Intermittent Administration Regimen of Sirolimus for Refractory Cervicofacial Lymphatic Malformation

Abstract

Background: The cervicofacial lymphatic malformations (LMs) often have poor outcomes due to their microcystic component and diffuse infiltration. Mostly, traditional treatments are inadequate for these refractory cases. Recent researches have shown that sirolimus is effective in the treatment of complicated LMs, however, there is still no standard strategy. Objective: To evaluate the efficacy and safety of intermittent oral sirolimus in treating refractory cervicofacial LMs as a second-line treatment. Methods: Fifteen pediatric patients of refractory cervicofacial LMs were retrospectively analyzed in this study. All the cases had received traditional therapy before, but could not completely control the symptoms and eliminate lesions. As a remedy, sirolimus was then proceeded with an intermittent administration regimen, that is 3 continuous months as a course and started the next course after 1 month interval. The clinical characteristics, imaging data of patients, the changes in the signs and symptoms observed, and associated adverse effects were collected and analyzed. Results: The patients initiated sirolimus therapy at the average age of 2.3 years (range 28 days-8 years 9 months). At the end point of the study, 2 patients remained on sirolimus in continuous courses of treatment. Of 13 patients who withdrawn therapy, 4 had restarted due to recurrence of symptoms and re-expansion of LMs. All patients demonstrated reduction in residual LMs and complete disappearance of symptoms during treatment, and 2 patients with complete resolution on imaging. Toxicity was tolerant in this series. There was no patient develop opportunistic or systemic bacterial infection. Conclusions: Sirolimus is commended as a second-line treatment to treat intractable cervicofacial LMs after failure of traditional therapy. The intermittent administration regimen is efficacious to completely control symptoms and partially reduce residual lesions with good tolerance and limited side effects.

Sirolimus for Pediatric Cervicofacial Lymphatic Malformation: A Systematic Review and Meta‐Analysis

“…Ten studies did not use prophylaxis; of these, only eight studies reported safety data. 16,20,21,[23][24][25][26][27] Pooled analysis of this data showed 6 grade 3-4 events out of N. 80. The Newcastle-Ottawa score tool 9 was followed with the addition of an overall judgement of risk of bias by the review authors.…”

“…Out of 70 patients in the retrospective case series, 19–28 there were 40 episodes of grade 2 side effects, 3 episodes of grade 3 side effects and 2 episodes needing intensive care treatment (1 chest infection, 1 cellulitis). One death was reported shortly after starting sirolimus; the authors suggest this was due to the general poor and deteriorating condition of that patient even prior to commencing sirolimus 25 …”

“…Duration of sirolimus treatment ranged from 4 to 67 months, with patients who experienced a response continuing it for between a year and 2 years in most cases. Several studies 16,19,20 described symptom recurrence upon cessation of sirolimus, with a good response upon restarting it. Those studies that reported their surveillance regimen checked full blood count, renal profile, bone profile, hepatic profile, and sirolimus levels monthly 16,28 …”

“…Out of the total of 33 patients in these studies, 4 patients had grade 3–4 events during treatment. Ten studies did not use prophylaxis; of these, only eight studies reported safety data 16,20,21,23–27 . Pooled analysis of this data showed 6 grade 3–4 events out of N. 80.…”

“…One of these studies, Ozeki et al, 17 included adults and children but only the pediatric data was extracted for this review. Ten retrospective case series [19][20][21][22][23][24][25][26][27][28] and five individual case reports [29][30][31][32][33] of sirolimus use in cervicofacial LMs were also included; these are summarized in Table II. Assessment of risk of bias for all included studies is shown in Table III.…”