Initial dose intensity has limited impact on the outcome of ABVD chemotherapy for advanced Hodgkin's Lymphoma (HL): Data from UKLG LY09 (ISRCTN97144519)

Johnson, P.W.M., Sydes, M.R., Stenning, S.P., Cullen, M.H., Radford, J.A. and Hancock, B.W. , Engert, Andreas (ed.) (2007) Initial dose intensity has limited impact on the outcome of ABVD chemotherapy for advanced Hodgkin's Lymphoma (HL): Data from UKLG LY09 (ISRCTN97144519). Haematologica, 92 (Suppl/5-P111), 68-69.

Abstract

Background. Response-adjusted therapy is attractive in the treatment of HL, to avoid over-treatment of patients with a good prognosis and to maximise the chance of cure. However, it is not clear whether the intensity of initial therapy prior to early response assessment is critical to the outcome, or whether subsequent intensification may compensate for less intense initial treatment. We investigated whether dose intensity in the first two cycles of standard ABVD chemotherapy is predictive of progression- free survival (PFS).
Methods. Data for 379 eligible patients allocated to receive ABVD in the UKLG LY09 trial and who received at least two cycles of chemotherapy were included. All patients were planned to have 6 cycles of chemotherapy, extended to 8 where there was evidence of continuing response at 6. Growth factor support was permitted following delays or reductions in treatment. Radiotherapy was recommended for residual masses or at the sites of prior bulk disease. Patients were recruited between 1998 and 2002 with median follow-up of 52 months. Observed dose was standardised by dividing by expected dose for the first two cycles. Dose intensity was defined as standardised dose divided by [observed duration for two cycles divided by expected duration for two cycles]. These were calculated separately for doxorubicin, bleomycin, dacarbazine and vinblastine and averaged. Landmark analyses were timed from the start of cycle 3. The analyses include 96 PFS events: disease progression or death from HL.
Results. 93/397 (25%) of patients received treatment at >97% intended DI (averaged across all 4 drugs) for cycles 1-2, whilst 137 (37%) received 86-97% and 147 (39%) less than 86%. Dose and dose intensity in cycles 1-2 correlated well with dose and dose intensity in the remaining cycles 3-6 for all drugs. There was no good evidence from unadjusted univariate analyses of the four drugs individually and their average, that higher dose intensity in the first two cycles was associated with better PFS. Adjusting for baseline IPI score, the strongest effect of a 10% increase in DI in cycles 1-2 was from Doxorubicin. This was associated with a hazard ratio of 0.90 (95%CI 0.78, 1.02); bleomycin HR=0.90 (95%CI 0.78, 1.05), dacarbazine HR=0.92 (95%CI 0.79, 1.06), vinblastine HR=0.94 (95%CI 0.81, 1.09). Among 82 patients who had cycles 3-6 delivered at over 97% DI on average, patients who received average DI below 86% in cycles 1-2 had the same long-term PFS as those patients who received average DI over 97% in cycles 1-2. Poorer DI in cycles 1-2 was associated with increased use of G-CSF during subsequent cycles.
Discussion. We have found no evidence of improved PFS with higher dose intensity in the first two cycles of ABVD. This is a non-randomised comparison and caution is needed in the interpretation of such retrospective data. However, the data comes from a large cohort of patients following a standard treatment regimen, ABVD, in the context of a randomised controlled trial. It is possible that following initial low dose intensity, growth factors were effectively used to restore the efficacy of treatment and/or chemotherapy was continued for more cycles and/or consolidation radiotherapy used. This does not appear to support the introduction of a policy of maximising initial dose intensity without testing in a further prospective study.

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Contributors

Author: P.W.M. Johnson

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