in the management of gestational, management of gestational trophoblastic disease. So next slide. So we'll be discussing on epidemiology, clinical presentation, investigations, phagostaging, management and follow-up of the GTD disease. Next. So coming to our introduction, gestational trophoblastic neoplasia refers to a group of malignant neoplasm, which consists of abnormal proliferation of trophoblastic tissue and may follow a hydratiform mole or a non-molar pregnancy. Next. So as we know, it comprises the following histological types, and we already discussed in our TMR board also, like invasive mole, choriocarcinoma, placental site trophoblastic tumor, epitheloid trophoblastic tumor, ETT. Next. Now coming to epidemiology. Next slide. So hydratiform mole, it consists of around 80% of all GTD, invasive mole, it consists of around 15% of all GTD, and choriocarcinoma and other rare types of GTN accounts for 5% of GTD. Next. So this is about the prevalence. There is an article published in NJOG back in 2013, gestational trophoblastic disease, review of cases managed at BP Coelala Memorial Cancer Hospital, which was a descriptive study done from January of 2001 to December of 2007, and 45 patients were there, and the mean age group was 29.1 years, where from 16 years to 50 years of female were enrolled in the study, and among those patients, the hydratiform mole accounts for 37.8%, and invasive mole 13.3%, and choriocarcinoma was 48.8%. So choriocarcinoma was high. So next. So there is a study which shows that it is present in, it is frequent at the extremes of reproductive age, that is less than 15 and more than 45 years of years, and it is more 5 to 10 times increased risk after 45 years. Next. So now coming to clinical presentation, the patient may present with abnormal vaginal bleeding, bleeding from metastatic sites like liver, spleen, intestine, lung, or brain. Patient may have pulmonary symptoms like chest pain, pleural effusion, and patient may have, if the patient had brain metastasis, then they may present with neurological signs and symptoms also. Now coming to the prognosis, we know that it had a very good prognosis. So the cure was approached approximately 100%, and treatment typically allows for fertility preservation. Now coming to the investigation and how to assess the gestational trophoblastic disease, we need to do history and physical examination, then complete blood count, metabolic profile, imaging. We already discussed like chest x-ray and CT scan of the chest with contrastive high suspicion of pulmonary metastasis and contrast enhanced brain MRI if high suspicion of brain metastasis, and like SCG, and we need to determine the phagostaging and prognostic score. Next. So these are the photographs where we can see an ultrasound. Then in chest x-ray, we can see the pulmonary metastasis. In brain, we can see the space-occupying lesion with perilesional edema. And in contrast enhanced CT of chest, we can see the metastasis. So these are the imaging moralities. Next. So now coming to our management. So today, I'll be discussing on hydrative hormone management and gestational trophoblastic neoplasia management. So coming to ASMOL, in women who wish to preserve fertility, suction, dilatation, curettage is the treatment of choice. So prophylactic chemotherapy at the time of uterine evacuation is controversial. And so I'll say what is the role of prophylactic chemotherapy in the next slide. And it may reduce the incidence of postmolar GTN by only 3 to 8%. We also discussed in our TMR board in previous time. So now coming to the role of prophylactic methotrexate or dactinomycin in patient with postmolar GTN. So the role is very controversial. So however, it can be considered in patient with high risk patient, like if the age is more than 40 years, SC level is more than 100,000 milliunit per ml. If the patient has excessive uterine enlargement and the thicker lutein cyst is larger than 6 centimeter. And what I want to add is like those patients who do not monitor frequently in that scenario also we can consider for prophylactic chemotherapy. And now how to monitor SCG. SCG, assay monitoring should be done every one to two weeks until levels have normalized, defined in various guidelines as a three consecutive normal assays, as we know. Next. So following the initial normalization of SCG, it should be measured twice in three months interval to ensure the level remains normal. And if SCG levels remain elevated, then it should be treated as per the postmolar GTN protocol. Now coming to phagostaging criteria for postmolar GTN. And that should meet one or more of the following criteria. Next. Right. So SCG, either SCG level plateau for four conjugative values over more than or equal to three weeks. Second is SCG level rise by more than 10% for three values over more than or equal to two weeks. And they are the SCG persistence six months or more after molar evacuation. So these are the criteria. Next. Now the phagostaging and classification of gestational tropholastic neoplasia. Stage one refers to when the tumor is confined to uterus, that is stage one. When the tumor extends to other genital structure, then it's stage two. And if there is a long metastasis, then it's stage three. And all other distant metastasis are categorized as stage four. This is a WHO scoring system, which includes age, antecedent pregnancy, interval from index pregnancy, pre-treatment SCG, largest tumor size, site of metastasis, and number of metastasis, previous failed chemotherapy. And the risk can be given a zero, one, two, three, and four. Then we can sum up the total score and we can do the classification. We can prognosticate the disease. Next. So if it is less than seven, then it's a low risk disease. And if it is more than or equal to seven, then it's a high risk disease. Now the treatment of low risk GTNs, single agent methotrexate or actinomycin D. And the protocols is like we can use eight day regimen of methotrexate polyunic acid. The only thing is in this, the patient may come in a Saturday as it is our holiday. Next is a five day regimen. Another is actinomycin five day regimen or pulse regimen. Next. So the currently supported regimens and what we are using is like five day regimen of actinomycin D, 10 to 12 microgram per kg or flat 0.5 mg dose. IV repeated every two weeks. The primary remission rate is 77% to 94%. And the second use regimen is methotrexate where a five day course of methotrexate 0.4 mg per kg IV or IM daily for five days repeated every two weeks can be used. And the primary remission rate is 87% to 93%. And the surveillance should include