Outcomes of ovarian germ cell tumors: ten years of experience at the Brazilian National Cancer Institute.

ORIGINAL STUDY

Outcomes of Ovarian Germ Cell Tumors Ten Years of Experience at the Brazilian National Cancer Institute Jesse Lopes da Silva, MD, Nelson Luiz Renna, Jr, MD, Eduardo Paulino, MD, and Andre´ia Cristina de Melo, MD, MSc Objective: Ovarian germ cell malignancies are a rare group of chemosensitive malignances that predominantly occur in young women. Bleomycin, etoposide, cisplatin (BEP) regimen was consolidated, by previous studies, as the standard treatment. This Brazilian single institutional study was performed to evaluate our experience in treating patients with ovarian germ cell tumors (OGCTs). Methods/Materials: A retrospective analysis of all patients as having OGCTs, from April 2003 to July 2013, was carried out at the Brazilian National Cancer Institute. Results: Data on 30 patients were obtained, and 19 patients were treated with BEP. Median overall survival and progression-free survival were not reached. Just 4 (13.3%) patients had progressed and 5 (16.7%) had died up to the date of analysis. The proportion of patients who had dysgerminoma was 53.3%. From the 18 patients considered to have had an incomplete resection, 84.6% achieved objective response (partial or complete response) with chemotherapy. Patients with stage IV and incomplete resection had markedly ominous prognosis. Alopecia was the most frequent adverse event; grade 2 was presented in 17 (89.4%) patients. Nausea and vomiting were related by more than one-half of the patients. Grade 3 and 4 neutropenia was presented in 5 (26.3%) patients. One patient died of pneumonitis related to bleomycin. Conclusions: Our study confirms the effectiveness of BEP regimen and the great prognosis for patients with OGCTs. Advanced-stage and persistent disease configured as an important risk factor for survival. The chemotherapy regimen was associated with significant but manageable toxicity. Key Words: Bleomycin, Etoposide, Cisplatin, BEP, Ovarian tumor germ cell, Adjuvant chemotherapy, Palliative chemotherapy Received August 21, 2014, and in revised form February 5, 2015. Accepted for publication February 5, 2015. (Int J Gynecol Cancer 2015;25: 786Y791)

germ cell tumors (OGCTs) are a rare group of O varian malignancies derived from primordial germ cells of the

ovary.1 These tumors usually affect young and otherwise healthy females between 10 and 30 years of age, representing 70% of ovarian neoplasm in this age group.2 The histopathologic classification of OGCTs includes dysgerminomas, mixed germ cell tumors, teratomas (immature, mature, and monodermal types), and endodermal sinus tumors,

together accounting for 90% of the cases. Less commonly, there are the embryonal carcinoma, polyembrioma, and nongestacional choriocarcinoma.2 There are no Brazilian data regarding OGCT incidence and prevalence. However, findings of the American Cancer National Database from 1973 to 2002 revealed pure dysgerminomas in 32.8%, teratomas (immature and mature with malignant transformation) in 35.6%, and mixed cell types in 28.7% of the cases.3

Instituto Nacional do Caˆncer, Hospital do Caˆncer II, Rio de Janeiro, RJ, Brazil. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000432

Address correspondence and reprint requests to Jesse Lopes da Silva, MD, Instituto Nacional do Caˆncer, Hospital do Caˆncer II, Equador Street, 831, 3rd floor - Santo Cristo, Rio de Janeiro, RJ 22220-410, Brazil. E-mail: [email protected]. The authors declare no conflicts of interest.

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International Journal of Gynecological Cancer

& Volume 25, Number 5, June 2015

Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.



