Role of Radical Surgery and Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: Report on the Consensus Paper

Leuven

Essen
Ignace Vergote, MD, PhD
University Hospital Gasthuisberg Leuven, Belgium, European Union

Role of Radical Surgery and Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: Report on the Consensus Paper

Vergote I, du Bois A, et al. Gynecol Oncol. 2013;128(1):6-11.

12th Biennial Meeting IGCS Bangkok 2008

Randomized 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
Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

12th Biennial Meeting IGCS Bangkok 2008

Randomized 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
Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

Randomized EORTC-GCG/NCIC-CTG Trial on NACT + IDS vs PDS

Ovarian, tubal, or peritoneal cancer
FIGO stage IIIc-IV (N = 718) Randomization Primary debulking surgery
3 x platinum-based CT Interval debulking (not obligatory) 3 x platinum-based CT 48 patients excluded from 1 center N = 670

Neoadjuvant chemotherapy
3 x platinum-based CT

Interval debulking if no PD

3 x platinum-based CT

Primary endpoint: Overall survival Secondary endpoints: Progression-free survival, quality of life, complications
Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

NACT + IDS vs PDS: ITT Overall Survival

Median survival
PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.84, 1.13)

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

Optimal Debulking and Treatment Arm: PP1

(19% R0)

(51% R0)

Optimal = no residual tumor Suboptimal = 1-10 mm residual Other >10 mm

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

Optimal Debulking and Treatment Arm: PP1

(19% R0)

(51% R0)

In the multivariate analysis, having no residual tumor is the most important independent prognostic factor both after PDS AND IDS!
Optimal = no residual tumor Suboptimal = 1-10 mm residual Other >10 mm
Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

Survival Per Country: ITT

PDS R0 63%

PDS R0 11%

PDS vs PDS+IDS vs IDS: ITT Overall survival Overall Survival

100 90 80 70 60 50 40 30 20 10 0 0 O N 195 263 41 54 211 298 2 4 6 13 1 13 8 2 0 2 Number of patients at risk : 150 51 34 193 11 46 (years) 10 Debulking Primary only Primary + Interval Interval only

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

NACT + IDS vs PDS: ITT Survival Time: WHOPS Survival time: WHO PS
EORTC 55971 0 1 2 Events / Patients Statistics Upfront debulking Neo-adj. chemo (O-E) Var. 113 / 153 107 / 141 32 / 40 105 / 147 105 / 143 35 / 44 1.6 0.9 0.6 54 52.1 16.5 (Upfront debulking HR & CI* : Neo-adj. chemo) |1-HR| % SD

Total

252/ 334 (75.4 %)

245/ 334 (73.4 %)

3.2

122.6 0.25 0.5 0.8 1.0 2.0 4.0 Upfront debulking Neo-adj. chemo better better Treatment effect: p>0.1

3% 9 increase

Test for heterogeneity Chi-square=0.01, df=2: p>0.1

*90%CI everywhere

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

NACT + IDS vs PDS: ITT Survival Time: Age Survival time: Age
EORTC 55971 <50 50-70 >70 Events / Patients Statistics Upfront debulking Neo-adj. Chemo (O-E) Var. 26 / 37 172 / 229 55 / 70 31 / 47 155 / 210 59 / 77 1.2 3.3 -1.4 13.6 81.4 27.7 (Upfront debulking HR & CI* : Neo-adj. Chemo) |1-HR| % SD

Total

253/ 336 (75.3 %)

245/ 334 (73.4 %)

3.1

122.7 0.25 0.5 0.8 1.0 2.0 4.0 Upfront debulking Neo-adj. Chemo better better Treatment effect: p> 0.1

3% 9 increase

Test for heterogeneity Chi-square=0.23, df=2: p>0.1

*90%CI everywhere

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

NACT + IDS vs PDS: ITT SurvivalSurvival Time: Histology time: Histology

Events / Patients Statistics EORTC 55971 Upfront debulking Neo-adj. chemo (O-E) Var. serous mucinous clear cell endometroid undifferentiated unclassifiable mixed other unknown 167 / 220 7/ 8 5/ 6 7 / 11 29 / 43 22 / 26 2/ 3 1/ 2 13 / 17 136 / 194 8 / 11 4/ 4 2/ 5 40 / 56 28 / 34 0/ 0 6/ 6 21 / 24 8.8 0.6 0.8 2.1 -2.3 2.3 0 -0.7 -2.4 75.3 3.2 1.9 1.9 17 11.8 0 1.2 8.2 HR & CI* (Upfront debulking : Neo-adj. chemo) |1-HR| % SD

Total

253/ 336 (75.3 %)

245/ 334 (73.4 %)

9.2

120.4 0.25 0.5 0.81.0 2.0 4.0 Upfront debulking Neo-adj. chemo better better Treatment effect: p>0.1

