Academic Editor: Laura Avagliano
Background: Low-risk post-molar gestational trophoblastic neoplasia is
sensitive to chemotherapy, but there is no consensus regarding the best treatment
regimen for low-risk post-molar gestational trophoblastic neoplasia. This study
aimed to assess the efficacy, toxicity and cost-effectiveness of actinomycin D
and methotrexate in low-risk post-molar gestational trophoblastic neoplasia.
Methods: 210 patients with Federation International of Gynecology and
Obstetrics(FIGO)-defined low-risk post-molar gestational trophoblastic neoplasia
received either a first-line five-day methotrexate intramuscular injection
biweekly (MTX group) or a five-day actinomycin D infusion biweekly (Act-D group).
Demographic information, disease manifestations, initial treatment plan,
treatment-related adverse events, cost-effectiveness and the effects of drugs on
ovarian function and quality of sexual life were recorded and retrospectively
compared. Results: The complete response rates were 72.73% for the
Act-D group and 75.41% for the MTX group, with no statistically significant
difference. Compared to the Act-D group, the MTX group had a significantly
shorter total number of chemotherapy cycles and average hospitalization expenses
(p
Gestational trophoblastic neoplasia (GTN) arises from the abnormal proliferation
of placental trophoblasts, comprising invasive moles, choriocarcinoma, placental
site trophoblastic tumors, and epithelioid trophoblastic tumors. Most of these
tumors can be cured by chemotherapy without surgery [1]. According to the
International Federation of Gynecology and Obstetrics (FIGO) standards, National
Comprehensive Cancer Network (NCCN) guidelines diagnose post-molar GTN based on
one of the following conditions: (1) the serum
Based on the staging system of FIGO 2000 [2], including the World Health
Organization’s (WHO) scoring system, patients are divided into low risk (stages
I–III, score
According to all guidelines low-risk GTN should be treated with single-agent chemotherapy, either MTX or actinomycin D. However, there is a wide variety of treatment protocols, with differences regarding the route of administration, doses, frequency, and medication used, but there is still lack of sufficient data to strongly support one over another [4, 5, 6, 7, 8]. There is no consensus on the best single-agent regimen, and the choice of both the drug and regimen is usually institution-specific [9]. Based on treatment experience and good therapeutic effect, we usually use MTX intramuscular injection for five days biweekly and an endogenous bolus dose of Act-D for five days biweekly. Rare studies have evaluated the use of biweekly five-day MTX and Act-D. This retrospective study compared the results of these regimens, administered as first-line and as total single-agent chemotherapies.
We conducted a retrospective review of medical records to identify patients with low-risk post-molar GTN between 2010 and 2020 in the department of Gynecologic Oncology, Tianjin Central Hospital of Gynecology Obstetrics, China. We identified a total of 210 patients with available response data.
Pretreatment evaluations included chest X-ray, CT scans of the lung,
transvaginal ultrasound, and serum
The inclusion criteria were as follows: (1) the previous pregnancy was a
hydatidiform mole; (2) the prognosis score of FIGO (2000) was
The MTX regimen consisted of a five-day intramuscular injection (MTX, 0.4 mg/(kg/d) repeated every 14 days. The maximum dose was 25 mg/d). The Act-D regimen consisted of a five-day intravenous injection (Act-D, 0.5 mg; (10–13 ug/kg) repeated every 14 days).
Evaluation criteria for chemotherapy included monitoring serum
Adverse events were defined and classified according to standardized criteria (Common Terminology Criteria for Adverse Events-CTCAE v4.0). Complete blood cell count, and renal and liver function tests were regularly assessed during chemotherapy. We also assessed the total number of chemotherapy cycles, hospitalization duration, and the cost of hospitalization.
A questionnaire was conducted by telephone to investigate the situation of patients half a year after chemotherapy, including: (1) The menstrual situation of patients, including menstrual cycle, menstrual period and menstrual volume before and after chemotherapy, so as to evaluate ovarian function; (2) sexual life problems mainly include changes in sexual desire, vaginal dryness, sexual life satisfaction and sexual intercourse pain after chemotherapy.
