Evolving Treatment Paradigms for Primary Mediastinal Diffuse Large B-Cell Lymphoma

Primary mediastinal diffuse large B-cell lymphoma (PMBL) was first described in the 1980s as a distinct clinicopathologic entity. In the last three decades we have realized significant advances in our understanding of its disease biology while developing therapeutic regimens associated with high cure rates. PMBL is defined by a rapidly growing dominant mediastinal mass, frequently accompanied by local invasiveness and superior vena cava syndrome; involvement outside of the thorax at initial presentation is infrequent and virtually never includes bone marrow. Relapses have been reported disproportionately to involve extranodal sites such as liver, kidney, and CNS. The median age at presentation is in the third to fourth decade with a female predominance. For the practicing oncologist, the clinical similarities to Hodgkin lymphoma (HL) at presentation are striking. Fascinatingly, these similarities also extend to the molecular level, with gene expression profiling demonstrating greater similarities between HL and PMBL than with diffuse large B-cell lymphoma (DLBCL), likely reflecting convergent biologic mechanisms for neoplastic evasion of immune responses. Recent work has identified PMBL disease biology as dependent on molecular pathways involving REL, JAK-STAT, PDL1/PDL2 and nuclear factor (NF ). The relative rarity of this diagnosis (only 6% to 10% of all DLBCL) has impeded the ability to perform prospective trials. Historic reports with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) –like chemotherapy and radiation consolidation revealed suboptimal outcomes characterized by early progression and poor salvage options, which were potentially overcome by more dose-intensive regimens. In the current chemoimmunotherapy era, reports integrating rituximab with CHOP or third-generation regimens (eg, methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin [MACOP-B]) have resulted in quite favorable outcomes with cure rates generally in the range of 80% compared with approximately 50% prerituximab. Efforts are now focusing on minimizing long-term toxicity while maintaining high cure rates. One of the major concerns, again paralleling clinical problems common to the HL patient, are the long-term risks of mediastinal radiation therapy (RT) in a young, predominantly female population including hypothyroidism, accelerated atherosclerotic heart disease, and lung and breast cancer. Retrospective reports before rituximab integration have suggested that nonradiation containing dose-dense approaches such as NHL-15 are associated with excellent long-term outcomes. Current efforts to address these concerns have focused on two approaches: (1) restricting the need for involved field radiation therapy (IFRT) by utilizing functional imaging adapted approaches to limit the use of radiation or (2) developing chemo-immunotherapy programs without intended radiation consolidation. The integration of positron emission tomography (PET) imaging into the end of therapy response assessment in aggressive lymphoma was made part of the standard of care with the revised response criteria reported in 2007. Given early reports in Hodgkin lymphoma where PET dichotomized patients into excellent and poor predicted outcomes based on negative and positive results, it has been enticing to believe we can use functional imaging as an early biomarker to risk adapt therapy. However, many questions remain surrounding PET interpretation if we are to use this modality to adjudicate the need for additional therapy in DLBCL. In an idealized setting, a discriminating biologic predictor (such as PET scanning) assessed at end of treatment should possess both a high-negative predictive value for relapse if one is to safely reduce or limit therapy and possess a high-positive predictive value for relapse if one is to identifies a population where more intensive or alternative therapies should be explored. In that regard, it is generally accepted that the negative predictive value of PET imaging in DLBCL, both as an interim assessment or at end of therapy, has been high ( 90%). Unfortunately, this has not necessarily held true regarding the positive predictive value of PET imaging in DBLCL. In a Memorial Sloan Kettering Cancer Center (MSKCC) study rigorously confirming positive interim PET scans with biopsy, the false positive rate was exceedingly high (only 13% demonstrated lymphoma) and often reflected inflammatory processes or necrotic tumor rather than viable tumor. Similar concerns exist for PET at the end of therapy for PMBL, where PET-positive rates of approximately 50% after DAEPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxiorubin plus rituximab) were associated with excellent outcomes despite no further therapy. Nevertheless, the British Columbia Cancer Agency has presented a retrospective analysis of 96 PMBL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) by treatment era, where IFRT was routine for all patients before 2005 and utilized only in PET-positive instances after 2005. Of 59 patients, 59% were PET negative (33 of 35 no RT) and 41% were PET positive (23 of 24 received RT) with no reported survival difference at 5 years. With the caveat that this was a retrospective analysis of different practice patterns and not a controlled trial, it suggests functional imaging may define a population where RT can be omitted. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 17 JUNE 1