Good morning. Good afternoon. Good evening. My name is Alex Olawaye and it's a pleasure to discuss gestational trophoblastic disease with you today. And I am based at the University of Pittsburgh. Objective of this discussion would be to understand the etiology of gestational trophoblastic disease and the basics of management, understand recent alterations in surgical therapy for GTD, understand medical management for low and high risk disease, and understand the role of immune checkpoint inhibition for GTD. The outline is that we're going to discuss gestational trophoblastic disease and gestational trophoblastic neoplasia as a refresher course in definitions, evaluation, and management. Gestational trophoblastic neoplasia, latest and greatest, one of those is surgery, the role of second DNC, hysterectomy, choice of chemotherapy for low risk disease, and choice of chemotherapy for high risk disease. And as mentioned earlier, immunotherapy and the scientific rationale and clinical data. I mean, here is a little bit about placenta embryology. As you can see on the left side, you have the blastocyst cavity with the trophoblast and the inner cell mass, the embryoblast, as they are called. And the chorionic villi are categorized into three, as you can see on the right side of the screen. The primary chorionic villi, of course, which lacks the vascular lacunae. The secondary chorionic villi, which does have the vascular lacunae, but does not have the cytotrophoblastic shell. And of course, the tertiary chorionic villi, which really does have everything. And gestational trophoblastic disease includes all abnormalities related to placenta trophoblast. Not all of them are malignant. And there is complete and partial hydatidiform bone. And the incidence of these in North America is approximately 1 in 500 to 1 in 1,500. And the highest incidence of this disease is in Taiwan, where the incidence can be as high as 1 in 50 pregnancies. There is placenta site mildew that we'll talk about later. And then GTN is the malignant component of GTD. And therefore, it's a subset of GTD. And thankfully, it's a small subset of GTD. So let's talk about molar pregnancy. Hydatidiform mole, first known description was by Hippocrates in 400 BC. Tumors of gestational, not maternal, tissue are related to aberrant fertilization. Diagnosis is by elevated human chorionic gonadotrophin, ultrasonography, and of course, pathology. This has eventually evolved and has changed over time. Complete moles are diploid, i.e. they have two sets of chromosomes. And partial mole, however, are triploid. And they are P57 positive. As you can see in the picture here, on the left side, you have a representation of a complete mole. And that ultrasonography on the right side is a representation of partial mole. And this is a very busy slide for which I apologize, but it compares partial mole versus complete mole. So partial mole tends to be triploid, 69XXX or 69XXY. And complete mole is 49XX or 46XY. The pathology, there's often a fetus present for partial mole, and fetus is absent for complete mole. The amnion and fetal red blood cells usually present in partial mole and absent in complete mole. Velocidema is variable. It can be focal in partial mole and is very diffused in complete mole. Trophoblastic proliferation is again focal in partial mole and diffused in complete mole. A clinical presentation, typically partial mole presents as missed abortion. And complete mole really is diagnosed as molar gestation, typically because patient has abnormal bleeding and ultrasonography is done. And then it shows the typical characteristic picture of molar gestation. The uterine size tends to be small in partial mole, and it is larger than expected or larger than gestational age in complete mole. Thick allotensis are rare in partial mole, and they're very common in complete mole. Medical complications are not very common in partial mole, and they occur more commonly in complete mole, although less than 25%. Now, post-molar malignant sequelae, i.e., the gestational trophoblastic disease becoming gestational trophoblastic neoplasia occurs in less than 5% of partial moles, but actually in approximately 20%, the range is 6 to 32% of complete moles. Another basic slide, but this is just addressing malignant transformation of molar pregnancy. And the way this is diagnosed is you follow up beta STG weekly until negative patient has been diagnosed with complete or partial mole. And six months, if you look at the population of patients diagnosed with complete or partial mole, if beta STG is still present six months, then you have to diagnose them as having GTN, and the risk of that happening is about 1 in 1,400. Once you've had two negative beta STG for somebody with partial mole, then the risk that that person could have GTN goes significantly down to 1 in 3,200, so very, very low. Diagnosis of GTN is based on the following criteria. A, sustained ACG level or plateau, which means the drop is within 10%, higher or lower, of four values over three weeks. A, sustained ACG level rise, greater than 10% of three values over two weeks. Persistent or detectable beta ACG six months after an initial diagnosis of molar pregnancy, as