1. Role of lymphadenectomy in ca
ovary….
Early to advanced….
Dr Priyanka Malekar
DNB 2nd year Resident, Surgical Oncology
4/3/2019
1
2. Introduction…
• Epithelial ovarian cancer (EOC) is a gynecologic tumor that spreads
frequently through the lymphatic system.
• Lymphadenectomy is an important step in the surgical treatment of EOC
and has a diagnostic, prognostic, and, perhaps, therapeutic value.
2
5. • Some important questions concerning the lymphadenectomy procedure of
choice in EOC in patients with stage I disease remain:
1. Should lymphadenectomy be unilateral or bilateral?
2. Should it be performed in patients with stage IA disease?
3. Should it be performed in all histologic subtypes?
5
6. • Involvement of pelvic nodes have been reported to occur in 8– 15%
Piver et al, 1978; Burghadt et al, 1991.
• Paraaortic nodes in 5–24% of patients with stage I disease
Musumeci et al, 1977; Burghadt et al, 1991.
6
7. • Tumor localized to one ovary:
• Pelvic node and paraortic LN : 7% respectively
• Combined : 4 %
Panici PB et al 2005
7
9. • The presence of node metastases upstages the patients to FIGO stage IIIc
disease and these patients are appropriate candidates for adjuvant
postoperative chemotherapeutic treatments.
9
10. • Unselected series including all International Federation of Gynecology and
Obstetrics stages reported a 44% to 53% rate of lymph node metastasis
detected by systematic lymphadenectomy.
Morice et al 2003
Harter et al 2007
10
11. • 22% rate of lymph node metastasis diagnosed by systematic pelvic and para-
aortic lymphadenectomy.
• Increases to 70% after systematic lymphadenectomy in advanced-stage
disease.
Maggioni et al 2006
Panici PB et al 2005
11
12. J Am Coll Surg 2003;197:198–205
1. Between 1985 and 2001, 276 women with epithelial ovarian
carcinoma underwent systematic bilateral pelvic and paraaortic
lymphadenectomy.
2. Exclusion: nonepithelial and borderline cancers
12
15. • The overall frequency of lymph node involvement was 44% (122 of 276).
• The frequency of pelvic and paraaortic metastases were 30% (82 of 276) and
40% (122 of 276), respectively.
15
16. • The rates of nodal involvement according to the stage of the disease in
patients who underwent an initial restaging operation (without preoperative
chemotherapy) and in patients who received chemotherapy (before
lymphadenectomy) were:
1. 19% and 21% in stage I disease
2. 50% and 33% in stage II
3. 53% and 51% in stage III, respectively
16
18. Given these high rates, a significant number of patients even with stage I
disease would profit from lymphadenectomy, so it should not be omitted in
patients with early stage disease.
But should this procedure be performed in all cases of early stage disease?
18
19. Tumor grade: vital role
• The rate of nodal involvement is:
• 24% in grade 1,
• 51% in grade 2,
• 47% in grade 3 disease.
In this study none of the stage 1A grade 1 disease had node positivity….can be
omitted….!!!!
19
20. Histology….selective.!
• Nodal rate is higher in undifferentiated/ anaplastic and clear cell histology.
• Lowest in mucinous tumors ( excluding extraovarian involvement ):
variations in rate of node involvement reported in literature…can be
omitted.
• Endometroid tumor: 0-9%..need further studies.
20
21. • For patients with stage III or IV, the most important prognostic factor is the
size of the residual disease after cytoreduction surgery.
• Because of this high rate of involvement in stage III and IV ovarian cancer,
optimal debulking surgery (residual disease on the peritoneum 2 cm) should
theoretically include pelvic and paraaortic lymphadenectomy in order to
remove retroperitoneal tumor sites.
21
22. • Survival of optimally debulked patients with stage III and IV disease is
similar to that in patients with:
1. Negative nodes.
2. Positive microscopic nodes.
3. Positive macroscopic nodes after complete surgical resection.
( till date no RCTs were published on advanced cancers for survival outcome)
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24. 1. 195 underwent systematic pelvic and paraaortic lymphadenectomy.
2. Histologic lymph node metastases were found in 53%.
3. The highest frequency was found in the upper left para-aortic region (32% of all patients)
4. Between vena cava inferior and abdominal aorta (36%).
5. Contralateral lymph node involvement
24
25. • Neither intraoperative clinical diagnosis nor frozen section of pelvic nodes
could reliably predict para-aortic lymph node metastasis: sensitivity of only
50% in ovarian cancer confined to the pelvis and 73% in more advanced
disease.
