Okay, can everyone see my slides? Yep. Great. Okay, so I was asked to give a talk on post-operative management of cervical cancer. I think it was the theme last month, which I couldn't attend, but so here's the lecture. This is a practice in New York City. Here's a picture of New York City with Central Park in the foreground and the skyscrapers in the background, and Mount Sinai Hospital is in the bottom left corner of the screen, and so I have the pleasure of working in New York pretty close to Central Park. So just in general for cervix cancer, there's obviously three main treatment options. We have hysterectomy, chemotherapy, and radiotherapy. Radiation can be broken up into external radiation and brachytherapy, and I'll be going into those in a little bit more detail as we go through the talk, but external radiation is usually given on a linear accelerator. Is there a radiation oncologist in Nepal on this call? No, okay. I'm not sure what kind of radiation machines they have in Nepal, but I'll be curious to know. Nevertheless. We have a linear accelerator. Oh, okay, great. Excellent. Okay, fantastic. Great. Okay. And the other treatment options for cervix cancer include brachytherapy, which can be tandem and ovoid brachytherapy, which is what is seen in the left picture where the tandem goes through the cervical os and into the uterus, and the ovoids sit at the vaginal fornices to really surround the cervix with dose. And what's also become popularized more recently, probably over the last 10 or 15 years, is the tandem and ring applicator, which is on the top right. This is similar concept to the tandem and ovoids, except there's just one ring that at the external os, and again, is there to surround the cervix with dose for those patients who have an intact cervix. However, in this talk, we're focusing on postoperative management, and in certain situations after patients have hysterectomies, we would give external radiation and brachytherapy with a cylinder, which is the bottom right picture. Because the patient's posthysterectomy obviously don't have a uterus, you cannot insert a tandem so then you would just use a vaginal cylinder. Does the group in Nepal, do you know if they have all of these applicators available? All applicator available, yeah. We have all applicator available here in Nepal. Fantastic. Great. Okay. And you use Iridium-192? Yes. Oh, great. Okay. Good. So just to kind of outline the treatment by stage, for stage 1A1 cancers, we typically do a type 1 hysterectomy. You can do something more limited if the fertility preservation is a goal. For type 1A2, we typically do either a type 2 or type 3 hysterectomy. 1B1, typically a type 3 hysterectomy, but in certain situations you can do a type 2. And then 1B2 cancers and higher, we generally prefer definitive chemoradiation. So this talk is really going to be focusing on what is clinically considered early stage patients, but pathologic specimen, we sometimes need to be more aggressive based on the results. So this is a classic trial published in 1997 in the Lancet from an Italian group comparing radiation versus surgery in early stage cervix cancer patients. There was 337 patients with clinically stage 1B to 2A cervical cancer, 90% of the patients had 1B cancer, a third of the patients had tumors bigger than four centimeters, 15% of the patients had positive lymph nodes on the vangiogram. And there were two arms. The first arm was radical hysterectomy with lymph node dissection, which was considered the standard of care at the time. And then the second arm was external radiation with brachytherapy. In the arm one, they did give post-op radiation if there were certain risk factors noted, because it was known at that time that surgery alone may not be curative. And so they gave some of the patients post-op radiation. And in the end, it actually ended up to be about two thirds of the patients had radiation in that arm one after surgery. So quite a significant proportion. So it was essentially, you can argue, a trial of surgery plus radiation versus radiation alone. And what this trial showed was that the survival and the disease-free cancer rates and local control were equivalent in the two arms. There really was no difference in any outcome other than you can argue toxicity. And if patients had surgery and radiation, they had more side effects versus if they had radiation alone. So this trial really, in the conclusions, the authors stated that they tended to lean towards surgery alone for patients who are younger and perhaps radiation alone for patients who are older. It was also felt that if you could have some kind of preoperative probability score to say what is the likelihood someone's going to need radiation after surgery, perhaps those patients shouldn't have surgery if there was felt to be a significant risk of needing radiation after because it's showing that bimodality treatment of surgery and radiation ended up being more toxic than radiation alone. Therefore the therapeutic ratio was perhaps in favor of radiation alone. Now in the U.S. for sure, in 1B1 patients, surgery is more common. They're probably about two thirds of patients in the U.S. with 1B1 cancer will end up having surgery up front. So the question is who needs radiation after surgery? In that Landoni Italian trial, they had some various factors they looked at based on historical data, but it wasn't really proven who really needed the radiation, who's going to benefit from radiation after surgery. So another classic trial was GOG92, which was published by Sedlis et al. in the Guide Onc Journal in 1999, and there was updated by Dr. Rotman in 2006. This is a trial of 277 patients with what was considered intermediate risk factors for cervix cancer after hysterectomy. And this summary here of the risk factors is just that, it's a summary. The actual trial had some more complicated algorithm of who qualified for post-op radiation, but most of the clinicians I work with tend to use this simplified version of at least two of these three risk factors. And so you