Cervical Cancer Evidence

hi and welcome to Raton talks a lecture series designed for students and residents of radiation oncology my name is Ria I am a pgy4 resident at the University of Pittsburgh and this is our second installment of our gynecologic cancer Series in the first talk we addressed some of the very general basics of cervical cancer including workup staging and treatment Paradigm in this talk we're going to dig deeper into the evidence behind cervical cancer management and discuss some of the seminal trials that guide our practice if you recall from the cervical cancer overview lecture we discussed

that cervical cancer can kind of be divided into two buckets the first bucket is very early stage disease that can be treated with upfront surgery followed by tailored post-operative management depending on certain risk factors and there are really two critical trials that guide our post-operative management for early stage cervical cancer after hysterectomy so we will discuss those then we'll get into the trials that um are more relevant to the definitive management of cervical cancer with definitive concurrent chemor radiotherapy followed by brachi therapy boost and then finally we will address the some of the some of

the key pearls from Embrace studies uh that are really useful to us when it comes to treatment treat planning so that first bucket of cervical cancer patients includes the very early stage patients that are amenable for upfront surgery so I think of this as disease that's less than 4 cm in size and not yet invading into the parametria once it's greater than 4 cm or invading the parametria or Beyond um it's a little bit to too advanced for upfront surgery so very very early stage disease they can be treated with upfront surgery there are fertility

sparing approaches but most of the time the standard treatment is going to be a radical hysterctomy where we're dissecting the parametria as well and removing um the upper part of the vagina along with some type of surgery for the lymph nodes and that could include Sentinel lymph node biopsy or a pelvic lymph adenectomy I think in the modern era a lot of folks have moved towards Sentinel lymph node biopsy so radical hysterectomy plus Sentinel lymph node biopsy and ideally after that surgery and the Sentinal lymph node biopsy patients can just be observed however if certain

risk factors are present then we may need to consider adant therapy with either radiation alone or adant chemo radiotherapy so what are those risk factors and how do we decide whether patients should get adant radiation alone versus adant chemal radiation the answers to these questions come from important clinical trials which we will discuss now most of the trials that we're going to cover in this talk came from the Gog which is the gynecologic oncology group so most of these are Gog trials with various numbers at the end of their name um the first trial we're

going to talk about is gg92 um and the first author on this trial was sess uh which is probably worth remembering and and probably easier to remember than the number of the trial gg92 ran um in the late ' 80s and early 9s and they took patients with Stage 1B cervical cancer who had certain risk factors based on a prior study uh Gog 49 the risk factors um which were the eligibility criteria for this study are outlined in the table on the right hand side um so they looked at three different things they looked at

the lymphovascular space invasion they looked at the depth of stromal invasion so they divided it into thirds and middle or deep stromal invasion was considered a risk factor and they also looked at the tumor size now as you can see in that table The lvsi strumal Invasion and tumor size are um kind of complicated to remember um a simplified way of remembering these criteria is that you basically just need two out of three of the risk factors you either need to have lvsi you need to have deep stromal Invasion which is middle or deep 1/3

strumal Invasion or you need to have a tumor size greater than 4 cm that's a simplified way of remembering it the table that's shown there is the way that it was actually included in this trial um but but think of it as you needed to have two out of three of certain risk factors and these are lvsi strong Al Invasion or size greater than 4 cm and if they met these criteria so if they had these risk factors they were randomized to either radical hysterectomy with pelvic lymph node dissection or radical hysterectomy pelvic lymph no

dissection followed by adant radiation these patients were just treated with adant radiation um to 46 to 50.4 grade of the pelvis and no vaginal brachy therapy was allowed the results of this study showed that there was a significant Improvement in local Regional recurrence as well as progression free survival with the addition of radiation so the 12-year local recurrence rate went from 31% to 18% with the addition of radiation and the progression free survival went from 65% to 78% with the addition of radiation there was no significant benefit in overall survival um and the grade 3

