Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial.

BACKGROUND

With CHOP, the standard protocol of recent decades, about 30% of long-term survival has been reported. A number of studies using more aggressive multidrug regimens or alternating chemotherapies have recently suggested higher CR rates and increased survival. In 1989 we reported similar results with a combined-modality treatment administering 6 cycles of CHOP supplemented with etoposide and an involved field irradiation for patients in PR or CR.

PATIENTS AND METHODS

To confirm the efficacy of this approach, we initiated a prospective randomised trial comparing 4 cycles of CHOP-VP16 (CHOEP) with 4 cycles of two alternating regimens, 'hCHOP and IVEP'. One hundred seventy-five patients with high-grade non-Hodgkin's lymphomas stages II-IV were stratified for age, stage and LDH and randomised to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone (CHOEP) in arm A or four cycles of chemotherapy with a dose-intensified CHOP (hCHOP) alternating with ifosfamide, etoposide, vindesine, prednisolone (IVEP) in arm B. After four cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission.

RESULTS

Of the 185 randomised patients, 175 were eligible and 171 evaluable for response and survival. One hundred forty-six of the 171 patients (85%) achieved complete remission (CR) with 87% and 84% CRs in arms A and B, respectively. With a median follow-up of 36 months the estimated overall survival at 2 years is 66% and 73% for arms A and B, respectively. The percentage of all patients in first CR is estimated to be 59% and 55% at 2 years for arms A and B, respectively. None of the differences in CR rate, survival, or relapse-free survival are statistically significant. Multivariate analysis of subgroups incorporating the factors of sex, age, performance status, stage, B symptoms, bulky disease, LDH and histology revealed that only stage and LDH were factors which independently affected outcome. The estimated 2-year survival rate of patients with stages II, III and IV is predicted to be 84%, 62% and 52%, respectively. Patients with LDH > 250 U/l have an estimated survival of 52% at 2 years versus 84% for patients with LDH < or = 250 U/l. According to the newly proposed international score system, the 2-year survival was 81% for low-risk-, 64% for low intermediate risk-, 50% for high intermediate risk-, and 43% for high-risk patients. The toxicity in both arms was tolerable. Three patients died of treatment-related causes (2 in arm A, 1 in arm B). The main toxicity was haematological with 75% of patients suffering from grades 3 or 4 neutropenia at some point during treatment.

CONCLUSIONS

We observed no superior benefit for alternating regimens, and conclude that both are effective treatment protocols for aggressive histologic-type malignant lymphomas. The results obtained with four cycles of poly-chemotherapy followed by an involved field irradiation are comparable to programs using more aggressive and/or prolonged chemotherapy.