So, I'm going to do a high-level summary and allow Denise, thank you for translating each of the slides so you'll have these long-term access. So, let's talk about strategies for fertility-sparing surgery. So, the idea behind, or the rationale behind fertility-sparing surgery and early ovarian cancer is to preserve reproductive function and quality of life. And that means saving at least a part of an ovary and the uterus. Do we want to translate this as we go or translate it entirely later? I think probably for time's sake and later, yeah. Okay, that's fine. So, fertility-sparing surgery depends on the stage, the grade, the histology, and the prognosis, which really gets to exactly what Nargisa was just asking. So, this requires informed consent, reproductive age. In the literature, we say less than 40, but we just heard from Dr. Matthews that less than 42 confers a higher ability to conceive. Compliance, pathology review, and staging. There are three major groups of ovarian cancer, and we consider these separately, epithelial, germ cell, and stromal. Importantly, each of these patients, even with early stage disease, must be fully staged. Staging maintains a common language for treatment planning, determines appropriate adjuvant therapy, and very importantly, the recommendations vary by histology. When we talk about epithelial ovarian cancers, of course, this is the 90% of ovarian cancers that we see the most often, and these include serous carcinomas, both high and low grade, mucinous endometrioid, and clear cell carcinomas. Here's an excellent summary that was published not too long ago that looks at the recurrence rate and fertility outcomes among the published studies in patients with stage one epithelial ovarian cancer. What we see is, in all of these, approximately a 12% relapse rate and a 94% five-year overall survival. Approximately 66% of patients did become pregnant, and this resulted in 224 published live births. So, to summarize, in early ovarian cancer, fertility-sparing surgery results in a 12% relapse rate, a 94% five-year overall survival, 66% of patients who desired pregnancy were able to conceive, yielding 224 reported live births to date. If we look at the seven best studies, because those other studies, it was a jumble, you know, with some large studies, some small studies, when we take the seven best studies in terms of the number of patients who were fully staged and the length of follow-up, we see that actually the recurrent rate in stage 1A, grade one, is the lowest. And this makes sense. Remember, our terminology has changed, and we know that grade one or low-grade serous carcinomas are very, very different from our high-grade serous carcinomas, the currently classified grade three. Usually, grade two carcinomas have been reclassified as grade three. We don't even talk about grade two cancers anymore. So, basically, what we're looking at is a difference in recurrence rate in stage 1A, low-grade versus high-grade, of 6 to 42%. And you can see that these act very differently. I think this is very interesting, because it really highlights the biological difference between low-grade and high-grade serous carcinomas. I think that this is very provocative data. We haven't talked a lot about this, in fact, but it suggests that fertility-sparing surgery is much safer in low-grade serous carcinomas and perhaps not as safe in high-grade serous carcinomas as we've previously discussed. Interestingly, stage is also important. There's a big difference for stage 1A versus stage 1C, and recurrence risk is higher with advancing grade, even when you separate out stage 1C patients. We also know in the newest studies, Dubois published stage 1B and C versus 1A, and that advance in stage yields an odds ratio of 1.72. So, higher risk for stage 1B or C disease. They also showed that high-grade was worse than low-grade. And their summary stated that fertility-sparing surgery was only advisable for unilateral grade one tumors. That's very different from all of the summary guidelines that we have. And in fact, the other new study, Zapartiel, disagreed. They found an 11% recurrence rate, 4% of whom presented with an isolated recurrence in the contralateral ovary with a five-year overall survival over 90% for patients died of their disease. And their conclusion was the opposite. Their conclusion was that they thought it was okay to extend fertility-sparing surgery to grade 2, 3, and 1C tumors. Preoperative rupture, we also know, is worse than intraoperative rupture. And we see that an intraoperative rupture really does not worsen prognosis. But preoperative rupture, surface involvement, and positive washing are significantly worse than in patients with stage 1A disease. Tadayama and their group concluded that we should not do fertility-sparing surgery in cases with preoperative rupture, surface involvement, positive psychology, or high-grade lesions. There is a large fear database study that Jason Wright published to try and make sense of all this, because as you can see, these are all very small studies that try and make conclusions off of just a few patients. What Dr. Wright showed in this fear database study was that stage 1C had no impact on survival. But he also concluded that all studies were underpowered, so there was no way to make any definitive conclusions based on what is published. And in fact, it would take over 1,200 patients with 52 deaths to detect a 20% difference in survival for patients