So, hi everyone, we will begin in a couple of minutes as we are waiting for people to join in. So hello everyone. We will start in one minute as we are allowing time for people to join. So hello everyone. Welcome to the interactive updates on selected topics in gynecology oncology webinar. Today our program will be focused on cervical cancer. So I am Reitan Ribeiro. I'm a surgical oncologist with the Rastoguerra Hospital in Brazil. And I will be your moderator today. So today's webinar will be provided in Spanish, English and Portuguese. A handout with detailed instructions will be found in the chat. As well as in this slide in Portuguese. And in this slide in Spanish. Select your interpretation icon. Then select the language you would like to hear. You may also mute original audio and hear interpreted language only if you want. If you have any questions regarding interpretation, please chat IGCSEducation. IGCSEducational portal within a week. We encourage you to submit questions via the Q&A feature at the bottom of your screen. Following each session, we will have time for questions. And we will do our best to address as many questions as possible. We have a great session outlined for today's webinar. Focused on cervical cancer. And now it's my honor to introduce today's speakers. Pedro Ramirez from the United States. Aldo Lopez Blanco from Peru. Mauricio Lema from Colombia. Anuja Gingram from the United States. And Renato Moretti Marques from Brazil. Without further ado, to kick off today's presentation. We are going to share Dr. Pedro Ramirez's presentation on surgical treatment of cervical cancer. LAC trial impact. Thank you very much to the IGCS for the invitation to present on this topic. The subject of this discussion is going to be the surgical management of patients with cervical cancer. And the impact of the LAC trial. During this presentation, I'm going to be addressing the final results of the LAC trial. Which were presented at the SGO meeting in Phoenix in 2022. And this is reflective of all the patients followed to four and a half years. I'm going to speak also about some of the literature that has been published since 2019. When initially the LAC trial was published. What have been some of the patterns of practice in the United States since the publication of the LAC trial. And I'm also going to address some of the unresolved issues that still remain. Particularly looking at vaginal protective maneuver. And the issue of patients with less than two centimeters as potentially being candidates for minimally invasive surgery. Certainly, I think these are topics that deserve further discussion. And lastly, to talk about the impact of the LAC trial on all of the current guidelines. Both national and international. As many of you know, the LAC trial was a prospective randomized trial. Evaluating open versus minimally invasive radical hysterectomy. Which showed that in the minimally invasive approach, the recurrence rate was higher. The disease-free survival and overall survival were also worse in patients undergoing minimally invasive radical hysterectomy. Subsequently, there was another study published in the same issue of the New England Journal of Medicine in 2018. By Alex Melamed and their group. Where they evaluated a large national cancer database. Also comparing open versus minimally invasive surgery. Demonstrated that the minimally invasive approach was also associated with worse survival outcomes for these patients. In the recent meeting of the Society of Gynecological Oncology. I had the opportunity to present the final analysis of the LAC trial. And in that presentation, I spoke about the outcomes on disease-free survival. And overall survival in patients who underwent open versus minimally invasive surgery at four and a half years. In other words, this was when 100% of eligible patients were followed to four and a half years. In addition, we perform an exploratory analysis. And this again, highlighting. This was an exploratory analysis. None of these points were in the initial design of the study. But because this was of interest to the community of gynecological oncologists. We decided to look at the impact of residual disease on the hysterectomy specimen. Whether the open or minimally invasive approach had an impact outcome on these patients. Stratifying patients with tumors less than two centimeters. Versus those of tumors greater than two centimeters or equal to two centimeters. The impact on prior colonization. The rate of carcinomatosis. And certainly also the pattern of recurrence. As you know, in the trial initially, we accrued a total of 631 patients. And as I mentioned here, this is the breakdown stratification of all the patients that reached four and a half years. Which in fact totals 83% of all patients entered onto the study. Reached a follow-up of four and a half years. As you can see, we had data completeness of 100% for all eligible patients. For both the primary outcome of disease-free survival and overall survival. And in our final analysis, we showed just as in the initial publication. That both in the intent-to-treat analysis and the per-protocol analysis. Minimally invasive surgery was associated with worse outcomes. And therefore, radical hysterectomy favors the open approach for these patients. When evaluating the disease-free survival. As you can see here, in terms of events of recurrence. The events of recurrence were four times higher in patients undergoing minimally invasive surgery compared to open surgery. In addition, progression-free survival was also worse in patients undergoing minimally invasive surgery compared to open surgery. Disease-specific survival was also nearly three times worse in patients undergoing minimally invasive surgery compared to open surgery. And then certainly in the local and regional recurrence. Which is also an interest to us as gynecologic oncologists. The recurrence rate in patients undergoing minimally invasive surgery was almost five times higher. In patients that had the laparoscopic or the robotic approach. And then lastly, very importantly, the overall survival. At the completion of the lag trial. After four and a half years. When 100% of the patients had been followed. We showed that the minimally invasive approach had almost three times worse overall survival. In other words, three times higher death rates from cervical cancer. When compared to the open approach. And obviously this was an important finding. Because it solidified and rectified the initial publication in the New England Journal of Medicine in 2018. As I mentioned, we performed an exploratory analysis as well. And we first looked at whether the impact of residual disease on a hysterectomy specimen had any bearing on the outcomes. In other words, patients who have no residual disease after a radical hysterectomy. It's important to highlight that when looking at that particular component. There were very few patients who had no residual disease. So 60 patients in the open and 60 patients in the minimally invasive approach. And as you can see here, there were no events of recurrence in the patients who had open surgery. And there were only two events of recurrence in the patients who had minimally invasive surgery. There were no events of deaths in either open or minimally invasive surgery in patients who had no residual disease. So in other words, in patients who had no residual disease. We really could not tell anything regarding the two different approaches. Because there were no events to then evaluate whether there was a difference or not between these two approaches. What we can take from this information is that most likely in patients who have no residual disease in the hysterectomy specimen. The approach may not have an impact on the oncologic outcomes. But again, the study was not designed to show this. The numbers were too few and there were no events to appropriately and statistically evaluate this question. As it pertains to tumors size. As you can see here, this is a tumor more than two centimeters evaluating minimally invasive versus open. And it was clearly shown that in patients who have a tumor greater than two centimeters. The likelihood of recurrence by minimally invasive surgery is just over four times worse when the tumor is greater than two centimeters. When the tumors are less than two centimeters of note here, we cannot evaluate whether there was a statistical significance. Because again, there were no events in the open surgery group. However, one should note, but looking at just the absolute numbers, there were no recurrences in the open surgery group. However, there were seven recurrences in the patients who have minimally invasive surgery who had tumors less than two centimeters. So once again, because there were no events of recurrence, we're not able to evaluate a statistical analysis on this patient population. The issue of previous colonization obviously is also an important one. And here we evaluated patients who did not have a cone prior to surgery. And in this group, the minimally invasive surgery group had almost six times worse recurrence rates than the open surgery group. So once again, a much higher recurrence rate by minimally invasive surgery if the patient has not had a colonization. Interestingly, in the patients who did have a previous colonization, there was no difference in outcomes whether the patient had minimally invasive surgery versus open surgery. But again, this is probably highlighting the fact that patients who had a previous colonization, most likely those patients had either very small tumors, microscopic tumors, or the patients had no evidence of any residual disease in the hysterectomy specimen. So therefore, in those patients, there was no difference in the recurrence rates when comparing the two surgical approaches. Interestingly, also, we evaluated the rate of carcinomatosis when patients had recurrence of their disease. And we found that when the patient had open surgery in the recurrences, there were no cases of carcinomatosis. But if a patient had a recurrence with minimally invasive surgery, 24% of those patients manifested with carcinomatosis. Certainly we also published on the adverse outcomes of the LAG trial, and this is a previous publication in the American Journal of Obstetrics and Gynecology, and also on the quality of life. Just briefly, Andreas Overmaier reported on the adverse events, and he showed that when comparing minimally invasive versus open surgery, there was a very similar overall incidence of intraoperative and postoperative adverse events. In addition to that, Michael Frumowitz published in Lancet Oncology the quality of life assessment, again with multiple score system evaluations, and he found that in that patient population, the postoperative quality of life was similar between the two treatment groups. So again, as a composite of all the results of the LAG trial, we found that the recurrence rates were higher, disease-free survival was worse for minimally invasive radical hysterectomy, and the quality of life was similar between the groups. So what has happened since 2018, when it was originally published in the New England Journal of Medicine? There have been a number of institutions that have looked at their data to determine whether there was any difference in their evaluation, and consistently, most institutions found that the oncologic outcomes were worse for minimally invasive surgery when compared to open surgery. Certainly here, this is a publication that exemplifies exactly this as well from Europe, where the laparoscopic approach had worse disease-free survival compared to the open approach. Interestingly, in this publication, I'd also like to highlight that when patients have recurrences in the laparoscopic group, 43% of those recurrences were actually carcinomatosis. In our study, we found 24%. Another study that I like to highlight is this one by Javier Magrina in the Mayo Clinic, which is a study that basically highlights the fact that whether an expert surgeon has the same outcomes as a novice or somebody who's going through the learning curve. So obviously, this is an institution that has an extensive experience with robotic radical hysterectomy, and in that study, they found that patients who underwent robotic radical hysterectomy had inferior progression-free survival and overall survival compared to open surgery. So once again, very similar results to the LAC trial, even in an institution of high expertise in minimally invasive surgery. This is a publication by Juliana Rodriguez from Latin America and select institutions in Europe that also showed that the minimally invasive approach was associated with worse outcome in a study of over 1,000 patients. One of the questions that also has come up is what's been the practice change in the United States, and this is a study that looked at what has happened since the publication and the presentation of the LAC trial in patients in the United States, and as you can see here, the LAC trial was initially presented at the SGO in March of 2018, and then it was published in November of 2018, and as you can see here in the blue line on this graph, there has been a gradual decrease in the number of minimally invasive surgeries that are performed in the United States. This is a reflection of the 12 months after the LAC trial was presented at the SGO in terms of patterns of practice of minimally