Gestational Trophoblastic Neoplasia and GTN Chemotherapy
Episode Notes
Gestational trophoblastic neoplasia (GTN) vs. Gestational trophoblastic (GTD)
GTD = benign and malignant tumors. Includes GTN as well as complete and partial hydatidiform mole (benign GTD)
Epidemiology of GTD
Reported incidence varies by region:
US: 1/1,000. In Asia, reported incidence is higher –may be due to true higher incidence or differences in pregnancy care (differences in rates of home births/documentation of normal pregnancies)
Benign GTD
Molar pregnancies are premalignant > risk of developing into malignancy
Subtype breakdown
80% of GTD = hydatidiform moles/non-malignant entities
15% = invasive mole
5% = other subtypes of GTN (choriocarcinoma, placental site trophoblastic tumor – PSTT, epithelioid trophoblastic tumor –ETT)
Molar pregnancies -subtype differentiation (brief overview)
Complete = egg without maternal DNA is fertilized > diploid
No fetal tissue
Ultrasound = snowstorm appearance
Absent p57 staining on pathology
Risk of postmolar GTN: 15-20%
Higher hCG > more likely to have “classic” molar pregnancy symptoms: HTN, size >dates, increased N/V, AUB, pre-eclampsia
Partial = normal egg fertilized with two sperm or altered sperm > triploid
Some fetal tissue
P57 positive on pathology
Risk of postmolar GTN: 5%
More likely to be diagnosed incidentally, lower hcg values
Short Tandem Repeat analysis, flow cytometry: molecular genotyping which can help distinguish between complete and partial moles.
Rate of postmolar GTN has not decreased despite earlier diagnosis of molar pregnancy –malignant potential is intrinsic, rather than due to disease progression/duration
Preop labs: hCG, T&S
Consider thyroid labs, pre-eclampsia labs (especially if later presentation with higher risk for complications)
Chest xray: for all with pulmonary symptoms (consider routinely ordering chest xray)
Measurement of hCG, issues:
Hook effect = negative hCG on serum assay in the setting of extremely high hCG (>1 million): detection antibody is supersaturated with BhCG >test fails
Serial dilutions of sample can reveal/diagnose this effect
hCG molecular in molar pregnancies are different than those from normal pregnancy: assay must be able to detect all forms of hCG to get an accurate measurement
Management
Suction D&C > hcg monitoring is most common management
Hysterectomy w/ BS: preferred if patients have completed childbearing, if likely to have a complete mole, AND have risk factors for postmolar GTN
Risk factors for postmolar GTN: hcg >100,000, markedly enlarged uterus, large theca lutein cysts, age >40 yo, signs of myometrial invasion on imaging
Emerging ways to predict risk of malignant transformation/postmnolar GTN: microRNA, DNA methylation status
Medication management not recommended.
Special management considerations
Hyperthyroidism: at risk for thyroid storm.
Administer beta-blocker prior to surgery to manage symptoms related to thyroid storm (fever, HTN, tachycardia, potentially ARDS)
Rhogam for Rh negative patients
Ultrasound guidance recommended during D&C (ensure evacuation, reduce risk of uterine perforation)
Oxytocin for improved post-evacuation myometrial contraction
During hysterectomy: MIS preferred if feasible
Postop complications
Cardiopulmonary symptoms: respiratory distress syndrome.
Etiologies: thyroid storm or throphoblastic embolization
Management: supportive: resp support
Clinical course: self-resolving, usually within 2-3 days, as hCG levels decline
HCG monitoring postoperatively
Protocols vary by institution
Options:
Weekly hCG until undetectable, then monthly x 3 months (complete mole)
Weekly hCG levels until undetectable, followed by one hCG level in one month (partial mole)
Appropriate fall = 10%
No effective interventions to prevent of postmolar GTN
Cochrange review 2017: 3 RCTs investigating prophylactic adjuvant chemotherapy
Conclusion: insufficient evidence to recommend
NCCN guidelines: prophylactic methotrexate or dactinomycin can be considered for patients we think of as being high-risk for development of postmolar GTN
Postmolar chemotherapy NOT recommended for patients treated primarily with hysterectomy.
Diagnosis of postmolar GTN
Increase by >10% across three values in a two-week period
Plateau (+/- 10%) across four values in a three-week period
*plateau is less concerning than rise > requires more values
Diagnostic criteria no longer used: hCG persistently elevated at 6 months despite appropriate dropping values
Consider GTN diagnosis in any reproductive aged patient with unexplained hCG elevation, even if no clear antecedent pregnancy
Alternative causes of elevated hCG
New pregnancy
Quiescent GTN: can occur during/after the treatment of GTN or nonmolar pregnancy, in which hcg levels stay persistently elevated, for at least three months after initial treatment, in the absence of any other detectable disease.
