EJGO European Journal of

Gynaecological Oncology

BEP for high-risk gestational trophoblastic tumor:

results from a cohort of 45 patients

S.Q. Song1*, C. Wang2*, G.N. Zhang1, Y. Shi1, Y. Zhu3, T. Hu1, S.Q. Xu1, Z.R. Yang1
1 Department of Gynecological Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan
2 Chengdu First People’s Hospital, Chengdu, Sichuan
3 Department of Ultrasound, Sichuan Cancer Hospital, Chengdu, Sichuan (China)

Summary
Aim: To evaluate the effectiveness and safety of combination chemotherapy of bleomycin, etoposide, and cisplatin (BEP) regimen in
patients with high-risk gestational trophoblastic neoplasia (GTN). Materials and Methods: The authors analyzed the clinical response,
toxicity, and the occurrence of secondary tumors of 45 patients with high-risk GTN under BEP. Results: The total complete remission
(CR) rate of BEP regimen was 88.89% (40/45). Five patients developed drug-resistance after average 4.8 courses of BEP, and the reg-
imen converted to etoposide, methotrexate, and dactinomycin (EMA) / cyclophosphamide and vincristine sulfate (CO). Ultimately, four
cases achieved CR and one case died of cancer. There were no severe anaphylaxis and obvious impairment of cardiac, liver, pulmonary
and kidney function, except one patient who developed grade IV bone marrow suppression and worsened pulmonary fibrosis after
chemotherapy. None of survival patients developed secondary tumor during the follow-up. Conclusion: For young high-risk GTN pa-
tients, BEP may represent a safe and effective regimen.

Key words: High-risk gestational trophoblastic neoplasia; BEP regimen; Adverse reaction of chemotherapy.

Introduction
The total of 45 patients followed the inclusion criteria, average
Gestational trophoblastic neoplasia (GTN) is a highly ag- age 30.5 years (20 - 49). The serum β-hCG level was 6,756 ~
gressive gynecological malignancy. Although it is sensitive 22,124 U / L (average 12,523 U / L) before chemotherapy. Ac-
cording to the GTN diagnostic criteria, ten patients were diagnosed
to chemotherapy and more than 90% patients reach recov- with post-mole GTN, 35 cases with non-postmolar GTN, including
ery, there are still 15% of GTN patients, especially with ten choriocarcinoma and two invasive mole, which were evaluated
high-risk, developed failure to treatment. How to improve by experienced pathologists. The prognostic scores of 45 patients
the treatment efficacy and prognosis of GTN patients has were 7 to 18 points (average 11.4 points); eight in Stage II, 32 in
drawn intensive thinking of gynecological oncologists. The Stage III, five in Stage IV. There were two cases with brain metas-
tases, 37 with lung metastases., and 24 with reproductive system
Sichuan Provincial Cancer Hospital has adopted
(except the uterus) metastases. One case each with dorsum subcu-
bleomycin, etoposide, and cisplatin (BEP) regimen since taneous, liver, bowel, and omentum metastases, respectively.
January 1997 for treatment of GTN patients and achieved
favorable results. Here, the authors report their experience Treatment
in 45 patients with high-risk GTN. BEP regimen. All of 45 patients in this study underwent BEP
chemotherapy. The specific usage was: bleomycin 15 mg + saline
20 ml, intravenous injection in the first to third days; etoposide
Materials and Methods 100 mg/m2 + saline 300 ml, intravenous infusion, first to fifth
days; cisplatin 20 mg / m2 + saline 250 ml, intravenous infusion,
Patients first to fifth days, every three weeks. To prevent the bleomycin
GTN patient who received BEP regimen chemotherapy in the induced pulmonary toxicity, the treatment was stopped when the
Sichuan Provincial Cancer Hospital from January 1997 to Octo- cumulative dose of 360 mg was reached. Chemotherapy was con-
ber 2012 were included for this study. Ethical approval for the tinued until the serum β-hCG was negative, symptoms and signs
project was obtained from the Sichuan Cancer Hospital Research disappeared, and when the primary and metastatic lesions disap-
Ethics Committee.Patients were re-diagnosed according to the peared. For patients with good compliance and in full knowledge
standard of diagnosis of GTN, staged, and scored for prognosis of the premise, according to FIGO recommendations, three cy-
according to the FIGO 2000 staging and scoring system [1]. Cri- cles of chemotherapy was conducted after serum β-hCG was neg-
teria for inclusion in the study were established as follows: (1) ative, regardless of whether there was radiographic lesion.
Patients who were diagnosed with high-risk GTN (prognosis score Surgical treatment. For deep bleeding lesions, hemostasis by
≥ 7); (2) continuous use of ≥ two courses of BEP regimen, the en- arterial embolization was conducted, for superficial bleeding le-
tire follow-up period after chemotherapy was ≥ three months. sions hemostasis by local compression was conducted; for the
uterus, lungs, brain, or other parts of a solitary metastasis who, in
*
Contributed equally to this article.

