Gcig cervix committee november 14 2008
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GCIG Cervix Committee November 14, 2008. Regimen I Paclitaxel 135 mg/m 2 IV d1 (24h) Cisplatin 50 mg/m 2 IV d2 Q21d to progression/toxicity. GOG 240 Schema. R A N D O M I Z E. Regimen II Paclitaxel 135 mg/m 2 IV d1 (24h) Cisplatin 50 mg/m 2 IV d2

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GCIG Cervix Committee November 14, 2008

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Gcig cervix committee november 14 2008

GCIG Cervix CommitteeNovember 14, 2008


Gog 240 schema

Regimen I

Paclitaxel 135 mg/m2 IV d1 (24h)

Cisplatin 50 mg/m2 IV d2

Q21d to progression/toxicity

GOG 240Schema

R

A

N

D

O

M

I

Z

E

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

Eligibility:

1. Primary stage IVB or

Recurrent/persistent

carcinoma of the cervix

2. Measureable disease

3. GOG PS 0-1

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

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 240 statistical design

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 240 toxicity monitoring

GOG 240Toxicity monitoring


Gog 240 exploratory endpoints

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 240 cellsearch tm circulating tumor cell ctc test

GOG 240CellSearchTM 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

GOG 240International Collaborators

Norway:

Gunn Kristensen MD

Germany:

Falk Clemens Thiel MD

South Korea:

Jong-Min Lee MD PhD

Spain:

Ana Oaknin Benzaquen


Gcig cervix committee november 14 2008

GOG 240International Collaborators

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. 21­23 91054 Erlangen Germany

Tel. +49 9131 8533553


Gcig cervix committee november 14 2008

GOG 240Status

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


Gcig cervix committee november 14 2008

John H. Farley MD

Associate Professor Obstetrics and Gynecology

Uniformed Services University of the Health Sciences

CVM0503


Gcig cervix committee november 14 2008

  • 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


Gcig cervix committee november 14 2008

  • 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


Gcig cervix committee november 14 2008

  • 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


Gcig cervix committee november 14 2008

  • 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

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 219October 23, 2008


Gog 219

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

ENROLLMENT BY QUARTER

GOG-0219


Amendment

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


Amendment1

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


Amendment2

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

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 10081

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 10082

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


Gcig cervix committee november 14 2008

KCCH Retrospective Results

RH with BPLND

FIGO stage IB – IIA cervical cancer patients

735 cases

172 cases

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 10083

CVM 0801/KGOG 1008


Gcig cervix committee november 14 2008

CVM 0801/KGOG 1008

Control Arm; Radiation therapy

Randomization

Cervical cancer

Stage IB-IIA

Radical hysterectomy+BPLND

>2 of intermediate risk factors

CRT Arm; Weekly CDDP 40mg/m2concurrent to radiation


Cvm 0801 kgog 10084

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 10085

CVM 0801/KGOG 1008


Cvm 0801 kgog 10086

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 10087

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 10088

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 10089

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

RTOG/GOG combined study for high-risk early stage Cervical Carcinoma

Anuja Jhingran

RTOG-0724


Background

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


Gcig cervix committee november 14 2008

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 CervixGOG 109:Peters et al JCO 2000


Gcig cervix committee november 14 2008

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 CervixGOG 109:Peters et al JCO 2000


Gcig cervix committee november 14 2008

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 trialMonk et al Gyn Onc 2005


Proposed intergroup trial stage i iia cervical cancer

Proposed Intergroup trialStage 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

PI’s A. Jhingran RTOG

H. Gray GOG

RTOG-0724

400 pts


Hypothesis

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

Endpoints

2.1Primary objective:

Disease-free survival

2.2Secondary 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

RTOG 0724

RTOG-0724

IMRT allowed.

Vaginal Brachytherapy allowed.


New concepts in locally advanced cervix cancer

New Concepts in Locally Advanced Cervix Cancer

Nick Reed

Personal thoughts

for debate at GCIG Nov 2008


Need for improvement

Need for Improvement

Improving outcomes of bulky locally advanced cervix cancer

New Approaches

Induction / neoadjuvant schedules

Maintenance treatments

Targeted agents

Functional Imaging


Diagnostic pathway

Diagnostic Pathway

CCRT

Newly diagnosed Stage 1B2 – 4A

Baseline Imaging

NACT Induction

Reassessment

Imaging and CCRT


So where is my evidence

So where is my evidence?


Newer approaches induction

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

The Study Options

Maintenance chemotherapy

NACT Induction

CCRT

Observation


Reed s observations

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

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 pathway1

Diagnostic Pathway

CCRT

Newly diagnosed Stage 1B2 – 4A

Baseline Imaging

NACT Induction

Reassessment

Imaging and CCRT

TR Biopsy

Imaging

TR Biopsy

Imaging


Chemo rads ccrt

Chemo-Rads CCRT

Proceed to standard  concomitant chemoradiotherapy (CCRT)

Try for international consensus on EBRT dose and also BT


The other option maintenance

The Other Option - Maintenance

Why?

Tierney IPA suggests benefit

Which maintenance?

How many cycles

Conventional or TAT or both

Candidates


The next steps

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


Gcig cervix committee november 14 2008

The Study Options

Maintenance chemotherapy

NACT Induction

CCRT

Observation


Where next

Where next?

Discussion

Manchester SOTS??


A pilot study of adjuvant chemotherapy for high risk cervical cancer

A pilot study of adjuvant chemotherapy for high-risk cervical cancer

Linda Mileshkin, Danny Rischin, Kailash Narayan

ANZGOG


Background1

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


Background2

Background

ANZGOG

  • 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 2007


Background adjuvant chemo

Background – adjuvant chemo

ANZGOG

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


Background adjuvant chemo1

Background – adjuvant chemo

ANZGOG

  • 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


Research plan

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:

Pelvic nodal involvement on:

staging PET scan

staging CT if >15mm diameter, or

- frozen section during planned surgery leading to abandonment of planned hysterectomy

b) Uterine involvement on MRI

ANZGOG


Aims and objectives

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

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

Future phase III study

4 cycles

Carboplatin + Paclitaxel

Standard

chemoXRT

Standard

chemoXRT

ANZGOG

Stage Ib-IVa

Cervical cancer

Node positive

and/or

Uterine invasion


Gcig consensus cervical brachytherapy

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.


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