invasive radical hysterectomy. I also encourage and invite all of you to look at this presentation that was in the New England Journal of Medicine on the effect of randomized controlled trial on surgery in cervical cancer, also demonstrating a significant decrease in the rate of radical hysterectomies performed by minimally invasive surgery in the United States, and this is the most recent publication actually out of the National Inpatient Sample Database, over 6,000 patients by Koji Matsuo and Jason Wright, and what they found was that the rate of minimally invasive radical hysterectomy decreased significantly since the presentation of the LAC trial at the SGO, and they also do note that there was an initial increase in the number of complications affecting the change from a traditional minimally invasive approach prior to the LAC trial presentation to an open approach after the LAC trial presentation. So, certainly what they found was that the use of minimally invasive hysterectomy decreased significantly by 63% by December of 2018, which was just one month after the publication of the LAC trial. Minimally invasive surgery rates were about 18%, so certainly there was also a noted increase in complications in patients now than having open radical hysterectomy. Now just very briefly, I want to talk about the vaginal protective maneuver. This is a maneuver that has been published by Chris Tarkoler and their team, and in their study they showed that basically by performing a vaginal protective maneuver, one may avoid the adverse outcomes, oncologic outcomes, of a laparoscopic or robotic approach. So, there are a number of centers where they're suggesting that the vaginal protective maneuver may be of benefit, but again, this was a retrospective study where we don't have information about the indications for the vaginal protective maneuver, nor the type of patients that were entered onto those studies with a vaginal protective maneuver. Similarly, the Sucor study by Luis Chiva from Spain also demonstrated that the minimally invasive approach was worse compared to the open approach, and certainly this was consistent both for relapses and the incidence of death. One of the things that they also evaluated was, again, the vaginal protective maneuver. One of the things they highlight is that by performing the vaginal protective maneuver, the outcomes may be very similar to the open approach, as you can see here from the blue and red lines, and certainly the outcomes are significantly worse if there is no protective maneuver. So, again, suggesting that this may have a bearing in terms of outcomes. I'd like to also point out the issue of tumors less than 2 centimeters, because some have suggested that if the tumor is microscopic, if the tumor is very small, then perhaps the patients can still undergo a minimally invasive approach. This was studied by UPAL and a number of institutions in conjunction with the University of Michigan, and what they found was that even in patients with less than 2 centimeters, minimally invasive radical hysterectomy had inferior disease-free survival compared to the open approach. A similar study from China also showed worse disease-free survival by the minimally invasive approach when evaluating patients that had less than 2 centimeters. So, again, a number of studies also showing that in less than 2 centimeters, the outcomes were worse. This was a study by Giovanni Scambia, where they showed that in more than 2 centimeters, there was definitely a difference, but in less than 2 centimeters, there was no difference, and therefore, they suggested that the laparoscopic approach might be feasible in patients less than 2 centimeters. A little bit of warning. When evaluating these studies, these are retrospective studies that have very low numbers of patients, so therefore, they actually conclude in their study that to show a significant difference between open and laparoscopic surgery in cases with tumors less than 2 centimeters, a larger sample size than what they had needed to be evaluated. This is a study by Demetrius Natsiotis, a much larger sample size, over 2,000 patients, and in that study, they did show that patients who had minimally invasive surgery had worse overall survival than those who had open surgery in the less than 2 centimeters. So, again, highlighting the fact that in less than 2 centimeters, the minimally invasive approach may still have worse oncologic outcomes. And certainly, this is a subsequent analysis that he compiled all of the literature for patients with less than 2 centimeters, and again, favoring the open surgical approach. And then lastly, microscopic disease. There are some who would suggest if you remove all of the tumor and all the margins are negative, clearly, there's not going to be a difference. Interestingly, what do we have in terms of data on patients that have very small microscopic tumors? This is a study on patients with stage 1a cervical cancer, and what he showed was, again, this is a national database study, and over 1,000 patients, nearly 2,000 patients that underwent this procedure, and the overall survival was comparable between laparoscopy and laparotomy. So, one of the things that is very important to highlight that in that study, the overwhelming majority of patients, three-quarters of the patients were actually stage 1a, so these were not even patients that would require a radical hysterectomy, and low-risk patients, over 80% of patients had no evidence of lymphovascular disease. So, it's important to highlight that when evaluating these studies of very small tumors, an overwhelming majority of patients were patients who actually did not need a radical hysterectomy anyway. This was a meta-analysis of over 9,000 patients by Roni Nitesky from MD Anderson, and again, what she showed was that when evaluating all of these retrospective studies, there were still outcomes in favor of open surgery for recurrences and all-cause mortality, and again, highlighting the fact that the minimally invasive surgery approach was associated with a higher risk of recurrence and death compared to open surgery. So, in conclusion, it has been shown that there were oncologic outcomes with minimally invasive surgery, similar outcomes pertaining to complications, similar outcomes pertaining to quality of life. All of the guidelines support the open surgery, and minimally invasive surgery should only be used in the setting of clinical trials. There are now three ongoing trials, one trial from China, another trial from Europe, which is the RAC trial, and another trial in the United States called the ROC trial. They're all evaluating open versus minimally invasive surgery. Those trials are ongoing and likely will have completion of those trials in 5 to 10 years from now. Lastly, again, as I wanted to mention, the overwhelming majority of the guidelines now suggest that the open approach should be the new standard of care. Thank you very much. That was great. So, thank you, Dr. Ramirez. Attendees, remember to submit your questions using the Q&A feature. And let's begin the Q&A portion with a poll for the attendees. So, what's considered the current standard of care for surgical management of patients with early stage cervical cancer, 1A2 to 1B2 FIGU 2018 classification? Just a few more moments for everyone who responded. Okay, so just wait about, we are now closing the poll. Okay, so Pedro. Hi, Raytan. Hey, how are you? Good to see you. Great to see you. So when, can you see the polls result? Yeah, so I saw the I saw the results. And, you know, it I think it's a very reflective of what we're seeing also here in in the United States where most institutions now offer the open approach for patients with cervical cancer. And I wanted to just obviously start addressing some of the questions in the interest of time. Because those are, I think, important questions that are coming up on the on the chat. One of the questions was the issue of colonization. And again, you know, it's very important to highlight that a colonization is not indicated for gross cervical disease. If you see a lesion, they teaches this all the way from residency, if you see a lesion, you don't need a comb, you all you need to do is get a biopsy, because that's already that's not a microscopic tumor. So I think it's important that we don't misinterpret some of the literature that is suggesting that patients who have a cone do better. Because, you know, certainly, we anticipate that patients that have a cone are going to do better, not because they have the cone. But because these are smaller microscopic tumors, when you compare that to a gross, large exophytic tumor. So therefore, the suggestion should not be let's do a cone to minimize the size of the tumor in terms of, you know, I've heard in one paper already, the term colonization debulking, which, you know, makes absolutely no sense, zero sense. So that should not be the message moving forward. You know, Arthur asked that, you know, do we do a vaginal protect, I mean, a vaginal protective maneuver for open radical hysterectomy. And we already do that when you put the clamps below the surveys to do the colpotomy. That's already a vaginal protective maneuver. So during open surgery, the tumor is not exposed to the abdominal cavity. So I think that that's important to highlight about the cone. There's another question regarding would you offer a minimally invasive surgery in a tumor smaller than two centimeters? The answer is no. In our institution, we don't perform any minimally invasive surgery for cervical cancer. Now, of course, in tumors less than two centimeters, we have the results of the CONSERVE trial. The CONSERVE trial showed that most likely those patients do not need a radical hysterectomy. So therefore, then the question is, well, would you do a laparoscopy on a patient in less than two centimeters if you're doing a simple hysterectomy? You know, certainly again, we don't have data to suggest that that is safe. We know that from the CONSERVE trial, 94% of patients had a laparoscopy. But again, it's a hundred patient study is not large enough to determine whether open versus minimally invasive is different. So we also have to wait for the SHAPE trial that will be comparing radical versus simple. And most likely most of those patients are going to have minimally invasive surgery. So certainly I'm interested in hearing those results as well. So those are those are points that I'd like to highlight. There's a question that says, what was the rationale in the LAC trial behind conization for tumors that were macroscopic? This was not part of the LAC trial. The LAC trial did not require conization for macroscopic tumor. Again, let me highlight, a gross tumor does not need a conization. So a patient with a gross tumor should not have a conization. So this was not part of the LAC trial. Does it make sense to use the knowledge in radical hysterectomy to define surgical approach for radical tricolectomy? That's a good, that's a great question. So we don't know. We offer patients open radical tricolectomies in our institution, based on the results of the LAC trial. The IRTA study, which is a retrospective, multi-institutional study, did not show any difference between open and minimally invasive surgery. But certainly again, I mean, it's a retrospective study. And we don't know if in a prospective fashion, this would be the same. For us to be safe, we perform open tricolectomies. So Pedro, for you, it doesn't make any sense to do a like conization if you are not sure radical hysterectomy is a good option. I mean, if you may believe that the patient will have set positive criteria for radiation, don't you feel like maybe doing a conization before the radical hysterectomy doesn't make any sense? No, I mean, as long as you have gross tumor, so basically, you know, the way we approach it, and I think that's the way this NCCN guidelines suggested, is that if you have a pap smear or a biopsy that tells you you have cervical cancer, and on your examination, you don't see anything, that patient should have a cone. If you see a patient that has any size lesion, you take a biopsy, you don't need to determine whether there is invasion or no invasion. I mean, that patient has a gross lesion already. So then that patient should have a radical hysterectomy or a radical trachelectomy based on their wish for future fertility. But we don't do conizations whenever you have gross tumor. Okay, so there are two questions from the Q&A. For survival analysis, can you sign new fever staging 2018 or 2021 to assess the outcomes in surgery done about 10 years ago? Okay, so this is a good question. Do you have? Okay, yeah. Yeah, I mean, you know, certainly the the FIGO staging has changed. Because obviously, now we classify patients less than two centimeters greater than two centimeters. Now, the survival analysis should not change because we didn't include patients greater than four centimeters in the in the lag trial. So basically, the survival outcomes are going to be the same on the interpretation of those of those studies. But again, I mean, you would only have a stratification by less than two and more than two centimeters. And again, our study was not designed to evaluate greater than two centimeters or less than two centimeters, we did not have a power analysis for those two groups of patients. But the FIGO staging shouldn't change the outcomes