1. Lymphadenectomy in Epithelial Ovarian Cancer
Ginger J. Gardner, MD
Associate Professor, Weill Cornell Medical College
Associate Member, Gynecology Service
Director, Survivorship Program
Department of Surgery
Memorial Sloan-Kettering Cancer Center

2. Ovarian Cancer Debulking Surgical Outcomes
Suboptimal
Residual > 1 cm
Optimal
Residual ≤ 1 cm
Complete Gross Resection
No visible residual
CGR = greatest survival advantage
Bristow RE et al, JCO 2002.
Elattar A et al, Cochrane Database Syst Rev 2011.
Outcomes of cytoreductive surgery for advanced ovarian cancer are usually categorized as suboptimal, optimal, or complete gross resection.
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In the last decade, it has been established that complete gross resection (or CGR, defined as excision of all macroscopically visible disease) confers the greatest survival advantage; therefore, when safely achievable, CGR should be the surgical goal.

3. Diaphragm peritonectomy Splenectomy/distal pancreatectomy
Given that the prognosis of advanced ovarian cancer is associated with residual tumor burden, many gynecologic oncologists are committed to spending hours performing complicated resections such as these.
Because LNs may harbor disease, it is possible that a comprehensive lymphadenectomy would also benefit patient outcome.
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However, is it reasonable to add the surgical time and morbidity of an extensive lymphadenectomy to these already heavy surgical cases if there is no benefit on survival?
Photos: Levine DL, et al. Atlas of Procedures in Gynecologic Oncology 2nd Ed., ©Informa, London 2008.
Cul de sac obliteration for recto-sigmoid resection

4. Ovarian Cancer Debulking Indication for Lymphadenectomy
Suboptimal
Residual > 1 cm
Optimal
Residual ≤ 1 cm
Complete Gross Resection
No visible residual
RCT N=61
HR for OS 1.23 (95%CI )
(Saygili et al, JSO 2002)
RCT N=427
HR for PFS 0.75 (95%CI )
No difference in OS
(Benedetti-Panici et al, JNCI 2005)
Retrospective N=966 with CGR
HR for OS 0.75 (95%CI )
Included IIB-IV all grades/histologies
(du Bois et al, JCO 2010)
No LND
In patients with suboptimal debulking, a small trial revealed no advantage to performing lymph node dissection. This reflects the general clinical practice.
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In patients with optimal debulking, a large randomized controlled trial compared systematic lymphadenectomy to resection of bulky LNs only. They found a 25% improvement in progression free survival with systematic lymphadenectomy but no difference in overall survival. Therefore in this population, bulky LNs must be removed in order to consider all residual tumor sites 1cm or less, however clinically normal LNs need not be excised,.
As for cases where debulking results in CGR, no prospective trials are available to date. A large retrospective study evaluated the role of lymph node dissection and did show improved overall survival, however this study included a diverse population of stage IIB to IV ovarian cancer of all grades and histologies.
For the time being, bulky LNs must be removed in patients with CGR, but it is unclear whether non-enlarged LNs should also be excised.
Bulky LNs only
Bulky LNs
Other LNs?

5. Objective
To determine if the extent of LND is associated with improved PFS and OS in patients otherwise achieving CGR at primary cytoreductive surgery for advanced stage high grade serous ovarian cancer.
The purpose of our study was to determine if the extent of lymphadenectomy is associated with improved Progression Free and Overall Survival in patients otherwise achieving Complete Gross Resection at primary cytoreductive surgery for advanced stage high grade serous ovarian cancer.

6. Patient population Inclusion: Exclusion: Stage IIIC-IV Ovarian cancer
Serous histology
Grade 3/high grade
Primary debulking between 10/ /2009
Surgical outcome = CGR
Exclusion:
Neoadjuvant chemotherapy
Loss at follow-up ≤ 30 days
Stage IIIC patients based on LN metastasis alone
Following IRB approval, we identified all patients with FIGO stage IIIC and IV, grade 3 or high grade serous ovarian cancer who underwent primary debulking surgery during an 8 year period at our institution.
We included only patients whose surgery resulted in complete gross resection.
Patients were excluded if they had undergone neoadjuvant chemotherapy or if they were lost to follow-up within 30 days of surgery.
Patients who were categorized as stage IIIC based on lymph node metastasis alone were also excluded, therefore all patients had intraperitoneal tumor measuring at least 2cm outside the pelvis.

7. Definitions - Extent of LND: Extent of LND: Group C: ≥ 20 LNs removed
Group A: No LND
Group B: 1-19 LNs removed
Group C: ≥ 20 LNs removed
Lymphadenectomy was at the discretion of the surgeon.
The extent of lymphadenectomy was evaluated based on the number of LNs removed and patients were categorized into Group A: no lymphadenectomy; Group B: 1-19 LNs removed; Group C: ≥ 20 LNs removed. A cutoff of 20 was chosen to represent a threshold above which the surgeon had made a significant effort to perform lymph node dissection beyond that of simply sampling the most easily accessible LNs.

