In Part 1, we reviewed the role of interim positron emission tomography (PET)/CT scans in Hodgkin lymphoma. In advanced Hodgkin lymphoma, interim PET is a useful prognostic tool that can be used to implement risk-adapted therapy with potential benefits for both patients who have negative interim scans and those whose scans are positive. Interim PET/CT has not shown as encouraging results in diffuse large B-cell lymphoma (DLBCL), with the exception of germinal center B-cell DLBCL. Thus, quantitative methods of interpreting interim PET scans have been pursued in an effort to improve their predictive value. Early results using the change in maximal standardized uptake value between baseline and interim PET (ÎSUVmax) to quantitatively interpret interim PET scans in DLBCL patients showed promise, but later results were contradictory. Thus, there is not firm evidence of a prognostic value for interim PET interpreted using either visual or ÎSUVmax-based analysis in patients with DLBCL. Nor are there data to support altering treatment in DLBCL on the basis of an interim PET scan. More sophisticated methods of quantitative interpretation of interim PET, using metabolic tumor volume and tumor lesion glycolysis measurements, have been investigated in both Hodgkin lymphoma and DLBCL. Although to date studies of these approaches have been small and heterogeneous, they do provide some support for the potential of a PET-derived volumetric approach to discriminate between risk groups better than ÎSUVmax; this remains to be proven in well-designed large-scale studies.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell non-Hodgkin lymphoma; it accounts for approximately 35% of B-cell non-Hodgkin lymphomas and 80% of aggressive lymphomas.[1] DLBCL is a heterogeneous disease that is subdivided, on the basis of gene expression profiling or immunohistochemistry, into three distinct molecular cell-of-origin subtypes: germinal center B-cell (GCB) lymphoma, non–germinal center (activated B-cell [ABC]) lymphoma, and primary mediastinal B-cell lymphoma. The treatment of patients with DLBCL has remained relatively unchanged for 14 years, since the Groupe d’Etude des Lymphomes de l’Adulte (GELA) demonstrated the superiority of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R-CHOP) compared with CHOP alone.[2,3] These data were subsequently confirmed by a US Intergroup study.[4] Attempts to improve on these results using a more dose-dense R-CHOP-14 regimen have not been successful.[5] The first results of the Cancer and Leukemia Group B (CALGB)/Alliance 50303 randomized trial comparing dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) plus rituximab (EPOCH-R, or R-EPOCH) vs R-CHOP also failed to show a benefit for the newer regimen over R-CHOP, despite a less favorable toxicity profile.[6] Nevertheless, only about 60% of patients are cured with R-CHOP.[2,3] Thus, much like in Hodgkin lymphoma, the early identification of patients most likely to have an unfavorable outcome with standard therapy might lead to alterations in treatment strategy, which hopefully would be associated with an improved patient outcome-and early recognition of therapeutic ineffectiveness might help avoid high cumulative toxicity and morbidity.
Nonadapted Interim PET Studies
Although several, mostly earlier, studies suggested a good correlation between interim positron emission tomography (PET) results and survival in patients with DLBCL,[7-14] the majority of recent studies have not corroborated these results.[11,15-21] The significant discrepancy between these studies could be ascribed, in part, to the false-positive results caused by the inflammatory response associated with chemoimmunotherapy. Early studies differed in the proportion of patients who received immunotherapy and in the type of chemotherapy used, while more modern studies were conducted in the era of rituximab combined with chemotherapy.[22,23]
A recent meta-analysis of 11 studies and 1,081 DLBCL patients treated with rituximab-based chemoimmunotherapy reported a low prognostic value for interim PET results, with a pooled hazard ratio of 2.96 for a positive PET result. The complete remission (CR) rates were higher in the interim PET–negative group than those in the PET-positive group (relative risk, 5.53 [95% CI, 2.59–11.80]).[24] In another meta-analysis of 6 studies with a total of 605 DLBCL patients treated with R-CHOP, the summary estimates of sensitivity and specificity for predicting treatment failure were only 52% and 68%, respectively.[25] The pooled positive likelihood ratio and negative likelihood ratio were 1.78 and 0.71, respectively. Furthermore, end-of-treatment 18F fluorodeoxyglucose (FDG)-PET yielded unsatisfactory predictive results, according to another meta-analysis, which reported that approximately 14% of R-CHOP–treated patients with DLBCL who achieve a PET-based CR experience disease relapse during follow-up.[26]
