Chemotherapy Relative Dose Intensity and Therapy Efficacy in Hodgkin and Non-Hodgkin Lymphoma: The Effect of Dose Reductions and Delays on Cure

Introduction: The fundamental design behind combination chemotherapeutic regimens for hematologic malignancies is based on mathematical modeling that attempts to achieve rapid tumor reduction with appropriate cytotoxic doses given at predetermined intervals designed to minimize the chance of regrowth during treatment. The current standard primary treatment for Hodgkin lymphoma includes combination chemotherapy with Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine given at 14 day intervals (ABVD). For high-grade Non-Hodgkin lymphoma, the most common first line combination chemotherapy regimen includes Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone given at 21 day intervals (RCHOP-21). In clinical practice, it is common for patients to experience chemotherapy dose reductions or treatment delays due to various factors leading to a decrease in relative dose intensity (RDI). The relationship between chemotherapy relative dose intensity (RDI) and treatment efficacy was investigated.

Methods: Patients with Hodgkin lymphoma (HL) who received ABVD and patients with diffuse large B cell lymphoma (DLBCL) who received RCHOP-21 at our institution between 2004-2014 were retrospectively studied in 2 different cohorts. The following data was collected: age, sex, ethnicity, stage, Charleston Comorbidity Index (CCI), duration of follow-up, chemotherapy RDI, treatment outcome (remission vs primary refractory/relapse). The HL cohort consisted of 46 patients with the following characteristics: average age 36 years (range 18-74 years), 50% male/50% female, 50% Hispanic/50% Non-Hispanic, 44% early stage/56% late stage, 75% CCI 2/29% CCI >2, average follow-up 34 months (range 2-118 mo). The DLBCL cohort consisted of 104 patients with the following characteristics: average age 53 years (range 19-82 years), 50% male/50% female, 59% Hispanic/41% Non-Hispanic, 49% early stage/51% late stage, 60% CCI 2/40% CCI >2, average follow-up 34 months (range 2-163 mo).

Results: The HL cohort treated with ABVD had a mean RDI of 83% (range 50-100%) with outcomes as follows: remission 38 (82%), primary refractory 4 (9%), relapsed 4 (9%). Univariate analysis showed no difference in outcome between patients who received ABVD RDI >90% vs 80-89% vs <80% (p=0.6). The DLBCL cohort treated with RCHOP-21 had a mean RDI of 86% (range 32-100%) with outcomes as follows: remission 81 (79%), primary refractory 16 (15%), relapse 7 (6%). Univariate analysis showed no difference in outcome between patients who received RCHOP-21 RDI >90% vs 80-89% vs <80% (p=0.6). For both cohorts, there was no difference between outcomes based on stage (early vs advanced) or ethnicity (Hispanic vs Non-Hispanic). In the Hodgkin lymphoma cohort, there was a correlation between comorbidity index and RDI. Patients with higher CCI scores has a significantly lower average ABVD RDI compared to patients with lower CCI scores (77% vs 86%, p = 0.04).

Conclusions: There was no correlation between chemotherapy relative dose intensity and treatment efficacy in two cohorts of patients with Hodgkin lymphoma and diffuse large B cell lymphoma. These findings may suggest that for patients with these potentially curative hematologic malignancies, small dose reductions or short delays between chemotherapy cycles that result in decreased chemotherapy relative dose intensity may not affect overall outcomes. However, further studies are needed to determine the level at which a decreased relative dose intensity becomes significant.