1. PDS vs NACT+İDS İn ASEOC
Ayhan Ali, MD
Baskent University School of Medicine
Department of Obstetrics and Gynecology Division of Gynecologic Oncology

2. Ovarian Cancer
No effective screening More than 60% stage III-IV Agressive cytoreduction + chemotherapy(TC) Cure rate is 25-30%(5y)

3. Therapy depends on: Patients’ factor Tumor factors Genetic alterations
(Age, performance)
Tumor factors
(Histology, grade, molecular)
Genetic alterations
Surgeon factor
Clinical factors
(Accurate diagnosis, extend of tumor,
experienced team, high-volume hospital)

4. Currently Standard Upfront Therapy İn Advanced stage EOC
In advanced epithelial OC primary debulking surgery aiming to remove all visible tumor tissue followed by adjuvant CT with Platinum/Taxane±Bevacizumab

5. Pre-operative work-up
History-Examination
(systemic, abdominal, pelvic)
Lab studies
(cyto, chemical marker… etc )
Imaging
( USG, CT, if needed MRI,PET, diff MRI if needed)
L/S (open) or Small Incision L/T
( Primary or metastatic possibility of surgery – Fagotti’s, Bristow’s,
Leuven-Essen criterias)
M. Petrillo et al. Gyn Oncol 139 (2015) 5-9
Vergote et al. J Clin Ocol Vol 34 No 32 (Nov
10), 2016 Leisewortz et al.Int J Gynecol Cancer 2017

6. Genomic Profiling, Defining Populations and Determining Clinical Activity of an Agent

7. OC Mutations by Histology
Norquist et al JAMA Oncol 2016

8. PDS IDS SDS Debulking Surgery VATS Upper Abdominal
Middle & Lower Abdominal
Upper Abdominal
Hysterectomy
Oopherectomy
Bowel resection
Appendectomy
LND (Pelvic,aortic)
Diaphragm
Splenectomy
Distal Pancreatectomy
Liver resection
Porta Hepatis resection
Others
VATS

9. Extended Surgery

10. Limitation of PDS (Metastatic sites and dissemination)
658 patients
578 upfront surgery
191 had residual disease
p: 0.001
Location of Residuel Tm
ALL
N:191
TR 1-10 mm
N:144 (75,4%)
TR>10 mm
N:47 24,6% p
Small intestine
150(79,8%)
124(87,9%)
26(55,3%)
<0.001
Portahepatis
Lig.hepatoduodenale
19(10,1%)
7(5%)
12(25,5%)
Parenchymal
Liver met.
8(4,3%)
1(0,7%)
7(14,9%)
Supradiaphragmatic
25(14,9)
21(14,9%)
1.000
Pancreas
15(8%)
4(2,8%)
11(23,4%)
Stomach
6(3,2%)
2(1,4%)
4(8,5%)
0.035
T.coeliacus
5(2,7%)
3(6,4%)
0.101
Residue
OAS
(months) R0 56
0-10 mm 32
>10 mm 17
Heitz et al Gynecol Oncol May;141(2):264-70

11. ESGO criteria of inoperability in
advanced ovarian cancer (I)
Central or multisegmental parenchymal
liver metastases
• Multiple parenchymal lung metastases
(preferably histologically proven)
• Nonresectable lymph node metastases
• Brain metastases

12. ESGO criteria of inoperability in advanced ovarian cancer (II)
Diffuse deep infiltration of the root of small bowel mesentery
• Diffuse carcinomatosis of the small bowel involving such large parts that resection would lead to a short bowel syndrome (remaining bowel <1.5 m)
• Diffuse involvement/deep infiltration of stomach/duodenum** head or middle part of pancreas***
• Involvement of truncus coeliacus, hepatic arteries, left gastric
artery****
Querleu D et.al. IJGC 2016

13. What is the Survival Impact of Cytoreduction
Overall survival, stage IIIC ovarian cancer, 1989–2003.
Residual disease Pts Median OS
(mo)
Micro
<0,5cm
0,5-1cm
1-2cm
>2cm
D.S. Chi et al. / Gynecologic Oncology 103 (2006) 559–564

14. HR (95% CI) 1-10 mm vs 0 mm 2.62 (2.26;2.81) >10 mm vs 1-10 mm
1.36 (1.24;1.60)
0 mm
n:1046
898
690
539
389
232
111 58 32 17 7
E:563
1-10 mm
n:975
653
311
178
117 75 43 22 14 11 5
E:817
>10 mm
n:1105
610
234
146 85 46 16 2 1
E:995
HR (95% CI)
1-10 mm vs 0 mm
2.70 (2.37;3.07)
>10 mm vs 1-10 mm
1.36 (1.21;1.49)
du Bois et al. Cancer 2009
0 mm
n:1046
996
900
773
566
333
147 70 36 19 8
E:359
1-10 mm
n:975
886
669
451
293
157 73 18 12 5
E:653
>10 mm
n:1105
933
650
435
247
116 40 15 6 2
E:829

