Hello, everyone. Good morning, everyone. Welcome to the update on Selected Genetic Models in Gynecology and Oncology. Today, our program will be focused on uterine collar cancer. I am Reitan Rivero. I am a surgical oncologist at Erasto Garner Hospital in Brazil. I will be the moderator today. Today, the webinar is going to be recorded in Spanish, English, and Portuguese. These are the instructions. You will find them in the chat. How to connect. Here we can see the instructions in English and Spanish. Here we have the interpretation button and you can choose the language. You can mute the original audio if you wish. If you have questions regarding the interpretation, please contact IGCS. This webinar is being recorded and will be available on the IGCS portal. The IGCS portal is at the bottom where it says Q&A. In these sessions, we will have questions at the end of each session and we will try to answer as many as possible. In today's webinar, we will focus on uterine collar cancer. I would like to introduce today's speakers. Pedro Ramirez, from the United States. Aldo Lopez Blanco, from Peru. Mauricio Lema, from Colombia. Anuja Jingram, from the United States. And Renato Moretti Marquez, from Brazil. To kick off today's presentation, we are going to share Dr. Pedro Ramirez's presentation on uterine collar cancer and the impact of the LAC study. Thank you very much to the IGCS for the invitation to present on this topic. The subject of this session is going to be cervical cancer and the impact of the LAC trial. During this presentation, we are going to address the final results of the LAC study presented in Phoenix in 2022. This is a summary of all the students who have been here for four and a half years. We are going to talk about the literature published since 2019, where the LAC trial was published, and some patterns of practice in the United States. And I'm just going to address some of the unresolved themes that continue to look back at the issue of patients with less than two centimeters of tumor, and also the invasion of tumors with less than two centimeters of tumor. And finally, I'm going to talk about the impact of the LAC study on national and international guidelines. As you know, the LAC study was a randomized prospective study evaluating minimally invasive surgery versus open surgery. The recurrence rate was higher, and survival rates were generally worse in patients who had minimally invasive surgery. There was also another study published in the New England Journal in 2018 by Alex Melamed and his group, where they evaluated a national database comparing open versus minimally invasive, and it demonstrated that minimally invasive surgery was also associated with worse survival for these patients. In the recent meeting, in the recent oncology meeting, I presented the final analysis of the LAC study, and in that presentation, I spoke about the results in the survival of free disease and general survival at four and a half years. This is when 100% of patients, well, followed up to four and a half years. And additionally, we did an exploratory analysis, and none of these points were in the original design of the study, but since this was of interest to the community of gynecologists, we analyzed the impact of residual disease in the endothelial specimen, the results of tumor size, the previous conusection, the rates of carcinomatosis, and the recurrence patterns, and as you know, in the study, we initially recruited 631 patients, and as I mentioned, here, this is the final stratification of all the patients that reached that four and a half years, which is 83% of all the patients that entered the study that reached those four and a half years. As you can see, we had 100% complete data for all eligible patients for both primary outcome and general survival. And in our final analysis, we showed, as we did in the initial publication, that in the intention to treat analysis and the PER protocol analysis, this was associated with the worst outcomes in favor of minimally invasive surgery. Okay, so just wait about... Very good. We are now closing the poll. We are now closing the poll. Okay, so, Pedro. Hi, Raytan. Hey, how are you? Great to see you. So, can you see the... Can you see the... Can you see the results of the poll? Yes, I saw the results. I think it's very reflective of what we are seeing. I think it's very reflective of what we are seeing here in the United States, where the majority of institutions offer open approach for patients with cervical cancer. And I wanted to just obviously start with the questions because I think those are, I think, important questions that are being asked in the chat. One of the questions was it's very important to highlight that a conization is not indicated for a lesion that can be seen in the cervix. And they teach us from the residency. If you see the lesion, you don't need a cone, just a biopsy because it's not a microscopic tumor. So, it's important that we don't misinterpret and suggest that patients with a cone are better off because we anticipate that patients with a cone are better off not because they have a cone but because they are microscopic tumors when we compare them to a large exophytic tumor. So, the suggestion is not to make a cone to reduce the tumor size. In a study, the term is debulking conization. This doesn't make sense. So, that should not be the message. Arthur asked that if we do a vaginal protective maneuver for an open sterectomy and that's what we do when we put the clamps under the cervix to do the colpotomy, that's already a vaginal protective maneuver. So, in an open surgery, the tumor is not exposed to the abdominal cavity. There's another question. Would you offer a minimally invasive surgery in a tumor less than 2 centimeters? The answer is no. In our institution, we don't do any minimally invasive surgery for cervical cancer. In tumors less than 2 centimeters, we don't know the results of the CONSERVE study. This study showed that most likely these patients don't need a radical sterectomy. So, the question is, would you do a laparoscopy in patients less than 2 centimeters if you're doing a simple sterectomy and we don't have data that suggests that it's safe? We know that from the CONSERVE study. 94% of the patients do a laparoscopic surgery, but it's a study of 100 patients. It's not very big to determine if minimally invasive surgery versus open surgery is different. We also have to wait for the SHAPES study, which will compare radical sterectomy versus simple in this type of patient. These patients will have minimally invasive surgery, so we have to wait for these results. There's a question that says, what was the rationale for the LAC trial for macroscopic tumors? No, this was not part of the LAC trial. They didn't require macroscopic tumors. A large tumor does not need a macroscopic tumor. A patient with a large tumor should not need a macroscopic tumor. A large tumor with a large tumor should not have a macroscopic tumor. That was not part of the LAC study. Does it make sense to use the knowledge of radical sterectomy to define... That's a great question. We don't know. We offer patients open trachelectomy in our institution based on the results of the LAC study, which is a multicentric study. It didn't show any difference between open and minimally invasive, but again, it's a retrospective study, and we don't know if prospectively it's going to be the same. For us, to be sure, we do open trachelectomy. So, for you, does laconization make sense? If sterectomy is not a good option, that is, if you believe that the patient is going to have positive radiation criteria, you don't feel like doing laconization before radical sterectomy. It doesn't make sense. As long as you have a large tumor, the way we approach it and the way it's in the guides is that if you have a cytology, or a biopsy, and you have cervical cancer, and you don't see anything in the exam, then the patient is going to get a cone. If you have a patient who has any injury of any size, and you do a biopsy, you don't have to determine a large tumor, then you should do one sterectomy, another radical trachelectomy, but we don't do laconization when we have large tumors. There are two questions from the Q&A. The first one is about the survival analysis. If you can do the FIGO 2018 study to evaluate the results. The FIGO study has changed. Now we classify patients with less than 2 centimeters and more than 2 centimeters. The survival analysis should not change because we don't include the FIGO study, so basically the survival results are going to be the same in the interpretation of those studies, but again, we only have that stratification of less than 2 centimeters. Our study was not designed to evaluate more than 2 centimeters or less than 2 centimeters. We did not have to change the results because we did not include patients with more than 2 centimeters. We have a clearer communication with the FIGO study. The rate of carcinomatosis is higher since there is literature that also analyzes open abortion. The rates are definitely higher and it is something not only us in the LAX study, but other studies also showed that 42% of patients who had recurrence had carcinomatosis. This is probably related to the neumocytopenia and the spread of disease through the abdominal cavity. So this is something and another reason why we don't do minimally invasive surgery. What makes laparoscopy inferior to open surgery? Is it due to the spread of the tumor or was it not completely removed? No, we did not have a difference in the rate of positive margins. This is due to carcinomatosis and our study was not designed to find the reason why and it is probably contamination of the tumor and neumoperitoneum. Sorry, go ahead. There is a question. Some surgeons say that if you have more positive margins, you should not do sterectomy. There are many people