Hugo J.A. Adams

Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary?

BACKGROUND This study aimed to systematically review and meta-analyze published data on the diagnostic performance of (18)F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma, and to determine whether FDG-PET/CT can replace blind bone marrow biopsy (BMB) in these patients. PATIENTS AND METHODS The PubMed/Medline and Embase databases were systematically searched for relevant studies. Methodological quality of each study was assessed. Sensitivities and specificities of FDG-PET/CT in individual studies were calculated and underwent meta-analysis with a random effects model. A summary receiver operating characteristic curve (sROC) was constructed with the Moses-Shapiro-Littenberg method. The weighted summary proportion of FDG-PET/CT-negative patients with a positive BMB among all cases was calculated under the fixed effects model. RESULTS Nine eligible studies, comprising a total of 955 patients with newly diagnosed Hodgkin lymphoma, were included. Overall, the studies were of moderate methodological quality. The sensitivity and specificity of FDG-PET/CT for the detection of bone marrow involvement ranged from 87.5% to 100% and from 86.7% to 100%, respectively, with pooled estimates of 96.9% [95% confidence interval (CI) 93.0% to 99.0%] and 99.7% (95% CI 98.9% to 100%), respectively. The area under the sROC curve was 0.9860. The weighted summary proportion of FDG-PET/CT-negative patients with a positive BMB among all cases was 1.1% (95% CI 0.6% to 2.0%). CONCLUSION Although the methodological quality of studies that were included in this systematic review and meta-analysis was moderate, the current evidence suggests that FDG-PET/CT may be an appropriate method to replace BMB in newly diagnosed Hodgkin lymphoma.

Bone marrow 18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography cannot replace bone marrow biopsy in diffuse large B-cell lymphoma

This study aimed to investigate whether visual and quantitative 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography/computed tomography (FDG‐PET/CT)‐based bone marrow assessment can replace blind bone marrow biopsy (BMB) in newly diagnosed diffuse large B‐cell lymphoma (DLBCL). This retrospective study included 78 patients with newly diagnosed DLBCL who had undergone both FDG‐PET/CT and BMB. FDG‐PET/CT images were visually evaluated for bone marrow involvement. Patient‐based sensitivity of visual FDG‐PET/CT assessment was calculated using BMB as the reference standard. Metabolically active volume, maximum standardized uptake value, 3D partial volume corrected mean standardized uptake value, and 3D partial volume corrected mean metabolic volume product (cMVPmean) of FDG‐avid bone marrow lesions were measured. Cox regression analysis was used to determine the influence of (potential) prognostic factors (BMB status, visual [dichotomous] FDG‐PET/CT bone marrow status, metabolically active volume, maximum standardized uptake value, 3D partial volume corrected mean standardized uptake value, 3D partial volume corrected mean metabolic volume product, and International Prognostic Index score) on progression‐free survival and overall survival. FDG‐PET/CT detected bone marrow involvement in 34 (43.6%) cases and BMB in 16 (20.5%) of 78 cases, of whom 11 were also detected by FDG‐PET/CT, resulting in a patient‐based sensitivity of 68.8% (95% confidence interval = 44.2%–86.1%) for FDG‐PET/CT. In the multivariate Cox proportional hazards model, only BMB status was an independent predictive factor of progression‐free survival (P = 0.016) and overall survival (P = 0.004). In conclusion, FDG‐PET/CT misses bone marrow involvement that has been detected by BMB in a non‐negligible proportion of patients. Furthermore, both visual and quantitative FDG‐PET/CT‐based bone marrow assessments are prognostically inferior to BMB. Therefore, FDG‐PET/CT cannot replace BMB in newly diagnosed DLBCL. Am. J. Hematol. 89:726–731, 2014.

Prognostic value of complete remission status at end‐of‐treatment FDG‐PET in R‐CHOP‐treated diffuse large B‐cell lymphoma: systematic review and meta‐analysis

This study systematically reviewed and meta‐analysed the prognostic value of complete remission status at end‐of‐treatment 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) in diffuse large B‐cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R‐CHOP‐treated DLBCL patients who were in complete remission at end‐of‐treatment FDG‐PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end‐of‐treatment FDG‐PET ranged from 7·0% to 20·0%, with a weighted summary proportion of 13·7%. Five of seven studies reported progression‐free survival (PFS) of these patients at various specific time points, i.e., 2‐year PFS (n = 1), estimated 3‐year PFS (n = 3) and 5‐year PFS (n = 1), which was 83%, 85–86·4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3‐year OS (n = 2) and estimated 5‐year OS (n = 1), which were 90%, 93·6% and 83%, respectively. In conclusion, a non‐negligible proportion of R‐CHOP‐treated DLBCL patients who achieve complete remission according to end‐of‐treatment FDG‐PET experiences disease relapse during follow‐up.

