detect it, be detected in a standard serum, um, assay, which will measure less than that should be less than three to five MIU per ML, depending on the assay that your serum assay that you're using. Now that national comprehensive cancer network recommends, uh, that we obtain monthly HCG surveillance for about 12 months after admission in the UK, where they have centralized healthcare, they continue HCG monitoring for up to 10 years. Um, recurrent or relapse GTN is defined by an elevation of HCG after remission with or without radiologic evidence of disease. And so I just wanted to touch on some risk factors for, uh, relapse prevention of relapse, um, evaluation, and then a subsequent therapy and just kind of a quick hitter today. Next slide, please. So, um, you know, risk factors for developing recurrence are if a patient has high risk disease versus low risk, um, disease at initial chemotherapy and high risk disease, the recurrence rates range between 8.6 to about 26%. And then low risk disease, um, the published, um, data range between about three and 8.3% with most series showing recurrence rates of less than 5%, a large metastatic burden, uh, versus a single metastasis or non-metastatic disease is also a risk factor for recurrence patients who have an HCG value above a hundred thousand at initial, uh, diagnosis of GTN are also at higher risk. And if someone's had to receive multiple chemotherapy cycles beyond about three or four cycles, there is, um, an increased risk of about 6.7 to eight fold versus patients who have less than four cycles to achieve remission. Some studies have shown that a histologic diagnosis of choreo carcinoma, um, or GTN occurring after a non molar pregnancy increases the risk about, uh, four to, uh, eight fold versus patients who have a clinical diagnosis of invasive mole in antecedent term. Pregnancy increases the risk up to 8.6 fold versus an antecedent mole. And then, uh, there are some studies that suggest that a lack of consolidation therapy, uh, or a short course of consolidation chemotherapy, uh, will increase the risk for recurrence because we want to treat until we've theoretically, uh, killed all viable, uh, trophoblast cells. Next slide, please. So, um, we assume that consolidation chemotherapy, um, is going to help prevent recurrent GTN. Um, there are no randomized trials and all the studies that have been reported are really retrospective case series, including, uh, some of the largest studies. Next slide, please. So in low risk disease, we, it's commonly recommended that, um, patients receive at least one cycle of consolidation therapy, the NCCN and, uh, FIGO recommend two to three cycles of, of chemotherapy. There was a study in great Britain and the Netherlands where they compared two different services in one service in the UK, they gave three cycles of a consolidation after low risk disease. And in the, um, in the Netherlands, they only gave two, the group in the Netherlands had almost twice the relapse rate as the group in the United Kingdom, but that group also, because they were retrospectively compared also had more patients who had higher HCG values, more patients who had metastatic disease. And so it's very difficult to come up to a conclusion that two is less good compared to three. And my experience, um, I was at Duke for 24 years and I've been at UNC for one or two years since. Um, and at Duke, we found that giving a cycle of consolidation therapy decreased the recurrence rate from about 10% down to about 3%. And so my practice has evolved to the point where if I have a patient who, uh, enters remission after, uh, less than four or fewer cycles of chemotherapy, I'll give one cycle of consolidation therapy. If they, um, have required more than four cycles of a single regimen, like methotrexate or methotrexate folinic acid, I'll give two cycles of consolidation. And if I've had to, uh, change to an alternative single agent in the United States, dextenomycin, um, or if I've had to go to multi-agent therapy to achieve a remission, I'll give three cycles of consolidation of whatever regimen got them into remission. Next slide, please. So how about high-risk disease? Um, most recommendations are for three or more cycles of consolidation therapy. I think the NCCN says, um, at least two cycles. FIGO recommends, um, up to four cycles of consolidation therapy. Uh, back in the, um, seventies, um, at Duke, they found that if you did not give consolidation therapy for patients who had high-risk disease, the recurrence rate was about 26%. And it was cut in half. If you gave three