I'm Andreas Obermeyer and I'm joined by my colleagues René Pareja and Jiong-Yeol Park. It's a pleasure to be here today, moderating this session together with my friends. We have an incredible line-up of presentations for this session. We strongly encourage interaction and conversations with all of you in the audience. So please submit questions through the IGCS 2023 mobile app or come to the floor microphone. Let's get started. Our first presentation is from Dr. Park, who will present Sentinel lymph node biopsy in early stage cervical cancer. Dr. Park, please. Good afternoon, everyone. I will talk about Sentinel lymph node biopsy in early stages cervical cancer. This is my disclosures, this is the content of my talk. Firstly, I will talk about concept and history of sentinel lymph node mapping in cervical cancer briefly. As you know, the sentinel lymph node is the first lymph node drained from an organ. Because there are multiple lymphatic pathways from one organ, there may be multiple sentinel lymph nodes in one lymph node station. The concept of sentinel lymph node was described in 1960s for the first time in peritoneal gland. The successful sentinel lymph node mapping was reported in 1977 for the first time in penile cancer. The first sentinel lymph node biopsy in cervical cancer was reported in 2000 by Dr. O'Boyle and Dr. Darjang. Since then, numerous studies were reported in the literature. So, the ideal tracer and injection sites for sentinel lymph node mapping in cervical cancer are well defined. There are three tracers evaluated in the studies. Blue dye, radio tracer, indocyanin green plus fluorescent camera. The ICG plus fluorescent camera is known to be more accurate than the blue dye or radio tracer alone or blue dye plus radio tracer. Therefore, ICG plus fluorescent camera is considered a gold standard for sentinel lymph node mapping now. Film trials showed the superiority of ICG compared to blue dye in a randomized controlled trial. Overall, sentinel lymph node detection rate and bilateral sentinel lymph node detection rate were better for indocyanin green. In several meta-analyses, overall and bilateral sentinel lymph node detection rates were better for indocyanin green compared to blue dye alone, radio tracer alone, and a combination of both. Several injection sites were also evaluated in sentinel lymph node mapping in cervical cancer. Cervical injection, hysteroscopic injection, and fundal injection. But cervical injection is a preferred injection site because the feasibility and detection rates were high still. Next is the accuracy and oncologic outcomes of sentinel lymph node mapping in cervical cancer. Numerous studies evaluated the accuracy of sentinel lymph node mapping in diagnosing lymph node metastasis. Santicore study is the representative one. In this study, technetium plus blue dye was used as a tracer. The sensitivity was 92% and the negative predictive value was 98% in diagnosing lymph node metastasis. So, sentinel lymph node mapping can be a reasonable alternative to lymph node dissection. But the sentinel lymph node detection rate, sensitivity, and negative predictive value were different according to the size of the tumor in ASIO group study. For tumors larger than 2 cm, detection rate and accuracy of sentinel lymph node mapping decreased significantly. In meta-analysis, pooled detection rate was 85% for small tumor and 67% for larger tumor. There has never been the results of randomized trial on oncologic outcomes. Actually, Santicore 2 trial was an RCT comparing the morbidity of sentinel lymph node mapping and lymph node dissection. But recurrence-free survival was reported in this trial. In this study, 3-year recurrence-free survival rate was not different between sentinel lymph node mapping group and sentinel lymph node mapping followed by bag of lymph node dissection. In recent meta-analysis including 927 patients from 6 studies showed that disease-free survival and overall survival did not differ between sentinel lymph node mapping and lymph node dissection. In Santicore 2 study, complication rate and patient-reported lymph edema was significantly higher for lymph node dissection group. Based on these evidences, current NCCN guidelines suggest sentinel lymph node mapping in stage 1A1 and stage 1B1, 1B2, and 2A1 cervical cancer. NCCN guidelines also suggest that ICG is more accurate than adult dye and detection rate and accuracy decreased in tumors larger than 2 cm. Next is surgical technique of sentinel lymph node mapping. Pelvic sentinel lymph node mapping requires a proper understanding of the pelvic lymphatic pathway. There are two pelvic lymphatic pathway. The upper cervical pathway is a pathway that comes out along the uterine artery and drains to the obturator lymph node, external iliac lymph node, and then common iliac lymph node. This pathway is found in more than 90% of cases. The lower cervical pathway is a pathway that drains to the internal iliac lymph node and then to the presacral and common iliac lymph node. And this pathway is found in only about 20% of cases. We can see the upper and lower pelvic cervical pathway. This is a left paralectal space. This pathway is a lower cervical pathway drained to internal iliac and common iliac. We can see the sentinel lymph node in the common iliac area. And the other pathway is upper pelvic pathway drained through the uterine artery to obturator area and external iliac area. Now I'm harvesting the sentinel lymph node in the lower cervical pathway around the common iliac vessel. And this is the external iliac sentinel lymph node drained through the upper cervical pathway. As I told you in the first part of my presentation, there may be several sentinel lymph nodes in your body. Because there may be several lymphatic pathways drained from one organ. This is the left obturator sentinel lymph node. This is the right side. This is the upper cervical pathway drained to the obturator area. And this is the lower cervical pathway drained to the common iliac area. This is the paralectal space. This is the paralytic lymphatic pathway. There are also two paralytic lymphatic pathways. The first is isolated paralytic lymphatic pathway drained from the corneal area to the upper paralytic area directly. And the other is a paralytic lymph node drained from the pelvic lymphatic pathway. This is a paralytic lymphatic pathway drained from the pelvic lymphatic pathway like this. And if we inject the ICG in the corneal area, we can see the isolated paralytic pathway drained through the infundibular pelvic ligament. Through this way. This way is the isolated paralytic pathway. If we see the paralytic area, we can differentiate the isolated paralytic pathway like this. And this is the paralytic pathway drained from the pelvic lymphatic pathway. So the paralytic centenal lymph node is this one. For pelvic centenal lymph node mapping, ICG is injected into the cervix. Injection is performed at two or four sites around the cervical os and two-site injection is mainly used. One milliliter of superficial injection and one milliliter of deep injection are performed on each area. But superficial injection is more important. 20 milligrams of ICG powder is diluted in 20 milliliters of normal saline. So the concentration becomes 1.25 milligrams per milliliter. This is the surgical procedure to detect the pelvic centenal lymph node. After evaluating the pectoral cavity, we clamped the tube and obtained the cytology. And then developing the pelvic spaces, paraphysical space and pararectal space. And firstly, we identified obliterated umbilical vessel first. Now we can see the upper pelvic pathway drained through the uterine artery to the obturator area here. And if we develop the pararectal space, we can see the lower pelvic pathway drained through the internal iliac vessel to the common iliac area. This is the obturator centenal lymph node. After removing it, we take it out using a spoon pulse. And we check the exofluorescence and we palpate it again to avoid the empty pocket. This is the left side. I identified the obliterated umbilical vessel here. This is the upper pelvic pathway drained through the uterine artery to the obturator lymph node. And now I'm developing the pararectal space to find our lower pelvic pathway drained to the internal iliac and the common iliac presacral area. Now I'm harvesting the left pelvic centenal lymph node. This is a robotic surgery using an X-ray model. After injecting the ICG into the cervix, we can clearly see the upper pelvic pathway drained to the obturator lymph node. We can perform a centenal X-ray. We can perform a centenal lymph node mapping in open surgery also. The fluorescent camera is commercially available also for open surgery. The enlarged, suspicious non-centenal lymph node should be removed during centenal lymph node mapping. This is a robotic centenal lymph node mapping using SP robotic system. This is the upper pelvic pathway drained to the left external iliac area. After removing it, I move to the right pelvic cavity and now I open the peritoneum. Usually, I cut the round ligament and the IP ligament and then developing paravesical and pararectal space here. And we can see the upper pelvic pathway drained to the obturator area and there is no uptake in the lower pelvic pathway. This is a right pelvic centenal lymph node, but there is another enlarged non-centenal lymph node here, so I removed the enlarged lymph node also. The most important