GCIG Cervix
Committee
November 14, 2008
GOG 240
Schema
Eligibility:
1. Primary stage IVB or
Recurrent/persistent
carcinoma of the cervix
2. Measureable disease
3. GOG PS 0-1
R
A
N
D
O
M
I
Z
E
Regimen I
Paclitaxel 135 mg/m2 IV d1 (24h)
Cisplatin 50 mg/m2 IV d2
Q21d to progression/toxicity
Regimen II
Paclitaxel 135 mg/m2 IV d1 (24h)
Cisplatin 50 mg/m2 IV d2
Bevacizumab 15 mg/kg IV d2
Q21d to progression/toxicity
Regimen III
Paclitaxel 175 mg/m2 IV d1 (3h)
Topotecan 0.75 mg/m2 d1-3 (30m)
Q21d to progression/toxicity
Regimen IV
Paclitaxel 175 mg/m2 IV d1 (3h)
Topotecan 0.75 mg/m2 d1-3 (30m)
Bevacizumab 15 mg/kg IV d1
Q21d to progression/toxicity
GOG 240
Primary & Secondary Endpoints
• Primary Endpoints
– 1. Survival time from date of randomization
– 2. Frequency & severity of adverse events
• CTCAE version 3.0
• Secondary endpoints
– 1. PFS from date of randomization
– 2. Frequency of objective tumor response
GOG 240
Statistical Design
•
•
•
•
Randomized, phase III trial
2x2 factorial design (n=450)
Intent to treat principle
Random assignment to the four arms balanced for
– Disease status
– Performance status
– Prior platinum therapy with pelvic RT
• Reduction of hazard of death by 30% by addition of
either bevacizumab or non-platinum doublet
important to detect
• Interim analysis to be conducted after 173 deaths
GOG 240
Toxicity monitoring
Topotecan-Paclitaxel-related toxicities – DSMB evaluation
(Myelosuppression and infection)
Stage
Cummulative Patients
Min # Events
1
50
19
2
100
30
Bevacizumab-related toxicities – DSMB evaluation
(Bowel perforation, hemorrhage, necrosis, fistula, PE)
Stage
Cummulative Patients
Min # Events
1
50
12
2
100
18
GOG 240
Exploratory Endpoints
• Health-Related Quality of Life
– FACT-Cx TOI
– FACT-GOG/Ntx subscale (neuropathy symptoms)
– BPI single item for pain
• Prospective validation of prognostic markers
• Smoking behavior
– Prevalence of active smoking
– Extent of nicotine dependence
– Nicotine dependence with PFS & OS
• Translational science
GOG 240
CellSearchTM Circulating Tumor Cell (CTC) Test
Number of CTCs
- Correlation with PFS & OS
Clearance of CTCs
- Correlation with response
- Correlation with OS & PFS
GOG 240
International Collaborators
Norway:
Gunn Kristensen MD
Germany:
Falk Clemens Thiel MD
South Korea:
Jong-Min Lee MD PhD
Spain:
Ana Oaknin Benzaquen
GOG 240
International Collaborators
NORWAY
KOREA
Kristensen, Gunnar
Department of Gynecologic Oncology,
Rikshospitalet-Radiumhospitalet Medical
Center, Oslo, Norway
Department of Medical Informatics,
University of Oslo, Oslo, Norway
Jong-Min Lee, MD, PhD
Associate Professor
Department of Obstetrics and Gynecology
East-West Neo Medical Center
Kyung Hee University
149 Sangil-dong, Gangdong-gu, Seoul, 134-090,
South Korea
E-mail; kgo02@hanmail.net, kgo02@naver.com
Office; 82-2-440-6140
Cell;82-11-738-3725
Fax; 82-2-440-7894
SPAIN
Dra. Ana Oaknin Benzaquen
Oncología Médica. División de Ginecología
Institut Català d´Oncologia. Hospital Duran i
Reynals
Tel :+34.93.260.77.44
Fax:+34.93.260.77.41
e-mail:aoaknin@iconcologia.net
GERMANY
Falk Clemens Thiel, MD
Department of Gynecology
University Hospital Erlangen
Universitätsstr. 2123
91054 Erlangen
Germany
Tel. +49 9131 8533553
GOG 240
Status
This protocol has received approval by the NCI and
Central IRB and we anticipate activation within the
upcoming 2-3 months.