+4 toxicity was numerically higher in radiation but again it was not statistically significant so 6% with radiation versus 2% without radiation and So based on this trial because it offered a local recurrence benefit as well as a progression-free survival benefit for patients who undergo hysterectomy for cervical cancer either pelvic lymph node dissection or now Sentinel lymph node biopsy in the modern era if they meet these risk factors which are defined as the said lless criteria because we know it has a local control and progression-free survival benefit we offer them adant radiation to the pelvis so

that's nowadays we're doing 45 um to 50.4 gray um some folks will offer 50.4 gray to the post-operative pelvis um just because there's a risk of of hypoxia in the in the postsurgical environment so an easy way to remember what the said list criteria are is said list Lis remember the Lis risk factors so lvsi Invasion into the cervical stroma or size greater than 4 cm so if you have two out of three of these said list criteria l i that means that you might benefit from adant radiation and what is the benefit that adant

radiation provides it's not an overall survival benefit but it's a local control and progression-free survival benefit the local control was improved from 31% down to 18% with the addition of radiation also keep in mind that these Lis the two out of three for lvsi Invasion and size these are simplified criteria the ACT ual criteria are a little bit more um involved and I would look up that table whenever you actually need to to look this up but keep in mind that these are a simplified way of remembering the indications for adant radiation after hysterectomy the

criteria for adant chemo radiation come from The Trial goog 109 um and the first author on Gog 109 is Peters so we call these criteria the Peters criteria after Gog 109 so this study also ran in the early 9s and they took patients with early stage cervical cancer 1 a 1B or 2A cervical cancer who had undergone radical hysterectomy and lymph node dissection and in order to be included on Gog 109 they had to have at least one risk factor either positive margin positive nodes or parametrial involvement so positive margin is something that you know

at at the time of surgery if they're not able to get the disease out completely and if the tumor extends right up until the margin that's something that's found at the time of surgery positive nodes and parametrial involvement are basically functions of getting upstaged at the time of surgery right um keep in mind also that at this time they didn't have access to like MRIs and pet scans the way we do now um so they probably also had a harder time clinically staging these patients up front so they were more likely to get upstaged at

the time of surgery but if they had positive margin or if they were upstaged with findings of positive nodes or parametrial involvement they were included on this trial and they were randomized to one of two arms so they either received adant pelvic radiation alone or they received pelvic radiation with concurrent and adant chemotherapy which included cisplatin and 5fu so cisplatin and 5fu were administered for four Cycles every 3 weeks um so two cycles were given with the radiation and then two cycles were given adant and the idea for giving cisplatin and 5fu with the radiation

is for radio sensitization so to kind of synergistically work with the radiation and help it have a better effect um and it was given every 3 weeks so what they found is that with the addition of concurrent chemotherapy there was not only a progression free survival benefit but also an overall survival benefit so the 4-year progression free survival went from 63% all the way up to 80% with chemo so almost you know 15 to 20% PFS benefit and then there was a 10% overall survival benefit where um addition of chemotherapy to the adant radiation improved

overall survival from 71% up to 81% so a 10 % benefit um and they also saw that patients that had adoc carcinoma histology tended to have a worse prognosis versus squa Cell carcinoma so that's something that we've realized is that adnoc carcinoma tends to be a little bit worse prognosis compared to Squam cell carcinoma but the the bottom line from Gog 109 is that this study established the Peter's criteria um which guide us in choosing patients that are candidates for adant chemo radiation so these criteria remember the three PS are the Peters criteria so positive

margin positive nodes and parametrial involvement and I think of this kind of in the sense that if we knew before the surgery that they had positive nodes or that they had parametrial involvement they would have been considered a higher stage anyway right parametrial involvement you're stage 2B positive nodes you're stage 3 c um and so if if we knew that before going into the surgery they would have received definitive chemo radiation anyway but instead they they were thought to be early stage went for surgery and then upstaged at the time of surgery and so now

