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PURPOSE: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [18F]FDG PET (PET) in follicular lymphoma patients. METHODS: Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS). RESULTS: Overall, 807 follicular lymphoma patients-52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3-5)-were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4-5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%-70%). The 5-yr PFS rate for PET neg (DS1-3) and PET pos (DS4-5) patients was 71% (95%CI: 67%-75%) and 36% (95%CI: 25%-46%), respectively, with HR 3.49 (95%CI: 2.57-4.72). Five-year PFS was worse as DS increased, with 74% (70%-78%), 58% (48%-67%; HR 1.71; p = 0.001)] and 36% (25%-46%; HR 3.88; p < 0.001) in DS1-2, DS3 and DS4-5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%-96%), with 96% (95%CI: 94-97) and 82% (95%CI: 72%-89%) in EOI PET negative (DS1-3) and positive (DS4-5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1-2 with high FLIPI-2 (3-5) experienced worse OS than patients with DS1-2 and low FLIPI-2 (1-2) (p = 0.003). CONCLUSION: This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1-2 patients.
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OBJECTIVES: To assess the incidence (1 year) and the cumulative incidence (3 years) of the condition of patients accruing cumulative effective doses (CED) of ≥ 100 mSv and their variability among different hospitals. To establish and validate a reference level for the CED in patients with recurrent exposures (RERL) and provide a RERL value. METHODS: Data of CT exposure was collected in 9 similar hospitals. The database included 294,222 patient*years who underwent 442,278 CT exams in 3 years. The incidence proportion of patients with CED ≥ 100 mSv in a given year (I100;1) and the 3-year cumulative incidence of patients with CED ≥ 100 mSv over 3 consecutive years (I100;3) were calculated and compared among different institutions. RESULTS: I100;1 ranged from a minimum of 0.1% to a maximum of 5.1%. The percentage of recurrent patients was quite uniform among centres ranging from 23 to 38%. The I100;3 ranged from a minimum of 1.1 to 11.4%. There was a strong positive correlation between the third quartile values of yearly CED and yearly incidence (r = 0.90; R2 = 0.81; p < 0.0001). RERL value in our study was found at 34.0 mSv. CONCLUSION: The management of patients with recurrent exposures is highly variable among hospitals leading to a 50-fold variation in I100;1 and to a tenfold variation in I100;3. RERL could be established and used by taking as a RERL quantity the CED and as a RERL value the 75th percentile of the third quartiles of the distribution of the yearly CED obtained by surveying different hospitals. CLINICAL RELEVANCE STATEMENT: This is the first ever multicentre study that quantifies recurrent exposures in terms of incidence and cumulative incidence of patients with CED ≥ 100 mSv. RERL establishment and use could benefit the optimisation of radioprotection of patients with recurrent exposures. KEY POINTS: This is the first multicentre study estimating yearly incidence and 3-year cumulative incidence of patients with cumulative effective doses ≥ 100 mSv. In this study, a 50-fold inter centre variation between the maximum (5.1%) and the minimum value (0.1%) of yearly incidence of patients with cumulative effective doses ≥ 100 mSv was reported. The range of the 3-year cumulative incidence extended from 1.1 to 11.4% (a tenfold variation) The third quartile of the yearly cumulative effective doses in a centre showed a strong positive correlation with the yearly incidence of patients with cumulative effective doses ≥ 100 mSv, with a potential of being used to set reference levels for recurrent exposures.