John H. Farley MD
Associate Professor Obstetrics and Gynecology
Uniformed Services University of the Health Sciences
CVM0503
• To determine if combining Cetuximab with cisplatin
during radiation therapy increases overall survival (OS)
when compared with weekly cisplatin and radiation
therapy in patients with cervical cancer metastatic to
high common and/or para-aortic lymph nodes.
– Secondary Objective
• To determine if the addition of Cetuximab to cisplatin and radiation
therapy in this patient population improves progression-free survival
(PFS).
• To determine the relative toxicities of the addition of Cetuximab to
cisplatin in this patient population.
CVM0503
• Test the hypothesis that Cetuximab will
be more effective in tumors that express
low compared with high levels of the
hypoxia marker Hypoxia Inducible
Factor-1α (HIF-1α) and epidermal growth
factor receptor (EGFR),
CVM0503
• Concurrent Weekly Cisplatin + Cetuximab (preferably
Monday)
– Cisplatin 30mg/m2/week x 6 weeks
– Cetuximab 400 mg/m2 initial loading dose week 1, then 250
mg/m2 x 5 weeks
• VERSUS
• Cisplatin 30mg/m2/week x 6 weeks
• In patients receiving extended field radiation therapy;
pelvis and para-aortics.
–
–
–
–
4500 cGy in 29 fractions to the para-aortic nodes
(150 cGy/fraction)
4500 cGy in 25 fractions to the pelvis
CVM0503
(180 cGy/fraction)
• Trial population
• Cervical cancer patients with positive
para-aortic and/or pelvic nodes :
– Squamous Cell Carcinoma, Adenocarcinoma,
Adenosquamous Carcinoma,
• Clinical stages
– IB, IIA, IIB, IIIA, IIIB, IV
• Number of subjects: 328
CVM0503
GOG-0233/ACRIN-6671
• UTILITY OF PREOPERATIVE FDG-PET/CT
AND FERUMOXTRAN-10 MRI SCANNING
PRIOR TO PRIMARY CHEMORADIATION
THERAPY TO DETECT RETROPERITONEAL
LYMPH NODE METASTASIS IN PATIENTS
WITH LOCOREGIONALLY ADVANCED (IB2,
IIA 4 CM, IIB-IVA) CARCINOMA OF THE
CERVIX.
• Has accrued 22/325 patients
GOG 219
October 23, 2008
GOG 219
• ACCRUAL TO DATE = 301 PATIENTS
– Enrollment primarily from U.S. sites
– International participation increasing,
specifically NCI Canada
• Factors (pro)
– Starting dose reduced after 1st toxicity evaluation
– NCIC sites gaining experience with regimen
• Factors (con)
– Regulatory bodies in other countries
– International shipment of drug
GOG-0219
ENROLLMENT BY QUARTER
40
35
30
25
20
15
10
5
0
1ST
Q
2006
3RD
Q
2006
1ST
Q
2007
3RD
Q
2007
1ST
Q
2008
3RD
Q
2008
GOG-0219
AMENDMENT
• The Data Monitoring Committee (DMC) of the Gynecologic
Oncology Group convened to review the interim safety analysis
as outlined in section 11.5 of the study. In reviewing toxicity
data, there was a higher than 20% incidence of Grade 3 or 4
toxicity in the form of leucopenia and metabolic toxicity.
Median length of radiation therapy was similar in both arms
and there were no deaths related to study participation. Based
on their review in assessing the clinical impact of the toxicity,
the DMC recommended decreasing the starting dose on
regimen II to by one dose level rather than two dose levels as
originally stipulated in section 11.5. The starting dose on trial
(now dose level I) is the previous dose level -1 from former
versions (prior to NCI Version Date 10/03/2007).
GOG-0219
AMENDMENT
• Regimen II: Concurrent Cisplatin and TPZ and
Radiation Therapy (10/23/2007)
•
Cisplatin 60mg/m2 (max = 105 mg) administered IV
over 30-60 minutes days 1, 15 and 29 with radiation
therapy
• TPZ 220mg/m2 (max = 385 mg) IV administered
over two hours prior to Cisplatin on days 1, 15 and
29
• TPZ 220mg/m2 (max = 385 mg) IV over two hours
days 8, 10, 12, 22, 24, 26 with radiation therapy.
