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Gestational trophoblastic disease
1. What every clinician should know Are you sure your patient has disease? What should you expect to find?
Gestational trophoblastic disease (GTD) comprises a spectrum of diseases of placental origin that affect women primarily of reproductive age. GTD includes abnormal products of conception with malignant potential (partial and complete hydatidiform moles) as well as malignant gestational trophoblastic neoplasia (GTN).
GTN includes a variety of neoplasms including invasive moles, gestational choriocarcinomas, and more rarely, placental site trophoblastic tumors or epithelioid trophoblastic tumors. Most of these conditions are associated with an active or identifiable antecedent pregnancy event and secrete abnormal levels of human chorionic gonadotropin (hCG).
Hydatidiform moles are identified in approximately 1:1000 pregnancies while gestational choriocarcinoma complicates 1:20,000-40,000 pregnancies in the United States. Approximately 1500 women are treated annually in the US for GTN.
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The epidemiology of GTD is poorly defined. This is partially caused by studies that combined patients with molar gestations and postmolar GTN with patients who had nonmolar GTN, predominantly gestational choriocarcinoma, in case-control studies.
Many of the older studies used hospital-based cohorts rather than population-based cohorts of patients for reporting case-controlled studies, which probably inflated the incidence of molar pregnancies and GTN because of referral bias.
Hydatidiform mole
Patients with hydatidiform moles are usually treated by evacuation of the pregnancy using dilatation and evacuation of the uterus (D&E) and are followed with serial quantitative serum hCG values until hCG levels normalize. Assays with threshold values of at least less than 5 IU/L are used for monitoring.
Patients are usually monitored after normal values are obtained before an attempt at another pregnancy is encouraged. If hCG values do not fall appropriately during surveillance, they are diagnosed as having postmolar GTN solely on the basis of the hCG level information.
A complete mole is a result of fertilization of an empty ovum by a single sperm that duplicates or simultaneous fertilization with two sperms, resulting in a 46XX or 46XY karyotype with all chromosomal material derived from paternal genome.
A partial mole arises from fertilization of a haploid ovum by two sperm or duplication of a single sperm, most often resulting in a complete triploid karyotype (69XXX; 69XXY; 69 XYY). In partial moles, one third of the chromosomal complement is maternal, while 2/3 is paternally derived.
Prior mole increases the risk of hydatidiform moles in subsequent pregnancies and is the strongest risk factor. Patients with a prior mole have a 1-2% risk of a second mole, with the risk rising to 10% after a second, and 30% after a third mole. Some families have increased risk of moles in pregnancies.
The incidence of moles is increased in women under 18 and increases progressively with advancing of age greater than 35 years. Increasing paternal age is also associated with a slight increased risk for moles. While ethnicity has been emphasized in the past, dietary factors, including animal fat intake and reduced amounts of beta carotene, may account for this difference.
Prior pregnancy loss, type A maternal ABO blood type, and exposure to environmental toxins have weaker associations with increased risk of molar pregnancy.
Gestational trophoblastic neoplasia
Women with postmolar GTN are most often identified through hCG surveillance and can usually be cured with relatively simple chemotherapy regimens. Patients with nonmolar GTN may present many months after a pregnancy with symptoms of vaginal bleeding from uterine tumors or symptoms from distant metastases. The majority of patients with postmolar GTN have invasive mole, while nonmolar GTN comprises predominantly gestational choriocarcinoma.
Unlike patients with other solid tumors, the majority of patients with advanced stage GTN can be cured with aggressive treatment. Most patients treated for GTN can preserve fertility. Any woman of reproductive age who presents with metastatic malignancy from an unknown primary site, CNS hemorrhages, or pulmonary lesions should be screened with a serum hCG; a significant elevation of hCG would raise suspicion of GTN.
Complete hydatidiform moles are the highest risk factor for choriocarcinoma. Up to 3-9% of patients with complete moles will have choriocarcinoma, with a much lower risk following partial moles. Increasing maternal age also correlates with an increased risk of choriocarcinoma and GTN after a mole. Other factors have much weaker associations with the development of choriocarcinoma.
2. Diagnosis and differential diagnosis
Hydatidiform mole
Patients with hydatidiform moles are usually identified during evaluation of a diagnosed pregnancy. Patients with partial moles present with a positive pregnancy test and usually have a "missed spontaneous abortion" identified by an ultrasound that is obtained because of a uterus that is smaller than expected for gestational age or hCG values that are lower than expected for gestational age.
Patients with complete moles may present with a similar clinical scenario, but many will present with vaginal bleeding, uterus enlarged greater than expected dates, hCG higher than expected for gestational age, and will have an ultrasound demonstrating an absent fetus and a heterogeneous mass of fluid-filled vesicles filling the uterus ( Figure 1).
Histology from suction D&E will confirm the diagnosis. Histologically, complete moles will have edematous chorionic villi with marked trophoblastic proliferation and no evidence of a fetus. Partial moles will have a variable amount of villous edema and trophoblastic proliferation. There is usually at least histologic evidence of a fetus, at least in the form of blood vessels in the villi that contain fetal red blood cells.
Very rarely, patients with a normal twin fetus and a mole will be identified by ultrasound. These pregnancies require rigorous evaluation and management by a team of specialists experienced in ultrasound, high-risk maternal/fetal medicine and management of GTD.
Gestational Trophoblastic Neoplasia
Postmolar GTN
After molar pregnancy evacuation and histologic identification as a partial or complete mole, patients are followed with serial weekly serum quantitative beta hCG assays. Approximately 2.5-5% of patients with partial and approximately 20% of patients with complete moles will be identified as having postmolar GTN.
Pre-evacuation hCG greater than 100,000 IU/L, theca lutein cysts, uterine enlargement greater than 2-14 weeks' gestational size, or medical complications (hyperthyroidism, pregnancy-induced hypertension, or respiratory compromise after evacuation) associated with hydatidiform mole increase the risk of postmolar GTN.
Usually, the diagnosis is made by hCG value rise, plateau, or persistence more than 6 months after evacuation. The presence of identifiable metastases or histological diagnosis of gestational choriocarcinoma in uterine curettings also define postmolar GTN. Because most patients are diagnosed on the basis of serum hCG values and treated without hysterectomy, a precise histologic diagnosis is usually lacking.
Based on studies before chemotherapy, approximately one third of postmolar GTN was gestational choriocarcinoma, with the remaining two thirds of cases having invasive or proliferative moles. Postmolar GTN constitutes approximately 50-65% of all cases treated for GTN.
Although practitioners may use other criteria for initiating treatment in individual patients, current FIGO criteria for the diagnosis of postmolar GTN include:
A significant (>10%) rise in serum hCG values sustained over 2 weeks' duration, confirmed by three values obtained at weekly intervals (x, x + 7 days, x + 14 days).
A sustained plateau (<10% drop) in serum hCG values obtained over 3 weeks' duration, confirmed by four values obtained at weekly intervals (x, x + 7 days, x + 14 days, x + 21 days).
Persistent hCG for more than 6 months after molar evacuation.
Presence of metastatic disease on physical examination or radiographic evaluation.
Histological diagnosis of choriocarcinoma, placental site trophoblastic tumor, or epithelioid trophoblastic tumor.
Using hCG criteria that requires a sustained rise or plateau avoids treating patients who may have a transient hCG rise but go on to enter spontaneous remission,
Nonmolar GTN
Gestational choriocarcinoma, placental site trophoblastic tumors (PSTT), and epithelioid trophoblastic tumors (ETT) will sometimes be diagnosed in patients on the basis of histology from uterine curettings, hysterectomy, or biopsy of metastatic lesions.
Gestational choriocarcinomas are composed of a dimorphic cell population of anaplastic multinucleate syncytotrophoblasts and cytotrophoblast cells with no identifiable villi. Metastases of choriocarcinoma are often highly vascular, with a tendency for hemorrhage with biopsy. Therefore, a presumptive diagnosis of gestational choriocarcinoma is often made when there is metastatic disease of unidentified primary site associated with high levels of serum hCG in a woman of reproductive age.
Intermediate trophoblast cells in PSTT and ETT usually secrete low levels of hCG detectable by conventional assays. Thus, these two forms of GTN are usually diagnosed by histology.
While 50-65% of gestational choriocarcinoma follow a mole, the remainder are roughly equally divided among cases that follow a normal pregnancy and those diagnosed after a spontaneous miscarriage, ectopic pregnancy, or other nonmolar pregnancy event. Gestational choriocarcinoma accounts for approximately 98-99% of nonmolar GTN.
Hematogenously disseminated metastases and rapid doubling times are hallmarks of choriocarcinoma. Gestational choriocarcinoma is usually extremely sensitive to chemotherapy, including single-agent methotrexate and actinomycin-D.
PSTT may follow any type of pregnancy. In addition to differences in amount of hCG production, these tumors are less aggressive than choriocarcinoma. Local invasion of the uterus is the most common stage at diagnosis, and lymphatic metastases are more frequently encountered than in choriocarcinoma. In contrast to choriocarcinoma, placental site trophoblastic tumors are usually resistant to single-agent methotrexate and actinomycin-D.
ETT are the least common form of GTN. Although they are often confined to the uterus, these tumors may metastasize widely and are often resistant to chemotherapy.
3. Management
A. What therapies should you initiate immediately (ie, emergently)?
Hydatidiform mole
Patients with a suspected hydatidiform mole should undergo pelvic ultrasound, which may provide the radiographic definitive diagnosis and will provide an estimate of the volume of the uterine contents ( Figure 1).
If typical findings of a uterus filled with a mass of vesicular structures are seen, the patient should be prepared for a uterine suction D&E or, in rare patients who desire sterilization, hysterectomy.
