A Randomized Phase III Trial of Cisplatin and

Tumor Volume Directed Irradiation Followed by

Carboplatin and Paclitaxel vs. Carboplatin and
Paclitaxel for Optimally Debulked, Locally
Advanced Endometrial Carcinoma
A Gynecology Oncology Group/NRG Oncology Study
Daniela Matei, Virginia Filiaci, Marcus Randall, David Mutch, Margaret Steinhoff, Paul
DiSilvestro, Katherine M. Moxley, Byoung Kim, Matthew A. Powell, David M. O’Malley, Nicola M.
Spirtos, Krishnanu S. Tewari, Edward Richards, John Nakayama, David Miller

Northwestern University; NRG Oncology SDMC, Buffalo, NY; University of Kentucky, Women and Infants Hospital in Rhode Island, University of Oklahoma Health Sciences Center, Samsung
Medical Center, Sungkyunkwan University School of Medicine,; Washington University School of Medicine in St. Louis,; The Ohio State University College of Medicine; Womens’ Cancer Center;
University of California Irvine Medical Center, Lewis Cancer and Research Pavilion at St. Joseph's/Candler, University Hospital; The University of Texas Southwestern Medical Center

Presented by: Daniela Matei, MD

Locally Advanced Endometrial Cancer (III/IVA)
• Endometrial cancer statistics:
– 61,380 cases
– 10,920 deaths
• Stage III/IVA EC -heterogeneous group -10-15% of all cases,
account for >50% of deaths
• Five year survival ranges from 50-70%
• High risk of local (~ 20-30%) and systemic recurrence (~40%)
Siegel R et al. CA Cancer J Clin 2013;63:11-3; Cook AM et al. Br J Radiol 1999;72:485-8; Statistics, 2017
Behbakht K et al. Gynecol Oncol 1994; 55:363-7; Greven KM et al. Cancer 1993;71:3697-702; ACS Grigsby PW et al. Gynecol Oncol 1987;27:44-57.

Presented by: Daniela Matei, MD

Stage III/IVA Endometrial Cancer (FIGO 2009)
• STAGE IIIA : Tumor invades serosa of the corpus and/or adnexae
• STAGE IIIB: Vaginal or parametrial metastases
• STAGE IIIC : Metastases to pelvic and/or para-aortic lymph nodes
IIIC1: Positive pelvic lymph nodes
IIIC2: Positive para-aortic lymph nodes
• STAGE IVA : Tumor invades bladder and/or bowel mucosa
• STAGE IVB: Distant metastases including intra-abdominal and/or
inguinal lymph nodes
Either G1, G2 or G3
Endocervical glandular involvement is now considered Stage I and no more as Stage II
Positive cytology has to be reported separately without changing the stage.

Presented by: Daniela Matei, MD

 Stage III/IVA EC-Background
Local Distant
Clinical trial Stage Treatment arms recurrence recurrence 5 yr Survival

WAI 13% WAI 38% WAI 42%

GOG 122 III/IVA WAI vs. AP
AP 18% AP 32% AP 53%

(5 yr RFS)
EBRT followed
GOG 184 III/IVA 10% 30% AP 56%
by AP vs. TAP
TAP 59%

EBRT 12% EBRT 26% EBRT 69%

Maggi IC/II/III EBRT vs. CAP
CAP 15% CAP 20% CAP 66%

WAI = whole abdominal irradiation TAP=paclitaxel + doxorubicin + cisplatin Randall, JCO, 2006;24:36-44
EBRT=external beam radiotherapy CAP=cyclophosphamide+ doxorubicin + Homesley, Gynecology Oncology, 112 (3), 543-552, 2009
AP=doxorubicin + cisplatin cisplatin, RFS=Recurrence-Free Survival Maggi R et al. Br J Cancer 2006; 95:266-71

Presented by: Daniela Matei, MD

 Research Hypothesis
Combined systemic chemotherapy and tumor volume
directed radiotherapy (C-RT) improves recurrence-
free survival and overall survival compared to
systemic chemotherapy alone (CT) in patients with
optimally debulked stage III/IVA EC.

