FDG-PET/CT in the management of lymphomas

Transcription

1 FDG-PET/CT in the management of lymphomas Olivier Gheysens, MD, PhD Dept. of Nuclear Medicine, UZ Leuven BHS, Feb 4th 2017 Brussels Dept. of Nuclear

2 Overview Introduction on FDG-PET/CT Staging Response assessment Surveillance Conclusions

3 C E=mc² ~180 o 511 kev 511 kev F Positron Emission Tomography (PET)

4 Hybrid PET-CT preparation ~60 min min resting Injection of FDG CT-scan followed by PET-scan from pelvis up to head Fasting > 6 hrs No insulin injection No physical efforts

5 18 F-Fluorodeoxyglucose (FDG) Normal cell Glucose 6-phosphatase FDG-6-P FDG Cancer cell/wbc Glucose 6-phosphatase FDG-6-P Glycolytic pathway Hexokinase Hexokinase Glycolytic pathway G6P Glucose 6-phosphatase D-glucose G6P Glucose 6-phosphatase = Glucose transporter

6 18 F-FDG Biodistribution Normal Physiological variants

7 18 F-FDG PET-CT in Lymphoma PET = whole body imaging (standard skull- mid thigh) Sensitivity depends on FDG avidity Size Background activity surrounding tissue Specificity Inflammatory tissue Physiological uptake in brown fat, gut, urinary system PET-CT Combination of metabolism and anatomy Increase in sensitivity and specificity

8 18 F-FDG avidity of lymphoma PET-CT should be recommended as the gold standard for routine staging of FDG-avid, nodal lymphomas; essentially all histologies except chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma/waldenström s macroglobulinemia, mycosis fungoides, and marginal zone NHLs, unless there is a suspicion of aggressive transformation. JCO, 2014, Barrington et al,

9 18 F-FDG avidity of lymphoma Variable FDG uptake within same histological subtype FDG uptake ~ Ki67 (r=0.75) Ngeow et al. Annals of Oncology 2009 Shou et al. J Cancer Research and Therapeutics 2012

10 Staging A modified Ann Arbor staging system is recommended; however, patients are treated according to prognostic and risk factors. Suffixes A and B are only required for HL. The designation X for bulky disease is no longer necessary; instead, a recording of the largest tumor diameter is required. JCO, 2014, Cheson et al,

11 Isasi et al. Cancer 2005 Staging Diagnostic performance of FDG PET-CT: meta-analysis (20 studies, 854 pts, >3500 lesions) upstaging : median 13.2% ( ) downstaging: median 7.5% ( ) Detection of extra-nodal sites and bone marrow involvement Detection of involvement of non-enlarged lymph nodes

12 Bone Marrow Involvement BMI detected by BMB is a poor prognostic feature in most lymphomas Prevalence increases with disease stage Identification of indolent, discordant BMI in DLBCL: important for prognosis and follow-up FDG uptake pattern is the most important feature: FOCAL (uni- vs multifocal) HL, DLBCL, Burkitt Lymphoma => high accuracy for PET-CT > biopsy DIFFUSE (homogeneous) Indolent lymphoma, mainly FL Low volume e.g. small cell lymphoma => lower sensitivity for PET-CT < biopsy

13 Bone Marrow Involvement (HL) Diffuse homogeneous BMB - Bifocal BMB- Multifocal BMB +

14 Bone Marrow Involvement (HL) Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? H. J. A. Adams 1, T. C. Kwee 1 *, B. de Keizer 1, R. Fijnheer 2, J. M. H. de Klerk 3, A. S. Littooij 1 & R. A. J. Nievelstein 1 1 Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht; 2 Departments of Hematology; 3 Nuclear Medicine, Meander Medical Center, Amersfoort, The Netherlands Table 5. Results of seven of nine included studies that allowed calculation of sensitivity and specificity Received 28 August 2013; revised 19 October 2013; accepted 24 October 2013 Study (year) Sensitivity (%) Specificity (%) Value 95% CI Value 95% CI Cortés-Romera et al. (2013) [17] Agrawal et al. (2013) [18] Muzahir et al. (2012) [19] El-Galaly et al. (2012) [20] Mittal et al. (2011) [22] Cheng et al. (2011) [23] Moulin-Romsee et al. (2010) [24] Pooled estimate N = 955 patients weighted summary proportion of patients PET/CT negative and BMB positive 1,1% (95% Cl 0,6 2,0%)

15 Bone Marrow Involvement (DLBCL) N = 654 patients ; weighted summary proportion of patients PET/CT negative and BMB positive 3,1% (95% Cl 1,8 5,0%) PET/CT positive and BMB negative 12,5% (95% CI 8,4 17,3%)

16 Bone Marrow Involvement Lugano Classification 1. BMB is not longer indicated for HL. 2. PET may also obviate the need for BMB in DLBCL unless discordant histology is considered important for management. (as a negative PET does not rule out small cell involvement in the marrow) 3. BMB is required for other lymphomas. Cheson BD, J Clin Oncol 2014

