master session at IGCS 2021. This master session is dedicated to cervical cancer. And since it's the first master session, I can't wait to get started. So I better start sharing my screen. My name is Gonzalo Dornelli, and I have the honor to co-chair this session with my dear colleagues, Dr. Jyoti Maledev and Dr. Leslie Randall, both from US. We hope you all agree that master sessions are an excellent way to comprehensively assess gynecological malignancies. And today we will do so with cervical cancer. At the end of the presentation, we'll have time for a segment of discussion and Q&A. So do not hesitate to send your questions through the Q&A pathway. And we'll try to address them all by the end of the presentation. So these are my disclosures. They're right in it. I'm gonna start by presenting a case on prevention. This is a 42-year-old patient who comes from a low-income country. She was too old to be vaccinated when the law was passed in Argentina 10 years ago. This is her OB history. And since she lives in an underserved area, she has difficult access to health care facilities. That's why her last screening test was done eight years before she was diagnosed. She started with symptoms by the late 2019. And two months later, she had a biopsy confirming a cervical neoplasia that was a poorly differentiated invasive squamous carcinoma. So our first presenter is Dr. Laia Bruni from Barcelona, Spain. She will address the subject of how do we get to eradication? How do we fulfill the human day by 2030? Is it by catch-up vaccination? Dr. Bruni, your audience. Many thanks. Just sharing my screen. Okay. Many thanks and good afternoon to everyone. Thank you very much for this invitation. It's a pleasure to be here and to be able to present and discuss this relevant topic on cervical cancer elimination and the use of HPV vaccination in older populations. We are going to try to answer these questions. How do we get to eradication? Is catch-up vaccination worthy in older than teenagers? Is the solution for vulnerable economies? There is now very good evidence that HPV vaccination, particularly at young ages, strongly reduces cervical cancer. This is a data that came out last year. This is from Sweden. Laia and colleagues showed an 88% reduction in cervical cancer among young women who had been vaccinated before the age of 17. You can see here in the figure, this flat green curve, no, this flat line, sorry, in those girls that were vaccinated before 17 years of age and almost no cervical cancer was observed in these cohorts. There is, well, there was also an observed reduction of 53% clinical relevant on women that got their vaccine later, between 18 years of age and 30 years of age, but was not statistically significant. Early this year, Susan Kier and colleagues from Denmark confirmed similar results. As you can see, they observed significant decreases at population level in cohorts vaccination before age 20. The stronger the effect, the younger the age at vaccination. They observed 86% decrease in cervical cancer among vaccinated before 16. 68%, in that case, statistically significant. You can see here how the lines, the red lines, and these are the confidence intervals do not overlap with the unvaccinated cohorts, but they couldn't observe an immediate effect in women that were vaccinated between the age of 20 and 30 years of age. But we have also to stress that this is cervical cancer, the incidence of cervical cancer before age 30 that could be measured. So maybe for these cohorts, we need some more time to see if there is an effect. And later, at later ages, these two curves diverge. Maybe it's still too early to see an effect at those ages. But what it's clear is that there is a strong effect in girls vaccinated before 20 years of age. From clinical trials, we know that vaccines are highly effective in HPV vaccine, and, sorry, in HPV-negative women at time of vaccination. The efficacy is very high against vaccine types and against incident infection. However, exactly, we see this loss of effectiveness when we look at the data, irrespective of HPV status at the baseline, we see the older the age, there is a decrease in the effect, in the efficacy of these vaccines. So there is still uncertainty on what exactly is this age cutoff point at population level at which vaccination loses this effectiveness due to previous exposure of HPV infection. In the U.S., observational data from the Kaiser Permanente in Northern California show no significant effectiveness. This is real data. This is effectiveness. They show no effectiveness in girls that were vaccinated after 20 years of age. And compared to when, no, you compare this effect, this is against the endpoint of CAN2+, or CAN3, we see exactly the same pattern. No high protection when girls were vaccinated before 17 years of age, a little, no, less effectiveness, but statistically significant and clinical relevant when they were between 18 and 20 years of age when they received the first dose, but no effect at older ages. So what happened in 2019, based on this data and observed data, but also on mathematical modeling, at the end, the U.S. Advisory Committee on Immunization Practices, they decided to recommend catch-up vaccination for all persons to the age of 26 years, okay? Regarding older ages than 26, they said that there was no public health benefit or it was so minimal, the cost-effectiveness, no, was not so beneficial. So it was more a shared clinical decision. So it was more a recommendation on the individual level rather than at the public health level. We have to stress that here, there is something very important that there are a lot of variation in results across the different mathematical models. And this is due to some uncertainties about the HPV natural history. And this is because there are some gaps in knowledge regarding precisely about age. And one of the key factors that we need, still we need to know and to clarify a little bit more is exactly to know what's the risk of developing cancer by the age of HPV infection acquisition. So we need, it seems by the data, no, that it's not the case, but we need to know if a person acquires an HPV infection the age of 30 or at the age of 40, if the risk of developing eventually a cervical cancer, it's the same if that HPV infection was acquired before. So it seems, no, the later the age. So at the end, most of the cervical cancer that we are observing is due to infections that were acquired very early at very early ages. However, this is still a question research. So when, if we switch to the global level, now WHO last year launched the global strategy to accelerate the elimination of cervical cancer as a public health problem. This strategy is based on what they call a triple intervention strategy, and they have set three aspirational goals. It's what we call the 90, 70, 90 targets. So the idea is if we want to eliminate cervical cancer, we have to reach, this is set by 2030, 90% of girls had to receive the vaccine by the age of 15, 90% that are 15 had to be received 90% the vaccine. 70% of women have to be screened by a high performance test at least twice between the age of 35 and 45. And we have to ensure that at least 90, well, at least more if possible, 90% of women that are diagnosed with precancerous lesions or cervical cancer receive treatment. And this is targets at the global level. If we reach this, what will happen? So based on, again, on modeling is this shows what will happen if, let's say, if in 2020, we know that that's not the situation now, but let's say we already reached these goals, the 90, 70, 90%, what will happen in the next 100 years? What will happen is that we could really eliminate cervical cancer to low so much the incidence rate that it will not be a public health problem anymore. The green line is the incidence, the curve of incidence in a scenario on when we only vaccinate girls. This is the most important strategy. All the elimination strategy is based on HPV vaccination, extended vaccination and to reach a coverage of 90% of girls globally. But we know that in some countries with the highest cervical cancer incidence, we will not reach elimination by vaccination alone. By vaccination, of course, sorry, alone. We need also to combine this vaccination with the screening. And if we also combine vaccination with the screening, we also will swift this, sorry, again, this curve to the left. So preventing this, just this change to the left of this curve, the green one, this is the triple strategy, vaccination plus two, at least plus two lifetime screens. This means this translates on millions of deaths and cervical cancer cases. And also impacts faster. This is the same figure, but not in terms of incidence, but in terms of deaths and mortality. So again, if we had already reached this 90, 70, 90 goals, by 2013, we will at least decrease mortality 30%. And in 15, in 50 years, sorry, it will have decreased to 92%. This is the purple line. This is a triple strategy projection of the impact in cervical cancer deaths. The blue line, this one, is the same scenario, but only starting with 90% coverage and girls-only vaccination. So all these are the gains, this difference between this curve and this curve are the gains added by screening, okay? And here in orange, we have the same curve, if we only vaccinated girls, plus multi-age catch up until 25 years of age. So there is some benefit, but it's not so huge as with combining with the screening. Other, because of that, in the field of public health and cervical cancer prevention, one of the topics of discussion are what we know as faster strategies. The faster concepts consist on how we can combine screening and HPV vaccination in such a way that we maximize the combined impact of both measures. We have to understand that until now, usually HPV vaccination programs and cervical cancer prevention programs were run separately at the government level, but now maybe we have to have a more comprehensive approach and try to combine. So what, this is not evidence-based, we still need more data to support all these, but just to cover a quick glimpse on what will be, is, so we have to keep, this is the most important strategy, adolescent vaccination, we have to keep vaccinating girls before the age of 15, but we will cannot, an extended vaccination, we are not clear until what age to, this will be a decision based on every country and depending on the epidemiology and the transmission and sexual behavior patterns in a population level, but also there is another option, is plus two vaccination, not only a screen, but to offer vaccination when we are screening. So when a woman comes to receive her HPV test, then we also offer her vaccination. In the case that the woman is HPV negative, we have already seen that she will be protected very efficaciously for new incident infections. In the case she's HPV positive, will not serve her infection, but maybe, and this is under a study, she will not acquire new infections and also maybe it will also stop transmission of her prevalent infection. And also something that it's under research is if we do this screen plus vaccination at the same visit, if this will also decrease the periodicity and screening needs afterwards. And this is also, and also we have the boys vaccination, added to the girls vaccination with the same concepts. But again, also we know that we could achieve a cancer elimination in one