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The impact of pelvic retroperitoneal invasion and distant nodal metastases in epithelial ovarian cancer
Surgical Oncology 23 (2014) 40e44
Contents lists available at ScienceDirect
Surgical Oncology journal homepage: www.elsevier.com/locate/suronc
Review
The impact of pelvic retroperitoneal invasion and distant nodal metastases in epithelial ovarian cancer Augusto Pereira a, *, Tirso Pérez-Medina c, Javier F. Magrina b, Paul M. Magtibay b, Ana Rodríguez-Tapia d, Federico Pérez-Milán a, Luís Ortiz-Quintana a a
Department of Gynecologic Surgery, Gregorio Marañón University General Hospital, Madrid, Spain Division of Gynecologic Surgery, Mayo Clinic, AZ, USA Department of Gynecologic Surgery, Puerta de Hierro University Hospital, Madrid, Spain d Department of Gynecology and Obstetrics, College of Medicine, Autonoma University, Madrid, Spain b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 10 October 2013
Background: The absence of disease after debulking surgery is the most important prognostic factor in the treatment of advanced epithelial ovarian cancer (EOC). Occasionally, the presence of extra-abdominal disease complicates the ability to obtain a complete surgery, considering some locations of the metastatic disease as unresectable. The objective of the study was to estimate the survival impact of pelvic retroperitoneal invasion and extrapelvic and aortic distant nodal metastases in EOC patients. The anatomical landmarks of primary cytoreductive surgery will be discussed. Material and methods: We reviewed data from 116 consecutive Mayo Clinic patients with epithelial ovarian cancer (EOC) stage IIIC and IV, undergoing primary cytoreduction surgery between 1996 and 2000. Univariate and multivariate analysis for patients with positive distant nodes and pelvic retroperitoneal invasion was performed, including 57 patients with no residual disease after surgery. Kaplan eMeier curves were used to estimate the probability of survival. Results: The median patient’s age was 65 years (range 24e87 years). The 5 years overall survival was 44.8% (range 30.1e57.9 months) and the median length of survival was 39.9 months (range 0.13e60 months, 95% confidence interval: 30.1e57.9). Pelvic retroperitoneal invasion was present in 22 EOC patients (18.9%) and distant positive nodes were noted in 11 (9.5%): suprarenal/celiac (5.2%), inguinal (4.3%) and supraclavicular (0.9%). Univariate and multivariate Cox regression analysis, identified distant positive lymph nodes and pelvic retroperitoneal invasion as factors statistically associated with overall survival (p ¼ 0.002 and p ¼ 0.025, respectively). Conclusions: Metastatic distant nodes and pelvic retroperitoneal invasion are independent prognostic factors for survival in patients with advanced EOC. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Ovarian cancer Suprarenal/celiac, inguinal, supraclavicular nodes Retroperitoneal, parametrial invasion
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
* Corresponding author. Department of Gynecologic Surgery, Gregorio Marañón University General Hospital, C/ Maiquez, 7, Madrid 28009, Spain. Tel.: þ34 915 868 000; fax: þ34 915 868 018. E-mail address: [email protected] (A. Pereira). http://dx.doi.org/10.1016/j.suronc.2013.10.005 0960-7404/Ó 2013 Elsevier Ltd. All rights reserved.
A. Pereira et al. / Surgical Oncology 23 (2014) 40e44
41
Introduction
Results
There is universal agreement that maximal removal of intraperitoneal disease has a survival benefit for patients with metastatic epithelial ovarian cancer (EOC), which is especially true when no visible disease remains at the completion of the operation [1e3]. There is also agreement that detection of nodal metastasis is important in patients with disease clinically limited to the pelvis, to determine surgical stage, prognosis and the need for adjuvant therapy [4,5]. There however is controversy in the role of detection and removal of positive nodes in patients with advanced, metastatic intraperitoneal disease as this does not affect surgical stage and its therapeutic benefit remains unclear [6,7]. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) [8], revised and included in its staging classification of female genital cancers the prognostic significance of direct retroperitoneal tumor invasion in cervical, endometrial and vulvar cancer. Positive groin nodes were added to the staging of vulvar (stage III) and endometrial (stage IVB) cancers. EOC patients with “positive retroperitoneal or inguinal nodes” were included as stage IIIC [9]. The prognostic role of other metastatic nodal sites or retroperitoneal pelvic invasion in EOC remains unclear. The objective of this study was to estimate the survival impact of pelvic retroperitoneal invasion and distant nodal metastases, other than that of the pelvic and para-aortic nodal regions in advanced EOC patients. The anatomical landmarks of primary cytoreductive surgery in EOC patients will be discussed.