we alluded to earlier, that will automatically qualify as GTN. Now, presence of metastatic disease, of course, will give the diagnosis away straight away. Histology of the GTN, if invasive molar pregnancy is seen, gestational coreocarcinoma, placental site trophoblastic disease, and epithelioid trophoblastic disease. If you look on the right side of this picture, it basically outlines the risk of somebody who is diagnosed with molar pregnancy eventually going on to have a GTN. I'm not going to go through the diagram, but it's self-explanatory. Now, gestational trophoblastic neoplasia, as we said, is a subset of gestational trophoblastic disease. It's a situation where a molar pregnancy is followed by persistently elevated ACG in the invasive mole scenario or coreocarcinoma that is based on gestational status. Placental site trophoblastic tumor is the third category, and then epithelioid trophoblastic tumor. These four categories are bunched together and referred to collectively as GTN. The good news about them is once they develop, if they are picked up, the overall cure rate is approximately 98%. Lung is the most common metastatic site for gestational trophoblastic neoplasia. Now, the gestational trophoblastic neoplasia is governed by a combined FIGO staging, but much more important than the FIGO staging is actually the World Health Organization risk scoring, which is used to triage patients for treatment. The FIGO stage is basically anatomic, so disease confined to the uterus will be stage one, disease extending outside of the uterus but limited to the genital structures will be stage two, disease extending to the lung with or without known genital tract involvement is stage three, and all other metastatic sites including liver, brain, gastrointestinal tract, kidney, spleen, etc. will qualify as stage four. The WHO score is outlined here, and I'm not going to go through that, except that from this score, you generate a number that starts from one all the way could be as high as 14 or 15. But here is what I have to say about it. A score between one and six is considered low risk group. A score of seven and above is considered high risk, but we now have a category that we call super high risk, which would be somebody with a score of above 12. Now, if you look at the epidemiology of GTN, a recent NCDB data demonstrate that stage does affect prognosis, as you can see here, the Kaplan-Meier curves shows, of course, that stage four disease would have the worst prognosis, and stage one disease would have the best prognosis. Now, after a molar pregnancy has occurred, here are the management logarithms. All women with molar pregnancy followed with ACG we spontaneously resolve. After the evacuation of the molar pregnancy, the problem is following them up with beta ACG, of course, can generate anxiety because of the numerous tests that need to be done, and of course, they are anxious because they are also often told to delay future pregnancies so that we can monitor them for recurrence in the short interval, and so generally, that is somewhere between six months and one year, depending on the type of gestational pleuroplastic neoplasia. Now, you know, it typically does not require additional tissue diagnosis. Risk factor for post-molar GTN includes enlarged uterus at the time of initial diagnosis, beta ACG of more than 100,000, and presence of thicker lutein cysts. Now, choriocarcinoma is the most aggressive, of course, subcategory, is highly malignant form of GTN. Metastasis is by direct invasion of uterine blood vessels and hematologic spread. 25 to 50% of these choriocarcinoma cases follow non-molar gestation. Diagnosis may be delayed, and frequently, they present with significant hemorrhage, either from the uterus or even hemoptysis. Placenta-site trophoblastic tumor and epithelioid trophoblastic tumor, these are very rare histologies from intermediate trophoblast, no chorionic villi. They form 1 to 2% of GTN after non-molar gestation. They tend to follow non-molar gestation, as just said. Relatively, they are chemo-resistant. Beta ACG is not a consistent marker for them. Some of them may secrete human placental lactogen, and if they secrete beta ACG, it usually is at low level, not anything compared to the typical molar gestation. Now, there is work being done with glycosylation fraction to differentiate the placenta-site trophoblastic tumor from other gestational trophoblastic neoplasia, but this is still in research. Time from antecedent pregnancy correlates with prognosis and treatment whenever possible is surgical, i.e., hysterectomy. Initial evaluation of GTN patients, you need to confirm diagnosis when possible with pathology, and if necessary, please have review pathology done so that the diagnosis can be solidly confirmed. Repeat beta ACG in the same lab, and consider sometimes that there can be false positive beta ACG. One easy way to deal with that is to check beta ACG in urine at the same time that you are doing the quantitation in blood, and typically, if the urine is positive, it is likely that the elevation in beta ACG is real because the pseudomolecules that can mimic beta-ACG in blood tend not to cross into urine. Now, assessment for metastatic