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Laparoscopic staging of apparent early stage ovarian cancer: Results of a large, retrospective, multi-institutional series
Gynecologic Oncology 135 (2014) 428–434
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Laparoscopic staging of apparent early stage ovarian cancer: Results of a large, retrospective, multi-institutional series V. Gallotta a,⁎, F. Ghezzi b, E. Vizza c, V. Chiantera d, M. Ceccaroni e, M. Franchi f, A. Fagotti g, A. Ercoli h, F. Fanfani a, C. Parrino a, S. Uccella b, G. Corrado c, G. Scambia a, G. Ferrandina a a
Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy Department of Oncological Surgery, Gynecologic Oncologic Unit, “Regina Elena” National Cancer Institute, Rome, Italy d Gynecologic Oncology Unit, Fondazione “Giovanni Paolo II”, Campobasso, Italy e Department of Obstetrics and Gynecology, Gynecologic Oncology and Minimally-Invasive Pelvic Surgery, Sacred Heart Hospital, Negrar, Verona, Italy f Department of Obstetrics and Gynecology, University of Verona, Verona, Italy g Division of Minimally Invasive Gynecologic Surgery, Department of Surgery, St Maria Hospital–University of Perugia, Terni, Italy h Policlinic of Abano Terme, Padova, Italy b c
H I G H L I G H T S • Stage of disease is still the most important prognostic factor in early ovarian cancer. • Among early ovarian cancer patients there is a non-negligible percentage of upstaged patients. • A complete and accurate surgical staging can be safely achieved through laparoscopic surgery, when performed in referral centers.
a r t i c l e
i n f o
Article history: Received 12 August 2014 Accepted 6 September 2014 Available online 16 September 2014 Keywords: Ovarian cancer Early ovarian cancer Laparoscopy
a b s t r a c t Objective. The aim of this study is to analyze the safety, adequacy, perioperative and survival figures in a large series of laparoscopic staging of patients with apparent early stage ovarian malignancies (ESOM). Patients and methods. Retrospective data from seven gynecologic oncology service databases were searched for ESOM patients undergoing immediate laparoscopic staging or delayed laparoscopic staging after an incidental diagnosis of ESOM. Between May 2000 and February 2014, 300 patients were selected: 150 had been submitted to immediate laparoscopic staging (Group 1), while 150 had undergone delayed laparoscopic staging (Group 2) of ESOM. All surgical, pathologic, and oncologic outcome data were analyzed in each group and a comparison between the two was carried out. Results. Longer operative time, higher blood loss, more frequently spillage/rupture of ovarian capsule and conversion to laparotomy occurred in Group 1. No significant differences of post-operative complications were observed between the two groups. Histological data revealed more frequently serous tumors (0.06), Grade 3 (p = 0.0007) and final up-staging (p = 0.001) in Group 1. Recurrence and death of disease were documented in 25 (8.3%), and 10 patients (3.3%%), respectively. The 3-year disease free survival (DFS) and overall survival (OS) rates were 85.1%, and 93.6%, respectively in the whole series. There was no difference between Group 1 and Group 2 in terms of DFS (p value = 0.39) and OS (p value = 0.27). Conclusion. In this very large multi-institutional study, it appears that patients with apparent ESOM can safely undergo laparoscopic surgical management. © 2014 Elsevier Inc. All rights reserved.
Introduction
⁎ Corresponding author at: Dept. of Obstetrics and Gynecologic, Catholic University, L.go A. Gemelli, 8, 00168 Rome, Italy. Fax: +39 0635508736. E-mail address: [email protected] (V. Gallotta).
http://dx.doi.org/10.1016/j.ygyno.2014.09.006 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Ovarian cancer accounts for one quarter of malignancies of the female genital tract, but represents the fifth most common cause of cancer death in women [1]. Only 20–25% of patients are diagnosed at early stage disease at diagnosis, a condition associated with a significantly improved survival rate [1]. However, as reported by previous studies,
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
almost 30% of apparent early stage ovarian cancer patients are upstaged due to peritoneal or lymph node involvement [2–6]. In this context, accurate evaluation of spread of disease through surgical staging is critical to ensure appropriate treatment and optimal survival [7–11]. Traditional approach for staging of apparent early stage ovarian cancer includes laparotomy with an extended midline incision that exposes the whole peritoneal cavity; according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines, optimal procedures include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies as well as pelvic and aortic lymph node dissection [12]. In the last decade many investigators have assessed feasibility and adequacy of laparoscopic staging of apparent early stage ovarian malignancies (ESOM), thus advocating the use of minimally invasive approaches in accurately selected patients [13–27]. Most retrospective series report survival rates around 90%, which are in the range observed in patients conventionally staged by laparotomy [26]; however, minimally invasive surgical techniques are not routinely performed in early stage ovarian tumors, perhaps because of persisting doubts about adequacy of these procedures in the identification of occult metastatic disease. In particular, the following criticisms have been raised: inadequate exploration of abdominal cavity, lower lymph node yield, possible risk of port site metastases, risk of tumor cell spread due to abdominal CO2 pressure, risk of intraoperative mass rupture, and lack of tactile sensation [28,29]. While the need to design a prospective, randomized study assessing staging performance and oncologic outcome of laparoscopic management of ESOM has been reiterated in the Cochrane analysis [30], such a study is expected to be hardly realized considering both the rarity of early stage ovarian tumors and the high level of skillfulness required for laparoscopic comprehensive staging. Moreover, most of the retrospective studies included in a recent metaanalysis refer to a relatively small series [31], thus limiting the possibility to reliably compare different subgroups. In this context, a retrospective, multicenter study has been launched within referral Gynecologic Oncology Units in Italy with the aim to analyze perioperative and survival figures in a large series of patients with laparoscopically staged apparent ESOM. Patients and methods This is a retrospective, multi-institutional study conducted in patients with apparent ESOM managed by a laparoscopic approach in 7 referral Gynecologic Oncology Units: Catholic University of the Sacred Heart in Rome, University of Insubria in Varese, “Regina Elena” National Cancer Institute in Rome, Fondazione “Giovanni Paolo II” in Campobasso, Sacred Heart Hospital in Negrar, Verona, University of Verona and Policlinico of Abano Terme, Padova. Data were collected from patients with imaging and/or intraoperative findings suggestive of disease involving only one or both ovaries, and/or Fallopian tubes, who underwent comprehensive immediate laparoscopic staging at time of primary diagnosis or delayed laparoscopic staging after an incidental diagnosis of ovarian malignancy. All histologic subtypes of the malignant ovarian tumors (epithelial, stromal and germ cell tumors) were included in the data search and collection. Cases with borderline tumors were excluded. Patients were staged according to FIGO criteria [12], using macroscopic findings, as well as cytologic and histological results of specimens obtained at immediate or delayed laparoscopic staging. Laparoscopic staging procedures had to be performed by surgeons with extensive training in gynecologic oncology and minimally invasive surgery. All tissue specimens were required to be analyzed by a dedicated Gynecologic Oncology pathologist. The following data were planned to be collected: clinical characteristics (age, menopausal status, body mass index — BMI, history of endometriosis), number of previous abdominal surgeries, type of surgical procedures at staging, conversion to laparotomy as well as operative time, length of hospital stay, estimated blood loss — EBL, and transfusion
429
requirement. Intraoperative mass rupture was defined as any rupture, intentional or unintentional, that resulted in the release of cystic content into the peritoneal cavity. If a mass was drained intentionally within a collection bag to facilitate removal without resulting in peritoneal spill, the mass was not considered ruptured. Data about fertility preserving surgery (FPS) were registered as well as intraoperative and postoperative complications. Details about the administration of adjuvant treatment, obstetric outcome, and survival outcome have been collected. Statistical analysis The χ2 test or Fisher's exact test for proportion was used to analyze the distribution of clinico-pathological variables according to different subgroups. Wilcoxon rank sum non-parametric test was used to analyze the distribution of continuous values. Disease-free survival (DFS) was calculated from the date of surgery to the date of relapse or the date of the last follow-up; overall survival (OS) was calculated from the date of diagnosis to the date of death or the date of the last follow-up. Medians and life tables were computed using the product limit estimate by the Kaplan–Meier method [32], and the log-rank test was used to assess the statistical significance among groups [33]. Statistical analysis was carried out using SOLO (BMDP Statistical Software, Los Angeles, CA, USA). Results Between May 2000 and February 2014, 300 patients with apparent ESOM according to the predefined criteria underwent laparoscopic staging according to FIGO guidelines. In particular, 150 patients were submitted to immediate laparoscopic staging at initial diagnosis (Group 1), while 150 patients underwent delayed laparoscopic staging after an incidental diagnosis of ESOM. Clinical characteristics of patients in the whole series and in the 2 groups are summarized in Table 1. Overall, median age was 49 years (range = 11-81), and median BMI was 22.8 (range = 16.6-49.9). At time of surgery, 148 out of 296 patients were postmenopausal; 135 patients (45%) had been already submitted to at least 1 abdominal
Table 1 Patient characteristics. Variable
Whole series N. (%)
All cases 300 Age, years Median 49 (11–81) (range) BMI, kg/m2 Median 22.8 (16.6– (range) 49.9) Menopause No 148 Yes 148 not specified. 4 Previous abdominal surgery None 165 1 100 2 25 3 5 4 5 History of endometriosis No 246 Yes 54
Group 1 Immediate staging N. (%)
Group 2 Delayed staging N (%)
p valuea
150
150
–
53 (13–81)
45 (11–73)
0.0002
23.4 (17.0–39.0)
22.8 (17.0– 49.9)
n.s.