The median patient’s age was 65 years (range 24e87 years). The median number of pelvic and/or aortic nodes removed was 31 (range 1e123) and the median number of metastatic nodes was 5 (range: 1e42). Demographics of the cohort and their survival have been previously reported [7,11,12]. Pelvic retroperitoneal invasion was present in 22 patients (18.9%), including ureteral obstruction with or without hydronephrosis (n ¼ 10), proximal parametrial involvement (n ¼ 5), proximal parametrial involvement with ureteral obstruction (n ¼ 4), parametrial involvement to pelvic wall and ureteral obstruction (n ¼ 1), ureteral obstruction with tumor extension into the recto-vaginal space (n ¼ 1) and direct tumor extension to the pararectal space (n ¼ 1). Distant positive nodes were noted in 11 patients (9.5%), with the following locations: inguinal (n ¼ 4), suprarenal/celiac (n ¼ 5), inguinal and suprarenal (n ¼ 1), and left supraclavicular (n ¼ 1). On univariate Cox regression analysis (Table 1), positive distant nodes and pelvic retroperitoneal invasion were significant factors for survival (p ¼ 0.002 and p ¼ 0.025, respectively). On multivariate analysis (Table 1), patients with positive distant nodes in addition to pelvic and/or aortic positive nodes had a lower survival as compared to those with nodal metastases limited to the pelvic and/ or aortic areas (52.5% vs 81.8%, respectively, Hazard ratio (HR): 0.25, and 95% CI: 0.05e1.20, p ¼ 0.025). On multivariate analysis (Table 1), patients with pelvic retroperitoneal invasion had a lower survival as compared to those without it (50% vs 77.3%, respectively, HR: 0.29, and 95% CI: 0.10e
Materials and methods Data was collected retrospectively from 116 patients with primary EOC and positive nodes (FIGO stage IIIC: 81 and stage IV: 35), treated at Mayo Clinic between 1996 and 2000. Approval was granted by the Mayo Clinic Institutional Review Board. Abstracted data included patient’s age, tumor type and grade, FIGO stage, extent of peritoneal disease before debulking (clinical stage) and size of maximal residual tumor diameter after cytoreductive surgery. All patients received adjuvant postoperative paclitaxel and platinum-based chemotherapy. Abstracted data included overall number of nodes and number of positive nodes removed from the pelvic and aortic areas, sites of positive distant nodes removed, and the presence of pelvic retroperitoneal invasion as noted in operative and/or pathology reports. The anatomic borders for pelvic lymphadenectomy were from the deep circumflex iliac vein distally to the aortic bifurcation proximally. For the aortic lymphadenectomy, borders were defined from the aortic bifurcation to the left renal vein. The term positive or metastatic distant nodes were used for positive nodes removed from sites other than the pelvic and aortic areas. Follow up was measured in months from the time of primary surgery until death or censoring. Censoring for survivors was performed at a minimum of 5 years of follow up. Actuarial 5 year overall survival (5 yr OS) was calculated for all patients who died from any cause. Univariate Cox regression analysis was used between factors and risk of death. Any p value of less than 0.25 in univariate analysis was subjected to multivariable analysis [10]. Survival analysis and predictors of outcome was calculated using KaplaneMeier and Cox proportional hazard methods. On multivariate analysis p value of less than 0.05 was considered as significant. The homogeneity of the groups compared in survival analysis, was confirmed by subsequent Bonferroni correction test. Statistical analysis was performed using SPSS statistical package.
Table 1 Univariate and multivariate Cox regression analysis for survival. n
5 OS (%)
Univariate analysis Stage IIIC 81 38 (46.9) IV 35 14 (40.0) Clinical stage IeIIIB 33 23 (69.7) IIIC 71 28 (39.4) IV 12 1 (8.3) Residual tumor VR ¼ 0 57 32 (56.1) VR > 1 cm 41 15 (36.6) VR < 1 cm 17 4 (23.5) Overall number of nodes removed 1e40 74 28 (37.8) >40 42 24 (57.1) Distant metastatic nodes No 105 50 (47.6) Yes 11 2 (18.2) Retroperitoneal invasion No 94 47 (50.0) Yes 22 5 (22.7) Multivariate analysis Clinical stage IeIIIB 33 23 (69.7) IIIC 71 28 (39.4) IV 12 1 (8.3) Overall number of nodes removed 1e40 53 13 (24.5) >40 30 16 (53.3) Distant metastatic nodes No 105 50 (47.6) Yes 11 2 (18.2) Retroperitoneal invasion No 94 47 (50.0) Yes 22 5 (22.7)
HR
95% CI
p
1.0 1.38
0.83e2.33
0.220
1.0 2.48 7.0
1.24e4.94 2.92e16.8
0.010 0.001
1.0 1.59 2.42
0.92e2.76 1.28e4.94
0.098 0.007
1.0 0.64
0.37e1.09
0.105
1.0 0.25
0.05e1.20
0.050
1.0 0.30
0.10e0.87
0.017
1.0 2.48 7.0
1.24e4.94 2.92e16.8
0.010 0.001
1.0 0.52
0.29e0.45
0.032
1.0 0.25
0.05e1.20
0.025
1.0 0.29
0.10e0.86
0.002
Abbreviation: n ¼ patients, HR ¼ Hazard ratio, CI ¼ Confidence interval, p ¼ p value.
42
A. Pereira et al. / Surgical Oncology 23 (2014) 40e44
0.89, p ¼ 0.002). The Kaplan Meier survival curves are shown in Figs. 1 and 2. The survival analysis for patients with positive distant nodes, or pelvic retroperitoneal invasion is shown in Table 2. The survival analysis for patients achieving complete debulking (no visible residual disease) is shown in Table 3.
