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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!