59 (39.9) 87 (58.8) 4
89 (60.1) 61 (41.2)
80 (48.5) 50 (50.0) 16 (64.0) 2 (40.0) 2 (40.0)
85 (51.5) 50 (50.0) 9 (36.0) 3 (60.0) 3 (60.0)
n.s.
134 (54.5) 16 (29.6)
112 (45.5) 38 (70.4)
0.0009
0.0001
n.s. = not significant. a Calculated by Wilcoxon rank sum non-parametric test or Fisher's exact test for proportion.
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V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
Table 2 Surgical procedures and intraoperative details. Variable
Group 1 (Immediate staging) N. (%)
Group 2 (Delayed staging) N. (%)
All cases Time interval to laparoscopic staging (days) Median (range) Surgical procedures at staging laparoscopy Bilateral salpingo-oophorectomy Hysterectomy Unilateral salpingo-oophorectomy Appendectomy Omentectomy Peritoneal washing Peritoneal biopsies Pelvic lymphadenectomy Aortic lymphadenectomy Fertility preserving surgery (FPS) No Yes Operative time, min Median (range) Estimated blood loss, ml Median (range) Intraoperative transfusions No Yes Spillage/rupture of ovarian capsule No Yes Laparotomic conversion No Yes
150
150
p valuea
– b
n.a.
51 (3–181)
–
137 (91.3) 135 (90.0) 13 (8.7) 75 (50.0) 143 (95.3) 96 (64.0) 111 (74.0) 120 (80.0) 117 (78.0)
14 (9.3) 76 (50.7) 67 (40.7) 39 (26.0) 123 (82.0) 63 (42.0) 83 (55.3) 102 (68.0) 109 (72.7)
n.a.
142 (94.7) 8 (5.3)
110 (73.3) 40 (26.7)
0.0001
250 (60–525)
195 (48–453)
0.0001
200 (10–3000)
100 (20–800)
0.0008
146 (97.3) 4 (2.6)
150 (100) 0
0.0032
132 (88.0) 18 (12.0)
147 (98.0) 3 (2.0)c
0.0016
126 (84.0) 24 (16.0)
147 (98.0) 3 (2.0)
0.0001
n.a. = not applicable. a Calculated by Wilcoxon rank sum non-parametric test or Fisher's exact test for proportion. b Time interval from initial diagnosis of ESOM and delayed laparoscopic staging; the longest time interval (181 days) was reported in a patients who initially refused restaging procedures. c This rate was calculated in all cases of Group 2, thus including also cases who had no tumor left at first surgery.
As far as intraoperative details are concerned, operative time was significantly longer in Group 1 compared to Group 2 (p value = 0.0001); also the amount of EBL was higher in patients submitted to initial staging versus restaging (p value = 0.008). Intraoperative transfusion was required in 4 cases of Group 1, while there was no need in Group 2 (p value = 0.0032). Rate of spillage/rupture of ovarian capsule was higher in Group 1 versus Group 2 (12.0% versus 2.0%, p value = 0.0016); laparotomic conversion was documented in 16.0% of cases in Group 1 compared to only 2% of Group 2 patients (p value = 0.001). No port site metastases were documented. Length of hospital stay was significantly longer in Group 1 (median = 4 days, range 1–20) than in Group 2 (median = 3 days, range 1–30: p value = 0.0032). As shown in Table 3, intraoperative complications occurred in 6 patients of Group 1, and were represented by 4 vascular injuries (inferior vena cava, N = 3; lumbar vein, N = 1), and 2 medical morbidities. As far as Group 2 is concerned, we recorded 2 vascular lesions (common iliac vein, N = 1; epigastric vein, N = 1). All vascular complications were immediately managed and did not require laparotomic conversion. In Group 1, 16 patients experienced postoperative complications of which 6 were lymph-vascular (lymphorrhea, N = 4; deep venous thromboembolism, N = 2). In Group 2, 17 patients experienced postoperative morbidities for a total number of 23 complications of which 8 were lymph-vascular ones. Table 4 summarized the main histopathologic data: serous tumors appeared more frequently reported in Group 1 versus Group 2, while endometrioid and mucinous histotypes were diagnosed less frequently in Group 1 versus Group 2; nonetheless, the low number of some histotypes did not allow carrying out reliable comparisons. On the other hand, poorly differentiated tumors were found more frequently in Group 1 compared to Group 2 (57.8% versus 35.4%, p value = 0.0007). Upstaging was defined as definitive staging higher than FIGO stage IIA (without uterus involvement): according to this definition, the rate of upstaging was 24.9% in Group 1 versus 7.4% in Group 2
Table 3 Intraoperative and postoperative complications. Variable
surgery, while 35 had undergone ≥ 2 previous surgeries; 54 patients (18.0%) referred a history of pelvic endometriosis. Patients submitted to delayed laparoscopic staging of ESOM were younger than patients undergoing primary laparoscopic staging (p value = 0.0002), and more frequently premenopausal (p value = 0.0001). History of pelvic endometriosis was more frequently reported in Group 2 than in Group 1 (p value = 0.0009). Considering that major differences characterized Group 1 versus Group 2, subsequent analyses were performed in each of them, and comparisons were carried out. Table 2 summarizes details about surgical procedures employed in Group 2; in Group 2 median time interval from the initial diagnosis and delayed staging was 51 days (range = 3–181). Patients of Group 1 were more frequently submitted to bilateral salpingo-oophorectomy and hysterectomy, thus leading to a lower rate of FPS compared to Group 2 (5.3% versus 26.7%, p value = 0.0001). Also omental and peritoneal assessments were more frequent in Group 1 versus Group 2. In the whole series, pelvic and/or aortic lymph node staging was performed in 250 patients (83.3%). In particular, pelvic lymphadenectomy was performed in 80.0% of cases in Group 1 versus 68.0% in Group 2: median number of lymph nodes removed was 20 (range: 2–44) in Group 1 versus 9 (range 2–41) in Group 2, p value = 0.0001. Aortic lymphadenectomy was performed in 78.0% of cases in Group 1 versus 72.7% in Group 2: median number of lymph nodes removed was 10 (range: 2–50) in Group 1 versus 12 (range: 1–39) in Group 2 (p value = 0.81). Overall, 266 patients (88.7%) underwent full staging.
