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In reply:

British Columbia Cancer Agency, Vancouver, British Columbia, Canada

We thank Dr Alliot for her comments. This study¹ was designed with a control arm that was arrived at by consensus among a fairly representative sample of hematologists and medical oncologists across Canada. At that time, in the early 1990s, re-treatment with alkylator-based regimens until demonstrated refractoriness was the common practice, as there were few other options. Purine analogs and monoclonal antibodies were still in the investigational phase. The impression of treating physicians was that a majority of patients who responded to one course of alkylating-agent treatment or CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) would respond again the second or third time. There were few data from controlled studies to actually address this, as there was nothing to control with. In fact, our study provides these data, as 52% of patients treated with CVP did respond, with a 9.1-month median progression-free survival for the group. The question that was addressed by the study was whether fludarabine would indeed be superior to re-treatment with an alkylator-based regimen in this setting, in a phase III study. Although many phase II studies using a variety of agents alone and in combination had been reported in the 1980s, none of these were in widespread use within our community. The decline in social functioning scores, as mentioned in our article, was mostly as a result of certain side effects, such as alopecia, with CVP treatments. A more detailed analysis of quality of life for both groups in this study has been completed and will be published in the future. Phase II studies of novel agents alone and in combinations are always being performed concurrently with phase III studies, with each having their own distinct purpose.

Our phase III study¹ was designed to determine if there was a role for fludarabine earlier in the treatment of relapsed low-grade non-Hodgkin’s lymphoma, before outright alkylator refractoriness. Phase II studies had previously demonstrated that fludarabine did indeed have a high level of activity in this particular situation. Similarly, novel combinations of drugs that look promising in phase II studies must now be subjected to the more rigorous test of a phase III comparison against a standard treatment in order to determine their place in clinical practice.

REFERENCE

1. Klasa RJ, Meyer RM, Shustik C, et al: Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin’s lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 20:4649–4654, 2002[Abstract/Free Full Text]

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