YGYNO-975407; No. of pages: 6; 4C: Gynecologic Oncology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
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Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, People's Republic of China Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, People's Republic of China
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Keywords: Alpha-fetoprotein Endodermal sinus tumor Neoadjuvant therapy Prognosis
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• This was the first series of applying NACT in OYST with the largest number of advanced patients. • The tumor status and general condition of the patients were improved significantly after NACT. • Patients treated with NACT showed less peri-operative morbidities and better optimal cytoreduction rate, which was the independent prognostic factor.
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Article history: Received 23 December 2013 Accepted 20 February 2014 Available online xxxx
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Objective. The aim of the study was to identify the role of neoadjuvant chemotherapy (NACT) in the treatment of the patients with advanced stage ovarian yolk sac tumor (OYST). Methods. The comparative study was based on 53 cases with advanced stage OYST registered at Peking Union Medical College Hospital from 1995 to 2010. Twenty one cases were treated with NACT followed by interval debulking surgery (IDS). Thirty two cases were treated with primary debulking surgery (PDS). Data on patient characteristics, treatment and survival were analyzed and compared between two groups to assess the outcome of NACT. Results. After NACT, the overall status of the patients was improved significantly. Patients in NACT had better optimal cytoreduction rate and less peri-operative morbidities. Seven patients (13.2%) suffered from relapse. There was a significantly better PFS for patients with ovarian tumor size N20 cm in the NACT than those underwent PDS. Residual disease N 2 cm was the independent risk factor of relapse. Conclusions. NACT is the better treatment option for some patients with advanced stage OYST, especially for those with unresectable tumors and poor general condition. © 2014 Published by Elsevier Inc. All rights reserved.
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stage or complex ovarian tumors were transferred to our institution from peripheral hospitals, more than half of our patients presented with extra-pelvic disease. To our knowledge, we reported herein the largest series of patients treated for advanced stage OYST. Some advanced stage patients did not appear to be suitable for performing optimal cytoreductive surgery at the initial presentation, which encouraged us to explore an alternative treatment. It has been reported that neoadjuvant chemotherapy (NACT) prior to surgery is a better alternative option in some patients with advanced stage epithelial ovarian cancer (EOC) [6]. Though the benefits to survival still remain controversial, studies have mostly confirmed the effect of NACT to increase the feasibility of optimal cytoreduction [7–11]. The post-operative rates of adverse effects and mortality tended to be less after interval debulking than after primary debulking [9–11]. Though widely documented in EOC, the role of NACT in MOGCT has not been investigated yet. The aim of our study was to evaluate the outcome of
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Yan Lu a, Jiaxin Yang a, Dongyan Cao a, Huifang Huang a, Ming Wu a, Yan You b, Jie Chen b, Jinhe Lang a, Keng Shen a,⁎
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Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor
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Introduction
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Ovarian yolk sac tumor (OYST) is a rare malignancy that primarily occurs in young women and adolescents. It accounts for 20% of malignant ovarian germ cell tumor (MOGCT) representing about 1% of all ovarian malignancies [1]. Before the advent of combination chemotherapy, OYST was almost universally fatal. Current therapy of surgery followed by post-operative cisplatin-based chemotherapy has dramatically improved the prognosis [2–5]. As a highly aggressive malignancy that shows early dissemination and metastasis, approximately 30% to 40% of OYST is International Federation of Gynecology and Obstetrics (FIGO) stage III or IV [1]. Because patients with advanced
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⁎ Corresponding author at: No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, People's Republic of China. Fax: +86 10 65212507. E-mail address: [email protected] (K. Shen).
http://dx.doi.org/10.1016/j.ygyno.2014.02.029 0090-8258/© 2014 Published by Elsevier Inc. All rights reserved.
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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In total, 127 consecutive cases of OYST registered at Peking Union Medical College Hospital from 1995 to 2010. Eighty cases (63%) were classified to have stage III or IV diseases according to the FIGO staging system. Among them, 53 patients who had both debulking surgery and chemotherapy with intact records at our institution were eligible for this comparative study. Twenty one patients had NACT followed by interval debulking surgery (IDS) and adjuvant chemotherapy. Thirty two patients underwent primary debulking surgery (PDS) followed by adjuvant chemotherapy. The information of patient's age, clinical manifestation, imaging finding, tumor marker, histology, treatment modality, outcome of the treatment and results of follow-up were collected from the medical records and clinical database.
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Diagnosis
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Physical examination, detection of serum alpha-fetoprotein (AFP) and computerized tomography (CT) scans of chest, abdomen and pelvis were performed before and after treatment to evaluate the tumor status. Of the 21 patients in the NACT group, eleven were clinically diagnosed as OYST owing to the distinctive characteristics of young age, large ovarian mass, massive ascites and extraordinarily elevated AFP with the exclusion of pregnancy, liver disease and other factors. The diagnosis was confirmed by the post-operative pathology in all of these 11 cases. The other 10 patients of the NACT group had undergone laparotomic or laparoscopic biopsy and the pathology revealed OYST. The patients of the PDS group were diagnosed by surgical pathology. The histology was confirmed by at least two pathologists based on the distinctive Schiller–Duval bodies and immunohistochemical stain for AFP.