In a more recent prospective study, Mamot et al, using central review and the Deauville five-point scale (5PS) criteria, found a 2-year event-free survival (EFS) rate of 41% for the patients who were PET-positive after 2 courses of treatment (PET-2–positive) and 76% for the patients who were PET-negative after 2 courses of treatment (PET-2–negative) (P < .001). The end-of-therapy PET yielded the most accurate results for those patients who received R-CHOP-14 treatment.[21]
The predictive power of FDG-PET may also be dependent on the molecular profile. In a prospective study of 147 DLBCL patients treated with R-CHOP, the ability of PET-2 results to identify patients with a very good prognosis was associated with cell of origin. The 30-month progression-free survival (PFS) rate was 100% for PET-2–negative and 60% for PET-2–positive patients with GCB DLBCL (P = .001). However, PET-2 results showed no statistically significant differences in PFS or overall survival (OS) in the non-GCB DLBCL subgroup.[27]
Earlier response evaluation has also been pursued. Mylam et al prospectively assessed response after a single cycle of R-CHOP in 112 patients with DLBCL. PET after 1 course of chemotherapy was not able to identify differences in prognosis for PET-positive and PET-negative patients, using either International Harmonization Project (IHP) or Deauville 5PS criteria.[28]
Change in Maximal Standardized Uptake Value Between Baseline and Interim PET (ÎSUVmax)
In an effort to improve the predictive value of interim PET, ÎSUVmax was extensively investigated by GELA in multiple retrospective studies. This group of investigators demonstrated that with a ÎSUVmax cutoff of 66%, the prognostic value of interim PET was improved compared with visual analysis in patients with DLBCL.[10,12,29-31] Casasnovas et al reported preliminary results of the LNH2007-3B study[30] in 113 patients with DLBCL who were randomly assigned to two different rituximab-doxorubicin–based combination treatments. For both PET-2 and PET after 4 courses of treatment (PET-4), ÎSUVmax predicted PFS better than visual assessments using both IHP and Deauville 5PS criteria. The best delineation of prognostic groups after PET-4 was achieved by combining a ÎSUVmax of > 70% with the Deauville 5PS results; those patients with a dual-negative result using these two criteria had a 2-year PFS rate exceeding 90%. Itti et al, for an international multicenter retrospective study (N = 114) led by the GELA group,[31] reported a slightly inferior predictive value for 3-year PFS using visual assessment of PET-2 with Deauville 5PS criteria (59% for PET-2–positive patients vs 81% for PET-2–negative patients) compared with use of a 66% ÎSUVmax cutoff (44% for PET-2–positive patients vs 79% for PET-2–negative patients [P = .0002]) in patients treated with a rituximab-containing regimen. The ÎSUVmax also had favorable interobserver reproducibility.
Contradictory results were also obtained comparing ÎSUVmax analysis with visual analysis.[12,16,17,32] Safar et al found slightly better results with visual analysis (compared with the same ÎSUVmax cutoff value of 66%) in 112 patients undergoing treatment with an anthracycline-based regimen plus rituximab.[12] The 3-year PFS rate in the ÎSUVmax analysis was 77% in the PET-2–negative group vs 37.5% in the PET-2–positive group (P = .002), while corresponding values for visual analysis using background as the reference were 84% and 47%, respectively (P < .0001). Interestingly, the prognostic value of PET-2 for PFS remained significant in the conventional therapy group (R-CHOP-21) and in the dose-dense groups (R-CHOP-14/R-ACVBP [rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone]); however, the difference in OS between the PET-2–positive and PET-2–negative cohorts was not significant in the dose-dense group. In a recent study from Belgium,[32] Nols et al reported similar results for interim PET performed after 3 or 4 cycles of therapy with an anthracycline-based regimen plus rituximab in 73 patients with DLBCL. The ÎSUVmax reduction of > 66% was not superior to the Deauville 5PS criteria for the prediction of PFS (P < .0001 vs P = .02). In a small subset of patients (n = 33), combining a favorable age-adjusted International Prognostic Index (IPI) score and a negative interim PET result (either by Deauville 5PS or ÎSUVmax criteria) identified a group with a particularly good outcome at a median follow-up of 2.4 years (PFS, 88%; OS, 94%). The limited patient population, retrospective design, relative disparity between treatment types, and inconsistent time points for interim PET evaluation were limitations of this study. Likewise, Mamot et al, in a recent prospective study using central review and Deauville 5PS criteria,[21] found that a quantitative analysis with a ÎSUVmax threshold of 66% was not superior to visual analysis: 2-year EFS for the PET-2–positive vs PET-2–negative groups was 42% vs 61% (P = .1) for the quantitative analysis compared with 41% vs 76% (P < .001) for the visual analysis.