Revised manuscript accepted for publication June 11, 2014

Eur. J. Gynaecol. Oncol. - ISSN: 0392-2936 7847050 Canada Inc.
XXXVI, n. 6, 2015 www.irog.net
doi: 10.12892/ejgo2707.2015
 S.Q. Song, C. Wang, G.N. Zhang, Y. Shi, Y. Zhu, T. Hu, S.Q. Xu, Z.R. Yang 727

Table 1. — Clinical characteristics and treatment of the five cases with high-risk GTN who developed BEP regimen re-
sistance
Number FIGO FIGO Surgical approach before Courses Concurrent regimen Therapy after resistance Outcome
Stage Score chemotherapy of BEP radiotherapy
1 III 13 None 5 None EMA/CO 7 courses CR
2 III 10 Uterine repair 4 Whole lung EMA/CO 10 courses CR
3 III 15 Hysterectomy 7 None EMA/CO 3 courses + whole
lung irradation CR
4 IV 18 Resection of 5a None EMA/CO 6 courses + whole
intracranial lesions lung irradiation + lobectomy CR
5 IV 16 Hysterectomy 3 None EMA/CO 16 + fluorouracil +
cisplatin + dactinomycin + and so on Death
a
represents concurrent intrathecal methotrexate injection while BEP chemotherapy was given.