Baseline laboratory evaluation should include:
Serum hCG for baseline
Complete blood count
Electrolyte and renal functions
Thyroid function tests, especially if the hCG is more than 100,000
High elevations of hCG may result in secondary hyperthyroidism because of homology between the alpha subunit of hCG and thyroid stimulating hormone. Physical manifestations of hyperthyroidism should be treated prior to surgery. Beta blockers, such as metoprolol, may be required to control tachycardia and hypertension associated with secondary hyperthyroidism.
If the uterus is less than 8 weeks' gestational size, D&E may be performed in an ambulatory surgical center, but patients with larger uterine size should undergo evacuation in an operating room with facilities for exploratory laparotomy if uterine perforation or severe hemorrhage occurs during evacuation.
Uterine enlargement greater than 12-14 weeks: size increases the risk for postoperative respiratory distress or trophoblastic embolization; baseline oxygen saturation or arterial blood gas measurements in these patients are advisable. Blood type and screening should be performed on all patients, and RhoGAM should be administered following evacuation if Rho negative.
A post-evacuation chest X-ray should be performed within 48 hours to screen for trophoblastic embolization that can lead to metastatic disease.
Patients are followed with serial quantitative serum hCG assays every 1-2 weeks after evacuation to diagnose postmolar GTN. When hCG values normalize after molar evacuation, continued monthly surveillance is usually recommended for at least 6 months, although the incidence of postmolar GTN drops to under 0.4% when two or more normal hCG values have been recorded.
Gestational trophoblastic neoplasia
Patients with GTN should undergo staging with risk assessment and stabilization for chemotherapy. Secondary hyperthyroidism, if present, should be treated. Chemotherapy should be administered as soon as possible because of the potential for rapid progression of choriocarcinoma.
Rare patients with high-risk disease and large tumor burden will require ventilatory and intensive care support at presentation; it is critical that support be given during the initial phases of treatment, even if widely metastatic disease is present, because of the relatively good survival rates (eg, 75% for patients with brain metastases) in patients who can receive adequate therapy.
Patients diagnosed with GTN should undergo physical examination and radiographic evaluation to establish stage and also undergo a risk factor assessment to establish a risk score that will be used to determine the intensity of initial treatment.
Studies for staging should include:
Chest x-ray
Pelvic examination and ultrasound
Computed tomography (CT) of chest, abdomen and pelvis
Magnetic resonance imaging (MRI) or contrasted CT scans of the brain
A baseline (pretherapy) hCG is important for assigning risk score.
Complete blood count, renal functions, electrolyte panel, and liver function tests are important for monitoring during chemotherapy. As in hydatidiform moles, patients with high hCG values should have thyroid function tests evaluated.
Staging of GTN
Staging is based on anatomic sites of disease involvement. The lungs are the most frequent site of metastases from GTN. Table I states the anatomic staging of GTN by the International Federation of Gynecology and Obstetrics (FIGO).
Table I.
|Stage I: Strictly confined to the uterine corpus
|Stage II: Extending to the adnexa or to the vagina, but limited to genital structures
|Stage III: Extending to the lungs with or without genital tract involvement
|Stage IV: All other metastatic sites
It has long been recognized that clinical factors other than anatomic stage influence outcome, especially in patients with stage III disease (lung metastases). In 2000, FIGO accepted the recommendation that a modification of the World Health Organization (WHO) risk score be used to triage patients into low-risk and high-risk groups ( Table II).
Table II.
|Age (years)
|Antecedent pregnancy
|Term pregnancy
|Interval from index pregnancy(mo)
|Pretreatment hCG (IU/L)
|1000 – 10,000
|≥10,000 -100,000
|Largest tumor sizeincluding uterus (cm)
|Site of metastases
|Number of metastases identified
|Previous failed chemotherapy drugs
|Single drug
|2 or more
Factors incorporated into the risk score include age, antecedent pregnancy, interval from antecedent pregnancy, pre-therapy hCG level, largest tumor size (including intrauterine tumor), site of metastatic involvement, number of metastases, and prior therapy.
Each factor is given an individual factor score ranging from 0 to 4.
The sum of the individual factor scores is the total risk score; patients with a risk factor score of 6 and under are low risk, while those with risk-factor score of 7 and higher are high risk.
Pulmonary lesions detected only by CT scan do not affect outcome and are not used to count number of metastases.
Both the patient's stage and risk score should be recorded.
Clinical studies have shown excellent correlation between survival and FIGO risk score. In general, patients in the low-risk group (risk score <7) have an excellent prognosis, approaching 100% survival when treated initially with single-agent chemotherapy.
Patients in the high-risk group (risk score ≥7) have a much worse outcome when treated initially with single-agent regimens, but have an excellent outcome (overall survival > 80-90%) when treated with multiagent chemotherapy and multimodality therapy at centers that have experience treating GTN.
B. What should the initial definitive therapy for the cancer be?
Hydatidiform mole
Molar evacuation
Evacuation is the initial step in management of a molar pregnancy. In almost all patients, uterine D&E is used. The cervix should be dilated and a 9-2mm suction cannula is used to remove the uterine contents if a complete mole is present.
Pitocin intravenous infusion at 20U/L is begun after cervical dilatation to prevent uterine contractions against an undilated cervix. Gentle sharp curettage is usually performed after suction curettage to ensure complete evacuation. Intraoperative ultrasound can be useful to ensure complete evacuation in patients with an enlarged uterus.
Sharp curettage must be performed with caution, however, because of the risk of uterine perforation in moles, and the rare potential to form intrauterine senechiae that can lead to amenorrhea and infertility (Asherman's syndrome).
Ergotamines may be given following suction D&E to promote uterine involution.
Patients should be followed with weekly serum quantitative hCG assays to ensure complete regression of the mole. Postmolar GTN will be diagnosed in approximately 20% of patients after D&E, as described above.
Some patients may wish concurrent evacuation and sterilization. Women over 35 years of age are at an increased risk for postmolar GTN. If the patient is clinically stable, abdominal or laparoscopic hysterectomy is an acceptable choice for evacuation in these women.
Normal ovaries can be retained because adnexal metastases are rare. The risk of postmolar GTN is reduced from approximately 20% after D&E to less than 5% after hysterectomy, at the expense of a major operative procedure. Because of the risk of postmolar GTN, hCG monitoring is still indicated after hysterectomy.
Other methods of uterine evacuation of moles, such as abdominal hysterotomy, sharp curettage, and prostaglandin induction of labor are not recommended because of an increased operative risk of these procedures and increased risk for postmolar GTN when compared with suction D&E.
Prophylactic chemotherapy after evacuation
Two randomized studies have shown that a single course of methotrexate with leucovorin rescue or actinomycin D will significantly reduce the risk of postmolar GTN in patients with high-risk moles from 50% to less than 15%, with very little toxicity.
The already low incidence of postmolar GTN in patients with low-risk moles, however, was not affected. Patients who developed GTN after treatment with methotrexate appeared to have an increased risk for methotrexate resistance, although this was not suggested in the trial that used actinomycin D as the treatment arm.
This treatment strategy is rarely used in the US. Overall, high-risk moles account for only half to two thirds of patients treated for postmolar GTN. Omitting prophylactic chemotherapy avoids unnecessary exposure to chemotherapy for many patients with high-risk moles. Furthermore, patients with postmolar GTN have an excellent outcome when they are treated at the time of rising hCG.
Prophylactic chemotherapy is usually reserved for patients with high-risk moles who are predicted to be noncompliant with hCG surveillance, but given the risk of post-treatment GTN, hCG follow-up is still recommended after prophylactic chemotherapy.
Gestational trophoblastic neoplasia
Low-risk GTN
Patients with nonmetastatic and metastatic GTN who have FIGO risk scores of 6 or lower have an excellent outcome when initially treated with single-agent regimens, usually consisting of actinomycin D or methotrexate.
The majority of these patients have postmolar GTN diagnosed on the basis of hCG criteria, and many do not have gestational choriocarcinoma. In most series, survival approaches 100%. Over 85-90% retain fertility, and less than 5-10% of patients require combination therapy.
Patients are monitored during therapy with weekly hCG levels and at least biweekly CBC, renal functions and electrolytes, and liver function tests.
Treatment is continued as long as hCG levels are declining more than 10% each 14-day cycle. Resistance is usually defined as a rise in hCG of more than 10% that is sustained over 14 days, a plateau of approximately 10% sustained over 21 days, or the appearance of new metastases.
Patients who fail a single-agent regimen are re-assessed with FIGO risk score, and if they remain in the low-risk group are treated with an alternative drug regimen; patients with a high-risk score are treated with a multiagent regimen as if they have high-risk GTN. Usually one to two cycles of chemotherapy are given after normalization of hCG, with recurrence rates less than 5% after primary treatment for low-risk GTN.
Chemotherapy for low-risk GTN
Many single-agent regimens have been used to treat patients with low-risk GTN. Because of the relative rarity of GTN, only a few phase II and few randomized phase III chemotherapy trials have been reported in this group of patients to date.
While etoposide and 5-fluorouracil regimens have been used in Southeast Asia and China, the majority of studies in the US and other international centers have evaluated methotrexate (MTX) and actinomycin D (ACT) regimens. The results of the most frequently used regimens are summarized and discussed in Table III.