thing during centenal lymph node mapping is how to solve the problem when mapping is failed. Firstly, we re-inject the ICG. If mapping is failed after first injection of ICG, there is no ICG signal here. I injected the ICG again. After second injection of ICG, we can see the upper pelvic pathway clearly here. This is the upper pelvic pathway. If the mapping still fails after injection of the second round of ICG, side-specific lymph node dissection is recommended. This is the centenal lymph node mapping algorithm. If mapping fails, re-injection of ICG and side-specific lymph node dissection is recommended. Side-specific lymph node dissection is recommended and enlarged non-centenal lymph nodes should be removed together. If we adhere to this algorithm, sensitivity and negative predictive value will increase. The NCCN guideline also recommends this algorithm. The last one is ongoing clinical trials. There are two clinical trials in cervical cancer. The first one is CENTICOR. It is an international randomized multicenter single-blinded trial. The primary endpoint is three-year disease-free survival. This is the only RCT-comparing survival in cervical cancer. The second one is CENTICS. It is a prospective international multicenter observational study. The primary endpoint is recurrence after any four months of surgery. These are the protocols, but limitation of time, I will skip this one. In conclusion, centenal lymph node mapping is a reasonable alternative to lymph node dissection in early-stage cervical cancer. Centenal lymph node mapping is more accurate for tumors less than 2 cm. And cervical injection of ICG and evaluation on the fluorescent camera is recommended. And we should adhere centenal lymph node mapping algorithm. And the randomized controlled trials evaluating surgical survival outcomes are ongoing. The results are awaited. Thank you for your kind attention. Thank you very much, Dr. Park. Now, Florencio Noel from Argentina will present what will be the future of radical surgery in early-stage cervical cancer after shared results. Flor, the polling is yours. Well, hello, good afternoon. Thank you for the kind presentation and for the invitation. And well, we are going to start the presentation and I want to tell you something about my personal life. Since I got started in gynecology, I always heard the phrase, we are expecting the shape results since I was in university. So today I'm honored to talk about the next steps to be taken in the early stage cervical cancer after the results of this long expected trial. I have nothing to disclose. So before moving forward, let's first discuss the current state of cervical cancer. It is the fourth most diagnosed cancer and the leading cause of cancer death in women worldwide. About 85% of these cases and death occur in low and middle income countries where the burden of disease remains unchanged due to the lack of effective organized program for cervical cancer screening. Radical surgery is the standard treatment and as a complex surgery, it is related to potential complications and it requires a really extensive surgical training. Radical surgery is considered a treatment of choice in patients with stage 1A2 and 1B1 cervical cancer and it implies the removal of the uterus, cervix, upper vagina, parametrium and pelvic leaf nodes. The radicality of the technique is defined by the extension of the paramedial and paracerbical tissue removal and the objective is to remove microscopic tumor and achieve tumor-free resection margins. However, lately, the usefulness of this radical resection in women with early stage cervical cancer has been questioned. Although radical surgery is highly effective treatment in low risk patients with a disease-free survival almost hitting 97%, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel and sexual function. So back in the 90s, 30 years ago, there was already a trend to less radicality. There were a lot of retrospective studies suggesting that the incidence of paramedial tumor involvement in carefully selected patients with low volume disease was too low to justify parametrectomy. So people started wondering if we did need to offer radical surgery or not. So to sum up, retrospective data reported that less than one percent of women with early stage disease and favorable pathologic characteristics had parametral spread, suggesting that less radical surgery might be a safe option for these patients and with less morbidity. But prospective evidence on this issue was still lacking. So the trend was starting. One of the largest retrospective studies comparing simple to radical hysterectomy favoring simple hysterectomy showed a rising trend from 2004 to 2014 in patients with stage 1A1 and 1B1, sorry, 1A2 and 1B1 during that period, with no difference in disease-free survival during that period. In 2021, a prospective singular multicentral trial enrolled 100 patients with early stage low-risk cervical cancer, the CONSERVE trial. Cervical colonization was performed with pelvic lymph node assessment, and those not desiring fertility preservation underwent simple hysterectomy with pelvic lymph node assessment too. The CONSERVE trial was a feasibility trial that showed that after a median follow-up of 25 months, recurrent risk was diagnosed in only three patients, so 3.5 percent of recurrence rate, concluding that non-radicality may be offered as an option for early stage low-risk patients. However, CONSERVE did not test for efficacy. As a result, global guidelines recommend this conservative treatment suggesting cervical colonization or simple hysterectomy for patients who meet these safety criteria. That means tumor less than 2 centimeters, no LBSI, negative margins, and no deep cervical stromal invasion. Currently, the updated guidelines suggest that the prognostic factors considered for selecting the type of radical surgery are tumor size, deep of stromal invasion, the presence of LBSI, and obviously the status of the lymph nodes. The second prospective trial is a resilient study with almost the identical design to shape, but with only 40 patients. This trial showed no difference in three years disease-free survival between these two approaches. However, Dr. Planté noted that this study was underpowered to assess efficacy between these two approaches. The GOG278 trial is still ongoing. This trial evaluates the physical function and the quality of life for patients with stage 1 cervical cancer before and after undergoing simple hysterectomy or con biopsy. So, at present, our most burning question is, should radical hysterectomy be replaced by simple hysterectomy? All the experts in the field that both are here in moderating this session agree that SHAPE trial must demonstrate its efficacy before we can consider simple hysterectomy as the standard of care. Thankfully, in May, Dr. Planté presented the results of this high-anticipated international randomized phase 3 trial, the SHAPE trial. This study included 700 patients with low-risk early-stage cervical cancer, defined as phagostage 1A2 and 1B1, grade 1, 2, and 3, and lesions less or equal to 2 centimeters. They were randomized to receive pelvic lymphoid dissection and either radical hysterectomy or simple hysterectomy. The primary endpoint of the study was to determine whether the pelvic recurrence rate at three years for simple hysterectomy was not inferior to radical hysterectomy. To highlight one of the main differences is that LBSI was not an exclusion criterion, quite different from COMSAR trial. In the ASCO meeting, Dr. Planté showed the preliminary results and pelvic recurrence rate at three years with simple hysterectomy was not inferior to radical hysterectomy. In addition, simple hysterectomy was associated with fewer complications, as well as better quality of life and sexual function. These results suggest that radical hysterectomy may no longer be required for women with low-risk disease and simple hysterectomy could be established as the standard of care. But it also means that we should select the patients who fit this very specific criteria. So the real questions after the J-results are, what is the future of radical surgery, but also what is the future of the patient selection strategy of the surgical approach? We should change the strategy for pelvic node assessment, and who should be the surgeon? About patient selection strategy, tumor size predicts parametral invasion, and that's obviously related to oncologic outcomes. So we need to select who fits this very specific criteria. Tumor size less or equal to two centimeters, sorry, and deep of strolling invasion less than one centimeter, 10 millimeters. For this purpose, the gold standard tool is the MRI, also the ultrasound, it's a strategy. Both have a highly accurate in measuring tumor size, delineating cervical tumor boundaries, and also local tumor extension. So radiologists should be working together with the surgeons, and they should have expertise in gynecology, and that's mandatory. Another challenging situation related to tumor size is residual disease. In patients with previous large cervical conitations and residual disease in the hysterectomy specimen, the final tumor dimension pose a challenge for pathologists. Some authors suggest that reporting both specimens when measuring the tumor, the final tumor size, it's one of strategy. So the pathologists also need to work together with the surgeon to select the type of surgery we're going to