their surgery. Another target is agent that we tend to use and predominantly again, ovarian cancer but has been using other cancers as well. Apart, inhibitors and homologous recombination deficiency um is what we're trying to target. So it's a biomarker that we're looking at and as you know, D N A is constantly being damaged and being repaired, and we've got genes that help repair those damage, that those damaged chromosomes. However, cells can't correctly repair their damage, that they're known as cells which have got some sort of homologous recombination deficiency and this is caused by a number of different genetic mutations. But the one that you're probably familiar with is the bracket mutation, which makes patient's at increased risk of breast and ovarian cancer. Um So how the parp inhibitors works? That part is an enzyme which is involved indian in single strands of breaks of D N A if we um so we have a, a single strand break, which if the pop enzyme gets involved, it will then try and repair it. If it is unable to be repaired. Because we've blocked the part with a Park inhibitor, then it will cause a double strategy in a break. If we have a patient with normal or Bracha or normal genes, and that can, that can effectively fix that double strap break, then then it will fix the cell and you'll have continued cell proliferation. However, if you block part and then you have an H R D deficient pathway, then there's no way of those double stranded breaks from being repaired and it causes cell there. And that's something called synthetic lethality. Um There are three parp inhibitors that we use in ovarian cancer, elaborate niraparib and Rucaparib. Um and the main toxicities from these drugs, a hematological. So we see quite a lot of an email with one of the drugs. We see quite significant and profound, we can see quite significant and profound thrombocytopenia, neutropenia. And again, as I talked about earlier and talking about long term toxicities. There are reports, there's approximately 1% chance of getting a ML on mine latest Static Syndrome. Sometime in the future, they can cause a lot of gi side effects, fatigue, headaches, high BP, deranged LFTs and so on. So I'm just going to give you an example of a patient who actually has um with ovarian cancer, who has is on maintenance treatment with both services. Um an annual approved. So she's a 48 year old female who really presented, presented last year um with, with no significant past medical history but was quite fairly symptomatic. They had a performances in one when we first met her in the clinic. Um So in January 2021 she presented with a large pleural effusion and that stage um cytology of the poor profusion was negative and the working diagnosis at that time was a pneumonias with a large parapneumonic effusion. However, in February, um 2021 she represented with shortness of breath. And at that stage had a ct chest abdomen, pelvis, which showed a very large right side of pleural effusion with mediastinal shift. At that point, she had a societies and peritoneal disease, which is what we very commonly seen with ovarian cancer. She had an a mental a pleural biopsy which confirmed a stage for a high grade serous ovarian cancer and she commenced neoadjuvant chemotherapy. So she, she had near adjuvant treatment because she had a last large burden of disease. She had pleural based disease. And at that point, her disease was not opera formed. She had three cycles of neo, a different treatment went on to have interval debulking surgery and where they managed to take out all of her tumor. And there was no evidence of any residual disease after her operation. At that point, we sent her tumor off for biomarker testing. And although she didn't have any broken mutations, so she didn't have a germline recommendations. There was no inherited mutation that would have caused her ovarian cancer. She was noticed to have hrd, she was hrd positive, which is what we talked about with Park inhibitors. So she then went on to have another further three cycles of chemotherapy and we added in devices um um one of the anti angiogenic drugs with her cycle six of chemotherapy. So it was about 8, 10 weeks following her large surgery. And then we started the lap group, which is a pop inhibitor. Um when she completed her chemotherapy and completed her 15 months of bevacizumab and is now on a lap rub alone. Um and with no evidence of disease. And so this is an example of a patient who's had new adjuvant chemotherapy. She's had surgery and she's now in combination maintenance treatments. The first one we give for 15 months and the second one we give for two, for two years. So the next drugs that I'm going to talk about are hormonal endocrine therapies. How do they work? So, this is opportunity, grand glands. Um We've got ovaries, adrenal glands that all produce hormones and the drugs that we can use, either block off our FSH or LH um they or essentially Eastern or testosterone production because we essentially use hormone agents in mostly in breast cancers and prostate cancers. Um So majority of breast cancers are hormone dependent. They, when we look in the microscope in any patient that's diagnosed with breast cancer, we have a look at their Eastern receptor and if they're positive and also that progesterone receptors and then the primary regulators of breast tissue growth in differentiation. There's a number of different endocrine therapies that we can use or