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The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?
YGYNO-976327; No. of pages: 5; 4C: Gynecologic Oncology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified? Beyhan Ataseven a,⁎, Philipp Harter a, Christoph Grimm a,b, Florian Heitz a, Sebastian Heikaus c, Alexander Traut a, Annett Kahl a, Christian Kurzeder a, Sonia Prader a, Andreas du Bois a a b c
Department of Gynecology and Gynecologic Oncology, Evangelische Huyssens-Stiftung, Kliniken Essen-Mitte, Essen, Germany Department of Gynecology and Gynecologic Oncology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria Center for Pathology, Kliniken Essen-Mitte, Am Deimelsberg 34, 45276 Essen, Germany
H I G H L I G H T S • Current FIGO classification envisages a subclassification of stage IV in IVA and IVB. • Prognostic impact of subclassification in stage IVA and IVB was evaluated. • Revised FIGO IV subclassification did not add additional prognostic information.
a r t i c l e
i n f o
Article history: Received 22 April 2016 Received in revised form 15 May 2016 Accepted 17 May 2016 Available online xxxx
a b s t r a c t Objective. The revised 2014 FIGO staging system for epithelial ovarian cancer (EOC) included many changes of the previous system, particularly dividing FIGO stage IV in two subgroups. We evaluated if classifying patients with EOC in FIGO stage IVA and IVB has any prognostic implication. © 2016 Elsevier Inc. All rights reserved.
Keywords: New FIGO classification Stage IV epithelial ovarian cancer Overall survival
Patients and methods We analyzed our prospectively maintained institutional database for primary EOC and included only consecutive FIGO stage IV patients treated between 2000 and 2014. Patients were classified in two cohorts: FIGO IVA and FIGO IVB. Patients with abdominal-wall-metastasis after laparoscopy as the only manifestation of distant metastasis were excluded. Survival analyses included the Kaplan-Meier method, log-rank test and Cox proportional hazards models. Results In total, 240 consecutive patients with FIGO stage IV disease were identified. According to the new classification 102 (42.5%) and 138 (57.5%) patients were classified into FIGO IVA and FIGO IVB, ⁎ Corresponding author at: Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Henricistrasse 92, 45136 Essen, Germany. E-mail address: [email protected] (B. Ataseven).
respectively. In 45 of 138 (32.6%) patients with FIGO stage IVB at least two or more metastatic manifestations each of them defining stage FIGO IV were detected. Median overall survival was 25 and 28 in FIGO IVA and IVB (p = 0.299), respectively. In multivariate analysis, only performance status, lymph node status, ascites volume and residual tumor after surgery, but not FIGO stage IV subgroups were significantly associated with overall survival. Conclusion In the present analysis, the revised FIGO system for stage IV did not add prognostic information for patients with FIGO IVA or FIGO IVB challenging this particular part of the new FIGO system. 1. Introduction The primary goal of cancer classification systems is not only to provide an international accepted, intuitive, descriptive and easy usable language between oncologists, but also to reflect the prognosis of the disease in order to adapt and compare study results for different
http://dx.doi.org/10.1016/j.ygyno.2016.05.021 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
2
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
oncologic treatments [1,2]. Therefore, periodical reevaluation and adoption of the classification system due to new research information, better diagnostic and/or surgical options in order to optimize the meaningfulness of the system is mandatory. In 2014 the International Federation of Gynecology and Obstetrics (FIGO) published an updated classification for epithelial ovarian, fallopian and peritoneal cancer (EOC) [3]. The three major changings are related to following disease stages: (1) Subgrouping of stage FIGO IC patients in FIGO IC1, IC2, and IC3 based on the occurrence of intraoperative surgical spillage, capsule rupture before surgery or extracapsular tumor spread, and detection of malignant ascites, respectively. (2) Revision of stage III patients with respect to the presence of retroperitoneal lymph node involvement without intraperitoneal dissemination beyond the pelvis (IIIA1), microscopic peritoneal metastasis beyond the pelvis irrespective of retroperitoneal lymph node metastasis (IIIA2), and macroscopic extrapelvic tumor spread up to 2 cm (IIIB) or N2 cm (IIIC) both irrespective of the presence of retroperitoneal lymph node metastasis, respectively. (3) Subgrouping of stage IV patients in FIGO IVA including patients with malignant pleural effusion or pleural lesions and FIGO IVB describing patients with intra- and extraabdominal parenchymal metastases and extra-abdominal lymph node metastasis. Moreover, patients with inguinal lymph node metastasis and transmural bowel infiltration with mucosal involvement are now considered as FIGO stage IVB. However, despite these changes some controversial issues, especially with respect to FIGO stage IV remain still unsolved [3]. For example, how does the prognosis of patients with solely transmural bowel infiltration differ from those patients with distant extraabdominal metastasis (e.g. lung, breast, mediastinal or cervical lymph nodes) or is this only a fact of stepwise continuous tumor spread caused by time passing due to e.g. delayed preoperative diagnostic procedure or waiting time for surgery? Moreover, should isolated parenchymal liver and splenic metastasis susceptible for complete resection rather be classified as stage IIIC disease than IVB? There is also a controversial discussion whether patients with umbilical deposits should more appropriately be classified as stage IIIC than IVB [3] as the prognosis of these patients seem to be better than of those patients with distant extraabdominal metastasis. Recently, we were able to demonstrate in a large cohort of patients with abdominal-wall-metastases (AWM), that the prognosis of patients classified as FIGO IVB based only on AWM was significantly superior compared with patients who were classified as stage IV because of other metastasis, but did not differ significantly from patients classified as FIGO stage IIIC (in press). The first aim was to examine whether the increased complexity of the new FIGO IV classification with a separation into FIGO IVA and IVB resulted in improved prognostic accuracy. The second aim was to evaluate the prognostic impact of multiple versus single distant metastatic locations on overall survival.