because, again, we didn't include anybody greater than two centimeters. There's a question also about, I'm sorry, what's that? I guess just we have a clear, more clear communication using the new FIGO staging. So it's about communication. Then Eric Estrada is asking, carcinomatosis rate is much higher in MIS. What are your thoughts regarding this issue? And he completes saying, since also there is literature also presented in open approach. Yeah, so right. So, you know, certainly the rates are much higher. Definitely the rates are higher. And it's something that we not not only we in the in the lag trial, but also other studies showed, you know, I mentioned the Giovanni Scambia study that showed that 42% of patients that had a recurrence had carcinomatosis. Most likely this is this is a related to the pneumoperitoneum and the and the spread of disease of gross disease through the through the abdominal cavity. So certainly it's something again, I mean, another reason why not performing the the minimally invasive approach. Okay, there's a question. What makes laparoscopy fear to open is due to tumor spread or, or not completely excised? No, I mean, we don't we don't think that is not completely excising it because we didn't have a difference in terms of rates of positive margins. Most likely it is because of the carcinomatosis. You know, our again, because our study was not designed to find the reason we don't know what the reason is, but most likely it is from tumor contamination and pneumoperitoneum. Okay. There's a Spanish question. I'm just trying to figure out. Okay, you can read it. Yeah, the the other thing is also is, you know, that they're in terms of one of the, go ahead. I'm sorry. Go ahead. No, no, no. There is one question sometimes I hear some some surgeon is saying, well, if you have a positive, you should abort the radical hysterectomy. So what if some people are doing they are doing laparoscopy to do the left anectomy, then they do frozen section. And if it's negative, they think then they completely diverge now approach the radical hysterectomy. How do you think about it? Yeah, so I was just actually in Austria. And that's part of the routine assessment, they, they do a laparoscopic evaluation of the lymph nodes first, then they do frozen section, and then they decide, you know, what to do. You know, one thought that I with regards to that approach is that when now when you're looking at patients that undergo a radical hysterectomy, the large majority of them do not have positive lymph nodes. So in other words, for example, in the conserved trial, less than two centimeter patients, the rate of positive lymph nodes was 5%. So that means you will be doing 95 unnecessary laparoscopies, frozen sections, and evaluation of those lymph nodes in patients with less than two centimeters. So again, that overwhelming majority are exposing the patient to procedures that most likely they don't need. Then the two to four centimeters, then those are the patients, you're going to have a higher rate of lymph node involvement, seven to 12% of, of lymph node involvement. Again, most of those involvement may, you know, certainly, when you look at those patients, the issue that our pathologists have is that they say when most likely, a good majority of those patients, we're not going to be able to tell you in frozen section, because they're going to have either isolated tumor cells or micrometastases. So therefore, we're not going to be able to tell you in frozen section. So in addition to that, in terms of the fear of grossly positive lymph nodes, now with pelvic MRIs and PET CTs, it is unlikely that you're going to have a surprise in the operating room. So therefore, we routinely do not perform a lymph node evaluation prior to the to the surgery. Good. So there are two questions that I think it's kind of connected. One, it's from Joel Loffer. It's what type of incision do you choose to open radical hysterectomy? And if you some clinical aspects for this decision, then we have another question. It's I think that's kind of connected. It's for patients with BMI more than 40. How do you proceed? Do you still do open? Do you choose a different approach? And for lymph node with not clear compromise in the image, do you still do the surgery if you would like it's in? It's not clear if it's just suspected or Yes. Yeah. So for the first question, we do a fan and steel incision. And, you know, either a fan and steel or a churning incision, we don't do a midline incision for open radical hysterectomies. Patients go home usually the next day after the surgery because they're on enhanced recovery. So either one or two days after the surgery, they will they will go home. For the obese patients. Again, let me highlight, let me stress that at MD Anderson, we do not perform minimally invasive surgery for anybody, no one. So even an obese patients, they will undergo a, an open radical hysterectomy. And again, of course, obviously, we look at all of the factors as we do for every other patient with regards to preoperative imaging, and in MRIs, PET, CTs, to determine if that patient actually does need a radical hysterectomy. But again, no minimally invasive surgery at MD Anderson for cervical cancer. And then I think your last question was on the lymph nodes. Yeah, but before that, just to continue with this rationale, are you doing open radical tracheotomy? Yes. Okay. So that's one of the questions. Then about when you have a lymph node that's not clearly metastatic, do you still do surgery? Or do you send for chemo radiation? Or how do you deal with those? No, if there is, if there is a suspicious lymph node, or nonspecific lymph node, what we do is we have a discussion with an interventional radiologist to see if they can get us a biopsy by CT guided biopsy, we have a great interventional radiology team. So they will often just do the biopsy for us prior to the surgery by CT guided. And if it shows that it's consistent with cancer, then yes, they go straight to chemo radiation. Okay, we have lots of questions. So I would like Pedro to to try to answer them on the Q&A. And I'm sorry, we don't have time. This is very exciting, but we have to move on. So thank you, Pedro. Thank you. Awesome presentation. Great to see you again. So our next presentation will be Dr. Lopez Blanco speaking about cervical cancer in pregnancy. Estimados colegas, reciban un cordial saludo. Soy el Dr. Aldo López Blanco, ginecólogo oncólogo del Instituto Nacional de Enfermedades Neoplásicas de Lima, Perú. En esta oportunidad voy a hablarles de cáncer de cerviz y gestación. Quiero agradecer al comité organizador de la ICCS, de la Sociedad de Internacional del Cáncer Ginecológico, por invitarme a dar esta charla. En verdad me siento muy complacido. Inviting me for this talk. To give this talk, I don't have disclosures. It's important to highlight the magnitude of the problem. We know that cervical cancer is a problem in Latin America. Second place in incidence, 56,000 new cases per year. And third in mortality with 28,000 new cases per year. Pregnancy and cervical cancer, it can be seen in 0.05, 0.01% of all the pregnancies. Its presentation is a little bit strange and less frequent. Along with the more frequent malignant neoplasia is breast cancer followed by cervical cancer, hematologic and melanoma neoplasias represent 70% of cancers associated with pregnancy. Here we see a pie chart and shows the cancers associated with pregnancy. And we see breast cancer in first place and cervical cancer in second place. In this graph, we see all the neoplasias associated to pregnancy. Among them we see here cervical cancer. And in the colors here we see the staging of the disease. In here we see that cervical cancer associated to pregnancy is seen in early stages. What is different from non pregnant women that frequently it is diagnosed in advanced stages. Here we see the frequency of gynecological cancers during pregnancy. First place is cervical cancer, then ovarian cancer, then borderline ovarian masses, vulva and vaginal cancer. Other general considerations, like we saw in the previous slides, gynecological cancer, that's more commonly diagnosed during pregnancy, cervical cancer, it is rare. And the treatment is challenging and complex because the treatment can affect the oncological prognosis of the mother. Also, we have to analyze that teratogenic risk and intrauterine growth retardation, even death of the fetus. And when we do studies or by the use of chemo radiotherapy, that prognosis of uterine cervix is the same in pregnant and non pregnant women. These kind of patients must be referred to specialized center for multidisciplinary treatment. During the treatment, we have to include the oncologist, gynecologist, the clinical oncologist, radiotherapist, pathologist, neonatologist, OBGYN, psychologist, and the patient. It is very important to listen to the patient to define treatment. It is important to analyze the context of the regulation and the laws of each countries or each region for this treatment. Among the diagnostic studies and extension studies, it's important to consider that these studies may affect the development of the fetus. The exposure to radiation must not be above 100 milligrams. It has been reported that the incidence of cancer throughout the lifetime for a doses of 50 milligrams, it is calculated approximately 2% if the fetus is exposed after 15 weeks of pregnancy, but in an exact quantification is almost impossible. So the procedures of images that are non ionizing, such as ultrasound and MRI are safe techniques for pregnant women. And about gadolinium, we do not know that there are teratogenic effects of gadolinium. So it is not recommended in pregnant women. So to consider the treatment, we have to analyze if there is no compromise the size of the tumor, the histological stage, the staging of the disease, and gestational age to determine the treatment. We have different options of treatment. One is delayed treatment after the pregnancy is over, or end the pregnancy to do a definitive treatment for cancer or surgical treatment. Preserving the pregnancy like conization, simple or radical trachelectomy without lymphadectomy, or neoadjuvant chemotherapy could be used while we preserve gestation until the fetus is feasible. There are several expert guidelines. Here are the most important ones. This one is ESMO, published in 2019. Here we see two groups. The first group is patients with less than 22 weeks of pregnancy staging 1A1, just a simple cone. If the lymphovascular permeabilization is negative in tumors less than two centimeters, 1A1 plus 1A2 and 1B1 lymphadenectomy, pelvic lymphadenectomy. If the nodes are negative, observation and neoadjuvant chemotherapy, they are positive, including micrometastasis and end the pregnancy. 1B2 is pelvic lymphadenectomy, is neoadjuvant chemotherapy. Stage 1B3, neoadjuvant chemotherapy. Lymphadenectomy is controversial in staging. 2B is to end pregnancy. And it is important to highlight that some experts about pelvic lymphadenectomy, they have a lot of controversies to its use. In the other group, group two, in women greater than 22 weeks of pregnancy, in the early stages, neoadjuvant chemotherapy versus observation. It depends on what week the patient is in and the risk of disease progression. In greater stages of 2B, it's recommended to end the pregnancy, or it could be optional if the patient wants to continue with the pregnancy, neoadjuvant chemotherapy until the pregnancy is over. This is a summary of the previous slides. Here we highlight in red, inpatient with early stages associated to pregnancies. If they have less than 22 weeks pregnancy, it is recommended pelvic lymphadenectomy because this patient might just be observed and its initial stages, and we have to decrease the node compromise. Here, as part of the staging, the pelvic lymphadenectomy is very controversial. And here in green, we see the use of neoadjuvant chemotherapy in different scenarios. Here, a little bit about neoadjuvant chemotherapy during pregnancy, and there are many series published about this and small reports of cases. But among these, it's the fear about the effects of chemotherapy on the fetus. It's important to highlight that it is contraindicated in the first trimester of pregnancy because it can be associated 10, 20% to congenital malformation. After the 14 weeks of gestation, it can be used like taxons, platen, antracyclines, ectoposid, and bleomycin. There are several studies that speak about the rate of fetal malformation, and it is comparable to the general population. So chemotherapy can be used after the first trimester of pregnancy. It is important to consider that there should be a window between chemotherapy and the delivery to recover the bone marrow. It's important to consider the ototoxic effects of cisplatinum, depending on the dosage. And they say that carboplatin is safer. Also consider the relative effect, the myelotoxic effect of etoposid, and consider the cardiotoxic effects of antracyclines. Data about toxicity in the long-term after the exposure of chemotherapy in children with cancer. We have seen cardiotoxicity, hearing loss, neurocognitive problems, endocrine, affection, and a secondary neoplasia, and an increase in mobility. So it is not clear if the effects and the exposure of intrauterine chemotherapy are similar to the effects of exposure in small children with cancer. That is why it's so important, the follow-up. This is a big series published by Dr. Lancheron in 2015, where he gathers 39 cases of cervical cancer, a small series where more than 60% of the patients have advanced staging. Most of the patient had response to chemotherapy, allowing the pregnancy to finish. The most used drug is cisplatin, even though the duration of the treatment varied among the authors. And one of the conclusions is that fetal well-being, it was not compromised in none of the cases. Also, there are other series that speak about the safety of toxins during the second and third trimester of pregnancy as a safe option. There's a publication of 2018 where they include 39 studies or case record, 88 patients with cervical cancer, where they administrated platinum during the pregnancy. 