anti Eastern's that we can use in breast cancer. Some of them are all, some of them subcutaneous um injections. Oh, sorry. Um And again, with prostate cancer, um prostate cancer is driven by testosterone and generally the first line of treatment for prostate cancer is essentially making a man castrate. So, blocking off the testosterone production. And again, we can do that either by by blocking off the pituitary hormones or by blocking off testosterone front, front of testes themselves. And these are some examples of some of the um some of the anti androgens or hormonal agents that are used in prostate cancer. What are the symptoms of endocrine therapy? So you can imagine if you're blocking off Eastern and progesterone production, then we're pushing patient's into menopause or men into andropause. Um And as you, as you can see, it can cause a lot of different symptoms that have a major impact on one's quality of life. And these are things that we really need to be aware of when we're consenting patient's for treatment and also how to manage these because these patient's can be on hormonal agents for a number of years. So this is a case study of a gentleman with no significant past medical history, presented with the performance status of one. Sorry, I left after slides um and presented in July 2020 with metastatic prostate cancer. And he was given a combination of chemotherapy and hormonal therapy at the time. And he's, he still remains on hormonal therapy. And the biggest thing that he's suffering from at the moment is hot flashes. Um And he's tried a lot of different agents. So, antidepressants uh uh and so on and they're really significantly impacting it's quality of life. But the other considerations um that we need to take into account with patient's and long term hormonal therapy is their bone health. So they're at risk of osteoporosis that we would always do a baseline dexa scan. They should be on calcium and vitamin D. You need to consider bisphosphonates if they have evidence of Austria keratosis and also the psychological support because there can be lots of mood changes and lots of libido and particularly men impotence when we basically cut off their testosterone production. Um, so lastly, I'm just gonna talk a little bit about immunotherapy, which sometimes comes under the umbrella of targeted therapy. But I think is really a treatment in itself, um, and works very differently to the other therapies that we've talked about so far this evening. Um, they're, they're fairly novel agents. Um, they work by trying to activate the immune system to fight against the cancer and we're increasingly using them in clinic. We use them both in the adjuvant setting and in the metastatic setting. Um And there are lots of clinical trials still trying to establish the role of immunotherapy and some cancers that don't seem to respond as well. And as junior doctors, you're very likely to see your patient's with immunotherapy talks toxicities, regardless of the specialty that you work in or the hospital you're working in. So how do they work? Is essentially, there's um two types that we tend to use and there's a CTLA four pathway which we block with the drug called Ipilimumab, which is the one that we use most commonly. And then we've got the PD one pathway. So these are all inhibitory proteins that inhibit um T cell activation. And so what we're trying to do is um when the PD one antibody binds the PD L1 on the tumor, they will prevent the T cell from killing the cancer. What we're doing by giving an anti PD one antibody is preventing that inhibition and allowing the immune system to therefore fight and, and kill the cancer cell. Um Where do we use immunotherapy where we use them? A lot of solid tumor's use them in Melanoma, lung cancer, blood accounts is triple negative breast cancer, renal cancers and so on. Um the some of the drugs that you may encounter equal um A which is the anti CT, therefore that we use and the volume and Prebble is um about PD one inhibitors and these are PDR one inhibitors. Uh I think the thing to, to kind of take into account with these drugs is that these drugs tend to take time to work. So, so chemotherapy will kill rapidly dividing cells and therefore, we should see a response to treatment fairly quickly, targeted therapies will target the protein or the abnormal protein that's, that's driving the cancer to grow. And we, and we'll again, work quite quickly with, with immunotherapy, they don't work quickly. So if you have someone that's coming with a very large burden of disease and is very symptomatic, they're unlikely to benefit from immunotherapy in the way that they may benefit from some of the other agents that we can use. However, saying that if one does respond and the clinical trials and even in really, in, in our practice, we see durable responses, so long term responses with these treatments. Um but what toxicities can we see? So the answer is any. Um So what we're trying to do is trying to activate the immune system. So, so what do they sometimes do is is that they tell the immune system to, to target something that should be there and it recognizes it as foreign. So it's basically any autoimmune or in the immediate of side effects that can affect any organism body. If you give combination treatment's, that's a CT A, they fall with the PD one inhibitor. The risk of some sort of side effect is close to 100% with about 60% chance of getting a significant side