suspicious cardiophrenic lymph nodes ≥10 mm in their small diameter in pre-operative CT-scan were removed, if performance status allowed this additional procedure and intraabdominal cytoreduction was achieved. For further evaluation we re-categorized all patients with respect to the new FIGO classification [3] and focused for further analysis only on FIGO IV patients. Hence, we excluded patients, who were categorized as FIGO IVB due to only AWM (n = 86), as we could demonstrate in a previous analysis, that the prognosis of these patients was similar to patients with FIGO IIIC disease, but significantly better compared with FIGO IV patients (in press). The remaining FIGO IV patients were grouped as stage FIGO IVA (n = 102) and stage FIGO IVB (n = 138). Based on the amount of distant metastatic locations, FIGO IVB patients were subdivided in FIGO IVB-uni (n = 93, only one metastatic lesion) or FIGO IVB-multi (n = 45; more than one metastatic lesion), if only one or more distant metastatic locations were present, respectively. Surgery was performed by accredited gynecological oncologists including a routine intraoperative second opinion model for all cases, if complete resection could not be achieved. In these cases, a second gyneco-oncologist evaluated independently the situs and had to confirm, that complete resection was not possible. Platinum-based chemotherapy was recommended stage adapted after surgery according to standard guidelines [4,5]. In all patients with pleural effusion, cytologic evaluation for staging purpose was mandatory. Patients, who presented simultaneously with malignant pleural effusion and other distant metastasis, were categorized as FIGO IVB-multi. Patients with malignant pleural effusion and AWM, but no further distant metastasis, were categorized as FIGO IVA. All patients gave informed consent for documentation of clinical data in the associated clinical tumor registries for clinical research and quality assurance. 3. Statistics Standard statistical analyses were used to evaluate descriptive statistics such as mean, median, frequencies, and percentages: frequency (%) for categorical variables; median/range for ordinal variables and age; mean (standard deviation = SD) for normally distributed metric variables. Uni- and multivariable survival analyses were performed using Kaplan-Meier and Cox proportional hazard models, respectively. A logistic regression model was conducted to analyze the association of FIGO IV subgroups on OS adjusting for potential confounding variables. Overall survival (OS) was calculated from the date of surgery to either the last follow-up or the date of death. All statistical tests were two-sided, and p-value of b0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 20.0 (IBM Corporation, New York, USA).
2. Patients and methods
4. Results
Our prospectively maintained institutional ovarian cancer database was analyzed. Between January 2000 to December 2014 1.087 consecutive patients with primary EOC were treated at our tertiary gynecologic oncology centers (Kliniken Essen-Mitte, Essen and Dr.-Horst-SchmidtKliniken, Wiesbaden). In general, all patients treated with neoadjuvant chemotherapy (including those with stage FIGO IV), borderline tumors, and non-epithelial ovarian neoplasms were excluded. Beside gynecologic examination vaginal and abdominal ultrasound were performed in every case. In addition, abdominal CT-scan was performed routinely and chest-CT-scan was performed in most patients (some patients in earlier years had only chest X-rays). PET-CT, MRI, and video-assisted thoracoscopy (VATS) was only performed in selected cases. In patients with pleural effusion cytologic examination was conducted in all cases and in all cases not showing contraindications (e.g. poor performance status or inoperability defined anyhow) the pleural cavity was opened and biopsies were taken in case of suspicious lesions. Since 2013 all
4.1. Patient's characteristics A total of 240 patients with FIGO IV disease were included into the present study. Patients' characteristics are shown in Table 1. The vast majority (n = 151; 62.9%) of the patients were 65 years and younger, presented in a good performance status (ECOG 0, 72.5%), had large volume ascites at diagnosis (N 500 mL; 60.0%), were node positive in 62.5%, and had high grade serous EOC (87.9%). Complete tumor resection could be achieved after primary debulking surgery in 98 (40.8%) patients. FIGO stage IV was due to the presence of pleural effusion and/ or pleural metastasis in 102 patients (42.5%). In the remaining 138 patients, which are categorized as FIGO IVB, 93 patients had only one metastatic location (FIGO IVB-uni) and in 45 patients more than one metastatic location was detected (FIGO IVB-multi). The distribution of the FIGO IVB patients and their most frequent metastatic location is shown in Table 2.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
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Table 1 Patient's characteristics of women with stage FIGO IV epithelial ovarian cancer. FIGO IV total
FIGO IVA
FIGO IVB total
FIGO IVB uni
FIGO IVB multi
n
%
n
%
n
%
n
%
n
%
Total
240
100
102
100
138
100
93
100
45
100
Age (years) ≤65 N65
151 89
62.9 37.1
62 40
60.8 39.2
89 49
64.5 35.5
58 35
62.4 37.6
31 14
68.9 31.1
Performance status ECOG 0 174 ECOG N0 66
72.5 27.5
73 29
71.4 28.4
110 37
73.2 26.8
70 23
75.3 24.7
31 14
68.9 31.1
Ascites (mL) b500 mL N500 mL
96 144
40.0 60.0
36 66
35.3 64.7
60 78
43.5 56.7
43 50
46.2 53.8
17 28
37.8 62.2
Tumor-stage T1-3b T3c/x
23 217
9.6 90.4
5 97
4.9 95.3
18 120
13.0 87.0
15 78
16.1 83.9
3 42
6.7 93.3
Nodal status N0 N1 NX
23 150 67
9.6 62.5 27.9
10 66 26
9.8 64.7 25.5
13 84 41
9.4 60.9 29.7
9 60 24
9.7 64.5 25.8
4 24 17
8.9 53.3 37.8
Histology HGSOC Others
211 29
87.9 12.1
94 8
92.2 7.8
117 21
84.8 15.2
81 12
87.1 12.9
36 9
80.0 20.0
40.8 59.2
33 69
32.4 67.6
65 73
47.1 52.9
47 46
50.5 49.5
18 27
40.0 60.0
Residual disease after surgery RD 0 98 RD N0 142
ECOG = Eastern Cooperative Oncology Group performance status RD residual disease HGSOC = high grade serous ovarian cancer.