Consequently, despite some encouraging results, the ÎSUVmax-based quantitative analysis has yet to be prospectively validated so as to confirm or refute the results of the aforementioned studies. Currently, the available data do not conclusively point to an improved prognostic value for interim PET using ÎSUVmax–based quantitative analysis in patients with DLBCL.
PET-Adapted Treatment in DLBCL
Only about 60% of patients with DLBCL are cured with standard treatment, leaving considerable room for improvement. Interest in an adapted approach in these patients began with a study by Spaepen et al,[7] in which patients with aggressive lymphoma underwent a PET scan after 3 or 4 cycles of CHOP therapy. Those with a negative scan experienced an 84% PFS rate at a median follow-up of 1,107 days, compared with virtually none for those with a positive scan. Subsequent studies[8,9] yielded similar but not identical results, due to differences in patient populations, histology, methods of scan interpretation, and the variable use of rituximab. As discussed in the previous section, a number of other studies have perpetuated the controversy over the value of interim scans.[15-17] Whereas the negative predictive value is high in most studies, the positive predictive value is disappointingly low as a result of false-positive scans caused by inflammation and necrosis.[18] This fact bears on the larger issue of whether altering treatment on the basis of an interim scan improves patient outcomes. To address this question, Moskowitz et al treated patients with 4 cycles of intensified R-CHOP followed by a PET scan.[18] If the scan was negative, patients received ifosfamide, carboplatin, and etoposide for 3 cycles, followed by observation. If the PET scan was positive, patients underwent a biopsy. Those with a negative biopsy were managed as if the scan had been negative. Those with a positive biopsy received intensive chemotherapy followed by autologous stem cell transplantation. Altogether, 97 patients had an interim scan. The scan was negative in 59 patients, of whom 51 remained progression-free at a median follow-up of 44 months. Of the 38 patients with a positive scan, the biopsy was positive in only 5, of whom 3 remained progression-free. The other 33 patients with positive scans had a negative biopsy, with 26 of these remaining free of progression. Thus, the outcomes in the biopsy-negative group were similar to those of the PET-negative group, with an 81% false-positive rate. To date, available data fail to support obtaining an interim PET scan in patients with DLBCL unless there is a clinical indication to do so.
The PETAL trial has investigated whether a change in treatment protocol may improve the outcome of patients with a positive scan (defined by quantitative analysis) after 2 cycles of R-CHOP. Although the patients in this trial who had a positive scan reportedly relapsed six times more frequently than did patients with a negative scan,[33] the outcome results of the trial have not yet been published.
Key Points in the Use of Interim PET in DLBCL:
- Interim positron emission tomography (PET)/CT has low prognostic value in patients with DLBCL.
- The high likelihood of inflammatory processes in patients receiving chemoimmunotherapy contributes to false-positive PET results.
- No prospective studies thus far have shown improvement in DLBCL outcomes based on altering therapy on the basis of interim PET/CT results.
- New applications of PET being studied to improve on its role in DLBCL include using the five-point Deauville score, change in standardized uptake value, and pretreatment metabolic tumor volume.
- Quantitative methods of PET evaluation must be standardized before such a strategy is implemented.
In summary, no encouraging data exist to support altering treatment on the basis of an interim PET scan in DLBCL, and intensification of therapy based on interim PET results could lead to overtreatment of a substantial proportion of patients.