8. Definitions ASA score: HBOC:
Surrogate for general state of health (pre-operative)
HBOC:
Known genetic mutation or
Personal/family history highest risk categorya (20-25%)
American Society of Anesthesiologists (or ASA) classification was used as a surrogate for patients’ general state of health going into surgery.
For the purposes of this study, Hereditary Breast and Ovarian Cancer (or HBOC) was considered positive if there was either a known BRCA mutation, or a personal and/or family history placing the patient in the highest-risk category for familial predisposition based on ACOG criteria.
aACOG Practice Bulletin No. 103, Obstet Gynecol 2009.

9. Definitions OR Tumor Indexa (score 0-2) Score of 0 Score of 1
1 point for carcinomatosis
1 point for bulky upper abdominal diseaseb
As a measure of the intraoperative assessment of tumor burden, we used an OR tumor index
Patients received 1 point each for the presence of carcinomatosis and/or bulky upper abdominal disease which was defined as the presence of tumor implants >1 cm located cephalad to the greater omentum (such as involvement of the diaphragm, liver, spleen, or pancreas).
Score of 0
Score of 1
Score of 2
aTanner et al, Gyn Onc 2012 (in press).
bZavanovic o, et al, Gyn Onc 2008.

10. Statistics Chi square Kruskal-Wallis Kaplan-Meier survival analysis
Categorical variables
Kruskal-Wallis
Continuous variables
Kaplan-Meier survival analysis
Log rank test
Cox regression multivariate model
Descriptive statistics were performed on the group, and standard statistical tests were used.

11. Results – Patient Selection
Stage IIIC-IV HG serous ovary Ca 385 pts
Primary debulking
323 (84%)
Suboptimal
66 (20%)
Optimal
257 (80%)
CGR
109 (34%)
Neoadjuvant chemo
62 (16%)
99 patients included
We identified 385 pts with stage IIIC or IV high grade serous ovarian cancer.
Of the 323 patients who underwent primary debulking surgery, 80% of patients achieved optimal cytoreduction and 109 or 34% achieved complete gross resection. Of these, 99 met all inclusion criteria for further analysis.
7 pts IIIC nodal only
3 pts loss at follow up

12. Patient characteristics by extent of lymphadenectomy
Group A
(No LND)
N=31
Group B
(1-19 LNs)
N=34
Group C
(≥ 20 LNs) P
Age, median [range]
61 [39-80]
57 [30-81]
58 [32-78]
0.148
Family history / HBOC
12 (39%)
11 (32%)
12 (35%)
0.866
Intraperitoneal chemotherapy
14 (45%)
18(53%)
0.341
FIGO stage
IIIC
27 (87%)
26 (77%)
31 (91%) IV
4 (13%)
8( 24%)
3 (9%)
0.219
ASA score 1
3 (10%) 2
18 (58%)
21 (62%)
24 (71%) 3
10 (32%)
10 (29%)
7 (21%)
0.854
Patient characteristics by extent of lymphadenectomy are presented here.
While these columns represent findings based on subgroups, the overall median age was 59 and approximately one third of patients had HBOC according to our definition.
All patients received platinum-based adjuvant chemotherapy and intraperitoneal treatment was administered in 45, 53, and 35% for Groups A, B, and C, respectively.

13. Surgical characteristics by extent of lymphadenectomy
Group A
(No LND)
N=31
Group B
(1-19 LNs)
N=34
Group C
(≥ 20 LNs) P
Procedures performed
Liver resection
3 (10%)
5 (15%)
4 (12%)
0.822
Splenectomy
7 (23%)
7 (21%)
0.478
Diaphragm peritonectomy
13 (42%)
20 (59%)
14 (41%)
0.262
Any bowel surgery
19 (61%)
21 (62%)
17 (50%)
0.544
Supradiaphragmatic LND
6 (18%)
1 (3%)
0.011
OR Tumor Index score
11 (32%) 1
10 (29%) 2
11 (36%)
13 (38%)
0.273
Consistent with the fact that these patients all had advanced disease, upper abdominal procedures and bowel surgery were frequently performed in all groups.
In addition to pelvic and para-aortic lymphadenectomy, 7 patients had enlarged supradiaphragmatic LNs on preoperative imaging and underwent supradiaphragmatic or mediastinal lymph node dissection in order to achieve complete gross resection.
We noted that an OR tumor index of 0 was present in only 23% of Group A patients but in 41% of Group C patients

14. Results – LN status among all pts
Study population
99 pts
Clinically suspicious LNs
44 pts
LN metastases
34 pts (77%)
Clinically normal LNs
55 pts
16 pts (29%)
All patients with clinically suspicious LNs underwent lymphadenectomy and 77% of them had LN metastases.
While 29% of patients with clinically normal LNs were demonstrated to have nodal disease, this proportion includes patients who did not undergo LN sampling therefore it likely underestimates the prevalence of metastases in this group.