Discussion The radicality of primary surgical management in EOC has a direct effect on survival [13]. A previous report on this same cohort of EOC patients with positive nodes and advanced peritoneal disease >2 cm revealed that the extent of initial peritoneal spread and the radicality of the lymphadenectomy (>40 lymph nodes removed) were important prognostic factors for survival [7,11,12]. The present study showed two additional independent prognostic factors for survival, the presence of distant, metastatic nodal disease and pelvic retroperitoneal invasion. The abdominal cavity is the single most important site for disseminated primary ovarian cancer as noted in about 91%of patients [14]. The pelvic and aortic nodes are involved in 4e27% [15], of patients with early clinical stages as compared to 62e75% in clinically advanced stages [16e18]. Distant nodal disease was noted preferably in patients with advanced clinical stages (Table 2). The reported frequency of involvement of distant nodal sites, by order of frequency, is as follows: suprarenal/celiac 3e5% [19e23], inguinal 0.5e3% and supraclavicular 1e2% [14,19]. In the present study, 9.5% of patients with advanced clinical stage disease (IIIC and IV) were noted to have metastatic nodal sites in the suprarenal/ celiac (5.2%), inguinal (4.3%) and supraclavicular (0.9%) areas. The presence of positive suprarenal/celiac nodes is indicative of advanced upper abdominal disease as these nodes receive lymphatic drainage from the supramesocolic region of the peritoneal cavity. Supraclavicular metastases are usually indicative of nodal spread via the subcarinal nodes, although drainages routes through the subaortic nodes or along the left phrenic nerve through the para-aortic nodes, or from hilum of lung to mediastinum have been described [24,25]. Inguinal lymph node metastases probably result from retrograde lymphatic drainage as a result of metastatic
Figure 2. Kaplan Meier 5 years overall survival curve by retroperitoneal invasion (p < 0.002).
pelvic nodes [26,27]. The presence of positive nodes at any of these sites is associated with a reduced survival of 18.2% as compared to 47.6% for patients without metastatic distant nodes. We found no 5-year survivors among patients with positive inguinal nodes or supraclavicular nodes (the only patient with left supraclavicular nodal metastasis survived 11.9 months). For patients with suprarenal/celiac lymph node mestastasis, the 5 year survival was 20%, as compared to 44.8% 5-year survival for the entire cohort of EOC patients (range 30.1e57.9 months) [7]. Positive groin nodes are a significant prognostic factor for patients with vulvar and endometrial cancers. These patients are staged as III and IVB [8], respectively with corresponding 5 yr survival rates of 53% and 15%, respectively [28]. This is much lower when compared to patients with negative groin nodes. Parametrial involvement is considered as an adverse prognostic factor in the FIGO staging of cervical (IIB, IIIB) endometrial (IIB), and vulvar malignancies (stage IVA) [8], with corresponding decreased
Table 2 Analysis of positive distant nodes and pelvic retroperitoneal invasion with survival and clinical stage. Survival analysis in relation with the extent of disease
Overall
I/II/IIIAeB IIIC
IV
5 yr OS (%)
5 yr OS (%)
5 yr OS (%)
(0) (20) (100) (0) (18.2)
e 0/1 (0) e 0/1 (0) 0/2 (0)
0/2 1/4 1/1 e 2/7
(30)
0/3 (0)
3/6 (50)
(40) (0)
1/2 (50) 0/2 (0)
1/3 (33.3) e 0/2 (0) 0/2 (0)
5 yr OS (%)
Figure 1. Kaplan Meier 5 years overall survival curve by presence of distant lymph nodes (p < 0.025).
Distant positive nodes. n [ 11 Inguinal 0/4 Suprarenal/celiac 1/5 Inguinal and suprarenal/celiac 1/1 Supraclavicular 0/1 Total 2/11 Retroperitoneal invasion. n [ 22 Ureteral obstruction/ 3/10 hydronephrosis Proximal parametrial 2/5 0/6 Parametrial with ureteral obstruction/pelvic wall/rectovaginal space Pararectal space 0/1 Total 5/22
Clinical stage
(0) (25) (100)
0/2 (0) e e e (28.6) 0/2 (0) 0/1 (0)
(0) e 0/1 (0) e (22.7) 1/7 (14.3) 4/12 (33.3) 0/3 (0)
Abbreviation: n ¼ number of patients, 5 yr OS ¼ 5 year overall survival.
A. Pereira et al. / Surgical Oncology 23 (2014) 40e44 Table 3 Analysis of positive distant nodes and pelvic retroperitoneal invasion in patients with no residual tumor post debulking (RD ¼ 0). Complete debulking Metastatic distant nodes Clinical stage IeIII B No Yes Total Clinical stage IIIC/IV No Yes Total Retroperitoneal invasion Clinical stage IeIIIB No Yes Total Clinical stage IIIC/IV No Yes Total
43
Conflict of interest statement
n ¼ 57
5 yr OS (%)
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome.
