Evaluating treatment strategies in advanced Waldenstrom macroglobulinemia:use of quality-adjusted survival analysis

A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubi cin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemi a in first relapse or with primarily resistant disease, was conducted on th e behalf of the 'Groupe Cooperatif Macroglobulinemie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of o verall survival (OS), although a significant benefit in terms of time to di sease progression and event-free survival (EFS) was noted. In this rare dis order, where few randomized trials have been conducted, we took advantage o f this trial to assess treatment differences while integrating quality of l ife considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWIST) app roach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWIST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWIST and summed up giving the so-called Q-TWiST. No difference was found between ran domized groups in terms of mean CT. Mean TOX in the two groups were similar ly close except when considering alopecia as a relevant toxic event. By con trast, mean TWIST was 5.9 months longer in the FAMP group than in the CAP g roup (P=0.006). Unsurprisingly, given the absence of difference in OS but t he difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P=0.047). As a result, benefit of FAMP in term s of average Q-TWiST only relied on the value of the utility coefficient at tributed to REL (U-REL), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely .