Gestational Trophoblastic Neoplasia and GTN Chemotherapy

Gestational Trophoblastic DiseaseChemotherapy
Written By Sydney Oesch

Episode Notes

  1. Gestational trophoblastic neoplasia (GTN) vs. Gestational trophoblastic (GTD)

    1. GTD = benign and malignant tumors. Includes GTN as well as complete and partial hydatidiform mole (benign GTD)

  2. Epidemiology of GTD

    1. Reported incidence varies by region:

      1. 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)

  3. Benign GTD

    1. Molar pregnancies are premalignant > risk of developing into malignancy

    2. Subtype breakdown

      1. 80% of GTD = hydatidiform moles/non-malignant entities

      2. 15% = invasive mole

      3. 5% = other subtypes of GTN (choriocarcinoma, placental site trophoblastic tumor – PSTT, epithelioid trophoblastic tumor –ETT)

    3. Molar pregnancies -subtype differentiation (brief overview)

      1. Complete = egg without maternal DNA is fertilized > diploid

        1. No fetal tissue

        2. Ultrasound = snowstorm appearance

        3. Absent p57 staining on pathology

        4. Risk of postmolar GTN: 15-20%

        5. Higher hCG > more likely to have “classic” molar pregnancy symptoms: HTN, size >dates, increased N/V, AUB, pre-eclampsia

      2. Partial = normal egg fertilized with two sperm or altered sperm > triploid

        1. Some fetal tissue

        2. P57 positive on pathology

        3. Risk of postmolar GTN: 5%

        4. More likely to be diagnosed incidentally, lower hcg values

      3. Short Tandem Repeat analysis, flow cytometry: molecular genotyping which can help distinguish between complete and partial moles.

    4. Rate of postmolar GTN has not decreased despite earlier diagnosis of molar pregnancy –malignant potential is intrinsic, rather than due to disease progression/duration

    5. Preop labs: hCG, T&S

      1. Consider thyroid labs, pre-eclampsia labs (especially if later presentation with higher risk for complications)

      2. Chest xray: for all with pulmonary symptoms (consider routinely ordering chest xray)

      3. Measurement of hCG, issues:

        1. Hook effect = negative hCG on serum assay in the setting of extremely high hCG (>1 million): detection antibody is supersaturated with BhCG  >test fails

          1. Serial dilutions of sample can reveal/diagnose this effect

        2. 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

    6. Management

      1. Suction D&C > hcg monitoring is most common management

      2. Hysterectomy w/ BS: preferred if patients have completed childbearing, if likely to have a complete mole, AND have risk factors for postmolar GTN

        1. Risk factors for postmolar GTN: hcg >100,000, markedly enlarged uterus, large theca lutein cysts, age >40 yo, signs of myometrial invasion on imaging

        2. Emerging ways to predict risk of malignant transformation/postmnolar GTN: microRNA, DNA methylation status

      3. Medication management not recommended.

      4. Special management considerations

        1. Hyperthyroidism: at risk for thyroid storm.

          1. Administer beta-blocker prior to surgery to manage symptoms related to thyroid storm (fever, HTN, tachycardia, potentially ARDS)

        2. Rhogam for Rh negative patients

        3. Ultrasound guidance recommended during D&C (ensure evacuation, reduce risk of uterine perforation)

        4. Oxytocin for improved post-evacuation myometrial contraction

        5. During hysterectomy: MIS preferred if feasible

    7. Postop complications

      1. Cardiopulmonary symptoms: respiratory distress syndrome. 

        1. Etiologies: thyroid storm or throphoblastic embolization

        2. Management: supportive: resp support

        3. Clinical course: self-resolving, usually within 2-3 days, as hCG levels decline

    8. HCG monitoring postoperatively

      1. Protocols vary by institution

      2. Options: 

        1. Weekly hCG until undetectable, then monthly x 3 months (complete mole)

        2. Weekly hCG levels until undetectable, followed by one hCG level in one month (partial mole)

        3. Appropriate fall = 10%

  4. No effective interventions to prevent of postmolar GTN

    1. Cochrange review 2017: 3 RCTs investigating prophylactic adjuvant chemotherapy

      1. Conclusion: insufficient evidence to recommend

    2. NCCN guidelines: prophylactic methotrexate or dactinomycin can be considered for patients we think of as being high-risk for development of postmolar GTN

    3. Postmolar chemotherapy NOT recommended for patients treated primarily with hysterectomy.

  5. Diagnosis of postmolar GTN

    1. Increase by >10% across three values in a two-week period

    2. Plateau (+/- 10%) across four values in a three-week period

      1. *plateau is less concerning than rise > requires more values

    3. Diagnostic criteria no longer used: hCG persistently elevated at 6 months despite appropriate dropping values

    4. Consider GTN diagnosis in any reproductive aged patient with unexplained hCG elevation, even if no clear antecedent pregnancy

  6. Alternative causes of elevated hCG

    1. New pregnancy

    2. 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.

