Keywords gestational trophoblastic disease - low-and-plateauing serum hCG levels - high-dose
vitamin A
Palavras-chave doença trofoblástica gestacional - níveis de hCG sérico baixos e em “plateau” - alta
dose de vitamina A
Introduction
Gestational trophoblastic diseases (GTDs) comprise a spectrum of occasional disorders
on human trophoblast derived from accidents occurred in the moment of fertilization.
Gestational trophoblastic diseases include six clinical and pathological entities
with different rates of remission, invasion and metastatic spread, from benign forms,
such as the complete and partial hydatidiform moles (HM), to malignant forms, classified
as gestational trophoblastic neoplasia (GTN), which include invasive HM, choriocarcinoma,
placental site trophoblastic tumor and epithelioid trophoblastic tumor.[1 ]
[2 ]
[3 ]
[4 ]
Human chorionic gonadotropin (hCG), a hormone produced by the placenta in any type
of pregnancy, is the biologic tumor marker of GTD. Quantitative serum hCG testing,
an aid in the diagnosis of HM and the pillar of postmolar follow-up, provides information
that may be used to predict cases that will go into spontaneous remission or, on the
contrary, that will develop GTN. The same information may be useful to control response
to chemotherapy (ChT) and to surgery, as well as to detect rare cases of relapse.[5 ]
[6 ]
Estimates of HM incidence indicate that it is 5 to 10 times more frequent in Brazil
than in the United States and Europe.[7 ]
[8 ]
[9 ]
[10 ] Epidemiological studies suggest that genetic, immunological and diet variations
may be responsible for this higher incidence.[2 ]
[5 ]
[11 ] Some studies found that a low level of vitamin A (Vit-A) in the diet may be associated
with a higher risk of HM incidence, as well as with its progression into GTN.[11 ]
[12 ]
[13 ]
[14 ]
During postmolar follow-up, persistence of low and plateauing (L&P) serum hCG levels
is not frequent, as it affects < 5% of the patients.[15 ]
[16 ] Although this condition may increase the emotional stress of HM for these women,
few treatment options are available, which may lead to a decision to initiate ChT
immediately to ensure cure.[15 ]
[16 ] Although the International Federation of Gynecology and Obstetrics (FIGO) recommended,
until 2018, ChT initiation 6 months after uterine evacuation for patients with L&P
serum hCG levels, some options have been put forth to avoid immediate ChT initiation,
such as prolonged hCG surveillance, repeat curettage, or treatment with high doses
of Vit-A.[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
In vitro and in vivo studies have demonstrated the beneficial effects of the administration
of high doses (HD) of Vit-A in cases of GTD. Chiu et al[21 ] studied choriocarcinoma cells in vitro and found that all-trans retinoic acid, a
Vit-A derivative, inhibited cell invasion and proliferation and induced apoptosis.
Andrijono et al[22 ] concluded that the increased apoptotic activity of trophoblastic cells was proportional
to the amount of retinoic acid used. The recommended dose of Vit-A is up to 10,000 IU/daily;
however, in studies including GTD patients, high-dose vitamin A (HD Vit-A) (200,000 IU/daily)
was administered to prevent postmolar GTN.[14 ] In 2010, Andrijono et al[14 ] published a clinical trial that found a significant reduction in the incidence of
postmolar GTN in patients treated with HD Vit-A (200,000 IU/daily) administered from
uterine evacuation to HM remission, with no GTD-associated morbidity.
The present study evaluated the same HD Vit-A use in a group of patients with L&P
serum hCG levels during postmolar follow-up. The identification of alternative treatments
for these cases of GTD may prevent the exposure of young women to chemotherapeutic
agents and their deleterious immediate and future adverse events.
Methods
This retrospective case series compared clinical outcomes of patients with HM and
L&P serum hCG levels followed-up in two independent cohorts by the same multidisciplinary
team at the GTD Reference Center (RC) of the Irmandade da Santa Casa de Misericórdia
Hospital (ISCMPA, in the Portuguese acronym), Porto Alegre, RS, Brazil. Control group
(CG): of the 1,370 patients with HM followed-up between January 1997 and December
2010 in the RC, 34 (2.5%) had L&P serum hCG levels and underwent expectant management
for at least 6 months after uterine evacuation.