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Treatment protocol
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Cisplatin-based combination chemotherapy was the standard treatment for NACT. The inclusion criteria of NACT candidates were as follows:(1) extensive metastasis on the surface of intra-abdominal and pelvic organ, (2) massive malignant ascites, (3) fixed big tumors predicting the patients to have surgically non-resectable disease; and (4) patients with severe medical co-morbidities or poor general condition leading to their inability to tolerate the debulking surgery in a short term. Patients received 1–3 cycles of NACT depending on the response and tolerance. IDS was performed when patients responded well to NACT. The evaluation criteria of good response to NACT were as follows: (1) relieving of the abdominal distension due to the reduction of the ascites, (2) favorable AFP decline on a common logarithmic scale, (3) a 50% or more decrease in ovarian tumor size, and (4) improvement of general status to tolerate the debulking surgery. In patients who desired fertility preservation, unilateral salpingooophorectomy was performed. In patients not requiring fertility preservation, total abdominal hysterectomy and bilateral salpingooophorectomy were performed. Peritoneal cytological study, resection of macroscopic lesions, omentectomy, and dissection or sampling of the retroperitoneal lymph nodes were performed regardless of preserving fertility or not. After debulking surgery, standard combination chemotherapy was administrated as adjuvant therapy. After AFP dropped to the level within the normal range (b20 ng/mL at our institution), 2 additional cycles of chemotherapy were given to consolidate the remission. All the patients received standard combination chemotherapy of PEB (cisplatin/etoposide/bleomycin) or PVB (cisplatin/vinblastine/
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Evaluation of treatment
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Optimal cytoreduction was considered to be achieved when the largest residual tumor was ≤ 2 cm. The definition of none residual disease was no macroscopic residual disease left at the completion of cytoreduction. Serum AFP was closely monitored after surgery and each cycle of chemotherapy, and chemotherapy was considered satisfactory when AFP declined on a common logarithmic scale. Chest X ray and ultrasonography of abdomen and pelvis after each cycle of chemotherapy and CT scans after the whole therapy were obtained to evaluate the tumor response. A complete remission (CR) was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease.
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Follow-up
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Patient follow-up included clinical examination, blood marker measurements and imaging at least every month during the first year following treatment and at gradually increasing intervals thereafter. Recurrence was defined as the return of disease after CR was achieved.
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Statistical analysis
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Progression free survival (PFS) was calculated from the date of the diagnosis to the date of the first event, defined as a relapse or death. Kaplan–Meier survival was applied in the univariate analysis to evaluate the prognostic factors for PFS. A multivariate Cox proportional hazard regression model was constructed to determine the independent prognostic factors. Only factors that were significant in the univariate analysis were subsequently incorporated into the multivariate model. P value below 0.05 was considered statistically significant.
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Patient population
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Materials and methods
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bleomycin) regimen. PEV regimen (cisplatin/etoposide/vincristine) was used after the total bleomycin dosage accumulated to 250 mg/m2 (according to the regulation of State Food and Drug Administration of China). Standard chemotherapy was considered to be the effective PEB/PVB regimen with full dose, adequate cycles and strict adherence. The administration of the chemotherapy regimen was described in S1 of the Supplementary materials.
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NACT and to identify the role of NACT in the treatment of the patients with advanced stage OYST.
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Table 1 Comparison of patients profile between the NACT and PDS groups. P value
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0.313
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22
Variables
NACT (N = 21)
PDS (N = 32)
Mean age (years) Ovarian tumor size N20 cm ≤20 cm AFP level N3.5 × 104 ng/mL ≤3.5 × 104 ng/mL Pleural effusion Present Absent Ascites N100 mL ≤100 mL Histology Pure OYST Mixed OYST Stage III IV
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16 (76%) 5 (24%)
4 (12%) 28 (88%)
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10 (48%) 11 (52%)
4 (12%) 28 (88%)
0.005
9 (43%) 12 (57%)
9 (28%) 23 (72%)
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20 (95%) 1 (5%)
24 (75%) 8 (25%)
0.071
14 (67%) 7 (33%)
23 (72%) 9 (28%)
0.686
13 (62%) 8 (38%)
27 (84%) 5 (16%)
0.063
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
Y. Lu et al. / Gynecologic Oncology xxx (2014) xxx–xxx
Results
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Patient characteristics
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Table 1 compares the patient profile between the NACT and PDS groups. The mean ovarian tumor size in the NACT group was significantly larger than that in the PDS group (20.7 ± 5.7 vs. 16.7 ± 4.7 cm, P = 0.009). The median serum AFP level was significantly higher in the NACT than that in the PDS group (3.6 × 104 vs. 2.2 × 104 ng/mL, P = 0.044). There were more patients in the NACT group who presented with extra-abdominal disease consistent with stage IV disease than that in the PDS group, but the difference was not significant (38% vs. 16%).
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Fifteen patients (71%) experienced three cycles of NACT, 5 patients (24%) experienced two cycles and 1 patient (5%) experienced one cycle. The mean number of NACT cycles was 2.7 ± 0.6. The mean number of total chemotherapy cycles in the NACT and PDS groups was 5.8 ± 0.9 and 6.1 ± 1.2, respectively. The mean number of chemotherapy cycles for serum AFP to decline to the normal range in the NACT and PDS groups was 3.7 ± 0.7 and 3.8 ± 1.0, respectively. No significant differences were observed between the two groups. Table 2 compared the tumor status before and after NACT according to the evaluation criteria of response. The mean ovarian tumor size decreased significantly after NACT (20.7 ± 5.7 vs. 17.0 ± 3.3 cm, P = 0.016) and the mean shrinkage was 15.3%. In the 15 patients that experienced three cycles of NACT, the mean tumor size at the initial presentation and after each cycle was 22.7 ± 5.2, 19.1 ± 3.4, 18.4 ± 3.1 and 18.2 ± 3.0 cm, respectively. The shrinkage between each cycle tended to be less and less (15% vs. 3.3% vs. 1.0%). The median serum AFP level declined significantly after NACT (3.3 × 104 vs. 6.6 × 102 ng/ mL, P b 0.001). The number of chemotherapy cycles for AFP to decrease more than 101 was one in 7 patients, two in 12 patients and three in 2 patients. When NACT was completed, the chest X ray showed that pleural effusion disappeared in 6 patients and deceased to variable degree in the remaining 3. IDS found that 15 (71%) patients had ascites ≤100 mL. The change of pleural effusion and ascites in patients treated with NACT was shown in Fig. 1. As shown in Fig. 2, the surgical pathology revealed OYST and metastasis in 12 (57%) patients (Figs. 2A and B), degenerated residual tumor consistent with post-chemotherapy alterations in 6 (29%) patients (Fig. 2C), and only necrosis or chronic inflammation without tumor signs in 3 (14%) patients (Fig. 2D).
