GCIG Rare Tumour Brainstorming Day

Transcription

1 GCIG Rare Tumour Brainstorming Day Relatively (Not So) Rare Tumours Adenocarcinoma of Cervix Keiichi Fujiwara, Ros Glasspool Benedicte Votan, Jim Paul

2 Aim of the Day To develop at least one clinical trial in adenocarcinoma of cervix. Consider the methodologies for studying relatively rare cancers

3 Key Points Difference between adenocarcinoma and squamous cell carcinoma of the cervix Individualization of the therapy

4 Histological Types of Cervical Carcinoma Squamous Cell Carcinoma 75% Adenocarcinoma 20-25% Adenosquamous cell carcinoma Others Small Cell Clear Cell etc

5 Epidemiology of Cervical Adenocarcinoma In creased infection of HPV-16 and HPV-18 (80%) HPV-18 infection (50%) SCC 15% Poorer prognosis than SCC 10-20% difference in 5-year survival rate Larger Tumor Size Higher LN Mets More ovarian mets/peritoneal dissemination Lower sensitivity to RT?

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7 JSGO 2013 Clinical Stage +

8 Pathology of Cervical Adenocarcinoma Macroscopic 50% - exophytic or polypoid 15% - No visible tumor Subtypes Mucinous Endometrioid Serous Clear cell Upregulated Gene Expression CEACAM5, TACSTD1, S100P, MSLN PIK3CA (25%), KRAS (17.5%)

9 Treatment for Cervical Adenocarcinoma: Current Consensus NCCN Guideline Not separated from SCC Early Stages Surgery Locally Advanced Stages ChemoRT Metastatic or Recurrent Disease Chemotherapy

10 Unanswered Questions Need Clinical Trials 1. Is AC more or less radiosensitive than SCC? 2. Does the prognosis of AC differ? 3. Is uterine preservation possible? 4. What is the recommended CCRT regimen? 5. Is neoadjuvant chemotherapy followed by RH is beneficial for patients with locally advanced AC? 6. What therapy can be used for the control of distant metastasis? 7. Which are the potential molecular target drug candidates?

11 Treatment for Cervical Adenocarcinoma Consensus with Controversial Points Adenocarcinoma in Situ Simple hysterectomy or conization for fertility preservation (FP) Stage IA1 Simple hysterectomy Conization or cylinderectomy for FP Stage IA2 Type B radical hysterectomy with LNDX

12 Conservative Surgery Concept Study format: observational 5y follow-up Eligibility: AIS, IA1 Pts wishing to preserve fertility Pre/postop. workup including HPV testing Treatment: cervical conization (free margins) Country-based centralized pathology review (slides & blocks)

13 Treatment for Cervical Adenocarcinoma Consensus with Controversial Points Stage IB/II Radical Hysterectomy or ChemoRT for tumor size < 2 cm ChemoRT for tumor size > 4 cm Pre-therapeutic aortic nodal staging by laparoscopy before RT Neoadjuvant chemotherapy followed by radical hysterectomy

14 Treatment for Cervical Adenocarcinoma Consensus with Controversial Points Stage IIIA-IVA ChemoRT Pre-therapeutic aortic nodal staging by laparoscopy before RT Systemic chemotherapy with cisplatin/carboplatin and paclitaxel Stage IVB and Metastatic Disease Platinum with paclitaxel or docetaxel with Bevacizumab

15 Unanswered Questions Need Clinical Trials 1. Is AC more or less radiosensitive than SCC? 2. Does the prognosis of AC differ? 3. Is uterine preservation possible? 4. What is the recommended CCRT regimen? 5. Is neoadjuvant chemotherapy followed by RH is beneficial for patients with locally advanced AC? 6. What therapy can be used for the control of distant metastasis? 7. Which are the potential molecular target drug candidates?

16 How Can we Answer these Questions? Studying rare sub-types of common tumours Include them in general trials Meta-analysis of sub group in several general trials Enhance the numbers of the sub-group Sub-type specific trials Umbrella trials including different anatomical or histological types in different arms of a common protocol

17 What we can learn from on-going trial? Study for NACT-Surgery vs CCRT EORTC55994 Role of Systemic Chemotherapy in addition to CCRT INTERLACE OUTBACK RTOG-0724 Antiangiogenesis Trial GOG240 CIRCCA ENGOT-cx/BGOG-cx