8% 9 increase

Test for heterogeneity Chi-square=4.92, df=7: p>0.1

*90% CI everywhere

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

NACT + IDS vs PDS: ITT SurvivalSurvival Time: FIGO Stage time: Figo stage
Events / Patients Statistics EORTC 55971 Upfront debulking Neo-adj. Chemo (O-E) Var. III IV 185 / 258 67 / 76 188 / 253 57 / 81 -6.4 10.1 92.7 30.4 HR & CI* (Upfront debulking : Neo-adj. Chemo) |1-HR| % SD

Total

252/ 334 (75.4 %)

245/ 334 (73.4 %)

3.8 123.1 0.25 0.5 0.8 1.0 2.0 4.0 Upfront debulking Neo-adj. Chemo better better Treatment effect: p>0.1

3% 9 increase

Test for heterogeneity Chi-square=3.7, df=1: p=0.05

*90% CI everywhere

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

NACT + IDS vs PDS: PP1

Overall Survival: Largest Metastatic Tumor Size OS: Largest metastatic tumor size
Events / Patients Statistics Upfront debulking Neo-adj. chemo (O-E) Var. 53 / 94 69 / 90 92 / 105 22 / 26 65 / 95 64 / 88 83 / 113 21 / 24 -12.7 6.9 8.4 -0.8 28.6 32.5 43 10.3 HR &CI* : Neo-adj. chemo) |1-HR| % SD

EORTC 55971 0-49 mm 50-99 mm 100-199 mm >200 mm

(Upfront debulking

Total

236/ 315 (74.9 %)

233/ 320 (72.8 %)

1.8 114.4 0.25 0.5 0.8 1.0 2.0 4.0 Upfront debulking Neo-adj. chemo better better Treatment effect: p>0.1

2% 9 increase

Test for heterogeneity Chi-square=8.8, df=3: p=0.03

*90%CI everywhere

<5 cm: HR, 0.64; 95% CI: 0.45-0.93

Vergote I, et al. N Engl J Med. 2010;363(10):943-953.

Algorithm for Ovarian Cancer

Epithelial ovarian cancer
Surgical skills and resources available? Send patient to another unit and do not abuse neoadjuvant therapy

No
75%

Yes
25%

Advanced stage FIGO IIB-IV

25% 50%

Early stage FIGO I-IIA

Comprehensive surgical staging

FIGO IIB-IIIB

FIGO IIIC-IV

Vergote I, du Bois A, et al. Gynecol Oncol. 2013;128(1):6-11.

Algorithm for Ovarian Cancer

25% 50%

FIGO IIB-IIIB

FIGO IIIC-IV
Patient fit for extended radical surgery?

45%

5% Yes No
Pathological diagnosis

Upfront debulking surgery aiming at complete resection

12%

33%

FIGO IIIC and extraovarian metastases <5 cm see also table 1

FIGO IIIC and extraovarian metastases >5 cm or FIGO IV see also table 1

Primary chemotherapy (or palliation)

Debulking to no residual seems feasible with reasonable morbidity (see table 1)

25%

Essen

Essen

Yes
Leuven

No
Leuven

8% 25%

8%

Vergote I, du Bois A , et al. Gynecol Oncol. 2013;128(1):6-11.

Algorithm for Ovarian Cancer

Primary chemotherapy (or palliation)

No interval debulking
5%

PD
Tumor spread was reason for upfront chemo (see GOG152)

2-3% 3 courses carboplatin paclitaxel IV 13% 30%

No PD
Interval debulking
5%
Pt characteristics improved (see table 1) Essen Initially operated w/o maximal effort Leuven No unterval debulking (pts not fit for IDS) Interval debulking (IDS; see table 1)

25%

2%

Vergote I, du Bois A, et al. Gynecol Oncol. 2013;128(1):6-11.

Criteria for Primary Chemotherapy and Interval Debulking Surgery in FIGO Stage IIIc and IV: Diagnosis
Diagnosis Biopsy Cytology Essen Criteria Leuven Criteria Biopsy with histologically proven epithelial ovarian (or tubal or peritoneal) cancer FIGO stage IIIc-IV Or FNAC proving the presence of carcinoma cells in patients with suspicious pelvic mass If CA125 (KU/L)/CEA (ng/mL) ratio is >25, If the serum CA125/CEA ratio is 25, imaging or endoscopy is obligatory to exclude a primary gastric, colon, or breast carcinoma

Criteria for Primary Chemotherapy and Interval Debulking Surgery in FIGO Stage IIIc and IV: Abdominal Disease
Essen Criteria Leuven Criteria

Involvement of the superior mesenteric artery Diffuse deep infiltration of the radix mesenterii of the small bowel Diffuse and confluent carcinomatosis of the small bowel involving such large parts that resection would lead to a short bowel syndrome (eg, resection >1 m) or total gastrectomy Intrahepatic metastases Multiple parenchymeous liver metastases in both lobes

Tumor involving large parts of the Infiltration of the pancreas and/or pancreas (not only tail) and/or Duodenum and/or Duodenum the large vessels of the ligamentum hepatoduodenale, Tumor infiltrating the vessels of truncus coelicaus, or behind the the lig. hepatoduodenale or porta hepatis truncus coeliacus