we're giving them concurrent chemo radiation in the adant setting um the other thing that's important to realize is that remember with the said list criteria we realized that radiation just had a local control and PFS benefit it did not affect the overall survival it the Peter's trial or Gog 109 the addition of concurrent chemotherapy does improve the overall survival and I think it's pretty easy to to think about why um radiation is a local treatment so we're providing a local control benefit and we see that in the sedus trial where adant radiation is the only

additional treatment there's a local control benefit and a progression benefit but not a overall survival benefit with the addition of chemotherapy we are now not not only helping the radiation to work better but we're also treating any potential microscopic disease that has spread distantly right and so that's why with the addition of chemotherapy we are now seeing this 10% overall survival benefit as well so that kind of wraps up the two studies I wanted to talk about for um adant treatment after surgery remember said lless criteria 2 out of three lvsi strumal Invasion or size

greater than 4 cm we offer adant radiotherapy Alone um if people have Peters criteria so positive margin positive nodes parametrial involvement those three PS uh we think about offering adant chemor radiotherapy with concurrent cisplatin uh one other note that I'll make is that in the modern era we don't give cisplatin every 3 weeks we actually give it weekly and the dose is 40 Mig per meter squared um so the chemotherapy Gog 109 was a little bit dated we're not giving cisplatin plus 5fu anymore and we're not giving it every 3 weeks we're just giving cisplatin

40 mgram per met squar weekly so that was adant therapy and we learned that sometimes um especially in the era that the go1 92 and go 109 studies were conducted you know sometimes staging isn't perfect and patients might get upstaged at the time of surgery and they might have certain risk factors like size greater than 4 cm or positive nodes or parametrial involvement which lead us to to want to give agant therapy either radiation or um chemo radiation um nowadays with the utility of uh MRI as well as pet staging uh we're better able to

assess it's it's still not perfect but we're better able to assess the stage and we know that if patients have higher stage disease so if they have tumor greater than 4 centimeters clinically or if they have parametrial involvement uh distal vaginal involvement nodal involvement um we know that these patients are a little bit too advanced for upfront surgery and instead we treat them definitively with um chemor radiotherapy and a Breaky therapy boost so now let's get into some trials uh that guide our Management in this setting the first of these studies is Gog 123 and

go 123 um is kind of the rationale for why we are treating these patients with concurrent chemo radiation as opposed to just radiation alone go123 took patients with cervical cancer that measured greater than 4 cm and they were randomized to either external beam radiation alone with a low dose rate Brey therapy boost versus external beam radiation with concurrent weekly cisplatin 40 mg per met squar for up to six Cycles so that cisplatin dose of weekly cisplatin 40 milligrams per meter squared is what we are still continuing to give for radio sensitization um and they got

concurrent weekly sus platin along with the radiation at this time patients were still receiving extra fascial hysterectomy after that Neo adant treatment um in the next study we'll talk about why adant hysterectomy is no longer standard but just remember at this time we were still doing that it's not standard of care now um so these patients that had more advanced disease greater than 4 cm tumors when they were randomized to the radiation alone versus concurrent chemo radiation it turned out that chemo radiation improved progression-free survival as well as overall survival so that addition of CIS

platin provided both a PFS and an OS benefit does that sound fam Amar I think so we saw the overall survival benefit with the addition of chemo in the Peters trial as well right Gog 109 and here again we see that adding concurrent a spaten provides not only a progression free survival benefit but also an overall survival benefit so the PFS improved from 60% to 71% with chemo and the overall survival improved from 64% to 78% with uh chemotherapy um these numbers I think it's easy to remember they're very similar to Gog 109 just remember

the overall survival went somewhere in the neighborhood of around 70% to somewhere in the neighborhood of around 80% and and both of those were significant so go123 tells us that concurrent chemotherapy with radiation improves PFS and Os in the definitive setting I don't have a slide on r901 um but rt9 1 was an additional trial which similar to Gog 123 compared um pelvic radiation versus chemo radiation with concurrent chemotherapy they used cisplatin and 5fu similar to Gog 109 um in this setting and they also found a overall survival and disease-free survival benefit with the addition