Sometimes, when levels are persistently low (<200miu/mL), it can be due to quiescent GTN.
Measurement of hyperglycosylated hCg can support the diagnosis (should be <10% of total hCG)
Hyperglycosylated hCG produced by cytotrophoblast
Up to 10% risk of invasive GTN
Management: monthly hCG monitoring and avoidance of pregnancy
Etiology: small residual syncytiotrophoblast foci without cytotrophoblast
Peri/postmenopausal elevation: low levels of hCG due to LH upregulation with ovarian suppression/failure
Diagnosis:
hCG <25
LH level measurement (if near menopausal level, diagnosis is supported)
Administer estrogen to suppress LH > measure hCG
Familial hCG: rare genetic condition
Urine and serum levels elevated. Levels <200
Diagnosis of exclusion
Testing first degree family members of either sex can support the diagnosis
Heterophilic antibodies: antibodies interfere with antigens in hCG immunoassays
Less common with modern immunoassays
Diagnosis: measure urine hCG (will be negative in the setting of heterophilic antibodies)
Germ cell tumors of the ovary
GTN
Steps after diagnosis:
H&P
Do not biopsy vaginal nodules if present!
Labs: T&S, hCG quant, CBC, CMP, TSH
Imaging: CXray always
If CXray positive > CT C/A/P and brain MRI
Staging
FIGO stage
Stage I = limited to uterus
Stage II = adnexa or vagina, limited to genital structures
Stage III = pulmonary mets w/ or w/o pelvic involvement
Stage IV = other metastatic disease
WHO scoring: more prognostic
Score < 7 = low risk GTN
Score ≥7 = high risk GTN (high risk for resistance to single agent chemo)
Score ≥12 = ultra high risk
Often non-molar prior pregnancy, more likely to fail multi-agent chemo
WHO score does not apply to PSTT and ETT
Treatment of low risk GTN (WHO <7)
Single agent therapy: methotrexate vs. dactinomycin
No clear data on which agent or dosing schedule is best
GOG 174: 2011. Pulse dactinomycin vs. weekly methotrexate for patients with low risk GTN
Complete response rates low for both regimens, improved with pulse dactinomycin (70 vs. 52%)
Cochrane review: 2016: methotrexate more likely to fail in the front line setting, dactinomycin more likely to lead to a primary care
However most trials included utilized weekly methotrexate > has since been shown to be less effective than daily or every other day regimens
Weekly methotrexate regimen no longer recommended; very low success rate especially with higher WHO scores.
NRG/GOG 2075: 2020. Phase III trial of pulse dactinomycin vs. multi-day methotrexate for low risk GTN
5- or 8-day regimen for methotrexate
Trial closed early with <30 patients in each arm due to low recruitment
Cure rate not significantly different (88% methotrexate vs. 79% dactinomycin).
Survival rate 100%.
QOL similar between arms
Chemotherapies
Methotrexate: antimetabolite (see episode 7 for discussion of antimetabolites). Folate antagonist.
Admin: 5-day or 8-day regimen, repeated every 14 days
Side effects:
stomatitis most common w/ doses used to treat low risk GTN.
Other: hepatotoxicity, renal toxicity, GI toxicity (N/V, esp w/ higher doses), dermatologic, pulmonary sensitivity, encephalopathy
Cleared renally: caution in patients with renal disease
Minimize nephrotoxicity with hydration and alkalinization of the urine
Dermatologic: avoid sunlight
Leucovorin: folate analog; counters the toxic effects of methotrexate in normal tissue
Necessary if methotrexate doses are >250mg/m2
Compared to dactinomycin: less N/V, less alopecia, more mucositis and eye pain
Dactinomycin: antitumor antibiotic
Admin: can be given as 5-day regimen or large pulse dose every 2 weeks.