GOG-0219
AMENDMENT
• A second safety analysis will be performed
after treating 30 more patients on the TPZ
arm (with the new starting dose). In the
event Grade 3 or 4 toxicity continues to be
significantly higher among patients on the
TPZ arm or duration of radiotherapy is
prolonged significantly in any of the arms,
the trial committee may recommend further
dose modification or study termination.
GOG-0219
CVM 0801/KGOG 1008
A Randomized Trial of Concurrent
Chemoradiation for Postoperative Cervical
Cancer with Intermediate Risk Factors
Sang Young Ryu, M.D.
Korea Cancer Center Hospital
CVM 0801/KGOG 1008
•
Adjuvant CCRT- High Risk Factor
–
SWOG 97-97 Peters 2000: Stage <IIB, LN, RM, PM:
• FP CCRT(x2) + 2 FP vs RT
–
RR 0.50; PFS 80 vs 63%, OSR 81 vs 71%,
–
Local rec 20 vs 7, Distant rec 13 vs 9
–
No brachytherapy
–
Toxicity; 21 vs 4 Gr IV toxicity
• Aedno, adenosquamous CCRT; good but no statistic signif.
–
GOG 109; FP vs RT only; FP arm is superior to RT alone
arm
• high hematologic toxicity
• Standard treatment
CVM 0801/KGOG 1008
• Adjuvant CCRT-intermediate risk factors
– No Clinical Trials
– GOG 92 Sedlis 1999; IB intermediate,
adjuvant RT vs no RT;
• 2 of >1/3 stromal invasion, LVSI, tumor size
• Rec Rate; 28 vs 15%
• 2YDFS; 88 vs79%, RR 0.53
KCCH Retrospective Results
RH with BPLND
735 cases
172 cases
FIGO stage IB – IIA cervical cancer patients
Any of intermediate risk factor
34 cases
49 cases
89 cases
No further
treatment
RT only
CCRT
Fig. 1. Patients enrolled in this study
CVM 0801/KGOG 1008
CVM 0801/KGOG 1008
Control Arm; Radiation therapy
Stage IB-IIA
Radical hysterectomy+BPLND
>2 of intermediate risk factors
Randomization
Cervical cancer
CRT Arm; Weekly CDDP
40mg/m2 concurrent to radiation
CVM 0801/KGOG 1008
– Primary endpoint;
• 3 year recurrence free survival
– 6.3% (87% to 93.3%)
– Secondary endpoint;
• Recurrence rate
• Toxicity
– QoL
CVM 0801/KGOG 1008
CVM 0801/KGOG 1008
•
Pathology
– Review pathologic slides
• H&E only
• Tumor cell type
– Squamous, adenoca, adenosquamous
• Depth of stromal invasion
– in thirds of cervical thickness
• Tumor diameter; palpation, largest diameter on
section, imaging studies
• Presence or absence of the LVSI
CVM 0801/KGOG 1008
• Radiation (GOG 92)
– Within 4-6 weeks postop
• Weekly Hg >11mg/ml, ANC > 1000/ul, Plt >100,000/ul
• Tranfusion of P/C or IV iron if necessary
– ERT
• Four field box technique with megavoltage beam
• Dose 46Gy in 23 fraction,or 50.4 Gy in 28 fraction
• Treatment break for clinical problems allowed to total no more
than 1 week
– No brachytherapy
CVM 0801/KGOG 1008
•
Chemotherapy
– Eligible
• Total WBC > 2,000/uL, ANC> 1000 /ul, Plt >
100,000/uL
– Schedule (6 cycles)
• 40mg/m2 on days 1, 8, 15, 22, 29, and 36
– Dose Reduction
• 25% DR
–
grade 3 stomatitis
–
Nadir Plt < 50,000/ul, WBC <2000/uL->25% DR
• 50% grade 4 stomatitis
• Hold
–
Caluculated Ccr < 50ml/min
–
grade III, IV neuropathy
CVM 0801/KGOG 1008
• Statistics
– 6.3% increase of RFS
– Power 80%
– Type I error; 0.05
– Sample size: 480
– Total sample size: 534
– Total period: 54month
– Expected events: 36 recurrences in control
arm
RTOG/GOG combined
study for high-risk early
stage Cervical Carcinoma
Anuja Jhingran
RTOG-0724
Background
• 90% early stage cured with surgery or xrt
alone
• 15%-20% of early stage present with
positive nodes, parametrium or margins survival drops to 50-70% with surgery
alone
• Even with adjuvant xrt - 40% fail - 10% in
field and 10% out of field
• Recent update of the SWOG trial – 5-yr
survival with CT/RT – 2 or more positive