      1. Sometimes, when levels are persistently low (<200miu/mL), it can be due to quiescent GTN.

      2. Measurement of hyperglycosylated hCg can support the diagnosis (should be <10% of total hCG)

        1. Hyperglycosylated hCG produced by cytotrophoblast

      3. Up to 10% risk of invasive GTN

      4. Management: monthly hCG monitoring and avoidance of pregnancy

      5. Etiology: small residual syncytiotrophoblast foci without cytotrophoblast

    3. Peri/postmenopausal elevation: low levels of hCG due to LH upregulation with ovarian suppression/failure

      1. Diagnosis: 

        1. hCG <25

        2. LH level measurement (if near menopausal level, diagnosis is supported)

        3. Administer estrogen to suppress LH > measure hCG

    4. Familial hCG: rare genetic condition

      1. Urine and serum levels elevated. Levels <200

      2. Diagnosis of exclusion

      3. Testing first degree family members of either sex can support the diagnosis

    5. Heterophilic antibodies: antibodies interfere with antigens in hCG immunoassays

      1. Less common with modern immunoassays

      2. Diagnosis: measure urine hCG (will be negative in the setting of heterophilic antibodies)

    6. Germ cell tumors of the ovary

  7. GTN 

    1. Steps after diagnosis: 

      1. H&P

        1. Do not biopsy vaginal nodules if present!

      2. Labs: T&S, hCG quant, CBC, CMP, TSH

      3. Imaging: CXray always

        1. If CXray positive > CT C/A/P and brain MRI

    2. Staging

      1. FIGO stage

        1. Stage I = limited to uterus

        2. Stage II = adnexa or vagina, limited to genital structures

        3. Stage III = pulmonary mets w/ or w/o pelvic involvement

        4. Stage IV = other metastatic disease

      2. WHO scoring: more prognostic

        1. Score < 7 = low risk GTN

        2. Score ≥7 = high risk GTN (high risk for resistance to single agent chemo)

        3. Score ≥12 = ultra high risk 

          1. Often non-molar prior pregnancy, more likely to fail multi-agent chemo

      3. WHO score does not apply to PSTT and ETT

    3. Treatment of low risk GTN (WHO <7)

      1. Single agent therapy: methotrexate vs. dactinomycin

        1. No clear data on which agent or dosing schedule is best

        2. GOG 174: 2011. Pulse dactinomycin vs. weekly methotrexate for patients with low risk GTN

          1. Complete response rates low for both regimens, improved with pulse dactinomycin (70 vs. 52%)

        3. Cochrane review: 2016: methotrexate more likely to fail in the front line setting, dactinomycin more likely to lead to a primary care

          1. However most trials included utilized weekly methotrexate > has since been shown to be less effective than daily or every other day regimens

          2. Weekly methotrexate regimen no longer recommended; very low success rate especially with higher WHO scores.

        4. NRG/GOG 2075: 2020. Phase III trial of pulse dactinomycin vs. multi-day methotrexate for low risk GTN

          1. 5- or 8-day regimen for methotrexate

          2. Trial closed early with <30 patients in each arm due to low recruitment

          3. Cure rate not significantly different (88% methotrexate vs. 79% dactinomycin).

          4. Survival rate 100%. 

          5. QOL similar between arms

      2. Chemotherapies

        1. Methotrexate: antimetabolite (see episode 7 for discussion of antimetabolites). Folate antagonist.

          1. Admin: 5-day or 8-day regimen, repeated every 14 days

          2. Side effects: 

            1. stomatitis most common w/ doses used to treat low risk GTN.

            2.  Other: hepatotoxicity, renal toxicity, GI toxicity (N/V, esp w/ higher doses), dermatologic, pulmonary sensitivity, encephalopathy

              1. Cleared renally: caution in patients with renal disease

              2. Minimize nephrotoxicity with hydration and alkalinization of the urine

              3. Dermatologic: avoid sunlight

            3. Leucovorin: folate analog; counters the toxic effects of methotrexate in normal tissue

              1. Necessary if methotrexate doses are >250mg/m2

            4. Compared to dactinomycin: less N/V, less alopecia, more mucositis and eye pain

        2. Dactinomycin: antitumor antibiotic

          1. Admin: can be given as 5-day regimen or large pulse dose every 2 weeks.

          2. Side effects: emetogenic, alopecia, vesicant

            1. Avoid extravasation

            2. Rare risk of dermatologic toxicity like Stevens Johnson Syndrome

            3. Less hepatic and renal dysfunction than with methotrexate

            4. Similar risk of myelosuppression as with methotrexate

      3. Treatment of low-risk GTN: other considerations

        1. Repeat curettage: typically not performed/recommended

          1. When to consider

            1. Persistent vaginal bleeding causing significant symptoms

            2. Unclear if first curettage was complete in evacuating tissue

            3. Low risk GTN for no extrauterine disease: in some cases second curettage will avoid need for chemotherapy

              1. GOG 242: phase II trial, 60 patients w/ low risk GTN > second curettage

                1. Cure rate was 40%

        2. Hysterectomy after first D&C/diagnosis: consider for patients no longer desiring fertility with uterine confined disease