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Dosis de Radiación , Tomografía Computarizada por Rayos X , Humanos , Tomografía Computarizada por Rayos X/métodos , Adulto , Incidencia , Femenino , Masculino , Exposición a la Radiación/prevención & control , Valores de Referencia , Protección Radiológica/métodos , Persona de Mediana Edad , RecurrenciaRESUMEN
The Lugano classification for response assessment in lymphoma recommends the use of the 5-point-scale Deauville Score (DS) to assess response evaluation of end-of-treatment FDG-PET/CT (eotPET) in Hodgkin Lymphoma (HL); nevertheless, there is a paucity of data on its accuracy and reproducibility. We focus here on the cohort of advanced stage IIb-IV HL patients enrolled in the HD0607 clinical trial (NCT identifier 00795613) that having had a negative interim PET performed 6 cycles of ABVD (Doxorubicin, Vinblastine, Vincristine and Dacarbazine) and then performed an eotPET. Negative patients were randomized to radiotherapy and no further treatment while positive patients were treated based on local policies. eotPET was re-evaluated independently by two readers evaluated and progression free survival was analysed (PFS). eotPET of 254 patients were analysed. The median follow-up was 43 months. The best receiver operator characteristics cut-off values to distinguish positive and negative patients was 4. The area-under-the-curve was 0.81 (95%CI, 0.70-0.91). Three-years PFS was 0.95 (95% CI 0.90-0.97) in eotPET negative and 0.22 (95% CI 0.11-0.43) in eotPET positive. DS demonstrated a good reproducibility of positivity/negativity between the readers consensus and local site evaluation where the agreement occurred on 95.0% of patients. The present study demonstrates that eotPET is an accurate tool to predict treatment outcome in HL and confirms the appropriateness of the Lugano classification for eotPET evaluation.
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Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18/uso terapéutico , Dacarbazina/uso terapéutico , Vinblastina/uso terapéutico , Doxorrubicina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Reproducibilidad de los Resultados , Bleomicina/uso terapéutico , Tomografía de Emisión de Positrones , Resultado del TratamientoRESUMEN
Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Anciano , Ensayos Clínicos como Asunto , Ciclofosfamida/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Estudios Retrospectivos , Rituximab/administración & dosificación , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
PURPOSE: Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is included in the International Myeloma Working Group (IMWG) imaging guidelines for the work-up at diagnosis and the follow-up of multiple myeloma (MM) notably because it is a reliable tool as a predictor of prognosis. Nevertheless, none of the published studies focusing on the prognostic value of PET-derived features at baseline consider tumor heterogeneity, which could be of high importance in MM. The aim of this study was to evaluate the prognostic value of baseline PET-derived features in transplant-eligible newly diagnosed (TEND) MM patients enrolled in two prospective independent European randomized phase III trials using an innovative statistical random survival forest (RSF) approach. METHODS: Imaging ancillary studies of IFM/DFCI2009 and EMN02/HO95 trials formed part of the present analysis (IMAJEM and EMN02/HO95, respectively). Among all patients initially enrolled in these studies, those with a positive baseline FDG-PET/CT imaging and focal bone lesions (FLs) and/or extramedullary disease (EMD) were included in the present analysis. A total of 17 image features (visual and quantitative, reflecting whole imaging characteristics) and 5 clinical/histopathological parameters were collected. The statistical analysis was conducted using two RSF approaches (train/validation + test and additional nested cross-validation) to predict progression-free survival (PFS). RESULTS: One hundred thirty-nine patients were considered for this study. The final model based on the first RSF (train/validation + test) approach selected 3 features (treatment arm, hemoglobin, and SUVmaxBone Marrow (BM)) among the 22 involved initially, and two risk groups of patients (good and poor prognosis) could be defined with a mean hazard ratio of 4.3 ± 1.5 and a mean log-rank p value of 0.01 ± 0.01. The additional RSF (nested cross-validation) analysis highlighted the robustness of the proposed model across different splits of the dataset. Indeed, the first features selected using the train/validation + test approach remained the first ones over the folds with the nested approach. CONCLUSION: We proposed a new prognosis model for TEND MM patients at diagnosis based on two RSF approaches. TRIAL REGISTRATION: IMAJEM: NCT01309334 and EMN02/HO95: NCT01134484.