effect requiring high dose of steroids or hospital admission. And with a single agent, the risk of a hybrid toxicity is probably about half of that's about 30%. And why do they occur, as I've said before? Basically, the immune system is attacking itself and it results in information dysfunction. Most common toxicities that we see in clinic is probably colitis, the diarrhea um often see abnormal LFT. So just a rise in their, their, their A L T generally um skin rashes, but it can affect any organ in the body. How much patient's present well with anything. And sometimes they just present with just feeling non specifically unwell and there's nothing that you can really pinpoint when, when you see them in clinical, you see them in the emergency department, but they just feel not themselves um or they might present with, you know, significant diarrhea, um chest pain, if it's myocarditis, palpitations, rashes, um some visual disturbances. So it's just you have to keep an open mind when someone comes in and says they're just not feeling well and they're on immunotherapy. So as with the other guidelines, we have specific immune immunotherapy related guidelines because the management of these side effects are different to the management of the side effects that we see with chemotherapy. Um So what side effects um to hardly manage these? So I think the main thing is important to note is that it's really important to manage these with a good team and it's important to involve the organ specific specialist early. Um So the majority of patient's we have to treat with within, you know, suppression. Um So we give high dose of steroids. So if, if it's not a if it's a great to toxicity, then we may be able to just give oral steroids. That's normally we normally start at 1 mg per kilogram. So we've got a average 70 year old male or female at 70 kg, male or female, then you give them 70 mg of participating. So they're not insignificant doses of steroids. Um If they're really bad, then we do have to give them IV methylprednisolone and, and admit them to hospital. If they don't respond to high dose of steroids, then we do then need to consider some steroids, steroid sparing agents because obviously, we don't want patient's on steroids for a long time. And then if we do think they're going to end up being on steroids for quite a while, then we have to think about what are these potential side effects of the steroids? They think about bone health, we would always start a proton pump inhibitor. If we're starting to wanna high dose of steroids, have them run select blood sugars. And if we think they're going to be on high doses of 25 mg or more, then we have to think about PCP prophylaxis as they would be at risk of fungal infections. On long term steroids, we have to monitor these patient's really carefully and we have to re less steroids quite slowly because we can see a relapse of their symptoms if we go down too quickly. Um The only caveat to that is if we see any endocrine dysfunction. So the most commonly we see thyroid itis. So patient's will often become hyper thyroid and then the thyroid would burn out and then they will be hyperthyroid and then we give them hormone replacement therapy. So, thyroxin, um and the important thing to note with the endocrine dysfunction is that if they do have uh issues with any of their hormone glands, and generally they're going to end up on that hormone replacement therapy for the rest of their life. So this is not a reversible toxicity. So this is a case study of a young unfortunate lady who is currently under my care presented in 2021 with a one year history of chest pain. And she was, this was during COVID and virtual reviews and she was at that time that wise to take analgesia, but her symptoms continued to get worse. Um, alongside that she had some weight loss of about 1.5 stone. There wasn't, there wasn't any associated shortness of breath or cough or hemoptysis or fever and really the only significant past medical history with Melanoma, which was excised 11 years prior to that. And it was a high risk melanoma and she stayed under the dermatology team for five years of surveillance and was therefore discharged from their care. In 2015, she wasn't on any regular medications. Um, didn't have any allergies, lived alone, good performance status. Um, and just had an eight pack your history of smoking. Um, so she presented to her emergency department cause her symptoms weren't improving. A chest X ray showed a lesion in the left lower zone. She had a CT chest abdomen, pelvis, which then confirmed several lung lesion's and some lymph nodes in her chest and also liver metastasis. She went on to have a CT guided biopsy of one of the lung masses and this came back with metastatic melanoma and she was found to have a good reputation. So, um she again, sorry, she again had options of treatment. Um So one option was um, immunotherapy. Um And one option was be rough targeted therapy. And we know from data that we um from clinical trials that if we've got a patient with a good performance status, then we should be giving them um immunotherapy. Um Before we consider targeted therapy. So she was well enough for in the therapies that we started her on equal in modern and um nivolumab, which is the combination treatment that we give patients with metastatic melanoma. And after the first cycle, she was admitted to hospital with fevers. And so, while she's not at risk of neutropenic