• Systematic pelvic and para-aortic lymphadenectomy remains part of staging
in EOC.
• Patients with EOC should be offered the opportunity to receive state-of the-
art treatment including surgery
25
30. • Prevalance: conservative estimate: nearly 4th patients had mets in
retroperitoneal LNs in EOC. ( 22%)
• This trial lacked power to exclude clinically important effects of SL on
progression free and overall survival.
• Estimated HR for progression and death favoured systemic
lymphadenectomy.
30
31. • The role of systematic aortic and pelvic lymphadenectomy in patients with
optimally debulked advanced ovarian cancer is unclear and has not been
addressed by randomized studies.
31
32. Journal of the National Cancer Institute, Vol. 97, No. 8,
April 20, 2005
A randomized clinical trial to determine whether systematic aortic and pelvic
lymphadenectomy improves progression-free and overall survival compared with resection
of bulky nodes only
32
33. • From January 1991 through May 2003,
• 427 patients
• Systematic pelvic and para-aortic lymphadenectomy (n = 216) or resection of bulky nodes
only (n = 211)
• Median follow up 68.4 months
• Primary end point : OS
• Secondary end point : PFS
• 94% received adjuvant treatment after primary cytoreductive surgery.
33
34. • Eligibility:
1. Patients with histologically proven and optimally debulked (i.e., residual tumor of
≤ 1 cm) epithelial ovarian carcinoma with FIGO stages IIIB and IIIC were eligible
for participation in the study.
2. Stage IV patients were eligible if the only evidence of stage IV disease was
malignant cells in pleural effusion.
3. Additional eligibility criteria included age of less than 75 years,
4. Karnofsky performance status of ≥ 80, and no previous chemotherapy or
radiation therapy.
34
38. • The median times to disease recurrence in the systematic lymphadenectomy
arm (27.4 months) and control arm (22.4 months) suggest that most of the
patients did not have platinum-resistant disease because the patients relapsed
at least 6 months after first-line treatment.
• Second line chemotherapy was not a confounding variable.
38
39. • Therefore, it seems that second-line chemotherapies, with or without surgery
at the time of relapse, may confer a survival benefi t that is similar in the two
trial arms and is independent of the length of the progression-free survival
interval.
39
40. • This study provide the first direct comparison of systematic
lymphadenectomy with standard cytoreductive surgery (i.e., no
lymphadenectomy).
• This study found that :
1) The addition of systematic lymphadenectomy to cytoreductive surgery
prolonged progression-free survival, which, in turn, may have an important
impact on the quality of life of patients with advanced ovarian cancer
40
41. 2) Systematic lymphadenectomy did not prolong overall survival, probably
because effective platinum based first- and second-line (with or without salvage
surgery) chemotherapies might have diluted the impact of systematic
lymphadenectomy on the risk of death
3) Patients in the systematic lymphadenectomy arm had a higher number of
nodal metastases than patients in the no-lymphadenectomy arm.
41
42. German Study..
Primary surgery followed by platinum/taxane-based chemotherapy is the standard therapy in
advanced ovarian cancer.
The prognostic role of complete debulking has been well described; however, the impact of systematic
pelvic and para-aortic lymphadenectomy and its interaction with biologic factors are still not fully defined.
42
43. Exploratory analysis of AGO OVAR 3,5,7
1942 pts, cohort 1 and cohort 2( subset of cohort 1)
43
46. • Retrospective study: cannot rule out bias regarding patient distribution
• Generates hypothesis
• Needs more prospective studies.
46
47. LION (Phase III Trial): Lymphadenectomy for LN-
Negative Advanced Ovarian Cancer Following
Complete Resection
CCO Independent Conference Highlights*
of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
CCO Independent Conference Highlights*
of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
47
48. Update LION trial…
( Lymphadenectomy in ovarian neoplasm)
N Engl J Med 2019;380:822-32
48
49. Lymphadenectomy in Resected, LN-Negative Advanced Ovarian Cancer:
Background
1. In pts with advanced ovarian cancer
1. Upfront surgery achieving macroscopic complete resection part of current standard of
care[1]
2. Randomized trial of systematic pelvic and para-aortic LNE demonstrated significant
improvement in PFS, but not OS, in pts with little to no residual disease[2]
3. Retrospective analysis of phase III data suggested potential OS benefit of LNE in pts
without gross residual disease[3]
2. Current prospective, randomized phase III trial investigated PFS and OS benefits of LNE in
pts with LN-negative advanced ovarian cancer following macroscopic complete resection[4]
1. Goff BA. J Gynecol Oncol. 2013;24:83-91. 2. Panici PB, et al. J Natl Cancer Inst. 2005;97:560-566. 3. du Bois A, et al. J Clin
Oncol. 2010;28:1733-1739. 4. Harter P, et al. ASCO 2017. Abstract 5500.
