0920 vergote - role of radical surgery pdf

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

Leuven

Essen

Role of Radical Surgery and Neoadjuvant Chemotherapy in Advanced Ovarian Cancer:

Report on the Consensus Paper

http://gallery/v/beeldbank-UZ/luchtfoto/GHB_VVDL-5181-250811s.jpg.html?g2_imageViewsIndex=2

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.

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

12th Biennial Meeting IGCS Bangkok 2008

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

Randomization

Randomized EORTC-GCG/NCIC-CTG Trial on NACT + IDS vs PDS Ovarian, tubal, or peritoneal cancer

FIGO stage IIIc-IV (N = 718)

Primary debulking surgery

Neoadjuvant chemotherapy

3 x platinum-based CT

Interval debulking (not obligatory)

Interval debulking if no PD

3 x platinum-based CT

≥3 x platinum-based CT ≥3 x platinum-based CT

Primary endpoint: Overall survival

Secondary endpoints: Progression-free survival, quality of life, complications

48 patients excluded from 1 center → N = 670


NACT + IDS vs PDS: ITT Overall Survival

Median survival

PDS: 29 months

IDS: 30 months

HR for IDS:0.98

(0.84, 1.13)


Optimal Debulking and Treatment Arm: PP1

• Optimal = no residual tumor

• Suboptimal = 1-10 mm residual

• Other >10 mm

(51% R0)

(19% R0)


Optimal Debulking and Treatment Arm: PP1

• Optimal = no residual tumor

• Suboptimal = 1-10 mm residual

• Other >10 mm

(51% R0)

(19% R0)

In the multivariate analysis,

having no residual tumor is the

most important independent

prognostic factor both

after PDS AND IDS!


Survival Per Country: ITT

PDS R0 63%

PDS R0 11%

PDS vs PDS+IDS vs IDS: ITT Overall Survival

(years)

0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Debulking

195 263 150 51 13 2

41 54 34 11 1 0

211 298 193 46 13 2

Primary only

Primary + Interval

Interval only

Overall survival


NACT + IDS vs PDS: ITT Survival Time: WHOPS

EORTC 55971

Events / PatientsUpfront debulking Neo-adj. chemo

Statistics (O-E) Var.

HR & CI*:(Upfront debulking Neo-adj. chemo)

|1-HR|% ± SD

Survival time: WHO PSSurvival time: WHO PSSurvival time: WHO PS

*90% CI everywhere

Treatment effect: p>0.1

better betterChi-square=0.01, df=2: p>0.1

Upfront debulking Neo-adj. chemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.00.8

2 32 / 40 35 / 44 0.6 16.5

Total 252/ 334 245/ 334 3.2 122.6

(75.4 %) (73.4 %)

3% ±9

increase

1 107 / 141 105 / 143 0.9 52.1

0 113 / 153 105 / 147 1.6 54


NACT + IDS vs PDS: ITT Survival Time: Age

EORTC 55971

Events / PatientsUpfront debulking Neo-adj. Chemo


HR & CI*:(Upfront debulking Neo-adj. Chemo)

|1-HR|% ± SD

Survival time: AgeSurvival time: AgeSurvival time: Age

*90% CI everywhere

Treatment effect: p>0.1

better betterChi-square=0.23, df=2: p>0.1

Upfront debulking Neo-adj. ChemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.00.8

>70 55 / 70 59 / 77 -1.4 27.7

Total 253/ 336 245/ 334 3.1 122.7

(75.3 %) (73.4 %)

3% ±9

increase

50-70 172 / 229 155 / 210 3.3 81.4

<50 26 / 37 31 / 47 1.2 13.6


NACT + IDS vs PDS: ITT Survival Time: Histology

EORTC 55971Events / Patients

Upfront debulkingNeo-adj. chemoStatistics

(O-E) Var.HR & CI*

:(Upfront debulking Neo-adj. chemo)|1-HR|% ± SD

Survival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: HistologySurvival time: Histology

*90% CI everywhere

Treatment effect: p>0.1better betterChi-square=4.92, df=7: p>0.1


0.25 0.5 1.0 2.0 4.00.8

unknown 13 / 17 21 / 24 -2.4 8.2

Total 253/ 336 245/ 334 9.2 120.4(75.3 %) (73.4 %)

8% ±9increase

other 1/ 2 6/ 6 -0.7 1.2

mixed 2/ 3 0/ 0 0 0

unclassifiable 22 / 26 28 / 34 2.3 11.8

undifferentiated 29 / 43 40 / 56 -2.3 17

endometroid 7/ 11 2/ 5 2.1 1.9

clear cell 5/ 6 4/ 4 0.8 1.9

mucinous 7/ 8 8/ 11 0.6 3.2

serous 167 / 220 136 / 194 8.8 75.3


NACT + IDS vs PDS: ITT Survival Time: FIGO Stage

EORTC 55971

Events / PatientsUpfront debulkingNeo-adj. Chemo


HR & CI*:(Upfront debulking Neo-adj. Chemo)

|1-HR|% ± SD

Survival time: Figo stageSurvival time: Figo stage

*90% CI everywhere

Treatment effect: p>0.1better betterChi-square=3.7, df=1: p=0.05

Upfront debulking Neo-adj. ChemoTest for heterogeneity

0.25 0.5 1.0 2.0 4.00.8

IV 67 / 76 57 / 81 10.1 30.4

Total 252/ 334 245/ 334 3.8 123.1(75.4 %) (73.4 %)

