Cervical Cancer 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 pgy4 resident at the University of Pittsburgh and this talk is going to be the first in our gynecologic cancer series we're starting with an overview of cervical cancer cervical cancer is the fourth most common malignancy diagnosed in women globally and it's probably the Most common gynecologic cancer that affects women again globally in the United States it's not as common as endometrial cancer um just because cervical cancer incidents in the US is

fortunately decreasing uh due to our use of screening uh with tools such as the papsmear as well as vaccinations that are available for HPV um but it still does affect women especially globally especially in um underserved countries uh where they do not have access to to Screening or vaccinations the median age of diagnosis for cervical cancer is around 50 years old uh so it tends to affect uh younger patients compared to those that we classically think about with endometrial cancer most commonly around 80% of the time um the hystology is going to be squamous cell

carcinoma and a major risk factor for this is HPV or human papaloa virus which is responsible for over 95% of these cases the most common strains Of HPV that are implicated are HPV 16 and 18 accounting for around 70% um but HPV 31 and 33 are also important to be aware of so we'll divide our discussion on cervical cancer into two parts in this first part I'd like to focus on the presentation workup and staging and then also an brief overview of the management of cervical cancer in the next talk uh we will actually discuss

some of the evidence um behind cervical cancer and some of the seminal trials that kind of Guide our management of this disease let's start with some Basics on the presentation work up and staging of cervical cancer often times Cervical Carcinoma might be asymptomatic and just detected on screening and it's really important to be familiar with the screening guidelines for cervical cancer in the US so the US pstf re recommends that women ages 21 to 65 should be routinely screened for cervical cancer for ages 21 To 29 the recommendation is for cervical cytology alone every 3

years so that's a papsmear every 3 years for ages 30 to 65 they can certainly get a papsmear alone every 3 years but they can also have co- testing with the high-risk HPV testing plus uh cervical cytology every 5 years so that's an option as well and then if they are over age 65 and they don't have any history of moderate or severe dysplasia and if they've had three negative papsmear or two negative covid Tests in a row then they don't require any further screening at that point so for ages 21 to 65 routinely recommend

screening and then above age 65 uh no further screening unless there are certain risk factors in their history now we just said most of the time patients will be asymptomatic and it'll just be detected on screen um however if the cancer is a little more advanced then they might present with some symptoms and so what could Those symptoms be um sometimes they can have abnormal vaginal discharge they might have postcoidal bleeding disp peronia or pelvic pain as some examples um but again because we have such a robust screening program in the US um a lot

of the time these are going to be asymptomatic another thing to realize um and I guess this goes a little bit more with risk factors but it's important to realize that HPV infection and therefore cervical cancer can actually be Prevented by vaccination uh there is a nine veent vaccination available for children ages 11 to 12 years old with catchup vaccination through age 26 and now actually adults ages 27 to 45 may also be vaccinated as indicated so we have a vaccine which is a way of preventing this infection um and and thereby PR preventing preventing

HPV infection and therefore um protecting against cervical cancer and so that brings us to the risk Factors associated with cervical cancer and as we just said HPV is associated with over 90% of cases HPV 16 and 18 are the most important strains to be aw aware of um they're associated with over 70% of cases and then other cancer-causing strains include HPV 31 33 45 52 and 58 but again 16 and 18 are the most important ones to know about um and you know as we just said there is an HPV vaccine available and so uh

we're really trying to to vaccinate as many Folks as possible to try and prevent not just cervical cancer but other HPV Associated cancers as well some other risk factors for cervical cancer and a lot of times patients might have multiple risk factors um so it's important to be aware that some of these include smoking imuno compromis status young age at first intercourse multiple sexual partners so these are some just high-risk behaviors that can increase your risk of infection with HPV um multi parity lower socioeconomic status and then another risk factor is um diethyl sestola um

that has also been associated with clear cell carcinoma of the survey and vagina um so important risk factors to be aware of moving to Anatomy uh Just For A Brief Review uh remember that the cervix is located in the lower part of the uterus and it's kind of a cylinder um that that's located at the bottom of the Uterus and it's right on top of the vagina the cervix is I think of it like a tunnel going from the inside of the uterus to the inside of the vagina and the endocervical canal so the inside

of that tunnel is lined by by columnar epithelium and then the outside of that tunnel um the part that's that's at the top of the vagina is known as the Ecto cervix and it's lined by squamous epithelium so where those two different types of epithelia Meet the columnar Versus the squis it's called the squo columnar Junction and it's located at the external o which is the outside part of the cervix um so that external o where that squo columnar Junction is located is actually the most common site for carcinogenesis so right at that Junction um

so so just keep in mind some of those those terms about cervical Anatomy the internal o versus the external o and that squo columnar Junction the other thing to keep in mind is that whenever cervical cancer spreads one of the first places that it can go besides the vagina is to the attachments that help anchor it in the pelvis right and so one of those attachments is called the Cardinal ligament it's a ligament that actually attaches the cervix to the pelvic side wall and when we use the word parametria we're talking about all of the

