Pediatric Hodgkin Lymphoma: Predictive value of interim 18F-FDG PET/CT in therapy response assessment

Abstract

We investigated the prognostic value of interim F-FDG PET/CT (PET-2) in pediatric Hodgkin lymphoma (pHL), evaluating both visual and semiquantitative analysis.Thirty pHL patients (age ≤16) underwent serial F-FDG PET/CT: at baseline (PET-0), after 2 cycles of chemotherapy (PET-2) and at the end of first-line chemotherapy (PET-T). PET response assessment was carried out visually according to the Deauville Score (DS), as well as semiquantitatively by using the semiquantitative parameters reduction from PET-0 to PET-2 (ΔΣSUVmax0-2, ΔΣSUVmean0-2). Final clinical response assessment (outcome) at the end of first-line chemotherapy was the criterion standard, considering patients as responders (R) or nonresponders (NR). Disease status was followed identifying patients with absence or relapsed/progression disease (mean follow-up: 24 months, range 3-78).Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of visual and semiquantitative assessment were calculated; furthermore, Fisher exact test was performed to evaluate the association between both visual and semiquantitative assessment and outcome at the end of the first-line chemotherapy. The prognostic capability of PET-2 semiquantitative parameters was calculated by ROC analysis and expressed as area under curve (AUC). Finally, progression-free survival (PFS) was analyzed according to PET-2 results based on the 5-point scale and semiquantitative criteria, using the Kaplan-Meier method.Based on the outcome at the end of first-line chemotherapy, 5 of 30 patients were NR, the remnant 25 of 30 were R. Sensitivity, specificity, PPV, NPV, and accuracy of visual analysis were 60%,72%,30%,90%,70%; conversely, sensitivity, specificity, PPV, NPV, and accuracy of semiquantitative assessment were 80%, 92%, 66.7%, 95.8%, 90%. The highest AUC resulted for ΔΣSUVmax0-2 (0.836; cut-off <12.5; sensitivity 80%; specificity 91%). The association between ΔΣSUVmax0-2 and outcome at the end of first-line chemotherapy resulted to have a strong statistical significance (P = 0.0026). Both methods demonstrated to influence PFS, even if the semiquantitative assessment allowed a more accurate identification of patients with a high risk of treatment failure (P = 0.005).Our preliminary results showed that PET-2 visual assessment, by using Deauville criteria, can be improved by using the semiquantitative analysis. The SUV max reduction (ΔΣSUVmax0-2) evaluation might provide a support for the interpretation of intermediate scores, predicting with good confidence those patients who will have a poor outcome and require alternative therapies.

Figure 1

¹⁸F-FDG PET/CT performed in a 16-year-old female affected by Nodular Sclerosis Hodgkin lymphoma at stage IIIA. (A) PET-0 (coronal view): intense ¹⁸F-FDG uptake in the upper diaphragmatic lymph nodal basins (red arrows), considered involved by disease. (B) PET-2 (coronal view): residual involvement in the mediastinal and axillary lymph nodes (red arrows) that showed moderately increased ¹⁸F-FDG uptake compared to the liver. (C) Overlapped PET-0 (black areas)/PET-2 (yellow areas): the direct comparison of the 2 images provides an intuitive response evaluation. ¹⁸F-FDG PET/CT = fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography; PET-0 = PET baseline; PET-2 = PET ad interim.

Figure 2

¹⁸F-FDG PET/CT performed in a 16-year-old female affected by Nodular Sclerosis Hodgkin Lymphoma at stage IIIA, at baseline (A–D) and after 2 cycles of chemotherapy (E–H). (A, E) MIP whole-body image of PET-0 and PET-2, respectively. VOI was drawn semiautomatically on each nodal basins with pathologically increased ¹⁸F-FDG uptake visually detected on PET-0, and still present on PET-2, in the coronal (B, F), sagittal (C, G), and transaxial plans (D, H), respectively (red areas). The Σ of SUVmax and SUVmean of each VOI at baseline were 20.60 and 11.40, respectively, whereas the Σ of SUVmax and SUVmean of each VOI at PET-2 were: 9.90 and 6.50, respectively. ΔΣSUVmax 0–2 and ΔΣSUVmean 0–2 resulted to be: 10.70 and 4.90, respectively. Abbreviations: ¹⁸F-FDG PET/CT = fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography; PET-0 = PET baseline; PET-2 = PET ad interim; MIP = maximum-intensity-projection; VOI = volume of interest; SUVmax = maximum standardized uptake value; SUVmean = mean standardized uptake value; Σ = sum; Δ = decrease; ΔΣSUVmax 0–2 = decrease of the sum of SUVmax from PET-0 to PET-2; ΔΣ SUVmean 0–2 = decrease of the sum of SUVmean from PET-0 to PET-2.

