me to give this lecture on fertility issues. So let me close this first, right. So for patients with, well, younger than 45, in fact, the most common cancer is breast cancer. In terms of gynecological cancer, it is pretty rare. The second most common will be cervical cancer, but the incident was still far behind breast cancer. For example, in Hong Kong, we have reviewed the figures in the past almost 20 years, and it's a bit alarming that for the incidence of cervical cancer, it's been stable, even with the introductions of pap smear, HPV test, and also HPV vaccination. And for uterine cancer and ovarian cancer, the incidence among young patients were actually rising. For example, in the latest data in 2018, the incidence of cervical cancer, uterine cancer, and ovarian cancer, it composed of about 10% among all patients in Hong Kong. And in particular, to young patients, anti-cancer treatments will pose a great effect on their fertility, either the direct tissue effects damage, or it can be due to the other adjuvant treatments like radiotherapy, chemotherapy. And on top of these, the patient's age, psychosocial status, and so on, will all contribute to the effect or harmful effects on fertility. And as a gynecologist, most of the times, we will be dealing with the surgical aspects in the fertility preservation. So let's look at cervical cancer first. The both NCCN guidelines and also ESCO has recommendations on fertility sparing surgeries in cervical cancer, and the recommendation are pretty similar in these two guidelines. For example, in the stage 1A1 disease that is based on the 2009 classification, most of them will recommend a cone biopsy. In NCCN, they recommend cold night cone biopsy. Whereas in the ESCO guideline, they suggested either loop biopsy, or they will recommend a laser instead of cold night cone biopsy. I guess the rationale is because of a cold night cone biopsy will may be more prone to get a deeper margin and then jeopardize their fertility potential. And then the less controversial one will be the stage 1B1 disease that is tumor, gross tumor less than two centimeter. So most recommend reticulotriculectomy as a fertility sparing surgery. And then somewhere in between 1A1 with lymphovascular permeation or 1A2 disease. So most of the authorities recommend a simple trachelectomy. Some will also accept a cone biopsy with negative margins. So for cone biopsy, well, there were a lot of data on that. For example, in one article that was published almost 10 years ago, they look at more than 800 patients, and they found that the five year survival rates was pretty similar, no matter what they receive cone biopsy or hysterectomy. And it is for all patients with stage 1A1 disease. And in the past, people think that the behavior of adenocarcinoma might be different from squamous cell carcinoma. And in these articles, it showed that the survival rates was also similar for those who underwent cone biopsy compared to hysterectomy, even for adenocarcinoma. For reticulotriculectomy, the usual selection criteria will be squamous cell carcinoma, HPV-related adenocarcinoma, and also adenosquamous carcinoma. So it's noted that for adenosquamous carcinoma, it was not included in the ASCO guideline, but I think the prognosis was pretty similar. And for those with high risk adenocarcinoma, like clear cell carcinoma, serous carcinoma, or even some other like neuroendocrine carcinoma, they should not receive reticulotriculectomy. And most recommended to a patient with a tumor less than two centimeter will be eligible for reticulotriculectomy. So this is one meta-analysis which revealed the recurrence rates and also other survival data for patients who underwent reticulotriculectomy. The overall recurrence rate is about 3.3%, and the time to recurrence is about two years. The five-year survival rate was pretty high, it's talking about like 97%. And in this table, the authors tried to divide the survival data among the vaginal, abdominal route, and also laparoscopic route, but the data were too small. So the next question you will ask is whether minimally invasive surgery will be safe for tricolectomy? The answer is not clear so far because the case number is pretty small and there are no randomized trials as the lab trial or the coming lab trial. This one, the IRTA study is an upcoming study that is a multinational trials, a retrospective data collection. And so it's just started and we'll need to wait for the results before we can have more data on this aspect. So it's not uncommon that patients with survival cancer will need or will require pelvic irradiation. So there's been a question whether ovarian transplantation will be beneficial. So again, there are no good trials to give us data on this aspect. And there have been some systematic review, for example, in this article, they try to compare URT and also ovarian transposition compared with surgery and also ovarian transposition alone. So they use FSH, LH level, and also symptoms as the markers. So for those patients who underwent surgery and also ovarian transposition, about 90% of them will be able to retain their ovarian function. However, for a patient who underwent URT, even after ovarian transposition, only about 65 of them will be able to retain ovarian function. So it seems that the use of ovarian transposition was not very good according to this systematic review. And then in fact, the ovarian survival data were quite variable after ovarian transposition. And for someone in Hong Kong, we have lots of discussion with our clinical oncologists whether we'll need to have ovarian transposition. And in fact, their recommendation is no. I'm not sure if it is because for Asian ladies, they're usually not very tall. So no matter how high we transpose our ovaries, they will still be able to subject to the radiation. So next, we're