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 the University of Pittsburgh and today is part two of our discussion on adult hodkin lyoma um in the previous talk we really went into an overview uh focused on the staging and some details on the treatment paradigms um in this talk we will be getting more into the actual evidence and the clinical trials that guide our treatment paradigms as we discussed in the previous talk hodkin lymphoma is typically
divided into three different treatment groups or three different uh risk groups I should say um so early stage disease is divided into favorable versus unfavorable um and early stage disease typically means stage one to two disease so think of disease on one side of the diaphragm and then Advanced stage disease so disease either on two sides of the diaphragm or with a lot of extr noal involvement um that's considered stage three to four disease and it has its own treatment Paradigm for dividing early stage favorable versus unfavorable different study groups such as the German hodkin
study group as well as EC will have different criteria for making a patient unfavorable um and really those criteria have to do with the inclusion criteria for the different studies so in the overview talk um there's a nice table from nccn that sort of outlines what those risk factors are and how um the Germans versus um EC uh how they kind of separate favorable versus unfavorable and we will review it too when we review the trials kind of what these criteria are um but keep in mind that whatever criteria you use to kind of divide
a patient into a particular risk category you should use that same study groups criteria for treating the patient so what I'm trying to say is if a patient is considered unfavorable by the German Hoskin study group criteria then they should really be treated as per the German unfavorable uh treatment Paradigm um they should not be considered unfavorable by German but then treated by the eortc Paradigm um is basically what I'm trying to say the other note that I will make is um you know a lot of these historic studies that we're going to talk about
they utilize a radiation modality called ifrt it's the same exact radiation but we're basically saying involved field radiation or ifrt meaning that we're not just covering the particular area that was involved um preemo we covering the entire field so even if there was just one cervical node they're covering the entire cervical chain um and and that is really what was used historically uh in the modern era involved site radiotherapy or involved node radiotherapy are accepted as standard in the US uh typically we just use isrt um involved nodal radiotherapy requires having the preemo PET CT
in the radiation treatment position um whereas involved site radiotherapy does not um so for purposes of board exams and things like that um especially for folks in the US um it's very safe to say isrt as your radiation modality when you're asked let's begin by diving into the evidence for treatment of early stage favorable disease so just to review here is the table of unfavorable risk factors for early stage disease for the different study groups so we're actually going to start by talking about some of the trials from the German hodkin study group so for
a moment let's just focus on those risk factors so in this table in the that First Column are all of the risk factors for the German hod study group that make you unfavorable and so in this section we're really focusing on favorable disease so think of favorable Disease by German criteria to be disease involving only one to two noal sites no extra noal lesions the medial Mass ratio has to be less than 1/3 and the ESR is low so that's defined as less than 50 if they do not have b symptoms or less than 30
if they do have b symptoms but one to two noal sites no extra notal involvement low bulk so that medial ratio is low um and the ESR is low as well the German hd10 is the first trial to know about and they basically took patients with favorable risk hodkin lymphoma um as defined by the risk factors that we just previously discussed and they performed a 2 by two randomization so they were first randomized to get chemotherapy with ABV D for either four Cycles or for two cycles and the Cycles were given in monthly Cycles with
infusions on Days 1 and day 15 and so they were first randomized to either four Cycles or two cycles of abvd and then four to 6 weeks after completing chemotherapy there was a second randomization to either involved field radiation for 30 gray versus 20 gray and remember involved field radiation is what was used in a lot of these older trials um but we now know from our illr guidelines that that is an outdated um technique it uses it just R gives too much radiation to too large of a field we have now narrowed down our
fields to involve site radiotherapy so it's safe to kind of apply these treatment paradigms knowing that the studies used involved field radiotherapy but in the modern era we use involved site radiotherapy anyway so 2x2 randomization abvd * 4 versus * 2 and then 4 to 6 we weeks later either radiation to 30 gray or to 20 gray as you can imagine the results showed more significant grade 3 to four acute toxicity when patients had more cycles of chemotherapy and when they had a higher dose of radiation um so the the toxicity was just significantly worse
the more chemotherapy you gave as well as the more radiation that you gave um of note um 5% of patients developed second cancers um approximately 7 and 1 12 years after um radiation and there was no significant difference in the development of second cancers between the two groups so whether you gave 30 gray or 20 gray um it was just around four to 5% rates of second cancer um in terms of the outcomes 97% of the patients had complete remission of disease and the regimen of abvd for two cycles followed by 20 gray were deemed