Quantitative PET Evaluation Using Advanced Methodologies
Although visual assessment using the Deauville 5PS criteria has been integrated into clinical practice for treatment response monitoring in all FDG-avid lymphoma histologies, the high rate of false-positive results, concerns about interobserver variability, and intrapatient variations in hepatic FDG uptake[34] have motivated development of quantitative tools to facilitate objective measurement of tumor response. As an added benefit, it has been suggested that the use of continuous variables for assessing therapy response will reduce sample sizes in clinical trials. SUV is significantly influenced by tumor heterogeneity because of its dependence on a single volume of interest. Given recent advances in software capabilities, tumor volumetric analysis using metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG) measurements has been proposed as a good way to determine the biologic activity of the whole-body disease burden-and as a tool that could potentially be used in risk stratification.[35]
MTV assessment in Hodgkin lymphoma
In Hodgkin lymphoma, the indirect measures of tumor burden-such as the number of disease sites, the extent of disease at involved sites, and the lactate dehydrogenase (LDH) level (used in the Ann Arbor staging system), as well as the universally used prognostic scoring systems-are not sufficient to stratify patients into disease risk categories. In one of the earlier studies by Song et al,[36] only older age, the presence of B symptoms, and a high MTV were found to be independently associated with PFS and OS (PFS, P = .008; OS, P = .007) in 127 patients with early-stage Hodgkin lymphoma treated with standard doxorubicin, bleomycin, vinblastine, and dacarbazine, with or without involved-field radiation therapy. Another retrospective study, by Kanoun et al,[37] yielded similar findings, suggesting that pretherapy MTV as a measure of metabolically active whole-body tumor bulk was a predictor of outcome when the prognostic value of the conventionally described tumor bulk (> 10 cm) did not reach significance in patients with Hodgkin lymphoma who were treated with anthracycline-based therapies. In contrast, Tseng et al reported that baseline SUV and MTV did not predict survival in 30 patients with Hodgkin lymphoma of mixed stages who were treated with varying combination therapies when IPI score was associated with PFS and OS. However, the ÎMTV (P < .01) and ÎSUVmax (P = .01) at the time of interim PET were associated with PFS and OS.[38] It is difficult to interpret these divergent results because of the small patient cohorts, the differences in methodologies, and the different therapy protocols.
Limited data are available concerning the predictive value of MTV derived from interim PET data.[37,38] Kanoun et al reported that both baseline MTV and ÎSUVmax at the time of PET-2 were independent predictors of PFS in a mixed-stage population.[37] The combination of MTV and ÎSUVmax identified three subsets of Hodgkin lymphoma patients with different PFS rates (4-year PFS rates: 92%, 49%, and 20%, respectively [P < .0001]). Consequently, the chemosensitivity of the tumor as assessed by interim PET appears to be a better predictor of survival than the initial tumor bulk. However, the studies reviewed above were marred by suboptimal retrospective designs that were inherently prone to biases because of nonstandardized protocols and patient selection. The use of various segmentation methodologies and varying MTV cutoffs also resulted in noncomparable and nongeneralizable results.
MTV assessment in DLBCL
In patients with DLBCL, and particularly in those with early-stage disease, a measure of objective tumor burden may be clinically relevant. Multiple retrospective studies have investigated pretreatment PET-derived volumetrics as a potential predictor of survival in mixed-stage cohorts of DLBCL patients undergoing R-CHOP therapy, with promising results.[39-47] While Ann Arbor staging failed to predict survival,[39,43] the patients with a higher MTV showed significantly inferior EFS[40] or PFS[43] compared with those with a lower MTV. These results were independent of the IPI score[38] or National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) score.
In a more recent retrospective study of 114 patients with DLBCL enrolled in a previously reported international validation study,[31] Sasanelli et al found that MTV was the only independent predictor of OS (P = .002) and PFS (P = .03) compared with other pretherapy indices, including tumor bulk (> 10 cm), LDH level, stage, and age-adjusted IPI score.[41] The estimated 3-year PFS rates were 77% in the low-MTV group and 60% in the high-MTV group (P = .04), and prediction of OS was even better (P = .0003). In a retrospective study of 147 DLBCL patients treated with R-CHOP,[47] Mikhaeel et al found that the pretreatment MTV was the strongest predictor of PFS, while the change in MTV at the time of PET-2 was less predictive. Combining baseline MTV and PET-2 data interpreted by Deauville 5PS criteria improved the predictive power of interim PET. This approach separated the study population into three distinct prognostic groups: good (MTV < 400; 5-year PFS > 90%), intermediate (MTV ≥ 400 + Deauville 5PS score of 1–3; 5-year PFS, 58.5%), and poor (MTV ≥ 400 + Deauville 5PS score of 4/5; 5-year PFS, 29.7%).[47] Several other retrospective studies have supported the findings of this study.[39,48]
There are, however, reports that contradict findings of some of the previously mentioned studies.[45,46] In a study by Gallicchio et al[45] in intermediate-risk DLBCL patients (N = 52), the baseline SUVmax was a better predictor of EFS (P = .0002) than MTV and TLG. Only an IPI score of 3 was significantly associated with poor outcome. In another study, by Adams et al,[46] in 73 DLBCL patients who had undergone R-CHOP therapy, the NCCN-IPI score was the only significant predictor of PFS (P = .024), although both the NCCN-IPI score and MTV were significant predictors of OS (P = .039 and P = .043, respectively).