century, but we are not there. This is the current situation. By June this year, 113 countries reported having introduced HPV vaccination in their schedule. But as we can see, there are huge geographical differences and the regions that have most of the cervical cancer burden that it's Asia, Eastern Europe, Africa, are the ones that are behind HPV introduction. And also it's not only about introduction, it's also about coverage. Very few countries perform over 90% coverage. This is the blue, the final dose, in yellow, the first dose coverage. But we can see regardless of the income status, more or less countries behave similarly with HPV vaccination. We see on average countries perform at 68% coverage for the first dose and 54% coverage with the last dose. So just to end up, we have seen that high HPV vaccine effectiveness against cervical cancer at the population level among girls vaccinated younger than 20 years through main national programs and catch-up. It still isn't clear the optimal maximum age for this HPV vaccination campaigns or extended catch-up programs. All the cohorts can be vaccinated for different purposes. One, it's at the public health level and other, it's to benefit the individual at the individual level. And this has to be an individual decision with her health work professional. Very few countries achieve a final HPV vaccination coverage higher than 90%. And this is key for cervical cancer elimination. For now, vaccination of the younger cohorts remains the priority, especially in low middle incomes. So now we have to focus on introduce on the countries that have not introduced yet and to increase current HPV vaccination rates. But however, we have to start thinking and we should not overlook the potential benefits of combining the strategies with the screening in the coming future. Many thanks. Thank you, Dr. Bruni. Thank you for an excellent presentation and very thought provoking, I hope. So I'm going to revisit my case now for staging. So this patient presented to my institution with a bulky tumor yet mobile. We suggested no growth parameter involvement and a PET CT scan was done for staging. We showed a high uptake at a cervical tumor with an SUV of 15 and a high burden of hypermetabolic I don't know, but it's at the level of the left chain with a proximal and also distal ones. So our final speaker in this first segment of the master session is Dr. Yifil Havvorsen from Bergen, Norway. She will address how to best stage our locally advanced cervical cancer patients. Dr. Havvorsen, please go ahead. Thank you for allowing me to present on this very exciting topic, PET-CT versus MRI to stage locally, local regional advanced cervical cancer, pros and cons. Should we rely on imaging for presurgical staging? I have nothing to disclose. Until 2018, cervical cancer has been primarily clinically staged without a formal role of imaging in phagostage assignment. However, the revised 2018 phagostaging system, which incorporates imaging and pathology findings in the staging system, has addressed the well-known limitation of clinical staging and acknowledged the value of imaging and histopathology for optimal risk stratification and treatment planning. The National Comprehensive Cancer Network guidelines state that pelvic MRI should be considered in all cervical cancer patients at initial diagnostic workup and PET-CT in patients with phagostage 1B1 or higher. Recent European Society of Urogenital Radiology guidelines also reiterate that pelvic MRI is the preferred imaging modality to evaluate local regional tumor extent. Furthermore, whole body FDG PET-CT is recommended for evaluation of lymph node metastases and distance spread in cervical cancer. For phagostage 1, defined as cervical cancer confined to the cervix with stage 1B comprising invasive carcinomas larger than 5 millimeters, tumors are categorized into substage 1B1, 2, and 3 based on tumor size below 2 centimeters, between 2 and 4 centimeters, or above 4 centimeters, respectively. Pelvic MRI using T2-weighted sequences shown to the right allows delineation of tumor margins, allowing measurement of maximum tumor size relevant for substaging into stage 1B1 to 3. Phagostage 2 is defined as tumors invading beyond the uterus, but not below the lower one-third of the vagina or to the pelvic wall. Pelvic MRI allows detailed assessment of vaginal spread and tumor size. In this patient with vaginal spread in the anterior vaginal wall. Furthermore, MRI has excellent soft tissue resolution and allows depiction of disrupted low signal intensity stromal rim shown to the right. The speculated parametral tumor growth depicted to the right of the cervix is considered pathognomonic of parametral invasion. Phagostage 3 is defined by tumor invasion of the lower one-third of the vagina, hydronephrosis, or pelvic wall extension, or pelvic or paraortic lymph node metastasis. MRI shows vaginal spread below the lower one-third, defining stage 3A. Pelvic sidewall extension is also nicely demonstrated by MRI. In the patient to the lower right, with tumor mass reaching the right pelvic sidewall, indicating stage 3B. Pelvic or paraortic lymph node metastasis, when massively enlarged like the case shown to the right, with a large left-sided pelvic lymph node metastasis, will be nicely depicted by both MRI and PET-CT. However, PET-CT is regarded as more sensitive for smaller lymph nodes. Phagostage 4 comprises tumors extending to the bladder or rectum, or tumors with distant spread. MRI in this patient depicts large tumor masses in the cervix and in the anterior vaginal wall, with non-preserved capillary between the bladder and the tumor, and tumor extension from the anterior vaginal wall into the bladder, and also dorsally into the rectum cranial to the posterior fornix of the vagina. PET-CT in the patient to the upper right shows FDG avid lung metastasis, and primary tumor in the pelvis. The same patient also had parametral invasion depicted by MRI. So, what are the pros and cons for PET-CT versus MRI, or for imaging at all, for successful staging of local regional advanced cervical cancer? MRI is the best imaging method for local staging of tumor sites, assessing tumor boundaries and invasion of neighboring structures. It is also clearly more accurate than clinical staging. PET-CT is the best imaging method for lymph node staging and metastasis detection. And detailed staging information based on these imaging methods facilitates tailored treatment strategies consisting of fertility sparing treatment, radical surgery, or concurrent chemotherapy. Cons to imaging at all in these patients can be limited access to scanners at many sites, high scanning costs, radiation exposure for PET-CT, and that incidental findings, particularly common for PET-CT, can cause costly follow-up exams and treatment delay. So, should we really rely on MRI and PET-CT for presurgical staging? How accurate are these imaging methods when compared with histopathologic results, and what is the inter-observer reproducibility for these imaging methods for the reported staging parameters? MRI-based tumor size measurements have been shown to be quite similar to that of microscopy and microscopy in hysterectomy specimen. Almost identical mean tumor size was reported in a recent study by DeBoer for MRI-measured and macroscopically-measured maximum tumor size, whereas MRI-measured tumor size had a mean of three millimeters shorter diameter than that based on microscopy. Importantly, the inter-observer agreement for MRI-based tumor size measurements was excellent. A meta-analysis by Woh including 14 relatively recent studies reported very high sensitivity and specificity of MRI for diagnosing perimetral invasion, 0.76 and 0.94, respectively. Furthermore, they found that the inclusion of the MRI-sequenced diffusion-weighted imaging, shown to the lower right, may additionally increase the conspicuity of tumor boundaries. And thus, the diagnostic performance of MRI. Importantly, the inter-observer agreement for reporting perimetral invasion based on MRI was excellent. PET-CT is the imaging method yielding best diagnostic performance for nodal staging in cervical cancer, and a recent meta-analysis reported patient-based sensitivity and specificity of 0.76 and 0.94, respectively, for diagnosing lymph node metastasis. Interestingly, diffusion-weighted imaging may yield comparable diagnostic performance, although the number of studies are not sufficient to conclude. The reported inter-observer agreement for nodal staging by PET-CT is excellent. In summary, what is the role of PET-CT and MRI for staging in local regional advanced cervical cancer? And should we rely on imaging for pre-surgical staging? The answer to this is yes. Imaging by PET-CT and MRI is way more accurate for pre-surgical staging than clinical staging alone. MRI enables accurate delineation of tumor margins and detailed assessment of local-regional disease extent. FDG PET-CT is optimal for valid identification of lymph node metastasis and distance spread. And MRI and PET-CT imaging at primary diagnostic workup allows more accurate pre-surgical staging, enabling better risk stratification, more tailored and targeted treatment strategies that will ultimately lead to better patient care. I want to acknowledge my collaborators at Bergen Gynecologic Cancer Research, I want to acknowledge my collaborators at Bergen Gynecologic Cancer Research Group, Bergen Cancer Imaging Research Group, and Moon Medical Imaging and Visualization Center, and the generous funders that support our projects. Thank you. Thank you, Dr. Haldorsen. That was an excellent presentation. Before we move on, we will have a poll for questions. And please place your vote on what your consideration is for the best management of this patient. Can we see the poll, please? Gonzalo, for some reason, I don't see the poll. I'm wondering if maybe we should skip it, just due to time. Okay. This is going to create a great debate, I think, on the management of locally advanced cervical cancer. We will have the pleasure to hear Dr. Jyoti Mayadev as a speaker, and also as a co-chair of this session. Jyoti, take it away, please. Thank you so much, Gonzalo. And thank you so much, everyone, for coming and participating in this great cervical session. I'm Jyoti Mayadev, and I have the opportunity to talk today about locally advanced cervical cancer and introduce our next two speakers. These are my disclosures. So we'll talk today about surgery versus chemoradiation for locally advanced cervical cancer. And just as a primer, we've put together a case. We have a 37-year-old Hispanic female from a low socioeconomic background. Her last pap smear was in 2015, and November 2020, experienced bleeding after intercourse. She then had a cervical biopsy after seeing a mask found on the cervix of the pelvic exam showing squamous cell carcinoma. The tumor was more than four centimeters on examination, but the PET-CT was negative for lymph nodes. So now our very esteemed colleagues, Dr. David Cibula, will talk about surgery for the next 10 minutes. And after that, Dr. Trey Leith will talk about chemoradiation, and we'll decide which one is better. Dr. Cibula. Dr. Cibula, are you there right now to share your screen? Sure. I'm trying to do so. And can you see my slide now? Yes, we can. Very good. Very good. Thank you. So join us. Thank you for your introduction. And I'd also like to thank organizers