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Results of surgery
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The overall rate of optimal cytoreduction with residual disease ≤2 cm was 89%. The difference was of no significance between the NACT and PDS groups (95% vs. 84%, P = 0.384). However, the rate of patients with nonresidual disease was 81% in the NACT group, which was significantly higher than that in the PDS group (44%, P = 0.007). Peri-operative parameters and post-operative complications between the NACT and PDS groups were compared in Table 3. The median amount of surgical blood loss in the NACT group was significantly less than that in the PDS group (200 vs. 450 mL, P = 0.018). The PDS
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Table 2 Tumor status before and after NACT (N = 21).
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The median follow-up was 46 months (range: 6–189 months). Recurrence was observed in seven patients (13.2%). The median time to recurrence was 10 months (range: 3–18 months). There was no significant difference of recurrence rate between the NACT and PDS groups (14.3% vs. 12.5%). The median PFS time could not be calculated because it had not yet been reached. Two patients died of the recurrent disease during the period of follow-up. One was in the NACT group and the other was in the PDS group. The difference was of no significance (4.7% vs. 3.1%). Details of the recurrent cases were described in S2 of the Supplementary materials. It was noted that ovarian tumor size and serum AFP level were significantly higher in the NACT group than that in the PDS group. As shown in Fig. 3, there was a significantly better PFS for patients with ovarian tumor size N 20 cm in the NACT group than that in the PDS group (P = 0.016). No difference in PFS was found for patients with AFP N 3.5 × 104 ng/mL between the NACT and PDS groups (P = 0.165).
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Results of long term follow-up
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Before NACT
After NACT
P value
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Mean ovarian tumor size (cm) Median AFP level (ng/mL) Presence of pleural effusion — n (%) Ascites N100 mL — n (%)
20.7 ± 5.7 3.3 × 104 9 (43) 20 (95)
17.0 ± 3.3 6.6 × 102 3 (14) 6 (29)
0.016 b0.001 0.040 b0.001
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Prognostic factors
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Kaplan–Meier univariate analysis was performed with PFS as the end point, and included the following variables: treatment group, initial ovarian tumor size, initial serum AFP level, FIGO stage, pleural effusion, ascites, histologic type, residual tumor and operation type (classified by fertility sparing or radical surgery). Tumor size N 20 cm, AFP N3.5 × 104 ng/mL, FIGO stage IV and residual disease N 2 cm were the risk factors of relapse (S3 in the Supplemental materials). However, NACT did not significantly influence the PFS (P = 0.838). The further Cox proportional hazard regression model proved that residual disease N 2 cm was the only independent risk factor for prognosis (P = 0.017) (S4 in the Supplemental materials).
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Discussion
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The results of the present study demonstrated that the tumor status and general condition of the patients were improved significantly after NACT. Patients treated with NACT followed by IDS shown better optimal cytoreduction rate, less peri-operative morbidities and similar PFS compared with those underwent PDS. And the optimal cytoreduction rate was proved to be the independent prognostic factor by the survival analysis. Before the initiation of NACT, the diagnosis of OYST should be made firstly by either pathology or clinical manifestation. Although pathology was the golden standard, diagnosis could also be made clinically. In our series, the diagnosis prior to surgery in 11 patients of the NACT group was mainly dependent on the clinical features, radiology examination and extraordinarily elevated serum AFP level. AFP plays key role in the differential diagnosis. Immature teratoma, embryonal carcinoma and polyembryoma also produce AFP, but the level is much lower than YST [12]. Talerman et al. [13] reported that patients with tumors composed of or containing YST elements had serum AFP levels measured in 100s or 1000s of ng/mL, whereas slightly elevated AFP up to 60 ng/ mL was noted in a few patients with pure embryonal carcinoma. Kawai et al. [14] reported that in 46 cases with MOGCT, AFP was above 1000 ng/mL in 23 of 25 cases with pure or mixed OYST (92%), while only in 1 of 17 cases with immature teratoma (6%). Elevation of AFP level above 1000 ng/ml strongly suggested the presence of YST. In rare cases, especially in children and menopausal and postmenopausal women, AFP might exceed 1000 ng/mL in other types of MOGCT [15–17]. However, in our series, the post-operative pathology
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group had more transfusion rate, longer median operation time and prolonged mean hospital course, but the differences were not significant. The rates of post-operative complications were of no significance between the two groups.
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Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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Patients with advanced stage OYST usually have bulky tumor burden and massive ascites with or without pleural effusion, whose general condition is too poor to tolerate PDS. Those features were exactly the selection criteria the present study made for NACT candidates. The survival analysis proved that in the subgroup of patients with ovarian tumor
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confirmed the OYST in all of those 11 cases. The pre-operative histology of OYST was usually acquired by biopsy. Petrakakou et al. [18] reported that paracentesis of ascitic fluid in the diagnosis of OYST was still challenging and required the correlation of cytology with the remaining clinical and laboratory data.
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Fig. 1. CT scans of pleural effusion and ascites in patients treated with NACT. (A) Pleural effusion at the initial presentation. (B) Pleural effusion disappeared after NACT. (C) Massive ascites at the initial presentation. (D) Ascites diminished after NACT.
