By Alexandra Morell, MD
Synopsis: This 28-year retrospective cohort study demonstrated that administration of a single 1.25 mg/m2 intravenous dose of actinomycin-D at the time of uterine evacuation for patients with high-risk complete hydatidiform molar pregnancies was associated with a significantly lower rate of post-molar gestational trophoblastic neoplasia (19% vs. 40%, P < 0.001) and a 52% reduction in relative risk (RR; RR = 0.48; 95% confidence interval, 0.35-0.66) in the development of post-molar gestational trophoblastic neoplasia.
Source: Hartmann Uberti EM, de Freitas Medeiros LR, Bernardes Cardoso R, et al. Primary prevention of post-molar gestational trophoblastic neoplasia in high-risk complete hydatidiform mole: A single-dose prophylactic actinomycin D, associated with uterine evacuation — a long retrospective cohort study. Gynecol Oncol. 2025;193:105-112.
Gestational trophoblastic disease (GTD) includes benign conditions, such as complete hydatidiform mole (also known as complete molar pregnancy), partial hydatidiform mole (also known as partial molar pregnancy), and placental site nodule, as well as malignant conditions, including invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor.1,2 The latter four malignant conditions are described collectively as gestational trophoblastic neoplasia (GTN).
Molar pregnancies are caused by abnormal proliferation of placental trophoblasts. Complete molar pregnancies result from the fertilization of an egg with absent or inactive maternal chromosomes and duplication of haploid sperm or, in 10% of cases, fertilization with two sperm. Complete molar pregnancies most commonly have a 46, XX or 46, XY karyotype and do not have any fetal tissue. These pregnancies are associated with a 15% to 20% chance of development of GTN. In contrast, partial molar pregnancies originate from the fertilization of a normal maternal ovum with two sperm, resulting in a triploid karyotype (most commonly 69, XXY), and are associated with a less than 5% chance of development of GTN.
Berkowitz et al identified high-risk factors associated with malignant progression for patients with complete molar pregnancies.3 These include age older than 40 years, excessive uterine enlargement, theca lutein cysts larger than 6 cm, associated medical comorbidities (such as hyperthyroidism, hyperemesis, preeclampsia, trophoblastic embolization, and disseminated and intravascular coagulation), and human chorionic gonadotropin (hcg) levels higher than 100,000 IU/L prior to uterine evacuation.
This was a retrospective cohort study conducted between March 1985 and December 2023 at a specialized center in Brazil aimed at investigating actinomycin-D for preventing GTN in patients with high-risk complete hydatidiform molar pregnancies (Hr-CHM). A total of 2,984 patients with GTD were identified during this period. Patients then were included if they had Hr-CHM diagnosed after 1996 (when actinomycin-D was routinely given for prophylaxis if possible) and underwent treatment and all follow-up at the trophoblastic disease center. Patients meeting high-risk criteria were administered a single intravenous (IV) dose of 1.25 mg/m2 actinomycin-D within 24 hours of uterine evaluation (Hr-CHM P-chem group). Patients who did not receive actinomycin-D comprised the control group (Hr-CHM control group) and included those who required urgent hospital admission, could not wait for evaluation by the trophoblastic disease team, declined the treatment, or were affected by a shortage of the medication. This group underwent standard uterine evacuation.
All patients were followed as outpatients after uterine evaluation with frequent hcg level measurement. Diagnosis of post-molar GTN was made according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines. Patients with post-molar GTN were treated primarily with methotrexate. Actinomycin-D was used if methotrexate was contraindicated, or resistance was noted.
For statistical analyses, power calculations identified a minimum number of 132 patients needed in each group. Qualitative variables were evaluated with absolute and relative frequencies. Quantitative variables were evaluated using Student’s t- tests or Mann-Whitney tests. The efficacy of actinomycin-D was described via relative risk. Kaplan-Meier curves and log-rank tests were used to evaluate overall survival and progression-free survival (PFS). In addition, a multivariable regression analysis was performed to account for confounding factors between the two groups.
A total of 136 patients comprised the Hr-CHM control group and 290 patients comprised to Hr-CHM P-chem group. The two cohorts differed regarding uterine enlargement greater than dates (65.2% P-chem vs. 58.8% control, P = 0.003), anemia (41% P-chem vs. 19.9% control, P < 0.001), blood transfusion (16.6% P-chem vs. 8.1% control, P = 0.027), hcg value prior to uterine evacuation (669 IU/L P-chem vs. 390 IU/L control, P < 0.001), and Berkowitz risk scores (5.34 P-chem vs. 4.85 control, P < 0.001).
Significantly fewer cases of post-molar GTN were seen in the Hr-CHM P-chem group compared with the Hr-CHM control group (19% vs. 40%, respectively, P < 0.001). Administration of actinomycin-D at the time of uterine evacuation was associated with a 52% relative risk (RR) reduction for development of post-molar GTN (RR 0.48; 95% CI, 0.35-0.66; P < 0.001). This corresponded with five individuals needing treatment with actinomycin-D to prevent one case of post-molar GTN.
