C hemo- R adiation in A dvanced Stage C arcinoma Cervi x Green - - PowerPoint PPT Presentation

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C hemo- R adiation in A dvanced Stage C arcinoma Cervi x Green Meta-analysis Update Cochrane Database Syst Rev05 Cochrane Review: Green et al, Cochrane Review: Green et al, The Lancet 01 Lukka Meta-analysis, Clin Oncol 02

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SLIDE 1
  • Cochrane Review: Green et al,

Cochrane Review: Green et al, The Lancet’ 01

  • Canadian Meta

Canadian Meta-

  • analysis : Lukka

analysis : Lukka et al, et al, Clin Oncol’ 02

  • Green et al meta

Green et al meta-

  • analysis on

analysis on concurrent concurrent chemoradiation chemoradiation: : Update Cochrane Database Syst Rev,

2005;Jul 20: (3) Wong, Gynecol Oncol’ 89 Tseng, Rose, Keys, Morris, Peters, Whitney NCI Clinical Announcement’ 1999 Pearcey, Proc ASCO’ 00 [abst] Green Meta-analysis, The Lancet’ 01 Lukka Meta-analysis, Clin Oncol’ 02 Green Meta-analysis Update Cochrane Database Syst Rev’05

Chemo-Radiation in Advanced Stage Carcinoma Cervix

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SLIDE 2

4/6/2010 2 AUTHOR ARMS RESULTS COMMENTS CRITICISMS

Whitney et

  • al. 1999

(GOG-85)

I I B-I I I B

RT+ Cisplatin / 5FU Vs. RT+ HU OS-55% Vs. 43% Better PFS and OS than HU with manageable toxicity

  • 1. Comparison of

two CTRT regimens

  • 2. No RT alone arm
  • 3. Sub optimal

(81Gy to pt A) 4. protracted RT (median duration 63 days) Morris et

  • al. 1999

(RTOG 9001) I B-

I VA

RT+ Cisplatin Vs. 5FU + RT OS-73% Vs. 58% CT had a survival advantage with decrease in both LR and distant failure

  • 1. RT optimal,

89Gy to pt A, 58 days

  • 2. Survival benefit

in I B-I I B, not in adv stage Keys et al. 1999 (GOG-123)

Bulky I B

RT+ Cisplatin+ SX Vs. RT+ SX OS-83% Vs. 74% Significant differences in PFS and OS favoring CTRT

  • 1. Suboptimal RT

dose

  • 2. Trial for pre op

regimen I B only

Critical Review of 5 trials

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SLIDE 3

4/6/2010 3 AUTHOR ARMS RESULTS COMMENTS CRITICISMS Peters et al. 2000

I A2-I I A

SX+ RT+ Cisplatin/ 5 FU Vs. SX+ RT OS-80% Vs. 63% Survival favored the chemoradiotherapy arm 1. Post op RT, no brachy 2. Early stage Rose et al. 1999 (GOG 120)

I I B-I I I - I VA

RT+ Cisplatin Vs. RT+ Cisplatin/ 5FU/ H U Vs. RT+ HU PFS–67% Vs. 64% Vs. 47% Superiority of concomitant CTRT regimen with cis alone was less toxic then 3 drug regimen 1. No RT alone arm 2. Comparison of 3 ctrt regimens 3. Low total RT dose & protracted Rx time

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SLIDE 4

‘ ‘CONCURRENT CHEMORADIATION FOR CERVICAL CANCER

CONCURRENT CHEMORADIATION FOR CERVICAL CANCER’ ’

in February 1999 in February 1999

“ “ Five major randomized phase III trials show that platinum based

Five major randomized phase III trials show that platinum based chemo chemo when given concurrently with RT prolongs survival in women with when given concurrently with RT prolongs survival in women with locally locally advanced cervical cancer stages Ib2 advanced cervical cancer stages Ib2 -

  • IVa as well as in women with stage

IVa as well as in women with stage I / IIa found to have metastatic pelvic lymph nodes, positive pa I / IIa found to have metastatic pelvic lymph nodes, positive parametrial rametrial disease and positive surgical margins at the time of primary sur disease and positive surgical margins at the time of primary surgery gery ”

”

BACKGROUND AND RATIONALE

NATI ONAL CANCER I NSTI TUTE CLI NI CAL ANNOUNCEMENT NATI ONAL CANCER I NSTI TUTE CLI NI CAL ANNOUNCEMENT

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SLIDE 5

Cochrane Collaborative Group (19 Trials)

Meta Meta -

  • analysis

analysis

  • 19 RCTs between 1981 and 2000 : 4580 pts

19 RCTs between 1981 and 2000 : 4580 pts

  • I ncrease in OAS by 12% & RFS by 16% (absolute

I ncrease in OAS by 12% & RFS by 16% (absolute benefit) (p= 0.0001) benefit) (p= 0.0001)

  • Greater benefit in patients in stages I B2 and I I B

Greater benefit in patients in stages I B2 and I I B

  • Decrease in local and systemic recurrence (p= 0.0001)

Decrease in local and systemic recurrence (p= 0.0001)

Green JA et al Lancet 358;781 (Sept. 2001)

  • Update in July 2005: 21 trials and 4921 pts
  • Similar findings (absolute benefit: 10%)
  • Test for Heterogeneity : Positive
  • No data on late toxicities

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002225.