Study group (SG): of the 734 patients with HM followed up in the RC from January 2011
to December 2017, 32 (4.3%) had L&P serum hCG levels and were administered Vit-A 200,000 IU/daily
from L&P hCG identification to the main outcome (spontaneous remission of the disease
or postmolar GTN)
After uterine evacuation of molar pregnancy, all patients underwent clinical and laboratory
follow-up at 7–14 days intervals with quantitative serum hCG testing using an electrochemiluminescent
immunoassay (DPC Immulite, Siemens, Los Angeles, CA, USA) until remission of the disease.[23 ] After that, testing continued monthly for at least 6 more months, in case of maintained
spontaneous remission of the disease, or for 12 months, in cases of remission after
treatment of GTN. The patients were then discharged from postmolar follow-up and were
told they might try to become pregnant again. At each visit, from uterine evacuation
to the completion of follow-up, all patients received instructions about the use of
contraceptives, and they were systematically asked about that use.[24 ] Gestational trophoblastic disease remission was defined as three consecutive weekly
serum hCG measurements < 5 IU/L.[6 ] Patients were diagnosed with L&P serum hCG levels when the results of four consecutive
weekly serum hCG measurements had a variation of ∼ 10% and were all < 1,000 IU/L.[15 ]
[16 ]
[25 ]
[26 ]
[27 ]
The diagnostic criteria of GTN for prompt ChT initiation were those established by
the FIGO 2000 guidelines:[28 ]
a) Four or more plateauing serum hCG results over 3 weeks, that is, on days 1, 7,
14 and 21;
b) Increase of serum hCG levels for ≥ 3 consecutive measurements for at least 2 weeks;
that is, on days 1, 7 and 14;
c) Histological diagnosis of choriocarcinoma;
d) Elevated hCG levels for 6 months or longer after uterine evacuation.
Patients with L&P serum hCG levels first underwent pelvic examination, pelvic transvaginal
Doppler sonography and chest X-ray to investigate the possible presence of invasive
HM or metastatic disease. In case the chest X-ray was not conclusive, or if there
were metastases > 1.00 cm, chest CT and brain MRI scans were used to magnify the screening
for metastases.[28 ]
If no uterine or metastatic lesions were detected during the postmolar follow-up of
patients with L&P serum hCG levels, those in the CG were only followed-up closely
with serum hCG measurements every 15 days until the outcome, or for 6 months after
uterine evacuation. After that time, if levels remained > 5 IU/L, the fourth FIGO
criterion for ChT initiation was confirmed.[28 ] For patients in the SG, HD Vit-A 200,000 IU/daily tablets PO was indicated after
informed consent and was administered from the plateau diagnosis to the main outcome,
for ∼ between 30 and 60 days. At each 15 days appointment of the postmolar follow-up,
the SG patients were asked if they had adverse events of HD Vit-A and, associated
with hCG measurements, also had control of hepatic toxicity with hepatic enzyme assessment
during and 1 month after HD Vit-A use. The primary outcome was spontaneous remission
or progression to GTN in both groups, according to the FIGO criteria. Secondary outcomes
were the evaluation of adverse events in patients treated with HD Vit-A and, in the
two groups, time to remission of the disease, clinical features of subsequent GTN,
relapse and death. The epidemiological variables under study in the two groups were:
age, parity, gestational age at time of uterine evacuation, HM histology, serum hCG
level at time of plateauing, time from plateau diagnosis to first normal hCG result
(< 5 IU/L), spontaneous disease remission or progression to GTN, clinical characteristics
of subsequent GTN, GTD relapse and death. For patients in the SG, the following variables
were also studied: time from HD Vit-A initiation and outcomes, and adverse events
associated with HD Vit-A use.