Fig. 2. Surgical pathology images of patients treated with NACT. (A) Yolk sac tumor with Schiller–Duval body (H and E, ×200). (B) Immunohistochemical staining for alpha-fetoprotein. The yolk sac component is positive (AFP, ×100). (C) Scattered yolk sac tumor residual consistent with post-chemotherapy alterations (H and E, ×200). (D) Necrosis and chronic inflammation without tumor signs (H and E, ×100).
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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Blood loss (mL) Transfusion needed — n (%) Transfusion (unit) Operation time (min) Hospital stay (days) Post-operative complications — n (%) Bowel obstruction Urinary tract infection Lung infection Wound infection Thromboembolism Total
200 3 (14) 3.3 ± 1.1 120 11 ± 1.9
450 8 (25) 3.2 ± 1.0 130 13 ± 2.7
0.018 0.494 0.910 0.121 0.062
1 (4.8) 3 (14) 0 2 (9.5) 1 (4.8) 7 (33)
5 (16) 3 (9.4) 1 (3.1) 1 (3.1) 0 10 (31)
0.384 0.671 1.000 0.555 0.396 0.874
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size N 20 cm, the PFS in the patients treated with NACT followed by IDS was significantly better than that in the patients treated with PDS. This finding suggested that advanced stage OYST with ovarian tumor size N20 cm was recommended to be selected as the inclusion criteria for NACT. The effects of NACT with PEB or PVB combination chemotherapy were favorable. The tumor size and serum AFP level decreased significantly. The ascites and pleural effusion were controlled very well. In 3 patients, IDS pathology did not even find the signs of tumor left. The optimal effects of NACT were prospected to be the improvements of patient general status to tolerate the debulking surgery and to achieve the optimal cytoreduction. The optimal number of NACT cycles was recommended to be no more than three. This recommendation was based on two reasons. Firstly, three cycles were enough for the patients to achieve the optimal effects of NACT. Secondly, it was estimated that the volume of remaining tumor and necrosis tissue would no longer shrink with NACT more than three cycles. Because in the 15 patients treated with three cycles of NACT, the tumor size tended to decrease less and less between each cycle (15% vs. 3.3% vs. 1.0%). The shrinkage between the second and third cycle was of no significant difference (P = 0.189). At this step of treatment, IDS, rather than further NACT, should be performed to resect the remaining lesions. Moreover, NACT did not increase the number of overall chemotherapy cycles, thus the drug toxicity would not be aggravated. NACT followed by IDS was associated with better optimal rate, but the difference was not significant compared with PDS, likely due to the limited population. However, the improvement of NACT to the rate of nonresidual disease was significant. The peri-operative morbidities seemed better in the NACT group than that in the PDS group, but not significant in all parameters. And the post-operative complications were similar between the two groups. Since the overall status of
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patients in NACT seemed to be worse than that in the PDS, no significant difference might actually reflect the improvements due to NACT. Due to the rarity of OYST, identifying prognostic factors has been quite challenging. It has been a consensus that standard PEB regimen is the most decisive prognostic factor [3,19]. Most reports suggested that the absence of bulky residual disease was a good prognostic factor for OYST [20–25]. Tong et al. [23] reported that in 76 cases of OYST, patients with residual tumors ≤ 2 cm showed a significantly better 5-year survival than those with residual tumors N2 cm (66.7% vs. 7.9%, P b 0.0001), but there was no difference between patients with none residual tumor and residual tumor ≤ 2 cm (71.2% vs. 66.7%, P N 0.05). The results were similar to ours. The survival analysis failed to prove that NACT had a significant impact on PFS. However, the patients in the NACT group had better optimal cytoreduction rate. Therefore, it was estimated that NACT might improve the prognosis by increasing the optimal cytoreduction rate. The limitations of our study include the non-randomized nature and the small size of population. Prior to surgery, specific selection criteria for NACT candidates and optimal number of chemotherapy cycles still need to be validated. With the development of value-based medicine in gynecological oncology, individualization treatment will be emphasized more and more in clinical decision making. The results of the present study proved the fact that NACT followed by IDS might be an alternative option for patients with advanced stage OYST, especially for those with surgically non-resectable tumors and those with poor general condition leading to their inability to tolerate the primary debulking surgery. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2014.02.029.
Table 3 Peri-operative parameters and post-operative complications between the NACT and PDS groups.
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Fig. 3. Kaplan–Meier curves of progression free survival in patients with ovarian tumor size N20 cm. Gray line: NACT group. Black line: PDS group.
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The authors have declared no conflicts of interest.
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Conflict of interest statement
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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[16] Takemori M, Nishimura R, Yamasaki M, et al. Ovarian mixed germ cell tumor composed of polyembryoma and immature teratoma. Gynecol Oncol 1998;69:260–3. [17] Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 2000;18:3809–18. [18] Petrakakou E, Grapsa D, Stergiou ME, et al. Ascitic fluid cytology of yolk sac tumor of the ovary: a case report. Acta Cytol 2009;53:701–3. [19] de La Motte Rouge T, Pautier P, Duvillard P, et al. Survival and reproductive function of 52 women treated with surgery and bleomycin, etoposide, cisplatin (BEP) chemotherapy for ovarian yolk sac tumor. Ann Oncol 2008;19:1435–41. [20] Kawai M, Kano T, Furuhashi Y, et al. Prognostic factors in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases. Cancer 1991;67:184–92.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
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Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, People's Republic of China Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, People's Republic of China
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Keywords: Alpha-fetoprotein Endodermal sinus tumor Neoadjuvant therapy Prognosis
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• This was the first series of applying NACT in OYST with the largest number of advanced patients. • The tumor status and general condition of the patients were improved significantly after NACT. • Patients treated with NACT showed less peri-operative morbidities and better optimal cytoreduction rate, which was the independent prognostic factor.
