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Ann Surg Oncol (2012) 19:3522–3527 DOI 10.1245/s10434-012-2400-9 ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY Systematic Pelvic and Aortic Lymphadenectomy in Advanced Ovarian Cancer Patients at the Time of Interval Debulking Surgery: A Double-Institution Case–Control Study Anna Fagotti, MD, PhD1, Pierandrea De Iaco, MD2, Francesco Fanfani, MD1, Giuseppe Vizzielli, MD1, Federica Perelli, MD1, Federica Pozzati, MD2, Anna Myriam Perrone, MD2, Luigi Carlo Turco, MD1, and Giovanni Scambia, MD1 Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy; 2Gynecology and Reproductive Medicine Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 1 ABSTRACT Background. The prognostic role of systematic lymphadenectomy remains unclear in advanced ovarian cancer (AOC). Only few retrospective case series have investigated the percentage of lymph node metastases after neoadjuvant chemotherapy. This multi-institutional casecontrol study analyzed the prognostic role of systematic lymphadenectomy in AOC patients at the time of interval debulking surgery (IDS). Methods. From January 2005 to December 2010, the records of patients with AOC admitted to IDS at the Catholic University of Rome (n = 101, controls) and at the University of Bologna (n = 50, cases) were retrospectively analyzed. The cases, routinely submitted to systematic pelvic and aortic lymphadenectomy, were matched 1:2 with the controls, who did not routinely undergo lymphadenectomy. To correctly assess the prognostic role of lymphadenectomy, only patients with optimally debulked disease were included. Progression-free survival and overall survival were analyzed by a log-rank test. Results. After an overall mean follow-up of 36 months (95 % confidence interval 33–39), 35 and 63 recurrences (70.0 vs. 62.4 %; p = NS) and 15 and 24 deaths due to disease (30 vs. 23.7 %; p = NS) were observed in the case Electronic supplementary material The online version of this article (doi:10.1245/s10434-012-2400-9) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2012 First Received: 10 January 2012; Published Online: 30 May 2012 A. Fagotti, MD, PhD e-mail: [email protected] and controls, respectively. The 2-year progression-free survival rate was 36 versus 25 % (p = 0.834), and the 2-year overall survival rate was 69 versus 88 % (p = 0.777), in the case and controls, respectively. The median operating time was longer, and the percentage of patients requiring blood transfusions was higher in the cases than in the controls (225 vs. 210 min, p = 0.023, and 54 vs. 22.8 %, p = 0.0001, respectively). Conclusions. Lymphadenectomy at the time of IDS could be omitted, at least in high-risk patients. Primary debulking surgery, including pelvic and aortic lymphadenectomy, is the cornerstone of treatment of advanced ovarian cancer (AOC).1,2 However, a percentage of patients, which varies between 10 and 50 % according to different selection criteria and surgical attitudes adopted in the centers, still undergo neoadjuvant chemotherapy followed by interval debulking surgery (IDS).3–6 At the time of surgery, these women are submitted to a large assortment of procedures as a result of different clinicopathologic response to chemotherapy. In this context, the role of systematic lymphadenectomy may be discussed.7 Indeed, lymphatic spread has been reported to be a common feature in AOC. In particular, from 50 to 80 % of these patients have positive lymph node at diagnosis, mainly in the para-aortic and iliac areas (68 and 49 %, respectively).8 In patients with optimal intraabdominal debulking (residual tumor\1 cm) at the time of primary cytoreduction, systematic lymphadenectomy has been shown to improve progression-free survival (PFS) without any impact on overall survival (OS).2 In this context, the weight of postoperative complications and consequently quality of life should be considered. Lymphadenectomy at Interval Debulking Surgery At present, an international prospective randomized trial in AOC patients without intraperitoneal residual tumor at primary debulking is ongoing, exploring whether the addition of complete resection of retroperitoneal microscopic disease may theoretically achieve a truly absent microscopic disease status and lead to a survival advantage.9 However, although there is some evidence for the role of lymphadenectomy in up-front surgery, only few retrospective case series have described the rate of lymph node metastases (which varies from 37.5 to 75 %) after neoadjuvant chemotherapy.10–12 Moreover, the prognostic impact of such treatment has not yet been clarified.12 The present study was a case-control analysis that aimed to investigate the prognostic role of systematic lymphadenectomy in AOC patients at the time of IDS after neoadjuvant chemotherapy. We also evaluated the rate of surgical complications. 