offer our patients. About surgical approach, do we need to change the standard? Although one third of the hysterectomies from this trial were performed by minimal invasive approach, the SHAPE trial was not designed to answer this question. So according to prospective evidence, the laparotomic approach is still the standard of care for cervical cancer patients. Anyway, there are three ongoing trials comparing open versus minimal invasive radical hysterectomy with recurrence-free survival at three and five years as primary endpoint. So we should wait for the results. Another question is, what about lymph nodes? In the SHAPE trial, the rate of positive lymph nodes was 5%, similar to previous publications. One third of the patients had sentinel lymph node mapping. So is the standard of care? Nearly 150 publications are trying to answer that question. And as Dr. Parr mentioned a few minutes ago, we need to wait for the results of SENTICLE trial, SENTICLE 3 trial, and SENTICS. Finally, the big question is, who should be the surgeon? Apart from being well-trained in surgery, gynecology skills are crucial to identify suitable candidates and to develop an effective treatment plan. In conclusion, the future after SHAPE results also will be achieving the 90-70-90 WHO recommendations about cervical cancer management, significantly reducing cases in poor regions by screening program implementation, carefully selecting patients who fit these very specific criteria to offer them less radical treatment, and also choosing providers not only skilled in surgery but also in gynecology. Thank you very much. Thank you, Dr. Naur. Now Dr. Pedro Ramirez will present the current landscape of surgical clinical trials in cervical cancer. Thank you so much. Good afternoon, everyone, for attending this session. The topic of this presentation is going to be on the current landscape of surgical trials and particularly looking at what are some of the gaps in terms of the knowledge that we have pertaining to surgical trials in early cervical cancer. I have no disclosures. The objective of the discussion is targeting those points beyond the studies that have been very well presented by the two prior speakers. Beyond those studies, what are some of the unanswered questions in early cervical cancer as it pertains to the surgical approach and then related topics with regards to the management of these patients? We'll talk about minimally invasive surgery in the setting of less than two centimeters. And this is a question that has frequently come up since the publication of the CONSERVE trial, since the publication of SHAPE, and a number of population-based studies. In other words, now that we have data on these studies that address this low-risk population, is it appropriate to proceed with a minimally invasive surgery approach, particularly after the results of the LAG trial? Many have also suggested that the vaginal protective maneuver will be the solution to continuing to perform laparoscopic or robotic surgery when performing radical hysterectomy in these patients. And we'll discuss some of the issues related to that assumption. I think it's very, very important to address the topic of conization prior to radical hysterectomy because there have been several suggestions regarding the fact that perhaps performing a conization is a protective maneuver so that the surgeon may safely continue with the approach of minimally invasive surgery. And since the results of the LAG trial as well, certainly the question of, if I have a patient who has very low-risk disease, in other words, a patient who has a 1A1 tumor, is that patient considered a safe candidate to undergo minimally invasive surgery? I think certainly focusing on the results of the CONSERVE trial, I'd like to address the point that the approach has been one of the potential suggestions as it pertains to these patients with low-risk disease. The fact is that the CONSERVE trial was a study looking at the conservative management of patients with very low-risk cervical cancer. And those patients, the majority, because those patients underwent surgery prior to knowing the results of the LAG trial, the majority of those patients underwent minimally invasive surgery. As you see here, 96% of patients underwent minimally invasive surgery in patients in the CONSERVE trial. The CONSERVE trial showed that there was a zero recurrence rate when a patient underwent a hysterectomy. So therefore, many have made the assumption that if 96% of patients underwent minimally invasive surgery and the recurrence rate was so low, then therefore that means that minimally invasive surgery is safe. So therefore, one strong and important classification, the CONSERVE trial was not designed to answer which surgical approach was the best approach for patients undergoing conservative management in this setting. And therefore, one should not assume that minimally invasive surgery is safe in this patient population. What are some of the unanswered questions after the CONSERVE? Obviously, we still don't know if MIS is the approach that is ideal for these patients. Also, what are some of the long-term outcomes in this patient population? The impact of conservative surgery on quality of life has also not been reported. And also, the definition of low-risk criteria. And we continue to associate just less than two centimeters as low-risk, but we have to be cognizant of the fact that there are a number of other low-risk inclusion criteria that should be highlighted when looking at the inclusion criteria of both the CONSERVE and the SHAPE trial. And then certainly, we don't know what is the impact of neoadjuvant chemotherapy for those patients not meeting this low-risk criteria. Flor talked about the SHAPE trial. And of course, obviously, we all know, and this has been previously presented in other meetings and in this meeting as well, with regards to the randomization of simple versus radical hysterectomy. In that study, we saw that there was no difference in terms of oncologic outcomes between simple and radical hysterectomy when managing patients with less than two centimeters cervical cancer. One of the other comments that has been made is, well, there's been a significant number of patients documented to undergo minimally invasive surgery in the SHAPE trial. Fifty-five percent in the simple hysterectomy arm, 44 percent in the radical hysterectomy arm. And of course, obviously, we all know the results that the pelvic recurrence rates were very low. So then therefore, again, looking at oncologic outcomes, there was no difference between simple and radical. And again, I stress and highlight that. The findings from that study was there was no difference in terms of oncologic outcomes between simple and radical hysterectomy. At no point should we assume that also we can also perform minimally invasive surgery based on the results of the SHAPE trial. I think, you know, certainly as we look at what are some of the unanswered questions, the role of minimally invasive surgery approach in simple hysterectomy remains unknown. And again, the trial was not designed to determine what is the ideal surgical approach. This trial was just designed to look at simple versus radical hysterectomy. So it's not meeting criteria. Again, going back to the focus on the low-risk population, more than 10 millimeters of death of invasion. What do we do about those patients? More than 50 percent death of invasion on MRI. What about the high-risk histologies? Can we assume the same results? What are the ideal assessments of tumor size? You know, certainly we know of the inaccuracies of the physical exam, the MRI, and the final pathology. And again, we don't know what is the impact of neoadjuvant chemotherapy in these patients with low-risk criteria. Moving on to the LAC trial, of course, obviously we all know the results of the LAC trial, higher recurrence rates in minimally invasive surgery compared to open surgery. But what are some of the unresolved issues in this case? As I mentioned, the concept of the vaginal protective maneuver has been previously published in our journal by Christa Kohler, and the technique is specified and outlined in that study. Dr. Luis Chiva, as part of the SUCCOR study, which was comparing retrospectively open versus minimally invasive surgery, also saw very similar results of poorer outcomes with the minimally invasive approach. But one of the questions they also had was, what about if we perform a vaginal protective maneuver? And again, what they showed was that the vaginal protective maneuver, as well as the open approach, had very similar oncologic outcomes, and then certainly worse recurrence rates if the vaginal protective maneuver was not performed. So therefore, many have assumed that by performing a vaginal protective maneuver, we will automatically see the same results as open surgery. I will remind you that is an assumption. Again, the study was not designed to explore that. That was a secondary objective of the study, and again, it's a retrospective study. So therefore, we don't have information as to what were the risk criteria or the patient selection for those who underwent a vaginal protective maneuver versus those who did not undergo a vaginal protective maneuver. And many certainly have questioned, what is the outcome of performing a vaginal protective maneuver, a radical hysterectomy, without using a uterine manipulator? What is the learning curve for