Side effects: emetogenic, alopecia, vesicant
Avoid extravasation
Rare risk of dermatologic toxicity like Stevens Johnson Syndrome
Less hepatic and renal dysfunction than with methotrexate
Similar risk of myelosuppression as with methotrexate
Treatment of low-risk GTN: other considerations
Repeat curettage: typically not performed/recommended
When to consider
Persistent vaginal bleeding causing significant symptoms
Unclear if first curettage was complete in evacuating tissue
Low risk GTN for no extrauterine disease: in some cases second curettage will avoid need for chemotherapy
GOG 242: phase II trial, 60 patients w/ low risk GTN > second curettage
Cure rate was 40%
Hysterectomy after first D&C/diagnosis: consider for patients no longer desiring fertility with uterine confined disease
Retrospective study, 2017: 66% cure rate
Monitoring during treatment
Hcg every 2 weeks until normalization > hCG monthly for one year
Chemotherapy continued for 2-3 cycles after normalization
Effective contraception during follow-up
OCPs traditionally thought to be necessary
Recent evidence: progesterone IUD is safe, wait until hCG normalizes
Chemo resistance diagnosis
hCG rises > 10% over two chemo cycles
hCG plateau (+/- 10%) over three chemo cycles
Predicting response
Patients with very elevated initial elevated hCG (>400,000) often won’t respond to single agent chemo
Metastatic disease or choriocarcinoma and an hCG >150k: will mostly need multiagent therapy
Treatment of chemotherapy resistance (previous single agent therapy)
Restage at time of recurrence or relapse if initial response
Single or multi-agent therapy acceptable: decisions not based on RCTs
If good initial response > plateau: consider another single-agent therapy
Complete response rate ~75%
Poor response to initial therapy or initial response but then quickly rising hCG: switch to multi-agent
EMACO: etoposide, methotrexate, actinomycin D, alternating with cyclophosphamide and vincristine
Typical choice of multi agen therapy
Cure rate close to 100%
Treatment of high-risk GTN
~90% cure rate (but 70% if stage IV disease, esp w/ liver or brain metastases)
Multi-agent therapy. Often requires inpatient admission. Options include:
EMACO
Standard due to high cure rate and relatively tolerable toxicities
EMA-EP: substitutes etoposide and cisplatin for the cyclophosphamide and vincristine of EMACO
May be more effective in ultra-high risk disease (but is more toxic)
Historic regimens: MAC and CHAMOCA
Ultra high-risk disease: consider induction chemotherapy with low-dose etoposide-cisplatin
Starting with full EMACO can result in tumor collapse > hemorrhage, metabolic acidosis, multi-organ failure > early treatment related death
Risk of early death <1% with induction chemo vs. 7% in historic cohort
Alifrangis 2013
CNS metastases
Incorporate high-dose methotrexate (1000 mg/m2)
Give additional oral doses of leucovorin
Intrathecal methotrexate is an option
Cure rate 85% vs. 70% with high-dose IV for CNS mets
Done routinely in the UK, but not in the US
Stereotactic brain radiation
Incomplete response or relapse after initial multi-agent therapy: salvage chemotherapy
Regimens involve etoposide and a platinum agent
Consider surgical resection for oligometastatic disease
Switch to EMA-EP if originally got EMACO (complete response rate 75-85%)
Other options
Cis/taxol alternating with taxol/etoposide
Need to incorporate G-CSF if using cisplatin/etoposide
BEP
Others
High-dose chemotherapy in combination for stem cell transplat (option in refractory/poor prognosis). Multiple regimens. Quite toxic and works better in patients with low hCG
Sequelae of chemo regimens
Risk of secondary cancers: increased risk of oral cancers, melanoma, meningioma, leukemia
Risk of leukemia increases significantly after lifetime dose of 2000mg
Risk of premature menopause
With EMACO: risk of 13% prior to age 40 and 36% prior to age 45
Methotrexate: similar to general population
Emerging agents
Immune checkpoint inhibitors (pembrolizumab or nivolumab)
GTN cells strongly express PD-L1
Ghorani et al: case series of 4 patients. Durable response in ¾ patients
When/how to incorporate not yet established. Multiple ongoing studies.
Intermediate Trophoblastic Tumors. Make up 0.23% of all GTD. Generally slow growing. HCG not reliably elevated. Less chemoresponse.
Clinical presentation: AUB, amenorrhea
30-50% metastatic at time of presentation (lungs most common site)
Prognosis: 80% 5-year survival, near 100% if locally confined
Poor prognostic markers: advanced stage, prolonged interval from last known pregnancy event
Pathology
PSTT
CD146 (MEL-CAM), hPL expression
ETT
P63, Cyclin E expression. CD146 and hPL less common.
Treatment: surgery
Hysterectomy with salpingectomy is SOC
Pelvic lymph node biopsy for apparent uterine confined disease
Debulking and resection for metastatic disease
Adjuvant therapy for metastatic disease: platinum-based regimen
Consider in stage I disease with poor prognosis
Regimens: EMA-EP, other options (see NCCN guidelines for details)
Monitoring after treatment: hCG monitoring, especially if initially elevated
PET/CT at completion of chemo, every 6-12 months for up to 3 years
Recurrences can occur remotely
Treatment of recurrence: options include re-attempt first-line therapy, alternate high-risk GTN regimens, or best supportive care
references
work in progress!