Six cycles of R-CHOP-21 are not inferior to eight cycles for treatment of diffuse large B-cell lymphoma: a Nordic Lymphoma Group Population-based Study
Authors: T. Wästerlid, J.L. Biccler, P.N. Brown, M. Bøgsted, G. Enblad, J. Mészáros Jørgensen, J.H. Christensen, B.E. Wahlin, K.E. Smedby, T.C. El-Galaly, M. Jerkeman
Journal: Annals of Oncology (2018)

The majority of randomised clinical trials that have established R-CHOP-21 as the current standard treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) have applied eight cycles of chemotherapy [1.Coiffier B. Lepage E. Briere J. et al.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 235-242Crossref PubMed Scopus (4490) Google Scholar, 2.Habermann T.M. Weller E.A. Morrison V.A. et al.Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.J Clin Oncol. 2006; 24: 3121-3127Crossref PubMed Scopus (1147) Google Scholar, 3.Cunningham D. Hawkes E.A. Jack A. et al.Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.Lancet. 2013; 381: 1817-1826Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]. Despite a lack of solid evidence to support the use of six instead of eight cycles of R-CHOP-21, six cycles are commonly assigned in clinical routine and endorsed in guidelines. No randomised trial has demonstrated superiority of eight compared with six cycles of R-CHOP-21. Therefore, we examined whether the use of six versus eight cycles of R-CHOP-21 had impact on survival probability, using data from the Danish and Swedish lymphoma registries, as previously described [4.Biccler J. Eloranta S. de Nully Brown P. et al.Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI.Cancer Med. 2018; 7: 114-122Crossref PubMed Scopus (19) Google Scholar]. This study includes 1170 adult patients diagnosed with DLBCL 2007–2014 in Sweden and Denmark, who received treatment with six or eight cycles of R-CHOP-21. Of these, 1013 (87%) were administered six cycles and 157 (13%) received eight cycles. Median follow-up time was 5.0 years (range 1.2–9.4). Reflecting the population-based setting, patient characteristics in the two treatment groups slightly differed and were marginally inferior in the cohort treated with eight cycles of R-CHOP-21. In survival estimates, crude 5-year overall survival (OS) rates were similar for patients treated with six and eight cycles of R-CHOP-21; 74% (95% CI: 71% to 77%) and 72% (95% CI: 63% to 79%), respectively (Figure 1). Furthermore, in a multivariate Cox model adjusting for IPI variables and gender, eight cycles of R-CHOP-21 was not associated with better outcome than six cycles [hazard ratio (HR): 0.92; 95% CI: 0.66–1.29; P= 0.63]. To further adjust for imbalances in prognostic factors, a matched sample analysis was carried out. Here, the 157 patients who received 8 cycles were compared with 157 patients who received 6 cycles of chemotherapy, matched according to IPI variables and bulky disease. Similar 5-year OS of 72% (95% CI: 63% to 79%) and 76% (95% CI: 67% to 83%) were observed in the cohort treated with eight and six cycles, respectively. Consistently, no evidence of a difference was observed in a multivariate analysis [HR with six cycles: 0.88 (95% CI: 0.54–1.44); P= 0.62]. Additionally, no evidence of a difference in outcome according to use of six or eight cycles of R-CHOP-21 were observed in subgroup analyses stratified according to age ≤/>70, low- and high-risk IPI score, and excluding patients treated with consolidative radiotherapy. These results are in line with results from the Eastern Cooperative Oncology Group/Cancer and Leukaemia Group B 9703 study, where the outcome of patients who received six cycles of R-CHOP-21 were comparable to those of patients with similar patient characteristics treated with eight cycles in the GELA study [1.Coiffier B. Lepage E. Briere J. et al.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 235-242Crossref PubMed Scopus (4490) Google Scholar, 2.Habermann T.M. Weller E.A. Morrison V.A. et al.Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.J Clin Oncol. 2006; 24: 3121-3127Crossref PubMed Scopus (1147) Google Scholar]. The RICOVER-60 trial demonstrated increased toxicity in absence of improved outcome with eight compared with six cycles of R-CHOP-14 [5.Pfreundschuh M. Schubert J. Ziepert M. et al.Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).Lancet Oncol. 2008; 9: 105-116Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar]. However, only elderly patients (aged 60–80 years) were included and a similar comparison of R-CHOP-21 has not been carried out. Thus, the present study contributes valuable data regarding the use of six cycles of R-CHOP-21 among patients of all ages and risk groups. In summary, we note that the majority of patients with DLBCL treated with R-CHOP-21 during the surveyed time period received six cycles, and conclude that outcomes following six or eight cycles of R-CHOP-21 for newly diagnosed DLBCL are comparable in terms of efficacy. None declared.