So good day, everyone, and thank you to the IGCS for giving me the opportunity to give a short didactic on gestational trophoblastic neoplasia and to react to the three cases. Gestational trophoblastic neoplasia comprises a malignant group of trophoblastic diseases that are known to invade locally and metastasize primarily to the lungs, but they can also be seen in other parts of the body, distant parts such as the brain and the liver. The cure rate for low-risk GTN is almost 100% worldwide, while for the high-risk GTN, cases will be cured up to as high as 94%. And this high cure rate is attributed to the following factors. First, the beta-HCG is an excellent tumor marker, which is used for both diagnosis and treatment surveillance of the disease. Second, we already have available and identifiable prognostic factors that could predict response to treatment and enhances individual-based, risk-based therapy. Early recognition could be achieved through different imaging modalities, and in the low- to middle-income countries, this is usually the ultrasound. This tumor's particular recoriocarcinoma also has the inherent sensitivity to chemotherapy, and moreover, higher cure rates can be achieved when we use combined treatment modalities such as surgery and radiotherapy. For our patients to be able to have the best possible prognosis, they should be properly staged and scored according to the FIGO 2000 staging and WHO prognostic scoring system. And this is unique for GTN. So for our three patients, they were subsequently stage one is low-risk, and the other two were high-risk patients. And similarly, they were treated as such. So for chemotherapeutic regimens, which remain to be the cornerstone of management of dystrophoblastic neoplasia. So for non-metastatic or stage one diseases, for which that was one of our patients, the single-agent chemotherapy in the form of methotrexate can be given. And this can also be given for stage two or three low-risk metastatic diseases. And we usually give two additional chemotherapeutic courses. This is what we call the consolidation or cleanup courses to make sure that all circulating tumor cells that cannot be picked up anymore by the assays can still be eradicated with a chemotherapeutic, that with the additional chemotherapeutic courses. And then for the metastatic high-risk cases, and this we're seeing in the other two cases, we can use the multi-agent chemotherapy, usually in the form of EMACO, and combine them with hysterectomy and any other form of adjuvant surgery, and as well as radiotherapy to achieve cure, plus give them additional three cleanup courses or consolidation courses. Okay, here is the 2019 National Comprehensive Cancer Network algorithm for the treatment of high-risk GTN. And our local guidelines, the Philippines guidelines on the treatment of GTN is very, very similar to this NCCN guideline. For our three cases, the low-risk patient was given single-agent chemotherapy, while the two were given high-dose EMACO regimen, okay, which entailed a higher dose of metotrexate to overcome the blood-brain barrier, and there's also concomitant increase in the dose and duration of the folic acid. So going back to the three cases that were presented, the gravity, and these are the different issues, these are the different concerns that should be looked up to when deciding to individualize the management. We have the guidelines, which would be the single-agent for low-risk or for your non-metastatic disease, and we have the high-risk, or for the multiple-agent for the ultra-high-risk or even just the high-risk cases. But in order to choose the best possible treatment regimen, then these are all the considerations that we have to think of or look into. So specifically for our patients, we have to look at their gravidity and parity and their desire for future reproduction, the availability, and the type of immunoassays that are available in our institution and even in the community as well. How reliable would be the laboratory in terms of coming up with a standardized number? And then we have the use of different diagnostic tools, such as your transvaginal ultrasound, you can have your CT scan, you can even have your MRI. And then we have to even think of what factors would make the patient comply or not comply with the treatment. Okay, so for the past two or three years, almost three years, we have been into the pandemic and this has greatly affected delivery of the services for our patients. Aside from that, we have to look at the medical status, the presence of comorbidities, the beliefs of our patients, the cost of the medications in order to plan quite well the treatment that will be given to them. What is quite striking in the cases that were presented, at least in the Philippines, we have, especially for the ultra high-risk patient that was placed where the surgery was done first, at least in our county, a high index of suspicion for any woman of reproductive age presenting with abnormal vaginal bleeding would always make us suspect trophoblastic neoplasia. Okay, so in most cases, it has been a practice in our country, in my country, that when we have a patient with abnormal uterine bleeding, we usually request for a pregnancy test, this may be qualitative or quantitative. And even in young patients who present with stroke and lateralizing lesions, we usually request the neurosurgical teams and the neurosurgery, neurosciences service, we usually refer to trophoblastic specialists for clearance just to make sure that this is not a metastatic lesion to the brain from for your carcinoma, okay? So going back to our didactics, as I have mentioned, according to the local guidance and even the international guidelines, okay, non-metastatic stage one and low-risk stage two that you will be given a single agent chemotherapy, which may be in the form of your methoxetamide and actinomycin, while combination chemotherapy must be administered to high-risk GTN. These are the different types of protocols that will be given, that may be given to our patient. I think for our low-risk