Ovarian Cancer Prof. Christina Fotopoulou Department of Surgery - - PowerPoint PPT Presentation

Surgery ry for Advanced Ovarian Cancer

• Prof. Christina Fotopoulou

Department of Surgery & Cancer Imperial College London, UK

Imperial College London

Topic ics

Tumor dissemination patters in primary advanced OC Prognostic value of postoperative residual disease Interaction of surgical effort and tumorbiology Value of pelvic and paraaortic LND surgical quality assurance criteria, morbidity and surgical evolution

• ver time

Timing of surgery

Topic ics

Tumor dissemination patters in primary advanced OC Prognostic value of postoperative residual disease Interaction of surgical effort and tumorbiology Value of pelvic and paraaortic LND surgical quality assurance criteria, morbidity and surgical evolution

• ver time

Timing of surgery

Complete exploration of the abdomen Infragastric omentectomy Assessment of pelvic and paraaortic LN TAH, BSO +/- Bowel resection Peritonectomy of involved peritoneum +/- liver capsule resection +/- splenectomy +/- resection of paracardiac nodes

Sehouli et.al. J Surg Oncol 2009

FIGO-stage I: 8.4% stage II: 2.4% stage III: 70.6% stage IV: 16.4%

Tumor dis issemin inatio ion patterns in in consecutiv ive ovaria ian cancer patie ients

≤2c m >2cm 5JOS 60% 25% 9% OS

(median)

85 mon 23 mon

In Intraoperativ ive tu tumor dis issemination pattern in in ad advanced OC requirin ing multivis isceral rese section techniques

97.5% 95.8% 83.1%

Fotopoulou et.al. Arch Obst & Gyn 2016 fistula fistula first 13–101) 6–104 fluid

Procedure performed N patients (%) (N = 118) Pelvic LN dissection 47 (40.0 %) Para-aortic LN dissection 47 (40.0 %) Colostomy 14 (11.8 %) Ileostomy 2 (1.7 %) Bowel resection (any) 84 (71.0 %) Small bowel 32 (27.1 %) Large bowel 81 (68.6 %) Liver/liver capsule resection 46 (39.0 %) Resection stomach/lesser sack 31 (26.3 %) Cholecystectomy 3 (2.5 %) Coeliac trunc/subdiaphragmatic LN removal 9 (8.0 %) Partial pleura resection 20 (17 %) Splenectomy 23 (19.5 %) Peritonectomy 115 (98.0 %) Diaphragmatic stripping/resection 79 (67.0 %) Operative morbidity/mortality fistula/perforation

• Meigs (1934) /

Maximal tumour reduction Mannel (1968)

• Griffith (1975)

„Debulking-Surgery“ residual mass and median survival: 0.5cm 40 months, 1.5 cm 18 months, >1.5cm 6 months

• Hoskins (1994)

residual tumour mass< 2cm: significant benefit

• Lichtenegger (1998)

residual tumour mass< 2cm: significant benefit

How did all beginn?

0,25 0,5 0,75 1 1 2 24 36 48 60 72 84

AGO-OVAR databasis metaanalysis (OVAR 3, OVAR 5, OVAR 7) 2,924 pts with OC FIGO IIB-IV and post- OP Carbo/Taxol (+)

Residual tumor size pts death Median survival

• Mos. (95%-CI)

p-value Logrank Hazard Ratio (95%-CI) p-value Wald 5-YSR [%] (95%-CI) 0 mm 1003 297

• (73.2; - )

1 63.7 (59.7;67.4) 1-10 mm 932 580 36.3 (34.5;40.0) <0.0001 2.81 (2.44;3.23) <0.0001 28.6 (24.9;32.4) > 10 mm 989 709 29.6 (27.4;32.4) 3.74 (3.26; 4.28) <0.0001 21.3 (18.2;24.6)