the tissues that help hold the the uterus and the cervix in Place and so the Cardinal ligament is part of the parametria that actually attaches the um cervix to the pelvic side wall other attachments to keep in mind that again make up the parametria include the broad ligament which attaches the uterus to the pelvic sidewall and the utero sacral ligament which attaches the low part of the uterus to the sacrum so some of those ligaments make up what we call the Parametria that Anatomy is important to consider when we're thinking about lymph node drainage or

if a cervical cancer arises then through which lymph node would it drain um so one of the first places that it could drain through is through those surrounding ligaments that we just talked about so the Cardinal starts with a C connects the cervix to the pelvic wall the broad ligament starts with a B connects the think of the body of the uterus to the pelvic Wall and then the uterosacral connects to the uterus to the sacrum so it's right in the name um so it can drain through those ligaments it can also drain to Regional

lymphatics so that includes the pre-sacral and it can drain through the uterosacral ligaments to the pre-sacral nodes it can drain to the obturator nodes internal and external iliac nodes and then eventually common iliac and Upstream of that par aortic lymph nodes as well so all of those Lymph nodes that are listed there are sort of the regional lymph nodes um that are associated with cervical cancer and then some of the common distant sites of metastasis include lungs liver and Bones which are pretty common for many other types of cancer as well um and with cervical

cancer we might also see supraclavicular lymph nodes and the reason for that is because those can drain there via the thoracic duct in terms of pathology of cical Cancer the vast majority are squamous cell carcinoma um because remember that cancer tends to arise right at that squo columnar Junction and so most of the time these are arising from the outside the cervix and it's sisel carcinoma and um you know somewhere in the neighborhood of 75 to 80% of of cancers are squamous cell carcinoma however cervical cancers can also be other histologies and if it's not

squamous cell carcinoma it's more Than likely to be an adenocarcinoma or an adenosquamous carcinoma so having that Ado carcinoma or [ __ ] squamous carcinoma it's less common somewhere around 20 to 25% of the time um but it does confer a higher risk these tend to be seen more commonly in younger patients they present with larger tumors you might see something called a barrel cervix so just a larger tumor um these tumors tend to have higher risk of local failure as we'll See in some of our um in some of our evidence and the pap

screening is less sensitive for adnoc carcinoma and so that Co testing with HPV actually helps improve our detection of these cancers so majority are going to be SEL carcinoma up to around 80% adoc carcinoma is going to be less likely and then we can sometimes see even more rare histologies such as clear cell small cell neuroendocrine um saroma or rabdom Myosarcoma in pediatric patients melanoma and adenoid cystic carcinoma in terms of workup for cervical cancer we always want to start with a full history and physical in this case we would focus on gynecologic history can

inquire about um vaccinations um and things like that obstetric history um sexual history menopausal history and then we want to obtain a complete pelvic and abdominal exam um whenever we're we're doing this Um we can also examine lymph nodes we can examine the super clavicular and anginal lymph nodes for example um but keep in mind that if disease is present in these lymph nodes these are both distant sites of metastasis even the inguinal lymph nodes are not considered Regional lymph nodes for cervical cancer that would make it metastatic um so so do that full full

workup in terms of labs we can always get a CBC a CMP consider HIV testing and a pregnancy Test is very important to consider as well as a discussion about fertility sparing in in women that are um you know that are of an age where where we might consider pregnancy and fertility issues in terms of procedures and obtaining pathology so these are often done by the gynecologist um but one way to get pathology is to do a colposcopy with cervical biopsy and this can also be called a leap procedure um so the loop excision procedure

that can Be one way of obtaining a biopsy um if cervical biopsy is inadequate then a more slightly more invasive method is what's called a cold knife cone biopsy where they actually remove um kind of like a conical piece of cervical tissue um and cold knife cone biopsy is important to realize it can actually be a definitive treatment if cancer is early stage enough and if we're trying for a fertility sparing approach so the leap procedure or the cold knife cone Biopsy are two options if if patients have advanced disease um they might actually need

an exam under anesthesia with cystoscopy and rectosigmoidoscopy to assess for um bladder or rectal invasion of the cancer um or you know if we can already tell clinically that they have bladder or rectal extension present it's really important to get that exam under anesthesia and in sometime sometimes the the cancer can be so aggressive into the Bladder it can actually um press on the URS and patients might need um Ural stents so so these cancers can be quite quite Advanced and they can you know invade into the bladder or the rectum um so so that

exam assessing the full extent of disease is really important and that would need to be done under anesthesia in terms of Imaging um a pelvic MRI with and without contrast as well as vaginal gel is really important to delineate the local extent of Disease so the local extent of disease can be nicely assessed with a pelvic MRI again with and without contrast the t2 weighted image is going to be most beneficial for us and in the next slide I'll show an example of of what we might be looking for but that really helps us to

ex examine the local extent of disease see if there's parametrial Invasion and things like that as well as if it's invading into the bladder or the rectum a pet CT scan is going to help us With nodal and distant staging so if lymph nodes in the pelvis light up on the pet C then that tells us that we have Regional lymph node involvement and it can also help us identify if there's any distant spread of the disease so pelvic MRI with and without contrast as well as PET CT are really necessary for for staging of

