Therapy with of RCHOP-14 Versus RCHOP-21 for People With Aggressive or Advanced Stage Indolent B-Cell Non-Hodgkins Lymphoma: A Systematic Review and Meta-Analysis

Background: With the advent of rituximab, RCHOP is considered the appropriate chemotherapy for aggressive or advanced stage indolent B-cell Non-Hodgkins Lymphoma(NHL). RCHOP-14 seems to achieve better outcomes than RCHOP -21 in aggressive or advanced stage indolent B-cell NHL patients in recent years. Methods: To verify the betting chemotherapy regimens for B-cell NHL patients, we searched the electronic databases for relevant English-language literature published through January 2020. The primary outcomes were complete response(CR),progression-free survival (PFS), overall survival(OS), and Adverse events (AEs). Six eligible Phase II and III clinical randomized controlled trials (RCTs) and two high-quality observational comparative studies (OCSs)were extracted, and 5565 B-cell NHL patients involved in evaluable. Results: The analysis demonstrated no signicant difference for CR rate (OR= 0.98,95%CI 0.77-1.24 (cid:0) P=0.85)between RCHOP-14 and RCHOP-21. Compared with RCHOP-21, the merged hazard ratio (HR) for PFS and OS was, respectively, 0.94 (95% CI: 0.84-1.06, P=0.32) and 0.91(95% CI: 0.83-1.01, P= 0.08) after treatment with RCHOP-14.A subgroup analysis based on the international prognostic index(IPI) score showed that both chemotherapy regimens were applicable in B-cell NHL patients with different prognosis. The frequency of toxic side-effects was similar between schemes. Conclusions: Therefore, the data presented suggest that the ecacy and safety of both regimens are comparable and that R-CHOP14 remains a viable plan in B-cell NHL patients who prefer a shorter therapy course. respectively, in accordance with the previously published guidelines for statistical reporting and a systematic review manual on Cochrane interventions. PFS and OS, as the dichotomous data, were reported with hazard ratios (HRs) and 95%CIs. is by the inverse of variance to weigh the size of the individual effect.CR rate was calculated by odds ratio (OR) with the random-effects model (M-H adverse to analyze using the Risk calculated either same forest map for meta-analysis was drawn. If possible, sensibility analysis is conducted to investigate the origins of heterogeneity. Funnel were performed to conrm attest to the presence of publication bias. statistical analyses


Background
Aggressive and indolent lymphomas are two subtypes of B-cell-derived NHL, and they have different chemotherapy regimens depending on the prognosis. Aggressive NHL is a highly aggressive malignancy with a poor outcome,which is a greatly chemo-sensitive tumor and is highly curable (1). Advanced stage indolent NHL is often incurable and can easily be converted to aggressive lymphoma, but it can be alleviated with a regimen of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) (2,3). Diffuse large B-cell lymphoma (DLBCL )is the most common subtype of aggressive lymphoma, which is a disease of biologically, histopathologically, and clinically heterogeneous entity (4). The median survival of NHL patients without prompt treatment was less than one year, on account of its aggressive nature (5,6). For a long time, the rst-line chemotherapy treatment for DLBCL is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which is more reasonable to choose CHOP-21 that is every 3 weeks in combination. Some RCTs were enquired about the survival analysis of dose-intensi ed regimens, and then showing that the two-week cycle of chemotherapy  is superordinate than the CHOP-21 (7,8).
There is a human/ murine chimeric anti-CD20 monoclonal antibody called rituximab, which has a credible e cacy. It has a well-de ned and adequately safe for patients with various lymphoid malignancies that CD20-expressing, such as aggressive and indolent forms of Bcell NHL (9). follicular lymphoma(FL) is a neoplasm comprising germinal center B cells, is a subgroup of indolent lymphomas, and the rituximab-CHOP is the standard option for advanced-stage FL patients (10). NHL(PMBL) is a unique subtype of DLBCL, which originates from thymic B-cells in the mediastinum. The RCHOP regimen with or without consolidative radiotherapy (RT) is the rst-line management of PMBL (11). For all of these diseases, which include DLBL, FL, mantle cell lymphoma (ML), and chronic lymphocytic leukemia, it can be proved that rituximab-based treatment not only extends the time of progression-free survival but also prolongs the overall survival time (12). Therefore, it is meaningful to discuss the choice of RCHOP-14 vs 21 chemotherapy regimen based on rituximab for aggressive or advanced stage indolent B-cell NHL.
We implement trails from RCTs and OCSs to estimate the e cacy and toxicity of a chemotherapy regimen as RCHOP-14 compared to RCHOP-21 for patients with B-cell NHL, the results as an on CR, PFS, OS and toxic.

