Hi, everyone, and welcome to IGCS Education 360 Journal Club. I am Carrie Langstraat, the co-chair of IGCS Surgical Education Workgroup, and I'm a G1 oncologist at the Mayo Clinic in Rochester, Minnesota. Before we begin, I want to mention a few housekeeping notes relevant to the Zoom platform for today's Journal Club. We are recording today's discussion, and the recording will be available publicly. Questions with camera turned on may appear in the video recording. We ask that everyone please keep your microphones muted so everyone can hear the presentations. If you are having any difficulties or questions, please send a message in the chat and our technical support will assist you. We will have time for questions and answers and encourage you to submit questions via the chat function throughout today's session. I am joined today by my co-chair, Dr. Raytan Ribeiro. Raytan, please introduce yourself and our invited speaker. Thank you. Thank you, Carrie. I'm Dr. Raytan Ribeiro. I'm one of the co-chairs of IGCS Surgical Education Workgroup, and I'm an Associated Professor at McGill University in Montreal. And today we'll be discussing the article Surgical versus Clinical Staging Prior to Chemoradiation in Patients with Cervical Cancer Stages 2b and 2.4 and the Oncological Results of the UTERUS-11, this multicentric trial. So the article is available online in the International Journal of Gynecology and Oncology, and it's free so you can just download it. And we are joined today by the co-author, Audrey Tsunoda from Brazil, my good colleague from Brazil. So, Audrey, thank you so much for joining us today and sharing more about the article. And I'm going to hand it over to you for the summary and to present the paper. Thank you, Audrey. Well, thank you very much, IGCS, Dr. Langstreth and Dr. Ribeiro, both very skilled and acknowledged by this topic as well. So it's a very nice opportunity to share some insights and some information about the background and how we did plan the study and how the study was performed, including with us in Brazil. So these are my co-authors, and the study was led by Dr. Simon Marnetz, radiation oncologist from Cologne University and crystal killer surgeon in Hamburg and Berlin. These are my disclosures. And first of all, everybody's asking, well, what would be the key lessons learned from UTERS-11 study? Well, let's see the context. First of all, we need to understand that cervical cancer is a disease from underserved areas most of the times, and we need to have resources, basic resources related to prevention and also for therapy. So no surgical staging would be completely useless if we lack basic resources. And what about access and feasibility of the surgical technique of surgical staging? Well, it should be a reproducible technique that we could mentor in raising reference centers and also quite innovative and sustainable. So at that time, when we started the study, all the key elements were favorable in favor of performing the study in our centers as well. And of course, mentorship would play a very strong role as we were starting our center in 2006 and starting in the study in 2011. Teaching would be interesting, and many of our former residents and fellows participated on the cases, on the research as well, and we elevated the level of medical practice in Brazil and in Barreto's cancer institution. Well, cervical cancer really respects a route of dissemination which starts local, regionally, and then most of the times in ascendant, in a cranial way, up to the lymph nodes and upper lymph nodes. And the new staging, FIGO staging from 2018, really includes the lymph node status, which is prognostic and may tailor therapy for us nowadays. At that time, we didn't have that type of resource. We should follow the MCCN guidelines because all high, all reference centers with high volume and that are adherent to MCCN guidelines, they do offer better oncologic outcomes for the patients. And that is really connected to the strong multidisciplinary team approach. At that time, we worked here in Barreto's with a very interested and engaged team. And the same in Erastogertner, nowadays I've been working there for 15 years. And here you may observe Reitan and Christa Kehler, Simone Marnitz and all our team members really engaged on elevating the level of therapy and the multidisciplinary management of these patients. Of course, we should count on technology and resources, as I mentioned, but mainly fundamentally a team that includes, for example, the anesthesia personnel, which are key elements for complex surgeries and complex procedures. We know that the key elements for therapy for locally advanced cervical cancer are chemoradiation, a combination of chemotherapy and radiation, and even bulky tumors could be really solved with these approaches since 1999. But the rationale for surgical staging is that 15 to 25 percent of the bulky tumors would present with positive parietic lymph nodes. And most of the imaging resources, they're not enough for us to adequately tailor those patients for extended field chemoradiation, for example. Even the PET-CT, the best source that we do have nowadays related to imaging, do present until now a false negative rate from 9 to 22 percent. And it really depends on the staging of the tumor, but not only the staging or the patient status, but also related to the experience of each group. As you may observe here, the comparison between PET-CT, MRI, and CT scan, but mainly when pelvic lymph nodes are positive, the parietic lymph nodes may be missed around 20 percent of the patients with a good PET-CT performed in referral centers. And staging would lead to up to 36 percent of upstaging