disease, chest x-ray is recommended for assessment of the chest. CT scan of the chest is not necessary. It is an overkill and World Health Organization does not recommend CT of the chest. You can repeat pelvic ultrasound if one was not done in an institutional center where a detailed report is available. Consider CT in special circumstances, CT of the chest, abdomen, and pelvis. And that is if there are some things seen on x-ray that suggest that other processes may be going on. MRI of the brain, especially if there is neurological symptom or brain metastasis is suspected from presentation. Assess the FIGO stage and please cross-check the WHO score and score the patient because this is critical for management. And if possible, recommend consultation with a GYN oncology and actually recommend treatment in a GTN center because comprehensive treatment of this condition is best for the most optimum outcome. Now, the therapeutic options for GTN management, on the left side, you see surgery, repeat dilatation and evacuation, hysterectomy, and in some situations, mastectomy. Now, chemotherapy can be single agent, which would include methotrexate or actinomycin D and the multi-agent, which we usually, of course, employ for high-risk disease includes Imaco, EMA-EP, and the TPTE chemotherapy combinations. And more recently, there is evidence that immunomodulation may work, especially checkpoint inhibitors. Now, surgery may serve certain purposes apart from, of course, primary elimination of the disease. In a study, 109 women with GTN in Netherlands underwent hysterectomy. 67.6% of the women with localized disease achieved remission after surgery. Hysterectomy also cured. 94.7 and 58.0% of women with single and multi-agent chemotherapy-resistant tumors, respectively. And shorter duration of therapy due to fewer cycles of chemo to achieve remission is necessary in those patients with persistent beta-ECG after surgery. And therefore, there is a lot of advantages, or there are a lot of advantages to surgery. In another series, again, in New England, between 1980 and 2009, 24 women underwent hysterectomy as primary treatment for GTN. 50% of them achieved remission. An additional 20% required only one cycle of chemotherapy. And 19 women who underwent hysterectomy for chemo-resistant disease were reported on, and 43% did not require further chemotherapy after surgery. Now, in a study done in the UK, 282 women with presumed persistent molar disease underwent second curettage between 1991 and 2000. So instead of going to chemotherapy at this center, they decided to take them for a second dialytational curettage procedures. And 60% of the women did not require chemotherapy subsequent to this second procedure following normalization of beta-ECG. And it's particularly most successful if beta-ECG is less than 1,500. And in another study at the Netherlands, 294 women with GTN were studied. 85 underwent second curettage. And again, in this particular study, 89% of the patients needed chemotherapy. Total number of cycles was, however, five versus six in the chemo alone group. 10% did not need chemotherapy. So this experience is a little bit different from the experience in the UK, and the number was also larger. 4.8% complication rate from dialytation and evacuation procedures with two patients losing more than one liter of blood and two patients had a uterine perforation. So the table below is just the table of treatment and the complications that occurred in the group that were studied in the Netherlands. Now, building upon retrospective data, GOG prospectively investigated the role of therapeutic D&C following gestational trophoblastic neoplasia. And in a single arms phase two study, 60 women with stage one low-risk post-molar GTN at first presentation were looked at. And these patients had adateliformo following initial curettage, persistent elevation of beta-ACG, and non-metastatic GTN was diagnosed. And basically all of them were low-risk patients because their score was between zero and six. And the second curettage was performed and then beta-ACG was monitored after the second curettage. And the results showed that overall 43% normalized their beta-ACG after the second curettage. And there was lower likelihood of cure at extremes of age. So patients older than 40 or less than 19 years of age had sort of a compromised cure rate. There was also lower likelihood of cure at intermediate WHO scores, i.e. those patients with scores of five to six compared to those with scores of less than five. Also the level of beta-ACG prior to treatment was indicative of who might be cured. So those who had beta-ACG of more than 100,000 were less likely to be cured. There was only two complications, one uterine perforation and one excessive hemorrhage. So the result from the GOG242 was more in agreement with the result from the UK. Now let's talk about chemotherapy regimens for GTM. It is governed by stage or risk factor as we have said before. So generally speaking for those patients with low risk disease, i.e. WHO score of six or less, the standard is to treat them with single agent chemotherapy, and if the score is more than seven, multi-agent therapy is advised. Pregnancy prevention