can see I've highlighted the S words in red, and this was a way I teach my residents how to memorize these risk factors. So Sedlis was the first author, his name began with an S, and so if you look at the stromal invasion, the space invasion for lymphovascular space invasion, and the size of the tumor, those were the risk factors. So more than 33% stromal invasion, LVSI in size greater than four centimeters. If you had two of those risk factors, it was felt that you were going to have at least a 30% risk of failure, and these were the patients who would benefit from adjuvant radiotherapy. So the trial included all patients who had radical hysterectomy and pelvic lymph node dissection, and then they were randomized to radiation or observation after the surgery, given that they had two of those three risk factors. Patients had external beam radiation only to about 50 gray, which is still considered a standard dose, and so that we consider it was an adequate dose of radiation. Patients were not given brachytherapy on this trial, so no one got that cylinder brachytherapy that I mentioned before. And what they showed was that if you had surgery alone, there was about a 70% chance of cure rate, and just as their nomogram predicted, there was about a 30% rate of recurrence if you had surgery alone. And the patients who had radiation after the surgery, actually their recurrence rates were cut in half. So instead of having a 30% chance of recurrence, it was about 15%. You can see that most of the benefit was in local control, going from 20% to 15%, but the distant recurrence has also slightly benefited the patients who had radiation. Grade three toxicity was slightly higher in those who had radiation, but I do not think it was statistically significant. And then you can also see that there was no statistical difference in survival, however, there was about a 9% absolute benefit in survival. And some people questioned was it not statistically significant because of the relatively low number of patients. However, it's still unclear if there would have been survival benefit if there was more patients. There was a meta-analysis done after this trial, based on another earlier trial, and this included probably twice the number of patients, and still no survival benefit was seen. So really the feeling is that radiotherapy helps with local regional recurrence, not so much with overall survival. So those are the patients who got post-operative radiation, but who can benefit from post-op chemoradiation? So this was a trial of GOG-109, this was the PETERS trial published in JCO 2000, another classic trial. These patients were thought to be at higher risk for recurrence, and their risk factors were based on either pelvic lymph node involvement, parametrial involvement, or positive margins. And these are the three P's for high-risk disease. So the SEDLIS trial had the three S's, and the PETERS trial has the three P's. And so these patients also had radical, everyone in the trial had a radical hysterectomy with lymph node dissection, everyone had radiation after, it was just a matter of did you have chemotherapy with the radiation or not. These patients also had about 50 gray of post-operative radiation in both arms, again, no brachytherapy included on this trial. And then half of the patients were randomized to cisplatin and 5-FU chemotherapy, given every three weeks for four cycles. These results actually did show a 10% overall survival benefit at four years. The four-year progression of resurvival was improved from 63% to 80%, also statistically significant. So this was a major trial showing that who would potentially benefit from chemotherapy. The typical radiation fields that we treat for post-operative cervix cancer involves a standard pelvis field where we treat the lymph nodes in the pelvis, we treat the remaining parametrium, even if patients have a type 3 hysterectomy, there may be some parametrium left along the pelvic brim. And then also we treat the vaginal cuff from where the cervix and uterus was removed. Patients typically get 45 to 50 gray over five weeks of treatment. The standard is to use a four-field box, we have two fields coming from the lateral aspects, one field from the front and one field posteriorly. Patients can be positioned on the table, either supine or prone. My practice is usually to do supine, though some of my colleagues do prefer prone. You can see the typical regions we treat are up to the top of L4, L5, which is where the aorta bifurcates and the common iliacs bifurcate at this level. We treat one to two centimeters lateral to the pelvis, in each order we get adequate coverage of the external iliacs. And then we treat down to the bottom of the obturator foramen to make sure we have adequate margin on the vaginal cuff. And this would be the field coming anteriorly and the mirror image would be the field coming posteriorly. And then the image on the right is the two fields we would use laterally. And you can see this is the L4, L5 inner space and bottom of the obturator foramen. Posteriorly, we tend to cover the entire sacrum of the cervix in order to get all the uterocycle ligaments and the pre-cycle nodes that may be laying posteriorly. And then anteriorly, we're at the pubic symphysis or maybe one to two centimeters anteriorly to make sure we have enough coverage on the external iliacs. This is a schematic showing the lymph node regions in here, in red you have the common iliac lymph nodes, in the magenta color you have the external iliacs, and in the green you have the internal iliacs and you can see how the standard fields cover these lymph node groups adequately. Posteriorly, we will treat with an extended field of radiation where we're targeting the periodic lymph nodes. In the U.S., this is typically done for patients who have positive lymph node involvement, whether it's seen radiographically or if it's actually been sampled in the post-operative setting or potentially even high common iliac nodes that are seen in the pelvis. We will sometimes go to the next echelon