Cervix Cancer Committee. Friday, June 3, 2016, 10:30 am 12:30 pm LaSalle I Room, DoubleTree Hotel, Chicago

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1 GYNECOLOGIC CANCER INTERGROUP (GCIG) Cervix Cancer Committee Friday, June 3, 2016, 10:30 am 12:30 pm LaSalle I Room, DoubleTree Hotel, Chicago Chair: Satoru Sagae Co-Chair: Brad Monk Harmonization Liaisons: Hiltz/Keller (Ops), Reuss (Stats)

2 PUBLISHED/IN PREPARATION: Advances and Concepts in Cervical Cancer Trials: A Road Map for the Future. Sagae S, Monk BJ, Pujade-Lauraine E, Gaffney DK, Narayan K, Ryu SY, McCormack M, Plante M, Casado A, Reuss A, Chávez-Blanco A, Kitchener H, Nam BH, Jhingran A, Temkin S, Mileshkin L, Berns E, Scholl S, Doll C, Abu-Rustum NR, Lecuru F, Small W Jr; Gynecologic Cancer InterGroup Cervix Cancer brainstorming day. Int J Gynecol Cancer Jan;26(1): CLOSED TRIALS: ( 3 minutes) RTOG (GOG) TIME-C IMRT study in endometrial or cervical cancer

3 CURRENT ACTIVE RANDOMIZED TRIALS WITH GCIG PARTICIPATION: 40 min. ( 3-5 minutes each) Surgery plus Radiation +/- CT 1. KGOG 0801 (GOG, RTOG) Post-Op RT vs CCRT (intermed.risk post op) Ryu 185->200->220/480 Chemoradiation 2. KGOG-THAI TACO (CCRN) (RTOG, GICOM, VietNam, + ) Ryu 168->200->210/ ANZGOG OUTBACK (CCRN) (GOG, RTOG, + ) Mileshkin 558 ->656->750/780-> MRC-NCRI INTERLACE (CCRN) (GICOM, MaNGO, + ) McCormack 60-> 89->129 /770

4 Minimal Invasive Surgery 5. (NCIC) CCTG SHAPE (CCRN) (DGOG, + ) Plante 81 -> 113->178/ G-GOC ConCerv Ramirez 77/ G-GOC LACC Ramirez 380 -> 405->443/ GOG 0278 Conservative surgery (cone/nodes or hyst/(nodes) in early stage cervical cancer. (evaluation of physical function and QOL) Monk 110 /220 Immunotherapy 9. GOG high risk maintenance (ADXS-HPV) immunotherapy Monk move to phase III Vulvar Cancer 10. GOG 0279 Phase II Trial Evaluating Cisplatin and Gemcitabine Concurrent with IMRT in Treatment of Locally Adv. SCC of the Vulva Monk 50/52 almost closed 11. DGOG GROINSS-V II (EORTC-GCG, GOG) van der Zee 1653pts enclosed 80% SN negative SN positive n=370 ( <2mm+ n=180) 0.025% recurrence

5 NEW/PROPOSED/DEVELOPING CONCEPTS(seeking groups): 1. RTOG Hypofractionation Jhingran/Small/Gaffney 2. (NCIC) CCTG Neo-adj. CT & fertility sparing surgery (stage IBI) Plante 3. NOGGO Sentinel lymph node biopsy Survey status Keller/Sehouli 4. GINECO SENTICOL-III A prospective obs. trial on sentinel lymph node mapping in patients with early stages cervical cancer Lecuru,Plante,Abu-Rustum 5. EORTC-GCG CURE-C Curative Radiotherapy to the primary tumor vs. best supportive care in initially metastatic cervical cancinoma Ottevanger 6. ANZGOG EXCISE EXcisional treatment Comparison for In Situ Endocervical adenocarcinoma Brand/Mileshkin 7. Management and Care of Women With Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline JGO Journal of Global Oncology Chuang/Berek

$Hypofraction Trial For Cervical Cancer 45 Gy/25 fractions VS. 37.$

6 Hypofraction Trial For Cervical Cancer 45 Gy/25 fractions VS Gy/15 fractions Brachytherapy schedule up to the site Endpoints: RFS and Patient reported Outcomes