going to discuss CA corpus. So it's very well known that for early stage of uterine cancer with grade one endometrioid histology and also those without myometry invasion or other distal metastases will be able to receive fertility sparing treatment. And in the ESCO guideline that was just published in November last year, they also added it's only recommended for those without genetic risk factors, but they didn't elaborate further. So I'm not quite sure what the patient with Lynch syndrome are not recommended to have fertility sparing treatment. But anyway, so the treatment is option there quite a lot. Most of them will suggest mitral progesterone or migase as the primary treatment. In the ESCO guideline, they also suggested to have a hysteroscopic resection prior to progestin therapy. Well, it's probably based on just a few case reports or case-case series. And in real life, in reality, most of these patients will have already underwent either DNC or systematic biopsy. So I think to a certain extent, these patients will have subjects to sort of mainly debunking before migase or mitral progesterone therapy. And some people will also use IUCD or Mirena to replace oral progesterone in order to avoid systematic side effect. In the ESCO guideline, they also suggested to add oral progestin with or without GnRH analog instead of Mirena alone. The role of metformin has been widely reported, although it's not in the guidelines till now. And similarly for GnRH analog with aromatase inhibitor, there are also lots of data on that, but it's not in the guidelines as well. For weight reduction, it is suggested in the NCCN guideline. However, the effect was variable and it may only be beneficial in those patients who have PCOS or diabetes. And for the performance or the use of progesterone, people have a lot of data on that. The overall response rate is in the range of about 80% with a complete response rate of about 50%. So the median time to complete response is about six months and about 25 of them will have persistent disease or even progressive disease. And well, there are no randomized trial to compare different modalities of progesterone. Some articles suggested that e-gaze may have a higher admission rates because of a higher bioavailability. However, at the same time, some people also found that neutral progesterone will be associated with a lower recurrence rate. So there are a bit ambiguous results on that. And for the median length of progesterone required for regression is about nine months. So we'll go over that in the next slide. And the overall pregnancy rate is about 32%. So there are other upcoming trials comparing meformin with oral progesterone or GnRH analog. So I think that we'll be able to have more data in future. And as for the follow-up, there are a little bit difference between the recommendation in NCCN and also the ESCO guidelines. For someone in the NCCN guideline, they suggested you have the first evaluation at around three months to six months. In the ESCO guideline, they suggested you have a first evaluation at three months and then another one in six months. But just now we heard that the median time that was required to achieve a country's response will be at least six months or some even up to nine months. So for someone in our units, we usually would perform the first evaluation as four to six months. And also in the ESCO guideline, it's suggested to recommend standard treatments if the patient failed to response in six months. And because of the same evidence that we talked just now, for someone in our units, we'll follow the NCCN guideline and we will only recommend a standard treatment that is hysterectomy if the patient failed to response up to six to 12 months. And after the initial response, we need to continue repeated sampling every six months. And for the use of assistive reproduction, that is safe for those that will involve some ovarian stimulation. And the life birth rate was actually higher after assistive reproduction compared with spontaneous conception. And immediate ART can not only increase the chance of life birth, it can also minimize the use of polonium or post-estrogen and the patient will be able to have undergo hysterectomy or completion surgery after pregnancy. So that's why the prompt referral to our reproductive medicine specialists will be important. And then the next we'll talk about ovarian cancer. So in NCCN guideline, they will recommend fertility sparing surgery for both stage 1A and also 1B. For stage 1B, they recommend a BSO and also comprehensive surgical staging. And the eligible patients should be having low grade disease, for example, low malignant potential, germ cells tumor or mucinous tumor. In the ESCO guideline, it's slightly more strict. For example, the patients should have a low grade serious or low grade endometrial carcinoma and also expands out mucinous tumor because the infiltrative type will be more aggressive. For other stage 1 sub-stages, the discussion should be individualized. And in the ESCO guideline, they did not recommend BSO for stage 1B because the data are not strong enough to support the use. And for the recurrence rates after fertility sparing surgery, in fact, it's quite safe. The recurrence rate is about 10% for stage 1A and low grade disease. Only for grade 3 disease, the recurrence rate will be higher. It can be up to about 20 to 30%. And also amongst patients in stage 1C disease, those with stage 1C2 and 3 will have a higher recurrence rate compared with 1C1. So another meta-analysis also shows similar results. For something, the figure on the left, patients with stage 1C and 2 will have a higher recurrence rate compared with stage 1 and also stage 1C1 disease. And the grading is important. For example, even for clear cell carcinoma, if the patient are at stage 1A or stage 1C1, the