In this study, the administration of a single dose of MTX within 24 hours before or after suction curettage did not show a statistically significant influence on spontaneous remission in patients with high-risk CHM. Additionally, PC with MTX did not affect the time interval to remission of high-risk CHM. Furthermore, if a high-risk CHM developed into PGTN, that single dose of PC with MTX did not reduce the frequency of metastatic disease, resistance to first-line chemotherapy, and the time interval to serum βHCG level normalization.
The current English literature on the efficacy of PC in patients with CHM is limited, with few randomized clinical trials (RCTs) available. Kim et al[17] conducted a study with seventy-one patients with CHM randomized into two groups: 39 patients who received a single course of MTX and citrovorum and 32 patients who were not treated. They found that in high-risk CHM patients, there was a lower incidence of PGTN in the MTX group compared to the untreated group (14.3% versus 47.4%, p-value < 0.05). Additionally, the MTX group had a longer time interval from evacuation of the mole to the development of PGTN (9.5 ± 2.4 versus 5.1 ± 1.6 weeks, p-value < 0.05). Moreover, in cases that developed PGTN, more courses of chemotherapy were required to achieve complete remission in the MTX group than in the control group (2.5 ± 0.5 versus 1.4 ± 0.5, p-value < 0.005). Our study did not show a statistically significant difference in the incidence of PGTN between the PC group (18.2%) and the control group (36.3%). Though not statistically significant, the trend aligns with Kim's findings regarding the potential benefit of PC in reducing PGTN incidence. Kashimura et al[18] evaluated 420 patients with molar pregnancy and, after a follow-up period of 5 to 15 years, reported that 7.5% of cases with PC (intramuscular or oral administration of 10 mg of MTX daily for 7 days) and 18.1% of the control group developed secondary trophoblastic disease (p-value < 0.01). Metastatic trophoblastic disease was found in 22.7% of the PC group and 21.7% of the control group (p-value: 0.178). Limpongsanurak et al[19] designed an RCT and randomly allocated high-risk CHM patients to either receive actinomycin D within one week of evacuation (PC group) or intravenous fluid and analgesic drugs (control group). The incidence of malignant sequelae was 13.8% (95% confidence interval [CI] = 3.9–31.7%) in the PC group and 50.0% (95% CI = 31.3–68.7%) in the control group. The risk reduction of malignant sequelae with one course of actinomycin D chemoprophylaxis in high-risk CHM was 72.4% (95% CI = 26.7–89.6%) (P = .005). In our study, the incidence of PGTN in the PC group was lower than that observed in the control group, which aligns with the findings of Limpongsanurak et al. The relatively small sample size in our study might have affected the ability to reach statistical significance. All three studies reached a common conclusion: PC has shown to be particularly useful in patients with high-risk CHM who cannot be closely followed, whose compliance is in question, and for whom careful follow-up is not available or is unreliable. These characteristics are well-matched to patients from underserved areas of developing countries. Therefore, we assume that single-dose MTX should be considered even as the treatment of choice in this group.
Since 2020, studies have attempted to reproduce the findings of these researches in a more controlled design. Wang et al[9] claimed that the previous studies had poor quality due to a high risk of bias.
Yamamoto et al[3] investigated 472 patients with high-risk CHM and found that gestational week, serum βHCG level at one week after the first evacuation, and pathological remnants were significantly associated with the development of PGTN. Aminimoghaddam et al[20] divided 102 patients with high-risk CHM into two groups: recipients and non-recipients of MTX (Methotrexate 1mg/kg in the odd days (1,3,5,7) and leucovorin 0.1 mg/kg (IM) in the even days (2,4,6,8)). In the MTX recipient group, 13.7% of cases developed PGTN, while in the non-recipient group, 31.4% of cases developed PGTN (p-value: 0.03). Also, the mean ± SD of the time interval of βHCG spontaneous remission was lower in the MTX recipient group than the control group (2.5 ± 1.33 Vs 3.2 ± 1.21 months, p-value: < 0.001). These studies emphasize the role of PC in patients with high-risk CHM to reduce the risk of PGTN, especially in countries with limited resources.
One of the controversies that needed to be addressed before prescribing PC for high-risk CHM patients is the possible drug resistance in the group who received it. Liu et al[21] sought to answer whether PC increased the drug resistance rate of PGTN and whether the first-line chemotherapy should be different from PC. They matched the PC group and the control group by age for low-risk and high-risk GTN separately. They reported that in patients with low-risk HM, the interval from CHM to PGTN was longer in the PC group and was statistically significant (p-value 0.001). However, in high-risk CHM patients, although the PC group had a longer time interval to reach a serum βHCG level normalization, it was insignificant (p-value: 0.309). An interesting finding of this study is that when low-risk CHM patients who developed PGTN received MTX as their PC, they needed more chemotherapy cycles to achieve βHCG normalization than patients who had alternative agents other than MTX as their PC. This finding was not true about high-risk CHM patients. Geng et al[22] administered PC to 23 patients with high-risk HM. Among these patients, 11 did not develop PGTN, while the other 12 developed PGTN and needed a regimen change to combination chemotherapy. They found that the median days needed for serum βHCG normalization were 71 and 120 days in the control group and the PC group, respectively. It was proposed that a serum βHCG level cut-off value of 750,000 IU/L can predict whether PC will be successful with a specificity of 91% and a sensitivity of 58%. The authors argued that in high-risk HM patients who developed PGTN and received PC, it's better to use double-agent or combination chemotherapy if the level of serum βHCG reached 750,000 IU/L to reduce therapy duration and prevent relevant chemotherapy resistance.
In our experience, one of the concerns that PGTN mothers had was about their fertility and reproductive outcome after discharge. This concern was so intense that one of the challenges in our center was to explain why a chemotherapeutic agent like MTX can be of little or no harm to their future pregnancy. Uberti et al[23] assessed the effect of one bolus dose of actinomycin D (Act-D) in patients with high-risk HM on reproductive outcomes in subsequent pregnancies. Their analysis showed that the percentage of patients that became pregnant, the type of subsequent pregnancy, and the rate of live births associated with pregnancies were not different in the two groups. They also proposed that chances of a subsequent pregnancy were higher in the low-age and low-parity subgroups.
Our study has a few limitations that need to be addressed in future RCTs to confirm the applicability of PC in high-risk CHM patients and prove the drug’s safety profile and its effect on future reproductive ability. The sample size of this study was small, so we could not reach statistical significance in any of our analyses. So, with properly powered studies, it may be proved that a single-dose MTX as PC is not an effective therapeutic option for preventing PGTN in patients with high-risk molar pregnancy.