Published online Oct 23, 2023.
https://doi.org/10.3802/jgo.2024.35.e19
Study of neoadjuvant chemotherapy in advanced malignant ovarian germ cell tumors at a tertiary center in western India
,
Shilpa M Patel,
Ruchi Arora,
Chetana D Parekh,
Pariseema Dave,
Bijal M Patel
and Priyanka Vemanamandhi
Abstract
Objective
To study clinical characters and outcomes in patients of malignant ovarian germ cell tumor (MOGCT) undergoing surgery following neoadjuvant chemotherapy (NACT).
Methods
Retrospective study of patients undergoing surgery following NACT for MOGCT at our institute. Platinum based chemotherapy was given in all patients in NACT.
Results
Between March 2013 and February 2023, 30 patients had surgery after NACT. Patient’s median age was 22 years (range, 12 to 35 years) and median follow up 42months (range, 6 to 132 months). Majority had endodermal sinus tumor (n=12), dysgerminoma (n=9) and mixed GCT (n=7). All had either International Federation of Gynecology and Obstetrics (FIGO) stage 3 (n=19) or FIGO stage 4 disease (n=11). Complete response to NACT seen in 5 patients and 23 patients had partial response. Fertility sparing surgery in 18 patients and complete surgery in 12 patients. Suboptimal surgery was seen in 4 patients. Currently, 20 of 30 patients are alive and disease free, 3 lost for follow up and 7 patients had progression after adjuvant therapy. Five patients had mortality—4 with progression and 1 with bleomycin toxicity. Fifteen of 17 eligible patients have resumed menstruation and one had successful pregnancy. Prognostic factors noted in study are stage, optimal surgery and viable tumor in histopathology. Dysgerminoma had better outcome than other histology.
Conclusion
NACT may be a reasonable option in patients with extensive unresectable disease or in whom fertility sparing is not possible or in the poor general condition. Fertility sparing surgery can be attempted post neoadjuvant chemotherapy without adversely affecting prognosis.
Synopsis
Neo-adjuvant chemotherapy (NACT) is an option for malignant ovarian germ cell patients with extensive unresectable disease or in whom fertility sparing is not possible or in the poor general condition. Fertility sparing surgery can be attempted post neoadjuvant chemotherapy without adversely affecting prognosis. Data regarding NACT in germ cell tumor is scarce even though they are highly chemosensitive.
INTRODUCTION
Malignant ovarian germ cell tumors (MOGCTs) derived from primordial germ cells of the ovary account for 5% of ovarian malignancies. Around 25%–30% of malignant germ cell tumors have advanced disease at presentation. Fertility sparing surgery whenever feasible, irrespective of stage is the standard treatment approach and adjuvant chemotherapy may be required based on final histopathology and stage of the disease [1]. However, upfront surgery may not be feasible in all patients either due to advanced stage bulky tumors in which complete resection or fertility sparing may not be possible or due to poor performance status. Neoadjuvant chemotherapy (NACT) followed by surgery might be considered for such patients [2]. But data regarding NACT in MOGCT are lacking even though they are highly chemosensitive. This study describes the clinical characters and outcomes in patients undergoing surgery following NACT for MOGCT at our institute.
MATERIALS AND METHODS
This retrospective study was conducted at The Department of Gynaecological Oncology at The Gujarat Cancer and Research Institute, Ahmedabad. Between March 2013 to February 2023, surgery following NACT was performed in 30 patients of MOGCT and were included in this study. Clinical data, tumor markers, imaging, International Federation of Gynecology and Obstetrics (FIGO) stage, histology, details of chemotherapy, surgical procedure and outcome, reproductive function, recurrence and mortality were collected from medical records.
1. Diagnosis and NACT
Diagnosis of Malignant germ cell tumors were based on clinical and radiological findings with tumor markers or with biopsy from tumor. Patients with advanced disease (FIGO stage 3 or 4 or gross ascites) in whom complete resection or fertility sparing not possible and patients with poor performance status were considered for NACT. Platinum based chemotherapy was given in all patients receiving NACT. Bleomycin, etoposide, and cisplatin (BEP) was most commonly used. Etoposide and cisplatin (EP) were used in patients with poor performance status and bleomycin subsequently added in further cycles as performance status improved. Pulmonary function test (PFT) was monitored in patients with decreased lung compliance and bleomycin omitted with worsening PFT.
