Background
Aggressive lymphoma is known to be a highly chemosensitive disease. Therefore, over the past few decades, constant attempts have been made to develop various types of combination chemotherapy including first generation combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) [
1]. However, particularly in patients with aggressive lymphoma in the higher International Prognostic Index (IPI) risk group, satisfactory outcomes have not been achieved, with a five-year survival of less than 50% [
2].
Several retrospective studies demonstrated that the relative dose intensity (RDI) of combination chemotherapy significantly influences survival in aggressive lymphoma [
3‐
7].
Moreover, rituximab, a chimeric monoclonal anti-CD20 antibody combined with CHOP chemotherapy (R-CHOP) has improved outcome in patients with diffuse large B-cell lymphoma (DLBL) [
8,
9]. Rituximab has direct, complement-dependent and antibody-dependent cellular cytotoxicity against B-cells. The drug also sensitizes B-lymphoma cells to chemotherapy [
10]. Therefore, a combined approach with rituximab plus CHOP could conceivably modify the effects of RDI. However, there is no evidence that even in combination chemotherapy with rituximab that higher RDI improves the outcome for aggressive B-cell type lymphoma. Hence, in our study, we retrospectively analyzed the impact of the RDI of chemotherapy with R-CHOP as an initial treatment on the survival of patients with DLBL, and furthermore, we determined the factors influencing RDI.
Discussion
In DLBL patients, our data demonstrated that a high RDI of CHOP trended towards a significant association with better survival, even when the CHOP was combined with rituximab. Only advanced age was identified as a risk factor for reduced RDI.
There are several previous studies of the relationship between the RDI of chemotherapy and survival in aggressive lymphoma. A high RDI of doxorubicin in CHOP, M-BACOD, or MACOP-B chemotherapy [
4], a high RDI of each drug (cyclophosphamide, doxorubicin or vincristine) and a high averaged RDI of these three drugs in CHOP for diffuse large cell lymphoma (DLCL) reportedly had a significant, positive impact on survival [
5]. In addition, in ACVB chemotherapy for aggressive lymphoma, the averaged RDI of doxorubicin and cyclophosphamide was strongly associated with survival [
6]. Furthermore, it was reported that in elderly patients with DLCL who received a higher dose of doxorubicin, the outcomes were comparable to those of young patients [
16]. In a recent study, a Belgian group also reported that maintaining a high RDI resulted in a favorable outcome in CHOP chemotherapy for DLBL patients [
7].
The addition of rituximab to CHOP or other chemotherapy regimens has reportedly led to a significant improvement in the prognosis of DLBL patients. Interestingly, it was suggested from preclinical models that rituximab chemosensitized drug-resistant B-lymphoma cells through down-regulation of anti-apoptotic factors and endogenous IL-10 expression [
17,
18], suggesting that rituximab is likely to have a significant therapeutic effect by augmenting the effect of anticancer agents in CHOP in a synergistic fashion and thereby compensating for a low CHOP RDI. However, from our results, it was clear that maintaining a high RDI remained crucial in the use of R-CHOP for DLBL patients, in a similar fashion to CHOP alone.
We identified advanced age as the only factor that reduced RDI. A nationwide study of RDI in CHOP-like chemotherapies in patients with non-Hodgkin's lymphoma (NHL) in the United States also showed that older age was a risk factors for reduced RDI, in addition to lack of use of prophylactic colony stimulating factor (CSF), advanced disease stage, poor PS and a lower serum albumin level [
19]. Moreover, the study indicated that prophylactic CSF use is important in maintaining a high RDI, particularly in elderly patients. The American Society of Clinical Oncology update guideline for the use of CSF, also recommends use of prophylactic CSF during curative and intensive chemotherapy for elderly patients with DLCL, to reduce the incidence of febrile neutropenia and infections [
14]. In addition, according to the European Organization for Research and Treatment of Cancer guideline on the use of G-CSF, when dose-dense or dose-intense chemotherapy has a survival benefit, prophylactic G-CSF use is recommended, especially in elderly patients [
20]. Indeed, in a prospective study on prediction of febrile neutropenia in the first cycle of chemotherapy for NHL, elderly patients were identified as candidates for primary CSF prophylaxis [
21]. Taking into account these reports as well as our results, prophylactic use of CSF could be recommend, at least in elderly patients with DLBL who are scheduled to receive R-CHOP chemotherapy in order to maintain RDI.
As our study was a retrospective cohort study with a small study population and/or short median follow-up periods, it was inevitable that treatment bias due to physician discretion in making treatment decisions would arise. Therefore, prospective randomized trials will be required to confirm the value of maintaining a high RDI. For instance, an alternative strategy to intensify RDI by shortening the intervals between cycles of chemotherapy, such as bi-weekly CHOP, may be promising [
22]. Indeed, Groupe d'Etudes de Lymphomes de L'Adulte (GELA) is now conducting a phase III prospective randomized trial to assess the difference between eight cycles of bi-weekly R-CHOP and three-weekly R-CHOP. The results of this prospective randomized trial are awaited.
Conclusion
In DLBL patients, mortality was affected by the RDI of R-CHOP as the initial treatment and the retention of high RDI could be crucial, especially in elderly patients. To optimize the RDI of conventional chemotherapy in order to achieve better outcomes for patients with DLBL, further investigation of RDI will be required.
Acknowledgements
We thanks for clinical research nurse. Yukari Umemoto (Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan) for assistance in obtaining clinical data and follow-up information.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All the authors contributed as mentioned. YT and HN conceived of the study and drafted the manuscript. RA obtained clinical data and follow-up information by reviewing the patients' medical records. MO reviewed the pathological specimens in this study. HK, ES, MA, EI, HK, TN, YT, MO, KK, TY, YN, KO, AM, and HT participated in designing the study and helped to write the paper. MH supervised the entire study. All authors have read and approved the final manuscript.