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Fluorodesoxiglucosa F18 , Mieloma Múltiple , Humanos , Mieloma Múltiple/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Estudios Prospectivos , RadiofármacosRESUMEN
We investigated the feasibility and activity of an intensified dose-dense ABVD (dd-ABVD) regimen in patients with early-stage unfavorable Hodgkin lymphoma (HL). This prospective, multicenter, phase II study enrolled 96 patients with newly diagnosed, unfavorable stage I or II classical HL. The patients received four cycles of dd-ABVD followed by radiotherapy. Interim PET (PET-2) was mandatory after two courses. Primary endpoints were the evaluation of dd-ABVD feasibility and activity (incidence of PET-2 negativity). The feasibility endpoint was achieved with 48/52 (92.3%) patients receiving > 85% of the programmed dose. The mean dose intensity in the overall patient population (n = 96) was 93.7%, and the median duration of dd-ABVD was 85 days (range, 14-115) versus an expected duration of 84 days. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%). In total, 90 (93.8%) patients showed complete response at the end of treatment. With a follow-up of 80.9 months (3.3-103.2), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 84 months, PFS and OS rates were 88.4% and 95.7%, respectively. No evidence for a difference in PFS or OS was observed for PET-2-negative and PET-2-positive patients. Infections were documented in 8.3% and febrile neutropenia in 6.2% of cases. Four patients died: one had alveolitis at cycle 3, one death was unrelated to treatment, and two died from a secondary cancer. dd-ABVD is feasible and demonstrates activity in early-stage unfavorable HL. The predictive role of PET-2 positivity in early-stage unfavorable HL remains controversial. The study was registered in the EudraCT (reference number, 2011-003,191-36) and the ClinicalTrials.gov (reference number, NCT02247869) databases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Dacarbazina/administración & dosificación , Dacarbazina/uso terapéutico , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Femenino , Enfermedad de Hodgkin/epidemiología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Qualitative assessment using the Deauville five-point Scale (DS) is the gold standard for interim and end-of treatment positron-emission tomography (PET) interpretation in lymphoma. In the present study we assessed the reliability and the prognostic value of different semi- quantitative parameters in comparison with DS for interim PET (iPET) interpretation in Hodgkin lymphoma (HL). METHODS: A cohort of 82 out of 260 patients with advanced stage HL enrolled in the International Validation Study (IVS), scored as 3 to 5 by the expert panel was included in the present report. Two nuclear medicine physicians blinded to patient history, clinical data and treatment outcome reviewed independently the iPET using the following parameters: DS, SUVmax, SUVpeak of the most active lesion, Qmax (ratio of SUVmax of the lesion to liver SUVmax) and Qres (ratio of SUVpeak of the lesion to liver SUVmean). The optimal sensitivity, specificity, positive and negative predictive value to predict treatment outcome was calculated for all the above parameters with the receiver operator characteristics analysis. RESULTS: The prognostic value of all parameters were similar, the best cut-off value being 4 for DS (area under the curve [AUC], 0.81 95% CI: 0.72-0.90), 3.81 for SUVmax (AUC 0.82 95% CI: 0.73-0.91), 3.20 for SUVpeak (AUC 0.86 95% CI: 0.77-0.94), 1.07 for Qmax (AUC 0.84 95% CI: 0.75-0.93) and 1.38 for Qres (AUC 0.84 95% CI: 0.75-0.93). The reproducibility of different parameters was similar as the inter-observer variability measured with Cohen's kappa were 0.93 (95% CI: 0.84-1.01) for the DS, 0.88 (0.77-0.98) for SUVmax, 0.82 (0.70-0.95) for SUVpeak, 0.85 (0.74-0.97) for Qres and 0.78 (0.65-0.92) for Qmax. Due to the high specificity of SUVpeak (0.87) and to the good sensitivity of DS (0.86), upon the use of both parameters the positive predictive value increased from 0.65 of the DS alone to 0.79. When both parameters were positive in iPET, 3-years Failure-Free Survival (FFS) was significantly lower compared to patients whose iPET was interpreted with qualitative parameters only (DS 4 or 5): 21% vs. 35%. On the other hand, the FFS of patients with negative results was not significantly different (88% vs. 86%). CONCLUSIONS: In this study we demonstrated that, combining semi-quantitative parameters with SUVpeak to a pure qualitative interpretation key with DS, it is possible to increase the positive predictive value of iPET and to identify with higher precision the patients subset with a very dismal prognosis. However, these retrospective findings should be confirmed prospectively in a larger patient cohort.
