Abstract
Importance
Current therapeutic options for patients with extracranial head and neck arteriovenous malformations are limited. Surgical intervention, such as sclerotherapy or resection, often result in rapid recurrence and progression of disease.
Objective
To assess the efficacy and tolerability of sirolimus as an adjuvant therapy for endovascular embolization in the management of complicated extracranial head and neck arteriovenous malformations.
Design, Setting, and Participants
This case series examined 6 patients with extracranial head and neck arteriovenous malformations treated from January 1, 2013, to December 31, 2017, at a multidisciplinary vascular anomalies clinic within Stanford Hospital and Clinics.
Intervention
Initiation of sirolimus at least 1 month prior to endovascular embolization, targeting a trough level of 10 to 15 ng/mL throughout the course of the endovascular embolization series and continued for at least 1 month after the series.
Main Outcomes and Measures
Clinical manifestations; disease progression and overall response to treatment were assessed via clinical evaluation and radiographic imaging.
Results
All 6 patients (4 male and 2 female patients; mean age, 24.5 years [range, 9-44 years]) responded favorably to the combination of sirolimus therapy followed by endovascular embolization, and 4 patients exhibited a near-complete response. The median duration of follow-up was 19 months (range, 6-40 months). One patient discontinued sirolimus soon after embolization and experienced regrowth of the arteriovenous malformation after 1 year. Sirolimus was resumed, which has stabilized his disease for more than 2 years. Mild adverse effects were noted in 4 patients. The combination therapy was well tolerated in all patients. One patient developed skin ulceration after embolization and required surgical debridement. Another patient developed pulmonary microthrombi after embolization with cyanoacrylate glue that resolved with a brief course of anti-inflammatory therapy.
Conclusions and Relevance
Although further prospective trials are needed, this report suggests the benefit of a mammalian target of rapamycin inhibitor as an adjuvant therapy for surgical embolization of complex, extracranial head and neck arteriovenous malformations. The optimal dosing and therapeutic duration of sirolimus treatment before and after embolization remain to be determined.
This case series assesses the efficacy and tolerability of sirolimus as an adjuvant therapy for endovascular embolization in the management of complicated extracranial head and neck arteriovenous malformations.
Key Points
Question
Is sirolimus an effective adjuvant therapy for endovascular embolization of extracranial head and neck arteriovenous malformations?
Findings
In this case series, all 6 patients with extracranial head and neck arteriovenous malformations had a favorable response to concurrent treatment with sirolimus and endovascular embolization. The combination therapy is also well tolerated for up to 3 years.
Meaning
The findings of this report suggest that the combination of sirolimus and embolization is clinically beneficial for patients with recurrent or complex, unresectable extracranial head and neck arteriovenous malformations and warrants further prospective study.
Introduction
Extracranial head and neck arteriovenous malformations (HNAVMs) are rare and challenging to manage. Treatment of arteriovenous malformations (AVMs) includes embolization, followed by complete surgical resection when feasible. For nonresectable HNAVMs, embolization is sometimes used to decrease flow and alleviate symptoms. Many HNAVMs are not amenable to complete resection owing to their size or local tissue extension into vital anatomical structures. Complications and rapid recurrence after resection are frequent concerns.
Mammalian target of rapamycin (mTOR) signaling has been shown to mediate angiogenesis via increased expression of vascular endothelial growth factor.1 Sirolimus, an inhibitor of the mTOR pathway, has demonstrated efficacy in the treatment of complicated vascular anomalies.1 Colletti et al2 hypothesized that antiangiogenic drugs, such as sirolimus, could limit recurrence of HNAVM if administered continuously 1 to 2 months before and at least 6 months after surgical intervention. We present a retrospective review of 6 patients with complicated, unresectable HNAVMs who were treated with a combination of sirolimus and transarterial embolization between January 1, 2013, and December 31, 2017.