Group 1 (Immediate staging) N. (%)
All cases 150 Intraoperative complications No 144 (96.0) Yes 6 (4.0) Type of intraoperative complications Inferior vena cava vein lesion 3 Lumbar vein lesion 1 Common iliac vein lesion – Epigastric vein lesion – Atrial fibrillation 1 Hypercapnia 1 Postoperative complications No 112 (87.7) Yes 16 (12.3) Not specified 20 Type of postoperative complications Lymphorrhea 4 DVT (#xternal iliac vein) 2 Infections 6 Ureteral stenosis 1 Ileus 1 Pulmonary edema 1 Hydrothorax 1 Gastrointestinal lesion – Vaginal cuff dehiscence – Bladder fistula – Hydronephrosis –
Group 2 (Delayed staging) N. (%)
p value
150 147 (98.0) 2 (1.3)
0.23
– – 1 1 – –
n.a.
116 (87.2) 17 (12.8) 17
0.69
8 – 6 – 3 – – 1 3 1 1
n.a.
DVT = deep venous thromboembolism; n.a. = not applicable.
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434 Table 4 Histopathologic data. Variable
Group 1 (Immediate staging) N. (%)
Group 2 (Delayed staging) N. (%)
All cases Hystology Serous Endometrioid Clear cell Mucinous Other epithelial Stromal tumors Germ cell tumors Grading G1 G2 G3 n.a. Definitive FIGO stage IA IB IC IIA IIB IIC IIIA IIIB IIIC Cases upstaged sites of occult disease Peritoneal surfaces Lymph nodes
150
150
68 (45.3) 35 (23.3) 13 (8.7) 7 (4.5) 13 (8.7) 9 (6.0) 5 (3.3)
33 (22.0) 49 (32.7) 20 (13.3) 18 (12.0) 5 (3.3) 21 (14.0) 4 (2.7)
0.06b
14 (10.4) 43 (31.8) 78 (57.8) 15
35 (31.0) 38 (33.6) 40 (35.4) 37
0.0007c
40 (26.7) 7 (4.7) 57 (38.0) 8 (6.0) 3 (2.0) 4 (2.7) 11 (7.3) 5 (2.7) 15 (10.0) 37 (24.9)
81 (54.0) 4 (2.7) 49 (32.7) 5 (3.3) 3 (2.0) 1 (0.7) 0 0 7 (4.7) 11 (7.4)
22 (59.4) 15 (40.6)
4 (36.4) 7 (63.6)
a b c d
p valuea
0.0001d
0.15
Calculated by Fisher's exact test for proportion. p value of X2 test not accurate because of the low number of cases in some subgroups. Calculated after grouping G1–G2 versus G3 tumors. Calculated after grouping Stage IA–IIA versus Stage IIB–IIIC.
(p value = 0.001). In Group 1, upstaging was due to peritoneal involvement in 22 out of 37 cases (59.4%), and to lymph node involvement in 15 cases (40.6%) including 7 cases with positive pelvic lymph nodes only, 7 cases with positive aortic lymph nodes only, and 1 case with both pelvic and aortic lymph node involvement. In Group 2, upstaging was due to peritoneal involvement in 4 cases (36.4%), and to lymph node involvement in 7 cases (63.6%) including 2 cases with positive pelvic lymph nodes only, 4 cases with positive aortic lymph nodes only, and 1 case with both pelvic and aortic lymph node involvement. Moreover, Table 5 shows that in the whole series the proportion of cases who resulted upstaged at definitive diagnosis was higher in poorly differentiated tumors compared to well, moderately differentiated ones (G3 = 27.1% versus G2 = 12.3% and G1 = 10.2%; p value = 0.0030). Overall, 224 patients were considered as requiring adjuvant treatment which was mainly represented by carboplatin/paclitaxel combination (N = 155, 69.2%). Adjuvant chemotherapy was administered to a significantly higher fraction of Group 1 versus Group 2 patients (87.2% versus 63.5%, respectively; p value = 0.0001).
Table 5 Distribution of cases with definitive FIGO staging up to stage IIA or higher than Stage IIA disease. Variable Grade 1 2 3
Stage IA–IIA N. (%)
Stage IIB–IIIC N. (%)
44 (89.8) 71 (87.7) 86 (72.9)
5 (10.2) 10 (12.3) 32 (27.1)
p valuea –
G1–G2 versus G3 tumors. a Calculated by Fisher's exact test for proportion after grouping.
0.0030
431
As of April 2014, median duration of follow-up was 24 months (range = 3–145): recurrence and death of disease were documented in 25 (8.3%), and 10 patients (3.3%%), respectively. The 3-year DFS and OS rates were 85.1%, and 93.6%, respectively in the whole series (Fig. 1A); considering only epithelial ovarian cancer patients, the 3year DFS and OS rates were 85.8%, and 95.2%, respectively (Fig. 1B). There was no difference between Group 1 and Group 2 in terms of DFS (p value = 0.39), and OS (p value = 0.27) (data not shown). Upstaged patients were reported to have a statistically significant lower PFS then the non-upstaged ones (p value = 0.0335). Table 6 summarizes the main clinical and pathological features of patients developing relapse of disease: 7 patients developed isolated pelvic recurrence, while isolated lung and liver recurrences were recorded in 2 and 1 cases, respectively. Isolated lymph node recurrence was documented in 3 cases, while carcinomatosis only, and mixed sites of disease were observed in 3 and 7 patients, respectively. Two out of 6 patients who had been treated with FPS developed relapse in the contra-lateral ovary. As far as patients undergoing FPS are concerned (N = 48), upstaging at definitive pathology was documented in 3 (6.2%) patients (stage IIB = 2 cases, stage IIIC = 1 case due to lymph node disease). Thirty cases had epithelial ovarian carcinoma, while 7 and 3 patients had stromal and germ cell tumors. Poor grade of differentiation was documented in 29.6% of cases. Adjuvant treatment was administered to 50% of patients; at time of analysis, relapse of disease was documented in 6 patients (15.0%); death of disease was recorded in 2 cases (5.0%). Data about obstetrical outcome was available in 24 cases: 5 patients (20.8%) conceived, and delivered 6 babies. Discussion The wider and wider diffusion of laparoscopic surgery, supported by improvement of technology, has revolutionized surgical management of gynecologic cancer patients in the last decades due to the well recognized advantages of minimally invasive surgery in terms of reduction of morbidities and postoperative time to recover. However, contrary to what documented for uterine and cervical tumors, the routine use of laparoscopic approach to ovarian malignancies seems far to be accomplished, despite the encouraging results of the literature, which otherwise is represented by few prospective, observational studies and relatively small retrospective series [13–27]. In this context, to our knowledge, this is the largest multi-institutional, retrospective study investigating feasibility and outcome of laparoscopic staging of ESOM. Due to the large size of this series, separate analysis of patients undergoing immediate laparoscopic staging or delayed laparoscopic staging was also possible. Indeed, major differences in terms of clinico-pathological parameters as well as type and outcome of surgery were seen between the 2 groups; therefore, our findings can provide useful information about performances of laparoscopic management of ESOM in these two clinical settings, which have been always analyzed altogether in previous studies despite the proportion of patients undergoing delayed laparoscopic staging accounted for 20.8% up to 100% of the whole series [21,25,27,31,34,35]. In our study, patients with delayed staging were more often younger and premenopausal, and these clinical features could likely have led to more frequently postpone staging surgery until definitive histology would become available, in order to plan proper counseling about the risk/benefit ratio of FPS. Indeed, cases presumed to bear just benign adnexal lesions on the basis of imaging findings, or history of endometriosis are often laparoscopically managed in centers lacking or not routinely using frozen section analysis, and are often referred to Gynecologic Oncology Units only after ESOM diagnosis. Besides the differences of clinical conditions, patients undergoing immediate laparoscopic staging were undoubtedly characterized by a higher frequency of adverse pathologic features, such as poor grade of differentiation. In this context, the higher rates of both comprehensive staging procedures and laparotomic conversion might be
432
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
Table 6 Clinical and pathological features of relapsing patients. N.
