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Fertility-sparing surgery in young women with invasive epithelial ovarian cancer
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EJSO 36 (2010) 404e408
www.ejso.com
Fertility-sparing surgery in young women with invasive epithelial ovarian cancer H. Kajiyama a,*, K. Shibata a, S. Suzuki a, K. Ino a, A. Nawa a, M. Kawai b, T. Nagasaka c, F. Kikkawa a a
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan b Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Japan c Division of Pathology, Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan Accepted 11 January 2010 Available online 8 February 2010
Abstract Objectives: The purpose of this study was to clarify the clinical outcome of patients with stage IA or more advanced epithelial ovarian cancer (EOC) treated with fertility-sparing surgery (FSS). Methods: After a central pathological review and search of the medical records from multiple institutions, a total of 60 stage I EOC patients treated with FSS were retrospectively evaluated in the current study. Results: The median age was 30 years (range: 12e40 years). The median follow-up time was 54.7 months (range: 4.8e243.8 months). The stage was IA in 30, IB in one, and IC in 29 patients. Fifty-two patients were alive without relapse and 8 patient experienced recurrences {IA, 2; IB, 1; IC(surface involvement), 1; and IC(positive cytology), 4}. However, all patients with stage IC(capsule rupture) (n ¼ 17) were alive without recurrence. Collectively, there was no significant difference in the overall survival between the stage IA and IC groups (P ¼ 0.256). Moreover, there was no significant difference in DFS and OS between patients with stage IC(capsule rupture) and those with stage IA. In contrast, DFS and OS of the patients with stage IC(surface involvement/positive cytology) were poorer than those of patients with stage IA {OS; P ¼ 0.030, and DFS; P¼ 0.005, respectively}. Thirteen pregnancies were observed in 9 patients. Conclusions: FSS may be considered a treatment option in women with stage I EOC, even in those with stage IC(capsule rupture) or more wishing to bear children. Ó 2010 Elsevier Ltd. All rights reserved. Keywords: Epithelial ovarian cancer; Fertility-sparing surgery; Pregnancy; Clinical outcome
Introduction Epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecological malignancy.1 The standard surgical treatment for patients with EOC is based on hysterectomy and bilateral salpingo-oophorectomy with peritoneal sampling (peritoneal washing, omentectomy, multiple peritoneal biopsies, and the removal of peritoneal implants) with or without lymph node sampling.2 However, several reports have estimated that 3e17% of all EOCs occur in woman under 40 years of age.3e7 In these patients, the preservation of reproductive and endocrine functions is crucial. In general, fertility-sparing surgery (FSS) has been adopted in young patients with borderline, germ
* Corresponding author. Tel.: þ81 52 744 2262; fax: þ81 52 744 2268. E-mail address: [email protected] (H. Kajiyama). 0748-7983/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2010.01.005
cell, and stromal tumors and some authors propose this treatment for stage I/grade 1 invasive EOC. However, because of the risk of leaving a microscopic contralateral tumor and thereby compromising curability, most gynecologists are reluctant to perform FSS in all other stage I invasive EOCs. Indeed, on selecting this surgical procedure, there may be a risk that the probability of recurrence and death is increased. The amount of evidence is too small to resolve this point because previous reports frequently involved few patients with multiple histologic tumor types including borderline tumors. After the central pathological review and scanning of the medical records of multicentric institutions between 1986 and 2006, a total of 60 patients with stage I EOC treated with FSS were enrolled in the present study. In this study, we retrospectively analyzed these cases to clarify the clinical outcome of EOC patients who would usually undergo radical surgery.
H. Kajiyama et al. / EJSO 36 (2010) 404e408
Materials and methods Between January 1986 and December 2006, a total of 1443 patients with EOC were registered and treated by the Tokai Ovarian Tumor Study Group, consisting of Nagoya University Hospital and affiliated hospitals. Data were collected from medical records and clinical followup visits. Seventy patients received FSS. Six patients were excluded from this study because of insufficient clinical data or being lost to follow-up immediately after surgery. Among the remaining 64 patients, 4 patients with stage II were excluded. In the current study, 60 stage I patients were picked up and retrospectively evaluated in the current study. The present series consisted of 60 carcinomas that were classified into the following histological types: mucinous, 34; serous, 5; endometrioid, 11; and clear-cell, 10. The histological cell types and histological grade (tumor differentiation) were assigned except that for clearcell carcinoma according to the criteria of the World Health Organization (WHO). Histological slides were reviewed by one of the authors under a central pathological review system with no knowledge of the patients’ clinical data. Clinical staging was defined according to the International Federation of Gynecology and Obstetrics (FIGO, 1985) criteria, using the macroscopic description during the surgical procedure and histological analysis of specimens removed during initial and restaging surgeries if the initial procedure was incomplete. In addition, patients with FIGO stage IC were classified into four subtypes according to the pathological characteristics: IC (a) for those with a tumor on the ovarian surface or preoperative capsule rupture, IC(b) for patients with intraoperative capsule rupture with negative cytology, and IC (1) or IC (2) for those with positive malignant cells in the positive peritoneal washing or ascites, respectively. In principle, patients were eligible if they: (1) had histologically confirmed stage IA grades 1, 2, or 3 EOC, (2) were less than 40 years of age at the time of the initial diagnosis, and (3) strongly desired to retain fertility. In patients with more than stage IB or clear-cell adenocarcinoma, FSS was carried out only when we could not obtain informed consent for our recommended surgical procedure from patients who strongly desired to preserve fertility. In a preoperative counseling session, these women were informed of the possible risks and benefits of FSS, and asked to sign a consent form. Several patients had received incomplete surgery elsewhere (for example, unilateral cystectomy of the tumor). During the initial or restaging surgery, all patients underwent salpingo-oophorectomy on the side of the ovarian tumor with at least a peritoneal staging including cytology of peritoneal washing or ascites, careful palpation and inspection throughout peritoneal cavity, and multiple peritoneal biopsies. Systemic retroperitoneal lymphadenectomy, wedge resection of the remaining ovary, omentectomy, and appendectomy were optional.