The data were statistically analyzed by SPSS software (version 22.0, Inc,
Chicago, IL, USA). The measurement data were described by mean
Of the 210 patients in this study, a total of 122 were treated with MTX and 88 patients were treated with Act-D. The characteristics of the two low-risk post-molar GTD treatment groups are summarized in Table 1. All participants received suction and curettage before chemotherapy for diagnosis and mass removal, and eight patients underwent hysterectomy before chemotherapy.
Characteristics | All | MTX group (n = 122) | Act-D group (n = 88) | p-value | |
Age (years) | 34.91 |
||||
146 (69.52%) | 86 (58.90%) | 60 (41.10%) | p = 0.76 | ||
64 (30.5%) | 36 (56.25%) | 28 (43.75%) | |||
Time from previous pregnancy | |||||
180 (85.71%) | 106 (58.89%) | 74 (41.11%) | p = 0.69 | ||
30 (14.29%) | 16 (53.33%) | 14 (46.67%) | |||
Pretreatment |
|||||
58 (27.6%) | 36 (62.07%) | 22 (37.93%) | p = 0.53 | ||
152 (72.38%) | 86 (56.58%) | 66 (43.42%) | |||
Tumor size (cm)* | |||||
0–3 | 165 (81.67%) | 93 (56.36%) | 72 (43.64%) | p = 0.58 | |
37 (18.32%) | 23 (62.16%) | 14 (37.84%) | |||
Lung metastasis | |||||
NO | 76 (36.19%) | 64 (84.21%) | 12 (15.79%) | p | |
YES | 134 (63.81%) | 58 (43.28%) | 76 (56.72%) | ||
WHO score | |||||
196 (93.33%) | 116 (59.18%) | 80 (40.82%) | p = 0.27 | ||
5–6 | 14 (6.67%) | 6 (42.86%) | 8 (57.14%) | ||
*Eight cases underwent hysterectomy before chemotherapy. |
CR was achieved in 75.41% (92/122) of the MTX group and 72.73% (64/88) of the
Act-D group. The difference was not statistically significant. In patients with
CR, the average total number of chemotherapy cycles was 5.70
A total of 54 participants (25.71%) showed resistance to the single-agent chemotherapy, all of them finally achieved a CR after combination chemotherapy (FA/EMA-CO). Forty-nine of 54 patients (90.74%) were treated with FA, and 5 (9.26%) were treated with EMA-CO.
The number of courses required to normalize the
MTX | Act-D | p-value | |
CR | 75.41% (92/122) | 72.73% (64/88) | p = 0.93 |
Chemotherapy cycles for serum |
3.37 |
3.28 |
p = 0.77 |
Total number of chemotherapy cycles | 5.21 |
6.06 |
p = 0.045 |
Hospitalization duration (d) | 7.03 |
7.48 |
p = 0.67 |
Average hospitalization expenses (RMB) | 3383.36 |
5103.44 |
p |
There were no severe adverse effects reported for either group. T Abnormal
laboratory tests (leukopenia and abnormal liver function) and gastrointestinal
disorders, followed by mucosal ulcer, were the most common adverse events of the
two regimens. However, in both regimens, most patients developed only mild (grade
1 or 2) chemotherapy-related toxicity. There was no significant difference in the
incidence of abnormal liver function, gastrointestinal disorders, and mucosal
ulcers between the two groups (p
MTX (n = 92) | Act-D (n = 64) | p-value | |
Leukopenia (grade 1 or 2) | 17.39% (16/92) | 59.38% (38/ 64) | p |
Gastrointestinal disorders | 19.56% (18/92) | 21.88% (14/64) | p = 0.84 |
Mucosal ulcer | 6.52% (6/92) | 6.25% (4/64) | p = 0.96 |
Abnormal liver function | 17.39% (16/92) | 18.75% (12/64) | p = 0.88 |
Chemotherapy had a certain impact on menstrual conditions and sexual life. Of
the 210 patients in this study, 8 patients underwent hysterectomy before
chemotherapy, and 202 patients with menstrual conditions could be investigated,
including 116 cases in MTX group and 86 cases in Act-D group. (1) menstrual
cycle: no amenorrhea occurred in both groups; there was no significant difference