nodes – 77%
RTOG-0724
Concurrent Chemotherapy and Pelvic Radiation
Therapy Compared With Pelvic Radiation Therapy
Alone as Adjuvant Therapy After Radical Surgery in
High-Risk Early-Stage Cancer of the Cervix
GOG 109: Peters et al JCO 2000
Concurrent Chemotherapy and Pelvic Radiation
Therapy Compared With Pelvic Radiation Therapy
Alone as Adjuvant Therapy After Radical Surgery in
High-Risk Early-Stage Cancer of the Cervix
GOG 109: Peters et al JCO 2000
Rethinking the use of radiation and chemotherapy after radical
hysterectomy: a clinical–pathologic analysis of a Gynecologic
Oncology Group/Southwest Oncology Group/Radiation Therapy
Oncology Group trial
Monk et al Gyn Onc 2005
Proposed Intergroup trial
Stage I/IIA Cervical Cancer
Radical Hyst:
+LN’s, - include para-aortic nodes, and parametrium
Randomize
ARM 1
ARM 2
XRT 45 - 50 Gy
Cisplatin 40 mg/m2 wkly
XRT 45 - 50 Gy
Cisplatin 40 mg/m2 wkly
Carboplatin AUC 5
Paclitaxel 135mg/m2 q3weeks X4
400 pts
PI’s A. Jhingran RTOG
H. Gray GOG
RTOG-0724
Hypothesis
• To determine if adjuvant systemic chemotherapy
following chemoradiation therapy will improve
disease-free and overall survival compared to
chemoradiation therapy alone in patients with
high-risk early-stage cervical carcinoma found to
have positive nodes and/or positive margins
and/or positive parametria after a radical
hysterectomy. The expected benefit would be
approximately 10%-15% – Acrrual - 400 patients.
RTOG-0724
Endpoints
• 2.1
Primary objective:
– Disease-free survival
• 2.2
Secondary objective(s):
–
–
–
–
1) Toxicity
2) Overall survival
3) Quality of life
4) To collect fixed tissue to identify tumor molecular
signatures that may be associated with patient outcomes.
- 5) To collect blood from serum and plasma - looking
factors correlated with toxicity and outcome
RTOG-0724
RTOG 0724
• IMRT allowed.
• Vaginal Brachytherapy allowed.
RTOG-0724
New Concepts in Locally
Advanced Cervix Cancer
Nick Reed
Personal thoughts
for debate at GCIG Nov 2008
Need for Improvement
• Improving outcomes of bulky locally
advanced cervix cancer
•
•
•
•
New Approaches
Induction / neoadjuvant schedules
Maintenance treatments
Targeted agents
Functional Imaging
Diagnostic Pathway
Newly
diagnosed Stage
1B2 – 4A
Baseline
Imaging
NACT
Induction
Reassessment
Imaging and
CCRT
CCRT
So where is my evidence?
Newer Approaches Induction
• Meta-analysis from data with Cis +/• Carboplatin vs Cisplatin
• Addition of Paclitaxel - Hoskin & GlynneJones
• Mexico- Duenas -Gonzalez
• UCL – McCormack CX2 study
• Still premature but exciting interest
The Study Options
Maintenance
chemotherapy
NACT
Induction
CCRT
Observation
Reed’s Observations
• I am convinced NACT is the way forward
• I am convinced dose dense and dose
intense schedules are needed
• I think a taxane is essential rather than
platinum alone
• I think TR and functional imaging
should be integral
So what would I propose??
• Fresh tissue for banking +/- serum
• Baseline scan , preferably PET CT +/- MRI (advice
from radiologists)
• Explore new imaging agents (hypoxia markers)
• 9 weekly doses of carbo/paclitaxel (AUC 2-3 and pac 6080 mg/m2)
• Reassess clinically and radiologically plus repeat samples
for freezing
Diagnostic Pathway
Newly
diagnosed Stage
1B2 – 4A
Baseline
Imaging
TR Biopsy
Imaging
NACT
Induction
Reassessment
Imaging and
CCRT
TR Biopsy
Imaging
CCRT
Chemo-Rads CCRT
• Proceed to standard concomitant
chemoradiotherapy (CCRT)
• Try for international consensus on
EBRT dose and also BT
The Other Option Maintenance
• Why?
