Corinne HaiounUnité Hémopathies Lymphoides

Hôpital Henri MondorCréteil, France

PET and Lymphoma

First and only rule: to cure the patient with first-line treatment

Residual masses at the end of therapy are frequent(70% HL, 50% NHL) but only a minority of patients relapse (<20% HL, 25% NHL)

Patients in apparent complete remission also relapse

Early treatment of residual activedisease may improve survival

Need for an accurate and sensitive tool

to detect residual disease

PET and Lymphoma : Background

• Hodgkin Lymphoma is a curable disease, with more than 75% of the patients free of disease 10 years or more after standard treatment.

• However, nearly 15-20% of the patients treated with ABVD fail therapy either for progression or relapse.

• FDG-PET scan could be a surrogate test for chemosensitivity, due to its ability to predict treatment outcome with an overall accuracy of 90-95%.

PET and Hodgkin Lymphoma : Background

HD prognostic score: clinical variables

Hasenclever d. NEJM 1998; 339:1506

HD prognostic score: 7y-FFP and OS

Hasenclever d. NEJM 1988; 339:1506

7% of the patients

According to IPS According to PET-2 (+vs.-) and IPS (0-2 vs 3-7)

HL prognosis: from IPS to PET

Intergruppo Italiano Linfomi

PET-0: 25.03.04

PET-2: 30.06.04

PET-6: 08.11.04

3210

Years after diagnosis

1.0

0.8

0.6

0.4

0.2

0.0

Pro

gre

ssio

n-f

ree s

urv

ival p

rob

ab

ilit

y

Gallamini: Hematologica 2006; 91, 475-81

Gallamini: JCO 2007; 25, 3743-52

Hutchings: Blood 2006; 107, 52-59Kostakoglu: Cancer 2006; 107:2678-87

H10 TrialH10 Trial

Ran

do

mis

ation

FDG-PET

1 cycle ABVDIN-RT 30 Gy(+boost 6 Gy

résiduals)

whatever

Favourable Group F

UnfavourableGroup U

Ran

do

mis

ation

ABVD 2 cycles

ABVD 2 cycles

ABVD 2 cycles

ABVD 2 cycles

FDG-PET

FDG-PET

FDG-PET

ABVD 2 cycles

BEACOPP2 cycles

esca

IN-RT 30 Gy(+ boost 6 Gy)

ABVD 4 cycles

2 cycles BEACOPPesca

IN-RT 30 Gy(+ boost 6 Gy)

ABVD 2 cycles IN-RT 30 Gy(+boost 6 Gy

résiduels)

négative

positive

negative

positive

The results

whatever

The results

Second registration

First registration

HodgkinLymphoma

Stage I/II

The situation in Diffuse Large B-Cell

Lymphoma

Weber W: J.Nucl. Med 2007: 48: 1580-82.

Current questions for DLBCL patients

Role of PET to individualize treatment ?

PET– (n = 54)

PET+ (n = 36)Pro

bab

ilit

y

p < 0.0001

Years after randomisation

Event-free survival

p = 0.006

Overall survival

100 100

0 1 2 3 0 1 2 3Years after randomisation

Pp

rob

abil

ity 80

60

40

20

0

80

60

40

20

0

PET– (n = 54)

PET+ (n = 36)

Interim PET after 2 cycles may help stratify patients ?

Haioun C, et al. Blood 2005

• All the sites of FDG uptake are scored in PET-0 and PET-

2.

• Each FDG uptake focus is quantified according to a score graded 1-

3 (1 low, 2 moderate, 3 high) for extension and intensity

• PET-2 negative: Negative was defined as having no residual

abnormal uptake or as having a unique residual site (with an extent

score of 1) associated with an intensity score of 1, whereas all the

other previously hypermetabolic sites were extinguished.

• PET-2 positive: Positive was defined as having at least one residual

site (with an extent score of 1) associated with an intensity score of

2, or as having 2 or more residual sites with any extent and

intensity scores.

Haioun, Blood 2005; 106: 1376-1381

Early (after 2 cycles) PET treatment evaluation with visual analysis

Before treatment At 2 cycles At 4 cycles

FDG-PET2 (+)

Early treatment evaluation

Haioun C, et al. Blood 2005; 106(4): 1376–81

FDG-PET2 (-)

Before treatment At 2 cycles At 4 cycles

Early treatment evaluation

Haioun C, et al. Blood 2005; 106(4): 1376–81

2-year outcome

Study n PET after . . . PET- PET+

Jerusalem 2000 28 median: 3 cycles

62% (PFS) 0% (PFS)

Spaepen 2002 70 median: 3 cycles

85% (PFS) 4% (PFS)

Kostakoglu 2002

30 1 cycle 85% (PFS) <15% (PFS)

Haioun 2005 90 2 cycles 82% (EFS) 43% (EFS)

Michaël 2005 121 median: 2 cycles

87% (PFS) 34% (PFS)

Jerusalem et al. Haematologica, 85(6): 613-8   2000; Spaepen et al. Ann Oncol, 13(9): 1356-63   2002; Kostakoglu et al. J Nucl Med, 43(8): 1018-27   2002; Haioun C et al. Blood 2005; 106(4): 1376–81; Mickaeel et al. 2005

Current questions for DLBCL patients

Role of PET to individualize treatment ?