who are doing laparoscopy and they do a frozen biopsy and they end up with vaginal abortion. That is the routine, the routine evaluation in Austria. They do a laparoscopic evaluation of the ganglions, then they do the frozen biopsy and then they decide what to do. A thought, when you look at patients who have radical sterectomy, a large majority of them do not have positive ganglions. For example, in the conservative study of less than 2 centimeters, the rate of positive ganglions is 5%. That is, one would do 95 laparoscopies and biopsies for useless freezing in patients with less than 2 centimeters. That large majority we are exposing patients to procedures they do not need. In 2 to 4 centimeters, they are patients who have more possibility of ganglion-lymphatic 7% to 12%. That ganglion-lymphatic commitment, when we look at these patients, is that our pathologists say a large majority of these patients will not be able to be diagnosed with frozen biopsy because they have macrometastasis, so it is not seen in the frozen section. In addition to this, in terms of the fear of having positive ganglions with magnetic pelvic resonances and PET-CT, we will not have surprises in the operating room. There are two questions that are connected. What type of incision do you use for open hysterectomy and clinical aspects for this decision? And there is another question that is connected with this. Patients with an IMC greater than 40, how do you proceed? Do you make it open? Do you choose a different approach? And for lymph nodes, when there is no clear commitment, when it is just a suspicion for the first question, we do a fan-steel incision, a fan-steel or we do a midline incision for open radical hysterectomy. The patient leaves the next day of surgery and one or two days after the surgery, they go home. For obese patients, and emphasize, in MD Anderson, we do minimally invasive surgery for no one, for no one. Even in obese patients, an open radical hysterectomy is done. Obviously, we analyze all the factors for any other patient, the pre-surgical images, resonances, PET-CTs, but again, we do not do minimally invasive surgery in MD Anderson for cervical cancer. And I think the last question was on the lymph nodes. To continue with this, do you do open radical hysterectomy? Yes. And when you have a lymph node that is not clearly metastatic, do you do surgery or do you do chemo? If there is a suspicious lymph node or not specific, we have a discussion with the radiologist to see if they can take a biopsy guided by CT, by TAC. And they do the biopsy for us before surgery, guided by TAC. And if it's cancer, then yes, they go to chemo and radio. We have lots of questions, but I would like Pedro to answer all of them, but we don't have time. The topic is exciting, but we have to continue. Thank you, Pedro. It has been an excellent presentation. Our next presentation will be by Dr. López Blanco talking about cervical cancer in pregnancy. Thank you. Dear colleagues, warm greetings. My name is Aldo López Blanco, oncologist, gynecologist from Instituto Nacional de Enfermedades Neoplásticas from Lima, Peru. In this opportunity, I'm going to speak about cancer in pregnancy. I want to thank the organizers of IGCS for inviting me. I would like to present approximately 0.05% to 0.01% of all pregnancies. Yes, it's true, your presentation is very rare. It's the most common neoplasia during pregnancy. Among the most common malignant neoplasias diagnosed during pregnancy are breast cancer, followed by ulcerative colitis, hematological neoplasia, and melanoma, which together represent 70% of pregnancies. Here we have a graph that shows us the cancers associated with pregnancy and their frequency, and where breast cancer is at the top, followed by ulcerative colitis. In this next graph, we have the neoplasias that are most often associated with gestational cancer. Within them, we can see cervical cancer, and in the colors, we can see the stage of the disease. And here we can see that cervical cancer, associated with gestation, is diagnosed or presents in the initial stages, which is different from non-pregnant women, who are more often diagnosed in advanced stages in Latin America. In this other slide, we see the frequency of gynecological cancers associated with gestation, where the first place is occupied by cervical cancer, followed by ovarian cancer, ovarian borrelian tumors, vulva cancer, and vaginal cancer. Other general aspects that we must consider is that, as we saw in the previous slides, the most common gynecological cancer associated with pregnancy is coliterin cancer. It is rare, and therefore its management is a challenge and complex, because the treatment could determine or hamper the mother's oncological prognosis. The risk of teratogenesis, as a possible delay in the growth of endothelium, and even the death of the fetus, should not be ignored, as long as we carry out studies of disease extension, the use of chemotherapy or radiotherapy to manage cancer. Another important aspect that we must consider is that the prognosis of coliterin cancer is the same in pregnant women and non-pregnant women. If we have a patient with a diagnosis of cervical cancer associated with gestation, these patients should be referred to specialized centers for multidisciplinary management. It is important that, during the management of coliterin cancer, the prognosis should be defined by the gynecologist, oncologist, clinical oncologist, radiotherapist, pathologist, oncologist, neonatologist, gynecobstetist, psychologist, and most importantly, the patient. It is important to listen to the patient to define the management. Within that, it is also important to see the context of the regulations or laws of each country or region for management. Within the studies of disease extension, when we have a patient with coliterin cancer diagnosis, it is important to consider that these studies could affect the development of the fetus in the future. Exposure to radiation should not exceed more than 100 milligrams. It has been reported that the incidence of cancer attributed throughout life for a dose of radiation above 50 milligrams is estimated at approximately 2%, if the fetus was exposed after 15 weeks. But an exact quantification of this risk for cancer in the future is almost impossible. Therefore, in the face of this, non-ionizing imaging procedures such as ultrasonography or pelvic magnetic resonance are the safe techniques for sterilization in pregnant patients. Regarding gadolinium, we do not know the therapeutic effects in the fetus. Therefore, it is not recommended to use it in pregnant women. To consider the management of cervix cancer associated with gestation, we have to take into account whether or not there is a compromise on the size of the tumor, the histological type, the stage of the disease, and the gestational age, which are important factors to determine the definitive management. We have several management options. One is to delay the treatment until the gestation is completed. Another option, the second option, would be to finish the gestation for a definitive cancer treatment. The third option would be a surgical treatment conserving the pregnancy, such as conization, simple or radical tracheolectomy, with or without lymphadenectomy. And non-invasive chemotherapy is the fourth option that could be used to do a downstaging or prevent the disease from progressing, conserving the gestation until the fetus is viable. There are several consensuses, several expert guides. Here I bring you the most significant ones. There is the ESMO, published in 2019. And within this, there are mainly two groups. Group 1 in minors under 22 weeks of gestation, where, according to the STADIO 1A, for example, it could only remain in a simple cone if the lymphocytic permeation is negative. In tumors less than 2 centimeters, such as 1A1 with positive infovascular permeation, 1A2 or 1B1, lymphadenectomy is indicated. If the ganglions are negative, it could remain under observation or be given chemotherapy. If the ganglions are concluded, it is recommended to terminate the gestation. This includes micrometastasis. In STADIOS 1B2, lymphadenectomy is recommended or neodymantic chemotherapy. In STADIOS 1B3, neodymantic chemotherapy, lymphadenectomy is controversial in these STADIOS. And in STADIOS 2B, what is recommended, what these guides recommend is to terminate the gestation. And it is important to emphasize that some experts regarding lymphadenectomy have quite a few controversies about its use. And in the other group, group 2, in women over 22 weeks of gestation, in the initial STADIOS, neodymantic chemotherapy is recommended versus observation. This will also depend on exactly what week of gestation the patient is in and the risk that this patient may or may not progress with the disease. And in STADIOS 2B, it is recommended to terminate the gestation in the vast majority of cases or optionally, if the patient decides to continue with the pregnancy, to give neodymantic chemotherapy until the gestation is completed. Within the previous slides, this is a summary of what is found. And I am highlighting it in red. In women in initial STADIOS with breast cancer associated with gestation, as long as they are under 22 weeks of gestation, lymphadenectomy is recommended. Why? Because these patients could remain in observation, and to remain in observation, as they are initial STADIOS, the risk of gangrene commitment should be reduced. But I repeat again, lymphadenectomy as part of surgical STADIFICATION in patients with cervical cancer and gestation is quite controversial. And I highlight in green the use of neodymantic chemotherapy in different alternatives, in different scenarios. Here we are going to talk a little more about neodymantic chemotherapy during pregnancy. And there are many series published about it, although it is true