Continued Risk of Relapse Independent of Treatment Modality in Limited-Stage Diffuse Large B-Cell Lymphoma: Final and Long-Term Analysis of Southwest Oncology Group Study S8736

Abstract

Purpose: Utility of combined-modality therapy for patients with limited-stage diffuse large B-cell lymphoma (DLBCL) was shown in the Southwest Oncology Group (SWOG) S8736 study, where three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus radiotherapy (CHOP3RT) improved 5-year progression-free (PFS) and overall survival (OS) compared with eight cycles of CHOP (CHOP8). Subsequent analysis showed an unexpected overlap of the PFS curves. We aimed to confirm and investigate this observation by performing long-term analysis of SWOG S8736 and evaluating these data alongside data from similar patients receiving rituximab and CHOP3RT (SWOG S0014 study).

Patients and methods: A subset of patients with limited-stage DLBCL randomly assigned to CHOP8 (n = 150) or CHOP3RT (n = 158) in S8736 was analyzed along with a 56-patient subset treated in S0014 for long-term PFS and OS.

Results: Median follow-up in S8736 was 17.7 years. In patients receiving CHOP8 and CHOP3RT, median PFS was 12.0 (95% CI, 8.8 to 14.3) and 11.1 years (95% CI, 8.9 to 14.4), respectively. There were no statistically significant differences in PFS between the groups (P = .73). Median OS was 13.0 (95% CI, 10.4 to 15.2) and 13.7 years (95% CI, 11.1 to 19.4) for patients treated with CHOP8 and CHOP3RT, respectively. Similarly, there were no statistically significant differences in OS between the groups (P = .38). With a median follow-up time 12 years in S0014, 5- and 10-year OS were 82% and 67%, respectively, with a persistent pattern of relapse despite the addition of rituximab.

Conclusion: Although 5-year PFS and OS were improved after early analysis in patients with limited-stage DLBCL receiving CHOP3RT versus CHOP8, extended survival data showed similar PFS and OS, with continuous treatment failure. The addition of rituximab (S0014) to combined-modality therapy did not mitigate the continued relapse risk, underscoring the value of prolonged clinical trial patient observation and possible unique biology of limited-stage DLBCL.

Trial registration: ClinicalTrials.gov NCT00005089.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

(A) Progression-free (PFS) and (B) overall survival (OS) of patients receiving CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for eight cycles (CHOP8) or CHOP for three cycles plus radiotherapy (CHOP3RT) with prolonged follow-up. 5-, 10-, and 15-year estimates are included. (*) Two-sided log-rank test.

Fig 2.

(A) Progression-free (PFS) and (B) overall survival (OS) of patients receiving three cycles of rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus radiotherapy (R-CHOP3RT) with prolonged follow-up. 5- and 10-year estimates are included. Median follow-up was 12 years.

Fig 3.

Cumulative incidence of (A) progression and (B) second malignancy for patients in S8736. Death before disease progression or death before development of a second malignancy was considered a competing risk. CHOP3RT, three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus radiotherapy; CHOP8, eight cycles of CHOP.

Fig A1.

CONSORT diagram for S8736. CHOP3RT, three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus radiotherapy; DLBCL, diffuse large B-cell lymphoma; DLCL, diffuse large-cell lymphoma; DSCC, diffuse small cleaved-cell lymphoma; FL-3, grade 3 follicular lymphoma; MALT, mucosa-associated lymphoid tissue lymphoma; MCL, mantle cell lymphoma; PTL, primary thyroid lymphoma; T-ALCL, T-cell anaplastic large-cell lymphoma.

Fig A2.

Progression-free survival by stage-modified International Prognostic Index (IPI). sa, stage-adjusted.