Mapisal Versus Urea Cream as Prophylaxis for Capecitabine-Associated Hand-Foot Syndrome.

of a randomized phase III trial of the AIO Quality of Life Working Group. This trial compared the effect of Mapisal (a new ointment; Medac, Hamburg, Germany) and urea cream on the primary end point of reduction of the incidence of hand-foot syndrome (HFS) within 6 weeks. Secondary end points were time to development of HFS of any grade and of HFS greater than grade 1 as well as quality of life analyses. A total of 152 patients were evaluable. Of these, 47 patients (30.9%) experienced HFS, with 39.5% in the Mapisal arm and 22.4% in the urea arm (stratified odds ratio, 2.37; P 5 .02). Time to any-grade HFS was significantly longer in the urea group than in the Mapisal-treated group (P 5 .03), and skin-related quality of life was significantly worse in the group treated with Mapisal. The trial by Hofheinz et al 1 showed the superiority of urea cream over Mapisal; however, there are a few controversial points regarding the interpretation of the results. We believe the following three points require clarification from the authors: First, regarding the rationale of the study, the authors concluded that this trial demonstrated, contrary to their hypothesis, that urea cream is superior to Mapisal in preventing HFS in patients with cancer who were treated with capecitabine. In addition, it was revealed that the new ointment was more likely to increase adverse events. Although this trial was conducted as a phase III study, a phase II study or an exploratory study does not seem to have been performed—a rationale for a phase III trial is absolutely required before conducting it. Furthermore, in calculating the sample size of their study, Hofheinz et al 1 did not describe how the incidence of HFS was estimated at 10% in the Mapisal group. Hence, the sample size of this trial was set without an appropriate rationale, and we doubt that this sample size has enough statistical power to prove their clinical hypothesis. The sample setting in this trial was based on only the data for the effectiveness of Mapisal for pegylated liposomal doxorubicin, and the evidence for capecitabine was not shown. Second, regarding the selection of patients in the control arm, to our knowledge, there is no evidence that uric acid–based creams offer effective prophylaxis for capecitabine-associated HFS. To review, uric acid–based creams were shown to be ineffective in the prevention of capecitabine-induced HFS. 2 A randomized phase II study demonstrated the effect of a urea-based cream on sorafenibassociated hand-foot skin reactions. 3 In the trial by Hofheinz et al, 1 urea cream treatment was selected as the treatment for the best supportive care control arm; however, best supportive care as a control arm in this trial was poorly defined. A study with a poorly defined control arm is in danger of either creating excessiveness in or of underestimating the comparator arms. 4 Third, we believe that the results of this trial would have no impact on clinical practice even if Mapisal were found to be significantly more effective than urea, because urea cream is not recognized as the standard treatment. Because a phase III trial requires many resources and considerable effort, including that by the patients, it should be conducted after careful planning, and any harm caused to patients by the experimental treatment should, of course, be avoided. We insist that a phase III trial without established evidence of safety, tolerability, and efficacy should not be performed. We doubt that any arguments of ethical adequacy were offered during the approval process of this trial.