Analyses were made using absolute frequencies and percentages, and results were compared
using the Student t , the Mann-Whitney and the Pearson chi-squared tests. The level of significance was
set at α < 0.05. The present study was approved by the Ethics Committee of the ISCMPA
under the number 1.662.695.
Results
[Fig. 1 ] is a flow diagram of the derivation of the patient population, with outcomes according
to the different types of treatment. The prevalence of patients with L&P serum hCG
levels undergoing postmolar follow-up was < 5%.
Fig. 1 Flow diagram summarizing the derivation of the study population.
[Table 1 ] shows the clinical variables for patients with L&P serum hCG levels according to
expectant management or use of HD Vit-A.
Table 1
Clinical variables for patients with low and plateauing serum human chorionic gonadotropin
levels according to expectant management or use of high-dose vitamin A
Variables
Expectant management (n = 34)
Vitamin A use (n = 32)
p-value
Age, years old1
31.4 ± 9.7 [16–52]
29.5 ± 7.5 [15–44]
0.369t
Number of gestations2
1 (1 - 2)
1 (1 - 2)
0.89M
Parity2
0 (0 - 1)
1 (0 - 2)
0.065M
Pre-evacuation hCG level, IU/L2
40,600 (285–195,779)
85,854 (741–166,890)
0.829P
Gestational age at diagnosis, weeks1
11.9 ± 3.8 (5–22)
11.8 ± 4.7 (5–29)
0.947t
HM histology – N (%)3
0.479M
Complete hydatidiform mole
21 (63.6)
21 (67.7)
Partial hydatidiform mole
12 (36.4)
10 (34.5)
hCG level at plateau, IU/L2
82.5 (35–207)
195 (61–664)
0.028P
Interval between uterine evacuation and hCG plateau, weeks
12.7 ± 5.8 [8–38]
9.8 ± 3.4 [5–17]
0.019t
Interval between hCG plateau and outcome, days
60 (39–91) [9–160]
50 (35–70) [16–290]
0.374M
Duration of vitamin A treatment, days2
–
40 (30–60)
–
Time to hCG normalization, days2
65 (44–95)
44 (30–71)
0.327P
Duration of follow-up, months2
14 (11–18)
10 (8–11)
< 0.001P
Required chemotherapy due to GTN – N (%)
10/34 (29.4%)
2/32 (6.3%)
0.034M
Abbreviations:GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin;
HM, hydatidiform mole.
1. Mean (Standard derivation, range); 2. Median (interquartile); 3. No histological
differentiation between complete or partial mole occurred in two cases; t, Student
t test.; M, Mann-Whitney test.; P, Pearson chi-squared test.
Mean age (CG = 31.4 ± 9.7 versus SG = 29.5 ± 7.5 years old; p = 0.369), median hCG serum level before uterine evacuation (CG = 40,600 versus SG = 85,854 IU/L;
p = 0.829), mean gestational age at HM diagnosis (CG = 11.9 ± 3.8 versus SG = 11.8 ± 4.7
weeks; p = 0.947) and HM histology (p = 0.479) were similar in both groups. At the time of hCG plateau, the median hCG
level was significantly higher in the SG (82.5 versus 195 IU/L; p = 0.028), as well as the frequency of serum hCG levels > 300 IU/L (CG =17.6% versus
SG = 46.9%; p = 0.014). In the group of patients treated with HD Vit-A, the occurrence of postmolar
GTN was 6.3%, significantly lower than that found in the group of those that underwent
expectant management (29.4%, p = 0.034). The duration of postmolar follow-up was significantly shorter in the SG
(CG = 14 months versus SG = 10 months, p < 0.001). The median duration of HD Vit-A use was 40 (30–60) days, and there were
no differences in frequency of effect when the duration was ≥ 30 days, as shown in
[Fig. 2 ].
Fig. 2 Duration of vitamin A use according to time from plateau to outcome (days).
[Table 2 ] compares the variables for patients treated for GTN after expectant management or
HD Vit-A use.