their serum β-hCG normal or near normal levels, pelvic surgery or solidation of two to three courses of chemotherapy. The CR
resection of metastases surgery was conducted. Ten patients un- rate of BEP regimen was 88.89% (40/45). Among the 40
derwent emergency surgery before BEP chemotherapy due to
CR patients, ten cases were postmolar GTN and 30 non-
vaginal bleeding or intracranial hypertension caused by intracra-
nial hemorrhage, or postoperatively diagnosed as high-risk GTN postmolar GTN. There were eight Stage II patients, 29
after surgery in other departments. Stage III, and three Stage IV. These patients received five
Radiotherapy. For serious brain, lung metastasis, lesions with to eight courses of BEP chemotherapy (average 6.3 cycles).
no obvious subside after three to five cycles after BEP chemother- The serum β-hCG level of these patients decreased to nor-
apy treatment, concurrent radiotherapy was conducted in addition mal after receiving average 3.65 courses (three to six
to chemotherapy. For patients with resistant lesions in the brain or
the lungs, chemotherapy regimen was adjusted and radiotherapy courses) and achieved CR after average 6.25 courses.
was given when necessary. Thirty-four of 40 cases were treated with BEP only. Four
cases followed with surgery, three patients were diagnosed
The diagnostic criteria for drug resistance and relapse as choriocarcinoma, and one patient was cancer free. Two
Drug resistance. Patients whose serum β-hCG level was not cases were given concurrent radiotherapy on the basis of
decreased logarithmically after two to three cycles of chemother-
apy, or showed a platform-like level, or even rise; or imaging ex-
the BEP chemotherapy (one case of brain radiotherapy, one
amination suggest metastases does not shrink or grow, or even the case of pulmonary radiotherapy).
emerge new metastatic lesions [2]. Five patients, including three in Stage III and two in
Recurrence. After treatment, the detection of serum β-hCG Stage IV, which were non-postmolar GTN, developed
level remained normal for three weeks, all tests showed (includ- drug-resistance after average 4.8 courses (three to seven
ing physical examination, imaging studies) that the lesions had
courses) of BEP. Four of them achieved PR after two to
disappeared, clinical symptoms disappeared. Up to three months
after the above criteria, the serum β-hCG levels increased (except six cycles of chemotherapy. Unfortunately, due to per-
for re-pregnancy) or other examination revealed new lesions [2]. sonal or family reasons, three patients delayed the next
cycle or ceased consolidation chemotherapy. One patient
The evaluation criteria of efficacy and side effects (49-years-old) failed to take regular monitoring of blood
Effects and side effects. Clinical complete remission (CR): serum leading to a serious bone marrow suppression, therefore
β-hCG was monitored once a week and remained normal in three
consecutive tests; clinical symptoms disappeared; all metastatic le- this patient was unable to receive the next course of
sions disappear. Afterwards, two or three cycles of chemotherapy chemotherapy and ultimately developed resistance. The
regimen was given. Then the patients were followed-up for three regimen of these four patients converted to etoposide,
months without recurrence. Partial response (PR): serum β-hCG methotrexate, and dactinomycin (EMA) / cyclophos-
levels decreased > 50%, and metastases was reduced. The side ef- phamide and vincristine sulfate (CO), and all of them ul-
fects of chemotherapy were evaluated according to the WHO anti-
neoplastic drugs acute and subacute indexing criteria. timately obtained CR. The other one case was in Stage IV,
The follow-up after the end of treatment. After patients dis- with the prognosis score of 16 points, had hysterectomy in
charged when CR standard was met, regular monitoring of serum another hospital due to vaginal and intra-abdominal bleed-
β-hCG level was required. In this study, all patients were followed ing before received BEP chemotherapy. The pathological
up until death or the cut-off in February 2013. The duration of fol- diagnosis was choriocarcinoma. For family reasons, the
low-up was from three months to 15 years.
patient was not able to receive regular chemotherapy,
which led to rapid recurrence after three cycles of BEP
Results chemotherapy. Then the regimen switched to EMA/CO
Efficacy and other kinds for 16 cycles. However, the patient died
Forty-five high-risk GTN patients received three to eight of brain metastasis ultimately, and survived for 14 months
courses of BEP (average 6.1 courses), including the con- after pathogenesis (Table 1).
728 BEP for high-risk gestational trophoblastic tumor: results from a cohort of 45 patients