88 were newborn out of 84 pregnancies. Among of all the newborns, 80% were totally healthy. At the end of the follow-up, around 20% of the patients were diagnosed with recurrence of cervical cancer, and 90% of them died because of the recurrence. One of the problems or the observations was that they did not reach the global survival median or progression-free survival in the series reported because of the short follow-up. These results showed that neoadjuvant chemotherapy based on cisplatinum can be favorable for patients with cervical cancer during the second and third trimesters. We published a study, a retrospective cases in Latin America chemotherapy, neoadjuvant chemotherapy, associated to patients with cervical cancer. It was a multi-centric Latin American study, and we wanted to describe the oncologic and obstetrical resistance of the neoadjuvant chemotherapy to patients with cervical cancer. It was a multi-centric Latin American study, and we wanted to describe the oncologic and obstetrical results of patients diagnosed with delivery after chemotherapy. The inclusion criteria were patient with cervical cancer 1B1 and 4A, according to FIGO2009, associated to pregnancy that received chemotherapy. There were 12 centers out of five countries that participated in this study. At the end, we gathered 33 patients. Here we see the average age was 34 years. Most of them, 60% had early stages, 1B, locally advanced, 40%. The most frequent histology was FAMUS with 90%. Most of the patients were diagnosed in the second trimester. 33% in the first trimester, and 6% in the third trimester. The images more used was the MRI with ultrasound in 90% of the cases. The neoadjuvant treatment was the most used with carboplatin and plaquete-like cells, 60%, and cisplatin and plaquete-like cells in 20%. Toxicity was only reported in 18% of the cases. About the neoadjuvant chemotherapy response, here we see stable, partial response, complete response, 27% among the obstetric results. There were obstetric diseases in 12% of the cases. 70% of the cases did not manifest obstetric disease. The gestational age at delivery was 35 weeks. The delivery, all were cesarean sections. Average weight was 2,340 kilograms. The height was 45.5 centimeters. And other characteristics that were comparable to the previous reports. About the definitive oncology treatment, almost 33% of the patients had radical hysterectomy, and chemo plus radiotherapy, 57% of the patients. Those that had radical hysterectomy, half were intrapartum and half were postponed postpartum. Patients that had radical hysterectomy that require adjuvant treatment was only 25% of the patients. In summary, the average age was 34 years. In this series, 90% was epidermoid carcinoma, 60% 1B staging, 60% were seen in the second trimester. The more used chemotherapy was carboplatin plus paclitaxel and cisplatinum and paclitaxel. The number of chemotherapy cycles were three and four. 86% of the patients are still alive. What were the weaknesses of the study? It's a retrospective study, and it's a small group of patients. And it's the biggest retrospective series up to now. It was a short follow-up, and the selection criteria were very heterogeneous. The strength of the study is that it's a retrospective, multicentric study of cervical cancer in pregnancy. And it was found that new adjuvant chemotherapy is an alternative to achieve fetal feasibility about our center. It's a reference center of Peru. How do we treat cervical cancer? We do multidisciplinary boards where we have different specialties. We use carboplatinum and paclitaxel every 21 days. We start adjuvant chemotherapy after the 14th week. To do the staging, we use MRI of abdomen and pelvis, and we do restaging after the pregnancy is finished, if it's operable. Then we defer the radical surgery after. As final recommendation, the treatment is challenging and complex because the treatment can affect the oncological prognosis of the mother. Also, we should include the therapeutic effects of the oncologic treatment. That is why we have to refer the patient to a specialized center for a multidisciplinary approach. It's important to consider the opinion of the mother. Also, the age of the pregnancy influences the staging of the disease. The evidence is based on case studies, retrospective studies, and experts' opinions. It is not feasible to do prospective study in this group of patients, so we are always going to have the level of evidence that it's not that high compared with a prospective phase 3 study. No adjuvant chemotherapy in cervical cancer, it's a treatment option. To finish the pregnancy without compromising the oncologic results and with minimum effects in the newborn, but we need more studies, a follow-up of these kind of patients that were exposed to intrauterine chemotherapy. Thank you so much for your attention. If there are any questions, I am available. So, thank you so much, Dr. Blanco. Thank you so much. So, some significant factors should be considered when evaluating pregnant women with cervical cancer. In your opinion, which is the correct option? So, we will wait about 30 seconds for answers to come in. Just a few more seconds. Seconds. Okay. Okay, can we see the answer, the results? Wow, this is a split decision. So, Aldo, hermano, when you are evaluating a patient who is pregnant with cervical cancer, what do you think is the incorrect option? Because here we are divided. So, it's a divided answer. So, are you seeing the response? It's a little bit divided. Thank you, Reitan, for sharing the survey. First, what we have of evidence in cervical cancer in pregnancy is more of a case report and expert's opinion. And like you have seen, some reviews with the biggest revision is not over 100 cases. So, we are going to have a lot of discrepancies and none of these recommendations have strong evidence. So, it is complex to treat. And the treatment of these patients is challenging and that's why we need them to be referred to a big center that is specialized and has multiple specialists. Aldo, on other surveys, how many cycles of chemotherapy for pregnant women in general? If we are going to use chemotherapy after 14 weeks of pregnancy, we do chemotherapy until the fetus is mature. Three, four cycles of chemo, maybe five, and that's what we have seen in the reports. It's also important to consider that there should be a window of three weeks after finishing the pregnancy because of the depression of the bone marrow so that it can recover. Not of the mother so much, but of the fetus recovering. The six weeks waiting after the cesarean section is why so long. In most of the series, this is not reported. There could be problems because of the depression of the bone marrow, but in the series that we published, we haven't had that kind of problems. We haven't seen problems in the newborn. When you have cervical cancer and a mass in the same patient, what do you do, Aldo? The CA-125 is high and there's a suspicion of an ovarian metastasis. Do you consider to do chemotherapy or radical hysterectomy, or you prefer to do first the ophorectomy and do the diagnosis of the ovarian mass? It's important to consider in cervical cancer, most of the reports recommend to keep the pregnancy in early stages. If we have the suspicion of advanced staging, we have to prioritize the mother and the patient has to go to surgery to rule out if it's a primary tumor of the cervix. We do a laparotomy and we study the anexal mass. If it's a metastasis, the prognosis is very bad and we prioritize the treatment of the mother. Dr. Hussein, if there's an early diagnosis of cervical cancer, then should you do a radical hysterectomy with the fetus in situ? At what age would you do it? Because of the legislation, it has to do with the legal norms. The legislation in Peru, it is indicated abortion when there is an imminent risk for the mother. In this case, the health of the mother is not at risk because it's just an initial cancer, an early cancer, and the guides do not recommend that. With the neoadjuvant chemotherapy that is being used more and more, we would not do what you're saying. What we do, if we have a patient in early stages of cervical cancer, like the guidelines say, and it's less than two centimeters tumor in gestational age in the first trimester, we observe the patient so that the disease won't progress. We just observe the patient. If the tumor grows and the gestation is more than 14 weeks, we could use neoadjuvant chemotherapy. One last question. In the complication of pregnant women in cervical cancer, especially bleeding of the tumor, how do you treat during pregnancy this? Obviously, with compressive treatment, compression treatment, we have frequent cases of cervical cancer associated to pregnancy, but we have not had these kind of problems very frequently. Maybe just mechanical treatment, and if that doesn't correct the problem and the health of the mother is at stake, then we have to do something as an emergency treatment. If it's a bleeding that cannot be stopped with mechanical and mechanical maneuvers, then we could do emergency radiotherapy. Excuse me. I see that there's a question. Why do we do hysterectomy six weeks after the pregnancy is over? And there's also discrepancy in experts. If we do it immediately after the cesarean section, the anatomy has changed and the vessels are pretty big, so there can be bleeding, so we wait. Sometimes in the general hospitals where we refer the patients and we don't have this kind of equipment, that's why we do it after six weeks of pregnancy and the uterus is at normal size and the risk of bleeding is less, and this would not influence the oncologic prognosis of the patient. Okay, so I'm sorry, but we have to move forward. We have a small issue with the transmission of Dr. Lema, so we are going to go to the break, then we have five minutes, and we'll be right back for the next presentation. So see you in five. I am the scientific director of the Clinica Oncologia Storga in Medellin, Colombia. I wish to thank the IGCS and my dear friend René Pareja for this invitation. Over the next few minutes, I will discuss the state of art of immunotherapy in cervical cancer. These are my conflicts of interest, non-pertaining to our talk. According to guidelines, non-metastatic cervical cancer is treated with either surgery or chemoradiation therapy. Systemic therapy becomes the mainstay of treatment in metastatic relapse and recurrent disease. The addition of bevacizumab to chemotherapy in first line, or as a single agent in later lines, became the last significant advance prior to the immunotherapy era. And it was based on the GOG240, a phase III trial that compared chemotherapy alone versus chemotherapy plus bevacizumab in the first-line setting. An overall survival advantage was demonstrated in the bevacizumab arm with a medium overall survival of 16 months, a three-month improvement over chemo alone. Cancer cells are allowed to proliferate when T-cells are hindered by the so-called immune checkpoints. One such T-cell inhibitory system stems from the interaction of PD-1 in the T-cells and PD-L1 in both the tumor and tumor-infiltrating mononuclear cells, including lymphocytes and macrophages. The disruption of the PD-1-PD-L1 axis can potentially restore anti-tumor T-cell activity. This can be achieved with anti-PD-1 monoclonal antibodies such as pembrolizumab, nivolumab, balstilimab, camrylizumab, and cepilimab. In many disease settings, anti-PD-L1 agents such as atezolizumab or durvalumab are also effective. Immune checkpoint inhibitors is the basis of current immunotherapy in cancer. Immunosuppression has been postulated as a mechanism for tumor invasion in HPV-related neoplasms, including cervical cancer. These include tumor infiltration by immune-suppressive mononuclear cells and PD-L1 overexpression, among others. This immunosuppressive milieu forms the basis for immunotherapy as a strategy in cervical cancer. As it is often the case in oncology, paradigm changes begin at the end of the clinical spectrum, such as second- or third-line therapy. If effective, they steadily move to first-line therapy and even into the non-metastatic setting. We will briefly discuss some key trials of immunotherapy beyond first-line in cervical cancer. Keynote 158 is a basket trial that included a cohort of 98 cervical cancer patients that had progressed or were intolerant to first-line therapy. Patients received pembrolizumab and anti-PD-L1 monoclonal antibody every 3 weeks for up to 2 years. Their primary endpoint was overall response rate. Key patient characteristics included a median age of 