cycles of chemotherapy and that was older chemotherapy, that was Mac, not Emico, which we, um, currently hold up as the standard of care for high-risk disease. So in my practice, all high-risk patients, uh, that I treat with Emico or an Emma type regimen will receive consolidation therapy. And again, if the, if we can get them into remission in four or fewer cycles of chemotherapy, they'll receive three cycles of consolidation. If there's toxicity concerns, sometimes I'll drop the co or the EP and just treat with Emma. Um, if remission takes more than four cycles, um, I'll give at least four cycles of consolidation. And again, if they're intolerant, uh, I might drop the co or the EP and just recycle Emma. My reason for that is that there are retrospective studies using methotrexate, etoposide, and actinomycin D that have a primary response rate. That's very similar to Emico. So I don't, I, I think I'm sacrificing the least effective drugs so that I can give additional consolidation therapy. Next slide, please. So when does recurrence actually present our patients? When our patients out of the woods, uh, we did a study at Duke and we found that actually the majority of patients relapsed within about four months, 55%, 70% of the relapses occurred less than 12 months. And by 18 months, we saw 85% of our relapses, um, or study by Yang et al. Um, and they found that more than half of their patients relapsed before a year and about 75%, less than eight, 80 than 18 months, um, study from, um, from the Netherlands showed that the mean interval to relapse was about 11 months. And, uh, again, the majority of their recurrences or relapses occurred before a year. The largest study, um, out of the United Kingdom, uh, found that in patients who are low risk, 73% of their recurrences occurred in the first year, 85%, um, by the second year and, um, 96% had occurred by 36 months. And again, the highest risk interval was really the first 12 months in high risk disease. They found that the majority, um, relapsed before 12 months and almost all patients relapsed within the first two years after treatment. Next slide, please. So, um, you know, I think that in a patient who's achieved remission, I'll monitor, uh, patients with HCG quantitative levels monthly, uh, after they've hit remission, uh, for 12 months. Again, the NCCN recommends discontinuing monitoring after 12 months. And in the UK, they now recommend, uh, following patients for 36 months. So my practice is in low risk patients, the risk of recurrence after 12 months is about a 10th of a percent. And so I'll discontinue monitoring, um, those patients at that point in time for high risk patients, the risk of recurrence at 12 months is still less than a percent. Um, and I'll discontinue monitoring in those patients who've achieved remission rapidly. Uh, but if patients have required extended, uh, chemotherapy to achieve remission, I'll follow them at about three to six month intervals for the first 36 months, um, after they achieved remission. Next slide. So, um, what about the rare patient who develops recurrence? You know, I'd recommend that, um, they undergo a complete radiologic staging, uterine ultrasound, uh, to evaluate for intrauterine tumor, contrasted CT of the chest, abdomen, and pelvis, and either contrasted CT or MRI of the brain, quantitative HCG. And then I recalculate the FIGO risk score at that point in time. They've already picked up some points for, uh, having been exposed to chemotherapy and, uh, they've had an extended duration of their disease from the prior pregnancy, but I'll triage patients based on, um, on their previous score, as well as their recurrence score. Patients who were previously low risk and they're still low risk by score, um, I'll usually treat with the alternative single agent. For example, if I have treated someone with methotrexate or methotrexate folinic acid, I'll probably use actinomycin D, uh, actinomycin to treat those patients. Patients who are non-metastatic, especially if they're not desiring future fertility, I'll do a simple hysterectomy. In patients who have recurrent high risk score, um, if they haven't received multi-agent therapy or, um, if they reached remission, uh, with Emoco, I'll recycle Emoco. I'll, I'll treat those patients with Emoco if they achieved a remission with Emoco previously, or, uh, if, uh, they had required, uh, multiple regimens to, to achieve remission. If they've received Emoco, uh, before and any other salvage therapy, usually I'll treat those patients with etoposide cisplatin slash Emma, or if they were