3523 TABLE 1 Patient characteristics Characteristic No. of all patients Age (years), median (range) Value, cases 50 Value, controls 101 63 (35–76) 62 (31–80) 0.607 Stage, n (%) 0.408 III 37 (74.0) 81 (80.2) IV 13 (26.0) 20 (19.8) Histotope, n (%)a Type I Type II No. of cycles of neoadjuvant chemotherapy, median (range) 0.194 3 (6.0) 47 (94.0) 2 (2.0) 99 (98.0) 6 (6–10) 4 (3–9) 41 (82.0) 79 (78.2) 9 (18.0) 22 (21.8) 49 (98.0) 96 (95.0) 1 (2.0) 5 (5.0) Clinical response (RECIST), n (%) Complete/partial Stable PATIENTS AND METHODS Stable From January 2005 to December 2010, the medical records of patients with AOC (International Federation of Gynecology and Obstetrics stage IIIC–IV disease) admitted to IDS at the Catholic University of Rome (control group) and the University of Bologna (case group) were retrospectively analyzed. All patients were submitted to three or more courses of neoadjuvant platinum-based chemotherapy. The median number of neoadjuvant cycles were different at the centers. However, the preoperatively assigned clinical response according to both radiologic Response Evaluation Criteria in Solid Tumors and serologic Gynecological Cancer InterGroup (GCIG) criteria were homogenous in both groups (Table 1).13,14 Only patients with complete, partial, or stable response were submitted to IDS. The extent of debulking surgery was classified as standard, radical, and supraradical, except for lymphadenectomy.15 All cases were submitted to systematic pelvic and aortic lymphadenectomy, whereas only bulky nodes were removed in the control group. At the end of surgery, the size and site of residual tumor were registered, and two or more cycles of chemotherapy were administered. In order to correctly assess the prognostic role of lymphadenectomy at IDS, only cases that experienced optimal residual tumor (B1 cm) after surgery were included in the analysis. Cases were considered those women submitted to systematic pelvic and aortic lymphadenectomy, as routinely performed at Bologna University. They were matched as closely as possible with a nearly double number of controls; control subjects did not routinely undergo lymphadenectomy at the Catholic University of the Sacred Heart in Rome. The whole count of pelvic and aortic lymph nodes removed as well as the number of bulky and metastatic nodes were registered. Operative time was calculated starting from the skin incision to the end of all surgical procedures. The decision 0.0001 0.588 Clinical response (GCIG), n (%) Complete/partial p 0.382 Bold value indicates statistically significant (p \ 0.05) RECIST Response Evaluation Criteria in Solid Tumors GCIG Gynecological Cancer InterGroup a According to Kurman and Shih17 of performing an autologous blood transfusion was made during or after surgery according to patient hemodynamic conditions and hemoglobin levels. Postoperative recovery was calculated starting from the first postoperative day to the day of hospital discharge. Classification of postoperative complications was made according to Dindo et al.16 Briefly, this classification categorizes the complications into five grades, as follows: grade 1 (minor events not requiring therapy), grade 2 (complications requiring medications only without invasive procedures), grade 3 (complications leading to lasting disability or organ resection), grade 4 (life-threatening complication requiring intensive care or treatment in the intensive care unit), and grade 5 (death due to complications). The incidence of lymphocele was also analyzed at follow-up by computed tomographic scan. Lymphadenectomy Pelvic lymphadenectomy dissection began at the origin of the external iliac vessels and continued caudally along the medial border of the psoas muscle, with the lower limit of the external iliac lymphadenectomy being represented by the deep inferior epigastric vessels. The lateral boundaries of lymphadenectomy were delineated superficially by the fascia covering the psoas muscle and deeply by the fascia covering the internal obturator and levator ani muscles. The medial margin of lymphadenectomy was represented by the 3524 A. Fagotti et al. umbilical artery. The clearing of the obturator space began with identification of obturator nerve and removal of the superficial obturator nodes. Lymph nodes along the external iliac vessels were removed en bloc with those adjacent to the common iliac vessels. Aortic lymphadenectomy dissection began at the aortic bifurcation by removing the superficial intercavoaortic, precaval, and preaortic nodal groups. Lymph nodes located lateral to the vena (i.e., paracaval nodal group) were separated from the vena cava, then removed en bloc. Lymph nodes behind the vena cava were removed if enlarged. Removal of the lateroaortic nodes was performed up to the level of the left renal vein. Statistical Analysis Univariate analysis was performed to verify any difference between the two groups. Univariate analysis included chisquare analysis or Fisher’s exact test when appropriate for categorical variables and the Student t test and Mann–Whitney test when appropriate for continuous variables. Survival time was measured from the day of histologic diagnosis to the date of recurrence (PFS) or death (OS). Mean and life tables were computed by the product-limit estimate by the Kaplan– Meier method and then analyzed by the log-rank test. All statistical tests were two sided, and differences were considered significant at p \ 0.05. Statistical