Accuracy and prognostic impact of FDG PET/CT and biopsy in bone marrow assessment of follicular lymphoma at diagnosis: A Nation-Wide cohort study.

BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.

PET-Based Staging Is Cost-Effective in Early-Stage Follicular Lymphoma.

The objective was to assess the cost-effectiveness of staging PET/CT in early-stage follicular lymphoma (FL) from the Canadian health-care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding staging PET/CT versus using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a noncurative approach, or no change in RT treatment as planned. The subsequent disease course was described using a state-transition cohort model over a 30-y time horizon. Diagnostic characteristics, probabilities, utilities, and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars), and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs) and was cost-effective in 89% of simulations (i.e., either saved costs or had an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis showed that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT before curative-intent RT.

Visible and near-infrared hyperspectral imaging techniques allow the reliable quantification of prognostic markers in lymphomas: A pilot study using the Ki67 proliferation index as an example.

In this study, we examined the suitability of visible and infrared (Vis-NIR) hyperspectral imaging (HSI) for the quantification of prognostic markers in non-Hodgkin lymphoma on the example of the Ki67 proliferation index. Ki67 quantification was done on six follicular lymphomas (FLs) and 12 diffuse large B-cell lymphomas (DLBCLs) by applying classic immunohistochemistry. The Ki67 index was comparatively assessed visually, using HSI-based quantification and a digital imaging analysis (DIA) platform. There was no significant difference between visual assessment (VA), DIA, and HSI in FLs. For DLBCLs, VA resulted in significantly higher Ki67 values than HSI (p = 0.023) and DIA (p = 0.006). No such difference was seen comparing analysis by HSI and DIA (p = 0.724). Cohen's κ revealed a "substantial correlation" of Ki67 values for HSI and DIA in FLs and DLBCLs (κ = 0.667 and 0.657). Here we provide the first evidence that, comparably to traditional DIA, HSI can be used reliably to quantify protein expression, as exemplified by the Ki67 proliferation index. By covering the near-infrared spectrum, HSI might offer additional information on the biochemical composition of pathological specimens, although our study could not show that HSI is clearly superior to conventional DIA. However, the analysis of multiplex immunohistochemistry might benefit from such an approach, especially if overlapping immunohistochemical reactions were possible. Further studies are needed to explore the impact of this method on the analysis and quantification of multiple marker expression in pathological specimens.

Optimisation of metabolic criteria in the prognostic assessment in patients with lymphoma. A multicentre study. / Optimización de los criterios metabólicos en la valoración pronóstica de los pacientes con linfoma. Estudio multicéntrico.

OBJECTIVE: To compare sensitivity, specificity and predictive value of Deauville score (DS) vs. ΔSUVmax in interim-treatment PET (iPET) and end-treatment PET (ePET), in patients with diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and follicular lymphoma (FL). METHOD: Retrospective longitudinal multicentre study including 138 patients (46 DLBCL, 46 HL, 46 FL), on whom 3 18F-FDG PET/CT were performed: baseline, iPET, and ePET. Visual (DS) and semi-quantitative (ΔSUVmax) parameters were determined for iPET and ePET. Predictive value was determined in relation to disease-free interval. RESULTS: Statistical analysis. iPET for DLBCL, HL, and FL: 1) sensitivity of DS: 76.92/83.33/61.53%; specificity: 78.78/85/81.81%; 2) sensitivity of ΔSUVmax: 53.84/83.33/61.53%; specificity: 87.87/87.50/78.78%. ePET for DLBCL, HL and FL: 1) sensitivity of DS: 61.53/83.33/69.23%; specificity: 90.90/85/87.87%; 2) sensitivity of ΔSUVmax: 69.23/83.33/69.23%; specificity: 90.90/87.50/84.84%. Predictive assessment. iPET study: in DLBCL, DS resulted in 10.3% recurrence of negative iPET, and 17.1% in ΔSUVmax at disease-free interval; in HL, both parameters showed a 2.8% recurrence of negative iPET; in FL, DS resulted in 15.6% recurrence of negative iPET, and 16.1% in ΔSUVmax, with no statistical significance. ePET study: in DLBCL, DS resulted in 14.3% recurrence of negative ePET, and 11.8% in ΔSUVmax at disease-free interval; in HL and FL, both methods showed 2.8 and 12.5% recurrence in negative ePET, respectively. CONCLUSION: DS and ΔSUVmax did not show significant differences in DLBCL, HL and FL. Their predictive value also did not show significant differences in HL and FL. In DLBCL, DS was higher in iPET, and ΔSUVmax in ePET.

Basal (18)F-FDG PET/CT in follicular lymphoma: A comparison of metabolic and clinical variables in the prognostic assessment.