Presented by: Daniela Matei, MD

 Study Schema
Regimen 1: C-RT (n=407)

Randomization 1:1
Cisplatin 50 mg/m2 IV Days 1 and 29 plus Volume-directed
radiation therapy (45Gy+/- brachytherapy)
followed by
Carboplatin AUC 5* plus Paclitaxel 175 mg/m2 q 21 days
for 4 cycles with G-CSF support
TAH/BSO, Pelvic and para-aortic
lymph node sampling optional
Eligibility: Regimen 2: CT (N=406)
Surgical Stage III or IVA EC (FIGO 2009)
Stage I or II clear cell or serous EC + cytology Carboplatin AUC 6 plus Paclitaxel 175 mg/m2
q 21 days for 6 cycles
GOG Performance Status of 0-2
Adequate organ function
Ineligible Patients Stratification:
Carcinosarcoma Age >/< 65 CT scans q 6months X 2 years, q 12 months X 3 years
Recurrent EC Gross residual disease
Residual tumor after surgery > 2 cm

Presented by: Daniela Matei, MD

 Study Objectives
Primary Objective:
 To determine if C-RT increases recurrence-free survival (RFS) vs. CT.

Secondary Objectives:
 To determine if C-RT reduces the rate of death (i.e., increases survival)
when compared to CT.
 To compare acute and late adverse effects of C-RT and CT.
 To determine patient-reported quality of life during and following treatment.

Presented by: Daniela Matei, MD

 Patient Enrollment & Randomization
813 patients were enrolled
and randomized 40 ineligible
37 ineligible 13 wrong stage
24 inadequate path
14 wrong stage
0 wrong cell type
16 inadequate path
407 assigned to C-RT 406 assigned to CT 2 second primary
2 wrong cell type
1 other
2 second primary
3 other

24 did not receive 5 did not receive

study Tx study Tx

370 included in efficacy analysis 366 included in efficacy analysis

346 included in safety analysis 361 included in safety analysis

139 disease recurrence or death 131 disease recurrence or death

79 died 84 died
Enrollment period: 6/29/2009-7/24/2014
Data cut off 3/9/2017
Median FU 47 months

Presented by: Daniela Matei

 Patient Characteristics
C-RT (N=370) CT (N=366)
Characteristic
N % N %
Age (mean, range) 60.5 (31-88) 60 (31-85)
Race
White 291 78.6 279 76.2
Black/African American 37 10.0 42 11.5
Asian/other/not specified 42 11.3 45 12.2
Performance Status
0 278 75.1 268 73.2
1 88 23.8 96 26.2
2 4 1.1 2 0.5
FIGO Stage (2009)
Stage 1 or 2 6 1.6 11 3.0
Stage 3A 69 18.6 78 21.3
Stage 3B 15 4.1 13 3.6
Stage 3C 277 74.9 261 71.3
Stage 4A 3 0.8 3 0.8
Histology/Grade
Endometrioid, grade 1 87 23.5 79 21.6
Endometrioid, grade 2 103 27.8 118 32.2
Endometrioid, grade 3 64 17.3 61 16.7
Serous 66 17.8 65 17.8
Clear Cell 10 2.7 12 3.3
Mixed Epithelial/Other 40 7.7 30 6.3
BMI Category
Median (range) 32.9 (11.2-65.3) 32.9 (18-60.2)
Normal or underweight 72 19.5 71 19.4
Overweight 84 22.7 81 22.1
Obese Class I-III 214 57.8 214 58.4

Presented by: Daniela Matei, MD

Treatment Delivery and Discontinuation
Characteristic C-RT CT
Received EBRT, no brachytherapy 174
Received EBRT, + brachytherapy 201
Received 2 cycles of Cisplatin with EBRT 352
Received ≥ 4 cycles of Carboplatin 310 374
Reason Off Study treatment
Completed regimen 278 314

