We're going to talk about locally advanced cervical cancer, and like I said, unfortunately, this isn't something that you can do in the PGs, but we'll talk about why it is important to have radiation therapy. So we'll start with, it's a 47-year-old female who had several months of vaginal discharge. She had an exophytic lesion involving the entire cervix. It was six CMs and involved the upper one-third of the vagina. Biopsy was positive for a poorly differentiated squamous cell carcinoma, and actually both the cervix and we did an endometrial biopsy, and they were both positive. So, you know, in the United States or in a lot of places, we do a PET CT, and this is an example of a PET CT. So this is normal ureters, but here she has a positive right external iliac node. As you can see, it did involve the uterus as well as the cervix. So the entire uterus and cervix were involved. So the question is, you know, with the new staging system, what is her stage? And we'll just kind of go, we'll skip to where the staging system has changed, right? So with the new staging system, we've added a 3C. The 3C is that now we can actually look at pelvic nodes, and that's part of our staging system. So in this lady's case, she actually has a positive external iliac node. So she would be a stage 3C1R because we saw it in imaging. So we didn't biopsy it, but we saw it in imaging. So key thing is, you know, the new FICO staging has added lymph nodes, and now we have a stage 3C, which is new, and that is positive nodes. So C1 is positive pelvic nodes, and C2 is positive periodic nodes. The other thing I think that has changed also is, and this may be before too, but 2A has been divided to 2A1, which is less than 4CMs, and 2A2, which is greater than 4CMs. So treatment. How do you treat a locally advanced cervical cancer, especially a patient with stage 3C1 cancer? So key is, for locally advanced tumors, radiation therapy is the mainstay treatment. But key is, you've got to do the radiation therapy correctly. And what that means is that you've got to treat the known disease as well as the microscopic disease. You've got to give the right dose. So, you know, for boards, these are things that you need to know. What is the dose, right? The dose that you want to give for locally advanced tumors is really 85 to 95 gray to 0.8, and it should include brachytherapy, whether it's HDR or LDR, but it should be both radiation from the outside and radiation therapy from the inside. So both external beam and brachytherapy. It also needs to be done within 60 days, and I'm going to show you some data on why it needs to be done within 60 days. So this is just data from MD Anderson. This was actually pre-chemo, right? And this just shows you that radiation therapy works just by itself as well. So as you can see, for stage 3, even pre-chemo, our central recurrences were very low. So we were curing about 70% of our patients with stage 3. And you can see death from disease, we were curing about 50 to 60% of our patients just with radiation therapy alone. And these are your typical fields. Again, for boards, this is important. Key is you want, as I talked about, we have to treat the known disease as well as the microscopic disease. So the microscopic disease is what you're going to take out when you do a hysterectomy, right? So you're going to take out your external iliac nodes, your internal iliac nodes, your obturator nodes, your common iliac nodes, right? So that's what's included in this. So the purple is my nodes, and that's my external iliac, that's my internal iliac. The red is my cervix and my uterus and my vagina, right? So here's the common iliacs, and we're going to treat the pre-cycles, and we're going to treat the obturator nodes, which is right here. We are now changing the field. So the field is you go to the top of the bifurcation, so you're including the entire common iliac chain. You want to go three CMs below the inferior extent of the disease, or at least to the bottom of the obturator foramen. And you want to include at least a pre-cycle nodes up to about L4, L5. I'm sorry, S4, S5. So that's what is here. So this is your sagittal, this is your axial, and this is your coronal. So again, just showing you again the fields. And like I said, the superior border now really is the bifurcation of the aorta. If you have positive common iliac nodes, you're going to go to the top of L2. If you have positive periodic nodes, you want to go to the top of the renal vessels, or T12. And then inferiorly, it is the obturator foramen, or three to four CMs below the inferior extent of your disease. You do want to make sure, and we do now contour. So this is my lymph nodes right here. Here's my uterus and cervix. We do contour everything. We want to make sure all of that is in my field. So this is the radiation doses. But again, these are things that you really want to know. Even if you don't get radiation therapy in Fiji, you want to make sure that whoever is doing the radiation from the outside is giving the correct dose, right? So with chemotherapy, you give about 45 gray from the outside. And actually, the new guidelines are you don't really want to give more than 45 gray, because then you're giving too much dose to the bladder and rectum, and it limits your brachytherapy. So key is you want to give about 45 gray in 25 fractions. So it's five weeks of treatments, Monday through Friday with external beam, and then you do your brachytherapy. And the goal to the brachytherapy is you want to give a total of 85, 80 to 95 gray to the cervix and the known disease. Postoperatively, here's the doses for post-op, which we're not going to talk about because we're really talking about more the locally advanced disease, but the doses are here. Just an example of how well external beam works, here is a patient with an MRI, huge cervical cancer, three months later, completely gone, and she's actually disease-free. So radiation really does work because we can do the radiation from the outside and the radiation from the inside. So