Group
FIGO stage
G
Histotype
Surgery
Adjuvant therapy
Time to recurrence (months)
Relapse
Death
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
IIIC IIIA IIIB IIIC IC IC IA IC IA IA IIIA IC IA IC IC
2 3 3 3 n.s. 3 3 3. 3 n.s 3 2 3 3 1
Mucinous Serous Serous Serous Granulosa Other epithelial Endometrioid Endometrioid Serous Serous Other epithelial Squamous MMMT Clear cell Small cell
nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS FPS
11 32 41 9 33 32 14 51 33 23 11 4 12 18 17
Pelvis Pelvis Mixed Lymph nodes Pelvis Peritoneal Mixed Mixed Liver Mixed Peritoneal Lymph nodes Peritoneal Pelvis Mixed
Yes No No No No No No No Yes Yes Yes Yes Yes No Yes
16 17 18 19 20 21 22 23 24 25
1 1 2 2 2 2 2 2 2 2
IC IC IIIC IA IA IC IIB IIIC IA IC
2 3 2 n.s 2 2 3 2 3 2
Mucinous Serous Serous Serous Endometrioid Endometrioid Serous Clear cell Mucinous Serous
nFPS nFPS nFPS nFPS FPS FPS FPS nFPS FPS FPS
Carbo/PTX Carbo/PTX Carbo/PTX Carbo/PTX CDDP/B/VP16 Carbo/PTX Carbo/PTX Carbo/PTX Carbo Carbo Carbo/PTX Carbo CDDP/IFO Adriamycin Carbo/PTX IFO/Carbo VP16 Carbo/PTX Carbo/PTX Carbo/PTX Carbo Carbo Carbo/PTX Carbo/PTX Carbo/PTX Carbo/PLD Carbo/PTX
32 50 28 8 6 8 9 15 15 59
Lymph nodes Mixed Lung Sigma Pelvis Ovary Ovary Lung Pelvis Mixed
No Yes No No Yes No No Yes No No
n.s.: not specified; Group 1: Immediate staging; Group 2: Delayed staging; FPS: fertility preserving surgery; nFPS; not fertility preserving surgery; Carbo = carboplatin; PTX = paclitaxel; CDDP = cisplatin; B = bleomycin; VP16 = etoposide; IFO = ifosfamide; PLD = pegylated liposomal doxorubicin; MMMT = Malignant Mixed Mullerian Tumor.
likely dictated by concerns about risk of leaving sites of peritoneal and/or lymph node disease as unidentified. Indeed, while the rate of upstaging was 16.0% in the whole series, a figure in line with those reported in previous studies employing laparoscopic as well as open surgical approach [19,20,31,35], the rate of upstaging was N3-fold higher in Group 1 compared to Group 2. This difference is more likely to be sustained by the intrinsic biologic and morphological features of tumor aggressiveness between the two groups rather than to the completeness of staging, although we cannot exclude that it could have contributed to reveal a certain number of cases with occult disease [31]. In fact, it is interesting to note that rate of upstaging was higher in patients with poorly differentiated versus
Grade 1–2 tumors; moreover, occult peritoneal disease contributed to almost 60% of upstaging in Group 1, but accounted for only 36.4% of upstaging in Group 2. With the limits inherent in our retrospective, though very large series, it is conceivable that patients accurately studied at preoperative workup, who are shown to bear Grade 1–2 tumors, might be very safely managed through laparoscopy staging taking into great account retroperitoneal assessment, especially at aortic level [36]. In this context, it has to be highlighted that 75% of patients in our series underwent pelvic as well as aortic lymphadenectomy, and that the extent of aortic lymph node yield was comparable to those reported in the literature [17,19,21,34]. Despite that, the rate and profile of intraoperative and postoperative
%
%
A
100
B
100
80
80
DFS 60
OS
DFS 60
OS
40
40
20
20
Relapse N=25 Death
Relapse N=21 Death
N=10
0
N= 7
0 0
20
40
Months
60
80
0
20
40
60
80
Months
Fig. 1. Kaplan and Meier curves for DFS and OS in the whole series (A), and in the group of epithelial ovarian cancer patients (B).
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
complications did not differ compared to previous studies [19,25,27], although the limits inherent in the risk of underreporting, especially for late morbidities and for certain types of sequelae cannot be underestimated. As far as clinical outcome is concerned, we reported a recurrence rate of 8.3%, which confirms in a large series the results provided both in retrospective as prospective studies [19,25,27], and suggests that there is a good possibility that laparoscopy and laparotomy could be comparable in terms of ESOM relapse rate, according to what postulated by Park et al. [31] on the basis of metaanalysis of pertinent data. Also, the 3-year DFS and OS rates in our series were comparable to those reported in the literature dealing with both laparoscopic and open surgical management of ESOM [31,35,37]. Although no difference was found in survival figures between patients undergoing immediate versus delayed staging, these results should be taken with great caution considering the relatively short follow-up. This issue becomes even more relevant considering the higher request of FPS for apparent ESOM in young women who have not yet started or completed their reproductive program; in fact, FPS necessarily implies incomplete staging, thus possibly translating into a higher risk of disease recurrence. Indeed, in our group of 48 patients undergoing laparoscopic FPS, rates of recurrence and death of disease were 15% and 5%, respectively; these figures appear similar to those obtained from an extensive review on FPS in young women with apparent early stage ovarian cancer [38], and patients submitted to radical surgery [39]. In this context, the advantages provided by minimally invasive surgery in terms of higher chances of reducing adhesions, pelvic inflammation and functional anomalies potentially impairing fertility are of utmost importance in this delicate subset of patients. Our data on obstetrical outcome did not allow expressing the rate of pregnancy according to the number of patients attempting to conceive; however, we reported a rate of pregnancy around 20% which is comparable to that reported by Nam et al. [38]. In conclusion, thanks to the successful cooperative efforts of multiple referral Gynecologic Oncology Units across the country, we confirmed in a very large series that laparoscopic staging of ESOM is feasible and safe, and provides survival outcomes comparable to those obtained with open surgical approach [31]. Different clinical and pathological features have been shown to distinguish patients undergoing immediate versus delayed laparoscopic staging, and this could be useful in order to plan the extent of comprehensive staging according to risk of upstaging. Finally, adequate preoperative work up and availability of a dedicated Gynecologic Oncology Pathology Unit play a major role in the selection of patients with apparent ESOM who can be more safely offered laparoscopic comprehensive staging. Even though a prospective, randomized study comparing clinical outcome of laparoscopic versus laparotomic staging of ESOM is far from being accomplished, several efforts should be made to provide good scientific evidence helping to reliably quantify through meta-analytic approaches the risks and benefits of laparoscopy for adequate management of ESOM [40]. Conflict of interest statement The authors declare that they have no conflicts of interest.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Laparoscopic staging of apparent early stage ovarian cancer: Results of a large, retrospective, multi-institutional series V. Gallotta a,⁎, F. Ghezzi b, E. Vizza c, V. Chiantera d, M. Ceccaroni e, M. Franchi f, A. Fagotti g, A. Ercoli h, F. Fanfani a, C. Parrino a, S. Uccella b, G. Corrado c, G. Scambia a, G. Ferrandina a a
Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy Department of Oncological Surgery, Gynecologic Oncologic Unit, “Regina Elena” National Cancer Institute, Rome, Italy d Gynecologic Oncology Unit, Fondazione “Giovanni Paolo II”, Campobasso, Italy e Department of Obstetrics and Gynecology, Gynecologic Oncology and Minimally-Invasive Pelvic Surgery, Sacred Heart Hospital, Negrar, Verona, Italy f Department of Obstetrics and Gynecology, University of Verona, Verona, Italy g Division of Minimally Invasive Gynecologic Surgery, Department of Surgery, St Maria Hospital–University of Perugia, Terni, Italy h Policlinic of Abano Terme, Padova, Italy b c
H I G H L I G H T S • Stage of disease is still the most important prognostic factor in early ovarian cancer. • Among early ovarian cancer patients there is a non-negligible percentage of upstaged patients. • A complete and accurate surgical staging can be safely achieved through laparoscopic surgery, when performed in referral centers.