non inferior to any of the more intense options so when they first compared um the four cycles of abvd versus two cycles the failure of free survival was 93% versus 91% and abvd * 2 was not inferior and then in a second comparison when they compared 30 gray of radiation versus 93 uh sorry 30 gray versus 20 gray of radiation the failure free survival was 93% in both groups so again non inferior and so the conclusion from German hd10 trial was that the progression free survival is noninferior with two cycles of abvd followed by 20
gray of involved site radiotherapy for early stage um favorable hodkin Disease by the German hodkin study group criteria and again I make the caveat I wrote isrt there in that green box remember they used ifrt um because this trial was done more than 20 years ago um but in the modern era we use isrt and then again just to review um which patients would have qualified for this trial um it's early stage favorable patients so stage 1 to2 disease one to2 nodes no extr noal disease a mediastinal mass ratio less than 1/3 and a low
ESR um so these are the favorable early stage patients by German criteria and then if they met those criteria um per the German hd10 trial abvd * 2 followed by 20 gray of isrt was non- inferior hd10 was done in a prepet era so we were not using pet scans to assess the response to upfront chemotherapy the next trial we're going to discuss was the German hd16 trial that did utilize pet scan and they asked the question if patients have a compl complete clinical response to abvd time 2 Cycles up front and then they're negative
on the Pet Scan can we just omit any further radiation and so they took patients with Stage 1 to2 favorable um hodkin Disease by the German hodkin study group criteria um and note that they did also include patients with the nodular lymphocytic and then the non nodular hkin lymphoma patients um but again think of these as just early stage favorable hodkin patients and they randomize them to either the standard of care based on hd10 which was abvd * 2 Cycles followed by 20 gray radiation for everyone or a pet directed approach where they treated with
abvd * 2 Cycles followed by no further RT if they had a complete clinical response on the Pet Scan and what is a complete clinical response so in this trial it was defined as a doval score of 1 to three remember three is where uptake is greater than the medyum but less than the liver um so anything three or less was considered pet negative and these patients did not receive any further radiation and then if they did have continued pet positivity so a doval of four to five then the patients received 20 gray now interestingly
what they found is that bulky disease defined as greater than 5 centimeter disease was more frequent among patients who had pet positive disease um so 34% of the patients with residual pet positive had bulky disease versus 18% um in the patients that did not and then the the major outcome from this study is that the omission of radiotherapy was not non-inferior in terms of progression free survival um and so the progression free survival was 93% in the patients that received abvd * 2 followed by 20 gray if they had a pet negative disease versus 86%
if they just received abvd * 2 Cycles alone and no further radiation and so there was the the omission of radiation in pet negative patients could not be considered noninferior um and so the primary end point was not met in this study um of note the out of field recurrence was around 4 to 7% in both arms um so it was not significantly different but the rate of infield recurrence was only 2% with radiation versus 11% without radiation so radiation really does provide a significant local control benefit and that translates to a progression free survival
benefit of you know somewhere around 7 to 10% of note the overall survival was similar in both arms at 98% and the reason that the overall survival was not worse is because there is a good Salvage option so the patients that failed after receiving abvd alone ended up undergoing Salvage chemotherapy with or without autologous stem cell transplant to maintain equivalent overall survival so the conclusion from the German hd16 trial is that abvd alone for two cycles without observation is not non-inferior for progression free survival in patients that are pet negative um so for favorable early
stage hodkin disease if they do get two cycles of abvd and then have a complete clinical response on pet scan we still need to give them 20 gray um adant um to maintain that progression free survival however note that the overall survival was very similar in both arms um and because there's a good Salvage option of chemotherapy um plus or minus autologous stem cell transplant uh we do maintain that overall survival between the two groups and so I think this is where um a bit of controversy and and just discussion really is generated um because
the question is what is better for patients is it better to undergo just two cycles of abvd and then uh 20 gray of radiation or do we just watch them and then Salvage um with with further chemotherapy and Transplant if needed um it's always a risk benefit situation and it's important to kind of keep in mind that abvd is also not without toxicity um you know each cycle of abvd is thought to be equivalent to around four gray of a mean heart dose um and so when you at some point when you keep adding more