these cancers um other Imaging that you might think about which is allowed per NCC n include chest x-ray baramma skeletal X-ray and intravenous Pyram so all of these can be included in um in our Imaging but the most important ones to think about I would say are the pelvic MRI and the pet C so let's take a look here at an example of a T2 weighted MRI and as we said T2 weighted MRI is really the best to visualize um visualize uh gynecologic cancers in general um so typically on a t two weighted MRI the

cervix itself is going to appear hypointense uh so darker compared to the The rest of the surrounding tissues and in comparison the tumor will appear a little bit brighter more hyper intense um now the way you can tell this is a T2 weighted MRI is if you look at the bladder um which is located just anterior to the the uterus and the cervix it's full of fluid and on T2 weighted MRI fluid appears bright so T2 I remember H2O is what appears very bright um so here we see a T2 weighted MRI and in pane

a we're looking at A Sagittal section in B we're looking at an axial section so on the sagittal section you can see there's a lesion sort of of in intermediate intensity I would say and it's basically replacing the entire normal cervix and it's invading into the lower segment of the uterus if we look on the axial section there's this nodular soft tissue extension that's the those side arrows are kind of pointing at it in pain B so the axial section is showing this Nodular soft tissue extension that's indicative of parametrial involvement so we wouldn't be

able to see this level of detail um and delineate these soft tissues as well on a CT scan and so that's why that that T2 weight at MRI is really important to help us with staging and so finally that brings us to the staging of cervical cancer and I'm going to spend some time here um because it's really important to be able to you know be able to clinically stage Patients and the reason for this is that that guides our management and how we treat these patients um so on board exams and in real life

it's really important to be familiar with the staging for cervical cancer the most recent system of staging that we have is the 2018 Figo staging and it divides cervical cancer into stages 1 to four um very simply stage one is confined to the cervix in stage two we're starting to invade beyond the uterus in stage three It's more extensive with invasion of the lower vagina or the pelvic sidewall or we have Regional lymph node involvement so stage three can be a lot of different things and then finally in stage four we're either invading into adjacent

organs or we have distant metastases so very simply that's Figo stages 1 through 4 now of course on the Raton boards they're not going to ask it that simply we have to get into the nitty-gritty Details and and understand the substages of cervical cancer so stage one confined to the cervix is actually Divi divided into two different stages stage 1 a versus 1 B just remember that in stage one 1 a we have less than or equal to 5 mm depth of stromal invasion so 5 mm or less depth of stromal invasion 1 A1 is

less than or equal to 3 mm and 1 A2 is 3 to 5 mm but 1 a is less than or equal to 5 mm depth of invasion in stage 1B we are now getting Into more invasive depth of invasion so greater than or equal to 5 mm depth of invasion and then 1b1 2 and 3 are based on the size so 1b1 is less than 2 cm 1 B2 is 2 to 4 cm and 1 B3 is greater than 4 cm but the most important delineation is in stage one 1 a is less than

or equal to 5 mm and 1 B is greater than or equal to 5 mm depth of invasion if it's 2 to 4 cm it's 1 B2 and if it's greater than 4 cm it's then 1 B3 that is stage 1 and in stage one the cancer is confined to the cervix in stage two the cancer starts to invade beyond the uterus but it doesn't quite invade into the pelvic sidewall or the lower vagina so in stage 2 A1 we have invasive carcinom less than or equal to 4 cm and extending beyond the uterus and

in stage 2 A2 we have greater than 4 cm tumor that's extending beyond the uterus so stage 2A we're starting to extend beyond the uterus 2 A1 is less Than or equal to 4 cm 2 A2 is greater than 4 cm and then stage 2B is where we have invasion of the parametria but not up to the pelvic wall so 2B we're starting stting to see that parametrial Invasion um so it's starting to invade beyond the uterus and it's actually involving some of those ligaments that are anchoring the cervix to the pelvic sidewall so parametrial

invasion is stage 2B and that is really Important to remember of all of the stages I've said so far if you really remember any of them I would remember that stage 2B is invading the parametria that brings us then to stage three so stage three is invading into the lower onethird of the vagina or the pelvic side wall so 3A is actually Invasion into the lower third of the vagina without involving the pelvic side wall and then in 3B it's extending into the pelvic side wall and Remember we said that sometimes cervical cancer can be

so aggressive it actually presses on the urits and it causes it can cause hydron nephrosis and lead to um kidney dysfunction if that happens so if you have a cancer that's so aggressive that it's either extending to the pelvic side wall or it's pressing on the the uror and causing hydron nephrosis that is considered stage 3B and that's another very important one That I would one of the most important ones that I would memorize is that stage 3B is pelvic sidewall or causing hydrosis so 3A is lower 1/3 of the vagina 3B is extending to

the pelvic sidewall or causing hydron nephrosis and then 3C is if we have lymph node involvement and 3C is divided into 3c1 versus 3c2 depending on which ndes are involved so 3c1 is only involving the pelvic lymph node metastases so the the lower nodes in the pelvis that are close Clos to the cervix 3c2 is more advanced and so now we're moving North and we're actually getting some par aortic lymph node metastasis as well so pelvic nodes is 3c1 and Par aortic nodes is 3c2 and then finally that brings us to stage four so in