405
Forty-two patients (70.0%) were treated postoperatively with 3e6 cycles of adjuvant chemotherapy; 24 patients received platinum-based chemotherapy, and 18 patients received platinum plus taxane chemotherapy. At the end of the treatment, all patients underwent a strict follow-up, consisting of clinical checkups such as a pelvic examination, ultrasonographic scan, CA125 evaluation, and periodic CT scan. The univariate survival analysis was based on the KaplaneMeier method. Comparison between the survival curves was analyzed using the Log-rank test. The overall survival (OS) was defined as the time between the date of surgery and the last date of follow-up or death due to EOC. Disease-free survival (DFS) was defined as the time interval between that of surgery and the date of recurrence or the last follow-up. The distributions of clinicopathological events were evaluated using the Chi-square tests. Stat View software ver.5.0 (SAS, Institution Inc., Cary, NC, USA) was used for all statistical analyses, and a P-value of <0.05 was considered significant. Results The clinical and histological characteristics of the patients studied are illustrated in Table 1. The median age was 30.0 years (range: 12e40 years). The median followup time was 54.7 months. All patients were nulliparous. The stage was IA in 30 patients, IB in one, and IC in 29. In stage IC patients, 3 patients were at stage IC(a) {i.e.,IC (surface involvement)}, 17 were at stage IC(b) {i.e.,IC(capsule rupture)}, and 9 were at IC(2) {i.e.,IC(positive cytology)}. Nineteen patients underwent a routine wedge resection of the contalateral ovary (normal in all cases). Table 1 Patient demographics and tumor characteristics in cases studied (N ¼ 60) Age Median Range
30 12e40
FIGO stage IA IB IC IC(a) IC(b) IC(2)
30 1 29 3 17 9
(50.0%) (1.7%) (48.3%) (5.0%) (28.3%) (15.0%)
Histological type Serous Mucinous Endometrioid Clear-cell
5 34 11 10
(8.3%) (56.7%) (18.3%) (16.7%)
Grade G1 G2 G3 N.C.
41 7 2 10
(68.3%) (11.7%) (3.3%) (16.7%)
N.C., not classified.
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Eight patients had recurrence of carcinoma (Table 2). Two patients experienced carcinoma recurrence involving the contralateral ovary alone. Thus, among all the patients who underwent FSS, the rate of recurrence in the remaining ovary was 3.3% (2/60). One woman (No.4) treated conservatively for a stage IB serous carcinoma was suspected to have tumor recurrence in the remaining ovary 128 months after the initial surgery. Despite our recommendation of additional surgery, she initially refused it. Although she underwent radical surgery of salpingo-oophorectomy of the remaining ovary and hysterectomy and subsequent chemotherapy, she died of intraperitoneal carcinomatosis 34 months after the diagnosis of recurrence. One patient (No.6) with stage IC(2) endometrioid adenocarcinoma experienced recurrence of the remaining ovary 49.4 months after the initial surgery. She underwent additional surgery of salpingo-oophorectomy of the remaining ovary and hysterectomy. With regard to the patients’ prognosis, 52 patients, including above Case No.6, are alive without evidence of recurrence after the initial treatment. Both 5-year OS and DFS rates of stage I patients who received FSS were 89.8%. Subsequently, we performed further survival analysis of patients with stage 1A and 1C. Fig. 1 shows the OS and PFS curves stratified by the FIGO stage (IA and IC). Although patients who were at stage IC showed a trend toward shorter survival duration than those at stage IA, it was not significant (OS, P ¼ 0.256; DFS, P ¼ 0.190, respectively). In addition, we again analyzed survival with further stratification by sub-classification of the FIGO IC. In this analysis, we classified patients with IC into two sub-groups: IC(b) and IC(a/ 2) {i.e.,IC(surface involvement/positive cytology)}. As a result, there was no significant difference in DFS and OS between patients with stage IC(b)and those with stage IA. In contrast, DFS and OS of the patients with stage IC(a/2) were poorer than those of patients with stage IA {OS; P ¼ 0.030, and DFS; P ¼ 0.005, respectively} (Fig. 2). When the histological type was considered, we observed four recurrences in 5 serous tumors (80.0%), one in 33 mucinous (3.0%), two in 11 endometrioid (18.2%), and one in 11 clear-cell (9.1%) types. In all, the recurrence rate in patients with the serous type was higher than those in patients
