F. Courbon

Interobserver Agreement of Qualitative Analysis and Tumor Delineation of 18F-Fluoromisonidazole and 3′-Deoxy-3′-18F-Fluorothymidine PET Images in Lung Cancer

As the preparation phase of a multicenter clinical trial using 18F-fluoro-2-deoxy-d-glucose (18F-FDG), 18F-fluoromisonidazole (18F-FMISO), and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) in non–small cell lung cancer (NSCLC) patients, we investigated whether 18 nuclear medicine centers would score tracer uptake intensity similarly and define hypoxic and proliferative volumes for 1 patient and we compared different segmentation methods. Methods: Ten 18F-FDG, ten 18F-FMISO, and ten 18F-FLT PET/CT examinations were performed before and during curative-intent radiotherapy in 5 patients with NSCLC. The gold standards for uptake intensity and volume delineation were defined by experts. The between-center agreement (18 nuclear medicine departments connected with a dedicated network, SFMN-net [French Society of Nuclear Medicine]) in the scoring of uptake intensity (5-level scale, then divided into 2 levels: 0, normal; 1, abnormal) was quantified by κ-coefficients (κ). The volumes defined by different physicians were compared by overlap and κ. The uptake areas were delineated with 22 different methods of segmentation, based on fixed or adaptive thresholds of standardized uptake value (SUV). Results: For uptake intensity, the κ values between centers were, respectively, 0.59 for 18F-FDG, 0.43 for 18F-FMISO, and 0.44 for 18F-FLT using the 5-level scale; the values were 0.81 for 18F-FDG and 0.77 for both 18F-FMISO and 18F-FLT using the 2-level scale. The mean overlap and mean κ between observers were 0.13 and 0.19, respectively, for 18F-FMISO and 0.2 and 0.3, respectively, for 18F-FLT. The segmentation methods yielded significantly different volumes for 18F-FMISO and 18F-FLT (P < 0.001). In comparison with physicians, the best method found was 1.5 × maximum SUV (SUVmax) of the aorta for 18F-FMISO and 1.3 × SUVmax of the muscle for 18F-FLT. The methods using the SUV of 1.4 and the method using 1.5 × the SUVmax of the aorta could be used for 18F-FMISO and 18F-FLT. Moreover, for 18F-FLT, 2 other methods (adaptive threshold based on 1.5 or 1.6 × muscle SUVmax) could be used. Conclusion: The reproducibility of the visual analyses of 18F-FMISO and 18F-FLT PET/CT images was demonstrated using a 2-level scale across 18 centers, but the interobserver agreement was low for the 18F-FMISO and 18F-FLT volume measurements. Our data support the use of a fixed threshold (1.4) or an adaptive threshold using the aorta background to delineate the volume of increased 18F-FMISO or 18F-FLT uptake. With respect to the low tumor-on-background ratio of these tracers, we suggest the use of a fixed threshold (1.4).

Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study

PURPOSEnTo assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma.nnnPATIENTS AND METHODSnThis multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently.nnnRESULTSnThirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia.nnnCONCLUSIONnTemozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18 F-Misonidazole PET/CT in Patients with Non–Small Cell Lung Carcinoma (RTEP5 Study)

See an invited perspective on this article on page 1043. This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non–small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO–positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO–positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%–71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO–positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77–0.96) and 0.63 (95% CI, 0.49–0.74), respectively. DFS was longer in the 18F-FMISO–negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

Staging, Restaging, and Treatment Response Assessment in Lymphomas: What We Should Know

administered, DXR dose-dependently increased myocardial 18F-FDG accumulation. Second, as suggested by Finessi et al. in their previous study (6), the extra-steroid administration might be a strong, independent thought ‘‘transient’’ variable able to affect myocardial 18F-FDG accumulation. However, in our retrospective analysis, left-ventricular (LV) SUV was significantly increased in DXR-treated patients with respect to controls at the third PET study but remained persistently elevated 6 mo after chemotherapy (and eventually extra-steroid) discontinuation. Finally, and more importantly, when we focused on adriamycin, bleomycin, vincristine, dacarbazine–treated patients who accepted to undergo a later clinical evaluation, the occurrence of DXR-induced cardiotoxicity was significantly related to lower values of LV-SUVat baseline, in which patients did not received any therapy. Altogether these observations seem to indicate that whatever its degree, the effect of cortisone therapy should have been transient and independent from baseline condition.

Intérêt de la TEP/TDM 18F-FCH comme marqueur prédictif de la toxicité hématologique du Radium223 dans les cancers prostatiques métastatiques osseux

Introduction Une proportion importante de patients porteurs d’un adenocarcinome prostatique developpe des metastases, ainsi qu’une resistance a la castration hormonale. Dans l’essai ASLYMPCA, le Radium223 (Ra223) a montre une amelioration de la survie globale. C’est neanmoins un traitement onereux, peu disponible et dont la toxicite hematologique est parfois importante. La selection des patients profitant au mieux du traitement est donc importante. L’objectif principal de notre travail etait de rechercher un biomarqueur TEP/TDM 18F-FCH permettant de predire le risque de complications hematologiques du Ra223. L’objectif secondaire etait d’etudier l’impact d’une TEP/TDM 18F-FCH pre-therapeutique sur l’initiation du traitement. Materiels et methodes Tous les patients se voyant proposer une radiotherapie interne vectorisee par Ra223xa0en RCP ont ete inclus retrospectivement. Une TEP/TDM 18F-FCH a ete realisee avant traitement pour evaluer les contre-indications au traitement et le volume osseux metastatique. Un nouveau biomarqueur a ete calculexa0: le RVV (volume tumoral osseux dont le SUV ≥3,4/volume osseux total de densite >160xa0HU). L’interet de la TEP initiale sur l’initiation du traitement a egalement ete analyse. Resultats Dix-huit patients ont ete inclus entre janvier 2015xa0et juin 2016. Six patients (33xa0%) ont ete recuses du fait d’une contre-indication au traitement par Ra223. Les causes d’exclusion etaient l’atteinte ganglionnaire/viscerale (17xa0%), un volume osseux trop important (5xa0%), mais le plus souvent mixte (11xa0%). Huit patients ont finalement beneficie du traitement et 4xa0n’ont pas desire poursuivre la prise en charge. Malgre cette selection stricte, 4xa0patients (50xa0%) ont presente une toxicite hematologique avec 5xa0cytopenies de grade 2. Le RVV etait significativement correle a la diminution du taux d’hemoglobine r xa0=xa00,88 ( p xa0=xa00,004). Pour la diminution de la numeration plaquettaire r etait de 0,88 ( p xa0=xa00,004) et pour la diminution de la formule leucocytaire r etait de 0,44 ( p xa0=xa00,27). L’aire sous la courbe ROC etait de 0,75xa0pour un meilleur seuil RVV a 7,1 ( p xa0=xa00,26). Conclusion L’ensemble de ces donnees montre l’interet de la TEP/TDM a la 18F-FCH pour la selection des patients relevables du traitement par Ra223. Cet examen permet un bilan a la fois ganglionnaire, visceral et quantitatif de l’atteinte osseuse. Le RVV developpe dans ce travail pourrait etre integre a la discussion pre-therapeutique comme biomarqueur predictif de toxicite hematologique.