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Secondary Cytoreduction

In Recurrent Ovarian Cancer

Robert L. Coleman, M.D.Professor & Vice Chair, Clinical Research

Department of Gynecologic OncologyUniversity of Texas, M.D. Anderson Cancer Center

Surgery in Relapsed Disease: Why?

• Palliation - bowel obstruction, fistula, etc• Make a diagnosis - recurrence, lesion not amenable to biopsy, second primary, etc• Evaluate extent of disease• Cytoreduction

Surgery in Relapsed Disease: Why?

• Palliation - bowel obstruction, fistula, etc• Make a diagnosis - recurrence, lesion not amenable to biopsy, second primary, etc• Evaluate extent of disease• Cytoreduction

Remember When…

Gynecol Oncol 51: 127-135, 1993

Why Don’t We Have An Answer?

• Bias, Bias, Bias…• For the most part, we do not know who

and not to offer the procedure• For the most part, we don’t have a reliable

way to predict post-surgical goal• Adjuvant therapy has changed

Background “Noise”: Platinum Sensitive

Author

TB HuininkGordonICON4AGOOVA-301CALYPSOOCEANS

Year

1997200120032006200920102012

Agent

TopotecanPLDPaclitaxel/CarboGem/CarboPLD/TrabectedinPLD/CarboGem/Carbo/Bev

TFI (mos)

46% > 6 mos44% > 12 mos 75% > 12 mos60% > 12 mos67% > 6 mos

65% > 12 mos60% > 12 mos

Survival (mos)

15*(overall)253218293133

Range 15-33 mos

Secondary Cytoreduction: Typical Report?

• 57 patients– Neg SLL (PCR)– All platinum-based

• Median TFI: 20 mos• Median survival

overall: 19 mos • Prognostic factor:

residual disease (P < 0.0001)

< 0.5 residual (14 pts)

> 0.5 residual (24 pts)

Not Explored(19 pts)

Vaccarello Gynecol Oncol 57:61, 1995

Secondary Cytoreduction: Bias?

• Selection Bias?– Median time to recurrence

between cohorts– Balance of surgical covariates

• PS• Recurrence criteria (16/57 found

by CA125)• Volume of disease (median 2-5

cm)• Location of disease

– Is the survival in the subtotal resection cases any different than expected?

• Uncensored events– 4/19 unexplored pts dead in 3 mos

< 0.5 residual (14 pts)

> 0.5 residual (24 pts)

Not Explored(19 pts)

Vaccarello Gynecol Oncol 57:61, 1995

Summary Data

Whom are the Best Candidates?

Incomplete Responders Don’t Benefit?

• Successful cytoreduction– 72% Clinical CR’s– 44% Clinical PR’s– P = 0.004

• Morbidity– Death (1)– Major (13)– Transfusion (62)

Segna J Clin Oncol 11:434, 1993

Median = 11.7 mos

Patients with Preop Chemotherapy Don’t Benefit?

• All TFI > 6 mos and pretreated before referral

• 23 “resistant” - no response to platinum retreatment

• 19 “sensitive” – responded to treatment– 10 retreated with non-

platinum– 9 retreated with platinum

Preoperative Salvage

Chemotherapy

No PreoperativeChemotherapy

P=0.001

Eisenkop, Cancer (2000) 88:144

Category N Median OS

“Resistant” 23

21.5 mos

“Sensitive” – Other treatment 10

25.0 mos

“Sensitive” - retreatment 9 34.8 mos

P 42

NS

Patients with Early TFI’s Don’t Benefit?

• Patients (n = 106)– Optimal (no visible tumor):

82%– All cisplatin based– Disease-free: 6 mos

• Time to second surgery: 16.8 mos (6 - 109)

6-12 mos

13-36 mos

>36 mos

Eisenkop Cancer 88:144, 2000

TTP Definition

mos>12

>12>17.5>36>24

12-24>24>24>18>30>24

Survival by TTP

Author

JanickeSegnaZangGadducciEisenkopMunkarahScarabelliTayZangSalaniChiOksefjellTotal/Range

N

30276030

11425

14846

11755

157217814

SurgeryMedian

mos16

16.613

11.516.837.6

10-1226

15.432

6-1110 - 37.6

TTP Definition

mos<12<12<12

<17.5<12<24<12<123-12<18<126-24

SurvivalMedian

mos8

8.88

152542126

183

3019

6-42 (15)

Survivalmedian mos (P)

29 (0.004)

12 (0.02)25 (0.04)

56.8 (0.005)57 (NS)

32 (0.001)39 (0.001)40 (0.04)

49 (0.001)51 (0.005)54 (0.001)12-57 (40)

Patients with Diffuse Disease Don’t Benefit?