28 e 28
22/28 (78.6) e 22/28 (78.6)
Authorship statement
28 1 29
10/28 (35.7) 0/1 (0) 10/29 (34.5)
25 3 28
21/25 (84.0) 1/3 (33.3) 22/28 (78.6)
21 8 29
9/21 (42.9) 1/8 (12.5) 10/29 (34.5)
Abbreviation: n ¼ number of patients, 5 yr OS ¼ 5 year overall survival.
survivals as compared to patients without parametrial invasion [28]. Hydronephrosis or non-functioning kidney are also an adverse prognostic factor and included in cervical FIGO staging as advanced stage, IIIB [8]. Our study demonstrates that parametrial involvement in patients with EOC also adversely affects prognosis, with corresponding decreases in survival when other prognostic factors are taken into account. The 5-year survival of patients with pelvic retroperitoneal invasion was 22.7%. The survival impact was more pronounced in patients with early clinical disease (clinical stage IeIIIB), who had a dismal 5 year survival of 14.3%. The extent of retroperitoneal invasion (proximal vs pelvic wall extension) was also noted to be a significant factor for survival. In patients with early retroperitoneal invasion (proximal parametrial involvement) and clinical stage IIIC, the 5-yr survival was 50%. However, it decreased to 17% with advanced retroperitoneal invasion reaching to the pelvic wall, invading the rectovaginal or pararectal spaces or resulting in hydronephrosis (only 1/6 patients survived 5 years). Direct retroperitoneal invasion and distant metastatic nodes also had an adverse survival impact on the group of patients with the most favorable debulking outcome, those with no residual visible tumor. In patients with early clinical stage (IeIIIB), the presence of retroperitoneal invasion resulted in a 50.7% lower survival as compared to patients with no retroperitoneal invasion (33.3% vs 84.0%). A similar effect was observed for patients with advanced clinical stage (IIICeIV) with and without retroperitoneal invasion, with a 34.4% difference in survival (12.5% vs 42.9%, respectively) (Table 3). Metastatic distant nodes appear to be a sign of more advanced disease progression, as this was present in only two patients with early clinical disease (Table 2) and in patients with clinical advanced disease (IIICeIV), there was only one patient who achieved complete debulking. She died of her disease, as compared to a 5 year survival of 37.5% for similar patients without distant metastatic nodes. Distant bulky positive nodes to the pelvic and aortic area or an extensive EOC disease involving the retroperitoneum announce an incomplete cytoreduction, being surgically unresectable disease the most important reason to not achieve optimal results. In conclusion, distant, metastatic nodes and pelvic retroperitoneal invasion are independent prognostic factors in patients with EOC resulting in reduced survival. Distant metastatic nodes are indicative of advanced clinical disease.
Guarantor of the integrity of the study: A. Pereira, T. PerezMedina, L. Ortiz-Quintana. Study concepts: A. Pereira, T. Perez-Medina. Study design: A. Pereira, T. Perez-Medina. Definition of intellectual content: A. Pereira, J.F. Magrina, P.M. Magtibay. Literature research: A. Pereira, A. Rodriguez-Tapia. Clinical studies: A. Pereira, J.F. Magrina, P.M. Magtibay. Data acquisition: A. Pereira, A. Rodriguez-Tapia. Data analysis: A. Pereira, T. Perez-Medina, F. Perez-Milan. Statistical analysis: A. Pereira, F. Perez-Milan, A. RodriguezTapia. Manuscript preparation: A. Pereira, J.F. Magrina, P.M. Magtibay. Manuscript editing: A. Pereira, J.F. Magrina, P.M. Magtibay. Manuscript review: All authors. References [1] Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al. The effect of diameter of largest residual disease after primary cytoreductive surgery on survival in patients with suboptimal residual epithelial ovarian carcinoma: a Gynecologic Oncology Group Study. Am J Obstet Gynecol 1994;170:974e80. [2] Eisenkop SM, Nalick RH, Wang HJ, Teng NN. Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: impact on survival. Gynecol Oncol 1993 Nov;51(2):224e9. [3] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003 Aug;90(2):390e6. [4] Benedet JL, Pecorelli S. Why cancer staging? Int J Gynecol Obstet 2006;95(Suppl. l):S3. [5] Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006 Nov;95(Suppl. 1):S161e92. [6] Panici PB, Maggioni A, Hacker N, Landoni F, Ackermann S, Campagnutta E, 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 Apr 20;97(8):560e6. [7] Pereira A, Pérez-Medina T, Magrina JF, Magtibay PM, Millan I, Iglesias E. The role of lymphadenectomy in node-positive epithelial ovarian cancer. Int J Gynecol Cancer 2012 Jul;22(6):987e92. [8] Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009 May;105(2):103e4. [9] FIGO Cancer Committee. Staging announcement. Gynecol Oncol 1986;25:383. [10] Hosmer DW, Lemeshow S. Applied logistic regression. Wiley-Interscience; 2000. [11] Pereira A, Magrina JF, Rey V, Cortes M, Magtibay PM. Pelvic and aortic lymph node metastasis in epithelial ovarian cancer. Gynecol Oncol 2007 Jun;105(3): 604e8. [12] Pereira A, Magrina JF, Magtibay PM, Pérez-Medina T, Fernández A, Peregrin I. The impact of peritoneal metastases in epithelial ovarian cancer with positive nodes. Int J Gynecol Cancer November 2011;21(8):1375e9. [13] Wimberger P, Kimmig R. The role of radical lymphadenectomy. Experiences from the AGO Ovarian Cancer Study Group. Urologe A 2009 Jan;48(1):26e31. [14] Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, et al. Metastatic patterns in adenocarcinoma. Cancer 2006 Apr 1;106(7):1624e33. [15] Desteli D. Lymph node metastasis in grossly apparent clinical stage Ia epithelial ovarian cancer: Hacettepe experience and review of literature. World J Surg Oncol 2010 Nov;30(8):106. [16] Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, Rabitti C, et al. Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol 1993;51:150e4. [17] Morice P, Joulie F, Camatte S, Atallah D, Rouzier R, Pautier P, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg 2003;197:198e 205.