Bristow et al. JCO 2002

Ø <2cm

Residual tu tumor outranks FIG IGO-stage

duBois et al. Cancer 2009

3126 patients

Initial FIGO stage No macroscopic residual tumor Any residual tumor

HR (95% CI)

No residual tumor Any residual tumor

HR (95% CI)

• Pts. (n)

PFS (mos) Pts (n)

PFS

(mos)

median OS (months)

FIGO IIB-IIIB 497 91.7 317 19.1

0.37 (0.31; 0.45)

108.6 48.3

0.37 (0.30; 0.47)

FIGO IIIC 486 35.0 1293 14.5

0.39 (0.35; 0.45)

81.1 34.2

0.36 (0.31; 0.42)

FIGO IV 63 19.2 467 12.1

0.53 (0.39; 0.72)

54.6 24.6

0.49 (0.34; 0.70)

HR = Hazard Ratio, reference class for HR is “Any residual tumor” Initial FIGO stage residual tumor 1-10 mm residual tumor > 10 mm HR (95% CI) residuals 1-10 mm residuals > 10 mm HR (95% CI) FIGO IIB-IIIB 205 22.2 112 16.7

0.73 (0.56; 0.95)

52.3 41.0

0.75 (0.55; 1.01)

FIGO IIIC 613 15.9 680 13.7

0.78 (0.70; 0.88)

35.6 30.7

0.80 (0.70; 0.91)

FIGO IV 156 13.5 311 11.5

0.84 (0.69; 1.03)

26.2 23.9

0.86 (0.69; 1.07)

HR = Hazard Ratio, reference class for HR is “residual tumor > 10 mm”

How much tumor needs to be resected in every tumor stage?

+ 60,3 Mon. + 46,9 Mon. + 30,0 Mon.

+ 11,3 Mon. + 2,3 Mon.

+ 4,9 Mon.

duBois et al. Cancer 2009

RECTUM UTERUS

Topic ics

Tumor dissemination patters in primary advanced OC Prognostic value of postoperative residual disease Interaction of surgical effort and tumorbiology Value of pelvic and paraaortic LND surgical quality assurance criteria and surgical evolution over time Timing of surgery

18

R

Systematic LND  pelvic  25 LN  para-aortic  15 LN

 systematic LND

 only: removal of“bulky nodes”

FIGO IIIB - IV (pleura)  75 years intraabdominal residual disease  1 cm

Value of systematic LND vs removal of only bulky LN (P. Benedetti Panici et al., JNCI 97, 2005)

PFS OS

% 5 years: 31.2 vs. 21.6 % 49.5 vs. 48 % HRall: 0.75 (p = 0.01) 0.97 (n.s.) HRper protocol: 0.69 0.93 medianHR:

+ 7 months + 2.4 months

(22.4 vs. 29.4) (56.3 vs. 58.7) median roh: + 5 months + 5,6 months

Removal of bulky nodes only: inferior PFS, same OS

Panici et al. J Natl Cancer Inst 2005

R

• system. LND

 pelvic  para-aortal

no LND

• Epithelial Ovarian ca
• FIGO IIB - IV
• ECOG 0/1 and no

contraindication for LND

• R0
• NO “bulky” Lymphknoten

endpoints: OS, PFS, QoL Strata: centre, age, PS

Lymphadenectomy In Ovarian Neoplasms

AGO – OVAR OP.3 (LION)

