a beginner’s guide to pet in lymphoma · high rates of glycolysis. •overexpression of glut-1....

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.


DLBCL & PCP INFECTION


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






Category Definition






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.


Baseline

Stage IV DLBCL

Post x6 R-CHOP

PMR – Deauville 5

3 month follow-up PET-CT

?


Baseline Post x6 R-CHOP 3 month follow-up PET-CT

CMR - Deauville 1X


• 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

a beginner’s guide to pet in lymphoma · high rates of glycolysis. •overexpression of glut-1....

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