46, Zikoc 1 in 65%, PD-L1 positive in 83%. Close to 80% of the treatment population had received more than one line in the metastatic setting. In total, objective response was achieved in 14 patients, or 14%. There were 5 complete responses. All of the responses occurred in the PD-L1 group, based on the combined positive score, or CPS. Anti-PD-L1 is assayed in the tumor sample, which is comprised by tumor cells and mononuclear cells. A formula will provide a number. PD-L1 is deemed positive if CPS is 1 or greater. Back to Keynote 158, median progression-free survival and overall survival were 2 and 9.4 months respectively. Toxicity was acceptable. With these results, the FDA granted approval for PD-L1 positive cervical cancer in the second line and beyond. Balstelimab, another anti-PD-L1, was tested in 161 patients in a Phase II trial. Patient characteristics of this trial are shown in the slide. Again, there was a preponderance of young symptomatic patient population, most of them pre-treated for metastatic disease. The agent was effective, as shown in the graphs. Overall response rate was similar to Keynote 158 and no new safety signals were found. Of note, there were some responses in the PD-L1 negative patient population. Also in the second line setting was the CLABS study conducted in China. In the CLABS study, 45 patients were enrolled and 41 patients received the anti-PD-1 camrylizumab plus apatinib, an oral anti-angiogenic agent. Response rate of the combination was 55%. The combination was associated with significant grade III for toxicity of 71%, probably derived from the anti-angiogenic agent. Patient characteristics of these three trials are somewhat similar. So are the main outcomes, with exception of the overall response rate in the CLABS study that included another potentially active component. The combination of anti-PD-L1 and anti-angiogenic agent was explored in this small cohort of 11 patients treated with atezolizumab and anti-PD-L1 agent plus bevacizumab. With no confirmed responses, the study was deemed negative. The only phase III trial of immunotherapy in the pretreated setting is the EMPOWER Cervical-1 trial. Semiplimab, another anti-PD-1 monoclonal antibody, was studied against the investigator's choice chemotherapy. The primary endpoint was overall safety. The trial recruited 608 patients, including a significant minority of adenocarcinomas. EMPOWER Cervical-1 was positive with a 3.5-month improvement in overall survival over the control arm. The median overall survival in the experimental arm was 12 months. The survival benefit was observed across both histologies. But benefit appeared to be restricted to the PD-L1-positive population. Notwithstanding, the authors concluded that semiplimab was active regardless of the PD-L1 status. Based on these trials, the study was deemed positive. The study was deemed positive. Based on these trials... can conclude that there is a plethora of active anti-PD-1 agents in the pre-treated cervical cancer patient population. Now let us move to the first-line setting. Keynote 826 is the only phase 3 trial published to date in first-line metastatic setting in cervical cancer. The trial enrolled 617 patients with metastatic relapsed or recurrent cervical cancer with no prior systemic therapy for metastatic disease. The patients were stratified according to PD-L1 expression among other variables. The control arm was standard chemotherapy with or without bevacizumab. Pembrolizumab was added to chemotherapy in the experimental arm. The dual primary endpoints were progression-free survival and overall survival. Keynote 826 recruited a young population. About half had symptomatic disease. Almost 90% of the patients enrolled were PD-L1 positive. A 35% improvement in progression-free survival was observed in the Pembrolizumab arm in the intention to treat analysis. Overall response rate was also higher in the Pembrolizumab containing arm. 65% in the experimental and 50% in the control arm obtained complete or partial responses respectively. Treatment-related toxicities were similar in both arms with expected immune-related adverse reactions in the Pembrolizumab containing arm. Even though the results are still immature, overall survival is superior in the Pembrolizumab arm. The overall survival in this arm is estimated at 24 months, an important improvement over the 16-month mark established by the GOG-240 trial. Keynote 826 is a practice-changing trial and the FDA granted approval for Pembrolizumab with chemotherapy in PD-L1 positive cervical cancer patients in the first-line metastatic setting. This is the state-of-the-art. There are several ongoing trials involving immune checkpoint inhibitors in cervical cancer. Some of these are exploring the addition of either anti-PD-1 or anti-PD-L1 agents in the locally advanced, that is, in the non-metastatic setting. I'm very fortunate to say that in our center we were able to enroll five patients in one of them, the keynote 818, with Dr. Diego Moran as the principal investigator and with the help of René Pareja. Some other key interesting avenues are also being studied. In conclusion, anti-PD-1 monoclonal antibodies have demonstrated anti-tumor activity both as single agents and in combination in patients with advanced cervical cancer. Regulatory approval in the United States for Pembrolizumab was granted for PD-L1 positive patients. Pembrolizumab has been included in the NCCN practice guidelines. If regulation and access were not an issue, I would incorporate anti-PD-1 agents using this tentative algorithm. In short, I would use Pembrolizumab in first- or second-line therapy for patients with PD-L1 positive disease and I would even consider the use of Semiprimab if approved in the second-line setting in patients even without PD-L1 positive disease as there's some evidence of activity. But that if is almost impossible to overcome. And with that I want to thank you all. Thank you Dr. Lema. Let's begin with the Q&A portion with Apu for the attendees. So immunotherapy in cervical cancer has been proven to be effective in randomized controlled phase 3 trials in the follow-up scenarios. So choose one of those. We are waiting just a little bit for more people can vote. Okay, so Dr. Lemma, I think most people, oh, it's a split decision also, it's only most people, 30% respond only in PD-L1 positive disease. So let me know your thoughts about it. Actually the true response that I was expecting is that along with the cytotoxic chemotherapy in first line setting, that was the expected response that I thought was positive. But I can understand why the audience chose only in PD-L1 positive because that's what the FDA has granted approval for. And most of the trials, most of the trials do have a very clear demarcation in the response rates in PD-L1 positive patients. But not only PD-L1 patients, there's some data in PD-L1 negative patients also have some response, specifically in the SEMIPLIMAP trial, the CLAP trial, there was some rather important responses in PD-L1 negative patients. So the one that I was expecting was C, but I can live with B. Okay, and there's a question from Dr. Lozano, do you think Bevacizumab adds any benefit when using Pembrolizumab in the first line setting, or will you use it without Bevacizumab? Well actually, I don't have access to Pembrolizumab in my country for cervical cancer, so this is a very truly hypothetical question to me, but I would probably wouldn't add Bevacizumab to Pembrolizumab. I would use only chemotherapy plus Pembrolizumab. Okay, good. So if the attendees have any questions, you can send through the Q&A feature, it's in the bottom of your screen. But if I can say something before any question is a comment, is that one thing is for sure, is that immunotherapy has a role in cervical cancer patients, especially in the advanced setting, and I'm almost sure that the studies that are being conducted in the local advanced setting are going to be positive as well. And so what Audrey is asking, which are the future perspectives of immunotherapy in cervical cancer, and how far do you think it is from Latin American patients, how do you see we using it in the near future? Well there are some access issues because these agents are particularly expensive, and that can be a barrier to the incorporation of these agents, but I think that in the end, at least in Colombia, I would expect that the regulatory agency will eventually include the Pembrolizumab because it's done so to a host of other disease settings, with results that are even less remarkable than the ones in the keynote date 26. So I would expect to be one standard of care, but in Colombia it takes, the lag time is about two years between the FDA approval and the, in VIMA, our regulatory approval agency. So I would say that by 2023 we might be able to use it in first-line setting, and whether it can be used along with chemoradiation therapy, it depends on the results of the trials that are ongoing. Yeah, in Brazil we also have this small gap for private practice, but in the public health system it usually takes like 10 years, that's the time lapse between getting to the private sector then going to the public health care. So and that's what, there are those, Brazilian, in Montreal now, he's asking how do you feel about the financial issues and about using immuno. I think that's it, we have to solve this question, right? Dr. Miguel Correa is asking, the results of immunotherapy are better in some kind of histological cancers? There are lots of histologies that are included in all these trials, obviously the preponderance of squamous cell tumors, but it appears to work also in adenocarcinomas. The only one that I wouldn't use is in small cell, in a neuroendocrine histology, I would probably not use it in that particular setting. So Florencia from Argentina, she's asking you, so she is congratulating for your presentation and her question is, what's the time that you consider appropriate to wait between radiotherapy as a treatment for local management and the administration of pembro, there is a time? Well, no, I don't, I actually, I mean, pembrolizumab is not, right now it's not expected to be used after radiotherapy or with radiotherapy, so, but the time lag that I use in other disease settings when I'm going to use pembrolizumab is about two weeks after finishing radiation therapy, mostly for concerns that I think that are not related to pembrolizumab itself, but because I tend to use that lag for when I'm using cytotoxic agents, I'm pretty sure that we could use pembrolizumab very close to radiation therapy, even with radiation therapy, but I'm a little afraid of doing that. Okay, so we are a little short of time, so we have two more questions and then Dr. Lemo will respond to other questions on the chat. So when, in which patients with cervical cancer, metastatic cervical cancer, would you use bevacizumab? Well, if right now in everyone, pretty much, I would use the DoD 240 inclusion criteria for using them, bevacizumab, because I don't have access to pembro and I do think that the DoD 240 was a practice changing, nothing has been better than that ever since it was published. So, at this moment, I would add bevacizumab to pretty much all chemotherapy backbones in the, at least at the first line setting in chemotherapy. Most of the time, I use a platinum plus paclitaxel backbone as it was used also in the DoD trial. Okay, last question, it's Dr. Xiao, he's asking when you have a recurring cervical cancer progression after anti-PD-1 and bevacizumab with chemo, what are your suggestions? Well, if we are now in second line, it's actual progression, I would probably consider some other agents such as stopotecan, I guess, but we know that the issue is not, I mean, the patient is not likely to do well. I've had some responses with a combination of platinum plus gemcitabine, I know it's platinum refractory, but I think that gemcitabine by itself doesn't add too much, so I give a little AUC of platinum and gemcitabine and I've had some short-lived responses, most of those patients don't fare well. So thank you so much, Dr. Lema, and we are moving forward. So our next presentation will be Dr. Anuja Gingram about advances in radiation oncology for cervical cancer. Good morning, everyone. Today I'm going to be talking about advances in radiation therapy in cervix cancer. And for those who know me, you know I have to start off with a story, so we'll start off with a story. So as we all know, radiation therapy is the mainstay treatment for advanced cervix cancer. The principles of radiation therapy include that you need to include all the volume that is known and all the microscopic extensions. You have to give sufficient dose, so you need to give 85 to 90 gray, 2.8, or the high-risk CTV, which I'm going to talk about later today. Brachytherapy is really important and must be used whenever possible, and the overall treatment time should not prolong beyond 56 days. So this is just, as I said, we start off with a story, right? So the starting of the story is that cervical cancer is cured by radiation therapy alone. As we can see, this is data actually pre-chemo that shows you that radiation therapy alone really works well, even for stage 3 disease. With stage 3 disease, radiation therapy alone resulted in a 70% local control rate and a 50% overall survival, right? So just for stage 3, radiation therapy worked alone. However, radiation