for inviting me. My role is to argue for surgery in the management of locally advanced cervical cancer. Well, you could put it in presentation mode if you'd like. Yeah. This is better? Perfect. There you go. Thanks. I'm able to improve. Thank you. So this is my disclosure. And this is our case in a nutshell about 40 years old lady with 4 centimeters squamous cell cancer. And on PET scan, there is one but suspicious iliac lymph node, 25 millimeters. So my lecture can be very short because all international guidelines almost agree that the right management of lymph node positive cases is definitely chemo radiotherapy. This belongs to high risk early stage cervical cancer, and the management is quite clear. We have recently with NGOT contributed a little bit to this field with a very specific focus to one concrete clinical situation if the positive lymph node is detected intraoperatively by frozen section. It was a retrospective study on European or even global effort. And we did not find any benefit from completion of radical hysterectomy. So there was identical survival of patients in whom a radical hysterectomy was finished or abandoned. Even local control was the same. And we didn't find even a signal towards better survival in any of the subgroups, including the patients with different tumor types or different tumor size. So even in this clinical situation, we supported that the role of completion of radical hysterectomy is very questionable, and the abandonment of radical surgery should be preferred. But our case is not black and white. There is one positive lymph node on PET scan. So what is, how accurate is our clinical staging currently? Well, the literature is quite in agreement that the sensitivity of imaging is not the best. It's between 40 to 60 percent. And it's quite logic because if we diagnose very small metastasis by pathology, these cannot be detected by imaging. And the sensitivity is related to the intensity of our pathological staging. So if we use ultra staging, we detect micrometastasis, our sensitivity gets down. This is one of the trials showing a relatively high false negativity of parabolic staging using PET scan. But in our case, more important is specificity. And in this case, literature is quite in agreement that the specificity is very high. I disagree. Because if you look at those papers, majority of them simply compared one imaging with another imaging method. We usually don't operate patients with positive lymph nodes in the pelvis. We send them for primary chemoradiation. In our institution, we started to use parabolic staging in patients with positive pelvic lymph nodes on imaging several decades ago. And we also do a biopsy of that positive lymph node in the pelvis. And our data are different. Our data shows that there is quite a high probability of false positive finding on imaging. And the reason is obvious, there is a large tumor with a lot of inflammation. So there is good reason why to have accumulating and large lymph node in the pelvis. So if there is such a possibility that this one lymph node is actually negative, can we use S1 biopsy? Because one of the myths in surgical literature in gynecology is that S1 biopsy can be used only in small tumors. Of course, it can be used. But the method of tracer application must be different. We cannot just inject a tracer superficially into the neck part of tumor, we have to go deeply below the tumor, find the residual stroma and apply the tracer there. And if we use such an adjusted method, then the detection rate is pretty comparable. And also bilateral detection rate and sensitivity is quite equal in tumors below two centimeters between two and four and even above four centimeters. So still, there are people who will say that, you know, it's a four centimeter tumor. So it's a bulky tumor, it's a locally advanced case. So there is a good literature, you know, very good evidence that chemoradiation is superior. In NCCM guidelines, it says that it's a category one for primary chemoradiation. And again, I disagree. Because this is the list of the evidence. And from the whole list, there is only one study, which really compared surgery with radiotherapy. This study was conducted several decades ago, and in Italy, it was actually not studied on locally advanced cancer, because the majority of tumors were below four centimeters. And even in this study, there was no superiority of chemoradiation, both techniques were equal in the outcome. And all other papers, which are shown in the references and are usually referred, simply compared radiotherapy with chemoradiation. So yes, we have good evidence that chemoradiation is better than radiotherapy. But no evidence or good evidence that chemoradiation is better than surgery. And it's also reflected in a clinical practice. This is ESGOS survey showing that the preference in the management of bulky tumors is still surgery. And it's surprisingly went even higher between two ESGO surveys from 2018 to 2021. But there is still one remaining question, which is burning. And it is this this tumour will definitely fulfil criteria for intermediate risk tumour. It's four centimetres, there will be deep, deep infiltration to the stroma. So if this patient must go for adjuvant radiotherapy, what's the role of surgery then? And again, here I would like to question or challenge this approach, because there's only one level A evidence study, which was conducted 35 years ago. So really one generation ago, it's GOG92 trial, which simply reflected in many aspects the time such a long time ago. And in this study, there was really shown benefit from adjuvant radiotherapy. But the outcome of patients after the surgery only was very poor in this study. Taking into consideration that all these cases were lymph node negative, but with combination of risk factors, one third of patients were cured after surgery. And there were other limitations too. We have published already in 2018, a large but retrospective study comparing the outcome of patients with or without adjuvant radiotherapy, and didn't find any difference and definitely much better outcome in both groups than in GOG92 trial. And since then, there have been many other trials, all of them retrospective, showing the same, that they did not find any survival benefit from adjuvant radiotherapy in lymph node negative cases. This was the reason why we developed together with an international community, this protocol has been reviewed by dozens of experts internationally, a prospective randomized study, which is ready to be launched next month. And this study should control for the quality of surgery, which was absent in GOG92 trial, and radiotherapy, and a randomized patient to no adjuvant treatment or adjuvant chemo radiation. So this is my conclusion slide. Primary chemo radiation in this case is definitely not a mistake. That's optional management, but surgery is an option too. In case of surgery, I would recommend to start in this case with acetylene biopsy, frozen section, so we can precise the management. If acetylene is negative, then proceed by open surgery with radical hysterectomy and full lymphadenectomy. And what is important, if lymph nodes are negative, including out of staging, I would not recommend any adjuvant treatments. Thank you for your attention. Thank you so much for that wonderful presentation. Now we'll have Dr. Trey Lee talking about chemo radiation. Slight technical glitch here. There we go. I'd like to thank Drs. Powell-Oakman and Maideb, as well as President Coleman for allowing me to present today and review perhaps an unusual position for a surgeon, namely the role of aborting surgery in favor of definitive radiation in women with early stage cervical cancer that are found to have positive nodes intraoperatively at the time of planned radical hysterectomy. These are my disclosures. Today, I plan to review historical data on the management of no positive cervical cancer after radical hysterectomy, review the potential impact of improved imaging and its role in making historical research perhaps antiquated, and finally put the results of ABRAX into clinical context. As we know, cervical cancer is a global problem with greater impact in the developing world and representing approximately 3% of both cancer cases and mortality annually. Fortunately, many women will be cured with surgery alone, especially those with very small tumors that often can undergo fertility preservation surgery. These are not the patients we're discussing, though. This is really the floor of the patients that we are discussing, namely those that require radical hysterectomy or radiation with or without chemotherapy, as well as those that Dr. Sabula mentioned that have larger tumors. Dr. Sabula also noted one of the most important historical trials evaluating the role of early stage cervical cancer management in the landmark trial from Landoni and colleagues published in the Lancet in 1997. This randomized control trial compared radical hysterectomy versus radiation alone in women with stage 1b through 2a cervical cancer with other eligibility criteria depicted here. Importantly, patients underwent preoperative lymphangiography with a relatively small proportion of patients thought to have nodal spread. Dr. Sabula noted that as designed, this would have a relatively small proportion of patients who would meet the current definition of locally advanced disease. Both disease-free as well as overall survival were similar, although not surprisingly, differences in overall survival were seen based on tumor size at presentation. And although this was not the primary endpoint of the study, it is important to remember the potential impact of larger tumor size. Importantly, the worst outcome was for women that underwent both surgery and radiation, which was indicated secondary to the presence of one of multiple pathologic risk factors. The pathologic risk factors are depicted here, finding a much larger tumor, having a closer margin, performing a suboptimal radical hysterectomy with cut through, and also finding lymph node metastasis, which again, in the final pathology, had doubled from the preoperative imaging. While a different study design and clearly clinically indicated, Peters and colleagues evaluated the role of chemoradiation versus radiation alone for women with high risk factors, predominantly positive lymph node metastasis following radical hysterectomy. Again, substantial complications do occur for women being treated with radiation after radical hysterectomy, supporting the need to avoid this dual oncologic treatment. If we needed any additional information, and although not perspective, a series of 50 patients that underwent radical hysterectomy at UAB was reported by Barter and colleagues. In this series, a 30% major complication rate was reported for women undergoing post-radical hysterectomy radiation. Patients with recurrence were not considered to have had a complication. Overall, 8 or 16% of patients underwent additional surgery, with one patient ultimately dying from bowel complications after failed surgical salvage. Although rates of aborted radical hysterectomy as high as 30% have been reported, other series, including a large pathologic-based series from GOG49, as well as work from our institution, have suggested that it is probably less than 10% overall. Considering current guidelines, preoperative imaging for non-fertility-preserving