Hodgkin Lymphoma Overview

Hi and welcome to Raton talks a lecture series designed for students and residents of radiation oncology my name is Ria I am currently a pgy5 resident at University of Pittsburgh and today we will be discussing adult hodkin lymphoma um keep in mind that for hodkin lymphoma there is a difference between adult and pediatric treatment paradigms um and in this talk and this series really we're really going to be focusing on um adult Treatment paradigms the term lymphoma actually encompasses a very heterogeneous entity of cancers um different types of cancer arising from our lymph nodes essentially

um when we broadly think about lymphoma we think about hodkin Lymphoma versus non-hodgkin lymphoma and classically uh what has always characterized hodkin lymphoma is the presence of Reed Sternberg cells um these are unique cells that have this binucleated Appearance um and they are cd15 and cd30 positive um and they have that classic Aly appearance um and you know that is sort of the classic feature of hodkin lymphoma and we see it in classical hodkin lymphoma um non- hodkin lymphoma is a completely different um entity and there are aggressive and indolent sub sub types of non-

hodkin lymphoma um there is something called nonclassic hodkin lymphoma um also known as nodular Lymphosan lymphoma um which does not have Reed Sternberg cells it actually has something called popcorn cells which are multilobulated and historically thought of as kind of a variant of Reed Sternberg cells um that historically was classified as a non-classic hodkin lymphoma um but we always knew that it behaved more similarly to an early stage lowgrade kind of an indolent non- hodkin lymphoma and it was managed very differently than hodkin lymphoma it was Treated like a lowgrade um B cell lymphoma and

in fact it is now actually being reclassified as a nodular lymphocytoma so I only include it here because historically it was classified as a non-classic hhin lymphoma um but when you think about lym um what you should realize is that there are many different types of lymphoma there are very kind of complicated ways of classifying them but very basically when when we think of lymphoma it's Either hodkin lymphoma or non- hodkin lymphoma and the classic feature of hodkin lymphoma is um the presence of these Reed Sternberg cells so in terms of epidemiology um hodkin lymphoma

is actually relatively uncommon um accounting for Just Around 10% of lymphoma as in the United States it tends to have a bimodal age distribution affecting adults in their 20s and then it has a second Peak um around the age of 65 it does have a slight male Predominance with a ratio of around 1.2 to1 and overall uh it's important to realize that hodkin lymphoma has a pretty excellent prognosis it's highly responsive to therapy and the 5-year overall survival rates are um on the order of 85 to 90% if not higher um and so it's important

to realize that the prognosis is very excellent um because these patients have a an expected long-term survival that's very good and so when we think about treating them It's really important to consider the long-term toxicity of all of our treatments um because we do expect these patients to live a long time um and so we really want to be careful with our treatments and and spare them the long-term toxicities uh whenever we can my hope in this overview talk of hodkin lymphoma is to review the presentation and workup um of hodkin's disease uh talk about

staging and risk stratification um and focus on how we Risk stratify early stage disease into favorable versus unfavorable um and then how we think about Advanced stage disease in hodkin lymphoma um and then finally uh we will end by talking about the treatment paradigms um so discussing some of the important aspects of chemotherapy and um radiotherapy uh for this disease um in the next talk then we will get into the evidence um and some of the important trials that kind of Define These paradigms so let's start with some basic background most commonly hodkin lymphoma presents

with painless lymphadenopathy and when the disease spreads it typically spreads to contiguous lymph nodes around 90% of the time so patients can actually present with a pretty large uh lymph known conglomerate if there is organ involvement it can either be via direct extension or via hematogenous spread and The spleen is the most common site of extranodal disease so you want to assess for splin omegal as well when we're evaluating these patients we always want to ask if they have presence of something called b symptoms um b symptoms are present in around one-third of patients and

um presence of b symptoms is a negative prognostic factor um and it actually uh goes into our staging and risk stratification so what are b symptoms b symptoms are there There's three things so fever greater than 38 de C or 10.4 de F weight loss of greater than 10% in 6 months and drenching night sweats um the type of night sweats that make patients have to you know change their shirt at night or something like that really drenching night sweats so fever greater than 38 Celsius weight loss of over 10% in the last 6 months

unintentional weight loss and then uh drenching night sweats if any of these are present um that Qualifies as having b symptoms and remember that that is a negative prognostic factor other symptoms that patients might complain of which are not classified as b symptoms um include [Music] and of course family history so remember that workup always starts with a full history and physical exam always inquire about history of those b symptoms um pay attention to lymph node regions on exam um and Perform a chest and abdominal exam especially examining for splenomegaly and hepatomegaly um especially in

our younger patients um folks that are maybe in that 20 to 29 age group where we have that first Peak um you definitely want to discuss fertility preservation or really anyone that would be an appropriate candidate for fertility preservation Labs you can think about getting a CBC with a differential um CMP so you know basic metabolic panel but Also checking lfts into albumin on that CMP um you can check for LDH and ESR um get a pregnancy test in our um younger patients that may be pregnant um and also test for HIV hbv and hcv