therapy did cause complications. So 10-year overall look at our patients of about 4,000 patients, grade 3 or higher toxicity, all type, radiation therapy resulted in 11% long-term complications. And as we all know, in 1999, several studies showed that chemo-radiation was better than radiation therapy alone. And as you can see, the benefit was highest in stage 1 and 2s, but it also benefits stage 3s, but by only 3%. So the big question is, and why I'm giving this talk is, how can we improve, right? So the conclusion was chemo-radiation therapy was better than radiation therapy, but the benefit wasn't as high for stage 3, and there was still room for improvement in stage 2. We also know by modern data, there's about a 14-21% distant visceral relapse rate after chemo-radiation, a 9-12% periodic relapse rate after chemo-radiation, and a 13% pelvic failure rate after chemo-radiation. And as I've already shown you, radiation therapy does increase toxicity, especially bowel. So the big question is, how can we improve? And which is the whole point of my talk today. So how can we improve? The biggest improvement that we have in radiation oncology is in investments in technology. So this was our old field, the 3D conformal field, which we all are very familiar with. What was a disadvantage of the 3D conformal fields, which is what caused our bowel toxicity? We treated all the bowel to the full dose. So this is where IMRT comes in. And I know you guys have already heard about IMRT, but I just want to talk about it again, because really, this is one of our major advancements, right? So this is actually a randomized trial looking at IMRT in post-op cervix and intermedial cancers. So patients were treated with IMRT or 3D conformal. And what we found was outcomes were the same between the two. So that was great. But this was the most important thing. Patients who got IMRT, and what this trial looked at was patient-reported outcomes, so that's even more important. Patients who received IMRT reported less diarrhea, less use of Imodium or Lamodil than patients who got 3D conformal during treatment and one year after treatment. They also really interestingly reported less urinary toxicity, specifically after treatment, and then three years after treatment. So the conclusion is that IMRT reduces patient-reported outcomes, both acute and late, both GI and GU, without affecting local control or overall survival. So IMRT has become the standard of care, both for post-op cervix as well as intact cervix in the U.S. and in Europe. EMBRACE-2, which is a prospective database study that has just completed, only used IMRT slash VMAT in their patients. And the goal of EMBRACE-2, which we should have results soon, is to reduce toxicity and improve local control. So moving on to brachytherapy, because we are talking about improved technology. One, as I've already said, brachytherapy is really important in the treatment of cervix cancer. A database study showed that there's been a decline in the use of brachytherapy since about 2003. And this is really when IMRT came into play. And what this database showed is that patients who got brachytherapy did much better than the patients who got no brachytherapy. So the important point of this is, again, brachytherapy very important in the treatment of cervix cancer. And again, just showing you decrease in the utilization of brachytherapy, a decrease in survival. Okay, so brachytherapy really important. So what are the advances in brachytherapy? And for some people we know we went from plain films to 3D, to MRI, to 3D, which includes both CT and MRI. The advantage of image guided brachytherapy is that you can see the tumor and you can see the normal anatomy. So we're going away from 2D and we're going to 3D even in brachytherapy. So advantages of image guided brachytherapy is we can define the disease, we can define the normal tissue and we can shape based on what we see and not on bony landmarks or thoughts of where the disease is. This is just an example of an MRI in a patient with cervix cancer and what we as radiation therapists outline. And what we see here, this is what we call the intermediate risk disease, which is really your point B. Here is your high risk CTV and that's your cervix plus your perimetrium. And this is your GTV. So we actually can now outline and see exactly what we have to give dose to. We can also see the normal tissues, right? Here's the sigmoid, here's the rectum, here's the bladder. So then we also know exactly where the doses are. And in fact, data shows that image guided brachytherapy improves local control, improves overall survival and reduces toxicity. But the biggest advantage is we can see the disease, right? So we can see, look, there's residual disease here. And if we did standard treatment, we would overdose the sigmoid or the rectum. And this is where interstitial needles have come in. You put needles directly into that. So you treat the disease without over-treating your normal tissue. Again, another example of where the needles come in, you can see there's residual posterior disease. If we just treated it with tandem monovoids or tandem rings, we would have had to push the dose out, which would have treated the sigmoid and the rectum. By putting these needles in, we can load those needles and not treat the normal tissue. So again, another advantage of image guided brachytherapy is you can see, right? So you can actually treat a patient individually. And in fact, we have shown that interstitial brachytherapy plus tandem monovoids or tandem and ring improves local control. But the key is it improves toxicity, improved both bladder toxicity and bowel toxicity. So this is a combination of intercavitary plus interstitial. And this is just data comparing intercavitary alone plus versus intercavitary plus interstitial. And you can see it reduces both bladder and rectal toxicity. So the big advantage of image guided brachytherapy is that we're starting to add more needles to areas that we need and reducing toxicity. We've also changed our idea on what doses we can give and what doses we should give compared to what ICRU did. So we are changing our dosing. So as you can see, the rectal dosing has been reduced. So now we have to keep the rectum less than 65. We're looking at the vaginal dose and we have increased our dose to the high risk CTV. So what image guided brachytherapy has done is this helped us identify the tumors, whether it's an external beam or in brachytherapy. So it has allowed us to identify the tumor, has allowed us to identify the microscopic disease as well as normal tissue, which has allowed us to conform the dose around the areas we want and reduce the dose of the normal tissue. So what it has allowed us to do is reduce acute and long-term toxicity and hopefully improve local control and maybe dose escalation. So IMRT-V MAT is now become pretty much a standard for external beam for intact cervix, both in Europe and U.S. and other places where it's available, including India. Image guided brachytherapy is now the gold standard for all patients with cervical cancer if it's available in your country. It helps identify the disease and it helps us identify and conform the dose. Interstitial is actually recommended and in embraced two, 30% of the patients should have been treated with interstitial. And actually the long-term data shows that actually 70% of the embraced two patients were treated with a combination of intercavitary and interstitial. So that's really one of the biggest advantages we've had in radiation therapy. And this has allowed us to improve the quality of life of our patients and reduce toxicity. So where else can we take this new technology, right? Well, is brachytherapy important? And as I already showed you that brachytherapy is important. And what was happening in America at least was when IMRT came in, brachytherapy was the use of brachytherapy was reduced and it did change the survival, but it can be used, right? IMRT or SBRT can be used if you can't use brachytherapy. And there are situations when you can't. And this is just, you know, the technique would be you would get 30 gray and five to six fractions. And this is just an example and a picture of SBRT in place of brachytherapy. And yes, you can give conformal doses using SBRT to the cervix that are comparable to brachytherapy. The disadvantage of the SBRT is brachytherapy gives you hotspots inside the disease, which increases the dose to that disease, which SBRT doesn't. SBRT is much more conformal. So actually there's probably less dose to the disease using SBRT than it is using brachytherapy. But the data does show that SBRT can be used, but you can see local control is definitely a lot less than if you use brachytherapy, but it is reasonable if you don't have brachytherapy or if the patient cannot receive brachytherapy because of poor response. So in conclusion, brachytherapy is the right treatment, period. But SBRT can be used in place of brachytherapy if you have poor response or if you don't have brachytherapy available, but it has to be done carefully and has to be planned. So what is our biggest and most, and more forwarding improvement in radiation therapy? And that is really in the treatment of metastatic disease. So one, and this is actually really an interesting study that I wanna show you because I think this is really relevant, especially in most of the world, right? And this is in metastatic disease. This is actually a national cancer database study that looked at definitive pelvic RT. So this is definitive pelvic RT plus brachytherapy, right? In patients with metastatic disease, there were 3,000 patients. And of those 900 received chemotherapy alone and the rest received chemotherapy plus radiation therapy. And what they found in this database study was that the patients who received definitive chemo RT did better in overall survival than the patients who received chemotherapy alone. So as you can see, even here in all patients, so this is the chemotherapy RT arm compared to the chemotherapy arm, right? The chemo RT patients did much better in overall survival than the chemotherapy arm. And this is just matched. So these are patients who are matched based on factors, right? Again, chemo RT did better than chemotherapy in overall survival. So even in metastatic disease, adding definitive chemo RT in some patients would really improve your overall survival. But how about oligometastatic disease? So this is actually really important, both in the era of immunotherapy as well as in the era of bevacizumab, right? So all the data really started from these four trials that were presented from 2017 to 2019. And all these trials, not in GYN tumors, showed that patient who had oligometastatic disease, who received systemic therapy, right? And if you added radiation therapy to systemic therapy to those oligometastatic disease, the patients who received the radiation therapy did better than the patients who received just systemic therapy. Key is these are all very small trials, 49 patients, 29 patients, 62 patients, 99. But it did show that maybe treating those oligometastatic disease with radiation and ablating them, adding systemic therapy may be better than just systemic therapy alone. And this just shows you a case presentation of a patient who was treated with definitive chemo radiation. And you can see all image-guided brachytherapy and external beam. Patient fails, patient fails one in the liver, right? So you can see the liver lesion right here, treated with stereotactic radiation therapy. Another lesion in the liver, treated with stereotactic radiation therapy. Also had red meths right here and right here, all treated. And this actually patient did, and the patient then received systemic therapy as well. And he actually is alive five years later and doing very well. Just an example, but good case, right? There is actually data that does show that treating the oligomets may improve survival. And this is just one of many studies that looked at cervical cancer patients. This is a study done in Italy, 83 cervix patients. Majority of the cases were lymph nodes, but about 44% had parenchymal metastatic disease. The medium dose was 35 gray, 10 gray to 60 gray and five fractions. Complete response, almost 60%. So 46 patients had a complete response. 