analysis was performed by SPSS statistical software (SPSS, Chicago, IL). RESULTS Patient demographics are shown in Table 1. Preoperative clinical characteristics did not significantly differ TABLE 2 Operative and postoperative details between the groups. Patients presented to surgery with similar percentages of radiologic and serologic response in both groups, independently from the number of cycles of neoadjuvant chemotherapy. All women underwent IDS, achieving an optimal cytoreduction with macroscopically absent residual tumor in almost 80 % of the patients, at the price of supraradical surgical procedures in about a third of the case and control subjects (26 vs. 36.6 %; p = NS). The median number of lymph nodes removed was 38 in the cases and 4 in the controls (p = 0.0001). Rates of bulky nodes did not differ between the groups (12 vs. 8.9 % for case and controls, respectively, p = 0.550), as well as the rates of histologic confirmed positive nodes (14 of 50, 28 %, for cases vs. 3 of 9, 33.3 %, for controls; p = 0.708). The comparison of rates of positive bulky nodes was not statistically different between the groups (3 of 6, 50.0 %, in the cases vs. 3 of 9, 33.3 %, in the controls, p = 0.519). No statistical comparison can be performed for micrometastases. Regarding operative parameters, patients submitted to systematic pelvic and aortic lymphadenectomy showed a statistically significant median longer operative time, more blood loss, and higher rates of blood transfusions, but they had comparable lengths of stay with respect to controls (Table 2). The analysis of complications showed an overall low grade of complications in about 85 % of patients (Table 3). A statistically significant higher rates of blood transfusions (grade II) were observed in cases than in controls (p = 0.001), but equal percentages of grade III–IV complications occurred in both groups (18 vs. 11.9 %; p = NS). In particular, grade III complications consisted of Characteristic Value, cases No. of patients Type of surgery, n (%) 50 Value, controls 101 a Standard 10 (20.0) 29 (28.7) Radical 27 (54.0) 35 (34.7) Supraradical 13 (26.0) 37 (36.6) Residual tumor (cm), n (%) 0 NA not applicable, DHb g/dl largest variation in hemoglobin levels between preoperative and intra- or postoperative day 1 a According to Sharma et al.15 0.075 0.791 41 (82.0) 81 (80.2) 9 (18.0) 20 (19.8) Yes 6 (12.0) 9 (8.9) No 44 (88.0) 92 (91.1) 11 (78.5) NA NA 38 (15–84) \1 Bulky nodes, n (%) Bold values indicate statistically significant (p \ 0.05) p Microscopic positive nodes, n (%) No. of lymph nodes removed, median (range) 0.550 4 (1–14) 0.0001 Operative time (min), median (range) 225 (125–390) 210 (90–400) 0.023 Blood loss (DHb g/dl), median (range) 3.25 (0.02–5.10) 1.40 (0.01–6.20) 0.0001 27 (54.0) 23 (22.8) 0.0001 8 (4–23) 9 (4–20) 0.232 Patients transfused, n (%) Hospital stay (d), median (range) Lymphadenectomy at Interval Debulking Surgery 3525 Cumulative survival TABLE 3 Postoperative complications Characteristic Value, cases Value, controls No. of all patients 50 101 p Grade of surgical complications, n (%)a I 20 (40.0) *P = 0.777 1.0 Events Totals Lymph 15 50 No lymph 24 101 0.8 73 (72.3) 0.0001 II 21 (42.0) 16 (15.8) 0.001 IIIa 0 1 (1.0) 0.480 IIIb 1 (2.0) 2 (2.0) 0.993 IVa 8 (16.0) 9 (8.9) 0.195 IVb 0 0 NA 0.6 0.4 0.2 Bold values indicate statistically significant (p \ 0.05) NA not applicable a Classified according to Dindo et al.16 0 12 24 36 48 22 32 14 6 Months Cumulative survival *P = 0.834 1.0 Lymph No lymph Events 35 63 Totals 50 101 0.8 Patients at risk 50 101 44 89 33 64 FIG. 2 Kaplan–Meier curves for ovarian cancer patients submitted to IDS stratified by surgical performance: lymphadenectomy (lymph, black line) vs. no lymphadenectomy (No lymph, gray line); p = 0.777, log-rank test. OS is expressed in months on the x axis 0.6 0.4 0.2 0 12 24 36 48 Months Patients at risk 50 101 48 95 22 38 to disease (30 vs. 23.7 %; p = NS) were observed in cases and controls, respectively. No differences were observed in terms of site of relapse according to the surgical procedure adopted (Supplementary Table 1). Two-year PFS was 36 versus 25 % in cases and controls, respectively (p = 0.834) (Fig. 1). Two-year OS was 69 versus 88 % in cases and controls, respectively (p = 0.777) (Fig. 2). DISCUSSION 13 6 6 2 FIG. 1 Kaplan–Meier curves for ovarian cancer patients submitted to IDS stratified by surgical performance: lymphadenectomy (Lymph, black line) vs. no lymphadenectomy (No lymph, gray line); p = 0.834, log-rank test. PFS is expressed in months on the x axis three reinterventions for bowel occlusion and one postoperative pleural drainage. The apparent high incidence of grade IV complications has to be related to postoperative admission to the intensive care unit, established at preoperative anesthesiologic evaluation. Follow-up computed tomographic scan revealed a higher rate of postoperative lymphocele in the cases (26 %) than in controls (0.9 %) (p = NS). Follow-up update was stopped after 48 months so we would have comparable results for survival analysis. Mean follow-up was 36 (95 % confidence interval 31–41) and 35 (95 % confidence