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Transcript of Clique para editar o título mestre. Secondary Cytoreduction In Recurrent Ovarian Cancer Robert L....
![Page 1: Clique para editar o título mestre. Secondary Cytoreduction In Recurrent Ovarian Cancer Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research.](https://reader036.fdocuments.in/reader036/viewer/2022081519/56649e855503460f94b87234/html5/thumbnails/1.jpg)
Clique para editar o título mestre
![Page 2: Clique para editar o título mestre. Secondary Cytoreduction In Recurrent Ovarian Cancer Robert L. Coleman, M.D. Professor & Vice Chair, Clinical Research.](https://reader036.fdocuments.in/reader036/viewer/2022081519/56649e855503460f94b87234/html5/thumbnails/2.jpg)
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
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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
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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
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Remember When…
Gynecol Oncol 51: 127-135, 1993
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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
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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
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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
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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
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Summary Data
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Whom are the Best Candidates?
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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
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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
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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
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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)
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Patients with Diffuse Disease Don’t Benefit?
Salani, Cancer (2007) 109:685
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Survival by Post-op Residuum
Fader J Clin Oncol (2007) 25:2873
38
13
55%
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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
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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
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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
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Candidate Selection
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Modeling
Tian Ann Surg Oncol (2012) 19:597
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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
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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
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Where Do We Go From Here?
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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)
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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
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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
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AGO DESKTOP OVAR II – Surgical Results
Harter P, Int J Gynecol Cancer (2011) 21:289
57% went to surgery
98 (76%) had R0
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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?
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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
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Thank You!