29 patients had a partial response and 16 patients had a stable response. Toxicity was very mild. 19% had mild acute toxicity and 5% had late toxicity. The conclusion from this study was that there actually was a link between complete response to improve local control, progression-free survival and overall survival. The other thing that they concluded was that it delayed systemic therapy, usually by two lines. So it could be two to three years if the patient did recur before they needed systemic therapy again. The last conclusion from this study, which I do think is most relevant from this is that SBRT can be combined with other systemic therapy, especially immunotherapy, which may actually give us a much better systemic response and maybe overall survival and improved local control, overall survival and progression-free survival. So what is the future for this? So we are looking at several trials that are randomizing systemic therapy versus systemic therapy plus SBRT in one to five metastatic sites. NRG is looking at this, EMBRACE is looking at this, Estro is looking at this. The systemic therapy can be anything, whether it's chemotherapy or immunotherapy, but they are looking at systemic therapy versus systemic therapy plus radiation therapy. And I think those trials are really gonna help us understand the role of stereotactic radiation therapy in oligometastatic disease. There are also multiple registry trials that are ongoing as well that hopefully will help address this with larger group of patients. So adjuvant therapy, and I'm really gonna briefly talk about adjuvant therapy because really we have two new studies out that I think we need to discuss, and then we need to discuss where the future of adjuvant therapy is, right? So the key, the first one which we all know that I need to talk about is Outback, right? And this is just a statement from the Outback PI that basically said that Outback confirmed that chemotherapy and radiation therapy alone is the best standard of treatment for patients with locally advanced cervical cancer, that adjuvant chemotherapy should not be used at this time. So really interesting results in a 800 patient trial. So the next study that's, I think, the most important study that's just come out now, and we don't have the full details, this is the CALA study, and this is a huge study that actually looked at immunotherapy with chemoRT versus chemoRT alone. And again, a very large study, and the results just came out, and this is a press release from Dr. Monk that basically showed that there was no statistical significance in the addition of immunotherapy to chemoRT versus chemoRT alone. So again, the standard still right now, even based on the CALA trial, is that chemoRT is the standard treatment for patients with locally advanced tumors. So in conclusions, advances in radiation therapy, image guided therapy, whether it's external beam and brachytherapy is where we are and where we're going. We are also going to more precise and local treatments, which include, which is basically SBRT. Really, this is gonna be relevant in oligometastatic disease, but may be used in special cases when brachytherapy is not allowed. But what we really need to do is move to more trials that are using radiation therapy with novel and unique therapies. And we need to find how we can put these two together, whether it's in the metastatic setting or the local advanced setting. So thank you again for letting me talk. I hope I helped explain the advances in radiation therapy, and I hope you guys have a wonderful morning. Thank you. So thank you so much, Dr. Gingham. That was a wonderful presentation. I have lots of questions, but we'll begin this Q&A portion with Apu. So what's the incorrect option regarding principles of radiation therapy in cervical cancer? So you can choose one option. We'll have a few more seconds. We have lots of people responding, so. So let's say, okay. So I guess you sent your message to Jinger. Do you wanna comment on that? I'm sorry? Okay, I guess you made it. So 62% of people say the wrong answer is brachytherapy. Exactly, so that's the correct answer. People were listening to my talk. Yeah, it was great. Yeah, yeah, you sent the message. That's good. So I have, maybe it's even a personal question. So then we can go to Q&A and others. So how far you feel radiotherapy is from being one option for fertility sparing in initial tumors, let's say. Do you feel like there will be one day when we will say, okay, you can go to chemo radiation and still preserve fertility for cervical cancer? Yeah, the problem is I think you still have to treat the uterus, right? So I'm not sure we're anywhere close to that because you have to have a margin. And so right now I think we're very, very far away from fertility sparing if you wanna talk about uterus. I think you can spare the ovaries. And we've already talked about that, but I bet we could do it even without you transposing it. We're gonna be closer and closer to that, but we're not. In those patients that are going to radical trachelectomies, for instance, they don't treat the uterus. How do you feel you can do something like that? We could. Yeah? Yeah. With stereotactic radiation therapy, we probably could. Yeah. Okay, awesome. Yeah, I mean, that's a good question. It would be interesting to explore, wouldn't it? Yeah. Okay, so you can send your questions through the Q&A feature. It's in the bottom of the screen if you want to. I have another question also while we wait for questions. We know from Landoni's papers from the 80s and 90s that radiotherapy after radical risks, we have lots of complications. Do you feel like we are reducing it using new technologies and how different is it from the past? So much different. In fact, I'm gonna be honest with you. One of my senior colleagues who you probably all know very well, who was a huge component of just radiation alone, has actually gone to where she thinks that some people should have a hysterectomy followed by chemoradiation. Because with our new technologies, we really do have less side effects. And some young patients may do better with surgery followed by chemo RT because we're giving less dose to the vagina. And you could also, so yes, I think our toxicities is really much improved with our new technology. And maybe some patients may be better with surgery followed by chemo RT because of the less toxicity to the vagina and less dose throughout. So there may be some patients that may benefit from all three now versus having more toxicity. We have come a long way, a long, long way. I mean, a great question. Yeah, yeah. I feel like some studies we should do it again. Yeah, no, I agree. I think some studies we should definitely do again. And I'll be, we do actually for our younger patients are looking at, even if we think they're gonna need radiation, going ahead and doing the surgery because we give less dose. You know, you're not giving 80 grade to the vagina. You're only giving 45 to 50, which is huge for these young patients. A big deal. Big deal, yeah, I agree. So there was a question you have responded on the Q&A, but it's, I think that's an interesting questions. For patients with a large metastasis, more than 10 centimeters to the ovaries, would you consider, do you think radiation is still effective and would you consider doing it before chemo and how do you feel about it? I saw your answer. Yeah, so I, you know, I think it goes back to that study that I just showed you, right? I think this is the one patient where I would get chemotherapy first, even though I'm not a big fan of chemotherapy first, right? But I think you give chemotherapy first and then you add radiation afterwards because 10 CMs is still, especially in the ovary, is a lot for me to treat. If you can take it out, that's even better. Then I would come back and I do have a patient just now, and I will tell you, I have a patient who actually had a tricholectomy and came back and get this. She actually had an ovarian mat, right? Two, three years, and it was 10 CMs. So they actually, my surgeon, who we all know, took it out and I'm giving post-op radiation therapy now. So that worked out great. So he did actually a hysterectomy and took this 10 CM ovarian mat out and now I'm giving radiation. So yes, if you can take it out, that's great. Otherwise I would do chemo. So either or, whether you debulk it or you give chemo, because I can't control a 10 CM ovarian mat, I'm going to be honest. So either debulking or giving chemo first and then following it with radiation is a much better idea. Okay, so we are getting lots of questions now. What's your opinion on, yeah, yeah, he's asking about your opinion on oligometastatic disease. So what's your- So I'm going to be, so we do treat oligometastatic disease and we're treating quite a bit of it. We are actually going up on treating oligometastatic disease. Now, whether on the upfront setting or not, that's up to you to decide, but we are coming back, you know, when we've done chemo RT and the patient comes back with metastatic disease, if they have up to three sites that I can treat, I will treat it. Otherwise we'll do systemic therapy or we do both. I have actually a trial open right now at Anderson where we are comparing systemic therapy to systemic therapy plus SBRT in these patients. So big believer, like I said, NRG is going to have a trial doing the same thing with five or less. So I do believe that radiation therapy for ablation for five or less isolated lesions is a good answer plus systemic therapy. Okay, so there's one other question. What's the reason behind giving three cycles of BRCA in primary cases after chemo radiation and only two doses after surgery requiring radiation? Huh, that's an interesting question. I'm not sure where that question came from and I think it all depends on what dose they're giving with the brachytherapy. So I would have to know a little bit more about that before I could answer that question. Okay, so unfortunately we are short of time and we have to move on. Yeah, there's a lot of questions. I'm going to try to answer these while the next talk goes on and think about these answers. I'll do that. Thank you so much. So we are going to move forward and I'm going to invite Dr. Renato Moretti to present his lecture on surgical treatment in advanced cervical cancer. Hello everyone. Hello everyone. It's a great pleasure and honor to be with you and represent my institution in this incredible event of the International Gynecological Cancer Society to talk about the surgical treatment of advanced cervical cancer. I would like immensely to thank the invitation to the entire organization, especially Dr. Aldrich and Dr. Renato Moretti and say it's a great privilege to be at the side of the most important names for the treatment of gynecological cancer in the world. I would like to introduce myself. My name is Renato Moretti Marques. I'm the coordinator of Department of Gynecological Oncology and Robotic Surgical Program in Gynecology at Hospital Edith Albert Einstein in Brazil, in Sao Paulo, Brazil, and member of International Gynecological Cancer as an international mentor of global curriculum and mentorship program and a member of Grupo Brasileiro de Tumores Ginecológicos. I have no potential conflicts of interest to this talk. We are focused on the cervical cancer, advanced cervical cancer. Cervical cancer represent almost 6,000, 600,000 new cases each year. And unfortunately half of those patients will die in five years. Most of these cases occur in low and middle income countries and are diagnosed in the advanced stage. The FIGU staging the FIGU stage system evaluates the local extension by clinically, imaginatively, and histopathologically. And the lymph node status well evaluate by PET-CT and other image tools. The standard of treatment of local advanced cervical cancer from stage 2b up to 4a is concurrent chemoradiation based on many important studies. The gynecological oncologist have to be aware the prognosis and the reason of failure of treatment. Local extension, renal failure, bleeding, spasticity performance, length of radiotherapy, radiotherapy response, age, advanced age, many of important prognosis factors that impact the response of treatment. The upfront surgical, radical surgery, radical hysterectomy, and cell disintegration are really known standard strategies. Some groups, Japanese and Italian, try to evaluate the impact of surgical approach upfront. And unfortunately, this strategy is really not well accepted due to the high toxicity treatment related. Especially in local, in place that the resource are low and the radiotherapy it's not available could have some role of surgical approach as no option treatment. As far as the pelvic considerations, a primary pelvic considerations, primarily a rare situation that we can propose for stage IV-A with no lateral extension are diagnosed and the difficult to manage fistulas urinary and gastrointestinal fistulas sometimes it's complicated the situation and where the radiotherapy is unavailable. The new advanced chemotherapy was evaluated for two large randomized clinical trials involving about 1,250 patients published in 2018. For Professor Gupta and 2019 for Professor Cantor using different chemotherapy schedules, but in both the studies, there is no gain in survival in groups exposed to chemotherapy followed by surgery when compared to standard treatment and a higher related toxicity was observed in the group exposed to chemotherapy. Several authors conclude, including the principal investigators conclude the new advanced chemotherapy is reserved just for research settings or areas where radiotherapy is not available. The clinical stage of FIBO and the presence of nodal involvement are closely correlated and the higher rate, the higher stage are correlated with higher rates of pelvic and parietal metastasis. The diagnosis of this metastasis, those metastases is well done by PET-CT but other methods like CT scan and MRI present just affectful rates of false negatives. The German group led by Professor Christa Keller for a long time proposed our clinical anatomy as a standard treatment of local evidence of surgical cancer to understanding the needs to extend the radiation field treatment. To confirm these ideas, he proposed the surgical staging versus clinical staging in pre-treatment chemo radiation in patients with local evidence of surgical cancer and adjusting the treatment in the surgical ward after pelvic and parietal lymphadenectomy. If you have