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Fluorodesoxiglucosa F18 , Enfermedad de Hodgkin , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/terapia , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To enhance the positive predictive value (PPV) of chest digital tomosynthesis (DTS) in the lung cancer detection with the analysis of radiomics features. METHOD: The investigation was carried out within the SOS clinical trial (NCT03645018) for lung cancer screening with DTS. Lung nodules were identified by visual analysis and then classified using the diameter and the radiological aspect of the nodule following lung-RADS. Haralick texture features were extracted from the segmented nodules. Both semantic variables and radiomics features were used to build a predictive model using logistic regression on a subset of variables selected with backward feature selection and using two machine learning: a Random Forest and a neural network with the whole subset of variables. The methods were applied to a train set and validated on a test set where diagnostic accuracy metrics were calculated. RESULTS: Binary visual analysis had a good sensitivity (0.95) but a low PPV (0.14). Lung-RADS classification increased the PPV (0.19) but with an unacceptable low sensitivity (0.65). Logistic regression showed a mildly increased PPV (0.29) but a lower sensitivity (0.20). Random Forest demonstrated a moderate PPV (0.40) but with a low sensitivity (0.30). Neural network demonstrated to be the best predictor with a high PPV (0.95) and a high sensitivity (0.90). CONCLUSIONS: The neural network demonstrated the best PPV. The use of visual analysis along with neural network could help radiologists to reduce the number of false positive in DTS. KEY POINTS: ⢠We investigated several approaches to enhance the positive predictive value of chest digital tomosynthesis in the lung cancer detection. ⢠Neural network demonstrated to be the best predictor with a nearly perfect PPV. ⢠Neural network could help radiologists to reduce the number of false positive in DTS.
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Inteligencia Artificial , Procesamiento de Imagen Asistido por Computador , Neoplasias Pulmonares/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Anciano , Algoritmos , Detección Precoz del Cáncer/métodos , Humanos , Modelos Logísticos , Neoplasias Pulmonares/diagnóstico por imagen , Aprendizaje Automático , Persona de Mediana Edad , Redes Neurales de la Computación , Radiología , Reproducibilidad de los Resultados , SemánticaRESUMEN
á : FDG PET/CT (18F-fluoro-deoxy-glucose positron emission tomography/computed tomography) is a useful tool to image multiple myeloma (MM). However, simple and reproducible reporting criteria are still lacking and there is the need for harmonization. Recently, a group of Italian nuclear medicine experts defined new visual descriptive criteria (Italian Myeloma criteria for Pet Use: IMPeTUs) to standardize FDG PET/CT evaluation in MM patients. The aim of this study was to assess IMPeTUs reproducibility on a large prospective cohort of MM patients. MATERIALS AND METHODS: Patients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN® and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff's alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease). RESULTS: Eighty-six patients (211 FDG PET/CT scans) were included in this analysis. Median patient age was 58 years (range, 35-66 years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff's alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4. CONCLUSIONS: IMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway.
