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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2685-2693
PLENARY PAPER
Dose-adjusted EPOCH chemotherapy for untreated large B-cell
lymphomas: a pharmacodynamic approach with high efficacy
Wyndham H. Wilson,
Michael
L. Grossbard,
Stefania Pittaluga,
Diane Cole,
Deborah Pearson,
Nicole Drbohlav,
Seth M. Steinberg,
Richard F. Little,
John Janik,
Martin Gutierrez,
Mark Raffeld,
Louis Staudt,
Bruce D. Cheson,
Dan L. Longo,
Nancy Harris,
Elaine S. Jaffe,
Bruce A. Chabner,
Robert Wittes, and
Frank Balis
From the Center for Cancer Research, National Cancer
Institute, Bethesda, MD; Holy Cross Hospital, Ft Lauderdale, FL; St
Luke's-Roosevelt Hospital and Beth Israel Medical Center, New York,
NY; National Institute on Aging, Baltimore, MD; and Massachusetts
General Hospital, Boston, MA.
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 × 109/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
P2 = .08 and r = 0.45 and
P2 = .034, respectively). Free-etoposide
clearance increased significantly during successive cycles
(P2 = .015). Lymphomas with proliferation of
at least 80% had somewhat lower progression and those expressing bcl-2
had significantly higher progression
(P2 = .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 EPOCH may
produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in
younger patients, and compensate for increased drug clearance over time.
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