Prognostic value of interim FDG-PET in Hodgkin lymphoma : systematic review and meta-analysis

This study aimed to systematically review and meta‐analyse the value of interim 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) in predicting treatment failure in Hodgkin lymphoma. MEDLINE was systematically searched for original studies that used standardized international criteria for interim FDG‐PET interpretation. Included studies were methodologically assessed. Summary receiver operating characteristic (sROC) analysis was performed, and pooled sensitivity and specificity were calculated using a random effects model. Heterogeneity in diagnostic odds ratios (DORs) across studies was assessed and potential sources for inter‐study heterogeneity were explored using subgroup analyses. Ten studies, comprising a total of 1389 Hodgkin lymphoma patients, were included. Sensitivity, specificity, positive predictive value and negative predictive value of interim FDG‐PET for predicting treatment failure ranged between 0·0–81·5%, 72·2–96·6%, 0·0–86·0% and 84·4–98·6%, respectively. The area under the sROC curve was 0·877. Pooled sensitivity and specificity were 70·8% [95% confidence interval (CI): 64·7–76·4%] and 89·9% (95% CI: 88·0–91·6%). There was heterogeneity in DORs across individual studies (I2 = 72·7). The overall prognostic value of interim FDG‐PET appears to be moderate for excluding and relatively high for identifying treatment failure in Hodgkin lymphoma. However, interim FDG‐PET cannot yet be implemented in routine clinical practice due to moderate‐quality evidence and inter‐study heterogeneity that cannot be fully explained yet.

Prognostic value of interim and end-of-treatment FDG-PET in follicular lymphoma: a systematic review

This study aimed to systematically review the prognostic value of interim and end-of-treatment 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in follicular lymphoma during and after first-line therapy. The PubMed/MEDLINE database was searched for relevant original studies. Included studies were methodologically assessed, and their results were extracted and descriptively analyzed. Three studies on the prognostic value of interim FDG-PET and eight studies on the prognostic value of end-of-treatment FDG-PET were included. Overall, studies were of poor methodological quality. In addition, there was incomplete reporting of progression-free survival (PFS) and overall survival (OS) data by several studies, and none of the studies incorporated the Follicular Lymphoma International Prognostic Index (FLIPI) in the OS analyses. Two studies reported no significant difference in PFS between interim FDG-PET positive and negative patients, whereas one study reported a significant difference in PFS between the two groups. Two studies reported no significant difference in OS between interim FDG-PET positive and negative patients. Five studies reported end-of-treatment FDG-PET positive patients to have a significantly worse PFS than end-of-treatment FDG-PET negative patients, and one study reported a non-significant trend towards a worse PFS for end-of-treatment FDG-PET positive patients. Three studies reported end-of-treatment FDG-PET positive patients to have a significantly worse OS than end-of-treatment FDG-PET negative patients. In conclusion, the available evidence does not support the use of interim FDG-PET in follicular lymphoma. Although published studies suggest end-of-treatment FDG-PET to be predictive of PFS and OS, they suffer from numerous biases and failure to correct OS prediction for the FLIPI.

Opportunities and limitations of bone marrow biopsy and bone marrow FDG-PET in lymphoma

Bone marrow involvement in lymphoma may have prognostic and therapeutic consequences. Bone marrow biopsy (BMB) is the established method for the evaluation of the bone marrow. (18)F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) plays an important role in lymphoma staging, but its value in the assessment of the bone marrow and whether it can replace BMB is still a topic of debate and investigation. The purpose of this scientific communication is to provide an evidence-based overview about the opportunities and limitations of BMB and FDG-PET in the evaluation of the bone marrow in patients with lymphoma. This article first reviews the basic properties, opportunities and limitations of BMB and bone marrow FDG-PET, and then focuses on the clinical utility of BMB and bone marrow FDG-PET in three major lymphoma subtypes including Hodgkin lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.

Prognostic superiority of the National Comprehensive Cancer Network International Prognostic Index over pretreatment whole-body volumetric-metabolic FDG-PET/CT metrics in diffuse large B-cell lymphoma

This study aimed to determine the prognostic value of whole‐body maximum standardized uptake value (SUVmax), whole‐body metabolic tumor volume (MTV), and whole‐body total lesion glycolysis (TLG) at pretreatment 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography/computed tomography (FDG‐PET/CT) in patients with newly diagnosed diffuse large B‐cell lymphoma (DLBCL).

Diffusely increased bone marrow FDG uptake in recently untreated lymphoma: incidence and relevance.

To determine the incidence of diffusely increased bone marrow 18F‐fluoro‐2‐deoxy‐D‐glucose (FDG) uptake at positron emission tomography (PET) in recently untreated lymphoma and to assess the frequency of lymphoma‐positive bone marrow biopsies (BMBs) in these patients.

