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.

Objectives: Methotrexate and actinomycin-D are both effective first-line drugs for low-risk (WHO score 0-6) Gestational Trophoblastic Neoplasia (GTN) with considerable debate about which is more effective, less toxic, and better tolerated. The primary trial objective was to test if treatment with multi-day methotrexate (MTX) was inferior to pulse actinomycin-D (ACT-D). Secondary objectives included evaluation of severity and frequency of adverse events, and impact on quality of life (QOL).
Methods: This was a prospective international cooperative group randomized phase III two arm non-inferiority study (Clinical Trials Identifier: (NCT01535053). The control arm was ACT-D; the experimental arm was multi-day MTX regimen (institutional preference of 5 or 8 day). Outcome measures included complete response rate, recurrence rate, toxicity, and QOL as measured by FACT-G and FACIT supplemental items.
Results: The complete response rates for multi-day methotrexate and pulse actinomycin-D were 88% (23/26 patients) and 79% (22/28 patients) (p = NS) respectively, there were two recurrences in each arm, and 100% of patients survived. Significant toxicity was minimal, but mouth sores (mucositis), and eye pain were significantly more common in the MTX arm (p = 0.001 and 0.01 respectively). Quality of life showed no significant difference in overall quality of life, body image, sexual function, or treatment related side effects. The study was closed for low accrual rate (target 384, actual accrual 57), precluding statistical analysis of the primary objective.
Conclusions: The complete response rate for multi-day methotrexate was higher than actinomycin-D, but did not reach statistical significance. The multi-day MTX regimens were associated with significantly more mucositis and were significantly less convenient.
Competing Interests: Declaration of competing interest Dr. Julian Schink, Dr. Jeanne Carter, Dr. Matthew Winter, Dr. Nancy Anderson, Dr. Katherine Moxley, Dr. Akira Yabucoa, Dr. Sarah Taylor, Dr. Christina Kushnir, Dr. Neil Horowitz and Ms. Helen Huang have nothing to disclose. Dr. Virginia Filiaci reports grants from NIH, during the conduct of the study; grants from GOG Foundation, Inc., from null, outside the submitted work. Dr. Tidy reports personal fees from Zilico Ltd., outside of the submitted work. Dr. David Miller reports personal fees received as consultant for Tesaro, Eisai, Incyte, Karyopharm and Genentech. Dr. Miller also reports money was paid to his institution by Merck and grants received from nVision Medical, Advenchen, Forty Seven, Merck and Syros
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