Figure 3

ROC curves of the semiquantitative PET-2 parameters. The highest AUC resulted for ΔΣSUVmax 0–2 (0.836; cut-off <12,5, sensitivity 80%, specificity 91%) that proved to be suitable to separate good from poor responder patients at the end of first-line of treatment. ΔΣSUVmax 0–2 = decrease of the sum of SUVmax from PET-0 to PET-2, ΔΣSUVmean 0–2 = decrease of the sum of SUVmean from PET-0 to PET-2, AUC = area under curve, ROC = receiver-operating-characteristics.

Figure 4

(A–C) ¹⁸F-FDG PET/CT performed in a 16-year-old male affected by Mixed Cellularity Hodgkin lymphoma at stage IIB. (A) PET-0 (MIP whole-body image): intense ¹⁸F-FDG uptake in the upper diaphragmatic lymph nodal basins, considered involved by disease; (B) PET-2 (MIP whole-body image): residual involvement in the neck and mediastinal lymph nodes (red arrows) that showed a mild ¹⁸F-FDG uptake, greater than mediastinum but not greater than liver. Visual analysis considered the patient negative (DS = 3), whereas the semiquantitative analysis considered the patient as a poor responder (ΔΣSUVmax 0–2 = 9,70); (C) PET-T (MIP whole-body image): persistent and new sites of upper diaphragmatic lymph node involvement. Patient was defined nonresponder at the end of the first-line chemotherapy; he died at 40 months’ follow-up despite of additional treatment approach. ΔΣSUVmax 0–2 = decrease of the sum of SUVmax from PET-0 to PET-2, ¹⁸F-FDG PET/CT = fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, DS = Deauville score, MIP = maximum-intensity-projection, PET-0 = PET baseline, PET-2 = PET ad interim, PET-T = at the end of first-line chemotherapy.

Figure 5

(A–C) ¹⁸F-FDG PET/CT performed in a 9-year-old male affected by nodular sclerosis Hodgkin lymphoma at stage IIIB. (A) PET-0 (MIP whole-body image): intense ¹⁸F-FDG uptake in the upper diaphragmatic lymph nodal basins, considered involved by disease; (B) PET-2 (MIP whole-body image): residual involvement in the neck and axillary lymph nodes (red arrows) that showed moderately increased of ¹⁸F-FDG uptake compared to the liver. Visual analysis considered the patient as positive (DS = 4), whereas the semiquantitative analysis considered the patient as a good responder (ΔΣSUVmax 0–2 = 31,00); (C) PET-T (MIP whole-body image): negative. Patient was considered responder at the end of first-line chemotherapy and still responder at 10 months’ follow-up. ¹⁸F-FDG PET/CT = fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, ΔΣSUVmax 0–2 = decrease of the sum of SUVmax from PET-0 to PET-2, DS = Deauville score, MIP = maximum-intensity-projection, PET-0 = PET baseline; PET-2 = PET ad interim, PET-T = at the end of first-line chemotherapy .

Figure 6

Kaplan–Meier plot showing PFS for PET-2 results according to the visual analysis (Deauville 5-point-scale). Patients with a visually positive PET-2 showed a lower PFS than PET-2-negative patients (Log rank = 6.483, P = 0.011). DS = Deauville score, PET-2 = PET ad interim, PFS = progression-free survival.

Figure 7

Kaplan–Meier plot showing PFS for PET-2 results according to the semiquantitative assessment (ΔΣSUVmax 0–2). Patients who did not reach a ΔΣSUVmax 0–2 >12.5 had a significantly lower PFS than those who did (Log rank = 7.948, P = 0.005). The semiquantitative assessment allowed a more accurate identification of patients with a high risk of treatment failure than visual analysis. ΔΣSUVmax 0–2 = decrease of the sum of SUVmax from PET-0 to PET-2, PET-2 = PET ad interim, PFS = progression-free survival.