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Meta-analysis of radiotherapy for DLBCL
ommendations are not fully supported by the results of this meta-analysis, especially by the results of the strati- fied analysis provided in Figure 5. The International Lymphoma Radiation Oncology Group (ILROG) has recently updated its guidelines, albeit in the relapsed and refractory setting.39 The trials analyzed in our meta-analy- sis did not specifically include patients with extranodal DLBCL for which both ESMO40 and ILROG41 have pub- lished separate guidelines. Specifically, consolidative mediastinal radiotherapy is currently recommended in responding primary mediastinal B-cell lymphoma (PMBL) patients after treatment with standard-dose chemoim- munotherapy.40 However, extrapolation of the data of our meta-analysis on DLBCL not otherwise specified (NOS) to and from entities such as primary mediastinal lym- phoma, primary central nervous system (CNS) or testicu- lar lymphoma is discouraged. The safe omission of whole brain radiotherapy for CNS lymphomas is conceptually controversial.42,43 As the role of adjuvant mediastinal radiotherapy in PMBL patients with complete remission after chemotherapy is unclear and a large number of patients are cured by chemotherapy alone with DA- EPOCH-R,44 it is important to note that accrual in IELSG- 37 (clinicaltrials gov. Identifier: NCT01599559) has recently been completed; this potentially practice chang- ing randomized trial with a non-inferiority design has evaluated the role of consolidation radiotherapy in PET- negative patients.
Our meta-analysis provides further evidence that
patients with a complete morphologic remission after chemotherapy or initial bulky disease are unlikely to par- ticularly profit from consolidation radiotherapy.25,38 PET has become an integral part of the treatment of DLBCL patients, although the prognostic value of interim PET is limited,45,46 and a PET-based escalation of chemotherapy was unable to improve the outcome.47 None of the trials that we included in our meta-analysis used a truly PET- guided treatment approach. This was applied in limited stage DLBCL in a retrospective32 and also a prospective,30 albeit non-randomized trial. In order not to add also radiotherapy to the recent painful flaws in clinical DLBCL research,3,4 our meta-analysis should be taken into account when a new trial is planned. We provide evidence on patients that we should rather not selective- ly irradiate, but we still do not know how to use consol- idation radiotherapy. Besides its wide and established use in localized disease,5 we see the rationale use of radiotherapy in DLBCL patients analogous to the current situation in Hodgkin’s disease, e.g., for insufficient responses to chemo-immunotherapy. Considering retro- spective trials,38,48 radiotherapy could be restricted to PET-positive rests. Among other unanswered questions, this would be practice changing. Ideally, this hypothesis needs corroboration in two separate prospective trials to randomly apply radiotherapy in trial 1 for patients with PET-negative, and trial 2 for patients with PET-positive rests. The first trial would be a non-inferiority trial to proof whether it is safe to not irradiate patients perceived
Figure 5. Stratified progression free survival analysis on the effect of consolidation radiotherapy. Circles are proportional to stratum size i.e., overall number of patients in stratum; color of circles reflects number of trials in stratum i.e., from black (seven trials) to light grey (one trial); age, stage, and bulky disease are char- acteristics of the study population and cannot be interpreted on the individual participant level (ecological fallacy). CI: Confidence Interval.
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