fever per se, we do sometimes see um fevers within a therapy and her blood cultures were negative. She was treated for an infection and treated with board spectrum antibiotics and she also developed a rash and, and some fatigue secondary to her treatment. Um she then on the routine blood test in April. Um for a year after starting treatment, she initially had a suppressed TSH, which then burned itself out and then ended up hyperthyroid and was commenced on both Roxon. She needed regular monitoring of a thyroid function test in order to titrate up to the adequate to go to thyroxin, which can take a number of months um to normalize again. She then had a CT scan after four cycles of IPI Nevo and she had some new lung Asians, but a reduction in the size of her, her lung and and liver mets. And so at that time, she was deriving clinical benefit and the lung lesions, we weren't 100% sure. This was definitely metastatic new metastatic disease. So, the decision at that time was to continue maintenance. Nivolumab, despite some of the toxicities that she's already had. Um So then she presented in May last year with feeling generally unwell, more crampy abdominal pain, blood revealed a great to rise in her A L T. So she had a transaminitis. She was treated with A PPI without a sickness medication and commenced on a fairly low dose of prednisoLONE um because it was only a slight rise in her A L T. She then developed diarrhea. So clouds opening 10 to 20 times a day. Um and this was treated in a new mediated and colitis and she required that she intravenous methylprednisolone, but really didn't improve significantly. And every time we tried to wean the steroids or switches them. So, oral steroids and the symptoms came back and she had a flexible sigmoidoscopy which confirmed a severe colitis. And, and in the end, she required a fairly long course of steroids and three doses of Infliximab, which is a steroid sparing agent that we use um with colitis. Once the toxicity settled, we continued on the maintenance nivolumab because it was holding her disease. And then she developed really terrible joint aches and pains and was restarted on some steroids with very minimal symptom relief. And she was requiring quite a lot of pain relief and it was really impacting her quality of life. She was then sent to the rheumatologist for review. She was given some intra articular steroid injection. She was commenced on methotrexate, a steroid sparing agent with really very minimal relief her symptoms um in October last year, there was a marginal increase in size of the left lower lobe lesions but no new disease. But at that point, because of all of her toxicities and its impact on her quality of life. And we made a decision that as a team to stop having the therapy and switch to targeted therapy. And at the moment, she is still really suffering from her joint aches and pains. She's very cushingoid because she's been on and off steroids for months and months and months and it's really impacting her quality of life. So this patient in summary, had a number of different toxicities along the way with her in therapy, she's hyperthyroid and is likely to remain on thyroxine. Now, for the rest of her life, she had liver toxicity. She has about toxicity and she's got uh you know, joint toxicity, which is really significantly impacting her quality of life and may never improve fully despite what we're doing. So, in summary, so that was a very risk op tour through some of the systemic therapies that we give to patients with cancer. Um We've got different agents that we can use. They work in different ways. They've got different side effect profile and they all have their limitations. Um um And um but we do have a number of different options, which is great. Um uh the time to response to these agents are very different with different agents. And actually there is, you know, oncology is very exciting and specialty at the moment because there is personalized medicine where, you know, there's a lot of research going on in the labs and trying to understand what, what causes cancer to grow, trying to individualize our management for every patient, which is why biopsies are incredibly important. But whilst we're doing that, our patient's are living longer, there is a risk of significant toxicities and the management of all of these different side effects differ. So it's just good to remember that there is uh you know, every hospital has some sort of acute apology service, there are fantastic resource. Um And there's always some trust guidelines and people that you can turn to for help these patient's. I think that is it for me from this evening. Does anyone have any questions? Um I can see here that's um just looking at the, so there's a question at 7 54 PM. Do you need to wean the dose of steroids down to a certain level prior to restarting immunotherapy agent? And the answer to that is yes. Um So ideally, we want them off steroids before restarting because what we're trying to do with the immunotherapy is trying to enhance the immune system um but um and, and steroids will dampen the immune system. So very occasionally will restart immunotherapy. Um when they're down to 10 mg of prednisoLONE, but ideally, we want them off steroids before we restart. Um Sometimes if it does take a long time, what they've had really, really significant toxicities, we will stop treatment. But what we've seen in clinical trials that even if we've had to