15. Results – LN status among pts with LND
All patients with LND
68 pts
Clinically suspicious LNs
44 pts
LN metastases
34 pts (77%)
Clinically normal LNs
24 pts
16 pts (67%)
If we exclude patients who had no LNs removed, we find that 16 of 24 patients with clinically normal LNs in fact had LN metastases, amounting to 67% of this group.

16. LN status by extent of LND (among 68 pts with “any” LND)
No metastatic LN
≥ 1 metastatic LN p
Group B (1-19 LNs)
12 (35%)
22 (65%)
Group C (≥ 20 LNs)
6 (18%)
28 (82%)
0.099
Again within the group of 68 patients who had at least 1 LN removed, those with more extensive lymphadenectomies showed a trend towards a higher likelihood of having at least 1 metastatic LN: Group C “82%” versus Group B “65%”

17. Univariate survival analysis
Variable
Progression free survival
Median (95% CI) p
Overall survival
HBOC
Positive
28.6 ( )
102.6 (---)
Negative
23.4 ( )
0.129
57.9 ( )
0.047
Stage
IIIC
26.1 ( )
78.8 ( ) IV
17.2 ( )
0.140
38.0 ( )
0.002
OR tumor index
50.5 ( )
92.4 ( ) 1
24.2 ( )
58.5 ( ) 2
19.3 ( )
0.001
46.6 ( )
0.007
ASA score
29.0 ( )
Not Reached
24.2 ( )
63.9 ( ) 3
21.0 ( )
0.878
56.7 ( )
0.0499
On univariate analysis, we found that progression free survival was only associated to OR tumor index. However HBOC, stage, OR tumor index and ASA score were all associated with overall survival.

18. Univariate survival analysis
Variable
Progression free survival
Median (95% CI) p
Overall survival
Metastatic LN
Yes
23.4 ( )
63.9 ( ) No
25.1 ( )
0.447
92.4 ( )
0.647
Type of LND
Group A
23.1 ( )
58.5 ( )
Group B
23.6 ( )
56.7 ( )
Group C
28.6 ( )
0.610
87.0 ( )
0.428
IP chemotherapy
26.1 ( )
Not Reached
19.3 ( )
0.296
57.9 ( )
0.053
The presence of metastatic LN did not seem to significantly affect survival in these patients with advanced stage by peritoneal criteria. The extent of lymphadenectomy was not associated with PFS or overall survival.
Of note, LN count was also evaluated as a continuous variable and it did not show association with survival.

19. Survival curves Progression Free Survival Overall Survival A: No LND
B: 1-19LNs
C: ≥ 20 LNs
p=0.610
p=0.428
These are the survival curves depicting PFS and OS by extent of LND. There is no difference in progression free survival for the 3 groups.
While there does appear to be some separation of the red overall survival curve for Group C, this was not statistically significant.

20. Multivariate survival analysis
Variable
Progression free survival
Hazard Ratio (95% CI) p
Overall survival
Hazard Ratio (95% CI) p
HBOC (pos vs. neg)
0.54 ( )
0.023
0.41 ( )
0.024
Stage (IIIC vs. IV)
0.90 ( )
0.766
0.36 ( )
0.009
OR tumor index
Ref. level
0.001
0.013 1
2.47 ( )
1.60 ( ) 2
4.06 ( )
3.31 ( )
ASA score
0.946
0.113
1.11 ( )
1.18 ( ) 3
1.03 ( )
2.35 ( )
We performed a multivariate analysis and this showed that the presence of HBOC, stage IIIC, and a lower OR tumor index remained independently associated with survival in this group of high risk patients.

21. Conclusions LNs harbor disease
77% of pts with suspicious LNs -> metastases
67% of pts with normal LNs -> metastases
In conclusion:
LNs can frequently harbor disease in advanced ovarian cancer. We found that 77% of patients with suspicious LNs had metastases. Of patients who had clinically normal LNs but still underwent LN sampling, 67% had metastatic spread.

22. Conclusions
Among patients with stage IIIC-IV high grade serous ovarian ca achieving CGR at primary debulking:
HBOC, stage, and OR tumor index are strong prognostic factors
Extent of LND was not associated with PFS or OS
Selection bias?
Sample size?
Lymphadenectomy In Ovarian Neoplasms (LIONS) trial
Among patients with stage IIIC (by peritoneal criteria) or stage IV high grade serous ovarian cancer who achieve complete gross resection at primary debulking: we found that
HBOC, stage, and tumor burden at initiation of therapy are strong prognostic factors. This emphasizes the importance of tumor biology in determining clinical outcome for advanced ovarian cancer.
We found that extent of LND was not associated with progression free or overall survival.
For the moment, our data do not support performing routine extended LND upon achieving CGR in this group of patients. While the survival curves for patients that undergo extensive LND show some separation from patients with a more limited or no lymph node dissection, this does not reach statistical significance.
As with any retrospective study, we are limited by bias, in particular selection bias because lymphadenectomy was at the discretion of the surgeon. Therefore these findings warrant further investigation with larger sample size, such as a prospective German study, the LIONS trial, that is currently accruing in Europe.