Some biologic markers (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and lactic dehydrogenase [LDH]) can be detected in the presence of specific histologic subtypes. In the clinical practice, they help to confirm the diagnosis and are useful for monitoring response and for posttreatment follow-up.4 Ovarian germ cell tumors grow rapidly and tend to be quite large, unlike other epithelial ovarian neoplasms. The initial approach for patient suspected of having OGCT is surgery, both for diagnosis and for therapy, including detailed inspection, palpation, and, if necessary, staging biopsies and peritoneal wash, to thoroughly determine the disease extent.6 Considering the chemosensitivity and the young age of many patients, the extension of surgical resection must be balanced. Even in the face of metastatic disease, a fertilitysparing procedure preserving the normal contralateral ovary can be performed. One promising approach for spare fertility in patients with advanced tumors is the use of neoadjuvant chemotherapy, albeit the data are scant in this area.7 An alternative option for patients with well-staged OGCT who are at low risk for recurrence is surveillance. Many of these reports are from pediatric population, where the staging of germ cell tumors is different from adults and the risk of late adverse effects, including second malignancies, are more frequent. A study of Pediatric Oncology Group and the Children’s Cancer Group reported that observation was sufficient after complete surgical resection in 41 girls with ovarian immature teratoma, in whom 13 had grades 2 and 3, and 10 patients with mixed tumors (immature teratoma plus yolk sac tumors). Only one recurrence occurred and was salvaged with bleomycin, etoposide, and cisplatin (BEP).8 Another study from the University of Milan reported only 2 recurrences (1 case of mature teratoma and 1 case of gliosis) in 32 prospectively followed patients with pure immature teratoma (9 had grades 2 and 3 stage IA).9 Also, in a more recent analysis, Billmire et al10 evaluated 25 girls with stage I OGCT enrolled onto Children’s Oncology Group study (AGCT0132; most of them with yolk sac tumor). Twelve patients have recurred and 11 were successfully treated with chemotherapy, showing that at least half of the girls were spared of cytotoxic drugs. Unlike testicular cancer, the finding of residual mass after chemotherapy completion is less common because these women are likely to have tumor debulking at the time of the diagnostic procedure. However, it is now recognized that occasional patients who have received chemotherapy for immature teratoma, or mixed germ cell tumor containing teratoma, will have bulky residual disease after chemotherapy. There are anecdotal reports of progressive mature teratoma after chemotherapy,11 and patients with bulky residual teratoma may develop malignant tumors overtly.12,13 Considering this information, it seems appropriate to resect persistent masses in patients with negative markers. The chemotherapy evolved during the past 30 years in the same line of the treatment used to testicular germ cell tumors.14 The first effective chemotherapy treatment used postoperatively for patients with advanced OGCTs was the VAC regimen (vincristine, dactinomycin, and cyclophosphamide). In the Gynecologic Oncology Group trial, 54

Outcomes of Ovarian Germ Cell Tumors

patients were treated after removal of all gross disease, 28% have failed, and 30% of the entire group had unacceptable toxicity. These data have suggested that VAC regimen was insufficient for OGCTs.15 In the mid 1970s, the first cisplatin-based combination was introduced to treat OGCTs. The earlier reports revealed a 74% complete remission rate using the PVB regimen (cisplatin, vinblastine, and bleomycin). Thereafter, the superiority over the VAC regimen was confirmed and the PVB became the standard therapy used by most centers.16 Subsequently, in the early 1980s, the vinblastine was substituted to etoposide in the treatment of testicular tumors, providing at least similar efficacy, acceptable toxicity profile with less neurologic toxicity, constipation, and abdominal pain, and improving survival in patients with high tumor volume.17 In 1990, Gershenson et al18 reported their good experience in treating 26 patients with BEP after initial surgery. All 4 patients with measurable disease had a complete response, and all 4 patients who underwent second-look laparotomy had negative findings (no active tumor). Twenty-five patients (96%) sustained remission 10.4 to 54.4 months from the beginning of the chemotherapy treatment. In 1994, Willians et al1 in a Gynecologic Oncology Group prospective study evaluated the role of the BEP regimen in the adjuvant treatment of OGCTs. Of the 93 patients assessed, 91 were free of disease in the date of the final analysis and the acute toxicity was moderate. There area no Brazilian data evaluating clinical features, treatment characteristics, and outcomes of the female adult population diagnosed as having OGCTs. This study aimed to assess it at one single institution.

PATIENTS AND METHODS Patients Selection and Data Collection This study was approved by the ethics in human research committee of the Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil, and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Adult women as having OGCTs treated at INCA between 2003 and 2013 were identified through internal database. The following data were retrospectively collected from the medical charts: demography; pathology; cytoreductive surgery; stage at diagnosis; serum levels of AFP, LDH, and QHCG; chemotherapy; any further surgery; toxicity according to National Cancer Institute Common Toxicity Criteria, version 3.0; and details on clinical status. Response to chemotherapy in patients with measurable residual disease was determined by repeated imaging studies and defined as follows: complete response, partial response), progressive disease, and stable disease. The radiologic evaluation was based on the Response Evaluation Criteria in Solid Tumors, version 1.0. Before the first cycle of BEP, the patients had a complete medical history and physical examination. Before each cycle, the patients had a medical evaluation including adverse events, complete blood count, and serum biochemistry panel.