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Mieloma Múltiple/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adulto , Anciano , Femenino , Fluorodesoxiglucosa F18 , Humanos , Italia , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Estudios Prospectivos , Radiofármacos , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos XRESUMEN
METHODS: After primary treatment, biochemical relapse (BCR) occurs in a substantial number of patients with prostate cancer (PCa). PET/CT imaging with prostate-specific membrane antigen based tracers (68Ga-PSMA) has shown promising results for BCR patients. However, a standardized image interpretation methodology has yet to be properly agreed. The aim of this study, which was promoted and funded by European Association of Nuclear Medicine (EANM), is to define standardized image interpretation criteria for 68Ga-PSMA PET/CT to detect recurrent PCa lesions in patients treated with primary curative intent therapy (radical prostatectomy or radiotherapy) who presented a biochemical recurrence. In the first phase inter-rater agreement between seven readers from seven international centers was calculated on the reading of 68Ga-PSMA PET/CT images of 49 patients with BCR. Each reader evaluated findings in five different sites of recurrence (local, loco-regional lymph nodes, distant lymph nodes, bone, and other). In the second phase the re-analysis was limited to cases with poor, slight, fair, or moderate agreement [Krippendorff's (K) alpha<0.61]. Finally, on the basis of the consensus readings, we sought to define a list of revised consensus criteria for 68Ga-PSMA PET/CT interpretation. RESULTS: Between-reader agreement for the presence of anomalous findings in any of the five sites was only moderate (K's alpha: 0.47). The agreement improved and became substantial when readers had to judge whether the anomalous findings were suggestive for a pathologic, uncertain, or non-pathologic image (K's alpha: 0.64). K's alpha calculations for each of the five sites of recurrence were also performed and evaluated. First Delphi round was thus conducted. A more detailed definition of the criteria was proposed by the project coordinator, which was then discussed and finally agreed by the seven readers. After the second Delphi round only four cases of disagreement still remained. These were evaluated for a final round, allowing a final agreement table to be written. CONCLUSION: We hope that by developing these consensus guidelines on the interpretation of 68Ga-PSMA PET/CT, clinicians reporting these studies will be able to provide more consistent clinical reports and that within clinical trials, abnormality classifications will be harmonized, allowing more robust assessment of its diagnostic performance.
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Ácido Edético/análogos & derivados , Interpretación de Imagen Asistida por Computador/normas , Oligopéptidos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Consenso , Isótopos de Galio , Radioisótopos de Galio , Humanos , Masculino , Recurrencia , Estándares de ReferenciaRESUMEN
The International Extranodal Lymphoma Study Group (IELSG)-37 is a prospective randomized trial assessing the role of consolidation mediastinal radiotherapy after immunochemotherapy to patients with newly diagnosed primary mediastinal large B-cell lymphoma (PMBCL). It is a positron emission tomography (PET) response-guided study where patients obtaining a complete metabolic response on an end-of-therapy PET-computed tomography (CT) scan evaluated by a central review are randomized to receive radiotherapy or no further treatment. The aims of this study were to measure agreement between reviewers reporting PET-CT scans for this trial and to determine the effect of training upon concordance rates. The review panel comprised 6 experienced nuclear physicians who read PET-CT scans using the 5-point Deauville scale. Interobserver agreement (IOA) was measured at 4 time points: after a blinded review of a "training set" of 20 patients with PMBCL from the previous IELSG-26 study (phase 1); after the first 10 clinical cases enrolled in the IELSG-37 (phase 2); and after 2 further groups of 50 (phase 3) and 40 clinical cases (phase 4). After feedback from the training set and the first 10 cases, a meeting was held to discuss interpretation, and a detailed set of instructions for the review procedure was agreed and acted upon. Between 2012 and 2014, the first 100 patients were reviewed. Using Deauville score 3 as the cutoff for a complete metabolic response, the overall IOA among the reviewers was good (Krippendorff α = 0.72.) The binary concordance between pairs of reviewers (Cohen κ) ranged from 0.60 to 0.78. The IOA, initially moderate, improved progressively from phase 1 to 4 (Krippendorff α from 0.53 to 0.81; Cohen κ from 0.35-0.72 to 0.77-0.87). Our experience indicates that the agreement among "expert" nuclear physicians reporting PMBCL, even using standardized criteria, was only moderate when the study began. However, agreement improved using a harmonization process, which included a training exercise with discussion of points leading to disagreement and compiling practical rules to sit alongside commonly adopted interpretation criteria.