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Article history: Received 23 December 2013 Accepted 20 February 2014 Available online xxxx
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Objective. The aim of the study was to identify the role of neoadjuvant chemotherapy (NACT) in the treatment of the patients with advanced stage ovarian yolk sac tumor (OYST). Methods. The comparative study was based on 53 cases with advanced stage OYST registered at Peking Union Medical College Hospital from 1995 to 2010. Twenty one cases were treated with NACT followed by interval debulking surgery (IDS). Thirty two cases were treated with primary debulking surgery (PDS). Data on patient characteristics, treatment and survival were analyzed and compared between two groups to assess the outcome of NACT. Results. After NACT, the overall status of the patients was improved significantly. Patients in NACT had better optimal cytoreduction rate and less peri-operative morbidities. Seven patients (13.2%) suffered from relapse. There was a significantly better PFS for patients with ovarian tumor size N20 cm in the NACT than those underwent PDS. Residual disease N 2 cm was the independent risk factor of relapse. Conclusions. NACT is the better treatment option for some patients with advanced stage OYST, especially for those with unresectable tumors and poor general condition. © 2014 Published by Elsevier Inc. All rights reserved.
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stage or complex ovarian tumors were transferred to our institution from peripheral hospitals, more than half of our patients presented with extra-pelvic disease. To our knowledge, we reported herein the largest series of patients treated for advanced stage OYST. Some advanced stage patients did not appear to be suitable for performing optimal cytoreductive surgery at the initial presentation, which encouraged us to explore an alternative treatment. It has been reported that neoadjuvant chemotherapy (NACT) prior to surgery is a better alternative option in some patients with advanced stage epithelial ovarian cancer (EOC) [6]. Though the benefits to survival still remain controversial, studies have mostly confirmed the effect of NACT to increase the feasibility of optimal cytoreduction [7–11]. The post-operative rates of adverse effects and mortality tended to be less after interval debulking than after primary debulking [9–11]. Though widely documented in EOC, the role of NACT in MOGCT has not been investigated yet. The aim of our study was to evaluate the outcome of
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Yan Lu a, Jiaxin Yang a, Dongyan Cao a, Huifang Huang a, Ming Wu a, Yan You b, Jie Chen b, Jinhe Lang a, Keng Shen a,⁎
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Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor
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Introduction
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Ovarian yolk sac tumor (OYST) is a rare malignancy that primarily occurs in young women and adolescents. It accounts for 20% of malignant ovarian germ cell tumor (MOGCT) representing about 1% of all ovarian malignancies [1]. Before the advent of combination chemotherapy, OYST was almost universally fatal. Current therapy of surgery followed by post-operative cisplatin-based chemotherapy has dramatically improved the prognosis [2–5]. As a highly aggressive malignancy that shows early dissemination and metastasis, approximately 30% to 40% of OYST is International Federation of Gynecology and Obstetrics (FIGO) stage III or IV [1]. Because patients with advanced
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⁎ Corresponding author at: No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, People's Republic of China. Fax: +86 10 65212507. E-mail address: [email protected] (K. Shen).
http://dx.doi.org/10.1016/j.ygyno.2014.02.029 0090-8258/© 2014 Published by Elsevier Inc. All rights reserved.
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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In total, 127 consecutive cases of OYST registered at Peking Union Medical College Hospital from 1995 to 2010. Eighty cases (63%) were classified to have stage III or IV diseases according to the FIGO staging system. Among them, 53 patients who had both debulking surgery and chemotherapy with intact records at our institution were eligible for this comparative study. Twenty one patients had NACT followed by interval debulking surgery (IDS) and adjuvant chemotherapy. Thirty two patients underwent primary debulking surgery (PDS) followed by adjuvant chemotherapy. The information of patient's age, clinical manifestation, imaging finding, tumor marker, histology, treatment modality, outcome of the treatment and results of follow-up were collected from the medical records and clinical database.
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Diagnosis
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Physical examination, detection of serum alpha-fetoprotein (AFP) and computerized tomography (CT) scans of chest, abdomen and pelvis were performed before and after treatment to evaluate the tumor status. Of the 21 patients in the NACT group, eleven were clinically diagnosed as OYST owing to the distinctive characteristics of young age, large ovarian mass, massive ascites and extraordinarily elevated AFP with the exclusion of pregnancy, liver disease and other factors. The diagnosis was confirmed by the post-operative pathology in all of these 11 cases. The other 10 patients of the NACT group had undergone laparotomic or laparoscopic biopsy and the pathology revealed OYST. The patients of the PDS group were diagnosed by surgical pathology. The histology was confirmed by at least two pathologists based on the distinctive Schiller–Duval bodies and immunohistochemical stain for AFP.