surgery is recommended with PET-CT scan preferred. I think we have to ask ourselves again, as Dr. Sabula noted, what is the role of modern imaging? Specifically, with better imaging, can we do better than lymphangiography as used in the Landoni randomized controlled trial? As most of you know, GOG233 evaluated locally advanced cervical cancer patients who underwent pre-radiation nodal dissection. This data suggests we will still miss nodal disease on preoperative PET-CT imaging, although this does not address his suggestion of sentinel lymph node dissection. This brings us to the ABRAC study, which again, Dr. Sabula has already presented, and who noted had dual objectives. Specifically, does the completion of a radical hysterectomy following interoperative discovery of lymph node involvement improve oncologic outcomes, and do prognostic parameters, including tumor size, histology, LVSI, the number of lymph nodes, the type of metastasis, impact or perhaps suggest a potential benefit of completing a radical hysterectomy in women with bigger tumors? As designed and presented at the 2020 virtual ESMO conference, the study hoped to identify over 700 patients and then evaluate standard oncologic outcomes, including recurrence-free as well as overall survival, in addition to the assessment of potential predictive risk factors. A flowchart of the study is depicted in the included figure. Ultimately, 515 patients, including 361 or 70% had completion surgery versus 154 or 30% whose radical was abandoned and were included in the trial. Age, BMI, stage, histology, and tumor size were relatively similar, although the proportion of tumors greater than four centimeters was higher in the completed radical hysterectomy group at 31 versus 20%. Surgical route and procedures were different between the two groups. Outcomes, on the other hand, were not different regardless of the completion of radical hysterectomy versus abandonment. Moreover, recurrence rates, including pelvic recurrence and death, were similar in the two treatment groups. As expected, typical predictors of patient outcomes, including larger tumor size, higher cancer stage, and lymph node involvement were all associated with undesirable oncologic outcomes, including recurrence and inferior survival. A multivariable analysis was performed in women whose radical hysterectomy was abandoned. Not surprisingly, higher stage predicted overall as well as pelvic recurrence as well as death. As noted by the authors of this very robust multi-institutional retrospective study, there does not appear to be any obvious clinical scenario that favors completion of a radical hysterectomy when positive nodes are found intraoperatively, and I think we can suggest if we know, as Dr. Sabula suggested as well, known prior to surgery, as patients will need postoperative radiation and chemotherapy. Moreover, considering the overall rarity of events, a prospective randomized control trial is not feasible. Considering together the historical data as well as the more recent data from MAVRAX, women undergoing radical hysterectomy that are found to have positive nodes should not have their radical completed but rather abandoned in order to proceed with postoperative chemoradiation therapy. Again, I would like to thank the organizing committee for the opportunity to present today as well as the audience for their attention. Thank you so much. We will now share my screen. Okay, so everybody, now we're going to talk about the addition of systemic therapy to radiation and chemoradiation, and in general, you know, the treatment paradigm to augment chemoradiation in the neoadjuvant space, concurrent space, the adjuvant space, what's the best timing and sequencing, and what are the clinical trials available for our patients? And there's no one better to talk about this than Dr. Bradley Monk. Dr. Monk is a pioneer, an expert, a clinical trialist, and is really on the forefront of local advanced cervical cancer and therapeutic options for our patients. Dr. Monk is a professor and really a cervical cancer global expert. Dr. Monk. Yeah, thank you. I think you just made me sound old, but I'm not really sure, so thank you. Good to be with you guys. These are always challenging because you guys are actually the experts, and so I'm going to try to be a little philosophical, if you will, and maybe add some perspective and some things that maybe you haven't thought about. These are my disclosures. It's hard to imagine that within the first years after my fellowship that no patient with cervical cancer received systemic therapy, not one. I remember talking to very learned experts that thought that this was a chemotherapy-resistant tumor, that the idea that adding systemic therapy to radiation was really unethical until this happened. An NCI clinical alert, you're all familiar with it, but I sort of tried to devote my entire career to teaching people and working with you to show that chemotherapy has a very important role, and I mean systemic therapy because we have anti-angiogenics and antibody drug conjugates in immunotherapy. So, this is a cartoon. I know some of you helped me make this, but think of all the individuals that touch the patient on their journey from biopsy and referral to diagnosis, staging, and assessment to treatment and to follow-up. So, this is team approach, right? This is a team approach, and it's really exciting to be part of that, and we can sit there and argue, but they're actually guidelines. And the NCCN guidelines, which some of you sort of talked, participated in, talk about surgical staging on the left, which we do infrequently, radiologic imaging on the right, and then ultimately the integration of radiation, generally IMRT, image-guided brachytherapy, and systemic therapy. So, I think all of you know the NCCN guidelines, but I worked with some of my colleagues to go through sort of my friends to the south, and it's interesting when you look at the lack, locally advanced cervical cancer, when surgery is not a good option, you can see that, you know, as you looked at Brazilian-Mexican guidelines, they actually use different staging. Mexicosis, maybe pelvic exoneration is a good idea. They're pretty agreeable to weakly cisplatin and radiation, but there's some distinctions here, and I get it. The guidelines maybe haven't been updated. Well, then we need to update them. We all, it's a team approach. There's one way to treat this locally advanced cervical cancer, and so here I added on the right the Japanese and Korean. And again, the Asian surgeons are a little bit more assertive, and there's no dose on the cisplatin, and even the Japanese guidelines do not sort of formally discuss the whole pelvic irradiation. So, I think that's the way it is, but I do want to really focus on the similarities rather than the differences, that concomitant chemotherapy and radiation is the standard, and it's generally cisplatin, not carboplatin, right, and it's generally at 40 milligrams. I think it's six doses, not five, and I don't really think that we intend to cap the dose at 70, which is what GOG120 did. Brachytherapy, ideally image-guided. Neoadjuvant chemotherapy probably is not evidence-based with recent studies. We really need to use the 2018 staging system and the best technology that we have available, and I think all of you are aware of Outback. That was interesting, right, but it failed. Think of it, 900 patients, and we really didn't accomplish much, okay, and it was a great opportunity for us to do something, and we didn't do much, and again, I wouldn't call it a failure, because I think there were some lessons learned, but the addition of four additional doses of carboplatin and paclitaxin did not improve progression-free survival or overall survival. So, what are the lessons? What are the lessons from Outback? Well, the first is that the addition of more cycles of systemic therapy has to start from the beginning. When you do this switch maintenance, so let's do the chemotherapy and radiation and then sort of have this transition phase, there's dropout, and I think that as we develop more immune-related therapies, the switch maintenance probably is a bad idea. When there's long progression-free survival or post-progression-free survival, overall survival is not a good endpoint. We should use PFS, and I think you'll see that sometimes PFS and OS go together, but PFS is probably the new endpoint now, and when there's crossover, right, because GEOG204 showed that when you recur, you should get carboplatin and paclitaxel, so if there's complete crossover, then how would there be an overall survival advantage? And you have to use the best agents at the time, and the best agents at the time when this Outback trial was developed was no question platinate and ataxan, but over time, antigenics and immune therapy became important opportunities. So, we're moving faster and beyond the Outback, and sort of the next trial to report, probably, will be the CALA trial. Same sort of opportunity, chemotherapy, radiation, but again, because you don't want to do switch maintenance, during the chemotherapy and the radiation, drivalumab is added and then continued in the maintenance phase versus placebo at monthly doses every four weeks, 1,500 milligrams, fixed dose of drivalumab for two years. So, this is what we're really excited about. You see in the red box at the bottom, this trial has been closed since February 2020, and these are high-risk patients. These are not the sort of patients that are in Outback. These are patients that have positive pelvic or aortic nodes, so the event rate will be higher, and as I talked about, the primary endpoint is progression-free survival. So, I think we have a better endpoint. I think we have patients that really need our help, and it's done with your help, 131 sites and 714 patients, and in fact, it's such a good idea that we decided to do it again. I always say it takes two trials to convince anyone of anything, right? And the second trial is Keynote 818, a very similar trial, actually a larger study with 980 patients. And I'm really excited that we're creating more opportunities. And I look at these as complementary studies, not competitive. And there are earlier studies, ipilimumab as a dose finding after CCRT, and the atomic trial, which is dostarlimab, I think that's a misprint, that 980. I need to fix that. I'm sorry. So that's where we're headed. In 1999, we changed the world with the addition of cisplatin. We've been stagnant despite our hard efforts, including Outback. But I'm hoping that CALA and Keynote 818 will be the next phase. And after that, I think we need to do PD-1 CTLA-4 or PD-1 anti-angiogenic or PD-1 anti-TIGIT. So this will continue to evolve until that very nice presentation on vaccination catches up. So thank you for having me. Thank you, Dr. Monk and everyone who presented. We'll now go on to our third case presentation, led by Dr. Leslie Randall. Thanks, Chiodi. Excuse me. Thanks, Chiodi. I'm going to share my screen here. So this is a great session so far. And I think, you know, the whole day today, starting out with Dr. Tewari's very first presentation this morning, followed by the debate, and then the tumor board really leading up to my section. And here are my disclosures. The treatment of recurrent and metastatic disease. So anytime we change the standards of care, we're really starting with our later lines of therapy and moving up