Clinical studies in aggressive non-Hodgkin's lymphoma with special reference to elderly patients

Sammanfattning: The age-adjusted incidence rate of non-Hodgkin´s lymphoma (NHL), in particular diffuse large B cell lymphoma, has increased continuously during several decades. Patients with aggressive NHL are potentially curable but the 5-year overall survival (OS) is still less than 50% in the whole group. Elderly patients with aggressive NHL constitute a large and clinically heterogeneous group. The prognosis of elderly patients is in general considerably worse than that of younger patients. Chemotherapy induced myelosuppression is the major dose-limiting toxicity. The overriding goal of the present study was to improve clinical management of patients with aggressive NHL, with special reference to the elderly. The addition of etoposide (E) to the conventional CHOP regimen was studied in 132 patients (median age 54 years) with previously untreated aggressive NHL. The complete remission (CR) rate was 70% and the 5-year OS 53%. The CHOP-E regimen was an effective treatment, but mainly due to severe myelosuppression, frequent dose/interval modifications were required. Only a minor fraction of patients received granulocyte colony-stimulating factor (G-CSF). The results were not obviously superior to those achieved with conventional CHOP. The addition of G-CSF may reduce dose-limiting myelosuppression. Oral low-dose etoposide given to 32 heavily pretreated patients (median age 68 years) with indolent and aggressive NHL, acute myeloid and lymphoid leukemia, multiple myeloma, and myelodysplastic syndromes had a moderate clinical effect. The toxicity was substantial, in particular leukopenia, the degree of which correlated with the area under the curve of the free fraction of etoposide. Oral etoposide may be used successfully in special clinical situations excluding patients with too advanced disease. Toxicity may be reduced by dose adjustments based on determination of free-etoposide concentrations. In 458 patients (>60 years; median age 71 years) with aggressive NHL receiving G-CSF (filgrastim) during CHOP (doxorubicin 50 mg/m2) or CNOP (mitoxantrone 10 mg/m2) induction chemotherapy, the incidence of severe granulocytopenia (WHO grade IV) and granulocytopenic (WHO grade IV) infections were reduced and the cumulative proportion of patients receiving ³90% of allocated chemotherapy was higher. However, administration of G-CSF did not improve time to treatment failure (TTF), CR rate or OS. CHOP ± G-CSF treated patients had a higher CR rate and a better TTF/OS than patients receiving CNOP ± G-CSF. Thus, standard-dose CHOP is better than CNOP. A further increase in relative dose intensity in patients given CHOP plus G-CSF may improve outcome. The reproducibility of treatment response evaluation performed by an independent review committee (RC) was assessed in a study cohort of 60 patients (>60 years) with aggressive NHL. The rate of discrepancy between two repeated assessments of treatment response was 13.3%. However, in only 6.7% of patients this difference influenced the CR rate, a favourable result compared with the discrepancy observed between the local investigators and the first review of the RC. An independent RC may be regarded as a prerequisite for uniform response evaluation in phase II and III trials. However, in the phase III setting end-points other than the CR rate, such as TTF and OS, remain the most valid. The prognostic predictive capacity of parental longevity in a study cohort of 254 patients (>60 years) with aggressive NHL was elucidated. Maternal lifespan below median was associated with a significantly reduced outcome, whereas paternal lifespan below median was associated with a slight and borderline significantly improved outcome. Thus, maternal and paternal lifespan may predict survival in aggressive NHL, but with opposing effects. However, parental age is not a clinically useful predictor of prognosis.