Proportion of false-positive lesions at interim and end-of-treatment FDG-PET in lymphoma as determined by histology : Systematic review and meta-analysis

PURPOSE To systematically review and meta-analyze the proportion of false-positive lesions at interim and end-of-treatment 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in lymphoma using biopsy as reference standard. MATERIALS AND METHODS Medline was searched for original studies. Methodological quality of included studies was evaluated, and results were meta-analytically summarized using random effects (in case of interstudy heterogeneity [I2≤50%]) or fixed effects (in case of no interstudy heterogeneity [I2>50%]). RESULTS Eleven studies, comprising 139 patients who underwent biopsy of an FDG-avid lesion during or after completion of antilymphoma treatment, were included. Overall methodological quality was moderate. The proportion of false-positive results among all biopsied FDG-avid lesions at PET performed during of after completion of treatment ranged between 7.7% and 90.5% (the vast majority was due to inflammatory changes), with a weighted summary proportion (random effects, I2=75.7%) of 55.7% (95% confidence interval [CI]: 32.6-76.6%). There were no available studies on interim FDG-PET in Hodgkin lymphoma. The pooled summary false-positive proportions were 83.0% (95% CI: 72.0%-90.2%) for interim FDG-PET in non-Hodgkin lymphoma (fixed effects, I2=27.7%), 23.1% (95% CI: 4.7%-64.5%) for end-of-treatment FDG-PET in Hodgkin lymphoma (random effects; I2=67.1%), and 31.5% (95% CI: 3.9%-83.9%) for end-of-treatment FDG-PET in non-Hodgkin lymphoma (random effects, I2=68.3%). CONCLUSION Both interim and end-of-treatment FDG-PET scans in patients with lymphoma suffer from a very high number of false-positive FDG-avid lesions. This finding, in combination with the previously reported high number of false-negative FGD-PET scans for residual disease detection, suggests that the role of interim and end-of-treatment FDG-PET should be reconsidered.

Do Not Abandon the Bone Marrow Biopsy Yet in Diffuse Large B-Cell Lymphoma

TO THE EDITOR: We read with interest the updated guidelines that were recently published in Journal of Clinical Oncology on the role of imaging inthestagingandresponseassessmentof lymphoma. Thenew guidelines claim that focal [F]fluorodeoxyglucose (FDG) uptake within thebonemarrowishighlysensitiveforbonemarrowinvolvementinboth Hodgkin lymphoma and aggressive non-Hodgkin lymphoma, and may obviate the need for a bone marrow biopsy (BMB). Although we agree thatFDG–positronemissiontomography(PET)/computedtomography can replace BMB in Hodgkin lymphoma, we believe that this is not the case in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Sevenoriginalstudiesthatwereincludedinarecentmeta-analysison thevalueofFDG-PET/CTfor thedetectionofbonemarrowinvolvement in DLBCL reported FDG-PET/CT to have a high patient-based sensitivity, ranging between 70% and 95%. However, all studies that were included in that meta-analysis used both BMB and follow-up FDGPET/CT studies as a reference standard. Although a positive BMB can be considered as definitive proof of bone marrow involvement, FDG decrease at follow-up may not be sufficient evidence to confirm pretreatment bone marrow involvement. Benign bone marrow lesions may also exhibit a decrease in FDG uptake after treatment, and one cannot confidently discriminate between the two entities without histologic proof. Thus, the actual diagnostic value of FDG-PET/CT in this setting is likely lower than previously quoted. Indeed, when BMB is used as the only reference standard, the sensitivity of FDG-PET/CT declines, as has been shown by recent studies that reported that FDG-PET/CT can be negative in up to 25% to 50% of patients with a positive BMB. Moving from a patient-based analysis to a local, head-to-head comparison between FDG-PET/CT and BMB in the posterior iliac crest, our preliminary data even show that FDG-PET/CT can be negative at the posterior iliac crest in up to 80% of patients with a positive BMB. Interestingly, this observation applies to both low and high tumor–volume bone marrow involvement, andtobothlarge-cell(concordant)andsmall-cell(discordant)bonemarrow involvement. Another important issue is that, although a positive BMB has been established as a major adverse prognostic marker in DLBCL, this is not the case for FDG-PET/CT–based bone marrow involvement. Of the four publishedstudiesontheprognostic implicationsofFDG-PET/CT–based bone marrow assessment, three studies showed that focal pathologic FDG uptake in the bone marrow did not have any prognostic value at all. These observations also support the notion that focally increased bone marrow FDG uptake is not pathognomonic for lymphomatous involvementinDLBCL.Notsurprisingly,therecentlydevelopedNational Comprehensive Cancer Network International Prognostic Index for DLBCL does not incorporate imaging-based bone marrow involvement and only accepts histologically confirmed bone marrow involvement for risk stratification. In conclusion, it is our opinion that FDG-PET/CT has not (yet) been proven to be able to replace BMB in DLBCL, both from a diagnostic and prognostic perspective. Until convincing scientific evidence emerges in favor of FDG-PET/CT, we believe that BMB should not be abandoned when evaluating the bone marrow in patients with newly diagnosed DLBCL.