stage 4 a we're starting to invade into adjacent organs such as the bladder or the bowel and you'll see in a lot of different cancers stage 4A often times is tumor that's so locally Advanced it's you know invading Into nearby organs so in the case of the cervix it's the bladder and the bowel which are you know right adjacent anteriorly and posteriorly and then finally we have stage 4 B where we have spread to distant organs so remember earlier we said if we have even if we have like inguinal lymph node involvement or supraclavicular lymph

node involvement that would count as a stage 4B just because those are distant sites those Are not considered Regional lymph nodes so that was a lot but that is the staging and it's really really important to to kind of memorize this um because it shows up on exams and then in in real life um we need to have have a sense of the stage so that we know how to manage these patients um one thing that that came up when I was doing some practice questions that I'll share is um risk of lymph node involvement

and how that correlates to The stage very very roughly um something you might be familiar with is the rule of 15s and it just kind of corresponds to the risk of pelvic node involvement based on the stage and the rule of 15s is just 15% 30% 45% so a stage one cancer has a 15% risk of pelvic lymph node involvement stage two has a 30% risk of pelvic node involvement and stage three has around a 45% of pelvic lymph node involvement and then for any of those the risk of par aortic lymph Node involvement would

be around half of that so stage two for example if it has 30% risk of pelvic node involvement would have around a 15% risk of par aortic involvement so that's just a a basic rule that you might you might want to be familiar with but these are very very rough estimates most important things that I would remember from this staging section is 2b we're invading the parametria but not the pelvic wall 3B we are now Invading the pelvic wall or causing hydrosis and then 3A is if fits into the lower third of the vagina 3

C uh 3c1 is involving the pelvic lymph nodes 3c2 is involving the par aortic lymph nodes and then we have stage four and 4 a is where you're invading into adjacent organs such as the bladder and bowel so this is hard staging is hard it's something you just have to memorize in practice um you know if you're not Sure of anything it's always prudent to look it up um but I think if you do it often enough then you then you learn it really well um but for board exams we do have to memorize these

stages so now that we have a sense of staging and work up let's talk a little bit about the management of cervical cancer so in a nutshell you can think about localized cervical cancer in in two groups the first is early stage disease that might be amenable for a Surgical approach roach with tailored adant therapy or it's locally Advanced disease where the disease is so Advanced that we actually don't do upfront surgery and we just treat them with definitive concurrent chemo radiation followed by a Breaky therapy boost so early stage patients are candidates for surgery

and if they have particular risk factors we might offer adant radiation or agant chemo radiation and then there are locally Advanced patients where we Would not even offer surgery as treatment and we would just treatment treat them with definitive chemor radiation followed by a brachy therapy boost so two buckets for cervical cancer early stage patients that are amenable to upfront surgery I have the stages listed there 1 A1 1 A2 1b1 and 1 B2 as well as 2A but if you if you go back to the staging the the easiest way to think about it

is tumor that is minimally invasive and just less than or Equal to 4 cm the earliest stage of cervical cancer is amenable to surgery at the time of surgery if we learn that they have particular risk factors so when we look at the pathology after surgery is done then there are particular risk factors for which we might recommend further treatment so let's say they have surgery and most of the time it's going to be radical hysterectomy but we'll talk more in detail about the surgery most of the Time they'll have radical hysterectomy and say they

have that and then there are risk factors certain risk factors would lead us to recommend adant radiation so for adant radiation we point to the S lless criteria which is based on a clinical trial that we will discuss in our next talk but the S lless criteria very simplified you just need two out of three of these criteria so these risk factors are are lvsi or lymphovascular space Invasion deep Stromal Invasion which is Middle 1/3 stromal Invasion or deeper or tumor size greater than or equal to 4 cm so if any of these risk factors

are seen on pathology these are indications for adant radiation alone if patients have more I guess more elevated risk factors or higher risk fact factors that fall under what are known as the Peters criteria which is actually based on another clinical trial that We'll talk about in the next talk these would be indications for adant chemo radiation so the Peters criteria are positive nodes positive margins or parametrial involvement the three PS so s lless criteria of lvsi deep stromal Invasion and tumor size greater than or equal to 4 cm those would be indications for ad

radiotherapy alone and the Peters criteria which are positive nodes positive margins or parametrial involvement would be Indications for adant chemo radiation um following surgery so that is all for early stage disease the earliest stage of cervical cancer that would actually even be amenable to a radical hysterectomy for more locally Advanced disease so once we have either stage 1 B3 disease so clinically we can tell that the tumor is already 4 cm or if there is um you know Invasion into the parametria or anything you know anything Beyond that then we don't treat with surgery up

front and we just offer definitive chemo radiation with a Breaky therapy boost so chemoradiation consists of pelvic radiation to 45 gray in 25 fractions um and we typically boost the involved nodes and following the the external beam radiation which is given with concurrent weekly sus platin will actually follow up with a brachy therapy boost and and Treat that the the tumor that's in the cervix um with additional radiotherapy very very localized using Breaky therapy um and and kind of boost the tumor that way you might wonder why don't we do everything with external beam radiation

