Group A Optimal All N=75 Group B No lymph node sampling N=46 Group C No blind biopsies N=14 P-value A versus B/ A versus C Age 55 54 56 0.92/0.91 FIGO stage Ia Ib Ic ovarian surface Ic capsule rupture Ic ascites/washings IIa 23 (30.7%) 6 (8.0%) 11 (14.7%) 21 (28.0%) 9 (12.0%) 6 (6.7%) 19 (41.3%) 3 (6.5%) 6 (13.0%) 11 (23.9%) 5 (10.9%) 2 (4.3%) 6 (42.9%) 1 (7.1%) 1 (7.1%) 2 (14.3%) 3 (21.4%) 1 (7.1%) 0.91/0.75 Histologic type Serous Mucinous Endometrioid Clear Cell Undifferentiated Other Unknown 22 (29.3%) 12 (16.0%) 28 (37.3%) 10 (13.3%) 1 (1.3%) 1 (1.3%) 1 (1.3%) 15 (32.6%) 11 (23.9%) 12 (26.1%) 4 (8.7%) 1 (2.2%) 0 3 (6.5%) 7 (50%) 1 (7.1%) 3 (21.4%) 1 (7.1%) 0 1 (7.1%) 1 (7.1%) 0.62/0.31 Differentiation Grade Well Moderately Poorly 7 (9.3%) 44 (58.7%) 24 (32.0%) 8 (17.4%) 18 (39.1%) 20 (43.5%) 2 (14.3%) 7 (50%) 5 (35.7%) 0.10/0.78
Table 4. Site of progression in early ovarian cancer patients according to the extent of surgical staging Site of progression (n %) Surgical Staging Group (recurrences/ Number of pts) % Pelvis Outside pelvis Intraperitoneal Retroperitoneal
Both pelvis and outside pelvis Group A (11/75) 14.6% Group B (16/46) 34.8% Group C (5/14) 35.7% 1 (1.3%) 6 (13.1%) 2 (14.3%) 4 (5.3%) 3 (4%) 4 (8.7%) 3 (6.5%) 2 (14.3%) 1 (7.1%) 3 (4%) 3 (6.5%) 0
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Figure 2. Kaplan - Meier curves for overall survival in patients with early ovarian cancer in the observation arm of the trial. Patients in the optimal group A (n=75) and patients with blind biopsies omitted group C (n=14).
P = 0.003 using the log-rank test.
Figure 1. Kaplan - Meier curves for overall survival in patients with early ovarian cancer in the observation arm of the trial. Patients in the optimal group A (n=75) and patients with no para-aortic or pelvic lymph node
sampling (LNS) group B (n=46). P = 0.01 using the log-rank test.
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Figure 1. Kaplan - Meier curves for overall survival in patients with early ovarian cancer in the observation arm of the trial. Patients in the optimal group A (n=75) and patients with no para aortic or pelvic lymph node sampling (LNS) group B (n=46).
P = 0.01 using the log-rank test. 1,0 ,9 ,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0 Group A Optimal Group B No LNS 12 24 36 48 60 72 84 96 108 120 p=0.01
Overall survival (months)
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Figure 2. Kaplan - Meier curves for overall survival in patients with early ovarian cancer in the observation arm of the trial. Patients in the optimal group A (n=75) and patients with blind biopsies omitted group C (n=14).
P = 0.003 using the log-rank test. 1,0 ,9 ,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0 Group A Optimal Group C No Biopsies p=0.003
Overall survival (months)
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DISCUSSION
Lymph node sampling is one of the cornerstones of the surgical staging in early ovarian cancer. Surgical skills are required to carry out a lymph node dissection and the procedure is not without risk or side effects. The morbidity described for a lymphadenectomy includes lymphocyst, nerve and vessel injury and increased operation time and blood loss [3,8].