cycles of chemotherapy um you might sway yourself towards just pursuing radiation therapy to avoid further chemotherapy when you can um and so it's definitely an area of discussion but it's important to be aware that you know radiation does provide a significant PFS benefit um for these patients it's not non-inferior to omit the radiation entirely okay so hd10 and hd16 are trials from the German hodkin study group and for patients that are considered early stage favorable per the German criteria are acceptable C for abvd * 2 followed by 20 gray isrt and remember we always do
abvd * 2 we assess clinical response with a pet scan and um assuming that the patients do have a complete clinical response we can treat with 20 gray isrt now we're going to move on now and talk about some eortc studies for early stage favorable and so I want to take a moment to just go back to the risk factors and talk about what qualifies as early stage favorable per the German versus EC so for EC the biggest differences compared to the German criteria are that one to three nodal sites are considered favorable whereas for
German only one to two were considered favorable if you had three that automatically made you unfavorable also for eortc we really care about the age so if you're less than 50 years old you can be favorable but if you're 50 years or older that automatically makes you unfavorable and then with German they did care about having an Extron noal lesion with eortc that is not a criteria but having a mediastinal thoracic ratio greater than. 35 and having an elevated ESR um those are risk factors that are pretty consistent between eortc and German so the biggest
differences for EC versus German are 1 to two sites is considered favorable for German but 1 to three is considered um acceptable for EC and the way I remember that is that if you write the number three backwards so if you write if you kind of flip it the mirror image along the vertical axis a three becomes an e so eortc allows you to have one to three nodes whereas the Germans only let you have two and then for EC we also care about the age so age greater than or equal to 50 makes you
unfavorable the other point point I want to review from the overview lecture is that remember the German study group versus eortc also group the lymph node regions differently so the biggest difference I think is if you think about above the diaphragm and specifically the infra clav and subpectoral nodes so Germans group The infr clav subpectoral nodal region along with the cervical and sulav so for the German hodkin study group infr clav and sulav are together for eortc the infr clav is grouped with the axela so more like your traditional breast noal regions that you think
about so German the infr clav goes with the super clav for eortc the infra clav goes with the um axela and remember both German and eortc study groups consider the media stum and bilateral hila as just one group so the point I'm trying to make is that if you have an infra clav node an axillary node and then say a mediastinal node by German criteria that would be considered three lymph node regions making the patient unfavorable early stage by eortc criteria that would actually just be considered two lymph node regions and even if they had
three lymph node regions by the eortc criteria they would still be considered favorable and so this is where I think it gets a little bit confusing and whenever you are kind of risk stratifying patients as favorable versus unfavorable and determining a treatment Paradigm for them um you really have to be conscious of which study groups um Paradigm you're using um for grouping the lymph node regions and Counting them for classifying them as favorable versus unfavorable and then whichever study group you classify the patient based on is the study group that you should sort of treat
the patient based off of as well so now that we understand um that eortc and German Hodgkin study group group the lymph nodes differently and they have slightly different um factors that make you favorable versus unfavorable we realize that patients that are considered favorable by the eortc criteria might not necessarily be considered by the German criteria so as long as you understand that there are some subtle differences in terms of how these patients are grouped together um I think I think that is the major Point here so we talked about German hd10 and hd16 we're
now going to move on and talk about eortc h10 uh which was a trial that asked the question can we omit involved nodal radiation in patients that are pet negative after two cycles of abvd and this is a very similar question actually to the question that was asked by the German hd16 trial um but what EC did is that they took patients and let's just focus on the favorable arm for now we'll talk about unfavorable when we're talking about unfavorable disease um let's just focus on h10 F which is the favorable arm they randomized patients
to either two cycles of abvd followed by a pet scan and regard of the response they received an additional cycle of abvd plus inrt so three cycles of abvd chemo followed by radiation or they were randomized to two cycles of abvd and then treatment tailored based on the pet response so in that tailored arm if they were pet Negative they just received two more cycles of abvd and no further radiation if they were pet positive then theyed two cycles of escalated bacop remember that is the more aggressive form of chemotherapy just a very much aggressive
regimen um so if they were pet positive so if they had partial response or residual disease um they got escalated bacop for two cycles followed by radiotherapy um and keep in mind that you know the German trials that we talked about were using involved field radiation uh the eortc trials were using involved nodal radiation because they were run in Europe you know here we would do involved site radiotherapy um but involved R involved node radiation so let smaller Fields compared to the German trials that we talked about previously so just to review the two arms