extensively treated and rapidly recur, I'll usually start at least with a taxol etoposide taxol cisplatin regimen, which is a, uh, chemotherapy is administered every two weeks on a 28 day cycle. If the risk score is extremely high, when you rescore them, I'll probably use an induction low dose etoposide cisplatin regimen. Um, the group in the United Kingdom, uh, showed that this reduces the acute, um, mortality rate, uh, from tumor lysis and, and, uh, excessive, uh, tumor response if there's a heavy burden of disease. And, um, if there's an isolated single metastatic site, a pulmonary, uh, lesion, for example, um, I also consider a surgical extirpation, um, via thoracotomy, um, or radiation if it's, um, if it's in a, an organ that is, uh, able to be radiated easily, um, to try to, um, bring under control an isolated metastasis that's been a site of, of safe harbor for tumor cells during the prior treatment. Next slide. So, uh, EMICO, um, I, I would bet that, uh, you're familiar with this chemotherapy regimen. Um, it's basically two days of etoposide, actinomycin D, a methotrexate infusion, and, uh, on the second day, toposide, uh, actinomycin D, and, uh, folinic acid rescue, recycle on, recycle it every 14 days. And on day eight, patients get cyclophosphamide and finchristine. For patients with brain metastasis, usually we'll increase the methotrexate to a gram per meter squared and, uh, extend the folinic acid rescue. Um, in great Britain, they advocate, or one of the two centers advocates using intrathecal methotrexate, um, but giving a gram per meter squared methotrexate will give therapeutic levels of methotrexate in, uh, the CSF and in the central nervous system. So I typically don't give, um, intrathecal methotrexate. Next slide. And again, we'll modify the chemotherapy, increase the methotrexate if they're brain metastases. Um, and if you're giving that, you want to alkalinize the urine during the methotrexate infusion, um, you can consider intrathecal methotrexate. I personally have never given it, um, cytokine support with, uh, neupogen. For example, if you're unable to recycle at 14 day intervals, and if patients are unable to tolerate amico because of toxicity, um, I'll usually recycle the EMA portion at 14 day intervals without the, um, day eight chemotherapy. Next slide. Uh, this is EP-EMA, um, and, uh, basically it's one day of etoposide cisplatin on day eight. There's a single day of etoposide actinomycin D and methotrexate, uh, with folinic acid rescue, and that's particularly, um, useful if a patient has either a plateau of, um, HCG values during amico chemotherapy or a patient who's been exposed to amico and relapses rapidly. Next slide. Um, this is the EP induction chemotherapy, uh, that I talked about for patients who have a very high risk, uh, FIGO score, and usually I'll recycle, uh, this induction chemotherapy, uh, at least once, uh, about every week, uh, to stabilize the patient before, uh, sailing into, um, the amico or EP-EMA. Next slide. And then this is the paclitaxel or taxol cis, uh, taxol atoposide, uh, regimen, um, and in patients who have multi, uh, resistant disease, uh, this is, uh, successful in about 40% of patients in, in achieving, uh, remission. Next slide. And then there are deep salvage chemotherapy, uh, regimens, and almost everything has been used more recently. Uh, immunotherapy with, uh, PD-L1 inhibitors, um, has been shown to be successful in selected patients, and I'm sure that we're going to hear more about that in the, in the future, even though it's not, um, upfront therapy, uh, currently. Next slide. I think I've got one more. I don't? Oh, well, um, so I guess some people will get breakfast and I'll get supper. Um, the, um, when a patient develops recurrent GTN, there are several, um, studies that show that we can achieve a remission in more than half of patients at the time of remission. And even patients who relapse more than once at their second relapse, at their third relapse, um, there's about a 50% chance that you can place that patient into remission. If you're aggressive, appropriately aggressive with chemotherapy, about half of those patients will require some type of surgery, um, to achieve remission. And, um, most patients with even high-risk disease, um, can be cured, um, at the time of relapse or the time of primary therapy. And I'd be glad to take questions. Thank you, Dr. Sofa. That was a great, uh, you know, we occasionally have GTN and it's always the

gestational trophoblastic neoplasia

placenta cancer

HCG levels

monthly surveillance

recurrent GTN