earlier, as you're seeing with Dr. Monk's presentation that he just gave. I want to talk about our typical patient here, 28-year-old African-American female. We're very bad at, this is a patient who was a vaccine candidate and did not get vaccinated, unfortunately. We're not good at implementing vaccine in the U.S., getting better, but we still have racial disparities in that. Status post chemo radiation four years prior. So made it quite far out from first treatment. And then had new onset recurrent UTI and urinary incontinence. And on physical exam only had vaginal fibrosis. Was noted to have a fistula and right lower extremity edema, but no evident tumor on physical exam. Underwent PET CT and had three separate masses, both in the radiation field and outside of the radiation field, both soft tissue and nodal in character. But this is a typical distribution of disease that we see post chemo RT in the recurrent setting. So now we have to decide how to treat this patient. So in this day, what are the optimal standards of care? How soon is that likely to change? We've been talking about this all day. What's the role of immune therapy? What are the non IO options? When do you give what? And it's really changing by the day. And if you feel confused, it's because you're writing the upward trajectory. It's going very quickly and you're witnessing history changes in the way we treat cervical cancer. So today I am so delighted to have for you to discuss these issues of very esteemed, our very esteemed colleagues, Dr. Anna Oakman, Nicole Conson, and Dr. Dimitri Zamarron to talk about first, this immunotherapy era, this is really a huge shift in the standard of care for cervical cancer. And then following that, we're going to talk more in depth about to sodium avidotin. You've heard about that a little bit today. If you're not familiar with this brand new medication, we need to get familiar with it very quickly because it's likely to be available to our patients very soon. And then to top it off, Dr. Zamarron will talk about how do we put all this together and the new dilemmas of biomarkers and sequencing of IO and TV and other therapies in cervical cancer. So without further ado, I'm going to stop sharing. I'm going to hand this over to our esteemed Dr. Oakman. Dr. Oakman, thank you. Thank you, Leslie, for your kind introduction. It's my great pleasure to be with you all here. And I'm very happy, you know, to deliver this topic, entering the immunotherapy era in cervical cancer, the seismic shift in the treatment plan escapes. This is my disclosure. Well, during the previous talk, we have learned that cervical cancer still represents a major public health problem and how those patients diagnosed at an early stage can be cured by radical surgery. And those diagnosed with locally advanced disease may also be cured with chemoradiation. However, the management of women with recurrent disease who are not candidate for pelvic exanteration and those who present with metastatic disease have represented an unmet clinical need for decades. What has gone before? As you are quite aware, a turning point in the treatment of cervical cancer was led by our knowledge in angiogenesis. We learned that angiogenesis plays a central role in the development and growth of cervical cancer, and the BGF has an immunosuppressive role as well. Therefore, anti-BGF agent, vivacizumab, was tested. The proof of concept of the activity of anti-BGF therapy in cervical cancer comes from the phase three clinical trial, GOG240, that you all know very, very well. The study shows that the addition of vivacizumab to first-line chemotherapy improved overall survival. However, despite this improvement, most patients progress after first-line therapy with median overall survival post-progression that varies between six and to 8.7 months. Thus, there is still room to improve our first-line outcome. Then, where are we going now? We are working on incorporating immunotherapy as a new strategy to improve our cervical cancer patients' outcome. And why? What is the rationale to pursue immunotherapy in cervical cancer? We know that these cells play a central role in the prevention of virus-associated tumors, and we also know that cervical cancer is the consequence of persistent infection by oncogenic HPV subtype. So, in the setting of HPV infection, acquisition of immunosuppressive mechanism leads to tumor immune invasion and development of invasive cancer. Therefore, what are those mechanisms of immune inhibition? Very, very briefly, the mechanism of immune inhibition or regulatory checkpoint may occur either during the priming phase. CTL4 suppresses the activation of immune response during the effector phase. The binding between PD-1 and its ligand, PD-L1, leads to T-cell exhaustion. In addition, we know that PD-L1 is significantly upregulated in ischemic cervical cancer and in adenocarcinoma. All these findings suggest that targeting CTL4 and PD-1 pathway may be therapeutically effective in the treatment of cervical cancer. So, what data do we have so far with checkpoint inhibitor after failure platinum therapy? This is a very busy slide. However, I will walk you through the most important point. All these phase 2 trials but Keynote-158 have enrolled patients regardless of PD-L1 status. Indeed, when you look at across the trial, all of them have more than 50% of tumors either PD-L1 positive or CPS positive. Moreover, Keynote-158 enrolled only 5% of patients with adenocarcinoma histology in contrast with the vintrafus alpha and bastillimab trial that enrolled up to 40% of adenocarcinoma populations. Regarding activity, all agents but pembrolizumab show efficacy regardless of PD-1 expression with overall response rate that ranges from 12% in the overall population for pembrolizumab, 15% for bastillimab, to 24% for vintrafus alpha. But please take into consideration the limitation of cross-trial comparisons. These data speak by themselves about the role of PD-L1 status as an accurate biomarker. However, Dimitri will address this topic deeply later on. The most remarkable point is the duration of response. The median duration of response has not yet been reached in the majority of these trials, which means that those patients who respond to IO have long-lasting responses. Following this data, the key question is whether these agents are superior to a standard of care, namely chemotherapy in second line. This question was addressed by the Empowered Cervical Warmth Trial neatly presented by Professor Tewari earlier today. In a brief manner, Empowered Trial enrolled 1,600 patients with recovered metastatic cervical cancer who have progressed after first-line therapy based on platinum. Remarkably, we enrolled patients regardless of PD-L1 status, and we enrolled almost 80% skeletal cervical carcinoma and about 20% adenocarcinoma. Patients were randomized in a one-to-one fashion to semiplimab of investigator-short chemotherapy. Primary endpoint, overall survival, and I would like to stress that the trial has a hierarchical analysis. Firstly, in a skeletal carcinoma, if this data were positive, then we move to the total population, and here the results. The trial met its primary endpoint with hazard ratio 0.73 and highly significant p-value, median overall survival, 11 months for semiplimab compared with 80.8 for chemotherapy. So, according to hierarchical analysis, we continue with the total population and we analyze the overall survival here. Semiplimab was also superior to chemotherapy with a median overall survival of 12 months compared with 8.5 for chemotherapy. So, running in parallel to these studies in second line, immunotherapy was also studied in the first-line therapy. There are a few trials on the horizon. However, the first completed one was the keynote A26. The trial enrolled 600 patients with recurrent metastatic cervical cancer who have not received systemic therapy for their condition. Patients were randomized in a one-to-one fashion to receive standard therapy based on platinum-based chemotherapy plus myelovebacizumab or experimental arm adding pembrolizumab. I would like to stress that the use of bebacizumab was not mandatory. Indeed, bebacizumab use was a stratification factor alongside PD-L1 status, primary endpoint, PFS, and overall survival. Well, in June this year, Merck announced that the trial met its dual primary endpoint. Pembrolizumab plus platinum-based chemotherapy with or without bebacizumab demonstrated a statistically significant improvement in overall survival and PFS compared to standard therapy. The other important trial running in first line in the BCC trial, this is a phase 3 randomized trial to assess the efficacy of atezolizumab concurrent with the combination of platinum paclitaxel plus bebacizumab in first line therapy. The study is designed to test the hypothesis that breaking of immuno-tolerance by PD-1 and PD-L1 blockade will enhance the efficacy of anti-BGB therapy in this cervical cancer population. Here, the study designed for 104 patients with recurrent metastatic cervical cancer without previous systemic therapy. Patients randomized in a one-to-one function, cisplatin paclitaxel plus bebacizumab, the pure GOG240, or experimental are the same regimen plus atezolizumab. I would like to stress that an important difference with the keynote 826 is that BCC trial, all patients must be eligible for bebacizumab since bebacizumab is mandatory. The study is closed for recruitment, primary endpoint, overall survival. The results from this is more, I'm sorry, I'm going to skip. Okay, and the latest trial that I want to discuss in first line is the FERMATA trial. This trial is analyzing the role of the new anti-PD-1 BCD-100 in combination with platinum-based chemotherapy plus minovebacizumab, and this trial has also as primary endpoint overall survival. So, in conclusion, immunotherapy is changing the face of cervical cancer treatment. The anti-PD-1 agent semiplimab is the first immunotherapy to demonstrate a statistically significant and clinically meaningful survival benefit in recurrent metastatic cervical carcinoma following progression after first-line platinum-containing chemotherapy. The combination of platinum paclitaxel plus pembrolizumab with or without bebacizumab handshows superiority in terms of PFS and overall survival over a standard of care in first-line therapy for recurrent metastatic cervical cancer. BCC trial may provide further information on the role of anti-BGF therapy plus anti-PD-L1 in first-line therapy, but what will be the upcoming scenario? What may the patient most benefit from anti-PD-1 therapy, second or first line? Is there any rationale to use anti-PD-1 agents after anti-PD-1? Could anti-PD-1 agents replace by themselves platinum-based therapy? We have a very, very exciting pathway ahead of us. Thank you for your attention. Thank you so much, Dr. Ogden, for that excellent presentation. I think you outlined the issues really nicely. And next, we'll have Dr. Consign, who will discuss, she's going to turn on the TV. Let's talk about Tisodamab. Dr. Consign, thank you. Do you want to just put that in the presenter mode, Nicole? Yes, I try. So, it's wonderful to be here. Thank you very much for the kind invitation. It's my pleasure to report on an experimental drug named Tisodamab vedotin and the current status of clinical data that we have on this drug. My disclosures, I also want to mention, as this is