* 2015 IGCS and ESGO


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TABLE 1. Patient and histopathologic characteristics No. Patients (%) Age, y Median Range Histology Dysgerminoma Immature teratoma EST MGCT Stage I II III IV

26 18Y63 16 8 4 2

(53.3) (26.7) (13.3) (6.7)

7 1 13 9

(23.3) (3.3) (43.4) (30.0)

EST, endodermal sinus tumor; MGCT, mixed germ cell tumors.

Imaging studies were done in a frequency according to the physicians’ discretion.

Treatment The standard administration schedule of BEP consisted of a 3-week cycle of bleomycin 30 mg administered either intravenously (IV) on days 1, 8, and 15; etoposide 100 mg/m2 IV on days 1 to 5; and cisplatin 20 mg/m2 on days 1 to 5, with appropriate prehydration and posthydration. Treatment doses were decreased, as well as delayed, according to the presented toxicities. There was not a fixed pattern of dose-level reductions in this retrospective study.

Statistical Analysis Overall survival (OS) was estimated from the time of the first treatment day until death, or for living patients, the last available follow-up. Disease-free survival was measured from the date of the first chemotherapy infusion to either the first progression or death or the date of last contact for patients who were alive and free of disease, in both cases using the Kaplan-Meier method. All analyses were performed with the SPSS software, version 18.0.

RESULTS Between January 2003 and July 2013, 30 patients with pathologically confirmed OGCTs were treated at INCA. The patient and disease characteristics are shown in Table 1. The median age at the initial diagnosis was 26 years (range, 18Y63 years). More than one-half of the patients (53.3%) had dysgerminoma; 26.7%, immature teratoma; 13.3%, endodermal sinus tumors; and 6.7% mixed cell germ tumors. The stage II was uncommon, represented by only 1 patient (3.3%), and the rest was split into stage I (23.3%), stage III (43.4%), and stage IV (30%), as shown in Table 1. The serum level of LDH was measured in 13.3% of the patients at the initial diagnosis, but the other 2 biochemical

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markers were measured for most of them. Levels of Q-HCG and the AFP were elevated in 43.3% and 30% of the patients, respectively. All patients were submitted to surgical approach. Complete resection (R0) was acquired in 43.3% of the patients, as exposed in Table 2. Approximately 36.7% of them had single unilateral salpingo-oophorectomy (USO) as a fertility-sparing surgery. More extended procedure, bilateral salpingo-oophorectomy (BSO) with total abdominal hysterectomy (TAH), was performed in approximately 33.3% of the patients, and lymphadenectomy was performed in 26.7%. The BEP regimen was administered to 19 of 30 patients assessed in this study. The number of treatment cycles was defined according to patient’s International Federation of Gynecology and Obstetrics stage, extent of residual disease, clinical response, and patient tolerance. The mean number of chemotherapy cycles was nearly 3 (ranged from 2 to 4 cycles). Of the 16 patients considered to have had an incomplete resection, 84,6% achieved an objective response (partial or complete response). The median progression-free survival and the OS were not reached. Just 4 patients (13.3%) had progressed and 5 (16.7%) had died up to the date of analysis. Table 3 shows the characteristics of the 4 patients who have progressed to the chemotherapy. All of them had stage IV disease with incomplete resection and 50% had dysgerminoma. In general, they had a shorter time to first progression (mean, 3.4 months). As shown in Figures 1 and 2, patients with stage IV and incomplete resected tumors had markedly ominous prognosis. One patient submitted to USO died of surgical complications. Of the 4 patients with relapsed disease, 2 did not receive a second-line chemotherapy regimen because of fast clinical deterioration. One patient received initially etoposide, ifosfamide, and cisplatin for 2 months and, after disease progression, five 3-weekly cycles of paclitaxel and gemcitabine. The last one was treated with ifosfamide, carboplatin, and etoposide for 2 months and, after progression, with paclitaxel and gemcitabine for 3 months. Considering the possible bias of this retrospective assessment and the lack of information regarding toxicities in

TABLE 2. Surgery characteristics Initial Surgery

No. Patients (%)

USO USO + lymph Metastasis biopsy BSO + TAH BSO + TAH + lymph Status of margin R0 R2

12 6 1 4 9

(37.5) (18.7) (3.1) (12.5) (28.2)

14 (43.7) 18 (56.3)

Lymph, lymphadenectomy; R0, no residual disease; R2, gross residual disease.






