Gestational trophoblastic neoplasia
Diagnosis
Historically, different countries have used different criteria in the diagnosis of GTN which result in a wide range of quoted incidence, from 8% in the United Kingdom to 20% in the United States.
Consensus criteria were reached by the International Federation of Gynecology and Obstetrics (FIGO) in 2000 (16) and this is now used internationally to diagnose GTN:1. GTN may be diagnosed when the plateau of hCG lasts for four measurements over a period of 3 weeks or longer, that is, for days 1, 7, 14, and 21.
2. GTN may be diagnosed when there is a rise in hCG for three weekly consecutive measurements or longer, over a period of at least 2 weeks or more, on days 1, 7, and 14.
3. GTN is diagnosed when there is histological diagnosis of choriocarcinoma.
4. GTN is diagnosed when the hCG level remains elevated for 6 months or more.
The use of a common definition internationally would be helpful in comparing the incidence and outcome of treatment and in the understanding of the natural course of the disease.
Investigations
Having diagnosed GTN, further investigations are needed to stage the disease and assess the risk. The FIGO Oncology Committee also defined the investigative tools suitable to assess metastases (16). Lung metastases and the number of metastases should be evaluated by chest X-ray. Lung computed tomography can be used if available. Liver metastases may be diagnosed by ultrasound or computed tomography scanning while brain metastases may be diagnosed by magnetic resonance imaging or computed tomography scanning.
Staging of gestational trophoblastic neoplasia
In conjunction with the consensus definition of GTN, FIGO also revised the staging system in 2000. The FIGO 2000 staging include the stage of the disease (I-IV) and the World Health Organization (WHO) risk score (Table 66.1) (16). Those with a risk score of 7 or above would be classified as high risk while those with a risk score of 6 or below would be classified as low risk (16).
Comparison of the FIGO 1992 staging, the WHO scoring system, and the FIGO 2000 staging systems showed comparable results though fewer patients were categorized in the high-risk group (17).Treatment
Since GTN is highly chemosensitive, the mainstay of treatment is chemotherapy. The choice of chemotherapy depends on the risk.
Low-risk GTN
Methotrexate with or without folinic acid rescue has been the most commonly used first-line regimen for low-risk disease while actinomycin D is an effective alternative (Table 66.2). In recent years, randomized controlled trials were carried out comparing methotrexate with actinomycin D. Overall, actinomycin D has higher primary cure rates with no significance difference in side effects, although side effects data were too heterogeneous to be conclusive (18). Once the hCG level has normalized, three cycles of consolidation chemotherapy is associated with about a 50% lower recurrence rate compared to two cycles (19). Other single agents known to be effective include etoposide and 5-fluorouracil. For patients resistant to methotrexate, a change of chemotherapy would be able to salvage almost all patients. Patients with serum hCG levels below 300 IU/L can change to actinomycin D while those with hCG levels above 300 IU/L would require combination chemotherapy as for high-risk disease (20). With appropriate management, the overall survival rate in low-risk disease approaches 100%.
High-risk GTN
Combination chemotherapy is required for high-risk disease. The earliest combinations include MAC (methotrexate, actinomycin
| FIGO anatomical staging | |
| Stage I | Disease confined to the uterus |
| Stage II | GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) |
| Stage III | GTN extends to the lungs, with or without known genital tract involvement |
| Stage IV | All other metastatic sites |
Modified WHO prognostic scoring system as adapted by FIGO
| Scores | 0 | 1 | 2 | 4 |
| <40 | ≥40 | - | - | |
| Antecedent pregnancy | Mole | Abortion | Term | - |
| Interval from index pregnancy (months) | <4 | 4-6 | 7-12 | ≥13 |
| Pretreatment serum hCG (IU/L) | <103 | 103-<104 | 104-<105 | ≥105 |
| Largest tumour size including uterus (cm) | - | 3-4 | ≥5 | - |
| Site of metastases | Lung | Spleen, kidney | Gastrointestinal | Brain, liver |
| Number of metastases | - | 1-4 | 5-8 | >8 |
| Previous failed chemotherapy | - | - | Single drugs | 2 or more drugs |
Source data from FIGO Oncology Committee.