After accounting for confounding factors, the RR was 0.43 (95% CI, 0.19-0.98; P = 0.045). In addition, prophylactic actinomycin-D was associated with a reduction in GTN relapse (RR, 0.04; 95% CI, 0.00-0.55; P = 0.016) and a reduction in need for hysterectomy (RR, 0.43; 95% CI, 0.19-0.98; P = 0.04). Furthermore, a significantly higher percentage of patients in the Hr-CHM P-chem group (63.4%) had a pregnancy following GTD treatment compared with 42.9% in the control group (P = 0.009). PFS at six months was 99.6% vs. 94.9% for the Hr-CHM P-chem and Hr-CHM control groups, respectively (hazard ratio, 0.06; 95% CI, 0.01-0.40; P = 0.007).
Regarding clinical parameters associated with morbidity in GTN treatment, the median time to GTN diagnosis (six weeks P-chem vs. seven weeks control, P = 0.089), response to chemotherapy (69.1% P-chem vs. 61.1% control, P = 0.50), and median time to GTN remission (19.5 weeks P-chem vs. 21.9 weeks control, P = 0.072) did not differ between the two groups.
Commentary
This retrospective cohort study demonstrated that prophylactic actinomycin-D administered at the time of uterine evacuation of complete hydatidiform molar pregnancies significantly reduces the risk of developing post-molar GTN. In addition, patients who received prophylactic actinomycin-D had a reduced risk of GTN recurrence and need for hysterectomy without an increased risk of resistance to chemotherapy at the time of treatment for GTN. One notable limitation of the study is that patients in the prophylactic chemotherapy arm did have higher risk factors for development of post-molar GTN at baseline, including a larger percentage with uterine size greater than gestational age and higher hcg levels prior to uterine evacuation.
Currently, the administration of prophylactic chemotherapy for patients with Hr-CHM is controversial. The National Comprehensive Cancer Network (NCCN) guidelines for gestational trophoblastic neoplasia posit that prophylactic chemotherapy using methotrexate or dactinomycin can be considered for prevention of post-molar GTN in patients with high risk for malignant transformation and when hcg follow-up is limited.4 This guideline is based on a systematic review of three randomized controlled trials involving 613 participants that demonstrated a reduced risk of post-molar GTN in patients receiving prophylactic chemotherapy (RR, 0.37; 95% CI, 0.24-0.57; P < 0.00001).5 However, the study commented that two of the randomized controlled trials included in the systematic review had poor methodological quality. The European Organization for Treatment of Trophoblastic Diseases (EOTDD) does not echo the NCCN guidelines and does not have any recommendations for prophylactic chemotherapy for patients with Hr-CHM.6
Although prophylactic chemotherapy seems as though it could be beneficial in patients with Hr-CHM at high risk for malignant transformation to GTN, treating all patients with Hr-CHM would expose many patients to chemotherapy, which is not without toxicity, who would not go on to develop post-molar GTN and would never need chemotherapy in the future. In addition, patients who develop low-risk GTN (defined as a World Health Organization score of less than 7 based on risk factors) have excellent treatment responses to chemotherapy and surgery, with remission rates approaching 100%.2 The rate of post-molar GTN in patients treated with prophylactic chemotherapy still was 19% in this study. If a patient with Hr-CHM develops low-risk GTN, there is a high likelihood that treatment at the time of diagnosis will be successful and these patients potentially could avoid needing to be exposed to chemotherapy twice (once in the prophylactic setting and then again when being treated for post-molar GTN). Additional considerations for the use of prophylactic chemotherapy in this setting are cost effectiveness and the availability of the medications.
Overall, this study adds value to the existing literature and demonstrates a potentially beneficial effect of preventive chemotherapy for the development of post-molar GTN in patients with Hr-CHM. However, it does seem that an individualized approach is necessary when considering which patients should receive prophylactic chemotherapy as described by the NCCN. Its use likely is most helpful for patients with difficulty getting frequent hcg levels in the surveillance period after diagnosis of HR-CHM.
Alexandra Morell, MD, is Adjunct Instructor, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY.
References
1. Lurain JR. Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol. 2010;203(6):531-539.
2. Horowitz NS, Eskander RN, Adelman MR, Burke W. Epidemiology, diagnosis, and treatment of gestational trophoblastic disease: A Society of Gynecologic Oncology evidenced-based review and recommendation. Gynecol Oncol. 2021;163(3):605-613.
3. Berkowitz RS, Goldstein DP, DuBeshter B, Bernstein MR. Management of complete molar pregnancy. J Reprod Med. 1987;32(9):634-639.
4. Abu-Rustum NR, Yashar CM, Bean S, et al. Gestational trophoblastic neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17(11):1374-1391.
5. 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):CD007289.
6. Lok C, van Trommel N, Massuger L, et al; Clinical Working Party of the EOTTD. Practical clinical guidelines of the EOTTD for treatment and referral of gestational trophoblastic disease. Eur J Cancer. 2020;130:228-240.
This 28-year retrospective cohort study demonstrated that administration of a single 1.25 mg/m2 intravenous dose of actinomycin-D at the time of uterine evacuation for patients with high-risk complete hydatidiform molar pregnancies was associated with a significantly lower rate of post-molar gestational trophoblastic neoplasia (19% vs. 40%, P < 0.001) and a 52% reduction in relative risk (RR; RR = 0.48; 95% confidence interval, 0.35-0.66) in the development of post-molar gestational trophoblastic neoplasia.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content