New Standards Proposed for Treating Aggressive NHL-Age a Factor

HOMBURG, Germany—After conducting trials comparing CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) with and without etoposide and varying time intervals, the German High-Grade Non-Hodgkin’s Lymphoma Study Group concluded that CHOP plus etoposide is the new standard regimen for younger patients with low-risk non-Hodgkin’s lymphoma (NHL), and CHOP at 2-week intervals is the new standard regimen for aggressive NHL in older patients.

The two trials had the same objectives, though with different age groups: to improve treatment results in patients with aggressive NHL by shortening treatment intervals and/or adding CHOP to etoposide. Among the group of 18- to 60-year-olds, CHOEP (CHOP plus etoposide) achieved the objective. Among the group of 61- to 75-year-olds, shortening the time interval between CHOP treatment courses from 3 to 2 weeks achieved the objective. Michael G. Pfreundschuh, MD, of Medizinische Klinik I, Universität des Saarlands, Homburg, Germany, reported the results at the 43rd Annual Meeting of the American Society of Hematology.

Same Regimens and End Points

In both studies, patients were randomized to receive six cycles of CHOP(21) (CHOP every 3 weeks), CHOP(14) (CHOP every 2 weeks), CHOEP(21) (3-weekly CHOEP), or CHOEP(14) (2-weekly CHOEP). In both CHOEP groups, the etoposide was administered at 100 mg/m² on days 1 to 3. Patients in the 2-weekly regimens also received granulocyte colony-stimulating factor (G-CSF [Neupogen]) starting on day 4.

The primary end point for both studies was time to treatment failure. The interim analyses for both studies included patients who had either follow-up of more than 3 months after therapy, or an event (defined as disease progression, relapse, death, or initiation of alternative treatment).

Younger and Low Risk

The younger age group included 18- to 60-year-olds with untreated low-risk aggressive NHL. Low risk was defined as normal pretreatment lactate dehydrogenase (LDH). Inclusion criteria also included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, normal white blood count and platelets, and no major organ dysfunction.

Dr. Pfreundschuh presented interim data from July 2001 on 659 patients with a median age of 48. Sixty-six percent had no risk factors, according to the age-adjusted International Prognostic Index, 31% had one risk factor, and 3% had two risk factors. Twenty-eight percent of patients had bulky disease, defined as greater than 7.5 cm, and received 36 Gy of radiotherapy to the site. "All four regimens had a high relative dose intensity, clearly above 95%," Dr. Pfreundschuh reported.

Better Response in Etoposide-Containing Regimens

At nearly 84%, "the etoposide-containing regimens had a complete remission rate of 89.3%, vs 83.9% with CHOP," Dr. Pfreundschuh said. "In contrast, in this population, which did not have patients with elevated LDH indicating relatively fast-growing tumors, the effect of the time interval reduction was not significant. Similarly, there is no difference in time to treatment failure between the 2-weekly and 3-weekly regimen, but there is significant difference in the time to treatment failure with respect to the addition of etoposide." At a median time of observation of 40 months, time to progression was 72.8% for CHOEP vs 67.5% for CHOP. "The difference is not judged significant for overall survival," Dr. Pfreundschuh added.

Adding etoposide had the greatest effect—increasing the remission rate by 17%—among patients with one risk factor. "We are suggesting that the addition of etoposide compensates for one risk factor," Dr. Pfreundschuh said. After 40 months, there was also a 22% difference in time to treatment failure and a 15% difference in overall survival.

"CHOEP regimens have somewhat more hematologic toxicities," Dr. Pfreundschuh reported, and required more transfusions. There were no major differences in nonhematologic toxicities.

"We conclude that CHOP plus etoposide is superior to CHOP in young low-risk (low-LDH) patients," Dr. Pfreundschuh said. "Interval reduction did not improve outcome in patients with aggressive lymphoma and normal LDH. "CHOEP is no more toxic than CHOP, is well tolerated in this population of younger patients. We should therefore consider CHOEP(21) as the new standard regimen for low-risk (low-LDH) patients."

Older and Higher Risk

Patients in the second trial reported by Dr. Pfreundschuh were not only older (61 to 75 years old) but more likely to have elevated LDH and advanced disease (50%) and bulky disease (40%) requiring additional radiotherapy. Other inclusion criteria were the same as for the younger patients.

"Adherence to the protocol was quite good," Dr. Pfreundschuh reported, "except for the double-intensive CHOEP(14), where the relative dose dropped to 87%."

The interim analysis included 612 patients, with a median age of 67 years. Complete response rates ranged from 63.2% for CHOP(21) to 77% for CHOP(14), with the CHOEP rates in between (Table 1). "It is mostly patients with elevated LDH, a surrogate model for aggressive growth, that profit from this time interval reduction," Dr. Pfreundschuh said. "Whereas complete response rate only increased by 8% in patients with normal LDH, complete remission rate for patients with elevated LDH increased from 48% to 70%. This translates into significant differences in time to treatment failure. With a median time of observation of 40 months, difference in time to treatment failure is 14% between the worst arm—CHOP(21)—and the best arm—CHOP(14). This difference is similar for overall survival."

Hematologic toxicities in the 2-weekly regimen were not increased significantly, due to G-CSF. Patients in the CHOEP regimens had more cycles with platelets below 50,000/µL.

New Reference Standard

"In summary, CHOP(14) is superior to CHOP(21)," Dr. Pfreundschuh said. "It is the best of the tested arms in elderly patients with aggressive NHL. The 2-weekly regimen is feasible and toxicity is not increased over CHOP(21) due to the use of G-CSF. CHOP(14) is our new reference standard for this population."

Dr. Pfreundschuh related this finding to the presentation and conclusion by Bertrand Coiffier, MD (see "R-CHOP Benefits Increase Over Time for Aggressive Large B-Cell Lymphomas in Elderly"), that rituximab (Rituxan) plus CHOP is the new standard for elderly patients. "Although the trials cannot be compared directly, it is evident that the improvements achieved by either rituximab or the interval reduction are very similar. We have similar improvement in remission rates. We have identical improvement in 1- and 2-year survival rates (14%), only our trial has a 4-year survival rate that shows this advantage is stable.’’

"We have longer observation," he continued, "and the addition of rituximab costs about $24,000, compared to $12,000 for G-CSF."

Dr. Pfreundschuh called for trials to determine whether rituximab plus CHOP(14) can improve results through additive, synergistic, or complementary mechanisms. The new trial would compare CHOP(14) at either 6 or 8 cycles, with and without rituximab. "We hope to recruit 880 patients in 4 years," he said. "But it would be nice if we could considerably decrease the recruitment time by having the participation of cooperative groups from other countries."