is key, and this is really to make sure that if a recurrence would occur, pregnancy does not confuse that situation. Remission really is typically durable and is expected to be approaching 100%. Now, there is a group, as I said at the beginning of the lecture, that we call ultra-high or super-high risk group, if you like. These are patients with stage four disease or with WHO score of more than 12. In this group, before we go to multi-agent chemotherapy, we like to start by giving them induction etoposide with cisplatin chemotherapy. Now, the initial chemotherapy for GTN is discussed on the slide. Numerous methotrexate and actinomycete regimens exist for the treatment of low risk GTN. As you can see detailed here, one regimen is the so-called multi-day regimen where you give the methotrexate at 0.4 milligrams per kilogram body weight, maximum of 25 milligrams per day, IV or IM, for five days, and you repeat this regimen every 14 days. Second regimen there is methotrexate that is given 30 to 50 milligrams per meter squared body surface area and given intramuscularly on a weekly basis. Regimen three, again, is also a multi-day regimen at a slightly higher dose of one milligram per kilogram given intramuscularly and on alternating days of one, three, five, and seven with folinic acid rescue at a dosage of 0.1 milligram per kilogram body weight and given intramuscularly on the, of course, interceding days between the methotrexate regimen. This is a very popular regimen and there are other regimens there that I'm not going to go through, but I will mention that actinomycin D can be given also on a multi-day regimen and repeated every 14 days. If you do that, you do it at 10 to 13 micrograms per kilogram body weight and intravenously for five days, once a day for five days and repeat every 14 days. The alternative regimen that is actually more popular with the actinomycin D drug is to do 1.25 milligrams per meter squared body surface area intravenously every two weeks. The primary remission rate associated with these regimens is what you're seeing here. As you can see, the alternating methotrexate and actinomycin D regimen one and five, which is the multi-day regimen documented in one and the one documented in five actually achieves in studies a remission of 100%, but beside that, the remission rate associated with any of the other regimens is very, very high. I would like to point attention to regimen two, which is the weekly methotrexate dosing. That's a regimen that we're trying to stay away from because it tends to have the lowest remission rate of the treatment regimens. Now here, there was a study done that is called GOG174, which compared methotrexate to actinomycin D in 240 women. But as you can see here, the weekly methotrexate regimen at 30 milligrams per meter squared the body surface area was utilized and compared with dactinomycin D 1.25 milligrams per meter squared body surface area IV push. This again was given every two weeks in the case of dactinomycin and weekly in the case of methotrexate. Basically what they found was more women achieved complete response with dactinomycin, fewer, dactinomycin is actinomycin D, let me just make that clear. Fewer chemotherapy cycles were required, which was like eight in the methotrexate group but four in the dactinomycin group. There were two recurrences, one in each arm and the dactinomycin more low grade GI toxicity according to dactinomycin group. And also they had more nausea and vomiting and rash and alopecia with neutropenia. But this trial suggested that the dactinomycin as using this trial might be more effective. But as I told you before, people were critical of the way this trial was done because the dosage of methotrexate that was used was that dosage that I showed you in the table was associated with the lowest remission rate. So it felt as though methotrexate was short changed in this study. Another study was done, GEOG275 tested actinomycin D against two more commonly utilized methotrexate regimens. This was actually a follow-up study to the one that I presented early and patients in arm one were given actinomycin D as used in the previous study, 1.25 milligrams per meter squared body surface area every 14 days. And then the multi-day regimen of methotrexate, two of them were used in arm two. You could either use, if you remember this was the number one regimen on the table, 0.4 milligrams per kilogram body weight for five days every 14 days or do the alternating day regimen that is incorporated with folinic acid rescue. In this case, the study was closed early due to poor accrual, but the results suggested that there was no difference in the methotrexate regimen as used in this GEOG275 study compared to actinomycin. Complete response was seen in 75% of patients in the actinomycin D group versus 88% in the multi-day methotrexate regimen. Recurrence was seen in two patients, 7% in each arm and survival was 100% in the study. There was no one required multi-agent chemotherapy. One hysterectomy was done on the methotrexate arm and the adverse events that were seen were more mycositis in the methotrexate group. There was no difference in alopecia and no grade four or five toxicities were