of small reports of cases, but within this there is always the fear of what are the effects of chemotherapy on the effect. It is important to emphasize that chemotherapy is contraindicated in the first trimester of pregnancy, since it can be associated with 10 to 20% of congenital malformations. After 14 weeks of gestation, a series of drugs could be administered as part of chemotherapy, including taxan, platin, antracyclines, eletroposide, and valiumicin. There are several studies that talk about the rate of general malformations, and these indicate that they are similar to the general population. Therefore, chemotherapy can be used after the first trimester of pregnancy. It is also important to consider that the window that must be given from the last cycle of chemotherapy must be three weeks before birth, so that the recovery of the mother's and the child's medulla can be given, especially in children who are premature. It is also important to consider the auto-toxic effects of cisplatin. This will depend on the dose, and apparently some guides, some experts, recommend that carboplatin, compared to cisplatin, is safer. Relative use should also be considered, the relative effect of myelotoxin and eletroposide, the cardiotoxin effect of antracyclines. Long-term toxicity data, after the exposure to chemotherapy in children with infantile cancer, have shown, in some cases, cardiotoxicity, in other cases, irreversible hearing loss, neurocognitive problems, endocrine disorders, a lower proportion of secondary neoplasia, and a general increase in morbidity. But it is not yet clear whether the exposure to intrauterine chemotherapy is similar to the effects of exposure in small children with cancer. That is why it is still important to monitor this population of newborns who have been exposed to intrauterine chemotherapy. This is a large series published by Professor Lancharan in 2015, where he summarizes, more or less, 39 cases of cervical cancer from different small series published, where more than 60% are patients with advanced stages of cervical cancer. The vast majority of these patients had chemotherapy allowing the pregnancy to be prolonged, and in the vast majority it culminated. The most widely used drug in this report was cisplatin, although the duration and schemes vary between the authors. And one of the conclusions of this article was also fetal well-being, which was not compromised in any of the announced cases. There are also other series that talk about the safety of the use of toxins during the second and third trimesters of pregnancy as a safe option. Song recently published in 2018, which includes 39 studies or reports of cases, 88 patients with colorectal cancer, in which chemotherapy was administered during the pregnancy. There were 88 births, 84 pregnancies, obviously there were twin pregnancies and triplets pregnancies, of which, of all the births, 80% were completely healthy at birth. At the end of the follow-up, although it was not a long follow-up, approximately 20% of patients were diagnosed with recurrent recovital cancer and almost 90% of these died from recurrence. But one of the problems, one of the observations, was that neither free nor free-of-progress survival was achieved in this series reported by the very short follow-up. These results showed that neodymantic chemotherapy based on platinum could be a favorable option for the management of recurrent cancer in women during the second and third trimesters of pregnancy. We published a study, a series of cases in Latin America, neodymantic chemotherapy associated with patients with cervical cancer. It was a multicentric Latin American study. The objective was to describe the oncological and obstetrical results in patients diagnosed with recurrent cancer during the pregnancy that had a successful birth after neodymantic chemotherapy. As I mentioned, it was a retrospective study. The inclusion criteria were patients with histological cancer diagnosis of cervical cancer with 1B1 states, a 4A state according to the 2009 figure, who were associated with gestation and received chemotherapy from 2007 to 2018. There were about 12 centers from 5 countries that participated in this study. In the end, 43 patients were collected, where it should be noted that the average age was 34 years. The vast majority of patients, 60%, were 1B1 states, and locally advanced, almost 40%. The most frequent histological type was scabious carcinoma, 90%. The vast majority of patients were diagnosed in the second trimester of pregnancy, 33% in the first trimester, and 6% in the third trimester. The most widely used imaging studies were magnetic resonance with ultrasonography in about 90% of the cases. Among the drugs, the most commonly used schemes were platinum and taxol in 60% of the cases, cisplatin and taxol in 21% of the cases, and other schemes. Toxicity was reported in only 18% of the cases. Regarding the response to neodymantic chemotherapy, there were between stable disease, partial response, and complete response, about 70%, 75% of the cases. Among the obstetric results, there were obstetric diseases only in 12% of the cases, almost 70% of the cases did not present obstetric diseases. The term of gestational age was 35 weeks. All patients completed the cesarean section. The average weight was 2,340 kilos, and the average size of the newborns was 45.5 centimeters. And other characteristics that were comparable to the reports prior to the cases. Regarding the definitive oncological result of the patients, almost 33% of the patients had radical hysterectomy, and chemotherapy plus radiotherapy, 67% of the patients. Among the patients who were subjected to radical hysterectomy, half were intrapartum, and the other half, 50%, were postpartum. Of the patients who had radical hysterectomy, the patients who required adjuvant treatment were only 25% of the patients. In summary, the average age was 34 years in our series of cases. The 90% was carcinoma epidermoid, the 60% was in stage 1, the 60% was in the second trimester of gestation, and the most used schemes of chemotherapy were carboplatin associated with Clitaxel, and cisplatin associated with Paclitaxel in 20% of the cases. The number of chemotherapy cycles was between 3 and 4. 86% of patients are currently alive. What were the weaknesses of the study? It is a retrospective study, although it is true, with small groups of patients, but, above all, it was the largest retrospective series published so far. The follow-up was not so long, there were short follow-ups. The selection criteria were quite heterogeneous. The strength of the study, which is a multisensory retrospective study of cervix cancer with gestation, in which it was found that chemotherapy is an alternative to achieve fetal viability without having an impact on oncological results. Referring to the center where I work, which is a center of reference at the level of Peru, how do we handle cervix cancer? Multidisciplinary meetings are held, where different specialists participate. The scheme we use for chemotherapy is platinum, carboplatin, and paclitaxel every 21 days. We start chemotherapy after every 14 weeks of gestation. To do the study we use magnetic resonance of the abdomen and pelvis. We do a re-study once the pregnancy is over, and if it is operable, the surgery differs after 6 weeks of gestation. As final recommendations, the management of cervical cancer associated with gestation is a challenge, it is complex, because the treatment can directly affect the oncological results of the mother, and it is also important to consider the therapeutic effects of the oncological treatment. That is why patients should be referred to specialized centers for multidisciplinary management. Within this management or conduct that will be followed, it is important to consider the opinion of the mother. It will also have a direct impact on the management of the patient and the state of the disease. The evidence we have is based on case studies, retrospective studies, and expert opinion. At the moment, prospective studies in this group of patients would not be viable, so we will always have the level of evidence that is not so high compared to a prospective study. So we'll wait about 30 seconds for answers to come in. Esperamos 20 segundos. Just a few more seconds. Okay. Okay. Can you see the answer? The results? Are you seeing the answers or not? Yes. Well, thank you, Reita, for sharing the survey. First, what we have of evidence in coveterin cancer associated with gestation is more report of cases, opinion of experts, and as we have observed, some revisions, the largest revision does not exceed 100 cases. So here we are going to have many discrepancies, and obviously none of these recommendations has strong evidence. That is, in the simple view, complex to handle. That is why it is always the handling of these patients in centers that handle high volumes of patients with cancer reserves, where we have a clinical oncologist, a radiotherapist at hand to be able to handle this type of patient. Okay. Well, Aldo, another survey. How many cycles, I don't know if this is an area that you do so much, but how many cycles of chemotherapy are given to patients who are pregnant in general? In general, if we apply or indicate chemotherapy after 14 weeks of gestation, on average, until the fetal maturity arrives, between 3 and 4 cycles of chemotherapy are applied, at most 5 cycles of chemotherapy is what has been seen in the reports. It is what is applied. It is also important to consider that there must be a window period of 3 weeks before ending the pregnancy. This is due to bone marrow depression, so that it recovers, not so much in the mother, but in the newborn. This is the problem that has been reported. Okay, okay. Well, this has to do with Horacio Moncho's question, which is, well, he waits for 6 weeks after cesarean section. Is