Search strategy
Firstly, we search to conduct a systematic and comprehensive search from original to January 2020 throughout databases, including PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov.The prede ned keywords with Boolean operators were used for the search: ("RCHOP-14 AND RCHOP-21" OR "dose-dense") AND "lymphoma". The electronic search was complemented by a manual search for additional articles in reference lists and previous reviews, rendering certain a full-scale investigation.

Results
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.

Type of patients
In total, ve 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.

Qualityassessment
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.

E cacy
We enrolled trials must meeting the below inclusion criteria: (1) studies based on RCTs and high-quality OCSs;(2) participants were newly diagnosed aggressive lymphoma at clinical stage I to IV or untreated advanced-stage indolent B-cell NHL;(3) comparative analysis of RCHOP-14 and RCHOP-21 for treating B-cell NHL; (4) follow-up duration longer than 36 months (5) CR PFS or OS was existence outcome in the articles. The containing of duplicated data that might lead to an overestimation of intervention effects was cautious. Review articles, conference abstracts, nonhuman studies, case reports, abstracts, and unpublished data were excluded from consideration. Moreover, studies had no extractable data that were also excluded. A senior referee was consulted if divergence regarding which studies to include.
Data extraction and quality assessment Relevant Data were extracted from included articles by two authors independently. The following data were extracted: the rst author, published year, location, disease, stage, median age, median follow-up, number of patients with IPI at different levels, sample size, number of cycles, and clinical outcomes, including CR,PFS OS and toxicity. We assessed the quality of RCTs using the Cochrane Collaboration's risk of bias tool Rev Man5.3. The quality of selected studies will be appraised with methodological domains as follows: risks of selection, performance, detection, attrition, and reporting biases. For the included study, types of bias are divided into 3 levels: low, unclear, high. The Newcastle-Ottawa-Scale(NOS) uses three categories: the selection of study groups, comparability, and outcome assessment, respectively, to evaluate the risk of bias of OCSs.

Statistical analysis
A meta-analysis of variables with three or more studies was performed when the outcome was reported. Statistical heterogeneity among individual studies was calculated by the P and I 2 test, and heterogeneity will be considered substantive if I 2 > 50% (13). The xed-effect model and the random-effects model were utilized for consistent and heterogeneous studies, respectively, in accordance with the previously published guidelines for statistical reporting and a systematic review manual on Cochrane interventions. PFS and OS, as the dichotomous data, were reported with hazard ratios (HRs) and 95%CIs. HR is calculated by the inverse of variance to weigh the size of the individual effect.CR rate was calculated by odds ratio (OR) with the random-effects model (M-H methods), and adverse events to analyze using the Risk Ratio(RR) were calculated either the same model. Then, the forest map for meta-analysis was drawn. If possible, sensibility analysis is conducted to investigate the origins of heterogeneity. Funnel plots were performed to con rm attest to the presence of publication bias. All statistical analyses were conducted in Review Manager 5.3.

Survival
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 signi cant between-trial heterogeneity was observed between PFS and OS, then, we choose the xed-effect model. The results of the OCSs were consistent with the RCTs, so we presented these data in a single graph and strati ed the clinical outcomes of patients with different prognoses based on IPI.For the comparison, PFS was curtailed in RCHOP-14, but it showed no signi cant 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 strati cation according to the IPI score, the OS of patients with different prognosis was in agreement with the outcome indicators of all patients.

