Gestational Trophoblastic Disease – Surgical management

Table III.

Regimen	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.

Figure 2.

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

EMA

• 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

CO

• 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.

Figure 3.

Figure 4.

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:

EMA

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

EP

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.

GTN

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.

GTN

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.)

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