it for something special or not? Why does he wait so long? Sure. Well, in most series, they hardly report this. They don't only report the problems that could be due to bone marrow depression, but in the series that we have published, there have hardly been this type of problem, or problems have been reported in the newborn. Okay. Well, when you have neck cancer, and an ovarian mass in the same patient, well, synchronic. What do you do, Aldo? The CA125 is high, as a suspicion of an ovarian metastasis or something like that. Do you consider doing chemotherapy followed by a radical stereotomy, or do you prefer to do an ophorectomy first, and see if you can diagnose the ovarian mass, what do you think? Of course. In any case, it is important to consider colluterine cancer. Most reports recommend, obviously, conserving gestation and pregnancy in initial stages. If we suspect a cancer, a suspicious mass, we are already considering an advanced stage. Here we have to give priority to the health of the mother. And consider the patient as if she were not pregnant. This patient has to go to surgery to rule out that this tumor is or is not primary of the uterus. We do a laparotomy, and the anexal mass is studied to see if it is or is not metastasis. If it is metastasis, obviously, the prognosis itself is very bad, and the treatment of the mother is prioritized. Dr. Fusen is asking, well, if there is an early diagnosis of neck cancer, and the indication is a radical hysterectomy with the fetus, at what gestational age does the hysterectomy take place? With the in-situ fetus. With the in-situ fetus. Yes. For us, particularly, it has a lot to do with local legislations. In the legislations, for example, in Peru, it is not indicated, let's say, the abortion and all that, when there is imminent risk, that is, risk at the time of the mother's pregnancy. In this case, the pregnancy, I mean, the health of the mother is not at risk for pregnancy because it is an initial cancer. So, I, particularly, neither do the guides recommend it, and even more so with the non-invasive chemotherapy that is entering into progression, its use. So, I would not recommend it, at least we do not handle it that way. What we do is, if we have a patient in the initial stage of co-uterine cancer, as the guides say, we have a tumor less than two centimeters and a gestational age, let's say, in the first trimester, what we do is observe the gestation in a way, let's say, normal, to prevent this disease from progressing. That is, we only observe the patient until it is viable. If at any time we see that the tumor grows and the gestation is greater than 14 weeks, we could opt for non-invasive chemotherapy. Okay, one last question, Aldo. And the complications of patients who are pregnant with co-uterine cancer, especially the bleeding of the tumor, how do you handle it during gestation? Obviously, with comprehensive treatment, nothing more. Generally, we do handle a relatively frequent number of cases of co-uterine cancer associated with gestation. We have not had many of these problems, but if with mechanical treatments, this does not yield, does not respond, we already have to see, because the health of the mother is running out, to see another type of treatment, such as ending the pregnancy and starting emergency radiotherapy. Then the handling becomes complicated. If we see that it is a bleeding that cannot be contained with mechanical procedures, with vaginal blocking, there will be anemia, and this complicates everything. Then we opt for the possibility of starting treatment with emergency radiotherapy. Okay, okay. Very, very good question. Sorry, a question I think that was also asked, why do we do the hysterectomy six weeks after the pregnancy is over? Yes, sometimes it is a question that, and it is a discrepancy of experts, but if we do radical hysterectomy immediately after the cesarean section, obviously the blood vessels are very large, the anatomy is a bit distorted, mainly because of the risk of bleeding. If you have a good blood bank team and expert surgeons in doing radical hysterectomy, it is a good team, you can do it, but generally sometimes in general hospitals, where we generally refer to patients, we do not have these teams, and that is why we recommend that it be after six weeks of gestation. This will not change the prognosis, because if the uterus already evolves to a normal size, the risk of bleeding is much lower, mainly because of this. And mainly this will not affect the colostomy prognosis. Okay, okay. Well, I agree, Aldo. Okay, so I'm sorry, but we have to move forward. Well, we have to continue now. Dr. Lema, we're going to take a break. We're going to have five minutes and we'll be back for the next presentation. So, see you in five minutes. I am the Scientific Director of the Clínica Oncología Astorga. It is the pillar in relapses and recurrences. The addition of bevacizumab in the first line or as a unique agent became the last advance before immunotherapy. And this is based on GOG240, which compared chemotherapy alone and chemotherapy plus bevacizumab in the first line. The general survival advantage was demonstrated with bevacizumab of three months of improvement of chemotherapy alone, and cancer cells proliferate when the T cells are obstacles in the control points. This comes from the interaction of PD-1 in the T cells and PD-L in both mononuclear and tumor cells, including mononuclear and macrophages. Access can be restored, the activity of T cells. This can be achieved with anti-PD-1 antibodies, pembrolizumab, nivolumab, valstilumab, camrylizumab, semipilimab. In many situations, atelizumab and durvalimab are also available, and this is the basis of cancer immunotherapy. Immunosuppression has been postulated for tumor invasion in neoplasms related to BPH. This includes infiltration by mononuclear cells and overexpression. This is the basis for immunotherapy as a strategy in cervical cancer. As is the case in oncology, the paradigms change and some are at the end of the clinical spectrum as factors and move to the first line of treatment, even in non-metastatic situations. We are going to discuss some immunotherapy studies beyond the first line. Keynote 158 is a basket study of 98 patients who were intolerant to the first line of treatment. They received pembrolizumab and mononuclear PD-L1 antibodies. The primary endpoint was the general response rate. Here we see Keynote 158, 46, PD-L1, 83%, and they had received more than one line in the metastatic state. Keynote 158, the efficacy reached 14%. All the responses occurred in the PD-L1 group based on the combined score or CPS. Anti-PD-L1 is in the tumor sample, which is composed of tumor cells and mononuclear cells. A formula is going to give us a number. PD-L1 is considered positive if CPS is greater than or equal to 1. Back to Keynote 158, free disease survival and general survival were 2 and 19 respectively. With this result, the FDA gave authorization for PD-L1 for the second line and beyond. Valstizumab was tested in 161 patients. Here we see the characteristics of the patient in the slide. There was a preponderance of young symptomatic patient population and previously treated for metastatic disease. The effect is seen in the graph. The response was similar to Keynote 158. There were some responses in the negative PD-L1. Also in the second line was a CLAP study in China. 45% were recruited and 41% received cambrelizumab plus apatinib, which is an anti-angiogenic agent. The combination of responses was 55% and a degree III of toxicity of 71%, probably derived from the anti-angiogenic agent. The patient characteristics in these studies are similar. And also the results with the exception of the response rate in the CLAP study that talked about another active component. The combination of anti-PD-L1 and an anti-angiogenic agent was examined with this small group of patients of atelizumab with bevacizumab. Without confirmatory responses, it was considered negative. The only phase III study is the Empower Cervical One. Semiplimab, another monoclonal PD-L1 antibody, was compared with the researcher's chemotherapy. The trial recruited 608 patients, including a minority of patients with adenocarcinoma. The Empower Cervical One was positive with 3.5 months of improvement on the control arm. Also the experimental arm, the survival was 12 months and the benefit was observed in both histologies. But the benefit was restricted to the positive population for PD-L1. Notwithstanding, the authors concluded that semiplimab was active regardless of PD-L1 status. Based on these trials, one can conclude that there is a plethora of active PD-L1 agents in pre-treated cervical cancer. Now let's move to the first line. Keynote 826 is the only phase III study in the metastatic trial. The study included 548 patients without systemic therapy for metastatic disease. The patients were statified with the PD-L1 expression, among other variables. The control arm was chemotherapy without or with bevacizumab. Pembrolizumab was added to the experimental arm and the primary endpoints were survival and general survival. This recruited a young population, half had symptomatic disease, almost 90% of the patients were PD-L1 positive. 