of EC h1f the standard arm was abvd * 3 followed by 30 gray and if they were in the pet directed tailored arm um they were treated based on their pet response so a doal 1 to2 was considered a negative pet response and everything else was considered a positive pet response so that's another subtle difference right because the German study group considered dovel 1 to3 as negative and eortc considered dovel 1 to2 as negative but if there was a doval 1 to2 response then patients were considered pet negative and they were just treated with abvd
for four Cycles total but if they had pet positive disease then they were treated with abvd * 2 followed by escalated bacop followed by 30 gray of radiation and interestingly the results of this study were very similar to what we saw in hd16 where the progression free survival was not non-inferior with abvd alone so in patients that were pet negative doval 1 to2 after two cycles of abvd if they were treated with radiation um or if they were treated with abvd for one more Cycle Plus plus radiation then the 5-year PFS was 99% however if
they were treated with just four cycles of abvd total then their PFS was 87% so just around a little over 10% less the 5year overall survival rates again were very similar in both arms 99 to 100% not significantly different but the PFS again was not non-inferior and it was around 10% worse in the patients that did not receive any r ration in terms of the pet positive patients um the 5-year progression free survival did improve with escalated bacop so the 5-year PFS was 77% with abvd plus inrt um in the standard arm versus 91% in
the bacop escalated times 2 plus inrt however um bacop is a very very toxic regimen and has significant rates of grade three to four human IC toxicity um so it's actually not really used in the US it's more commonly used in Europe but we really don't use it in the US um but the big takeaway from eortc h10 f is that even with an excellent pet response doal 1 to2 abvd alone is not noninferior to abvd * 3 plus 30 gray inrt and again there was no significant difference in overall survival I think these results
very sharply mirror what we saw in hd16 and keep in mind that in h1f they were looking at even more quote unquote favorable patients because they had such an excellent response they didn't even include doval 3 response um but despite that there was more than 10% PFS benefit with the addition of radiation um so from EC we then get the treatment Paradigm of abvd * 3 followed by 30 gray of radio radiotherapy the last trial I'll mention for early stage favorable disease is UK rapid um from which we get the treatment Paradigm of abvd times
three Cycles um and no further therapy if patients are pet negative um so this trial took patients with stage 1A to 2A classical hodkin disease um they took non-bulky disease but actually around 30% of patients were unfavorable um based on German and eortc risk criteria um and they were treated with abvd * three Cycles followed by a pet scan and if they were pet Negative they were randomized to no further therapy versus 30 gray of involved field radiation and if they were pet positive then they received a total of four cycles of abvd followed by
30 gray involved field radiation and what they found is that the three-year progression free survival again was not non-inferior with abvd alone so just like we saw in hd16 and then EC c10f radiation does seem to confer a progression free survival benefit um however if you look at the absolute values you know the three PFS was 95% with the radiation group versus 91% with no radiation so still very good progression free survival it was just not non-inferior um with the omission of radiation the three overall survival just like we saw in those other trials was
excellent 97 to 99% in both arms for the patients that were in the pet positive arm the three-year progression free survival was 88% remember they got abvd * 4 followed by 30 gray of involved field radiation and then um there was a subset of patients that did undergo progression and underwent stem cell transplant so UK rapid just adds evidence um to our growing Bank of studies that show that abvd alone is not non-inferior to abvd plus radiation even in patients that are pet negative however we know that they have excellent overall survival and that is
because there are good Salvage options and the PFS in UK rapid was actually fairly good in both arms so 91% with the omission of radiation versus 95% with radiation so I think the major takeaways for early stage favorable classical hotchkin disease um you know it has a very excellent prognosis with a perform progression-free survival of somewhere around 90% and an overall survival of probably somewhere around 99% so these patients do very very well and they have a lot of treatment options a lot of folks will favor omitting radiation to spare patients the toxicity of radiation
and it's true that radiation does cause significant long long-term toxicity in the sense of cardiac toxicity as as well as risk of second malignancy um but know that when we do omit radiation although patients still have an equivalent overall survival the progression-free survival is not non-inferior in any of these studies um and based on the studies that we talked about radiation provides an absolute progression free survival Improvement of somewhere in the neighborhood of 7 to 10% so in terms of a treatment Paradigm when you're asked how would you treat a patient with favorable early stage
