Chemotherapy initiation with single-course methotrexate alone or combined with dactinomycin versus multi-course methotrexate for low-risk gestational trophoblastic neoplasia: a multi-centric randomized clinical trial

Abstract

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX+ dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference –5.1%, 95% confidence interval (CI) –19.4% to 9.2%, P=0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P=0.577). For the single-course MTX+ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%–36.6%, P<0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P=0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN.

Keywords

gestational trophoblastic neoplasia (GTN) / methotrexate (MTX) / dactinomycin (ACTD)

References

[1] Alazzam M, Tidy J, Hancock BW, Osborne R, Lawrie TA. First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev 2012; 7(7): CD007102

[2] Lawrie TA, Alazzam M, Tidy J, Hancock BW, Osborne R. First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev 2016; (6): CD007102

[3] Ngan HYS, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, Lurain JR, Massuger L. Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynaecol Obstet 2018; 143(Suppl 2): 79–85

[4] National Comprehensive Cancer Network. Gestational Trophoblastic Neoplasia, version 3.2020, NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network, 2020

[5] Maestá I, Nitecki R, Horowitz NS, Goldstein DP, de Freitas Segalla Moreira M, Elias KM, Berkowitz RS. Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience. Gynecol Oncol 2018; 148(1): 161–167

[6] 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; 29(7): 825–831

[7] Lee YJ, Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT, Nam JH. Comparing and evaluating the efficacy of methotrexate and actinomycin D as first-line single chemotherapy agents in low risk gestational trophoblastic disease. J Gynecol Oncol 2017; 28(2): e8

[8] Abrão RA, de Andrade JM, Tiezzi DG, Marana HR, Candido dos Reis FJ, Clagnan WS. Treatment for low-risk gestational trophoblastic disease: comparison of single-agent methotrexate, dactinomycin and combination regimens. Gynecol Oncol 2008; 108(1): 149–153

[9] Lertkhachonsuk AA, Israngura N, Wilailak S, Tangtrakul S. Actinomycin D versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer 2009; 19(5): 985–988

[10] Taylor F, Grew T, Everard J, Ellis L, Winter MC, Tidy J, Hancock BW, Coleman RE. The outcome of patients with low risk gestational trophoblastic neoplasia treated with single agent intramuscular methotrexate and oral folinic acid. Eur J Cancer 2013; 49(15): 3184–3190

[11] Berkowitz RS, Goldstein DP, Bernstein MR. Ten year’s experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986; 23(1): 111–118

[12] Berek JS. Gestational trophoblastic disease. In: Novak’s Gynecology. 13th ed. Philadelphia: Lippincott Williams &Wilkins, 2002. 1369

[13] Garrett AP, Garner EO, Goldstein DP, Berkowitz RS. Methotrexate infusion and folinic acid as primary therapy for nonmetastatic and low-risk metastatic gestational trophoblastic tumors. 15 years of experience. J Reprod Med 2002; 47(5): 355–362

[14] Eiriksson L, Wells T, Steed H, Schepansky A, Capstick V, Hoskins P, Pike J, Swenerton K. Combined methotrexate-dactinomycin: an effective therapy for low-risk gestational trophoblastic neoplasia. Gynecol Oncol 2012; 124(3): 553–557

[15] Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, Seckl MJ, Sasaki S, Soper JT. Trophoblastic disease. Int J Gynaecol Obstet 2012; 119(Suppl 2): S130–S136

[16] Berek JS. Berek & Novak’s Gynecology. 15th ed. Philadelphia: Lippincott Williams & Wilkins, 2012

[17] Chan KK, Huang Y, Tam KF, Tse KY, Ngan HY. Single-dose methotrexate regimen in the treatment of low-risk gestational trophoblastic neoplasia. Am J Obstet Gynecol 2006; 195(5): 1282–1286

[18] Growdon WB, Wolfberg AJ, Goldstein DP, Feltmate CM, Chinchilla ME, Lieberman ES, Berkowitz RS. Evaluating methotrexate treatment in patients with low-risk postmolar gestational trophoblastic neoplasia. Gynecol Oncol 2009; 112(2): 353–357

[19] Chapman-Davis E, Hoekstra AV, 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

[20] Frijstein MM, Lok C, van Trommel NE, Ten Kate-Booij MJ, Massuger L, van Werkhoven E, Short D, Aguiar X, Fisher RA, Kaur B, Sarwar N, Sebire NJ, Seckl MJ. Lung metastases in low-risk gestational trophoblastic neoplasia: a retrospective cohort study. BJOG 2020; 127(3): 389–395

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