TABLE 3. Characteristics of patients who failed chemotherapy Age, y 29 22 20 21

OS, mo

Histology

Stage

Site of Relapse

Response

TTP, mo

21 26 6 9

Dysgerminoma Dysgerminoma Immature teratoma Endodermal sinus tumor

IV IV IV IV

Retroperitoneum; meningeal Mediastinum Pelvic Pelvic

Partial response Partial response Stable disease Stable disease

2 4 5 3

some cases, the BEP-related toxicities are summarized in Table 4. Alopecia was the most frequent adverse event, grade 2 in 17 (89.4%) and grade 1 in 2 patients (10.6%); nausea and vomiting were encountered in more than one-half of the patients; grade 3 and 4 neutropenia was presented in 5 (26.3%) patients. There was no neurotoxicity-related and renal toxicity was uncommon. From the 3 patients with some grade of toxicity, one had severe presentation and the only one chemotherapyrelated death was attributed to the bleomycin pulmonary injury (BPI). No case of secondary neoplasm was registered so far.

DISCUSSION To the best of our knowledge, this cohort represents the first BEP treatment analysis of Brazilian women with OGCT. Our results strongly confirmed the effectiveness of BEP regimen and the great prognosis. Previous series1,5,17 of patients with OGCTs who have received BEP as an adjuvant or for advanced or recurrent disease demonstrated that such treatment is curative in most patients. The great prognosis and the restricted number of events (deaths, resistant or progressive disease) explain the fact of not reaching the median progression-free survival or the median OS. Indeed, 66.7% of the 30 patients analyzed were disease-free and 86.7% were alive at the last follow-up. The objective response rate of 84.6% among patients with gross residual disease was similar to the 80% shown by the report by

Dimopoulos et al14 and to the 38 patients with complete response out of 46 surgically reassessed in the multicenter prospective study by Williams et al.1 However, the mean time to progression was quite short for the 4 patients who progressed, suggesting a specific refractory disease profile with unfavorable prognosis in this small group. Lin et al20 recently made some molecular and genetic analysis in their report, suggesting that some alterations may alter the clinical outcome, like the amplification of c-kit and karyotype mosaicism; the microRNA 371Y373 cluster and microRNA 302 that is thought to affect the p53-mediated pathway. Dysgerminoma was the most frequent subtype in our cohort, comprising 53.3% of the patients assessed. In previous data, this proportional incidence varied from 24% to 42%.6,14,16 Some reports have suggested the endodermal sinus tumors as a risk factor for failure, exposing its aggressive behavior.1,15 Schwartz et al21 showed that 3 of 11 patients with recurrent or persistent disease had endodermal sinus tumors and 2 of 4 patients who died of recurrent germ cell tumor had this histologic subtype. In our results, of the 4 dead patients, only 1 had endodermal sinus tumor. The stage IV and the suboptimal cytoreduction, with gross residual disease, had expectedly ominous outcomes. As stated in Table 4, all 4 patients who failed the first treatment in our study had advanced with persistent disease. The survival curve by stage (Fig. 2) shows that, different from the other stages, the stage IV deeply drops in the beginning of the follow-up. Segelov et al22 in their Australian retrospective analysis reported 5 deaths of 6 patients with advanced and persistent disease. TABLE 4. Chemotherapy toxicity No. Patients (%)

FIGURE 1. Overall survival by margin status.