recurrence rate will be lower compared with patients with grade 2 and 3 histology. And the overall recurrence rate was similar to the last meta-analysis. It's in the range of about 11 to 15%. And after fertility sparing, keeping the other ovary, the contralateral ovarian relapse is less than 5%. And for the pregnancy outcome, successful conception rate was pretty high. It's in the range of 60 to almost 100%. And in this meta-analysis show that chemotherapy did not affect fertility. So what happened to the, what's the effects of chemotherapy? So this reveals a look at the toxicity of different chemotherapy agents to the fertility risk. For example, the commonly used carboplatins, cisplatin, they will pose medium risk on the ovarian function, whereas for the other chemotherapy like tracheotesto, the bleomycin, atopozyte, the risk is pretty low. The higher risk will be cyclophosphamide, but we seldom use it unless if the patient, for example, need to require something like the Amico for GTN. So there are lots of guidelines on the use of fertility, preservation. Of course, I'm not a reproductive medicine specialist, but here's a one summary table. So there are different methods that we can consider to use to preserve the fertility or building family. The most commonly used will be the oocyte cryopreservation or embryo cryopreservation. So both have pros and cons, but some involves a patient who has not been married or even they don't have any partner, or of course, they won't be able to have an embryo. So what we may consider is only oocyte cryopreservation, but then those who have a partner, embryo cryopreservation will be more preferable because this technique is more well-established. So both of these methods will require about two weeks of ovarian hyperstimulation. So in other words, we may potentially delay the cancer treatments for about a month. So some people are worried about the risk of ovarian stimulation, especially on those estrogen-sensitive tumor like CA corpus. Well, the risk is not really well-known, but if we are worried, the reproductive medicine specialists will also have some other protocols. For example, those using aromatase inhibitors that may pose less risk on the recurrence. And how many eggs are enough? Well, for example, these articles suggested an algorithm that can help the doctors to predict how many material oocytes will be required. For example, for those are less than 55 years old in the brown curve here. So in order to achieve a reasonable pregnancy life birth rates like 75%, they will require about 10 mature eggs. However, those are, for example, age 40, if they want to achieve 75 life birth rates, they will require almost 40 mature oocytes. So this is very, almost impossible. So that's why counseling will be very important. And some people may also consider to use GnRHN a lot as a cytoprotective agents. However, the efficacy is controversial and there's also no data on the long-term effect on ovarian reserve or primary ovarian insufficiency. So there, in fact, are lots of barriers on fertility preservation, both on the doctor's side and also on the patient's side. On the doctor's side, for some of the, some surveys on, especially on breast cancer, some, about one third of the healthcare professional forgot or did not discuss the issues of fertility. And so largely, it was due to a lack of information and also lack of referral system. And then on patient's side, both external and also internal barriers. For example, they may not be aware of any access to the fertility counseling and also the treatment options. And internally, they, well, of course, they will be already experienced lots of psychological stress, physical stress, and so on. They may not have enough support or mental power to deal with the fertility issue. So in order to establish a good fertility preservation program, so rapid access will be very important because we need to, for example, we need to stimulate the ovaries early enough so that the patients will have early treatments. And that would usually involve multidisciplinary team, including the oncologists, reproductive surgeons, and the chronologists, and so on. And in our units, we have a protocol. So patients who are less than, younger than 35 years old, those who are married, those are not married, those who do not have any living child, and for those who have good life expectancy, so they will be eligible for counseling. And for those who are a bit older, like in the range of 36 to 40, well, they would need to receive individual counseling before fertility preservation treatments will be considered. So this is my last slide. So fertility sparing treatment is possible in selected patients. However, most of the data are based on retrospective studies, and there are no big randomized trials. So that's why it's important to tell the patients that both of the treatments may not be the standard treatment. And MDT approach is important from staging to treatments. For example, we need to have experienced pathologists to establish the diagnosis, and we need to have a very well-experienced radiologist to help us to interpret the preoperative or pre-treatment findings. Counseling to both the patients and their partners are important. And for the follow-up issue, so there are different recommendations. I think the most important one is we need to be aware of our limitation and the patient need to comply to our follow-up protocol. So thank you for your attention. And I would like to thank my colleague, Dr. Jennifer Koh, who contributed to this presentation. Colleague, Dr. Jennifer Koh, who contributed parts of the slides, especially on the reproductive medicine, because she's a reproductive medicine specialist. Thank you.

fertility issues

cancer

preserving fertility

surgical methods

chemotherapy

fertility preservation program