Salani, Cancer (2007) 109:685

Survival by Post-op Residuum

Fader J Clin Oncol (2007) 25:2873

38

13

55%

DESKTOP-I: Surgical Endpoint of Surgery at Relapse

no residualsmedian OS 45.2 mo

residuals > 10 mm

residuals 1-10 mm

Surv

ival

pro

babi

lity

0

1.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 12 24 36 48

Months from Randomization

Developing a Prospective Eligibility Algorithm

* Initial FIGO-stage I/II vs III/IV alternatively, if residual disease after 1st surgery is unknown

Variables HR (95% CI) P-value

PS ECOG 0 mm> 0mm

12.56 (1.49 – 4.42)

< 0.001

Residual disease (after 1st surgery)

0 mm> 0 mm

12.09 (1.20 – 3.64)

0.009

Ascites (cut-off 500 ml)

< 500 ml≥ 500 ml

14.26 (1.62 – 11.24)

0.003

Predictors of R0 at Secondary Cytoreduction

How do We Synthesize this Information?

• Incomplete responders to frontline therapy• Patients undergoing salvage therapy first• Patients with short TFI• Patients with diffuse disease at surgery• Patients with post op tumor residuum

Poor Surgical Candidates

Candidate Selection

Modeling

Tian Ann Surg Oncol (2012) 19:597

Background “Noise”: Platinum Sensitive

AuthorTB HuininkGordonICON4AGOOVA-301CALYPSOOCEANS

Year1997200120032006200920102012

AgentTopotecanPLDPaclitaxel/CarboGem/CarboPLD/TrabectedinPLD/CarboGem/Carbo/Bev

TFI (mos)46% > 6 mos

44% > 12 mos 75% > 12 mos60% > 12 mos67% > 6 mos

65% > 12 mos59% > 12 mos

Survival (mos)15*(overall)

253218293136

Range 15-36 mos

Comparison Group: No Surgery

• Platinum-Sensitive (n=84)• Retrospective study focused on

use of Paclitaxel/Platinum for recurrent disease

• Median TFI: 22 mos• N = 21 (25% debulked)

– Minimum 12 mos– 18 (86%) complete

• PFI: 11 vs 17 mos (p=0.04)

• OS - 3 yrs: No Difference

Debulked at TFI > 12 mos

Dizon, J Clin Oncol 20:1238, 2002

Where Do We Go From Here?

Phase III Surgical Trials: Recurrent Disease

• EORTC 55963:– Opened 8/2000 (N ~ 700) - Terminated– Chemo x 3 then randomized to IDS or Chemo x 3 (Similar to GOG

152 but in recurrent setting)• GOG 213:

– Opened 12/2007 (N ~ 660, 330 surgical arm)– Bifactorial Design: Surgery vs. No Surgery; Chemo ± bevacizumab

• DESKTOP III:– To open 8/2009 (N ~ 408)– Feasibility-directed patient selection (DESKTOP II) followed by

randomization to Surgery vs. no Surgery (standard chemotherapy to follow)

AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

EOC, FT, PP• PFI > 6•No prior recurrence

chemotherapy•Complete resection

seems feasible and positive AGO score:

• PS ECOG 0• No ascites >

500 ml• Prior complete

debulking or initial FIGO I/II

Secondary Cytoreduction

Chemo

Regimens post-randomization• Carboplatin/paclitaxel• Carboplatin/gemcitabine• Carboplatin/PLD

No surgery

R

N = 100/408 planned

Frequency of complete resection by applying the AGO Score

AGO DESKTOP OVAR II – Surgical Results

With a prevalence or complete resection in 76% of the study collective =

AGO score could prospectively predict complete resection in at least 2 out of 3 patients

75 7668

0

10

20

30

40

50

60

70

80

90

100

Score positive Score positive Score positive

all patients 1st relapse 2nd relapse

DESKTOPHypothesis

Score Pos1st Relapse

Score Pos2nd Relapse

Score PosAll Patients

AGO DESKTOP OVAR II – Surgical Results

Harter P, Int J Gynecol Cancer (2011) 21:289

57% went to surgery

98 (76%) had R0

PI: Coleman

Recurrent Ovarian, PPT and FT CancerTFI ≥ 6 mos

Yes No

Randomize

Surgery No Surgery CarboplatinPaclitaxel or Gemcitabine

CarboplatinPac or Gem

Bevacizumab

Bevacizumab

GOG-213

To Chemotherapy Randomization

Randomize

Surgical Candidate?

Summary

• Defined study population • Strong recruitment bias exists in available trials• Feasible

– Success depends on endpoint• Lasting chemosensitivity important to survival

• Null Hypothesis:– 2º debulking + chemo = chemo alone – Endpoint = Survival– Fair comparison requires balance of known risk factors

• Randomization

Thank You!