with other histological types (P ¼ 0.007). With regard to tumor differentiation, six recurrences were recorded in 40 G1 (well-differentiated) tumors (15.0%), and two in 9 G2eG3 (moderately or poorly-differentiated) tumors (22.2%). Although patients with G1 tumor showed a trend toward a longer survival duration than those with G2eG3 tumor, it was not significant (P ¼ 0.091). Following treatment, 13 pregnancies were observed in 9 patients (15.0%). These patients showed 9 full-term pregnancies, one premature delivery at 35 gestational weeks, and 3 spontaneous abortions. There were no congenital anomalies reported in any of the babies. Discussion A lot of young women with early stage EOC wish to preserve fertility without compromising survival. However, the application of conservative management in EOC continues to be controversial in the literature since data concerning such surgical management of EOC are uncommon. Needless to say, it is optimal for FSS to be proposed to young patients with stage I disease, an encapsulated tumor, no invasion of the capsule, a welldifferentiated tumor, and negative peritoneal washings along with a close follow-up. With regard to the FIGO stage, to what extent can FSS be selected safely without adversely affecting the prognosis? Morice et al. reported 33 patients with stage I EOC (IA, 30; IC, 3), who were treated with unilateral salpingo-oophorectomy in different institutions.2 They observed 11 relapses, seven of which were at stage IA (23.3%), and three of which were stage IC (100%). Thus, they recommend not performing this procedure in patients beyond stage IA. However, the number of patients with IC or IA/G3 was too small to draw a definitive conclusion regarding the legitimacy of FSS. In addition, in three relapsed patients with IC, recurrent tumors had spread to distant regions or throughout the peritoneal cavity, and so were not confined to the remaining ovary. Therefore, it is questionable whether recurrence was attributable to the choice of FSS at the initial operation.
Table 2 Clinical characteristicse of patients with tumor recurrence. Case
Age
Initial surgery
PT
Substage
Histological type
Grade
Adjuvant chemotherapy
Prognosis
Follow-up (months)
DFS (months)
1
39
RSO þ wedge
IC
IC(2)
C
1
Platinum-based
DOD
36.8
20.3
2 3 4 5 6 7 8
36 29 28 30 37 14 32
LSO RSO þ wedge RSO þ wedge LSO LSO þ OM RSO RSO
IA IC IB IC IC IC IA
(-) IC(2) (-) IC(2) IC(2) IC(a) (-)
S E S S E M S
2 1 1 3 1 1 1
Platinum-based Platinum-based Platinum-based Platinum-based Platinum-based Platinum-based Taxan þ platinum
DOD DOD DOD DOD NED DOD DOD
8.6 67.9 195.7 6.7 128.5 12.7 42.2
3.3 5.2 138.9 4.2 128.5 9.3 20.5
Recurrence site Brain, abdominal wall PC PC Ovary PC Ovary PC PC
LSO, left salpingo-oophorectomy; RSO, right salpingo-oophorectomy; OM, omentectomy; wedge, wedge resection of the contralateral ovary; Histological type: S, serous cystadenocarcinoma; E, endometrioid adenocarcinoma; M, mucinous cystadenocarcinoma; C, clear-cell adenocarcinoma; DOD, died of the disease; NED, no evidence of the disease; DFS, disease-free survival; PC, intraperitoneal cavity.
H. Kajiyama et al. / EJSO 36 (2010) 404e408
407
Figure 1. KaplaneMeier estimated OS (A) or DFS (B) of patients who underwent FSS stratified by FIGO stage (IA and IC). Survival curves stratified by FIGO stage {IA (n ¼ 30), solid line and IC (n ¼ 29), dotted line}. Although patients who were at stage IC showed a trend toward a shorter survival duration than at stage IA, it was not significant (A: OS, P ¼ 0.256; B: DFS, P ¼ 0.190, respectively).