FIGO staging for gestational trophoblastic neoplasia 2000. IntJ Gynaecol Obstet 2002;77:285-87.
Table 66.2 Low-risk GTN treatment-single-agent chemotherapy
| Chemotherapy agents | Common regimens |
| Methotrexate | 5-day regimen 0.4 mg/kg/day (max. 25 mg) for 5 days IM or IV, repeat cycle every 2 weeks |
| 8-day alternating regimen 1 mg/kg IM on day 1,3, 5 and 7 plus folinic acid 15 mg PO 30 hours after each methotrexate dose on days 2, 4, 6 and 8, repeat cycle every 2 weeks | |
| Weekly regimen 30-50 mg/m2 weekly IM | |
| 100 mg/m2 IV bolus, then 200 mg/m2 IV infusion over 12 hours plus folinic acid 15 mg IM or PO every 12 hours for 4 doses, initiate 24 hours after start of methotrexate, repeat cycle every 2 weeks | |
| Actinomycin D | 5-day regimen 12 mcg/kg/day or 0.5 mg/day for 5 days IV bolus, repeat cycle every 2 weeks |
| Pulsed actinomycin D 1.25 mg/m2 IV bolus every 2 weeks |
IM, intramuscular; IV, intravenous; PO, orally.
Table 66.3 High-risk GTN treatment-multiple-agent chemotherapy
| EMA-CO given every 2 weeks | Day 1 | Actinomycin D 0.5 mg IV bolus Etoposide 100 mg/m2 over 30 minutes Methotrexate 100 mg/m2 IV bolus and then 200 mg/m2 IV infusion over 12 hours |
| Day 2 | Actinomycin D 0.5 mg IV bolus Etoposide 100 mg/m2 over 30 minutes Folinic acid 15 mg IV or PO every 12 hours for 4 doses, initiate 24 hours after start of methotrexate | |
| Day 8 | Vincristine 0.8 mg/m2 IV bolus (max. 2 mg) Cyclophosphamide 600 mg/m2 IV over 30 minutes |
IV, intravenous; PO, orally.
D, and cyclophosphamide), CHAMOMA (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, vincristine, melphalan, and doxorubicin), or its modified regimen without melphalan and doxorubicin, CHAMOC (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine). After etoposide was found to be very effective, EMA-CO (etoposide, methotrexate, and actinomycin D alternating weekly with cyclophosphamide and vincristine) (Table 66.3) has become the most widely used regimen worldwide (21). Up until now, there has been no randomized controlled trial comparing EMA-CO with other regimens (22). For those with very high hCG levels or extensive metastases, starting with low-dose etoposide and cisplatin (EP) for the first 1-3 weeks can reduce the risk of major complications such as a metabolic catastrophe or haemorrhage (23).
Ultra-high-risk GTN and resistant disease
The majority of patients will respond to first-line chemotherapy as mentioned previously. However, those with very high FIGO risk scores (>12), and liver, brain, or multiple metastases have a high risk of drug resistance (24). About 20% of high-risk patients may require second- line salvage chemotherapy (25). Second-line chemotherapy such as EP-EMA (EP alternating weekly with EMA) or TE/ TP (Taxol and etoposide alternating two-weekly with Taxol and cisplatin) regimens can salvage over 70% of patients (Table 66.4) (26). Other regimens such as MBE (methotrexate, bleomycin, etoposide) and BEP (bleomycin, etoposide, cisplatin) have also been used with reasonable outcomes (27, 28). Due to the rarity of the disease, it is difficult to carry out sufficiently powered randomized studies to evaluate the best regimen in these situations. In patients with brain metastasis, high-dosage methotrexate which can cross the bloodbrain barrier or intrathecal methotrexate in addition to intravenous chemotherapy may offer a better outcome (29).