stop treatment early, we still see ongoing response is even with maybe the sub, what we think is a sub optimal number of cycles of treatment that we can give any uh questions. I don't know if you've seen ones higher up as well. I can't, no, I haven't seen the ones higher up. Sorry, we've got, what is the antibiotic choice in February neutropenia? So every trust will have different, different guidelines. So we use to person and a stat dose of amikacin in um at Bart's when I was training, it was, I think it was Tassan and Gentamicin. But I think we've moved away from gent but, but every every trust will have guidelines as to what? So it's just broad spectrum antibiotics and then, you know, once cultures come back or once their counts start to recover or if you have a clear source of infection, then you may target the antibiotics towards and you know, if it's definitely chest, then you might give them antibiotics to cover their chest. Um Yeah, we've got is transaminitis connected with autoimmune hepatitis after immunotherapy, um as into they have long term toxic. I think what you mean by that question is, is do they end up with some sort of long term hepatitis? And the answer is generally what we see is, um, is just a rise in the LT first which tends to come down with steroids but doesn't, doesn't tend to give long term damage. But unfortunately, um, you know, some patients do have significant toxicities that never, never seem to go back to normal, but generally they will approve of steroids. I hope that answers the question. We've got a question saying cases you have presented here sound like they have experienced serious, sorry. The cases you presented the patient's sound like they have experienced serious side effects. Is it like this for the for the majority of our patient's? So the answer is no. So I I presented these patient's um to show kind of the sorts of things that we have to think about and, and some of the more complex patient's that we see. But, but it's not like this for all the patient's like particularly last patient that I presented, I think she's been very, very unlucky. Um But it is just examples of some of the damage that some of these drugs can cause. Um We've got a question asking how is immunotherapy effective when the 1st and 2nd line chemotherapy failed on palliative patient's. So, um so basically, so in a lot of the, a lot of the cancers where we use immunotherapy, um, we might now use them first line. So, I mean, I don't treat every single cancer, but certainly in Melanoma, we don't tend to use chemotherapy anymore because chemotherapy doesn't work. So, actually, first line treatment for Melanomas, immunotherapy, um generally, the cancers, generally the cancer is that it, um that, that we use them on, um we will have a high new antigen burden. So it's to do with, with the tumor micro environment and they tend to, they tend to work um with cancers with a high near antigen burden um in lung cancer. I know they do check their pedia one status. So, so they look under the microscope and patient's with a high PD, a higher pedia, one expression will respond to treatment um response to treatment better than those that don't have a PD L1 expression. Um But they work differently and different and, and as time goes on and we do more trials where immunotherapy falls in in the timeline of when we give, it will differ with different cancers. So because they work differently and even, you know, you can give 1st, 2nd, 3rd line chemotherapy. So, you know, initially, you know, give first line treatment and the patient will have response for a while and then they'll, they'll relapse and you're given different chemotherapy and they'll still respond because the mechanism of action of every single drug is a little bit different. I hope that answers the question. Um There's one final question. Do we have time for that one? Um Yeah, I'm happy to answer it. Yeah. And I'll just add, ask the E G bit. So does the risk of toxicity um with immunotherapy accumulate with further time or therapy or is it more a case that certain patient's are just more likely to tolerate it and others more sensitive? So the answer is the time on it doesn't make a difference. So you might see toxicity very early on. And actually with patient's on immunotherapy, even after they've stopped treatment, they always have to be, remember that there is a risk of an immune mediated toxicity even after cessation of treatment. So for example, um in Melanoma, when we give immunotherapy in the adjuvant setting, we give 12 months of treatment and they stop, but we'll still check their thyroid function every six months. And if they come in and well, you just have to have the back of the mind that they have had immunotherapy in the past. So for example, you know, they come in and well, and you want to check their cortisol to make sure that the adrenal function normally. So, um it's not necessarily related to your, the time that you've been exposed to treatment. I think that's all the questions. So, thank you so much. I'm sure you'll all agree. That's been a fantastic tour. Really, really interesting. And helpful. Um, make sure you all fill out the feedback for all of us because they're doing this voluntarily in their evenings after their full time jobs. So it's really useful for us to get the feedback. Um, make sure you register for our next talk on the ninth and have a good evening, everybody. Bye. Thanks very much. Good night.