35% improvement in survival and general survival in the Pembrolizumab arm in the intention to treat. The rate was also higher in the Pembrolizumab. The general response rate was also higher in Pembrolizumab. And here we see the partial or complete responses, respectively. The toxicity was similar in several arms with the expected adverse effects in the Pembrolizumab arm. Although the results are immature, the general survival rate is higher in the Pembrolizumab arm. An important 24 months is estimated compared to 16 months established by the GeoGev study. Keynote 826 is a study that changes the practice and the FDA gave approval for Pembrolizumab in patients with PD-L1. This is the state of the art. There are several ongoing studies that are currently being done. Some of these are exploring the possibility of either anti-PD-L1 or anti-PD-L1 in the non-metastatic setting. Non-metastatic state, locally advanced. And we were able to enroll five patients with Dr. Diego Morana as the main investigator and with the help of Dr. René Pareja. Some of the interesting avenues are also being studied. In conclusion, anti-PD-1 monoclonal antibodies have demonstrated anti-tumor activity as unique agents and combined with advanced cervical cancer. The approval for Pembrolizumab was granted for PD-L1 positive patients and Pembrolizumab has been included in the NCCA. If regulation and access were not an issue, we would incorporate anti-PD-1 agents. We would use Pembrolizumab in the first or second line of treatment for patients with anti-PD-1 positive disease. And I would consider the use of Semiplimab if it were approved in the second line, even without being positive for anti-PD-1 because there is some evidence of activity. But this is if it could be like this and this is almost impossible to exceed. So with that, I want to thank you all. Thank you, Dr. Lema. Let's begin with the questions and answers. Let's start with the question for our audience. So immunotherapy in cervical cancer has been proven to be effective in PACE-3 randomized controlled studies in the following scenarios. Choose one of these. We have a few more seconds. We are waiting just a little bit for more people can vote. We are waiting just a little bit for more people can vote. Well, Dr. Lema, it's a split decision. 30% said PdL1 is a positive disease. So, tell me what you think. The true response that I was expecting is that we are going to talk about chemotherapy in first line settings. That was the only chemotherapy that I thought was positive. But I can understand why the audience chose only PdL1 positive. But I can understand why the audience chose the number D. Most of the trials have a very clear demarcation in the PdL1 patients. But not only in these patients. There are some data, PdL1 data, that also responds to PdL1 negatives. Specifically, in the Semiplima CLAP study, there were some important responses in PdL1 negative patients. And what I was expecting was C, but it could also be D. Okay, and there's a question from Dr. Lozano. Do you think Bevacizumab is beneficial when you use Pembrolizumab in first line or do you use it without Bevacizumab? I don't have access to Pembrolizumab in my country for cervical cancer. So, it's a very hypothetical question. But I wouldn't add Pembrolizumab to Bevacizumab. I would use only chemotherapy plus Pembrolizumab. So, if you have any questions, you can send to the Q&A. The audience has a question. You can ask it through the Q&A. Questions and answers are on your screens. I'm going to say something before any question. is that one thing for sure, immunotherapy has a role in preventing cervical cancer, especially in advanced cases. And I'm pretty sure that the studies that are being conducted at this moment are going to be positive as well. And so, what Aldo is asking, which are the future perspectives in how far is the immunotherapy in cervical cancer and how far is it from Latin American patients in the near future? What do you see in the near future? There are some access problems because these agents are expensive and that can be a barrier to the incorporation of these agents. But in the end, at least in Colombia, we would hope that the regulatory agencies will eventually include Pembrolizumab to a host of other disease settings with even less remarkable effects on other diseases. So, one standard of care that is expected, but it takes about two years in Colombia while it is approved by the FDA and then it is approved by the INVIMA, which is our regulatory agency. So, I would say that by 2023, we could use it for the first line, whether it can be used alone or with radiation chemistry, it depends on the studies that are being done. We also have a small gap for private practice, but for the public, it is about 10 years that goes from the private sector to the public sector of health care. Aldos, how do you face the financial part and the immunotherapy? So, this is a question that needs to be solved. Dr. Miguel Correa? This is a good question. So, do you also use histology to determine which patients are going to get immunotherapy or not? Actually, no. There are hotspots of... So, Florencia from Argentina is asking you, she is congratulating you for your presentation and her question is, what is the time that you consider to wait between radiotherapy for local management and the administration of Pembrolizumab? Pembrolizumab, at this time, it is not expected to be used after radiotherapy or with radiotherapy, but the time that I use in other diseases when I'm going to use Pembrolizumab is more or less two weeks because of concerns that are not related to Pembrolizumab. I use it as a lapse when I use cytotoxic agents, but we can use Pembrolizumab very close to radiation therapy or with radiation therapy. So, we are a little short of time, so we have two more questions and Dr. Lema can answer other questions in the chat. In which patients with cervical cancer, metastatic, would you use Bebacizumab? Right now, in everyone, I would use the DOD240 and the DOD240 criteria because I don't have access to Pembrolizumab and I think the DOD240 changed the practice. So, at this moment, I would add Bebacizumab to almost all chemotherapies, at least in the first line of chemotherapy. Most of the time, I use Platinum plus Paclitaxel as the main axis, also in the DOD. Last question, Dr. Xiao, he asks, when you have a recurrence of cervical cancer or progression with Bebacizumab, what do you suggest? Well, if we are now in second line and there is progression, I would probably consider other agents. But we know that the patients are not doing well. I have had some response with a combination of Platinum plus Gemcynabine. I think that Gemcynabine does not add much. So, I give them a little bit of Platinum with Gemcynabine and I have had a little response. Those patients are not doing well. Thank you very much, Dr. Lema. We are moving forward. Our next presentation is Dr. Anuja Jinger about advances in radiation therapy. Good morning, everyone. Today we are going to be talking about advances in radiotherapy for cervical cancer. For those who know me, let's get started. As we all know, radiation therapy is the pillar for advanced cervical cancer. The treatment principles include all the volume that is known and the microscopic extensions. We have to give enough dose, and a higher CTV, which I will talk about later. The brachytherapy is very important and must be used when possible. The general treatment must not be prolonged beyond 56 days. As I said, let's start with a story. The beginning of the story is that cervical cancer is cured with radiotherapy. Here we show that it works well, even for stage 3 disease. Here we see that the result is 70% local control and 50% general survival. Radiotherapy worked well alone, but it caused complications. At 10 years old, we analyzed almost 4,000 patients and the radiotherapy resulted in 11% complications in the long term. As we all know, in 1999, several studies showed that chemo-radiotherapy was better than radiotherapy alone. It was similar in stage 1 and 2, but it also benefited a little in stage 3 at 3%. So the question is, how can we improve? So the conclusion was that chemo-radiotherapy was better than radiotherapy, but the benefit was not very high for stage 3 and we could still improve in stage 2. And we know, according to modern data, that there is a 14% to 21% after chemo-radiotherapy and 9% to 12% parabolic relapse and 13% pelvic failure after chemo-radiotherapy. And as I said, chemo-radiotherapy increases toxicity, especially in the intestines. So how can we improve this? The advance we have is in technology. This is our old 3D field that we all know very well. What was the disadvantage of this type of 3D field? It caused intestinal toxicity because we used full doses in the intestine. That's where the IMRT comes in. I know you've heard about the IMRT, but this is one of our main advances. This is a randomized study analyzing IMRT in endometrial cancer and post-surgical cervix. And what we found is that the results were similar between both, but the most important thing was this, patients who were given IMRT are the results reported by the patients. Patients who received IMRT reported less diarrhea, less use of Imodium and Lomotil in patients who were given 3D during the treatment and a year after the treatment. It's also really interesting that it showed less urinary toxicity after the treatment because the conclusion is that the IMRT reduces the patient-reported outcomes seen by the patient early and late gastrointestinal and urinary hygiene. So the IMRT has become the standard of care both for post-surgical cervix and intact cervix in the United States and in Europe. In the EMBRACE 2, which is a prospective study that has just finished, they only used IMRT slash VMAT in their patients and the goal of EMBRACE 2, which we are going to have results soon, is to reduce toxicity and improve local control. Continuing the BRACI therapy, as I have already said, BRACI therapy is very important in the treatment of cervical cancer. A database study has shown that there has been a decrease in the use of BRACI therapy. This is 2003 and this is when the IMRT came in and what it shows here is that patients who were given BRACI therapy and the BRACI therapy is very important in the treatment of cervical cancer. And here to show a decrease in the use of BRACI therapy and a decrease in survival. So BRACI therapy is very important. What are the advances in BRACI therapy? And for some people we went