a r t i c l e
i n f o
Article history: Received 12 August 2014 Accepted 6 September 2014 Available online 16 September 2014 Keywords: Ovarian cancer Early ovarian cancer Laparoscopy
a b s t r a c t Objective. The aim of this study is to analyze the safety, adequacy, perioperative and survival figures in a large series of laparoscopic staging of patients with apparent early stage ovarian malignancies (ESOM). Patients and methods. Retrospective data from seven gynecologic oncology service databases were searched for ESOM patients undergoing immediate laparoscopic staging or delayed laparoscopic staging after an incidental diagnosis of ESOM. Between May 2000 and February 2014, 300 patients were selected: 150 had been submitted to immediate laparoscopic staging (Group 1), while 150 had undergone delayed laparoscopic staging (Group 2) of ESOM. All surgical, pathologic, and oncologic outcome data were analyzed in each group and a comparison between the two was carried out. Results. Longer operative time, higher blood loss, more frequently spillage/rupture of ovarian capsule and conversion to laparotomy occurred in Group 1. No significant differences of post-operative complications were observed between the two groups. Histological data revealed more frequently serous tumors (0.06), Grade 3 (p = 0.0007) and final up-staging (p = 0.001) in Group 1. Recurrence and death of disease were documented in 25 (8.3%), and 10 patients (3.3%%), respectively. The 3-year disease free survival (DFS) and overall survival (OS) rates were 85.1%, and 93.6%, respectively in the whole series. There was no difference between Group 1 and Group 2 in terms of DFS (p value = 0.39) and OS (p value = 0.27). Conclusion. In this very large multi-institutional study, it appears that patients with apparent ESOM can safely undergo laparoscopic surgical management. © 2014 Elsevier Inc. All rights reserved.
Introduction
⁎ Corresponding author at: Dept. of Obstetrics and Gynecologic, Catholic University, L.go A. Gemelli, 8, 00168 Rome, Italy. Fax: +39 0635508736. E-mail address: [email protected] (V. Gallotta).
http://dx.doi.org/10.1016/j.ygyno.2014.09.006 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Ovarian cancer accounts for one quarter of malignancies of the female genital tract, but represents the fifth most common cause of cancer death in women [1]. Only 20–25% of patients are diagnosed at early stage disease at diagnosis, a condition associated with a significantly improved survival rate [1]. However, as reported by previous studies,
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
almost 30% of apparent early stage ovarian cancer patients are upstaged due to peritoneal or lymph node involvement [2–6]. In this context, accurate evaluation of spread of disease through surgical staging is critical to ensure appropriate treatment and optimal survival [7–11]. Traditional approach for staging of apparent early stage ovarian cancer includes laparotomy with an extended midline incision that exposes the whole peritoneal cavity; according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines, optimal procedures include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies as well as pelvic and aortic lymph node dissection [12]. In the last decade many investigators have assessed feasibility and adequacy of laparoscopic staging of apparent early stage ovarian malignancies (ESOM), thus advocating the use of minimally invasive approaches in accurately selected patients [13–27]. Most retrospective series report survival rates around 90%, which are in the range observed in patients conventionally staged by laparotomy [26]; however, minimally invasive surgical techniques are not routinely performed in early stage ovarian tumors, perhaps because of persisting doubts about adequacy of these procedures in the identification of occult metastatic disease. In particular, the following criticisms have been raised: inadequate exploration of abdominal cavity, lower lymph node yield, possible risk of port site metastases, risk of tumor cell spread due to abdominal CO2 pressure, risk of intraoperative mass rupture, and lack of tactile sensation [28,29]. While the need to design a prospective, randomized study assessing staging performance and oncologic outcome of laparoscopic management of ESOM has been reiterated in the Cochrane analysis [30], such a study is expected to be hardly realized considering both the rarity of early stage ovarian tumors and the high level of skillfulness required for laparoscopic comprehensive staging. Moreover, most of the retrospective studies included in a recent metaanalysis refer to a relatively small series [31], thus limiting the possibility to reliably compare different subgroups. In this context, a retrospective, multicenter study has been launched within referral Gynecologic Oncology Units in Italy with the aim to analyze perioperative and survival figures in a large series of patients with laparoscopically staged apparent ESOM. Patients and methods This is a retrospective, multi-institutional study conducted in patients with apparent ESOM managed by a laparoscopic approach in 7 referral Gynecologic Oncology Units: Catholic University of the Sacred Heart in Rome, University of Insubria in Varese, “Regina Elena” National Cancer Institute in Rome, Fondazione “Giovanni Paolo II” in Campobasso, Sacred Heart Hospital in Negrar, Verona, University of Verona and Policlinico of Abano Terme, Padova. Data were collected from patients with imaging and/or intraoperative findings suggestive of disease involving only one or both ovaries, and/or Fallopian tubes, who underwent comprehensive immediate laparoscopic staging at time of primary diagnosis or delayed laparoscopic staging after an incidental diagnosis of ovarian malignancy. All histologic subtypes of the malignant ovarian tumors (epithelial, stromal and germ cell tumors) were included in the data search and collection. Cases with borderline tumors were excluded. Patients were staged according to FIGO criteria [12], using macroscopic findings, as well as cytologic and histological results of specimens obtained at immediate or delayed laparoscopic staging. Laparoscopic staging procedures had to be performed by surgeons with extensive training in gynecologic oncology and minimally invasive surgery. All tissue specimens were required to be analyzed by a dedicated Gynecologic Oncology pathologist. The following data were planned to be collected: clinical characteristics (age, menopausal status, body mass index — BMI, history of endometriosis), number of previous abdominal surgeries, type of surgical procedures at staging, conversion to laparotomy as well as operative time, length of hospital stay, estimated blood loss — EBL, and transfusion
429
requirement. Intraoperative mass rupture was defined as any rupture, intentional or unintentional, that resulted in the release of cystic content into the peritoneal cavity. If a mass was drained intentionally within a collection bag to facilitate removal without resulting in peritoneal spill, the mass was not considered ruptured. Data about fertility preserving surgery (FPS) were registered as well as intraoperative and postoperative complications. Details about the administration of adjuvant treatment, obstetric outcome, and survival outcome have been collected. Statistical analysis The χ2 test or Fisher's exact test for proportion was used to analyze the distribution of clinico-pathological variables according to different subgroups. Wilcoxon rank sum non-parametric test was used to analyze the distribution of continuous values. Disease-free survival (DFS) was calculated from the date of surgery to the date of relapse or the date of the last follow-up; overall survival (OS) was calculated from the date of diagnosis to the date of death or the date of the last follow-up. Medians and life tables were computed using the product limit estimate by the Kaplan–Meier method [32], and the log-rank test was used to assess the statistical significance among groups [33]. Statistical analysis was carried out using SOLO (BMDP Statistical Software, Los Angeles, CA, USA). Results Between May 2000 and February 2014, 300 patients with apparent ESOM according to the predefined criteria underwent laparoscopic staging according to FIGO guidelines. In particular, 150 patients were submitted to immediate laparoscopic staging at initial diagnosis (Group 1), while 150 patients underwent delayed laparoscopic staging after an incidental diagnosis of ESOM. Clinical characteristics of patients in the whole series and in the 2 groups are summarized in Table 1. Overall, median age was 49 years (range = 11-81), and median BMI was 22.8 (range = 16.6-49.9). At time of surgery, 148 out of 296 patients were postmenopausal; 135 patients (45%) had been already submitted to at least 1 abdominal
Table 1 Patient characteristics. Variable
Whole series N. (%)
All cases 300 Age, years Median 49 (11–81) (range) BMI, kg/m2 Median 22.8 (16.6– (range) 49.9) Menopause No 148 Yes 148 not specified. 4 Previous abdominal surgery None 165 1 100 2 25 3 5 4 5 History of endometriosis No 246 Yes 54
Group 1 Immediate staging N. (%)
Group 2 Delayed staging N (%)
p valuea
150
150
–
53 (13–81)
45 (11–73)
0.0002
23.4 (17.0–39.0)
22.8 (17.0– 49.9)
n.s.