after a staging procedure in previous literature. At the current NCCN guidelines, a surgical staging would lead to modification, a tailoring of the field of the radiation therapy to the left renal vein. So that would change our therapy probably for at least 20 percent of the patients, a medium of 20 percent. And the previous information, previous literature about this topic includes this analysis of the GIG studies where overall survival was really improved by surgical staging, although it was not really the main objective of the studies. But as you may observe here, even our viral survival and disease-free survival. And according to the French data, negative lymph nodes would have a very good prognosis and comparable to very small microscopic lymph node metastasis in the parietic space. So if we do tailor the therapy based on surgical staging for those patients that do have pelvic positive lymph nodes at the PET scan and negative parietics, we would benefit those patients in a very significant manner. As we observe here, over the time, the effect was compared among all the institutions, the French institutions. A previous randomized trial was performed, but it had to be interrupted due to different reasons, but mainly the radiation techniques in the surgical staging, which was performed open or minimally invasive. So they couldn't conclude if this was really good practice at that time. We had some Brazilian experiences. And in 2011, Paulo Zanveto published this paper with their first experience on surgical staging. And at that time, the overall survival for patients with locally advanced cervical cancer was around 56 percent. So we started UTERS-11 and in this study in Brazil, we included 95 percent out of the 250 from the study. And in this study, divided into arms, the inclusion criteria was FIGO 2009, stage 2B to 4A. And as a reminder, it was independent on the lymph node status at that time. And imaging was counting on CT scan and or MRI, but PET-CT was optional. Since most of the developing centers didn't count on PET-CT as a regular tool for staging at that time. So patients were randomized into surgical staging versus clinical staging, and all the patients with suspicious periortic lymph nodes from the clinical arm were also biopsied by CT scan, guided percutaneous biopsy. And if the lymph node was positive, confirmed positive, the patient did receive extended field chemoradiation. And on the surgical arm, all patients with positive periortic nodes would receive primary chemoradiation. It's important to highlight that in this study, the lymphadenectomy was performed as a routine pelvic entire complete pelvic lymphadenectomy, both sides and the periortics up to the left of the renal vein, independently of the lymph node status at the imaging. So that included a huge amount of patients without any signs of lymph node suspicion, and of course, bulky lymph nodes on the pelvis and the periortics. So the randomization occurred with included 255 patients, and these are the allocations of the patients. And surgical staging included minimally invasive techniques, all of them were performed with the regular laparoscopy, most of the times with this trocar placement. And here you may observe Bruno Zefeta and Rayton Ribeiro performing surgery with me. And the some paradigms were shifted after this study, for example, the the profile of complications after standardized and complete pelvic and periortic lymphadenectomy. Major complications were related interoperative, were related to vessel injury, and they were 2% in the study, conversion to laparotomy in one patient, and post-operative mortality zero, and some complications, most of them minor, were related to thrombosis, symptomatic lymphocele, ilus, and nerve irritation, and two others. One of them was actually not related to the study. And the rate of upstaging after a surgical procedure was around 8% for the clinical arm and 33% for the surgical arm. And another paradigm that was shifted after this was performing chemoradiation with this extended field after a surgical staging. And of course, as we performed transperitoneal lymphadenectomy, the possibility of more adhesions and more toxicity in the surgical arm. Time to start chemoradiation, which was another bottleneck that we should face to reduce the time or to keep the time controlled. It was performed from 7 to 21 days following the surgery. Techniques most of the times were IMMRT, but also 3D radiation therapy, and no grade 5 toxicities were observed. As you may observe here, the GI toxicity in the clinical and surgical arms and the JUU toxicities were really comparable among both arms, and that really shifted the mindset that prior experiences described too much toxicity or unbearable toxicity related to the combined therapy after a surgical staging. Unfortunately, the oncologic results, final results, didn't support the idea that the surgical staging really improved either disease survival or overall survival. Both of them had a clear tendency, but they were not significant. But for a specific stage, yes, stage 2b patients really benefited from surgical staging and probably because the recurrence of the stage 2b patients were not locally and regionally and not systemically as patients from stage 3 and 4. Cumulative incidents and the median follow-up was 90 months, and cancer related survival benefited surgical staging as well. So the conclusions of the study included that laparoscopy is surgical staging is quite safe. Up to 30% of the patients were upstaged after that procedure. Surgical staging really didn't delay chemoradiation and didn't impair the complications or elevated or increased the complications. We demonstrated