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Treatment protocol
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Cisplatin-based combination chemotherapy was the standard treatment for NACT. The inclusion criteria of NACT candidates were as follows:(1) extensive metastasis on the surface of intra-abdominal and pelvic organ, (2) massive malignant ascites, (3) fixed big tumors predicting the patients to have surgically non-resectable disease; and (4) patients with severe medical co-morbidities or poor general condition leading to their inability to tolerate the debulking surgery in a short term. Patients received 1–3 cycles of NACT depending on the response and tolerance. IDS was performed when patients responded well to NACT. The evaluation criteria of good response to NACT were as follows: (1) relieving of the abdominal distension due to the reduction of the ascites, (2) favorable AFP decline on a common logarithmic scale, (3) a 50% or more decrease in ovarian tumor size, and (4) improvement of general status to tolerate the debulking surgery. In patients who desired fertility preservation, unilateral salpingooophorectomy was performed. In patients not requiring fertility preservation, total abdominal hysterectomy and bilateral salpingooophorectomy were performed. Peritoneal cytological study, resection of macroscopic lesions, omentectomy, and dissection or sampling of the retroperitoneal lymph nodes were performed regardless of preserving fertility or not. After debulking surgery, standard combination chemotherapy was administrated as adjuvant therapy. After AFP dropped to the level within the normal range (b20 ng/mL at our institution), 2 additional cycles of chemotherapy were given to consolidate the remission. All the patients received standard combination chemotherapy of PEB (cisplatin/etoposide/bleomycin) or PVB (cisplatin/vinblastine/
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105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129
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96 97
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94 95
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92 93
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90 91
Evaluation of treatment
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Optimal cytoreduction was considered to be achieved when the largest residual tumor was ≤ 2 cm. The definition of none residual disease was no macroscopic residual disease left at the completion of cytoreduction. Serum AFP was closely monitored after surgery and each cycle of chemotherapy, and chemotherapy was considered satisfactory when AFP declined on a common logarithmic scale. Chest X ray and ultrasonography of abdomen and pelvis after each cycle of chemotherapy and CT scans after the whole therapy were obtained to evaluate the tumor response. A complete remission (CR) was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease.
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Follow-up
132 133 134 135 136
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Patient follow-up included clinical examination, blood marker measurements and imaging at least every month during the first year following treatment and at gradually increasing intervals thereafter. Recurrence was defined as the return of disease after CR was achieved.
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Statistical analysis
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Progression free survival (PFS) was calculated from the date of the diagnosis to the date of the first event, defined as a relapse or death. Kaplan–Meier survival was applied in the univariate analysis to evaluate the prognostic factors for PFS. A multivariate Cox proportional hazard regression model was constructed to determine the independent prognostic factors. Only factors that were significant in the univariate analysis were subsequently incorporated into the multivariate model. P value below 0.05 was considered statistically significant.
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Patient population
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Materials and methods
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bleomycin) regimen. PEV regimen (cisplatin/etoposide/vincristine) was used after the total bleomycin dosage accumulated to 250 mg/m2 (according to the regulation of State Food and Drug Administration of China). Standard chemotherapy was considered to be the effective PEB/PVB regimen with full dose, adequate cycles and strict adherence. The administration of the chemotherapy regimen was described in S1 of the Supplementary materials.
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NACT and to identify the role of NACT in the treatment of the patients with advanced stage OYST.
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Table 1 Comparison of patients profile between the NACT and PDS groups. P value
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0.313
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22
Variables
NACT (N = 21)
PDS (N = 32)
Mean age (years) Ovarian tumor size N20 cm ≤20 cm AFP level N3.5 × 104 ng/mL ≤3.5 × 104 ng/mL Pleural effusion Present Absent Ascites N100 mL ≤100 mL Histology Pure OYST Mixed OYST Stage III IV
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25
16 (76%) 5 (24%)
4 (12%) 28 (88%)
b0.001
10 (48%) 11 (52%)
4 (12%) 28 (88%)
0.005
9 (43%) 12 (57%)
9 (28%) 23 (72%)
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20 (95%) 1 (5%)
24 (75%) 8 (25%)
0.071
14 (67%) 7 (33%)
23 (72%) 9 (28%)
0.686
13 (62%) 8 (38%)
27 (84%) 5 (16%)
0.063
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
Y. Lu et al. / Gynecologic Oncology xxx (2014) xxx–xxx
Results
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Patient characteristics
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Table 1 compares the patient profile between the NACT and PDS groups. The mean ovarian tumor size in the NACT group was significantly larger than that in the PDS group (20.7 ± 5.7 vs. 16.7 ± 4.7 cm, P = 0.009). The median serum AFP level was significantly higher in the NACT than that in the PDS group (3.6 × 104 vs. 2.2 × 104 ng/mL, P = 0.044). There were more patients in the NACT group who presented with extra-abdominal disease consistent with stage IV disease than that in the PDS group, but the difference was not significant (38% vs. 16%).
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Fifteen patients (71%) experienced three cycles of NACT, 5 patients (24%) experienced two cycles and 1 patient (5%) experienced one cycle. The mean number of NACT cycles was 2.7 ± 0.6. The mean number of total chemotherapy cycles in the NACT and PDS groups was 5.8 ± 0.9 and 6.1 ± 1.2, respectively. The mean number of chemotherapy cycles for serum AFP to decline to the normal range in the NACT and PDS groups was 3.7 ± 0.7 and 3.8 ± 1.0, respectively. No significant differences were observed between the two groups. Table 2 compared the tumor status before and after NACT according to the evaluation criteria of response. The mean ovarian tumor size decreased significantly after NACT (20.7 ± 5.7 vs. 17.0 ± 3.3 cm, P = 0.016) and the mean shrinkage was 15.3%. In the 15 patients that experienced three cycles of NACT, the mean tumor size at the initial presentation and after each cycle was 22.7 ± 5.2, 19.1 ± 3.4, 18.4 ± 3.1 and 18.2 ± 3.0 cm, respectively. The shrinkage between each cycle tended to be less and less (15% vs. 3.3% vs. 1.0%). The median serum AFP level declined significantly after NACT (3.3 × 104 vs. 6.6 × 102 ng/ mL, P b 0.001). The number of chemotherapy cycles for AFP to decrease more than 101 was one in 7 patients, two in 12 patients and three in 2 patients. When NACT was completed, the chest X ray showed that pleural effusion disappeared in 6 patients and deceased to variable degree in the remaining 3. IDS found that 15 (71%) patients had ascites ≤100 mL. The change of pleural effusion and ascites in patients treated with NACT was shown in Fig. 1. As shown in Fig. 2, the surgical pathology revealed OYST and metastasis in 12 (57%) patients (Figs. 2A and B), degenerated residual tumor consistent with post-chemotherapy alterations in 6 (29%) patients (Fig. 2C), and only necrosis or chronic inflammation without tumor signs in 3 (14%) patients (Fig. 2D).