why can't we just give a big dose of external beam radiation and eradicate the tumor well the reason is the cervix is located very close to the small bowel which is very sensitive to radiation and so we're not able to successfully treat To a high enough dose to the cervical tumor without blasting the bowel and so the best way that we have found through clinical trials to successfully escalate the dose to the cervix without causing significant bowel toxicity is actually to to do a Breaky therapy boost so this is a a procedure where an applicator

is actually inserted into the the cervical cavity and the in the part of the uterus and and we treat with a radioactive isotope um sort of Very close to the tissue which is which is what makes it Breaky therapy so that was a lot of information and we're going to break it down a little bit and talk more in detail about the surgery as well as the the radiation and chemotherapy considerations um but if you know just to start this talk about the management of cervical cancer think of it as two different buckets so bucket

one is early stage disease that's you know tumor less than 4 cm and not extending into the Parametria these patients may be amenable to upfront surgery and if they do undergo surgery then there are certain risk factors for which we would do adant radiation or adant chemo radiation and then for locally Advanced disease that's greater than 4 cm or invading the parametria or more than that um then we would treat with concurrent Cho radiation and a brachy therapy boost so let's talk about treatment a Little bit more in detail now and let's start with that

bucket one those early stage patients that have disease that's less than 4 cm and no parametrial involvement these patients may be amenable for treatment with surgery alone and then tailored adant approaches depending on their risk factors so with surgery um there are certain patients that might desire fertility sparing approaches patients are only candidates for Fertility sparing if first of all they are able to have children so if it's a a woman that's that's premenopausal and is thinking about having children um and then the disease is you know early stage enough if it's too advanced that

we cannot offer fertility sparing then that's not even a question so if a patient is considering fertility sparing procedures there's a couple of things we could do so one of the things we could do is a cold knife Cone exision and remember we talked about this as a potential biopsy technique where a a large area of tissue around the cervix like a cone-shaped lesion is actually removed for pathology well a cold knife cone excision can also be used as as a treatment um assuming that you know it it's enough and the margins are negative and

everything so cold knife cone excision is one option for for a fertility sparing surgical Procedure if it's very minimally invasive if it's more if it's too invasive for a for a cold knife a radical trachelectomy is another alternative and in a radical TR trachelectomy we're removing the cervix the upper vagina and parametria but the uterus is going to remain in place with a cirage or a per string Stitch at the distal end to kind of keep that bottom part of the U is closed and replace the function of the Cervix so a radical trachelectomy can

also be considered if patients are really Desiring a fertility sparing procedure so they'll remove the cervix upper vagina and parametria while keeping the uterus in place now with these fertility sparing procedures it's important to make sure that we're doing an oncologic surgery and removing everything we want to remove um so after the procedure it's important to evaluate the margins as well as the lvsi status If the margins are negative and there's no lvsi then we may pursue observation but if there are positive margins um and no lvsi then a repeat cone biopsy or trachelectomy may

be indicated and finally if there is positive lvsi then a repeat trachelectomy with pelvic um lymph node assessment either via Sentinel lymph node biopsy or lymph adenectomy may be indicated um so it's important to realize that after these these fertility sparing procedures the Margin status and the lvsi is important to us for patients that are not Desiring a fertility sparing approach um the the standard really surgical management for cervical cancer is is hysterectomy and there's a few different types of hysterctomy to be familiar with so a type one hysterctomy which is also known as a

simple or total hysterectomy involves removal of the uterus and the cervix but the parametria are left Intact a modified radical hysterectomy which is a type 2 hysterectomy removes the uterus and cervix as well as the upper 1 to2 cm of the vagina and performs a wide local excision of the parametria so a little bit more advanced now we're removing upper 1 to 2 cm of the vagina as well as wide local excision of the parametria in a Type 3 hysterectomy which is also called a radical hysterectomy we're taking out the uterus And the cervix a

quarter to a third of the vagina and the parametria are dissected to the pelvic sidewall or sacrum so this is the most extensive of the three lit listed here and it's really a radical hysterectomy that is needed for patients that are stage 1 B1 or above that do not desire a fertility sparing approach so if patients have um you know greater than 5 mm stromal Invasion um which makes you stage 1b1 these are the patients where radical Hysterectomy is indicated additionally we also need to address the lymph nodes either via Sentinel lymph node biopsy or

lymph node dissection so radical hysterectomy and Sentinel lymph node biopsy or lympo dissection for most patients with cervical cancer is what is considered standard for patients that have less than 5 mm of invasion so stage 1A disease a modified radical hysterectomy may be acceptable but if it's greater Than 5 mm invasion they really need a radical hysterectomy and all patients should have lymph node evaluation now one thing I want to note is that when we do surgery we really only do it in The Upfront setting for patient PTI s that have early stage disease we

are not routining routinely offering adant hysterctomy um because this has been studied and we'll talk about it in our next lecture but there's really no benefit in overall survival or Disease free survival with an agant hysterectomy so if patients are in that early stage bucket that's the only time we would offer upfront surgery and and kind of guarantee them to getting surgery but if we're treating with definitive chemo radiation then adant hysterectomy is is typically not thought about the goal with surgery is typically to select patients that are at low risk for needing adant radiation