and Imaging um PET CT is really the gold standard and we can also think about other tests such as an echocardiogram or a muga scan um if we're considering um dxor rubesin for chemotherapy because remember that affects our cardiac function um and also Pfts and dlco if we're thinking about chemo including bomy um so kind of thinking ahead of of what the treatment is going to be and what those drugs are going to be um additionally if patients are going to need splenic radiation um you can consider um tically vaccinating them um with encapsulated organisms

so our um pacal hemophilus influenza and menocal vaccinations um the encapsulated organs that the spleen protects us from um once you have kind of that basic um Imaging workup it's also really important to get a biopsy and excisional biopsy is the best um the best biopsy um and it's really needed to see that the full lymph NOA architecture also remember that the Reed Sternberg cells that are kind of pathon neonic for hodkin disease are very uncommon compromising only 1 to 2% of our tissue sample so we want to get an excisional biopsy whenever possible um

sometimes you might be be presented with something Like a large mediastinal mass or something that's not amenable to an upfront exisal biopsy and in that case um the correct answer is to get a Core biopsy a core biopsy can be considered Ade if exisal biopsy is not possible but remember that an FNA is absolutely inadequate um you know if the core biopsy is non-diagnostic then you need to repeat the core biopsy but getting an FNA is is definitely not the answer typically we do not pursue bone Marrow biopsy unless patients have unexplained cytopenias or there

is concern for um bone marrow involvement based on the pet C scan um there's less than 5% % likelihood of bone marrow involvement so typically for hodkin disease we're not routinely pursuing bone marrow biopsy one thing to keep in mind when you are evaluating the pet scans for these patients is kind of noting how many different lymph node regions are Involved the reason it's important to identify how many different lymph node regions are involved is because that factors in when we think about the patients stage as well as their risk stratification um and it's especially

important for risk stratification for early stage hodkin lymphoma I think it's kind of confusing because different study groups um have different systems for the anatomical Grouping of lymph node regions um and so an arbor system for example um all of the different Supra diaphragmatic and infradiaphragmatic nodal regions are listed here in this table from nccn the biggest difference among the groups is that the EC and the German hodkin study group kind of group the super diaphragmatic noal regions a little bit differently so in Anarbor you know cervical um infr clav and axillary lymph Nodes on

each side are all separate right you have your cervical then you have your infra clab and then you have your axillary and Anarbor keeps them all separate for the left as well as for the right EC groups the infra clav and subpectoral nodes along with the axillary nodes on each side so kind of think of how um the the lymph nodes that are involved in in breast cancer like those infraclavicular nodes um the think how in breast cancer we all kind of lump Them all together um eortc does the same thing and lumps together the

infr clav and the axillary nodes the German hodkin study group lumps the infra clav nodes with the cervical and super clavicular nodes so the German Hodgkins study group is different than EC in how they group The infra clav remember an arbor keeps them all separate eortc groups the infra clav with the axillary and German Hodgkin groups the infra clav with the cervical And the super clave um the other big difference is that an arbor separates out the mediastinal versus the right hilar versus the left hlar nodes eortc and German both grew group the medium and

both of the hila together so that is just considered one noal region for purposes of EC and German Hodgkins um risk stratification and then in the infr diaphragmatic region remember that the Eortc and an arbor both group the par aortic nodes with um the Celiac and splenic hilum but the German groups the par aortic nodes with the mesenteric nodes and so this is something that you know you will ultimately end up looking up probably when you're taking care of these patients if you can't remember these different lymph node regions um but for the purposes of

the boards it's probably good to kind of memorize one system of doing it and I think Supra Diaphragmatic is probably the most important part to memorize and remember that infra clav is kind of a a differentiator between the three groups so an arbor keeps it separate eortc groups it with the axela German groups it with the super CL um and then remember that Ann Arbor separates the medius dyum the right hilum versus the left hilum those are all three separate regions whereas EC and German study groups just lump Together the media dyum and the bilateral

hila that's only one group um so that's probably the most important takeaway and then the other thing I'll mention real quickly is that um wald's ring as well as the spleen are considered extra noal for staging purposes moving on now uh let's talk a little bit about the pathology of hodkin lymphoma so the classic finding um and what is known as classic hodkin lymphoma is the Presence of the Reed Sternberg cell um this is that binucleated cell that has that alzy appearance and it's pretty rare in tissue samples it only constitutes around 1 to 2%

of the total tumor volume and so that's why we said whenever possible it's important to try for an excisional biopsy um because these cells are few and far between um the classic markers that you should know for hodkin lymphoma are cd15 positive and cd30 positive um and Pax 5 can be Weak positive there are four subtypes within classic hodkin lymphoma um nodular sclerosing which has a good prognosis um and is probably the most commonly seen subtype um mixed cellularity is the next most common sub type um and it's less favorable compared to nodular sclerosing and

