th break.

Primary vs. Interval Cytoreduction: Which is Best?

Thomas J. Herzog, MD Paul & Carolyn Flory Endowed Professor

Deputy Director, UC Cancer Institute Vice Chair Quality & Safety, Dept Ob/Gyn

University of Cincinnati

Disclosures • Scientific Advisory Boards:

• AZ, Caris, Clovis, Genentech, GSK/Tesaro, J & J,Merck

th break.

A Front-line Treatment Controversy:

• “When” should we surgicallytreat Front-line disease & thus“what” is the role ofneoadjuvant chemotherapy?

Email questions to Dr. Wendel Naumann at education@igcs.org for discussion during the break.

Diagnosis

Chemo #1

Evaluation / Surveillance Progression

Chemo #2 Chemo #3+

Supportive Care

+/- Maintenance

Cure

Evaluation Progression

Treatment Paradigm

Symptoms

Primary PFS (12-28 mos)

Recurrence Rx (12-38 mos)

+/- Maintenance

10 Surgery / Staging

z

Email questions to Dr. Wendel Naumann at education@igcs.org for discussion during the break.

Treatment Paradigm

Primary PFS

(12-28 mos)

Recurrence Rx (12-38 mos)

Diagnosis

Chemo #1

Evaluation / Surveillance Progression

Chemo #2 Chemo #3+

Supportive Care

+/- Maintenance

Cure

Evaluation Progression

Symptoms

Surgery / Staging

+/- Maintenance

HIPEC ?

Neoadjuvant

EORTC 55971: Neoadjuvant Chemotherapy

Stage IIIC/IV Ovary

Peritoneal Fallopian tube

Primary cytoreductive Maximal effort

Open: 9/21/98 Accrual: 670 pts (632 eval)

Chemotherapy Taxane (paclitaxel or docetaxel) Platin (cisplatin or carboplatin)

Neoadjuvant: Primary

Chemotherapy x 3 cycles

62% had Lesions > 10 CM

Vergote, I. N Eng J Med, 2010

R A N D O M I Z E

0 2 4 6 80

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :259 361 183 68 16 2251 357 191 56 11 1

urgery

(years)10

TreatmentUpfront debulkings Neoadjuvant chemotherapy

Overall survival

EORTC 55971: Neoadjuvant Chemotherapy

Vergote N Eng J Med, 2010

PDS: 29 months IDS: 30 months HR: 0.98 (0.85, 1.14)

EORTC 55971: 1o Cytoreduction vs. Neoadjuvant & Interval Cytoreduction

Primary Cytoreduction

Interval + Neoadjuvant

< 1 cm residual 42% 81%

R-0 20% 52%

Death (< 28d) 2.5% 0.7%

Gr ¾ Hemorrhage 7.4% 4.1% Infection 8.1% 1.7% VTE 2.6% 0% QOL QLQ-C30 NS Difference

Vergote N Eng J Med, 2010

Optimal Resection after Neoadjuvant Chemotherapy

PDS NACT

% HR Median OS % HR Median

OS

No Residual 20% 1.00 45.0

(34.4-53.6) 52% 1.11 (0.82-1.51)

38.2 (32.7-44.0)

Optimal 24% 1.37 (0.97-1.93

32.3 (26.9-37.4) 30% 1.73

(1.25-2.40) 27.0

(24.3-31.7)

Suboptimal 55% 1.87 (1.39-2.50)

25.7 (21.6-28.6) 18% 1.71

(1.19-2.46) 25.5

(19.9-31.9)

Vergote I, NEJM 363(10):942 (Supp.), 2010

Ph III CHORUS Trial: Chemo or Upfront Surgery

Presumed Stage III/IV Ovary, PP,

Fallopian tube CA125: CEA > 25

Primary cytoreduction

Chemo x 3

Chemo x 6

Interval Cytored

Chemo x 3

Bx

N = 276

N = 274

Kehoe, S. Lancet, 2015

34%- Tumor > 10 cm

RCOG

R A N D O M I Z E

CHORUS Results

PDS: 22.6 months IDS: 24.1 months HR: 0.87 (0.72, 1.05)

