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1630 Part XI: Malignant Lymphoid Diseases Chapter 98: Diffuse Large B-Cell Lymphoma and Related Diseases 1631

etoposide)/CytaBOM (cytarabine, bleomycin, vincristine, methotrex- statistically significant findings (p <0.05). These results suggest that
ate), and MACOP-B (high-dose methotrexate, doxorubicin, cyclophos- six cycles of rituximab with a CHOP-like regimen is the best therapy
phamide, vincristine, prednisone, bleomycin) appeared to show superior for young patients with good-prognosis DLBCL. Subset analysis sug-
response rates compared to previously published results achieved with gested that patients with an IPI of zero and no bulky disease represent
CHOP. However, the benefits demonstrated in single-institution stud- a very favorable subgroup with a 3-year EFS of 89 percent whereas
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ies could not be replicated in multiinstitutional studies, or with extended patients with an age-adjusted IPI of 1 and bulky disease represent a less-
followup. A prospective randomized study that compared m-BACOD favorable subgroup with only a 74 percent 3-year EFS.
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with CHOP showed no difference in the CR rates, DFS, or OS. Because Investigators have attempted to improve the efficacy of R-CHOP
of these conflicting data, a four-arm phase III study was conducted and by reducing the time between doses to every 14 days (R-CHOP-14),
enrolled patients in a randomized prospective trial comparing CHOP, thereby increasing the “dose-density.” Unfortunately, three randomized
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m-BACOD, MACOP-B, and ProMACE/CytaBOM. This landmark trials have shown no improvement in EFS, PFS, or OS with R-CHOP-14
trial enrolled 897 patients with intermediate- or high-grade lymphoma, compared to R-CHOP-21, and the dose-dense regimen was associated
of whom 85 percent had diffuse or follicular large cell lymphoma. In with increased hematologic toxicity. 60,61 On the other hand, an intensi-
the trial, each of these regimens produced equivalent results. The fied combination chemotherapy regimen developed for younger patients
DFS was 35 to 40 percent with a 4-year survival of 36 percent in the by GELA, known as R-ACVBP (rituximab, doxorubicin, cyclophos-
patients who received CHOP, 34 percent in the m-BACOD group, 45 phamide, vindesine, bleomycin, and prednisone as induction, followed
percent in those treated with ProMACE/CytaBOM, and 39 percent in by consolidation, including methotrexate, etoposide, and cytarabine)
the MACOP-B group (p = 0.14). CHOP chemotherapy was the safest was shown to have superior EFS (81 percent vs. 67 percent) and OS
regimen, with only 1 percent treatment-related mortality compared to (92 percent vs. 84 percent) compared to R-CHOP-21 in a randomized
6 percent mortality with MACOP-B. In this randomized phase III trial, trial of 379 DLBCL patients younger than the age of 60 years with an
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the more intensive regimens offered no improvement in the remission age-adjusted IPI of 1. However, patients experienced a substantially
rate, DFS, or OS compared to the simpler and safer CHOP regimen. In higher risk of hematologic toxicity and serious adverse events with
retrospect, the improved complete response rates observed in the ini- R-ACVBP (42 percent vs. 15 percent with R-CHOP).