of chemo um so Gog 123 is not the only evidence we have there's also r901 let's go back for a second uh to that question of why adant hysterectomy is no longer done um remember we said in Gog 1223 all of the patients were still receiving extra fascial hysterectomy but that's no longer the standard of care the reason for this um comes from the trial g71 which randomized patients with um they were randomized to either radiotherapy alone versus radiotherapy followed by an extrafascial hysterectomy keep in mind in this trial patients were not receiving concurrent chemo

radiation because this trial was started at a time where go123 and rtog 901 were not yet published so they were just receiving radiation alone and then either radiation alone followed by observation or radiation followed by a hysterectomy and what this study showed is that there was no significant Improvement in the progression free survival or the overall survival with the addition of extra fascial hysterctomy so there was no real benefit to the addition of extra fascial hysterctomy and so what we've realized now is that if patients are already receiving definitive chemo radiation we really don't need

to pursue Tri modality it just adds toxicity adds morbidity without actually providing a PFS or an OS benefit there was an unplanned subgroup analysis of this study which suggested that local control might be improved with the addition of hysterectomy if patients have larger tumors greater than 4 to 6 cm um and as always unplanned subgroup analyses should always be taken with a grain of salt um but I think the big takeaway is that typically we are not doing agiven hysterectomy um it's something that can be considered if patients continue to have residual disease after chemor

radiation and brachi therapy boost so so far we've talked about two very important trials that support our concurrent um Paradigm for the definitive management of cervical cancer with chemor radiation radiation therapy um so we talked about goog 123 that was the justification for treating with chemo radiation as opposed to radiation alone and we talked about g71 uh which did away with the adivan hysterectomy for the most part um we're we're typically just treating these patients with radiation and not offering them um adant hysterectomy standardly now you'll notice that in some of the trials the chemotherapy

regimens varied a little bit but we've been saying all along that the standard regimen is weekly cisplatin 40 mgram per meter squared that also comes from level one evidence and the evidence for that is this trial goog 120 that compared three different chemo regimens uh given concurrently with radiation so they took patients with Stage 2B to 4 a cervical cancer who were receiving radiation and randomized them to one of three concurrent regimens so cisplatin 40 mgram meter per meter squared weekly versus hydroxy UA versus cisplatin 5fu and hydroxy Ura the results showed that Hydrox hydroxy

UA alone was the loser it had the worst overall survival in progression-free survival however for both cisplatin based arms showed similar outcomes So cisplatin based chemotherapy had Superior progression free survival as well as overall survival and So based on this trial you know when you have two different regimens that yield the same results one has just one drug the other has three drugs it's a no-brainer you want to do the simple thing right which is just to give the one drug and so that is why the standard dose of concurrent chemo radiation is cisplatin 40

MGR per met squared and it acts as a radio sensitizer it helps the radiation work better and because it acts as a radio sensitizer um it's important to realize that when we're doing it with radiation we like to have the Astin infusion scheduled towards the beginning of the week if we schedule them towards the beginning of the week then cisplatin is in the patients bloodstream while they're receiving the radiation Monday through Friday on the other hand if they were to get it at the end of the week Thursday or Friday um the you know they're

they're spending two days of the weekend where they're not getting any radiation and the is platin is in their system um so we we try to time it so that cattin is given at the beginning of the week so that it's in their bloodstream um during the week while they're getting the radiation the other thing that's important to remember with cisplatin is that it's a chemotherapy agent and especially given along with the radiation when they work synergistically uh radiation can also affect blood counts it can affect your lymphocytes um deplete lymy counts the chemotherapy can