in menstrual cycle changes between the two groups (p = 0.6689); (2)
Menstrual period: menstrual period shortening was the main manifestation. The
incidence of menstrual period changes in MTX group and Act-D group were 70.69%
and 75.58% respectively, with no significant difference (p = 0.5231);
(3) Menstrual volume: the menstrual volume of most patients decreased. The
decreased menstrual volume accounted for 62.93% in MTX group and 68.98% in
Act-D group respectively, but there was no significant difference between the two
groups (p = 0.4671); (4) After chemotherapy, there were some changes in
sexual desire, vaginal dryness, sexual life satisfaction and sexual intercourse
pain in both groups, but there was no significant difference between the two
groups (p
Characteristics | MTX group (n = 116) | Act-D group (n = 86) | p-value | |
Menstrual cycle | ||||
Normal | 62 (53.45%) | 49 (56.98%) | p = 0.6689 | |
Abnormal | 54 (46.55%) | 37 (43.02%) | ||
Menstrual period | ||||
No change | 34 (29.31%) | 21 (24.42%) | p = 0.5231 | |
Change | 82 (70.69%) | 65 (75.58%) | ||
Menstrual volume | ||||
No change | 43 (37.07%) | 37 (43.02%) | p = 0.4671 | |
Change | 73 (62.93%) | 49 (68.98%) | ||
Sexual desire change | ||||
No change | 68 (58.62%) | 45 (52.33%) | p = 0.3928 | |
Change | 48 (41.38%) | 41 (47.67%) | ||
Vaginal dryness | ||||
NO | 61 (52.59%) | 44 (51.16%) | p = 0.8872 | |
YES | 55 (47.41%) | 42 (48.84%) | ||
Sexual satisfaction | ||||
YES | 45 (38.79%) | 37 (43.02%) | p = 0.5650 | |
NO | 71 (61.21%) | 49 (56.98%) | ||
Sexual pain | ||||
No | 87 (75%) | 69 (80.23%) | p = 0.4018 | |
YES | 29 (25%) | 17 (19.77%) |
The cure rate for low-risk GTN approaches 100%, primarily because of the high
sensitivity of GTN to chemotherapy [11, 12, 13]. It has been reported that single-agent chemotherapy is the first choice for low-risk GTN [14], and the usual chemotherapy medicines include MTX, Act-D, 5-FU, and VP-16. However, the remission rates of single-agent chemotherapy vary from 50%
to 90%. Chemotherapy resistance occurs in 20%–30% of patients with low-risk
GTN, who then require salvage chemotherapy or operation [11, 15]. Therefore, the
effectiveness, risk factors, and resistance associated with single-agent
chemotherapy for low-risk GTN have become an important research focus. 210 cases
were included in this study and divided into MTX group and Act-D group. The
results showed that the complete remission rates of Act-D group and MTX group
were 72.73% and 75.41% respectively, with no significant difference. Compared
with Act-D group, the total chemotherapy cycle and average hospitalization cost
in MTX group were significantly shorter (p
While both MTX and Act-D are effective first-line drugs for low-risk GTN, there is a lack of consensus on the preferred regimen [4]. There are several different chemotherapy regimens for low-risk GTN, which have produced inconsistent results in non-randomized and retrospective studies [4, 9, 16, 17]. There is currently no worldwide consensus regarding the best initial chemotherapy for GTN. The choice of treatment depends on the clinician’s own experience or preference. In our hospital, the five-day MTX and the five-day Act-D protocols are the most commonly used single-drug chemotherapy regimen for low-risk GTN. There is currently rare report comparing the two chemotherapy regimens.
In our study, the total CR rate of single-drug chemotherapy (MTX and Act-D) was
74.29%, the CR rates of the MTX group and Act-D group was 75.41% and 72.73%.