15. A review about cytoreduction
Tumor Size N
MOS
No Gross Residue
3593
77.8
Residu tm <1cm
4780 39
Residu tm >1cm
3518
31.1
S.-J. Chang, R.E. Bristow / Gynecologic Oncology 125 (2012) 483–492

16. Survival impact of Optimal Debulking(Ro vs Others)
447 patients n:
PFS
OAS
RD 0 cm
199 24 57
RD cm
138 16 35
RD cm 51 12 29
RD > 1 cm 59 22
Wallace et al. Gynecol Oncol 2017

17. What about Extended Surgery
PCR vs ES
5-year OS(%)
Median OS(mts)
5-year PFS(%)
Primary Cytoreduction 35 43 14
Extended Surgery 47 54 31
Also significantly more optimal cytoreduction
and less gross tumor in ES
D.S. Chi et al. / Gynecologic Oncology 114 (2009) 26–31

18. GOG 182 2655pts with optimal CR(<1cm)
482(18,1%) pts - 590UAP performed
351 (13,1%) diaphragmatic surgery
112 (4,2%) liver surgery
108 (4%) splenectomy
12 (0,5%) pancreatectomy
(0,2%) porta hepatis surgery
UAS vs non UAS
PFS : 18,2 vs 14,8 mts (p<0,01)
OAS : 49,8 vs 43,7 mts (p: 0,01)
No RT (n:141) vs Minimal (<1cm) RT (n:341)
OAS : 54,6 vs 40,4 mts (p: 0,0005)
UAS should be performed when no residual tm is attainable
N. Rodriguez et al /Gynecologic Oncology 130(2013)

19. MSKCC Primary Cytoreduction OS and CGR Rates
Leary et al. ESGO Educational Book 2016

20. Liver Resection in EOC Study Ptx N Optimal CRS (%)
Negative Resection Margin (%)
OS (m)
Meredith et al (2003) 26
80,8 NA
26,3
Optimal 27,3
Suboptimal 8,6
Yoon et al (2003 24
66,7
54,1 62
Loizzi et al (2005) 29 25
Abood et al (2008) 10
100 50 33
Pekmezci et al (2010) 8
Roh et al (2010) 18
38 (3-78)
Niu et al (2012) 60 90
39 (5-79)
Neumann et al (2012) 70
Optimal 42
Suboptimal 4,6
Kolev et al (2014) 27
92,6%
88,9
56 (12-249) 11
Gasparri et al., J Cancer Research Clin Oncol Dec 2015

21. Survival Impact of Splenectomy
OAS%
DFS%
Splenectomy 33
66,6
30,3
No splenectomy 99
59,6
33,3
Splenic met prevelance : 2,3-7,1%
Incidence up to 20% in autopsies
Zapardel et al; Intenational Journal of Gynecological Cancer, vol 22,2012

22. Survival Impact of Diaphragmatic Surgery(n:181)
5 yrs s. %
Surgery 41 55
Non Surgery
140 28
Aletti et al, Gynecol Oncol 2006; 100, 283

23. Porta Hepatis Surgery 11 patients, heterogenous history of disease
Multidisciplinary approach for prevention of morbidity
Limited number direct survival effect is unclear
Indirectly YES
Y.J. Song et al. / Gynecologic Oncology 121 (2011) 253–257

24. Optimal Debulking Surgery in Stage IV Ovarian Ca
Study
Optimal debulking n (%)
Criteria (cm)
Optimal Median OS* (m)
Suboptimal Median OS* (m)
Curtin et al 1997
41 (45) ≤2 40 19
Liu et al 1997
14 (30) 37 17
Munkarah et al 1997
31 (31) 25 15
Bristow et al
25 (30) ≤1 38 10
Akahira et al
70 (31) 32 16
Aletti et al
50 (46)
Winters et al 2008
78 (22)
0.1-1 29 20
* All SS
Curr Treat Options in Oncol 2016; 17:1