deplete your um platelet counts as well so it's really important to keep an eye on patients blood counts um and if they do drop below a certain level sometimes the the gyon that's administering the chemo May opt to hold the concurrent chemotherapy if the blood counts are dangerously low um if they're very very low then sometimes we need to hold the chemo radiation as the the radiation therapy in addition to the chemo uh remember we try not to interrupt the radiation just because we know that overall treatment time matters getting these patients done within you

know no more than 7 to 8 weeks maximum is really important um for the otherwise there's a detriment to the local control so we really try to get through without treatment breaks but it's important to realize that you know this can be a pretty toxic treatment and patients can get sick while they're on therapy so it's really important to keep a close eye on them make sure that we're checking weekly Labs um make sure that we're repleting you know electrolytes if they're down just because patients might have diarrhea with radiation um it's also really important

to keep an eye on their blood counts and and keep an eye on whether or not we need to be holding that concurrent chemotherapy um so that was a little bit long- winded um into getting into an explanation of of CIS platin and and managing that during radiation um but the the key takeaway is that go 120 compared a few different chemotherapy regimens and from this trial CIS platin 40 MGR per met squared emerged as the winner um because it was the simplest way to to have the best possible um outcomes the last trial I

want to talk about for um for the purposes of backing up our definitive management with chemor radiation and breiky therapy is the Outback trial um which look looked at the addition of adant chemotherapy with carop platin and pxel following um chemo radiation with brachi therapy so Outback additional adant chemotherapy adding chemotherapy Outback um so this trial looked at patients that were undergoing definitive chemo radiation for cervical cancer and um you know in addition to the brachi therapy boost and these patients were randomized to the standard cisplatin based chemor radio therapy with Breaky therapy boost alone

or the standard therapy followed by adant carop platin and pet taxel given every 3 weeks for four Cycles the results showed that there was no improvement in progression free survival or overall survival with the addition of that Outback chemotherapy the progression free survival was just around low 60% 61 ver is 63% in both arms and the 5-year overall survival was you know just a little bit higher in the low 70s 71% versus 72% so this trial tells us that adding Outback chemotherapy does not improve progression free survival or overall survival so standardly um if we're

treating patients with definitive radiation for cical cancer we're doing concurrent chemo radiation and towards the tail end of the external beam portion we adding in that Brey therapy boost um and we looked at whether adding adant carbot taxol out back helps improve outcomes and this trial was negative so so we are not standardly adding adant therapy after the chemo radiation so we've talked about a lot of studies now and I just want to take a little bit of a break uh to give the major major takeaways from everything we've talked about until this point and

maybe try give you some pneumonics to remember these trials um because I think there are some some boards questions that could show up where you actually have to identify the trial by its name and it it's very hard for me to remember all of these so I I've come up with some Silly Ways and I'll try to share those um in case it's helpful so we first talked about patients that are early stage and amenable for upfront surgery um and there are certain indications for post-operative treatment uh with either radiation or chemo radiation so gg92

gave us the said list criteria for adant radiation alone and simplified said list criteria are two out of three of the lvsi stromal invasion and size greater than 4 cm and then Gog 109 gave us the Peters criteria for adant chemo radiation which were the three PS positive nodes positive margins and parametrial involvement if you need to remember the the the stupid simple way that I remember the name of these trials is 92 if you draw a two backwards it kind of looks like an S and for 109 if you draw an N backwards it

kind of looks like the p and then I just remember the said list and the Peters because the l i are the said list criteria and Peter's criteria are the 3ps um so that's my my silly way of remembering g92 and Gog 109 moving on to the definitive managements when we're doing definitive radiation we talked about a few different trials so 123 gave us the chemo RT okay 123 told us that chemo RT with concurrence of spaten provides a PFS and Os benefit versus radiation alone so my my little pneumonic is just like this little