Table 2. — Side effects of 45 cases with high-risk GTN re- 91% respectively. Internationally, the first choice is the
ceived 273 cycles of BEP chemotherapy. EMA/CO program [5]. Although the efficacy of current treat-
Types (degree) Courses Incidence ment GTN has been satisfactory, it is reported that about 20
I II III IV In total (%) - 30% of patients with high-risk GTN failed to respond to
Nausea, vomiting 92 87 17 0 196 71.80 first line chemotherapy regimens and required remedial
Neutropenia 101 68 16 1 186 68.13
chemotherapy [6]. Therefore, more effective chemotherapy
Thrombocytopenia 33 10 1 0 44 16.12
Hemoglobinpenia 12 18 2 0 32 11.72
regimen need to be developed.
Alopecia 28 61 180 0 269 98.54 BEP regimen is recognized as the preferred choice in the
Peripheral neuropathy 51 69 0 0 120 43.96 treatment of malignant ovarian germ cell tumors (including
Impaired liver function 32 0 0 0 32 11.72 primary ovarian choriocarcinoma). The regimen has been re-
Pulmonary toxicity 7 0 0 0 7 2.56 ported in the literature for its good effect in early, advanced
Decreased heart function 11 0 0 0 11 4.03 and recurrent malignant ovarian germ cell tumors. The ad-
verse reactions are relatively mild and the cure rate of ma-
lignant ovarian germ cell tumor could reach over 90%.
BEP chemotherapy side effects Following these strategies, most patients will be cured and
As shown in Table 2, major side effects of BEP the vast majority will still be able to give birth [7, 8]. How-
chemotherapy were alopecia, gastrointestinal toxicity, and ever, there is few research on the effects of BEP regimen in
bone marrow suppression, followed by mild liver dysfunc- GTN. In 1988, it has been reported, for the first time, that
tion, peripheral neuritis, and occasional mild pulmonary one refractory GTN patient with drug resistance was suc-
toxicity. The study did not show a severe allergic reaction cessfully cured with the BEP regimen [9]. Moreover, one
and obvious heart, liver, lung, and kidney dysfunction in case that developed resistant under etoposide and cisplatin
patients. Except for one case in which severe bone marrow (EP) regimen, obtained CR after adjusting to BEP regimen.
suppression occurred leading to chemoresistance, the other It has been demonstrated that most of patients who failed pri-
patients were not influenced by the side effects in the mary treatment with EMA/CO had complete clinical re-
course of chemotherapy. sponses to secondary chemotherapy with BEP [10, 11].
However, the other study found that five of six drug-resistant
The follow-up results patients with low-risk GTN obtained CR with BEP, and only
During the follow-up period, one patient died in multiple three of nine high-risk GTN patients obtained CR [12]. Al-
chemotherapy drug resistance; one patient under BEP reg- though the prior reports were cases or small studies, it can be
imen obtained CR after four courses, but the serum β-hCG inferred that BEP program is often used as first-line remedi-
level rose again which implicated recurrence after one year. ation therapy in GTN patients with failed chemotherapy. The
The patient obtained CR after receiving BEP and EMA/CO BEP treatment has a secure effect in resistant GTN patients.
regimen and has been followed up for 17 months with no However, whether the regimen can be used for initial treat-
signs of recurrence. Forty-three patients are alive with no ment of high-risk GTN as well as its efficacy and side ef-
signs of recurrence or secondary tumors. fects has not been reported so far. In the present study, it has
been certified that BEP is an effective regimen for high-risk
GTN as the same as EMA/CO or fluorouracil-based
Discussion
chemotherapy. Moreover, it has been indicated that, BEP
Although GTN is a highly malignant gynecological tu- combined with surgery as well as radiotherapy for high-risk
mors, because of its high sensitivity to chemotherapy and GTN patients may be helpful to improve the prognosis.
hCG serves as an ideal tumor marker to monitor the dis- In the present study, five patients under BEP developed re-
ease, its prognosis has become one of the best among all sistance, who were non-postmolar GTN in late clinical stage
cancers [2]. Currently the cure rate of low-risk GTN is and high prognosis score (averaging 14.4 points). In addi-
nearly up to 100%; the survival rate of patients with high- tion, for most of them, the chemotherapy regimen was not
risk GTN is about 86% [3]. standardized (chemotherapy was delayed or consolidation
Currently the treatment principle of high-risk GTN is com- therapy was not given after symptoms improved). As a result,
binational chemotherapy as the first choice, and on this basis, resistance occurred. Therefore, the present authors believe
radiotherapy and (or) other treatments such as surgery are that if the management of patient is strengthened, patient
given when appropriate [4]. So far, many chemotherapy reg- confidence to overcome the disease is enhanced, the side ef-
imens have been used for treatment of patients with high- fects of chemotherapy are given more attention to personal-
risk GTN, the representative regimens include methotrexate ize treatment, which ensures that patients can schedule
+ dactinomycin and cyclophosphamide (MAC), hydrox- regular chemotherapy; hence better efficacy of BEP program
yurea + cyclophosphamide + dactinomycin + A aminopterin is expected which remains to be further studied.
+ leucovorin + vincristine + doxorubicin (CHAMOCA), Chemotherapy-related toxicity was in keeping with the
EMA/CO scheme; the response rates were 68%, 71%, and present authors’ expectations. Nevertheless, one patient died
 S.Q. Song, C. Wang, G.N. Zhang, Y. Shi, Y. Zhu, T. Hu, S.Q. Xu, Z.R. Yang 729