Our results regarding the CR rates of the single-agent chemotherapeutics are
similar to those of the GOG study and other reports [18, 19], which shows
that our regimens are effective and feasible. Another randomized trial came to
the opposite conclusion, which compared a low dose of MTX (30 mg/m
The most common adverse event was myelosuppression, which usually represented mild or moderate leukopenia. In our study, there was no severe adverse effect reported for either group, but the Act-D group was associated with significantly higher mild myelosuppression (59.38% vs. 17.39%). While grade 1 and 2 toxicities did not necessitate a change in treatment, they can affect the patients’ quality of life. Other adverse events, including liver damage, gastrointestinal reactions, and mucosal ulcers, were also mild and could be relieved after symptomatic treatments. No patient changed their chemotherapy strategy because of severe adverse events. This may be partially because a part of our quality and safety measures involved encouraging our patients to call whenever they had any questions or concerns about their treatment and contacting them weekly about treatment-related adverse effects. Nonetheless, most of our patients experienced only mild chemotherapy-related toxicity with both regimens, as reported by others [21, 22].
We also analyzed other factors involved in different treatment options, such as
chemotherapy cycles for serum levels of-HCG that decreased to normal, the average
total number of chemotherapy cycles, duration of hospitalization, and average
hospitalization expenses. We conclude that compared to the Act-D group, the MTX
group had a significantly shorter total treatment course of treatment and lower
average hospitalization expenses (p
Chemotherapy has a certain impact on ovarian function. For GTN patients, most of them have not completed childbirth or have requirements for reproduction, therefore, we should pay attention to the effect of drugs on ovarian function at the same time of treatment. In this study, 69.52% were younger than 40 years old, of which 27.5% were 22–29 years old, therefore, it is particularly important to choose chemotherapy regimen which has little impact on ovarian function.
This study was conducted by telephone follow-up after chemotherapy. It was found that the effect of chemotherapy on ovarian function was mainly manifested in different degrees of menstrual volume reduction and menstrual cycle disorder during and after chemotherapy, but this menstrual change was reversible. Most patients could return to normal menstruation within 1 year after chemotherapy. However, this study only investigated menstruation by means of questionnaires to assess ovarian function. Further clinical data are needed to confirm this study.
GTN patients are mostly in the sexually active stage, and the problem of sexual function deserves attention. Chemotherapy can temporarily inhibit or permanently affect ovarian function to a certain extent, lead to the decrease of estrogen level in the body, and cause vaginal dryness and other symptoms. This study also confirmed that the two groups had a certain impact on the quality of sexual life after chemotherapy, but there was no significant difference in sexual desire, vaginal dryness, sexual life satisfaction and sexual pain between the two groups. This may be related to the small sample size of this study, which needs to be increased for further research.
Our study has several limitations. It was a retrospective, single center, non-randomized, cohort study of two regimens, which may not reflect the outcomes in the Chinese general population. We are working with other centers to expand the sample size to continue our research. In addition, this study is a retrospective questionnaire survey, which still needs a large sample size, prospective and long follow-up clinical observational study to further explore the effects of different chemotherapy regimens and cumulative doses on patients’ ovarian function and quality of life.
GTN is a gynecological malignant tumor related to pregnancy. Gynecological oncologists should not only pay attention to the curative effect of treatment, but also pay attention to the changes of patients’ ovarian function, sexual function, emotion and psychology, so as to ensure that patients will not cause psychological fear and trauma while treating diseases. Because this is a single center retrospective study, the results can only reflect local practice and can not be generalized.
In conclusion, there were similar complete response rates and no severe adverse effect reported for Five-day MTX and Act-D, but the total treatment course was shorter and the average hospitalization expenses were lower in the MTX group. Five-day MTX intramuscular biweekly injections remain the treatment of choice for patients with low-risk post-molar gestational trophoblastic neoplasia. Chemotherapy will have a certain impact on ovarian function. Gynecological oncologists should pay attention to the protection of ovarian function in patients with gestational trophoblastic neoplasia during perioperative chemotherapy.
JX and XW—conception and design; PQ—administrative support; PQ—provision of study materials or patients; JX—collection and assembly of data; JX and XW—data analysis and interpretation; all authors, manuscript writing and final approval of manuscript. All authors read and approved the final manuscript.
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Institutional Review Board of Tianjin Central Hospital of Gynecology Obstetrics (NO.: KY081) and individual consent for this retrospective analysis was waived. Written informed consent for publication was obtained from all participants.
Not applicable.
This research received no external funding.
The authors declare no conflict of interest.