4.2. Prognostic factors of overall survival in subgroups
5. Discussion
After a median follow-up of 32 months (interquartile range 13– 85 months), 133 (55.4%) patients had died. We observed a median OS of 25 months (95% CI = 19–30 months) in the total cohort. Median OS between the two subgroups FIGO IVA and FIGO IVB did not differ significantly with 25 and 28 months, respectively (p = 0.299, Fig. 1). In addition, OS did not differ significantly between the FIGO IVB groups broken down by number of metastatic localizations and was 26 months (95% CI = 11–41 months) and 25 months (95% CI = 8–42 months) in FIGI IVB-uni and FIGO IVB-multi, respectively (p = 0.166). Univariate analysis revealed patients' age (N 65 years), poor performance status (ECOG N 0), high intraabdominal tumor stage (pT3c), large ascites volume (N 500 mL), positive nodal status, and postoperative residual tumor (RD N0 mm) as significant prognostic factors for OS (Table 3). In multivariate analysis, poor performance status, nodal status, ascites ≥500 mL, and residual tumor remained independently associated with worse OS (Table 3).
The staging system for ovarian, fallopian tube, and primary peritoneal cancer underwent a major revision in 2014 [3]. In the current study, we outlined the prognostic impact of the subgroups within the revised FIGO stage IV on overall survival. Our analysis was based on a large cohort of EOC patients, who were treated at a single institution with high expertise in the treatment of EOC over 14 years. Overall, our results revealed no prognostic relevance of the FIGO IV subclassification for overall survival of patients with EOC. Moreover, no prognostic difference was found within the FIGO stage IVB subgroups with one (FIGO IVBuni) compared to multiple metastatic locations (FIGO IVB-multi) at the time of diagnosis. In general, the aim of a staging system is manifold including a clear descriptive way to represent the stage of disease, an intuitive schedule of cancer terminology offering an easy communication among oncologists, a consistency for clinical trials, and a prognostic accuracy for patients to individualize and adopt treatment modalities. Next to various other changes the current FIGO classification provides more
Table 2 Distribution of metastatic location in FIGO IVB patients. FIGO IVB-uni
FIGO IVB-multi (↔) Spleen
Spleen Pleural⁎ Liver Lung Ext. LN⁎⁎ Pancreas Stomach Others
12 0 28 3 41 1 0 8
Pleural*
Liver
Lung
Ext. LN⁎⁎
Pancreas
Stomach
Others
2
2 6
0 4 4
3 9 5 2
1 2 0 0 0
1 1 0 0 1 0
2 2 1 1 3 0 0
⁎ Patients with malignant pleural effusion und metastatic parietal pleural dissemination. ⁎⁎ Metastatic extraabdominal lymph node.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
4
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
Fig. 1. Overall survival in patients with stage IV epithelial ovarian cancer according to subgroup FIGO IVA or FIGO IVB.
Table 3 Univariate and multivariate analysis for overall survival (OS) in patients with FIGO stage IV epithelial ovarian cancer. Overall survival
Age (years) ≤65 N65
Total
Events
Univariate
Multivariate
n
n
%
p-value
HR
CI 95%
0.002
1 1.41
0.98–2.02
0.065
1 2.02
1.36–3.10
b0.001
1 1.55
1.03–2.31
0.034
0.026
1 1.23
0.62–2.42
0.558
1.26–2.95 1.53–6.52
0.009 0.002
151 89
p-value
82 51
54.3 57.3
79 54
45.4 81.8
40 93
41.7 64.6
23 217
12 121
52.2 55.8
23 150 67
11 75 47
47.8 50.0 70.1
b0.001
1 2.50 3.15
211 29
112 21
53.1 72.4
0.837
1 1.06
0.59–1.91
0.845
Residual disease after surgery RD 0 98 37 RD N0 142 96
37.8 67.6
b0.001
1 1.65
1.03–2.65
0.037
FIGO IV stage IVA IVB IVB-uni IVB-multi
57.8 53.6 44.7 67.9
0.65–1.40
0.812
Performance status ECOG 0 174 ECOG N0 66 Ascites (mL) b500 mL 96 N500 mL 144 Tumor stage T1-3b T3c/x Nodal status N0 N1 NX Histology HGSOC Others
102 138 85 53
59 74 38 36
b0.001 b0.001
0.299 0.122
1 0.96 – –
–
ECOG = Eastern Cooperative Oncology Group performance status HR (95% CI) = hazard ratio (95% confidence interval) HGSOC = high grade serous ovarian cancer RD = residual disease.