25. NACT Setting: A Translational Research Oppurtinity
Leary et al. ESGO Educational Book 2016

26. Tumor Biology Effects The Response to First-Line Platinum-Based Chemotherapy
Response rates in High Grade Serous OC approaches to 75%
Tumor Subtype
No. Of patients With Evaluable Disease
Activity
Study
Low Grade Serous OC 24
< 5%
Schmeler et al
Clear Cell OC
23-68, 4 studies
22%-41%
Kita et al, Sugyama et al, Ho et al, Takano et al
Muscinous OC
9-50, 5 studies
13%-60%
Hess et al, Alexandre et al, Pectasides et al, Gore et al, Shimada et al
Leary et al. ESGO Educational Book 2016

27. PDS vs IDS in Stage III or IV
Year
Study
Primary Endpoint
Study Arm n
Stg IV
(%)
No Residual
PFS
(Months)
OAS
(months)
2016 Scorpion
(Fagotti’s)
Surgical Comp.
NACT
PCS 55 7 15 58 46
Not reported
2015 CHORUS OS
274
276 25 39 17
12.0
10.7
24.1
22.6
2014 JCOG
0602
152
149 30 32 63
2010 EORTC
5591
334
336 24 23 51 19 12 29
Wright et al. Gynecol Oncol 143 (2016) 3-15

28. Rates of NACT usage
İncreased overall to 22 % Up to 34 % in Stage III C Up to 62 % in Stage IV İn USA
S Clinical Oncology

29. What About Long Term Survival?
PDS vs IDS
Median survival (m)*
PDS
IDS
Total OS 43 33 41
PFS 17 14 16
*All SS
n:14182 (PDS; IDS; 2311) median follow-up 43 m
Subgroups after Complete Resection
Median survival (m)*
PDS
IDS OS 69 46
PFS 29 18
*All SS
Ann Surg Oncol. 2016 May;23(5):

30. PDS vs IDS Any Residual *R0 Resection
n:14182 (PDS; IDS; 2311) median follow-up 43 m
Ann Surg Oncol. 2016 May;23(5):

31. PDS (Only one or never) 43 36 NACT+IDS (More than one) 27,3 31
Multiple Cycles of NACT Associated with Poor Survival in Bulky Stage IIIC and IV Ovarian Cancer
n:408
Median OS (m)
5y OAS (%)
PDS
(Only one or never) 43 36
NACT+IDS
(More than one)
27,3 31
p: 0,032
IJGC 2015; 25:

32. PDS:240 NACT:270 Groups 1. R0 2. ≤1cm single location (≤1cm-SL) 3
PDS:240 NACT:270 Groups 1. R0 2. ≤1cm single location (≤1cm-SL) 3. ≤1cm multiple location (≤1cm-ML) 4. Suboptimal residual (>1cm)

33. OVERALL SURVIVAL: PDS 95 total deaths (39.6%) Median OS
-R0: Not yet reached
-≤1cm-SL: 64 months
-≤1cm-ML: 50 months
-Suboptimal: 49 months

34. OVERALL SURVIVAL:NACT
132 total deaths (48.9%)
Median OS
-R0: 58 months
-≤1cm-SL: 37 months
-≤1cm-ML: 26 months
-Suboptimal: 33 months

35. patients undergoing neo-adjuvant versus adjuvant chemotherapy
Stage III&IV
Kaplan-Meier OS (A) and PFS (B) curves in function of type of protocol comparing
patients undergoing neo-adjuvant versus adjuvant chemotherapy
Kessous et al. Gynecologic Oncology 144 (2017) 474–479

36. Stage IIIC
Kessous et al. Gynecologic Oncology 144 (2017) 474–479

37. PDS vs IDS in Stage IV PDS (n:1488) 27 15 63 IDS (n:308) 29 35 32
Median OS (m)
Complete Cytoreduction %
OAS (m)
PDS (n:1488) 27 15 63
IDS (n:308) 29 35 32
Ann Surg Oncol. 2016 May;23(5):

38. 263 patients were included in the study analysis
Gynecologic Oncology 144 (2017) 474–479
263 patients were included in the study analysis
127 patients received NACT with IDS
Platinum sensitivity
72.2%
Debulking results
Complete 65.9%
PFS: 14.5 mo
OS: 71 mo
Sub optimal
34.1%
PFS: 8 mo
OS: 36 mo
136 patients had primary debulking and adjuvant CT
77.4%
Complete 40.2%
PFS: 40 mo
OS:106 mo
59.8%
PFS: 10 mo
OS: 55 mo
Higher rates of CR
But OAS?