Centre random screened AGO-OVAR OP.3 (31.1.12) Charite Berlin (Sehouli) 78 201 HSK Wiesbaden (du Bois -> Hils) 57 161 Düsseldorf Diakonie (Lampe) 48 113 Milano (Raspagliesi) 32 57 EVK Düsseldorf (Meier) 30 94 Praha (Cibula) 26 52 KEM Essen (du Bois) 23 46 UFK Greifswald (Mustea) 22 61 UKE Hamburg (Mahner) 21 68 UFK Jena (Runnebaum) 21 60 München rdI (Schmalfeldt) 21 43 München-Großhadern (Burges) 20 51 I.E.O. Milano (Landoni) 19 45 UFK Essen (Kimmig) 17 64 Roma (Scambia) 16 143 Napoli (Greggi) 16 39 UFK Kiel (Hilpert) 15 35 UFK Freiburg (Hasenburg) 14 39 MHH Hannover (Hillemanns) 12 50 Aviano (Giorda) 12 27 Leuven (Vergote) 12 26 Albertinen Hamburg (von Leffern) 10 32 UFK Ulm (Kreienberg) 7 19 Wolfsburg (Petry) 7 15 Malteser Bonn (Gropp -> Hampel) 6 21 UFK Dresden (Schindelhauer) 6 20 UFK Bonn (Pölcher -> Zivanovic) 6 18 Monza (Buda) 6 16 Khs Lich (Kullmer) 6 14 Fürth (Hanf) 5 18 UFK Göttingen (Emons) 5 16 Seoul (Kim) 5 13 UFK Tübingen (Solomayer -> Rothmund) 5 11 Innsbruck (Marth) 5 9 UFK Regensburg (Enzinger) 4 23 Ravensburg (Gropp-Meier) 4 10 UFK Erlangen (Thiel) 3 38 UFK Frankfurt (Kaufmann) 3 16 UFK Marburg (Wagner) 3 11 Martin Luther Berlin (Ulrich) 3 11 Deggendorf (Stuth) 3 9 Torino (Biglia) 3 7 Remscheid (Forner) 2 9 Berlin Lichtenberg (Glaser -> Elling) 2 6 Bad Homburg (Denschlag) 2 5 SKS Solingen (Pfisterer) 1 10 Aalen (Gnauert) 1 6 Graz (Tamussino) 1 6 Wien (Reinthaller) 1 4 Donauwörth (Both) 1 4 München 3.Orden (von Koch) 1 2 UFK Köln (Valter) 1 1 Roma (Ferrandina)

• 8

Carpi (Marchesin)

• 4

Wels (Bogner)

• 2

Lüneburg (Boetel)

• 1

Neumarkt (Scholz)

• 1

Offenburg (Schwörer)

• 1

Ansbach (Hornbacher)

• 1

JoHo Wiesbaden (Hoffmann)

• 1

Bremen (Aydoglu)

• 1

Sum 650 1.895

650 Patients Median LN number: 28 paraaortic 19 each pelvic side

Topic ics

Tumor dissemination patters in primary advanced OC Prognostic value of postoperative residual disease Interaction of surgical effort and tumorbiology Value of pelvic and paraaortic LND surgical quality assurance criteria, morbidity and surgical evolution

• ver time

Timing of surgery

Pleural effusion Pneumothorax Pneumonia, ARDS Pancreatic leakage Pancreatitis/pancreatic pseudocyst Intra-abdominal collection requiring drainage Pulmonary embolus / DVT Subphrenic abscess and pancreas - pleural fistula Anastomotic leak/ Bowel obstruction Reoperation (hemorrhage) Coagulopathy Sepsis Gastro-intestinal bleeding Perforated duodenal ulcer Cardiopulmonary failure

Surgical morbidity aft fter ultraradical procedures

fistula fistula first 13–101) 6–104 fluid

Operative morbidity/mortality Major complications 22 (18.6 %) Deep venous thrombosis 2 (1.7 %) Pulmonary embolism 4 (3.4 %) Anastomotic leak 1 (0.8 %) GI fistula/perforation 4 (3.4 %) Myocardial infarction 1 (0.8 %) Intraabdominal abscess formation 1 (0.8 %) Persistent lymphorrhea 7 (5.9 %) Nerve compression injury 3 (2.5 %) Fulminant liver failure 1 (0.8 %) Renal failure 2 (1.7 %) Postoperative bleeding 2 (1.7 %) Systemic sepsis 4 (3.4 %) Secondary wound healing (vacuum dressing) 2 (1.7 %) Reoperation 4 (3.4 %) Readmission 28 days 12 (10 %) Mortality 2 (1.7 %)

