Epirubincin Does Not Lower The Risk Of Cardiac Toxicity Than Doxorubicin In Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma Grade 3 (FLG3): Results From a 398-Case Prospective Randomized Phase III Clinical Trial (NCT00854568)

Anthracylcine based regimens (i.e. cyclophosphamide, doxorubicin/epirubincin, vincristine and prednisone [CHOP/CEOP]) are standard chemotherapy in DLBCL and FL. On the other hand, the risk of anthracycline-induced cardiac toxicity (5%-26%) influences physician-treatment selection in certain patient populations (i.e. elderly, multiple co-morbid conditions, etc) and may affect negatively clinical outcomes especially in DLBCL patients. Previous research incicated that eprirubicin induced less cardiac toxicity compared to doxorubicin at the same dosage in breast cancer. However, higher dosage of eprirubicin is required in lymphoma regimen. Therefore, there is a need to study the cardiac toxicity differences between anthracycline-based regimens in the lymphoma treatment.

To this end, we prospectively randomized previously untreated DLBCL (Stage I-IV, N = 359) or FLG3 patients (Stage I-IV, N=38) to receive (ratio 1:1): cyclophosphamide at 750mg/m² on day (D) 2, vincristine at 1.4mg/m² on D2 (Cap at 2mg/dose), prednisone 100mg on D2-6 and epirubicin at 70mg/m² on D2 (CEOP) or cyclophosphamide at 750mg/m² on D2, vincristine 1.4mg/m² (Cap at 2mg/dose) on D2, prednisone 100mg on D2-6 and doxorubicin at 50mg/m² on D1(CHOP) with or without rituximab (based on antibody availability) at 375mg/m²on day 1. Cycles were repeated every 21 days for a total of 6-8 cycles. Demographic, clinical and pharmacological characteristics were recorded for each patient. Baseline and post-4 cycles of therapy assessment of left ventricular ejection fraction (LVEF) by multi gated acquisition (MUGA) scan was performed in each patient and as needed thereafter. Primary and secondary endpoints were: differences in the incidence of cardiac toxicity (as defined by grade 2 or higher cardiac dysfunction according to New York Heart Association Functional Classification or an LVEF <50% or at least 10% decrease in baseline LVEF during treatment), differences in clinical outcomes (i.e. response rate, progression free survival [PFS] and overall survival [OS]) and adverse events across treatment groups.

A total of 398 patients were randomly assigned to either CHOP/R+CHOP (N= 198, 56/142) or CEOP/R+CEOP (N=199, 67/132). Analysis was performed in evaluable patients (i.e. those patients completed at least 4 cycles of the planned therapy, N=348). Baseline demographic and clinical characteristics (i.e. stage, histology, IPI score, LVEF, etc.) were equally distributed among treatment groups. Surprisingly, CEOP/R+CEOP did not have lower cardiac toxicity incidence than CHOP/R+CHOP (15.6% vs. 16.7% P=0.778).

The risk of cardiac toxicity was similar across treatment groups after adjustments for age (≤65vs. >65yr), histology subtype (DLBCL vs. FL), co-morbid conditions, rituximab combination condition and/or cumulative anthracycline dose. The overall response rate (ORR) CHOP/R+CHOP vs. CEOP/R+CEOP (95.8% vs. 96.1%, P=0.895) and complete remission rate (CR) (70.0% vs. 72.6%, P=0.695) was similar between CHOP/R+CHOP and CEOP/R+CEOP treated patients. The ORR and CR were similar across treatment groups after adjustment for histology subtype (DLBCL vs. FL) and rituximab combination condition. Although more CHOP/R+CHOP treated patients exhibited febrile neutropenia when compared to CEOP/R+CEOP (27.4% vs. 17.2%, P=0.023), the difference of neutropenia and thrombocytopenia was not statistically different.

Our data suggests that CEOP/R+CEOP are not superior to CHOP/ R+CHOP in terms of cardiac toxicity. So CHOP/ R+CHOP are well tolerable and effective chemotherapy regimens for previously untreated DLBCL and FLG3. Moreover, CHOP regimen is more economic, especially in developing countries. However, CEOP/R+CEOP appear to induce less myeloid suppression than CHOP/R+CHOP. Longer follow up is necessary to determine differences in PFS, OS and delayed cardiac toxicity between these two anthracycline-based chemotherapy regimens.