poem G13 gave us chemo RT g71 we compared uh radiation plus or minus agiven hysterectomy and this was a negative trial so agiven hysterectomy did not add the benefit so g71 is why surgery is not done another little poem pneumonic and then Gog 120 um we compared CIS platin alone versus hydroxyurea versus cisplatin hydroxyurea and 5fu and cisplatin alone was the the winning it was the same as the cisplatin plus hydroxy area and 5fu but giving weekly cisplatin alone is more simpler and so that is why that is the standard concurrent chemotherapy that we do

so for 1 120 cisplatin was the hero um so that's how I remember go 120 compared all of those arms one 120 cisplatin was the hero and then finally we have the Outback trial which I think this one it's in the name there's no benefit to adding adant carbot taxol out back so adant after the definitive chemo radiation so those are my little pneumonics to remember these studies3 chemo RT 71 surgery is not done and one 120 cisplatin is the hero and then Outback it's in the name and remember this was a negative trial so

no benefit to adant chemo Outback we briefly mentioned the Embrace studies in the talk on cervical cancer overview um which really give us a lot of a lot of good planning pearls for when we're doing um chemor radiation as well as the Brey therapy boost um and so I just want to take a little bit more time and delve deeper into the Embrace studies and um just share some of the data that has come out of them and how that guides and influences our treatment planning the Embrace study group is based in Europe I believe

and their prospective protocols embrace one and embrace 2 have enrolled patients not only in Europe but also in uh North America as well as Asia um before the embrace one data came out um there was a retroembrace study that looked at Patients um retrospectively that were treated with cervical cancer and this first analysis established a dose volume relationship of tumor control probability so let's break that down the first thing they realized is that the bigger the tumor the worse the local control which makes sense bigger tumor more aggressive worse local control the second thing they

realized that also very much makes sense is the higher the dose to the tumor the better the local control so if we if we treat it to a higher dose um the local control is improved the the dose that we're treating these tumors comes primarily from the Breaky therapy boost so we can give external beam radiation up to 45 gray and then we give an additional Breaky therapy boost and when we calculate the equivalent dose in two gray per fraction um we're almost doubling that dose so taking it up to a dose of somewhere between

80 to 90 gray and that was kind of the recommendation before retro Embrace came out to try and cover the the highrisk CTV to a D90 of somewhere around 80 to 90 gray with retro Embrace they actually established a minimum cut off of 85 gray for the hrctv D90 and a dose of 85 gray corresponded to a local control of 94% for tumors that were 20 CC's 93% for tumors that were 30 cc's and 86% for tumors that were 70 CC's and in this analysis they found that each 10cc increase in volume required an additional

five gray to achieve an equivalent to local control so basically this is telling us that we should at least try to obtain an hrctv D90 of 85 gray for cervical Cancers and so that comes from the brachy therapy boost combined with the 45 gray that we're delivering to the pelvis if we're dealing with a larger tumor then then ideally we would try to increase the coverage to those larger tumors because we know larger tumors are more aggressive and in order to get the same level of local control uh we need to kind of boost the

dose a little bit further as we're able without compromising toxicity obviously it's it's very challenging in reality to do that um but theoretically if you want to improve the local control for these larger tumors for each 10 CC increase in volume we need to add an additional five gray for an equivalent local control the data also told us that each week that we delay the total treatment time Beyond 7 weeks we notice a decrement in overall survival and we need to add an additional five gray for equivalent local control so there was an older retrospective

study that gave us a Time cut off of 56 days which corresponds to eight weeks and then Based on retroembrace data that cut off was shifted to 7 weeks which is 49 days um so so two important things from retro Embrace number one our minimum Target hrctv D90 should be at least 85 gray and then if we have larger tumors we think about increasing that eqd2 even higher to get the equivalent level of local control and then secondly the recommended total treatment time is 7 weeks which is 49 days so subsequently we started to see