A systematic review of 702 DLBCL patients in 7 retrospective studies,[44] including some of the above-referenced studies, although with significant heterogeneity, suggested that both SUVmax and MTV were significant prognostic factors for PFS (P = .038 and P = .000, respectively). For OS, only high MTV was a strong predictor of poor prognosis (P = .000). Overall, the outcomes of the included studies were inconsistent, mainly because of varying treatment protocols and the use of different risk scoring systems across studies. The seven studies varied widely in the optimal cutoff values for survival prediction, with these values ranging from 10 to 30 for SUVmax, and from 220 to 550 mL for MTV; even more variability (700%) was observed for TLG. Moreover, the small number of patients might have influenced the reliability of the results.
Common shortcomings of these studies included the use of mixed-stage and mixed-risk patient populations, varying treatment schemes, use of nonvalidated and varying methodologies, the lack of multicenter harmonization and cross-calibration across scanners in the multicenter studies, and the lack of comparative analysis of volumetric results vs SUV-based results to determine the superior methodology. Also, gradient-based methods that factor in the background activity are considered more accurate tumor volume segmentation methods compared with fixed-thresholding methods,[49] which were the predominantly used technique in the previous studies. Still, although these studies were not optimally designed, their results underscore the potential of a PET-derived volumetric approach to better discriminate between risk groups, making them thus better able to individualize treatments in DLBCL. The predictive superiority of MTV or TLG over SUVmax for survival is yet to be proven in well-designed, large-scale prospective multicenter studies.
Future Directions
PET/CT scans have markedly improved the staging and assessment of treatment response in most lymphoma histologies. The use of the Deauville 5PS has improved standardization of interpretation and comparability among studies. However, a number of substantive issues still remain. To improve on the discrimination of PET/CT scans, a number of investigators have explored additional quantitative methods of interpretation. Quantitative assessment with PET-derived volumes is still evolving, and the preliminary findings suggest that it can be potentially useful in the prediction of clinical outcome and may improve on the predictive value of conventional risk-stratifying systems. However, the prognostic and predictive value of functional tumor volume remains to be further investigated. Additionally, FDG is not a sufficiently specific molecular imaging agent to evaluate therapy response. Preliminary results suggest that 18F fluorothymidine (FLT)-PET/CT may do a better job as a proliferative marker after 2 cycles of therapy. FLT-PET/CT had a significantly higher PPV (91%) for the prediction of residual disease than did FDG-PET/CT (46%).[50] Moreover, advanced image evaluation using radiomics algorithms may overcome the inability to evaluate intratumoral heterogeneity, which limits the accuracy of imaging-based tumor characterizations and response profiles.[51]
Given the cost, radiation exposure, and false-positive results seen with current PET/CT scanning, alternatives for assessing response and following patients after treatment are needed. In the future, novel imaging methods and quantitative methods for measuring tumor burden may prove helpful in response assessment. Studies have shown a correlation between interim PET and eradication of minimal residual disease in chronic lymphocytic leukemia and follicular lymphoma.[52] There is currently growing interest in the use of next-generation sequencing techniques for detecting minimal residual disease in a number of lymphoma subtypes; studies are also evaluating the use of circulating tumor cell DNA for response assessment.[53] PET may be difficult to interpret in the context of possible flare reactions,[54] and cell-free clonotypic assays may be useful in distinguishing these false-positive findings from progressive disease in patients being treated with immunotherapeutic agents such as checkpoint inhibitors.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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