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New Treatments for Trophoblastic Tumors

Trophoblastic disease  is a rare disease occurring in young, reproductive age women. Trophoblastic diseases have a very reliable tumor marker; beta-hCG that needs to be measured in a quantitative fashion when these patients are being managed. It is also a disease that is exquisitely sensitive to chemotherapy, and there are several chemotherapy options. It is important to realize and recognize that most patients with even widely metastatic disease, liver and brain metastases for example, can be cured with appropriate treatment.

The majority of gestational trophoblastic disease that would be treated with chemotherapy are the end results from a molar pregnancy, a hydatidiform mole. Not all of these require chemotherapy, just the minority. But of those needing chemotherapy, about half come from hydatidiform moles as a precursor. A partial mole is a different diagnosis and is a less aggressive and less likely to result in malignant sequelae.

Molar pregnancy disease. This usually presented in women who were thought to be pregnant, early in their pregnancy, in the first or second trimester. It either presented with bleeding, hyperemesis, gravidarum, preeclampsia - which you wouldn’t normally expect early in pregnancy - uterine size larger than expected, or even maybe presenting with hyperthyroidism or some combination of these medical conditions being classic symptoms. Today with the widespread use of ultrasound early in pregnancy, there is a trend toward earlier diagnosis because of ultrasound screening to look for fetal defects and dating of pregnancies. The ultrasound findings in most molar pregnancies are an absent fetus and a cystic appearance of the placenta, sort of a "snowstorm" pattern. But a snowstorm pattern with no identifiable fetus is a classic ultrasonographic finding, which would lead the gynecologist to proceed.

Post-operatively there is a particular syndrome. Some people call it deportation syndrome, but a respiratory collapse to the point of patients requiring intubation for several days to support them. This is thought to be caused by either the deportation of trophoblastic emboli at the time of the suction D&C, potentially fluid overload associated with the use of IV oxytocin. Of course these other medical conditions can lead to pulmonary compromise as well.

Following the evacuation of that molar pregnancy, the patient needs to be monitored carefully with this tumor marker, beta-hCG. It needs to be quantitative, to use a urine pregnancy test or a screening pregnancy test is totally inappropriate and malpractice. The patients need to have a quantitative hCG monitored and we would recommend they would be monitored weekly.

In the patient that doesn’t achieve titer remission and stay there for six months - and that accounts for about 20% of patients after molar pregnancy is evacuated, and even about 5% after hysterectomy is performed as primary therapy for this molar pregnancy - these patients will have either an elevation or a plateau of their hCG. And that suggests that either the patient has persistent disease in the uterus or in the myometrial wall, or potentially metastatic disease. The risk factors for this condition are listed here. Older patients, high level of hCG - over one million international units - size of the uterus greater than 20 weeks at the time of initial evacuation, presence of the cal luteum cysts which are induced by high levels of hCG in the ovaries.

The diagnosis of malignant trophoblastic disease not only includes those molar pregnancies that have a rising hCG, but they account for about 50-60% of our patients that are going to require chemotherapy. But also can occur after spontaneous miscarriage, after therapeutic abortion, after ectopic pregnancy, or even after a term therapy of a live fetus. This group all together, who would be a group of women that you wouldn’t necessarily have a high index of suspicion might have gestational trophoblastic disease makes up nearly 50% of those who will ultimately have trophoblastic disease requiring chemotherapy. The index of suspicion therefore has to be fairly high, so women after an ectopic pregnancy or term pregnancy, or even miscarriage, that continue to bleed ought to be considered as having the possibility of having gestational trophoblastic disease.

The group of patients needing chemotherapy first would be those that have any histology, whether it’s at the time of initial D&C or hysterectomy, that have evidence of an invasive mole, choriocarcinoma or placental site trophoblastic tumors.

The initial evaluation obviously includes the complete history and physical and looking at liver functions. In searching for metastatic sites, the most common metastatic site is lung. Chest x-ray or chest CAT scan fits into the staging studies. Pelvic examination; vaginal metastases occur in about 30% of patients that have metastatic disease. Intraperitoneal disease in the abdomen or pelvis, about 20%, and liver and brain about 10% of patients that have metastatic disease will have it in their liver or brain. One could argue that to be cost effective you get a chest x-ray and if that’s negative and if the patient has no neurologic symptoms and has normal liver function.

The optimal treatment is really determined by the initial staging. There are three staging systems that are out there. One by the International Federation of Gynecologists and Obstetricians, which is an anatomic staging system. A clinical classification that came out of the NIH back in the 1960s, and the World Health Organization criteria. Those risk factors being a very high pre-therapy serum hCG or duration of the disease greater than six months.

Those after staging studies that are non-metastatic and then those that are metastatic. And the metastatic disease patients are divided into a good prognosis and a poor prognosis group, based on the criteria listed here. The good prognosis metastatic disease patients are those who do have metastases but have a short duration since their initial pregnancy or initial symptoms, have an hCG level less than 40,000 in the serum, no metastasis to brain or liver - if they have brain or liver metastasis they become poor prognosis - no antecedent term pregnancy- that portends a worse prognosis - and those patients with no prior chemotherapy. So if they fit into this group they are considered a good prognosis group of patients, and if they don’t fit into that group.

For patients that are found to have low risk on the WHO scale or who have no metastatic disease, or low risk metastatic disease patients, there are a variety of regimens that have been looked at over the years. Most of them are based either on the use of methotrexate up front or dactinomycin up front. The one that’s probably been studied the most extensively is the five day regimen of methotrexate. Methotrexate with folinic acid was popularized by the New England group. The Gynecologic Oncology group has investigated this regimen, giving methotrexate on a weekly basis, 30 mg per meter squared and in fact I think most of us consider that the standard of care for patients who have no evidence of metastatic disease, for initial therapy. One could use dactinomycin either on a five day cycle or a bolus every two week cycle, and etoposide.

The clinical staging. These would be patients with low risk metastases or a WHO score of less than 7. The treatment again is the same with single agent methotrexate or dactinomycin. We would treat these patients with two cycles of therapy after achieving hCG level remission or negative hCG and do very well with this group of patients. The high risk group of patients are those that have poor prognostic factors, such as liver and brain mets or a WHO score of greater than 7. The treatment in this group, I think It is very important that these patients get multi-agent chemotherapy from the outset. To start any of these patients that fit into this high risk category with single-agent chemotherapy, methotrexate or dactinomycin, would be malpractice and would compromise that patient’s chance of being cured.

The high- risk patient that needs multi-agent therapy can be treated with a number of different regimens. The standard of care today for up front therapy is EMA-CO. Other alternatives though, long standing over the years, have used methotrexate, dactinomycin, DMAC regimen. The GOG compared that to Bagshaw’s regimen in a randomized trial and I think the therapeutic ratio came closer to the methotrexate, actinomycin D and cyclophosphamide regimen if you were trying to compare these two regimens. But you can see the remission rates here and this is again the high risk, poor prognosis group of patients. The EMA-CO regimen is in the syllabus. It combines the use of etoposide, methotrexate, actinomycin D on the first two days of therapy. And then on day eight, a combination of vincristine and cyclophosphamide.