Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy

Abstract

We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 ؋ 10 9 /L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r ‫؍‬ ؊0.54 and P 2 ‫؍‬ .08 and r ‫؍‬ ؊0.45 and P 2 ‫؍‬ .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P 2 ‫؍‬ .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P 2 ‫؍‬ .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EP-OCH may produce more cell kill than CHOPbased regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time. (Blood. 2002;99:2685-2693

Activity and safety of dose‐adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab in very elderly patients with poor‐prognostic untreated diffuse large B‐cell non‐Hodgkin lymphoma

“…Etoposide was omitted and, in view of an outpatient care program, cyclophosphamide was administered on Day 1 together with rituximab to deliver both the noncontinuously infused drugs on the same day of each cycle. Our data confirm efficacy and safety of dynamic dose adjustment of infusional doxorubicin in DLBCL patients, providing additional support for results already published with DA-EPOCH-R, [15][16][17][18] albeit not specifically restricted to elderly population (Table 6). …”

“…As expected, the most frequent grade 3 to 4 AEs were neutropenia and febrile neutropenia, which occurred in 48% and 13% of patients, respectively. However, the observed rates of AEs with DA-POCH-R did not differ from those reported in other dose-adjusted regimens [14][15][16][17] and were substantially lower than AE rates observed in a series of doxorubicin-free protocols [31][32][33][34][35][36][37][38][39][40]42,44 specifically tailored for elderly patients with DLBCL (Table 6).…”

“…13,14 Dynamic dose adjustment of the EPOCH regimen (DA-EPOCH) has resulted in dose escalations, limited hematopoietic toxicity, and no cardiac complications or treatment-related deaths, even in patients with acquired immunodeficiency syndrome (AIDS) -related lymphoma. [15][16][17][18] The addition of rituximab (monoclonal anti-CD20 antibody) to the conventional CHOP regimen (R-CHOP) has been reported to increase the likelihood of response and long-term event-free survival, with no overlapping toxicity, in elderly patients with poor-prognosis DLBCL. 19 The objective of this study was to assess efficacy and safety, with special attention to hematological and cardiac toxicity, of the combination of rituximab and dose-adjusted infusional CHOP chemotherapy (DA-POCH-R) for patients with poor-prognostic untreated DLBCL aged >70 years and over.…”

Contiguous papillary thyroid cancer and mediastinal lymphoma

“…Patients described in the literature tend to be young, with bulky disease that is most often confined to the thorax and contiguous structures [10] . Most patients have an excellent clinical response to multidrug chemotherapy, with 80% complete response rates, and 60%-80% relapse-free survival at five years [10][11][12][13] . In the present case, the temporal association between the discovery of the macroscopic papillary thyroid cancer and a contiguous mediastinal mass suggested a unifying diagnosis of aggressive, locally invasive thyroid cancer.…”

Human T cell lymphotropic virus-associated leukemia/lymphoma

“…An infusional regimen, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, is currently being evaluated in combination with interferon-α and combivir in the National Cancer Institutesponsored clinical study #AMC 033. The etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen was chosen on the basis of its activity in refractory lymphomas and in HIV-associated lymphomas [43,44].…”