monthly SCG for one year, along with contraception. OCP is preferred for contraception. After the SCG level has returned to normal, then consolidation with two to three more cycles of therapy will decrease the chance of recurrence. Overall complete remission rate is close to 100%. There are no RCT data on second line therapy for low risk GTN. General evidence and consensus supports a chance to the alternate single agent chemotherapy for patients. Those patients who have had a good initial response to chemotherapy but experience SCG value, and those who experience toxicity that limits the dose or frequency of treatment. And the response rate of dacrinomacin is around 75% with methotrexate resistant GTN. And then adjuvant hysterectomy and self-injection can be done in patients with localized disease in the uterus. Now coming to criteria to switch into multi-agent regimen. If the SCG plateau or decline by less than 10% over three weeks, a rise in SCG level or new metastasis to first line chemotherapy. Second is who relapsed after cure as defined by normalization of SCG level, that is undetectable SCG or SCG less than five international unit per liter. Now in second line setting, the currently supported regimen as we discussed is a EMACO regimen which consists of etoposide, methotrexate and dacrinomacin alternating with cyclophosphamide and vincristine. The cure rates approach 100% even in the presence of relapsed or resistant low-risk GTN. Now coming to high-risk GTN, the cure rates even in high-risk GTN approach 90% including almost all patients with only lung or vaginal metastasis, 70% for patients with stage 4 disease. Now factors associated with poor outcomes include liver and brain metastasis, particularly if they occur together. Now multi-agent chemotherapy, like previous in low-risk, we can use EMACO regimen. About 20% of patients who were on EMACO may fail to this therapy. Overall survival rate is 95%, complete response of around 62% to 70% and long-term survival rates approach from 85% to 94%. Now this was also discussed earlier. Now ultra-high-risk GTN and salvage therapy. Ultra-high-risk GTN can be defined as FIGO scores of more than 12 with extensive pulmonary hepatic and brain metastasis. Those patients who do poorly when treated with first-line multi-agent chemotherapy, they are regarded as ultra-high-risk GTN. The overall survival and early death rate is 94.3% and 0.7% respectively with induction therapy. So, in induction therapy, we can use low dose of etoposide 100 mg per meter square IV and cisplatin 20 mg per meter square IV on day 1 and 2, every 7 days for 1 to 3 courses prior to starting of EMACO regimen. So, in ultra-high-risk patients who are at significant risk for pulmonary intraperitoneal or intracranial hemorrhage. So, for such high-risk patients, a longer consolidation with 4 cycles of chemotherapy should be considered. Now coming to brain metastasis, rates of CNS metastasis are low with post-molar GTN, but approximately 20% of patients with choriocarcinoma have CNS involvement, as we can see in this imaging also. Next. And so, EMACO should be modified to include high-dose methotrexate 1 gram per meter square to encourage sufficient blood-brain barrier penetration in patients with brain metastasis. Or another is we can use intrathecal methotrexate 12.5 mg and intrathecal methotrexate can be given at the time of cyclophosphamide and benzylpristine when EMACO is used or with EP in the EMIEP regimen. Additional treatment modalities in brain metastasis involve brain irradiation with radiotherapy, concurrent with chemotherapy, or stereotactic or gamma knife radiation can be used to treat existing or residual brain metastasis after chemotherapy. So, the cure rates, even in GTN with brain metastasis range from 50 to 100% 50 to 80%. Now, what are the SALBASE therapies? The SALBASE therapy, approximately 30 to 40% of high-risk patients will have an incomplete response to first-line therapy or experience relapse from remission. Next. So, how to, when to use SALBASE therapy? We need to first diagnose what is a recurrent disease or resistant disease. So, recurrent disease means the patient whose SCG level re-elevates after becoming undetectable for three consecutive weeks are considered to have recurrent disease. By contrast, those patients whose SCG level remains elevated despite treatment are considered to have a resistant disease. Patients treated for high-risk GTN have an 8 to 10% chance of recurrence dependent on STAGE and RICS score and which can be detected by re-elevation in the quantitative serum SCG level after three consecutive weeks of undetectable quantitative SCG levels. Patients failing to EMACO are mostly salvaged with, we discussed earlier, in first-line setting we use EMAEP regimen, then other regimens include TETP regimen and the cure rates is about 75 to 85% even with SALBASE therapy. So, the disease has a good prognosis. So, other regimens include MBE regimen, VIP or ICE regimen, BEP regimen, it could be FAEB which includes fluoxetine, actinomycin D, itoposide or bencrystine or gemcitabine chiroplatin or there are some literature showing the role of high-dose chemotherapy with autologous bone marrow transplant and another is as we discussed immunotherapy with pembrolizumab also. So, now coming to the role of surgery. So, hysterectomy can be considered if the patient is having uncontrolled uterine bleeding. Laparotomy may be needed to stop bleeding. Selective arterial embolization in organs such as liver, gastrointestinal tract, kidney and spleen. And neurosurgery, those patients who have brain metastasis, we should ask neurosurgeon to see the cases. So, neurosurgery is needed if there is bleeding into the brain or if the patient is having signs of increased intracranial pressure and the resection of isolated drug resistant tumor may also be curative. So, these summarize the role of surgery. Now, what is the role of radiotherapy? So, radiotherapy has a limited role in gestational trophoblastic neoplasia except in the treatment of brain metastasis as we discussed earlier. Although its efficacy has been compared with intrathecal methotrexate is controversial. So, now I am coming to the end of slides. So, now how to do follow-up? SCGs should be monitored every month for at least 12 months for surveillance of relapse. And future fertility, pregnancy and offspring are not affected. Although psychosocial and social counseling should be done and it is needed to the patient. So, thank you. Thank you all for your patience listening.

gestational trophoblastic disease

clinical presentation

investigations

management

follow-up