an investigational drug, not approved yet, that I've been PI in the first in-human trial on this drug for the Catholic University in Leuven and co-published the cervical cancer cohort, the expansion cohort of this trial, as a co-first also together with my colleague David Tong. So, what is tissue factor? Tissue factor is a transmembrane protein, and under normal physiological condition, it activates the extrinsic pathway of the coagulation cascade after damage of the vessel. In oncogenesis, it promotes tumor growth, metastasis, and angiogenesis. Tissue factor is overexpressed on several solid tumors, particularly strong overexpressed in cervical cancer, and importantly, not only in squamous, but also in adenocarcinoma. Tisodamab vedotin is an antibody drug conjugate and is directed against this tissue factor. After binding to tissue factor, the whole complex is internalized into the cancer cell, and the Aristotene analog MMAe, so this is the payload, is released intracellularly and causes cell cycle arrest and apoptosis. And this direct cytotoxic effect is augmented by further effects of this drug, which are mainly immune-related. It causes also immunogenic cell death, antibody-dependent cellular toxicity, and antibody-dependent cellular phagocytosis. So, this is the first in human trial. It consisted of an escalation part and then an expansion cohort in several different solid tumors, among them also cervical cancer. This was really heavily pre-treated patients, two and more previous systemic lines, and we saw an investigator-assessed objective response rate of 24 in these patients, and it was really nice to suddenly have a drug in hand, which works in these heavily pre-treated patients. The toxicities that we saw were new by that time, primarily ocular toxicity. We did not have an eye care plan in place by then, so we really discovered the toxicities and implemented the protective measures while we were going, which led to significant reduction of conjunctivitis in these patients. Median duration of response was four months. This first in human trial prompted the follow-up trial, a pivotal phase two single-arm multicenter study, also recurrent and metastatic cervical cancer, but this time a maximum of two prior lines. Hisotomab vedotin was given every three weeks on a dose of two milligrams per kilogram, and the primary endpoint was confirmed objective response rate by an independent review committee. So, the primary endpoint outcome was, again, confirmed objective response rate of 24 percent. We've seen seven complete responses and 17 partial responses, and about 50 percent of patients got a stable disease with this drug. The median duration of response was 8.3 months. Importantly, the responses were seen amongst several subgroup analyses. I don't want to go through all of them, but just show you this trial had about one-third of non-squamous histologies in their adenocarcinoma and adenosquamous carcinoma, and we saw response of 25 percent in these patients. Also important to mention that about 60 percent of patients had prior vivacisumab in combination with doublet chemotherapy in frontline treatment, and also in this BEV pretreated patient, we saw clinically meaningful responses. PFS, median PFS in these patients were 4.2 months, and median OS was 12.1 months. So what's about toxicity of this drug? Here, the treatment-related adverse events that occurred in more than 10 percent of patients are displayed. Most of these adverse events were grade 1 and grade 2, and importantly, no new safety signal was reported in comparison to the first in-human trial. There were a total of four deaths on treatment in this trial, and one, the one due to septic shock, was considered to be related to the drug by the investigator. There are adverse events of specific interest, and they are shown here. Ocular toxicity, bleeding, adverse events, and peripheral neuropathy. The ocular events, importantly, were mainly grade 1 and grade 2, and they occurred in about, well, more than 50 percent of patients. They resolved in almost 90 percent within short time, which is important to mention. So this was not really the problem to take patients off study. In this trial, there was an upfront, very careful eye management plan implemented. Bleeding disorders were mainly grade 1, and the big majority of bleeding disorders was epistaxis, and also this adverse event resolved in 90 percent of cases. Important to mention, the follow-up time per protocol for the adverse events was 30 days. Peripheral neuropathy, which is common in these pre-treated patients with taxons, and also this toxicity we see in other MMAE using antibody drugs conjugates, we saw 17 percent of grade 1, 9 percent of grade 2, but also 7 percent of grade 3 peripheral neuropathy, and as you can see here, in only 20 percent of cases, this adverse event resolved. Importantly, again, the 30 days of follow-up time per protocol, so this low rate of adverse event resolution might, in part, also be related to the short follow-up time. This trial is now currently being confirmed by a phase 3 randomized trial in the same patient population, recurrent metastatic cervical cancer patients, after one to two prior lines of systemic treatment, and tisotomab vedotin is randomized versus investigator choice chemotherapy with the primary endpoint of overall survival. An interesting early phase trial that has recently completed enrollment this year is this trial where combinations are investigated in metastatic and recurrent cervical cancer, namely tisotomab vedotin together with pevacizumab, pembrolizumab, and carboplatin. It includes a dose escalation path and then expansion cohorts, and interestingly, the combination with pembro and with carbop is also applied in chemo-naive patients in the frontline treatment, and I'm looking forward to learn about these results. Leslie already said it, it's still an experimental drug, no approvals nowhere in the world, but FDA filing of the BLA of tisotomab vedotin for accelerated approval was announced in April this year, and the FDA target action date for the priority review is the 10th of October, so interesting news, we'll learn about it soon probably. Thank you for your attention. Thank you so much, Nicole, that was excellent. We're going to talk more about tisotomab vedotin with Dr. Mung's presentation on Thursday and our distillation, so all of you in the audience will get to know this medication better as it starts to come online. My great pleasure to hand this over to Dr. Zamorin, who's going to discuss kind of what this all means in the grand scheme of things, and then we'll have time for question and answer afterwards. Thank you. Well, thank you so much to the organizing committee for this kind invitation and for this marathon of beautiful talks that we're hearing today, so I'm going to try to synthesize what the speakers before me have highlighted and to see how we can all fit it together into management of cervical cancer, so here are my disclosures. So, as highlighted before by Dr. Mung in opening, we have now upcoming clinical trials, some of them have already resulted where immune checkpoint inhibitors, namely PD-1 and PD-L1 inhibitors, are being incorporated into management of both locally advanced cervical cancer and also first-line treatment of recurrent metastatic disease. Here are some of the trials that were highlighted in the earlier talks, including CALA for the combination of cisplatin with chemoradiation and duralumab, Keynote A18 looking at cisplatin with radiation and pembrolizumab, and then a couple of the two trials in the advanced disease setting, including BCC utilizing the GeoG240 type of regimen in combination with atezolizumab, as well as Keynote A26 looking at the very similar combination with pembrolizumab with bevacizumab being optional, and as Dr. Oakden has highlighted, the Keynote A26 has already met its primary endpoints of PFS and overall survival, and we're anxiously awaiting the results to be actually presented. So assuming and hoping that all of these trials will be positive, when will be the best time to use the ICIs? Should we use them up front for newly diagnosed metastatic disease or second-line therapy? So over the next few minutes, I want to make a few arguments for whether we should use them up front or in a recurrent disease setting, and hopefully this will open up some room for discussion afterwards. So here are some arguments for the early ICI setting. This is a nice slide sort of highlighting the concept of immunoediting, meaning how do tumors arise, and we know that the immunoediting proceeds through several different steps, where it starts with elimination, where the immune cells are capable of recognizing and completely eliminating cancer cells, followed by equilibrium, where an equilibrium exists between the cancer cells being killed by the immune cells, but also developing mechanisms of resistance, and then finally, the escape of the cancer cells from the immune-mediated killing through acquisition of various immunosuppressive functions, such as upregulation of PD-L1, amongst others. We know that this process does not just happen through the development of early cancers. This happens throughout the evolution of the cancer, even in the advanced stage. So one may, of course, predict that as the cancers evolve through the natural history, they are becoming more and more resistant to immunotherapies, which would argue that perhaps using immunotherapies earlier would be more beneficial for patients before they have developed all of these different mechanisms of resistance. It's not just the cancers that evolve, the host evolves as well, both as a natural immunosuppression from the cancer, but also due to therapies that we administer to them. So, for example, this is a study of adjuvant chemotherapy in early-stage breast cancer, where the patients were characterized for their T-cell repertoires that were collected before chemotherapy and afterwards, and afterwards meaning one to five years after chemotherapy. And what this study nicely demonstrated is that the patients had these long-term changes in their peripheral T-cell repertoires where they never really completely recovered the pre-treatment repertoire. And in fact, in here, there was a significant reduction of this naive-like CD4 T-cells in the peripheral blood circulation and increase of this inflammatory Th17-like memory T-cells. Does this affect responsiveness to immune checkpoint inhibitors? We don't know, but clearly these data do demonstrate, among other studies, that what we give to the patients, meaning cytotoxic therapies, does alter their immune response. How does this impact clinical efficacy? Well, here are some studies of early incorporation of immune checkpoint inhibitors into therapies. This is a specific trial, which was durvalumab that was given after chemoradiation in stage 3 non-small-cell lung cancer, clearly demonstrating improvement in both progression-free survival, but also overall survival. And again, these patients did have access to immune checkpoint inhibitors upon their cancer recurrence. And this nice separation of curves certainly highlights that earlier treatment with immune checkpoint inhibitors can improve subsequent outcomes and hopefully even increase the cures in this disease that has high incidence of recurrence. We see this in some of this already in cervical cancer as well. Here are the data that