from normal X-rays to 3D-TAC and 3D resonances. The advantage of BRACI therapy guided by images is that you can see the tumor and we can see the normal anatomy. So we move away from 2D and we move to 3D even with BRACI therapy. The advantages of BRACI therapy guided by images is that we define the disease, we define what is normal, what is the risk tissue and we give the form to the dose and it is distributed according to what we see. This is an example of resonance in a patient with cervical cancer and what we see and underline, this is what we see the intermediate risk disease which is point B. This is the high risk CTB and this is the cervix plus the parametrium and this is the GTB. So we can outline exactly where we want to put the dose. Here we see normal tissue, the rectum, the bladder, and we also know exactly where the doses are going to go. And in fact, this shows that brachytherapy, guided by images, improves local control, general survival, and toxicity. The advantage is that we can see the disease. Here we see residual disease here. And if we did standard treatment, we would overdose the sigmoid or rectum. This is where the interstitial needles come in. They are inserted directly and we treat the disease only without overdoing the adjacent normal tissue. Another example of where the needles come in. Here we see residual disease later on. If we treated it with rings or tandem or voids, then we would treat the rectum and the intestine. Here we can load the needles and not treat the normal tissue. So this is another advantage of brachytherapy guided by images. So we can treat the patient in an individual way. And in fact, we have shown that interstitial brachytherapy plus rings or voids, tandem rings or tandem or voids improves both bladder toxicity and intestine toxicity. This is a combination of both. This is intercavitary alone versus intercavitary plus interstitial. Here we see that it reduces bladder toxicity and intestine toxicity. So the big advantage of this type of brachytherapy is that we add more needles to areas that we need, and this reduces toxicity. We've also changed our idea about the doses that we should give compared to what ICRU did. So we changed the doses. Here we see the rectal doses have decreased. The rectum is now less than 65. Here we see the vaginal dose, and we've increased the doses in the risk CTRV. This has helped us identify tumors, whether it's an external ray or in brachytherapy. So it has allowed us to identify the tumor, has allowed us to identify macroscopic disease and normal tissue, which has allowed us to adjust the dose exactly where we want it, and reduce the dose in normal tissue. So it has allowed us to reduce the toxicity in the short and long term, and it improves local control and dosage escalation. So IMRT-IV MAT has become a standard for intact service in Europe and other parts where it's available, including India. Imaging-guided brachytherapy is not the golden 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 adjust the dose. Interstitial is recommended in EMBRACE-II. 30% of the patients should have been treated with interstitial. And the long-term studies show that 70% of the patients with EMBRACE-II were treated with a combination of intracavitary and interstitial. So this is one of the big advantages we have in radiation therapy, and it allows us to improve the quality of life of our patients and reduce toxicity. So where can we take this new technology? Is brachytherapy important? I already showed you that it is important. And what was happening in America, at least when IMRT arrived, is that brachytherapy was reduced, and it didn't change the survival. But it can be used. And in MRT, SBRT can be used if we can't use brachytherapy. And this is the technique. SBRT, we would get 30 gray in five or six fractions. And this is just an example of SBRT instead of brachytherapy. And we can give an adequate dose using SBRT to the cervix, which are comparable to brachytherapy. The disadvantage of SBRT is that brachytherapy gives us these hot spots inside the disease, which increases the specific dose to that disease, and SBRT does not. This is more general. So there is probably a specific dose directed to SBRT. But the data shows that SBRT can be used, but we see that local control is less than if we use brachytherapy. But it is reasonable to use it if we don't have brachytherapy, or the patient cannot receive brachytherapy for a poor response. So in conclusion, brachytherapy is the adequate treatment, period. But SBRT can be used instead of brachytherapy if we have a poor response or we don't have brachytherapy available, but it has to be done carefully and planned. So what is the biggest and more forwarding improvement in radiation therapy? And that is metastatic disease. So, one, this is an interesting study that I want to show you because it is very relevant, especially in most of the world, and that is metastatic disease. This is a national cancer database that analyzed SBRT in metastatic disease. There were 300,000 patients, and of those 900, they received only chemotherapy, and the rest received chemo plus radiation therapy. And what they found in this database is that patients who received definitive chemoRT did better in overall survival than chemotherapy alone. So as you can see, even all patients, this is the chemoRT arm compared to the chemoRT arm, right? The chemoRT patients did much better in survival than the chemoRT patients. And this is based on matching, based on the factors, right? Again, chemoRT did better than the chemoRT patients in overall survival. So even in metastatic disease, adding chemoRT in some patients would improve overall survival. But how about all the patients with metastatic disease? This is actually really important in the era of immunotherapy and in the era of bevacizumab, right? All the data was started from these four studies presented from 2017 to 2019. And all of these studies are not GYN tumors. And patients who had metastatic disease, oligometastatic disease, who received systemic therapy, and if we add radiation to systemic therapy, to that oligometastatic disease, the patients who received radiation therapy did better than those who only received systemic therapy. These are small studies, 49 patients, 62, 29, 99. But it shows that possibly treating this oligometastatic disease and giving them radiation and adding systemic therapy is better than just systemic therapy alone. And this shows a case study of a patient who was treated with definitive chemoradiation. Here we see all of the guided brachytherapy and external ray and it fails. And here we see a metastasis in the liver, here treated with stereotactic radiation. Another lesion treated with stereotactic therapy. They also had others here, here, all treated. In fact, this patient then received systemic therapy as well. And she is alive five years later and she is doing well. It's just an example, but a good case, right? There is data that shows that treating oligometastasis can improve survival. And this is just one of many studies that we were doing with cancer patients. This is patients with cervical cancer, 83 patients. The majority were lymphatic ganglia and about 45% were in mucous pathogeny. The median dose, 35 gray, the range 10 to 60 gray in five fractions. Complete response, almost 60%, so 46 patients had a complete response, 29 patients partial response, and 16 patients stable response. The toxicity was very mild, 19% mild acute toxicity and 5% late toxicity. The conclusion of this study was that there was a link between complete response to local control, free survival of provision and general survival. Other conclusion was late systemic therapy, usually by two lines, two to three years, and then recovery with systemic therapy again. The last conclusion of this study, which I think is most relevant, is that probably that SBIRT can be combined with other systemic therapies, especially immunotherapy, and may give us a better systemic response and probably general survival and local control and free survival. So, what is the future? We are looking at several studies that are randomizing systemic therapy and systemic therapy plus SBIRT in one to five patients with metastasis, in one to five patients with metastasis, in one to five places. Systemic therapy can be chemotherapy or immunotherapy, but they are analyzing systemic therapy versus systemic therapy plus radiation, and these studies are going to help us understand the role of stereotactic radiation in oligometastatic disease. There are also several studies that have larger groups of patients. So, adjuvant therapy, and I'm going to briefly talk about adjuvant therapy because we have new data and studies that we need to discuss, and I think we need to discuss where the future of adjuvant therapy is, right? And what we all know and what we need to talk about is Outback, and this is a statement from the Outback PI that basically says that, but at the same time, adjuvant therapy alone is the best standard of treatment for patients with advanced cervical cancer and adjuvant chemotherapy should not be used at this time. So, really interesting in 800 patient trials. The other study that I think just came out, we don't have all the details yet, is the CALA study. This is a huge study that looks at immunotherapy plus chemo-RT versus chemo-RT alone, and a huge study, and the results just came out, and this is a press release from the Journal that basically shows that there was no statistical significance in the addition of immunotherapy to chemo-RT versus chemo-RT alone. So, again, chemo-RT with systemic therapy, even in the CALA study, chemo-RT is the standard of treatment for locally advanced tumors. So, in conclusion, advances in imaging-driven therapy, whether it's external radiotherapy or brachytherapy, is where we're going. We're also going to have a more precise local treatment with SBRT, and basically SBRT is relevant in oligometastatic disease, but it can be used in special cases where brachytherapy is not allowed. But what we really need to do is move to finding more studies that are using radiotherapy with novel and unique therapies and we want to understand how we can bring these two treatments together, with metastatic disease and locally advanced disease. So, I hope this has explained the advances in radiotherapy and have a good morning. Thank you very much. Thank you so much, Dr. Gingham. That was a wonderful presentation. I have lots of questions. Dr. Gingham, let's start with the question to the public. What is the incorrect option according to the principles of radiation therapy in cervical cancer? You choose an option. We'll have a few more seconds. Demos unos cuantos segundos más. We have lots of people responding, so... Hay muchas respuestas. So, let's say, okay. So I guess you sent your message to Jingo. I think your message has arrived. Do you want to comment on this result? I'm sorry? Okay, I guess you made it. I think your message has arrived. 