–
information regarding FIGO stage IV patients, as patients with malignant pleural effusion or metastases are distinctly separated from other patients with distant metastasis. As demonstrated by Eitan et al. [6] the overall survival of patients with malignant pleural effusion was significantly poorer compared with patients with stage IIIC disease (30 versus 58 months, p = 0.016). However, the authors did not compare patients with malignant pleural effusion to patients with other distant metastasis. A recent retrospective study based on 37 FIGO IVA and 57 FIGO IVB patients detected no significant differences for progressionfree and overall survival in patients with FIGO stage IVA and FIGO stage IVB [7]. This result is in line with our findings when we compared a considerably larger cohort and also failed to detect any improvement of survival accuracy by the new nomenclature even after adjusting for established prognostic confounders. Furthermore, we analyzed whether a greater distant tumor burden as represented by two or more metastatic sites has an impact on patients' overall survival. Again, we detected no significant difference between these two subgroups. This is of particular interest, as the likelihood for complete macroscopic tumor resection in FIGO stage IV patients depends at least partially on the localization of the metastasis. Of course, it has to be taken into account that OS of patients with EOC depends in addition to tumor stage on a variety of other prognostic factors. For example, the prognostic impact of residual disease on overall survival of EOC patients has been clearly demonstrated previously for advanced disease. Patients with stage FIGO IIB-IIIB, FIGO IIIC, and FIGO IV gained an absolute survival benefit through a complete tumor resection by 60, 47, and 30 months, respectively [9]. More recent publications showed a significant improvement of the complete resection rate from 38% to 62% (observation period 2000–2005 versus 2010–2014) in FIGO IV disease with consecutively improved two-year-overall survival rates (48% versus 62%) [8]. However, even including these prognostic factors into multivariate analysis did not detect a prognostic relevance of FIGO stage IVA and IVB. The present study has some limitations. Firstly, as already mentioned, this is a retrospective study and selection bias cannot be ruled out. We tried to account for this by including all consecutive patients fulfilling the inclusion criteria. Secondly, patients were re-categorized with emphasis on the new FIGO classification specifications. However, some information due to the up-staging of previously FIGO IIB-FIGO
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
IIIC patients with solely transmural bowel infiltration might be missed because we did not focus on these criteria in earlier years. However, we analyzed the prospective prevalence of patients with solely transmural bowel infiltration in 2014/2015 and found this event to be extremely rare (5 cases of transmural bowel infiltration in 105 FIGO IVB cases; data not shown). Thirdly, extent of surgery and subsequently complete resection rates has changed slightly within the last 14 years, but the standard of systemic treatment has not changed. In summary, the differentiation of stage FIGO IV in the revised 2014 FIGO staging system for ovarian, fallopian tube and primary peritoneal cancer did not lead to an improved prognostic accuracy. Further tumorbiological factors may help to better differentiate EOC in the future. Conflict of interest The authors declare no conflicts of interests with respect to the topic of this work. References
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[2] F. Odicino, S. Pecorelli, L. Zigliani, W.T. Creasman, History of the FIGO cancer staging system, Int. J. Gynaecol. Obstet. 101 (2008) 205–210. [3] J. Prat, Staging classification for cancer of the ovary, fallopian tube, and peritoneum, Int. J. Gynaecol. Obstet. 124 (2014) 1–5. [4] A. du Bois, M. Quinn, T. Thigpen, J. Vermorken, E. Avall-Lundqvist, M. Bookman, et al., 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004), Ann. Oncol. 16 (Suppl. 8) (2005) viii7–viii12. [5] G.C. Stuart, H. Kitchener, M. Bacon, A. duBois, M. Friedlander, J. Ledermann, et al., Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference, Int. J. Gynecol. Cancer 21 (2010) 750–755. [6] R. Eitan, D.A. Levine, N. Abu-Rustum, Y. Sonoda, J.N. Huh, C.C. Franklin, et al., The clinical significance of malignant pleural effusions in patients with optimally debulked ovarian carcinoma, Cancer 103 (2005) 1397–1401. [7] E.S. Paik, Y.Y. Lee, E.J. Lee, C.H. Choi, T.J. Kim, J.W. Lee, et al., Survival analysis of revised 2013 FIGO staging classification of epithelial ovarian cancer and comparison with previous FIGO staging classification, Obstet. Gynecol. Sci. 58 (2015) 124–134. [8] B. Ataseven, C. Grimm, P. Harter, F. Heitz, A. Traut, S. Prader, et al., Prognostic impact of debulking surgery and residual tumor in patients with epithelial ovarian cancer FIGO stage IV, Gynecol. Oncol. (2015). [9] A. du Bois, A. Reuss, E. Pujade-Lauraine, P. Harter, I. Ray-Coquard, J. Pfisterer, Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux pour les Etudes des cancers de l'Ovaire (GINECO), Cancer 115 (2009) 1234–1244.