then rarely we might see lymphocyte depleted subtypes lymphosis of these subtypes and lymphocyst prognosis so remember nodular Sclerosing is the most common accounting for over 70% of cases and has a pretty good prognosis mix cellularity is the next most common accounting for around 20% of cases less favorable than nodular sclerosing and then lymphocyte depleted are both rare and they are the best and worst respectively so lymy rich is the best it's good if you're rich and lymphocyte is the worst and then historically uh nodular lymphosan lymphoma was actually Classified as a non-classic hodkin lymphoma um

but it's actually now being reclassified as a nodular lymphocytic B cell lymphoma and indeed it does have um very indolent Behavior it actually behaves like an indolent uh lowgrade B cell lymphoma hence the reclassification and the um pathic finding for the nodular lymy predominant subtype is that popcorn cell and it is actually cd15 negative and cd30 negative um but it is cd20 and cd45 positive and Pax 5 is usually a strong positive um so the nodular lymphocytic Bell lymphoma is treated uh like an indolent B cell lymphoma um and the treatment Paradigm is totally different

than for classic hodkin lymphoma I think once we start talking about staging and risk stratification um then some of the stuff about you know the different lymph node regions and how they're classified is going to start to make more sense in Terms of how this is actually applicable lymphomas are staged using something known as the Anarbor staging system um for most other cancers we stage them using the tnm staging system um but for lymphomas remember it's just the an arbor staging system um so stage 1 through 4 and it's fairly easy to remember so stage

one is just a single node or nodal group um or you can have a single extra nodal site without nodal involvement so basically just one place Um is stage one stage two disease is if you have two or more groups on the same side of the diaphragm or if you have limited contiguous extra notal involvement that makes it stage two so stage one think just one nodal conglomerate stage two is two or more groups but on the same side of the diaphragm if you have nodes on both sides of the diaphragm then that makes stage

three or if you have nodes above the diaphragm for example plus Splenic involvement then that makes it stage three as well and then finally stage four is if you have non-contiguous extranodal involvement so if you have nodal involvement but then you also have non-contiguous extranodal involvement um so in addition to the stage number so one two three or four uh we will also often add modifiers to the staging system so if you add a modifier of a so stage 1 a for example that means that the patient does not have any b symptoms If you

add 1B then that means that they do have b symptoms and remember b symptoms are greater than 10% unexplained weight loss in 6 months fever greater than 38° C or drenching night sweats and this does go into the patient's risk stratification because remember presence of b symptoms is a negative prognostic factor um we can add a modifier e if have extra lymphatic involvement so for instance if they had splenic involvement um then we would add An e as a modifier and then finally um we'll often add an X if the patients have bulky disease um

which has been defined differently by different study groups um but it's accepted as bulky disease if it's greater than or equal to 10 cm or if it takes up um oneir or more of the thoracic diameter so bulky disease has an X at the end um and so that is the Anarbor staging in a nutshell I think this image helps us to visualize It nicely so stage one disease is a single lymph node region or a single extra lymphatic site stage two is if you have two or more lymph node regions but they're on the

same side of the diaphragm um and if there's contiguous um like limited contiguous extranodal involvement that can still be considered stage two if there are multiple lymph node regions that are occupying both sides of the diaphragm um then that is classified as stage three or if you have Super diaphragmatic nodes and splenic involvement that's stage three and then finally stage four is really defuse um extra lymphatic disease so involving something like the liver the bone marrow the lung or the skin um that would make it stage four so once we have staged the patients The

Next Step before we treat them is to actually risk stratify them and you will see that the treatment paradigms defer based on the patients risk Stratification so when we think about risk stratification the first thing to keep in mind is what stage disease do they have do they have early stage meaning do they have stage one or two disease where their disease is limited to one side of the diaphragm or do they have advanced stage disease stage three to four where the disease is involving both sides of the diaphragm and um once we have figured

that out um the treatment paradigms are Different for early stage versus Advanced stage for early stage disease there's actually a further subclassification of favorable versus unfavorable risk so we kind of risk group the early stage patients into favorable versus unfavorable and we'll talk about what factors we think about and how we risk ratify them and also keep in mind that there's different consensus statements so for example the EC versus the German hodkin study group They have different ways of of kind of splitting up up favorable versus unfavorable um so just remember for now that early

stage is divided into favorable versus unfavorable and that determines the treatment Paradigm and then Advanced stage is Advanced so it kind of has its own treatment Paradigm for advanced stage we can use something known as the international prognostic score or the IPS to prognosticate their outcome but it doesn't really affect our Management Advanced stage are typically managed all the same and then for early stage management is different for fa aable versus unfavorable let's start by tackling early stage disease and identifying the risk factors that help us to differentiate favorable versus unfavorable um early stage hotchkin

lymphoma so just like we went through the different study groups and showed how they classify the lymph node regions Differently remember there was an arbor versus eortc versus the German Hodgkins study group um the the way way that we RIS ratify patients is also different across the different study groups and this confused me for ages but really it just has to do with how these different study groups RIS stratified patients when they were enrolling them into their clinical trials and as a result um we just have to kind of know that these differences exist for