62% of the people say that the answer... the correct answer is B. You're listening to my talk. So the message has arrived. Yeah, I have a... Maybe it's even a personal question. It's not even a personal question. How far do you feel radiotherapy is going to be in initial tumors, let's say? Do you feel that one day when the day will come where we say, okay, let's do chemo, radiation, and preserve the effectiveness? Yeah, you know, the problem is I think we still have to treat the uterus. So I'm not sure we're anywhere close to that. I think we still have to treat the uterus. So, I think we're very, very far from that right now if we want to preserve the fertility. But I think we can preserve it and we're going to be closer and closer to that. But we're not. In those patients that are going to rest, for instance, they can treat the uterus. Do you feel you can do something like that? Like a colorectal cancer that doesn't treat the uterus? With stereotactic therapy, I think so. That's a good question. It would be interesting to explore. Okay, so you can send your questions through the Q&A if you want to. I have another question, though. While we wait for the questions. We know from Lendon his papers from the 80s and 90s. Radiotherapy after radical risks. We have lots of complications. Do you feel like using new technologies? How different is it from the past? It's much different. In fact, I'm going to be honest with you. One of my senior colleagues who you probably know very well, who used to use radiation on her own, she said that many patients should have hysterectomy followed by chemoradiation. Our new technologies have less side effects. And some young patients are doing better with surgery plus RT chemo because we give less dose to the vagina. So our toxicity has really improved a lot with the new technologies. And some patients are doing better with surgery plus RT chemo for less toxicity to the vagina and less dose. So there may be some patients that benefit from all three. And we have come a long way. A great question. Very good question. I feel like some studies we should do. Yeah, I agree. I think some studies we should definitely do again. Yes, of course. And in younger patients, even if we think they're going to need radiation, we do the surgery because we give less dose. We're not giving 80 to the vagina, but 40 or 45. Which is very big. Very important with these patients. There's a question. And it's interesting. For patients with large metastases, more than 10 centimeters in the ovaries, would you consider that radiation is still effective? Or would you consider doing it before chemo? Or what would you do? I think it goes back to that study that I just showed you. This is one diapositive I showed you. There are patients that I would give chemotherapy first. But I think that sometimes it's chemo first. Especially in the ovary, it's a lot for me to treat. Because that size in the ovary is very large. Suddenly I would take it out first. I have a patient now that actually had a tracheotomy and came back. And she had an ovarian metastasis at 2, 3 years old. And it was 10 centimeters. So my surgeon took it out. And I'm doing post-surgical radiotherapy. So they did the ovarian metastasis. So if you can take it out, it would be wonderful. If not, I would go to chemo. So I can't control a 10-centimeter ovarian mass. So the idea is surgery and then radiation. So we are getting lots of questions now. Okay. What's your opinion? Yeah, he's asking about your opinion on metastatic disease. What's your... So we do treat oligometastatic disease. In fact, up to you to decide. But we are coming back. When we've done chemo RT, and the patient comes back with metastatic disease, if they have more than three sites that I can treat, I would treat it. Or if not, we would do systemic therapy. At this time, there is a study in Anderson where we compare systemic therapy with systemic therapy plus chemo RT. NRG is also in the study with five or less. So I think radiation therapy, speaking therapy for five or less lesions is a good answer, plus systemic therapy. Okay, so there's another question. What's the difference between having three cycles of brachytherapy in primary cases after chemo or radiation and only two doses after surgery? Huh, that's an interesting question. I'm not sure where that question came from, but I think it depends on what doses they're giving you. So we would have to know more about brachytherapy to be able to answer that question. Unfortunately, we are short of time. There's a lot of questions, so I'm going to try to answer them while the other talk goes on. I'm going to invite Dr. Renato Moretti to give a surgical treatment in advanced cervical cancer. Hello, everyone. Good afternoon. It's a great pleasure to be with you and represent my institution. I'm going to ask Dr. Renato Moretti to give a surgical treatment in advanced cervical cancer. I'm going to represent my institution in this great webinar on gynecological cancer to talk about the surgical treatment in advanced cervical cancer. I would like to thank the organization and Dr. Renato Moretti. It's a privilege to be alongside the most important names in cervical cancer treatment. My name is Renato Moretti Marquez. I am the coordinator of the Department of Gynecology and Gynecological Robotic Surgery at the Israelita Hospital Albert Einstein in Brazil, Sao Paulo. I am a member of the International Association of Gynecology and I am a mentor of the mentoring program. I have no conflicts of interest in this talk. We are focused on the cervical cancer, advanced cervical cancer. We are going to focus on cervical cancer which represents 600,000 new cases each year and 341,000 of these patients will die each year. 80% of the cases are in low and middle income countries. The FIGO staging system. Here we see local clinical extension with imaging and histopathologically. Also the status of the lymphatic ganglia is also evaluated with PET-CT and other images. The standard of treatment in cervical cancer stage 2b to 4a is chemotherapy based on many important studies. The gynecologists have to be aware of the prognosis and the reasons for the failure to treat. Local extension, renal failure, bleeding, the duration of radiotherapy, response to radiotherapy, lymphovascular invasion. These are important factors for the prognosis and that affect the prognosis of the treatment. The initial or initial radical surgery is a personalized radical hysterectomy and here the impact of the surgical approach is evaluated. Unfortunately, this is not available. So we are looking for a surgical approach as no option. As far as the pelvic exfiltration, primary pelvic exfiltration is an extremely rare situation. We can have a 4A stadium with no lateral extension. Only central disease. There are difficulties to manage the fistula. It is complicated. There is a high rate of complications and lower survival. Neuroassistive chemotherapy was evaluated in two randomized studies involving about 1250 patients published in 2018 by Dr. Gupta and 2019 by Dr. Cantor using different chemotherapy schemes. But in both studies, there is no improvement in survival in groups exposed to chemotherapy followed by surgery compared to standard groups. Here we see the two groups. Several authors, including the main researchers, conclude that neuroassistive chemotherapy should be reserved for these research stages. The clinical stage of FIGO, which we see here, and the higher rate, the higher the probability of metastasis. Here we see that metastasis can be diagnosed by UNTAC, resonance, or PET-CT. And here we see the sensitivity and specificity, false negatives and false positives. The German group, led by Dr. Christa Keller, for a long time proposed a standard treatment of local evidence of cervical cancer. The surgery, the need to extend the stage, first the surgery and then the radiotherapy. He proposed the surgical stage versus the pre-treatment, pre-treatment in the local radiation with local evidence. Here we see the surgical treatment. If we have positive lymphatic ganglia, we can extend the radiation field. Unfortunately, there is no difference between the surgical and clinical stages. The authors could find better results in the 2B stage. There is no end of the story. Many authors and studies, Dr. Chinoda, Michael Frumovitz, and other groups think could be extension surgical stages. Therefore, patients with cell-linked nodes, more than 20% have disease in the priority nodes undetected on PET-CT. Unfortunately, in the local, in those low-resource areas where we don't have the available PET-CT, the concept of auxiliary procedures, the hysterectomy after chemoradiation, is described in this meta-analysis. Unfortunately, there are only two randomized clinical studies available. This type of radiation, this hysterectomy after chemoradiation, is continuing as auxiliary procedures. So, the pre-treatment, the debulking, if you have a 2-centimeter-long lymphatic ganglion in your axis, the results say that the chemoradiation is not very good. And the volume of radiation treatment expected to sterilize this huge mass. So, these results potentially give us a higher rate of toxicity. 