with bulking for advanced ovarian cancer. And I just want to point out, we know cervix cancer leads the only pelvic cancers around the world with more than 500,000 new cases a year, but ovarian cancer is about 200,000. It's not quite half the number of cervical cancer and yet the death, you see 125,000 death years a year. And as opposed to cervical cancer, 250,000 death a year, so ovarian cancer is, like everyone knows, it's very lethal because usually it presents with advanced stage in almost 2 3rd to 3 4th of a time. The long-term survival is poor and this is the sixth most commonly diagnosed cancer among women in the world. So you see a typical patient like this patient here, a large tumor, a lot of tumor on the omentum mesentery, like the one here, so often present us a challenge to perform surgery and for patient with advanced ovarian cancer, most patients with ovarian cancer, combination surgery and chemotherapy such as platinum pacotexel. And today, maybe even with maintenance therapy, is considered standard. Among all the prognostic factors, they are all very important, but residual disease was often cited as very important. We like to get to really no residual or zero or very small residual. We usually call it as optimal of less than one centimeter residual. So surgery in advanced ovarian cancer, typically in the past, we like to do a primary cytoreduction and these days with neoadjuvant chemotherapy and interval cytoreduction after neoadjuvant chemotherapy is often done. And the other modality like second look surgery or secondary cytoreduction, it's not really what we will cover today and it's not really commonly done today. And primary cytoreduction really started by Dr. Thomas Griffith almost 50 years ago. And what he reported was his very first serious 100 patient and with stage two and three, and he noted residual disease as an indicator for survival. The less you have left behind after the surgery, the better the survival. And as we all know here, the percentage maximum cytoreductive surgery from zero to 100, and it's really correlates very well with survival. The more you debulk, the better the survival. And actually over these last 40, 50 years, the effort in maximal cytoreduction had improved to today we are able to get to optimal debulking often cited in the literature about in the 70%. And this was a very early study looking at what is the impact of residuals on survival. The blue line is microscopic residual, the green line is less than one, the purple line less than two, the yellow line is greater than two centimeter residuals. As you can see the blue line with left with minimal microscopic live a lot longer than the one with greater than two centimeter residuals. Then his chief of Memorial actually look at his series of patients from Memorial Sloan Kettering and look at the survival correlates with the residuals. When there's no residuals, they can live to 106 months that long. And with less than 0.5 centimeters, 66 months, less than one centimeter, 48 months, greater than two centimeters, 34 months. So try to remember here, Dennis Chu is probably the one that is really go spend a lot of hours and maximal effort. If he had a patient with no gross residual, he can achieve 100 months overall survival. If he had less than one centimeter, it's 48 months. So please remember there's 148. And which you would use, you can use this to compare with the other studies, but these were really done by the best of hands. And Rob Bristow, I just want you to see that in his study, looking at a meta analysis, what he found was every 10% increase in the maximum cytoreductive surgery was associated with a 5.5% increase in median survival, meaning that you take away 10% more, you will increase median survival by 5.5%. So it's really important that we maximize our effort in debulking surgeries, because it can translate into an improvement in the survival for the patients. And here compared to a 25% maximal debulking versus 75%, a 25% debulking overall survival in 22 months and greater than 75% 33 months, a 50% increase. So it's very significant in this debulking. Today, we like to achieve maximal cytoreduction, oftentimes means not just to do a hysterectomy, but it may mean stripping the peritoneum, doing a mantectomy, removing the small bowel and large bowel when they are affected by tumor, perhaps lymphadenectomy, if they are grossly enlarged, diaphragmatic stripping, removing the spleen or distal pancreas removal, or even part of a liver removal. In my experience, about one in four patients with ovarian cancer, oftentimes would need a sigmoid resection in order to achieve a optimal debulking in the primary setting. So let's go back to Dennis Chee's in his experience. The first report back in 2010 was that he was able to achieve a 90% optimal debulking with 30% no residuals. The second study later on done by him was able to go to a 71% optimal cytoreductive reductions. So if you remember this number, this is really in the best of hand, and maybe a lot of gynecological oncologists in the big centers are able to get to a 70% optimal cytoreductions. So go to neoadjuvant chemotherapy. The concept is in patient with large tumors, extensive tumors, first perform a needle biopsy to give three cycles of chemotherapy, usually perform an interval debulking followed by three cycles of chemotherapy. So this is really a wonderful large European study or the