2. Surgery and follow up
Patients are usually assessed after each cycle of chemotherapy for response and resectability. Response evaluation is done as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and tumor markers. Fertility sparing surgery or complete surgery is decided on case-to-case merit. Gonadotropin-releasing hormone analogues were given prior to chemotherapy in patients planned for fertility sparing surgery. Pathological response was noted in final histopathology report. Adjuvant chemotherapy is given to complete 4 cycles of chemotherapy. Follow up is done as per standard protocol i.e., every 2 months for 1 year, every 3 months for next 1 year and every 6 months up to 5 years and then annually. The study was approved by the Institutional Review Board of the Gujarat Cancer and Research Institute.
3. Statistical analysis
Descriptive statistics was used to characterize the patient population. χ2 test was applied in the univariate analysis to evaluate the prognostic factors for PFS. Kaplan–Meier plot analysis was done to study factors affecting progression-free survival (PFS) and overall survival (OS).
RESULTS
1. Clinical characteristics
Total 129 patients had germ cell tumors of whom 51 patients (39.5%) had advanced MOGCT. Thirty one of these advanced MOGCT patients (60.7%) received NACT and one was lost for follow up after 2 cycles and hence excluded from study. Thus, we included 30 patients of advanced MOGCT undergoing surgery after NACT at our institute.
Median follow up period was 42 months (range 6 months to 132 months) and the median age was 22 years (range, 12 to 35 years). Six patients had poor Eastern Cooperative Oncology Group (ECOG) performance status (≥2). Symptomatology and clinical characteristics are described in Table 1. Two patients were premenarchal and rest had reached menarchae and were regularly menstruating. Ten patients had completed family. Eleven patients had stage 4 disease i.e., 4 patients had lung metastasis, 3 patients had liver metastasis, 1 patient had abdominal wall metastasis, 1 had positive pleural fluid cytology, 1 had mediastinal mass, and 1 patient had positive supraclavicular node. Most common histopathology was endodermal sinus tumor or yolk sac tumor in 12 patients (40.0%) followed by dysgerminoma in 9 patients (30.0%). Tumor markers were elevated in 27 patients with alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) being most commonly elevated markers in 21 patients (in 70.0% patients). Three patients had no elevated marker (2 with immature teratoma and 1 with dysgerminoma). LDH was elevated in 21 patients, this includes 8 patients of dysgerminoma, 6 patients with mixed germ cell tumor and 6 patients with yolk sac tumor. All 8 dysgerminoma patients and 5 of 6 mixed germ cell tumor patients with elevated LDH had levels >1,000 U/L. AFP was elevated in 21 patients, with all 12 patients with yolk sac tumor having level >10,000 ng/mL. Beta human chorionic gonadotropin was elevated in 12 patients (5 patients with mixed germ cell tumor and 7 patients with dysgerminoma).
Table 1
Clinical details of patients (n=30)
2. Response to chemotherapy
All patients received BEP regimen for NACT. The number of cycles ranged between 1–4. Response to chemotherapy and resectability were assessed after each cycle. EP was given in first cycle in 4 patients with poor ECOG and bleomycin was added in subsequent cycles. Most patients received 1 or 2 cycles (57% patients) and 5 patients (17%) were operated after 4 cycles (3 referred from outside after chemotherapy).
Response to chemotherapy is shown in Table 2. As per RECIST criteria assessment, complete response was seen in 5 patients, all having dysgerminoma. No progressive disease was observed during neoadjuvant chemotherapy. Since tumor markers represent tumor burden in germ cell tumor, their fall was also studied and is shown in Table 2. Most had >50% fall (range, 86% to 100%). Complete pathological response was observed in 15 patients (50.0%). It is observed that among dysgerminoma, 8 out of 9 patients (88.9%) had complete pathological response where as only 4 out of 12 yolk sac tumor (33.3%) and 3 out of 7 mixed germ cell tumor (42.8%) had complete response. Toxicity was monitored and bleomycin was skipped in 2 patients after 1st cycle due to abnormal pulmonary function test. One patient died due to bleomycin associated pulmonary toxicity post completion of adjuvant chemotherapy.