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Contents lists available at ScienceDirect
Surgical Oncology journal homepage: www.elsevier.com/locate/suronc
Review
The impact of pelvic retroperitoneal invasion and distant nodal metastases in epithelial ovarian cancer Augusto Pereira a, *, Tirso Pérez-Medina c, Javier F. Magrina b, Paul M. Magtibay b, Ana Rodríguez-Tapia d, Federico Pérez-Milán a, Luís Ortiz-Quintana a a
Department of Gynecologic Surgery, Gregorio Marañón University General Hospital, Madrid, Spain Division of Gynecologic Surgery, Mayo Clinic, AZ, USA Department of Gynecologic Surgery, Puerta de Hierro University Hospital, Madrid, Spain d Department of Gynecology and Obstetrics, College of Medicine, Autonoma University, Madrid, Spain b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 10 October 2013
Background: The absence of disease after debulking surgery is the most important prognostic factor in the treatment of advanced epithelial ovarian cancer (EOC). Occasionally, the presence of extra-abdominal disease complicates the ability to obtain a complete surgery, considering some locations of the metastatic disease as unresectable. The objective of the study was to estimate the survival impact of pelvic retroperitoneal invasion and extrapelvic and aortic distant nodal metastases in EOC patients. The anatomical landmarks of primary cytoreductive surgery will be discussed. Material and methods: We reviewed data from 116 consecutive Mayo Clinic patients with epithelial ovarian cancer (EOC) stage IIIC and IV, undergoing primary cytoreduction surgery between 1996 and 2000. Univariate and multivariate analysis for patients with positive distant nodes and pelvic retroperitoneal invasion was performed, including 57 patients with no residual disease after surgery. Kaplan eMeier curves were used to estimate the probability of survival. Results: The median patient’s age was 65 years (range 24e87 years). The 5 years overall survival was 44.8% (range 30.1e57.9 months) and the median length of survival was 39.9 months (range 0.13e60 months, 95% confidence interval: 30.1e57.9). Pelvic retroperitoneal invasion was present in 22 EOC patients (18.9%) and distant positive nodes were noted in 11 (9.5%): suprarenal/celiac (5.2%), inguinal (4.3%) and supraclavicular (0.9%). Univariate and multivariate Cox regression analysis, identified distant positive lymph nodes and pelvic retroperitoneal invasion as factors statistically associated with overall survival (p ¼ 0.002 and p ¼ 0.025, respectively). Conclusions: Metastatic distant nodes and pelvic retroperitoneal invasion are independent prognostic factors for survival in patients with advanced EOC. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Ovarian cancer Suprarenal/celiac, inguinal, supraclavicular nodes Retroperitoneal, parametrial invasion
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
* Corresponding author. Department of Gynecologic Surgery, Gregorio Marañón University General Hospital, C/ Maiquez, 7, Madrid 28009, Spain. Tel.: þ34 915 868 000; fax: þ34 915 868 018. E-mail address: [email protected] (A. Pereira). http://dx.doi.org/10.1016/j.suronc.2013.10.005 0960-7404/Ó 2013 Elsevier Ltd. All rights reserved.
A. Pereira et al. / Surgical Oncology 23 (2014) 40e44
41
Introduction
Results
There is universal agreement that maximal removal of intraperitoneal disease has a survival benefit for patients with metastatic epithelial ovarian cancer (EOC), which is especially true when no visible disease remains at the completion of the operation [1e3]. There is also agreement that detection of nodal metastasis is important in patients with disease clinically limited to the pelvis, to determine surgical stage, prognosis and the need for adjuvant therapy [4,5]. There however is controversy in the role of detection and removal of positive nodes in patients with advanced, metastatic intraperitoneal disease as this does not affect surgical stage and its therapeutic benefit remains unclear [6,7]. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) [8], revised and included in its staging classification of female genital cancers the prognostic significance of direct retroperitoneal tumor invasion in cervical, endometrial and vulvar cancer. Positive groin nodes were added to the staging of vulvar (stage III) and endometrial (stage IVB) cancers. EOC patients with “positive retroperitoneal or inguinal nodes” were included as stage IIIC [9]. The prognostic role of other metastatic nodal sites or retroperitoneal pelvic invasion in EOC remains unclear. The objective of this study was to estimate the survival impact of pelvic retroperitoneal invasion and distant nodal metastases, other than that of the pelvic and para-aortic nodal regions in advanced EOC patients. The anatomical landmarks of primary cytoreductive surgery in EOC patients will be discussed.