Disease progression 10 6

Death 2 2

Toxicity 38 30

Patient Refused 23 12

Other 19 2

Presented by: Daniela Matei, MD

 Acute Toxicity
Adverse Events Grd 1-2 Grd 3-5
C-RT CT C-RT CT
(n=346) % (n=361) % (n=346) % (n=361) %
Constitutional* 81 78 6 2
Fatigue* 79 73 5 2
Cardiac 12 16 3 4
Endocrine 11 11 1 0
Gastrointestinal** 77 75 13 4
Renal/Genitourinary* 31 10 2 1
Blood/Bone Marrow** 55 38 40 52
Infection 19 15 4 5
Lymphatics 17 15 <1 <1
Musculoskeletal** 16 12 3 1
Metabolic/Laboratory* 33 35 15 9
Neurology 69 74 7 5
Pulmonary 29 26 2 1
Pain 62 63 8 5
* p<0.05 Grd. 5 events: 3 in CT arm, none in C-RT:
** p<0.01
Presented by: Daniela Matei, MD
Cumulative Incidence of Recurrence
Vaginal Recurrence Pelvic and PA Recurrence
Vaginal recurrence 3% 7% Pelvic/PA recurrence 10% 19%
Incidence at 5 years Incidence at 5 years

C-RT vs. CT : HR=0.36 (CI: 0.16-0.82) C-RT vs. CT : HR=0.43 (CI: 0.28-0.66)

Presented by: Daniela Matei, MD

Cumulative Incidence of Recurrence
Distant Recurrence

Distant recurrence 27% 21%

incidence at 5 years

C-RT vs. CT : HR=1.36 (CI: 1.00-1.86)

Presented by: Daniela Matei, MD

Recurrence-Free Survival

Events Total HR 90% CI

132 370 0.90 (.74, 1.10)
139 366

Presented by: Daniela Matei, MD

 Exploratory Subset Analysis RFS Forest Plot Data

# Events Total HR 95% Confidence p-value

Interval
FIGO Stage 0.15
Stage 1,2,3A 51 164 0.77 0.44 - 1.36
Stage 3B 17 28 1.80 0.66 - 4.88
Stage 3C/3C1 133 411 1.14 0.81 - 1.61
Stage 3C2/4A 70 133 0.66 0.41 - 1.08
Age at Entry 0.44
Age 65 or Younger 165 532 0.98 0.72 - 1.33
Age over 65 106 204 0.81 0.55 - 1.19
Gross Residual Status 0.83
No Gross Residual 260 719 0.93 0.73 - 1.19
Gross Residual 11 17 0.81 0.23 - 2.87
Cell Type/Grade 0.76
Endometrioid, Grade 1 32 166 0.98 0.49 - 1.96
Endometrioid, Grade 2 67 221 1.05 0.65 - 1.70
Endometrioid, Grade 3 48 129 1.09 0.62 - 1.92
Serous 74 131 0.85 0.54 - 1.34
Other 50 89 0.68 0.39 - 1.19
BMI 0.86
Normal or Underweight 53 143 1.09 0.64 - 1.87
Overweight 74 165 0.92 0.58 - 1.45
Obese Class 1-3 144 428 0.92 0.67 - 1.28
Primary Analysis 271 736 0.90 0.71 - 1.15
p value is for a test of homogeneity of treatment effect

Presented by: Daniela Matei, MD

 Overall Survival

Events Total
86 370
79 366
5 year OS estimates
C-RT: 70%
CT: 73%
Data cut-off 03/09/2017 Data not mature for final analysis

• Presented by: Daniela Matei, MD

 Conclusions
• Chemo-RT did not improve RFS compared to chemotherapy (HR=0.9, CI
0.74-1.1).
• Acute toxicities for chemo-RT and chemotherapy were similar.
• 75% patients completed study therapy in C-RT arm compared to 85%
patients in CT arm.
• Chemo-RT reduced the incidence of vaginal, pelvic and para-aortic
recurrences compared to CT.
• Distant recurrences were more common with C-RT vs. CT.
• Survival and QOL endpoints will be reported in the future.

Presented by: Daniela Matei, MD

 Acknowledgements

Ginny Filiaci David Mutch Marcus Randall Margaret Steinhoff David Miller

Buffalo SDMC Study participants

Betty Stonebraker, CCRP Family caregivers
Heather Lankes, PhD Participating investigators
Helen Huang, MS Clinical research staff

National Cancer Institute grants to the Gynecologic

Oncology Group (GOG) Administrative Office (CA
27469), the Gynecologic Oncology Group Statistical
Office (CA 37517), NRG Oncology SDMC (1U10
CA180822) and NRG Operations (U10CA180868)

Presented by: Daniela Matei, MD Northwestern University, Chicago