Publications from Embrace 1 which is a prospective multicenter cohort study that enrolled patients um and they were treating patients with MRI based planning using image-guided adaptive brei therapy so getting MRIs with every fraction and and planning out the Brey therapy treatment on MRI the advantage of MRI compared to using a CT scan is that on MRI you're better better able to delineate the the soft tissue so you're better able to see the the GTV the high-risk CTV and uh you're also better able to actually see the organs at risk and Contour them a little bit

more appropriately um the downside with MRI is that um with CT scans you can account for the density because that's what CT scan is based off of the density of the tissues so you can account for the difference in attenuation between the different tissues um with Mr you can't account for that difference in attenuation of the radiation and so for our breakie therapy calculations we actually don't do that if we're doing um we typically don't do that we just you know assume that everything is homogeneous um and given how strong the dose is and and

how sharp the dose falloff is um that's sort of adequate for our breaki therapy calculations so anyway utilizing MRI based planning they had this prospective study and the outcomes were really good they showed 92% 5-year local control rates with an average of around 7% grade 3 to 5 toxicity depending on which exact toxicity endpoint you were looking at um so minimizing the toxicity trying to maximize the local control and with longterm followup there were some key findings um that I want to point out so there was one publication that compared um toxicity in patients that

were treated to a pelvic dose of 45 Gray versus 50 Gray and what they found is that the external beam radiation dose of 50 Gray corresponded to worse grade 2 plus diarrhea so the threeyear so the long-term grade two or Worse diarrhea was around 10% in patients that were treated with 45 gray versus 20% in patients that were treated with 50 Gray so the the grade two or Worse long-term GI toxicity kind of doubled with 50 Gray versus 45 gray um the GI toxicity also actually increased with a larger lymph node boost volume so if

that lymph node was very large you can imagine the bowel is getting more dose as well um but we can't control when lymph nodes are very large we need to cover them and we need to treat them what we can control is the dose that we're giving to the entire pelvis and it turns out there's actually no data showing improved local control with doses above 45 gray and now we have this data from embrace one showing that the grade two or Worse late GI toxicity approximately doubles if we use 50 Gray versus 45 gray and

so the recommendation is typically to treat the pelvis to a dose of 45 gray external beam radiation in the setting of definitive chemo radiation for cervical cancer another publication that came out of the embrace one data um compared the the outcomes for adoc carcinoma versus squel carcinoma um they they compared a few different risk factors but what they found is that adnoc carcinoma histology is actually associated with worse local control compared to squa cell and remember that was seen in in one of our earlier studies as well I believe it was Gog 109 where they

pointed out um adnoc carcinoma tended to have worse local control so if they looked at patients that got an hrctv D90 of at least 885 gray uh that corresponded to a 95% threeyear local control for Sasol carcinoma versus an 86% local control in patients with adnoc carcinoma so um some practitioners might actually consider increasing their target eqd2 um for adnoc carcinoma versus Sasol carcinoma so aiming for something like 90 gray eqd2 if it's an Ado versus at least 85 gray if it's a sisol carcinoma um so that's just you know more evidence we already know

this but further evidence that ad no carcinoma is associated with worse um local control it's a more aggressive histology so key takeaways from from these Publications um that came from embrace one our standard external beam radiation dose is 45 gray in 25 fractions because 5050 gray has not actually shown a benefit in any data that we have and we know that it's associated with worse late GI toxicity and then um we also know that adnoc carcinoma hystology is more aggressive player worse local control so it might consider going aiming for a higher Breaky therapy boost

if it's add no carcinoma and then finally we have Embrace 2 um the protocol for embrace 2 is available um I don't believe that there are any Publications from this yet um but similar to embrace one Embrace 2 is additionally a prospective study I believe at this point it has completed enrolling patients um but we're just waiting for the results to be reported um but basically in Embrace 2 they took the data that they had from retro Embrace and embrace one and they derived a protocol for image-guided adaptive brei therapy but now we're in an