The median patient’s age was 65 years (range 24e87 years). The median number of pelvic and/or aortic nodes removed was 31 (range 1e123) and the median number of metastatic nodes was 5 (range: 1e42). Demographics of the cohort and their survival have been previously reported [7,11,12]. Pelvic retroperitoneal invasion was present in 22 patients (18.9%), including ureteral obstruction with or without hydronephrosis (n ¼ 10), proximal parametrial involvement (n ¼ 5), proximal parametrial involvement with ureteral obstruction (n ¼ 4), parametrial involvement to pelvic wall and ureteral obstruction (n ¼ 1), ureteral obstruction with tumor extension into the recto-vaginal space (n ¼ 1) and direct tumor extension to the pararectal space (n ¼ 1). Distant positive nodes were noted in 11 patients (9.5%), with the following locations: inguinal (n ¼ 4), suprarenal/celiac (n ¼ 5), inguinal and suprarenal (n ¼ 1), and left supraclavicular (n ¼ 1). On univariate Cox regression analysis (Table 1), positive distant nodes and pelvic retroperitoneal invasion were significant factors for survival (p ¼ 0.002 and p ¼ 0.025, respectively). On multivariate analysis (Table 1), patients with positive distant nodes in addition to pelvic and/or aortic positive nodes had a lower survival as compared to those with nodal metastases limited to the pelvic and/ or aortic areas (52.5% vs 81.8%, respectively, Hazard ratio (HR): 0.25, and 95% CI: 0.05e1.20, p ¼ 0.025). On multivariate analysis (Table 1), patients with pelvic retroperitoneal invasion had a lower survival as compared to those without it (50% vs 77.3%, respectively, HR: 0.29, and 95% CI: 0.10e
Materials and methods Data was collected retrospectively from 116 patients with primary EOC and positive nodes (FIGO stage IIIC: 81 and stage IV: 35), treated at Mayo Clinic between 1996 and 2000. Approval was granted by the Mayo Clinic Institutional Review Board. Abstracted data included patient’s age, tumor type and grade, FIGO stage, extent of peritoneal disease before debulking (clinical stage) and size of maximal residual tumor diameter after cytoreductive surgery. All patients received adjuvant postoperative paclitaxel and platinum-based chemotherapy. Abstracted data included overall number of nodes and number of positive nodes removed from the pelvic and aortic areas, sites of positive distant nodes removed, and the presence of pelvic retroperitoneal invasion as noted in operative and/or pathology reports. The anatomic borders for pelvic lymphadenectomy were from the deep circumflex iliac vein distally to the aortic bifurcation proximally. For the aortic lymphadenectomy, borders were defined from the aortic bifurcation to the left renal vein. The term positive or metastatic distant nodes were used for positive nodes removed from sites other than the pelvic and aortic areas. Follow up was measured in months from the time of primary surgery until death or censoring. Censoring for survivors was performed at a minimum of 5 years of follow up. Actuarial 5 year overall survival (5 yr OS) was calculated for all patients who died from any cause. Univariate Cox regression analysis was used between factors and risk of death. Any p value of less than 0.25 in univariate analysis was subjected to multivariable analysis [10]. Survival analysis and predictors of outcome was calculated using KaplaneMeier and Cox proportional hazard methods. On multivariate analysis p value of less than 0.05 was considered as significant. The homogeneity of the groups compared in survival analysis, was confirmed by subsequent Bonferroni correction test. Statistical analysis was performed using SPSS statistical package.
Table 1 Univariate and multivariate Cox regression analysis for survival. n
5 OS (%)
Univariate analysis Stage IIIC 81 38 (46.9) IV 35 14 (40.0) Clinical stage IeIIIB 33 23 (69.7) IIIC 71 28 (39.4) IV 12 1 (8.3) Residual tumor VR ¼ 0 57 32 (56.1) VR > 1 cm 41 15 (36.6) VR < 1 cm 17 4 (23.5) Overall number of nodes removed 1e40 74 28 (37.8) >40 42 24 (57.1) Distant metastatic nodes No 105 50 (47.6) Yes 11 2 (18.2) Retroperitoneal invasion No 94 47 (50.0) Yes 22 5 (22.7) Multivariate analysis Clinical stage IeIIIB 33 23 (69.7) IIIC 71 28 (39.4) IV 12 1 (8.3) Overall number of nodes removed 1e40 53 13 (24.5) >40 30 16 (53.3) Distant metastatic nodes No 105 50 (47.6) Yes 11 2 (18.2) Retroperitoneal invasion No 94 47 (50.0) Yes 22 5 (22.7)
HR
95% CI
p
1.0 1.38
0.83e2.33
0.220
1.0 2.48 7.0
1.24e4.94 2.92e16.8
0.010 0.001
1.0 1.59 2.42
0.92e2.76 1.28e4.94
0.098 0.007
1.0 0.64
0.37e1.09
0.105
1.0 0.25
0.05e1.20
0.050
1.0 0.30
0.10e0.87
0.017
1.0 2.48 7.0
1.24e4.94 2.92e16.8
0.010 0.001
1.0 0.52
0.29e0.45
0.032
1.0 0.25
0.05e1.20
0.025
1.0 0.29
0.10e0.86
0.002
Abbreviation: n ¼ patients, HR ¼ Hazard ratio, CI ¼ Confidence interval, p ¼ p value.
42
A. Pereira et al. / Surgical Oncology 23 (2014) 40e44
0.89, p ¼ 0.002). The Kaplan Meier survival curves are shown in Figs. 1 and 2. The survival analysis for patients with positive distant nodes, or pelvic retroperitoneal invasion is shown in Table 2. The survival analysis for patients achieving complete debulking (no visible residual disease) is shown in Table 3.