49
50. LION: Study Design
Multicenter, prospective, randomized, open-label phase III
trial
– All centers required to demonstrate surgical skill prior to
participation
Primary endpoint: OS
Secondary endpoints: PFS, QoL, number of resected LN
Adult pts with suspected or proven FIGO
stage IIB-IV epithelial ovarian cancer,
macroscopic complete resection, ECOG PS 0/1,
and clinically/ radiologically negative pelvic and
para-aortic LN; no prior CT or LN dissection
(N = 647)
Lymphadenectomy
(n = 323)
No lymphadenectomy
(n = 324)
Harter P, et al. ASCO 2017. Abstract 5500.
Stratified by center, age, ECOG
PS
50
53. LION: Efficacy and QoL Outcomes
No difference in QoL between arms at baseline, discharge,
end of chemotherapy, or 6 mos post chemotherapy
Harter P, et al. ASCO 2017. Abstract 5500.
Outcome All Pts (N = 647)
Median OS, mos (95% CI)
5-yr OS, %
67.2 (61.2-74.8)
55.9
Median PFS, mos (95% CI) 25.5 (21.9-28.6)
Outcome, Mos
LNE
(n = 323)
No LNE
(n = 324)
HR (95% CI) P Value
Median OS 65.5 69.2 1.057 (0.833-1.341) .65
Median PFS 25.5 25.5 1.106 (0.915-1.338)
53
54. LION: Intraoperative Outcomes
Outcome
LNE
(n = 323)
No LNE
(n = 324)
Difference P Value
Study procedure per randomization, n
(%)
320 (99.1) 313 (96.6)
Median total resected LN (IQR)
Para-aortic
Pelvic
57 (45-73)
22 (16-33)
35 (26-43)
LN metastases, n (%) 180 (55.7)
Median surgery duration, min (IQR) 340 (270-420) 280 (210-360) + 1 hour < .001
Median blood loss, mL (IQR) 650 (400-1000) 500 (300-900) + 150 mL < .001
Transfusions, n (%)
Massive (> 10 RBC/24 hrs)
205 (63.7)
7 (2.2)
181 (56.0)
2 (0.6)
+ 8% .005
.09
Fresh-frozen plasma, n (%) 117 (36.3) 96 (29.7) + 7% .07
Intermediate/intensive care unit, n (%) 250 (77.6) 223 (69.4) + 8% .01
Harter P, et al. ASCO 2017. Abstract 5500.
54
56. LION: Conclusions
In pts with advanced ovarian cancer, intra-abdominal complete resection,
and clinically/radiologically negative lymph nodes:
– Median OS: 67.2 mos; 5-yr OS: 55.9%; median PFS: 25.5 mos
– Systemic pelvic and para-aortic LNE
–Did not improve OS or PFS despite removal of subclinical LN metastases in 56% of
pts
–Significantly increased postoperative morbidity and mortality
Investigators conclude that systematic LNE not recommended in this pt
population
Harter P, et al. ASCO 2017. Abstract 5500.
56
57. Adequetely powered
This multicenter trial add level 1 evidence to long standing discussion about the role of
lymphadenectomy in advanced ovarian cancer.
Pitfall:
? NACT
Follow up protocol
Pattern of relapse or recurrence?
57
High frequency of retroperitoeal spread in advanced disease and poor prognosis with lymphatic metastasis, frequent finding of nodes in second look surgery: suggest lymphadenectomty has a role in cytoreduction surgery. when lymphadenectomy is performed in curative intent then systematic approach has to be performed. when optimal cytoreduction is achieved (residual disease <1 cm), node dissection should be by systematic approach ( pelvic and paraortic).
We found that patients who underwent systemic lymphadenectomy had a 25% improvement in progression-free survival when compared with patients who had
removal of bulky nodes only
this improvement in progression-free survival did not translate into an improvement in overall survival. Two possible explanations for this discrepancy are that 1) follow-up
may have been too short and 2) there were differences in secondline chemotherapy. Median overall survival for both trial arms in this study was good because all patients had optimal residual disease at the completion of their cytoreductive surgery, in keeping with other studie
help refine the prognosis of patients with advanced ovarian cancer and to tailor their follow-up.
