gcig cervix committee november 14, 2008. gog 240 schema eligibility: 1. primary stage ivb or...
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GCIG Cervix Committee
November 14, 2008
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GOG 240Schema
Eligibility:
1. Primary stage IVB orRecurrent/persistentcarcinoma of the cervix
2. Measureable disease
3. GOG PS 0-1
Regimen IPaclitaxel 135 mg/m2 IV d1 (24h)Cisplatin 50 mg/m2 IV d2Q21d to progression/toxicity
Regimen IIPaclitaxel 135 mg/m2 IV d1 (24h)Cisplatin 50 mg/m2 IV d2Bevacizumab 15 mg/kg IV d2Q21d to progression/toxicity
Regimen IVPaclitaxel 175 mg/m2 IV d1 (3h)Topotecan 0.75 mg/m2 d1-3 (30m)Bevacizumab 15 mg/kg IV d1Q21d to progression/toxicity
Regimen IIIPaclitaxel 175 mg/m2 IV d1 (3h)Topotecan 0.75 mg/m2 d1-3 (30m)Q21d to progression/toxicity
RANDOMIZE
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GOG 240Primary & 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
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GOG 240Statistical 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
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GOG 240Toxicity monitoring
Bevacizumab-related toxicities – DSMB evaluation
(Bowel perforation, hemorrhage, necrosis, fistula, PE)
Stage Cummulative Patients
Min # Events
1 50 12
2 100 18
Topotecan-Paclitaxel-related toxicities – DSMB evaluation
(Myelosuppression and infection)
Stage Cummulative Patients
Min # Events
1 50 19
2 100 30
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GOG 240Exploratory 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
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GOG 240CellSearchTM Circulating Tumor Cell (CTC) Test
Number of CTCs - Correlation with PFS & OSClearance of CTCs - Correlation with response - Correlation with OS & PFS
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GOG 240International Collaborators
Spain:Ana Oaknin Benzaquen
Norway:Gunn Kristensen MD
South Korea:Jong-Min Lee MD PhD
Germany:Falk Clemens Thiel MD
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NORWAY
Kristensen, GunnarDepartment of Gynecologic Oncology,
Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
Department of Medical Informatics, University of Oslo, Oslo, Norway
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:[email protected]
KOREA
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; [email protected], [email protected]
Office; 82-2-440-6140 Cell;82-11-738-3725 Fax; 82-2-440-7894
GERMANY
Falk Clemens Thiel, MD
Department of Gynecology University Hospital Erlangen
Universitätsstr. 21 23 91054 Erlangen
Germany
Tel. +49 9131 8533553
GOG 240
International Collaborators
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This protocol has received approval by the NCI and Central IRB and we anticipate activation within the upcoming 2-3 months.
GOG 240Status
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John H. Farley MDAssociate Professor Obstetrics and Gynecology
Uniformed Services University of the Health Sciences
CVM0503
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• 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
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• 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
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• 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 – (180 cGy/fraction)
CVM0503
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• 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: 328CVM0503
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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
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GOG 219October 23, 2008
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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
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ENROLLMENT BY QUARTER
05
10152025303540
1STQ
2006
3RDQ
2006
1STQ
2007
3RDQ
2007
1STQ
2008
3RDQ
2008
GOG-0219
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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
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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
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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
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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
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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
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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
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KCCH Retrospective Results
735 cases
172 cases
34 cases 49 cases 89 cases
No further treatment RT only CCRT
RH with BPLND
FIGO stage IB – IIA cervical cancer patients
Any of intermediate risk factor
Fig. 1. Patients enrolled in this study
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CVM 0801/KGOG 1008
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Cervical cancer
Stage IB-IIARadical hysterectomy+BPLND >2 of intermediate risk factors
Control Arm; Radiation therapy
CRT Arm; Weekly CDDP 40mg/m2 concurrent to radiation
Random
ization
CVM 0801/KGOG 1008
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CVM 0801/KGOG 1008
– Primary endpoint;
• 3 year recurrence free survival
– 6.3% (87% to 93.3%)
– Secondary endpoint;
• Recurrence rate
• Toxicity
– QoL
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CVM 0801/KGOG 1008
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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
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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
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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
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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
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RTOG/GOG combined study for high-risk early stage Cervical Carcinoma
Anuja Jhingran
RTOG-0724
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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
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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
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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
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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
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Proposed Intergroup trialStage I/IIA Cervical Cancer
XRT 45 - 50 GyCisplatin 40 mg/m2 wkly
Carboplatin AUC 5Paclitaxel 135mg/m2 q3weeks X4
Radical Hyst: +LN’s, - include para-aortic nodes, and parametrium
Randomize
ARM 1 ARM 2
XRT 45 - 50 GyCisplatin 40 mg/m2 wkly
PI’s A. Jhingran RTOG H. Gray GOG
400 pts RTOG-0724
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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
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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
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RTOG 0724
• IMRT allowed.• Vaginal Brachytherapy allowed.
RTOG-0724
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New Concepts in Locally Advanced Cervix Cancer
Nick Reed
Personal thoughtsfor debate at GCIG Nov 2008
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Need for Improvement
• Improving outcomes of bulky locally advanced cervix cancer
New Approaches• Induction / neoadjuvant schedules• Maintenance treatments• Targeted agents• Functional Imaging
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Diagnostic Pathway
NACT Induction
Newly diagnosed Stage 1B2 – 4A CCRT
Baseline Imaging
ReassessmentImaging and CCRT
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So where is my evidence?
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Newer Approaches - Induction• Meta-analysis from data with Cis
+/-• Carboplatin vs Cisplatin• Addition of Paclitaxel - Hoskin &
Glynne-Jones
• Mexico- Duenas -Gonzalez
• UCL – McCormack CX2 study
• Still premature but exciting interest
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The Study Options
NACT Induction
CCRT
Maintenance chemotherapy
Observation
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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
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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 60-80 mg/m2)
• Reassess clinically and radiologically plus repeat samples for freezing
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Diagnostic Pathway
NACT Induction
Newly diagnosed Stage 1B2 – 4A CCRT
Baseline Imaging
ReassessmentImaging and CCRT
TR BiopsyImaging
TR BiopsyImaging
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Chemo-Rads CCRT
• Proceed to standard concomitant chemoradiotherapy (CCRT)
• Try for international consensus on EBRT dose and also BT
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The Other Option - Maintenance• Why?• Tierney IPA suggests benefit• Which maintenance?• How many cycles• Conventional or TAT or both• Candidates
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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
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The Study Options
NACT Induction
CCRT
Maintenance chemotherapy
Observation
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Where next?
• Discussion
• Manchester SOTS??
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A pilot study of adjuvant chemotherapy for high-risk cervical cancer
Linda Mileshkin, Danny Rischin, Kailash Narayan
ANZGOG
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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
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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
Narayan K 2006 and 2007ANZGOG
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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
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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
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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 hysterectomyb) Uterine involvement on MRI
ANZGOG
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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
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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
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Future phase III study
Stage Ib-IVaCervical cancerNode positiveand/orUterine invasion
Standard chemoXRT
Standard chemoXRT
4 cyclesCarboplatin + Paclitaxel
ANZGOG
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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.