Discussion The radicality of primary surgical management in EOC has a direct effect on survival [13]. A previous report on this same cohort of EOC patients with positive nodes and advanced peritoneal disease >2 cm revealed that the extent of initial peritoneal spread and the radicality of the lymphadenectomy (>40 lymph nodes removed) were important prognostic factors for survival [7,11,12]. The present study showed two additional independent prognostic factors for survival, the presence of distant, metastatic nodal disease and pelvic retroperitoneal invasion. The abdominal cavity is the single most important site for disseminated primary ovarian cancer as noted in about 91%of patients [14]. The pelvic and aortic nodes are involved in 4e27% [15], of patients with early clinical stages as compared to 62e75% in clinically advanced stages [16e18]. Distant nodal disease was noted preferably in patients with advanced clinical stages (Table 2). The reported frequency of involvement of distant nodal sites, by order of frequency, is as follows: suprarenal/celiac 3e5% [19e23], inguinal 0.5e3% and supraclavicular 1e2% [14,19]. In the present study, 9.5% of patients with advanced clinical stage disease (IIIC and IV) were noted to have metastatic nodal sites in the suprarenal/ celiac (5.2%), inguinal (4.3%) and supraclavicular (0.9%) areas. The presence of positive suprarenal/celiac nodes is indicative of advanced upper abdominal disease as these nodes receive lymphatic drainage from the supramesocolic region of the peritoneal cavity. Supraclavicular metastases are usually indicative of nodal spread via the subcarinal nodes, although drainages routes through the subaortic nodes or along the left phrenic nerve through the para-aortic nodes, or from hilum of lung to mediastinum have been described [24,25]. Inguinal lymph node metastases probably result from retrograde lymphatic drainage as a result of metastatic
Figure 2. Kaplan Meier 5 years overall survival curve by retroperitoneal invasion (p < 0.002).
pelvic nodes [26,27]. The presence of positive nodes at any of these sites is associated with a reduced survival of 18.2% as compared to 47.6% for patients without metastatic distant nodes. We found no 5-year survivors among patients with positive inguinal nodes or supraclavicular nodes (the only patient with left supraclavicular nodal metastasis survived 11.9 months). For patients with suprarenal/celiac lymph node mestastasis, the 5 year survival was 20%, as compared to 44.8% 5-year survival for the entire cohort of EOC patients (range 30.1e57.9 months) [7]. Positive groin nodes are a significant prognostic factor for patients with vulvar and endometrial cancers. These patients are staged as III and IVB [8], respectively with corresponding 5 yr survival rates of 53% and 15%, respectively [28]. This is much lower when compared to patients with negative groin nodes. Parametrial involvement is considered as an adverse prognostic factor in the FIGO staging of cervical (IIB, IIIB) endometrial (IIB), and vulvar malignancies (stage IVA) [8], with corresponding decreased
Table 2 Analysis of positive distant nodes and pelvic retroperitoneal invasion with survival and clinical stage. Survival analysis in relation with the extent of disease
Overall
I/II/IIIAeB IIIC
IV
5 yr OS (%)
5 yr OS (%)
5 yr OS (%)
(0) (20) (100) (0) (18.2)
e 0/1 (0) e 0/1 (0) 0/2 (0)
0/2 1/4 1/1 e 2/7
(30)
0/3 (0)
3/6 (50)
(40) (0)
1/2 (50) 0/2 (0)
1/3 (33.3) e 0/2 (0) 0/2 (0)
5 yr OS (%)
Figure 1. Kaplan Meier 5 years overall survival curve by presence of distant lymph nodes (p < 0.025).
Distant positive nodes. n [ 11 Inguinal 0/4 Suprarenal/celiac 1/5 Inguinal and suprarenal/celiac 1/1 Supraclavicular 0/1 Total 2/11 Retroperitoneal invasion. n [ 22 Ureteral obstruction/ 3/10 hydronephrosis Proximal parametrial 2/5 0/6 Parametrial with ureteral obstruction/pelvic wall/rectovaginal space Pararectal space 0/1 Total 5/22
Clinical stage
(0) (25) (100)
0/2 (0) e e e (28.6) 0/2 (0) 0/1 (0)
(0) e 0/1 (0) e (22.7) 1/7 (14.3) 4/12 (33.3) 0/3 (0)
Abbreviation: n ¼ number of patients, 5 yr OS ¼ 5 year overall survival.
A. Pereira et al. / Surgical Oncology 23 (2014) 40e44 Table 3 Analysis of positive distant nodes and pelvic retroperitoneal invasion in patients with no residual tumor post debulking (RD ¼ 0). Complete debulking Metastatic distant nodes Clinical stage IeIII B No Yes Total Clinical stage IIIC/IV No Yes Total Retroperitoneal invasion Clinical stage IeIIIB No Yes Total Clinical stage IIIC/IV No Yes Total
43
Conflict of interest statement
n ¼ 57
5 yr OS (%)
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome.
28 e 28
22/28 (78.6) e 22/28 (78.6)
Authorship statement
28 1 29
10/28 (35.7) 0/1 (0) 10/29 (34.5)
25 3 28
21/25 (84.0) 1/3 (33.3) 22/28 (78.6)
21 8 29
9/21 (42.9) 1/8 (12.5) 10/29 (34.5)
Abbreviation: n ¼ number of patients, 5 yr OS ¼ 5 year overall survival.
