Discussion
The current study found that liver or brain metastases were
exceptionally rare, which is consistent with previous reports6, 9, 10.However, early death and a dramatically high
drug-resistance rate with initial treatment remains a critical problem
in ultra-high-risk GTN patients with liver and brain metastases.
We found that liver or brain metastases accounted for 1.3% and 2.7% in
all GTN patients, respectively, which is supported by previous reports
from China9, 10, France12, and the
United Kingdom (UK) 7, 11. At Peking Union Medical
College Hospital, GTN patients with liver metastases reportedly
accounted for 1.9%9 and brain metastases accounted
for 3.4% of patients 10, respectively. Similarly, the
incidence of liver metastases was only 1.8% (38/2100) of all GTN
patients in the Charing Cross GTN database from 1975 to 200716 and the incidence of brain metastases in GTN
patients was only 1.7% (21/1251) in a 17-year retrospective study in
France12. The difference between studies in Asia and
Europe could be owing to differences in prevalence, discrepancies
between hospital-based and population-based data, or disparities in the
availability of central pathology review. The reason for the rare
prevalence of liver or brain metastases might be related to sensitivity
to chemotherapy in patients with GTN.
However, liver metastases (HR: 34.05; 95% CI: 1.65–703.7;P =0.02) and brain metastases (HR: 49.19; 95% CI: 5.6–432.1;P =0.01) were found to be independently significant risk factors
for death in GTN patients in our study. Similar findings have been
reported, showing that the presence of liver or brain metastases is a
strong indicator of a poor outcome in GTN 5, 7, 9,
such as cerebral hemorrhage 12, neurological sequelae12, less than 40% 5-year survival rate7 and early death 2. The survival
rate of GTN patients with brain metastases is only 35%–70%10, 17, and 27%–48% 7, 16 for
liver metastases. Additionally, we found a significantly lower CR rate
(0% vs. 28.6%, P <0.01) and higher drug-resistance
rate (90.0% vs 42.9%, P <0.01) after initial treatment
between the subgroups with and without liver or brain metastases in
ultra-high-risk GTN patients. Hence, this confirms that liver or brain
metastases is a crucial risk factor for ultra-high-risk GTN patients,
which can lead to poorer outcome than ultra-high-risk GTN patients
without liver or brain metastases.
In this study, one ultra-high-risk patients with concomitant liver and
brain metastases had early death only four days after treatment
initiation (before adequate chemotherapy could be given). The patient
died from cerebral hernia and multiple organ failure. Similarly, other
studies have reported that early death remains a critical problem in GTN
patients with liver and brain metastases. One study found that early
death was significantly associated with ultra-high-risk GTN, occurring
in 13.8% of these patients 2. Many deaths happened
soon after admission for hemorrhage or metabolic results of overwhelming
disease4. When deaths within four weeks were excluded,
survival in patients with brain metastases (86%) was equivalent to that
for other patients 18. Similarly, in 37 patients with
liver metastases treated between 1977 and 2005, OS increased to 48% at
five years. However, when early deaths were excluded, survival was 68%
in a UK study 16. For GTN patients with liver or brain
metastases and massive disease, starting with standard first-line
multidrug chemotherapy may cause sudden tumor collapse with severe
bleeding, metabolic acidosis, myelosuppression, septicemia, and multiple
organ failure, any or all of which can result in early death6. To minimize early deaths in patients with very
advanced disease, starting chemotherapy with low-dose induction EP
chemotherapy (etoposide 100 mg/m2 and cisplatin 20
mg/m2 on days 1 and 2) before commencing EMA-CO may
help to reduce tumor edema4 and can remarkably reduce
the early death rate from 7.8% to 0.7%19.
Additionally, EP chemotherapy can enable a more gradual reduction in
tumor bulk during the initial weeks of treatment to minimize the risk of
early death 19. Several series have also suggested
that the use of low-dose induction etoposide and cisplatin may benefit
GTN patients with a FIGO score ≥13 2, 6, 12, 20, 21,
especially if their increased risk score is due to a large tumor burden
or metastases to the brain, liver, or extensive metastases6, 14 owing to hemorrhagic sequelae at the tumor
sites22.
Ten patients among 11 ultra-high-risk GTN patients with liver or brain
metastases were treated with EMA-CO as first-line chemotherapy in our
study. The results were consistent with previous studies, showing that
the most commonly used multiple-agent chemotherapy for high-risk GTN
worldwide remains the EMA-CO protocol 6, 11, 14, 19,
23-25, which is considered to have the best effectiveness-to-toxicity
ratio13. The cumulative 5-year survival rate of
patients given EMA-CO is between 75% and 90% 4, 19.