Table 2
Response to neoadjuvant chemotherapy
3. Surgery
Fertility sparing surgery was done in 18 patients and consisted unilateral salphingo-oophorectomy with individualised debulking depending on disease burden which included pelvic or para-aortic lymphadenectomy or removal of all visible disease and omentectomy. Seventeen of them had optimal surgery. One patient had suboptimal surgery due to para-aortic node adherent to inferior vena cava. This patient responded after adjuvant chemotherapy and had complete response. Complete surgery i.e., hysterectomy with bilateral salpingo-oophorectomy with removal of all visible disease and omentectomy was done in 12 patients. Ten patients had completed family, 1 was post hysterectomy and 1 patient with dysgerminoma was diagnosed with streak gonads (Karyotyping revealed Turner syndrome). Nine patients among complete surgery had optimal surgery. Suboptimal surgery was seen in 3 patients, 1 with liver metastasis and disease on greater curvature of stomach and 2 with peritoneal metastasis with bowel and mesenteric involvement. Surgery was followed by adjuvant chemotherapy to complete 4 cycles of BEP and 3 patients with viable tumor in final histopathology had change of chemotherapy to etoposide, ifosfamide, and cisplatin. No perioperative morbidity of more than grade 3 Clavien-Dindo classification was observed except for one patient with wound complication requiring resuturing. Summary of surgery is shown in Table 3.
Table 3
Surgery following neoadjuvant chemotherapy
4. Fertility and menstrual outcome
Fifteen patients among fertility sparing resumed menstruation within 3 months of treatment completion. Two patients had amenorrhoea for which hormonal treatment was given. One of them resumed spontaneous menstruation after stoppage of hormonal therapy and other is on hormones. One patient attained menarchae after surgery and is regularly menstruating. One patient had successful pregnancy with healthy baby and is 4-year-old now. One patient had missed abortion. Table 4 summarises the menstrual and reproductive outcome.
Table 4
Reproductive function among eligible patients (n=17)
5. PFS
Total 7 patients (23.3%) developed progressive disease (4 after partial response and 3 after complete response at the end of adjuvant treatment). All patients with progression either had yolk sac tumor (5 patients) or mixed germ cell (2 patients) histology. Among these 7 patients, 3 had suboptimal surgery, 6 were with stage 4 disease, 2 had fertility sparing surgery and all had viable tumor in final histopathology. Table 5 shows the characteristics of patients with progressive disease and Table 6 shows analysis of prognostic factors. Three patients (10.0%) were lost for follow up including one with recurrence. Five patients had mortality, discussed further. Rest of 20 patients are disease free till last follow up.
Table 5
Details of patients with progression after complete or partial response to adjuvant treatment
Table 6
Analysis of prognostic factors
6. Mortality
Total 5 patients had mortality (16.6%). Among these, 4 had progression and one died due to bleomycin induced pulmonary toxicity. Three patients had yolk sac tumor histology and 2 had mixed germ cell tumor histology. Three patients had suboptimal surgery and 2 had stage 4 disease. All 4 patients who died of progression had viable tumor in final histopathology. Table S1 shows the characteristics of patients with mortality.
7. Prognostic factors
On analysing risk factors for recurrence or progressive disease and mortality (as per Table 6, Table S1), age, tumor marker fall after NACT or normalisation did not have any statistically significant influence on outcome. Stage of disease had influence on progression but not on mortality. Even though statistically not significant, none of dysgerminoma patient had mortality, only one out of 9 had suboptimal surgery and only one out of 9 had viable tumor in final histopathology. Hence dysgerminoma has better outcome compared to non-dysgerminoma patients. Fertility sparing surgery had better outcome compared to complete surgery. Surgical outcome i.e., optimal surgery had statistically significant influence on prognosis and mortality. No viable tumor in final histopathology i.e., complete pathological response had favorable outcome which were statistically significant with none of patients in this group having recurrence or progressive disease.
