Discussion
asthenia, toxicity, slow-flow vascular malformations, cancer, malignancies, skin rash, mucositis, headache, Toxicity
MALIGNANCIES, CANCER, MUCOSITIS
To date, this is the largest prospective clinical phase III trial evaluating the efficacy of a 2-year sirolimus treatment in slow-flow vascular malformations. In this mid-term study evaluating 132 patients, a clinical benefit rate of 85% was observed. This corroborates the results of the phase II trials (Sirolimus had a relatively rapid effect on slow-flow vascular malformations; 50% of patients reported improvement of their symptoms within the first month of treatment. The proportion of patients with benefit increased with time, even if a transient deterioration in symptomatology was detected in up to 20% of patients during the first month of treatment. This highlights the importance of avoiding premature discontinuation of sirolimus and of informing patients that symptoms can transiently worsen at the beginning of the treatment. Sirolimus allowed surgery or sclerotherapy in patients who were initially deemed ineligible for such therapies. This underscores the essential role sirolimus may have if introduced before invasive therapies.The range of serum sirolimus levels was very large in this trial, ranging from 4.3 to 15.2 ng/mL. This could be explained by the fact that patients with a clinical benefit on sirolimus, whatever the trough level, were allowed to continue with the same dose; some of them had a low serum level of sirolimus. This reflects the interindividual variation in sensitivity to sirolimus. Treating very young children may require a close follow-up with more frequent clinical visits during the first weeks, in order to avoid toxicity, as sirolimus levels may change rapidly in a short period of time.The toxicity profile was consistent with previous reports; 18% of patients had a grade 3–4 toxicity, mainly asthenia, mucositis, headache, and skin rash. A higher frequency of grade 3–4 mucositis was observed in children, while adults had more frequently grade 3–4 asthenia. No hematological toxicity was observed in children or adults. Toxicity resulted in definitive discontinuation in 7 patients. The absence of hematological toxicity was consistent with our previous experience in our clinical pilot trial and our phase II study (Based on our experience with phase IB and II studies (Two patients developed cancer during sirolimus treatment, yet these malignancies were unlikely to be related to sirolimus. First, these malignancies appeared too early after the initiation of sirolimus to have a relationship with sirolimus itself. Secondly, the association between sirolimus and cancer remains unclear. Even if we do not have specific studies evaluating risk of cancer occurring during sirolimus monotherapy, the risk of developing cancer in graft-recipient patients on sirolimus treatment seems lower than that observed on a calcineurin inhibitor (Influence of sirolimus on fertility has been a concern, mostly based on studies on organ transplantation patients (Only 36% of the patients who completed the 2-year sirolimus treatment had to restart sirolimus, suggesting that the majority of patients do not need to remain on sirolimus indefinitely (The limitations of the current study include the small number of children, the relative heterogeneity of the patient population, the small number of patients in some diagnostic groups, and the low number of genetic analyses. Yet, this phase III prospective trial underscores the important role that sirolimus treatment can play in the multimodal management of slow-flow vascular malformations.