Performing a lymph node sampling in early ovarian cancer patients can cause problems in daily practice. Most of the patients with early ovarian cancer are diagnosed by a general gynecologist, sometimes unexpected when the patient is operated for acute abdominal pain or a pelvic mass. In this setting the lymph nodes are often not removed and the patient is not always restaged thereafter. Where and by whom the patient with early ovarian cancer is treated depends on the particular organisation of the health care. In the Netherlands there is no referring obligation of patients with early ovarian cancer but a gynaecologic oncologist has to be part of the operating team for a staging surgery which is not in all cases done. To change a system is difficult and solid evidence that centralisation of these patients improves the prognosis, is needed. Studies regarding the prognostic value of all staging steps including lymph node dissection and taking of blind biopsies should contribute to the general application of these steps in the surgical staging of early ovarian cancer patients. In a recent publication Verleye et al. [19] proposed EORTC Gynaecologic Cancer Group (GCG) quality indicators for staging laparotomy in ovarian cancer grossly confined to the pelvis in order to improve the quality of surgery in ovarian carcinoma patients. Kommoss et al. [4] showed that the introduction of a quality assurance and management program for treatment of early ovarian cancer patients represents a major improvement of patient care.
The impact of lymph node sampling, lymphadenectomy or positive nodes on prognosis in early ovarian cancer remains controversial. Baiocchi et al. conducted a multivariate analysis and revealed that lymph node status was the most valuable prognostic factor in patients with disease limited to the ovary [8]. In a recent randomized study in macroscopic early ovarian cancer patients Maggioni et al. [15] performed either a systematic pelvic and para-aortic lymphadenectomy (n=138) or a random sampling of lymph nodes (n=130). The incidence of positive nodes was significantly higher in the lymphadenectomy group than in the sampling group, respectively 22% and 9%, while the recurrence rates were 22% versus 30%. No significant difference in 5-year overall survival (84.2% versus 81.3%) and 5-year progression-free survival (78.3% versus 71.3%) was found between both groups, but this could have been expected as the number of patients randomized was too small to detect a significant difference with a reasonable
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power. Also no difference in the sites of progression was found [15]. In our current study, we found in the group of optimally staged patients only one pelvic recurrence (1%), while in the group without pelvic and or para-aortic lymph node sampling 13% of the patients recurred only in the pelvis. Our study differs from that of Maggioni et al. [15] in various aspects. First, our analysis was a subgroup analysis of a randomized trial with a study design that was not primarily intended to study the omission of particular surgical steps during the staging procedure. Second, Maggioni et al. [15] compared restrictive versus extensive lymph node removal whereas the current study compared lymph node sampling versus no sampling at all. And third, an unknown percentage of patients in Maggioni’s study received postoperative chemotherapy versus no patients in the current study. Contrary to Maggioni’s conclusions we found a significant difference in DFS as well as OS in favour of completely staged patients in our study.
The prognostic significance of lymphadenectomy in the staging of early ovarian cancer is supported by a large retrospective study of stage I ovarian cancer patients of Chan et al. [20]. Lymphadenectomy improved the disease-specific survival of all patients from 87% to 92.6%. Furthermore, they found that the extent of lymphadenectomy (0 nodes, less than 10 nodes, and 10 or more nodes) was a significant prognostic factor for improved survival in the multivariable analysis [20].
We are aware of the limitation of our study with small number of patients especially for the group of patients without blind biopsies. Therefore, we should be careful to draw too strong conclusions, on the other hand all analyses were statistically significant. Furthermore these data were derived from a randomized trial and one of the largest series of early ovarian cancer patients who were treated in a standardized way with well described surgical staging steps.
In our study we have shown that both 5-year DFS and 5-year OS were statistically significantly better for optimally staged patients compared to those in whom either sampling of lymph nodes or taking of blind biopsies were omitted. The 5-year OS decreases from 89% in patients who were optimally staged to 71% when lymph node sampling was not performed. Optimal surgery improved survival by correcting false stage allocation and upstaging.
In conclusion we demonstrated the importance of lymph node sampling and taking of blind peritoneal biopsies in the surgical staging for the prognosis of early ovarian cancer patients in this study.
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