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Results of surgery
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The overall rate of optimal cytoreduction with residual disease ≤2 cm was 89%. The difference was of no significance between the NACT and PDS groups (95% vs. 84%, P = 0.384). However, the rate of patients with nonresidual disease was 81% in the NACT group, which was significantly higher than that in the PDS group (44%, P = 0.007). Peri-operative parameters and post-operative complications between the NACT and PDS groups were compared in Table 3. The median amount of surgical blood loss in the NACT group was significantly less than that in the PDS group (200 vs. 450 mL, P = 0.018). The PDS
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Table 2 Tumor status before and after NACT (N = 21).
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The median follow-up was 46 months (range: 6–189 months). Recurrence was observed in seven patients (13.2%). The median time to recurrence was 10 months (range: 3–18 months). There was no significant difference of recurrence rate between the NACT and PDS groups (14.3% vs. 12.5%). The median PFS time could not be calculated because it had not yet been reached. Two patients died of the recurrent disease during the period of follow-up. One was in the NACT group and the other was in the PDS group. The difference was of no significance (4.7% vs. 3.1%). Details of the recurrent cases were described in S2 of the Supplementary materials. It was noted that ovarian tumor size and serum AFP level were significantly higher in the NACT group than that in the PDS group. As shown in Fig. 3, there was a significantly better PFS for patients with ovarian tumor size N 20 cm in the NACT group than that in the PDS group (P = 0.016). No difference in PFS was found for patients with AFP N 3.5 × 104 ng/mL between the NACT and PDS groups (P = 0.165).
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Results of long term follow-up
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Before NACT
After NACT
P value
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Mean ovarian tumor size (cm) Median AFP level (ng/mL) Presence of pleural effusion — n (%) Ascites N100 mL — n (%)
20.7 ± 5.7 3.3 × 104 9 (43) 20 (95)
17.0 ± 3.3 6.6 × 102 3 (14) 6 (29)
0.016 b0.001 0.040 b0.001
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Prognostic factors
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Kaplan–Meier univariate analysis was performed with PFS as the end point, and included the following variables: treatment group, initial ovarian tumor size, initial serum AFP level, FIGO stage, pleural effusion, ascites, histologic type, residual tumor and operation type (classified by fertility sparing or radical surgery). Tumor size N 20 cm, AFP N3.5 × 104 ng/mL, FIGO stage IV and residual disease N 2 cm were the risk factors of relapse (S3 in the Supplemental materials). However, NACT did not significantly influence the PFS (P = 0.838). The further Cox proportional hazard regression model proved that residual disease N 2 cm was the only independent risk factor for prognosis (P = 0.017) (S4 in the Supplemental materials).
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Discussion
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The results of the present study demonstrated that the tumor status and general condition of the patients were improved significantly after NACT. Patients treated with NACT followed by IDS shown better optimal cytoreduction rate, less peri-operative morbidities and similar PFS compared with those underwent PDS. And the optimal cytoreduction rate was proved to be the independent prognostic factor by the survival analysis. Before the initiation of NACT, the diagnosis of OYST should be made firstly by either pathology or clinical manifestation. Although pathology was the golden standard, diagnosis could also be made clinically. In our series, the diagnosis prior to surgery in 11 patients of the NACT group was mainly dependent on the clinical features, radiology examination and extraordinarily elevated serum AFP level. AFP plays key role in the differential diagnosis. Immature teratoma, embryonal carcinoma and polyembryoma also produce AFP, but the level is much lower than YST [12]. Talerman et al. [13] reported that patients with tumors composed of or containing YST elements had serum AFP levels measured in 100s or 1000s of ng/mL, whereas slightly elevated AFP up to 60 ng/ mL was noted in a few patients with pure embryonal carcinoma. Kawai et al. [14] reported that in 46 cases with MOGCT, AFP was above 1000 ng/mL in 23 of 25 cases with pure or mixed OYST (92%), while only in 1 of 17 cases with immature teratoma (6%). Elevation of AFP level above 1000 ng/ml strongly suggested the presence of YST. In rare cases, especially in children and menopausal and postmenopausal women, AFP might exceed 1000 ng/mL in other types of MOGCT [15–17]. However, in our series, the post-operative pathology
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group had more transfusion rate, longer median operation time and prolonged mean hospital course, but the differences were not significant. The rates of post-operative complications were of no significance between the two groups.
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Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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Patients with advanced stage OYST usually have bulky tumor burden and massive ascites with or without pleural effusion, whose general condition is too poor to tolerate PDS. Those features were exactly the selection criteria the present study made for NACT candidates. The survival analysis proved that in the subgroup of patients with ovarian tumor
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confirmed the OYST in all of those 11 cases. The pre-operative histology of OYST was usually acquired by biopsy. Petrakakou et al. [18] reported that paracentesis of ascitic fluid in the diagnosis of OYST was still challenging and required the correlation of cytology with the remaining clinical and laboratory data.
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Fig. 1. CT scans of pleural effusion and ascites in patients treated with NACT. (A) Pleural effusion at the initial presentation. (B) Pleural effusion disappeared after NACT. (C) Massive ascites at the initial presentation. (D) Ascites diminished after NACT.
