GCIG Cervix Committee: Prague 2010 William Small Jr. Satoru Sagae

Activity Since Chicago Conference calls were held in July and September Separate radiotherapy calls were accomplished to finalize the radiotherapy section for the upcoming ANZGOG outback trial. Significant progress was made on completing open trials and developing concepts.

Publications/Presentations Kitchener H.C., Thomas G., Hoskins W., Small W. Jr., Trimble, E.L. on behalf of the Cervical Cancer Consensus Group. The Development of Priority Cervical Cancer Trials: A Gynecologic Cancer InterGroup Report. Int J Gyn Can, 20(6): , August Viswanathan, A.N., Creutzberg, C., Craighead, P., McCorm ack, M., Toita, T., Narayan, K., Reed, N., Long, H., Kim, H. J., Marth, C., Lindegaard, J., Cerrotta, A., Small, W Jr., Tri mble, E. Brachytherapy Practice Patterns in the Gynecol ogic Cancer Intergroup. In Press, Int J Radiol Oncol Biol Phys, 2010.

ACTIVE GCIC TRIALS

Confidential S-1+CDDP vs single agent CDDP Phase3 study in Cervical cancer (IVB/Rec) Patient enrollment status (01/Jun/2010) Japan: 151 / 200 pts (75.5%) Korea: 71 / 100 pts (71.0%) Taiwan:32 / 60 pts (53.3%) Total:254 / 360 pts (70.3%) Arm SP: 126pts Arm P: 128pts (not treated: 7pts)

Confidential JGOGDT-104/GCIG S-1 Trial Accrual Total 338 Japan 208, Korea 86, Taiwan 44

GOG 240 (GOG 204 Replacement) 2 x 2 Factorial Design –First randomization: Winner of GOG 204 (Cisplatin + Paclitaxel) vs Topotecan + Paclitaxel –Second Randomization: Bevacizumab vs No Bevacizumab Primary Endpoint = survival, superiority trial (30% reduction in HR) Accrual Goal = 450 patients KS Tewari Study Chair

GOG 263 Randomized Phase III Clinical Trial of Adjuvant Radiation vs Chemoradiation In Intermediate Risk, Stage I/IIA Cervical Cancer Treated With Initial Radical Hysterectomy and Pelvic Lymphadenectomy Sang Young Ryu, M.D. Korea Cancer Center Hospital Seoul, Korea

GOG 263 Cervical cancer Stage I-IIA Radical hysterectomy+BPLND >2 of intermediate risk factors >2 of intermediate risk factors Control Arm; Radiation therapy CRT Arm; Weekly CDDP 40mg/m 2 concurrent to radiation Randomization

RTOG-0724 (GOG): ChemoRT with and without adjuvant chemotherapy in high risk cervix cancer after hy sterectomy

Developing Concepts – Discussions

THE OUTBACK TRIAL A Phase III trial of adjuvant chemotherapy following chemo-radiation as primary treatment for locally advanced cervical cancer compared to chemo-radiation alone

Design: International randomized phase III study

Countries that have expressed interest ANZ (18 sites)Canada (NCIC) USA (GOG and RTOG)Spain (GEICO) BrazilIndia RomaniaNetherlands (DCGOG)

Timelines Lead HREC approval: Aug administrative amendment just approved CTEP approval of concept: Aug 2010 CRFs finalized: Sept database development in process First ANZ site open: Dec 2010 First patient on study: Dec 2010 Last patient on study: Dec 2014 Follow-up completed: Dec 2019

the SHAPE Trial: Simple Hysterectomy And Pelvic node dissection in Early cervix cancer Comparing radical hysterectomy and pelvic node dissection against simple hysterectomy and pelvic node dissection in patients with low risk cervical cancer Chair: Marie Plante Laval University, Quebec City An NCIC Clinical Trials Group proposal for the Gynecological Ca ncer Inter Group (GCIG) Prague - October 2010

SHAPE trial Background Rad hyst/nodes: standard treatment Acute/long term side effects: % Low risk disease Low risk disease < 2cm & < 50% stromal invasion < 2cm & < 50% stromal invasion Risk of parametrial infiltration < 1 % Risk of parametrial infiltration < 1 % Less radical surgery (simple hyst + nodes) may be be adequate tre atment Less radical surgery (simple hyst + nodes) may be be adequate tre atment < 5% pelvic relapse rate < 5% pelvic relapse rate Success of salvage therapy in 65 % (RT/SX) Success of salvage therapy in 65 % (RT/SX) Overall survival should not be co mpromised Overall survival should not be co mpromised

