Data generated by a randomized phase III trial involving 1,080 patients indicate that treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP 14) administered every 14 days does not improve overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma compared with standard 21-day treatment (R-CHOP 21). David Cunningham, MD, of The Royal Marsden Hospital, presented the trial results on behalf of the U.K. National Cancer Research Institute Lymphoma Clinical Study Group during the Lymphoma and Plasma Cell Disorders Oral Abstract Session on Saturday afternoon (Abstract 8000).
Treatment-naïve patients were randomly assigned in equal numbers (540 patients in each arm) to receive either eight cycles of RCHOP 21 or six cycles of R-CHOP 14 plus granulocyte colony-stimulating factor (GCSF) succeeded by two cycles of single-agent rituximab. The trial arms were balanced with respect to median age, B symptoms, bulky disease, disease stage, and IPI. Fifty-two percent of patients were age 60 or older; none were younger than age 19.
The study was designed to demonstrate an 8% difference in 2-year OS, the primary endpoint, from 75% to 83% with 5% significance level and 90% power following 233 deaths. However, after a median follow-up of 37 months and 237 deaths, Kaplan- Meier curves revealed hazard ratios of 0.96 (p = 0.75) for OS and 1.0 (p = 0.98) for PFS. The comparison of 88% overall response rate among patients receiving R-CHOP 21 with a 90% overall response rate in the R-CHOP 14 arm was not significant (p = 0.11).
Furthermore, patient status at 39 months as measured by death, survival without progression, survival with progression or relapse, deaths without documented progression, and progression or relapse followed by death was virtually identical for the two cohorts. No obvious subgroup appeared to derive a greater benefit from accelerated R-CHOP, including age older than 60, high International Prognostic Index (IPI) score, and two presumed predictors of prognosis in this disease: MIB1 status and the non-germinal center phenotype.
Although grade 3/4 nonhematologic toxicities were comparable in the two trial arms, neutropenia and febrile neutropenia were significantly more frequent in patients receiving the 21-day regimen (p < 0.01). This was probably a result of primary prophylaxis with G-CSF in patients receiving accelerated treatment. In contrast, thrombocytopenia was significantly more frequent (p < 0.01) in the R-CHOP 14 arm, probably as a consequence of greater therapeutic intensity. Toxicities, progressive disease, death, and patient choice contributed substantially to early termination of treatment in the accelerated arm (58 patients) and with standard treatment (107 patients).
he rationale for this trial was based on two established premises. First, it has been demonstrated that the addition of rituximab to six to eight cycles of CHOP improves OS in this disease setting by 10% to 16%. Second, six cycles of CHOP 14 has been shown to be superior to an equal number of cycles of CHOP 21 in patients older than age 60, improving 5-year OS by 13%. Dr. Cunningham concluded, however, that there is no evidence that combining these two premises clinically supports a shift in standard practice to R-CHOP 14.
In her discussion of Dr. Cunningham’s presentation and three other trials involving alternative treatments for diffuse large B-cell non-Hodgkin lymphoma, Julie M. Vose, MD, of the University of Nebraska Medical Center, said that R-CHOP 21 remains the standard treatment for patients older than age 60 and for younger patients with low IPI. For younger patients with high IPI, however, R-CHOP 21 followed by consolidation autotransplantation of peripheral stem cells should be offered as a standard of care.
Treatment-naïve patients were randomly assigned in equal numbers (540 patients in each arm) to receive either eight cycles of RCHOP 21 or six cycles of R-CHOP 14 plus granulocyte colony-stimulating factor (GCSF) succeeded by two cycles of single-agent rituximab. The trial arms were balanced with respect to median age, B symptoms, bulky disease, disease stage, and IPI. Fifty-two percent of patients were age 60 or older; none were younger than age 19.
The study was designed to demonstrate an 8% difference in 2-year OS, the primary endpoint, from 75% to 83% with 5% significance level and 90% power following 233 deaths. However, after a median follow-up of 37 months and 237 deaths, Kaplan- Meier curves revealed hazard ratios of 0.96 (p = 0.75) for OS and 1.0 (p = 0.98) for PFS. The comparison of 88% overall response rate among patients receiving R-CHOP 21 with a 90% overall response rate in the R-CHOP 14 arm was not significant (p = 0.11).
Furthermore, patient status at 39 months as measured by death, survival without progression, survival with progression or relapse, deaths without documented progression, and progression or relapse followed by death was virtually identical for the two cohorts. No obvious subgroup appeared to derive a greater benefit from accelerated R-CHOP, including age older than 60, high International Prognostic Index (IPI) score, and two presumed predictors of prognosis in this disease: MIB1 status and the non-germinal center phenotype.
Although grade 3/4 nonhematologic toxicities were comparable in the two trial arms, neutropenia and febrile neutropenia were significantly more frequent in patients receiving the 21-day regimen (p < 0.01). This was probably a result of primary prophylaxis with G-CSF in patients receiving accelerated treatment. In contrast, thrombocytopenia was significantly more frequent (p < 0.01) in the R-CHOP 14 arm, probably as a consequence of greater therapeutic intensity. Toxicities, progressive disease, death, and patient choice contributed substantially to early termination of treatment in the accelerated arm (58 patients) and with standard treatment (107 patients).
he rationale for this trial was based on two established premises. First, it has been demonstrated that the addition of rituximab to six to eight cycles of CHOP improves OS in this disease setting by 10% to 16%. Second, six cycles of CHOP 14 has been shown to be superior to an equal number of cycles of CHOP 21 in patients older than age 60, improving 5-year OS by 13%. Dr. Cunningham concluded, however, that there is no evidence that combining these two premises clinically supports a shift in standard practice to R-CHOP 14.
In her discussion of Dr. Cunningham’s presentation and three other trials involving alternative treatments for diffuse large B-cell non-Hodgkin lymphoma, Julie M. Vose, MD, of the University of Nebraska Medical Center, said that R-CHOP 21 remains the standard treatment for patients older than age 60 and for younger patients with low IPI. For younger patients with high IPI, however, R-CHOP 21 followed by consolidation autotransplantation of peripheral stem cells should be offered as a standard of care.
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