So, today we already had a really great presentation about the medical management of recurrent ovarian cancer. I'm going to focus a little bit on platinum-sensitive ovarian cancers and on cytoreduction. So we'll just go over some of the studies that are out there right now. So just in terms of statistics, and I'm sorry that some of these are US-specific statistics. I was trying to find Nepal-specific statistics and couldn't, but in 2023, the American Cancer Society estimated that almost 20,000 women will receive a new diagnosis of ovarian cancer, and that in that same year, that 13,000 women will die of ovarian cancer. And worldwide, we can extrapolate that a little bit because based on SEER database, there were 313,000 new ovarian cancer cases in 2020. The five-year overall survival rate for invasive epithelial ovarian cancer is right around 50% at 49%. And a really large driver of this low survival rate is because recurrence is very common. So in patients who have early stage 1 ovarian cancer, about 25% of them actually do recur. And when people have a more advanced stage ovarian cancer, up to 80% have a recurrence. And that's important because most ovarian cancers are diagnosed at stage 3 or later. There's been a lot of debate about the role of primary cytoreduction versus using neoadjuvant chemotherapy in a initial treatment of ovarian cancer, so it's not surprising that that same debate has come up in recurrent ovarian cancer. So there are five studies that are, two of them are completed, one of them is still looking at data, and two of them were stopped due to poor accrual. But I wanted to go over those studies. So we actually already heard about GOG213 from the medication chemotherapy side of things. So this was a multicenter, randomized controlled trial that included 485 patients in the surgical arm. It's interesting and somewhat unique to the other trials that were looked at because there were two components. So the first component was, is this patient a candidate for secondary cytoreduction prior to chemotherapy or not? And if the patient was a candidate for surgery, they were enrolled in the surgical arm of the study, and that was followed with them being enrolled concurrently in the chemotherapy arm as well. If they were not a candidate for surgery, then they were enrolled in the chemotherapy arm alone, which looked at adding bevacizumab to a standard platinum-based therapy. For the patients who had surgery, they then subsequently went on to have a platinum-based therapy, and most patients actually did receive bevacizumab, and that was compared to patients who did not have surgery that were placed into this group. So the inclusion criteria for this was that a patient had to have a recurrent ovarian, primary peritoneal, or fallopian tube cancer, that they had to have had a complete response to platinum-based therapy and greater than six months of platinum-free survival interval. And there was no strict criteria on how they deemed if a patient was a, that if complete surgical resection was possible for a patient or not, it was really left up to the decision of the surgeon who would be potentially doing this surgery. So once each individual surgeon at each individual institution had reviewed a case and thought, yes, I could resect this or I couldn't, the patient was then placed in either the chemotherapy trial or the surgical trial, and the surgical trial, again, was looking at cytoreduction followed by chemotherapy and comparing it to chemotherapy alone, and does the cytoreduction improve overall survival? And then there was a secondary primary endpoint, really within the surgical arm of this study as well, that does bevacizumab, adding that to platinum-based chemotherapy improve overall survival. So just to review this, so 67% of the patients that were deemed potential for complete surgical resection had complete neurosurgical resection. So that's about two thirds of the patients. And 84 of the patients in both of the study arms actually received a platinum-based chemotherapy and bevacizumab. So the majority of patients in the study received bevacizumab. There were no significant survival differences between the two groups, meaning that the patients who had surgery and the patients who had chemotherapy alone, that both of these patients over the course of 84 months, which is how far out they followed the patients, had similar survival outcomes. And interestingly, the median survival of all groups was longer than they had expected going into the study, so 50.6 months in the surgical group and 64.7 months in the chemo-only group, and that didn't achieve statistical significance. For patients who underwent secondary cytoreduction, they had a decreased quality of life in that immediate post-op period, but that difference resolved by six weeks. So you can see here for overall survival, this is the no surgery line, and this is the cytoreductive surgery line. And you see that overall survival, the no surgery line actually does better, but by 84 months, that benefit has disappeared. And that in the progression-free survival, that again, the surgery line does better, but that is not statistical. So that was one of the first randomized controlled trials that came out looking at cytoreductive surgery followed by chemotherapy compared to chemotherapy alone. And obviously, this was disappointing for anyone who wanted to do surgery because it implied that maybe surgery is not helpful. At the same time, there were multiple other trials that were running concurrently. So the other major trial that has completed and has published their data is the desktop three. So this is also a multicenter randomized controlled trial. The GOG study was primarily based in the United States, but did also have some European sites. The desktop three was primarily European sites. This is also a multicenter