Table III.
|Complete response rate range
|MTX 30-50mg/m2 IMrecycled every 7 days
|70-80% Nonmetastatic GTN48-80% Mixed low-risk GTN
|MTX 0.4mg/kg IM X 5 days recycled every 14 days
|90-94% Nonmetastatic GTN60-90% Mixed low-risk GTN
|MTX 1mg/kg days 1, 3, 5, 7Leucovorin factor 0.1mg/kg days 2, 4, 6, 8 recycled every 14 days
|70-75% Nonmetastatic GTN60-70% Mixed low-risk GTN
|ACT 1.25mg/m2 IV bolusrecycled every 14 days
|70-93% Mixed low risk
|ACT 300mcg/m2 IV X 5 daysrecycled every 14 days
|85-90% Mixed low risk
In the early 1990s, many centers in the US adopted weekly MTX as their standard regimen for low-risk GTN. Subsequently, biweekly ACT was shown to have higher complete response rates, but also substantially higher gastrointestinal toxicity in phase III trials. However, use of hysterectomy and multiagent therapy was equivalent after initial therapy with either agent.
To date, no randomized trials have compared other multidose MTX or ACT regimens with the biweekly ACT pulse regimen.
Salvage regimens for patients failing primary therapy have been poorly detailed, with most investigators reporting a change to the alternative single agent, without detailing regimens, toxicity, or response rates. A prospective Gynecologic Oncology Group trial documented a 70% CR among patients treated with biweekly ACT who had failed MTX as their primary treatment of low-risk GTN.
Some patients who are treated initially with biweekly ACT or weekly MTX can be salvaged with multidose regimens of the same agent. Because of the concern for future fertility and chronic toxicity in patients who have a good chance for cure, it is reasonable to consider this strategy in selected patients who have a low FIGO risk score after failure of both of the single-dose ACT and MTX regimens.
Surgery in low-risk GTN
Because of the high success rate for primary chemotherapy in treating low-risk GTN, and dismal results using surgery alone even in the treatment of nonmetastatic GTN before effective chemotherapy was developed, surgical procedures are rarely used in the management of these patients.
The use of a second D&E to induce remission has mixed results in the literature, with complications leading to hysterectomy in up to 8% of patients. In the US, a second D&E is usually used only in patients who have low-risk GTN with symptomatic uterine bleeding and who need to be stabilized before or during chemotherapy.
Hysterectomy ( Figure 2) is most often used as a salvage procedure after failed primary or secondary chemotherapy. However, several studies have demonstrated that primary hysterectomy reduces the amount of chemotherapy required to treat patients with low-risk nonmetastatic and selected patients with low-risk metastatic GTN. Both abdominal and laparoscopic hysterectomy have been used with no significant increase in complications when they are performed during chemotherapy for GTN.
Because of the high recurrence rates reported for women with nonmetastatic GTN treated by hysterectomy alone in the pre-chemotherapy era, single-agent chemotherapy should be given to all patients undergoing hysterectomy during treatment for GTN.
High-risk GTN
Multiagent chemotherapy is indicated as the primary modality for treatment of patients with high-risk GTN. While long-term remission rates of more than 80% are cited, it should be recognized that these reflect the experience of centers specializing in the treatment of GTN.
Several studies have reported worse survival for patients with high-risk disease who receive initial treatment outside of specialized centers; therefore, it is important to consult with a physician experienced in the management of this relatively rare malignancy during treatment.
Patients with high-risk GTN will more often have a prior nonmolar pregnancy and are more likely to have a histologic diagnosis of choriocarcinoma than low-risk patients. They often have a larger tumor burden, with higher initial hCG levels and often have metastases to high-risk anatomic sites. These metastases put the patient at risk for bleeding complications from metastases to the lungs, liver, or brain.
Mortality from high-risk GTN follows a biphasic pattern, with early deaths in the first 2 to 3 weeks of treatment caused by acute complications related to tumor distribution and late deaths related to chemoresistant disease. Multimodality therapy is often required to successfully treat these patients.
It is critical to evaluate patients early in the course of treatment for potential complications from metastatic involvement and provide supportive care during the early phase of therapy.
First-line chemotherapy for high-risk GTN
In the early GTN chemotherapy experience, patients with high-risk factors rarely had complete responses to single-agent MTX or ACT regimens. Combination chemotherapy with MTX, ACT, and either chlorambucil or cytoxan (MAC) was initially developed in the 1960s as a salvage regimen for patients who failed single-agent therapy, but it was recognized that patients with high-risk disease who were initially treated with MAC had a much higher complete response rate than patients who received MAC as second- or third-line therapy.
MAC regimen for GTN
MTX 15mg daily (days 1-5) fixed dose, IM, X 5 days
ACT 8-10mcg/kg IV X 5 days
Chlorambucil 8-10mg PO or cyclophosphamide 3mg/kg IV X 5 days
Repeat cycles every 14-21 days
Variations of the MAC regimen were used throughout the 1980s but have largely been replaced by the alternating weekly etoposide-MTX-ACT/cyclophosphamide-vincristine (EMA/CO) regimen as the initial treatment for high-risk GTN.
Although randomized trials have not compared the two regimens, it appears that EMA/CO has less acute toxicity than MAC regimens and has a higher response rate among patients with very high-risk scores. Some clinicians still use MAC regimens for patients with relatively low-risk scores (<9-10) to avoid the leukemogenic potential of etoposide.
EMA/CO regimen for high-risk GTN
Day 1 – ACT 500mcg IV bolus, etoposide 100mg/m 2 IV, MTX 100mg/m 2 IV bolus and 200mg/m 2 12-h IV infusion
Day 2 – ACT 500mcg IV bolus, etoposide 100mg/m 2 IV, leucovorin factor 15mg PO or IV q 6 hours X 4 doses
Day 8 – Vincristine 0.8-1mg/m 2 IV bolus (max 2mg), cyclophosphamide 600mg/m 2 IV
Repeat cycle at day 15.
Patients with brain metastases should be evaluated for craniotomy with resection of isolated metastases or radiation to control hemorrhage from multiple metastases early in the course of treatment ( Figure 3). Likewise, patients with hepatic metastases ( Figure 4) may benefit from tumor embolization, hepatic radiation or surgical resection early in treatment.
In medically unstable patients or those who have extensive metastatic burden and hCG levels of over 500,000 IU/L, an initial treatment with MTX infusion/leucovorin rescue or etoposide 100mg/m2 +/- cisplatin 50-75mg/m 2 is sometimes given to avoid catastrophic hemorrhage from high-risk sites of metastases, with EMA/CO initiated as soon as possible.
Patients are monitored with hCG values every week and with appropriate monitoring of CBC, renal functions, electrolytes and liver function tests. It is not uncommon to observe a rise in hCG approximately 7 days after the initial treatment, but usually, the hCG will begin to respond by day 14 of the first cycle of EMA/CO.
If a patient has responded to EMA/CO and is tolerating treatment well, therapy can be administered as an overnight hospitalization for days 1 and 2 of EMA, with outpatient infusion of the CO portion of treatment.
Repeated radiologic imaging is used only for clinical indications or after remission is established, as a baseline. hCG is usually an extremely sensitive tumor marker for this disease. It has been estimated that threshold hCG levels detect a tumor burden of more than 10,000 to 100,000 cells. For this reason additional cycles of chemotherapy should be given after hCG values normalize.
Complete response rates ranging up to 85% have been reported for first-line therapy with EMA/CO in high-risk GTN. Patients with high-risk GTN who receive maintenance chemotherapy have recurrence rates of less than 12.5% compared with 25% among patients if chemotherapy is stopped when hCG normalizes.
It is important to avoid treatment delays because gestational choriocarcinoma can exhibit extremely rapid growth with doubling of serum hCG values within less than 14-day intervals in some cases. Acute grade 4 hematologic toxicity is observed in less than 10% of patients treated with EMA/CO, but patients will often develop low-grade neutropenia or thrombocytopenia during therapy.
Cytokine growth factor support with granulocyte stimulating factor given on non-treatment days may be needed for granulocyte support to allow prompt recycling.
If hematologic toxicity is limiting scheduled retreatment and the patient is responding to EMA/CO, the CO portion of the regimen can often be dropped and the patient treated with EMA cycles. Of note, small series of patients treated primarily with EMA have similar response rates to series of patients treated with EMA/CO, but randomized trials have not been performed.
Others have substituted an etoposide/cisplatin doublet (EMA/EP) for CO and reported similar response rates at the expense of increased grade 4 hematologic toxicity. Because the collective experience is greatest with EMA/CO, most investigators continue to use this as their preferred first-line regimen for high-risk GTN.
Remission is defined as three successive weekly hCG values that are below threshold. As mentioned above, viable trophoblast cells may remain after a normal hCG value. For this reason, maintenance chemotherapy is recommended beyond normal hCG levels. When one to two cycles are given in low-risk GTN, recurrence rates are less than 5%, while recurrence rates drop from 25% to less than 12.5% in high-risk patients who receive at least three maintenance cycles.
Second-line chemotherapy for high-risk GTN
A relatively small series of patients with chemo-refractory GTN previously exposed to EMA/CO have been reported. Many of the reports include patients who underwent hysterectomy or metastectomy during salvage therapy, which reduces the ability to judge the activity of the chemotherapy regimen.
One option is EMA/EP; cisplatin-etoposide is substituted for the cyclophosphamide and vincristine in EMA-CO:
Day 1
ACT: 500mcg IV bolus
Etoposide: 100mg/m2 IV
MTX: 100mg/m 2 IV bolus and 200mg/m2 12-h IV infusion
Day 2
ACT: 500mcg IV bolus
Etoposide: 100mg/m2; IV
Leucovorin factor: 15mg PO or IV q 6 hours X 4 doses
Day 8
Etoposide: 100mg/m2 IV
Cisplatin: 80mg/m2 IV
Repeat cycle at day 15.
