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

GCIG Rare Tumour Brainstorming Day

Relatively (Not So) Rare Tumours Adenocarcinoma of Cervix

Keiichi Fujiwara, Ros Glasspool Benedicte Votan, Jim Paul

Aim of the Day

To develop at least one clinical trial in adenocarcinoma of cervix.

– Consider the methodologies for studying “relatively rare” cancers

Key Points

• Difference between adenocarcinoma and squamous cell carcinoma of the cervix

• Individualization of the therapy

Histological Types of Cervical Carcinoma

• Squamous Cell Carcinoma 75% • Adenocarcinoma 20-25% • Adenosquamous cell carcinoma • Others

– Small Cell – Clear Cell etc

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?

JSGO 2013 Clinical Stage +

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%)

Treatment for Cervical Adenocarcinoma: Current Consensus

• NCCN Guideline – Not separated from SCC

• Early Stages – Surgery

• Locally Advanced Stages – ChemoRT

• Metastatic or Recurrent Disease – Chemotherapy

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?

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

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)



• 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



• 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



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?

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

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

NACT-RH

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

Concurrent Chemotherapy

• JGOG Proposal to add paclitaxel to cisplatin for the CCRT chemo-regimen.

Niibe Y, et al. Jpn J Clin Oncol 2010;40:795-9

20.2%

0.566 CCRT using CDDP (n=20)

5-yr OS

no CCRT (n=41)

15.8%

23.4%

p

CCRT using CDDP alone (n=8) 5-yr OS 25.0%

Nagai Y, et al. Anticancer Res 2012;32:1475-9

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

RT (n=14) 5-yr OS 15.4%

Nagai Y, et al. Anticancer Res 2012;32:1475-9

External beam radiotherapy (50Gy/25Fr. 、40Gy- center shield) High-dose rate brachytherapy （point A dose 18Gy/3Fr.） CDDP 50 mg/m2 tri-weekly + PTX 50 mg/m2 weekly

OS Central DFS

CDDP 30 mg/m2, weekly PTX 50 mg/m2, weekly

CCRT for Advanced Cervical Adenocarcinoma; CCRT-TP vs. CCRT-P

CCRT-TP CCRT-P (n=9) (n=7)

Recurrence rate 33% (3/9) 71% (5/7)

OS Median (months) PFS Median (months)

40（5-72） 21（3-40）

40（0-72） 4（1-27）

Umayahara, et al. Int J Gynecol Cancer 2009;19:723-7

Recommendation dose

Tanigawa T, et al., Abstract of the 50th Annual Meeting of Japan Society of Clinical Oncology

Cervical adenocarcinoma, FIGO IIIA, IIIB, IVA術 Histologically confirmed adenocarcinoma, and adenosquamous carcinoma

age; 20 - 70、PS 0-1、no paraaortic lymphnode enlargement

Randomization

Control Arm CCRT-P

CDDP 40 mg/m2 weekly

Treatment Arm CCRT-TP

CDDP 30 mg/m2 weekly

PTX 50 mg/m2 weekly

Schema

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

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 0.6523

• Accrual Duration 6.5 years

• Control Arm （P-CCRT） 120 • Experimental Arm（TP-CCRT） 120

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



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?

Which Target? PI3K pathway

– 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 ADXS11-001 in recurrent cervical

cancer (GOG).

*Wright, Alexi A; Howitt, Brooke E; Myers, Andrea P; et al. Cancer 119: 21, p3776-83

Targeted Therapy

• Randomized discontinuation trial – multiple tumour types in an umbrella design – analyse results by molecular phenotype as well as

by anatomical site/histology

Randomise SD

Experimental

Standard for tumour type

Experimental

Prog/ Lack of tolerance

CR/PR

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.

Questions?

GCIG Rare Tumour Brainstorming DayAim of the DayKey PointsHistological Types of �Cervical CarcinomaEpidemiology of Cervical AdenocarcinomaSlide Number 6Slide Number 7Pathology of Cervical AdenocarcinomaTreatment for Cervical Adenocarcinoma: Current ConsensusUnanswered Questions�Need Clinical TrialsTreatment for Cervical �Adenocarcinoma�Consensus with Controversial PointsConservative Surgery ConceptTreatment for Cervical �Adenocarcinoma�Consensus with Controversial PointsTreatment for Cervical �Adenocarcinoma�Consensus with Controversial PointsUnanswered Questions�Need Clinical TrialsHow Can we Answer these Questions?What we can learn from on-going trial?NACT-RH Concurrent Chemotherapy Slide Number 25Slide Number 26Slide Number 27Slide Number 30Slide Number 31Statistical ConsiderationsDiscussion Points for JGOG ConceptUnanswered Questions�Need Clinical TrialsWhich Target?Targeted TherapySlide Number 37Proposed Trials for AC CervixQuestions?

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