What is the treatment for uterine choriocarcinoma?

Treatment of Uterine Choriocarcinoma

For uterine choriocarcinoma, treatment is determined by risk stratification using the FIGO prognostic scoring system, with low-risk disease (score 0-6) treated with single-agent methotrexate or dactinomycin, and high-risk disease (score ≥7 or stage IV) requiring multiagent chemotherapy with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) as the standard first-line regimen. 1

Risk Stratification and Initial Assessment

The FIGO prognostic scoring system is the critical first step that determines the entire treatment pathway. 1 This scoring incorporates age, antecedent pregnancy, interval from index pregnancy, pretreatment hCG level, largest tumor size, sites of metastases, number of metastases, and previous failed chemotherapy. 1

• Low-risk GTN is defined as FIGO stages I-III with prognostic score 0-6 1
• High-risk GTN is defined as FIGO stages II-III with prognostic score ≥7, or any FIGO stage IV disease 1

Approximately 20% of patients with choriocarcinoma have CNS metastases, which requires additional treatment considerations. 1

Treatment for Low-Risk Choriocarcinoma (FIGO Score 0-6)

First-Line Single-Agent Chemotherapy

Single-agent methotrexate is the preferred initial treatment for low-risk choriocarcinoma. 1, 2 The standard regimen is intramuscular methotrexate 50 mg on days 1,3,5, and 7 with oral folinic acid 15 mg on days 2,4,6, and 8 in 2-weekly cycles. 2

• For low-risk choriocarcinoma with FIGO score 0-5, single-agent methotrexate achieves sustained complete response in approximately 35% of patients 2
• Alternative single-agent therapy is dactinomycin, which can be used if methotrexate causes unacceptable toxicity or if resistance develops 1
• Treatment continues for 2-3 additional cycles after hCG normalization to minimize recurrence risk 1

Important caveat: Not all patients with low-risk choriocarcinoma who have had primary surgical intervention (such as hysterectomy or uterine evacuation) will require chemotherapy, provided hCG levels continue to decline to normal. 2 However, patients with FIGO score 6 or FIGO stage III disease should be counseled that they may benefit from proceeding directly to combination chemotherapy rather than single-agent therapy. 2

Second-Line Treatment for Low-Risk Disease

If hCG plateaus over 3 consecutive cycles or rises over 2 consecutive cycles, this indicates chemotherapy resistance. 1

• Switch to the alternative single-agent (dactinomycin if methotrexate was used first) for patients with good initial response but hCG plateau 1
• Dactinomycin achieves complete response in approximately 75% of methotrexate-resistant low-risk GTN 1
• Clinicopathologic diagnosis of choriocarcinoma (versus postmolar GTN) is significantly associated with resistance to secondary dactinomycin 1
• If resistance develops to sequential single-agent regimens, transition to multiagent chemotherapy with EMA/CO 1

Treatment for High-Risk Choriocarcinoma (FIGO Score ≥7 or Stage IV)

Primary Multiagent Chemotherapy

EMA/CO is the most commonly used and standard initial regimen for high-risk choriocarcinoma, with cure rates approaching 90%. 1 The regimen alternates EMA and CO on weekly cycles. 1

The EMA/CO protocol consists of: 1

• Day 1: Etoposide, methotrexate, actinomycin D
• Day 2: Etoposide, folinic acid rescue
• Day 8: Cyclophosphamide, vincristine

Alternative combination regimens that have been used include: 1

• EMA/EP (etoposide, methotrexate, actinomycin D alternating with etoposide and cisplatin)
• FA (5-FU and dactinomycin)
• MEF (methotrexate, etoposide, and 5-FU)
• CHAMOCA (methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine)

EMA/EP is considered superior to EMA/CO for ultra-high-risk disease (FIGO score >12) but its use as standard initial therapy is limited by increased toxicity. 1

Induction Chemotherapy for Ultra-High-Risk Disease

Patients with FIGO prognostic score >12 have widespread metastatic disease and poorer prognosis. 1 Initiation of standard combination chemotherapy in these patients can lead to tumor collapse with hemorrhage, metabolic acidosis, septicemia, and/or multiple organ failure, resulting in potential early death within 4 weeks. 1