Table 2
Treatment and outcomes of women with gestational trophoblastic neoplasia and persistent
low and plateauing serum human chorionic gonadotropin levels after postmolar follow-up
according to expectant management or high-dose vitamin A use
Variable
ChT after expectant management
N = 10
ChT after high-dose Vitamin A use n = 02
p-value
Age, years old, mean ± SD,1 [min - max]
33.8 ± 9.5 (25–51)
22.5 ± 2.1 (21–24)
0.136t
Evacuation – N (%)
1.000P
In the RC
7 (70)
2 (100)
Out of the RC
3 (30)
0
Pre-evacuation hCG level, IU/L, median ± IQA2
556.000
(369–1.317.065)
283.663 (193.755–373.571)
0.909M
Gestational age at diagnosis, weeks, mean ± SD,1 [min - max]
13.1 ± 1.5 (11–16)
10 ± 0 (10–10)
0.017t
HMc histology – N (%)
1.000P
Complete hydatidiform mole
9 (90)
2 (100)
Partial hydatidiform mole
1 (10)
0 (0)
hCG level at plateau, IU/L, median ± IQA2
82.5 (43–409)
658.5 (654–663)
0.030M
Time from evacuation to ChT initiation, weeks, median ± IQA2
25 (13.8–28)
16 (16–16)
0.727M
Pretreatment hCG level, IU/L, median ± IQA2
90.5 (53.3–314)
3.231 (567–3.231)
0.182M
Occurrence of metastasis – N (%)
1.000P
No
10 (100)
2 (100)
Yes
0
0
WHO/FIGO prognostic risk score – N (%)
1.000P
Low risk
10 (100)
2 (100)
High risk
0
0
Treatment – N (%)
1.000P
Clinical, single-agent ChT
8 (80)
2 (100)
Clinical, multi-agent ChT
0
0
Hysterectomy + single-agent ChT
2 (20)
0
Number of ChT cycles to remission, mean ± SD,1 [min–max]
1.8 ± 1.3 (1–5)
2.5 ± 0.5 (2–3)
0.407t
Lenght of follow-up, months, median ± IQA2
48 (15–67)
39.5 (35–44)
1.000M
Occurrence of relapse or death – N (%)
0
0
–
Abbreviations: ChT; Chemotherapy; hCG, human chorionic gonadotropin; HM; Hydatidiform
mole; RC, referral center; SD, standard deviation; WHO/FIGO,. World Health Organization/
International Federation of Gynecology and Obstetrics.
1. Mean (Standard deviation, range); 2. Median (interquartile); t. Student t test; P. Pearson chi-squared test; M. Mann-Whitney test.
The following variables were similar: mean age, place where uterine evacuation was
performed, serum hCG values before uterine evacuation, HM histology, time between
molar evacuation and ChT initiation, serum hCG values before ChT, occurrence of metastases,
World Health Organization (WHO)/FIGO prognostic risk score, type of treatment, number
of ChT cycles until GTN remission, and duration of follow-up. Among patients with
persistent L&P serum hCG levels initially treated with Vit-A, serum hCG levels were
significantly higher than those in the group that received expectant management (CG = 82.5 IU/L
versus SG = 658.5 UI/L; p = 0.030).
In the group treated with HD Vit-A, no patient had hepatic toxicity according to serum
aspartate aminotransferase levels; only one (3.3%) patient had a mild side effect,
dry skin, being resolved after the drug was discontinued. In both groups, adherence
to follow-up was good; most patients received a medical discharge after postmolar
follow-up was complete (CG = 88.2% versus SG = 90.6%; p = 0.553). There were no cases of relapse or death of patients followed-up in the
present study.