Toxicity Nausea/Vomiting Alopecia Anemia Neutropenia Platelets Renal Pulmonary Mucositis Diarrhea Fatigue

Grades 1Y2 11 (57.9) 19 (100) 4 (21.2) 8 (42.4) 3 (15.9) 2 (10.6) 2 (10.6) 7 (37.1) 4 (21) 7 (36.8)



Grades 3Y4 2 (10.6) V 2 (10.6) 5 (26.3) 1 (5.3) 0 (0) 1 (5.3) 0 (0) 1 (5.3) 1 (5.3)

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FIGURE 2. Overall survival by stage. The serum markers are an important factor for diagnosis of disease at advanced stages and for prediction of early relapsing condition. The alteration of Q-HCG or AFP preceded the radiologic and clinical progression detection in the most of the cases. However, considering all the patients at the diagnosis, just nearly 45% had one of these markers elevated. Dimopoulos et al14 reported elevation of serum AFP in 32% of patients at diagnosis and Q-HCG in 18%, but they did not make any correlation between these previous elevated serum markers and the prognosis for death or treatment failure. The USO, a sparing-fertility surgery, performed in more than one-third of the patients, did not seem to increase the risk of progression or death related to disease, and the only one death among patients submitted to USO was attributed to procedure complications. Williams et al1 showed that 65 of 93 patients submitted to USO were fully cured, preserving the contralateral organ. That is important for the younger population affected by the OGCTs, who is willing to experience childbearing. Kumar et al7 recently showed a retrospective analysis of 23 patients with advanced OGCT in whom a fertility procedure was done after neoadjuvant chemotherapy with BEP regime. Eighteen of 21 could undergo fertilitysparing surgery and have resumed menstruation. An important area for further study is the impact of modern chemotherapy on menstrual function and fertility. Epipodophyllotoxin etoposide has been reported to be associated with the development of an acute leukemia that has typical morphologic and cytogenetic features.19 The incidence of this second neoplasm is very low, and no longer follow-up is necessary because the onset of this secondary leukemia is ordinarily closer to the chemotherapy exposure.23 None of the 19 patients who received the courses of BEP regimen developed this complication.

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The chemotherapy regimen was associated with significant toxicity, but the incidence of severe complications was manageable and acceptable given the high response and cure rate of this treatment. Long-term toxicity was not documented in our study. Myelotoxicity, represented mainly by neutropenia and febrile neutropenia, was confirmed as an important cause of hospitalization and severe acute toxicity, but BPI and fatigue were major causes of morbidity. The only death related to toxicity was caused by severe pneumonitis derived from BPI. It is already known that monitor respiratory function in patients using bleomycin must be rigorously carried out. However, for logistical issues, it was not performed routinely in our institution during some periods. Segelov et al22 reported on 3 patients with severe BPI confirmed by lung biopsy, and these patients interestingly had normal pulmonary function before the chemotherapy, contradicting the known fact that severe BPI generally occur in patients with previous pulmonary comorbidities. In conclusion, despite the great effectiveness of the BEP regimen, there is a lack of larger prospective randomized trials focusing on the definition of reliable prognostic and predictive factors, involving clinical and molecular features, and improving survival for patients with advanced and incomplete resected disease. Furthermore, the long-term toxicity impact of BEP is still unknown and the definition of the management of severe pneumotoxicity remains a challenge.

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17. Willians SD, Birch R, Einhorn LH, et al. Treatment of disseminated germ cell tumors with cisplatin, bleomycin and either ‘‘’’vinblastine or etoposide. N Engl J Med. 1987;316:1435Y1440. 18. Gershenson M, Morris M, Cangir M, et al. Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide and cisplatin. J Clin Oncol. 1990;8:715Y720. 19. Pulsoni A, Pagano L, Lo Coco F, et al. Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience. Blood. 2002;100:1972Y1976. 20. Lin KY, Bryant S, Miller DS, et al. Malignant ovarian germ cell tumorVrole of surgical staging and gonadal dysgenesis. Gynecol Oncol. 2014;134:84Y89. 21. Schwartz PE, Chambers SK, Chambers JT, et al. Ovarian germ cell malignancies: the Yale University experience. Gynecol Oncol. 1992;45:26Y31. 22. Segelov E, Jenny C, Ng M, Tattersal M, et al. Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience. J Clin Oncol. 1994;12:378Y384. 23. Kumar TN, Krishnamani, Gandhi LV, et al. Therapy-related acute promyelocytic leukemia following etoposide-based chemotherapy in non-seminomatous germ cell tumor. J Postgrad Med. 2014;60:84Y85.



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