recorded. And there was no difference in quality of life. Now, if you go to the high-risk GTN group, this would be the group whose score of seven or higher. There are so many regimens that can be used, but I want you to look down to the middle of the table and you see Emacol there, which it really is the most popularly utilized multi-agent chemotherapy regimen, but there are others. I mean, as you can see here, you can just do MAC, which is the methotrexate and dactinomycin, you can do the ChAMOCA regimen. There are so many variations of this in the literature, but as I said, Emacol, MIEP, and TPTE are the most popularly utilized multi-agent chemotherapy regimen for GTN. I'm not gonna go through these business slides, but it gives you the studies, what was utilized and the outcome that was achieved in the last column. Now, multi-agent chemotherapy for high-risk GTN presents with numerous historical regimens utilized by centers of excellence throughout the world. And some of these regimens have not been well studied because, of course, of the reality of patients that need multi-agent chemotherapy. That is because of how successful initial therapy is for this disease. Most regimens have similar rates of remission anyway. Death from GTN is very rare, and refractory disease is truly an oncology challenge in this space. So just going into more details about the multi-agent chemotherapy, especially addressing the more popularly utilized ones. So AMI is a toposide, usually given at 100 milligrams per meter squared, body surface area. This is given over 30 minutes. Dactinomycin, it's 0.5 milligram in this regimen, given intravenous bolus. And methotrexate is given at 300 milligrams per meter squared body surface area intravenously for 12 hours. This is on day one. On day two, we repeat the toposide as 100 milligrams. We repeat dactinomycin as 0.5 milligrams intravenous bolus. And then we give a folinic acid rescue of 15 milligrams intramuscularly or aura every 12 hours for four doses, starting from day two. And then on day eight of the regimen, we do the CO. So basically just after a week of starting the treatment, we then give Benchrystin and at one milligram per meter squared intravenously as a bolus, maximum of two milligrams. And then we give a Cytoxan or cyclophosphamide at 600 milligrams per meter squared body surface area intravenously as an infusion over 30 minutes. So the emarco response have been linked to the nature of metastasis of patient's age. And as you can see here, you know, it appears that when the patient is older, the regimen tends to be less effective. And as shown here in patients more than 39 years of age, the survival rate was 62.5% in this particular study. And when the patient was less than 39 years of age or equal to 39 years of age, the survival rate was 91.3%. And you can go down the table and look at how different factors affect what was achieved in each scenario. Of course, as you can see, there was no metastasis. The survival rate was 100% and the more metastasis were present, especially metastasis to the brain, the more the survivor dropped. As I talked about earlier, and the last thing there is also, of course, the number of metastatic organs that were affected. The higher the number, the worse the outcome. Now, the MIEP regimen has also been established as the first line choice for PSTT and ETT. Let me just quickly say that for these disease, if we're lucky to diagnose them, because these are actually, unfortunately, sometimes difficult to diagnose when they are still confined to the uterus. But if we're lucky to diagnose the disease when it's still confined to the uterus, the overwhelming preference and the safest treatment is hysterectomy, no question. Because as I mentioned before, this disease tends to be, or this group tends to have a chemo-resistant profile. However, unfortunately, some of them have metastatic disease at the time of initial diagnosis and therefore they need some attempt at treatment. So this MIEP regimen is one where you give a toposite with acnomycete A and methotrexate as documented here on day one, on day two, a toposite and acnomycete D similar to the EMACO regimen with folinic acid rescue starting on day two. And then instead of oncovine, instead of vincristine and cyclophosphamide on day eight, here we give cisplatin and a toposite. The cisplatin are 60 milligrams per meter squared body surface area and the toposite are 100 milligrams per meter squared by infusion. Methotrexate generally is increased to 1000 milligrams per meter squared body surface area if intracranial metastasis is present and weekly toposite with cisplatin induction is used if there is a high risk of bleeding and it reduces early mortality. There is also EPEMA, which again in some studies has been shown to be effective as you can see in this couple of our curve here, it was used in 34 patients and a durable remission was achieved in 32 of those 34 patients. This is similar to the MIEP regimen, except that you switch everything around and give the toposite of cisplatin at the beginning, i.e. on day one. As a last resort for SAVAGE, high dose induction chemotherapy with peripheral blood stem cell transplant has been described. This