Kehoe, S. Lancet, 2015

CHORUS: 1o Cytoreduction vs. Neoadjuvant & Interval

Cytoreduction Primary Cytoreduc*on Interval+

Neoadjuvant

< 1 cm residual 41% 73% R-0 17% 39% Death (< 28d) 6% 0.3% Any Gr ¾ Event 24% 14% Infection 6% 3% VTE 2% 0% QOL QLQ-C30 NS Difference

Kehoe, S. Lancet, 2015

SCORPION trial

Stage IIIC / IV

Fagotti Score ≥ 8 at laparoscopy

Paclitaxel 175 mg/m2 Carbo AUC 6 x 8 cycles

Interval Surgery

Optimal cyto (93%)

Maximal Cytoreductive Effort

Primary Chemotherapy with Paclitaxel and Carboplatin AUC 6

R A N D O M I Z E

1° - PFS Superiority of NACT & morbidity 2° - OS and QOL

n=84

n=87

Median F/U = 42 months 80% reached PFS 43% reached OS

Fagotti A, J Clin Oncol 36, 2018 (suppl; abstr 5516)

Optimal cyto (100%)

Operative Mortality = 8%

SCORPION Trial

Fagotti A, SGO 2019

SCORPION Trial

Fagotti A, SGO 2019 9

SCORPION Trial

Fagotti A, SGO 2019

Optimal

Suboptimal Paclitaxel 175 mg/m2 Carboplatin AUC 6 x 4 cycles Possible Interval cytoreduction TC × 4 cycles

Interval Surgery TC x 4 cycles

Interval cytoreduction (88%)

Maximal Cytoreductive Effort

Primary Chemotherapy Paclitaxel 175 mg/m2

Carboplatin AUC 6

q 3 wk x 4 cycles

RANDOMIZE

α = 0.05 β = 0.8 ΗΡ = 1.16 (5% difference at 3 yr)

33% had Interval Surgery

Paclitaxel 175 mg/m2 Carboplatin AUC 6 x 8 cycles

Planned sample size was 300 with 3-year OS of 25% in PDS arm, 30.3% in NAC arm and non-inferiority margin of hazard ratio (HR) of 1.161 (these corresponds to median OS of 18 months in PDS arm, 20.9 months in NAC arm and non-inferiority margin of 2.5 months), one-sided alpha of 5% and 80% power.

n=149

n=152

Primary Debulking Surgery versus Neoadjuvant Chemotherapy for St III/IV Ovarian Cancer - A JCOG Trial

StratifyAgeStageInstitutionPS

Stage IIIC / IV Ovary

Peritoneal Fallopian tube

> 2 cm nodulesoutside of pelvis

Onda T, ASCO 2014

1° - Non-inferiority OS 2° - Length surgery & surgical morbidity

Primary Neoadjuvant

EROTC (n = 718) 42% 81%

CHORUS (n = 550)

39% 75%

JCOG (n = 297) 62% 81%

up to 2x

Surgical Outcomes: Primary Debulking vs. Neoadjuvant Chemo

Optimal Resection (≤ 1 cm)

Primary Neoadjuvant

EROTC (n = 718) 18% 45%

CHORUS (n = 550)

16% 40%

JCOG (n = 297) 30% 63%

up to 2x

Surgical Outcomes: Primary Debulking vs. Neoadjuvant Chemo

No Gross Residual (R-0)

Primary Neoadjuvant

Permanent Colostomy

24% 6%

Reop for Complication

21% 3%

Surgical Time 276% 211%

Surgical Outcomes: Primary Debulking vs. Neoadjuvant Chemo

Onda T, Exp Rev Anticancer Ther ;11(7):1055, 2011

PFS OS

Design 1° n PDS NACT HR PDS NACT HR

EROTC Non-

inferiorty (0.80)

OS 718 12 12

1.01 (0.89-1.16

) 29 30 0.98

(0.84-1.13)

CHORUS Non-

inferiorty (0.85)

OS 550 10 12

0.90 (0.75-1.07

) 23 25 0.87

(0.72-1.06)

JCOG Non-

Inferiorly (0.86)