me personally it's Easiest to just memorize one study group's way of doing it and for me that's the German Hodgkins study group I just memorize how they um kind of classify their noal regions how they risk stratify favorable versus unfavorable and then for their trials kind of keeping in mind how they treat their favorable versus unfavorable risk factor patients if you have the capacity for boards to memorize all of them um that's fine um for me it's easier to Just kind of stick with one um but really it's whatever floats your boat so across the

different groups um three of the the things that we're looking at are going to be identical so the ESR the size of the mediastinal mass and the number of lymph nodes where you know ESR the size of the mediastinal mass and the number of lymph nodes are the same across all of these different groups so the things that are different is that German Hodgkins cares about if there's Extranodal extension EC Cares about if there's if they're elderly patients so greater they cut they Define an age cut off as greater than or equal to 50 and

um nccn cares about bulk so if it's greater than or equal to 10 cm but they're all thinking about the ESR the medial Mass ratio and the number of nodal sites the cut off for the number of nodal sites for German Hodgkins is three so if you have one to two nodal sites that's considered um favorable but If you have three or more it's considered un un favorable for eortc and nccn the cut off is four so if you have one to three noal sites it's favorable but if you have four or more it's unfavorable

so German Hodgkins is a little bit more conservative with regard to the number of nodal sites all of the groups pretty much have the same exact mediastinal Mass ratio so if the mass that's occupying the medium takes up greater than oneir of the Maximum um intrathoracic kind of um width then that is considered unfavorable for eortc they Define it slightly different they use the mediastinal thoracic ratio which is the maximum width of the mediastinal mass over the intrathoracic diameter specifically at T5 to T6 level um but just remember mediastinal Mass ratio greater than 1/3 across

all of the groups and then finally um the ESR of greater than 50 is considered Unfavorable if there's no b symptoms but if patients do have b symptoms then an ESR of greater than 30 is considered unfavorable and that applies for the German Hodgkins and eortc nccn says if you have any b symptoms then you're considered unfavorable um or if you have an ESR of 50 or higher and then those are kind of the the things that are consistent across all the groups so ESR andb symptoms the medial Mass ratio and the number of noal

sites And remember for German hodkin study group the cut off is three for eortc the cut off is four so for German three or more makes you unfavorable for eortc four or more makes you unfavorable and same for nccn and then that final risk factor for Germans hodkin study group is extranodal ex extension or sorry an extranodal lesion um for EC it's the age cut off of greater than equal to 50 years old and for nccn it's having bulky disease um greater than or equal to 10 Um keep in mind um sometimes with Hodgkins you'll

hear 7.5 cm as a cut off for bulk and that just comes from retrospective data from Memorial Salone ketering which uses 7.5 cm as a cut off for bulky definition in areas other than the medyum um so sometimes you might hear that 7.5 cm and that always confused me as well but again it just has to do with different studies and how they Define things differently So big takeaway early stage disease is risk stratified into favorable versus unfavorable um based on four risk factors and those four risk factors differ between the different study groups um

but remember that the treatment paradigms are different for early stage favorable versus unfavorable Advanced stage disease has its own treatment Paradigm um so this is stage 3 to four disease and there there's not really you know for for Early stage we classify as favorable versus unfavorable and then our treatment actually differs based on that classification um for advanced stage disease they're all treated the same but there is something to be familiar with um it's called the international prognostic score or the IPS um and it's basically just seven factors that all go into a scoring system

and the more factors you have the more unfavorable factors on this seven-point system that You have um the worse the expected progression free survival and overall survival so wor these are all bad prognostic factors essentially and the more that you have um the worse the prognosis so there's a nemonic um for this IPS system it's called saw meal and saw meal stands for um each of the seven factors and you get one point per Factor so what are those factors so s is stage 4 a is age greater than or equal to 45 w Q

is a white blood count of 15,000 Or greater m is male gender e is e stands for erthrocytes and it's really your hemoglobin of less than 10.5 is a bad prognostic Factor albumin so if you have low albumin or less than four and then finally L is lymphocytes so if lymphocytes are less than 600 or less than 8% of your white blood cells um so just remember saw meal is the pneumonic and they each stand for each of those letters stand for one of the seven factors and as your score increases from Zero to seven

um there is worse and worse predicted prognos or progression free survival as well as overall survival so worse prognosis and so now that we understand how we stage hodkin disease and how we divide into early stage favorable versus early stage unfavorable and then Advanced stage uh we can now get into some of the treatment paradigms the easy thing about hodkin lymphoma is that no matter which risk Category you fall under whether it is early stage favorable early stage unfavorable or Advanced stage the first step is always going to be the same it's always going to

be abvd chemotherapy for two cycles and after those two cycles of abvd the next step is to get a restaging pet scan and it's really the result of that restaging pet scan that determines the next step so if the result is good so if it looks like the initial disease that was present on pet scan has Responded then you can imagine the subsequent therapy is going to be less aggressive than if the response on the Pet Scan is bad meaning either the tumor did not respond or it progressed right and so the first step for