17 Spleen Involvement Pathological uptake : Uptake significantly higher than liver uptake (cut-off not defined yet : 1.5 fold liver uptake?) Focal vs. diffuse Focal uptake is likely to indicate spleen involvement in diseases with predominantly focal/multifocal involvement e.g. HL, DLBCL Diffuse uptake should be interpreted according to lymphoma subtype and BM uptake. DD: reactive/hyperplastic changes (HL) vs spleen involvement (SMZL). Increased dimensions of the spleen (max diameter > 13 cm) should be reported (worse prognosis)

18 Spleen Involvement LNH073B trial, 85 patients with DLBCL, PET/CT baseline Different patterns seem to predict different risk levels

19 Spleen Involvement Diffuse uptake with enlargement of spleen Multifocal spleen involvement Image courtesy S. Stroobants

20 Extranodal Involvement - Can affect anyorgan - Lesions with superficial spread (typically in organs e.g. stomach and gut) less detectable and present more frequently as diffuse uptake - CNS lesions: often difficult to detect => MR => Interpretation according to lymphoma subtype DLBCL (n=443) treated with R-CHOP El-Galaly et al. Am. J. Hematology 2015

21 Staging: conclusions PET/CT most accurate technique for staging Improved detection of extra-nodal disease! PET/ceCT preferred to increase accuracy and for more precise measurement of nodal size in clinical trials (one-stop shop) Bone marrow biopsy not required anymore for HL, only in PET equivocal/negative cases in NHL when discordant histology is important for therapy Baseline scan improves response assessment Future: Tumor metabolic volume or other metrics to predict survival

22 Response Assessment baseline 1x R-CHOP 4x R-CHOP 8 x R-CHOP

23 Response Assessment N=260

24 Response Assessment DEAUVILLE CRITERIA 5-point scale 1. No uptake 2. Uptake mediastinum 3. Uptake > mediastinum but liver 4. Moderately increased uptake compared to liver 5. Markedly increased uptake compared to liver and/or new lesions X. New areas of uptake unlikely to be related to lymphoma ** markedly increased uptake is taken to be uptake > 2-3 times the SUV max in normal liver Good interobserver agreement has been reported in HL, DLBCL and FL. JCO, 2014, Barrington et al,

25 Response Assessment Escalation study: high PPV Positive scan Negative scan Score 1 no uptake Score 2 uptake mediastinum Score 3 uptake > mediastinum but liver Score 4: uptake > liver at any site Score 5 uptake > liver and new sites of disease

26 Response Assessment De-escalation study: high NPV Score 1 no uptake Score 2 uptake mediastinum Score 3 uptake > mediastinum but liver Score 4: uptake > liver at any site Score 5 uptake > liver and new sites of disease Positive scan Negative scan

27 Problems Response Assessment - Optical illusion: difference in contrast vs difference in intensity - Distance between lesion and reference organ, target to background

28 Response Assessment Quantitative assessment (SUV) DS4 ~ 1.2 to 1.4 times liver uptake DS5 ~ 2 to 3 times liver uptake Use of SUV max or mean? DLBCL ipet after 2 cycles Interobserver = Interobserver = 0.83 Deauville < 4 (n = 63) SUV > 66% (n = 89) PFS=81% Deauville 4 (n = 51) PFS= 79% P = = 8.58 PFS=59% P = = SUV 66% (n = 25) PFS= 44% IVS: 114 pts, 5 centers, 3 observers, PET 2 cycles; med FU 39 months Itti, 2013, Eur J Nucl Med Mol Imaging

29 Response Assessment Lugano Classification 2014 CATEGORY CMR PMR NMR PMD Lugano Classification Metabolic Response Categories Score 1,2,3* in nodal or extranodal sites with or without a residual mass using 5-DS *In response-adapted trials exploring treatment de-escalation, a more cautious approach may be preferred, judging a score of 3 to be an inadequate response to avoid under treatment. Score 4 or 5, with reduced uptake compared with baseline and residual mass(es) of any size. At interim, these findings suggest responding disease At end of treatment, these findings indicate residual disease Bone marrow: residual marrow uptake > normal marrow but reduced compared with baseline (diffuse changes from chemotherapy allowed). If there are persistent focal changes in marrow with a nodal response, consideration should be given to MRI, biopsy or interval scan. Score 4 or 5 with no significant change in uptake from baseline At interim or end of treatment Score 4 or 5 with an increase in uptake from baseline and /or New FDG-avid foci consistent with lymphoma At interim or end of treatment Cheson et al. JCO 2014

30 Response Assessment:HL UK-NCRI RAPID Trial PET neg : DS 1-2 PET POS ABVD x 1 + IFRT 30 Gy Non inferiority phase III trial ABVD x 3 PET IFRT 30 Gy PET NEG RANDOM No further therapy End Point: <6% in 3-y PFS in non-irradiated vs. irradiated arm : 602 pts.; 420 randomized: IFRT vs. NFT Stage I A or II A (F and UF) by CT scan, no mediastinal bulky Radford J. N Eng J Med 2015; 372: 1598

