Recently revised response criteria by the International Working Group (IWC) incorporated PET scans as part of therapy response assessment of aggressive NHLs [1
]. The rationale for integrating PET into previous IWC criteria was based on several retrospective studies carried out mostly in the prerituximab era that demonstrated improved diagnostic accuracy of PET scans compared with the previous gold standard CT scans ( and ). These studies demonstrated that mid-therapy PET scans in nonrituximab-treated patients exhibit PPV of 71%–100%, NPV of 67%–100%, Se of 42%–100%, and Sp of 75%–100% for prediction of lymphoma relapse or progression. Similarly, posttherapy PET scans in the same patient population exhibited PPV of 79%–100%, NPV of 65%–100%, Se of 43%–100%, and Sp of 81%–100%. Furthermore, Juweid et al. reported that in 54 patients with aggressive NHL (47 DLBCL) treated with an anthracycline-based regimen (only 29 patients received rituximab), posttherapy PET increased the number of CR patients, eliminated the CRu category, and enhanced the ability to discern the difference in PFS between patients with CR and PR [16
The role of mid-therapy PET during first-line therapy of aggressive NHL
There are several limitations of these previously reported studies including the use of now outmoded chemotherapy and the retrospective nature of the studies. The current gold standard therapy has evolved to include rituximab with chemotherapy. This therapeutic evolution might result in a change in the predictive value of PET scans, as was previously reported for biological markers, requiring reevaluation of PET accuracy in patients treated with rituximab–chemotherapy combination. This is especially important since the mechanism of action of rituximab may involve inflammatory changes associated with recruitment of immune cells to the tumor which might lead to false-positive PET results. Similar findings were previously reported in animal models [17
In comparison to previous reports in nonrituximab-treated patients, our study demonstrates lower PPV and Se of mid and posttherapy PET for prediction of lymphoma relapse. Of note, similarly low PPV for mid-therapy PET scans was recently reported by Haioun et al. in a group of 90 patients with B- and T-cell NHL, 37 of which were treated with rituximab-containing therapies [9
]. In our study, nonspecific inflammation and necrosis were the most common pathological changes in patients with false-positive PET scan that underwent biopsies. In a recent prospective study of dose-dense R-CHOP followed by risk-adapted consolidation therapy presented by Moskowitz et al. [18
] in an abstract at the American Society of Hematology annual meeting in 2006, mid-therapy PET scan was positive in 31 of 81 patients (36%) of which only four (13%) had evidence of lymphoma. Similar to our findings, nonspecific inflammatory changes and necrosis accounted for false-positive PET scans in the remaining patients. There was no difference in PFS and OS between PET-positive and -negative patients, as was also observed in our study. Overall, these initial observations suggest that in rituximab-treated patients, mid- and/or posttherapy PET positivity does not necessary imply persistence of lymphoma and requires biopsy to confirm presence of lymphoma and to rule nonspecific inflammatory changes and necrosis. In patients with dissociated response (persistence of FDG uptake in one locus and disappearance of uptake in other previously avid sites) or appearance of FDG uptake in a previously nonavid site, biopsy should be carried out to rule out unrelated secondary neoplasm, as was shown in three of our patients.
Although incorporation of rituximab into the therapeutic regimen likely accounts for the discrepancy in PET predictive value between our study and historical studies, other causes might contribute to the observed differences. In contrast to our study that included only patients with aggressive B-cell NHL (DLBCL and MCL), other studies frequently also included patients with Hodgkin’s lymphoma, T-cell lymphomas, and different B-cell lymphoma subtypes. In addition, the reported studies differ in the definition of positive PET imaging, in the timing of PET imaging relative to chemotherapy, and in the chemotherapeutic regimen used. In our study, mid-therapy PET was carried out 2 weeks postchemotherapy and posttherapy PET scan was carried out at least 1 month after the last cycle of chemotherapy. Performance of mid-therapy PET scan 2 weeks after preceding therapy might contribute to higher incidence of false-positive scans.
In the present study, we also examined the clinical potential of surveillance PET scans for detection of lymphoma relapse postcompletion of chemotherapy. Follow-up PET scans were usually carried out at 3–6 month intervals postchemotherapy completion. Our results demonstrate that in majority of patients, lymphoma relapse could be diagnosed based on new patients complains, clinical examination findings, and/or findings on CT scans. Furthermore, false-positive surveillance PET scans were common. Consequently, our findings suggest that routine postend of therapy surveillance PET scans should not be carried out for detection of lymphoma relapse.
Although a major strength of this study is that it is one of the first that has evaluated the value of PET scans in assessing patients with B-cell NHL uniformly treated with rituximab–chemotherapy combination, it harbors several potential limitations. The study was retrospective and included only patients who had pretreatment and treatment evaluation PET scans, thus potentially introducing bias in patient inclusion. Furthermore, not every patient with a positive PET scan underwent diagnostic biopsy. However, our findings are consistent with preliminary results of a prospective study reported by Moskowitz et al. in which all patients with mid-therapy PET had biopsies that in majority of cases demonstrated inflammatory changes without evidence of lymphoma. Another limitation of our study is nonhomogeneous diagnosis and incorporation of patients with both DLBCL and MCL. MCL is currently considered a noncurable disease and majority of patients relapse following standard therapy. MCL patients included in this study were treated on phase II investigational protocol that resulted in 100% CR rate with only one relapse during the follow-up period. Five of these patients had positive mid-therapy PET scan results and two of these five patients also had a positive posttherapy PET that became negative during further follow-up. These findings might contribute to the lower PPV stemming from a higher false-positive rate. However, separate analysis limited only to DLBCL patients still demonstrated lower PPV and Se compared with reported studies in nonrituximab-treated patients (data not shown).
In conclusion, our findings suggest that mid- and end of therapy PET positivity may have a limited prognostic implication in the treatment of patient with aggressive B-cell NHL in the era of rituximab. Given this low PPV, positive PET imaging in residual masses of patients with aggressive B-cell NHL treated with rituximab-based chemotherapy requires histological confirmation of lymphoma persistence before a change in therapeutic plan and institution of salvage chemotherapy. Similar to prerituximab era, mid- and end of therapy negative PET scans are associated with prolonged PFS of patients with aggressive B-cell NHL. Large prospective clinical trials of NHL patients with homogeneous histological subtype treated with a uniform rituximab–chemotherapy regimen and evaluated based on standardized criteria are warranted to validate our data.