Criteria for Primary Chemotherapy and for Interval Debulking Surgery in FIGO Stage IIIc and IV: Extra-Abdominal Disease
Essen Criteria Leuven Criteria All excluding: Multiple parenchymal Resectable inguinal lung metastases lymph nodes (preferably histologically Solitary resectable proven) retrocrural or paracardial nodes Nonresectable lymph Pleural fluid containing node metastases/ cytologically malignant cells without proof of the Brain metastases presence of pleural tumors

Criteria for Primary Chemotherapy and for Interval Debulking Surgery in FIGO Stage IIIc and IV: Other Patient Characteristics
Essen Criteria Leuven Criteria Impaired performance status and comorbidity not allowing a maximal surgical effort to achieve a complete resection Patients nonacceptance of potential supportive measures as blood transfusions or temporary stoma

Criteria for Interval Debulking

Essen Criteria
Upfront surgical effort in an institution without expert surgical skills/infrastructure Barrier for initial surgery has disappeared (eg, improved medical condition) Not, if reason for primary surgery was tumor growth pattern diagnosed during surgery by an expereinced gynecologic oncologist under optmal circumstances (as in GOG 152 study)

Leuven Criteria
No progressive disease, and In case of extra-abdominal disease at diagnosis the extraabdominal disease should be in complete response or resectable, and Performance status and comorbidity allowing a maximal surgical effort to no residual diseases

How to Select Patients?

How to Select Patients:Essen

Essen starts with a limited open surgery via midline incision with systematic stepwise evaluation of the site not passing a point of no return First, the peritoneum of the paracolic gutters is resected, and the complete colon is mobilized, the omentum removed, and the lesser sac opened At this point, the pancreas, truncus coeliacus, hepatic artery, and ductus choledocus are evaluated Next, the small bowel is dissected, and the radix mesenterii, superior mesenteric artery, and small bowel are evaluated

Leuven Approach: Predictive Models for Optimal Cytoreduction

CA125 Imaging (CTscores/PET-CT/CT peritoneography) Microarrays THESE MODELS ARE SIMPLY NOT GOOD ENOUGH

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 )1 90% of the patients with advanced ovarian carcinoma (n = 173) judged to be operable were optimally debulked (Vergote et al)1

This figure of 90% optimal debulking after laparoscopy is confirmed by 2 Italian series (Fagotti et al2 and Angioli et al3) and is much higher than for every published CT scoring system, CA125
1. Vergote I, et al. In J Gynecol Cancer. 2005;15(5):776-779. 2. Fagotti A, et al. Gyncol Oncol. 2005;96(3):729-735. 3. Angioli R, et al. Gyncole Oncol. 2006;100(3):455-461.

Whole-Body Diffusion Weighted MRI and PET-CT

T2 DWI PET-CT 1/ Peritoneal carcinomatosis

? ? ?

? ?

? 1 ? ?

Improved visualization of total burden of intraabdominal disease

Michielsen K, et al. Int J Gyncol Cancer. 2012;22(8 supplement 3): Abstract E154.

Whole-Body Diffusion Weighted MRI and PET-CT

T2 DWI PET-CT
2/ Gastrosplenic

Improved visualization of total burden of intraabdominal disease

Michielsen K, et al. Int J Gyncol Cancer. 2012;22(8 supplement 3): Abstract E154.

Whole-Body Diffusion Weighted MRI and PET-CT

T2 DWI PET-CT
3/ small bowel: meso and serosa

3 ?

Improved visualization of total burden of intraabdominal disease

Michielsen K, et al. Int J Gyncol Cancer. 2012;22(8 supplement 3): Abstract E154.

Whole-Body Diffusion Weighted MRI and PET-CT

T2 DWI PET-CT

4/ sigmoid: meso and serosa

Improved visualization of total burden of intraabdominal disease

Michielsen K, et al. Int J Gyncol Cancer. 2012;22(8 supplement 3): Abstract E154.

WB-DWI and PET: Extra-Abdominal Metastases

DWI PET

WB-DWI and PET: Extra-Abdominal Metastases

DWI PET

WB-DWI is a very promising imaging tool to predict tumor burden and operability, is superior to PET-CT and is in selected cases replacing laparoscopy in Leuven.

Future Study?

Future Study?
Vergote I, du Bois A, et al. Gynecol Oncol. 2013;128(1):6-11.
Patients fit for radical surgery and chemotherapy Histologically proven epithelial ovarian cancer Clinically FIGO stages IIIC-IV No metastases excluding resection (must be specified) Center recruiting consecutive patients (no extra selection) Surgery in center with excellence (proven/monitored)

Random 1:1:1

Primary surgery

3 courses primary chemotherapy

Systemic treatment (chemo +/- biologic) No interval debulking

Interval surgery

Completion of systemic treatment (chemo +/- biologic)

Completion of systemic treatment (chemo +/- biologic)