59 (39.9) 87 (58.8) 4
89 (60.1) 61 (41.2)
80 (48.5) 50 (50.0) 16 (64.0) 2 (40.0) 2 (40.0)
85 (51.5) 50 (50.0) 9 (36.0) 3 (60.0) 3 (60.0)
n.s.
134 (54.5) 16 (29.6)
112 (45.5) 38 (70.4)
0.0009
0.0001
n.s. = not significant. a Calculated by Wilcoxon rank sum non-parametric test or Fisher's exact test for proportion.
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V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
Table 2 Surgical procedures and intraoperative details. Variable
Group 1 (Immediate staging) N. (%)
Group 2 (Delayed staging) N. (%)
All cases Time interval to laparoscopic staging (days) Median (range) Surgical procedures at staging laparoscopy Bilateral salpingo-oophorectomy Hysterectomy Unilateral salpingo-oophorectomy Appendectomy Omentectomy Peritoneal washing Peritoneal biopsies Pelvic lymphadenectomy Aortic lymphadenectomy Fertility preserving surgery (FPS) No Yes Operative time, min Median (range) Estimated blood loss, ml Median (range) Intraoperative transfusions No Yes Spillage/rupture of ovarian capsule No Yes Laparotomic conversion No Yes
150
150
p valuea
– b
n.a.
51 (3–181)
–
137 (91.3) 135 (90.0) 13 (8.7) 75 (50.0) 143 (95.3) 96 (64.0) 111 (74.0) 120 (80.0) 117 (78.0)
14 (9.3) 76 (50.7) 67 (40.7) 39 (26.0) 123 (82.0) 63 (42.0) 83 (55.3) 102 (68.0) 109 (72.7)
n.a.
142 (94.7) 8 (5.3)
110 (73.3) 40 (26.7)
0.0001
250 (60–525)
195 (48–453)
0.0001
200 (10–3000)
100 (20–800)
0.0008
146 (97.3) 4 (2.6)
150 (100) 0
0.0032
132 (88.0) 18 (12.0)
147 (98.0) 3 (2.0)c
0.0016
126 (84.0) 24 (16.0)
147 (98.0) 3 (2.0)
0.0001
n.a. = not applicable. a Calculated by Wilcoxon rank sum non-parametric test or Fisher's exact test for proportion. b Time interval from initial diagnosis of ESOM and delayed laparoscopic staging; the longest time interval (181 days) was reported in a patients who initially refused restaging procedures. c This rate was calculated in all cases of Group 2, thus including also cases who had no tumor left at first surgery.
As far as intraoperative details are concerned, operative time was significantly longer in Group 1 compared to Group 2 (p value = 0.0001); also the amount of EBL was higher in patients submitted to initial staging versus restaging (p value = 0.008). Intraoperative transfusion was required in 4 cases of Group 1, while there was no need in Group 2 (p value = 0.0032). Rate of spillage/rupture of ovarian capsule was higher in Group 1 versus Group 2 (12.0% versus 2.0%, p value = 0.0016); laparotomic conversion was documented in 16.0% of cases in Group 1 compared to only 2% of Group 2 patients (p value = 0.001). No port site metastases were documented. Length of hospital stay was significantly longer in Group 1 (median = 4 days, range 1–20) than in Group 2 (median = 3 days, range 1–30: p value = 0.0032). As shown in Table 3, intraoperative complications occurred in 6 patients of Group 1, and were represented by 4 vascular injuries (inferior vena cava, N = 3; lumbar vein, N = 1), and 2 medical morbidities. As far as Group 2 is concerned, we recorded 2 vascular lesions (common iliac vein, N = 1; epigastric vein, N = 1). All vascular complications were immediately managed and did not require laparotomic conversion. In Group 1, 16 patients experienced postoperative complications of which 6 were lymph-vascular (lymphorrhea, N = 4; deep venous thromboembolism, N = 2). In Group 2, 17 patients experienced postoperative morbidities for a total number of 23 complications of which 8 were lymph-vascular ones. Table 4 summarized the main histopathologic data: serous tumors appeared more frequently reported in Group 1 versus Group 2, while endometrioid and mucinous histotypes were diagnosed less frequently in Group 1 versus Group 2; nonetheless, the low number of some histotypes did not allow carrying out reliable comparisons. On the other hand, poorly differentiated tumors were found more frequently in Group 1 compared to Group 2 (57.8% versus 35.4%, p value = 0.0007). Upstaging was defined as definitive staging higher than FIGO stage IIA (without uterus involvement): according to this definition, the rate of upstaging was 24.9% in Group 1 versus 7.4% in Group 2
Table 3 Intraoperative and postoperative complications. Variable
surgery, while 35 had undergone ≥ 2 previous surgeries; 54 patients (18.0%) referred a history of pelvic endometriosis. Patients submitted to delayed laparoscopic staging of ESOM were younger than patients undergoing primary laparoscopic staging (p value = 0.0002), and more frequently premenopausal (p value = 0.0001). History of pelvic endometriosis was more frequently reported in Group 2 than in Group 1 (p value = 0.0009). Considering that major differences characterized Group 1 versus Group 2, subsequent analyses were performed in each of them, and comparisons were carried out. Table 2 summarizes details about surgical procedures employed in Group 2; in Group 2 median time interval from the initial diagnosis and delayed staging was 51 days (range = 3–181). Patients of Group 1 were more frequently submitted to bilateral salpingo-oophorectomy and hysterectomy, thus leading to a lower rate of FPS compared to Group 2 (5.3% versus 26.7%, p value = 0.0001). Also omental and peritoneal assessments were more frequent in Group 1 versus Group 2. In the whole series, pelvic and/or aortic lymph node staging was performed in 250 patients (83.3%). In particular, pelvic lymphadenectomy was performed in 80.0% of cases in Group 1 versus 68.0% in Group 2: median number of lymph nodes removed was 20 (range: 2–44) in Group 1 versus 9 (range 2–41) in Group 2, p value = 0.0001. Aortic lymphadenectomy was performed in 78.0% of cases in Group 1 versus 72.7% in Group 2: median number of lymph nodes removed was 10 (range: 2–50) in Group 1 versus 12 (range: 1–39) in Group 2 (p value = 0.81). Overall, 266 patients (88.7%) underwent full staging.