era where we are routinely utilizing imrt as well if you recall from the um overview lecture we talked about the time C trial um that showed a Improvement in toxicity with imrt compared to 3D um so we're routinely using imrt for our external beam radiation and we're also using image guided radiotherapy um so Embrace 2 is really kind of pushing forward and establishing modern guidelines for for brachi therapy for cervical cancer um so I just have some screenshots of dose constraints from the protocol I think these are helpful um references for when we're actually planning

in clinic and one thing I'll point out about the Embrace 2 study um in addition to their protocol um and they have you know they're they're kind of pushing forward um you know pushing it at the front lines of of Breaky therapy for cervical cancer and I think they are advising that we try to aim for covering the tumor with an hrctv D90 of at least 90 gray as opposed to um 85 gray so so that's something that they're investigating and it'll be interesting to see the data that comes from Embrace 2 um one other

thing I wanted to point out is that um Embrace 2 is investigating the role of prophylactic prophylactic um par aortic nodal or radiation in patients that are pelvic lymph node positive so just to give a little bit of background on this when we're treating um the pelvis for definitive chemo radiation um whether or not patients have lymph nodes we're always going to do pelvic radiation right so that's going to include our common iliac lymph nodes our internal and external iliac lymph nodes the pre-sacral lymph nodes typically down to around S3 and the obturator lymph node

so that's kind of our standard volume for pelvic radiation and and there are contouring guidelines out there for that that are good references when you're actually um dealing with this in in treatment planning um so that's our standard pelvic radiation now if patients have para aortic lymph nnes that are positive at the time of diagnosis then we certainly will need to boost those and cover the par aortic um noal regions as well the question is is there any role for prophylactic parotic nodal or radiation um and there is some data retrospective data by Dr Vargo

at our at my institution where I'm training um and this was a retrospective study of patients with Stage 1 B to 4 a cervical cancer treated at our institution um and they assessed patients with um a PET CT and patients that had pet positive lymph nodes um in the pelvis were treated with extended field imrt so they sied the involved lymph nodes up to 55 gray and then they gave 45 gray and 25 actions with concurrent chemo radiation um to the extended field so not just the pelvis but also the par aortic lymph nodes around

2third of the patients in this retrospective study had pelvic lymph nodes only and around 13d of them had um positive par aortic lymph nodes as well in this retrospective study what they found is that for the patients that had um paraortic lymph node radiation prophylactically so patients that only had pelvic lymph nodes positive and then had prophylactic parotic radiation the rate of paraortic failure was only 2.5% um unfortunately with cervical cancer the majority of failures tend to be distant so these patients tend to have distant metastases but if we're prophylactically treating the P parotic lymphnodes

it looks like we're definitely reducing their risk of par aortic lymph n failure um there's a a picture that I've included from another trial that came out of embrace that looked at patterns of failure and they found that um patients with presence of common iliac lymph nodes three or more positive lymph nodes or bulky lymph nodes were actually at increased risk of para aortic um nodal failure and you'll see that in that picture if they looked at the location of nodal failure a lot of these patients were feeling when they did fail in the lymph

nodes um up to 68% of failures were in the parotic nodal chain and so practice patterns can vary but some Physicians will actually favor treating the paraortic nodes prophylactically especially if there are highrisk features like positive nodes in the common iliac chain greater than two or three pelvic nodes large pelvic nodes um and I just wanted to point out that this is actually an area of Investigation and embrace too so so hopefully when this is published we'll have some further data to to guide our Management in this space so that brings us to an end

of our discussion of the evidence um for cervical cancer management um as with any disease site um we're never able to cover every every trial that has been done um about that particular disease site um but I tried to include some of the the seminal trials that are commonly tested important to know and a lot of these uh Gog trials are older you saw you know they were running the late 90s um but they're still actually very relevant um to our practice today and they they still um are relevant in terms of the treatment Paradigm

for cervical cancer um so hopefully between this talk and the overview talk um you are able to get a sense of the general treatment Paradigm for cervical cancer and then and some of the literature um to kind of back up the the reasons for why we do what we do um so I hope this was helpful to you and thank you so much for your time and attention