a specific cancer-specific survival benefit and a special benefit for patients 2b. And with regard to global survival, probably distant metastasis should be considered. And the studies that followed UTERUS-11 trial after 2020 included many advances in systemic therapy that really improved overall survival for those patients, for those higher risk patients. So the trial ongoing in this scenario is the PAROLA trial leaded by Dr. Alejandro Martinez, and that includes patients that do have positive lymph nodes in the pelvis and pariartic negatives, which means 3C1 patients in the neophygos staging. And it estimates a final accrue up to 2027. So I would like to thank Christa Kehler and Simone Martinez for the mentorship all over these 20 years of partnership and all the educational and work that we've been developing. Here you may observe Carlos Andrade from Barretos and Christa Kehler that was mentoring us to start a study. And then after the study finished, the crew was giving some some some sightseeing. And it's been a great journey for all of us. We've really improved a lot after the study. So we tried the key lessons. So we talked about those. And most of the times we forget that we need teamwork. We need to select adequately the patients. And we believe that probably in the near future, we're going to select the best patient subgroup to receive surgical staging and extended field chemo radiation. Probably those that are not really included in the keynote A18 or the interlaced trial, because they're like intermediate. They're not like high risk groups because we have to understand the disease, the pathology, but also the patient. And with this study, we really changed some of the paradigms in the previous literature. So thank you very much for your attention. And let's go for the discussion. Thank you for this wonderful summary, Audrey, we will now spend the remaining time answering a few questions. Attendees are encouraged to enter questions within the chat or you can raise your hand as well on the Zoom platform. But I'll get things started. You did a really great job summarizing these results. And you did show that potentially there is a subgroup within the group that that you studied that might benefit from surgical staging. So as you think about moving this forward, which which groups do you think would be most beneficial? And are there groups now that you would offer surgical staging to in your clinical practice? Actually, after the study, probably we would at that time when the study was published, we would offer probably for patients with stage 2b or 3c1 patients that had not so big primary tumor and small pelvic lymph nodes, small volume pelvic lymph nodes, one or two lymph nodes in the pelvis, and the negative parietic nodes in the PET-CT. And that's why, because those patients maybe wouldn't be the best candidates for really a combination of more systemic therapy because they're like intermediate, they're not really high-risk patients, but they're not so simple as a completely negative patient would be. And of course, after the trial and after some other evidences that came afterwards, we would reduce the extension of the staging into a very straightforward, sharp procedure, very low morbidity, like one or 1.5%, which would be including the bifurcation of the aorta up to the IMA. So that would be really, you know, more feasible, reproducible, and efficient for that specific subgroup of patients. And in our clinical practice, we try to select that type of subgroup of patients, but we're always recommending the current evidence. So we could, of course, perform the standard chemoradiation. We could include that patient in an extended systemic therapy protocol, but there's fewer evidence for those in the current literature. So we offer the options for the patient, and if she does understand the options, we could perform the staging if the patient agrees. Andrei, when you think about the paper, what are the main factors that say that the strengths of the paper? When you look at it, you say, well, that's important, that's one of the strengths of the paper. Well, actually, I think at that time, we had many confusing information in the literature, and there was a lot of prejudice about MIS surgery and, you know, standardized and adequate pelvic and periortic lymphadenectomy. People were always talking about very high morbidity and too many complications, like forbidden, almost forbidden, surgical staging, because patients wouldn't tolerate chemoradiation afterwards. So I think the idea that in the study, the, you know, the core idea was not really achieved, like, overall benefit in overall survival, disease-free survival, maybe because we couldn't select adequately the patients based on the previous FIGO staging, but some concepts really changed after the study, and including that patients from developing countries, for example, in Brazil, could be included safely in a surgical study like this. So it was very nice, because I think it changed a little bit how we understood a surgical staging at that time. Yeah, it makes sense. So I agree, because I have this feeling that this study was done in centers that really have the disease, and it's like a real-world scenario in places you don't have access to PET-CT. So I think that's wonderful. And as you mentioned, maybe one of the weakness might be related to the, you know, I wouldn't say selection, but I think because I feel like there were the cases where that's the patient we want to see, but do you feel like maybe there was some kind of statistical analysis or different sampling that could have been done and changed the final results of the paper? Because as you know, you