On the other hand, Schilder et al. reported about 42 stage IA and 10 stage IC patients who were treated with FSS in eight different institutions.8 They observed only one relapse in 10 stage IC patients. Moreover, Zanetta et al. reported 22 stage IC patients who underwent FSS. They observed one relapse, which was in the pelvis.9 They concluded that, considering the long-term survival of both IA and IC patients treated with FSS, FSS was acceptable even for stage IC patients with EOC. According to the survival analysis in our current study, we showed that there was no significant difference in OS and PFS between stage IA and IC patients. In our series, we observed no relapse in stage IC(b), but did in stage IA/IC(a/2) patients. However, the DFS and OS of the patients with stage IC associated with preoperative rupture or positive ascites were poorer than those of stage IA. Moreover, on comparing stage IA to IC patients associated with intraoperative rupture, the difference in survival was not significant. Although there was the limitation of the small number of patients, the results suggest that, focusing on the FIGO stage, FSS may be selected at least for stage IC(b) patients as safely as for IA patients. On the other hand, what about for stage IC excluding IC(b)? In our current analysis, we experienced five
recurrences in 13 IC(a/2) patients undergoing FSS (Table 2). However, in four of these 5 patients, recurrent tumors were observed in the peritoneal cavity or comprised distant lesions despite platinum-based chemotherapy. This implies that occult chemoresistant micrometastases might already exist in sites other than the remaining ovary. Table 3 summarizes the recurrence sites observed in stage I EOC patients treated with FSS in the literature.2,8e11 According to a review of 310 patients including the current subjects, the recurrence rates in the remaining ovary alone were 3.9% in stage IA and 1.0% in IC. In contrast, those of the peritoneal cavity/distant sites were 8.3 and 12.5%, respectively. Therefore, a question arises as to whether recurrence could have been avoided in these IC cases, if radical surgery had been performed in the initial operation. Unless there is a specific risk of recurrence in the remaining ovary, the outcome in women with preoperative cystic rupture or positive cytology may depend on the susceptibility to postoperative chemotherapy rather than more aggressive surgery. Accordingly, despite a likelihood of recurrence, FSS may be considered in these patients after obtaining adequate informed consent. Moreover, performing FSS to patients with stage IB is extremely rare. If we wish to preserve unilateral ovary in
Figure 2. A, B: KaplaneMeier estimated OS (A) or DFS (B) of patients who underwent FSS stratified by the sub-classification of FIGO IC. IC(b), patients with intraoperative capsule rupture with negative cytology; IC(a), patients with a tumor on the ovarian surface or preoperative capsule rupture; IC (2), patients with positive malignant cells in ascites. In this analysis, we classified patients with IC into two groups: IC(b) and IC(a/2), that consisted of IC(a) and IC(2). Solid line: IA (n ¼ 30), Dotted line: IC(b) (n ¼ 17), and Broken line: IC(a/2) (n ¼ 12). DFS and OS of patients with stage IC(a/2) were poorer than those of stage IA {IA vs. IC(a/2); P ¼ 0.030 (OS; A) and P ¼ 0.0054 (DFS; B), respectively}.
H. Kajiyama et al. / EJSO 36 (2010) 404e408
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Table 3 Series of stage IA and C EOC patients treated conservatively in the literature. Reference
Schilder et al. (2002) Morice et al. (2005) Zanetta et al. (2005) Colombo et al. (1994) Park et al. (2008) Current report Total
FIGO stage
Site of recurrence
IA
IC
IA
IC
RO
PC/distant
RO
PC/distant
42 30 32 36 36 30 206
10 3 22 19 21 29 104
0 5 1 1 1 0 8 (3.9%)
4 2 3 2 4 2 17 (8.3)%
0 0 0 0 0 1 1 (1.0%)
1 3 1 0 4 4 13 (12.5%)
RO, remaining ovary alone; PC, peritoneal cavity; Distant, distant metastasis, including brain, lung, liver, spleen, and retroperitoneal lymph node.
this stage, we must remove tumor-existing ovarian tissue by the partial resection. However, occult tumor cells may be present in the remaining ovary in spite of intraoperative microscopic and macroscopic inspections. In fact, our current case treated conservatively for a stage IB had tumor recurrence in the remaining ovary after the long time from initial surgery, and consequently died of intraperitoneal carcinomatosis. On the other hand, Park et al., documented that 2 patients who underwent FSS were alive without evidence of disease.11 Since the number of reported cases is very small, we are not able to make a definite conclusion about this issue at present. At least, we had better keep in mind that to select FSS to this stage may have considerable risk of tumor recurrence. The most important finding of the current examination is that patients with stage I EOC treated with FSS have a comparatively much more favorable prognosis compared to those receiving radical surgery. We should understand that a risk of recurrence in itself is not necessarily caused by selecting FSS. However, our current study is based on too small a number of retrospective data to verify the actual legitimacy of FSS. Concerning the specificity of this surgical procedure and patient background, it seems very difficult to perform a randomized controlled study. It is desirable for further investigations to be conducted with a worldwide, clinical registry system in which stage I EOC patients treated with FSS can be enrolled in the future. Conflict of interest statement The all authors declare that there are no conflicts of interest.