of brain metastasis. A retrospective analysis showed that she [2] Jiaxin Y., Yang X., Qingguo C., Xiuyu Y., Hongzhao S.: “Diagnosis
received non-standard chemotherapy for family and finan- and treatment of the malignant gestational trophoblastic tumor with
pulmonary metastasis complicated with pulmonary tuberculosis”.
cial reasons. If this case is excluded, acute toxicity was ac- Chin. Med. Sci. J., 1999, 14, 229.
ceptable and severe toxicity was infrequent [8], although [3] Ngan S., Seckl M.J.: “Gestational trophoblastic neoplasia manage-
grade I - III myelosuppression was observed in the major- ment: an update”. Curr. Opin. Oncol., 2007, 19, 486.
ity of patients, specifically neutropenia [13]. Currently, the [4] Golfier F., Labrousse C., Frappart L., Mathian B., Guastalla J.P., Tril-
let-Lenoir V., et al.: Evaluation of treatment relating to gestational
administration of G-CSF would help to manage such toxic- trophoblastic tumor registered to the French Trophoblastic Disease
ity. In the present study, the oldest patient occurred severe Reference Center (TDRC) in Lyon from 1999 to 2005”. Gynecol.
bone marrow suppression (grade IV) after BEP required Obstet. Fertil., 2007, 35, 205.
transfusion therapy, implicating that older patients with BEP [5] Kim S.J., Bae S.N., Kim J.H., Han K.T., Lee J.M., Jung J.K.: “Effects
of multiagent chemotherapy and independent risk factors in the treat-
were prone to severe bone marrow suppression. ment of high-risk GTT—25 years experiences of KRI-TRD”. Int. J.
The present authors did not observe any severe ototoxic- Gynaecol. Obstet., 1998, 60, S85.
ity, or nephrotoxicity, which is consistent with the results of [6] Ma Y., Xiang Y., Wan X.R., Chen Y., Feng F.Z., Lei C.Z., Yang X.Y.:
Tangir et al. and Kang et al. BEP trials for GNT [7, 14]. “The prognostic analysis of 123 postpartum choriocarcinoma cases”.
Int. J. Gynecol. Cancer, 2008, 18, 1097.
Etoposide may cause secondary tumors, including myeloid [7] Tangir J., Zelterman D., Ma W., Schwart P.E.: “Reproductive func-
leukemia, and colorectal and breast cancers [15]. However, tion after conservative surgery and chemotherapy for malignant germ
in the present study there were no secondary tumors during cell tumors of the ovary”. Obstet. Gynecol., 2003, 101, 251.
the follow-up period. [8] de La Motte Rouge T., Pautier P., Rey A., Morice P., Haie-Meder C.,
Kerbrat P., et al.: “Survival and reproductive function of 52 women
It is reported that pulmonary toxicity is the major side ef- treated with surgery and bleomycin, etoposide, cisplatin (BEP)
fects of bleomycin with a rate of 6.8%, and it is positively chemotherapy for ovarian yolk sac tumor”. Ann. Oncol., 2008, 19,
correlated with the cumulative dose of bleomycin, patient 1435.
age, poor renal function (creatinine clearance rate in partic- [9] Willemse P.H., Aalders J.G., Bouma J., Sleijfer D.T.: “Chemother-
apy-resistant gestational trophoblastic neoplasia treated successfully
ular) [16]. In severe cases, pulmonary fibrosis may occur, al- with cisplatin, etoposide, and bleomycin”. Obstet. Gynecol., 1988,
though rare, but it is potentially a deadly threat [17]. 71, 438.
Willemse et al. [9] reported that a drug-resistant and refrac- [10] Jiang J., Nan F.F., Yang X.S., Zhang ., Wang B., Kong B.H.: “Com-