disease um abvd * 2 followed by a pet scan is always a great way to start off so you do two cycles of abvd get an interim pet scan if the patients have a doval four response so meaning a partial response to upfront chemotherapy then we know that we need to give them more chemotherapy because they did not respond as well as we would have liked to The Upfront two cycles so if they're doval four then they get more abvd so four Cycles total and then if they have a good response to that we can
treat them with 30 gray of involved site radiation so abvd * 4 followed by 30 gray if they have a doal 1 to3 response however we have several treatment options so abvd * 2 pet scan and then 20 gray of radiation if they're favorable per the German hodkin study group criteria if they are favorable per the eortc h10 F criteria we can always do abvd * 3 followed by 30 gray UK rapid does actually give us some evidence for just treating solely with abvd * 3 to four cycles and even with e1f remember the overall
survival for the patients that were treated with just abvd * 4 was pretty comparable to the patients that received radiation it was just the progression free survival that was worse and then another trial that we will talk about when we get to our Advanced stage section is UK rathl um there is an option to do abvd * 2 and then actually drop the bomy and do four more cycles for AV of avd Alone um so there is some data for that which we'll talk about down the road but just remember abvd * 2 assess the
pet response if they have a poor response they need more chemo and 30 gray radiation but if they have a good response then we have many different options based on the trials that we talked about so moving on now let's talk about early stage unfavorable disease and remember these tend to be patients that have multiple noal sites so three or more per the German four or more per EC um and they also often have bulky disease so starting with the German hodkin study group uh hd11 was a trial from the German hodkin study group that
looked at unfavorable uh early stage disease and the treatment Paradigm that emerges from this trial for unfavorable disease is abvd * 4 followed by 30 gray so this trial included patients that were considered unfavorable for the German criteria and they underwent a 2X two randomization so the randomization was to bacop for four Cycles versus abvd for four cycles and the second randomization was 30 gray versus 20 gray of involved field radiation and across all of the arms that overall survival was excellent 93 to 95% um and when they compared the radiation dose with abvd they
found that 20 gray was not non-inferior to abvd * 4 + 30 gray so the 5year PFS was 82% with abvd * 4 followed by 20 gray versus 87% in all of the other arms so the bacop arms actually both did really well whether they got 20 gray or 30 gray the outcomes were equivalent um however bacop was associated with significantly higher hologic toxicity um very very rough for patients to tolerate and so the standard arm that was preferred from this trial was abvd * 4 followed by 30 gray that was equivalent to bacop Time
4 followed by 30 gray or 20 gray but remember bacop had significant toxicity and abvd * 4 followed by just 20 gray um had worse progression free survival so abvd * 4 followed by 30 gray is the standard for early stage unfavorable disease based on German hd11 now this trial was again performed in the prepet era um in the modern era we would look for pet response after abvd * 2 to make sure we're on the right track and then patients would get abvd for four Cycles total followed by 30 gray of radiation so that
was the German trial for unfavorable disease uh we're back now to eortc h10 and this time we're going to focus on h10 U uh which is the unfavorable arm and very similar to h10 F they did they took patients with unfavorable disease this time and randomized them to standard which was four cycles of abvd followed by inrt versus two cycles of abvd followed by uh treatment based on the pet response so pet negative patients received four additional cycles of abvd for a total of six cycles and pet positive patients um just like in the favorable
arm actually received two cycles of escalated bacop followed by inrt and I think no surprises here but just like we saw with e c10f it turns out that PFS uh was not non-inferior with abvd alone so PFS not non-inferior if we omit radiotherapy the 5-year PFS was 92% with abvd * 4 plus inrt versus 90% with abvd alone and so the conclusion is not non-inferior because it did not meet the threshold for non-inferiority but if you look at the absolute values again 92% versus 90% you know one wonders you know how much of an absolute
benefit does that really provide and when you look at the overall survival it was 97 to 98% in both arms and so again you can see why um you know folks May draw the conclusion that we understand that the progression free survival is not non-inferior with the omission of radiation however it's still really really good and because the Salvage rates are so good maybe we can just spare the patients the toxicity of radiation um so again I think this is a very common thread we saw this in favorable we see it again in unfavorable but
the progression free survival is not not non-inferior with the radiation um but it's still very good in terms of the escalated bacop arm for the the pet positive patients um again the 5year progression free survival did improve with the escalated bacop but again we saw higher um grade 3 to four hematologic toxicity jumping back uh to the German hodkin study group for a second I want to mention uh this 2+2 chemo therapy regimen that you might hear about which came from the German hd14 trial um so this was a patient of a study of patients