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SLIDE 6

Cisplatin based Concomitant Chemo-radiation Significant improvement in Overall Survival

  • Advanced Stages (Only 30% tumors)
  • Bulky IB tumors (prior to surgery)
  • High risk early disease (post-surgery)

Toxicities Acute Grade 3/4 Hematological and G.I significantly higher : all short lived 2 deaths due to the toxicities No significant late toxicities seen Canadian Group (9 Trials) - 4 year survival data

Meta-analysis

Lukka et al, Clinical Oncology 14;203(June 2002)

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SLIDE 7

Heterogenous patient data Suboptimal Radiotherapy Schedules Used Non-uniform use of CT drugs and Sequencing QOL issues : Unknown Cost effectiveness ? Hence Concomitant chemo-radiation needs to be tested

  • ptimally in our setting

Sparse literature form Developing Countries

Critical Review of Trials Chemo-radiation in Carcinoma Cervix

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SLIDE 8

Chemo-Radiation in Advanced Stage Carcinoma Cervix

(FIGO IIIB): A Phase III Randomized Trial (CRACx Trial) HSRC / HEC Project No: 114/2003 Clinicaltrials.gov ID : NCT00193791 Protocol ID : TMH/114/2003/CRACx TRIAL

TMC Cervix Working Group

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SLIDE 9

425 patients

Radical Radiotherapy Ext RT+ICA 50 Gy(MLB at 40)/5wks + LDR/HDR LDR: 30Gy or HDR: 7Gyx3#

425 patients

Concomitant chemotherapy weekly Cisplatin and Radiotherapy

  • Hypothesis: Improvement in OAS by 10% (35% to 45%)
  • Power of detection: 80% (alpha error: 0.05)
  • Intent to treat basis
  • Accrual Period: 5-6 years
  • Interim analysis : Twice One at 50 % and another at 75 % event rates

Carcinoma Cervix Stage FIGO IIIB Carcinoma Cervix Stage FIGO IIIB

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial ): 2003

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SLIDE 10

Aims & Objectives Aims & Objectives Aims & Objectives

Primary

1. 1.

To compare the overall and disease free survivals To compare the overall and disease free survivals

2. 2.

To compare acute toxicities To compare acute toxicities

3. 3.

To evaluate single agent chemotherapy To evaluate single agent chemotherapy ‘ ‘Cisplatin Cisplatin’ ’

Secondary

1. 1.

To compare distant metastasis rate. To compare distant metastasis rate.

2. 2.

To compare late toxicities in both groups. To compare late toxicities in both groups.

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

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SLIDE 11

Pre-treatment Evaluation Pre-treatment Evaluation

  • Pelvic Examination / EUA (

Pelvic Examination / EUA (sos sos) / ) / Gynae Gynae Joint Clinic Joint Clinic

  • Complete Blood Profile

Complete Blood Profile

  • Serum Biochemistry (

Serum Biochemistry (Liver+ Renal Liver+ Renal functions+ Electrolytes) functions+ Electrolytes)

  • Chest X

Chest X-

  • Ray

Ray

  • USG (A + P) / CT Scan (A+ P) : Optional

USG (A + P) / CT Scan (A+ P) : Optional

  • ECG

ECG

  • Cystoscopy

Cystoscopy: if indicated. : if indicated.

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

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SLIDE 12

I nclusion Criteria I nclusion Criteria

  • Squamous carcinoma

Squamous carcinoma

  • Performance index WHO Grade 0 or 1

Performance index WHO Grade 0 or 1

  • Age < 65 years

Age < 65 years

  • FI GO stage I I I B

FI GO stage I I I B

  • Normal ECG and Cardiovascular systems

Normal ECG and Cardiovascular systems

  • Normal hematological parameters.

Normal hematological parameters.

  • Normal renal & liver function test.

Normal renal & liver function test. Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial ) Exclusion Criteria Exclusion Criteria

  • Co

Co-

  • morbid conditions like medical renal disease.

morbid conditions like medical renal disease.

  • Medical or psychological condition that would preclude Rx.

Medical or psychological condition that would preclude Rx.

  • History of previous treatment.

History of previous treatment.

  • Patient unreliable for treatment completion & follow

Patient unreliable for treatment completion & follow-

  • up.

up.

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SLIDE 13
  • External RT : Whole Pelvis with AP/PA or four field box technique
  • Dose : 50 Gy / 25 # / 5 Weeks (40 Gy open + 10 Gy with MLB)
  • Brachytherapy :

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

LDR : 30 Gy X 1 # to pt A Or HDR : 7 Gy X 3 # to pt A

  • Chemotherapy

Patient randomised to CT+ RT receive Inj. Cisplatin 40 mg/m2 wkly

Treatment Protocol Treatment Protocol

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SLIDE 14

Evaluation of Response & Toxicity Evaluation of Response & Toxicity Evaluation of Response & Toxicity

  • Response :

Response : WHO Criteria WHO Criteria

  • Toxicity Scoring

Toxicity Scoring

  • Acute toxicities : CTC version 2.0

Acute toxicities : CTC version 2.0

  • Late toxicities : RTOG / LENT

Late toxicities : RTOG / LENT-

  • SOMA scoring criteria.

