Phase III Randomized Trial of Postoperative Adjuvant Conventional Radiation (3DCRT) versus Image Guided Intensity Modulated Radiotherapy (IG- IMRT) in Cervical (PARCER): Final Analysis

Supriya Chopra, MD Tata Memorial Centre Disclosures

Research Funding PARCER Trial • Department of Science and Technology, • Department of Atomic Energy, Clinical Trials Centre, India.

• Other Research Funding: Varian International, Terry Fox Foundation, Terry Fox International, Department of Atomic Energy Clinical Trials Centre, India

• Full author list: S. Chopra,1 T. Dora,2 S. Gupta,1 S. Kannan,1 R. Engineer,3 S. Menachery,1 R. Phurailatpam,1 U.M. Mahantshetty,4 J. Swamidas,1 J. Ghosh,1 A. Maheshwari,4 S. TS,4 R. Kerkar,4 K. Deodhar,4 P. Popat,5 and S.K. Shrivastava4; 1ACTREC,Tata Memorial Centre, Homi Bhabha National Institute, Navi , India, 2Homi Bhabha Cancer Hospital, Tata Memorial Centre, Sangrur, India, 3Tata Memorial Hospital, Mumbai, India, 4Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India, 5Homi Bhabha National Institute, Mumbai, India Background

• Postoperative Radiation indicated for Cervix and Endometrial . • Increase in GI symptom burden and toxicity in long term survivors after adjuvant radiation • Phase II Studies • RTOG 0418/ RTCMIENDOMETRE demonstrated 27-28% acute GI toxicity with IMRT • No comparator arm • Phase III Trial • NRG 1203: Improvement in patient reported outcomes at wk 5 and year 1 with IMRT as compared to 3DCRT. • No difference at 3 years with IMRT. • Lack of Clarity on Long Term Impact of Postoperative IMRT Hypothesis

IG-IMRT will improve late GI toxicity free survival in patients undergoing adjuvant RT for cervix cancer.

Conducted across 3 clinical sites of Tata Memorial Centre

NCT01279135/CTRI2012/120349 Study Eligibility

Inclusion Criteria Exclusion Criteria

• • Positive Para aortic nodes or • Age >18 years indication for extended field RT. • Type III Hysterectomy with • History of multiple previous intermediate or high risk abdominal surgeries/radiation features • Any medical condition • Type I/II hysterectomy predisposing to bowel toxicity necessitating adjuvant CRT Trial Schema: PARCER

3DCRT

Scheduled Follow up, Clinical evaluation , Quality of Life, CTCAE, Every 3 monthly Study Randomization for 2 years. Every 6 monthly year 2-5. Inclusion yearly thereafter. Censoring at last follow up or relapse

Central review of IMRT Target Delineation.

Baseline QOL/CTCAE Weekly CTCAE

Q Q Q Q Q Q Q Q

Wk 1 2 3. 4 5. 6 7. 8 Q QOL CTCAE version 3.0 (number censored) (number risk Number at

Grade > II GI Toxicity Free Survival IGIMRT 3DCRT

0.00 0.25 0.50 0.75 1.00 142 141 0 p p Adjusted for stratificationfactors - (14) (19) log rank 112 101 12 Primary Endpoint Primary (19) = (28) 0.009 76 60 24 , Time assignment (months) randomsince (10) (13) - CI 0.30 (95% 0.47 HR 44 61 36 (3) (11) 39 49 48 (12) (12) 27 35 60 0.74) RT type and (9) (12) 17 23 72 (5) (12) 12 11 84 xtype Sx (8) (9) 78% vs. 57% 78% 96 2 2 IGIMRT 3DCRT (2) (2) 108 0 0 (0) (0) 120 0 0 Number at risk (No. censored) PelvicRelapse Free Survival IGIMRT 3DCRT

Pelvic Relapse Free Survival

0.00 0.25 0.50 0.75 1.00 142 141 0 p p (11) (13) log rank 127 124 12 = (24) (21) 0.84, HR 0.91 (95% CI - CI 0.39 0.91 (95% HR 0.84, 100 99 24 Time assignment (months) randomsince (17) (17) (17) 80 80 36 (18) (17) 62 63 48 (15) (20) 47 43 60 2.15) (17) (11) 30 32 72 (10) (9) 20 23 84 (11) (15) 9 8 96 (7) (7) 108 IGIMRT 3DCRT 2 1 (2) (0) 120 0 0 Planned Subgroup Analysis

Haz. Ratio

Events/Patientsevents/patients Hazard Ratio P SubgroupSubgroup (95% CI) 3DCRT3DCRT IGIMRTIGIMRT (95% CI) (Interaction)

CTRT_vs_RTaloneType of RT CT+RT 0.40 (0.23, 0.69) CT+RT 41/10741/107 2020/110/110 0.40 (0.23, 0.69)0.204 13/ 34 9/ 32 RTRT Alone Alone 0.78 (0.33, 1.84)0.78 (0.33, 1.84)

Type_of_SxType of Surgery WertheismWertheim’s 29/7114620/75 0.61 (0.34, 1.08)0.61 (0.34, 1.08)0.165 9/67 SimpleSimple Hyst. . 25/70137 0.32 (0.15, 0.69)0.32 (0.15, 0.69)

54/141 29/142 OverallOverall 283 0.47 (0.30, 0.74)0.47 (0.30, 0.74)

.125 1 8 .125 1 8 FavoursFavorsIGIMRT IGIMRT FavoursFavors 3DCRT 3DCRT Conclusions

• IG -IMRT is superior to 3DCRT in reducing Late GI toxicity in women undergoing postoperative pelvic RT.

• Greater Benefit of IG-IMRT in those receiving radio-sensitizing concurrent .

• No difference in tumour control rates in the pelvis with use of IG-IMRT

• IG-IMRT should represent the new standard of care for postoperative pelvic RT in women with gynecological cancers.