1. Surgery in Stage IIb-IV Ovarian Carcinoma
Ignace Vergote
University Hospitals Leuven, European Union
VVOG Eerste Jaarvergadering 2009
AIOM 2000

2. 1-A 1: Is there a need to strictly define the extent and type of surgery for patients in first-line trials?
Tissue should be obtained for histopathologic diagnosis to confirm the presence
of primary ovarian or peritoneal carcinoma.
Staging should be performed according to FIGO guidelines. For example, this
includes at least lymph node sampling and peritoneal staging in early stage
invasive disease (FIGO I – IIA).
Up-front maximal surgical effort at cytoreduction with the goal of no residual
disease should be undertaken.
When cytoreductive surgery is not possible initially, it should be considered in
patients who do not have progressive disease after 3 to 5 cycles of
chemotherapy.
Patients with ovarian cancer should have their surgery performed by an
appropriately trained surgeon with experience in the management of ovarian
cancer.
Level of Acceptance: 13 / 13

3. TOTAL RESIDUAL TUMOR LOAD Stage III – Vergote Gyn Oncol 1998
< 1g: no visible residual tumor
1 - 10g: less than 10 residual lesions of < 1 cm

4. Systematic Pelvic and Paraaortic Lymphadenectomy in Ovarian Cancer
Stage
Number
+ ve Pelvic
+ ve PA
- ve PA
- ve Pelvic II 7
3 (43%)
1 (14%)
III 67
34 (51%)
9 (13%) IV 11
8 (73%)
1 (9%)
Burghardt E et al. Gynecol Oncol 1990; 40: 103 – 106.

5. Randomized Prospective Study of the Role of Lymphadenectomy
Stage III – IVA Epithelial Ovarian Cancer Intraperitoneal residual tumor < 1 cm
Pelvic and paraaortic lymphadenectomy
Resection of bulky nodes
6 cycles of PC or PT
Second-look optional
Benedetti-Panici J Nat Cancer Inst 2005; 97: 1-6

6. LYMPHADENECTOMY FOR ADVANCED OVARIAN CANCER Overall Survival1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
Overall Survival
Years from Randomization
Lymphadenectomy
No Lymphadenectomy
P = 0.768
Events Totals

7. CHARACTERISTICS Benedetti-Panici JNCI 2005
Characteristic Control % Lymphadenectomy %
(N=211)
(N=216)
Median Age 56 yr 53 yrs
FIGO stage
IIIB
IIIC
IVA
Residual disease
None
< 1 cm
1-2 cm
Missing data

8. AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms R n = 640
epithelial invasive
ovarian cancer
FIGO IIB - IV
ECOG 0/1 and
no CI against LNE
no visible extra-
and intra-abdominal
tumor residuals
no bulky lymph nodes
System. Lymphadenectomy
pelvic
para-aortic R
n = 640
no Lymphadenectomy
Endpoints: OS, PFS, QoL Strata: centre, PS ,age

9. Neoadjuvant or primary debulking
Neoadjuvant or primary debulking? Ovarian carcinoma Stage II-IV Leuven Series (n = 288) Median survival 56 months
< 1 cm
No residual tumor
Primary debulking (n = 192)
86%
78%
Interval debulking (n = 96)
79%
TOTAL
Vergote et al, IGCS 2004

10. Indications for neoadjuvant chemotherapy Leuven Policy 1993 - 2008: 15% IIIc-IV
1. Tumors larger than 2 cm around the superior mesenteric artery or behind the porta hepatis, or
2. Intrahepatic (multiple) metastases or several extraabdominal metastases (excluding resectable inguinal or supraclavicular lymph nodes) larger than 2 cm , or
3. Poor general condition (e.g. > 80 years) making a “maximal surgical effort” to no residual tumor impossible, or
4. Extensive serosal invasion (e.g. plaques) of the intestines necesitating bowel resections of > 1.5 m

12. Extraperitoneal hysterectomy with
resection of pelvic peritoneum

13. Liver
AIOM 2000

14. Pleura
AIOM 2000

15. Lung
AIOM 2000

16. Optimal Cytoreduction Rates for Advanced Ovarian Cancer at MSKCC

17. Advanced Ovarian Cancer Median Survival: 1975 - 2008
Memorial Sloan Kettering Cancer Centre 80 60
months 40 20
1975
1983
1986
1996
1998
2003
2006
Alkeran
multi-drug
cisplatin
paclitaxel
IP therapy

18. IGCS Meeting October 25th Bangkok
Randomised trial comparing primary debulking surgery (PDS) with neoadjuvant chemotherapy (NACT) followed by interval debulking (IDS) in stage IIIC-IV ovarian,fallopian tube and peritoneal cancer.

19. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS
Ovarian, tuba or peritonal cancer
FIGO stage IIIc-IV (n = 718)
Randomisation
Primary Debulking Surgery
Neoadjuvant chemotherapy
3 x Platinum based CT
3 x Platinum based CT
Interval debulking
(not obligatory)
Interval debulking if no PD
> 3 x Platinum based CT
> 3 x Platinum based CT
Primary Endpoint: Overall survival
Secondary endpoints: Progression Free Survival, Quality of Life, Complications

20. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical findings and results (PP1)
Metastases before > 2 cm
95%
68%
Metastases before > 10 cm
62%
27%
No residual after surgery
21%
53%
≤ 1 cm after surgery
46%
82%
Unknown substracted.
* % calculated on the 306 patients who underwent IDS.

21. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS ≤ 1cm residual per country (PP1)
Total
PDS
(n = 329)
NACT -> IDS
(n = 339)*
Difference PDS-IDS
Belgium (n=133)
83%
72%
94%
22%
Argentina (n=48)
71%
68%
74% 6%
The Netherlands (n=104)
59%
40%
77%
37%
Sweden (n=23)
75%
35%
Norway (n=82)
55%
73%
38%
Italy (n=38)
52%
64%
34%
Spain (n=62)
49%
44%
58%
14%
UK (n=101)
47%
63%
Canada (n=84)
29%
Unknown substracted in PDS - IDS arm nog te corrigeren in PP1 voor IDS in primaire arm. Totaal voor unknown nog te corrigeren.

22. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1)
Postoperative mortality
(< 28 days)
2,7%
0,6%
Postoperative fever G3-4 8% 2%
Fistula (bowel/GU)
1,2% / 0,3%
0,3% / 0,6%
Operative time (minutes)
0/1-10mm/> 10 mm
180
300/190/120
199/180/140
Red blood cell transfusion
51%
53%
Hemorhage Grade 3/4 7% 1%
Venous Gr 3/4
2,4%
0,3%
Range operation time to te voegen. Hospitalisatieduur? Tijd van randomisatie tot PDS of NACT. Omit red blood cell transfusion in slide?

23. NACT + IDS versus PDS: ITT
Median survial
PDS: 29 months
IDS: 30 months
HR for IDS:0.98 (0.85, 1.14)

24. NACT + IDS versus PDS: PP1
Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

25. NACT + IDS versus PDS: PP1
Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.
< 5 cm : hazard ratio: 0.74; 95% confidence intervals

26. Multivariate analysis for OS(PP1)
P values
Optimal (no residual) debulking
0.0001
Histological type (9 categories)
0.0003
Largest tumor size at randomisation
0.0008
Figo Stage (IIIc vs IV)
Country (14 categories)
0.0014
Age
0.0020
WHO PS NS
Differentiation Grade
Treatment arm
Largest tumour size, age, FIGO stage and country are strong independent prognostic factors.
The prognosis deteriorates with larger tumour size, older age and FIGO stage IV
Differentiation grade and histologic type are competing prognostic factors.
ordered from best to worst: mixed, endometrioid, serous, undifferentiated, mucinous and clear cell
WHO PS is significant as a univariate factor. Its effect is absorbed mainly but not exclusively through Age).
Treatment arm is not at all a prognostic factor.

27. Criticisms/Questions on 55971 in Bangkok
Why still stressing the importance of optimal debulking ( = no residual tumor)?
Multivariate analysis
And …
Does no residual at IDS have the same impact as at PDS?

