Six Courses of Intensified CHOP Plus G-CSF Compared to Eight Courses of Standard CHOP in Patients with Intermediate-Risk Aggressive Non-Hodgkin Lymphoma Results of a Prospective Randomized HOVON Trial.

Between November 1994 and February 2004 a total of 513 untreated patients with aggressive intermediate-risk NHL, aged 16–65 years, were recruited to the randomized HOVON-26 trial comparing intensified (I)CHOP plus G-CSF (given every 2 weeks for 6 courses) with standard CHOP (given every 3 weeks for 8 courses). I-CHOP included doxorubicin (D) at 70 mg/m² and cyclophosphamide (C) at 1000 mg/m² together with standard dose vincristine and prednisone. So, dose intensity (mg/m²/week) for both D and C was doubled in the I-CHOP arm compared to CHOP, whereas the cumulative dose of D and C was similar in both treatment arms. Intermediate-risk aggressive NHL was defined (HOVON criteria) as stage II disease with increased LDH and stage III/IV disease with normal LDH, corresponding to the low-intermediate (L-i) and high-intermediate (H-i) risk groups of the age-adjusted (aa) IPI score. The endpoints were CR rate, overall (OS), disease-free (DFS) and event-free survival (EFS).

Of 513 patients, 477 were eligible of whom 239 were randomized to CHOP and 238 to I-CHOP. Patients were well balanced for all risk factors. According to the aa-IPI score, in the L-i group 161 patients received CHOP and 137 I-CHOP, whereas in the H-i group 68 patients received CHOP and 80 patients I-CHOP.

As of July 1^st 2005, median follow-up of all patients still alive is 50 months. Ninety-nine patients in the CHOP arm died and 85 patients in the I-CHOP arm died. NHL was the main cause of death in both treatment arms (76 and 61 patients, respectively). Treatment-related mortality (8%) was similar in both arms, however WHO grade 4 side-effects occurred twice as often (20 vs 10 events) in the I-CHOP arm. I-CHOP did result in better CR rate and 5 years estimates of OS, DFS, and EFS, but the differences were not significant (table 1). However, although not originally planned, subgroup analysis showed improved OS, DFS, and EFS in the low-intermediate group (table 2).

Although I-CHOP was not significantly better than CHOP in intermediate-risk aggressive NHL patients, subgroup analysis indicates a possible improvement in outcome for patients with low-intermediate risk aggressive NHL. Another advantage of I-CHOP might be that therapy duration is markedly reduced.