A BEGINNER’S GUIDE TO PET IN LYMPHOMADr Manil Subesinghe – Clinical Lecturer in PET imaging
Lymphoma Management Course – 25th June 2018
OVERVIEW
• Basic concepts
• PET-CT, FDG uptake, Image acquisition, Radiation dose
• Lymphoma guidelines: Lugano Classification
• RCR/RCP indications for PET-CT in Lymphoma
• Staging
• Interim PET-CT (iPET-CT)
• End of treatment PET-CT (ePET-CT)
BASIC CONCEPTS – WHAT IS PET-CT?
• PET: Positron Emission Tomography
• Proton-rich radionuclides decay by
positron emission.
• Annihilation reaction.
• Coincidence detection.
• Cyclotron produced radionuclides:
• 11C, 13N, 15O, 18F, 64Cu, 124I, 89Zr.
• 18F – 110 minutes (t1/2).
BASIC CONCEPTS – FDG UPTAKE
• Radiopharmaceutical = radionuclide
+ organic molecule.
• 18F-FDG: 2-deoxy-2-[18F]-D-glucose.
• Warburg effect:• Tumour cells generate energy via non-
oxidative/anaerobic metabolism. i.e.
high rates of glycolysis.
• Overexpression of GLUT-1.
• Increased levels of hexokinase.
• Reduced level of glucose-6-phosphatase.
BASIC CONCEPTS – FDG UPTAKE
DLBCL & PCP INFECTION
BASIC CONCEPTS – FDG UPTAKE
GASTRIC DLBCL
&
LUNG CANCER
Non-fasted, i.e. hyperinsulinaemic state
BASIC CONCEPTS – IMAGE ACQUISITION
• 4-6hr fast prior to 18F-FDG injection.
• Can drink plain water.
• Avoid strenuous activity 24hrs prior.
• Take your regular medication.
• 60min uptake period.
• Rest comfortably.
• Empty bladder prior to scanning.
• CT scan ~ <30s. PET scan ~ 30min.
• Avoid close contact with friends and
relatives, for minimum of 4hrs post-injection.
BASIC CONCEPTS – IMAGE ACQUISITION
BASIC CONCEPTS – RADIATION DOSE
• Radiation = emission or transmission of energy in the form of waves or particles
through space or through a material medium.
BASIC CONCEPTS – RADIATION DOSE
• Radiation doses in medicine are closely controlled (As Low As Reasonably Possible – ALARP).
• FDG PET-CT dose: 14mSv nationally1 (400MBq of 18F-FDG – 7.6 mSv, CT – 6.5mSv).
• 5 years of background radiation (~ 2.7mSv/year).
• UK Background radiation ~ 2.7mSv/year (Cornwall ~ 7.8mSv/year (radon)2.
• 1000 chest x-rays (chest x-ray ~ 0.014mSv).
• 175 transatlantic flights (transatlantic flight ~ 0.08mSv).
• Lifetime risk of developing cancer is 1 in 2, i.e. 50%3.
• Each PET-CT examination confers an additional risk of fatal cancer of 1 in 1500, i.e. 0.07%
in 16-69 year olds4.
1. Iball et al. Nucl Med Commun 2017; 38: 459-470.2. https://www.gov.uk/government/publications/ionising-radiation-dose-comparisons/ionising-radiation-dose-comparisons3. http://www.cancerresearchuk.org/health-professional/cancer-statistics/risk/lifetime-risk4. https://www.gov.uk/government/publications/medical-radiation-patient-doses/patient-dose-information-guidance
LYMPHOMA GUIDELINES
LYMPHOMA GUIDELINES
• 1987: First article on PET in
lymphoma5.
• 67Ga-citrate vs. 18F-FDG PET.
• 5 patients with NHL pre-treatment.
• 4 positive 18F-FDG PET scans but
only 2 positive 67Ga-citrate scans.
• 18F-FDG PET more sensitive than 67Ga-citrate for NHL detection.
67Ga-citrate 18F-FDG
5. Paul et al. JNM 1987; 28: 288-292.
LYMPHOMA GUIDELINES
• Pre-1999: Widespread heterogeneity.
• 1999: International Working Group (IWG)6 published International Workshop
Criteria (IWC) for NHL (adopted by HL groups).
• 2007: International Harmonisation Project (IHP)7:
• Inclusion of FDG PET for end of treatment response assessment.