randomized controlled trial with 407 patients. The inclusion criteria were that this had to be a first relapse of ovarian cancer, that there had to have completed primary cytoreduction. The GOG trial didn't actually specify how they were treated the first time around, just that they had had a complete response, and that there had to be greater than six months of platinum free interval. They also had an EGOG performance status of zero. So five would have been the worst, zero is the best. So these are patients who are high functioning, and they also had to have a CITES of less than 500. The desktop one trial had looked at a primary treatment of an initial ovarian cancer and shown that you needed to do complete cytoreduction to have benefit from surgery. And the desktop two had actually used these criteria. So the EOG performance status, the CITES, and a couple of other criteria that were included in the desktop three as well, just to show that when you applied these criteria and to more objectively selecting who might benefit from cytoreductive surgery, that those patients did have a higher rate of cytoreduction than compared to the GOG study, for instance. The primary endpoint was similar to the GOG study to look at a secondary cytoreduction before chemo increases disease-free survival compared to chemo alone. And this had a completely different outcome. So 75.5% had complete growth resection. In the surgery group, 76.7%, and in the chemotherapy only group, 79.6% eventually received a platinum containing therapy, but only 47 patients in each group received bevacizumab. So that represented about 23% of the patients total. And overall survival was 61.9 months with complete resection, 53.7 months with surgery, regardless of whether that resection was complete or not, 46 months with chemotherapy alone, and 27.7 months with incomplete resection. So you can see that when a patient underwent cytoreductive surgery that had an incomplete resection, their overall survival was significantly decreased compared to patients who had complete cytoreduction at 61.9 versus 27.7 months survival. When they looked at multiple different subgroups, every analysis except for the subgroup that had an incomplete resection showed a survival benefit from surgery and the quality of life was the same between groups. So over here, you can see that cytoreductive surgery has an increased overall survival and an increased progression-free survival. And in this analysis, it did reach statistical significance. So these are two very, very different outcomes of studies that were run with somewhat similar setups. So there is a third trial, and this one is still underway. So this is the SOC1, and that is a multicenter randomized controlled trial. It accrued 357 patients. This was for large academic institutions in China. So we also represent multiple areas of the globe with these three studies. And the inclusion criteria were similar. They were platinum-sensitive tumors and initial relapse with greater than six months of platinum-free interval and a specific prediction model that they used to look for potentially resectable disease and that integrated PET-CT imaging into their prediction. The primary endpoint was the same as the other two trials. And then the interim analysis has been published for this trial, but the interim analysis was published at 36 months of follow-up, and their goal is to get to that 84 months that's similar to the other two trials. And what they see is that overall survival is increased in the surgery group. So at 58.1 months after surgery versus 53.9 months in the group that didn't receive surgery. And in this group of patients, only 1% of patients received bevacizumab. And again, these long-term data are pending. There were two other trials, and I just listed them here. They had very similar inclusion criteria, and both of these studies were canceled due to poor study accrual. So to review, GOG-213 did not show statistically significant difference between patients who had cytoreductive surgery prior to chemotherapy versus patients who had chemotherapy alone. Desktop-3 did show a statistically significant survival benefit in patients who underwent cytoreductive surgery prior to chemotherapy. And an interim analysis of SOC-1 shows a survival benefit in patients who underwent cytoreductive surgery, but that final data is pending. And all of these are really interesting, because anytime you have discordance in results like this, the question, I think, becomes why. The big things that I think were really different between these trials, one for GOG-213, the fact that the majority of patients received bevacizumab might have played a really big role in either improving the survival benefit and the survival outcomes in chemotherapy patients, so that you don't see that difference. So it's unclear whether in that study patients were having worse outcomes because of surgery or having better outcomes because of bevacizumab, and if that bevacizumab impacted the ability of the surgery to have a better impact. So that was a really big difference. And then I think another difference between these are also that both the Desktop-3 and the SOC-1 trials actually had somewhat more standard objective measures to determine if a cancer could achieve complete cytoreduction or not. SOC-1 didn't yet publish the number of patients that did, the percentage of patients who received a complete gross resection. But if you looked at the numbers between GOG-213 and Desktop-3, that was a pretty large difference, one with two-thirds and the other with 75% of patients getting complete gross resection. So I think that it's still up for debate, and Dr. Chuang, I'd love to hear your thoughts and everyone else's too about your preferences and what you do.

cytoreductive surgery

platinum-sensitive ovarian cancers

GOG213

Desktop3

SOC1