Group 1 (Immediate staging) N. (%)
All cases 150 Intraoperative complications No 144 (96.0) Yes 6 (4.0) Type of intraoperative complications Inferior vena cava vein lesion 3 Lumbar vein lesion 1 Common iliac vein lesion – Epigastric vein lesion – Atrial fibrillation 1 Hypercapnia 1 Postoperative complications No 112 (87.7) Yes 16 (12.3) Not specified 20 Type of postoperative complications Lymphorrhea 4 DVT (#xternal iliac vein) 2 Infections 6 Ureteral stenosis 1 Ileus 1 Pulmonary edema 1 Hydrothorax 1 Gastrointestinal lesion – Vaginal cuff dehiscence – Bladder fistula – Hydronephrosis –
Group 2 (Delayed staging) N. (%)
p value
150 147 (98.0) 2 (1.3)
0.23
– – 1 1 – –
n.a.
116 (87.2) 17 (12.8) 17
0.69
8 – 6 – 3 – – 1 3 1 1
n.a.
DVT = deep venous thromboembolism; n.a. = not applicable.
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434 Table 4 Histopathologic data. Variable
Group 1 (Immediate staging) N. (%)
Group 2 (Delayed staging) N. (%)
All cases Hystology Serous Endometrioid Clear cell Mucinous Other epithelial Stromal tumors Germ cell tumors Grading G1 G2 G3 n.a. Definitive FIGO stage IA IB IC IIA IIB IIC IIIA IIIB IIIC Cases upstaged sites of occult disease Peritoneal surfaces Lymph nodes
150
150
68 (45.3) 35 (23.3) 13 (8.7) 7 (4.5) 13 (8.7) 9 (6.0) 5 (3.3)
33 (22.0) 49 (32.7) 20 (13.3) 18 (12.0) 5 (3.3) 21 (14.0) 4 (2.7)
0.06b
14 (10.4) 43 (31.8) 78 (57.8) 15
35 (31.0) 38 (33.6) 40 (35.4) 37
0.0007c
40 (26.7) 7 (4.7) 57 (38.0) 8 (6.0) 3 (2.0) 4 (2.7) 11 (7.3) 5 (2.7) 15 (10.0) 37 (24.9)
81 (54.0) 4 (2.7) 49 (32.7) 5 (3.3) 3 (2.0) 1 (0.7) 0 0 7 (4.7) 11 (7.4)
22 (59.4) 15 (40.6)
4 (36.4) 7 (63.6)
a b c d
p valuea
0.0001d
0.15
Calculated by Fisher's exact test for proportion. p value of X2 test not accurate because of the low number of cases in some subgroups. Calculated after grouping G1–G2 versus G3 tumors. Calculated after grouping Stage IA–IIA versus Stage IIB–IIIC.
(p value = 0.001). In Group 1, upstaging was due to peritoneal involvement in 22 out of 37 cases (59.4%), and to lymph node involvement in 15 cases (40.6%) including 7 cases with positive pelvic lymph nodes only, 7 cases with positive aortic lymph nodes only, and 1 case with both pelvic and aortic lymph node involvement. In Group 2, upstaging was due to peritoneal involvement in 4 cases (36.4%), and to lymph node involvement in 7 cases (63.6%) including 2 cases with positive pelvic lymph nodes only, 4 cases with positive aortic lymph nodes only, and 1 case with both pelvic and aortic lymph node involvement. Moreover, Table 5 shows that in the whole series the proportion of cases who resulted upstaged at definitive diagnosis was higher in poorly differentiated tumors compared to well, moderately differentiated ones (G3 = 27.1% versus G2 = 12.3% and G1 = 10.2%; p value = 0.0030). Overall, 224 patients were considered as requiring adjuvant treatment which was mainly represented by carboplatin/paclitaxel combination (N = 155, 69.2%). Adjuvant chemotherapy was administered to a significantly higher fraction of Group 1 versus Group 2 patients (87.2% versus 63.5%, respectively; p value = 0.0001).
Table 5 Distribution of cases with definitive FIGO staging up to stage IIA or higher than Stage IIA disease. Variable Grade 1 2 3
Stage IA–IIA N. (%)
Stage IIB–IIIC N. (%)
44 (89.8) 71 (87.7) 86 (72.9)
5 (10.2) 10 (12.3) 32 (27.1)
p valuea –
G1–G2 versus G3 tumors. a Calculated by Fisher's exact test for proportion after grouping.
0.0030
431
As of April 2014, median duration of follow-up was 24 months (range = 3–145): recurrence and death of disease were documented in 25 (8.3%), and 10 patients (3.3%%), respectively. The 3-year DFS and OS rates were 85.1%, and 93.6%, respectively in the whole series (Fig. 1A); considering only epithelial ovarian cancer patients, the 3year DFS and OS rates were 85.8%, and 95.2%, respectively (Fig. 1B). There was no difference between Group 1 and Group 2 in terms of DFS (p value = 0.39), and OS (p value = 0.27) (data not shown). Upstaged patients were reported to have a statistically significant lower PFS then the non-upstaged ones (p value = 0.0335). Table 6 summarizes the main clinical and pathological features of patients developing relapse of disease: 7 patients developed isolated pelvic recurrence, while isolated lung and liver recurrences were recorded in 2 and 1 cases, respectively. Isolated lymph node recurrence was documented in 3 cases, while carcinomatosis only, and mixed sites of disease were observed in 3 and 7 patients, respectively. Two out of 6 patients who had been treated with FPS developed relapse in the contra-lateral ovary. As far as patients undergoing FPS are concerned (N = 48), upstaging at definitive pathology was documented in 3 (6.2%) patients (stage IIB = 2 cases, stage IIIC = 1 case due to lymph node disease). Thirty cases had epithelial ovarian carcinoma, while 7 and 3 patients had stromal and germ cell tumors. Poor grade of differentiation was documented in 29.6% of cases. Adjuvant treatment was administered to 50% of patients; at time of analysis, relapse of disease was documented in 6 patients (15.0%); death of disease was recorded in 2 cases (5.0%). Data about obstetrical outcome was available in 24 cases: 5 patients (20.8%) conceived, and delivered 6 babies. Discussion The wider and wider diffusion of laparoscopic surgery, supported by improvement of technology, has revolutionized surgical management of gynecologic cancer patients in the last decades due to the well recognized advantages of minimally invasive surgery in terms of reduction of morbidities and postoperative time to recover. However, contrary to what documented for uterine and cervical tumors, the routine use of laparoscopic approach to ovarian malignancies seems far to be accomplished, despite the encouraging results of the literature, which otherwise is represented by few prospective, observational studies and relatively small retrospective series [13–27]. In this context, to our knowledge, this is the largest multi-institutional, retrospective study investigating feasibility and outcome of laparoscopic staging of ESOM. Due to the large size of this series, separate analysis of patients undergoing immediate laparoscopic staging or delayed laparoscopic staging was also possible. Indeed, major differences in terms of clinico-pathological parameters as well as type and outcome of surgery were seen between the 2 groups; therefore, our findings can provide useful information about performances of laparoscopic management of ESOM in these two clinical settings, which have been always analyzed altogether in previous studies despite the proportion of patients undergoing delayed laparoscopic staging accounted for 20.8% up to 100% of the whole series [21,25,27,31,34,35]. In our study, patients with delayed staging were more often younger and premenopausal, and these clinical features could likely have led to more frequently postpone staging surgery until definitive histology would become available, in order to plan proper counseling about the risk/benefit ratio of FPS. Indeed, cases presumed to bear just benign adnexal lesions on the basis of imaging findings, or history of endometriosis are often laparoscopically managed in centers lacking or not routinely using frozen section analysis, and are often referred to Gynecologic Oncology Units only after ESOM diagnosis. Besides the differences of clinical conditions, patients undergoing immediate laparoscopic staging were undoubtedly characterized by a higher frequency of adverse pathologic features, such as poor grade of differentiation. In this context, the higher rates of both comprehensive staging procedures and laparotomic conversion might be
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Table 6 Clinical and pathological features of relapsing patients. N.