patient, methoxetamide with folinic acid, high-dose methoxetamide with folinic acid was given, while in the Philippines, our common protocol, our best protocol, and we hardly use any other protocol except this for our low-risk and for our non-metastatic patients. The only protocol that we usually use is to give 0.3 to 0.4 milligram per kilogram IM daily for five days for these patients, methoxetamide. We hardly use actinomycin. We only get to choose actinomycin even if it's available if our patients have severe ADRs to methoxetamide. So methoxetamide remains a cheap, relatively cheap chemotherapeutic drug that can be administered on an outpatient basis for our patients with low-risk GTN, and they do respond quite well. For the high-risk and ultra-high-risk GTN, one of the preferred and most widely used first-line combination chemotherapy will be EMACO. The toxicities of this regimen is mainly hematologic. Agarwal and colleagues found out that the complete response rate and long-term survival rate of high-risk patients when treated with this regimen would be as high as 97%. With the mentioned studies, we can still anticipate a good response for the two of our patients that were given EMACO. So just to share with you the local experience when it comes to EMACO, in the Philippines, in my institution, the Philippine General Hospital, our primary remission rate with the use of EMACO for our high-risk GTN is around 72%, with a sustained remission rate of 82%. For the past five years of up to 2020, you can see here that this will be our census, and almost all our patients will be high-risk patients with lung metastasis. We usually have only a few patients will present with brain metastasis and with metastasis preferable to other organ systems. We also have a sprinkling of low-risk and non-metastatic, which are given metotrexate on an outpatient basis. But in most cases, more than 50% of the cases that we deal with in our institution would be stage three high-risk. This data does not include what we have for this year, but I would just like to share that for 2022, it has been six months. We've already had three cases of patients with new cases with brain metastasis. Later on, I will share with you a bit of our experience with how we go on to treat these patients. So the effectiveness of chemotherapeutic agents for gestational trophoblastic neoplasia, this would show you, this study will show you that this results from the complete remission rate of 67%, okay, for a macroregimen. This is Shen's study, which came out in 2018, while the resistance rate was at 33%. Those with complete remission had no recurrence and no secondary tumors with the chemotherapy was noted, were noted. Approximately 25% of GTN tumors in a study by Alazam et al, okay, and this is the Cochrane database in 2012. Around 25% of patients will, okay, have resistance to EMACO or will have relapse after initial chemotherapy and may require salvage chemotherapy with or without surgery, okay. So this just shows you how we give EMACO in our institution and we have the, our salvage chemotherapy will usually be in the form of MIEP, okay. So this is how we define chemoresistance. If we have patients with two plateauing values over three consecutive serum beta-HCG determination. So we define plateau as a less than 10% increase or decrease from the baseline. Or if there is an actual rise in the beta-HCG value over two consecutive serum beta-HCG determination, or an increase in beta-HCG levels by one log over six weeks. And of course, during the screening with beta-HCG for plateau or rise, we also look for a concomitant presence of new metastasis. So we repeat all imaging studies, we repeat the metastatic workup to check where that resistance or that rise is coming from, or that plateau, or that rise is coming from. And these are the molecular mechanisms that have been plotted in terms of why around 25% of tumors will have resistance to the initial therapy. And basically, any mutation to any of these mechanisms may lead to chemo resistance. So the most effective drug for RGT-N would really be methochexate and etoposide. And this table presents the different molecular mechanisms for these two agents. For etoposide, researchers have found out that mutations in topoisomerase may lead to a decrease in your drug binding. Okay. So there are also multiple, for methochexate, there are multiple pro-survival signaling pathways. So Kim and colleagues identified risk factors for the prediction of treatment failure in RGT-N with the treatment using EMACO, and these are the different factors. What would be most looked at would be a tumor age of more than 12 months, the number and site of metastatic organs, and incomplete previous treatment. And I think this was also seen in the ultra-high-risk patients that were presented in this round table discussion. So we have incomplete previous treatment and a presence to the brain. For high-risk metastatic RGT-N, which have already resistance to EMACO, a platinum etoposide-based component is essential. So it will offer a cure rate of around 82% and a survival rate of 53%. And this is also what we follow in the local setting. For the Philippines, we usually give EP-EMA or EMA-EP after a failure or resistance with EMACO. Okay. Alanta, Raju, and colleagues conducted a retrospective study to assess the importance of salvage therapy in chemo-resistant high-risk RGT-N. So this was what they were looking at. They looked at 82 high-risk RGT-N patients with EMACO chemo-resistance, and their outcomes would be the clinical response, survival, and factors affecting outcomes as their end analysis points. These were the salvage chemotherapy that were investigated. Okay. And in the study, majority of the patients, those who had chemo-resistance were given etoposide and platinum-based chemotherapy. Some of these patients also underwent adjunctive procedures in the form of irradiation, hysterectomy, uterine resection, and even excision of resistant lung lesions. So this might be useful for one of the patients that was presented. Okay. They noted the complete response