7 Stage IB1 (2-4 cm) Cervical cancer treated with Neoadjuvant chemotherapy followed by fertility Sparing Surgery (CoNteSSa) Marie Plante (CCTG) Jeffrey Goh & Vivek Arora (ANZGOG)

9 Radical hysterectomy

10 Outcome measures Primary end point Successful fertility preservation defined as intact uterine corpus with no adjuvant XRT Secondary end points Response rates to chemotherapy Toxicity Recurrence rate 3 and 5 year disease free survival Proportion requiring trimodality treatment QoL indices Ovarian function indices Obstetrical outcome 10

11 Statistics and design Single arm phase-2 type of study (75 patients) Two statistical issues - Fertility preservation (realistically 50-60%) - assuming a 30% suboptimal response to NACT - assuming a 10-20% high-risk features in the trachelectomy specimen requiring rad hyst or RT - Recurrence rate: Safety monitoring guidelines - DSMC requirements - Based on literature: relapse rates for standard Tx - Based on accrual 11

12 - This study is doable within the GCIG Feasibility - Already an established large international and successful collaboration with numerous groups through SHAPE - Great interest for this study concept - We need strong support - Accrual and funding from all interested groups 12

13 International survey about the sentinel lymph node biopsy in cervical cancer Survey within the GCIG On behalf of the working group Jalid Sehouli, Filiberto Vercellino, Marie Plante, Nadeem Abu- Rustum, Fabrice Lecuru, Stefano Greggi

14 Group or Country Number of filled in Questionnaires AGO-AUST / Austria 6 AGO, NOGGO / Germany 32 BGOG / Belgium 14 DGOG / Netherland 1 GEICO / Spain 26 G-GOC, GOG / US 4 GINECO / France 12 Japan 6 KGOG / Korea 2 MITO, MaNGO / Italy 4 NCIC CTG / Canada 12 Great Britain 2 Switzerland 2 ANZGOG / Australia 1 NSGO / Norway, Denmark, Sweden, Finland 11 ISGO / Israel 5 GICOM /Mexico 2 Groups without country specification 24 Sum 166

15 Q35 Would you support international study concepts about the role of SLNB in the management of CC? 120 of 124 said yes 3 of 124 said no 1 of 124 is not sure

16 Cervix cancer committee SENTICOL III: International prospective validation trial of sentinel node biopsy in cervical cancer A Gynecologic Cancer intergroup (GCIG) trial, lead by the GINECO F Lecuru, N Abu-Rustum, P Mathevet, M Plante.

17 Objectives Main objective: «co-primary» disease free survival and health related quality of life non-inferiority of SLN biopsy vs lymphadenectomy for DFS superiority of SLN biopsy for QoL The hypothesis is that SLN biopsy alone provides similar survival and better quality of life. Secondary objectives: - Longitudinal and other dimensions of health related Quality of life. - Surgical morbidity and mortality. - Evaluation of mapping with Indocyanine green (ICG). - Outcome of patients with ITC and micrometastases. - Positive and negative predictive values of SLN biopsy. - Outcome of pn1 patients according to the size of metastasis and treatment. - Overall survival. - Recurrence free survival.

Cormier algorithm No dissection if neg SLN biopsy + PLN

18 Quality of life Disease free survival Schema SCC/Adk Stage IIa <40mm No pregnancy SLN biopsy SLN biopsy Cormier algorithm No dissection if neg SLN biopsy + PLN Dissection pn0 pn0 Randomized study Surgical quality assurance

19 Inclusion criteria: - Squamous or adenocarcinoma of the cervix (proven by biopsy or cone biopsy) - Stage Ia1 with lymphovascular emboli to IIa1 (clinical stage) - Maximum diameter 40mm on MRI - No suspicious node on pelvic and abdominal MRI (small axis 8-10mm and morphologic criteria) - Informed consent given Exclusion criteria: - Age <18 years - Pregnancy - Previous pelvic of abdominal cancer - Previous chemo and/or radiation therapy for the cervical cancer - Allergy to blue dye, isotope or Indocyanine green