31 Response Assessment:HL RAPID: Intention to treat analysis Median f-up : 60 months radiotherapy can be avoided for patients with negative PET findings 3 year PFS : 94.6% (PET ve, IFRT), 90.8% (PET ve, NFT) But overall a minority of patients relapse (4%) and OS is equal with salvage RT Radford J N Eng J Med 2015; 372: 1598

32 Response Assessment:HL EORTC H10- in early-stage HL: end point Is chemotherapy alone as effective but less toxic as combined modality treatment in PET2 neg patients? H10F 2 ABVD PET 1 ABVD + INRT 30 Gy (+6) R 2 ABVD P E T ABVD PET - : DS BEACOPPesc + INRT 30 Gy (+6) H10U 2 ABVD PET 2 ABVD + INRT 30 Gy (+6) R 2 ABVD P E T ABVD 2 BEACOPPesc + INRT 30 Gy (+6) Does early change from ABVD to BEACOPP escalated to improve the outcome of PET 2 positive patients?

33 Response Assessment:HL The H10 escalation arm 5 yrs PFS BEACOPPesc+INRT 91% ABVD+INRT 77% More aggressive treatment in selected patients improve the chance of a cure HR (95% CI) = 0.42 (0.23, 0.74); p=0.002 * Does early change from ABVD to BEACOPP escalated to improve the outcome of PET 2 positive patients?

34 Response Assessment:HL 2y-PFS escbeacopp = 91.6% ABVD = 88.3% «After 2escBEACOPP, reduction of therapy to ABVD achieve in PET-2 negative pts an equivalent outcome than standard escbeacopp» Casasnovas O. : Blood 2015; 126(23), Abstr. 577

35 Response Assessment: DLBCL Pre-Rituximab era Spaepen K, Ann Oncol 2002

36 Response Assessment: DLBCL Rituximab era Induction Chemotherapy (4 cycles) (R)-CHOP/3w (> 60y) R-ACVPB/2w ACVBP/ACE Baseline PET 2 N=90 PET 4 N=80 Comparison of PET results after 2 and 4cycles 13 patients PET2 positive PET4 negative (33%) Patients that were PET negative after 2 cycles remained PET negative after 4 Inflammatory response mimics residual disease Haioun et al Blood 2005

37 Response Assessment: DLBCL PFS according to response at I-PET and F-PET. Interim PPV 82 % NPV 100 % Using Deauville Score 1,2 3 to define CMR At END End Pregno P et al. Blood by American Society of Hematology

38 Response Assessment: DLBCL ipet escalation PETAL Trial 853 evaluable patients, 57 centres ipet (2 cycles R-CHOP)( SUVmax >66%) ipet neg proceed R-CHOP ipet pos B-ALL (Burkitt protocol) FU=33 months PET-ve 2y-TTF 79% vs 47% PET+ve Abstract ASH 2014, Dührsen et al.

39 Response Assessment: FL Interim 2-yr PFS PET-ve 86% vs 61% PET +ve End Deauville score 1-3 best to define CMR Dupuis et al. JCO 2012

40 Response Assessment: FL Conclusion: no evidence for i-pet in FL outside clinical trials Adams H et al K, Ann Hematol 2016

41 Response Assessment: FL Conclusion: suggest evidence to predict PFS and OS, but studies suffer from biases Adams H et al K, Ann hematol 2016

42 Surveillance Most relapses occur within first months No consensus on imaging surveillance strategy unclear if early treatment of subclinical relapse improves survival Frequency and duration depending on risk of relapse Is PET/CT better than CT? Higher cost Radiation burden (PET/low dose CT not worse than diagnostic CT) PET higher FPR (~ 20%), CT lower sensitivity

43 Surveillance Picardi M Radiology 2014; 272: 262

44 Surveillance Lugano Classification PET not routinely recommended Only in selected cases Equivocal end-of-treatment High risk of relapse Clinical suspicion

45 Staging PET TAKE HOME MESSAGES - most accurate technique - perform BMB only when PET is negative/equivocal and if it will impact patient management - recommended for accurate response assessment - limited vs extended disease, quantitative parameters (future?) Interim PET - usually as part of clinical trial - HL: -NHL: * evidence for PET-adapted treatment (DS 4/5: intensify) * not clear whether to start with strong chemo and de-escalate or vice versa * unsufficient evidence for PET-adapted treatment intensification except in non responding lesions compared to baseline

46 End-of-treatment PET TAKE HOME MESSAGES - standard of care in all FDG-avid lymphoma subtypes - DS 4/5 = chemorefractory disease => biopsy before salvage treatment - no additional radiotherapy in HL with CMR Surveillance PET - no routine use in clinical practice: high FP! - only in case of equivocal EOT PET, high risk pts or clinical suspicion - confirm PET positive lesions prior to any salvage treatment