Some investigators have eliminated the day-2 etoposide and ACT doses to reduce toxicity, while others have maintained the original EMA schedule. Approximately 95% of patients with persistent low-level plateaus of hCG during EMA/CO therapy will respond to EMA/EP, while responses in patients with rising hCG values are 75-80%, and only 43% among patients who develop recurrence after exposure to EMA/CO.
Modified germ-cell regimens using vincristine-bleomycin-cisplatin (VBP), bleomycin-etoposide-cisplatin (BEP), and ifosfamide-carboplatin-etoposide (ICE) are used most often in patients who have failed EMA/CO and/or EMA/EP.
Cumulative hematologic toxicity often limits treatment to salvage treatment. Partial responses are more frequently reported than complete responses. However, complete responses have been reported in up to 60% of patients with drug-resistant GTN when these regimens were incorporated into salvage therapy.
Anecdotal reports and small case report series have indicated complete responses to single-agent paclitaxel and paclitaxel/platinum regimens in patients with chemorefractory GTN.
Patients with drug-resistant GTN can be extremely difficult to treat because of accrued toxicity and resistance to prior chemotherapeutic agents. In this scenario, each patient must be carefully evaluated to determine whether surgery or radiation therapy will be beneficial.
Surgery and radiation therapy in high-risk GTN
At least a third to a half of patients with high-risk GTN will require multimodality treatment as part of their therapy: to treat complications of disease or treatment and allow initiation or continuation of therapy, as planned prophylaxis of complications, or to treat an isolated focus of disease with hysterectomy or metastectomy.
Primary hysterectomy does not appear to be beneficial in this group of patients. Unlike with low-risk disease, patients in the high-risk group often have a large metastatic tumor burden and primary hysterectomy has a negligible effect on the amount of treatment needed to control disease. Primary metastectomy is usually performed to prevent or treat hemorrhage from metastases and allow stabilization early in the course of treatment.
Patients with brain metastases are at high risk for intracranial hemorrhage and neurological decompensation early in the course of therapy. Options for management include concurrent whole brain radiation to approximately 25-30 Gy delivered during initial chemotherapy or craniotomy for resection if there are one or two surgically accessible metastases involving non-critical structures.
In patients with isolated lesions involving critical central nervous system structures, intensity-modulated or cyberknife radiation to the individual lesions may be employed.
Patients undergoing whole brain radiation should be treated with lower doses of MTX, because of the risk of long-term neurological complications from concurrent radiation and chemotherapy, while those undergoing excision or focal radiation to isolated lesions should be treated with MTX at doses of greater than 500mg/m 2/course with prolonged leucovorin rescue as part of their EMA/CO regimen. This results in therapeutic methotrexate levels in the cerebrospinal fluid and theoretically reduces the risk of central nervous system failure. Overall survival for patients presenting with brain metastasis is approximately 75% using either approach.
Liver metastases are the highest risk site of metastatic GTN, with overall survival rates of only 25% to less than 50%. Surgical resection is rarely used as a primary procedure because multiple liver lesions are usually present at presentation.
Selective embolization of liver metastases or irradiation of the liver to 20 Gy may be used to prevent or treat acute hemorrhagic complications of liver lesions. Whole liver radiation at this level does not substantially increase the risk of chemotherapy toxicity. Retrospective analyses of case series suggest that chemotherapy using etoposide-based regimens is superior to MAC chemotherapy when treating patients with liver metastases.
Splenectomy, pulmonary wedge resection, segmental bowel resection and nephrectomy have been used to treat hemorrhage from metastases in individual patients during the treatment of patients with metastases to these sites.
Radiation to vaginal or unilateral renal metastases may be also be used. It should be emphasized, however, that chemotherapy is the mainstay for treatment of patients with high-risk GTN and uncomplicated lesions at these sites will usually respond readily to chemotherapy without surgery or radiation.
Planned hysterectomy or metastectomy may be useful in highly selected patients with drug-resistant disease.
Patients who have limited disease burden at other sites, relatively low (<1000 IU/L) hCG, and options for effective chemotherapy regimens after surgery are the best candidates, which may remove focal drug-resistant clones of tumor, or remove tumor at sites that are relatively inaccessible for therapeutic doses of chemotherapy because of fibrosis and poor vascularity.
Surgical extirpation is usually performed during chemotherapy, and chemotherapy is usually continued after surgery.
Radiographic evidence of pulmonary metastases often persists for months or years after successful treatment of metastatic GTN. Because hCG is usually such a sensitive tumor marker for this disease, elective pulmonary resection of persistent pulmonary lesions is not recommended in a patient who is in remission with normal serum hCG values.
Placental site trophoblastic tumor (PSTT)
PSTT is a rare form of GTN with distinct histologic features, hormone secretion profile, and clinical characteristics when compared with choriocarcinoma. These tumors are composed of neoplastic intermediate trophoblastic cells. Usually low levels of intact hCG are secreted in comparison to tumor burden. In contrast to choriocarcinoma, PSTT is not usually responsive to single-agent MTX or ACT or the multiagent MAC chemotherapy regimens. The majority of patients present with disease localized to the uterus.
Retrospective case series suggest that hysterectomy should be incorporated into the primary treatment of PSTT, with survival rates of 90% in stage I disease, dropping to approximately 50% for stages II-IV.
Increasing interval from prior pregnancy greater than4 years appears to be a poor prognostic feature. EMA/CO and EMA/EP are the most active chemotherapy regimens for this disease, while BEP has produced anecdotal responses in chemorefractory disease.
Epithelioid trophoblastic tumor (ETT)
ETT are even more rare than PSTT. These tumors are also derived from intermediate trophoblast cells. Approximately one third have hydatidiform mole as the antecedent pregnancy, and intervals from prior pregnancy event to diagnosis are often longer than observed in PSTT or choriocarcinoma.
Serum hCG levels are elevated in the majority of patients, but usually at much lower levels than in choriocarcinoma, and are a poor marker for low-volume disease.
Hysterectomy is the mainstay for treatment of localized disease. Metastectomy should be considered in cases with isolated metastases, because chemotherapy has been reported only anecdotally, with conflicting results using EMA/CO-type regimens for treating disseminated disease.
4. Complications
A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?
Hydatidiform mole
Patients often present with anemia from vaginal bleeding. Rare moles present with overt hemorrhage; prompt evacuation with suction D&E is indicated if an ultrasound has typical features of complete mole.
Extremely high elevations of hCG usually correlate with increased volume of molar tissue. Because of homologies between the alpha subunit of hCG and other trophic hormones, secondary hyperthyroidism may complicate a mole, and thyroid hormone levels should be assayed if hCG is greater than 100,000 IU/L. Beta blockers, such as metoprolol, should be used to stabilize patients who are clinically hyperthyroid for molar evacuation. The hyperthyroidism will regress after evacuation of the mole.
Respiratory distress can occur after molar evacuation, usually in association with a large volume of molar tissue and uterine enlargement greater than 12-14 weeks' gestational size. This can be caused by high-output cardiac failure from anemia, pulmonary edema from aggressive intravenous crystalloids, idiopathic acute respiratory distress syndrome (ARDS), trophoblastic deportation, or pulmonary embolism.
Patients at risk should be monitored with oxygen saturation levels and may require intubation for ventilatory support while the underlying case is treated.
Patients with high-risk GTN are at risk for deaths related to hemorrhage from metastatic sites or tumor volume early in their course of treatment. Full radiographic evaluation is recommended to identify sites of high-risk metastatic disease (brain, liver, spleen, kidneys) before beginning therapy.
Vaginal metastases are highly vascular. Biopsy can produce life-threatening hemorrhage. These lesions will regress during chemotherapy. Rarely, selective embolization or radiation is required to control vaginal lesions of GTN.
Pulmonary metastatic disease ( Figure 5) can produce respiratory failure. Intubation for ventilatory support should be used if needed because of the relatively good prognosis for patients with GTN compared with other patients with disseminated solid tumors.
Brain metastases ( Figure 3) are at risk for producing elevated intracranial pressure from cerebral edema and acute neurological decompensation from hemorrhage into the metastases. Dexamethasone should be used to treat cerebral edema during brain irradiation, and neurosurgical consultation should be obtained early in the course of treatment for craniotomy and resection or decompression in the event of acute deterioration.
Hemorrhage from hepatic metastases is frequently encountered. Angiography with selective embolization can stabilize patients during the early phase of treatment (Figure 4).
Rare patients develop arteriovenous malformations in the uterus at the site of myometrial invasion after successful treatment for GTN. Most often they present with progressively worsening menometrorrhagia. Selective embolization can usually treat these lesions with preservation of fertility, but occasionally hysterectomy is required.
B. What complications could arise as a consequence of the management – Chemo, radiation and surgical?
Hydatidiform mole
Intraoperative use of ultrasound can be useful to ensure complete uterine evacuation at D&E and to prevent uterine perforation.
Patients with an extreme tumor burden or metastases at high-risk sites are at risk for developing massive hemorrhage following initial multiagent chemotherapy. Often an initial treatment with MTX 300mg/m 2, followed by folinic rescue, or a cisplatin/etoposide doublet are used to stabilize these patients.
Concurrent moderate-dose MTX (300mg/m 2) with whole brain radiation therapy increases the potential for chronic neurological sequelae of diminished mentation. Isolated brain metastases in noncritical locations can be resected or treated with stereotactic radiation (cyber knife or intensity-modulated techniques) if critical structures are involved. If whole brain radiation is not used, MTX doses greater than 500mg/m 2 should be used with prolonged folinic acid rescue and intrathecal MTX should be considered.
Myelosuppression is the most frequently encountered dose-limiting toxicity for EMA/CO or EMA/EP regimens. Filgrastim support is often required to allow recycling of chemotherapy during these regimens. This can be given on the non-treatment days to allow appropriate recycling of chemotherapy.
