Variations In Cycle Length With Dose Intensification Of Chop

The original cycle length of 21 days for CHOP was based on the average time needed for hematopoietic recovery. However, the introduction of effective hematopoietic stem cell growth factors such as filgrastim, sargramostin, and peg-filgrastim allow a shortening of cycle length with the goal of increased drug intensity. A phase II SWOG study demonstrated that the drugs in CHOP could be both intensified (CHOP-DI) and the cycle duration could be shortened safely in a group of over 100 patients with aggressive and highgrade lymphomas.43 CHOP-DI led to an improved OS at 5 years as compared to a historical control group; however, the main endpoint of the study was PFS, and no difference between the CHOP-DI patients and historical control patients could be demonstrated.

Two large German multicenter phase III randomized studies (NHL-B1 and NHL-B2) also address the issue of cycle shortening with or without the addition of etoposide to CHOP. The design for each study was a four-armed randomized (2 X 2 factorial) controlled trial in both younger (18-60 years) and older (61-75

years) patients.44,45 The following regimens were delivered for a total of six cycles: CHOP-21 (the standard arm), CHOP-14, CHOEP-21 (CHOP with addition of etoposide 100 mg/m2 on days 1 through 3), and CHOEP-14. All patients on the shortened cycle arms received growth factor support whereas for the 3-weekly regimens the growth factor support was at the physician's discretion. The NHL-B2 trial for older patients included both favorable prognosis patients (defined by normal LDH at diagnosis) and unfavorable prognosis patients (defined by an increased LDH at diagnosis). By contrast, the NHL-B1 study for younger patients included only favorable prognosis patients. Young patients with elevated LDH were enrolled on a competing trial. The NHL-B2 trial for older patients randomized 689 patients and, with a median follow-up of 58 months, shows that CHOP-14 significantly improved the EFS and OS compared with CHOP-21. The addition of etoposide did not improve these endpoints, and, when given in an every 14-day schedule, substantially increased the hematologic and non-hematologic toxicity. In the NHL-B1 study for young patients, shortening the cycle leneth did improve the OS at 5 years. The addition of etoposide substantially improved the complete response rate and the EFS; in contrast to the trial in older patients, CHOEP-21 and CHOEP-14 were successfully delivered without excessive toxicity. The authors suggest that CHOEP should be the preferred regimen for this population. However, these trials were designed before the routine addition of rituximab, and it remains to be seen if rituximab is able to overcome the need to intensify CHOP, either with or without etoposide.46

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