EORTC55971 trial. If you look at this, this is a phase three study, look at superiority study. Usually when you look at these phase three studies, they generally have six, 700 patients. It's a very large number of patients. And this study included not just advanced stage three and four, but in specific a stage three C, and not just stage three C, but the tumor has to be, a lot of them are greater than five centimeters. So it's pretty aggressive tumors. And they randomize these patients between primary debulking, followed by carbotaxel for six cycles versus neoadjuvant times three, followed by interval debulking and followed by chemotherapy. And what they show here was, there were no differences in the median survivals. The hazard ratio for death is near one, which means that it's no difference. And the study was like eight year, covered eight years time. But you look at here, only 46% were optimal in the primary debulking surgery arm. When you remember Dennis Cheese and the other people reported about 71% optimal debulking in primary debulking surgery. So this 46% is considered low. And there's also another problem with the EORTC study was that not all patients were treated with paclitaxel. But nonetheless, they showed the mobility mortality between neoadjuvant and primary debulking. And it's a lot more morbid, there's more death if you do a primary debulking surgeries. And here is what kind of complication they are seeing higher in primary debulking is the more death, more infection, more hemorrhage and more thrombotic events in the primary debulking arm. And the primary debulking only achieved a 42% optimal debulking while the interval debulking has achieved for 81% optimal debulkings. And the survivors, there were no differences between the two groups. And there were some indication of better survival actually in the primary debulking arm. If you look at the R0 in the neoadjuvant chemotherapy is 38 months and versus some primary debulking achieved 45 months. So there is a seven month better survival in the primary debulking, but this did not reach a significant level. What about for patient microscopic residual? There's also a five month improvement in the primary debulking arm in the survival. So if you can do a good job, here they are saying that you still can live longer, although in this study, they were not reaching a significant level. So what about the concern with this first study was that actually in the neoadjuvant chemotherapy arm, there were 10% of a patient ultimately did not undergo any surgical debulking. And either they were too sick or they couldn't really not responding. And there's also a small problem of 18 patients. In the 300 something patients, 3% of the patients, they were actually erroneous in the diagnosis, even with fine needle biopsy, final pathology not confirming this was ovarian cancer. So the concern with this EORTC study was that not everyone get the best chemotherapy, 78 and 88%. And there might be a selection bias getting the very sick patients enrolled in this study and very low R0 rate of 20%. And so that make us wonder whether in the primary debulking arm, the patient actually get the maximal effort. If you only have 40% optimal debulking. So if you are talking about you're leaving a lot of tumor behind, then this is almost like a neoadjuvant chemotherapy in some way and not getting the surgery done. So this was a question with that EORTC study. There are other studies with a core study from the UK by Kehoe was chemotherapy or upfront surgery trial. It is different. This is a non-inferiority study and include about 550 all stage three, four patients with 16% stage four optimal debulking. Since you can see 24%. So in Jaya, what was Denise Chi's optimal debulking rate? 71%, right? So this is really low. And the overall survival was very similar between the neoadjuvant and primary debulking. Very low. If you remember in Denise Chi's study was 48 month and the PFS 12 versus 10 month. And they concluded that neoadjuvant is not inferior to primary debulking study. And there's another Indian study, IQUMA. It was presented at IGCS 10 years ago. It was not really written up. I don't know, Dr. Sima, you might know about this. They included 139 patients. What they found was neoadjuvant chemotherapy had better optimal debulking. 85 versus 23% shorter inpatient stay. Less infection with neoadjuvant chemotherapy and lower death with neoadjuvant chemotherapy. The PFS and OS, there were no differences in Indian study. And there is a Italian study by Fagotti not looking at the survival, but in single institution, 110 patients. And they were able to achieve no differences in R0, 45 versus 57. This is quite remarkable. Pretty good, R0 rate. Primary debulking surgery, there were more complication, quality of life. Was better in the neoadjuvant chemotherapy arm. So a Japanese reported at the ASCO two years ago and about the neoadjuvant chemotherapy arm in an abstract format. And did not demonstrate non-inferior survival. Actually, they showed that as cohort of patient in primary debulking group has a better survival than patient with neoadjuvant chemotherapy. So currently, there's a large European study going on called TRUST study. So they like to have a very strict surgical quality control like maximize the effort. And I don't know whether you heard of in the German study. So Germans, if they have patients that are not able to