with early stage unfavorable disease um just like hd11 so unfavorable by the German criteria and they randomize patients to either abvd * 4 followed by 30 gray of radiation or the 2+ 2 chemo regimen followed by 30 gray now what's 2+ 2 2 plus 2 is two cycles of B cop and two cycles of abvd and then they followed that up with 30 gray of radiation their primary endpoint of freedom from treatment failure actually improved with the 2 plus2 regimen so the 5-year PFS was 95% with 2 plus2 versus 89% with abvd * 4 so
there was a 6% absolute Improvement there was no significant difference in overall survival between the two arms however and there was significantly higher acute toxicity with the two 2 plus2 regimen so I think it's quite striking the grade four toxicity was 56% with 2 plus2 versus only 6% with abvd and the grade 3 to four was 80% versus 51% so really really bad toxicity and you know you should know that intensification of therapy with um bacop is definitely more standard in Europe in general um in the US it's generally less accepted because it increases toxicity
it does improve progression free survival but since it does not provide an overall survival benefit it's generally less accepted in the US um and so the UK I think tends to use both bacop and radiation more commonly compared to the US um but I just want to mention you know this regimen which you might hear about and then following um hd14 uh the German hd7 trial was published that looked at radiation Omission um based on the pet response and interestingly so if patients the the pet guided response um was bacop times 2 plus abbd *
2 so the 2 plus2 regimen and they only treated with 30 gray of radiation if patients had doval 3 to five disease so remember dovel 3 was considered pet positive here doval 1 to two were considered negative and it turned out that 68% of patients in the pet guided arm had a dovel of one to two after the two plus two regimen and radiation was omitted and when they looked at the progression free survival it was actually non-inferior with petg guided Omission so the progression free survival was 97% with the standard arm versus 95% with
pet guided omission and that did meet the non-inferiority criteria so all these studies that we've done so far showed that with the omission of radiation progression free survival was not non-inferior it turns out that when we use escalated chemotherapy so the 2 plus 2 regimen of bacop * 2 followed by abvd * 2 if patients have a doval response of 1 to two then we can omit radiation and 68% of patients avoided radiation in this trial um so again bacop is not something that we standardly utilize in the US um but I think it is
good to be aware of this trial so I think the highlights um from our discussion of early stage unfavorable disease um again in the US we're very unlikely to use bacop just because it is an extremely extremely toxic um chemotherapy regimen um again abvd * 2 followed by a pet response is always a great way to start off um when you're asked how you would treat somebody and then response um kind of based on the based on the pet response we can kind of tailor further therapy and assuming that they have a good response generally
considered dovel 1 to three our treatment options include abvd times four Cycles total followed by 30 gray as an eortc h10 U um or again we can consider abvd * 2 followed by avd * 4 as per the UK raffle trial which we will talk about soon the radiation um the biggest difference is to keep in mind so with early stage favorable remember abvd * 2 followed by 20 gray as per the Germans or abvd * 3 followed by 30 gray as per the eortc um that was kind of the standard treatment Paradigm for favorable
and then for unfavorable It's abvd Time 4 followed by 30 gray and so finally this brings us to management of advanced disease um and the the evidence for for our management there um remember Advanced disease is disease that's stage three or four so involvement of both sides of the diaphragm or significant extranodal disease burden German hd15 trial compared bacop time 8 Cycles versus bacop time six Cycles um versus eight cycles of dose dense bacop so given every two weeks instead of um I believe every 3 weeks um and this was for patients with Advanced stage
so stage three to four Hodgkins disease and I won't spend too much time on this because we don't really use the bacop regimen in the US um but but basically uh there was a significant overall survival benefit to bacop time 6 versus bacop time 8 probably because there was less toxicity um with bacop time 6 um and of note um all of the three groups in this trial did receive 30 gray of petg guided radiotherapy for Legions that were 2.5 cm or greater that had residual fdg uptake um but again bacop time 6 versus bacop
* 8 um actually showed a significant survival benefit to bacop time 6 again bacop not very commonly used in the United States at all um so I actually think UK rthl is a more relevant trial to us um here in the US and um you know helps us to guide um further risk adapted therapy for hodkin disease so UK rathl um took patients with Advanced um Hodgkins disease who had a baseline pet C followed by two cycles of abvd and then again they tailored the response based on the pet so after two cycles of abvd
if they had a doval 1 to3 response on pet considered pet Negative they were randomized to either abvd times 4 Cycles or avd times 4 Cycles if they had a positive response so doval four to five after two cycles of abvd then they received three cycles of escalated bacop followed by an additional pet C and then escalated bacop * 1 or dose Den bacop 14 * 2 if they were pet negative no radiother theapy was given if the interim pet was negative um but they did in the study they said that they allowed radiation at