this is a key, and this is so important, is it really needs to be done within 60 days. And there's so much data that shows there's actually a 1% loss of local control per day, the longer it extends past 60 days. So it's really important from day one to know who's going to give the external beam, when the brachytherapy is going to start, and it's important to try to finish everything within that 60-day period. So what are some of the toxicities of radiation therapy? Again, these are things more for you and what's relevant to you. During treatment, everybody gets diarrhea. It starts about the fourth or fifth week into treatment. Antidiuretic medications, reducing the fiber in the diet, it's really important. Some patients get some bladder irritation and they do get tired. The new data, though, is you do not need to transfuse the patients to have a hemoglobin or 9 and 10 before you start the radiation therapy. In fact, we can't transfuse unless they're lower than 7 because that's the new guidelines. So we are no longer transfusing them to get it to 9 and 10. We will treat no matter what the hemoglobin is. So what are the long-term toxicities? And again, this is so important because this is what you guys are going to see, right? So even if they get radiation from somewhere else, this is what you're going to see. So radiation toxicities, long-term, it's about 11%. Majority of them are going to be bowel toxicity. So as you can see, at 10 years, rectal toxicity is about 3% to 4%. Small bowel is about 4%, and bladder is about 3%. Key is most of the small bowel, rectal, and sigmoid toxicities happen within the first two years. It's the bladder that continues to rise as you go 10 to 15 years later. So it's important to know that you could continue to have bladder toxicities even 10 to 15 years later, but majority of the bowel toxicities occur within the first two years after treatment. So what are some risk factors? Now, this is from America, so this is American population, so it's all different, but we do know the risk factors are definitely smoking. Patients who smoke during treatment have high risk factor for small bowel toxicity and rectal toxicity. Also physique. So skinnier patients, patients who have a BMI less than 22, have a higher risk of bowel toxicity. But if you are obese, having a BMI bigger than 31, you have a higher risk of bladder toxicity. And in the United States population, African Americans had a higher risk of bowel and bladder toxicity. And the other thing is dose, and this is why I was telling you, it's important, and really the data shows now, you really don't want to go above 50 grade with the radiation from the outside, but you really want to try to keep it at 45, because otherwise you're going to exceed your bladder and rectal doses, and really limit your brachytherapy. So how about concurrent chemotherapy? So we know this data, right? So we know in 1999 that concurrent chemo radiation was better than radiation therapy alone, and these are all the studies that showed that concurrent chemo radiation was better than radiation therapy alone. So I'm just going to go over one study, because I do want to show you that, yes, it was a home run in 1999, but it's not a hundred percent, okay? So let's look at RTOG 9001. Now RTOG 9001 was a little bit different, right? What it did was that it randomized patients to extended field radiation therapy versus pelvic radiation therapy, but they used cisplatinum and 5-FPU. But I'm using this study as an example to show you we really did improve survival somewhat, but again, it was not a home run. Key is, as you can see, radiation therapy was done well, medium dose was 85 gray, like I told you, so we got most of our patients done in 58 days, and majority of the patients finished their treatments, right? So what we found was for all patients, chemo radiation did better than radiation therapy alone, so we know that, right? For stage one and two, it was very significant, 79% versus 55%. This is important. For stage threes and fours, it was trending towards significant, but it wasn't significant, and it was only 59 versus 45. So chemo radiation works really well for the early stage cancers, but for stage three and four, yes, it's improving, but it isn't really significant. And this study actually showed that chemo radiation versus radiation, there really was no difference, and they said that if you did the radiation correctly, there may not be a difference. But I think this is the most important thing, and this is the meta-analysis that looked at all studies looking at chemo radiation versus radiation. So first thing they found was that no matter what chemo you used with the radiation, chemotherapy plus radiation was better than radiation alone for all locally advanced tumors, okay? Now, platinum is better, but it doesn't matter. You could use mitomycin CM5FU. That's still better than radiation therapy alone, okay? But, and this is what I want to show, but the biggest advantage of chemo radiation really is for stage ones and two Bs. You can see for stage threes and four, there's only a 3% improvement in adding chemotherapy. So we can do better, and we need to do better for these locally advanced tumors. And what we also found was that these patients weren't not just failing distantly, they were also failing locally. So these locally advanced tumors were doing better, but they were still failing. The other thing this meta-analysis found was that if you gave adjuvant chemotherapy, there was actually maybe a sign that those patients did better than patients who just got concurrent chemo radiation. So the conclusion was that chemo radiation is better than radiation therapy. But the biggest benefit is in patients who have stage one B, two to two B, and it's only 3% for stage three. So the question is, how can we do better, and what can we do better? So in the United States, we're actually using this new drug called triapine. It's a hypoxic drug, and it's actually going into a stage three setting, and patients are being randomized to