References 1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics. CA Cancer J Clin 2001;2001(51):15–36. 2. Morice P, Leblanc E, Rey A, et al. Conservative treatment in epithelial ovarian cancer: results of a multicentre study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer) and SFOG (Societe Francaise d’Oncologie Gynecologique). Hum Reprod 2005;20: 1379–85. 3. Duska LR, Chang YC, Flynn CE, et al. Epithelial ovarian carcinoma in the reproductive age group. Cancer 1999;85:2623–9. 4. Plaxe SC, Braly PS, Freddo JL, McClay E, Kirmani S, Howell SB. Profiles of women age 30e39 and age less than 30 with epithelial ovarian cancer. Obstet Gynecol 1993;81:651–4. 5. Rodriguez M, Nguyen HN, Averette HE, et al. National survey of ovarian carcinoma XII. Epithelial ovarian malignancies in women less than or equal to 25 years of age. Cancer 1994;73: 1245–50. 6. Swenerton KD, Hislop TG, Spinelli J, LeRiche JC, Yang N, Boyes DA. Ovarian carcinoma: a multivariate analysis of prognostic factors. Obstet Gynecol 1985;65:264–70. 7. Smedley H, Sikora K. Age as a prognostic factor in epithelial ovarian carcinoma. Br J Obstet Gynaecol 1985;92:839–42. 8. Schilder JM, Thompson AM, DePriest PD, et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol Oncol 2002; 87:1–7. 9. Zanetta G, Chiari S, Rota S, et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 1997;104:1030–5. 10. Colombo N, Chiari S, Maggioni A, Bocciolone L, Torri V, Mangioni C. Controversial issues in the management of early epithelial ovarian cancer: conservative surgery and role of adjuvant therapy. Gynecol Oncol 1994;55:S47–51. 11. Park J, Kim D, Suh D, et al. Outcome of fertility-sparing surgery for invasive epithelial ovarian cancer: oncologic safety and reproductive outcomes. Gynecol Oncol 2008;110:345–53.
EJSO 36 (2010) 404e408
www.ejso.com
Fertility-sparing surgery in young women with invasive epithelial ovarian cancer H. Kajiyama a,*, K. Shibata a, S. Suzuki a, K. Ino a, A. Nawa a, M. Kawai b, T. Nagasaka c, F. Kikkawa a a
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan b Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Japan c Division of Pathology, Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan Accepted 11 January 2010 Available online 8 February 2010
Abstract Objectives: The purpose of this study was to clarify the clinical outcome of patients with stage IA or more advanced epithelial ovarian cancer (EOC) treated with fertility-sparing surgery (FSS). Methods: After a central pathological review and search of the medical records from multiple institutions, a total of 60 stage I EOC patients treated with FSS were retrospectively evaluated in the current study. Results: The median age was 30 years (range: 12e40 years). The median follow-up time was 54.7 months (range: 4.8e243.8 months). The stage was IA in 30, IB in one, and IC in 29 patients. Fifty-two patients were alive without relapse and 8 patient experienced recurrences {IA, 2; IB, 1; IC(surface involvement), 1; and IC(positive cytology), 4}. However, all patients with stage IC(capsule rupture) (n ¼ 17) were alive without recurrence. Collectively, there was no significant difference in the overall survival between the stage IA and IC groups (P ¼ 0.256). Moreover, there was no significant difference in DFS and OS between patients with stage IC(capsule rupture) and those with stage IA. In contrast, DFS and OS of the patients with stage IC(surface involvement/positive cytology) were poorer than those of patients with stage IA {OS; P ¼ 0.030, and DFS; P¼ 0.005, respectively}. Thirteen pregnancies were observed in 9 patients. Conclusions: FSS may be considered a treatment option in women with stage I EOC, even in those with stage IC(capsule rupture) or more wishing to bear children. Ó 2010 Elsevier Ltd. All rights reserved. Keywords: Epithelial ovarian cancer; Fertility-sparing surgery; Pregnancy; Clinical outcome
Introduction Epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecological malignancy.1 The standard surgical treatment for patients with EOC is based on hysterectomy and bilateral salpingo-oophorectomy with peritoneal sampling (peritoneal washing, omentectomy, multiple peritoneal biopsies, and the removal of peritoneal implants) with or without lymph node sampling.2 However, several reports have estimated that 3e17% of all EOCs occur in woman under 40 years of age.3e7 In these patients, the preservation of reproductive and endocrine functions is crucial. In general, fertility-sparing surgery (FSS) has been adopted in young patients with borderline, germ
* Corresponding author. Tel.: þ81 52 744 2262; fax: þ81 52 744 2268. E-mail address: [email protected] (H. Kajiyama). 0748-7983/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2010.01.005
cell, and stromal tumors and some authors propose this treatment for stage I/grade 1 invasive EOC. However, because of the risk of leaving a microscopic contralateral tumor and thereby compromising curability, most gynecologists are reluctant to perform FSS in all other stage I invasive EOCs. Indeed, on selecting this surgical procedure, there may be a risk that the probability of recurrence and death is increased. The amount of evidence is too small to resolve this point because previous reports frequently involved few patients with multiple histologic tumor types including borderline tumors. After the central pathological review and scanning of the medical records of multicentric institutions between 1986 and 2006, a total of 60 patients with stage I EOC treated with FSS were enrolled in the present study. In this study, we retrospectively analyzed these cases to clarify the clinical outcome of EOC patients who would usually undergo radical surgery.