3% ±9increase

III 185 / 258 188 / 253 -6.4 92.7


NACT + IDS vs PDS: PP1 Overall Survival: Largest Metastatic Tumor Size

• <5 cm: HR, 0.64; 95% CI: 0.45-0.93

EORTC 55971Events / Patients

Upfront debulking Neo-adj. chemoStatistics

(O-E) Var.HR & CI*

:(Upfront debulking Neo-adj. chemo)|1-HR|% ± SD

OS: Largest metastatic tumor sizeOS: Largest metastatic tumor sizeOS: Largest metastatic tumor sizeOS: Largest metastatic tumor size

*90% CI everywhere

Treatment effect: p>0.1better betterChi-square=8.8, df=3: p=0.03


0.25 0.5 1.0 2.0 4.00.8

>200 mm 22 / 26 21 / 24 -0.8 10.3

Total 236/ 315 233/ 320 1.8 114.4(74.9 %) (72.8 %)

2% ±9increase

100-199 mm 92 / 105 83 / 113 8.4 43

50-99 mm 69 / 90 64 / 88 6.9 32.5

0-49 mm 53 / 94 65 / 95 -12.7 28.6


Algorithm for Ovarian Cancer


Epithelial ovarian cancer

Surgical skills and resources available?

Send patient to another

unit and do not abuse

neoadjuvant therapy

Advanced stage

FIGO IIB-IV Early stage

FIGO I-IIA

No Yes

Comprehensive

surgical staging

75% 25%

FIGO IIB-IIIB FIGO IIIC-IV

25% 50%


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

FIGO IIB-IIIB FIGO IIIC-IV

25% 50%

Patient fit for extended radical surgery?

Yes No

45% 5%

Pathological diagnosis

Upfront debulking

surgery aiming at

complete resection

Primary

chemotherapy

(or palliation)

12% 33%

FIGO IIIC and extra-

ovarian metastases

<5 cm

– see also table 1

FIGO IIIC and extra-

ovarian metastases

>5 cm – or FIGO IV

– see also table 1

Debulking to no residual seems feasible

with reasonable morbidity (see table 1)

Yes No Essen

Leuven

8%

25%

Essen

Leuven

25%

8%



Essen Leuven

No interval

debulking

Interval

debulking

Tumor spread

was reason for

upfront chemo

(see GOG152)

Pt characteristics

improved (see table 1)

Initially operated

w/o maximal effort

3 courses

carboplatin

paclitaxel IV

Interval debulking

(IDS; see table 1)

No unterval

debulking (pts not fit

for IDS)

PD

No PD

13%

30%

25%

2%

5%

5%

2-3%

Primary

chemotherapy

(or palliation)

Criteria for Primary Chemotherapy and Interval Debulking Surgery in FIGO

Stage IIIc and IV: Diagnosis

Diagnosis Essen Criteria Leuven Criteria

Biopsy Biopsy with histologically proven epithelial ovarian

(or tubal or peritoneal) cancer FIGO stage IIIc-IV

Cytology – 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

• Multiple parenchymeous liver

metastases in both lobes

• Intrahepatic metastases

• Tumor involving large parts of the

pancreas (not only tail) and/or

• Duodenum

• Infiltration of the pancreas and/or

• Duodenum and/or

• the large vessels of the

ligamentum hepatoduodenale,

truncus coelicaus, or behind the

porta hepatis

• Tumor infiltrating the vessels of

the lig. hepatoduodenale or

truncus coeliacus

Criteria for Primary Chemotherapy and for Interval Debulking Surgery in FIGO Stage IIIc

and IV: Extra-Abdominal Disease Essen Criteria Leuven Criteria

• Multiple parenchymal

lung metastases

(preferably histologically

proven)

All excluding:

• Resectable inguinal

lymph nodes

• Solitary resectable

retrocrural or paracardial

nodes

• Pleural fluid containing

cytologically malignant

cells without proof of the

presence of pleural

tumors

• Nonresectable lymph

node metastases/

• Brain metastases

Criteria for Primary Chemotherapy and for Interval Debulking Surgery in FIGO

Stage IIIc and IV: Other Patient Characteristics


• 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


• 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)

• No progressive disease, and

• In case of extra-abdominal

disease at diagnosis the extra-

abdominal 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 (CT-scores/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

Improved

visualization

of total burden

of intra-

abdominal

disease

T2 DWI PET-CT 1/ Peritoneal carcinomatosis

?

?

?

?

?

?

?

?

?

?

1

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


Improved

visualization

of total burden

of intra-

abdominal

disease

T2 DWI PET-CT

2/ Gastrosplenic

2 2 2



Improved

visualization

of total burden

of intra-

abdominal

disease

T2 DWI PET-CT

3/ small bowel:

meso and serosa

3

?

?



Improved

visualization

of total burden

of intra-

abdominal

disease

T2 DWI PET-CT

4/ sigmoid:

meso and serosa

4 4 ?


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

Completion of

systemic treatment

(chemo +/- biologic)

Interval surgery

Completion of

systemic treatment

(chemo +/- biologic)

0920 vergote - role of radical surgery pdf

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