For ultra-high-risk patients, low-dose induction chemotherapy with etoposide 100 mg/m² IV and cisplatin 20 mg/m² IV on days 1 and 2, every 7 days for 1-3 courses, should be administered before starting EMA/CO. 1 This approach improved overall survival to 94.3% with early death rate of only 0.7% in a case series of 140 high-risk patients. 1

CNS Metastases Management

Approximately 20% of choriocarcinoma patients have CNS involvement, requiring additional interventions. 1

For patients with CNS metastases, EMA/CO must be modified to include either high-dose methotrexate 1 g/m² or addition of intrathecal methotrexate to achieve adequate blood-brain barrier penetration. 1

Additional treatment modalities include: 1

• Whole brain irradiation
• Stereotactic radiosurgery
• Craniotomy with surgical excision for select cases
• Emergency intervention for intracranial bleeding or elevated intracranial pressure

Cure rates with brain metastases range from 50-80%, depending on symptoms and number, size, and location of brain lesions. 1

Salvage Chemotherapy for Resistant or Relapsed Disease

Approximately 30-40% of high-risk patients will have incomplete response to first-line therapy or experience relapse from remission. 1

EMA/EP or EP/EMA regimens are the most appropriate salvage therapy for patients who have responded to EMA/CO but develop plateauing or re-elevation of hCG. 1 Complete response/remission rates with EMA/EP for EMA/CO-resistant disease are 75-85%. 1

Additional salvage regimens containing etoposide and platinum agents include: 1

• TP/TE (paclitaxel and cisplatin alternating weekly with paclitaxel and etoposide)
• BEP (bleomycin, etoposide, and cisplatin)
• VIP (etoposide, ifosfamide, and cisplatin)
• ICE (ifosfamide, carboplatin, and etoposide)
• TIP (paclitaxel, ifosfamide, and cisplatin)

These etoposide-platinum regimens require granulocyte colony-stimulating factor support to prevent neutropenic complications and treatment delays. 1 Overall success of salvage therapy is approximately 80%. 1

Factors associated with worse survival outcomes in salvage therapy include: 1

• High hCG at start of salvage therapy
• Greater number of metastatic sites
• Metastases to sites other than lung and vagina (stage IV)
• FIGO score >12

Adjuvant Surgery

Adjuvant surgical procedures are important for chemotherapy-resistant disease, particularly for isolated disease in the uterus or lungs. 1

• PET/CT imaging is useful for detecting isolated metastatic sites amenable to targeted surgery 1
• Selective arterial embolization can manage bleeding from uterus/vagina or other tumor sites 1
• Nearly 50% of high-risk patients undergo some surgical procedure during treatment to effect cure 1
• Hysterectomy with bilateral salpingo-oophorectomy can be considered for patients with localized uterine disease who do not desire fertility preservation 1, 3

Special Considerations for Postmenopausal Choriocarcinoma

Choriocarcinoma occurring in postmenopausal women is extremely rare but highly chemosensitive. 3, 4

• Emergency hysterectomy with bilateral salpingo-oophorectomy may be required for intractable bleeding 3
• EMA/CO remains the standard chemotherapy regimen, though treatment may need modification if severe hypersensitivity reactions occur 4
• The tumor remains curable even in advanced stages with appropriate chemotherapy 4

Surveillance After Treatment

Monthly hCG monitoring for 1 year is mandatory after treatment completion, along with contraception (oral contraception preferred). 1

Critical Pitfalls to Avoid

• Do not use preserved formulations of methotrexate for intrathecal or high-dose therapy because they contain benzyl alcohol 5
• Do not delay treatment in ultra-high-risk patients (FIGO score >12) with standard-dose chemotherapy as this can cause tumor collapse with life-threatening complications; use induction chemotherapy first 1
• Do not use standard-dose methotrexate for CNS metastases without modification to high-dose (1 g/m²) or intrathecal administration 1
• Do not assume single-agent therapy will be adequate for choriocarcinoma with FIGO score 6 or stage III disease; these patients have higher resistance rates and should be counseled about proceeding directly to combination chemotherapy 2