          1. Retrospective study, 2017: 66% cure rate

      4. Monitoring during treatment

        1. Hcg every 2 weeks until normalization > hCG monthly for one year

        2. Chemotherapy continued for 2-3 cycles after normalization 

        3. Effective contraception during follow-up 

          1. OCPs traditionally thought to be necessary

          2. Recent evidence: progesterone IUD is safe, wait until hCG normalizes

        4. Chemo resistance diagnosis

          1. hCG rises > 10% over two chemo cycles

          2. hCG plateau (+/- 10%) over three chemo cycles

        5. Predicting response

          1. Patients with very elevated initial elevated hCG (>400,000) often won’t respond to single agent chemo

          2. Metastatic disease or choriocarcinoma and an hCG >150k: will mostly need multiagent therapy

      5. Treatment of chemotherapy resistance (previous single agent therapy)

        1. Restage at time of recurrence or relapse if initial response

        2. Single or multi-agent therapy acceptable: decisions not based on RCTs

          1. If good initial response > plateau: consider another single-agent therapy

            1. Complete response rate ~75%

          2. Poor response to initial therapy or initial response but then quickly rising hCG: switch to multi-agent

            1. EMACO: etoposide, methotrexate, actinomycin D, alternating with cyclophosphamide and vincristine

              1. Typical choice of multi agen therapy

              2. Cure rate close to 100%

    4. Treatment of high-risk GTN

      1. ~90% cure rate (but 70% if stage IV disease, esp w/ liver or brain metastases)

      2. Multi-agent therapy. Often requires inpatient admission. Options include:

        1. EMACO

          1. Standard due to high cure rate and relatively tolerable toxicities

        2. EMA-EP: substitutes etoposide and cisplatin for the cyclophosphamide and vincristine of EMACO

          1. May be more effective in ultra-high risk disease (but is more toxic)

        3. Historic regimens: MAC and CHAMOCA

      3. Ultra high-risk disease: consider induction chemotherapy with low-dose etoposide-cisplatin

        1. Starting with full EMACO can result in tumor collapse > hemorrhage, metabolic acidosis, multi-organ failure > early treatment related death

          1. Risk of early death <1% with induction chemo vs. 7% in historic cohort

            1. Alifrangis 2013

      4. CNS metastases

        1. Incorporate high-dose methotrexate (1000 mg/m2)

          1. Give additional oral doses of leucovorin

        2. Intrathecal methotrexate is an option

          1. Cure rate 85% vs. 70% with high-dose IV for CNS mets

          2. Done routinely in the UK, but not in the US

        3. Stereotactic brain radiation

      5. Incomplete response or relapse after initial multi-agent therapy: salvage chemotherapy

        1. Regimens involve etoposide and a platinum agent

        2. Consider surgical resection for oligometastatic disease

        3. Switch to EMA-EP if originally got EMACO (complete response rate 75-85%)

        4. Other options

          1. Cis/taxol alternating with taxol/etoposide

            1. Need to incorporate G-CSF if using cisplatin/etoposide

          2. BEP

          3. Others 

      6. 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

      7. Sequelae of chemo regimens

        1. Risk of secondary cancers: increased risk of oral cancers, melanoma, meningioma, leukemia

          1. Risk of leukemia increases significantly after lifetime dose of 2000mg

        2. Risk of premature menopause

          1. With EMACO: risk of 13% prior to age 40 and 36% prior to age 45

          2. Methotrexate: similar to general population

    5. Emerging agents

      1. Immune checkpoint inhibitors (pembrolizumab or nivolumab)

        1. GTN cells strongly express PD-L1

        2. Ghorani et al: case series of 4 patients. Durable response in ¾ patients

      2. When/how to incorporate not yet established. Multiple ongoing studies.

  8. Intermediate Trophoblastic Tumors. Make up 0.23% of all GTD. Generally slow growing. HCG not reliably elevated. Less chemoresponse.