OS 301 15 16

0.99 (0.74-1.26

) 49 44 1.05

0.84-1.33

SCORPION Superiority PFS 171 15 14

1.06 (0.77-1.46

) 41 NR -

PDS vs NACT: Randomized Trials

Cost Comparison PDS vs. Neoadjuvant

Rowland, M. AJOG 2015

Cost Comparison PDS vs. Neoadjuvant in Advanced Stage Ovary & > 65 yo

Rowland, M. AJOG 2015

Avg. Treatment Cost/Patient Comparison PDS vs. Neoadjuvant

Rowland, M. AJOG 2015

US Dollars

Predictors of Suboptimal (> 1 cm) Cytoreduction

Criteria (Mul*variateAnalysis)

OR 95% CI p = PredValuescore

Age > 60 1.32 1.06-1.63 0.01 1 CA-125 > 500 1.47 1.28-1.69 < 0.001 1 SAS 3-4 3.23 1.76-5.91 < 0.001 3 Retro LN > 1maboverenalhilum 1.59 1.58-1.60 < 0.001 1 Diffuse bowel thickening 1.87 1.86-1.87 < 0.001 1 Perispleniclesion>1cm 2.27 1.7-3.03 < 0.001 2 SM bowel mesentery lesion 2.28 1.08-4.8 0.03 2 Root SMA lesion > 1cm 2.4 1.34-4.32 0.003 2 Lesser sac lesion > 1 cm 4.61 4.39-4.84 < 0.001 4

Suidan, R. Gyn Onc 2014 N = 350 St III/IV; 10 Cyto; Prospective

Predictors of Suboptimal (> 1 cm) Cytoreduction

Predic*veValueScore

N=(%)

Op*mal Subopt SubOptRate

0 22/349(6%) 21 1 5%

1-2 79/349(23%) 71 8 10%

3-4 109/349(31%) 91 18 17%

4-5 85/349(24%) 56 29 34%

5-6 31/349(9%) 15 16 52%

6-7 23/349(7%) 6 17 74% Suidan, R. Gyn Onc 2014 N = 350 St III/IV; 10 Cyto; Prospective

• MIS was completed without conversion in 44/53 patients (83%) but 47%required hand port/mini-lap

• 10% of pts had a complete pathologic response to NACT (13% MIS & 8% Lap,p=0.494)

NACT Facilitates MIS

MIS Open Surgery

R0 32 (60.4%) 43 (44.3%)

Optimal 19 (35.9%) 41 (42.3%)

Suboptimal 2 (3.8%) 13 (13.4%)

p = 0.07

96% 87%

Drury L, Gynecol Oncol 149(3):620, 2018

No Difference in PFS or OS

PFS: 27 vs. 29 m p=0.45

OS: 37 vs. 35 m p=0.74

Drury L, Gynecol Oncol 149(3):620, 2018

0%

25%

50%

75%

100%

0 35 70 105 140

<1 mm

1-9 mm

>10 mm

Ove

rall

Surv

ival

HR (95%CI) 1-10 mm vs. 0 mm: 2.70 (2.37;

3.07)

>10 mm vs. 1-10 mm: 1.34 (1.21;

1.49)

log-rank: p < 0.0001

Generated from 3 prospective Ph III trials (OVAR 3,5, & 7)

N = 3126 pts

du Bois A, Cancer 115:1234, 200Months

The Impact of Residual Cancer

Rationale for Neoadjuvant

R-0Resection

Minimize M & M

Maximize OS Neoadjuvant Rx

Rationale for Neoadjuvant

R-0Resection

Minimize M & M

Maximize OS Neoadjuvant Rx

So Who Would Potentially Benefit from Neoadjuvant?

Medically Unfit -Morbidity scoring; Age

Research -New Approval Pathway

pCR -Target engagement

UnresectableDisease -Ascites

-CA-125 > 500 -Radiographic -Laparoscopic

Conclusions • Growing use of Neoadjuvant Treatment (NAT)• Key: Patient & Pattern of Disease Assessment• NAT with Less: M & M; colostomy creation, ORtime, & Likely less cost; Facilitates MIS approach • OS is key issue: Level 1 evidence NAT non-inferiorBUT:

-OS < Contemporary non-randomized controls

- Operator dependent?

- R-0 Not translating into benefit with NAT

• NAT = new research opportunity-Target engagement; Dynamic imaging

-Novel agent quick screen; Possible regulatory approvalpath

Grazie

Obrigado

Merci

ThankYou!

Spasiba

Gracias

Toa Chie

Khawp khun

Teşekkür

Ederim