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Linfocitos B/patología , Neoplasias del Mediastino/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Humanos , Neoplasias del Mediastino/patología , Variaciones Dependientes del Observador , Estudios ProspectivosRESUMEN
PURPOSE: To compare the lung nodules' detection of digital tomosynthesis (DTS) and computed tomography (CT) in the context of the SOS (Studio OSservazionale) prospective screening program for lung cancer detection. MATERIALS AND METHODS: One hundred and thirty-two of the 1843 subjects enrolled in the SOS study underwent CT because non-calcified nodules with diameters larger than 5 mm and/or multiple nodules were present in DTS. Two expert radiologists reviewed the exams classifying the nodules based on their radiological appearance and their dimension. LUNG-RADS classification was applied to compare receiver operator characteristics curve between CT and DTS with respect to final diagnosis. CT was used as gold standard. RESULTS: DTS and CT detected 208 and 179 nodules in the 132 subjects, respectively. Of these 208 nodules, 189 (91%) were solid, partially solid, and ground glass opacity. CT confirmed 140/189 (74%) of these nodules but found 4 nodules that were not detected by DTS. DTS and CT were concordant in 62% of the cases applying the 5-point LUNG-RADS scale. The concordance rose to 86% on a suspicious/non-suspicious binary scale. The areas under the curve in receiver operator characteristics were 0.89 (95% CI 0.83-0.94) and 0.80 (95% CI 0.72-0.89) for CT and DTS, respectively. The mean effective dose was 0.09 ± 0.04 mSv for DTS and 4.90 ± 1.20 mSv for CT. CONCLUSIONS: The use of a common classification for nodule detection in DTS and CT helps in comparing the two technologies. DTS detected and correctly classified 74% of the nodules seen by CT but lost 4 nodules identified by CT. Concordance between DTS and CT rose to 86% of the nodules when considering LUNG-RADS on a binary scale.
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Neoplasias Pulmonares/diagnóstico por imagen , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Intensificación de Imagen Radiográfica/métodos , Tomografía Computarizada por Rayos X , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Dosis de Radiación , Interpretación de Imagen Radiográfica Asistida por Computador , Sensibilidad y EspecificidadRESUMEN
PURPOSE: FDG PET/CT is able to detect active disease in patients with multiple myeloma (MM) and can be helpful for staging and assessing therapy response, but no standard interpretation criteria have been proposed for the evaluation of FDG PET/CT in MM. METHODS: A group of Italian nuclear medicine physicians and haematologists met to propose new visual interpretation criteria to standardize FDG PET/CT evaluation in MM patients (Italian Myeloma criteria for PET USe; IMPeTUs) and the reproducibility of these criteria was tested. This Italian multicentre protocol was set up as a subprotocol of EMN02, an international prospective multicentre trial of the European Myeloma Network. The criteria were agreed at multidisciplinary consensus meetings. They include a description of the metabolic state of the bone marrow (BM), number and site of focal PET-positive lesions, the number of osteolytic lesions, and the presence and site of extramedullary disease, paramedullary disease and fractures. A visual degree of uptake was defined for the target lesion and extramedullary lesions according to modified Deauville criteria. MM patients who had undergone FDG PET/CT at baseline (PET-0), after induction (PET-AI) and at the end of treatment (PET-EoT) were enrolled. The patients had been prospectively enrolled in EMN02 and their PET scans were a posteriori reinterpreted in a blinded independent central review process managed by WIDEN®. Five expert nuclear medicine physicians scored the scans according to the new criteria. A case was considered read when four out of the five reviewers completed the report. Concordance among reviewers on different metrics was calculated using Krippendorff's alpha coefficient. RESULTS: A total of 17 consecutive patients were enrolled. On PET-0, the alpha coefficients for the BM score, the score for the hottest focal lesion, the number of focal lesions and the number of lytic lesions were 0.33 and 0.47, 0.40 and 0.32, respectively. On PET-AI, the alpha coefficients were 0.09 and 0.43, 0.22 and 0.21, respectively, and on PET-EoT, the alpha coefficients were 0.07, 0.28, 0.25 and 0.21, respectively. BM was generally difficult to score since grades 2 and 3 are difficult to discriminate. However, since neither of the two grades is related to BM myelomatous involvement, the difference was not clinically relevant. Agreement on focal lesion scores and on the number of focal lesions was good. CONCLUSION: The new visual criteria for interpreting FDG PET/CT imaging in MM patients, IMPeTUs, were found to be feasible in clinical practice.