chemo radiation with cisplatinum versus cisplatinum triapine and radiation therapy. But what are some of the international trials that are going on? So one, we know about APAC, right? So this study has just finished, and these are patients with locally advanced tumors, and they were randomized to chemo radiation versus chemo radiation plus four courses of carboplatinum and metaxol. My understanding is this study's results will be published or presented at ASCO this year. So we'll find out, does it help by giving more chemo afterwards versus just giving chemo with the radiation? Another trial that's almost completed, it's based on this phase two study that looked at every week cisplatinum versus every three weeks cisplatinum, and the phase two study found that there was actually a benefit in patients receiving cisplatinum every three weeks, one in quality of life, but maybe in survival. So this study, which we'll finish by the end of next year, or actually by January, February of next year, is looking at cisplatinum every week versus every three weeks, and it's called the TACO trial. The last study that's presently going on is this question about how about neoadjuvant chemotherapy, right? So what I'm not talking about here, and we can talk about it because there's now new data looking at neoadjuvant followed by surgery versus chemoRT, right? But we're not going to talk about that. I do think I really should do a whole separate slide presentation on that, but this study is actually looking at neoadjuvant chemotherapy followed by chemoRT versus chemoRT. So not surgery, but so it's neoadjuvant chemo followed by chemoRT versus chemoRT. This study also will be finished by January, February of this year, so hopefully we'll have an idea how about adding neoadjuvant chemotherapy, would that help, right? So future directions we just talked about, you know, and we'll have some ideas on where we should go, but we definitely need to improve care for our patients with stage 3b or higher disease. So a little bit about brachytherapy. This is a really a quick overview, right? So brachytherapy, brachytherapy is so, so important, and I want to walk you to walk away with knowing that to treat and cure locally advanced tumors, you need both the radiation from the outside and the radiation from brachytherapy. So this is a study in the United States that looked at brachytherapy use going down, and what they have found as this brachytherapy use has gone down, survival has gone down, and in patients who got no brachytherapy did worse than patients who got brachytherapy, just showing you that brachytherapy is so important in the treatment of these patients. Another study, again showing what if we used radiation external beam alone, like SBRT or IMRT, these fancy things that we have, and again survival is worse in patients who got this external beam alone versus getting brachytherapy. So brachytherapy is just very, very important in treating these patients. And again, for a fellow, this is things that you do need to know, so let's talk about things that you need to know for the boards, right? So this is a film of a patient who has brachytherapy, right? So this is a tandem, this is what goes into the uterus, these are ovoids, this is what's going to be in the vaginal fornices. Now, in this case, we put little platinum seeds in the cervix, so that shows us where the cervix is. So we want to make sure that we're right up against the cervix, the flange is right up against the cervix, and these are my ovoids. So point A, point A is you go up right above, you go from the flange, two CMs up and two CMs over, that's point A, point A on the right and the left. What point A represent is your perimetrium, it's where the uterine artery crosses the ureter, okay? Then three CMs from point A is point B, and that's your sidewall disease, okay? Now, going to your lateral, this is how you're going to figure out where your rectal point and your bladder point is, right? So the bladder is, you put seven CCs in the Foley bulb, at midpoint of the bladder is your bladder point, and then your rectal point is, you're going to go midpoint from your ovoids, and five millimeters from the packing, or the posterior aspect of the ovoids, is your bladder point. So again, this is actually a great picture, this is your tandem, so that's in your uterus, and you can kind of see the uterus right there, right? Here's your ovoids, and you're, I'm right up against the cervix, so the bladder is going to point, I mean the bladder point is going to be right here in the Foley bulb, and the rectal point's right there, okay? So these are the doses that we talked about. Point A, you want to get to about between 85 to 95. Bladder, actually this is wrong, you can go up to 90, but actually you really don't want to go above 80 if you can not. Rectum and sigmoid, you want to go to 70, and the vaginal surface at 125. Key is, side effects are due to both the external beam and the brachytherapy, but they're both very, very important, and you've got to do it correctly. So this just shows you that brachytherapy, the way you do your brachytherapy is really important, if the brachytherapy is not done correctly, you also reduce over local control and survival. These are the most common regimens for brachytherapy, eight gray times three, seven gray times four, or nine gray times two, or you can do two low-dose rate implants. Just moving forward, we are no longer doing 2D or 3D in a lot of the world, we're actually doing image-guided brachytherapy, where we're actually looking at CTs and MRIs to make sure that we're away from the bladder and rectum, so we're not doing film-based, just to know that we're moving more and more away from films, and doing more image-guided brachytherapy, and we've actually shown by doing image-guided brachytherapy, we can improve local control, overall survival, and toxicity. So that's it, questions, any questions that I can answer?

locally advanced cervical cancer

radiation therapy

new staging system

external beam

brachytherapy