[1] M.K. Gospodarowicz, D. Miller, P.A. Groome, F.L. Greene, P.A. Logan, L.H. Sobin, The process for continuous improvement of the TNM classification, Cancer 100 (2004) 1–5.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified? Beyhan Ataseven a,⁎, Philipp Harter a, Christoph Grimm a,b, Florian Heitz a, Sebastian Heikaus c, Alexander Traut a, Annett Kahl a, Christian Kurzeder a, Sonia Prader a, Andreas du Bois a a b c
Department of Gynecology and Gynecologic Oncology, Evangelische Huyssens-Stiftung, Kliniken Essen-Mitte, Essen, Germany Department of Gynecology and Gynecologic Oncology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria Center for Pathology, Kliniken Essen-Mitte, Am Deimelsberg 34, 45276 Essen, Germany
H I G H L I G H T S • Current FIGO classification envisages a subclassification of stage IV in IVA and IVB. • Prognostic impact of subclassification in stage IVA and IVB was evaluated. • Revised FIGO IV subclassification did not add additional prognostic information.
a r t i c l e
i n f o
Article history: Received 22 April 2016 Received in revised form 15 May 2016 Accepted 17 May 2016 Available online xxxx
a b s t r a c t Objective. The revised 2014 FIGO staging system for epithelial ovarian cancer (EOC) included many changes of the previous system, particularly dividing FIGO stage IV in two subgroups. We evaluated if classifying patients with EOC in FIGO stage IVA and IVB has any prognostic implication. © 2016 Elsevier Inc. All rights reserved.
Keywords: New FIGO classification Stage IV epithelial ovarian cancer Overall survival
Patients and methods We analyzed our prospectively maintained institutional database for primary EOC and included only consecutive FIGO stage IV patients treated between 2000 and 2014. Patients were classified in two cohorts: FIGO IVA and FIGO IVB. Patients with abdominal-wall-metastasis after laparoscopy as the only manifestation of distant metastasis were excluded. Survival analyses included the Kaplan-Meier method, log-rank test and Cox proportional hazards models. Results In total, 240 consecutive patients with FIGO stage IV disease were identified. According to the new classification 102 (42.5%) and 138 (57.5%) patients were classified into FIGO IVA and FIGO IVB, ⁎ Corresponding author at: Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Henricistrasse 92, 45136 Essen, Germany. E-mail address: [email protected] (B. Ataseven).
respectively. In 45 of 138 (32.6%) patients with FIGO stage IVB at least two or more metastatic manifestations each of them defining stage FIGO IV were detected. Median overall survival was 25 and 28 in FIGO IVA and IVB (p = 0.299), respectively. In multivariate analysis, only performance status, lymph node status, ascites volume and residual tumor after surgery, but not FIGO stage IV subgroups were significantly associated with overall survival. Conclusion In the present analysis, the revised FIGO system for stage IV did not add prognostic information for patients with FIGO IVA or FIGO IVB challenging this particular part of the new FIGO system. 1. Introduction The primary goal of cancer classification systems is not only to provide an international accepted, intuitive, descriptive and easy usable language between oncologists, but also to reflect the prognosis of the disease in order to adapt and compare study results for different
http://dx.doi.org/10.1016/j.ygyno.2016.05.021 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
2
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
oncologic treatments [1,2]. Therefore, periodical reevaluation and adoption of the classification system due to new research information, better diagnostic and/or surgical options in order to optimize the meaningfulness of the system is mandatory. In 2014 the International Federation of Gynecology and Obstetrics (FIGO) published an updated classification for epithelial ovarian, fallopian and peritoneal cancer (EOC) [3]. The three major changings are related to following disease stages: (1) Subgrouping of stage FIGO IC patients in FIGO IC1, IC2, and IC3 based on the occurrence of intraoperative surgical spillage, capsule rupture before surgery or extracapsular tumor spread, and detection of malignant ascites, respectively. (2) Revision of stage III patients with respect to the presence of retroperitoneal lymph node involvement without intraperitoneal dissemination beyond the pelvis (IIIA1), microscopic peritoneal metastasis beyond the pelvis irrespective of retroperitoneal lymph node metastasis (IIIA2), and macroscopic extrapelvic tumor spread up to 2 cm (IIIB) or N2 cm (IIIC) both irrespective of the presence of retroperitoneal lymph node metastasis, respectively. (3) Subgrouping of stage IV patients in FIGO IVA including patients with malignant pleural effusion or pleural lesions and FIGO IVB describing patients with intra- and extraabdominal parenchymal metastases and extra-abdominal lymph node metastasis. Moreover, patients with inguinal lymph node metastasis and transmural bowel infiltration with mucosal involvement are now considered as FIGO stage IVB. However, despite these changes some controversial issues, especially with respect to FIGO stage IV remain still unsolved [3]. For example, how does the prognosis of patients with solely transmural bowel infiltration differ from those patients with distant extraabdominal metastasis (e.g. lung, breast, mediastinal or cervical lymph nodes) or is this only a fact of stepwise continuous tumor spread caused by time passing due to e.g. delayed preoperative diagnostic procedure or waiting time for surgery? Moreover, should isolated parenchymal liver and splenic metastasis susceptible for complete resection rather be classified as stage IIIC disease than IVB? There is also a controversial discussion whether patients with umbilical deposits should more appropriately be classified as stage IIIC than IVB [3] as the prognosis of these patients seem to be better than of those patients with distant extraabdominal metastasis. Recently, we were able to demonstrate in a large cohort of patients with abdominal-wall-metastases (AWM), that the prognosis of patients classified as FIGO IVB based only on AWM was significantly superior compared with patients who were classified as stage IV because of other metastasis, but did not differ significantly from patients classified as FIGO stage IIIC (in press). The first aim was to examine whether the increased complexity of the new FIGO IV classification with a separation into FIGO IVA and IVB resulted in improved prognostic accuracy. The second aim was to evaluate the prognostic impact of multiple versus single distant metastatic locations on overall survival.