tial, single-institution phase II clinical trials of the augmented regimens In a novel strategy to enhance chemotherapy efficacy, investiga-
appear to have been a result of enrollment of a disproportionate patients tors at the United States National Cancer Institute developed an infu-
with favorable IPI scores. sional chemotherapy regimen known as EPOCH (containing etoposide,
In 2002, a major randomized clinical trial conducted by GELA prednisone, vincristine, cyclophosphamide, and doxorubicin). In this
demonstrated not only increased efficacy, but minimal added toxicity, regimen, vincristine, etoposide, and doxorubicin are administered by
with the addition of the monoclonal antibody rituximab to CHOP in continuous infusion over 96 hours, and cyclophosphamide is admin-
older adults with DLBCL. 55,56 In this study, 399 patients 60 to 80 years istered as a bolus. The regimen is based on in vitro data that showed
of age with newly diagnosed DLBCL were randomized to receive either that lymphoma cells exhibited less chemotherapy resistance when
eight cycles of CHOP given every 21 days (CHOP-21) or the same che- exposed to prolonged low concentrations of vincristine, doxorubicin,
motherapy with eight infusions of rituximab. The combination of CHOP and etoposide than when exposed to brief, higher concentrations of
and rituximab significantly improved the CR rate from 63 to 76 percent, the same drugs. EPOCH was initially evaluated in 131 patients with
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EFS from 38 to 57 percent, and OS from 57 to 70 percent compared relapsed or refractory lymphoma and demonstrated a 74 percent over-
to CHOP-21 without rituximab. There were no differences in toxicity all response rate and tolerable toxicity. Pharmacokinetics demon-
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other than a higher risk of minor cardiac events, many of which were strated considerable interpatient variability and suggested the need for
attributed to rituximab infusion reactions. These results were confirmed dose adjustments to optimize outcomes for individual patients. This
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by an ECOG group trial, in which 632 older patients were treated with observation led to incorporation of a dose-adjustment strategy based
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six to eight cycles of CHOP-21 and randomized to the same chemother- on the observed hematopoietic nadir with each cycle of treatment.
apy plus five infusions of rituximab. In this study, 2-year failure-free Fifty patients with previously untreated DLBCL were treated with
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survival was 53 percent after a median followup of 3.5 years in patients dose-adjusted EPOCH and demonstrated a complete response rate of
receiving R-CHOP compared to 46 percent for patients receiving CHOP 92 percent with PFS and OS rates of 70 and 73 percent, respectively.
alone. A second randomization in this trial suggested that patients who In a subsequent trial, 72 patients with untreated DLBCL were treated
received R-CHOP did not benefit from maintenance rituximab therapy. with dose-adjusted EPOCH and rituximab with 5-year PFS and OS of
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In the RICOVER-60 study, 1222 elderly patients were randomized to six 79 percent and 80 percent, respectively. A randomized study comparing
or eight cycles of CHOP given every 14 days with leukocyte growth fac- rituximab plus EPOCH (R-EPOCH) to R-CHOP in untreated DLBCL
tor support (CHOP-14) or six to eight cycles of R-CHOP-14. Six cycles has recently been completed but the results have not yet been reported
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of R-CHOP-14 significantly improved EFS, PFS, and OS compared to (Cancer and Leukemia Group B study 50303). 68
six cycles of CHOP-14. No benefit was conferred by administering eight In summary, R-CHOP administered every 21 days has emerged
cycles of R-CHOP-14 rather than six cycles of R-CHOP-14. as the modern standard of care for DLBCL, based on the demonstra-
The benefit of adding rituximab to CHOP-like chemotherapy in tion of superior outcomes and acceptable toxicity compared to CHOP
younger patients was subsequently confirmed by The Monoclonal in randomized clinical trials. Neither intensifying therapy by add-
Antibody Therapeutic International Trial (MInT) Group. A total of ing chemotherapy agents, nor altering dose density, have substantially
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824 patients with a good prognosis and an age-adjusted IPI of 0 or 1, improved upon the therapeutic ratio of the standard R-CHOP regimen.
and stage II to IV disease or stage I with bulky adenopathy, were ran- As a novel approach, infusional chemotherapy with dose-adjusted R-
domized to receive six cycles of a CHOP-like regimens or the same EPOCH remains under investigation in a prospective randomized trial in
regimen plus rituximab. Patients with bulky (>5 cm) disease received the United States. An improved understanding of the heterogeneous biol-
additional radiotherapy to those areas. After a median observation time ogy of DLBCL, and identification of tumor-defined prognostic subgroups
of 34 months, the addition of rituximab increased the EFS from 59 with therapy modified accordingly, may soon permit tailored treatment
percent to 79 percent, and the OS from 84 percent to 93 percent, both approaches to maximize cure rates for the ABC and GCB subtypes.

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