SHAPE trial Objective: To show that simple hysterectomy in low risk cervix cancer is safe and is associated with less morbidity than radical surgery AND that overall survival will not be significantly different (between RHPND and SHPND) even if a slightly higher relapse rate occurs in the latter group  Primary endpoint Compare the 3-year pelvic recurrence rate between radical and simple hysterectomy patients

Patient Population Stage IA2-IB1 Cervix cancer Stage IA2-IB1 Cervix cancer Squamous, Adeno & Adenosquamous ca < 2cm and < 50% stromal invasion < 2cm and < 50% stromal invasion Grades 1,2 & 3 MRI/ CT node negative RANDOMIZATION Control Arm Radical Hysterectomy & PLND* +/- SLN Mapping** Experimental Arm Simple Hysterectomy with Upper Vaginectomy & PLND* +/- SLN Mapping** Post surgical quality of life & disease outcom es measured 3 monthly X 2 years, and 6 mo nthly for further 3 years * PLND – Pelvic lymph node dissection **SLN - Sentinel lymph node mapping optional Stratification Centers (performing SN mapping vs not) Mode of surgery (abd vs non-abd route) Stage (IA2 vs IB1) Histology (squamous vs adenoca) Grade (1-2 vs 3)

the SHAPE Trial: International collaborators Co-op groupsSpecialty groups AGO-Austria Belarus AGO-Germany Czech Republic ANZGOG-Australia Latria GEICO-Spain Lithuania MRC/NCRI-England Romania NSGO-Scandinavia Serbia SGCTG-Scotland SGOG-China

INduction ChemoThERapy in Locally Advanced CErvical Cancer-INTERLACE Mary McCormack for the NCRI Gynaecological Clinical Studies Group GCIG Prague Oct 2010

INTERLACE A phase III trial of weekly, dose dense, induction chemotherapy followed by chemoradiation versus chemoradiation alone in locally advanced cervical cancer

INTERLACE - Phase 3 trialRandomiseRandomise Carboplatin AUC2 & Paclitaxel 80mg/m 2 Weeks 1-6 Carboplatin AUC2 & Paclitaxel 80mg/m 2 Weeks 1-6 Weeks 7 – 13 Standard CRT Weeks 7 – 13 Standard CRT Follow-up 3 monthly for 2 years; 6 monthly for 3 years Follow-up Standard CRT : 40—50.4Gy in fractions plus Intracavity brachytherapy to give min total EQD2 d ose of 74-80Gy to point A/volume. Weekly cisplatin 40mg/m 2 x 6 weeks Standard CRT : 40—50.4Gy in fractions plus Intracavity brachytherapy to give min total EQD2 d ose of 74-80Gy to point A/volume. Weekly cisplatin 40mg/m 2 x 6 weeks

Proposal- Current Status Full Proposal for funding submitted August decision expected early November 2010 Open to recruitment –June/July 2011 Collaborators- UK ( 22 ) Eire ( 2 ) France India (1) South Africa (2) Contact: Lindsay James Cancer Research UK and UCL Cancer Trials Centre

A phase III trial comparing efficacy and cost-effectiveness between Weekly and Three-Weekly cisplatin Chemotherapy for Chemoradiation in Cervical Cancer An international, multi-center, randomized Phase III GCIG trial led by TGCS, KGOG (TAKO)

Schema Cervical cancer Locally advanced cervical cancer Stage IIB-IVA Control Arm; Weekly Cisplatin 40mg/m2 6 cycles Study Arm; Tri-weekly Cisplatin 75mg/m2 3 cycles Randomization

Principal Investigator: Dr. Sarikapan Wilailak Faculty of Medicine Ramathibodi Hospital, Mahidol university, Bangkok, Thailand Principal Investigator: Dr. Sang Young Ryu Korea Cancer Center Hospital Seoul, Korea

Cervical cancer in underdeveloped nations

Proposal for GCIG Cervix Cancer Network of Trial Centres in non-GCIG Countries

Clinical Trial Summary One trial looking at less radical surgery in low risk cervical cancer patients. Two advanced/recurrent randomized trials. One trial looking at chemo/RT vs. RT alone after hysterectomy in intermediate risk patients. Three trials investigating adjuvant chemotherapy in high risk cervical cancer. – +/- Neoadjuvant than chemo/RT. –Post-hysterectomy chemo/RT+/- adjuvant chemo –Chemo/RT +/- adjuvant chemo One limited resource trial looking at reduced frequency of concurrent cisplatin in chemo RT patients

Goals Activate developing trials. Foster collaboration and rapid accrual to open trials Develop a working group to help advance therapy in underdeveloped countries.

Please attend the site specific trials