is particularly those super high risk group that we talked about in a particular study reported from the UK. They reported a series of patients treated from 1995 to 2015, and they had 32 patients in that report and of the 32 patients, carboplatin, toposite and cyclophosphamide with toxin was utilized. The complete remission rate was seven of the 23 that were accessible. Six of them then relapsed. The mix of creocarcinoma and PSTT, i.e. placental cytoplastic tumor and epithelioid trophoblastic tumor was the dominant histology in this report. And beta-ACG was of more than 12,000 at the beginning of the treatment was predictive of treatment failure. There were three treatment related deaths. This is a group that is extremely difficult to treat and details of what happened is given in the diagram below. And you can, at a later time, take a closer look at that as these slides will be available to you. Now, the New England Trophoblastic Disease Center at Brigham and Women's Hospital and Benofava Cancer Institute confirms reports that pregnancy outcome following complete or partial mole is not dissimilar from the baseline population. And this is what is shown over here in a report looking at patients that were treated at the New England Trophoblastic Center from 1965 to 2001. The number of term pregnancies out of 877 patients was 68.6%. The stillbirth rate was 0.5%. Preterm delivery was only 7.4%. First trimester, you know, pregnancy loss was 17.3%. Just to give you a flavor of how this compares to the general population, that 17.4% or 0.3% will be expected to be about 15% in the general population. Second trimester loss was only 0.6%. And there were, of course, some terminations of pregnancy. And then ectopic pregnancy was seen as 0.9% of patients. Repeat molar gestation was fortunately very low, 1.4%. Congenital malformations were only seen in 4% of the patients. And only 18% of the patient population required cesarean section. Now, there are new directions that are coming out. And, you know, immune tolerance of pregnancies suggests that gestational trophoblastic neoplasia is reliant upon immune evasion to persist and metastasize. And there are numerous preclinical investigations that have demonstrated heightened programmed cell death, L, i.e. programmed cell death, ligand expression in trophoblastic disease. And PD-L1, as is referred to, expression is highest in abnormal placenta trophoblast of all adult human tissues. 73% of them demonstrate strong expression, 10% weak expression of PD-L1. And this is where you look at choreocarcinoma cases, placenta site trophoblastic tumor and epithelioid trophoblastic disease tend to have weaker expression of PD-L1. So this is the basis of looking at mitigating these checkpoint pathway in gestational trophoblastic neoplasia. And so a landmark case series was reported in 2017, which demonstrated how pembrolizumab induced durable remission in refractory ultra high risk patients. Pembrolizumab is an antibody that is targeted against PD-L1, so it inhibits PD-L1. As you can see, time from diagnosis to remission in the graphs shown on the left show the effectiveness of pembrolizumab with the beta-ACG basically crashing from as high as over 1,000 to close to zero or to normal range. So this represents a new opportunity for treatment, especially in refractory gestational trophoblastic neoplasia. Now there's also a TROFIMON phase two trial, which found that Avelumab, another checkpoint inhibitor, induced remission in 53% of 15 women with progressive gestational trophoblastic neoplasia after single agent chemotherapy. And this was reported by BNOTU. And the results of the efficacy end point as indicated by successful normalization of beta-ACG is shown here. After a median of nine cycles of treatment, 53% remission rate was achieved. And for the patients that were followed up for 29 months who achieved remission, there was no relapse after normalization of beta-ACG, which was really nice to see. First ever reported term pregnancy that was reported after immune checkpoint therapy was actually recently reported. And this is the baby that was shown in this pregnancy that was carried to term. Because imagine after a refractory disease that was now successfully treated with immune modulation, the concern of being able to ever have a pregnancy again is really real. And so it was reassuring to see this case that was a successful pregnancy that was carried to term after such a treatment. In conclusion, gestational trophoblastic disease encompasses a unique set of rare tumors at the intersection of OB-GYN and oncology. Most women are cured of the malignant manifestation of gestational trophoblastic disease with a combination of surgery and chemotherapy. Future pregnancies in women with low and high risk disease do not appear to differ from the general population if adjusted. And immune therapies are now being seen as promising in the treatment of those women with the rare disease, especially when refractory to standard therapy. Thank you very much.

gestational trophoblastic disease

etiology

medical management

molar pregnancies

diagnosis

treatment options

gestational trophoblastic neoplasia

chemotherapy regimens

immune therapies