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Fluorodesoxiglucosa F18/química , Interpretación de Imagen Asistida por Computador/métodos , Mieloma Múltiple/diagnóstico por imagen , Adulto , Anciano , Fracturas Óseas/complicaciones , Humanos , Procesamiento de Imagen Asistido por Computador , Italia , Persona de Mediana Edad , Imagen Multimodal , Estadificación de Neoplasias/métodos , Medicina Nuclear/normas , Variaciones Dependientes del Observador , Tomografía de Emisión de Positrones , Estudios Prospectivos , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos XRESUMEN
A retrospective, international, multicenter study was undertaken to assess: (i) the prognostic role of 'interim' positron emission tomography performed during treatment with doxorubicin, bleomycin, vinblastine and dacarbazine in patients with Hodgkin lymphoma; and (ii) the reproducibility of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin, vinblastine and dacarbazine ± involved-field or consolidation radiotherapy. Positron emission tomography scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. An international panel of six expert reviewers independently reported the scans using the Deauville five-point scale, blinded to treatment outcome. Forty-five scans were scored as positive (17.3%) and 215 (82.7%) as negative. After a median follow up of 37.0 (2-110) months, 252 patients are alive and eight have died. The 3-year progression-free survival rate was 83% for the whole study population, 28% for patients with interim positive scans and 95% for patients with interim negative scans (P<0.0001). The sensitivity, specificity, and negative and positive predictive values of interim positron emission tomography scans for predicting treatment outcome were 0.73, 0.94, 0.94 and 0.73, respectively. Binary concordance amongst reviewers was good (Cohen's kappa 0.69-0.84). In conclusion, the prognostic role and validity of the Deauville five-point scale for interpretation of interim positron emission tomography scans have been confirmed by the present study.
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Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/terapia , Tomografía de Emisión de Positrones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del Tratamiento , Adulto JovenRESUMEN
Background It has been proposed that in clinical trials in which the therapeutic strategy is driven by functional imaging, central review of the images should be done in real time. Purpose We report our experience with a new tool for image exchange and review, called Web-Based Imaging Diagnosis by Expert Network (WIDEN), which we implemented for the HD0607 prospective multicenter Italian clinical trial in which Hodgkin lymphoma treatment was adapted based on results of an interim positron emission tomography (PET) scan performed after the first two cycles of chemotherapy. Methods We used WIDEN for general management of the clinical trial, site imaging qualification, image exchange, workflow control, blinded independent central review, inter-observer variability assessment, consensus creation, audit, and statistical analysis. Results As of February 2013, the interim PET was available for 512 patients; upon central review, 103 of the scans were judged to be positive and 409 to be negative. The median scan uploading and downloading times were 1 min, 25 s and 1 min, 55 s, respectively; the average and median times for diagnosis exchange were 47 h, 53 min and 37 h, 43 min, respectively. The binary concordance between pairs of reviewers (Cohen's kappa) ranged from 0.72 to 0.85. The 5-point scale concordance among all reviewers (Krippendorf's alpha) was 0.77. Conclusions WIDEN proved to be an effective tool for medical imaging exchange and online review. Data security, simplicity, feasibility, and prompt scan review were demonstrated. Central reviews were completed promptly.
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Ensayos Clínicos como Asunto , Diagnóstico por Imagen/métodos , Gestión de la Información , HumanosRESUMEN
Lymphoma represents a condition that holds promise for cure with existing treatment modalities; nonetheless, the primary clinical obstacle lies in advancing therapeutic outcomes by pinpointing high-risk individuals who are unlikely to respond favorably to standard therapy. In this article, the authors will delineate the significant strides achieved in the lymphoma field, with a particular emphasis on the 3 prevalent subtypes: Hodgkin lymphoma, diffuse large B-cell lymphomas, and follicular lymphoma.