20 Statistics 1-DFS With a 3 years-disease free survival of 85% to demonstrate a non-inferiority of SLN biopsy vs SLN biopsy + lymphadenectomy with a non-inferiority margin of 5% (80 vs 85%, HR = 1.373). With a unilateral alpha error of 5%, and a power of 80%, 900 patients in 3 years, with 5 years of follow-up should be included to observe the required 263 events. An interim analysis is planned when at least 110 events will be observed to reject H0 or H1 using O Brien Fleming and alpha spending function. 2-HRQoL We target 3 HRQoL dimensions global health, pain and physical functioning of EORTC QLQC 30. To demonstrate a superiority of at least one of the 3 targeted dimensions without significant deterioration in at least one with a minimal important difference in mean score of at least 5 points (SD: 20), and a bilateral alpha type one error of (Bonferroni adjustment) it would be required to have 815 patients with available HRQoL scores to reach 85% statistical power. 900 patients have to be randomized An international collaboration is requested

21 CUrative Radiotherapy to the primary tumor vs. best supportive care in patients with initially metastatic Cervical carcinoma (CURE-C trial) EORTC ROG-GCG-QLG Study coordinator Igor Sirák, M.D., Ph.D Department of Oncology and Radiotherapy University Hospital Hradec Králové Czech Republic Joint study coordinator Fernanda G. Herrera, M.D. Lausanne University Hospital Department of Oncology Radiotherapy Service University of Lausanne Switzerland

22 Inclusion criteria Histologically confirmed cancer of the uterine cervix Stage IVB metastatic disease No clinical evidence of brain metastases Presence of untreated primary cervical carcinoma No need for urgent upfront radiotherapy for life threating symptoms No previous RT treatment in the pelvis or para-aortic area No prior history of Crohn s disease, ulcerative colitis; or other chronic bowel disease Performance status 0-2 Life expectancy 6 months Adequate hematological formulae

23 Phase II randomized trial PLATINUM-BASED CHT 4x (+/- BEV) R A N D O M I Z A T I O N RT S T A N D A R D A R M E X P E R I M E N T A L A R M BSC: including palliative RT up to 40Gy BED2 in case of symptomatic progression, 2 nd line CHT, etc.

24 Endpoints Primary: Time to progression Secondary: Quality of life (A Translational part of the research) Overall Survival Treatment toxicity Evaluation of treatment feasibility in a multi-institutional setting Stratification factors Response to initial chemotherapy by RECIST criteria: CR, PR vs. SD Performance status Bevacizumab yes/no

25 Statistics Due to the variability of the BSC, a comparative phase II design is proposed As proposed by Korn et al (JCO 2001), a phase II comparative screening design can be implemented as a superiority phase III trial design with an increased type I error and optimistic treatment effect For this trial, using a one sided log-rank test at a level of significance of 10% (alpha), to test for a HR=0.63 (increase from 50% to 65% event-free survival at 12 months) at 80% power would need about: 80 events ~100 patients in 1:1 randomization. The event-free curves between the two arms will be compared with a nonparametric test stratified for the stratification factors With the above assumptions, a hazard ratio of minimum would need to be observed 0.75 to reach significance

26 EXCISE EXcisional treatment Comparison for In Situ Endocervical adenocarcinoma Excisional treatment in women with cervical adenocarcinoma-insitu (AIS): a prospective randomised controlled non-inferiority trial to compare AIS recurrence after loop electrosurgical excision procedure (LEEP) to cold knife cone biopsy (CKC). P A Cohen, A Munro, J Codde, M Bulsara, C D H Wrede, McNally O M, Sykes P, Eva L, Rao A, Symcock B, Brand A 3 June 2016

27 Loop electrosurgical excision procedure (LEEP) Against LEEP Incomplete excision Thermal artefact Greater risk of a positive endocervical margin In favour of LEEP Avoid general anaesthesia Outpatient setting Lower morbidity, and reduced rates of obstetric complications

28 EXCISE Aim: to determine if the treatment of cervical AIS by LEEP is non-inferior to CKC with regard to 5-year recurrence rate in women managed conservatively Hypothesis: LEEP will not be inferior to CKC with regard to AIS persistence and recurrence in conservatively managed women Primary objective: to compare the 5-year recurrence rate of cervical AIS following LEEP to that after CKC, in conservatively managed women.