that patient population when performing the vaginal protective maneuver? And certainly, we have had publications in our journal. Denis Quirleau has been a very proponent of the vaginal protective maneuver, as well as Chris Tarcola. And in this article, certainly he highlights what are some of the techniques and the approaches. So as it pertains to the question of the protective maneuver, what are some of the unanswered questions? We don't have clear indications as to which patients underwent protective maneuver or not. Many of the publications on the vaginal protective maneuver are a single surgeon experience, and then therefore, one can deduct what is the value, the scientific value, of a single surgeon's maneuver. The expertise and the learning curve, we certainly talk about the learning curve of any surgeon's surgical procedure. We don't have data on what is the appropriate learning curve for performing a radical hysterectomy with a vaginal protective maneuver. And in addition to that, the median follow-up for protective maneuver patients often is unknown and undocumented in many of these studies, as well as the rate of adjuvant treatment in protective maneuver patients, the treatment at the time of recurrence, which is also a question when comparing two groups and looking at oncologic outcomes as a result of that study. And again, highlighting all of these are retrospective studies. And again, granted, the vaginal protective maneuver has been incorporated into the prospective studies, I should say some of the prospective randomized studies. The next question has been, well, what about patients less than 2 centimeters? Can we perhaps perform minimally invasive surgery in those patients? This is one of the first studies after the LAC trial that explored that question. Let's take a look and compare minimally invasive surgery versus open surgery in patients with less than 2 centimeters. What that study found was that even in patients less than 2 centimeters, minimally invasive surgery was associated with worse outcomes even in that patient population. And in fact, actually, a large database series study of over 2,000 patients by Dimitris Nasioudis also confirmed that in a large retrospective study, that there was evidence that the minimally invasive approach had worse oncologic outcomes compared to the open approach. So let's not assume that by defining a tumor as less than 2 centimeters, that it is absolutely safe to perform minimally invasive surgery. In addition to that, we need to take into account a number of other factors. The fact that we are not very good at having accurate measurements of tumors in the cervix. What about in tumors that are multifocal? When the patient has had a leap or a cone, the status of those margins, when there are multiple lesions in that specimen. And in addition to that, again, one of the things that I have to highlight, again, when we look at studies of less than 2 centimeters, is the fact that often the number of patients in those studies in comparative arms are not sufficient to answer the question of the approach. In other words, the event rates, the recurrences in that patient population is so small. We saw it from the shape trial, 3% recurrence rate in that patient population. When you have a population where the recurrence rate events are so small, you will need large numbers of patients to determine if one surgical approach is equivalent or non-inferior to the other. The high-risk histologies, also, we don't know what to do about those patients in terms of the surgical approach, particularly in less than 2 centimeters from the data that has been published. And the management of inadvertent simple hysterectomy is also a question. The question of cervical conization. Many have said, and some you have heard in this meeting, you say, well, if you do a cone, then you're going to debulk that tumor, and therefore, it is okay to proceed with a minimally invasive approach. This is a study, it's a sub-study of the SUCCOR series by Kike Chacon, and he suggested in that study that prior cervical conization had a significant lower risk of relapse and death, and that minimally invasive surgery without conization had a higher chance of relapse. It's very important to highlight that in that study, they highlight the fact that the present study should be hypothesis generating only. Hypothesis generating only. This is another study that often is quoted, referenced, about the fact of saying, well, if you do a cone, then you can do minimally invasive surgery. And this is the results that were found, again, showing that patients who have a cone do better. Patients who don't have a cone do worse. But one of the things that I always want to highlight is that when you look at those studies, of course, patients who have a cone do better than patients who don't have a cone. Why? Because patients who have a cone are usually patients who have microscopic disease, very small tumors, versus patients who don't have a cone, usually they have gross esophytic tumors, and therefore, that's why they didn't have the cone. So I think, of course, when you're looking at that patient population, you're not comparing an equal, balanced, risk factor population. You're looking at patients with small tumors versus patients with large tumors. Of course, you don't have to tell me what approach you take. The patients with small microscopic tumors are going to do better than patients with large tumors. So it is very important that we don't follow this concept as suggested in this study, that cervical conization could be considered a therapeutic procedure, a debulking procedure. It is not. A conization in the setting of gross disease is not indicated, and that's very important to highlight. What are some of the unanswered questions on prior conization? The indications for the conization often are not standardized in those studies. The margin status of the conization are often not highlighted. The type of conization, leap versus cold knife cone, and the outcomes based on the approach. The flaws in the data interpretation, again, cone, low risk, microscopic disease. No cone, high risk, gross disease. The second group is always going to do worse. Now, the last question is, well, what about if I have a patient who has a very, very small tumor, a microscopic tumor? Can I take a minimally invasive approach in those patients? And in this study, Demetrius Masiudis showed that overall survival was comparable. In other words, it's the same, whether you do minimally invasive surgery or not. But again, you're looking at a patient population that is very low risk, stage 1A1, patients usually without lymphovascular invasion. Those patients do not need a radical hysterectomy. And certainly, perhaps in those patients, it is okay to do a minimally invasive approach. What is the standard? Today, the standard for the approach on the surgical management of patients with early cervical cancer is the open approach. There are ongoing studies. Obviously, we know about the RAC trial, the ROC trial, and a Chinese study that is also evaluating the same question prospectively. So in conclusion, there are a number of unresolved questions. The vaginal protective maneuver is not prospectively evaluated on oncologic or surgical outcomes to date. There is no data on the learning curve. There's no data on quality of life. On the topic of tumors of less than 2 centimeters, adequately powered studies show that minimally invasive surgery is worse than open surgery. Conization improved outcomes in patients with a cone is not because of the cone, but rather the fact that patients who undergo a cone are much lower risk patients. And then on the question of 1A1 versus 1A2, MIS is likely okay, but patients do not need a radical hysterectomy in that situation, and now that is proven with prospective data. So thank you so much for your attention, and we'll be happy to take questions at the end. Thank you. Thank you, Pedro. Now, I would like to call Dr. Milechkin, who will present replacing surgery by targeted treatment for early stage cervical cancer, utopia, or future. Linda, please. Thank you, Andreas, and thanks for the invitation to speak at this session. These are my disclosures, and the important disclosure is that I'm a medical oncologist talking in a session about early cervix cancer. So when I first got this topic, I thought it seemed a bit strange, because as a medical oncologist, I think of targeted therapy as tyrosine kinase inhibitors. I don't think they're ever going to replace surgery, and I'm not going to talk about them today, but I do think that we can use targeted treatment approaches to reduce the need for surgery in cervix cancer. So I'm briefly going to talk about prevention, the ultimate targeted therapy to stop the need for surgeons, how we can improve the treatment of pre-invasive disease, improve patient selection for primary surgery, talk about fertility sparing treatment approaches, how we can improve treatments for locally advanced disease, and the need to improve access to radiotherapy, particularly brachytherapy, globally, and then touch on how we might incorporate some of our novel therapies into neoadjuvant approaches. So why would we even talk about this topic? Obviously surgery plays an essential role in both the diagnosis and the management of cervix cancer. It cures women, but we know that there's a critical shortage globally in the surgical workforce. The Lancet