Kaplan–Meier plots for the survival function of germ cell tumor patients in different categories was studied. Fig. S1 shows plot for PFS and Fig. S2 for OS. Figs. S1A and S2A shows Kaplan–Meier curve for stage 3 and stage 4 disease, Figs. S1B and S2B for Fertility sparing surgery versus non fertility sparing surgery, Figs. S1C and S2C for optimal surgery versus suboptimal surgery, and Figs. S1D and S2D in dysgerminoma versus non dysgerminoma patients. On log rank test analysis of these curves for PFS, no difference was found between histology (p=0.164). PFS was better with stage 3, fertility sparing surgery and optimal surgery (p=0.002, p=0.025, and p=0.026, respectively). On log rank test analysis of curves for OS, no difference in OS was found with histology and stage (p=0.164 and p=0.164, respectively). OS was better with fertility sparing surgery and optimal surgery (p=0.021 and p=0.003, respectively).
DISCUSSION
Around 25%–30% of MOGCTs are poor candidates for surgery either due to advanced unresectable disease or due to poor performance status. Initial management in such cases and extent of surgery remains unclear. Since the tumors present in young age and are highly chemosensitive tumors, neoadjuvant chemotherapy has been tried in such patients but literature regarding them is scarce. NACT in MOGCT was studied by Talukdar et al. [2] and Anjana et al. [3] with favorable outcome discussed further. Another study by Lu et al. [4] was done exclusively in yolk sac tumor patients.
We evaluated patients after each cycle of NACT for surgical resectability. Most of our patients received 2 cycles of NACT followed by surgery. In above mentioned studies, however, most patients received complete chemotherapy before surgery (i.e., 3–4 cycles). None of the international guidelines mention about number of NACT cycles. However, national cancer grid of India suggests 2 cycles of NACT followed by interval cytoreduction followed by 2 more cycles of adjuvant BEP for advanced unresectable disease or surgically unfit patients [5].
Talukdar et al. [2] studied NACT in 23 patients with majority having dysgerminoma (14 patients) and 3 yolk sac tumor patients. They had 3 patients with stage 4 disease. The 70% patients had complete response to NACT as per World Health Organization criteria. Twenty-one patients had fertility sparing surgery with optimal cytoreduction in 60% patients and complete pathological response in 72%. Mean disease-free survival (DFS) was 230 months. Total 13 pregnancies were noted and 85% resumed their menses. No recurrence or mortality was reported. Response to chemotherapy was noted as prognostic factor and stage, histology or age did not impact survival. This study also compared NACT patients with upfront surgery for advanced disease and found higher fertility preservation in NACT group and mode of treatment (i.e., NACT vs. primary surgery) did not have any impact on survival [2].
Anjana et al. [3] studied NACT in 28 patients with 12 patients of yolk sac tumor followed by 10 patients of dysgerminoma and 9 patients had stage 4 disease. Twenty-four patients underwent fertility sparing surgery. All patients had optimal cytoreduction and complete pathological response was seen in 89% of patients. Four pregnancies were noted and 76% resumed menses with 9.5% premenarchal patients. One recurrence was noted with mortality in same patient [3].
Our study had 30 patients with majority having yolk sac tumor (12 patients) followed by dysgerminoma (9 patients). We had more patients in stage 4 compared to other studies (11 patients). Complete response to chemotherapy was observed in 16% of patients in our study with partial response in most of patients (76.6%) as per RECIST criteria. Complete pathological response was seen in 50% of our patients and was associated with DFS. This difference in response to NACT compared to other studies can be attributed to higher number of yolk sac tumors in our study.
Lu et al. [4] studied 18 patients of yolk sac tumor receiving NACT, 8 of them having stage 4 disease. Viable tumor was seen in 57% of patients, degenerated residual tumor in 29% and no tumor in 14% of patients. Similarly in our study, comparatively poor pathological response was observed in yolk sac tumors. Optimal cytoreduction in Lu et al. [4] was 89%. The 14.3% recurrence with one mortality was noted. Residual disease >2 cm was the only independent risk factor for prognosis in this study. They also compared NACT with primary surgery and found higher optimal surgery and less perioperative morbidity, but both were statistically not significant. They found no survival difference between 2 groups [4].