survivals as compared to patients without parametrial invasion [28]. Hydronephrosis or non-functioning kidney are also an adverse prognostic factor and included in cervical FIGO staging as advanced stage, IIIB [8]. Our study demonstrates that parametrial involvement in patients with EOC also adversely affects prognosis, with corresponding decreases in survival when other prognostic factors are taken into account. The 5-year survival of patients with pelvic retroperitoneal invasion was 22.7%. The survival impact was more pronounced in patients with early clinical disease (clinical stage IeIIIB), who had a dismal 5 year survival of 14.3%. The extent of retroperitoneal invasion (proximal vs pelvic wall extension) was also noted to be a significant factor for survival. In patients with early retroperitoneal invasion (proximal parametrial involvement) and clinical stage IIIC, the 5-yr survival was 50%. However, it decreased to 17% with advanced retroperitoneal invasion reaching to the pelvic wall, invading the rectovaginal or pararectal spaces or resulting in hydronephrosis (only 1/6 patients survived 5 years). Direct retroperitoneal invasion and distant metastatic nodes also had an adverse survival impact on the group of patients with the most favorable debulking outcome, those with no residual visible tumor. In patients with early clinical stage (IeIIIB), the presence of retroperitoneal invasion resulted in a 50.7% lower survival as compared to patients with no retroperitoneal invasion (33.3% vs 84.0%). A similar effect was observed for patients with advanced clinical stage (IIICeIV) with and without retroperitoneal invasion, with a 34.4% difference in survival (12.5% vs 42.9%, respectively) (Table 3). Metastatic distant nodes appear to be a sign of more advanced disease progression, as this was present in only two patients with early clinical disease (Table 2) and in patients with clinical advanced disease (IIICeIV), there was only one patient who achieved complete debulking. She died of her disease, as compared to a 5 year survival of 37.5% for similar patients without distant metastatic nodes. Distant bulky positive nodes to the pelvic and aortic area or an extensive EOC disease involving the retroperitoneum announce an incomplete cytoreduction, being surgically unresectable disease the most important reason to not achieve optimal results. In conclusion, distant, metastatic nodes and pelvic retroperitoneal invasion are independent prognostic factors in patients with EOC resulting in reduced survival. Distant metastatic nodes are indicative of advanced clinical disease.
Guarantor of the integrity of the study: A. Pereira, T. PerezMedina, L. Ortiz-Quintana. Study concepts: A. Pereira, T. Perez-Medina. Study design: A. Pereira, T. Perez-Medina. Definition of intellectual content: A. Pereira, J.F. Magrina, P.M. Magtibay. Literature research: A. Pereira, A. Rodriguez-Tapia. Clinical studies: A. Pereira, J.F. Magrina, P.M. Magtibay. Data acquisition: A. Pereira, A. Rodriguez-Tapia. Data analysis: A. Pereira, T. Perez-Medina, F. Perez-Milan. Statistical analysis: A. Pereira, F. Perez-Milan, A. RodriguezTapia. Manuscript preparation: A. Pereira, J.F. Magrina, P.M. Magtibay. Manuscript editing: A. Pereira, J.F. Magrina, P.M. Magtibay. Manuscript review: All authors. References [1] Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al. The effect of diameter of largest residual disease after primary cytoreductive surgery on survival in patients with suboptimal residual epithelial ovarian carcinoma: a Gynecologic Oncology Group Study. Am J Obstet Gynecol 1994;170:974e80. [2] Eisenkop SM, Nalick RH, Wang HJ, Teng NN. Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: impact on survival. Gynecol Oncol 1993 Nov;51(2):224e9. [3] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003 Aug;90(2):390e6. [4] Benedet JL, Pecorelli S. Why cancer staging? Int J Gynecol Obstet 2006;95(Suppl. l):S3. [5] Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006 Nov;95(Suppl. 1):S161e92. [6] Panici PB, Maggioni A, Hacker N, Landoni F, Ackermann S, Campagnutta E, 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 Apr 20;97(8):560e6. [7] Pereira A, Pérez-Medina T, Magrina JF, Magtibay PM, Millan I, Iglesias E. The role of lymphadenectomy in node-positive epithelial ovarian cancer. Int J Gynecol Cancer 2012 Jul;22(6):987e92. [8] Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009 May;105(2):103e4. [9] FIGO Cancer Committee. Staging announcement. Gynecol Oncol 1986;25:383. [10] Hosmer DW, Lemeshow S. Applied logistic regression. Wiley-Interscience; 2000. [11] Pereira A, Magrina JF, Rey V, Cortes M, Magtibay PM. Pelvic and aortic lymph node metastasis in epithelial ovarian cancer. Gynecol Oncol 2007 Jun;105(3): 604e8. [12] Pereira A, Magrina JF, Magtibay PM, Pérez-Medina T, Fernández A, Peregrin I. The impact of peritoneal metastases in epithelial ovarian cancer with positive nodes. Int J Gynecol Cancer November 2011;21(8):1375e9. [13] Wimberger P, Kimmig R. The role of radical lymphadenectomy. Experiences from the AGO Ovarian Cancer Study Group. Urologe A 2009 Jan;48(1):26e31. [14] Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, et al. Metastatic patterns in adenocarcinoma. Cancer 2006 Apr 1;106(7):1624e33. [15] Desteli D. Lymph node metastasis in grossly apparent clinical stage Ia epithelial ovarian cancer: Hacettepe experience and review of literature. World J Surg Oncol 2010 Nov;30(8):106. [16] Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, Rabitti C, et al. Anatomical and pathological study of retroperitoneal nodes in epithelial ovarian cancer. Gynecol Oncol 1993;51:150e4. [17] Morice P, Joulie F, Camatte S, Atallah D, Rouzier R, Pautier P, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg 2003;197:198e 205.
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