positive parietal lymph nodes you could extend the radiation field. Unfortunately, there is no difference between the surgical and clinical staging arms but the authors could find out some good, better results between the surgical group in stage 2B. There is no end of the story. Many groups, many authors, including Dr. Snod, Professor Michael Prumovic and other groups think could be extension. Surgical staging could be considered for patients with pelvic and parietal lymph nodes but more than 20% have disease in the parietal nodes undetected on PET-CT. Especially in the local low-resource settings where the PET-CT is not available. As the concept of adjuvant procedure is hysterectomy after a concurrent chemo radiation was described in this meta-analysis. Unfortunately, just two randomized clinical trials including low number of patients are available. And seems this kind of procedure after concurrent chemo radiation is just find your place after histological the first stance of disease. As continuing as adjuvant procedures, the pre-treatment outcome for orthodontic mold, the bulking, is based on if you have the lymph nodes larger than two centimeters in your axis, the results of concurrent chemo radiations could be disappointed. And the volume of radiation treatment expected to sterilize this huge mass, lymph nodal mass is almost 75 grays. But the mobility related with this kind of volume of treatment, it's really high. So the argument is that we can achieve five-year surviving patients undergo lymph nodal bulking, a range in 30 up to 70%. As a salvage procedure, the pelvic incineration, anterior posterior total pelvic incineration could offer really benefit. So the proposal of the treatment is a curative and indicate for patients who have first stance or recurrence of cervical cancer after radiotherapy or concurrent chemo radiation. And especially in patients with have more favorable case with disease-free survival is more than two years and potential pre-margin could be achieved. And the tumor has less than five centimeters depending on the experience of the cancer center. As a contraindication, the presence of distance disorder metastasis through tonal contamination, invasion of nerve plexus and extra pelvic lymph nodes involvement. At the end of my talk, we could discuss the isolated retroperitoneal lymph node metastasis. This region, in fact, is the second most frequent location of recurrence, cervical cancer recurrence. The PET-CT is our best tool to exclude disease from a stance. And the therapeutic alternative is to isolate radiotherapy or isolate chemotherapy or surgical bulking following, follow it to after before the radiotherapy to after, before the radiotherapy or a concurrent chemo radiation. And could prolong survival in approximately 30%. It's important to describe. This is a really rare situation because isolated parathyroid lymph nodes, it's not very common. Frequently has other sites of metastasis. When you have this, the survival after parathyroid bulking is not so good, especially with other sites of known lymph nodes are positive, the survival is really, really low. In the isolated parathyroid lymph nodes, maybe a surgery or concurrent chemo radiation could be a nice alternative. And we have no numbers to support these structures yet as a standard. So as a take-home message, locally advanced cervical cancer represents the majority of cervical cancer in low and middle income countries. Concurrent chemo radiation is the best treatment, the standard of treatment. The gynecologist should be aware there is no failure of treatment. Upfront surgery as radical hysterectomal parathyroid inflammation is an exception. New advanced chemotherapy is just reserved for settings with radiotherapies are not available. Pre-treatment concurrent chemo radiation could have some role in FIGL-2b with self-positive nodes and perform below MIA and by immunohepatic surgery. The advanced hysterectomy after concurrent radiotherapy, concurrent chemo radiation should be performed just after histologically confirmed disease first step. The bulk parathyroid lymph nodes should be discussed in a tumor board and self-consideration is a good strategy for curative purpose after self-care request with a negative nodal disease. Thank you so much for your time. I'm available after this lecture to discuss the case. Thank you so much. So thank you, my good friend, Renato Moretti. Let's begin with the Q&A portion with the group for the attendance. So all of the next, are contraindications for performing on exoneration procedure accept? So what of those are not contraindications? So you have to choose one of those. So we have a few more seconds. Okay, let's see. Okay, good. So, do you wanna make a comment on that? Yes, hello Hayton, hello all. Thank you so much for your invitation and congratulations for the conduct this webinar. Absolutely, this scenario of central recurrence, it's one of the most important indication for surgical approach in local events, cervical cancer. The recurrence after histological confirmation with central disease, preferably less than five centimeters because the surgical margins could achieve easily or easier. And if you have more disease than the central disease, probably you will not achieve the surgical free margins. And the rates of overall survival is really low with you have lymph node metastasis or decent visceral metastasis of peritoneal dissemination. And this is, it's not a good scenario to perform the Belka's integration. Okay, so using this same scenario, what are your limit for, let's say, in a recurrence setting in a tumor where the patient was treated with chemoradiation and she has a central recurrence. There is a size limit. You still try a radical hysterectomy despite of exoneration. So what's your limit or there is no limit? These are wonderful questions because when you look the good results of surgical resections, we're talking about in this scenario after concurrent chemoradiation, we're talking about the surgical margin at least one centimeter. And depend the volume of disease, probably a radical hysterectomy is not just make sense to achieve this condition, especially when the disease is in pre-concurrent chemoradiation is achieved the anterior part of vagina. So if you have a huge volume, even the disease occurring centrally, we not indicate the radical hysterectomy to rescue this situation. We prefer before the pelvic concentration. And in the same thoughts, the rates of surgical complications, especially rectal fistula, ureteral fistula or bladder fistula is incredibly high after concurrent chemoradiation, especially if you have in a low resource settings with the high technology, radiotherapy is not available. Yeah, that's a good point. Usually we use two centimeters, but it has to be really central. It's a very difficult, it's not an easy procedure. Patients recur after it with certain reason also. And Dr. Dos Reis, our good friend is asking, do you consider disease-free survival as an indication for pelvic centration? It's more than six, more than 12 months. Yes, this is a paper that I forgot the reference, but it is a huge spectacular paper that describe the overall survival and disease-free survival after pelvic concentration that put as some limits like a platino sensitive that we have the concept in ovarian cancer. After, if the recurrence occur before six month, probably you talking about a high risk disease to not achieve the complete cure of these patients, especially patient after 24 month that appear recurrence disease could be the best patients to indicate the pelvic concentration. Thank you so much, my friend, Ricardo. So Dr. Grissell has a question. Because of the risk of lymph node capsule leakage during surgical resection, do you think it is feasible to perform a conventional treatment, chemo radiation and brachy? Sorry, could you repeat the question? Yeah, sure. So because of the risk of lymph node tumor leakage during surgical resection, do you think it's feasible to perform conventional treatment for advanced disease, chemo radiation and brachy and perform a resection of the lymph node if there is a persistence of this disease after initial treatment? So another excellent questions because one of the limits of the buccal lymph node metastasis especially when we don't have a good radiological exams to describe the vascular invasion and to describe the limits when you have the central part of the lymph nodes with necrosis, the risk of broken the oncological barriers, surgical oncological barriers during the procedure is one of our limits. So is it possible to consider if you'll have a huge mass with a vascular invasion with ureteral invasion and if you don't have limits to describe the possible surgical resection without broken the lymph node mass, it's possible go forward with concurrent chemo radiation but the imaging concepts of sterilizing or not to sterilize the lymph node metastasis is not well established as well before the concurrent chemo radiation, these limits is not well established in the literature which one is probably the best deal is during the surgery, you check if there is some borders well-defined to resect without broken the oncological barriers. Okay. So Dr. Perota from Argentina has a really good question. So, and I have this is connected to exoneration and rescue surgery after chemo radiation. So if you have a persistent disease after radiation would you indicate a hysterectomy, a radical hysterectomy or do you prefer an exoneration? I think we already touched this topic minutes ago and probably if you have some signals in imaging in a clinical exam that before concurrent chemo radiation including the anterior part of vagina, if you have a really huge mass with some radiological signs with edema of bladder mucosa, probably these patients will be better treated by pelvic exoneration. But if you have the really, really, really low volume and really, really central disease in the cervix, you could consider the radical hysterectomy as a good rescue way to treat. Okay, so and this is another question. It's in countries with low resources, would you consider a radical hysterectomy as a substitute for brachytherapy? In patients without access, in places without, I wouldn't say even in place or countries because probably there are so many countries without access to brachy. Professor Arnugia, come back. Even some rich countries have some limited access sometimes. So for places without access or limited access to brachy, would you consider substitute brachy with a surgery? Professor Arnugia, could you? Yeah, yeah, yeah, I saw. You know, Mexico has a study on that, right? So they've actually done a phase two and I think they were doing a phase three study looking at radical hysterectomy after external beam and have decent results. So, you know, and they've have, and you know, this Dave Cantu was the PI and I know they were doing a phase three study randomizing the patients to brachy or radical hyst. So it'd be interesting to see if he has data. But I do, I agree though, you do not have access to brachytherapy or it takes you three months to get to brachytherapy. In some patients, a radical hysterectomy may be a good option after external beam. Professor Arnugia, could I add some part of these questions? We're talking about unavailable resource of brachytherapy after external radiation, but we have another scenario. We have a patient that don't have anatomic conditions to perform the brachytherapy. Could you consider the radical hysterectomy is a good choice for this situation? Yeah, I don't know. You know, the question is if we can't do brachytherapy, can you do a hysterectomy, right? I mean, it's probably gonna be both the same reason, right? So if you could do a hysterectomy with negative margins and less complications, then yes. You know, the other option is to do interstitial template. If you can't do tandem and ovoids, that's another option. But yes, I mean, if you think you could do it, but if I can't do brachytherapy, the chances of you doing a radical hyst is probably just as hard, right? I completely agree with you. Yeah, yeah, yeah. So in the interest of time, unfortunately we have to end this session. This was a great discussion. Awesome, yeah. We should have more of this. So, but unfortunately we have to move on. So that's all the time we have for today, unfortunately. We would like to thank the program co-chairs, Audrey Tsunoda, Dr. Fernando Malufi, and René Parreira, who made this possible. So thank you so much. We would also like to thank to our speakers for today, expertise and insights. Lastly, I would like to thank you all for attending this session, and the recording will be available on the IGCS portal in a week. Remember to join us next Saturday for the second part of this webinar on endometrial cancer. Remember to register for the IGCS meeting in New York, because this is gonna be huge. So thank you so much and see you next week. Would our panelists like to take a photo? Yeah, let's do it. All right. 123. One more. There is sleeping. Perfect. Thank you so much. Thank you. Have a great weekend. Bye-bye. Thank you very much. Thank you so much. Thank you so much. Gracias.

immunotherapy

cervical cancer

systemic therapy

metastatic

relapsed

recurrent disease

bevacizumab

chemotherapy

PD-1/PD-L1 axis

pembrolizumab

disease control rate

overall response rate

GOG 3016

dostarlamab

surgical options