28. Optimal Debulking and treatment arm: PP1
Optimal = no residual tumor
Suboptimal = 1-10 mm residual
Other > 10 mm
PDS = primary debulking surgery
NACT = neoadjuvant chemotherapy
Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

29. PDS vs PDS+IDS vs IDS: ITT
Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

30. PDS vs PDS+IDS vs IDS: ITT
Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

31. Criticisms/Questions on 55971 in Bangkok
Why still stressing the importance of optimal debulking ( = no residual tumor)?
Does no residual at IDS have the same impact as at PDS?
The optimal debulking rate was too low, but
No effect of PDS over IDS in countries with high debulking rates, and..

32. AGO analysis (n=3126) – IGCS Bangkok
AGO-OVAR 3 (Cisplatin/Paclitaxel vs. Carboplatin/Paclitaxel) - A du Bois JNCI 2003
AGO-OVAR 5 / GINECO (Carboplatin/Paclitaxel +/- Epirubicine) – A du Bois JCO 2006
AGO-OVAR 7 / GINECO (Carboplatin/Paclitaxel +/- Topotecan) - J Pfisterer JNCI 2006
3,126 of 3,388 randomized pts. (92.3%) included of whom 1,837 (58.8%) had died within a median observation period of 53.9 months.
Age [median; range]
58.9 ( ) yrs
PS ECOG 0
1,190
38.1
ECOG 1
1,592
50.9
ECOG 2
326
10.4
Stage FIGO IIB-IIIA
448
14.4
FIGO IIIB
366
11.7
FIGO IIIC
1,779
56.9
FIGO IV
530
17.0
Grading G1
244
7.8 G2
998
31.9 G3
1,702
54.4
Histology Serous
2,296
73.4
Endometrioid
272
8.7
Mucinous
147
4.7

33. AGO analysis (n=3126) – IGCS Bangkok
64% ≤ 1 cm
33% No residual tumor
Age [median; range]
58.9 ( ) yrs
PS ECOG 0
1,190
38.1
ECOG 1
1,592
50.9
ECOG 2
326
10.4
Stage FIGO IIB-IIIA
448
14.4
FIGO IIIB
366
11.7
FIGO IIIC
1,779
56.9
FIGO IV
530
17.0
Grading G1
244
7.8 G2
998
31.9 G3
1,702
54.4
Histology Serous
2,296
73.4
Endometrioid
272
8.7
Mucinous
147
4.7

34. AGO analysis (n=3126) – IGCS Bangkok
64% ≤ 1 cm
33% No residual tumor
Stage IIIc – IV 57% ≤ 1 cm
Age [median; range]
58.9 ( ) yrs
PS ECOG 0
1,190
38.1
ECOG 1
1,592
50.9
ECOG 2
326
10.4
Stage FIGO IIB-IIIA
448
14.4
FIGO IIIB
366
11.7
FIGO IIIC
1,779
56.9
FIGO IV
530
17.0
Grading G1
244
7.8 G2
998
31.9 G3
1,702
54.4
Histology Serous
2,296
73.4
Endometrioid
272
8.7
Mucinous
147
4.7

35. AGO analysis (n=3126) – IGCS Bangkok
Stage IIIc - IV
≤ 1 cm
No residual
1 – 10 mm
AGO
57%
24%
33%
EORTC-NCIC
46%
21%
25%
Age [median; range]
58.9 ( ) yrs
PS ECOG 0
1,190
38.1
ECOG 1
1,592
50.9
ECOG 2
326
10.4
Stage FIGO IIB-IIIA
448
14.4
FIGO IIIB
366
11.7
FIGO IIIC
1,779
56.9
FIGO IV
530
17.0
Grading G1
244
7.8 G2
998
31.9 G3
1,702
54.4
Histology Serous
2,296
73.4
Endometrioid
272
8.7
Mucinous
147
4.7

36. AGO primary debulking analysis compared with
EORTC-NCIC PDS arm
My interpretation:
The modest differences in debulking rates can be explained by the fact that in small IIIc‘s are under represented (e.g. diagnosis of IIIc-IV was made on imaging, median size of largest metastases 8cm, …).