Fotopoulou et.al. Arch Obst Gyn 2016

Chi DS et al, Gynecol Oncol 2009 - MSKCC

Quali lity & radic icality of

• f surgery

ry: Evolu lution over tim ime

• En bloc rectosigmoid

resections

• Peritoneal stripping
• Infrarenal LND
• Diaphragmatic resections
• Splenectomy
• Liver resections
• Coeliac trunk and crura

diaphragmatica resections

• Pleura resections
• Paracardiac LN resections
• Extra-abdominal LN

resections

• ??

… Surgical morbidity in relation to sp specialisatio ion and tr training

Chi et.al. Gyn Oncol 2004

Other complication rates and length of hospitalization not significantly different between the two groups.

Group 1 (n=70) „Standard“ before 2000 Group 2 (n=70) incorporation of extensive upper abdominal debulking after 2001

Complete or optimal (<1cm) tumor resection 50% 76% p<0.01 Operative time 174 min 264 min p<0.001 Blood loss 460 ml 880 ml p<0.001

Aletti et.al. 2009 Am Coll Surg

Analysis is of

• f ou
• utcomes with

ith ap appropriate feedback an and education is is a a powerful tool l for qualit lity im improvement

No differences in

• perative morbidty

Im Improving quality of f care ac across Europe ESGO position

• To promote the training of gynecological surgeons treating especially

advanced stages of diseases

• To improve the average standard of surgical care for ovarian cancer

surgery and to build a network of certified centers.

• Centers meeting the targets will be granted an accreditation known

by doctors, patients, patient advocacy groups and governments.

31

Quality Assurance in Advanced (III-IV) Ovarian Cancer Surgery

, Paris

Querleu D et.al., Int J Gyn Can 2016. 32

QI I 1.2 Rate of f Pri rimary Debulking Surgery ry

% of PDS

Number of PDS Number all incoming patients with stage III/IV(a+b)

> 50%

QI I 1.1 Rate of f complete su surgical res esection

% Complete Resection

N of pts. with AOC with R0 All pts with AOC referred to the center

> 65 %

• Number of surgeries performed per center per year:
• Optimal target: N ≥ 100 (score 5)
• Intermediate target: N ≥ 50 (score 3)
• Minimum target: N ≥ 20 (score1)

≥ 95% of surgeries are performed by surgeons

• perating at least 10 patients

a year.

QI I 2. . Number of f cyt ytoreductive surgeries performed per r ce center and per r surgeon per r year

• Ovarian cancer patients will be operated by a certified

gynaecologic oncologist or, in countries where certification is not organized, by a trained surgeon dedicated to the management of gynecologic cancer.

• Skills to successfully complete complex abdominal and

pelvic surgery procedures necessary to achieve complete cytoreduction must be available.

QI I 3.S .Surgery ry performed by a gynecologic oncolo logist QI I 4.Center participating in in cli clinical l tr trials in in gyn gyn onc

Int J Gynecol Cancer 2009 Int J Gynecol Cancer 2005

• Ovarian cancer patients will be operated by a certified

gynaecologic oncologist or, in countries where certification is not organized, by a trained surgeon dedicated to the management of gynecologic cancer.

• Skills to successfully complete complex abdominal and

pelvic surgery procedures necessary to achieve complete cytoreduction must be available.

QI I 3.S .Surgery ry performed by a gynecologic oncolo logist QI I 4.Center participating in in cli clinical l tr trials in in gyn gyn onc

Int J Gynecol Cancer 2009 Int J Gynecol Cancer 2005

QI.

• I. 5 Treatment pla

lanned at t a multidiscipli linary ry Meeting.

