Improvement of Early ¹⁸F-FDG PET Interpretation in Diffuse Large B-Cell Lymphoma: Importance of the Reference Background

DISCUSSION

The most predictive criterion proposed so far for early PET interpretation in diffuse large B-cell lymphoma was to consider as positive (i.e., predictive of relapse) a SUVmax reduction of less than 66% between PET0 and PET2 in the most intense tumor (9). This approach dramatically reduced false-positive interpretations and, as such, is currently used in the PETAL study from the Essen group, Germany, to identify candidates for chemotherapy intensification (12). In the first 266 patients, with a median follow-up of less than 6 mo, lymphoma relapses across all International Prognostic Index risk groups have already occurred 3 times more frequently in PET2-positive than in PET2-negative patients, 23% (9/40) versus 8% (19/226), P = 0.021 (13). Importantly, this study will provide an external validation of the 66% SUVmax reduction criterion.

However, to be applicable, this criterion requires a baseline scan, which is not mandatory according to the International Harmonization Project criteria for response assessment of lymphoma and is, in fact, not routinely performed in most risk-adapted trials (6). An alternative approach investigated in the current study is to compare residual tumor uptake with an internal reference background, such as MBP or liver. SUV semiquantification was used to minimize subjectivity of PET2 interpretation as previously documented (11). Background intensities were stable between PET0 and PET2, indicating a relatively low influence of treatment regimens on MBP and liver uptake of ¹⁸F-FDG (Table 1). This finding is interesting, considering the observation that chemotherapy-induced steatosis and sinusoid obstruction affect liver imaging by CT, ultrasound, and MRI but apparently not, at least not to any significant extent, by ¹⁸F-FDG PET (14). In addition, there was little variability in the SUVs of both the liver and MBP between patients. This has been previously shown for the liver (15) and is now also shown for the MBP.

Our data clearly demonstrate that the liver is a reference background superior to MBP for early PET interpretation in diffuse large B-cell lymphoma, even when using the conservative >125% SUVmax criterion, which should perform similarly to visual interpretation of liver activity but with lower interobserver variability. Indeed, it seems justified to use a higher level of reference background because, at 2 cycles, residual “tumor” uptake likely represents a significant component of posttherapy inflammatory changes at this relatively early time after treatment, with or without a minimal amount of viable tumor cells likely to be eradicated with further treatment (16,17). Corticosteroids have been shown to help reduce the contribution of inflammatory cells to the ¹⁸F-FDG uptake and were included in our chemotherapy regimens (18). With liver uptake as the reference background (>125% SUVmax), PPV reached 48.6% for PFS prediction, corresponding to a reduction of 15 false-positives, compared with MBP in the same setting. The difference between MBP and liver uptake was only 0.5 units in terms of SUVmax (2.0 ± 0.6 vs. 2.5 ± 0.7, respectively) but was sufficient to reduce false-positives. Interestingly, the >125% SUVmax liver criterion resulted in performance similar to our previously published custom visual analysis allowing minimal residual uptake (9).

Receiver-operating-characteristic analysis has identified optimal thresholds (e.g., >168% of MBP SUVmax, >140% of liver SUVmax) leading to higher predictive values and accuracies. Obviously, these figures cannot be transposed to a visual scale of interpretation, but they strengthen the message that liver appears a better reference organ than MBP for early PET interpretation. Although the positive predictive value of the >140% liver SUVmax criterion remains lower than those obtained by measuring the SUV reduction or by waiting 2 additional cycles, this criterion results in a better sensitivity and slightly higher negative predictive value (9,19). With the caveats of the somewhat different outcome measure (PFS vs. event-free survival) evaluated using the >140% liver SUVmax criterion, SUV reduction after 2 cycles and SUV reduction after 4 cycles, the difference in overall accuracy between these 3 approaches was relatively small (72.8%, 76.1%, and 77.5%, respectively). For OS prediction, the accuracies were 75.0%, 84.8%, and 80.0%, respectively, but here again the higher accuracy with the SUV reduction (due to higher PPV) was at the expense of substantially lower sensitivity (66.7% for the >140% liver SUVmax criterion vs. 52.4% and 52.9% for SUV reduction at 2 and 4 cycles, respectively).

The concept of minimal residual uptake has been used in many studies, but its definition varies. For Mikhaeel et al., minimal residual uptake was defined as a focus of low-grade uptake in an area of previously noted disease, likely to represent inflammation but for which small-volume malignancy could not be excluded (20). Therefore, minimal residual uptake was a “gray zone” with intermediate prognosis, such as the “complete remission unconfirmed” category of conventional assessment (10). The definition of minimal residual uptake was more stringent in Hodgkin lymphoma: for Gallamini et al., the definition was uptake equal to or slightly higher than the MBP, with an SUV between 2.0 and 3.5 (3). In this case, minimal residual uptake was considered a negative finding. Finally, an international consensus for early PET evaluation has recently been reached favoring the use of the London criteria, which emphasize comparison of residual uptake with liver uptake (21). The London criteria are currently being validated and have already shown moderate to fair interobserver agreement (22,23).