Adjuvant chemotherapy of resistant high risk choriocarcinoma

Choriocarcinoma is a subtype of gestational trophoblastic disease. It is a very rare neoplasm, with incidence of about 1 case in 40.000 pregnancies. Gestational form of choriocarcinoma arises most commonly after abortion, while nongestational form develops from pluripotent germ cells. Choricarcinoma is highly malignant and highly chemosensitive type of tumor. A 43-year-old patient diagnosed with extra uterine pregnancy in September 2017 was treated with methotrexate with no response and had surgical removal of right Fallopian tube. Choriocarcinoma was diagnosed one and a half year after extra uterine pregnancy. Radiological imaging before treatment showed pulmonary and inguinal lymph node metastases and tumor invasion of the anterior uterine wall. Surgery was performed due to heavy bleeding and uterine wall invasion. As high risk patient she received chemotherapy. She was followed radiologically and her serum ?-HCG was monitored. Refractivity to the chemotherapy protocol during treatment was observed. Therapy response was achieved after administration of EMA-EP protocol modification i.e. three consecutive negative follow-up values of ?-HCG were obtained and radiological findings were disease free. One month after treatment patient had no signs of disease and ?-HCG level was normal.


INTRODUCTION
Choriocarcinoma is a subtype of gestational trophoblastic disease (1). This type of carcinomas develops from abnormal trophoblastic population which has undergone hyperplastic and anaplastic changes (2). Choriocarcinoma can have, gestational and non-gestational. Gestational form arises most commonly after abortion, while nongestational form develops from pluripotent germ cell. Due to their origin from pluripotent cell non-gestational form can develop in males as well (3). This neoplasm is very rare, with incidence of about 1 case in 40.000 pregnancies in America and Europe. It was notices that incidence is higher in some populations like Asian, Afro-American and American-Indian (2). Besides irregular or heavy menstrual bleeding, health care professionals should pay attention to symptoms that arise from other organ systems (hemoptysis, gastrointestinal bleeding etc.), because choriocarcinoma tends to metastasize (4). Due to its nature to metastasize in chest, brain, abdomen and pelvic area computed tomography or magnetic resonance imaging (MRI) is recommended in staging of choriocarcinoma (5). International Federation of Gynecology and Obstetrics and World Health Organization developed staging/classification system for choriocarcinoma (6) ( Tables 1 and 2). Chemotherapy recommendations for low risk choriocarcinoma (Score β7) and stage I to III are methotrexate or actinomycin D. For high risk cases of choriocarcinoma multi-agent chemotherapy is used (7).

CASE SUMMARY
A 43-year-old, previously healthy female, diagnosed with extra uterine pregnancy in September 2017 and treated with four ampules of Methotrexate had surgical removal of right Fallopian tube. Year and half following the treatment of extra uterine pregnancy she was diagnosed with choriocarcinoma. She was operated in local hospital and her right ovary was surgically removed. Pathohistological (PH) examination confirmed diagnosis of choriocarcinoma. Preoperative value of β-HCG at this point was 166084.50 IU/l. Two weeks after ovary removal value of β-HCG was 20462.89 IU/l. Radiological imaging showed metastases in lungs, inguinal lymph nodes and invasion of the anterior wall of uterus ( Figure 1). One month following surgery value of β-HCG was 605000 IU/l, and radiological imaging showed tumor mass in uterine cavity ( Figure 2). Due to heavy vaginal bleeding patient was admitted to Oncology institute of Vojvodina, Serbia where abdominal subtotal hysterectomy with removal of left ovary was performed in February 2019. Uterus and left ovary were sent do PH examination that confirmed diagnosis of choriocarcinoma. Two weeks following hysterectomy, during physical examination change on the anterior vaginal wall near introitus was noticed and resected. At this point value of β-HCG was 169528 IU/l. Pathohistological examination of change from vaginal wall confirmed choriocarcinoma diagnosis. In March 2019 she received first ampule of methotrexate. Value of β-HCG dropped to 101210 IU/l. Three weeks after she received second methotrexate treatment when value of β-HCG started to increase. Three days after second methotrexate treatment β-HCG value was 155255.09 IU/l, and continued to rise up to 216529.57 IU/l two weeks later. Therapy regiment was changed to EMA-CO protocol (etoposide, methotrexate, actinomycin -cyclophosphamide, vincristine) due to high values of β-HCG. In April 2019 patient received EMA part of the protocol, and value of β-HCG started to decline. Value continued to drop until third series of EMA-CO protocol, after which growth of β-HCG values was noticed (Table 3). After third series of EMA-CO protocol radiological imaging showed persistence of metastases in lungs and inguinal lymph nodes. Due to increase in β-HCG values and persistence of metastases, chemotherapy regimen was changed once again. In June 2019 patient received first EMA part of the first series of EMA-EP protocol (etoposide, methotrexate, actinomycin-etoposide, cisplatin). At the time she was given second EP part of the first series of EMA-EP protocol value of β-HCG was 3664.54 IU/l. After completion of first series of EMA-EP protocol value of β-HCG dropped to 434 IU/l, but started to increase again after second series. Radiological imaging was performed between EMA and EP part of fourth series of EMA-EP protocol that showed persistence of lung metastases, but inguinal metastases were not noticed on MRI. Total of four series of EMA-EP protocol were given (Table 4). Chemotherapy regimen was once again changed due to increase in β-HCG values and persistence of lung metastases. In October 2019 modified hospital protocol was administered to the patient, with first series of weekly EP (etoposide, cisplatin), after which values of β-HCG started to drop. Six series of weekly EP protocol were administered in total (Table 5). After six series of weekly EP protocol, patient values of β-HCG were normal and radiological imaging revealed that metastases were absent ( Figure 3).

DISCUSSION:
Choriocarcinoma most commonly occurs in women after gestation (3). Due to its rare appearance and manifestation by non-specific    (9). Choriocarcinoma can develop in any time between 5 weeks to 15 years after gestational event (10). Above mentioned data about age incidence and time between gestational event and appearance of malignancy are in accordance with our data. McGrath et al.
indicate that woman with pre-treatment β-HCG values >100000 and <400 000 can be treated with low-risk single-agent therapy, because it is less toxic than multiple-agent therapy (11). Beside the fact that single-agent drug therapy is less toxic, it will only prolong treatment by two weeks if a change to multiple-drug treatment is required (11). We started treatment with single drug agent methotrexate. After two series tumor developed resistance that could be expected because only 30% of patient can be cured with single agent therapy (11). Decision to switch from methotrexate to another single agent actinomycin D or multiple drug regimen can be made upon β-HCG values being <300 or >300 (12). In our case β-HCG values were much higher than 300, so we switched to EMA-CO protocol that was reported to have remission rate from 63.3% to 90.6% (12). During treatment with EMA-CO protocol we managed to decrease β-HCG values, but values reached plateau around 400 IU/l. The situation where there is response, but values of β-HCG reach plateau was described in literature, and this is the case when EMA-EP regimen is indicated (13). After reaching plateau we switched to EMA-EP protocol, following guidelines. Complete remission rates that have been mentioned in literature after EMA-EP protocol were in the range from 75% -85% (13). After four series of EMA-EP protocol increase in β-HCG level of our patient was seen. This can be explained by the fact that 10-20% of cases may develop incomplete response to methotrexate based protocols (14

Declaration of Interests
Authors declare no conflicts of interest.