all of the different risk categories like I said whether it's early stage favorable early stage unfavorable or Advanced stage it's easy to remember it's going to be abvd chemo times two cycles followed by a restaging PET CT and then on that Restaging PET CT is where we're going to actually get some of the response assessment and the way that we evaluate the response um is using something called the doville score and the doville score is it's really just named I believe after the city in France where somebody came up with it um but the do

score is a score that goes from 1 to five and it basically uh characterizes the degree of uptake relative to various things so a doal score of 1 to three is Typically considered a good response and a doval score of four to five is typically considered a bad response so what do all of these mean for me it's easy to just remember one number and what it means and everything else I can remember kind of um relative to that so if you think about a pet scan and what it normally looks like there is some

normal background uptake right so in the mediastinum there is some background uptake from the mediastinal blood pool The liver also pretty avidly takes up the Dy and the liver is usually more than the mediastinum so dovel 3 is what I always remember first and I know that I can figure out two and one and four and five based on knowing what dovel 3 is so three is right in the middle and the uptake of the lesion is greater than the mediastinum but it's less than the liver so doval 3 is greater than the medyum but

less than the liver it's three so It's right in the middle um doval four then is if uptake is greater than that of the liver and five is if the uptake is markedly greater than the liver or there are new Legions present so four is more than the liver five is markedly more than the liver or new lesions are present and then two and one are kind of on the other side of that Spectrum so three remember was greater than the medius stum but less than or equal to the liver two is less than or

equal to The medium and one is no uptake so similar to background so abvd * 2 followed by a restaging PET CT for pretty much all patients and then based on the doval score when you go to evaluate the response the rest of the therapies will kind of be determined and remember the number three three is greater than the medius dyum but less than or equal to the liver and if you remember three then you can work either forwards or backwards um for the rest of The scores between 1 and five and I know I

kind of probably oversimplified it by saying a doel of 1 to three is good and four to five is considered bad um the the reason I said that is because most trials consider dovel 1 to3 as a complete response and dovel four is a partial response and then five is really just refractory disease because it either did not respond or it progressed through chemo um but keep in mind that some trials Will consider dovel 3 as a partial response as well so like everything um when it comes to these trials nothing is completely black and

white um I think generally it is accepted that doval 1 to three is a complete response doval four is a partial response and then doval five is refractory disease so that's why I said doal 1: three is good four to five is bad but four keep in mind is is bad in the sense that it's not a complete response but it is at least a Partial response so now that we understand the doval score uh we can really talk about kind of a summary of management and there's a lot on this slide here and there

are a lot of different treatment options depending on the doval response I think a lot of this will make more sense after our next talk where we actually kind of one by one go through the different step studies and address these different treatment paradigms um For now just remember that for Hodgkins disease no matter what stage in Risk stratification so whether you're early stage favorable unfavorable or Advanced stage it's safe to say that the first step is going to be abvd time 2 Cycles followed by a restaging PET CT and then if you have a

doel 1 to three response so remember that's a complete response it's going to be a slightly less aggressive option versus if you have a doval four to five if you have a doval Four to five then it's either going to be more cycles of abvd or in the case of early stage unfavorable or Advanced stage disease um you can consider escalated therapy with a more aggressive chemotherapy regimen called bacop um this is a chemo regimen that's quite toxic and I think it's used more commonly in Europe than it is in the United States um so

so more aggressive chemotherapy Andor radiation typically I really do think that these treatment Paradigms are going to make a lot more sense when they are presented in the context of the clinical trials that kind of establish these paradigms and so I'm not going to you know read through the different treatment options for each of these right now I think it's important to understand that the first step for all of hodkin lymphoma is typically abvd * 2 followed by a restate in with pet scan for early stage disease there are trials that have employed radiation as

An option and there are also trials that have not employed radiation as an option um when we get into that data what you'll find is that the data does actually support a progression-free survival benefit with radiation um however despite that progression free survival benefit um many may choose to Omit radiation just because there is still very good overall survival with the regimens that do not employ radiation And there's also good Salvage with um aut autologous um stem cell transplants and so the idea is that this allows you to avoid the longterm toxicity of radiation um

it's important to realize though that the radiotherapy regimens and we're we're going to talk in a second about what abvd actually is and and what the toxicities of these agents are um that can also cause significant long-term toxicity right um the a in abvd stands for adriam which is also Known as doxorubicin it causes significant uh long-term cardiotoxicity and so it's always a trade-off it's always a risk benefit discussion um and it's always a multi-disciplinary discussion with the medical oncologist and the radiation oncologist to kind of decide which therapy is thought to have the least

long-term toxicity for these patients so understand that you know for all of these different um stages especially an early stage disease there Are options for just chemotherapy alone there are also options that utilize radiation um and it's always going to be a risk benefit discussion um and you know over time as the chemotherapy regimens have gotten better radiation has actually been used less for this disease site um for advanced stage lymphoma um it's you know most patients will actually respond fairly well to just um abvd for six cycles and um so for advanced stage lymphoma