there are times where patients will go to surgery And we will find information that we did not have on upfront clinical staging um and then in that case we would offer them adant radiation or chemo radiation as we discussed but the goal is to try and select patients uh who are at low risk for needing these adant therapies the patients that do require adant therapy are the patients that if we knew about certain things before they went to surgery we probably would have just treated them with definitive chemo Radiation in the first place um I

think that's an easy way to think about it because in the sist criteria we have size greater than or equal to 4 cm in the Peters criteria we have positive lymph node involvement and parametrial involvement these are things that if we knew them before they went to surgery we probably would have offered them definitive chemo radiation but the fact that these criteria exist is just a testament to the fact that clinical Staging is not always perfect and sometimes we do find out more information at the time of surgery than we would have had just based

on looking at Imaging so when patients are early stage clinically and then they go for surgery the indications for adant therapy uh kind of depend on on certain factors that we look for so remember we talked about said list criteria which are indications for adant radiation alone And a simple way to think of it is if they have two out of three of these factors so lvsi deep stromal Invasion or size greater than or equal to 4 cm for adant radiation and chemotherapy together we use the Peters criteria so if they have positive nodes positive

margins or parametrial involvement the three PS of thee Peters criteria then we treat not just with adant radiation but also with concurrent chemotherapy so what do we mean by adant Radiation typically we're talking about pelvic radiation 45 to 50.4 gray at 1.8 gray per fraction sometimes in the postoperative setting people will go to a slightly higher dose of 50.4 gray just because there's a thought that there might be some hypoxia in the post-operative tumor bed and so the radiation is not working as well in that hypoxic environment with our external beam Fields we're going to

be covering the Pelvic lymph nodes including the common external and internal iliac as well as the operator nodes and then the vagina and parametria so at least 3 cm from the vaginal Apex or 1 cm above the operator for forment whichever is lower in some cases P um physicians may consider adding a vaginal cuff Breaky therapy boost in the postoperative setting um you know two or three fractions at five gr per fraction um three fractions perhaps if there is a Positive margin just to the upper 3 cm of the vagina and this is considered by

some if there are close or positive margins or perhaps if a patient underwent an incidental simple hysterectomy rather than a a radical or modified radical if that was indicated so so that may be considered if needed and then with the external beam radiation we are giving um you know if it's indicated for those Peters criteria uh we're giving concurrent weekly Cisplatin and the dose is 40 milligrams per met squared so that was basically early stage disease um that was amenable for upfront surgery followed by tailored adant treatment for patients that have stage 2 A2 or

greater disease so anything that's greater than 4 cm or if we know that they have parametrial involvement or you know beyond that um we treat them with definitive chemo radiotherapy and with definitive chemor Radiotherapy we're treating pelvic radiation 45 Gray in 25 fractions sometimes we will simultaneously boost the involved nodes to 55 to 57.5 gray uh so that is called a CIB simultaneous integrated boost and with the external beam radiation all of these patients if they're getting definitive radiation then they're getting definitive chemo radiation so these are get these patient should be getting weekly sustin

40 Mig Per met squar unless there's some type of a contraindication to is platin so that's what we mean when we say definitive concurrent Cho radiation and the external beam pelvic radiation is followed up with an intracavitary Breaky therapy boost and with that Breaky therapy boost um we are aiming for a high-risk CTV dose to 90% of the highrisk CTV or so we call that the hrctv D90 of somewhere between 85 to 90 gray at minimum um if not greater so That's a lot of information um and we're going to kind of break that down

and talk about you know all of these different aspects of the definitive chemor radiation and brei therapy boost um but what I will start by discussing is the importance of the technique when it comes to delivering external beam radiotherapy there is a study um called time C or it's also known as rtog 1203 because that was the rtog protocol um but time C is is also the name of this Study and they basically took patients undergoing pelvic radiation for different types of gynecologic cancer so cervical as well as endometrial cancer and they randomize them to

receive 3D conformal radiation so just a four field approach AA and two lateral beams versus intensity modulated radiation and the dose that these patients were receiving was somewhere between 45 to 50.4 gray nowadays we just recommend 45 gray in 25 fractions um but remember we said there Might be different indications to go up to 50.4 gray so they compared 3D radiation to imrt and they found that there was a significant Improvement in patient reported GI and gu toxicity with the imrt approach and so for pelvic radiation imrt is really the preferred modality just because of

decreased toxicity and the time C trial gave us some nice dose constraints that are good references for when we're doing our plans um and these also do show up In practice questions so the small bowel recommended constraint was v40 less than or equal to 30% the rectal constraint was v40 less than or equal to 80% % bladder V45 less than or equal to 35% and bone marrow the v40 was recommended to be less than or equal to 37% and V10 less than or equal to 90% so these dose constraints are important and most importantly um

the time C trial tells us that when we're doing pelvic Radiation for gynecologic cancers imrt is preferred and we have level one evidence that it confers decreased tox toxicity compared to three-dimensional radiotherapy now remember we said that in order to eradicate cervical cancer we need to get to a pretty high dose so if we're thinking about equivalent dose at two gray per fraction we need to get to a dose of somewhere around 85 to 90 gray in order to successfully cure the cervical Cancer it's really difficult to get to that level of a dose using

