What can we learn from the ZOOM trial?

Abstract

1 Amadori D, Aglietta M, Alessi B, et al. Effi cacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 2013; 14: 663–70. 2 Martin M, Lopez-Tarruella S. Zooming in on the schedule of bone-modifying drugs. Lancet Oncol 2013; 14: 575–76. 3 Rosen LS, Gordon D, Kaminski M, et al. Long-term effi cacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma. Cancer 2003; 98: 1735–44. of the 12-weekly group would not be proven in this case. Furthermore, the skeletal morbidity rate is questionable as the primary endpoint, since the use of the skeletal morbidity rate is based on the assumption that all skeletalrelated events are independent of one another. This assumption is probably unrealistic because bone metastases often seem to be temporally clustered. In a previous study by Rosen and colleagues, which was the basis of the sample size calculation for this study, skeletal-related events occurring within a 21-day window were counted as one event. However, in Amadori and colleagues’ study, the authors do not mention that the same procedure was applied to avoid multiple counting of linked events. This fact weakens the comparability of the two studies and casts doubt upon the reliability of the design parameters. Moreover, the standard deviation in Rosen and colleagues’ study was very high—2·04 for a mean skeletal morbidity rate of 0·98. Thus, it would have been advisable to plan an interim analysis to adjust for these crucial design parameters. Another important point is that effi cacy analyses were only done in the intention-to-treat population, although it is well known and captured in regulatory guidelines that the primary analysis set in a noninferiority trial should be the perprotocol set. The intention-to-treat population should be used only for supportive analysis since the noncompliers will generally reduce the observed diff erence between the treatment groups and will therefore lead to bias towards non-inferiority. Finally, the original choice of a wide non-inferiority margin leads to a small sample size and wide confi dence intervals. Thus, the results of this study, which indeed look promising, are compatible with a wide range of scenarios. For instance, the skeletal mortality rate ratio of 0·97 is close to one. But with a 95% CI of 0·60–1·57, 7 Hutton B, Addison C, Mazzarello S, et al. De-escalated administration of bone-targeted agents in patients with breast and prostate cancer— a survey of Canadian oncologists. J Bone Oncol 2013; 2: 77–83. 8 Hutton B, Morretto P, Emmenegger U, et al. Bone-targeted agent use for bone metastases from breast cancer and prostate cancer: a patient survey. J Bone Oncol 2013; published online June 21. DOI:http://dx.doi. org/10.1016/j.jbo.2013.05.002. 9 Coleman R, Wright J, Houston S, et al. Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer. Proc Am Soc Clin Oncol 2012; 30 (suppl): 511 (abstr).