39. What About Survival Impact of HIPEC In After NACT
245 EOC pts
3 cycles of NACT ( at least stable disease ,NO progressive or refractory)
PLUS
Surgery ( complete resection or maxımum 10 mm residual tm)
± HİPEC (100 mg per sq Cisplatin)
HİPEC :122 pts
Without HİPEC:123 pts

40. HİPEC vs NO HİPEC
45,7 m vs 33,7 m
P=0,02
HİPEC vs NO HİPEC
14,2 m vs 10,7 m
P=0,003

41. NACT+IDS Short Term Advantages (n:1607, AOC Patients)
Optimal cytoreduction
Peri-operative morbidity
Mortality
Quality of life*
Better QOL than PDS*
Fatigue
Role of function
Emotional function
Cognitive function
Yang et al journal.pone

42. What about the Cost?
Retrospective cohort, btw , newly diagnosed stage III/IV EOC n=8188 Cumulative lifetime costs was NACT $ 134,576 PDS $ 117,159 Significantly lower surgical complication costs -$4987 but higher CT-related costs $6874 for the NACT group NACT is cost-effective in “normal levels” in the high-risk subgroup: -Stage IV tumor -Older age -Poor performance status However not for the overall sample or for non-high risk pts
Poonawalla et al. Value in Health 18 (2015)

44. The Incidence of (+) LN in Advanced Ovarian Cancer = 66%
Survival İmpact Of Lymphadenectomy İn Advanced Stage Ovarian Cancer
The Incidence of (+) LN in Advanced Ovarian Cancer = 66%
49% positive LN > 1 cm diameter
17% had positive LN > 1cm not identified by palpation or inspection
Eisenkop SM et al, Gynecol Oncol 2001

45. SEER Data
pts
Extension of LND
M.Variant Survival analsis
Survival Increased with the
number
of Lypmh node

46. Lymphadenectomy in ASEOC
No res. Tm. (n:996)
LNE (+)
LNE (-)
Median S. (mts)
103 84
5-year S. (%)
67,4
59,2
Lymphadenectomy associated with
superior survival
in patients with NO residual disease
du Bois et al. J Clin Oncol Vol. 28 No. 10 April 2010

47. 57 32 48,1 24,7 LNE (+) LNE (-) Median S. (mts) 5-year S. (%)
suspect LN (n:527)
LNE (+)
LNE (-)
Median S. (mts) 57 32
5-year S. (%)
48,1
24,7
significant impact of lymphadenectomy
ONLY IN PATIENTS WITH CLINICALLY SUSPECT NODES
(HR 0.72; 95% CI, 0.53 to 0.98;P.0379)
OS after LNE or no LNE in patients with postoperative residual tumor of 1 to 10 mm and with or without preoperative/intraoperative clinically uspect LNs (comparison 2A; cohort 2)
du Bois et al. J Clin Oncol Vol. 28 No. 10 April 2010

48. Opimally debulked 158 pts
Advanced stage
LND ≥20 nodes pts
LNS:<20 nodes pts
LND significantly İmproved
PFS and OS

49. Data From GOG 182
1.871 stage III C
RP exploration
269 LN met-
420 LN met +
Without RP exploration

51. 3 randomısed controlled
11 retrospective study
Lyphadenectomy is accociated with greater 5 year OS for all stages(p<0,001)
But
Higer PFS and Lower Recurrence Rate was observerd in Advances Stage EOC(p=0,011)

52. Survival after recurrence
Retrospective study
261 pts
Survival after recurrence
Survival After REC LN
135
NO LN
126
P value
43 m
32 m
0,013

54. İncreased relaparotomy İnfections Mortality within 60 days No LNE
LİON Results
M.O.S
Median PFS
Complication
LNE
65,5 m
25,5 m
Longer surgery time
İncreased Blood loss
İncreased relaparotomy
İnfections
Mortality within 60 days
No LNE
69,2 m
P value
0,65

55. New Approaches in the Management of EOC
Gene based chemotherapy
Novel biologic agents
( VEGF. PARP. m-TOR. inhibitors etc…)
IP chemotherapy (Regular and HIPEC)
NACT
Check-point inhibitors
(Vaccination & Immune therapy)

56. Conclusion
OC remains as the most lethal GYN neoplasm No effective screening programme More than 60% is advanced stage Currently PDS with no residual tm + Adjuvant CT is the standard of care NACT + IDS is not standard yet just in selected cases Platinum resistance after NACT is controversial NACT + IDS does not extend OAS? (unclear)

57. Conclusion
Incorporate the patient’s genetic and their tumor characteristics Effects therapeutic options (IP CT, PARP inh) Early diagnose or close follow up for family members Risk reduction for secondary or synchronous cancers

58. Thank you for your attention