The OS rate was 86.2% in all GTN patients after EMA-CO and 85.4% in
the high-risk group in a UK study 19. However, Bolze
et al. reported that the 5-year death rate approached 38.4% in patients
with FIGO score ≥13 treated with EMA-CO, with or without low-dose EP20.Furthermore, a Cochrane review found that 20% of
patients do not achieve a complete response with EMA-CO therapy6, and most can ultimately be salvaged with TP/TE or
EP-EMA 6, 12, 21, 26.
In
this study, the drug-resistance rate reached 90.9%
with
initial treatment in ultra-high-risk GTN patients with liver or brain
metastases. A retrospective series in India including 82 high-risk GTN
patients suggested that the resistance or relapse rate was only 31
(37.8%) after EMA-CO therapy 27. This discrepancy
might be owing to differences in study participants because the study in
India only reported the drug-resistance rate with initial treatment in
high-risk GTN patients rather than ultra-high-risk patients. The
extremely high drug-resistance rate with initial treatment in GTN
patients with liver or brain metastases in our study suggests that the
combination of chemotherapy with adjuvant immunological therapy or
surgery is needed, in comparison with chemotherapy alone, as initial
treatment 28. Immunological reactions might be
involved in the development of GTN from complete hydatidiform mole (CHM)29. Recent work suggests that checkpoint
immunotherapies represent an important new approach for the management
of drug-resistant GTN 2, 3, 5, 8. Additionally, poly
(ADP-ribose) polymerase inhibitors (PARP) and anti-angiogenesis agents
are novel treatments for drug-resistant GTN 15.
In the present study, adjuvant surgical procedures were performed in
eight (72.7%) ultra-high-risk GTN patients with liver or brain
metastases as a component of their therapy, among whom six ultimately
achieved long-term survivors. Similarly, several studies have found that
adjuvant surgery might be an effective choice for high-risk GTN patients5, 6, 10-12, 15, 21, 30, which is in accordance with
our results. Previous studies have confirmed that surgery not only
reduces the tumor burden but also removes isolated chemoresistant
lesions, such as in the lung or brain 2, 3, 5, 31, 32.
Hence, surgery (RR 0.336, 95% CI 0.177–0.641, P =0.001) is a
protective factor in the prognosis of ultra-high-risk GTN patients5. Generally, nearly 50% of GTN patients with
high-risk disease require some surgical intervention to achieve a cure33. Hysterectomy can be considered with uncontrolled
uterine bleeding and laparotomy might be needed to stop bleeding in
organs such as the liver, gastrointestinal tract, kidneys, and spleen6, 21, 31. To decrease the early death rate,
neurosurgery is needed if there is bleeding into the brain or increased
intracranial pressure 6, 11, 12, 21. However, with the
availability of uterine artery embolization, hysterectomy can often be
avoided 31. Additionally, selective angiographic
embolization is used to control hemorrhage from multiple liver
metastases30.
In our study, no patients had whole-brain radiation therapy, but three
patients had stereotactic radiotherapy for residual brain metastases at
the end of treatment. The strategy for treating GTN patients with brain
metastases at our center is intravenous multidrug chemotherapy and
intrathecal methotrexate. Stereotactic radiotherapy was used for 37.5%
(3/8) GTN patients with brain metastases for residual brain metastases
at the end of treatment. However, concomitant whole-brain radiotherapy
has rarely been used at our center owing to intellectual impairment in
patients over the long term. Our results are consistent with those of
previous studies showing that radiotherapy plays a limited role in the
treatment of brain 6, 12, 21 and liver metastases7 in GTN patients. An observational study performed at
Peking Union Medical College Hospital found that only 0.9% (2/109) of
GTN patients with brain metastases received brain irradiation during
1990–2013 because this can induce long-term intellectual impairment in
patients who are cured 10. However, some centers may
administer whole-brain radiotherapy (3000 cGy in 200 cGy daily
fractions) concurrent with chemotherapy or use stereotactic or gamma
knife radiation to treat existing or residual brain metastases after
chemotherapy 6. Neubauer et al. recommended an
approach using whole-brain irradiation combined with systemic
multi-agent chemotherapy to treat patients with brain metastases;
however, their reported OS was only 50%34. In the UK,
only one of 46 GTN patients with liver metastases received liver
irradiation between 1958 and 19947.
Although this study was limited owing to its retrospective design and
relatively small sample size, we reported our experience in the
management of ultra-high-risk GTN patients with liver or brain
metastases. Early death and the remarkably high drug-resistance rate to
initial chemotherapy remain two critical problems in GTN patients with
liver or brain metastases. We speculate that the combination of
chemotherapy with adjuvant immunological therapy or surgery, compared
with chemotherapy alone, as initial treatment may improve patient
prognosis. RCTs are needed to confirm our hypothesis. Furthermore,
starting chemotherapy with low-dose induction EP chemotherapy before
commencing EMA-CO might be helpful in these patients. Further work is
essential to explore optimal treatment strategies in this patient
population. Specialized multidisciplinary teams and tertiary specialist
centers are critical to the management of GTN.