• 2011-2014: The Lugano Classification8,9.
• September 2014: Journal of Clinical Oncology publication.
6. Cheson BD et al. J Clin Oncol 1999; 17: 1244-1253.7. Cheson BD et al. J Clin Oncol 2007; 27: 579-586.8. Barrington et al. J Clin Oncol 2014; 32: 3048-3058.9. Cheson BD et al. J Clin Oncol 2014; 32: 3059-3067.
LUGANO CLASSIFICATION
Barrington et al. J Clin Oncol 2014; 32: 3048-30588 Cheson et al. J Clin Oncol 2014; 32: 3059-30679
LUGANO CLASSIFICATION
• PET-CT is most effective in:• Hodgkin’s Lymphoma (HL). • Aggressive NHL, e.g. DLBCL, Burkitt’s lymphoma.• Follicular Lymphoma (FL).• Some T-cell Lymphomas.
• Staging, interim assessment (HL +/- DLBCL), end of treatment assessment.
• PET-CT provides improved detection of small involved nodes and extranodal sites of disease, not identifiable on CT10.
• Increased number of sites of disease upstaging.
• Results in changes in patient management (especially limited stage FL).
10. Schaefe et al. Radiology 2004;232:823-829.
STAGING – FL
STAGE I → STAGE IV
LUGANO CLASSIFICATION – BONE MARROW BIOPSY
• Routine bone marrow biopsy (BMB) not required for HL
and most cases of DLBCL.
• HL11: 950pts - Sensitivity: 96.9%, Specificity: 99.7%.
• 1.1% false negative PET-CT.
• Does not change risk assessment or treatment status.
• DLBCL12: 654pts – Sensitivity: 88.7%, Specificity: 99.8%.
• 3.1% false negative PET-CT.
• Low volume disease (<20% marrow involvement)
• Indolent lymphoma.
• 12.5% PET-CT positive/negative BMB.
11. Adams et al. Annals Oncol 2014; 25: 921-927.12. Adams et al. EJNMMI 2014; 41: 565-574.
LUGANO CLASSIFICATION – 5 POINT SCALE (5-PS)
• FDG PET-CT for response assessment
including interim (iPET-CT) and end of
treatment assessment (ePET-CT).
• Utilisation of the 5-point scale, i.e.
Deauville score for PET-CT reporting.
• 2007: IHP criteria for end of treatment
assessment7.
• 2007: Gallamini et al13 – minimal residual
uptake (MRU).
• 2009: 1st International Workshop on PET
in Lymphoma, Deauville, France.
Category Definition
1 No uptake, i.e. indiscernible from background level
2 Uptake ≤ mediastinal blood pool (MBP)
3 Uptake > MBP ≤ liver
4 Uptake moderately higher than liver
5 Uptake markedly greater than liver and/or new lesions
7. Cheson et al. J Clin Oncol 2007; 27: 579-586.13. Gallamini et al. J Clin Oncol 2007; 25: 3746-3752.
• Improve positive predictive value of iPET-CT.• Simple and reproducible.• Graded visual assessment reflects continuum of
FDG uptake.• Flexibility to change threshold between good and
poor response to explore response-adaptive strategies.
Category Definition
1 No uptake, i.e. indiscernible from background level
2 Uptake ≤ mediastinal blood pool (MBP)
3 Uptake > MBP ≤ liver
4 Uptake moderately higher than liver
5 Uptake markedly greater than liver and/or new lesions
Category Definition
1 No uptake, i.e. indiscernible from background level
2 Uptake ≤ mediastinal blood pool (MBP)
3 Uptake > MBP ≤ liver
4 Uptake moderately higher than liver
5 Uptake markedly greater than liver and/or new lesions
5-PS: SCORE 1
5-PS: SCORE 2
5-PS: SCORE 3
5-PS: SCORE 4
5-PS: SCORE 5
Partial Metabolic Response (PMR)
Score 5
Progressive Metabolic Disease (PMD)
Score 5
RCR/RCP INDICATIONS FOR PET-CT IN LYMPHOMA
INDICATIONS FOR PET-CT IN LYMPHOMA
STAGING – HL
STAGE I → STAGE III
STAGING – BROWN FAT
STAGING – DLBCL
STAGE IV DLBCL
RIGHT FEMORAL NECK FRACTURE
STAGING - OTHER INDICATIONS
Identification of suitable biopsy site in patients with low-grade lymphoma in whom
there is suspected high grade transformation.