got so close from reaching a statistic significance, so do you feel like there are weakness related to the sample size maybe, or something that you would do different now? Actually, we calculated, we estimated the sampling after the GOG study. So we really overestimated the benefits. And that was the huge, I think, the huge question, the huge issue for this statistical analysis. And that's why I think probably due to, you know, the prior calculation of the sample, we couldn't reach the difference, but probably if we, you know, were more conservative in the prior simulation, I think probably we would reach the positive target. That would have like, you would need like a bigger sample, right? Yes. Because when you look to the graph, so it's very clear that you cannot just ignore them and look to the p-value, obviously the p is like final. Do you feel like sub-analysis, that's a partial analysis in the middle of the trial or something like that could have helped with the trial or changing the sample size or something like that? Yeah, maybe, maybe potentially. To a more realistic scenario? A little bit more, yeah. But you know, the statisticians from Charité University which ran that analysis, they were so conservative. They closed the analysis only, you know, after 45 or 50 months of follow-up. They were so conservative. So we were so, you know, anxious to receive any news. They were so straightforward. No, we cannot close this because we don't have all the entire follow-up. So we were like, you know, I think potentially, maybe we could have corrected, but I don't know. As the trial was conducted from the General Center, I think it was challenging. We didn't perform that analysis. We just performed though many different safety analysis. They really reviewed all the surgical cases and all the complications. They took very seriously it. And that's really, you know, I think that's fantastic because if we do conduct a trial without surgery, it's quite simpler to understand the complications, toxicities and whatever. But as we ran a surgical trial, it's a little bit trickier, I think, to understand the complications and to relate the complications and describe all the complications after a surgical procedure. So it was quite unique, I think. There is a question in the chat. In the centers where laparoscopic approach is not widely available, is laparotomy feasible and safe? And would you consider a laparotomy for those patients? Actually, I wouldn't consider at all because I think laparotomy is too morbid and could really delay the chemo radiation. But as I mentioned, I believe, I don't know because they don't have that answer. All the patients from the study, they underwent MIS surgery. So I cannot tell you, but in our practice, we don't advise open surgery because it's not really adequate. We believe it's not really adequate because it's related to more morbidity and morbidity could impair or could delay the start of chemo radiation. In that scenario, I think, if you don't have laparoscopy, you should focus on advanced radiation therapy resources because I think they're really, you know, they're the key for improving survival for these patients. It's, they are more important than a surgical staging the scenario, I believe. Aldo, considering the actual literature by now, where do you feel the uterus 11 will like fit? Which patients do you feel like anywhere or how do you feel about this, using this data in the real world? How do you feel it? Yeah, I think this, these three C1 patients, which I believe would be the best candidates for surgical, for considering a surgical staging, would probably would undergo two different therapies, in my opinion, in the future. Surgical staging followed by systemic therapy after a surgical staging, and that would select a subgroup of patients with higher risk among those intermediate patients at the beginning, which means 20% of the patients, or reduce the investment or the resources for those patients that do have negative periodic nodes. So, and those patients will receive only chemo radiation because they're not so high risk as we considered, they're like intermediate low risk. So maybe in the future, we can recommend a better therapy for those three C1, which are nowadays in a huge different and heterogeneous subgroup of patients. Nowadays in our practice, as I mentioned, we offer a surgical staging for patients that are like intermediate or low risk, like with one or two small lymph nodes, pelvic lymph nodes and negative periodics. And we counsel about the opportunity of maybe receiving either more systemic therapy after a surgical staging, because if they do have periodic positive nodes, probably would receive more systemic therapy, like new adjuvant chemotherapy or immunotherapy after chemo radiation. So I think we can select a little bit better the patients, but the problem is it's not really reproducible into all the centers as the previous question was targeting. So in ideal scenario, I think surgical staging could be offered for that specific subgroup of patients and to select patients for one of those therapies if the lymph nodes are positives. So it's a combination of patient selection and maybe center like resources, right? So because some countries, let's say, we have now all the modern technology for radiotherapy and PET, CT and all that, that may be not so useful. Either for like countries, like very poor countries without access to laparoscopy, or also they may fail outside of the clinical picture of the trial. But I'm quite sure for most of the developing countries, they would have the things that we see in the trial, like a laparoscopy that works and it's not expensive. And they have