H. Kajiyama et al. / EJSO 36 (2010) 404e408
Materials and methods Between January 1986 and December 2006, a total of 1443 patients with EOC were registered and treated by the Tokai Ovarian Tumor Study Group, consisting of Nagoya University Hospital and affiliated hospitals. Data were collected from medical records and clinical followup visits. Seventy patients received FSS. Six patients were excluded from this study because of insufficient clinical data or being lost to follow-up immediately after surgery. Among the remaining 64 patients, 4 patients with stage II were excluded. In the current study, 60 stage I patients were picked up and retrospectively evaluated in the current study. The present series consisted of 60 carcinomas that were classified into the following histological types: mucinous, 34; serous, 5; endometrioid, 11; and clear-cell, 10. The histological cell types and histological grade (tumor differentiation) were assigned except that for clearcell carcinoma according to the criteria of the World Health Organization (WHO). Histological slides were reviewed by one of the authors under a central pathological review system with no knowledge of the patients’ clinical data. Clinical staging was defined according to the International Federation of Gynecology and Obstetrics (FIGO, 1985) criteria, using the macroscopic description during the surgical procedure and histological analysis of specimens removed during initial and restaging surgeries if the initial procedure was incomplete. In addition, patients with FIGO stage IC were classified into four subtypes according to the pathological characteristics: IC (a) for those with a tumor on the ovarian surface or preoperative capsule rupture, IC(b) for patients with intraoperative capsule rupture with negative cytology, and IC (1) or IC (2) for those with positive malignant cells in the positive peritoneal washing or ascites, respectively. In principle, patients were eligible if they: (1) had histologically confirmed stage IA grades 1, 2, or 3 EOC, (2) were less than 40 years of age at the time of the initial diagnosis, and (3) strongly desired to retain fertility. In patients with more than stage IB or clear-cell adenocarcinoma, FSS was carried out only when we could not obtain informed consent for our recommended surgical procedure from patients who strongly desired to preserve fertility. In a preoperative counseling session, these women were informed of the possible risks and benefits of FSS, and asked to sign a consent form. Several patients had received incomplete surgery elsewhere (for example, unilateral cystectomy of the tumor). During the initial or restaging surgery, all patients underwent salpingo-oophorectomy on the side of the ovarian tumor with at least a peritoneal staging including cytology of peritoneal washing or ascites, careful palpation and inspection throughout peritoneal cavity, and multiple peritoneal biopsies. Systemic retroperitoneal lymphadenectomy, wedge resection of the remaining ovary, omentectomy, and appendectomy were optional.
405
Forty-two patients (70.0%) were treated postoperatively with 3e6 cycles of adjuvant chemotherapy; 24 patients received platinum-based chemotherapy, and 18 patients received platinum plus taxane chemotherapy. At the end of the treatment, all patients underwent a strict follow-up, consisting of clinical checkups such as a pelvic examination, ultrasonographic scan, CA125 evaluation, and periodic CT scan. The univariate survival analysis was based on the KaplaneMeier method. Comparison between the survival curves was analyzed using the Log-rank test. The overall survival (OS) was defined as the time between the date of surgery and the last date of follow-up or death due to EOC. Disease-free survival (DFS) was defined as the time interval between that of surgery and the date of recurrence or the last follow-up. The distributions of clinicopathological events were evaluated using the Chi-square tests. Stat View software ver.5.0 (SAS, Institution Inc., Cary, NC, USA) was used for all statistical analyses, and a P-value of <0.05 was considered significant. Results The clinical and histological characteristics of the patients studied are illustrated in Table 1. The median age was 30.0 years (range: 12e40 years). The median followup time was 54.7 months. All patients were nulliparous. The stage was IA in 30 patients, IB in one, and IC in 29. In stage IC patients, 3 patients were at stage IC(a) {i.e.,IC (surface involvement)}, 17 were at stage IC(b) {i.e.,IC(capsule rupture)}, and 9 were at IC(2) {i.e.,IC(positive cytology)}. Nineteen patients underwent a routine wedge resection of the contalateral ovary (normal in all cases). Table 1 Patient demographics and tumor characteristics in cases studied (N ¼ 60) Age Median Range
30 12e40
FIGO stage IA IB IC IC(a) IC(b) IC(2)
30 1 29 3 17 9
(50.0%) (1.7%) (48.3%) (5.0%) (28.3%) (15.0%)
Histological type Serous Mucinous Endometrioid Clear-cell
5 34 11 10
(8.3%) (56.7%) (18.3%) (16.7%)
Grade G1 G2 G3 N.C.
41 7 2 10
(68.3%) (11.7%) (3.3%) (16.7%)
N.C., not classified.
