Description of studies
A total of 403 potentially relevant studies were ascertained after the initial search (Figure 1). Of these, 31 articles from PubMed, 59 from Embase, 173 from Web of Science, 134 from Cochrane Library and 6 from clinicaltrials.gov. Then, 181 papers not relevant articles and 142 duplicated articles were expurgated by carefully reviewing the titles and abstracts. 66 pieces of literature were deleted by reason that these trials were conference reports, non-original data or data scarcity, review or meta-analysis, not RCHOP-14 VS RCHOP-21 and relative results. Finally, 6 RCTs (Cunningham et al., 2013, Delarue et al.,2013, Payandeh et al.,2016, Watanabe et al.,2018, Li et al.,2019, Gleeson et al.2016)and 2 OCSs (Wästerlid et al.,2017, Knauf et al.,2019) met all inclusion criteria entered in this meta-analysis(14-21).
Type of patients
In total, five studies included 5565 patients with B-cell NHL, whom 2892 underwent RCHOP-14, and 2673 underwent RCHOP-21 only. The experimental characteristics of each RCT are summarized in Table 1. Most of the enrolled trials in different countries, four of which are included in Europe, four trails accounting for studies were in Asian. We collected patients with clinical stage I -IV aggressive lymphoma and untreated III-IVV stage indolent B-cell NHL, who were older than 18 years. G-CSF(Granulocyte ColonyFactor) was applied to both the RCHOP-14 group and the RCHOP-21 group to shorten CHOP. -Stimulating Moreover, the sample sizes for individual studies varied widely from 50 to 2106 despite were multi-center clinical trials.
Six RCTs were assessed as low risk in the light of a suitable option (Figure 2A and 2B). However, four of RCTs have a high risk of selection bias as Allocation concealment(14, 16, 18, 21). All funnel plots of PFS and OS were symmetrical, indicating no publication bias( Figure 2C and 2D). The selection of high-quality OCSs was based on a validated tool. Two OCSs were evaluated by NOS(Table 2), and the results suggested that both of them were high-quality literature.
Complete response rate data were available from 8 studies(14-21)，incorporating 2657 patients from the RCHOP-14 therapeutic regimen and 2415 patients from the RCHOP-21 regimen. As shown in Figure 3, we find that significant heterogeneity within these two regimes (χ2=17.69, P=0.007, I2=66 % )，then the random-effects model was used.CR rate not meliorated with RCHOP-14 regimens in patients (OR= 0.96, 95% CI 0.76–1.23, P= 0.76). The results of the RCTs and OCSs were consistent, so we calculated the data together and displayed it on a graph.
The PFS and OS of RCHOP-14 versus RCHOP-21 as the main long-term clinical outcome evaluation with B-cell lymphoma. Figure 4 and 5 suggest that no significant between-trial heterogeneity was observed between PFS and OS, then, we choose the fixed-effect model. The results of the OCSs were consistent with the RCTs, so we presented these data in a single graph and stratified the clinical outcomes of patients with different prognoses based on IPI.For the comparison, PFS was curtailed in RCHOP-14, but it showed no significant difference ( HR = 0.94, 95 % CI 0.84-1.06, P= 0.32). Results were not altered after differentiating patients with different IPI scores（Figure 4）, in other words, the two regimens of chemotherapy are equivalent for patients with aggressive or indolent lymphoma. As shown in Figure 5, regarding OS, there was a tendency that RCHOP-14 was superior to RCHOP-21 (HR=0.91, 95% CI 0.83–1.01, P= 0.08). However, there was still no statistical difference among the trials. After stratification according to the IPI score, the OS of patients with different prognosis was in agreement with the outcome indicators of all patients.
AEs with both RCHOP-14 and RCHOP-21 treatment protocol were reviewed in all RCTs, including both hematological and non-hematological toxicities. Table 3 summarizes the grade ≥ 3 adverse events.we have used RR( Risk Ratio) values to compare the adverse events of the five studies in the supplementary picture, the toxicity of RCHOP-14 regimen and RCHOP-21 regimen has no significant high risk ( RR=0.98, 95% CI 0.83–1.15, P=0.73). I2 = 85% suggested greater heterogeneity among the trials, which was statistically significant. The subgroup analysis results on hematological AEs that the incidences of thrombocytopenia(RR= 0.87, 95% CI 0.60–1.25, P= 0.44) were higher in the RCHOP-14 arm[9, 10, 12-14], although there is no statistical significance. One of subgroup analysis were observed with patients who received RCHOP-21, which has a higher trend to have Anemia when removing to Watanabe et.al. (RR= 1.15, 95% CI 0.88–1.50, P= 0.29 ) (14, 17, 18). The subgroup analysis on non-hematological AEs indicates that Patients treated with RCHOP-21 had a higher risk of neurological-related, which were not statistically significant(RR= 1.41, 95% CI 0.85–2.33, P= 0.18 ).