Grade I FL
SUVmax 42.3
SUVmax 6.3
Laparoscopic biopsy: DLBCL
INTERIM ASSESSMENT
• Interim PET-CT (iPET-CT) is now well established in the management of HL.
• Strong prognostic indicator; better than IPS or response on interim CECT.
• Several trials including UK based trials, e.g. RATHL14, support management
changes based upon the iPET-CT results in HL.
• iPET-CT in DLBCL evidence is more variable;
• It is a good prognostic indicator15,16, although end of treatment PET-CT may be
stronger predictor16.
• Treatment intensification not associated with improved outcome and is
associated with more toxicity16.
14. Johnson et al. NEJM 2016; 374: 2419-2429.15. Carr et al. J Nucl Med 2014;55:1936-1944.16. Duhrsen et al. J Clin Oncol 2018 DOI: 10.1200/JCO.2017.76.8093
RATHL study14 (stage IIB-IV)
14. Johnson et al. NEJM 2016; 374: 2419-2429.
5-PS: Score 1-3, i.e. CMR
ABVD or AVD
Stop Bleomycin
5-PS: Score 4-5
BEACOPP-14 or eBEACOPP
eBEACOPP/BEACOPP-14
3yr PFS: 67.8%
3yr OS: 87.8%
x4 ABVD
3yr PFS: 85.7%
3yr OS: 97.2%
x4 AVD
3yr PFS: 84.4%
3yr OS: 97.6%
INTERIM PET-CT
BLEOMYCIN LUNG
INTERIM PET-CT – TIMING
• Each cycle of ABVD lasts 28 days with 2 chemotherapy infusions in each cycle
(day 1 and day 15).
• The peak chemotherapy inflammatory response is 7-10 days after chemotherapy
infusion17.
• Imaging earlier risks reduced sensitivity, i.e. false negative result because of
chemotherapeutic stunning of cellular glucose metabolism.
• iPET-CT should be scheduled for day 11-13 of the second chemotherapy
administration (cycle 2B), i.e. day 25-27 of cycle 218.
17. Juweid et al. J Clin Oncol 2007; 21: 571-578.18. Gallamini et al. Blood 2012; 120: 4913-4920.
INTERIM PET-CT – TIMING
DAY 7 OF CYCLE 2B – TOO EARLY
INTERIM PET-CT
RIGHT LOWER LOBE PE
END OF TREATMENT PET-CT
• End-of-treatment remission assessment
is more accurate with PET-CT than CT,
especially in CRu or PR in HL, DLBCL
and FL.
• PET-CT is of particular value in
assessment of response of extra-nodal
disease, imperceptible on CT.
• Timing of ePET-CT:
• Minimum of 3 weeks but preferably 6-8
weeks post-chemotherapy17.
• 3 months post-radiotherapy18.
17. Juweid et al. J Clin Oncol 2007; 21: 571-578.18. Boellaard et al. Eur J Nucl Med Mol Imaging 2010; 37: 181-200.
END OF TREATMENT PET-CT
Baseline
Stage IV DLBCL
Post x6 R-CHOP
PMR – Deauville 5
3 month follow-up PET-CT
?
END OF TREATMENT PET-CT
Baseline Post x6 R-CHOP 3 month follow-up PET-CT
CMR - Deauville 1X
END OF TREATMENT PET-CT
• Stage IV DLBCL diagnosed in liver and
spleen.
• Interim CECT post x4 R-CHOP – 4 months.
• End of treatment CECT x6 R-CHOP – 7
months.
• PET-CT – 8 months – Deauville 5.
• CECT – 10 months.
• CECT – 22 months.
SUMMARY
• FDG PET-CT is a hybrid imaging technique that combines the benefits of both functional
and anatomical imaging.
• Specifics relating to image acquisition require understanding by both patient and
referring clinician.
• FDG uptake is non-specific (benign vs. malignant, differentiating types of malignancies).
• Histological confirmation of disease should always be considered.
• FDG PET-CT is established in the management of FDG avid lymphomas.
• Lugano classification, RCR/RCP guidelines.
• PET-directed therapy now part of routine clinical practice in HL.
Thank you
Any questions?
Email: [email protected]
: @manil1980
http://www.sthpetcentre.org.uk :@KCLGSTTpet