Before any surgery It is considered mandatory for every patient a decision making process within a structured multidisciplinary team including:

• Gynaecologic oncologist
• Radiologist with a special interest in gynecologic
• ncology.
• Pathologist (if a biopsy is available) with a special

interest in gynecologic cancer.

• Medical oncologist or Gyn oncologist certified to

deliver chemotherapy.

QI.

• I. 6 Required preoperative workup.
• Rule out unresectable parenchymal metastases by imaging.
• Rule out metastases from other primaries by any suitable method

(markers and or biopsy under radiologic or laparoscopic guidance)

QI.7 I.7 Pre-, in intra-, and post-operative management

• Adequate anesthesiological and perioperative care
• Access to an intensive care unit.
• Need for a comprehensive perioperative

management program value of

• Adequate pain management
• Implementation of ERAS program.
• The operative report must be structured.
• Size and location of disease at the beginning of the operation must be described.
• All the areas of the abdominal and pelvic cavity must be evaluated and described.
• The size and location of residual disease at the end of the operation.
• Reasons for not achieving complete cytoreduction must be reported.

QI.

• I. 8 Min

inimum required ele lements in in Op Reports.

https://www.esgo.org/wp-content/uploads/2016/10/ESGO-Operative-Report.pdf

• The pathology report should contain

all the required elements listed in the International Collaboration on Cancer Reporting (ICCR) Histopathology Guide

QI.

• I. 9 Minimum required el

elements in in path Reports QI.

• I. 10 S

Structured r reporting of f postop complications

• Reporting Surgical Morbidity and Mortality

during the first 30 days after surgery within structured meetings (M&M).

• Structured Database of survival/recurrence

events strongly encouraged.

ACCREDITED CENTER FOR OVARIAN CANCER SURGERY

Topic ics

Tumor dissemination patters in primary advanced OC Prognostic value of postoperative residual disease Interaction of surgical effort and tumorbiology Value of pelvic and paraaortic LND surgical quality assurance criteria and surgical evolution over time Timing of surgery

Ratio ionale le of neoadju juvant chemotherapy

• Reduce tumor burden

→ increase total macroscopic tumor clearance by lower multivisceral resection rates → reduce surgical morbidity and mortality → increase post- op QoL (lower stoma rates, less pain,

adhesions etc.)

→ reduce amount of healthcare ressources required

(theatre time, ITU-/, hospital stay, transfusion rates, fluid shifts)

Surgical morbidity an and mortality

• 28-days surgical mortality: 2.5% vs. 0.7%
• Grade 3 or 4 hemorrhage: 7.4% vs. 4.1%
• Infection 8.1% vs. 1.7%
• Venous complications: 2.6% vs. 0%

….in favor of interval debulking surgery

Vergote et.al. NEJM 2010

0.00 0.25 0.50 0.75 1.00 274 233 200 158 132 73 44 20 12 5 NACT 276 222 185 151 126 63 32 17 9 2 1 PS

N

6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time from randomisation (months)

PS NACT intention-to-treat population

Overall survival

0.00 0.25 0.50 0.75 1.00 274 212 122 69 44 22 15 9 5 3 NACT 276 192 112 65 37 22 11 6 4 1 1 PS

N

6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time from randomisation (months)

PS NACT intention-to-treat population

Progression Free Survival

Tim iming of

• f su

surgery ry: upfr front vs s neoadjuvat

Kehoe S et.al., Lancet 2015

Timing of debulking surgery has no significant impact in survival, but IDS has a lower morbidity profile

Vergote et.al. NEJM 2010

Median OS (months): 45 versus 25.6 mo (PDS) 38 versus 25.5 mo (IDS)

CHORUS tr trial: Surgical ch characteristics

PS (N=250)* NACT (N=216)* Optimal debulking 0cm 37 (16%) 77 (40%) ≤1cm 57 (25%) 67 (35%) >1cm 135 (61%) 49 (25%) Missing 21 23 Length of operation (minutes) Median (Range) 120 (30 – 450) 120 (30 – 330)