external beam approaches and there have actually been investigations looking at um boosting it with external beam approaches including sbrt techniques and it turns out that none of those approaches are nearly as effective as treating with Breaky therapy boost so the rationale for a Breaky therapy boost is that we treat the entire pelvis and we sort of Sterilize the the pelvic nodes that are at risk of involvement and we get to a certain level of dose 45 gray and 1.8 gray per fraction to the to the pelvis and to the cervix we then do a brachy

therapy procedure to internally treat the cervix and boost it to a higher dose um and because of the the physics of brachy therapy because we're inserting a radioisotope um that is much lower in energy compared to the MV photons that we're using for external beam treat Um the dose falloff is much sharper and so we're able to really nicely Target the cervix and get to really high doses inside of the cervix while sparing our normal tissues especially the small bowel and so that's really the rationale for a Breaky therapy boost now historically Breaky therapy for

gynecologic cancers was performed using a 2d planning approach also known as Point based plan planning so there was one system of um the of brachi therapy Called the Manchester system and they actually C prescribed a dose to a particular Point within the cervix so they inserted an applicator and usually with um cervical cancer the applicator that we're using for brachi therapy is a tandem which is a long stick that inserts inside of the uterus and then to get some more dose into the area that's around the that bottom part of the cervix we insert either

the either something called ovoids or a ring that Sits at the base of the cervix and so the ovoids and the ring help us to get more dose just to the where the cervix is and then the tandem helps us get really inside the cervix so you put put in this applicator either a tandam in ovoid or a tandem in ring and you take a film just a just a plain um you know an x-ray and you can see that that Ator is in place point a refers to a point that is 2 cm superior

to the external cervical L and 2 cm Lateral to the midline and and that point is where we prescribe the dose so basically they were you know blowing up the dose in a circle that that corresponded to a radius of where point a is and everything inside of that Circle was getting the prescription dose there's also point B which is 2 cm superior but then 5 cm lateral to the external cervical loss but point a is where they were prescribing the dose um And and this was a very simplistic approach um and what we've now

learned is we can do 3D planning rather than 2D planning and we can actually prescribe our dose to a volume rather than just to a point and with that 3D planning of approach it helps us to to kind of better Target the tumor and really Target where the tumor is located and theoretically it should also help us with sparing our organs at risk and causing less Toxicity so enter the 3D era of Brey therapy planning which is what a lot of centers have moved to in 3D volume based planning we actually insert an applicator and

then we obtain either a CT scan or an MRI and we draw out our volumes on that image and then the plan is is made so that our dose is prescribed to a volume the volume that we prescribe our dose to is known as the high-risk CTV or the HR CTV and and that is a more accurate way Of ensuring that the tumor is getting the Target that we want to treat which is the tumor is getting an adequate amount of dose and it also helps us to draw out our organs at risk and including

the bladder the rectum the sigmoid and better protect them and there's actually evidence that using 3D volume based planning improves local control and disease free survival outcomes compared to the point based system there is a series of studies that You should be familiar with including the these are called the Embrace studies and they are you know prospective observational studies of patients treated with MRI guided adaptive brei therapy the advantage of using MRI for breaky therapy planning is that we can better delineate not only the tumor but also the organs at risk um and it just

it it's better for um for breaky therapy treatment planning just because we can see things a little bit better than on CT that said CT is also miles ahead of you know just the 2D planning where we're prescribing dose to a point so we will talk about the Embrace studies more in detail in the next um talk but what should what you should know is that the embrace one study is a prospective observational study of chemor radiation and MRI guided adaptive Breaky therapy and they found very good local control so 92% 5-year local control and

a 67% overall survival for stages 1 through Four cervical cancer um with minimal grade three to five toxicities somewhere in the neighborhood of around 7% um the retroembrace studies was based on a retrospective um data but they actually derived a dose volume relationship of tumor control probability and they showed that the larger the tumor the less the likelihood of local control which makes sense and they also showed that if we cover our high-risk CTV with at least 85 gray so when we say cover our high-risk DTV we're really talking about the dose to 90% of

the hrctv that's called the hrctv D90 if we cover that with 85 gray and that again is an equivalent dose in two gray per fraction so we take our brai therapy fractionation and we convert it using radiobiological equations and we combine it with the external beam radiation dose which was 45 Grand 1.8 gr per fraction an eqd2 of 85 gray for the hrctv D90 is Correlated with Superior local control um so that came from retro Embrace and then we also have um Embrace 2 which is a prospective observational study using um not only image-guided adaptive

Breaky therapy with MRI planning but also imrt and igrt in this modern era and it's kind of prospectively validating these Embrace findings and their protocol is really excellent for detailed dvh constraints for both the external beam as well as the Breaky therapy treatment So the Embrace studies are really kind of the The Cutting Edge of of Brey therapy treatment planning and they're really good um good resources for us when we're when we're making um treatment plans in clinic so just to give a sense of what brachi therapy boost doses look like um after undergoing the

25 five treatments of pelvic um external beam radiation with the concurrent chemotherapy um patients will come in For their Breaky therapy treatments and typically it's just a handful of treatments somewhere in the neighborhood of four to six treatments um and the guidelines from American Breaky therapy Society um were published back in 2012 and they give us some good dose fractionation regimens to think about for the brachy therapy boost dose so example doses include 6 gray * 5 fractions 5 gray * 6 fractions or 7 gray times four fractions um and when we're Calculating our hrctv