were previously presented by Dr. Oknin for the combination of the clinical trial incorporating CTLA-4 and PD-1 blockade in advanced cervical cancer. In this case, the patients were treated either directly for their newly diagnosed metastatic disease or after progression on prior chemotherapy. And in both of the regimens that were used in this trial, the patients who were treated earlier, meaning without the prior chemotherapy, were the ones that have done better with regards to their overall response rate and progression-free survival. Here is another trial, which was also highlighted earlier. This is the Empower Cervical trial looking at PD-1 inhibitor simplumab in the setting of being treated after prior chemotherapy. This trial, as highlighted earlier, demonstrated an improvement in overall survival in the patients irrespective of their PD-1 status or histology. But I want to highlight here is that if you look at the progression-free survival curves, the amount of benefit that was seen, particularly in the adenocarcinoma population, was not great. In fact, there was no benefit for progression-free survival in the adenocarcinoma population, but there was a significant improvement in overall survival. So this highlights, even in the absence of apparent clinical benefit, these PD-1 or PD-L1 inhibitors have a potential to impact the disease biology and perhaps slow down the tumor growth or make the patients more responsive to subsequent therapies, which also makes us question about the endpoints that we use for these trials and whether the progression-free survival is the right type of an endpoint. Here are some arguments I have for later ICIs. Of course, as we all know, immunotherapies do come with the risk of toxicities, and some of these can be fatal or lead to long-term disabilities. Fortunately, for PD-1 inhibitors, these are relatively rare. We see them more commonly in the CTLA-4 inhibitors, and as I highlighted, this was actually a nice meta-analysis. Some of these can be quite significant with immune toxicities such as myocarditis, leading to a fatality rate of approximately 40%. There's also an argument to make that most of the patients with locally advanced disease or rather early-stage disease are cured with chemoradiation alone. This is the RTOG-90-01 study demonstrating that approximately 80% of these patients will never see their cancer come back. So will toxicities in two-year maintenance with immune checkpoint inhibitors be justified in the patients that have such a low risk of recurrence? And finally, we must not forget that ICIs are expensive. Two years of maintenance with an ICI in an adjuvant setting would amount to approximately $360,000 in the U.S. for each patient, and this is certainly cost-prohibitive in the U.S., and it will be virtually impossible to implement in developing countries. So here is the summary of everything that I have highlighted. There's certainly a lot of arguments for early incorporation of ICIs into the treatment of cervical cancer. We have patients with healthier immune systems and more diverse T-cell repertoires. The tumors may be more sensitive because they have not yet acquired the mechanisms of resistance that would resist the ICIs in a later-line setting. The hosts are healthier. Patients are more likely to tolerate immune checkpoint inhibitors earlier in the disease course. We already see evidence of improved overall survival with the upfront therapy with a keynote A26. There may be evidence for improved overall survival in other disease types for the adjuvant treatment. Of course, we haven't seen that yet in cervical cancer, but we're looking forward to the A18 and CALA data. And there may be a possible impact on subsequent disease biology, even in the absence of immediate apparent clinical benefit, irrespective of histology or PD-L1 status. Again, certainly highlighting that perhaps using these drugs earlier may be better, even if they don't necessarily generate a response rate. And finally, there are some arguments for the late ICIs, including the fact that the majority of the patients may be cured with chemotherapy alone. If ICIs are approved in the upfront setting, they'll require one to more likely two years of maintenance. This might not be possible in many countries, and including many patients might not be able to come in that often to receive these kinds of lines of therapy. And of course, as I highlighted, it is expensive. So in conclusion, it does seem to suggest that the early incorporation of ICIs into treatment of cervical cancer does have a very strong rationale, but we must balance it against the potential clinical and financial toxicities, particularly in the patients with early stage disease. And I thank you for your attention. Oh, that was awesome. Thanks so much, Dimitri. It was a great presentation, really putting things into perspective for us. So I'm going to ask my co-chairs to rejoin me, Gonzalo and Teodi. And we're going to go for, thanks everyone for being so great on time. We have time left for questions. We've got some great questions from the audience. And I think if all the panelists want to come back on, we're going to each of the moderators take the questions in order of our sections. And then for all of the participants on the panel, please feel free to chime in with your answer. So I'm going to go ahead and turn this back over to Gonzalo, who can take the questions from the top. And these are all from the audience, by the way, feel free to submit more questions. We have quite a bit of time here. Thank you, Leslie. I have two questions, one for Dr. Bruni. One is referred to the cost of vaccination, which is prohibitive in vulnerable economies. So I know there's little we can do about it, but Dr. Bruni, do you happen to know if there's any initiative either from the WHO or from the pharmaceutical companies to address this issue of the cost of vaccination in vulnerable economies? Yes, many thanks for these questions. This is really a key issue. And affordability remains a main concern everywhere, but we have to take into account that tendering processes for the immunization programs have succeeded really well in lowering marketed prices for vaccines. So it's not the same what programs pay for the vaccines, what a person has to pay in a pharmacy to get the vaccine. These are different prices. OK, so many countries now achieve by self-procurement prices between $15 and $40 per dose. OK, and there are currently two funding schemes. One is for Gavi countries that they're the low income countries that get prices about $5 per dose. And also there is the Bajo Revolving Fund for Latin American countries that more or less the price is about $10 per dose. OK, the problem is that the countries that are outside eligibility for these schemes, middle income countries that are not so poor but do not get into these kind of schemes. But we are expecting in the coming years new products, new vaccines from Chinese manufacturers, from Indian manufacturers. So we hope that also this will get more supply of vaccines and also this will lower the vaccine prices everywhere. Okay, thank you very much, Dr. Grundy. That was very clarifying. And the other two questions I have from the audience are for Dr. Haldorson. One is that from a colleague that is expressing his concern about whether CT scan can upstage patients and maybe patients who are not positive by CT scan cannot be operated and they should be operated. And the other question for Dr. Haldorson is that, what about CT scan as a staging tool? Can it replace rectoscopy or cystoscopy? And what is the role for these two examinations in staging cervical cancer? Hmm, thank you for the question. Concerning CT scan, I would say that it could be an alternative for assessment of distance spread like lung metastasis if you don't have PET-CT availability which would be the case, of course, at many centers. So CT is, I guess, more commonly done in low-income countries, of course, and also widely at centers with not having access to PET-CT. But I think it's well-documented though that PET-CT would be superior for assessing small distance spread foci. So I guess it depends on the availability of imaging infrastructure. Also, I agree that, of course, it could be a concern with all imaging diagnostics that at least both, it could lead to incidental findings that you have to somehow assess, which is a problem with PET-CT in particular. And of course, it has also been touched upon by other speakers that sometimes FTG avidity is not necessarily specific of distance, like metastasis, right? It could also be FTG avid foci due to inflammation. So this is not very easy at all, and I wouldn't claim so either, but still, it's the best we can offer the patients as per now, and of course, we need to learn more also. I also, I want to mention that, of course, new tracers, new radio tracers could also be, come in the future, that could also change quite a bit when it comes to targeted therapies for, yeah, for example, immunotherapy. So I think probably imaging, at least in some contexts, would definitely still be important. But we don't know exactly. Thank you, Dr. Haldorsen, I'm a big fan of your reviews here. I think Dr. Chibula has a quick comment. Yeah, well, if I can comment on the second question, which is the role of cystoscopy, rectoscopy, because this is something that I considered for many years, you know. Let me be very radical in my saying that if, you know, if you have accurate imaging available, either MRI, for local staging, either MRI, or expert ultrasound, so you have expert sonographist, then for me to do cystoscopy, rectoscopy, is like to investigate your heart by stethoscope in current days. You know, we are talking on MRI about millimeters. We can see the tumor, we can see the tumor exactly, the location in a infiltration. We can see delineate individual layers of the rectum and of the bladder. Many of those tumors which start invading bladder wall, or rectal wall, will have negative cystoscopy and rectoscopy simply because it's not true. But, you know, to sustain this very historical clinical practice and do cystoscopy, rectoscopy, you know, it has no clinical meaning in these days. You know, David, you and I are always aligned. I just texted that to Leslie. You did. As you were speaking, so. May I also comment that I fully agree as a radiologist. MRI is, of course, way better than, yeah. But ultrasound is a good alternative in trained hands, like you say. Thanks. Great discussion. Jyoti, I think you had some questions. Yeah, we have a couple of questions here for our group. If anyone really on the panel can take this one. Should we do a periuretic node dissection? In women who have positive intraoperative pelvic lymph nodes detected? That's one of our GYN oncologists. Dr. Leath, would you be willing to answer that one? I mean, yeah, I guess the beauty is certainly the data's gonna be relatively limited. I know there are several retrospective series that have evaluated, you know, the potential implications of staging and several that have looked at it from a mathematical standpoint. I think certainly an area of controversy is what to do with the bigger nodes, if you can resect those. And if with resection, you then improve the ability for radiotherapy to sterilize those nodal beds. I think in our institution, we've really gone away from assessing the aortic nodes with a positive pelvic node. I don't