tory GTN patient (age 53) was successfully cured with BEP, bination chemotherapy with etoposide and cisplatin for high-risk,
chemorefractory and recurrent gestational trophoblastic neoplasia”.
but developed moderate pulmonary toxicity. The present Zhonghua Fu Chan Ke Za Zhi, 2007, 42, 595.
study also showed that the incidence of pulmonary toxicity [11] Lurain J.R., Nejad B.: “Secondary chemotherapy for high-risk ges-
was 2.56%, lower than the incidence reported in the litera- tational trophoblastic neoplasia”. Gynecol. Oncol., 2005, 97, 618.
ture, and to a lesser extent. It may be related to conventional [12] Hoekstra A.V., Lurain J.R., Rademaker A.W., Schink J.C.: “Gesta-
tional trophoblastic neoplasia: treatment outcomes”. Obstet. Gy-
corticosteroid (dexamethasone) treatment, which may inhibit necol., 2008, 112, 251.
the growth of fibroblasts. However, it still remains to be fur- [13] Bakri Y.N., Ezzat A., Akhtar, Dohami, Zahrani: “Malignant germ
ther studied. The study also found the oldest patients, who cell tumors of the ovary. Pregnancy considerations”. Eur. J. Obstet.
experienced severe bone marrow suppression as well as pro- Gynecol. Reprod. Biol., 2000, 90, 87.
[14] Kang H., Kim T.J., Kim W.Y., Choi C.H., Lee J.W., Kim B.G., Bae
gressed primary pulmonary fibrosis after seven courses of D.S.: “Outcome and reproductive function after cumulative high-
chemotherapy, which implicated that older patients should dose combination chemotherapy with bleomycin, etoposide and cis-
be careful when receiving BEP. platin (BEP) for patients with ovarian endodermal sinus tumor”.
In summary, BEP is an effective and well-tolerated regi- Gynecol. Oncol., 2008, 111, 106.
[15] Rustin G.J., Newlands E.S., Lutz J.M., Holden L., Bagshawe K.D.,
men for high-risk GTN. Combinational surgery and radio- Hiscox J.G., et al.: “Combination but not single-agent methotrexate
therapy as well as adjuvant therapy can further improve the chemotherapy for gestational trophoblastic tumors increases the in-
outcome. Side effects after chemotherapy are tolerable for cidence of second tumors”. J. Clin. Oncol., 1996, 14, 2769.
most patients. However, older patients are prone to experi- [16] O’Sullivan J.M., Huddart R.A., Norman A.R., Nicholls J., Dearna-
ley D.P., Horwich A.: “Predicting the risk of bleomycin lung toxic-
ence severe side effects after chemotherapy and should be ity in patients with germ-cell tumours”. Ann. Oncol., 2003, 14, 91.
treated with caution. Therefore, for young patients with [17] Tewari K., Cappuccini F., Disaia P.J., Berman M.L., Manetta A.,
high-risk GTN, BEP program is a safe and effective Kohler M.F.: “Malignant germ cell tumors of the ovary”. Obstet. Gy-
chemotherapy regimen. Since this study was a retrospec- necol., 2000, 95, 128.
tive study, the number of cases was not enough to draw a
definitive result and it remains to be further studied. Address reprint requests to:
G.N. ZHANG, M.D.
Department of Gynaecologic Oncology,
References Sichuan Cancer Hospital,
[1] Kohorn E.I.: “The new FIGO 2000 staging and risk factor scoring No.55, Section 4, South People’s Road,
system for gestational trophoblastic disease: description and critical Chengdu 610041, Sichuan (China)
assessment”. Int. J. Gynecol. Cancer, 2001, 11, 73. e-mail: [email protected]