Patients who receive etoposide-containing regimens are at risk for developing leukemia. The overall risk is approximately 0.5% for patients treated with EMA/CO, but increases to 2% for patients who receive more than 2g/m 2 total cumulative dose during treatment.
C. What other therapies are helpful for reducing complications?
Evacuation of mole
Laminaria can be used cautiously to initiate cervical dilation, but are not usually needed.
Pitocin intravenous infusion at 20U/L is used to decrease bleeding during D&E and promote uterine involution. It is usually begun after cervical dilatation to prevent uterine contractions against an undilated cervix.
Ergotamines may be given following suction D&E to promote uterine involution.
Intraoperative ultrasound can be useful to ensure complete evacuation in patients with an enlarged uterus.
Many patients with complete mole present with or develop anemia from uterine hemorrhage and may require transfusion support. The possibility of hemorrhage during uterine evacuation should be anticipated, and patients should have at least a type and screen or cross-matched blood and a large-bore IV line during the procedure.
Beta-blockers may be useful in controlling manifestations of hyperthyroidism around uterine evacuation. Very rare patients will develop pregnancy-induced hypertension complicating a mole and may require treatment with intravenous magnesium sulfate to prevent eclampsia. RhoGAM (Rho immunoglobulin) should be administered to Rho-negative patients to prevent sensitization in future pregnancies.
Postoperative respiratory compromise may develop in up to 20% of patients after evacuation of moles with uterine enlargement more than 12-14 weeks' gestational size. Causes include ARDS, pulmonary edema from fluid overload, high-output cardiac failure caused by severe anemia or hyperthyroidism, pulmonary embolism, or trophoblastic embolization. This will occasionally require ventilator support in addition to treatment of the underlying cause.
Effective contraception is encouraged during hCG surveillance after molar evacuation. In the absence of contraindications, oral contraceptives are preferred and do not increase the risk of postmolar GTN.
Low-risk GTN
Uterine bleeding associated with postmolar GTN is frequently observed and usually will respond to chemotherapy. Uterine hemorrhage associated with molar proliferation that produces symptomatic anemia may require a second D&E. Intraoperative ultrasound should be considered to aid in avoiding uterine perforation.
The two most frequently utilized chemotherapy regimens, biweekly ACT or weekly MTX, have very rare high-grade toxicity. Conventional anti-emetics are usually sufficient to prevent emetogenic toxicity from weekly MTX or biweekly ACT pulsed therapy, but occasional patients will require 5-HT3 receptor antagonists, such as ondansetron, to control nausea. Severe myelosuppression is very rarely observed.
Hysterectomy should be considered a component of the primary treatment of low-risk GTN in patients who desire sterilization. Primary or secondary hysterectomy is usually performed immediately after a dose of single-agent chemotherapy, with no significant additional complications.
High-risk GTN
Because of the aggressive, rapidly recycled regimens used to treat high-risk GTN, indwelling central venous access, such as a port or peripheral indwelling central catheter, should be considered.
Urinary alkalinization with intravenous sodium bicarbonate should be used in patients receiving MTX infusions at doses more than 500mg/m 2, and methotrexate levels should be followed to gauge the duration of leucovorin rescue in these patients if there is an elevated creatinine clearance.
Myelosuppression is the most frequently encountered dose-limiting toxicity for EMA/CO or EMA/EP regimens. Filigrastim support is often required to allow recycling of chemotherapy during these regimens. This can be given on the non-treatment days to allow appropriate recycling of chemotherapy.
In most series of patients treated with EMA/CO, platelet level greater than 75,000 is considered adequate for recycling.
Although radiation therapy, hysterectomy, and metastectomy are rarely incorporated into primary therapy of high-risk GTN, they may play a role in stabilization during initial treatment or as part of salvage treatment.
Dexamethasone is used to treat cerebral edema from brain metastases at diagnosis and continued after craniotomy and resection or during whole brain irradiation. Craniotomy may be required acutely for neurological decompression in patients with multiple brain metastases and bleeding into a CNS lesion.
Selective angiographic embolization may be used to control hemorrhage from liver or vaginal metastases.
Because of the favorable survival of patients with even disseminated high-risk GTN, intensive care unit support with ventilatory support during the initial phases of treatment should be aggressively used if indicated.
Patients treated for GTN have increased levels of depression and anxiety, with decreased self-esteem, and may require appropriate counseling support during and after therapy.
5. Prognosis and outcome
A. What would you tell patient and family about the prognosis?
Hydatidiform mole
Patients with hydatidiform mole have an excellent prognosis. Eighty percent of complete moles and more than 95% of partial moles will undergo spontaneous remission after molar evacuation. Patients with postmolar GTN have an excellent chance of cure if they are promptly diagnosed during hCG surveillance.
The risk of postmolar GTN decreases sharply after hCG values normalize, especially if normal hCG values have been recorded for several months. Effective contraception is recommended during hCG surveillance to prevent interference in monitoring by the hCG associated with an intercurrent pregnancy.
Among patients who wish to preserve child-bearing capacity, future pregnancies do not appear to have increased complications, other than a 1-2% risk of a second mole. However, if a patient has a second mole, the risk of a third mole increases to approximately 10%, and the risk of repetitive moles rises thereafter.
The cause of repetitive moles is unknown, with implication of both maternal and paternal factors. However, even after three or four consecutive moles, the chance of a normal pregnancy is greater than the chance of a subsequent mole.
Patients should undergo an early obstetrical ultrasound in subsequent pregnancies to evaluate the placenta for a mole and should be screened with a serum hCG 6 to 8 weeks after delivery to ensure that the hCG normalizes.
Low-risk GTN
Patients with low-risk GTN have long-term cure rates that approach 100%. More than 90% of patients wishing to preserve fertility can achieve remission without undergoing hysterectomy and can avoid multiagent therapy that might result in premature ovarian failure or increase their risk of secondary malignancies.
Patients who are treated with single-agent regimens for GTN have apparent normal fertility rates, and other than the 1-2% increased risk of a second mole, do not have an increased incidence of pregnancy-related complications. Furthermore, there does not appear to be an increase in congenital abnormalities among the offspring of women treated for GTN with single-agent MTX or ACT regimens.
Similar to patients with moles, hCG surveillance is recommended. Effective contraception, usually using oral contraceptives, is recommended to avoid intercurrent pregnancy. Pregnancy can be encouraged after 12 months of normal hCG values. Early obstetrical ultrasound and chest X-ray with uterine shielding are encouraged during subsequent pregnancies. Similar to moles, hCG values should be evaluated after delivery.
High-risk GTN
Patients in the high-risk group have a relatively good prognosis for survival, with overall survival rates exceeding 85-90% and 75% survival rates reported for patients presenting with brain metastases.
Optimal survival is achieved when patients with high-risk GTN are managed by a physician or center with experience treating patients with this disease. Aggressive multiagent regimens and coordination of multimodality treatment may be required. Severe acute toxicity is more likely than among patients with low-risk GTN.
After remission, frequent hCG surveillance with effective contraception is recommended for at least 1 year. The prospects for future fertility may be compromised, compared to patients with low-risk GTN, but successful pregnancies after EMA/CO therapy have been reported.
Patients with GTN who are treated with etoposide-containing regimens have earlier menopause by only a few years compared with those treated with single-agent MTX or ACT.
Exposure to etoposide increases the risk of secondary malignancies compared with patients treated with MTX or ACT or to the general population. During long-term follow-up, increases in leukemia and colorectal cancers were the most frequent second malignancies. Patients treated with EMA/CO have an overall risk of leukemia of approximately 0.5%, but this rises to more than 2% when exposed to more than six cycles of EMA/CO.
Patients should be aware of this increased risk and the need for annual complete blood counts and appropriate colorectal screening after treatment.
B. "What if" scenarios
It should be emphasized that the FIGO risk score and other systems that segregate patients into high- and low-risk groups use the pre-therapy hCG value to assess risk. This refers to the hCG value determined at the time GTN is diagnosed, rather than an hCG obtained at the time of a mole evacuation.
Incomplete radiographic staging
The majority of patients diagnosed with postmolar GTN have relatively low hCG values and have a low risk of metastatic disease if a chest X-ray is normal and the uterus does not contain a large volume of disease on ultrasound.
However, at least 10% of patients with high-risk sites of metastatic GTN are reported to have negative chest X-rays at initial staging. Up to 40% of GTN patients with negative chest X-rays have small pulmonary metastases detected on chest CT scans.
To avoid missing a potentially curable site of high-risk metastasis, it is recommended that patients with nonmolar GTN, and those with molar GTN having hCG levels more than 1000 IU/L, undergo complete radiographic evaluation before initiating therapy.
Use of combination therapy in low-risk GTN refractory to initial chemotherapy
Fewer than 10% of patients with low-risk GTN will need combination chemotherapy. Because of the leukemogenic potential with etoposide-based regimens, it is recommended that patients with low-risk GTN be re-evaluated with a FIGO risk score if they fail the initial single-agent regimen.
If they have a risk score of 6 or lower at re-evaluation, they can be safely treated with an alternative single-agent regimen, with a good chance of success. Furthermore, patients treated with a single-dose MTX or ACT regimen may respond to a multi-dose regimen using the same agent, thus avoiding multiagent chemotherapy or hysterectomy in most of these patients.
Delays in chemotherapy recycling
Because of the potential for rapid growth of gestational choriocarcinoma, initial cycles of chemotherapy should be administered aggressively. If EMA/CO cannot be administered on a 14-day schedule because of hematologic toxicity, filgrastim support or dropping the CO portion of the chemotherapy should be considered.
