and hopefully this will work. Can you just see if I can, okay, perfect. Can you see the screen? Yeah, we can. Great, so really without sort of further ado, if we think what are the sort of the key questions in cervical cancer, and I think in early stage disease, we can think about which patients really need radical surgery and how radical do we need to be? Those questions are currently being addressed. When is fertility sparing surgery an option? And what about the nodes, the sentinel node versus full nodal staging? And when and how should this be investigated? And then when we think about more locally advanced disease, really the questions are, how can we improve the chances of a cure beyond what we can currently achieve with image-guided radiotherapy and image-guided adaptive brachytherapy? So that brings us to thinking about is there a role for additional chemotherapy? Is there a role for immunotherapy? And then when, for how long, and how much do we need to deliver? And how can we identify those patients who are most likely to relapse beyond what we know from the pathology report? So of course, we know that high-risk patients at high stage, nodal involvement, poor risk pathologies, particularly the non-squamous cancers, but how can we really drill down and identify that 30 to 40% of patients that are going to relapse and then intensify the treatment for those? So we look towards molecular pathology, perhaps biomarkers and functional imaging for the future to help us to determine this better. So there's no question that the way we answer, the way we answer these questions is through clinical trials. And there was supposed to be, so we can only answer these through well-designed clinical trials, which I think it's essential that we conduct across a diverse geographical setting and incorporating various different healthcare settings. And I think that's really important to ultimately implementing the outcome or the results of any of these clinical studies. So we can think about the cervical cancer challenges, or I tend to think about them as access to care and quality of care. I think the issues to do with access to care are really geopolitical and they're certainly regional and local. They're not just confined to low and middle income countries. I mean, there are many situations where people in higher income countries have difficulty in accessing quality care. There are always the financial and social challenges associated with managing this disease. And it generally tends to affect obviously younger women. So there's a whole issue of the family and the burden of the family. And then when we think about the quality of care, then this really feeds into outcome and survivorship. And that's partly what we're, certainly a large part of what we're involved with when we think about clinical trials. So thinking about the gynecancer intergroup, what are our aims? Well, this really is, it's made up of a network of different, I didn't spend a lot of time on this, but it's made up of a network really of different research groups, international research groups coming together. And their aims really are to promote and facilitate high quality clinical trials in order to ultimately improve the outcome of women with gynecological cancers. So within this GCIG sort of mothership, we have various different working groups. Now there was a need to look more closely at cervical cancer and how we could link with people in lower and middle income countries who perhaps had no access to, or didn't have national research groups. So the framework for this cervical cancer research network was established by Henry Kitchener, one of my UK colleagues from Manchester in 2011. And the main aims for this network were to connect with these sites where there are no national research groups. Particularly, this is especially important in cervix cancer, which we have, where we have fewer cases in our high income countries because many have established screening programs, but where there are many more cases in other parts of the world. It was also thought important to promote research and good clinical practice in cervical cancer. And purely by participating in clinical trials, it is well-recognized that this enhances and improves the care for all patients. Probably partly because teams become accustomed to working to protocols. And of course, we wanted to improve the participation in our GCIG cervical trials, cervical cancer trials. Just a quick map to show where there are CCRN sites, South America, Central America, a few in Africa, several that have registered sites in India and Southeast Asia, and some in Eastern Europe. So turning now to the CCRN cervix clinical trials. Just in the earlier stage disease, you will be aware of the SentiCOL3 trial. And of course, Colgo are participating in this, which is an international prospect of validation trial for the sentinel node procedure in cervical cancer. And this is for patients with stage 1A1 to 2A1 disease. So just very briefly, patients with the usual types of squamous or adenosquamous of the cervix with a tumor size less than four centimeters are deemed potentially eligible for the 1A1 up to 2A1 stages. Then following frozen section and bilateral detection and safety algorithms, patients are then randomized either to, sorry, patients are then, once you've got bilateral detection without macroscopic suspicious nodes and a negative frozen section on the sentinel node, i.e. that the pathologically node negative, they're randomized to the sentinel lymph node alone with hysterectomy and trachelectomy or to the sentinel lymph node procedure, as well as a pelvic lymphadenectomy. And of course, then hysterectomy or trachelectomy, whatever the local treatment is going to be for that particular patient. Then the endpoints are disease-free, relapse-free, survival, quality of life, and OS. You know this better than me because you're already participating in it, so well done. This is the SENTICOL-3 map, and it's nice to see Colgob-T or G in yellow with two to three sites in India. This is another study, another CCRN study in cervical cancer, and this is called CONTESA or NEOCONF. And this is really looking at fertility sparing surgery and whether we can push the boundaries a bit further in patients with stage 1b2 cervical cancer by looking at the role of neoadjuvant chemotherapy in this particular group. I'm not going to go into all of this, but really it's three cycles of neoadjuvant chemotherapy. They haven't specified whether this should be weekly or three-weekly, I think they've left that more open, but after three cycles of clinical assessment and a pelvic MRI and then subsequent therapies directed according to the response. So turning more to locally advanced disease, the questions we're still asking here with respect to chemotherapy is, does it have a role over and above the chemotherapy that we deliver concurrently with radiation? And if so, should we do it before or after the chemoradiation? Many of you will be aware that one of the CCRN trials was the OUTBAC trial, which was a randomized phase three study addressing the issue of additional chemotherapy given OUTBAC or after the standard chemoradiation. This trial was presented by Linda Milishkin, the CI at ASCO this year. And this randomized patients with locally advanced disease, the same criteria as we have for the interlaced trial to either concurrent chemoradiation alone or the same chemoradiation followed by four cycles of carboplatin and paclitexel on a three-weekly schedule. Primary