AIM: To analyze the relationship of clinical variables related to prognosis and tumor burden, with metabolic variables obtained in the staging (18)F-FDG PET/CT, and their value in the prognosis in follicular lymphoma (FL). METHODS: 82 patients with FL, a (18)F-FDG PET/CT at diagnosis and a follow-up for a minimum of 12 months, were retrospectively enrolled in the present study. Clinical variables (Tumor grade, Follicular Lymphoma International Prognostic Index (FLIPI) and Tumor burden) were evaluated. Metabolic variables such as SUVmax in the highest hypermetabolic lesion, extralymphatic locations, number of involved lymph node locations, bone marrow (BM) involvement, PET stage and diameter of the biggest hypermetabolic lesion, were analyzed in order to establish a PET score and classify the studies in low, intermediate and high metabolic risk. Clinical and metabolic variables (included metabolic risk) were compared. The relation among all variables and disease-free survival (DFS) was studied. RESULTS: The 28% of patients had a high-grade tumor. The 30.5% had FLIPI risk low, 29.3% intermediate y 40.2% high. The 42.7% presented a high tumor burden. The PET/CT was positive in 94% of patients. The tumor grade did not show significant relation with metabolic variable. FLIPI risk and tumor burden showed statistical relations with the SUV max and the PET score (p<0.008 and p=0.003 respectively). With respect to DFS, significant differences were detected for the PET stage and FLIPI risk (p=0.015 and p=0.047 respectively). FLIPI risk was the only significant predictor in Cox regression analysis, with a Hazard Ratio of 5.13 between high risk and low risk. CONCLUSION: The present research highlights the significant relation between metabolic variables obtained with FDG PET/CT and clinical variables although their goal as an independent factor of prognosis was not demonstrated in the present work.

PET/CT Assessment of Follicular Lymphoma and High Grade B Cell Lymphoma - Good Correlation with Clinical and Histological Features at Diagnosis.

BACKGROUND: Follicular lymphoma is a common type of non-Hodgkin's lymphoma observed in Western countries. The diagnosis of this disease is based primarily on morphological and immunohistochemical assessment. The proliferative index Ki67 correlates with histological grading and clinical aggressiveness. Currently, positron emission tomography/computed tomography scanning are not applied for standard staging at diagnosis of follicular lymphoma and its use is limited to those patients for whom the identification of residual disease is crucial for therapeutic decisions and only when transformation to a high-grade lymphoma is suspected. OBJECTIVES: Our aim was to assess whether a correlation exists between the maximal standardized uptake value (SUVmax) at the biopsy site as detected via positron emission tomography/computed tomography and pathological (Ki67 and FL histological grade) and clinico-biological features (e.g. LDH, beta-2-microglobulin, Ann Arbor stage and FL International Prognostic Index--FLIPI) at diagnosis. MATERIAL AND METHODS: We retrospectively identified 16 patients during the previous 3.5 years in whom node biopsies were guided, taking into account the SUVmax as detected upon PET/CT scan at diagnosis. The results of these biopsies were diagnostic of follicular lymphoma. We also included 6 patients with high grade B cell lymphoma: 5 diffuse large B cell lymphoma (DLBCL) and 1 FL 3b histological grade. A 2-tailed non-parametric Spearman's correlation analysis of the SUVmax with Ki67, histological grade, LDH and b-2-microglobuline was performed. RESULTS: The Ki67 (r=0.73) and follicular lymphoma histological grade (r=0.75) at the biopsy displayed a significant correlation with the SUVmax at diagnosis (p<0.01). CONCLUSIONS: Our results suggest that SUV detected by positron emission tomography/computed tomography correlates with histological grade in follicular lymphoma/high grade B cell lymphoma, Ki67 and LDH. Positron emission tomography/computed tomography should be considered for guiding lymph node biopsy when transformation to a high-grade B cell lymphoma is suspected.

PET/CT assessment in follicular lymphoma using standardized criteria: central review in the PRIMA study.

PURPOSE: We aimed to compare the standardized central review of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans performed after induction therapy for follicular lymphoma (FL) in the PRIMA study (Salles et al., Lancet 377:42-51, 2011; Trotman et al., J Clin Oncol 29:3194-3200, 2011) to scan review at local centres. METHODS: PET/CT scans were independently evaluated by two nuclear medicine physicians using the 2007 International Harmonization Project (IHP) criteria (Cheson et al., J Clin Oncol 25:579-586, 2007; Juweid et al., J Clin Oncol 25:571-578, 2007; Shankar et al., J Nucl Med 47:1059-1066, 2006) and Deauville 5-point scale (5PS) criteria (Meignan et al., Leuk Lymphoma 50:1257-1260, 2009; Meignan et al., Leuk Lymphoma 51:2171-2180, 2010; Barrington et al., Eur J Nucl Med Mol Imaging 37:1824-1833, 2010). PET/CT status was compared with prospectively recorded patient outcomes. RESULTS: Central evaluation was performed on 119 scans. At diagnosis, 58 of 59 were recorded as positive, with a mean maximum standardized uptake value (SUVmax) of 11.7 (range 4.6-35.6). There was no significant association between baseline SUVmax and progression-free survival (PFS). Sixty post-induction scans were interpreted using both the IHP criteria and 5PS. Post-induction PET-positive status failed to predict progression when applying the IHP criteria [p = 0.14; hazard ratio (HR) 1.9; 95 % confidence interval (CI) 0.8-4.6] or 5PS with a cut-off ≥3 (p = 0.12; HR 2.0; 95% CI 0.8-4.7). However, when applying the 5PS with a cut-off ≥4, there was a significantly inferior 42-month PFS in PET-positive patients of 25.0% (95% CI 3.7-55.8%) versus 61.4% (95% CI 45.4-74.1%) in PET-negative patients (p = 0.01; HR 3.1; 95% CI 1.2-7.8). The positive predictive value (PPV) of post-induction PET with this liver cut-off was 75%. The 42-month PFS for patients remaining PET-positive by local assessment was 31.1% (95% CI 10.2-55.0%) vs 64.6% (95% CI 47.0-77.6%) for PET-negative patients (p = 0.002; HR 3.3; 95% CI 1.5-7.4), with a PPV of 66.7%. CONCLUSION: We confirm that FDG PET/CT status when applying the 5PS with a cut-off ≥4 is strongly predictive of outcome after first-line immunochemotherapy for FL. Further efforts to refine the criteria for assessing minimal residual FDG uptake in FL should provide a reproducible platform for response assessment in future prospective studies of a PET-adapted approach.

