Bulky Aggressive B-Cell Lymphoma: To Radiate or Not to Radiate—That Is the Question

The role of radiation therapy (RT) in the management of lymphoma is an ongoing controversy. This is partly because of a generation of young patients with Hodgkin lymphoma (HL) who have been treated with mantle irradiation and ultimately cured of their HL, only to suffer significant serious sequelae years later. These late complications include secondary malignancies, particularly breast cancer, valvular heart disease, and premature coronary artery disease. The result has been excessive morbidity and mortality for patients, as well as polarization of treating physicians. Why not just do away with RT in lymphoma, for which we already have a pharmacy full of effective drugs? The fact is, if one considered RT a drug, it would be one of the most effective agents available. Consider the fact that 40 to 50 Gy of involved-field RT was more effective than five cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Southwest Oncology Group (SWOG) protocol 8736, which established the standard of care in limited-stage diffuse large B-cell lymphoma (DLBCL). However, since publication of the SWOG 8736 results, the role of RT in DLBCL has become less clear. At least three reports have been published that have demonstrated little or no value from consolidation RT in limited-stage DLBCL. Each of these studies differed in patient selection and trial design, and none used rituximab with the chemotherapy. Complicating matters, in the era of rituximab plus CHOP (R-CHOP), at least two trials suggest an ongoing role for consolidation RT. The net result is a potpourri of interpretations. Any savvy investigator can take this body of literature and make the case for or against RT. The National Comprehensive Cancer Network guidelines reflect the uncertainty. In limited-stage DLBCL, RT is recommended if one uses three cycles of R-CHOP, and it is considered optional (even when treating bulky disease) if one opts for a full six cycles of R-CHOP. In advanced-stage DLBCL, RT is considered optional if treating bulky disease. In the article that accompanies this editorial, Held et al provide compelling yet imperfect data that suggest substantial clinical benefit when 36 Gy of radiation is administered to sites of initial bulk, after six cycles of standard therapy, in patients with all stages of aggressive B-cell lymphoma. It is a complicated study with an even more complicated analysis. The data are generated from a spin-off from the Rituximab With CHOP Over 60 Years (RICOVER-60) trial, which was a randomized study testing CHOP-14 with and without rituximab (R) for either six or eight cycles in a 2 2 factorial design. Eligible patients were between the ages of 61 and 80 years, with any Ann Arbor stage. The RICOVER-60 protocol dictated 36 Gy of external-beam radiation to any extranodal sites and any sites of initial bulk (mass 7.5 cm). This strategy has been common practice in Germany for many years. After declaring R-CHOP-14 6 to be the winning arm, the protocol was amended and enrolled 166 additional patients, all of whom received R-CHOP-14 6 with no planned RT. These 166 patients (47 with bulky disease) were then compared with 306 patients (117 with bulky disease) from the parent study, forming the basis for the current report. Because this was not a randomized controlled trial, the two groups of patients were not balanced for important baseline characteristics. The proportion of patients with bulky disease decreased after amendment, suggesting that a selection bias may have emerged. However, patients with bulky disease who were enrolled after amendment (no RT) were more likely to have stage III to IV disease and a trend for higher-risk International Prognostic Index scores. With these caveats in mind, a per-protocol analysis reveals major clinical benefit for the inclusion of RT. This approach, which considers the patients on the basis of treatment received and ignores protocol violations, found that RT inclusion significantly improves progression-free and overall survival (hazard ratio [HR], 4.4; P .001, and HR, 4.3; P .002, respectively; Figs 2B and 2C of the Held article). However, by intentto-treat analysis, the differences in progression-free and overall survival are just trends, with HRs of 1.8 (P .058) and 1.6 (P .127), respectively. It is always difficult to know what to believe when the intent-to-treat analysis results differ from the per-protocol results. I suspect that the truth is somewhere in between. If correct, then the HRs in this instance will still favor RT inclusion. At the same time, it seems likely that the selection of patients for consolidative RT can be refined with functional imaging. Selecting an arbitrary cut point (7.5 cm) for RT inclusion is relatively crude. By this criterion, a 7-cm mass is managed in the same way as a 3-cm mass, and an 8-cm mass is managed in the same way as a 20-cm mass, whereas the 7-cm and the 8-cm masses are handled differently. Also, committing to the consolidation RT on the basis of baseline disease characteristics ignores features such rapidity and quality of response. This is sort of anti-Bayesian. End-of-treatment [F]fluorodeoxyglucose–positron emission tomography (FDG-PET) imaging has been demonstrated to be more accurate than computed tomography imaging for discerning complete from partial responses. Indeed, investigators at the British Columbia Cancer Agency have already demonstrated how FDG-PET imaging after R-CHOP can be used to successfully triage patients with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 11 APRIL 1