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)
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
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
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?
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
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?
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?