the discretion of the physician unfortunately radiation was not a randomized variable in this trial so it's kind of difficult to draw any conclusions about radiation from this study um but anyway 84% of the patients were pet negative after two cycles of abvd so they had doval 1 to three response and the progression free survival um was very um you know not super different between the two groups when you look at absolute values so PFS was 84% with avd versus 86% with abvd again it's of those situations where they were not able to conclude that two
cycles of abvd followed by four cycles of avd dropping the bomy was noninferior so it was not non-inferior but again the absolute difference between these two groups was very low only 2% here and the overall survival was extremely similar in both arms 97% to 98% um and so you know for these patients that have pet negative disease after two cycles UK rathl showed very good outcomes with abvd * 2 followed by avd * 4 and the major advantage of doing this is decreased pulmonary toxicity because you drop the bomy which remember causes significant pulmonary toxicity
and so abvd * 2 followed by avd * 4 is you know a regimen that is utilized in the us because we understand that the PFS was not non inferior however the absolute difference was very low the overall survival was extremely comparable and you know we get to drop that bomy and this um regimen also does not actually utilize any radiation um so so this was sort of the the interpreted conclusion of UK rathl I'll also mention that of the pet positive patients in UK rathl um 74% actually had a a clinical response um a
clinical complete response after three additional cycles of bacop and the three-year progression free survival was 68% the threeyear overall survival was 88% um so you know obviously these patients do a little bit worse because they have advanced stage Hodgkins and they did not have a good response to upfront two cycles of abvd um but but they did have a pretty good response when they got the escalated bacop um so the big conclusion from UK rle I think is abvd * 2 followed by avd * 4 for Advanced stage disease is technically not non-inferior however low
absolute difference in PFS and many centers will use this regimen and even extrapolate it to um early stage disease as we saw earlier there are a couple of Trials from the Italian study group um that I think are worth mentioning that investigated the role of consolidative radiotherapy for advanced stage hodkin disease that had a um complete clinical response to abvd so hd67 took patients with Advanced hodkin disease and bulky noal Mass uh so greater than or equal to 5 cm and these patients had to have a negative pet at cycle 2 after abvd as well
as after cycle 6 um so complete clinical response and they were randomized to either consolidation radiotherapy to 24 to 36 Gray or no further treatment the patients were then stratified based on the size of their tumor so 5 to 7 cm versus 8 to 10 cm versus greater than 10 cm which is what we classically think of as bulky greater than 10 cm and as you can see from the progression free survival in the green table on the right hand side there was no significant difference in the progression free survival between the groups in any
of the different subgroups with the addition of radiotherapy now of note I think this trial is difficult to interpret because the trial was not actually powered for a radiotherapy comparison um there was an additional randomization for the patients that were pet positive after two cycles of abvd those patients were randomized to four cycles of bacop um plus or minus rmab and then the trial actually showed no benefit to rmab um the six-year progression free survival was around 60% overall survival was around 90% um so that was for the pet positive arm escalated bacop plus or
minus rmab and it was negative um but in this pet negative Group after six cycles of abvd it seemed like there was not a benefit to consolidative radiotherapy regardless of how bulky the tumor again the trial was underpowered for this comparison um but that's sort of the conclusion another study from the Italian group that also I think sort of muddies the waters and doesn't totally answer our question about the role of consolidative radiation was hd81 um and they took patients with Advanced disease and randomize After abvd Time six Cycles randomized them to either consolidation radiotherapy
or um observation and they found that there was no significant Improvement um with the addition of consolidative radiotherapy the 2-year event-free survival was 88% with radiation versus 86% without radiation and the 2-year progression free survival was 91% with radiation versus 86% without radiation and so this trial showed no significant benefit to consolidative radiotherapy if um they had negative pet after cycle 2 as well as after cycle 6 um and six cycles of abvd and these again were bulky lesions um greater than 5 cm the reason I think um this trial is not totally informative is
because it was powered to detect a 20% benefit and remember from our earlier studies um the German hd10 um hd16 even EC remember that the progression free survival benefit from radiation was somewhere on the order of 7 to 10% um and so if the trial was powered to detect a 20 % benefit then of course it was negative um so it's again I think difficult to draw a conclusion from this trial as well but based on these two Italian Studies uh you know there's no evidence for consolidative radiotherapy in patients with Advanced stage disease and
bulky lesions measuring greater than 5 cm who have a complete response after two cycles of abvd and then again at after six cycles of abvd on pet scan there is an alternate systemic therapy option for advanced stage Hodgkin lymphoma um which is BV avd uh for six cycles and this is based on the echelon one trial so BV stands for brentuximab ADOT which remember is an anti- cd30 antibody and we use it because uh hjin lymphoma is cd15 and cd30 positive so we use this BV which is the anti- cd30 antibody and the echelon one