Fig. 2. Surgical pathology images of patients treated with NACT. (A) Yolk sac tumor with Schiller–Duval body (H and E, ×200). (B) Immunohistochemical staining for alpha-fetoprotein. The yolk sac component is positive (AFP, ×100). (C) Scattered yolk sac tumor residual consistent with post-chemotherapy alterations (H and E, ×200). (D) Necrosis and chronic inflammation without tumor signs (H and E, ×100).
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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Blood loss (mL) Transfusion needed — n (%) Transfusion (unit) Operation time (min) Hospital stay (days) Post-operative complications — n (%) Bowel obstruction Urinary tract infection Lung infection Wound infection Thromboembolism Total
200 3 (14) 3.3 ± 1.1 120 11 ± 1.9
450 8 (25) 3.2 ± 1.0 130 13 ± 2.7
0.018 0.494 0.910 0.121 0.062
1 (4.8) 3 (14) 0 2 (9.5) 1 (4.8) 7 (33)
5 (16) 3 (9.4) 1 (3.1) 1 (3.1) 0 10 (31)
0.384 0.671 1.000 0.555 0.396 0.874
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size N 20 cm, the PFS in the patients treated with NACT followed by IDS was significantly better than that in the patients treated with PDS. This finding suggested that advanced stage OYST with ovarian tumor size N20 cm was recommended to be selected as the inclusion criteria for NACT. The effects of NACT with PEB or PVB combination chemotherapy were favorable. The tumor size and serum AFP level decreased significantly. The ascites and pleural effusion were controlled very well. In 3 patients, IDS pathology did not even find the signs of tumor left. The optimal effects of NACT were prospected to be the improvements of patient general status to tolerate the debulking surgery and to achieve the optimal cytoreduction. The optimal number of NACT cycles was recommended to be no more than three. This recommendation was based on two reasons. Firstly, three cycles were enough for the patients to achieve the optimal effects of NACT. Secondly, it was estimated that the volume of remaining tumor and necrosis tissue would no longer shrink with NACT more than three cycles. Because in the 15 patients treated with three cycles of NACT, the tumor size tended to decrease less and less between each cycle (15% vs. 3.3% vs. 1.0%). The shrinkage between the second and third cycle was of no significant difference (P = 0.189). At this step of treatment, IDS, rather than further NACT, should be performed to resect the remaining lesions. Moreover, NACT did not increase the number of overall chemotherapy cycles, thus the drug toxicity would not be aggravated. NACT followed by IDS was associated with better optimal rate, but the difference was not significant compared with PDS, likely due to the limited population. However, the improvement of NACT to the rate of nonresidual disease was significant. The peri-operative morbidities seemed better in the NACT group than that in the PDS group, but not significant in all parameters. And the post-operative complications were similar between the two groups. Since the overall status of
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patients in NACT seemed to be worse than that in the PDS, no significant difference might actually reflect the improvements due to NACT. Due to the rarity of OYST, identifying prognostic factors has been quite challenging. It has been a consensus that standard PEB regimen is the most decisive prognostic factor [3,19]. Most reports suggested that the absence of bulky residual disease was a good prognostic factor for OYST [20–25]. Tong et al. [23] reported that in 76 cases of OYST, patients with residual tumors ≤ 2 cm showed a significantly better 5-year survival than those with residual tumors N2 cm (66.7% vs. 7.9%, P b 0.0001), but there was no difference between patients with none residual tumor and residual tumor ≤ 2 cm (71.2% vs. 66.7%, P N 0.05). The results were similar to ours. The survival analysis failed to prove that NACT had a significant impact on PFS. However, the patients in the NACT group had better optimal cytoreduction rate. Therefore, it was estimated that NACT might improve the prognosis by increasing the optimal cytoreduction rate. The limitations of our study include the non-randomized nature and the small size of population. Prior to surgery, specific selection criteria for NACT candidates and optimal number of chemotherapy cycles still need to be validated. With the development of value-based medicine in gynecological oncology, individualization treatment will be emphasized more and more in clinical decision making. The results of the present study proved the fact that NACT followed by IDS might be an alternative option for patients with advanced stage OYST, especially for those with surgically non-resectable tumors and those with poor general condition leading to their inability to tolerate the primary debulking surgery. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2014.02.029.
Table 3 Peri-operative parameters and post-operative complications between the NACT and PDS groups.
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Fig. 3. Kaplan–Meier curves of progression free survival in patients with ovarian tumor size N20 cm. Gray line: NACT group. Black line: PDS group.
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The authors have declared no conflicts of interest.
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Conflict of interest statement
Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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[21] Nawa A, Obata N, Kikkawa F, et al. Prognostic factors of patients with yolk sac tumors of the ovary. Am J Obstet Gynecol 2001;184:1182–8. [22] Umezu T, Kajiyama H, Terauchi M, et al. Long-term outcome and prognostic factors for yolk sac tumor of the ovary. Nagoya J Med Sci 2008;70:29–34. [23] Tong X, You Q, Li L, et al. Prognostic factors of patients with ovarian yolk sac tumors: a study in Chinese patients. Onkologie 2008;31:679–84. [24] Cicin I, Saip P, Guney N, et al. Yolk sac tumours of the ovary: evaluation of clinicopathological features and prognostic factors. Eur J Obstet Gynecol Reprod Biol 2009;146:210–4. [25] Lee CW, Song MJ, Park ST, et al. Residual tumor after the salvage surgery is the major risk factors for primary treatment failure in malignant ovarian germ cell tumors: a retrospective study of single institution. World J Surg Oncol 2011;9:123.
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Please cite this article as: Lu Y, et al, Role of neoadjuvant chemotherapy in the management of advanced ovarian yolk sac tumor, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.029
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