Maintenance chemotherapy
Maintenance chemotherapy beyond normalization of the hCG value reduces the incidence of recurrent GTN, as noted above. This is especially true in patients with high-risk GTN.
Even if the patient has had significant toxicity from prior therapy, every effort should be made to give one to two cycles of maintenance chemotherapy in low-risk disease and at least three cycles in high-risk disease.
Possible causes of "false positive" elevations of serum hCG levels
Early pregnancy
Patients should use effective contraception during hCG level surveillance after molar evacuation or treatment of GTN, so that hCG from a normal pregnancy does not result in the false diagnosis of GTN and result in inappropriate treatment in a desired pregnancy.
Early pregnancy ultrasound images may be non-diagnostic in spontaneous miscarriages, thus most partial and many complete moles are identified by histology after evacuation.
Twin and other multiple gestations may produce hCG levels that are abnormally high for gestational age; diagnosis of GTD should not depend on hCG value alone.
Placental bleeding can cause transient elevations of serum hCG. Rarely, a retroplacental hematoma complicating an otherwise normal pregnancy can produce both an abnormally elevated hCG and an ultrasound that suggests a twin concurrent molar gestation.
Phantom hCG
The term "phantom hCG" refers to situations when serum assay levels for hCG are falsely elevated in the absence of hCG, usually because of substances that cross-react with the monoclonal antibodies that are used for the capture and/or labeling antibodies in the assay techniques. In most cases, hCG values are relatively low, however, values over 500 have been reported, and are relatively static.
The most frequently documented cause of phantom hCG are heterophile antibodies, such as the human anti-murine antibody, that cross-react with the murine monoclonal antibodies used in currently available hCG assays.
A false-positive hCG value caused by heterophile antibodies will not exhibit an appropriate decrease with serial dilutions of serum, and will often register widely different hCG values when different assays are used.
It will be eliminated when antibodies are "stripped" from the patient's serum and will not produce a positive urine hCG test even when serum hCG levels are elevated above the threshold of the urinary hCG assay because the heterophile antibodies are not secreted in the urine.
The commercial assay most responsible for cases of "phantom hCG" reported in the late 1990s and early 2000s has been removed from the market, and most other commercial assays have been re-formulated to avoid this problem.
Lab errors in patient serum identification or assay contamination may also cause a false positive hCG
Quiescent gestational trophoblastic disease
Rarely patients who are followed after evacuation of a mole or treatment of GTN have persistent low levels of hCG that do not respond to chemotherapy. Also, this can be encountered after a pregnancy that has not been complicated by GTD. The majority of these patients have very low (<27%) to undetectable proportions of hyperglycosylated hCG relative to normal hCG.
Hyperglycosylated hCG is the form of hCG that is elaborated by invasive trophoblast cells. If the hyperglycosylated portion is less than 40% of the total hCG, chemotherapy is unlikely to be successful.
In the majority of patients with very low (<27%) hyperglycosylated levels, hCG production will ultimately regress with no further sequelae. Patients with low levels of hyperglycosylated hCG should be monitored closely, however, as up to one quarter of the patients will exhibit rising total hCG values and convert to malignant behavior.
Pituitary hCG
The pituitary gland normally produces low levels of normal hCG during ovulation and the luteal phase of the ovulatory cycle. In contrast to placental hCG, pituitary hCG is sulfated, but it can be detected by commercial assays, especially in patients after oophorectomy or in postmenopausal patients. Familial clusters of "inheritable hCG syndrome" with detectable tonic levels of pituitary hCG have been reported.
Secretion of hCG by nongestational tumors
Gonadal and nongonadal germ cell tumors, including nongestational choriocarcinomas and dysgerminomas, may secrete normal or hyperglycosylated hCG. Identification of an ovarian tumor or a midline mass in a woman with high levels of hCG should raise the possibility of a germ cell tumor.
Detection of free beta-chain hCG in the serum and beta-chain fragments of hCG in the urine have been frequently observed in patients with a variety of gynecologic and nongynecologic malignancies, but it is rare for other tumor types to secrete significant levels of normal hCG that would be detected by conventional hCG assays.
6. Follow-up surveillance and therapy management of recurrences
Recurrent GTN
Remission is monitored with at least monthly hCG levels for 1 year, when the risk of recurrence falls below 1%. During this interval, it is critical that patients prevent an intercurrent pregnancy because elevated hCG from a normal pregnancy would mask tumor hCG.
In high-risk patients, additional hCG monitoring is usually performed for an additional year at 3- to 6-month intervals. In a series reported from Duke, over 95% of recurrences occurred within 2 years of treatment, and all occurred within 36 months of treatment. Overall, 68% of patients were successfully treated for long-term remissions, with a significant improvement in outcome among patients treated after 1978.
Patients diagnosed with a recurrence should be carefully evaluated for metastatic disease and risk score; the majority will require multiagent chemotherapy. In many patients, however, metastatic disease is limited. Hysterectomy or metastectomy was incorporated into treatment of many of the Duke patients who were successfully treated for recurrent disease.
7. What is the evidence for specific management and treatment recommendations?
Alazzam, M, Tidy, J, Hancock, BW, Osborne, R, Lawrie, TA. "First-line chemotherapy in low-risk gestational trophoblastic neoplasia". Cochrane Database Syst Rev. vol. 1. 2009. pp. CD007102This Cochrane review analyzes and critiques the literature covering primary therapy of low-risk GTN.)
Cole, LA. "Biological functions of hCG and hCG-related molecules". Reprod Biol Endocrinol. vol. 8. 2010. pp. 102(Dr Cole is known as an authority in the field of hCG-related research. This review covers the functions and structures of various types of hCG and discusses situations in which false-positive and true-positive elevations of hCG can be observed in the absence of pregnancy or active GTD.)
"FIGO Committee on Gynecologic Oncology. Staging classifications and clinical practice guidelines of gynaecologic cancers". Int J Gynecol Obstet. vol. 70. 2000. pp. 207-312. (This publication by FIGO discusses the currently used FIGO staging and risk score for GTN.)
Hanna, RK, Soper, JT. "The role of surgery and radiation therapy in the management of gestational trophoblastic disease". Oncologist. vol. 15. 2010. pp. 593-600. (This is a comprehensive review of the role for surgery and radiation therapy in the management of GTD.)
Lurain, JR. "Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease and management of hydatidiform mole". Am J Obstet Gynecol. vol. 203. 2010. pp. 531-9.
Lurain, JR. "Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia". Am J Obstet Gynecol. vol. 204. 2011. pp. 11-8. (Authoritative reviews covering the current diagnosis and management of hydatidiform moles and GTN.)
Osborne, RJ, Filliaci, V, Schink, JC, Mannel, RS, Alvarez Secord, A, Kelley, JL. "Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study". J Clin Oncol. vol. 29. 2011. pp. 825-31. (This is the largest randomized study reporting the results of therapy in patients with low-risk GTN. The 2-week schedule of actinomycin D had a significantly better complete response rate than the weekly methotrexate regimen.)
Soper, JT, Mutch, DG, Schink, JC. "American College of Obstetricians and Gynecologists: Diagnosis and treatment of gestational trophoblastic disease. ACOG Practice Bulletin No. 53". Gynecol Oncol. vol. 93. 2004. pp. 575-85. (This is the current ACOG Practice Bulletin covering GTD.)
Tidy, JA, Gillespie, AM, Bright, N, Radstone, CR, Coleman, RE, Hancock, BW. "Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy". Gynecol Oncol. vol. 78. 2000. pp. 309-12. (This retrospective review of techniques for molar evacuation demonstrated an increased risk of postmolar GTN among women who underwent prostaglandin or other medical induction of labor compared to suction D&E.)
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- Gestational trophoblastic disease
- 1. What every clinician should know Are you sure your patient has disease? What should you expect to find?
- 2. Diagnosis and differential diagnosis
- 3. Management
- A. What therapies should you initiate immediately (ie, emergently)?
- B. What should the initial definitive therapy for the cancer be?
- 4. Complications
- A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?
- B. What complications could arise as a consequence of the management – Chemo, radiation and surgical?
- C. What other therapies are helpful for reducing complications?
- 5. Prognosis and outcome
- A. What would you tell patient and family about the prognosis?
- B. "What if" scenarios
- Incomplete radiographic staging
- Use of combination therapy in low-risk GTN refractory to initial chemotherapy
- Delays in chemotherapy recycling
- Maintenance chemotherapy
- Possible causes of "false positive" elevations of serum hCG levels
- Early pregnancy
- Phantom hCG
- Quiescent gestational trophoblastic disease
- Pituitary hCG
- Secretion of hCG by nongestational tumors
- 6. Follow-up surveillance and therapy management of recurrences
- 7. What is the evidence for specific management and treatment recommendations?


text:
We provide Counselling, Psychotherapy and Consultancy services designed to support adults, adolescents and young people.
Your first consultation is free of charge and obligation, however, if we agree to work together the cost per session will be arranged.
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subset: commoncrawl


text:
In August 2012, John Christy, a climate scientist from the University of Alabama, Huntsville, testified to the Senate Environment and Public Works Committee that the Earth is not warming.
In part, Christy's testimony, a controversial one, was based on what he described as a problem with how surface temperatures are measured and averaged.
Climate scientist Gilbert Compo's response to that was: Well, I'll measure those temperatures differently.
So he set out to use an entirely different method to determine if the Earth's surface temperature had increased 1.2 degrees Celsius since preindustrial times.
The answer: Undeniably yes.
This new method shows that it is not a factor of measurement error and that the Earth has in fact warmed, said Compo.