trial randomized patients with stage 3 to four disease to either abvd * 6 every 28 days or BVD BV avd for six Cycles every 28 days and um of note they did switch to the alternate arm if after two cycles their pet was still doville five um so then they switched to alternate therapy the 2-year progression free survival in this study was 82% with BV avd versus 77% with abvd um and the I think it's basically a toxicity trade-off so we know that abvd causes worse pulmonary toxicity but bvad causes significantly worse uh neuropathy so
the grade three or plus pulmonary toxicity was 1% with bvad versus 3% with abvd neuropathy however was 67% with bvab versus just 43% with avd so BV AV is another FDA approved um systemic therapy to be aware of for advanced hodkin lymphoma um however its limitations are um neurotoxicity and cost but it did have a progression free survival benefit that was significant um compared to standard abvd one other trial I think um that we should be aware of is um swag s 1826 um as far as I know the abstract for this study was presented
at ASCO 2023 and we are still awaiting publication um but this trial looked at different systemic therapy so they compared for patients with Advanced stage hodkin disease um BV avd which was established based on Echelon 1 compared to neolab and avd so BV avd compared to Neo avd and nalab is an immunotherapy that is a pd1 inhibitor and the primary end point um was progression free survival and in fact it was significantly improved um so the one-year progression free survival when they presented the abstract in Asco 2023 the one-year progression free survival was significantly improved
with Neo avd so it was 94% in the Neo arm versus 86% in the BV avd arm um there was lower peripheral neuropathy with the noolab um but greater grade three or Worse hematologic events um so obviously we need longer followup um survival data are probably maturing um but I think swag sat 1826 is an important study to be aware of as well um because it's looking at an alternative to BV um which is nivolumab avd so that concludes our discussion on Advanced stage uh literature and I think the major takeaways here are that most
patients with Advanced hodkin lymphoma will have a good response to six cycles of abvd and we don't really have good evidence um for radiation even if they have bulky disease if patients have um negative pet scans after two cycles and then after six cycles of abvd so those were those Italian Studies that we talked about and it seems like it is safe to Omit radiotherapy even if they had upfront bulky disease possible indications for involved site radiotherapy include patients that presented with initially bulky disease so greater than 5 cm and um pet positive disease after
two cycles of abvd so they did not have a complete response to two cycles of abvd or if they continue to have residual pet positive disease after the conclusion of chemotherapy so here is a quick summary slide um to kind of hopefully um cohesively summarize everything that we have talked about in terms of a treatment Paradigm for hodkin disease so regardless of what stage whether it's early stage favorable unfavorable or Advanced it's always correct to start with abvd * 2 cycles and then have a pet for response assessment most patients will respond well to the
therapy and typically a complete clinical response is described as doval 1:3 although remember there were um some select studies that we talked about that characterize doval 1:2 as a complete response um but most people accept doval 1:3 as a complete response and most of the patients will respond well and we can continue along the different Pathways that are outlined here if um they do not respond then we need to escalate and um bacop is a regimen that's often used in Europe um but we know that it has very significant toxicity um here in the US
I think it's more standard just give more cycles of a BVD or try BV D I'm sorry BV avd um but kind of you know escalating the chemotherapy giving them additional chemotherapy so abvd * 2 followed by a pet and then for early stage favorable if we use the German criteria abvd * 2 followed by 20 gray is an option if we use EC criteria abvd * 3 followed by 30 gray is an option and then there are also options where we omit radiotherapy understanding that there is a decrease in progression free survival but overall
survival is still very good um and those regimens include abvd * 3 to 4 as in UK Rapid or abvd * 2 followed by avd * 4 as in UK rathl for early stage unfavorable um we have to give a little bit more chemo so abvd * 4 followed by 30 gray or abvd * 2 followed by ABD * 4 and then for advanced disease again the ukl Paradigm um is possible so abvd * 2 followed by ABD * 4 or abvd * 6 with consideration of 30 gray um involv site radiotherapy only if they
had initially bulky disease um and pet positive after two cycles of abvd or if they continue to have resid ual pet positive disease after the full six cycles of abvd and then BV avd * 6 is also an option as per Echelon um and then be aware of the swag study that we talked about that is looking into um nivolumab avd so remember again all of these pathways are assuming that the patient has a doval 1 to3 response after two cycles of abvd and then if um they have a doval four to five response then
escalation of therapy is definitely warranted so that is all I have um hopefully this talk helped to shed some light on treatment paradigms for hodkin lymphoma um in an evidence-based manner um hopefully it was helpful and thank you so much for your time