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4Years

% survival

(High negative predictive value): NPV=

TN

TN +FN

(Low positive predictive value): PPV= TP

TP +FP

FN

FP

FDG-PET in DLBCL

Event-free survival and overall survival according to response at 2 cycles on

the basis of PET (n = 90)

PET– (n = 54)

PET+ (n = 36)Pro

bab

ilit

y o

f E

FS

p < 0.0001

Years after randomisation

Event-free survival

p = 0.006

median f/u: 2 years

Overall survival100 100

0 1 2 3 0 1 2 3

Years after randomisation

pro

ba

bil

ity

of

OS

80

60

40

20

0

80

60

40

20

0

Haioun C, et al. Blood 2005; 106(4): 1376–81

PET– (n = 54)

PET+ (n = 36)

PPV 50 %NPV 74 %Accuracy 68.5%

(Bq/g)

Activité injectéePoids du corps

C*totale =

(Bq/g)

Activité mesurée

Volume du foyerC*tissulaire =

C*tissulaire

C*totale

SUV =

Si distribution homogène, SUV = 1

=1g/cm3

SUV=Ci*()

dose/poids

Lin C.: J. Nucl. Med 2007; 48, 1626-1632

•92 patients

•PET baseline and after 2 courses of CT

•IPI 0-1: 38; IPI 2-3: 54

•Therapy: CHOP, R-CHOP, ACVPB/ACE, R-ACVBP

SUV-based Assessment versus Visual Analysis

SUV and EFS: Optimal cut-off point of SUVmax reduction: 65.7% (ROC analysis)

Lin C, Itti E. JNM 2007; 48:1626-32.

PPV 81.3%

NPV 75.0%

Accuracy 76.1%

Months After Randomization

> 65.7%

65.7%

SUV max Reduction

P < .0001

Pro

babili

ty o

f EFS

(%

)

Visual Analysis

PET (-)

PET (+)

P = .009

Visual Analysis versus SUV-based Assessment

n=34

n=58 n=76

n=16

Linh C, Itti E. JNM 2007; 48:1626-32.

MSKCC 01-142-DLBCL: Risk Adapted Therapy

Transplant-eligible, CS IIX, III or IV age-adjusted IPI 1, 2, or 3 Risk Factors

• Therapy interval-2 weeks with peg-filgrastim support

• PET 10-14 days post cycle 4

• Treatment is adapted by biopsy, not PET

• No radiation therapy permitted except for testicular disease

• IT methotrexate for aaHR, paranasal sinus, testis, BM

Moskowitz et al., Blood 108: Abstract 532, 2006

Moskowitz et al., Blood 108: Abstract 532, 2006

MSKCC 01-142-DLBCL: Risk Adapted Therapy

Transplant-eligible, CS IIX, III or IV age-adjusted IPI 1, 2, or 3 Risk Factors

Outcome based upon Interim Restaging PET scan

Interim PET does not predict EFS

Moskowitz et al., Blood 108: Abstract 532, 2006

Optimize PET interpretation

PET data sent over the internet via a dedicatedserver to 3 readers: review in 48 hours

Medical Gateway

AnonymizationDouble

encryption

Time : 10 mn

3 Readers

Time : 10 mn

Current questions for DLBCL patients

Role of PET to individualize treatment ?

LNH07-3BDLBCL ; <60 yearsaa-IPI = 2-3

PET 4

PET Results

Arm A

A1

A2

B2

B1

R

R-ACVBP14 + MTX IT + G-CSF

PET 2 PET 4

R-CHOP14 + MTX IT + G-CSF

Z-BEAM + ASCTMTX iv

MTX iv AraCR- IFM / VP16

Salvage : CORAL

PETPET

4+

PET Results

Salvage : CORAL

Arm B

A1

A2

B2

B1

2- /4 -

2+ /4 -

2- /4 -

4+

PET 0 PET 4 PET Final

R-CHOP14 + G-CSF

Role of PET to individualize treatment ?

Acknowledgements

• Lymphoma Unit– Karim Belhadj– Taoufik El Gnaoui– Isabelle Gaillard– Jehan Dupuis– Frederique Kuhnowski

• Radiology– Alain Luciani– Alain Rahmouni

• Biostatistics – François Hémery– Eric Lepage

• Nuclear Medicine

– Emmanuel Itti– Eva Evangelista– Sophie Lin– Michel Meignan

• Hematopathology– Christiane Copie– Karen Leroy– Philippe Gaulard