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Eight patients had recurrence of carcinoma (Table 2). Two patients experienced carcinoma recurrence involving the contralateral ovary alone. Thus, among all the patients who underwent FSS, the rate of recurrence in the remaining ovary was 3.3% (2/60). One woman (No.4) treated conservatively for a stage IB serous carcinoma was suspected to have tumor recurrence in the remaining ovary 128 months after the initial surgery. Despite our recommendation of additional surgery, she initially refused it. Although she underwent radical surgery of salpingo-oophorectomy of the remaining ovary and hysterectomy and subsequent chemotherapy, she died of intraperitoneal carcinomatosis 34 months after the diagnosis of recurrence. One patient (No.6) with stage IC(2) endometrioid adenocarcinoma experienced recurrence of the remaining ovary 49.4 months after the initial surgery. She underwent additional surgery of salpingo-oophorectomy of the remaining ovary and hysterectomy. With regard to the patients’ prognosis, 52 patients, including above Case No.6, are alive without evidence of recurrence after the initial treatment. Both 5-year OS and DFS rates of stage I patients who received FSS were 89.8%. Subsequently, we performed further survival analysis of patients with stage 1A and 1C. Fig. 1 shows the OS and PFS curves stratified by the FIGO stage (IA and IC). Although patients who were at stage IC showed a trend toward shorter survival duration than those at stage IA, it was not significant (OS, P ¼ 0.256; DFS, P ¼ 0.190, respectively). In addition, we again analyzed survival with further stratification by sub-classification of the FIGO IC. In this analysis, we classified patients with IC into two sub-groups: IC(b) and IC(a/ 2) {i.e.,IC(surface involvement/positive cytology)}. As a result, there was no significant difference in DFS and OS between patients with stage IC(b)and those with stage IA. In contrast, DFS and OS of the patients with stage IC(a/2) were poorer than those of patients with stage IA {OS; P ¼ 0.030, and DFS; P ¼ 0.005, respectively} (Fig. 2). When the histological type was considered, we observed four recurrences in 5 serous tumors (80.0%), one in 33 mucinous (3.0%), two in 11 endometrioid (18.2%), and one in 11 clear-cell (9.1%) types. In all, the recurrence rate in patients with the serous type was higher than those in patients
with other histological types (P ¼ 0.007). With regard to tumor differentiation, six recurrences were recorded in 40 G1 (well-differentiated) tumors (15.0%), and two in 9 G2eG3 (moderately or poorly-differentiated) tumors (22.2%). Although patients with G1 tumor showed a trend toward a longer survival duration than those with G2eG3 tumor, it was not significant (P ¼ 0.091). Following treatment, 13 pregnancies were observed in 9 patients (15.0%). These patients showed 9 full-term pregnancies, one premature delivery at 35 gestational weeks, and 3 spontaneous abortions. There were no congenital anomalies reported in any of the babies. Discussion A lot of young women with early stage EOC wish to preserve fertility without compromising survival. However, the application of conservative management in EOC continues to be controversial in the literature since data concerning such surgical management of EOC are uncommon. Needless to say, it is optimal for FSS to be proposed to young patients with stage I disease, an encapsulated tumor, no invasion of the capsule, a welldifferentiated tumor, and negative peritoneal washings along with a close follow-up. With regard to the FIGO stage, to what extent can FSS be selected safely without adversely affecting the prognosis? Morice et al. reported 33 patients with stage I EOC (IA, 30; IC, 3), who were treated with unilateral salpingo-oophorectomy in different institutions.2 They observed 11 relapses, seven of which were at stage IA (23.3%), and three of which were stage IC (100%). Thus, they recommend not performing this procedure in patients beyond stage IA. However, the number of patients with IC or IA/G3 was too small to draw a definitive conclusion regarding the legitimacy of FSS. In addition, in three relapsed patients with IC, recurrent tumors had spread to distant regions or throughout the peritoneal cavity, and so were not confined to the remaining ovary. Therefore, it is questionable whether recurrence was attributable to the choice of FSS at the initial operation.
Table 2 Clinical characteristicse of patients with tumor recurrence. Case
Age
Initial surgery
PT
Substage
Histological type
Grade
Adjuvant chemotherapy
Prognosis
Follow-up (months)
DFS (months)
1
39
RSO þ wedge
IC
IC(2)
C
1
Platinum-based
DOD
36.8
20.3
2 3 4 5 6 7 8
36 29 28 30 37 14 32
LSO RSO þ wedge RSO þ wedge LSO LSO þ OM RSO RSO
IA IC IB IC IC IC IA
(-) IC(2) (-) IC(2) IC(2) IC(a) (-)
S E S S E M S
2 1 1 3 1 1 1
Platinum-based Platinum-based Platinum-based Platinum-based Platinum-based Platinum-based Taxan þ platinum
DOD DOD DOD DOD NED DOD DOD
8.6 67.9 195.7 6.7 128.5 12.7 42.2
3.3 5.2 138.9 4.2 128.5 9.3 20.5
Recurrence site Brain, abdominal wall PC PC Ovary PC Ovary PC PC
LSO, left salpingo-oophorectomy; RSO, right salpingo-oophorectomy; OM, omentectomy; wedge, wedge resection of the contralateral ovary; Histological type: S, serous cystadenocarcinoma; E, endometrioid adenocarcinoma; M, mucinous cystadenocarcinoma; C, clear-cell adenocarcinoma; DOD, died of the disease; NED, no evidence of the disease; DFS, disease-free survival; PC, intraperitoneal cavity.
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Figure 1. KaplaneMeier estimated OS (A) or DFS (B) of patients who underwent FSS stratified by FIGO stage (IA and IC). Survival curves stratified by FIGO stage {IA (n ¼ 30), solid line and IC (n ¼ 29), dotted line}. Although patients who were at stage IC showed a trend toward a shorter survival duration than at stage IA, it was not significant (A: OS, P ¼ 0.256; B: DFS, P ¼ 0.190, respectively).