SOMA scoring criteria.

  • Follow Up :

Follow Up :

Clinical examination, Assessment of tumor response, late Clinical examination, Assessment of tumor response, late complications & relevant investigations / Rx will be done accord complications & relevant investigations / Rx will be done accordingly ingly

  • 1

1st

st follow

follow-

  • up: 6

up: 6 -

  • 10 weeks

10 weeks

  • Subsequently every 3

Subsequently every 3 -

  • 4 mths for the first 2 years.

4 mths for the first 2 years.

  • 6 monthly thereafter

6 monthly thereafter

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

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SLIDE 15

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

ACCRUAL DETAILS

  • Study Started

: August 2003

  • Pts randomised till Nov. 2008

: 627 pts

  • Audit of pts till Dec. 2007

: 528 pts

  • Planned Accrual Completion

: Dec 2009

  • Interim Analysis

: Jan 2010

  • Final Analysis

: Dec 2011

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SLIDE 16

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

AUDIT

  • Audit of pts till Dec. 2007

: 528 pts

  • RT Alone

: 255 pts

  • CT + RT

: 263 pts

  • Randomization

: Computerized (open label)

  • Analysis

: ITT

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SLIDE 17

Cisplatin Chemotherapy Compliance Cisplatin Chemotherapy Compliance

No of Cycles No of Cycles No of pts (263 pts) No of pts (263 pts) 6# 6# 03 03 4 4-

  • 5#

5# 226 (4# : 43 pts) 226 (4# : 43 pts) 3# 3# 17 17 2# 2# 7 (1pt had single kidney) 7 (1pt had single kidney) 0-

  • 1#

1# 10 (Incomplete Rx) 10 (Incomplete Rx)

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

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SLIDE 18

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

RESPONSE RATES (6-10 weeks Post Rx) RESPONSE RATES (6-10 weeks Post Rx) RT Alone RT Alone 255 pts 255 pts CT + RT CT + RT 263 pts 263 pts CR CR 229 229 227 227 PR PR 08 08 14 14 Prog

  • Prog. Disease

. Disease 05 05 06 06 Not assessed* Not assessed* 13 13 16 16

* 6-10 weeks Post Rx not completed

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SLIDE 19

ACUTE TOXICITIES RT Alone RT Alone 255 pts 255 pts CT + RT* CT + RT* 263 pts 263 pts

GI GI

Gr Gr II II Gr Gr III III 68 68 12 (4.7%) 12 (4.7%) 78 78 17 (7%) 17 (7%)

GU GU

Gr Gr II II Gr Gr III III 15 15 10 (4%) 10 (4%) 23 23 15 (5.7%) 15 (5.7%)

Skin Skin

Gr Gr II II Gr Gr III III 63 63 29 29 63 63 26 26

Anemia Anemia

Gr Gr II II Gr Gr III III 24 24 5 (2%) 5 (2%) 101 101 15 (5.7%) 15 (5.7%)

Neutropenia Neutropenia

Gr Gr II II Gr Gr III III 06 06 02 (0.7%) 02 (0.7%) 39 39 09 (3.5%) 09 (3.5%)

Thrombocytopenia Thrombocytopenia

Gr Gr II II Gr Gr III III 01 01 02 (0.7%) 02 (0.7%) 16 16 09 (3.5%) 09 (3.5%)

* 1 pt Dyselectrolytemia and death & 2 pt Gr IV Oto-toxicity (Irreversible)

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )

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SLIDE 20

RT ALONE RT ALONE (255 pts) (255 pts) CT + RT CT + RT (263 pts) (263 pts)

Recurrences Recurrences

47 47 38 38 Progressive Disease Progressive Disease Loco Loco-

  • regional Recurrence

regional Recurrence LR + Distant Recurrence LR + Distant Recurrence Distant Mets Distant Mets 04 04 13 13 07 07 23 23 04 04 11 11 04 04 19 19

Died due to Rx Complications Died due to Rx Complications

01 (Unknown) 01 (Unknown) 01 01

Lost to follow Lost to follow-

  • up (after 1

up (after 1-

  • 2 FU)

2 FU)

16 16 12 12

N= 486 pts: Follow-up: Median: 24 months (3 - 48 months)

Chemo-Radiation in Advanced Carcinoma Cervix (FIGO IIIB) (CRACx Trial )

* Acute Gr II/III Genitourinary/hematological toxicities higher in CT+ RT arm

* Grade II / III Procitiits seen in 7 pts in each arm so far Ongoing

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SLIDE 21

Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial ) AUDIT SUMMARY

  • Acute Grade III GI and Hematological toxicities : Higher with CT+ RT
  • Recurrence event rates comparable so far
  • Late toxicities yet to evaluated
  • Cost benefit analysis – most critical in our setting
  • Completion of accrual and outcome analysis
  • Report on 1st Interim Analysis : Jan 2010
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SLIDE 22

Thank You