* Includes: PS - 2 pts who had NACT + surgery; NACT – 2 pts who had PS

Kehoe S et.al., Lancet 2015

De Deaths with ithin in 28 28 days of

• f su

surgery ry

PS NACT

Surgery 14 (5.6%) 1 (0.5%)

• Review of deaths within 28 days of surgery
• PS
• Disease progression = 4
• Pulmonary embolism = 2; infection = 3;

problems with fluid balance or renal failure = 2; hemorrhage = 1; intra-operative problems = 1

• Still under review = 1
• NACT
• Pulmonary embolism = 1

Kehoe et.al. Lancet 2015

Very broad surgical quality range of: 3.9% – 62.9%

Vergote et.al. NEJM 2010

”Equivalent” chemotherapy trial

Paclitaxel 25 mg/m2 q21d Carboplatin AUC 1 q 21d Carboplatin AUC 2 q 21d Paclitaxel 35 mg/m2 q 21d

18 cycles (12 months)

R

Bevacizumab 1.5 mg/kg q3w

1:1

• High-risk FIGO stage I–

IIA or FIGO stage IIB–IV

• Surgically debulked

histologically confirmed OC No significant difference in OS & PFS But: higher toxicity in higher dose arm

• Pts. with ovarian-,

fallopian-tube or peritoneal-cancer FIGO stage IIIB, IIIC and resectable stage IV

S

C P C P C P C P C P C P C P C P C P C P C P C P

S

Bevacizumab 15mg/sq x 15

R

• Primary Endpoint OS ITT population.
• Secondary Endpoints PFS, resection rates, M‘nM after 6 months, QoL, „fragility Index“
• Strata: FIGO stage (III / IV), group/country, ECOG 0 vs 1/2
• Qualification process for participating centers to ensure high surgical quality

S

surgery C P Carboplatin AUC5 Paclitaxel 175 mg/sq

• Bev. 15mg 15 mon

Bevacizumab 15mg/sq x 15

suggested therapy, also weekly paclitaxel possible / or omission of Bev

TRUST Trial on Radical Upfront Surgical Therapy

QA process: assessment form

AGO OVAR 19/FRAGILE: Stratifying patients to the right treatment strategies

All patients with OC FIGO IIB/IV

PROSPECTIVE ASSESSMENT OF:

• Charlson-Comorbidity index
• HADS-Score
• time up and go test
• Symptoms:
• y/n
• abdominal bloating/n
• Abdominal pain y/n
• Dyspnea y/n
• Labor:
• Albumin, S-Kreatinin
• Hb, Leukozyten, Thrombozyten
• CA 125
• ASA
• ECOG
• FIGO IV y/n
• Volume of ascites
• Palliative preop drainage of

ascites/pleuraeffusion

• weight/BMI

Treatment according to physicians choice (TRUST study

• ptional, NACT
• ptional)

Follow-Up for 10 months after registration/rando mization

Primary Co-endpoint: Identification of patients that wont benefit from „standard“ treatment appraoch (OPCTX) (=progression/death within 10 months after randomisation) Secondary endpoints: 3 mo OS, cycles of chemotherapy, residual disease, stage, ECOG after 6 months, 6-months-PFS, relaparotomy rates)

Documentation of: Surgical outcome, FIGO-stage, histology, Complications, Relaparotomy, systemic treatment, number of cycles, ECOG after 6 months

Summary – recommendation for surgery in advanced OC

• Surgical effort only modifiable factor in advanced OC surgery

influencing survival

• Expertise and training lead to higher complete resection rates

without unjustifiable morbidity risk

• Timing of surgery still to be determined, but identification of
• ptimal surgical candidates keyfactor
• Role of systematic LND: TBC, in the presence of bulky LN

removal necessary as part of the debulking