Discussion
To our knowledge, no study has evaluated the use of HD Vit-A in the postmolar follow-up
of patients with persistent L&P serum hCG levels, as we did in this nonconcurrent
retrospective cohort. Even though serum hCG levels were higher in the SG, the administration
of limited HD Vit-A daily reduced significantly the development of postmolar GTN and
the length of follow-up. Clinically (external validity), our treatment of women with
a molar pregnancy and persistent L&P serum hCG levels using HD Vit-A resulted in a
3-fold increase in the number of cases of spontaneous remission, a finding that is
in agreement with that reported by Andrijono et al.[14 ] However, those authors used HD Vit-A for patients with complete HM since uterine
evacuation to GTD outcome, which led to a measurement bias in their results, as they
did not include the high percentage of expected spontaneous remission (∼ 80%), as
well as the possible risks of HD Vit-A supplementation for long periods.[1 ]
[2 ]
[3 ]
[4 ]
[5 ]
[6 ]
[7 ]
For patients initially treated with HD Vit-A in our study, even in cases that later
required ChT, the prognosis of treatment outcome was similar to that of patients that
underwent initially expectant management after the diagnosis of persistent L&P serum
hCG levels. This may be assigned to the short duration of HD Vit-A use (median of
40 days), which did not have any significantly important effects on time to ChT initiation,
WHO/FIGO prognostic risk score, or even response to ChT regimens in the group of patients
that progressed to GTN when compared with those patients that underwent expectant
management initially.
Treatment with HD Vit-A has been associated with inhibition of the development of
experimental tumors of the skin, breast, mouth, ovaries, lung, liver, gastrointestinal
tract, prostrate and urinary bladder.[29 ]
[30 ]
[31 ] All types of trophoblastic cells in the placenta, such as syncytiotrophoblasts,
cytotrophoblasts and intermediate trophoblasts, have receptors for retinoic acid (RA),
the final product of Vit-A metabolism in the organism. As RA binds to retinol binding
protein (RBP) receptors, the complex RA-receptor acts in the control of cell proliferation,
inducing trophoblastic apoptosis by stimulation of apaf-1, caspase-7, caspase-9 and
dab-2, and inhibition of Bcl-2.[22 ] According to Andrijono et al,[22 ] the administration of RA to trophoblastic cells increased their apoptotic activity
and interrupted the cell cycle at the G1 and S phases.[32 ]
The lowest effective dose of HD Vit-A to achieve remission of patients with molar
pregnancies and persistent L&P serum hCG levels, or in the associated treatment of
GTN, has not been determined.[33 ]
[34 ] The dose used in our study was the same suggested by Andrijono et al,[14 ] but we administered it for a shorter time, from the detection of persistent L&P
serum hCG levels to the outcome. The HD Vit-A dose in our study, 200,000 IU/day, did
not have any important adverse effects, evaluated at each follow-up visit. No patient
had any changes in hepatic function during follow-up, and only one patient had a mild
adverse effect, dry skin, which resolved after Vit-A discontinuation. These data are
in agreement with those reported by Andrijono et al.[14 ] The use of HD Vit-A for > 30 days did not improve prognoses, which suggests, therefore,
that there is an optimal period after which it would not be necessary to continue
the treatment.
One of the important limitations of our study is that, although data were collected
from a single GTD RC in Southern Brazil, where patient compliance is high because
patients have been followed-up by the same professional (one of the authors) since
1985, findings may not reflect the reality of other Brazilian RCs or the general population.
The reduced number of patients that progressed to GTN in both series has also limited
the analyses of our results. The most important study limitation, however, was its
design, as retrospective analyses have biases that may limit their generalization.
Conclusion
In the present study, postmolar GTN was less frequent and the length of follow-up
was shorter in the group of women with a molar pregnancy and L&P serum hCG levels
who received treatment with HD Vit-A. Vitamin A use was well tolerated in the population
under study, and there were very few side effects, which resolved after treatment
discontinuation. When HD Vit-A treatment failed and patients progressed to postmolar
GTN, prognoses were similar to those of women treated with ChT after initially expectant
management. Randomized multicenter studies with a higher impact should be conducted
to confirm our findings about the beneficial effects and safety of HD Vit-A use to
treat women with molar pregnancies and persistent L&P serum hCG levels.
