Radiotherapy Is NOT Essential to Cure Diffuse Large B-Cell Non-Hodgkin Lymphoma

The only defined role for radiotherapy (RT) in treating diffuse large B-cell non-Hodgkin lymphoma (DLBCL) is in the setting of limited disease: stage I and II, nonbulky disease that can be encompassed in a single radiotherapy port. That role was largely determined in studies of combined modality treatment (CMT) using initial doxorubicin-containing chemotherapy (CHOP) followed by involved-field radiotherapy (IFRT). Miller et al in a landmark trial (SWOG 8736) demonstrated that 3 cycles of CHOP followed by IFRT at doses of 40–50 Gy was associated with superior 5-year progression-free survival (PFS) and overall survival (OS) compared with 8 cycles of CHOP alone.[1] Connors et al showed virtually similar outcomes with their British Columbia Cancer Agency experience.[2] However, a subsequent study, ECOG 1484, showed that while IFRT was associated with statistically borderline improvement in disease-free survival (DFS) and local control in patients with complete response (CR) after CHOP, no difference in OS was noted.[3] Similar outcomes were noted with the LNH 93-4 and 93-1 trials that assessed CMT vs CHOP + dose-intense chemotherapy in older and younger patients, respectively.[4,5] Notably, all of these trials were conducted prior to the advent of monoclonal antibodies that have dramatically changed the treatment landscape in DLBCL.

To date, there have been no phase III data in the rituximab (Rituxan) era that have addressed IFRT in limited-stage DLBCL. Persky et al have shown that 3 cycles of R-CHOP + IFRT have been effective across high-risk groups in DLBCL. Importantly, analysis of sites of recurrence showed that most failures occurred at distant sites, echoing the theme observed in the prior trials.[6] Further, in retrospective analyses of patients in the Mabthera International Trial (MInT), bulky disease was shown to affect clinical outcomes, including OS, which suggests that IFRT after chemoimmunotherapy does not eliminate the unfavorable prognostic risk of bulky disease.[7,8] Analyses of the RICOVER-60 trial have also suggested that chemoimmunotherapy is sufficient, and that IFRT can be omitted without compromising outcomes.[9]

PET imaging is a sensitive diagnostic tool, and PET-adapted therapy is changing risk stratification in lymphoma. In data presented by Sehn et al, patients received 3 cycles of R-CHOP and were staged with a PET scan. PET-negative patients received an additional cycle of R-CHOP, and PET-positive patients received IFRT. Only 1/49 PET-negative patients relapsed, with an estimated 2-year PFS of 93%.[10] Similar results were observed with ECOG 3402; nearly all patients achieved a functional response without the requirement of IFRT.[11]

While the therapeutic landscape in DLBCL is rapidly evolving, with improved risk stratification using new modalities (eg, PET-adapted therapy) and emerging therapeutic advances, DLBCL of any stage remains a systemic disease with early hematogenous spread. Thus, arguments advocating the role of IFRT do not truly address disease biology, and all future efforts to cure patients will require improved systemic therapy.

References:

References

1. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med. 1998;339:21-6.

2. Shenkier TN, Voss N, Fairey R, et al. Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency. J Clin Oncol. 2002;20:197-204.

3. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004;22:3032-8.

4. Bonnet C, Fillet G, Mounier N, et al. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2007;25:787-92.

5. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005;352:1197-205.

6. Persky DO, Unger JM, Spier CM, et al. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008;26:2258-63.

7. Pfreundschuh M, Ho AD, Cavallin-Stahl E, et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol. 2008;9:435-44.

8. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379-91.

9. Pfreundschuh M. How I treat elderly patients with diffuse large B-cell lymphoma. Blood. 2010;116:5103-10.

10. Sehn L, Savage K, Hoskins P, et al. Limited-stage DLBCL patients with a negative PET scan following 3 cycles of R-CHOP have an excellent outcome following abbreviated immuno-chemotherapy alone. Ann Oncol. 2008;19(Suppl 4):abstr 052.

11. Witzig T, Hong F, Micallef I, et al. A phase II trial of R-CHOP followed by zevalin radioimmunotherapy for patients with previously untreated stages I and II CD20+ diffuse large cell non-Hodgkin’s lymphoma: an Eastern Cooperative Oncology Group Study (E3402). Blood (ASH annual meeting abstracts). 2012;120: abstr 2687.