Treatment-related toxicity
AEs with both RCHOP-14 and RCHOP-21 treatment protocol were reviewed in all RCTs, including both hematological and nonhematological toxicities. Table 3

Discussion
In clinical, RCHOP-14 and RCHOP-21 are the two different international standards, respectively, which were used for the treatment of B-cell lymphoma. This manuscript implies that the CR rate, PFS, and OS were higher in patients who assigned to RCHOP-14 therapy, but its outcomes did not differ signi cantly. This indicates that the CR rate, PFS, and OS in these patients may be unable to be improved through the way RCHOP-14. Whether the addition of radiotherapy can change this outcome requires more RCTs to con rm. The previous metaanalysis has shown that the treatment options of RCHOP were manifested to prolong OS when given every 14 days instead of 21 days as in case rituximab is omitted (22). In our analysis, it showed that RCHOP-14 and RCHOP-21 have no statistically signi cant difference in FPS and OS, which is inconsistent with previous ndings. Nevertheless, many researchers do not embrace that R-CHOP-14 is the rst-line treatment of DLBCL until bringing a randomized study with a control arm of R-CHOP-21 into force, also, the fear that it is too toxic of RCHOP-14 regimen is another reason.
Toxicity was an important endpoint of our study. There is a higher risk of infectious complications associated with RCHOP14,particularly febrile neutropenia, due to infections caused by opportunistic pathogens (23)(24)(25). But our study shows that the toxic of R-CHOP-14 regimen is the same as the RCHOP-21 regimen in B-cell patients, rather than exceed. One reason for the RCHOP-14 regimen has the same safety maybe that prophylactic recombinant human granulocyte colony-stimulating factor(G-CSF). G-CSF has often been used to potentiate the antibody-dependent cell-mediated cytotoxicity of rituximab (26,27), then can be shortened CHOP intervals (7,8,28,29).In spite of prophylactic recombinant human G-CSF, patients were given every 14 days developed more grade 3 to 4 neutropenia than reported previously (14). One of toxic is thrombocytopenia, which more obviously in the RCHOP-14 regimen, and thus may increase the chance of intravenous platelet. Meanwhile, RCHOP-21 is more likely to occur anemia events, which lead to the frequency of transfusion. Another obvious reason is that there is greater heterogeneity between subgroups and the results may be unreliable.
As far as we can see, it is the rst meta-analysis to assess the e cacy and toxicity based on rituximab with the CHOP regimen in patients with aggressive or advanced stage indolent B-cell NHL, and it is the rst to analyze survival outcomes for patients with different prognostic outcomes based on IPI scores. The data suggested that we would face type 2 errors in the RCTs, the main argument for including OCSs is trying to avoid making this mistake. But the meta-analysis is still some limitations. Firstly, two studies maybe cause performance and detection biases because of they were open-label trails. In the second place, the low number of included studies made it di cult to probe in-depth with in detail and to interpret potential underlying heterogeneity. When we ascertaining heterogeneity among individual studies for toxic, which is still signi cantly high after removing the relevant study. The reason for the high heterogeneity may be the different prognosis of B-cell NHL and the inconsistent chemotherapy cycle. Therefore, we need more RCT to explore the potential causes of heterogeneity. In the end, other covariates, such as supportive therapy, preventive measures of toxicity, and the pro ciency of the doctor, could not be balanced in the study.

Conclusions
To sum up, an analysis of data from clinical trials of RCHOP-14 treatment showed that the therapies are safe and effective compare with the RCHOP-21. However, it was no signi cant difference in PFS and OS, and that it produces clinical responses similar to those in CR rate. Additional considerations as regards the choice of followed treatment strategy and balancing treatment-related toxicity may help us to decide for treatment with RCHOP-14 or RCHOP-21.

Availability of data and materials
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
No potential con icts of interest were disclosed.   Figure 1 Flow diagram of the study selection process.