Oncology Commission that published in 2015 found that 80% of 15 million people diagnosed with cancer worldwide were going to need surgery, but only 25% actually had access to safe, affordable, and timely surgery, with the disparity being particularly worse in lower middle income countries. And publications since that time seem to only suggest that the situation is getting worse. I wanted to thank one of my colleagues, Emma Allinson, a gynae oncologist from Perth in Australia who shared with me some evidence from a recent study that she undertook with colleagues which looked at what was the actual global burden of cervix cancer needing surgery. And what this group did was look at the incidence of all cancers, and then specifically cervix cancer, extracted for each country from the WHO and IARC databases, and then estimated the need for surgery for cervix cancer in each country. They had data available for 175 of 194 countries, equating to nearly 3 billion females aged 15 or more. And what they found was that of over half a million cervical cancer cases, 322,000 or 57% would require surgery at some time for diagnosis, treatment, or palliation during their cancer journey. Importantly they found that the percentage of cervix cancers out of the whole group needing surgery was different in different areas of the world. So it was 15% of all cancers in the African region and 8.9% in the Southeast Asian region, compared to 1 to 3% in the rest of the world. And given that we know that around 50% of cervix cancer occurs in lower and middle income countries, obviously we don't have enough gynae oncologists globally. So obviously the ultimate way to prevent the need for surgery would be to target HPV, which we can do by vaccination. And you all know that the first vaccine was licensed in high income countries in 2006, but we've still got a long way to go. There's still countries without vaccine programs, and so less than one in three girls in the world aged 9 to 14 live in countries where there's a vaccination program, and less than one in eight are actually vaccinated globally. And this slide shows you that we are making improvements over time, particularly if you look at the graph on the left, you'll see how there's an increase in the number of countries with vaccination programs, particularly in high income countries, but a big lag in the lower and middle income country group. And globally we only have 13% coverage worldwide and 8% in lower and middle income countries. And 60% of cases of cervix cancer are occurring in countries where there's no prophylactic vaccine program. We've also seen a decline in immunizations across the board, not just against HPV as a result of the COVID pandemic and still trying to recover from that. The other approach is how can we use a targeted therapy approach to select the right patients for surgery? And I know in the center that I work in, the surgeons want to have an MRI and a PET scan before they think about operating on many patients with cervix cancer. We know that PET CT is very helpful to detect nodal metastases and distant metastatic disease with a sensitivity of around 75% and a specificity of 92%. But there are also global inequities in access to PET-CT for cancer management. And this recent publication and graph shows you different countries in the world and the number of PET scans available per million population. And you'll see some of the countries in gray, where we know there's a lot of cervix cancer, there are no PET-CT machines. So the authors found that there was one PET-CT per 600,000 of the population in high income countries, but in lower and middle income countries, it was one PET-CT per 10 million. So we can't select the right patients for surgery unless we can assist them properly. The other way that we can reduce the need for surgery in cervix cancer is to have better non-surgical treatments for local advanced disease. And it's been, in fact, I'll just go back one, because I think I might've missed one slide there. It's been great at this meeting to see the results represented of the interlace trial, showing that neoadjuvant therapy can improve survival rates and recurrence rates, as well as the use of adjuvant immunotherapy. Obviously, if our local treatments work better, there's less need for horrible surgeries like exenterations for recurrent disease. Also, if we use more target approaches with radiotherapy, we will improve outcomes and reduce local recurrence. And obviously, the EMBRACE studies have showed that if you use image-guided brachytherapy and actually treat the cancer where it is, rather than point A, outcomes appear superior. And that if you use more modern techniques such as IMRT, that you can reduce the toxicities of radiotherapy, some of which also result in need for surgery. But obviously, globally, there is a mismatch between where women are dying from cervix cancer and where the radiotherapy machines are. And it's not just about machines. There are also deficiencies in the numbers of staff and training requirements. And this is even an issue in high-income countries. For example, in the US, I believe that as part of residency, there's a minimum requirement to do only five interstitial procedures, which obviously is not enough to become competent. And this is really important because over time, we're seeing actually a decline in the use of brachytherapy. And it has been clearly documented in population studies that this is associated with worse survival rates, as you can see here. So how about novel therapies? How about using things like immunotherapy to reduce the need for surgery? So when we first started using immunotherapy in the clinic in medical oncology, we thought that it only worked in tumors with a high mutation burden. And cervix cancer is not one of those. It has only an intermediate mutation burden of between 2.5 and five mutations per megabase. And only around 4% to 8% of cases may be MSI high. But potentially, it may still be responsive to immunotherapy because of integration of the HPV virus into the tumor. So in terms of it being a target for vaccination, this has been a challenge for treating pre-invasive or existing cancers. Obviously, the prophylactic vaccines have been really successful. And what they do is produce neutralising antibodies against the L1 capsid proteins. However, what happens during progression from HPV infection to actual development of cervix cancer is that the virus becomes integrated into the nucleus and there are changes so that there's loss of E2 and increased expression of E6 and E7 and actually loss of this L1 target. So hence the current prophylactic vaccines can't be used to actually treat pre-invasive or indeed existing cancer. But it does provide an immunogenic foreign antigen and amplifies things like PD-L1 expression. And this slide shows you how the progression occurs from infection to established cancer. And so we can't rely on an antibody approach to treat established cancer. We actually need cell-mediated immunity to kick in and need the T cells to be able to attack and fight the cancer. But this has been really challenging in HPV because it has a very relatively slow life cycle and it's not cytolytic. It's also very good at evading both the innate and adaptive immune system. And it doesn't produce a high level of inflammation that might alert the host to infection. So in terms of therapeutic HPV vaccination, it's still a very active area of research. Ideally, you'd want it to both clear the infection as well as cause regression of precancerous lesions. And theoretically, it might be useful as secondary prophylaxis. You could give the woman a shot as she went out the door after you've treated the pre-invasive lesion and then they wouldn't need to come back. But however, the data hasn't been that spectacular so far. In a recent systematic review of completed phase two and phase three studies of therapeutic vaccines targeting CIN2 and 3, they identified 12 studies. And of the two arm studies, the regression rate post HPV vaccine was only about 50% higher than placebo. So given surgeons can cure these women, we've still got a long way to go. And obviously, actual therapeutic vaccines to treat established cancer are even further behind that with results so far being quite disappointing. What about neoadjuvant treatment? So we use this widely now in other cancers such as breast cancer, rectal cancer, ovarian cancer. The idea is you shrink the tumour, facilitate surgery or limit the extent of surgery that you need to do. And recent studies in breast cancer and melanoma have shown a good correlation between the pathologic response and long-term outcomes. It can be used to either then tailor, escalate or deescalate the adjuvant therapy. And it allows you to test novel combinations and actually get tissue for translational analysis. But there's obviously a risk of disease progression during neoadjuvant therapy. You don't want the patient to become incurable and also a potential for increased perioperative complications or morbidity. We do have some data about the news of neoadjuvant chemotherapy in the fertility preservation space which has been really championed by Marie Plant who we've heard mentioned several times already this afternoon. And we do have some data that intensive chemotherapy often very toxic chemotherapy can have a response rate as you can see listed in this slide. But some of the problems with the literature is it's mostly