Abstract & Commentary
Synopsis: Since the introduction of the 3-weekly CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) chemotherapy 25 years ago, many efforts have been undertaken to improve the efficacy of multicycle polychemotherapy for patients with aggressive lymphoma. A variety of regimens were invented by adding drugs and alternating schedules. In a prospective, randomized trial, the current every 3-week CHOP regimen was considered the standard chemotherapy regimen for aggressive lymphoma.1 This study was done in the era prior to the widespread use of hematopoietic growth factors. Studies with growth factors to increase dose intensity were not successful enough to alter the standard of care.2 In older patients, CHOP variants have also been published but have yet to yield improvement in overall outcome.3 The addition of rituximab to this standard has recently been shown to improve outcome in older patients.4 The German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) investigated whether specific intensifications of the classical 3-weekly CHOP regimen could improve overall outcome. One was the addition of another cytotoxic agent. Etoposide was chosen due to data showing efficacy in lymphoma. The second method was the shortening of the time intervals of the CHOP regimen. This was done with the use of G-CSF (filgrastim). Source: Wunderlich A, et al. Ann Oncol. 2003;14:881-893.
In 1993 the DSHNHL activated a multicenter, randomized phase III trial called NHL-B. Four treatment options were compared in a 2 x 2 factorial design. CHOP chemotherapy was planned to be given in 21-day intervals without rhG-CSF (CHOP-21) or in 14-day intervals with the addition of rhG-CSF (CHOP-14). Two further treatment arms resulted from the addition of etoposide (CHOEP-21 and CHOEP-14). The trial was formally split into 2 trials as 2 different groups of patients were enrolled. One trial (NHL-B1) included patients younger than 60 years of age with a low-risk profile lactate dehydrogenase [LDH] below the upper normal value). The second trial (NHL-B2) included patients between 61 and 75 years of age irrespective of the risk profile. Patients younger than 60 years of age with an elevated LDH value were included in a different trial of the study group (NHL-A), comparing conventional CHOEP-21 with a strategy including high-dose chemotherapy and autologous bone marrow transplantation. Wunderlich and colleagues have recently shown that CHOP-14 has improved outcome in older patients and that CHOEP-14 is superior in younger patients or those with low-risk disease.5,6
Comment by Stuart M. Lichtman, MD, FACP
This paper analyzes the practicality of the 4 CHOP variants by analyzing how well the intended schedules could be applied, to what extent dose erosion occurred, and what spectrum of dose-limiting toxicities occurred. The study analyses 959 patients, with slightly less than half (456 patients) being older than 60 years of age. The oldest patient in the study was 75 years. Chemotherapy regimens that were administered were G-CSF only in the 2-week regimens and were given for 10 days. The dose adherence in the NHL-B1 trial was excellent. The median relative dose actually given compared to planned dose exceeded 98% for the myelosuppressive drugs in all 4 regimens. Addition of etoposide, however, was accompanied by more dose erosion. CHOP-14 and CHOP-21 were similar regarding toxicity profile, rate of infection, use of antibiotics, rate of transfusions, and hospitalization. CHOEP schemes were associated with a higher rate of infections, more transfusion requirements, more antibiotic use, and longer hospitalization than the CHOP schemes, particularly in patients older than 60 years. Hematopoietic recovery was age- and treatment-related. The addition of etoposide is feasible and safe for patients up to 60 years old in both the CHOEP-21 and CHOEP-14 schemes. For patients older than 60 years of age, the addition of etoposide is associated with marked dose erosion due to increased toxicity. In this age group CHOEP should be used with caution. Wunderlich et al attempted to lower the duration of G-CSF to 7 days (RICOVER-60).7 CHOP-14 could be recycled as timely in RICOVER-60 as in NHL-B2. However, the rate of CHOP-14 cycles with WHO grade-3 and grade-4 infections doubled from 2.4% in the NHL-B2 trial to 5.2% in the RICOVER trial. Similarly, the cycles with the use of intravenous antibiotics rose from 15.2% to 20.8%. While reduced G-CSF application does not affect the feasibility of the bi-weekly CHOP-14 regimen in elderly patients with aggressive lymphoma, it increases infection rates considerably. They recommend a 10-day schedule of G-CSF starting on day 4 and caution against the substitution of filgrastim by PEG-filgrastim in the CHOP-14 regimen.
Therefore, these studies indicate that a change in the standard of care of aggressive lymphoma may be appropriate. A 14-day regimen of CHOP may improve outcome in older patients and CHOEP in younger patients. G-CSF must be used in the 14-day regimens in a 10-day schedule. Since the 14-day schedule did not include patients older than 75 or those with significant comorbidity, extrapolation of the results to these groups may be made with caution. The addition of rituximab to these regimens must be further explored.
1. Fisher RI, et al. N Engl J Med. 1993;328:1002-1006.
2. Shipp MA, et al. J Clin Oncol. 1995;13:2916-2923.
3. Lichtman SM. Crit Rev Oncol Hematol. 2000;33: 119-128.
4. Coiffier B, et al. N Engl J Med. 2002;346:235-242.
5. Pfreundschuh M, et al. Blood. 2002;99 (suppl 1):340a.
6. Pfreundschuh M, et al. Blood. 2002;99 (suppl 1):3060a.
7. Kloess M, et al. Proc Annu Meet Am Soc Clin Oncol. 2003;22:2402a.
Dr. Lichtman, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.