we employ Radiation even less frequently um oftentimes we're just utilizing it if patients have really bulky disease or if they have skeletal involvement or if they have residual pet positive disease or something like that so um for advanced stage it has you know it's used even less often so I'm not going to go through each treatment Paradigm right now it's definitely going to make more sense in the context of the evidence um what we will do now though is kind of Talk about the overarching principles of chemotherapy um as well as radiation and talk about

involved sight radiation what that is and how that's different from what was historically done before we get into that though I just want to take a moment to mention um the nodular lymphocytic hodkin lymphoma remember the one that's now being reclassified as nodular lymy predominant B cell lymphoma um this is not not treated the way hodkin lymphoma is it's a completely Different entity and it is treated very similarly to a lowgrade indolent B cell lymphoma so we don't actually use chemotherapy for this UPF front we typically just consider involved site radiotherapy alone uh to 30

to 36 gray for um stage 1A or 2A uh favorable um nodular lymphocytic disease so um typically the dose is 30 gray but if the tumor is greater than 5 cm we consider boosting it to 36 gray and so it's usually typically just treated with Involved site radiotherapy um if there are unfavorable FR um risk factors we can consider um rmab based chemotherapy um as we would for um non- Hotchkins lymphomas um because remember that the NL nlphl is cd20 positive um and so just like those other indolent B cell lymphomas that are CD 20

positive um if there are certain unfavorable factors we can consider rmab based chemotherapy um but this is a completely different treatment Paradigm Compared to hodkin I want to end the talk then by really just talking about some of the overarching treatment paradigms for hodkin lymphoma um and maybe not focusing so much on the memorization of what are the specific regimens at this point we will do that in our next lecture when we get into the evidence um but just kind of understanding um some of the general treatment Concepts starting with the chemotherapy regimens So you've

heard me say abvd a lot what is abvd what does that stand for so abvd stands for adriam uh which is also called doxorubicin bomy vinblastine and dacarbazine those are the agents in abvd abvd is given um in month L cycle so each cycle is one month so it's given every 28 days and each cycle requires two infusions per cycle so there's an Infusion on day one and there's an infusion on day 15 in the short term the acute toxicities are really things like nausea vomiting hair loss bone marrow suppression so typical things that you

would expect from chemotherapy the late toxicities mainly are cardiac toxicity and Pulmonary toxicity so adriamycin is the agent that is responsible for permanent cardiotoxicity and bomy is the agent That's responsible for pulmonary toxicity so remember back when we talked about the workup we said that these patients should be getting an echocardiogram or a muga scan for their cardiac function as well as pfts and a dlco that is because we know that they're going to need abvd um which which causes long-term Cardiac and Pulmonary toxicity so we need to establish a Baseline some of the studies

that we'll talk About in the next lecture um actually de-intensify the chemotherapy if patients have a good response up front to abvd 2 cycles and um the subsequent Cycles they actually consider de-intensify with just avd so they drop the bomy and just use avd to try and decrease some of that pulmonary toxicity so abvd adriamycin bomy Vin blastin and decarbos um the that's a really good you know you should know what that regimen is and what drugs are in it I will give A little pneumonic um that one of my senior um old senior residents

taught me um which is that you know there's abvd is the most common chemo regimen for hodkin and then our chop is the one that's very common for non- hodkin lymphoma like like diffuse large B cell lymphoma for example so in our chop um the O stands for anavin which is the brand name for Vin Christine and it's confusing because rchop has Vin Christine and abvd has Vin blastin and How do you remember which is Vin blastin and which is Vin Christin abvd has a b in it and so it has the VIN blasting which

also has a b in it and then the other one which is our chop has um the anavin which is also Vin Christine so if you can't remember which one has Vin Christin which one has Vin blasting remember that abvd has a b in it and so Vin blasting also has a b in it and so vinblastin belongs with abvd so abvd is aomy bomy vinblastine And DEC carbine we also briefly mentioned another alternate chemo regimen which was called bacop bacop has been utilized for early stage unfavorable as well as advanced stage hodkin lymphoma as

an intensified treatment um that has been used in the setting of a poor response for these higher risk patients however it is a very very very toxic regimen has a much higher incidence of Bone marrow suppression as well as alopecia and uh I have actually not seen it used because it's not commonly used in the united uh States it's typically it's used more often in Europe I believe but it's folks in the United States that I've talked to just really don't like it they really do not use it but bacop has bomy as well as

a toeside adamy Cy phosphamide vincristine procarbazine and prednizone so it has more drugs and as a result it's more toxic and so I I have Not seen it used very often but it has been studied in the setting of intensify treatment for patients that have a poor response if they have either um unfavorable early stage or Advanced stage disease and then an older um older study used the Stanford 5 regimen um which has nitrogen mustard doxorubicin Vin blastin VIN Christine bomy atopos and prazone um and this is a a quicker treatment because it takes Only