been small retrospective studies and there's been a lack of standardisation about the type of surgery, how they assess the lymph nodes and the choice of chemotherapy. So pleasingly the international community has got together to work on this trial involving both Marie's group and Frederic Amont's group from Belgium where they're going to actually do a study in stage 1B2 cervix cancer, sorry. Yeah, 1B2 cervix cancer that's two to four centimetres in size and give them three cycles of carboplatin and paclitaxel chemotherapy. And then if they've had a complete or partial response we'll go into fertility sparing surgery compared to if there's no response have chemo radiation. So what about using non-chemotherapy approaches and what can we learn from other cancers? This is a recently published study from the New England Journal in the melanoma space that looked at patients with locally advanced melanoma and randomised them to standard treatment with surgery followed by adjuvant immunotherapy or to a neoadjuvant arm where people had three cycles of pembrolizumab then the surgery and then further immunotherapy. And the neoadjuvant response was really successful. The response rate as you can see here was about 47%. So remember that we need about 50% to get a response. And they actually show improved event-free survival with the neoadjuvant approach as compared to the surgery and adjuvant approach. Looking further at mismatched repair deficient cancers that also respond really well to immunotherapy. There's this famous study where you can get a publication in the New England Journal with only 12 patients treated with six months of distalimab. Everyone had a complete response. Subsequently at ASCO last year, we saw the presentation of this NICHE2 study which was a single arm study of neoadjuvant therapy in locally advanced MMR deficient colorectal cancer. In this study, they just gave two cycles of neoadjuvant treatment. The first with nivolumab and ipilimumab and the second with nivolumab alone and then proceeded to surgery with important endpoints of safety and three-year disease-free survival. And we know now from this study that this approach was safe. So there was 100% R0 resections. The median time from the first dose of immunotherapy to surgery was five weeks and it appeared safe. 98% of patients underwent the surgeries safely. And again, the results were quite spectacular. A major pathologic response in 95% of patients and 67% having a complete response. So what about cervical cancer? Is it feasible or even a good idea to try something like this? In terms of the activity of immunotherapy in advanced cervical cancer, we probably can't use single agent checkpoint inhibitor. It only has a 15% response rate. But over time, we're seeing different combinations come out such as combination with CTLA-4, bispecific inhibitors, combinations with ADCs and more recently combinations with chemotherapy and we're now getting a response rate of around 66%. The most recent and active data shows that if you use a bispecific antibody and chemotherapy, maybe even together with bevacizumab, the response rate's really high. And you might say, this is never practical. This will never happen in the developed world. These drugs are so expensive. But actually, nivolumab comes off patent in 2028 and pembrolizumab will come off patent in Europe in 2028. So maybe it could happen. And I just wanted to briefly show you these results that presented at ASCO last year of the AK104 bispecific antibody. And you can see here the really dramatic response rates here and importantly, no patients progressing. So could we now design a potential trial for women seeking to preserve fertility and put this in there? So use three cycles of neoadjuvant dose-dense carbotaxel plus a PD-1 inhibitor. So I've just got a few more slides. Could we also use this approach in the neoadjuvant space? Obviously, we know that chemo radiation works better for locally advanced disease than neoadjuvant chemo followed by surgery, but this is not available in many parts of the world and so we need to use the neoadjuvant approach. So could we also potentially have a clinical trial design where we put in the PD-1 inhibitor with the neoadjuvant chemotherapy and maybe then we'd get more people in the good response arm who could go on successfully to diminutive surgery. So in conclusion, we still need surgeons. There are lots of targeted approaches we can think about and hopefully, if we can think together and think outside the box, we'll improve things for our patients. Thank you. Thank you, Dr. Mielewski. Please join us at the table. Our final presentation will be done by Hai-Suk Cheon who will present evidence for and against adjuvant radiation treatment in intermediate-risk cervical cancer. Dr. Suk. First of all, thank you so much for the invitation to present and discuss evidence for and against adjuvant radiation therapy in intermediate-risk cervical cancer. This is my disclosure. For the treatment of early-stage cervical cancer, the single-treatment modalities prefer the method given high risk of GI and GU complication from combined modality. And often, the surgery's preferred approach over primary radiation treatment given particularly young patients to preserve ovarian function. The patients undergoing surgery for early-stage cervical cancer may benefit from adjuvant treatment when they found to be intermediate-risk or high-risk. The terminology or definition of intermediate-risk group was defined by GOG-49. GOG-49 was conducted in early 1980s in over 500 patients whose disease confined to the cervix. They underwent a radical hysterectomy and a pelvic lymph node dissection. Ruled out being high-risk, the patient's three independent prognostic factor was identified including clinical tumor size, lymphovascular invasion, and depth of tumor invasion. The presence of these three factors increased the probability of the recurrence at three years to 31%. After defined intermediate-risk group of the early-stage cervical cancer, GOG-92 was conducted, which was a phase three randomized trial. Patients underwent a radical hysterectomy and a pelvic lymph node dissection. And when they have one of four combination of the risk factor, then randomized to either no further treatment or pelvic radiation to determine if post-operative radiation therapy would reduce the rate of the recurrence and the decreased mortality in this intermediate-risk group compared to the surgery alone group. As a result, there was a 47% reduction in the recurrence risk in the patients receiving adjuvant radiation treatment. Recurrence free rate at two years was 88% in the radiation group compared to 79% in non-further treatment group. As a post-hoc 12 years follow-up study of the GOG-92, post-operative adjuvant radiation arm continued to show 46% statically significant reduction in the risk of the recurrence. However, improvement in overall survival with the radiation did not reach statistical significance. Current guideline for management of the cervical cancer after radical hysterectomy with this intermediate group meeting SEDLIS criteria, NCCN guideline pelvic radiation is a category one recommendation. Similarly, European guideline also recommend adjuvant radiation in intermediate group. Over time, our experience and knowledge in this traditional intermediate-risk group has evolved. An increasing number of retrospective study have reported no significant benefit of adjuvant treatment in intermediate-risk group as opposed to GOG-92. First, this large retrospective study from single institution, among 338 patients with intermediate-risk group, 85 patients received no adjuvant treatment, 283 patients was treated with the radiation treatment. In the median follow-up 63 months, relapse rate was 12% in no adjuvant treatment group compared to 14% in the radiation group. There was no statistical difference. In addition, adjuvant radiation treatment was not associated with the disease-specific survival benefit compared to no adjuvant treatment group. Notably, this large study only included squamous cell carcinoma. Interestingly, when you're looking at each of four combination risk factor group, there was significant heterogeneity among the group. Higher risk of relapse and death occur in the patients with lymphovascular space invasion and the deep stroma invasion compared to other group. Moving into another large retrospective study from international multi-center consortium data, the surveillance in cervical cancer consortium consistent with the 20 tertiary centers located in Europe, Asia, North America, and Latin America. Total 692 patients with intermediate risk group was analyzed in this study. 271, about 40% of patients receive no adjuvant treatment. 