18 NACT-RH Expanding currently on-going EORTC Trial of NACT-RH vs CCRT after analyzing adenocarcinoma subpopulation

19 Concurrent Chemotherapy JGOG Proposal to add paclitaxel to cisplatin for the CCRT chemo-regimen.

20 Survival Curves of the FIGO IIIB Cervical Adenocarcinoma, 19 institutes in Japan Survival Curves of the FIGO IIB - IIIB Cervical Adenocarcinoma, University of the Ryukyus, Okinawa, Japan 20.2 % CCRT using CDDP alone (n=8) 5-yr OS 25.0% RT (n=14) 5-yr OS 15.4% CCRT using CDDP (n=20) no CCRT (n=41) 5-yr OS 15.8% 23.4% p Niibe Y, et al. Jpn J Clin Oncol 2010;40:795-9 Nagai Y, et al. Anticancer Res 2012;32:1475-9

21 External beam radiotherapy (50Gy/25Fr. 40Gy- center shield) High-dose rate brachytherapy (point A dose 18Gy/3Fr.) CDDP 50 mg/m 2 tri-weekly + PTX 50 mg/m 2 weekly OS Central DFS Nagai Y, et al. Anticancer Res 2012;32:1475-9

22 CCRT for Advanced Cervical Adenocarcinoma; CCRT-TP vs. CCRT-P CCRT-TP (n=9) CCRT-P (n=7) Recurrence rate 33% (3/9) 71% (5/7) Umayahara, et al. Int J Gynecol Cancer 2009;19:723-7 Recommendation dose CDDP 30 mg/m 2, weekly OS Median (months) PFS Median (months) 40(5-72) 21(3-40) 40(0-72) 4(1-27) PTX 50 mg/m 2, weekly Tanigawa T, et al., Abstract of the 50 th Annual Meeting of Japan Society of Clinical Oncology

23 Schema Cervical adenocarcinoma, FIGO IIIA, IIIB, IVA 術 Histologically confirmed adenocarcinoma, and adenosquamous carcinoma age; PS 0-1 no paraaortic lymphnode enlargement Randomization Control Arm CCRT-P CDDP 40 mg/m 2 weekly Treatment Arm CCRT-TP CDDP 30 mg/m 2 weekly PTX 50 mg/m 2 weekly

24 Endopoint Primary endpoint: 5-yr OS Secondary endpoints: 1) Completion rate (radiotherapy, chemotherapy) 2) Adverse events (early, and late) 3) 5-yr PFS 4) 5-yr local PFS 5) 5-yr distant PFS

25 Statistical Considerations α error (bilateral) 5% β error 20% Estimated 5Y OS Control Arm (P-CCRT) 20% Estimated 5Y OS Experimental Arm(TP-CCRT) 35% Estimated accrual per year 36 (inside Japan only) HR Accrual Duration 6.5 years Control Arm (P-CCRT) 120 Experimental Arm(TP-CCRT) 120

26 Discussion Points for JGOG Concept Including large (>7 cm) IB2, IIB disease To increase accrual Challenges Difference of radiation dose Will be managed by stratification Run in phase I for US-Europe dose of RT? Integration of systemic chemotherapy after CCRT Second randomization Using paclitaxel + carboplatin x4 cycles Tissue collection Need logistic setup under GCIG leadership

27 Unanswered Questions Need Clinical Trials 1. Is AC more or less radiosensitive than SCC? 2. Does the prognosis of AC differ? 3. Is uterine preservation possible? 4. What is the recommended CCRT regimen? 5. Is neoadjuvant chemotherapy followed by RH is beneficial for patients with locally advanced AC? 6. What therapy can be used for the control of distant metastasis? 7. Which are the potential molecular target drug candidates?

28 PI3K pathway Which Target? PIK3CA mutations 25% of AC and 38% in SCC*. Associated with poor prognosis Combine with other tumour types with high rates of PI3K activation in an umbrella trial? Angiogenesis GOG 240 CIRCCa ENGOT-Cx/BGOG-cxI Targeting HPV Ongoing vaccine trial of ADXS in recurrent cervical cancer (GOG). *Wright, Alexi A; Howitt, Brooke E; Myers, Andrea P; et al. Cancer 119: 21, p

29 Targeted Therapy Randomized discontinuation trial multiple tumour types in an umbrella design analyse results by molecular phenotype as well as by anatomical site/histology

30 CR/PR Experimental Experimental Randomise SD Prog/ Lack of tolerance Standard for tumour type

31 Proposed Trials for AC Cervix Metanalysis of on-going trials for systemic chemotherapy Amendment by reviewing the proportion of AC potentially extending the recruitment of AC Conservative Surgery Trial New CCRT Regimen Trial with secondary randomization for adjuvant chemotherapy Randomized discontinuation trial for target therapy in AC cervix.

32 Questions?