Group
FIGO stage
G
Histotype
Surgery
Adjuvant therapy
Time to recurrence (months)
Relapse
Death
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
IIIC IIIA IIIB IIIC IC IC IA IC IA IA IIIA IC IA IC IC
2 3 3 3 n.s. 3 3 3. 3 n.s 3 2 3 3 1
Mucinous Serous Serous Serous Granulosa Other epithelial Endometrioid Endometrioid Serous Serous Other epithelial Squamous MMMT Clear cell Small cell
nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS nFPS FPS
11 32 41 9 33 32 14 51 33 23 11 4 12 18 17
Pelvis Pelvis Mixed Lymph nodes Pelvis Peritoneal Mixed Mixed Liver Mixed Peritoneal Lymph nodes Peritoneal Pelvis Mixed
Yes No No No No No No No Yes Yes Yes Yes Yes No Yes
16 17 18 19 20 21 22 23 24 25
1 1 2 2 2 2 2 2 2 2
IC IC IIIC IA IA IC IIB IIIC IA IC
2 3 2 n.s 2 2 3 2 3 2
Mucinous Serous Serous Serous Endometrioid Endometrioid Serous Clear cell Mucinous Serous
nFPS nFPS nFPS nFPS FPS FPS FPS nFPS FPS FPS
Carbo/PTX Carbo/PTX Carbo/PTX Carbo/PTX CDDP/B/VP16 Carbo/PTX Carbo/PTX Carbo/PTX Carbo Carbo Carbo/PTX Carbo CDDP/IFO Adriamycin Carbo/PTX IFO/Carbo VP16 Carbo/PTX Carbo/PTX Carbo/PTX Carbo Carbo Carbo/PTX Carbo/PTX Carbo/PTX Carbo/PLD Carbo/PTX
32 50 28 8 6 8 9 15 15 59
Lymph nodes Mixed Lung Sigma Pelvis Ovary Ovary Lung Pelvis Mixed
No Yes No No Yes No No Yes No No
n.s.: not specified; Group 1: Immediate staging; Group 2: Delayed staging; FPS: fertility preserving surgery; nFPS; not fertility preserving surgery; Carbo = carboplatin; PTX = paclitaxel; CDDP = cisplatin; B = bleomycin; VP16 = etoposide; IFO = ifosfamide; PLD = pegylated liposomal doxorubicin; MMMT = Malignant Mixed Mullerian Tumor.
likely dictated by concerns about risk of leaving sites of peritoneal and/or lymph node disease as unidentified. Indeed, while the rate of upstaging was 16.0% in the whole series, a figure in line with those reported in previous studies employing laparoscopic as well as open surgical approach [19,20,31,35], the rate of upstaging was N3-fold higher in Group 1 compared to Group 2. This difference is more likely to be sustained by the intrinsic biologic and morphological features of tumor aggressiveness between the two groups rather than to the completeness of staging, although we cannot exclude that it could have contributed to reveal a certain number of cases with occult disease [31]. In fact, it is interesting to note that rate of upstaging was higher in patients with poorly differentiated versus
Grade 1–2 tumors; moreover, occult peritoneal disease contributed to almost 60% of upstaging in Group 1, but accounted for only 36.4% of upstaging in Group 2. With the limits inherent in our retrospective, though very large series, it is conceivable that patients accurately studied at preoperative workup, who are shown to bear Grade 1–2 tumors, might be very safely managed through laparoscopy staging taking into great account retroperitoneal assessment, especially at aortic level [36]. In this context, it has to be highlighted that 75% of patients in our series underwent pelvic as well as aortic lymphadenectomy, and that the extent of aortic lymph node yield was comparable to those reported in the literature [17,19,21,34]. Despite that, the rate and profile of intraoperative and postoperative
%
%
A
100
B
100
80
80
DFS 60
OS
DFS 60
OS
40
40
20
20
Relapse N=25 Death
Relapse N=21 Death
N=10
0
N= 7
0 0
20
40
Months
60
80
0
20
40
60
80
Months
Fig. 1. Kaplan and Meier curves for DFS and OS in the whole series (A), and in the group of epithelial ovarian cancer patients (B).
V. Gallotta et al. / Gynecologic Oncology 135 (2014) 428–434
complications did not differ compared to previous studies [19,25,27], although the limits inherent in the risk of underreporting, especially for late morbidities and for certain types of sequelae cannot be underestimated. As far as clinical outcome is concerned, we reported a recurrence rate of 8.3%, which confirms in a large series the results provided both in retrospective as prospective studies [19,25,27], and suggests that there is a good possibility that laparoscopy and laparotomy could be comparable in terms of ESOM relapse rate, according to what postulated by Park et al. [31] on the basis of metaanalysis of pertinent data. Also, the 3-year DFS and OS rates in our series were comparable to those reported in the literature dealing with both laparoscopic and open surgical management of ESOM [31,35,37]. Although no difference was found in survival figures between patients undergoing immediate versus delayed staging, these results should be taken with great caution considering the relatively short follow-up. This issue becomes even more relevant considering the higher request of FPS for apparent ESOM in young women who have not yet started or completed their reproductive program; in fact, FPS necessarily implies incomplete staging, thus possibly translating into a higher risk of disease recurrence. Indeed, in our group of 48 patients undergoing laparoscopic FPS, rates of recurrence and death of disease were 15% and 5%, respectively; these figures appear similar to those obtained from an extensive review on FPS in young women with apparent early stage ovarian cancer [38], and patients submitted to radical surgery [39]. In this context, the advantages provided by minimally invasive surgery in terms of higher chances of reducing adhesions, pelvic inflammation and functional anomalies potentially impairing fertility are of utmost importance in this delicate subset of patients. Our data on obstetrical outcome did not allow expressing the rate of pregnancy according to the number of patients attempting to conceive; however, we reported a rate of pregnancy around 20% which is comparable to that reported by Nam et al. [38]. In conclusion, thanks to the successful cooperative efforts of multiple referral Gynecologic Oncology Units across the country, we confirmed in a very large series that laparoscopic staging of ESOM is feasible and safe, and provides survival outcomes comparable to those obtained with open surgical approach [31]. Different clinical and pathological features have been shown to distinguish patients undergoing immediate versus delayed laparoscopic staging, and this could be useful in order to plan the extent of comprehensive staging according to risk of upstaging. Finally, adequate preoperative work up and availability of a dedicated Gynecologic Oncology Pathology Unit play a major role in the selection of patients with apparent ESOM who can be more safely offered laparoscopic comprehensive staging. Even though a prospective, randomized study comparing clinical outcome of laparoscopic versus laparotomic staging of ESOM is far from being accomplished, several efforts should be made to provide good scientific evidence helping to reliably quantify through meta-analytic approaches the risks and benefits of laparoscopy for adequate management of ESOM [40]. Conflict of interest statement The authors declare that they have no conflicts of interest.
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