407, about 60% of patients receive adjuvant treatment either radiation or chemoradiation. The five-year disease-free survival was 83.7% in no adjuvant group and 81.2% adjuvant group. There was no statistical difference. Similarly, there was no statistical difference in overall survival as well. How about metanalysis? This metanalysis included the patients with two comparative arm intermediate risk group, collectively two randomized clinical trial, two prospective trial, four retrospective trial was included in this metanalysis. Total, about 1,400 patients was included. Recurrence rate, there was no relative risk of the recurrence and the relative risk of mortality was similar, but both group independently whether they did or did not receive adjuvant treatment. As you can see, the no further treatment group, the recurrence rate was 16.4%. The radiation group was 11.8% which was lower than GOG92. So there has been some criticism about GOG92 as mentioned earlier, their recurrence rate and the mortality was higher in the GOG92. Possible explanation for that is in the GOG92 only clinical tumor size was measured. There was no pathology tumor size been reported. And in addition, negative lymphovascular space invasion unevenly distributed between adjuvant group and the no adjuvant group. And the no standard surgery was documented. Once again, high recurrence rate was noted, no survival benefit was noted. Since GOG92 had conducted, time has changed. We should take into consideration the selection of patients with intermediate risk group now is much more accurate than three decades ago. First, a FIGO staging has evolved too. In 1994, when the GOG92 has almost a complete bulky 1B was divided at four centimeter cutoff into 1B1 and 1B2 to establish a specific treatment strategy according to their different prognostic impact. In 2018, FIGO revised stage classification to allow clinical, radiological and pathologic finding as a valid tool to assign stage of disease. In addition, given the low recurrence rate in the tumor less than two centimeter in size, stage 1B was further subdivided into 1B1 less than two, 1B2 to two four centimeter and 1B3 greater than four centimeter. And during the time three decade, the radiologic imaging has evolved as well. PET-CT scan, as you hear earlier, useful for pre-treatment detection of retroperitoneal nodal metastatic cervical cancer. More, when the radiologic finding was incorporated into the staging system in 2018, this study reported that 30% of patients FIGO 2009 stage one to three were restaged to FIGO 2018 stage three C to identify high risk group. Surgical approach has been evolved as well. Sentinel lymph node detection and their ultra-staging able us to detect additional 10 to 15% of cases with a small macro or macro metastasis. Once again, another tool to identify a high risk group. For radicality of the surgery type two and type three, the details in the specific is now better established than the time of the GOG92. It is also important to consider histologic factor. Cervical adenocarcinoma is a distinct cervical cancer subtype. The risk factor for the recurrence differ between the squamous cell and adenocarcinoma. For instance, in adenocarcinoma, tumor size is the risk factor associated with highest risk of the recurrence. Squamous histology, the impact of a deep invasion is a significant risk factor for the recurrence. Treatment should be based on data specific to this subtype. Treatment modality with the radiation has evolved over time as well. In the SEDLIS criteria, heavy radiation was given fulfilled technique. Now, 2023, the standard radiation modalities, which make it possible to deliver those target volume with less toxicity to nearby critical structure. In the study of post-operative adjuvant radiation in the cervical cancer, in which patients were randomized to either three-dimensional radiation versus IMRT post-operatively. The late grade three or high GI toxicity was 2.9% in IMRT arm compared to 15.5% three-dimensional radiation arm. So modern radiation treatment less late toxicity, even less. Moving forward, this Cerventis trial is a modern version of GOG92, which is, this is a prospective international randomized non-inferiority phase three trial aiming to evaluate if adjuvant radiation is associated with the disease-free survival benefit after radical surgery in the patients with intermittent risk group. I think we still have some remaining questions for treatment intermediate risk group early stages of cervical cancer. To how to define true intermediate risk group in the modern era of the medicine. To answer to this question, what is acceptable rate, recurrence rate, and how to further define this heterogeneous group, how to incorporate histology factor to determine intermediate risk group. Another question might be the role of a primary radiation treatment in early stages of cervical cancer, such as stage 1b2, possibly tumor size three or four centimeter. To answer this, multiple factor need to be considered. Mobility of patients, also mobility of the radiation treatment itself. And then time commitment associated with the radiation and the long-term quality of life. In conclusion, to date, adjuvant radiation therapy should be considered in the presence of a combination of a risk factor at the final pathology. It is imperative to establish a new management alternative with the standardization of imaging, histopathology factor evaluation, and the radiotherapy technique to assess oncologic benefit of a different type of adjuvant treatment, including observation. The associated mobility, quality of life should be considered as outcome. Eligible patients should be encouraged to participate in clinical trial. Thank you for your attention. Thank you, Dr. Chong. We will have now 15 minutes for discussion. I would encourage you to submit your questions through the mobile app or come to the microphones on the floor, identify yourself. Yes, please. I have one question. I'm Kenrochi Kaza from Japan. I want to ask education of radical hysterectomy for our fellows because after shape trial, indication of radical hysterectomy is decreasing less and less and less. So do you think all fellows of gynecologic oncology experience radical hysterectomy or selected attending doctors should be educated about radical hysterectomy? Thank you. Yeah, I mean, I'll address that question. Certainly, obviously, we foresee that the number of radical hysterectomies, particularly after the shape trial, is going to continue to decrease. And I think also even further, as we start exploring that rate of adjuvant treatment in patients in the 1B2, so in other words, patients with more than three centimeters should those patients undergo primary radiation. Your slide suggested that perhaps a future potential possibility is anyone with a tumor above two centimeters will undergo radiation. So obviously, yes, I mean, there is going to be a potential compromise in terms of how many radical hysterectomies are exposed. But again, obviously, I think that we would all agree that we're not going to continue doing an unindicated procedure just to teach our fellows. We stopped doing the radical Halsted procedure for breast cancer because it wasn't indicated anymore. So today, no one gets exposure to the Halsted radical procedure. And therefore, again, we have to move forward as the evidence shows. So as your comment, only skilled attending and foreseen selected residents or selected fellows, he will be or she will be skilled attending. Such selected surgeon will educate about radical hysterectomy. Right, I think it goes back to the point of skilled. Can you define what's a skilled attending versus a non-skilled attending? I think that I don't think there's any surgeon that walks into the operating room and says, I am very unskilled. I am mediocre. So I think that again, that goes to a challenge in defining who is a skilled surgeon. I don't know any surgeon that walks into the operating room and says, I am unskilled, but I'm still going to do this surgery. Thank you very much for your question. Thank you. I would, it reminds me on a discussion that I'm sure the breast surgeons had about 100 years ago, whether we do Rotter-Halsted operations where we remove the pectoralis muscle, should we do pectoralis muscle removal of radical mastectomies to keep in practice of doing it and things like that. So all of us who are worried that we're losing skills, generations before us have been in similar situations and obviously survived. There is a question for Dr. Park that came through the app. Dr. Park, how can we do re-injection if we open most of the retroperitoneal spaces and there are interrupted lymphatic vessels? Would you mind answering that? Thank you for the good questions. To perform the pelvic dissection without interrupting pelvic lymphatic pathway, you should be aware of the usual lymphatic pathway. As I told you, there are two lymphatic pathway, upper pelvic and lower pelvic. Upper pelvic pathway is drained through the uterine artery to the obturator area in usual. So when we perform pelvic dissection, we do not cut this area. Usually we find out obliterated umbilical artery first and dissect the paraphysical space and then dissect the pararectal space. The upper pelvic pathway is usually between these two spaces. After developing these two spaces, if there is no ICG uptake, we re-inject the ICG again and if the injection is appropriate, we can identify the upper pelvic pathway drained through between the two spaces. And for lower pelvic pathway, usually it is located at the base of pararectal space. Usually we can find it without disrupting lymphatic pathway when we dissect the pelvic cavity. Thank you. Thank you. Would you mind identifying yourself and ask a question, please? Thank you very much. I'm Taufan from Indonesia. Very inspiring and nice lecture. My question is addressed to Dr. Professor Amiraz and Dr. Chan. Yes, I do agree that the patient with cervical cancer is depends treated by high resource or low resource and even very, very low resource. My question is, from a conserved study that's mentioned, squamous cell carcinoma is around 48% and