Gestational trophoblastic neoplasia

Section editor
	Alaina J. Brown, MD, MPH Vanderbilt University Nashville, TN, USA LinkedIn

4 regimens on this page 6 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

• 2013: Seckl et al. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Gestational Trophoblastic Neoplasia
  • 2019: Abu-Rustum et al. Gestational Trophoblastic Neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. PubMed

Low-risk, all lines of therapy

Dactinomycin monotherapy

Regimen variant #1, no cap

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Osathanondh et al. 1975	1965-1973	Non-randomized (RT)
Osborne et al. 2011 (GOG 0174)	1999-2007	Phase 3 (E-switch-ic)	Methotrexate	Seems to have superior CR rate (primary endpoint)

Chemotherapy

• Dactinomycin (Cosmegen) 1.25 mg/m² IV push once on day 1

14-day cycles "until the βhCG assay had reached the institutional normal, or until either a rise or plateau in the βhCG level was observed"

Regimen variant #2, capped

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schink et al. 2020 (GOG 275)	2012-2016	Phase 3 (C)	Methotrexate; multi-day	Did not meet primary endpoint of CR rate

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Dactinomycin (Cosmegen) 1.25 mg/m² (maximum dose of 2 mg) IV push once on day 1

14-day cycles until hCG values have returned to normal plus 1 cycle

References

1. Osathanondh R, Goldstein DP, Pastorfide GB. Actinomycin D as the primary agent for gestational trophoblastic disease. Cancer. 1975 Sep;36(3):863-6. link to original article PubMed
2. GOG 0174: Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley JL, Provencher D, Scott Miller D, Covens AL, Lage JM. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study. J Clin Oncol. 2011 Mar 1;29(7):825-31. Epub 2011 Jan 24. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003702
3. GOG 275: Schink JC, Filiaci V, Huang HQ, Tidy J, Winter M, Carter J, Anderson N, Moxley K, Yabuno A, Taylor SE, Kushnir C, Horowitz N, Miller DS. 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 Aug;158(2):354-360. Epub 2020 May 24. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01535053

Mercaptopurine & Methotrexate

Regimen

Study	Dates of enrollment	Evidence
Li et al. 1958	1955-1957	Pilot

Note: this is of historic interest.

Chemotherapy

• Mercaptopurine (6-MP) 600 to 800 mg PO once per day on days 1 to 5
• Methotrexate (MTX) 15 to 25 mg PO or IM once per day on days 1 to 5

5-day course

References

1. Li MC, Hertz R, Bergenstal DM. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N Engl J Med. 1958 Jul 10;259(2):66-74. link to original article contains dosing details in manuscript PubMed

Methotrexate monotherapy

Regimen variant #1, no escalation

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 1956	NR	Pilot
Li et al. 1958	1955-1957	Pilot
Osborne et al. 2011 (GOG 0174)	1999-2007	Phase 3 (C)	Dactinomycin	Seems to have inferior CR rate

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Methotrexate (MTX) 30 mg/m² IM once on day 1

7-day cycles "until the βhCG assay had reached the institutional normal, or until either a rise or plateau in the βhCG level was observed"

Regimen variant #2, with escalation

Study	Dates of enrollment	Evidence
Homesley et al. 1988	NR	Phase 2

Note: Dose was only escalated if "no major toxicity" was experienced.

Chemotherapy

• Methotrexate (MTX) as follows:
  • Cycles 1 to 3: 30 mg/m² IM once on day 1
  • Cycles 4 to 6: 35 mg/m² IM once on day 1
  • Cycles 7 to 9: 40 mg/m² IM once on day 1
  • Cycles 10 to 12: 45 mg/m² IM once on day 1
  • Cycle 13 onwards: 50 mg/m² IM once on day 1

7-day cycles for 1 cycle past normalization of β-hCG

References

1. Li MC, Hertz R, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med. 1956 Nov;93(2):361-6. link to original article PubMed
2. Li MC, Hertz R, Bergenstal DM. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N Engl J Med. 1958 Jul 10;259(2):66-74. link to original article PubMed
3. Homesley HD, Blessing JA, Rettenmaier M, Capizzi RL, Major FJ, Twiggs LB. Weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease. Obstet Gynecol. 1988 Sep;72(3 Pt 1):413-8. link to original article contains dosing details in manuscript PubMed
4. GOG 0174: Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord A, Kelley JL, Provencher D, Scott Miller D, Covens AL, Lage JM. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study. J Clin Oncol. 2011 Mar 1;29(7):825-31. Epub 2011 Jan 24. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003702
5. GOG 275: Schink JC, Filiaci V, Huang HQ, Tidy J, Winter M, Carter J, Anderson N, Moxley K, Yabuno A, Taylor SE, Kushnir C, Horowitz N, Miller DS. 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 Aug;158(2):354-360. Epub 2020 May 24. link to original article link to PMC article PubMed NCT01535053

High-risk, all lines of therapy

EMA/CO

EMA/CO: Etoposide, Methotrexate, Actinomycin D alternating with Cyclophosphamide & Oncovin (Vincristine)

Regimen

Study	Dates of enrollment	Evidence
Newlands et al. 1991	1979-1989	Non-randomized (RT)

Chemotherapy, EMA portion (odd cycles)

• Etoposide (Vepesid) 100 mg/m² IV over 30 minutes once per day on days 1 & 2
• Methotrexate (MTX) 300 mg/m² IV over 12 hours once on day 1
• Dactinomycin (Cosmegen) 0.5 mg IV push once per day on days 1 & 2

Chemotherapy, CO portion (even cycles)

• Cyclophosphamide (Cytoxan) 600 mg/m² IV over 30 minutes once on day 1
• Vincristine (Oncovin) 1 mg/m² IV push once on day 1

7-day cycles

References

1. Newlands ES, Bagshawe KD, Begent RH, Rustin GJ, Holden L. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol. 1991 Jun;98(6):550-7. link to original article contains dosing details in manuscript PubMed
2. Retrospective: Alifrangis C, Agarwal R, Short D, Fisher RA, Sebire NJ, Harvey R, Savage PM, Seckl MJ. EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol. 2013 Jan 10;31(2):280-6. Epub 2012 Dec 10. link to original article PubMed