know if that's a right or a wrong answer, but again, we do assess them at least clinically to make sure there's not, you know, a large bulkier node that may not be able to be sterilized with radiation. But in terms of routine assessment, I don't know that we have data to definitively support that. So, Dr. Sabola, what are your thoughts? Yeah, I absolutely agree with that. We have, you know, no evidence that, and it was interesting also, we had a long discussion with radiation oncologists about this topic when we were developing ESGO guidelines. And there was no clear answer or opinion from neither from them, whether there is the role for removing bulkier lymph node. And if so, is it the lymph node which is bigger than two centimeters or four centimeters, or is there any cutoff limit for the size? So, you know, this is still uncertain and we have very similar clinical practice. We do laparoscopic staging, if of course the case is suitable for that. And if there is a suspicious lymph node in the pelvis, we remove it. Because as I said, from our data set, it was really one of our surprises from analysis of our retrospective data that we found quite a high rate of false positivity from PET scan in these tumors. Yeah, I agree with that. And I think the question is, what do you do with the information that you find, right? And so historically we've used aortic nodes to define radiation fields. You know, the more we learn about no positive disease, it's high risk. You know, aortic node positive is high risk for prognostic for a reason. And probably that's the point at which we need to really sort of switch gears to more systemic therapy. And so, you know, we don't really, we haven't really defined our staging in that way, but maybe we need to continue to discuss that and look at that as a good discussion. Great question. Let's not lose fact though of the post treatment, whatever that is, let's say post pelvic chemotherapy and radiation three month PET scan. So even if you stage that patient and you tailor your intervention, this idea that let's do a three to four month post chemotherapy radiation PET and see what we missed, because you're going to miss things and there is a salvage of those patients. You know, one small piece of information, which I would like to highlight because for cervical cancer, there is a very specific situation, which is not comparable to other gynecologic pelvic tumors. And cervical cancer spread is really very predictable. In the majority of patients, it goes simply from cervix to lower pelvic lymph nodes, then to higher pelvic lymph nodes and then to parietal lymph nodes. Very rarely there is a case of, you know, meds jumping into parietal or somewhere else. And this is really very regular behavior. So that's why I think, you know, it's so important to start from the bottom and to investigate to those sentinel lymph nodes, which are also in majority located in the lower pelvis very carefully, because this gives us extremely important prognostic information. Lymph node negativity in cervical cancer, it's a different information than from, you know, breast cancer or other disease prognostically. So the situation is different if we have a patient with, you know, one positive lymph node in inter-iliac region, while we have one in pariotic or low pariotic or even common iliac region. It's simply the sign of, you know, one level up in this disease. Erin, I do want to just make a point about the lymph node size, just to clarify. You know, before the advent of IMRT, which would give us higher lymph node boost doses, we would often advocate that less than two to two and a half centimeters, or I should say greater than two to two and a half centimeters, we're not convinced that radiation could sterilize that lymph node. But now with the simultaneous integrated boost, lymph node disease, most radiation oncologists will give a lymph node boost to up to about a three centimeter tumor. And that is really due to the technology, advancements, and bowel sparing. So smart. It's so interesting how the paradigms are changing just with the technology, that's great. I would like to add something to Dr. Monk's statement, which is very interesting as usual. When you do a PET-CT scan after chemoradiation and you still find activity in the cervix, do you consider that persistence of disease and you consider that patient candidate for exoneration or you wait three months for another MRI or another PET-CT? And I love working with you guys and you're all so smart. What David said is so true is that many of these PET-CT scans are inaccurate, right? So you'll see an anatomically normal node and it has an SUV of three and it's not cancer. So you really have to sort of integrate the entire picture. In that specific patient, I would not do anything without histologically proven cancer and what I would do, we use those needles that are spring-loaded that they use to do a transrectal prostate biopsy. And so prostate biopsies are so common because everybody checks their BSA and it goes up and then they do a transrectal biopsy. You can use that gun and you can do six or so circumferential biopsies and really figure it out. So that's what I would do in that setting. Thank you, and I would like to add just a point. I think the timing is quite important. When did you perform the evaluation after chemotherapy? It's not the same, the outcome that you read when this test has been performing three months after or six months after. I think that we must be very, very careful with the timing about, I mean, about evaluating the response to chemoradiation. Yeah, so what happens is they go put the last implant in the radiation doctor and they call me and they say, Brad, there's still tumor there. And I'm like, I know. And I'm glad you gave her some more radiation. So you have to let the, the radiation takes time to work. And so that's such, again, so smart. Yeah, I mean, it's quite important. And, yes, one more point with that. I think we could talk all day about PET scans post-chemoradiation, but I agree wholeheartedly with the group. I mean, as we all know, a lot of the PET data came from WashU and essentially the easy way to remember it is that if you have a patient with persistent SUV uptake, now there's a lot of definitions of what that is. There's ratio pre to post, but if you are concerned, roughly 50% of those will resolve over time. Radiation works with what we call mitotic catastrophe. So like Dr. Monk saying, you have to go through the cell cycle to have the cell death. So definitely histological confirmation. One more thing is that in patients who get an interstitial brachytherapy implant, I have seen that these patients have a little bit more persistence at 12 weeks. I often wait a little bit longer, even up to 15 weeks on these patients. So things to keep in mind, but like we all know, every cervical cancer is just a little bit different. And that's why I said three to four months, right? Exactly, exactly. So I propose for the next master session in the IGCA meeting, we will discuss hysterectomy after chemoradiation due to persistent of cervical disease. Very, very controversial topic I would like to discuss with you all. I agree, that would be a great topic to address. And it's interesting because one, the argument to do the PET early and to detect this, I'm getting this undercurrent that you're trying to justify not finding the persistent disease as quickly as possible. You don't need to find it as quickly as possible. You can wait it out to get that overall readout on how the radiation is working because if they're gonna develop systemic disease, you really want to know that because as we learned from these talks earlier, there's a very narrow window for who would benefit from an exonerative surgery. And those are really who the people that you're really looking for with that PET. And the only justification of doing that PET earlier is to find that local disease. But if you wait, you'll find the patients who in retrospect would not have benefited from exoneration, which is most patients. So it gives you time to see that systemic disease develop. Dr. Chabula. Just a small note and to add what Bragg said about the biopsy and need of biopsy if there is a persistent activity. I strongly support that. And what we have very good experience is that this biopsy, if it's done imaging guided. So we use the same technique as IVF specialists use for all sites retrieval and transvaginal probe. So usually if it's hot on imaging, it's also, you can see it on ultrasound quite well. And you can do a direct biopsy. You can, so there is a bigger chance to really go to the epicenter of the finding, especially in larger tumors. Interesting. Very interesting. We only have another couple of minutes left. You're gonna switch over to some of the metastatic recurrent questions. Thanks everyone for these excellent questions. One question here, I found it curious that Empower adenocarcinoma cohort showed an OS advantage but the PFS was overlapping. Dr. Zamarin, you kind of touched on this. Why do you think this occurred? I wish I had a good answer for you, right? But I think we've seen that in some other diseases as well that our measurement of clinical benefit really primarily rely on the recessed response, right? So if you have a progression in your target lesions you will automatically be considered as somebody with a disease progression. But over and over, we do see that the patients may benefit from subsequent therapies in spite of having a no apparent clinical benefit from the drug. And that's because we think that when we give these drugs to the patients, we do change the disease biology not entirely clear how. I mean, ideally if we had biopsies pre and post-treatment we may see changes in the micro environment or perhaps other parameters. And then when the patients and the disease may start growing slower it's still growing, but it's growing slower. And perhaps it may respond better to other therapies in the future. We know how important the immune response is for responses to chemotherapy. So I would be very interested in seeing subsequent therapy responses in the Empower study that will help us to flush out this answer. And Dimitri, we can't overanalyze it, right? If you remember from 240, there was a discrepancy between the adeno and squamous results as well. And we sort of explained that that was false discovery. So I'm gonna do the same thing here that a lot of this is likely false discovery. I think the biologies between squamous tumors and glandular tumors are more similar than different. And we inherently want to sort things cut things up and analyze them. I think we need to look at the multiple comparisons are not controlled for. And just like bevacizumab works in adenocarcinomas checkpoint inhibitors probably don't work better or differently in adenocarcinomas in this setting. That's just my personal opinion. Great, thanks everybody for a wonderful session. I think we're going to get cut off here. This is really a great master session and look forward to next year and the rest of the meeting. Thank you. Thanks everyone. Bye bye. Thank you. Bye bye. Bye.

recurrent cervical cancer

metastatic cervical cancer

surgery

radiation therapy

chemotherapy

targeted therapy

immunotherapy

disease location

extent

previous treatment history

patient's overall health

shrink tumors

disease spread

specific molecules

immune system