8 to 12 weeks to deliver four to six Cycles versus abvd which took 16 to 24 cycles and it does include lower cumulative doses of doxorubicin and bomy but the Stanford 5 regimen has only been studied in in um you know in studies that utilized radiotherapy and so radiotherapy really should not be omitted if the Stanford 5 regimen is used again I have not seen this used um not like I've T seen a ton of lymphoma of hodkin lymphoma um but I have not Seen the Stanford 5 regimen used as well and then an even

older trial that I don't even have on this slide is something called mop which is a historic regimen you might hear of it has mustard Vin Christine procarbazine and prazone um it has high rates of sterility as well as secondary um non-lymphatic leukemia um and so it's really not used um very often at all um so I think the most commonly used chemotherapy regimen in the US for sure is just abvd so Definitely remember that remember the Cardiac and Pulmonary toxicity is late effects of abvd and then keep in mind that abvd can be de-escalated

if patients have a good response up front um and kind of De intensify to take out the bomy and just do avd some additional agents that you might see used in the setting of advanced relapsed or refractory disease um that I think are worth mentioning include um brentuximab votan as well as um theab so Brentuximab voten or you might see BV avd um and the BV stands for brentuximab voton this is a cd30 antibody so remember um hodkin lymphoma has read Sternberg cells which are C cd15 positive and cd30 positive so brentuximab actually targets that

cd30 and this is used in the setting of advanced as well as relapsed disease um and it's very expensive and as a toxicity it can actually cause severe neuropathy um and so that's definitely Something to keep in mind um you know big risk of neuropathy with Brent tuim avidin which is that cd30 antibody the other um immunotherapy agent um noolab which is a pd1 inhibitor um can be used in relapse refractory disease as well um one thing to keep in mind is that if disease relapses over one year after patients have had a complete response

then it's okay to consider repeating firstline systemic therapy um but if they have a relapse Within less than 12 months or if they're not responding to upfront chemotherapy then that tells you you need to change the agent and so if they don't have an upfront response to abvd or something like that that's when you know BRX midot or a pd1 inhibitor um would be employed and then from a radiotherapy perspective I think you know I did use the term involved site radiotherapy or isrt um I think I briefly mentioned that a little bit ago um

and I think it's Important to kind of talk about what isrt is and where it comes from and why we do it um so involved site radiotherapy whenever you're you're describing what type of radiation patients with lymphoma should get the correct answer is typically isrt or involved site radiotherapy at least for now and the field of lymphoma has actually come a long way um I should say the field of radiation when it comes to treating lymphoma has come a long way so In the 1970s and earlier um so really in the 2D era we used

to do what was called total nodal radiation so there was a mantle field and then an inverted y field and so the mantle field was really the top so treating the the neck and the axela and the mediastinum and then the inverted y field um was treating the par aortic and the pelvic notes so total no or radiation is what used to be done we then moved to subtotal no radiation and then we moved to involved field Radiation therapy in the 3D era kind of in the '90s and the early 2000s and involved field radiation

therapy involved so if you had a cervical node for example you would you would just treat the entire cervical chain um and then in the modern era where we actually can utilize PET CT fusion and you know we have a better sense of where the disease was to begin with and we have better Imaging such as the petct for staging and we have um more Sophisticated radiation techniques um we have moved to either involved node or involved site radiotherapy it always confused me what was the difference between involved node or involved site radio therapy um

so involved site radiation is typically what's used in the United States involved nodal radiation therapy requires having your prechemotherapy pet C in the same position that you would be in for your radiation treatment and Realistically in the US our preemo pet C is ordered by either a medical oncologist or someone that's not a radiation oncologist and it's just a diagnostic petct scan it's not acquired um in the simulation position and so for that reason we utilize involved site radiotherapy and this is typically what we do in the US involved nodal radiotherapy my understanding is that

it's often done in Europe where um the same oncologist that's going to be Administering the chemo is the one that's going to be planning the radiation um that in in Europe it's possible to get involved noal radiation because that preemo pet might be ordered by someone who knows how to deliver the radiation um but in the United States it's really involved site radiotherapy um that we use and so the the definition of involved sight radiation is really just treating the area where where the nodes were positive and it's it's less Involved than involved field radiation

for example where if there was a cervical node then you would just treat the entire cervical chain there are nice guidelines from ilog uh which is the international lymphoma radiation oncology group uh that kind of defines um the principles of involved site radiotherapy and essentially when we're doing involved site radiation what we're trying to do is treat where the disease Used to be but accounting for the anatomical changes that have happened since the disease has shrunk from our induction chemotherapy so with isrt we create a post chemo theapy clinical Target volume that our hope is

that this will Encompass our prechemotherapy tumor volume or GTV cropped out of any structures that were uninvolved or any barriers to spread um just given anatomic changes from tumor shrinkage um So for example if you had a huge medial lymphoma for example and it you received upfront abvd and the lymphoma shrank if you just fused your preemo pet scan and Drew that tumor there would be a significant portion of it going into the lung but there's really a a membrane there right the plur there and so you're not going to have actual tumor inside of

