GCIG Cervix Committee

November 14, 2008

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

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

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

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

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

GOG 240CellSearchTM Circulating Tumor Cell (CTC) Test

Number of CTCs - Correlation with PFS & OSClearance of CTCs - Correlation with response - Correlation with OS & PFS

GOG 240International Collaborators

Spain:Ana Oaknin Benzaquen

Norway:Gunn Kristensen MD

South Korea:Jong-Min Lee MD PhD

Germany:Falk Clemens Thiel MD

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:aoaknin@iconcologia.net

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; kgo02@hanmail.net, kgo02@naver.com

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

This protocol has received approval by the NCI and Central IRB and we anticipate activation within the upcoming 2-3 months.

GOG 240Status

John H. Farley MDAssociate 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 – (180 cGy/fraction)

CVM0503

• 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

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 219October 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

05

10152025303540

1STQ

2006

3RDQ

2006

1STQ

2007

3RDQ

2007

1STQ

2008

3RDQ

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

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

CVM 0801/KGOG 1008

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

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 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

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 thoughtsfor 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

NACT Induction

Newly diagnosed Stage 1B2 – 4A CCRT

Baseline Imaging

ReassessmentImaging and CCRT

So where is my evidence?

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

The Study Options

NACT Induction

CCRT

Maintenance chemotherapy

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 60-80 mg/m2) 

• Reassess clinically and  radiologically plus repeat samples for  freezing

Diagnostic Pathway

NACT Induction

Newly diagnosed Stage 1B2 – 4A CCRT

Baseline Imaging

ReassessmentImaging and CCRT

TR BiopsyImaging

TR BiopsyImaging

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

NACT Induction

CCRT

Maintenance chemotherapy

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

Narayan K 2006 and 2007ANZGOG

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 hysterectomyb) Uterine involvement on MRI

ANZGOG

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-IVaCervical cancerNode positiveand/orUterine invasion

Standard chemoXRT

Standard chemoXRT

4 cyclesCarboplatin + Paclitaxel

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.