with 1C disease. And so that's really not feasible. So all of these recommendations, all of this conversation that we're having about this is something that we can never definitively answer, because it is such a rare circumstance. The ESGO, European Society of Gynecologic Oncology, did provide consensus guidelines. And this is one of the two summary slides that you'll probably want to keep. ESGO says that fertility-sparing surgery is safe in stage 1A and 1C grade 1. So that's low-grade serous carcinomas. They think it's safe in stage 1A grade 2, which remember we don't really even use grade 2 designations anymore, and quote conventional histologic subtypes. But that is not something that is really defined. They say that they would consider as an option fertility-sparing surgery in stage 1C grade 2, which again is no longer defined, and in stage 1A clear cell carcinomas, though they state only European clear cell carcinomas, or I'm sorry, only Japanese clear cell carcinomas, not European. And that also is very ill-defined. They state that fertility-sparing surgery is contraindicated for grade 3 tumors, any patient with a stage over 1, and histologically aggressive tumors, which they don't define but suggest that anaplastic carcinomas fall into that. This is all based on the Frucio Italian study that showed that grade 3 patients had worse recurrent spree survival and overall survival. And that was supported by Ditto et al. that showed a 4.7-fold increase in recurrence for high-grade carcinoma compared with low-grade carcinoma. We know that other epithelial histologies show no difference in fertility-sparing surgery. So mucinous and clear cell, as long as they're stage 1A, have no difference in outcomes for fertility-sparing surgery. Now, the NCCN guidelines are a little bit different than the ESGO guidelines. And they are, in fact, very nonspecific. So the NCCN guidelines state for patients with apparent early-stage disease and or good-risk tumors like germ cell tumors, low-malignant potential tumors, early-stage invasive epithelial tumors, or sex cord stromal tumors who wish to preserve fertility, a unilateral palpingo oophorectomy preserving the uterus and contralateral ovary can be considered. Comprehensive surgical staging should still be performed to rule out occult higher-stage disease. I think important things, this does not refer to a cystectomy. There are no data on that. And staging is still performed. That includes washings, peritoneal biopsies, omentectomy, and lymphadenectomy. Interestingly, though, the details are not stated in the NCCN guidelines. So all of the details that we've gotten to with high-grade serous carcinomas, you know, grade 3 versus grade 1, stage 1A versus 1C, that's not spelled out in the NCCN guidelines. So I guess the question is, what do you think? It seems to me like reviewing the actual data rather than just the summary guidelines, fertility-sparing surgery is appropriate in reproductive-age women who desire fertility, unilateral stage 1A, possibly 1C disease, for low-grade, mucinous, endometrioid, or clear cell histology. These data actually make me worry about fertility-sparing surgery for high-grade patients. I think it's important, no preoperative rupture, and remember to always fully stage these patients. Beyond the scope of this talk is just a caveat that minimally invasive surgery is safe, and that's based on the citation below with Bogani. So when we talk about germ cell tumors, we see a lot of germ cell tumors in young patients for whom fertility-sparing surgery is very important. And we actually have a lot of data suggesting that fertility-sparing surgery is safe. You can usually spare one tube and ovary and the uterus in these patients. You can literally almost always conserve the uterus. There is a risk of infertility by taking out one tube and ovary, but we see very many patients who are so very chemosensitive that fertility-sparing surgery is very appropriate for early-stage germ cell tumors. That is also included in these data. Lymphadenectomy is performed in adult patients with germ cell tumors, but it's controversial because it's omitted in the pediatric population. With stromal tumors, we also have some data surrounding fertility. If childbearing is complete, of course, we remove the uterus, cervix, tubes, and ovaries. But conservative treatment with a unilateral salpingo-oophorectomy for a frozen section, avoiding rupture, and comprehensive staging is appropriate. And again, we can use different assistive reproductive techniques in these patients in whom, who wish to preserve fertility. Again, it does not refer to cystectomy. Dr. Matthews noted the details surrounding assisted reproductive technology. I'm not a reproductive endocrinologist, but my summary would be to consider this prior to surgery, chemotherapy, or radiation. There are several techniques that are possible prior to these interventions, and these include cryopreservation of the ovarian cortex for reimplantation. We see restoration of function in a median of four months, and there are well over 60 live births reported with this technique to date. Another technique is cryopreservation of mature oocytes after controlled ovarian stimulation. And a third technique is retrieval of immature oocytes followed by in vitro maturation and vitrification. And that's what I have to share. So, I hope this has helped.

fertility-sparing surgery

ovarian cancer

reproductive function

ovary

uterus