    1. Clinical presentation: AUB, amenorrhea

    2. 30-50% metastatic at time of presentation (lungs most common site)

    3. Prognosis: 80% 5-year survival, near 100% if locally confined

      1. Poor prognostic markers: advanced stage, prolonged interval from last known pregnancy event

    4. Pathology

      1. PSTT

        1. CD146 (MEL-CAM), hPL expression

      2. ETT

        1. P63, Cyclin E expression. CD146 and hPL less common. 

    5. Treatment: surgery

      1. Hysterectomy with salpingectomy is SOC

        1. Pelvic lymph node biopsy for apparent uterine confined disease

        2. Debulking and resection for metastatic disease

      2. Adjuvant therapy for metastatic disease: platinum-based regimen

        1. Consider in stage I disease with poor prognosis

        2. Regimens: EMA-EP, other options (see NCCN guidelines for details)

    6. Monitoring after treatment: hCG monitoring, especially if initially elevated

      1. PET/CT at completion of chemo, every 6-12 months for up to 3 years

      2. Recurrences can occur remotely

    7. Treatment of recurrence: options include re-attempt first-line therapy, alternate high-risk GTN regimens, or best supportive care

references

1.    Bower M, Newlands ES, Holden L, et al. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol. 1997;15(7):2636-2643. doi:10.1200/JCO.1997.15.7.2636

2.    Schink JC, Filiaci V, Huang HQ, et al. An international randomized phase III trial of pulse actinomycin-D versus multi-day methotrexate for the treatment of low risk gestational trophoblastic neoplasia; NRG/GOG 275. Gynecol Oncol. 2020;158(2):354-360. doi:10.1016/J.YGYNO.2020.05.013

3.    Chapman-Davis E, Hoekstra A V., Rademaker AW, Schink JC, Lurain JR. Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: Factors associated with resistance to single-agent methotrexate chemotherapy. Gynecol Oncol. 2012;125(3):572-575. doi:10.1016/j.ygyno.2012.03.039

4.    Eysbouts YK, Massuger LFAG, IntHout J, Lok CAR, Sweep FCGJ, Ottevanger PB. The added value of hysterectomy in the management of gestational trophoblastic neoplasia. Gynecol Oncol. 2017;145(3):536-542. doi:10.1016/J.YGYNO.2017.03.018

5.    Osborne RJ, Filiaci V, Schink JC, et al. Phase III Trial of Weekly Methotrexate or Pulsed Dactinomycin for Low-Risk Gestational Trophoblastic Neoplasia: A Gynecologic Oncology Group Study. Journal of Clinical Oncology. 2011;29(7):825. doi:10.1200/JCO.2010.30.4386

6.    Osborne RJ, Filiaci VL, Schink JC, et al. Second Curettage for Low-Risk Nonmetastatic Gestational Trophoblastic Neoplasia. Obstetrics and gynecology. 2016;128(3):535. doi:10.1097/AOG.0000000000001554

7.    Wang Q, Fu J, Hu L, et al. Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia. Cochrane Database Syst Rev. 2017;9(9). doi:10.1002/14651858.CD007289.PUB3

8.    Pezeshki M, Hancock BW, Silcocks P, et al. The role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease. Gynecol Oncol. 2004;95(3):423-429. doi:10.1016/J.YGYNO.2004.08.045

9.    Lawrie TA, Alazzam M, Tidy J, Hancock BW, Osborne R. First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev. 2016;2016(6). doi:10.1002/14651858.CD007102.PUB4

10.  Prouvot C, Golfier F, Massardier J, et al. Efficacy and Safety of Second-Line 5-Day Dactinomycin in Case of Methotrexate Failure for Gestational Trophoblastic Neoplasia. Int J Gynecol Cancer. 2018;28(5):1038-1044. doi:10.1097/IGC.0000000000001248

11.  Alifrangis C, Agarwal R, Short D, et al. EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol. 2013;31(2):280-286. doi:10.1200/JCO.2012.43.1817

12.  Savage P, Kelpanides I, Tuthill M, Short D, Seckl MJ. Brain metastases in gestational trophoblast neoplasia: an update on incidence, management and outcome. Gynecol Oncol. 2015;137(1):73-76. doi:10.1016/J.YGYNO.2015.01.530

13.  Frijstein MM, Lok CAR, Short D, et al. The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia. Eur J Cancer. 2019;109:162-171. doi:10.1016/J.EJCA.2018.12.033

14.  Frijstein MM, Lok CAR, van Trommel NE, et al. Management and prognostic factors of epithelioid trophoblastic tumors: Results from the International Society for the Study of Trophoblastic Diseases database. Gynecol Oncol. 2019;152(2):361-367. doi:10.1016/J.YGYNO.2018.11.015

15.  Ghorani E, Kaur B, Fisher RA, et al. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia. Lancet. 2017;390(10110):2343-2345. doi:10.1016/S0140-6736(17)32894-5

 

Sydney Oesch
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