On the other hand, Schilder et al. reported about 42 stage IA and 10 stage IC patients who were treated with FSS in eight different institutions.8 They observed only one relapse in 10 stage IC patients. Moreover, Zanetta et al. reported 22 stage IC patients who underwent FSS. They observed one relapse, which was in the pelvis.9 They concluded that, considering the long-term survival of both IA and IC patients treated with FSS, FSS was acceptable even for stage IC patients with EOC. According to the survival analysis in our current study, we showed that there was no significant difference in OS and PFS between stage IA and IC patients. In our series, we observed no relapse in stage IC(b), but did in stage IA/IC(a/2) patients. However, the DFS and OS of the patients with stage IC associated with preoperative rupture or positive ascites were poorer than those of stage IA. Moreover, on comparing stage IA to IC patients associated with intraoperative rupture, the difference in survival was not significant. Although there was the limitation of the small number of patients, the results suggest that, focusing on the FIGO stage, FSS may be selected at least for stage IC(b) patients as safely as for IA patients. On the other hand, what about for stage IC excluding IC(b)? In our current analysis, we experienced five
recurrences in 13 IC(a/2) patients undergoing FSS (Table 2). However, in four of these 5 patients, recurrent tumors were observed in the peritoneal cavity or comprised distant lesions despite platinum-based chemotherapy. This implies that occult chemoresistant micrometastases might already exist in sites other than the remaining ovary. Table 3 summarizes the recurrence sites observed in stage I EOC patients treated with FSS in the literature.2,8e11 According to a review of 310 patients including the current subjects, the recurrence rates in the remaining ovary alone were 3.9% in stage IA and 1.0% in IC. In contrast, those of the peritoneal cavity/distant sites were 8.3 and 12.5%, respectively. Therefore, a question arises as to whether recurrence could have been avoided in these IC cases, if radical surgery had been performed in the initial operation. Unless there is a specific risk of recurrence in the remaining ovary, the outcome in women with preoperative cystic rupture or positive cytology may depend on the susceptibility to postoperative chemotherapy rather than more aggressive surgery. Accordingly, despite a likelihood of recurrence, FSS may be considered in these patients after obtaining adequate informed consent. Moreover, performing FSS to patients with stage IB is extremely rare. If we wish to preserve unilateral ovary in
Figure 2. A, B: KaplaneMeier estimated OS (A) or DFS (B) of patients who underwent FSS stratified by the sub-classification of FIGO IC. IC(b), patients with intraoperative capsule rupture with negative cytology; IC(a), patients with a tumor on the ovarian surface or preoperative capsule rupture; IC (2), patients with positive malignant cells in ascites. In this analysis, we classified patients with IC into two groups: IC(b) and IC(a/2), that consisted of IC(a) and IC(2). Solid line: IA (n ¼ 30), Dotted line: IC(b) (n ¼ 17), and Broken line: IC(a/2) (n ¼ 12). DFS and OS of patients with stage IC(a/2) were poorer than those of stage IA {IA vs. IC(a/2); P ¼ 0.030 (OS; A) and P ¼ 0.0054 (DFS; B), respectively}.
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Table 3 Series of stage IA and C EOC patients treated conservatively in the literature. Reference
Schilder et al. (2002) Morice et al. (2005) Zanetta et al. (2005) Colombo et al. (1994) Park et al. (2008) Current report Total
FIGO stage
Site of recurrence
IA
IC
IA
IC
RO
PC/distant
RO
PC/distant
42 30 32 36 36 30 206
10 3 22 19 21 29 104
0 5 1 1 1 0 8 (3.9%)
4 2 3 2 4 2 17 (8.3)%
0 0 0 0 0 1 1 (1.0%)
1 3 1 0 4 4 13 (12.5%)
RO, remaining ovary alone; PC, peritoneal cavity; Distant, distant metastasis, including brain, lung, liver, spleen, and retroperitoneal lymph node.
this stage, we must remove tumor-existing ovarian tissue by the partial resection. However, occult tumor cells may be present in the remaining ovary in spite of intraoperative microscopic and macroscopic inspections. In fact, our current case treated conservatively for a stage IB had tumor recurrence in the remaining ovary after the long time from initial surgery, and consequently died of intraperitoneal carcinomatosis. On the other hand, Park et al., documented that 2 patients who underwent FSS were alive without evidence of disease.11 Since the number of reported cases is very small, we are not able to make a definite conclusion about this issue at present. At least, we had better keep in mind that to select FSS to this stage may have considerable risk of tumor recurrence. The most important finding of the current examination is that patients with stage I EOC treated with FSS have a comparatively much more favorable prognosis compared to those receiving radical surgery. We should understand that a risk of recurrence in itself is not necessarily caused by selecting FSS. However, our current study is based on too small a number of retrospective data to verify the actual legitimacy of FSS. Concerning the specificity of this surgical procedure and patient background, it seems very difficult to perform a randomized controlled study. It is desirable for further investigations to be conducted with a worldwide, clinical registry system in which stage I EOC patients treated with FSS can be enrolled in the future. Conflict of interest statement The all authors declare that there are no conflicts of interest.
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