D90 what we do is use radiobiological equations to convert it to an equivalent dose in two gray per fractions and when we do that what we're aiming for is that at least 90% of our HR CTV is is receiving at least 85 gray if not higher at the time of brachi therapy planning um in addition to thinking about the dose to 90% of the hrctv and I should note that um it's also recommended to consider the dose to 98% um but hrctv D90 is what came out of the retroembrace trial and so that's why I'm

kind of emphasizing that 85 gray minimum um so so we can look at a few different things and we can also Contour the GTV if we actually see residual tumor and um we can we can tailor the dose to the GTV as well and make sure that it's getting getting a really high dose um but in addition to looking at those things so the that's just kind of the coverage of our Target volumes um we Also need to be careful about our organs at risk and so the Embrace 2 protocol has some nice recommendations for

constraints in our Breaky therapy planning and these are all as well in equivalent dose at two gray per fraction assuming an alpha beta ratio of three so the planning aims are really soft constraints recommended by the Embrace to um trialists but these planning aims are typically what we aim for just because they they have hard limits as Well that are a little bit more generous um but the soft constraints are more I would say what we try to aim for when we're doing these treatment plans just because we do not want to cause patients severe

toxicity um and it can be severe such as fistula for example so the soft constraints are for rectum the dose to 2 C's of the rectum should be less than 65 gray the d2cc to the sigmoid should be less than 70 gray for the bladder d2cc should be less than 80 Gray and then for the rectovaginal point the recommendation is less than 65 gray to minimize the risk of vaginal stenosis so um these are sort of the soft constraints the if needed and if you're really in a fix you can go a little bit a

little bit higher on these constraints and and as so as you're not as long as you're not exceeding the hard constraints um but again as I said I think you know we try to aim for those soft constraints um 65 70 80 d2c to the Rectum sigmoid and bladder uh whenever possible the last thing I will point out is that when it comes to cervical cancer especially it it matters for all cancers but especially for cervical cancer total treatment time really matters so we aim to not exceed 8 weeks so absolutely no more than 56

days between the start of our chemor radio theapy and the end end of our breaki therapy each day of treatment prolongation Beyond 8 weeks corresponds To a decrease in local control of anywhere between 0.5 to 1% and if you if there are delays then you can actually add more fractions to kind of make up for that lost time um but it's really important to realize that if we if there are a lot of treatment breaks and if we are interrupting patients radiotherapy y then it does actually lead to a worse local control um so the

treatment package time matters and we don't want Our total treatment time to exceed more than 56 days and that number 56 days or 8 weeks is based on retrospective data that showed an increased risk of pelvic failure if the total treatment time is more than 56 days in retro Embrace they actually found that local control was worse if treatment time was over 7 weeks and so in Embrace 2 they're actually recommending that the overall overall treatment time should not exceed 49 days or 7 weeks um and so you might hear Either number 56 days or

49 days but keep in mind that we try to finish all of our treatment within 6 to 8 weeks each week that we increase the total treatment time we actually need to prescribe an additional dose of gray to make up for that loss of local control and so you really want to avoid treatment breaks whenever possible and for this reason um often times Breaky therapy boost might even be started by the middle to the end of the external Beam radiation course so there may be some overlap um they the patient probably wouldn't have both treatments

on the same day um but there might be some overlap they might have one day break in their external beam so that they can actually get started with the the Breaky therapy boost portion so total treatment time is really really important so let us just quickly recap what we talked about in our management overview uh remember we talked about two Buckets of cervical cancer so the first is early stage cervical cancer less than 4 cm no parametrial involvement most of the time these patients are going to get radical hysterectomy so if they have greater than

or equal to 5 mm stromal Invasion um radical Hy is typically the surgery of choice and in certain cases patients may need adant therapy though we try to select for patients that won't indications for postoper radiation alone Are the said list criteria which are tumor size greater than 4 cm deep stromal Invasion or lvsi and you need at least two out of three of these for postoper radiation um if patients have any of the three Peters criteria so positive margins positive nodes or parametrial involvement then they would need posttop chemo radiation so that is sort

of The Upfront surgery followed by tailored agiven approach for early stage cervical Cancer if disease is greater than four cenm or if there's parametrial involvement then right away or or if it's more extensive than that we know that we're not going to do upfront surgery and instead we're just going to treat with concurrent chemor radiation followed by a Breaky therapy y boost and that concurrent chemo radiation is 45 gray in 25 fractions to the pelvis with concurrent weekly cattin 40 mg per meter squared followed by a Breaky therapy Boost something like 28 gray and four

fractions for example and then when we calculate the equivalent dose in two gray per fraction for the Brey therapy Boost Plus the external beam radiation our Target hrctv D90 is at at least 85 gray based on the Embrace data now in the next talk we will talk about more talk get into the evidence for all of this including the trials from which we got the sist criteria the Peters criteria um and we'll talk about you Know more in detail about the Embrace trials as well hopefully this was a helpful overview of cervical cancer and some

of the important considerations for management and in our next talk like I said we will shed some more light on the evidence thank you so much for your time and attention