Data from ships' logs and Army bases
"If I had ever had any doubts about whether global warming was happening, then this [study], which I know has no relationship to the land-based observations, dashed all of my doubts," Compo said. The results of the study were published online Monday in the journal Geophysical Research Letters
The locations of weather stations, changes in instruments, the siting of weather stations in warmer urban areas, changes in land cover and other issues have all been cited as issues affecting the temperature trends often used to show that our planet is in fact warming.
Compo's method uses none of these. Instead, the researcher and his colleagues use historic measurements of air pressure and ocean temperatures, put into a model, to calibrate surface temperatures over the 20th century.
That project, called the 20th Century Reanalysis, gets those pressure data from historic data sources like ship logs and Army bases, which are compiled by volunteers at oldweather.org and ACRE, two efforts that catalog old weather data and make them available to researchers.
Those many, many pieces of air pressure data help Compo and his team piece together a snapshot of what was happening in the weather at a given point in time; every six hours since the 1870s, in fact.
If the researchers can spot pressure highs and lows, then they know where the wind is blowing, for instance. As they continue to add data points from around the globe and move forward in time, a process of elimination takes place until they know what the temperature is in, say, Washington, D.C., 100 years ago.
"When I know where the highs and lows are, I know where the hot and cold spots have to be, I can start to line them up," said Compo. "It's like Sudoku."
Skeptics remain skeptical
Eugenia Kalnay, a professor at the University of Maryland who reviewed the paper, called the model "very sophisticated."
Kalnay said it provides an answer to climate skeptics who point out that changes in land use or instrumentation make land-based temperature data unreliable.
Climate scientist Roger Pielke Sr. and Alabama's Christy, whose papers and testimony are cited in Compo's paper as part of the rationale for addressing the issue of whether surface temperatures have warmed, said they admired the research's approach but also said it does not address all the questions they have raised about warming trends.
Pielke, who said one issue ignored in the paper is that land surface temperature measurements over time show bigger warming trends than measurements from higher up in a part of the atmosphere called the lower troposphere, and that still needs more explanation.
Another issue, said Christy, is the role of maximum and minimum temperatures. Minimum temperatures have risen more than maximum temperatures, possibly due to land-use changes, which, as Christy pointed out in his Senate testimony, can be problematic when creating warming trend lines, since temperatures are calculated as an average of minimum and maximum.
Pielke agreed that despite this paper, the problem of maximum and minimum temperatures still exists.
"The Compo et al. paper is an original approach," Pielke said, "but they still need to look into this important issue."
Reprinted from Climatewire with permission from Environment & Energy Publishing, LLC. www.eenews.net, 202-628-6500


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As executions continue, youth pray for life and dignity
Our youth pro-life team organizes prayer for our parish community when an execution takes place.At St. Catherine of Siena, our Youth Pro-Life team meets monthly to engage in pro-life issues from "womb to tomb," including abortion, human trafficking, euthanasia, and the death penalty. Our youth team takes the lead in organizing prayer for our parish community whenever an execution is taking place in the state of Texas. The youth lead all who gather in praying the Rosary for Mercy. Praying together helps our community reflect and act on our Catholic commitment to protecting the life and dignity of all God's children, no matter who they are or what they have done. Our prayer together leads to challenging but respectful conversation about human life and dignity and our call as Catholics.
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Praying and acting to fight racism and division
As the nation faced unrest after the Ferguson and New York City court decisions, we held a candlelight vigil and mass to pray for peace, justice and an end to racism. Our students care about promoting unity by embracing cultural and ethnic diversity on our campus and in our nation. Following the national unrest after the court decisions in Ferguson, MO and New York City, The Black Students' Alliance of The Catholic University of America led an effort, in partnership with Campus Ministry to hold a candlelight prayer vigil and Mass for peace and justice. Student leaders spoke about the need to fight racism and division on our campus and in our nation. We sang hymns and walked in silent procession across campus to honor the victims of violence. Our campus chapel was standing room only for our Mass in honor of the Immaculate Conception, patroness of our country. We were called to recognize the way our individual action or inaction contributes to or hinders peace and respect for human dignity in our communities. Our university continues to promote unity and cultural diversity through our language and cultural student organizations, Campus Ministry, and the Office of Campus Activities. OCA produces intercultural programming, multi-cultural leadership training, culture and justice discussions, an intercultural speaker series, and educational opportunities on developing critical consciousness to avoid cultural stereotypes and assumptions.
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Seminarians follow the path of migrant workers
Our seminarians follow the path of migrant workers from south Florida to Virginia's outer banks, accompanying them and hearing their stories.Over the past twenty years, several dozen of our seminarians have followed the path of migrant workers, traveling from south Florida to the Virginia outer banks. They accompany migrant workers who spend 12-hour days doing back-breaking work in the fields. Our vocations office partners with the Richmond Diocese's Office of Justice and Peace to find volunteer placements for the seminarians, who spend the summer accompanying the migrants, getting to know them and their families, hearing their stories, and providing assistance. The experience is so impactful that our seminarians often come back saying that they received more than they gave!
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Homilies inspire our parish to be missionary disciples
Our pastor uses the Sunday homily to reflect on the ways Scripture calls us to live our faith by loving God and neighbor. Our pastor uses the Sunday homily as an opportunity to reflect on the ways that Scripture calls us to live our faith in our community. Father writes his homilies influenced by the social teachings of the Church and issues that our Social Justice Ministry and other ministries are involved in at our parish. This approach ensures that the social mission of the Church permeates our parish life, even our worship. Topics range from Faithful Citizenship to immigration reform and global solidarity. The homilies are true teaching moments and ground us in prayer and the scriptural call to do justice.
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Our faith called us to address foreclosure
We believe our faith community is called to share and respond to the struggles of our community--including foreclosure that impacted 120 of our parishioners.Six years ago, more than 120 people at our parish, Our Lady of Assumption, had homes in foreclosure. With the help of COPA, a local organization that receives funding from the Catholic Campaign for Human Development, we engaged in research and house meetings around the foreclosure issue in Monterey and Santa Cruz Counties. We learned about how to run foreclosure workshops and met with city, county and state officials about the problem. We also worked with some of the bigger banks to set up face to face meetings between loan officers and homeowners to request loan modification or principal reduction. Finally, our hard work paid off when 74 homeowners were able to keep their homes. We engaged in this work because we believe that our faith community is called to share and respond to the real struggles and challenges of our parishioners.
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Catholic groups mobilize to end the death penalty in Georgia
Our network of deacons, lay Catholics, and diocesan staff educate, pray, and advocate for an abolition of capitol punishment in Georgia. We are a network of deacons, lay people, and diocesan staff who seek to uphold the life and dignity of all people, including those on death row. In response to Church teaching that capital punishment is incompatible with the gospel and can no longer be justified in modern society, we work to educate Catholic parishes, schools, and faith groups and invite them to join our work to end the use of the death penalty in Georgia. Working closely with the Archdiocese of Atlanta and the Georgia Catholic Conference, we also serve as a Catholic presence at prayer vigils and legislative actions aimed at awareness, moratorium, and abolition of the death penalty and the promotion of a culture of life.
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Sister parishes create joyful international friendships
Our parish partners with a parish in an impoverished region of El Salvador and forms bonds of friendship and solidarity.
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Discovering solidarity through mutual encounter in Guatemala
Our parish and our sister parish in Guatemala mutually encounter, support, and pray for each other. Our parish, Queenship of Mary, has built up an ongoing friendship with the parish of Santa Cruz in Chiquimulilla, Guatemala. Through discernment by representatives of both communities, we decided together to develop a microfinance program in the village of La Morena, which is part of the parish of Santa Cruz. We send parishioners on bi-annual delegations to Santa Cruz and La Morena, and their pastor and some parishioners have visited our parish, leading to lasting friendships. In between visits, we strengthen our unity through correspondence and Skype gatherings, observing each community's special feast days, intercessions, bilingual songs, and by using palm branches from Guatemala on Palm Sunday. In the words of one of our parishioners, "I did not understand what solidarity really means until I went to Guatemala."
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Caring for God's creation, going solar
We are helping parishioners install solar panels on their homes, with proceeds benefiting the parish and other Catholic ministries.We are responding to the call to care for God's creation! Our Catholic Charities agency, together with several parishes, have launched an initiative to help parishioners install solar panels on their homes. Proceeds from the referral fees are shared by the parish, Catholic Charities, and the Catholic Climate Covenant. Our program is the first of its kind by a Catholic diocese in the U.S. Through it, families lower their carbon footprint, parishes get funding for their ministries, and Catholic Charities of Stockton gets support for its service to those in need.
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Sisters help others care for creation, live sustainably
We encourage care for creation and sustainable living through our programs and retreats. As Sisters of Providence, we take seriously the call to care for creation. We seek to live and minister in ways that recognize the interdependence of all of creation and the need for God's providence to bring hope and healing to our communities. We run a community center where we offer classes on sustainable cooking, gardening, and spinning and weaving; retreats; training in organic gardening; and community-supported agriculture. We also raise alpacas!
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Uniting a community through reaching out
We live the unity of the Body of Christ through reaching out in the community that surrounds our parish.Our parish created Aquinas Center, a ministry of Saint Thomas Aquinas Catholic Community in Philadelphia, PA, as a way to be a living example of the unity of the Body of Christ. We opened in January 2013 with a mission to build unity in diversity, support learning, and inspire thoughtful action. Our center is home to urban immersion experiences, counseling services, a legal clinic to help immigrants (regardless of documents), community organizing and advocacy efforts, English and literacy classes, and urban revitalization projects, such as a community garden. We are passionate about engaging people of all ages in overcoming the cultural barriers and injustices which can often divide our communities.