interval 32–38) months in cases and controls, respectively. During this time, 35 and 63 recurrences (70 vs. 62.4 %; p = NS) and 15 and 24 deaths due As a result of the lack of standard staging procedures at the time of IDS, the starting hypothesis of this study was that AOC patients would behave similarly both at primary cytoreduction and after neoadjuvant chemotherapy. In particular, the persistence of microscopic lymph nodal metastases would negatively influence the occurrence of lymph node recurrence, thus affecting disease-free survival but not OS.2 On the contrary, results from the present study suggested that systematic pelvic and aortic lymphadenectomy performed in AOC patients at the time of IDS after neoadjuvant chemotherapy had no value in terms of improvement in PFS and OS. In other words, because the rates of histologically confirmed disease-positive nodes were equal in cases and controls (28 vs. 33.3 %; p = NS), it seems that the removal of bulky nodes has only the same prognostic value as systematic lymphadenectomy at the time of IDS. However, as during primary surgery, systematic lymphadenectomy is associated with a statistically significant longer operative time and higher risk of blood loss, 3526 transfusion, and lymphocele occurrence. Although hemorrhage is a well-known complication during pelvic and aortic lymphadenectomy, our rates of blood transfusion are lower than those reported during primary surgery.2 This difference is obviously related to a more aggressive surgery during primary cytoreduction, although lymphadenectomy after chemotherapy may be more difficult as a result of a plastic reaction of the retroperitoneum. Although it could be argued that the number of women who could benefit from such a strategy would not be very numerous if the maximal surgical effort is always pursued at the time of primary diagnosis, results from clinical practice and from recent data of the European Organisation for Research and Treatment of Cancer 55971 phase III randomized trial suggest that approximately 30 % of AOC patients referred to a tertiary-level center do not receive an optimal cytoreduction at the time of primary surgery.18,19 In these cases, maximal surgical effort is widely accepted as a standard treatment for peritoneal disease and bulky lymph nodes, whereas the therapeutic value of systematic lymphadenectomy remains controversial, although it has been shown to be technically feasible and relatively safe.20–22 To our knowledge, this is the first case-control study analyzing the impact of systematic lymphadenectomy in this selected group of patients. Limitations of this study include its retrospective nonrandomized design, although the close matching between cases and controls should theoretically assure the quality of data. In particular, as a result of the prognostic objective of this study, only patients with no residual disease or minor residual disease with a maximum diameter 10 mm have been included. Moreover, type of surgery has been stratified according to an international classification, and no statistically significant differences were found between the groups except for lymphadenectomy.15 Similar data were published several years ago by an Italian group.21 This study analyzed patients submitted to systematic pelvic and aortic lymphadenectomy at secondlook laparotomy for ovarian cancer. They observed a comparable rate of positive nodes (25.8 %) and no differences in terms of 5-year survival in women with or without lymphadenectomy. The higher percentages of positive nodes after chemotherapy reported by other studies may be influenced by the small number of patients and the type of chemotherapy used.22,23 Finally, similar rates of positive nodes before and after chemotherapy have been reported, thus implying that nodal metastases are not as chemosensitive as peritoneal lesions.11 However, the study did not report a benefit in terms of survival associated with systematic lymphadenectomy in IDS patients. In conclusion, data currently available in the literature are confusing regarding the role of systematic A. Fagotti et al. lymphadenectomy in AOC women after neoadjuvant chemotherapy. However, as evaluated by an adjusted risk model, we believe that the strict statistical methodology of this study substantiates the hypothesis that this therapeutic option can be omitted, at least in high-risk patients.24 Further prospective randomized studies are needed to definitively resolve this question. ACKNOWLEDGMENT support. This study is not supported by any grant CONFLICT OF INTEREST conflicts of interest. The authors indicate nopotential REFERENCES 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Version 2.2012. NCCN.org. http://www.nccn. org/professionals/physician_gls/pdf/ovarian.pdf. Accessed 1 Mar 2012. 2. Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst. 2005;97:560–6. 3. Eisenkop SM, Freiedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol. 1998;69:103–8. 4. Schwartz PE. Neoadjuvant chemotherapy for the management of ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2002;16: 585–96. 5. Ozols RF. 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