75 gray is used, the general volume is 60 gray. The 5-year survival rate in patients who undergo the debulking of lymphatic ganglion, the 5-year survival rate. Salvation procedures, pelvic exfiltration. Here we see the patients who benefit. The survival rate after pelvic exfiltration for cervical cancer, here we see in the graph. Patients who have more favorable cases with a 2-year survival rate of pre-margin could be achieved. And the tumor has less than 5 centimeters, also depending on the experience of the cancer center. As a contraindication, these are the visual metastases at a distance, peritoneal dissemination, and invasion of the lumbosacral plexus or sciatic nerve. And at the end of my talk, we can talk about the metastasis of lymphatic ganglion isolated in the aortic section. And the retroperitoneal region corresponds to the second most frequent site in the recurrence of cervical cancer. The PCT is necessary to exclude the metastatic disease at a distance. Isolated metastasis is done by radiotherapy or chemotherapy or debulking of surgical lymphatic ganglions, and this can prolong survival by approximately 30%. And could prolong survival by approximately 30%. It's important to describe, this is a really rare situation. It's a very common situation. Frequently, when you have this, the survival after the debulking is not so good. Especially with other sites of known lymphatic ganglion sites. When there is a recurrence of isolated paraortic lymphatic ganglion, chemoradiation can be done. We have no numbers of patients to prove this. So, the messages to take home is that local advanced cervical cancer represents the majority of cervical cancers in low and middle income countries. Chemoradiation, concurrent with local advanced cervical cancers, stage 2b and 4a, is the treatment standard. The gynecologists must be aware of the reasons for the failure of the treatment. Using chemotherapy only when radiotherapy is not available. The pre-treatment of aortic ganglion dissection with chemotherapy should be reserved for stage 2b and pelvic positive ganglions. Adjuvant hysterectomy after chemoradiotherapy should be done for confirmed disease persistence histologically. The debulking of aortic and pelvic lymphatic ganglions must be discussed in a meeting before performing chemotherapy or surgery. Pelvic excentration is a good strategy for curative purposes after pelvic recurrence with a negative ganglion disease. Thank you for your attention. Thank you very much, Ernato Moretti. Let's start with the question for our audience. How of the next? Are contraindications for performance? So, we have a few more seconds. Okay, let's see. Okay, good. Do you want to make a comment on that? For this webinar, this scenario of recurrence, it's one of the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications for the most important indications lymph node metastasis, or lymphatic ganglion metastasis, or pelvic dissemination, or visceral metastasis is not a good scenario for pelvic dissemination. So, using this same scenario, what are your limits in a recurrence setting, in a tumor where the patient was treated with chemo radiation and now has a central recurrence? Is there a size limit to do the hysterectomy or the exfiltration? What are your limits or are there no limits? Wonderful question, because the good results of the resections in this scenario, after chemo radiation, the surgical margin at least one centimeter, and depending on the volume of disease, the radical hysterectomy, it does not make sense to achieve this condition when the disease is pre-chemo radiation, the pre-chemo radiation of the anterior part of the vagina. So, if we have a huge volume occurring centrally, we do not indicate the radical hysterectomy to rescue this situation. We prefer pelvic exfiltration. And the same thoughts, following the same line, the rate of surgical complications, especially the rectal or vaginal fistula, is very high after chemo radiation, especially if we are in a place with low resources and radiotherapy is not available. Yes, we usually use two centimeters, but it has to be very central. It is not an easy procedure when patients resort to it. And Dr. Douzé asks, do you consider disease-free survival a reason for pelvic exfiltration six months, nine months? Yes, it is a study, I forgot the reference, but it is a very good study that describes general survival after pelvic exfiltration, and this has limits as sensitive to platinum in ovarian cancer. If the recurrence is before six months, probably we are talking about a high-risk disease and not reaching the complete cure of this patient, especially patients after 24 months and the recurrent disease appears, this may be the best case for pelvic exfiltration. So, Dr. Rissell has a question. Because of the risk of leakage during surgical resection, do you think it is feasible to perform a conventional treatment? Could you repeat the question? Because of the risk of leakage during surgical resection, do you think it is feasible to perform conventional treatment, chemoradiation, and brachy? And perform a resection of the lymphatic ganglion if there is a persistence of this disease after the initial treatment? Another good question, because one of the limits of metastasis of lymphatic ganglions, of revulcan, when we don't have a good radiological exam that describes the limits and the invasion, when we have the central part of the lymphatic ganglion with necrosis, the risk of breaking these oncological barriers during the procedure is one of our limits. So, it is possible to consider if we have a large mass with a vascular invasion, with a luteal invasion, and if we don't have limits to describe the possible surgical resection without breaking the lymphatic mass, then you can do the chemoradiation. But the imaging, the concept of imaging, and the metastasis of the lymphatic ganglion is not well established before the chemoradiation, if it is not well established in the literature. Probably the best deal would be during the surgery to check if there are some borders that can be resected without breaking these oncological barriers. Dr. Perota from Argentina has a good question. And it is connected to exenteration and rescue surgery after chemoradiation. If you have a persistent disease after radiation, would you indicate a radical hysterectomy or would you prefer an exenteration? I think we already touched this topic a few minutes ago. And probably, if you have some signals in the images during the chemoradiation, including the anterior part of the vagina, if you have a really huge mass, some radiological signs, with edema of the bladder, probably these patients will be better treated by radiation, with pelvic exenteration. But if they have a really, really low volume and a very central disease in the cervix, we could consider a radical hysterectomy as a good way to treat it. Another question is in countries with low resources, would you consider a radical hysterectomy as a substitute for brachytherapy where there are no countries or places? Because in many countries, there are also rich countries that have access limits. So, in places where they have limited access to brachytherapy, would you replace it with surgery? Dr. Anuja. You know, Mexico has a study on this. They have done a phase 2 and they are doing a phase 3, and they are analyzing the radical hysterectomy after external radiation, and they have decent results. And I know they were doing a phase 3 study, randomizing the patients to brachy or radical hysterectomy. So, it's interesting to see the data. But if we don't have access to brachytherapy, or if it takes three months to get an appointment, then radical hysterectomy can be a good option after external radiation. Dr. Anuja, can I add something? We are talking about when there is no brachytherapy resource after external radiation. But there is another scenario, a patient who does not have the anatomical condition to do brachytherapy. Would you consider radical hysterectomy? Would it be a good option for this situation? Yeah, I don't know. You know, the question is, if we can't do brachytherapy, we can do hysterectomy, right? It would be probably the same reason. If you can do hysterectomy with negative margins and less complications, yes. The other thing would be to do an interstitial plate if we can't use the tandem or voids. But if you think you can do it, the chance of doing radical hysterectomy is probably just as hard. Yeah, yeah, yeah. So, in the interest of time, unfortunately, we have to finish the session. Very good discussion. Unfortunately, we have to move on. So, that is all the time we have for today, unfortunately. We would like to thank Dr. Fernando Malouf, René Pareja, and Dr. Audrey Tsounouda, who made this possible. We would also like to thank all of our speakers, for their expertise and insights. And I would like to thank you all for being in this session. The recording will be available on the IGCS portal in a week. Remember, there is a second part of the IGCS on Saturday in New York. You will need to have cancer. It will be on the other Saturday in New York. So, we will see you next week. And see you next week. Thank you.

genetic models

gynecology

oncology

uterine cervical cancer

LAC study

cervical cancer during pregnancy

immunotherapy

minimally invasive surgery

open surgery

neoadjuvant chemotherapy

anti-PD-1 antibodies

Keynote 158

metastatic cervical cancer

FDA approval

surgical management