the lung and so our posto CTV can be cropped out of that and we can kind of account for the anatomical changes that Have taken place since the tumor shrunk from that upfront chemotherapy typically the way that we think about this is that our cranial codal expan our cranial codal expansion um should really include the preemo volume in the kind of in the superiorly and inferiorly so in that cranial codal plane plus an additional margin for uncertainty and then axially so kind of in the horizontal plane um that's really where the boundaries of the lymph

node Compartment come into play so if you if you think about the neck or the axela or the the groin or something like that usually it's more we're more worried about cranial codal spread than axial spread and so our margins tend to be bigger and they tend to be more generous in the cranial codal plane in terms of dosing um these are just some relative guidelines um but typically we think about you know 20 to 30 gray for early stage favorable disease uh 30 to 36 gray For early stage unfavorable disease um so typically 30

gray but we can consider a sixth grade boost if there's bulky disease um same thing for advanced disease 30 to 36 gray um considering that sixth grade boost if we're trying to consolidate bulky disease or something like that and then if there is a partial response or if there is refractory disease uh we might consider increasing that dose from you know in somewhere in the range of 36 to 45 gray So 20 30 30 to 36 and 36 to 45 45 in the case of you know partial response or refractory disease again taking into account

what therapy they've had how bulky it was other risk factors and things like that um those are kind of the that's the realm of the doses that we're really talking about and then when it comes to pallative treatment um if that's what we're thinking about um there's many options ranging from anywhere from 4 to 30 Gray I sort of alluded to this earlier um but in the age of modern chemotherapy um there has there have been several trials that have come out that kind of omitted radiotherapy and showed no significant difference in overall survival and

there has been a move away from utilizing radiation um for lymphoma um because there is this idea that you know radiation caners increased toxicity um and so there is a rationale for omitting radiation um you Know equivalent overall survival without radiation we can achieve favorable Salvage rates with autologous uh stem cell transplant and we are concerned about long-term toxicities of radiation um and remember these patients have pretty excellent prognosis and so we we really do care about what their long-term toxicity profile looks like because it's going to affect their quality of life um it's important

to realize though that in those studies um Chemotherapy alone was not non-inferior to chemor radiotherapy in terms of progression free survival so radiation and we'll talk about this in our next lecture but radiation does confer a progression free survival benefit based on the data that we have um but that said there is still a reasonable rationale for the omission of radiation um given that equivalent overall survival and the Salvage rates and things like that so it's always going to Be a risk benefit discussion um but as radiation oncologists it definitely behooves us to understand that

chemotherapy also confers cardiotoxicity each additional cycle of abvd is confers around an equivalent of four gray mean dose to the heart um and so at some point and again you have to think about where the tumor is how big it is what the radiation field is going to look like and things like that but at some point um after enough cycles of Chemotherapy you might consider adding radiation and actually omitting additional cycles of chemotherapy um so it's always important to have multidisciplinary discussion you know keep in mind um you know considerations of what the plan

is going to look like and and what the dose distribution will be and things like that so I just want to end this overview talk uh with a quick summary slide on everything we've talked about so far so Remember hodkin lymphoma has an excellent overall prognosis and um that's why we think so much about what long-term toxicity is going to look like for our patients classic hodkin disease is characterized by the Reed Sternberg cell it is cd15 positive cd30 positive and there are four subtypes but nodular sclerosing is the most common and it has a

pretty good prognosis non-classic hodkin historically was thought of as non nodular lymphocytic hodkin disease But it's actually being reclassified as a B cell lymphoma it's characterized by having a popcorn cell which is cd20 positive and cd45 positive but it's cd15 and 30 negative it behaves similarly and it's treated similarly to an early stage low-grade non- hodkin lymphoma um so often times those are treated with just radiation alone at 30 to 36 gray for hodkin lymphoma we Stage IT using the Anarbor staging system and then we risk stratify it as well so early stage is Divided

into favorable versus unfavorable disease and then the treatment paradigms are different for favorable versus unfavorable things that we think about for making you unfavorable is typically based on the mediastinal mass ratio the number of extranodal sites the ESR and the BM symptoms and then remember criteria for favorable versus unfavorable vary depending on the study group so German hodkin versus EC versus Nccn so it's important to recognize which study group risk stratification system you're using and then based on that also which treatment Paradigm you're using and then remember for advanced stage we can prognosticate based on

the IPS um scoring system remember those saw meal those seven risk factors um but that's really just a progn ticat or it doesn't really affect our management and when it comes to the treatment Paradigm um the standard is Abvd * two followed by a pet response and then treatment options include subsequent radiotherapy or chemotherapy alone depending on the initial stage and risk F stratification as well as their pet response after two cycles of abvd in terms of doses think about 20 to 30 gray for early stage favorable 30 to 36 gray in all other cases

and then going up to 36 to 45 gray if patients have residual or refractory disease and when we talk about studies We will talk further about how radiation improves the progression free survival um but remember we mentioned that there is a rationale to AIT radiation um especially in young patients just because of equivalent overall survival with chemotherapy alone as well as favorable Salvage options um for these patients and so that ends our overview I will see you in the next talk um where we dig into the evidence thank you for your attention