lots of those patients in the real scenario. Yes, and either if we do consider systemic therapy if needed after that surgical staging, most of the developing countries, they can offer a new adjuvant chemotherapy because they do count on the resource. So we could better select patients for that strategy. That's interesting because we're huge countries and very heterogeneous as well. We have major cancer centers. For example, in Brazil, as I mentioned in Brazil, because some of the audience may feel that their reality is quite the same as in Brazil. We do have, we live with two big universes, different universes in Brazil. We do have highly high standard cancer centers and we live with underserved areas in the country. So we have to better select the tools for each scenario. But overall, I agree with you. I feel that the quality of MIS surgery really improved over the last 15 years in our countries. And that opens the opportunity to offer something better for our patients. You had mentioned that if you were to apply this now, you would just do the periortics from bifurcation to IMA. Does that mean you would omit, you would no longer do the pelvic nodal dissection? Actually, no, probably no, Karen, because at that time we had a lot of trouble with bulky pelvic nodes and bulky periortic nodes. As a rule, Karen, but I understand that if the radiation oncologist, he or she really asks us, would you please reduce the amount of disease, the volume of disease in the pelvis or in the periortics? We can evaluate after radiology review and then we can select the patient for like a debulking of the nodes, which I think also has a role in the therapy. And probably in the future, we can figure out that role. But we know that the lymph node recurrences are terrible for the patients. So we have to reduce the events that we could have on this scenario. So we do perform sometimes, but it's not like a regular basis. We do perform, most of the times if you have to, it's not really, you know, like a full package of lymph nodes from both sides with all the vessels skeletonized and all really dissected. At that time we did, and it was good to observe that the toxicity, later toxicity as well was not so high as we expected after such a procedure. And combining the surgical staging plus chemoradiation. But, you know, at the end of the day, I think we can offer, maybe us that do perform debulking are gonna become really dinosaurs, I don't know. Because I think in the future, patients would, you know, have a pill and everything is okay. But nowadays yet, we do need some debulking sometime of the lymph nodes. Thank you. Audrey, thank you very much for a lovely presentation. Just a question, with the benefit of hindsight, if you were designing the trial again today, would you do anything differently? Well, today I think we would do many different strategies to improve the results. I think probably a little bit more similar to the Parola trial design, which actually Christa Keller really contributed to the design. Because I think we, as I mentioned, we overestimated the potential benefit at that time, including that really different amount of patients and heterogeneous patients from 2B up to 4A, independently of the lymph node status. And so we would recalculate probably more than 500 patients in this trial. The second, we would of course exclude the patients with 3C2 disease, which were included in our study. And, but you know, overall, this study was remarkable for us in Brazil. It really marked a new era of clinical trials in our country and in Latin America, which was, you know, a huge step for all of us. And so, and that's why I do believe in research. And I am really positive that this network and opportunities like this one provided by IGCS are really open-minded and really, and can really elevate the level of the quality of the treatments that we do offer. Thank you. You're welcome. Very good. So I want to thank you so much, Audrey. It was a wonderful exploration and it's so good to see how things, you know, behind the curtains. So it's very easy to judge trials and we always do that, right? We always have a better explanation for the things, but it's so good to see how it was done and being done in a developing country. In Germany, obviously too, but I mean, including patients. And I, well, obviously things are changing. I'm in Montreal now, but I look now even more for developing countries. And I think we, as thinking in a Brazilian way, should do our own research, you know, looking for our own, like, what do we have to offer to the patients? And we can't be always relying in research from developing countries because those are really different, you know, realities. So if we just keep looking to the developing countries, there will be no research. And in the end, the patients from developing countries, there will be no advance because there is no research in that setting. So, and I think that's wonderful. So keep doing it. Yeah. So this journal club was very insightful and we hope you all enjoyed. And thank you so much for your time and take some time to evaluate the information and apply it in your own clinical practice. The recordings of today's journal club will be available on the IDCS educational portal later this week. And we will be launching the IDCS Surgical Film Library very soon. And we encourage you all to send your videos for the IDCS, for the journal. And that's going to be very important to update our library. Thank you so much and have a good weekend. Thank you. Thank you very much. Thank you, Audrey.

Uterus-11 trial

cervical cancer

surgical staging

chemoradiation

developing countries

laparoscopic surgery

treatment strategies