up and treat the periodic lymph nodes. These are typically done with an anterior and a posterior field and we can treat all the way up to T11, T12 to make sure we're covering the entire periodics. We typically treat this field to 45 gray. In the U.S., it's becoming more common to use intensity modulated radiotherapy. For the group in Nepal, do you use IMRT there? Yes, we have IMRT. We don't do regular cervix patient, but yeah, we have IMRT. Yeah, so it's becoming quite common to use IMRT in the post-operative setting for cervix patients and there's a kind of a newer trend to even use it in the definitive setting. So what IMRT allows us to do is deliver radiation a little bit more accurately to the targets. You can see here in the yellow outlines is where the lymph node regions are. Here are the external iliac vessels and the internal iliac vessels and the lymph nodes lie adjacent to them. So these are the targets for the lymph nodes and this area shaded in red is what the four field radiation can do. The one field coming anteriorly, another field coming posteriorly, and then the two fields coming from the sides give a rectangular dose of radiation to this area here. You can see that the lymph nodes are adequately covered with this red dose of radiation, which is typically 45 to 50 gray. But there is bowel in here that's unnecessarily getting radiation and that can lead to bowel toxicities such as acutely diarrhea and perhaps in the long-term, maybe bowel issues such as perforation. With IMRT, what we can do is really focus the radiation on just the areas at risk. So you can see the red area that's getting the highest dose is just limited to the areas in yellow that were delineated as a target and this bowel in the middle gets spared. And there was recently an RTOG study published in the US in the JCO in 2017, it was actually a randomized study comparing four field radiation versus IMRT and it actually shown an improvement in bowel and bladder acute toxicity. The data is still maturing to see if late toxicity is going to be improved with IMRT, but currently just data showing that the acute toxicity is better. So there are a couple of ongoing post-operative trials in the US. The first is GOG-263. This is a trial looking at intermediate risk patients, all patients who have had a radical hysterectomy with intermediate risk factors based on the set list criteria that I outlined earlier. The goal is to accrue 534 patients. The standard of care right now in the US is to give external beam radiotherapy and there's to see if cisplatin with the radiation would benefit these patients. The set list trial only looked at post-operative radiation alone and we're trying to see if chemotherapy would improve results in these patients. If you can remember, the radiation improved the recurrence rates by half, but there was not an absolute benefit in the survival. So adding chemotherapy, we're trying to see if that can further improve outcomes to these group of patients. And again, no brachytherapy allowed in this group. There's also an ongoing post-operative trial in high-risk patients. This is NRG-0724. This is a trial that patients get radical hysterectomy and if they have positive lymphoid involvement or parametral involvement, they're randomized to either the standard of care, which is cisplatin with radiation versus cisplatin radiation followed by further chemotherapy with carboplatin and Taxol every three weeks for four cycles. So trying to add four more cycles of chemotherapy to see if there's going to be an improvement really in distant control to try and help cure rates and overall survival. So just to briefly touch on the radiation toxicities acutely. These can be skin toxicities such as desquamation and pruritus in the treated field. GU side effects include dysuria, increased urinary frequency, and nocturia. Patients can have diarrhea, transient rectal bleeding, or hemorrhoids. And these are the side effects that were really improved by IMRT in that RTOG trial I mentioned that was published in 2017. GYN side effects, patients can get vaginitis or candidiasis. And then if they're using brachytherapy in the definitive setting, you can get uterine perforations and vaginal lacerations. Really not seen in cylinder treatments in the post-operative setting, but can be seen in patients who are getting tandem insertions for the definitive cases. Genetic toxicities from radiation are less than 5%. In GU, you can get ureteral strictures and urethral strictures. GI toxicities include intestinal obstruction or perforation. GYN toxicities, very rarely you can see fistulas between the vesicovaginal and rectovaginal and then vaginal stenosis. And then musculoskeletal complications include femoral neck fractures. So in conclusion, as I mentioned, 1A1 cancers typically are treated with a total hysterectomy in the U.S. You could use brachytherapy as the sole treatment, but by far and large, hysterectomy is the standard. 1A2 is a little bit more aggressive surgery with radical hysterectomy. You could do brachytherapy perhaps with external beam, but these are typically treated with surgery. 1B1, as I mentioned, in the U.S., these patients are typically treated with radical hysterectomy, though definitive radiation is certainly an option for these patients. As mentioned in the Italian trial, they have equivalent outcomes. 1B2 and higher, patients typically get chemoradiation. NCCN recommends chemoradiation for these patients. And in the post-op setting, I outlined that you get post-op radiation for patients who have at least two of the three risk factors of LVSI, more than one-third stromal invasion or a size greater than four centimeters. And in the post-op setting, patients who have high-risk features, such as pelvic lymph nephropositivity, positive emergence of parametrial invasion, these typically get chemoradiation. So that was all I wanted to present. I'd be happy to answer any questions, either now or by email.

post-operative management

cervical cancer

treatment options

radiotherapy

chemotherapy

clinical trials