Adjunctive treatment to chemotherapy
Surgery
GTN is highly responsive to chemotherapy and surgery is not necessary in most cases. Although hysterectomy in older women with low-risk non-metastatic disease with no fertility wish was reported to reduce by one cycle the amount of chemotherapy required (30),
Table 66.4 Ultra-high-risk and recurrent GTN treatment
| Chemotherapy regimens | |
| GTN resistant | EP-EMA given every 2 weeks |
| to EMA-CO or recurrence | Day 1 Etoposide 150 mg/m2 IV over 1 hour Cisplatin 75 mg/iTp IV infusion over 12 hours Posthydration |
| Day 8 Actinomycin D 0.5 mg IV bolus Etoposide 100 mg/m2 IV over 1 hour Methotrexate 100 mg/mP IV bolus and then 200 mg∕m2 IV infusion over 12 hours Folinic acid 15 mg IV or PO every 12 hours for 4 doses, initiate 24 hours after start of methotrexate | |
| GTN with brain metastases | EMA-CO with high-dose methotrexate (1000 mg/mP IV infusion over 24 hours) |
| Alternate combination chemotherapy | TE/TP (Taxol, etoposide/Taxol, cisplatin) MAC (methotrexate, actinomycin D, cyclophosphamide) BEP (bleomycin, etoposide, cisplatin) MBE (methotrexate, bleomycin, etoposide) FAEV (floxuridine, actinomycin D, etoposide, vincristine) FA (5-fluorouracil, actinomycin D) |
this is not a common clinical practice since most patients present in the reproductive age and the risk of hysterectomy needs to be balanced against the risk of one additional cycle of chemotherapy. Surgery is usually reserved for isolated chemoresistant tumour or life-threatening complications. Pulmonary lobectomy for isolated drug-resistant lung metastasis is the commonest surgery for resistant disease (31).
However, it is important to realize that residual lung lesions on imaging may still be seen after hCG has normalized. hCG would be a more accurate reflection of disease status and no treatment is required as long as hCG remains normal during monitoring. Hysterectomy for resistant uterine lesions is also indicated. On histological examination, the lesion may turn out to be a PSTT, which is known to be more chemoresistant than invasive moles. Uncontrolled haemorrhage is one of the commonest lifethreatening complications associated with GTN. Hysterectomy can be performed for uncontrolled vaginal bleeding and craniotomy may be performed for an intracranial bleed to relieve intracranial pressure. Laparotomy may be required for an intra-abdominal bleed from liver metastasis, but it is often difficult to control the bleeding. Arterial embolization may offer an alternative to surgery in some of these situations such as in patients with heavy vaginal bleeding but who would like to preserve fertility and in those with internal organ bleeding (32, 33).Radiotherapy
Radiotherapy has a relatively limited role in GTN. It can reduce tumour size and vascularity and hence decrease the chance of complications. In patients with brain metastases with a high risk of bleeding, whole-brain irradiation, together with craniotomy and combination chemotherapy (EP-EMA or EMA-CO) was reported to give the best outcome (34). Irradiation of large hepatic metastases may decrease the chance of spontaneous hepatic rupture and bleeding (35).
Follow-up after treatment
Most GTN recur within the first year after treatment, therefore, close monitoring with serum hCG (similar to postmolar pregnancy) is required. Women should be advised not to conceive for the first 12 months after treatment since hCG levels would be high during pregnancy and hCG would lose its role as a disease marker, leading to a delay in the diagnosis of recurrence. Moreover, repeat mole and increased pregnancy complications such as miscarriage or stillbirth have been reported if the pregnancy is within 6 months after treatment (36). However, the chance of relapse was not found to be increased in these patients compared to those who were not pregnant during the 12 months of surveillance (37). The reproductive performance and outcome of the offspring after treatment of GTN showed no difference from the normal population (38).