In our study among 26 patients with measurable tumor markers, normalisation of marker was observed in 5 patients and rest all had more than 50% fall. Most studies did not consider tumor marker fall in their study. However, tumor marker normalisation or fall was not significantly associated with prognosis (for mortality or disease progression).
We had 18 patients undergoing fertility sparing surgery with 89% optimal cytoreduction. The 94% resumed their menses and one successful pregnancy noted. Nine of 17 patients are yet to get married. Two patients had progressive disease and one death was noted in them. On statistical analysis, fertility sparing surgery following NACT in MOGCT did not negatively impact the PFS. As per Kaplan–Meier analysis, patients with fertility sparing surgery had better PFS and OS. Other studies also emphasise on feasibility of fertility sparing following NACT. We could not compare advanced MOGCT patients undergoing surgery following NACT with patients having upfront surgery for advanced MOGCT due to small number of patients and many being referred after primary surgery outside. Further randomised trials are required to confirm our findings.
Overall optimal cytoreduction was seen in 83% of patients which is comparable with other studies. Seven recurrences (23%) and 5 mortality were noted. As per Kaplan–Meier analysis, stage 3 had better PFS and optimal surgery had significantly better PFS and OS in our study. Stage, optimal surgery and complete pathological response were 3 important prognostic factors noted in our study. As discussed earlier, Optimal surgery and complete pathological response were considered as prognostic markers by other studies as well. Even though pulmonary toxicity due to bleomycin is rare, we had 1 patient with severe toxicity resulting in death.
In our study, dysgerminoma patients had excellent results with NACT. This was also noted in study by Talukdar et al. [2]. Median OS is not reached in our study. As per other studies, 5-year survival of 87% for stage 3 and 69% for Stage 4 are noted [1].
In conclusion, neoadjuvant chemotherapy may be a reasonable option in patients with extensive unresectable disease or in whom fertility sparing is not possible or in the poor general condition. Fertility sparing surgery can be attempted post neoadjuvant chemotherapy without adversely affecting prognosis. Dysgerminoma patients respond very well for NACT and have better outcome. Optimal surgery and no viable tumor in final histopathology are associated with favorable outcome.
SUPPLEMENTARY MATERIALS
Clinicopathological characteristics of patients having mortality (n=5)Table S1
Kaplan–Meier curves for the PFS function of germ cell tumor patients. (A) In stage 3 and stage 4 disease. (B) Fertility sparing surgery versus non fertility sparing surgery. (C) Optimal surgery versus suboptimal surgery. (D) Dysgerminoma versus non dysgerminoma patients.Fig. S1
Kaplan–Meier curves for the OS function of germ cell tumor patients. (A) In stage 3 and stage 4 disease. (B) Fertility sparing surgery versus non fertility sparing surgery. (C) Optimal surgery versus suboptimal surgery. (D) Dysgerminoma versus non dysgerminoma patients.Fig. S2
Conflict of Interest:No potential conflict of interest relevant to this article was reported.
Author Contributions:
Conceptualization: V.A., P.S.M., A.R., D.P.
Data curation: V.A.
Formal analysis: V.A., V.P.
Investigation: V.A.
Methodology: V.A., P.S.M., A.R.
Project administration: P.S.M.
Resources: P.S.M., A.R., D.P., P.B.M.
Supervision: P.S.M., A.R., P.C.D., D.P., P.B.M.
Validation: P.S.M., A.R., P.C.D., D.P., P.B.M.
Visualization: P.S.M.
Writing - original draft: V.A., V.P.
Writing - review & editing: P.S.M., A.R., D.P., P.B.M.
References
-
Berek JS, Hacker NF, editors. Berek and Hacker’s gynecologic oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
-
-
Anjana JS, Suchetha S, Rema P, Ranjith JS, Dinesh D, James FV, et al. Feasibility of fertility-sparing surgery after neoadjuvant chemotherapy for advanced malignant germ cell tumor of the ovary. Indian J Gynecol Oncol 2022;20:65.
-
-
Tata Memorial Centre, National Cancer Grid. Germ Cell Tumours of Ovary. Guidelines National Cancer Grid. Mumbai: National Cancer Grid; 2017.
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MeSH Terms
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