endpoint is overall survival with a number of secondary endpoints as listed. The results show that there was no difference in five-year overall survival between the chemoradiation alone group and those that received additional treatments. The overall survival was, as you can see here, 71 to 72%, which is higher than any of us might have anticipated when these trials were first developed and first opened. But there are possibly a number of explanations why, but one interesting point is that about a quarter of patients failed to complete the additional chemotherapy. Nevertheless, there was no survival advantage. So turning to neoadjuvant chemotherapy in cervical cancer, this, of course, has been the subject of trials for many years. In the pre-chemoradiation era, there were many heterogeneous small trials with inconclusive results. And in the era of chemoradiation, really since 1999, 2000, there's been a couple of large randomized trials, one from India, one from Europe, investigating neoadjuvant chemotherapy before surgery and comparing it with chemoradiation for stage one and two disease. The chemo in those studies was a 21-day, I think it was combination carboplatinum-paclitaxel in the Indian study, and a mix of different regimens in the ERTC study. Overall, the findings showed that chemoradiation was better than the neoadjuvant approach, neoadjuvant surgery approach, particularly in patients with stage two disease. The jury is still out, really, on stage one disease. There weren't as many patients and there wasn't a statistically significant difference in outcome between the two arms for stage one B disease. Another study, a phase two study from Brazil, which was published just a couple of years ago, again, investigated three-weekly chemotherapy given before chemoradiation in patients with locally advanced disease. They did not use a taxane, this was cisplatin and gemcitabine, and it was on a 21-day schedule. And the interval from completion of neoadjuvant chemotherapy to chemoradiation was up to 28 days. They showed that this approach was detrimental and the three-year PFS rates were 41% in the neoadjuvant arm and 60% in the chemoradiation arm. So when we think about what we're doing with weekly treatment, this is a new approach to the neoadjuvant chemo story. So we're reducing the cycle length and delivering our treatment weekly. This is the most dose-dense approach. We're incorporating a taxane and we're keeping the platinum, although we're not giving cisplatin, as we felt this was too likely to cause additional toxicity, particularly neuropathy. We've eliminated the delay between chemotherapy and definitive chemoradiation. And I think this is a very, very important point. We do not want to have a long interval between chemo and definitive chemoradiation to allow potential for repopulation. But overall, we're attempting to balance the need for systemic therapy with tolerability and ease of delivery, but without significantly delaying the definitive chemoradiation. So this was our phase two study that we did in the UK in three sites. We had 46 patients. It was a single-arm feasibility study. Was it feasible to look at this approach? Six weeks of carboplatin and paclitaxel followed by chemoradiation. When this study was done in the early 2000s, our radiation dose to point A was considerably lower than what we deliver today. Nevertheless, at the end of six weeks, we had 70% partial and complete response to the neoadjuvant chemo, and this was assessed on imaging. We had an 85% response at 12 weeks. Now, there were a mix of stages in some very advanced cases. So what we wanted to know, the questions we asked was, is this approach feasible? The answer was yes. Two, do we disadvantage our patients? And the answer was no. We had the same kind of response rate of three months as we might've expected anyway for this particular group of patients. So that allowed us to proceed with planning for a phase three study. I just wanted to quickly show you this data. It's a little bit cheeky because it's about to be published, but it's retrospective data on the neoadjuvant approach with patients with really quite extensive disease. So it's neoadjuvant and extended field chemoradiation in patients with locally advanced disease. What we've compared is two cohorts of patients, one cohort having extended field chemoradiation alone, and the other cohort having neoadjuvant chemotherapy followed by extended field chemoradiation, a la what we do for interlace. Those patients that were treated in this study, this does not include any of our interlace patients, and these patients had their disease was too advanced to be eligible to participate. So, I mean, what was quite striking for us was that with the extended field chemoradiation alone, three-year OS was 64% with five years about 43%. And this is really in line with what's published in the literature, and there isn't a great deal published on this topic. However, with those patients, that cohort that had neoadjuvant followed by extended field chemoradiation, the three-year and the five-year OS rates were over 80%. And this really was quite an interesting observation. So we're just putting it out there. We have submitted this for publication, so you'll be able to read about it in more detail. So just very briefly, you are participating in interlace, and I'm very excited that COGO-TRG have the trial open at two sites. And this, to remind those that might not, Aferodivus is a phase three trial of weekly induction chemo followed by the standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer. And this is the schema. So it's six weeks followed immediately in week seven, eliminating that gap, which is ultimately really important. We also, as you're aware, we have a prospective RTQA, and I think that's really important to ensure as far as we possibly can that the standards are maintained across this trial. So there's any difference that might be apparent ultimately cannot be attributed to treatment that's making up for poor quality radiation. Our overall treatment times are very important, and we're trying very hard to keep this under 50 days. And we have mandated a higher dose of radiation than what we used in cervix two, in line with the way this has changed internationally. So, so far, our target is 500. We have recruited 456, and we have six patients from India, four from Seroj Gupta, and two from CNCI. And again, thank you very much for your contributions. It's very valuable, and I'm delighted to be working with all of you. And thank you for inviting me to make this presentation today. Thanks. So, this is really just a conclusion. Ongoing and completed trials are still addressing these important questions. We don't know whether chemo will have a role, but certainly we want to complete the study and answer that question from an induction chemo perspective. And people still ask, is it relevant to talk about chemotherapy in the era of immuno-oncology? And I think the answer to that is yes, because chemo radiation in cervical cancer remains the standard of care in locally advanced disease. And I don't see this changing anytime soon. It's also worth remembering that, of course, the chemotherapy drugs are cheap, off-license, and widely available. And the prospects of immunotherapy ultimately being available to the masses, I think is some way off. Thank you again for your attention. I'll hand back to you, Asima.

cervical cancer treatment

radical surgery

chemotherapy

immunotherapy

clinical trials

patient selection