suspicious cardiophrenic lymph nodes ≥10 mm in their small diameter in pre-operative CT-scan were removed, if performance status allowed this additional procedure and intraabdominal cytoreduction was achieved. For further evaluation we re-categorized all patients with respect to the new FIGO classification [3] and focused for further analysis only on FIGO IV patients. Hence, we excluded patients, who were categorized as FIGO IVB due to only AWM (n = 86), as we could demonstrate in a previous analysis, that the prognosis of these patients was similar to patients with FIGO IIIC disease, but significantly better compared with FIGO IV patients (in press). The remaining FIGO IV patients were grouped as stage FIGO IVA (n = 102) and stage FIGO IVB (n = 138). Based on the amount of distant metastatic locations, FIGO IVB patients were subdivided in FIGO IVB-uni (n = 93, only one metastatic lesion) or FIGO IVB-multi (n = 45; more than one metastatic lesion), if only one or more distant metastatic locations were present, respectively. Surgery was performed by accredited gynecological oncologists including a routine intraoperative second opinion model for all cases, if complete resection could not be achieved. In these cases, a second gyneco-oncologist evaluated independently the situs and had to confirm, that complete resection was not possible. Platinum-based chemotherapy was recommended stage adapted after surgery according to standard guidelines [4,5]. In all patients with pleural effusion, cytologic evaluation for staging purpose was mandatory. Patients, who presented simultaneously with malignant pleural effusion and other distant metastasis, were categorized as FIGO IVB-multi. Patients with malignant pleural effusion and AWM, but no further distant metastasis, were categorized as FIGO IVA. All patients gave informed consent for documentation of clinical data in the associated clinical tumor registries for clinical research and quality assurance. 3. Statistics Standard statistical analyses were used to evaluate descriptive statistics such as mean, median, frequencies, and percentages: frequency (%) for categorical variables; median/range for ordinal variables and age; mean (standard deviation = SD) for normally distributed metric variables. Uni- and multivariable survival analyses were performed using Kaplan-Meier and Cox proportional hazard models, respectively. A logistic regression model was conducted to analyze the association of FIGO IV subgroups on OS adjusting for potential confounding variables. Overall survival (OS) was calculated from the date of surgery to either the last follow-up or the date of death. All statistical tests were two-sided, and p-value of b0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 20.0 (IBM Corporation, New York, USA).
2. Patients and methods
4. Results
Our prospectively maintained institutional ovarian cancer database was analyzed. Between January 2000 to December 2014 1.087 consecutive patients with primary EOC were treated at our tertiary gynecologic oncology centers (Kliniken Essen-Mitte, Essen and Dr.-Horst-SchmidtKliniken, Wiesbaden). In general, all patients treated with neoadjuvant chemotherapy (including those with stage FIGO IV), borderline tumors, and non-epithelial ovarian neoplasms were excluded. Beside gynecologic examination vaginal and abdominal ultrasound were performed in every case. In addition, abdominal CT-scan was performed routinely and chest-CT-scan was performed in most patients (some patients in earlier years had only chest X-rays). PET-CT, MRI, and video-assisted thoracoscopy (VATS) was only performed in selected cases. In patients with pleural effusion cytologic examination was conducted in all cases and in all cases not showing contraindications (e.g. poor performance status or inoperability defined anyhow) the pleural cavity was opened and biopsies were taken in case of suspicious lesions. Since 2013 all
4.1. Patient's characteristics A total of 240 patients with FIGO IV disease were included into the present study. Patients' characteristics are shown in Table 1. The vast majority (n = 151; 62.9%) of the patients were 65 years and younger, presented in a good performance status (ECOG 0, 72.5%), had large volume ascites at diagnosis (N 500 mL; 60.0%), were node positive in 62.5%, and had high grade serous EOC (87.9%). Complete tumor resection could be achieved after primary debulking surgery in 98 (40.8%) patients. FIGO stage IV was due to the presence of pleural effusion and/ or pleural metastasis in 102 patients (42.5%). In the remaining 138 patients, which are categorized as FIGO IVB, 93 patients had only one metastatic location (FIGO IVB-uni) and in 45 patients more than one metastatic location was detected (FIGO IVB-multi). The distribution of the FIGO IVB patients and their most frequent metastatic location is shown in Table 2.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
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Table 1 Patient's characteristics of women with stage FIGO IV epithelial ovarian cancer. FIGO IV total
FIGO IVA
FIGO IVB total
FIGO IVB uni
FIGO IVB multi
n
%
n
%
n
%
n
%
n
%
Total
240
100
102
100
138
100
93
100
45
100
Age (years) ≤65 N65
151 89
62.9 37.1
62 40
60.8 39.2
89 49
64.5 35.5
58 35
62.4 37.6
31 14
68.9 31.1
Performance status ECOG 0 174 ECOG N0 66
72.5 27.5
73 29
71.4 28.4
110 37
73.2 26.8
70 23
75.3 24.7
31 14
68.9 31.1
Ascites (mL) b500 mL N500 mL
96 144
40.0 60.0
36 66
35.3 64.7
60 78
43.5 56.7
43 50
46.2 53.8
17 28
37.8 62.2
Tumor-stage T1-3b T3c/x
23 217
9.6 90.4
5 97
4.9 95.3
18 120
13.0 87.0
15 78
16.1 83.9
3 42
6.7 93.3
Nodal status N0 N1 NX
23 150 67
9.6 62.5 27.9
10 66 26
9.8 64.7 25.5
13 84 41
9.4 60.9 29.7
9 60 24
9.7 64.5 25.8
4 24 17
8.9 53.3 37.8
Histology HGSOC Others
211 29
87.9 12.1
94 8
92.2 7.8
117 21
84.8 15.2
81 12
87.1 12.9
36 9
80.0 20.0
40.8 59.2
33 69
32.4 67.6
65 73
47.1 52.9
47 46
50.5 49.5
18 27
40.0 60.0
Residual disease after surgery RD 0 98 RD N0 142
ECOG = Eastern Cooperative Oncology Group performance status RD residual disease HGSOC = high grade serous ovarian cancer.