29 Procedures Randomization: Randomization will be 1:1 (CKC: LEEP). Sequence generation will be by computer with no blocking or stratification. Blinding: Study investigators and participants will not be blinded to the intervention. Those conducting data analysis will be blinded to the intervention.

30 Sample Size Estimated using a 2 group test of non-inferiority of proportions Primary end point is the AIS recurrence rate at 5 years and the comparison will be between CKC and LEEP, based on a 1-sided test for non-inferiority Assumes an 8% rate of AIS recurrence at 5 years after CKC, and a 5% non-inferiority margin (upper 95% confidence rate of AIS recurrence of 13% is still within the non-inferiority margin). Sample size needed is 730 (365 per group). Assuming a 10% drop-out rate, a total sample size of 810 participants (405 per group) would need to be randomised. (One-sided Type I error is set at 5% with 80% power. )

31 Management and Care of Women with Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline Chuang L, Temin S, Camacho R, Duennas-Gonzalez A, Feldman S, Gluten M, Gupta V, Horton S, Jacob G, Kidd E, Lishimpi K, Nakisige C, Nam J, Ngan H, Small W, Thomas G, Berek J Journal of Global Oncology May 25, American Society of Clinical Oncology All rights reserved.

32 Treatment Capacity Treatment Setting Basic Limited Enhanced Maximal Surgery Simple (extrafascial) hysterectomy or more extensive hysterectomy can be performed* *Where medical facilities exist to take care of women who are at high risk for postoperative complications Modified radical and radical hysterectomy Capable of performing most major surgeries, including radical hysterectomy, radical trachelectomy,* pelvic and para-aortic LN sampling, and pelvic exenteration* Following are not available: PET scan, interventional radiology, sentinel node biopsy/iort, and bevacizumab Radical hysterectomy, radical trachelectomy, pelvic and paraaortic LN sampling, sentinel node biopsy, and pelvic exenteration; radiation therapy, chemotherapy, interventional radiology, palliative care service, and bevacizumab are all available *Can be performed in some enhanced levels Chemo-therapy Availability of chemotherapy drugs is unpredictable Chemotherapy may be available Chemotherapy available; bevacizumab not available Chemotherapy available; bevacizumab is available Radiation therapy No radiation therapy available Limited external RT with no brachytherapy available; in some areas where there are only brachytherapy and no external RT, this will be considered as basic level RT including external beam and brachytherapy available; interventional radiology not available RT including external beam and brachytherapy available; interventional radiology available American Society of Clinical Oncology All rights reserved.

33 Recommendations for Stage IB and IIA Disease Type of Disease Setting Basic Limited Enhanced Maximal IB1, Non- FS Extrafascial hysterectomy Radical hysterectomy plus PLND or radical hysterectomy (see Note) with adjuvant RT or RT with concurrent low-dose chemotherapy (concurrent chemort), if needed Radical hysterectomy plus PLND Radical hysterectomy plus PLND; may offer SLN NACT if available, then extrafascial hysterectomy ChemoRT or RT followed by extrafascial or radical hysterectomy (see Note) ± PLND ± PANB* If no RT is available but chemotherapy is available, NACT may be used to shrink the tumor to make it removable by surgery (extrafascial or modified radical hysterectomy [see Note] ± PLND ± PANB*) Pelvic RT plus brachytherapy plus concurrent low-dose platinum-based chemotherapy Pelvic RT plus brachytherapy plus concurrent low-dose platinumbased chemotherapy Note Wherever radical hysterectomy with concurrent chemort listed as a surgical option above, extrafascial hysterectomy is recommended if there is residual disease after RT or chemort with a boost of Gy or initial tumor > 6 cm. Radical hysterectomy may be used following RT or chemort to a dose of 50 Gy American Society of Clinical Oncology All rights reserved.

Cervix Cancer Committee Tuesday, Nov.10, 2015, 3F Room, Jikei University, Tokyo

Cervix Cancer Committee Tuesday, Nov.10, 2015, 1:30p.m. 3:30 p.m. 3F Room, Jikei University, Tokyo Satoru Sagae (JGOG) Bradley Monk (GOG) Harmonization Liaisons: Hiltz (Ops), Reuss (Stats) AGENDA Published/