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Total metabolic tumor volume (TMTV) is prognostic in lymphoma. However, cutoff values for risk stratification vary markedly, according to the tumor delineation method used. We aimed to create a standardized TMTV benchmark dataset allowing TMTV to be tested and applied as a reproducible biomarker. Methods: Sixty baseline 18F-FDG PET/CT scans were identified with a range of disease distributions (20 follicular, 20 Hodgkin, and 20 diffuse large B-cell lymphoma). TMTV was measured by 12 nuclear medicine experts, each analyzing 20 cases split across subtypes, with each case processed by 3-4 readers. LIFEx or ACCURATE software was chosen according to reader preference. Analysis was performed stepwise: TMTV1 with automated preselection of lesions using an SUV of at least 4 and a volume of at least 3 cm3 with single-click removal of physiologic uptake; TMTV2 with additional removal of reactive bone marrow and spleen with single clicks; TMTV3 with manual editing to remove other physiologic uptake, if required; and TMTV4 with optional addition of lesions using mouse clicks with an SUV of at least 4 (no volume threshold). Results: The final TMTV (TMTV4) ranged from 8 to 2,288 cm3, showing excellent agreement among all readers in 87% of cases (52/60) with a difference of less than 10% or less than 10 cm3 In 70% of the cases, TMTV4 equaled TMTV1, requiring no additional reader interaction. Differences in the TMTV4 were exclusively related to reader interpretation of lesion inclusion or physiologic high-uptake region removal, not to the choice of software. For 5 cases, large TMTV differences (>25%) were due to disagreement about inclusion of diffuse splenic uptake. Conclusion: The proposed segmentation method enabled highly reproducible TMTV measurements, with minimal reader interaction in 70% of the patients. The inclusion or exclusion of diffuse splenic uptake requires definition of specific criteria according to lymphoma subtype. The publicly available proposed benchmark allows comparison of study results and could serve as a reference to test improvements using other segmentation approaches.
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BACKGROUND: The role of consolidation radiotherapy in primary mediastinal B-cell lymphoma (PMBCL) patients is controversial. METHODS: The IELSG37 trial, a randomized non-inferiority study, aimed to assess whether irradiation can be omitted in PMBCL patients with complete metabolic response (CMR) after induction immunochemotherapy. Primary endpoint was progression-free survival (PFS) at 30 months post-randomization. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a non-inferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomized. RESULTS: The observed events were considerably lower than expected, therefore, primary endpoint analysis was conducted when ≥95% of patients were followed for ≥30 months. Of 545 patients enrolled, 268 were in CMR after induction and were randomized to observation (n=132) or radiotherapy (n=136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95%CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95%CI, -0.97% to 7.46%). The 5-year overall survival was 99% in both arms.Non-randomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomized patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). CONCLUSIONS: This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.
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Imaging biomarkers (IBs) have been proposed in medical literature that exploit images in a quantitative way, going beyond the visual assessment by an imaging physician. These IBs can be used in the diagnosis, prognosis, and response assessment of several pathologies and are very often used for patient management pathways. In this respect, IBs to be used in clinical practice and clinical trials have a requirement to be precise, accurate, and reproducible. Due to limitations in imaging technology, an error can be associated with their value when considering the entire imaging chain, from data acquisition to data reconstruction and subsequent analysis. From this point of view, the use of IBs in clinical trials requires a broadening of the concept of quality assurance and this can be a challenge for the responsible medical physics experts (MPEs). Within this manuscript, we describe the concept of an IB, examine some examples of IBs currently employed in clinical practice/clinical trials and analyze the procedure that should be carried out to achieve better accuracy and reproducibility in their use. We anticipate that this narrative review, written by the components of the EFOMP working group on "the role of the MPEs in clinical trials"-imaging sub-group, can represent a valid reference material for MPEs approaching the subject.