to salvage therapy, and it was around 80%, but the overall survival rate is at 87%. So the survival rate for the salvage therapy is higher for this study as compared to the local study that we had. Okay. And they also found out that the beta-HCG levels at the start of salvage therapy is important for remission and survival, rather than the stage or the prognostic score. So I guess that would be quite logical because it would also be indicative of the tumor burden. Okay. So how low or high the HCG was at the start of the shift in the chemotherapeutic protocol would also help us determine how good the response is. Okay. One of the questions that was raised for one of the patients was the use of TPTE or your paclitaxel cisplatin or paclitaxel etoposide and paclitaxel etoposide combination. Okay. So your TPTE regimen is used as an alternative for MIEP with comparable cure rates of 70% in patients who have not been previously exposed to etoposide cisplatin treatment. Okay. So this regimen was also known to have lesser side effects. So this is probably the reason why you have, with your more experience with the use of TPTE, you would rather give your TPTE because of the less side effects rather than the MIEP. But in my institution, we have better experience with the use of MIEP or EPEMA. And our TPTE is actually a third line protocol. Okay. So Wang and colleagues launched a study to evaluate the efficacy and toxicity of TPTE regimen as salvage therapy of patients with high-risk GTN who had chemoresistance or cisplatin-based regimen. There were two groups of patients. Group A were patients who exhibited chemoresistance to cisplatin-based regimen, while group B included patients whose previous regimens were changed to TPTE due to treatment toxicity. Okay. So basically, they also looked at, they found a good outcome for this one. These are the different chemotherapeutic regimens that could be given if there is chemoresistance to EPEMA salvage therapy. Okay. So you can choose from this gamut of protocols as salvage therapies. So in the Philippine General Hospital, once our patients have passed on from the EPEMA, it's a free-for-all. We can choose from any of these regimens depending on the availability of the drugs in our hospital. Okay. Perhaps one other strategy that can be used, okay, would be, is that probably high-dose chemotherapy with peripheral stem cell transplants can also be given. And now, you already have, we can do immunotherapy in the form of pembrolizumab, but this is quite expensive in my country and it's not yet really out there for everybody to use. This is a monoclonal antibody, okay, and then which functions as a checkpoint protein for regulation of various immune cells. And then we also have other combinations such as your 5-FU-capacitabine and your gemcitabine and carboplatin. So some of these agents are not yet available in the Philippines as of the present. Aside from doing adjuvant chemotherapy or changing the protocols from our mainstay of metotrexate and EMACO, we also can do adjuvant surgical intervention. So we can do an actual hysterectomy, we can remove a resistant or persistent focus, we can, these are the reasons why we do these resections of tumors or even, yeah, solitary tumors. Basically, these are our reasons we would like to control bleeding, we would like to relieve obstructive symptoms and can also be to treat infections, especially if these tumors are now needless for abscesses. Okay, so these are the different surgical interventions that may be used, and in one of our patients, we had craniotomy, okay? So hysterectomy remains one of our most frequent adjuvant surgery in the Philippines, and the most common indication would still be chemoresistance and the presence of hemorrhage, okay? But this will serve the advantages of doing adjuvant hysterectomy for our patients in managing persistent or chemoresistant GTN would be the following, somehow it helps decrease tumor loads, the number of cycles of chemotherapy needed to achieve remission. Yeah, so that's our main management. So a word on radiotherapy, we usually administer it concurrently with chemotherapy. Once we have accurately diagnosed brain metastasis from choro-carcinoma, we don't do surgery. What we do is administer high-risk EMACO concurrently with radiotherapy. In our institution, we use the linear accelerator to deliver the doses, okay? So even for liver metastasis, we can also do the radiotherapy, and the following are the advantages of this adjuvant irradiation. The following are the most common adverse effects of chemotherapy that we see in our patients that have an adverse effect in terms of being able to give our protocols on time and our patients complying with the necessary treatment. Okay, so these are all quite difficult to administer, especially during this COVID pandemic. So for the three patients, the questions that were raised were that what was the best chemotherapeutic agent to give for the low-risk? I think methotrexate was still the best. We don't usually withhold TB medications if they are needed. Just make sure that there are no concomitant liver dysfunctions for our patients. We make sure that we treat the complications of chemotherapy. We also treat concomitant medical problems. So there was one patient with being given anti-tubercular medication. So in our country, we usually continue giving, especially if the patient also has active tuberculosis. And of course, we do protective measures to take for patient and surgeon during the COVID pandemic. So hopefully, I was able to answer some of the questions that were raised for our case discussion. And lastly, I would like again to invite everybody to the International Society Study for Trophoblastic Diseases. We will be having our Biennial World Congress on October 19 to 22, 2022, this coming October. And you can register. You may want to visit Australia, but the convention can also be, it will be also given on a hybrid platform. So thank you very much.

gestational trophoblastic neoplasia

treatment options

cure rates

beta-HCG

imaging modalities

chemotherapy