Comparison of survival between upfront primary debulking surgery - PowerPoint PPT Presentation

Comparison of survival between upfront primary debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomized trial: JCOG0602. Onda T, Satoh T, Saito T, Kasamatsu T, Nakanishi T, Takehara K, Miyamoto K, Wakabayashi M, Okamoto A, Ushijima K, Kobayashi H, Kawana K, Yokota H, Takano M, Omatsu K, Watanabe Y, Yamamoto K, Yaegashi N, Kamura T, Yoshikawa H, Japan Clinical Oncology Group UMIN Clinical Trials Registry: UMIN000000523 Takashi Onda 1 http://clicktoeditURL.com

Background • Two preceding studies, EORTC55971 and CHORUS comparing upfront primary debulking surgery (PDST) and neoadjuvant chemotherapy (NACT) for stage III/IV ovarian, tubal and peritoneal cancers demonstrated non-inferiority of NACT in overall survival (OS). • We have already reported reduced invasiveness of NACT compared to PDST in several parameters. Takashi Onda 2 http://clicktoeditURL.com

Results of Previous studies EORTC (2010) CHORUS (2015) PDST NACT PDST NACT (N=336) (N=334) (N=276) (N=274) Characteristics PFS(M) 12 12 11 12 OS(M) 29 30 23 24 HR for NACT in OS 0.98 0.87 Confidence interval (CI) 90% CI 0.84-1.13 95% CI 0.72-1.05 Non-inferiority margin 1.25 1.18 p value 0.01 NA Takashi Onda 3 http://clicktoeditURL.com

Comparison of Treatment Invasiveness Parameters for treatment invasiveness PDST(n=149) NACT(n=152) P value Average number of surgery 1.32 0.86 <0.0001 Median operation time (min) 341 273 <0.0001 Median Blood/Ascites loss (ml) 3447 619.5 <0.0001 Resection of Abdominal organs 56(37.6%) 36(23.7%) 0.0121 Distant metastases 16(10.7%) 6(3.9%) 0.0272 Transfusion* RCC 97(66.0%) 79(52.7%) 0.0247 FFP 42(28.6%) 25(16.7%) 0.0180 Post-operative G3/4 adverse events** 23(15.6%) 6(4.6%) 0.0029 *among all treated patients, **among all operated patients Takashi Onda 4 http://clicktoeditURL.com

Main Objective of the JCOG0602 • To prove non-inferiority of NACT compared with PDST in terms of OS. • Primary Endpoint Overall Survival (OS) • Secondary Endpoint Progression-free Survival (PFS) Takashi Onda 5 http://clicktoeditURL.com

Trial Design Multicenter (34 specialized institutions), Standard Arm (PDST) Randomized Phase III Trial R PDS 4x TC 4x TC a n PDS: primary debulking surgery d IDS* 4x TC o Clinically diagnosed m Stage III/IV ovarian, *; Optional for pts with suboptimal PDS. i Mandatory for pts with any of Ut/Adn/OM tubal, and peritoneal z Unremoved. a cancers Experimental Arm (NACT) t i o Balancing factors NAC (4x TC) IDS 4x TC n Institution, Stage III/IV IDS: interval debulking surgery PS 0-1/2-3, Age <60/≥60 TC regimen: PTX 175 mg/m 2 iv, CBDCA AUC 6.0 iv Takashi Onda 6 http://clicktoeditURL.com

Key Eligibility Criteria 1. Untreated stage III or IV ovarian, tubal, or peritoneal cancers based on CT, MRI, and cytological tests. 2. Malignancies of other origin should be excluded by endoscopy, opaque enema, or ultrasonography when suspected. 3. CA125 >200 U/ml and CEA <20 ng/ml 4. No metastasis to brain, bone, or bone marrow 5. Age 20 to 75 years 6. PS of 0 to 3 7. Adequate organ functions Takashi Onda 7 http://clicktoeditURL.com

Initial Statistical Considerations Planned sample size was 300 (Expected number of events was 276) • One-sided alpha of 0.05 • Power of 0.8 • Expected 3-year OS PDST = 25%, NACT = 30.3% • Non-inferiority margin = 5% in 3-year OS Corresponding HR of 1.161 • Accrual period: 3 years, Follow-up period: 5 years Takashi Onda 8 http://clicktoeditURL.com

Revised Statistical Considerations • Accrual period was extended to nearly 5 years • Follow-up period was extended to 6 years due to fewer events • Final number of events was 227, power was 0.73 • Interim analysis was performed twice Predetermined analysis and additional analysis due to the extension of study period Multiplicity adjusted alpha = 0.04598 Takashi Onda 9 http://clicktoeditURL.com

CONSORT Flow Diagram Enrolled (N=301) PDST arm (N=149) NACT arm (N=152) No TC NAC (N=2) No PDS (N=2) NAC (N=150) Discontinued NAC (N=20) PDS (N=147) IDS (N=130) No Post-ope CTx (N=4) No CTx (N=9) Post-ope CTx (1-4th) (N=138) Post-ope CTx (N=126) Discontinued CTx (N=23) Discontinued CTx (N=10) IDS (N=49) No Post-ope CTx (N=3) Post-ope CTx (5-8th) (N=125) Discontinued CTx (N=26) Complete Tx (N=99) Complete Tx (N=103) Takashi Onda 10 http://clicktoeditURL.com