End-therapy positron emission tomography for treatment response assessment in follicular lymphoma: a systematic review and meta-analysis.

PURPOSE: Use of 2[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in postchemotherapy response assessment in follicular lymphoma is still a controversial issue. Here, we conducted the first systematic review and meta-analysis to determine the predictive value of FDG-PET in predicting outcome after chemotherapy of follicular lymphoma. EXPERIMENTAL DESIGN: Comprehensive literature search in Ovid-MEDLINE and EMBASE databases was performed to identify studies which evaluate predictive value of end-therapy PET and/or computed tomography (CT) in patients with follicular lymphoma. To quantitatively compare the predictive value of PET and CT, pooled hazard ratios (HRs) comparing progression-free survival (PFS) between patients with positive and negative results were adopted as the primary indicators for meta-analysis. To explore the efficiency in determining complete remission (CR), pooled CR rates of PET- and CT-based response criteria were calculated. Pooling of these parameters was based on the random-effects model. RESULTS: Review of 285 candidate articles identified eight eligible articles with a total of 577 patients for qualitative review and meta-analysis. The pooled HRs of end-therapy PET and CT were 5.1 [95% confidence interval (CI), 3.7-7.2] and 2.6 (95% CI, 1.2-5.8), respectively, which implies that PET is more predictive of PFS after chemotherapy than CT. The pooled CR rates of PET- and CT-based response criteria were 75% (95% CI, 70-79%) and 63% (95% CI, 53-73%), respectively, which implies that PET is more efficient in distinguishing CR (without residual disease) from other states with residual disease. In addition, qualitative systematic review indicates the same findings. CONCLUSIONS: Consistent evidence favoring PET-based treatment assessment should be considered in the management of patients with follicular lymphoma.

FDG-PET in the assessment of patients with follicular lymphoma treated by ibritumomab tiuxetan Y 90: multicentric study.

BACKGROUND: The aim of this study is the 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) evaluation following radioimmunotherapy (RIT) with ibritumomab tiuxetan Y 90 in patients with non-Hodgkin's follicular lymphoma (FL). MATERIALS AND METHODS: We retrospectively analyzed data from 59 relapsed or refractory FL patients treated with ibritumomab tiuxetan Y 90 in four different PET centers who had a PET scan carried out before and after RIT. Possible predictive factors of progression-free survival (PFS) were studied through univariate and multivariate analysis. RESULTS: The post-RIT PET documented 45.8% complete responders (CR), 25.4% partial responders (PR) and 28.8% nonresponders [stable disease + progressive disease], with an overall survival of 71.2% (range 59.5%-90.9%). With a median follow-up period of 23 months, the univariate analysis documented a statistically significant relation between disease extent before RIT and response to treatment with respect to PFS (P = 0.015), while all the other prognostic factors showed no significant correlation. When carrying out the multivariate analysis, post-RIT PET resulted as the lonely independent predictor of PFS (P < 0.00001). CONCLUSIONS: RIT is an effective therapy in FL patients, as confirmed in our study too. Disease extension before treatment and response to RIT, as assessed by FDG-PET, result as main predictors of PFS, with the post-RIT PET result being the only independent predictive factor.

FDG PET CT assessment of treatment response after yttrium-90 ibritumomab tiuxetan radioimmunotherapy.

Yttrium-90 ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals Corp., San Diego, CA) is the first radioimmunotherapy agent approved by the U.S. Food and Drug Administration (FDA) for treatment of non-Hodgkin lymphoma. In a randomized clinical trial comparing Zevalin with rituximab, the overall response rate was 80% and 56%, respectively. Response was determined by assessing the size of lymph nodes on CT scans. FDG PET has been well accepted as an accurate imaging study for staging non-Hodgkin lymphoma and evaluating response to treatment. Simultaneous FDG PET and CT imaging (PET CT) provides coregistered functional PET images with anatomic CT images. We describe 2 cases of non-Hodgkin lymphoma treated in which response was followed using PET CT.