At least 11 studies have failed to show a benefit for high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as 1st line treatment in high-risk DLBCL patients. Other than the MInT trial among young low risk DLBCL patients, there is no randomised study in DLBCL using 6 cycles only of 21-day R-CHOP, either among young high risk (= 60 yrs) or elderly (60-80 yrs), patients.r
In the SWOG 9704 trial using 8 cycles of R-CHOP21 the PFS rate was only 54% in this high IPI risk group of DLBCL patients.r For R-CHOP patients, the 2-yr PFS = 63% in the control and 73% in the transplant group (HR, 1.56; 95% CI, 0.92 to 2.63; P=0.10). This 10% difference in PFS is not statistically significant, since the study was highly underpowered to allow a meaningful comparison. By international statistical standards, need a much larger sample size.r
For patients = 60 yrs with high risk DLBCL Age-Adjusted International Prognostic Index (aaIPI = 2-3), the best results recorded to date derive from the German randomised Mega-CHOEP studyr in which R-CHOEP14 x 8 cycles was associated with an EFS at 3 yrs of 74% and OS at 3 yrs of 85%. To date, these are the best results ever reported among high risk DLBCL aa IPI=2-3.
In the Italian FIL study among a similar cohort of DLBCL patients with aaIPI = 2-3, 6 cycles of R-CHOP14 was associated with a PFS of 62.7%r in a matched paired analysis with patients from the Mega-CHOEP study, although not statistically significantly different R-CHOP14 was still somewhat inferior compared to 8 cycles of R-CHOEP14 (62.7% vs 73.7% respectively, P=0.1776).
A retrospective Danish study among high risk DLBCL in patients = 60 years, showed superior PFS for R-CHOEP14 compared to R-CHOP14 with rates of 70% versus 58% at 4 yrs, respectively.r
In a recent population-based Swedish study among DLBCL patients = 70 yrs, there was no difference in survival outcomes between R-CHOP21 compared to R-CHOP14, however, R-CHOEP14 showed superior survival compared to both.r Patients had either R-CHOP-21 (n=302), R-CHOP-14 (n=872) or R-CHOEP-14 (n=157). At a median follow-up time of 49 months, 3-yr OS rates were 86.7%, 79.6% and 87.5% for R-CHOP-21, R-CHOP-14 and R-CHOEP-14, respectively. In a multivariable Cox regression model, R-CHOEP-14 was significantly superior to R-CHOP-21 (HR 0.53, CI:0.3-0.9, P=0.026) and R-CHOP-14 (HR: 0.63, CI: 0.4-1.0, P=0.048). Outcomes for R-CHOP-14 were similar to that for R-CHOP-21 (HR: 0.84, CI: 0.6-1.2, p=0.3), consistent with findings from randomised trials.
Although somewhat similar to R-CHOEP14, DA-EPOCH-R has never been tested in a multi-centre randomised clinical trial and has only ever been published as a single centre phase 2 study.r
Contentious issues include: i. whether 6 or 8 cycles of R-CHOEP14 is required in this young high-risk group of DLBCL patients; ii. whether in the pending US Intergroup randomised open label phase 3 trial, DA-EPOCH-R will be associated with outcomes that are superior to those of R-CHOP21 among all, low risk, or high risk DLBCL patients, and whether any incremental benefit in survival (PFS or OS) will be similar to that achieved with R-CHOEP14 among the young high risk DLBCL group; iii. whether the addition of novel agents such as Ibrutinib, Lenalidomide, or GA101 monoclonal antibody, will prove more beneficial among high risk DLBCL patients.
In the Mega-CHOEP study, 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months, 3-year event-free survival was 69·5% (95% CI 61·3-77·7) in the R-CHOEP-14 group and 61·4% (52·8-70·0) in the R-MegaCHOEP group (p=0·14; hazard ratio 1·3, 95% CI 0·9-2·0). In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects.
R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy.r
© Lancet Oncol 2012
Toxicity of R-CHOEP14 is primarily haematological. Grade 4 leucopenia was seen among 48 (58·5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. Grade 3-4 thrombocytopenia was seen in 26 (33·8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 40 (31·3%) of 128 patients treated with R-CHOEP-14.r
At this stage there is no data to indicate whether the addition of etoposide leads to any substantial increase in the risk of secondary MDS or AML.