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We fight poverty in Nicaragua as parish partners
We learned an important lesson in solidarity when our partner parish in Nicaragua raised $300 to help us rebuild our own parish after Hurricane Katrina.Our parish has encountered Jesus Christ through its global partnership program. We have a partner parish in Nicaragua and tithe a percentage of our monthly collections to help reduce poverty there. A group from our parish has visited Nicaragua several times to strengthen relationships face-to-face. We learned a powerful lesson in solidarity in 2005 when our Nicaraguan brothers and sisters raised $300 to help us rebuild our own parish in the aftermath of Hurricane Katrina. This program also has fueled our interest in other issues such as immigration reform and taught us to act with Christ's love as our guide.
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Art in action! Youth use art to fight landmines
Inspired by Pslam 34:15, we created a student club that works to end the use of landmines and cluster bombs.In 1999, our art teacher gave students an assignment to create an art project which educates about a global issue. Inspired by Psalm 34:15 ("Seek peace and pursue it.") the students chose "landmines" and learned about how children—often the most vulnerable in society—are victims of landmines and cluster bombs. The students created a student group called PSALM: Proud Students Against Landmines and Cluster Bombs. Over 15 years later, students at our school are still working to educate other students and the larger community about the dangers of landmines and cluster bombs and prevent future casualties. We make posters, hold awareness days and do presentations in our school, community and state on this issue. We believe that our faith calls us to seek peace and to advocate on behalf of children who suffer around the world because of landmines.
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Seminarians work for human life, peace and social justice
I'm Fr. Desmond Drummer. During my priestly formation, I participated in the Peace and Justice/Gospel of Life Apostolate.I'm Fr. Desmond Drummer and I'm a recently ordained priest in the Archdiocese of Atlanta. I completed my formation at Mundelein Seminary, where I was active in the Peace and Justice/Gospel of Life Apostolate. The Apostolate engages the seminary community in work for human life and the dignity of the human person through educational lectures, service events, and advocacy opportunities. The Apostolate encourages seminarians to follow Christ's example of care and concern for those who are vulnerable and to overcome the misconception that there is a gap between life issues and social justice.
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Practicing solidarity and sustainability through CRS Rice Bowl
We used CRS Rice Bowl to pray and learn about global poverty, and a Rice Bowl grant to create a parish garden.Our parish uses CRS Rice Bowl during Lent to engage our community—including our youth group, religious education programs, and families—in praying and learning about global poverty and then practicing almsgiving as an expression of our solidarity with our brothers and sisters around the world. And in praying, learning, and giving, we were also able to act. We used a grant from the CRS Rice Bowl program to create a parish garden which produces fresh, organic vegetables. Our parishioners work in the garden and share the harvest with St. Vincent de Paul programs which help those in need.
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Yakima seminarians take on "the smell of their sheep"
Our seminarians learn to take on "the smell of the sheep" through a ministry to accompany migrant workers in the fields. In the Diocese of Yakima in Central Washington, we respond to Pope Francis' call to take on "the smell of the sheep" through a special ministry with migrant workers. Throughout the season when migrants are laboring in the fields, our seminarians accompany them, working beside them in the fields six days a week and nine to ten hours a day, earning money for their own living expenses. On Sundays, they celebrate Mass with them. Not only does this provide seminarians an opportunity to live and experience daily life with those whom they will one day serve, it also has a deep impact on the seminarians as they experience the migrants' deep faith, learn about their way of life and the challenges they face, and expand their sense of the community of the Body of Christ.
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Parish celebrates diversity, forms leaders of many ethnicities
We ensure that leadership of our parish mirrors the diversity of our community, and coordinate opportunities for everyone to pray, learn and act together.
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Immigration team fosters participation and respect for human dignity
Our archdiocesan immigration team helps facilitate social ministry in Hispanic parishes and advocates for the dignity of immigrants. Our Immigration Team helps Catholics participate in transforming their own communities. We founded the team in 2013 to facilitate parish social ministry in parishes with large Hispanic populations, and to advocate for the dignity of all people and their right to participate in their communities. After holding almost 100 one-on-one meetings as well as trainings in organizing, storytelling and leadership skills, we formed our team of over 30 leaders drawn from 15 parishes representing 11 cities throughout the Archdiocese of Hartford. Our team has organized two regional "Pilgrimages for Immigration Reform," and distributed over 3,000 post cards to our state legislators. The team is currently working with parish social ministry leaders to help undocumented parishioners prepare for the Connecticut driver's license exam, though the creation of "community schools" in parish settings, serving over 1,500 parishioners. The team also helps to engage parishes around the diocese in local and national immigration issues.
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A school that builds bridges
Our school near the U.S.-Mexico border witnesses to the unity of the Body of Christ by serving as a bridge between people on both sides. Our school is located in Nogales, AZ, near the U.S.-Mexico border, in the area known as "Ambos Nogales," or "both Nogales." Our school is a bridge between the people on both sides of the border. Living out our call to be one Body of Christ, we welcome students from both sides at our school. We integrate social justice into our school's curriculum and do bridge-crossing through service and advocacy: Our older students serve at the Comedor, a soup kitchen on the border for deported migrants, and are also active in the Kino Border Initiative, through which they meet with their Congressional representatives to urge just and comprehensive immigration reform, and organize and participate in events to educate themselves and others about border issues.
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Teens put Catholic social teaching into action at youth retreat
Teens in our diocese gather at a retreat to do service and explore the root causes of problems facing the community.The Catholics in Action retreat program in the Diocese of Davenport helps our youth share God's love with others. During three-day retreats, teams of high school students from parishes in our Diocese pray, learn, and reflect on the Church's social mission. We explore the root causes of social issues, learn what is happening in our own communities, and participate in service projects. For example, participants learned how one local agency assists workers who have been victims of wage theft. The retreats help us get to know teenagers in other parishes as we put our faith into action.
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When we pray together, God transforms us individually and as members of the Body of Christ, sent on mission in the world.
Through service and relief, advocacy, and ethical living, we participate in God's work to transform individuals and communities.
Love for God and neighbor calls us to learn more about Catholic social teaching and about problems impacting our communities.
We are called to reach out and encounter our families, our faith community, our neighbors, and our world.


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A satellite image shows the dust plume raised by rockslides in the mountains near the epicenter. The link at Gawker.com includes a time lapse sequence of the satellite view, and a link to the video of the immense dust clouds from the ground.
UPDATE: Lee Allison at Arizona Geology has been on top of the latest developments on the Sierra El Mayer quake. He has posted a number of pictures of road damage on Highway 5 south of Mexicali, including this one (photographer Danny Ashcraft):
Note the right lateral offset of the road surface
UPDATE #2: The Southern California Seismic Network is beginning to release some of their 1,500 photographs of the fault ruptures on the Borrego fault and others. An example below!


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Make Mine Missile
Japan is just starting to climb back on its feet after the Tohoku Earthquake and Tsunami (as it's officially being called now). For long weeks toys have been the last thing on anyone's mind. But as we work to get much-needed supplies to those up north, dodging the occasional rolling blackout, and keeping an eagle eye on the damaged reactors simmering just a few hundred kilometers away, people in Tokyo are getting back to their normal lives.
My normal life involves toys. And I think it's telling that even in the midst of the chaos that followed the disaster, these toys showed up on my doorstep. Literally 24 hours after a magnitude 9 tremor rocked Japan's eastern seaboard, when the nation had ground to a virtual standstill, the Japanese post office still managed to deliver the frickin' mail. It still amazes me.
I didn't have a spare thought for, or even a chance to so much as open the package, for two weeks. And I'm glad I waited. Because these aren't just some of the most beautiful toys Japan has ever produced — they virtually demand attention. Normally I am not a big fan of reproductions of vintage toys. It's not that I don't understand why people buy them, but rather simply don't have an interest myself. I prefer knowing that a toy has a certain history to it. What was happening in the world when this first went on sale? How many hands has it passed through to get to mine? How rare that it's survived the decades in such good shape…
Most reissues, being simple copies of what came before, by their very nature lack this "weight of history." But Bullmark is the founding father of Japan's character toy scene, and Saburo Ishizuki — the same gentleman who managed sales for the company back in the Sixties and Seventies — is running its latest incarnation today. His mere presence gives these reissues the weight they wouldn't have had, coming from anyone else.
These particular replicas of Bullmark's old 1974 missile firing Mechagodzilla toy were sold exclusively via mail order earlier this year. (how's that for burying the lede, five paragraphs in.) They're color variations of the first missile firing Mechagodzilla reissue that was offered as a separate mail-away premium included with the Bullmark History Box Set, released last year. Physically, the design of these latest reissues is the same as the previous one: only the chest missiles actually fire, with the elbow and knee launchers disabled. (Actually, they're not even there; the missiles simply slot into the holes where they would be.)
The great thing about these latest two re-issues, the thing that sets them apart from the previous one, is that they aren't slavish duplicates; they add new value to the concept. Like the earlier reissue, the head is molded separately, capable of rotating — something the original 1974 model wasn't capable of doing. But the real eyeball grabbers are the all-new color patterns, totally unlike anything seen before. One is in "box colors," painted with metallic green highlights instead of gold to match the toy as it appeared in photos on the old package. The one that really gets me, though, is the second version. Molded entirely in glowing vinyl, it doesn't look like any missile-firing toy produced in the Seventies or anytime else, for that matter. The thing looks positively radioactive in the dark, which is appropriate both for the character and the strange times Tokyo finds itself in.
The bad news is, you can't order these anymore. The only way to get them was by placing an order on the Bullmark web site earlier this year. But there is a better than even chance that we'll be seeing either more, or more variations, soon. Which is good news for anyone who wants to get their hands on a little "new old history."