get optimally debulk, say I'm doing a surgery, I'm not able to get the patient optimally debulk, I will call Dr. Jitendra in, I will call Dr. Sima in, or don't call Dr. Smailer in to see, can you try to debulk it further? So with more people, they're trying to get a maximize the effort. I think that will be very meaningful because URT-CD optimal debulking was very low, 40%. So this is an ongoing study. So I just want to point out for the first case that you had, and you don't have laparoscopy, but if you have laparoscopy, Dr. Fagoti was suggesting to use laparoscopy to do assessment. And she created a Fagoti score with seven parameters. Each score is zero and two. Anyone of a score that's greater than or equal to eight, pretty bad disease should consider neoadjuvant chemotherapy. And her scoring is associated with 100% positive predictive value and 70% negative predictive value. So it's quite good. So the question now is, how can we identify patients for neoadjuvant chemotherapy? I think it's typical, right? Because looking at the scans, looking at a patient, I think if we have a patient that we could tell it's high volume tumor dissemination, like involving the mesentery, the duodenum, the celiac trunk, liver parenchyma, these are probably not really able to be resected. So neoadjuvant chemotherapy is good. Stage four patient or patient with poor performance status, a patient with older age, these are probably good group of patients who can see the neoadjuvant chemotherapy. After completing the neoadjuvant chemotherapy, I think debulking should be attended best by a surgeon that's trained like a gynecologist. And it should be considered, it should be offered to patients who show responses to neoadjuvant chemotherapy or at least have some stable diseases of the responses with neoadjuvant chemotherapy. Typically after three cycles, some people do it after four, after six. And at the time of debulking surgery, we really want to be prepared to do, maximize our effort. It could be upper abdominal debulking, and it could be bowel resections. And the approach I usually take is look at the most difficult part of a surgery first. If we can accomplish doing the most difficult part, then we will go ahead with the others, right? I mean, if you can't even resect a colon, there's probably not a reason to remove a sprain. So you choose a part that's most difficult to go ahead. And this is a study I find it really interesting. It was actually just published a few weeks ago. So a doctor of very well-known gynecologist, Dr. Havirasky from Duke, what she looked at was this. She did a survey using something called discrete choice experiment. And what she did was giving the woman a scenario. She said, yes, doing aggressive debulking, you're more likely to get a stochastomy. You might be more likely to die from it. You might have higher chance of remission, but you will have a better performance like progressive free survival and better overall survival. Would you be willing to sacrifice a little bit of more complication for a better chance of living longer? So the study was publishing cancer and the finding was that woman would say, I would rather like to live longer, even if that means, possibly I may be more likely to have complications. So this is very interesting. The study concluded that patient would accept a moderately higher risk of complications with surgical mortality in exchange of substantial gains in survival. But having said that, I think I'd like to come back and ask the question, what should we do for patients with advanced women cancers in settings where resources are limited? Maybe we really can't do a good diaphragmatic stripping. Maybe we really can't get surgeons to come and remove a spleen or part of the pancreas. Maybe we don't have a good ICU. What should we do? So that is a very good question. So I just want to end with three other slides Dr. Chitendra asked and you show us a very interesting case of neoadjuvant chemotherapy for advanced ovarian germ cell tumors. So I did a literature search and I found a study published by the Chinese in IGCS journal in 2018. And they had 58 patients, 18 inoperable, give BAP one to two cycles, have partial response in 94%, had 11% of pathologic complete response. So you have a better outcome. Your patient after two cycles have pathologic complete response, but there were no major complications. The survival was excellent in 94 patients. They did a fertility sparing and actually they have five infants delivered in six patients. And there was a very nice review article published in oncology looking at two studies, also neoadjuvant BAP and neoadjuvant BAP or PBB for York sac tumors. And they have excellent survivals comparing to primary alkane. And so this was similar to your case. So you did a great job and presenting. So I'm thinking like Sanjaya, you prepare your last year's outcome really well. It's really something you can publish your neoadjuvant chemotherapy experience and publishing the journals like with IGCS journal or GYN oncology reports. You know, we are really interested in research in St. Nepal to be published on your neoadjuvant chemotherapy and maybe adjuvant chemotherapy for the patient with germ cell tumors. So I want to thank you and this is really interesting and your cases were great.

advanced ovarian cancer

surgery

chemotherapy

optimal debulking

neoadjuvant chemotherapy

survival rates