• Tierney IPA suggests benefit
• Which maintenance?
• How many cycles
• Conventional or TAT or both
• Candidates
The Next Steps
• Next phase would be to consider
adding a biological/TAT,
maybe RCT phase 2
• Next phase would be to look at
maintenance or no maintenance
The Study Options
Maintenance
chemotherapy
NACT
Induction
CCRT
Observation
Where next?
• Discussion
• Manchester SOTS??
A pilot study of adjuvant
chemotherapy for high-risk
cervical cancer
Linda Mileshkin, Danny Rischin,
Kailash Narayan
ANZGOG
Background
• Early-stage cervical cancer is highly curable
with surgical approaches or chemoXRT
• Lower cure rates with more advanced
disease seen in those who have not
participated in screening
• Traditional main prognostic factor is the
FIGO staging system - principally based on
clinical examination
• Uterine and nodal involvement on imaging
also prognostic
ANZGOG
Background
• Prospective audit data from 238 pts treated
with primary chemoXRT for cervical cancer
• 170 (71%) had corpus invasion on MRI
- 41% of these recurred cf. 19% without
invasion
• FIGO stage and clinical diameter not
prognostic in the presence of uterine
invasion
• 108 (45%) had PET +ve nodal disease
- 51% PET +ve recurred cf. 22% in PET -ve
• Majority of recurrences distant
ANZGOG
Narayan K 2006 and 2007
Background – adjuvant
chemo
• Chemo concurrent with XRT improves
survival and is standard care
• Additional chemo after chemoXRT may treat
distant mets and ↑ survival in high-risk pts
• Few small retrospective studies with older
chemo in unselected patients suggest no
survival advantage and some toxicity
• Carboplatin/paclitaxel active in cervical ca
and likely more deliverable after XRT than
cisplatin/topotecan
ANZGOG
Background – adjuvant
chemo
• GOG 109: post-op chemoXRT for those with
+ve nodes/ margins or parametrium involved
:2 extra cycles of cis/5FU given after chemoXRT
: subset analysis suggested improved PFS and OS
with more cycles of chemo
ANZGOG
Research Plan
Design: Single-arm phase II study
(n=30:pragmatic)
Eligibility: Stage 1b-IVa cervical cancer
suitable for primary treatment with
chemoradiation with curative intent in
addition to one of the high-risk features of:
a)Pelvic nodal involvement on:
- staging PET scan
- staging CT if >15mm diameter, or
- frozen section during planned surgery
leading to abandonment of planned
hysterectomy
ANZGOG
b) Uterine involvement on MRI
Aims and Objectives
• Aim: To test the feasibility of the regimen
• Primary objective: To determine the
percentage of patients able to complete all
treatment components without significant
treatment interruptions or omissions due to
grade 3 or 4 toxicity
• Secondary objectives: To determine the
- Acute and long-term toxicities
- Patterns of disease recurrence
- Failure-free survival
ANZGOG
Intervention
• 45-50.4 Gy of external beam XRT in 25 to
28 fractions plus brachytherapy
• Cisplatin 40mg/m2 weekly during XRT
• Within 4 weeks of completion of XRT and
following recovery from toxicities, 4 cycles
of 3 weekly adjuvant chemotherapy using
Carboplatin AUC 5 and Paclitaxel 175
mg/m2
ANZGOG
Future phase III study
Stage Ib-IVa
Cervical cancer
Node positive
and/or
Uterine invasion
Standard
chemoXRT
4 cycles
Carboplatin
+ Paclitaxel
Standard
chemoXRT
ANZGOG
GCIG Consensus: Cervical
Brachytherapy
• Produce a document that can be used as a
template for upcoming GCIG trials that
contains “acceptable” evidence based
brachytherapy dosing.
• Akila Viswanathan has agreed to head the
project.
• Plan to work via e-mail and possibly
conference call(s) with goal of finalizing the
manuscript by the cervical SOTS meeting in
2009.