37. Criticisms/Questions on 55971 in Bangkok
Why still stressing the importance of optimal debulking ( = no residual tumor)?
Does no residual at IDS have the same impact as at PDS?
The optimal debulking rate was too low?
Was is the optimal timing for IDS?

38. Optimal timing of interval debulking surgery (Bristow & Chi 2006)

39. Predictive Models for Optimal Cytoreduction
CA125
Imaging (CT/MRI/PET)
Microarrays
THESE MODELS
ARE SIMPLY NOT
GOOD ENOUGH

40. Open Laparoscopy in stage III and IV ovarian carcinoma (n=228, 1995 - 2002)
55 patients (19%) with suspect ovarian mass in combination with omental cake and/or ascites had no ovarian carcinoma stage III or IV (metastases from other primaries, stage I-II, benign, ..)
90% of the patients with advanced ovarian carcinoma (n = 173) judged to be operable were optimally debulked. Vergote et al Int J Gynecol Cancer :776-9)
This figure of 90% optimal debulking after laparoscopy is confirmed by 2 Italian series (Fagotti et al and Angioli et al) and is much higher than for every published CT scoring system, CA125, and even microarrays, …

41. Open laparoscopy in advanced ovarian cancer
is the best technique to:
make a histological diagnosis,
exclude other primary tumors (or benign disease)
evaluate operability,
plan operating time of debulking surgery
refer patients to a tertiary center (video/CD).

42. Surgery in stage IIb-IV ovarian carcinoma (1)
In stage IIb – IIIb ovarian carcinoma is primary debulking the standard of care.
This surgery should include hysterectomy, bilateral oophorectomy, omentectomy and resection of all intra- and retroperitoneal suspicious lesions.
Pelvic and para-aortic systematic lymphadenectomy is recommended in stage IIb-IIIb (due to the high number of patients with metastatic lymph nodes - altough no randomized data are available).

43. Surgery in stage IIb-IV ovarian carcinoma (2)
4. No residual tumor is the only correct definition of optimal debulking in Stage IIb-IV disease.
5. Prior to surgery patients should undergo a complete imaging with at least a CT abdomen and gynaecological ultrasound. Pet-CT, MRI and CT thorax might be used, if available, in selected cases.
6. In cases with proven unresectable (e.g. extraabdominal) disease it is preferred to prove the diagnosis with BIOPSY (laparoscopy or tru cut).
If FNAC is used, the other strict criteria as used in the EORTC-NCIC-CTG trial, should be used to exclude other primary tumors.

44. Neoadjuvant or primary debulking in Stage IIIc or IV ovarian carcinoma
Neoadjuvant or primary debulking in Stage IIIc or IV ovarian carcinoma? Leuven opinion on the EORTC study
The EORTC-GCG NCIC-CTG study was performed in patients with very advanced Stage IIIc-IV disease on CT (62% > 10cm met’s at PDS).
In such cases neoadjuvant chemotherapy followed by interval debulking does not worsen the prognosis.

45. AND during the laparoscopy
Neoadjuvant or primary debulking in Stage IIIc or IV ovarian carcinoma? Leuven opinion on the EORTC study
3. Sometimes it is technically more difficult to obtain a no residual tumor status after interval than after primary debulking surgery (e.g. due to fibrosis).
4. Hence, in our institution, patients with suspicion of Stage IIIc or IV disease undergo laparoscopy to evaluate the extent of the disease
AND during the laparoscopy

46. Indications for neoadjuvant chemotherapy Leuven Policy 2009: about 50% (?) IIIc-IV
1. Tumors larger than 2 cm around the superior mesenteric artery or behind the porta hepatis, or
2. Intrahepatic (multiple) metastases or several extraabdominal metastases (excluding resectable inguinal or supraclavicular lymph nodes) larger than 2 cm , or
3. Poor general condition (e.g. > 80 years) making a “maximal surgical effort” to no residual tumor impossible, or
4. Extensive serosal invasion (e.g. plaques) of the intestines necesitating bowel resections of > 1.5 m
5. Patients that can not be (easily) debulked to no residual tumor (e.g. more than 1 bowel resection, expected operative time more than 4 hours, poor general condition, > 5cm met’s ..) are selected for neoadjuvant chemotherapy at laparoscopy.