4.2. Prognostic factors of overall survival in subgroups
5. Discussion
After a median follow-up of 32 months (interquartile range 13– 85 months), 133 (55.4%) patients had died. We observed a median OS of 25 months (95% CI = 19–30 months) in the total cohort. Median OS between the two subgroups FIGO IVA and FIGO IVB did not differ significantly with 25 and 28 months, respectively (p = 0.299, Fig. 1). In addition, OS did not differ significantly between the FIGO IVB groups broken down by number of metastatic localizations and was 26 months (95% CI = 11–41 months) and 25 months (95% CI = 8–42 months) in FIGI IVB-uni and FIGO IVB-multi, respectively (p = 0.166). Univariate analysis revealed patients' age (N 65 years), poor performance status (ECOG N 0), high intraabdominal tumor stage (pT3c), large ascites volume (N 500 mL), positive nodal status, and postoperative residual tumor (RD N0 mm) as significant prognostic factors for OS (Table 3). In multivariate analysis, poor performance status, nodal status, ascites ≥500 mL, and residual tumor remained independently associated with worse OS (Table 3).
The staging system for ovarian, fallopian tube, and primary peritoneal cancer underwent a major revision in 2014 [3]. In the current study, we outlined the prognostic impact of the subgroups within the revised FIGO stage IV on overall survival. Our analysis was based on a large cohort of EOC patients, who were treated at a single institution with high expertise in the treatment of EOC over 14 years. Overall, our results revealed no prognostic relevance of the FIGO IV subclassification for overall survival of patients with EOC. Moreover, no prognostic difference was found within the FIGO stage IVB subgroups with one (FIGO IVBuni) compared to multiple metastatic locations (FIGO IVB-multi) at the time of diagnosis. In general, the aim of a staging system is manifold including a clear descriptive way to represent the stage of disease, an intuitive schedule of cancer terminology offering an easy communication among oncologists, a consistency for clinical trials, and a prognostic accuracy for patients to individualize and adopt treatment modalities. Next to various other changes the current FIGO classification provides more
Table 2 Distribution of metastatic location in FIGO IVB patients. FIGO IVB-uni
FIGO IVB-multi (↔) Spleen
Spleen Pleural⁎ Liver Lung Ext. LN⁎⁎ Pancreas Stomach Others
12 0 28 3 41 1 0 8
Pleural*
Liver
Lung
Ext. LN⁎⁎
Pancreas
Stomach
Others
2
2 6
0 4 4
3 9 5 2
1 2 0 0 0
1 1 0 0 1 0
2 2 1 1 3 0 0
⁎ Patients with malignant pleural effusion und metastatic parietal pleural dissemination. ⁎⁎ Metastatic extraabdominal lymph node.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
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B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
Fig. 1. Overall survival in patients with stage IV epithelial ovarian cancer according to subgroup FIGO IVA or FIGO IVB.
Table 3 Univariate and multivariate analysis for overall survival (OS) in patients with FIGO stage IV epithelial ovarian cancer. Overall survival
Age (years) ≤65 N65
Total
Events
Univariate
Multivariate
n
n
%
p-value
HR
CI 95%
0.002
1 1.41
0.98–2.02
0.065
1 2.02
1.36–3.10
b0.001
1 1.55
1.03–2.31
0.034
0.026
1 1.23
0.62–2.42
0.558
1.26–2.95 1.53–6.52
0.009 0.002
151 89
p-value
82 51
54.3 57.3
79 54
45.4 81.8
40 93
41.7 64.6
23 217
12 121
52.2 55.8
23 150 67
11 75 47
47.8 50.0 70.1
b0.001
1 2.50 3.15
211 29
112 21
53.1 72.4
0.837
1 1.06
0.59–1.91
0.845
Residual disease after surgery RD 0 98 37 RD N0 142 96
37.8 67.6
b0.001
1 1.65
1.03–2.65
0.037
FIGO IV stage IVA IVB IVB-uni IVB-multi
57.8 53.6 44.7 67.9
0.65–1.40
0.812
Performance status ECOG 0 174 ECOG N0 66 Ascites (mL) b500 mL 96 N500 mL 144 Tumor stage T1-3b T3c/x Nodal status N0 N1 NX Histology HGSOC Others
102 138 85 53
59 74 38 36
b0.001 b0.001
0.299 0.122
1 0.96 – –
–
ECOG = Eastern Cooperative Oncology Group performance status HR (95% CI) = hazard ratio (95% confidence interval) HGSOC = high grade serous ovarian cancer RD = residual disease.