adenocarcinoma histotype is 52%. Is there any separation between endophytic types and exophytic type in these groups that we have to do the simple hysterectomy or radical hysterectomy? And my second question, is there any, how many time, I mean, how many months that we have, we can wait until the patient is eligible to do a total hysterectomy or simple hysterectomy? Because in our institution, Indonesia is really long queue to go for a surgical procedure for the patient. So if we would like to choose, this is a very strict size of the tumor size. It is two centimeters or less. So if the time is running and then the tumor is bigger, I think it is not allowed in the very low resource like us. And the last question for the last speaker, Dr. Chan. I think, yes, I do agree that the power of radiation is take place even in the early stage of cervical cancer. So my question is, do you have any study that endophytic types or exophytic types in even in early stage of cervical cancer give different outcome for radiation? Thank you. Yes, so thank you for your questions. With regards to the exophytic versus endophytic, the conservative trial did not specify whether the patient had an endophytic versus exophytic tumor. I think also, if you were to even consider that, if you were designing a study and I would describe, tell me what's an exophytic tumor versus an endophytic tumor. I think certainly there will be variations in terms of like how that would be defined. So these kinds of subjective terms are very difficult to implement into an inclusion criteria of a study. Because certainly one might question that a one centimeter tumor that is on the exo cervix, that is a very small tumor, it's a one centimeter tumor. Would you call that an exophytic tumor or would you not? So I think that it's, although we use a lot of this terminology, a lot of us don't know how to define that terminology. In terms of how long to wait, obviously, typically in the setting of having undergone a colonization, typically in our institution, we wait anywhere from four to six weeks to doing any additional procedure. But I think your question was more to the concern of like, if you have very prolonged delays, in that setting, I would just say, re-examine the patient close to the time of surgery. Because again, the patient ideally will have a physical examination one or two days before the surgery. And now if the tumor is two and a half centimeters, three centimeters, then there goes the plan. And then there needs to be a new plan. Yeah, yeah, okay. Thank you very much. But sometimes the objective one to measure the update about the tumor size is MRI, isn't it? But MRI in our institution, in our center, it needs three or months quick. So I think it is not eligible at all in our setting. So I just want to give me the correction if I'm wrong, that I think in our setting, in very, very low resource setting, we can decrease the limitation of the tumor size, let's say one centimeter or less or something, because sometimes it's not like in the high resource, yes. Yeah, and I think that for any of us, if we're considering that we're on the border as it pertains to, is this tumor less than two or more than two, then I think most of us would agree that we would proceed with the higher approach on treatment. So if you're wondering, is this tumor really two or 2.4 centimeters, a patient is going to get a radical hysterectomy. Similarly, if a patient has a tumor of 3.5 or 3.8, that patient most likely is going to get radiation therapy because you're going to see on imaging that there may be deep invasion or stromal invasion up into the upper cervix. So that patient most likely will benefit from radiation therapy. So always err on the higher end of that treatment. Yeah, thank you very much. Leticia. To answer your question about any different treatment modality between squamous cell carcinoma, adenocarcinoma, I don't have any answer to different approach or radiation treatment between histology, but take into consideration their risk factor, the recurrence between the squamous cell adenocarcinoma is quite different. So future study need to include those concept to determine intermediate risk group to decrease recurrence in the pelvic area. Yeah, because from the past, that we know that adenocarcinoma is a type of gift, more pure, yeah, more, yeah, not so good like SCC. So what is your opinion, Dr. Ramirez, about this? Because I am surprised that in the CONSERVE study, that is comparable between adenocarcinoma and SCC type, because we know that SCC is dominant, but it is comparable. I'm just mindful that we also want to give other people the opportunity to ask questions before we need to close the question. Thank you so much. There was one question here and then one question here. Hi, I'm Mingyin Lin, radiation oncologist from Melbourne. I had a question directed to Dr. Chon. So you mentioned about that IMRT has now, and radiation techniques have actually improved. Could you have comment on the role of, or if you've got any experience in small volume central field radiation, and perhaps comment on whether it's got a role now in that radiation techniques have improved in reducing toxicity? So my practice is very clear to choose one single modality of treatment in the radical hysterectomy or primary radiation hysterectomy, even 1B2. So that, as Dr. Ramirez mentioned, when I'm thinking about possibility 3.8 centimeter, I am going more upper side limitation to consider as locally advanced cervical cancer treated with the chemo radiation rather than do the radical hysterectomy and then do the adjuvant treatment. So that is my approach. To small volume of disease, I think definitely in the patients who is not the great surgical candidate, a lot of medical morbidity, I tend to, we obviously do more radiation treatment than not surgery. I don't know whether I answer your question. Not quite, I guess we'll talk about it later. Okay, so by the way, I'm gynecology oncologist. I'm a radiation oncologist. Thank you, thank you, there was a question here. Thank you, I am Janatul from Bangladesh. Actually in my country, disease burden cervical cancer is too high. Though I work in a high volume center, even there is a long queue of operation, many patients we have. And this session actually inspirational because of tumor less than two centimeter, low risk, we can do less radical procedure that will take less time, we can do more surgery. But one question to Sir Pedro Ramirez that if I assess a patient as a low risk and less than two centimeter based on gross examination and MRI, but after surgery, the report revealed, the pathology report revealed the size is more than two centimeter and LVSI positive, then additional adjuvant treatment is indicated, then it will create another load to our existing system because our radiotherapy facilities much less than the surgical facility. What is your comment on this, sir? Thank you. Yeah, and I think again, stressing the importance of that preoperative assessment and certainly we rely on physical examination. We know the high inaccuracy of physical examination, clearly also the MRI is another factor that has its potential limitations, particularly in the setting of a patient who has had a recent colonization as well, where there may be inflammatory changes that may mimic a tumor as well. So in the setting of having performed a surgery where the tumor subsequently is more than two centimeters, I think certainly one would need to assess what is the additional element of risk factor for that patient. And if considered a candidate for adjuvant treatment in the form of radiation therapy, then of course that patient would undergo that treatment. We had a prior studies, a retrospective study where there was an evaluation of patients who had a simple surgery for when it was needed as a radical surgery, looking at the risk factors for the conserved criteria. And I think certainly when you look at that patient population, still the likelihood of those patients having recurrences, it may still be low. And Rene, you may wanna add some additional information. You were the author of that study. I agree with all the things you have said. The definition of the tumor size is quite challenging and it should be clearly determined by physical examination imaging if you want in order to define the type of hysterectomy. Definitively, most of the patients who will receive the benefit of less invasive procedures are patients that had undergone a colonization, but trying to perform a simple hysterectomy in a visible tumor, you will need more support, maybe a mandatory MRI or ultrasound if you have a trine ultrasonographer at your center. And one thing to also add is to remember that patients, in order to qualify for the conserved trial, they had to have negative cone margins. And if they didn't, they had to have a repeat colonization to make sure that there were negative cone margins as well. Thank you very much, Pedro. That is all the time that we have for questions. Thank you for your participation and thank you for this exceptional panel and for their presentations. Please join us for the closing ceremony which begins at 3.55 in this place. Thank you very much.

Cervical cancer

Treatment

Conservative management

Global shortage

Surgical workforce

Access to surgery

Radiation therapy

Intermediate-risk

Advancements

Risk stratification

Preoperative assessment

HPV vaccination

Personalized treatment