HODGKIN AND NON-HODGKIN LYMPHOMA

Has PET/CT an established role in the management of HD and NHLs?

Dr. Umberto VitoloSC Ematologia 2 AOU San Giovanni Battista

Torino

The 1st World Congress on Controversies

in Hematology (COHEM)

Rome, Italy, 2-5 September, 2010

NO

• Questions:

1. Does PET play an essential role in staging

in HD and DLBCL?

2. Is early PET evaluation able to predict final

and long-term outcome?

3. Is PET performed at the end of

chemotherapy useful to evaluate

response?

• Questions:

1. Does PET play an essential role in staging

in HD and DLBCL?

2. Is early PET evaluation able to predict final

and long-term outcome?

3. Is PET performed at the end of

chemotherapy useful to evaluate

response?

Cheson B et al. J Clin Oncol 2007

Revised Response Criteria for Malignant Revised Response Criteria for Malignant LymphomaLymphoma

• Questions:

1. Does PET play an essential role in staging

in HD and DLBCL?

2. Is early PET evaluation able to predict final

and long-term outcome?

3. Is PET performed at the end of

chemotherapy useful to evaluate

response?

• “In lymphoma, computed tomography–PET (CT-PET) scans clearly identify more lesions than other imaging studies; however, stage is changed in only 10% to 30% of patients, and treatment is altered in even fewer patients, with no data to suggest that prognosis is improved based on this information.” Cheson B JCO 2009

• Most PET-detected lesions will remain without biopsy verification for obvious ethical and practical reasons.

• In patients with advanced disease according to conventional staging the addition of new lesions by PET has no practical importance. No differences in outcome to be expected after ABVD or R-CHOP as stages III and IV are usually managed together

• The fraction of patients with localized disease according to conventional staging (CT) whose stage is altered by PET is limited, i.e. ~ 10-30% (PET: extranodal lesions; small tumor load – not detected by CT). This has lead to therapy change in no more than 5% of patients.

StagingStaging

• PET does not substitute bone marrow biopsy to detect bone marrow involvement:

• 110 patients with DLBCL: 21 had Bone marrow involvement, only 10 were PET positive (Paone G et al Eur J Nucl Med 2009)

• 194 patients with HD and NHL: 27 had BM involvement, only 10 were PET positive; conversely 34 patients were PET positive in the bone and 24 had a BM biopsy negative (Pelosi E et al J Nucl Med 2008)

Staging 2Staging 2

Question 1:

Does PET play an essential role in staging in

HD and DLBCL?

NO

• Questions:

1. Does PET play an essential role in staging

in HD and DLBCL?

2. Is early PET evaluation able to predict final

and long-term outcome?

3. Is PET performed at the end of

chemotherapy useful to evaluate

response?

Early PET Evaluation in Hodgkin’s LymohomaEarly PET Evaluation in Hodgkin’s Lymohoma

Gallamini A, Hutchings M et al. J Clin Oncol 2007

PFS according to International Prognostic Score (IPS) group and positron emission tomography results after two cycles of

ABVD

Everything is already defined?

Predictive value of interim PET is valdid with BEACOPP?

In limited stage?

Altering treatment based on PET2 results in improved outcome? No data yet

In early PET negative patients is possible to deescalate treatment?

CS I/IIuntreated15-70 yrs

no LP nodular

®

F

ABVDx2 any outcomeof FDG-PET

ABVD x 1 IN-RT 30 Gy*

ABVDx2 PET BEACOPP esc x 2 IN-RT 30 Gy*

®U

ABVD x 2negative

positive

ABVDx2 PET any outcomeof FDG-PET

ABVD x 2 IN-RT 30 Gy*

ABVDx2 PET BEACOPP esc x 2IN-RT 30 Gy*

ABVD x 4negative

positive

PET

* boost 6 Gy to residual

H10 study H10 study

Do not deescalate treatment in PET negative Do not deescalate treatment in PET negative HD patients!HD patients!

H10 study: August 2010 interim analysisH10 study: August 2010 interim analysis

+

random

Rt bulky No Rt

stage IIB-IV

Staging including CT and PET scan or CTPET

2 ABVD

- PET

2 ABVD

Salvage HD0802

- CT + PET +

2 ABVD

CT scan optional

Advanced stage Hodgkin lymphoma

IIL-HD0801 protocol

Question 2:

Is early PET evaluation able to predict final

and long-term outcome in HD?

May be

no definitive proof has yet emerged that altering treatmentbased on this information results in superior survival

outcomes.

Do not modify treatment on PET2 results outside a clinical trial

• Questions:

1. Does PET play an essential role in staging

in HD and DLBCL?

2. Is early PET evaluation able to predict final

and long-term outcome in DLBCL?

3. Is PET performed at the end of

chemotherapy useful to evaluate

response?

Early clinical trials of interim PET in lymphomaEarly clinical trials of interim PET in lymphoma

Kostakoglu et al, Cancer 107: 2678, 2006

Haioun et al, Blood 106: 1376, 2005Mikhaeel et al, Ann Oncol 16: 1514, 2005

Spaepen et al, Ann Oncol 13: 1356, 2002

PET after 4th cycle

PET after 3rd cycle PET after 2nd cyclePPV 50 %NPV 74 %Accuracy 68.5%

PET after 1st cycle

Interim-PET +

EARLY/MID-THERAPY PET (AFTER 2-4 EARLY/MID-THERAPY PET (AFTER 2-4 COURSES) IN DLBCL: CHOP VS R-CHOPCOURSES) IN DLBCL: CHOP VS R-CHOP

CHOP n Rituximab PPV% NPV% Sens PFS PFS % PET pos PET neg

Spaepen 70 no 100 84 85 4% 85%Haioun 90 41% 44 90 76 43% 82%Mikhaeel 121 no 71 90 88 30% 93%