Patients’ Characteristics 1 (Balancing factors) PDST NACT Characteristics (N = 149) (N = 152) III 100 (67.1%) 105 (69.1%) Stage IV 49 (32.9%) 47 (30.9%) Median (Range) 59 (30-75) 60.5 (36-75) Age < 60 75 (50.3%) 72 (47.4%) ≥ 60 74 (49.7%) 80 (52.6%) 0-1 130 (87.2%) 131 (86.2%) PS 2-3 19 (12.8%) 21 (13.8%) Takashi Onda 11 http://clicktoeditURL.com

Patients’ Characteristics 2 PDST NACT Characteristics (N = 149) (N = 152) 200 <, ≤ 500 24 (16.1%) 29 (19.1%) 500 <, ≤ 1000 25 (16.8%) 34 (22.4%) CA125 (U/ml) 1000 <, ≤ 2000 26 (17.4%) 24 (15.8%) 2000 < 74 (49.7%) 65 (42.8%) ≤ 2cm 32 (21.5%) 42 (27.6%) 2 cm <, ≤ 5cm 42 (28.2%) 51 (33.6%) Upper abdominal tumor 5 cm <, ≤ 10cm 40 (26.8%) 35 (23.0%) 10cm < 35 (23.5%) 24 (15.8%) Takashi Onda 12 http://clicktoeditURL.com

Patients’ Characteristics 3 PDST NACT Characteristics (N = 149) (N = 152) Serous 115 (78.2%) 102 (78.5%) Endometrioid 6 (4.1%) 4 (3.1%) Histology* Mucinous 2 (1.4%) 2 (1.5%) (by surgical Clear 12 (8.2%) 4 (3.1%) specimen) Mixed 4 (2.7%) 1 (0.8%) Others 8 (5.4%) 17 (13.1%) Total 147 130 Chemotherapy Median (25%-75%) 8 (6-8) 8 (7-8) Cycles Average � SD 6.7 � 2.5 6.8 � 2.2 Treatment Completion 99 (66.4%) 103 (67.8%) *among all operated patients Takashi Onda 13 http://clicktoeditURL.com

Surgical Procedures PDST PDST NACT PDS PDS � IDS IDS (N = 147) (N = 147) (N = 130) Median Operation Time (min) 240 347 302 Complete Surgery (RT=0) 17 (11.6%) 45 (30.6%) 83 (63.8%) Optimal Surgery (RT=0 or <1cm) 55 (37.4%) 92 (62.6%) 107 (82.3%) Pelvic Lymphadenectomy 40 (27.2%) 59 (40.1%) 94 (72.3%) Para-aortic Lymphadenectomy 17 (11.6%) 29 (19.7%) 64 (49.2%) Abdominal Organ Resection 40 (27.2%) 56 (38.1%) 36 (27.7%) Distant Metastases Resection 8 (5.4%) 16 (10.9%) 6 (4.6%) RT: Residual Tumor Takashi Onda 14 http://clicktoeditURL.com

Overall Survival (N=301) 1.0 PDST NACT 0.9 (N=149) (N=152) 0.8 MST 49.0M 44.3M 0.7 Proportion 95% CI 38.7-56.2M 35.8-52.5M 0.6 0.5 0.4 0.3 0.2 HR=1.05 [90.8% CI 0.83-1.33] (p=0.24) + 0.1 + Cox proportional hazard model stratified by clinical stage, PS and age [for non-inferiority] 0.0 0 12 24 36 48 60 72 84 96 108 120 132 Months after randomization Pts at risk Arm A 149 140 112 91 76 57 50 34 22 15 4 0 Arm B 152 140 115 88 71 58 46 35 22 11 3 0 Takashi Onda 15 http://clicktoeditURL.com

Progression-free Survival (N=301) 1.0 PDST NACT 0.9 (N=149) (N=152) 0.8 MPFS 15.1M 16.4M 0.7 95% CI 13.4-18.1M 15.0-18.8M Proportion 0.6 0.5 HR=0.96 [95% CI 0.75-1.23] + 0.4 + Cox proportional hazard model adjusted by clinical stage, PS and age 0.3 0.2 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 132 Months after randomization Pts at risk Arm A 149 99 44 32 28 26 24 15 11 9 1 0 Arm B 152 112 48 32 23 20 19 14 11 6 1 0 Takashi Onda 16 http://clicktoeditURL.com

OS according to Debulking Results PDST RT MST NACT RT MST (N=147) 1.0 (N=130) 1.0 0 cm Not estimable 0 cm 67.0M 0.9 0.9 < 1 cm 54.9M < 1 cm 34.0M 0.8 0.8 ≥ 1 cm 43.0M ≥ 1 cm 32.0M 0.7 0.7 Proportion 0.6 Proportion 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 0 12 24 36 48 60 72 84 96 108 120 132 0 12 24 36 48 60 72 84 96 108 120 132 Months after randomization Months after randomization Pts at risk Pts at risk RT = 0cm 17 17 16 15 13 11 10 6 5 4 1 0 RT = 0cm 83 81 71 59 46 43 37 28 17 8 3 0 RT < 1cm 38 37 30 25 21 18 15 10 4 3 1 0 RT < 1cm 24 22 17 11 9 4 3 3 3 2 0 0 RT ≥ 1cm 92 86 66 51 42 28 25 18 13 8 2 0 RT ≥ 1cm 23 20 14 9 8 6 3 1 0 0 0 0 Takashi Onda 17 http://clicktoeditURL.com