–
information regarding FIGO stage IV patients, as patients with malignant pleural effusion or metastases are distinctly separated from other patients with distant metastasis. As demonstrated by Eitan et al. [6] the overall survival of patients with malignant pleural effusion was significantly poorer compared with patients with stage IIIC disease (30 versus 58 months, p = 0.016). However, the authors did not compare patients with malignant pleural effusion to patients with other distant metastasis. A recent retrospective study based on 37 FIGO IVA and 57 FIGO IVB patients detected no significant differences for progressionfree and overall survival in patients with FIGO stage IVA and FIGO stage IVB [7]. This result is in line with our findings when we compared a considerably larger cohort and also failed to detect any improvement of survival accuracy by the new nomenclature even after adjusting for established prognostic confounders. Furthermore, we analyzed whether a greater distant tumor burden as represented by two or more metastatic sites has an impact on patients' overall survival. Again, we detected no significant difference between these two subgroups. This is of particular interest, as the likelihood for complete macroscopic tumor resection in FIGO stage IV patients depends at least partially on the localization of the metastasis. Of course, it has to be taken into account that OS of patients with EOC depends in addition to tumor stage on a variety of other prognostic factors. For example, the prognostic impact of residual disease on overall survival of EOC patients has been clearly demonstrated previously for advanced disease. Patients with stage FIGO IIB-IIIB, FIGO IIIC, and FIGO IV gained an absolute survival benefit through a complete tumor resection by 60, 47, and 30 months, respectively [9]. More recent publications showed a significant improvement of the complete resection rate from 38% to 62% (observation period 2000–2005 versus 2010–2014) in FIGO IV disease with consecutively improved two-year-overall survival rates (48% versus 62%) [8]. However, even including these prognostic factors into multivariate analysis did not detect a prognostic relevance of FIGO stage IVA and IVB. The present study has some limitations. Firstly, as already mentioned, this is a retrospective study and selection bias cannot be ruled out. We tried to account for this by including all consecutive patients fulfilling the inclusion criteria. Secondly, patients were re-categorized with emphasis on the new FIGO classification specifications. However, some information due to the up-staging of previously FIGO IIB-FIGO
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021
B. Ataseven et al. / Gynecologic Oncology xxx (2016) xxx–xxx
IIIC patients with solely transmural bowel infiltration might be missed because we did not focus on these criteria in earlier years. However, we analyzed the prospective prevalence of patients with solely transmural bowel infiltration in 2014/2015 and found this event to be extremely rare (5 cases of transmural bowel infiltration in 105 FIGO IVB cases; data not shown). Thirdly, extent of surgery and subsequently complete resection rates has changed slightly within the last 14 years, but the standard of systemic treatment has not changed. In summary, the differentiation of stage FIGO IV in the revised 2014 FIGO staging system for ovarian, fallopian tube and primary peritoneal cancer did not lead to an improved prognostic accuracy. Further tumorbiological factors may help to better differentiate EOC in the future. Conflict of interest The authors declare no conflicts of interests with respect to the topic of this work. References
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[2] F. Odicino, S. Pecorelli, L. Zigliani, W.T. Creasman, History of the FIGO cancer staging system, Int. J. Gynaecol. Obstet. 101 (2008) 205–210. [3] J. Prat, Staging classification for cancer of the ovary, fallopian tube, and peritoneum, Int. J. Gynaecol. Obstet. 124 (2014) 1–5. [4] A. du Bois, M. Quinn, T. Thigpen, J. Vermorken, E. Avall-Lundqvist, M. Bookman, et al., 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004), Ann. Oncol. 16 (Suppl. 8) (2005) viii7–viii12. [5] G.C. Stuart, H. Kitchener, M. Bacon, A. duBois, M. Friedlander, J. Ledermann, et al., Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference, Int. J. Gynecol. Cancer 21 (2010) 750–755. [6] R. Eitan, D.A. Levine, N. Abu-Rustum, Y. Sonoda, J.N. Huh, C.C. Franklin, et al., The clinical significance of malignant pleural effusions in patients with optimally debulked ovarian carcinoma, Cancer 103 (2005) 1397–1401. [7] E.S. Paik, Y.Y. Lee, E.J. Lee, C.H. Choi, T.J. Kim, J.W. Lee, et al., Survival analysis of revised 2013 FIGO staging classification of epithelial ovarian cancer and comparison with previous FIGO staging classification, Obstet. Gynecol. Sci. 58 (2015) 124–134. [8] B. Ataseven, C. Grimm, P. Harter, F. Heitz, A. Traut, S. Prader, et al., Prognostic impact of debulking surgery and residual tumor in patients with epithelial ovarian cancer FIGO stage IV, Gynecol. Oncol. (2015). [9] A. du Bois, A. Reuss, E. Pujade-Lauraine, P. Harter, I. Ray-Coquard, J. Pfisterer, Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux pour les Etudes des cancers de l'Ovaire (GINECO), Cancer 115 (2009) 1234–1244.
[1] M.K. Gospodarowicz, D. Miller, P.A. Groome, F.L. Greene, P.A. Logan, L.H. Sobin, The process for continuous improvement of the TNM classification, Cancer 100 (2004) 1–5.
Please cite this article as: B. Ataseven, et al., The revised 2014 FIGO staging system for epithelial ovarian cancer: Is a subclassification into FIGO stage IVA and IVB justified?, Gynecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.021