R-CHOPHan 40 100% 33 68 33 77% 83%

NB: PFS in all 4 studies at 2 years

Han et al., Annals of Oncology 20, 309-318 (2009)

Early evaluation of 18-FDG-PET in DLBCL treated Early evaluation of 18-FDG-PET in DLBCL treated with RCHOP14: GELTAMO experiencewith RCHOP14: GELTAMO experience

By courtesy of D. Caballero, Menton 2010

INTERIM 18-FDG-POSITRON EMISSIONINTERIM 18-FDG-POSITRON EMISSIONTOMOGRAPHY/COMPUTED TOMOGRAPHY (PET) FAILED TO TOMOGRAPHY/COMPUTED TOMOGRAPHY (PET) FAILED TO

PREDICT DIFFERENT OUTCOME IN 82 DIFFUSE LARGE B-CELL PREDICT DIFFERENT OUTCOME IN 82 DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS TREATED WITH R-CHOP LYMPHOMA PATIENTS TREATED WITH R-CHOP

All patients had CT- PET scan performed:

at the diagnosis after 2-4 courses of R-CHOP: Interim PETInterim PET

at the end of treatment: Final PETFinal PET

All DLBCL patients were staged by conventional procedures (chest and abdomen CT scan and Bone Marrow biopsy) at the diagnosis and at the end of treatment

Pregno P, Vitolo U, ASH 2009 (abstract # 99) and EHA 2010 (abstract # 680)

Interim PET(%)

Final PET (%)

PPV 17 71

NPV 80 83

0%

20%

40%

60%

80%

100%

67%84%

33%16%

NegativePositive

FINALFINAL PETPET

INTERIMINTERIM PETPET

RESULTS (82 patients)RESULTS (82 patients)

Interim PET +

Interim PET -

Final PET+

12 1 13

Final PET -

15 54 69

27 55 82

PFS ACCORDING TO PET RESULTSPFS ACCORDING TO PET RESULTS

18-months PFS18-months PFSInterim PETInterim PET

18-months PFS18-months PFSFinal PETFinal PET

Median follow-up 18 monthsMedian follow-up 18 months

PET positive 61%

PET negative 84%

PET positive 74%

PET negative 84%

p.198 p. 015

Early evaluation of 18-FDG-PET in DLBCLEarly evaluation of 18-FDG-PET in DLBCL

Moskowitz CH, J Clin Oncol 2010

Reproducibility of interim PET interpretationReproducibility of interim PET interpretation

Horning S, Blood 2010

38 interim scans

Agreement complete: 68% by ECOG criteria 71% by London criteria

Range of PET interim scans: 16% - 34% (p ns) by reviewer.

Moderate reproducibility among nuclear medicine experts

Need to standardize PET interpretation in research and practice.

Interim PET interpretation: possible pitfallsInterim PET interpretation: possible pitfalls

Possible reasons for low PPV of Interim PETInterim biopsies show degree of inflammation or necrosis that may cause FDG uptake

Rituximab may increase lesion inflammation (C activation, ADCC) and FDG uptake

Different induction regimens may have different effect (CHOP vs RCHOP; 14 day vs 21 day interval) role of GCSF?

Different timing of PET imaging relative to chemotherapy (1-2 weeks after chemo in interim PET, 1 month after chemo in final PET)

Different criteria for PET positive among studies

Wide differences among observer and reviewers

Interim PET interpretationInterim PET interpretation

Friedberg JW, Blood 2010

….Until criteria for interpretation of PET scans are prospectively validated, and the experts can routinely agree on what is PET positive and what is PET negative, physicians should not change therapy for lymphoma based on an interim PET in practice, and probably should not even routinely perform such scans….

PPV ranged from 20-30% to 50% among various studies. A treatment change on this basis means that 50-70% of the patients can be overtreated

NPV is more reliable ranged from 70-80%

Question 2:

Is early PET evaluation able to predict final

and long-term outcome in DLBCL?

NOPhysicians should not change therapy based on

interim PET and should not routinely perform such scans outside a clinical trial

(patient anxiety ….)

We need definitive and careful guidelines validated in a homogenous cohort of DLBCL patients treated with R-CHOP before tailoring therapy on interim-PET results.

We are not ready yet for interim-PET based trials in We are not ready yet for interim-PET based trials in DLBCLDLBCL

StagingCT scan and 18-FDG-PET

R-CHOP14/R-MegaCHOP14 X 2

R-CHOP14/R-MegaCHOP14 X 2

R-MADx 2

Final restagingCT scan and 18-FDG-PET

Early response evaluation18-FDG-PET

Interim response evaluation by CT scan

R-CHOP14/RMegaCHOP14

18-FDG-PET pre ASCT

BEAM-ASCT

RESPONSE EVALUATION

NO CHANGE OF TREATMENT BASED ON EARLY 18-FDG-PET RESULTS

A randomized phase III study in young patients with untreated high A randomized phase III study in young patients with untreated high risk (aaIPI 2-3) Diffuse Large B-Cell Lymphoma. Study ID: IIL-DLCL04.risk (aaIPI 2-3) Diffuse Large B-Cell Lymphoma. Study ID: IIL-DLCL04.

G. Benevolo C. Boccomini B. Botto A. Chiappella C. Frairia L. Orsucci P. Pregno

Hematology 2 Lymphoma unitHematology 2 Lymphoma unitS.Giovanni Battista Hospital Torino S.Giovanni Battista Hospital Torino

Gianni Bisi Marilena Bellò Giancarlo Castellano Francesca Giunta Roberto Passera

Nuclear Medicine Nuclear Medicine University Torino University Torino

ACKNOWLEDGMENTSACKNOWLEDGMENTS

IIL CENTERSIIL CENTERS