Report of Cases
With retrospective medical record review, we recorded patient demographics, AVM location, clinical symptoms, clinical stage according to the Schöbinger staging system,3 all treatments before current intervention, number and technique of sclerotherapy sessions, duration of sirolimus treatment (Table 1),3 and complications resulting from combination treatment (Table 2). Six patients with a mean age of 24.5 years (range, 9-44 years) presented with HNAVMs. The results of clinical examinations showed enlarging palpable, pulsatile masses consistent with HNAVMs. With the exception of patient 5, whose condition was diagnosed clinically, all patients had also undergone magnetic resonance imaging to confirm their diagnoses. Four patients had been treated previously with several modalities (Table 1).3 In all 4 cases, recurrence of the malformations occurred within 2 to 3 months after the procedure. The most common symptoms reported were pain (5 patients), headaches (3 patients), and bleeding (2 patients). The Stanford University Institutional Review Board approved this study. All patients provided written consent.
Table 1. Demographics and Clinical Characteristics.
| Patient No./Sex/Age, y | Race/Ethnicity | Schöbinger Stage3 | AVM Locations | Prior Treatments | Embolizations, No. | Sirolimus, mo | Follow-up, mo | ||
|---|---|---|---|---|---|---|---|---|---|
| Before Embolization | After Embolization | MRI | Clinical | ||||||
| 1/M/44 | South Asian | 3 | Right inferior ear and neck | Surgical debulking | 1 | 1 | 1 | 18 | 18 |
| 2/F/9 | Hispanic | 3 | Right clavicle | None | 3 | 2 | 16 | 20 | 20 |
| 3/F/33 | White | 2 | Left upper lip and cheek | Embolization | 3 | 2.5 | 7.5 | 2 | 8 |
| 4/M/16 | Hispanic | 3 | Left cheek, ear and neck | Embolization | 4 | 2.5 | 16.5 | 18 | 40 |
| 5/M/32 | Asian | 3 | Tongue | None | 1 | 4 | 3 | 3 | 6 |
| 6/M/13 | Hispanic | 3 | Forehead | Surgical debulking | 2 | 4 | 9 | 8 | 15 |
Abbreviations: AVM, arteriovenous malformation; MRI, magnetic resonance imaging.
Table 2. Adverse Events and Outcomes.
| Patient No. | Adverse Events | Outcomes |
|---|---|---|
| 1 | Localized ulceration requiring debridement; skin infection requiring mupirocin; oral erosion | Near-complete resolution of bleeding episodes; decrease in volume by 75%; improvement in pain scale score |
| 2 | Oral erosion | 90% Volume reduction of AVM; resolution of vascular prominence; resolution of daily headaches |
| 3 | Oral erosion | 67% Volume reduction of AVM; complete resolution of headaches; complete resolution of facial pain and pressure |
| 4 | Pulmonary embolism due to cyanoacrylate glue; oral erosion | Notable volume reduction of AVM; improvement in pain scale; interval growth on follow-up MRI 2 y after treatment; reinitiation of sirolimus therapy stabilized growth for >15 mo |
| 5 | Oral erosion | Complete resolution of AVM; resolution of bleeding |
| 6 | Pruritus | 80% Volume reduction of AVM; improvement in pain scale score |
Abbreviations: AVM, arteriovenous malformation; MRI, magnetic resonance imaging.
Adjuvant sirolimus therapy was initiated for all patients at least 1 month before their first embolic procedure, with a target trough level of 10 to 15 ng/mL throughout treatment. The mean sirolimus treatment duration before embolization was 2.67 months (range, 1-4 months). All patients underwent at least 1 endovascular embolization; 3 patients underwent 3 embolization procedures in the span of 1 to 2 months. Immediately after the final embolization, all patients experienced immediate relief of their prior symptoms. Clinical follow-up demonstrated significant improvement in all patients; follow-up magnetic resonance imaging confirmed significant or complete resolution of malformations in all patients as well. Patients remained on sirolimus therapy for a mean of 8.83 months (range, 1-16.5 months). Patient 4 discontinued sirolimus therapy 2 months after embolization but was found to have some regrowth and physical sensations of pulsations approximately 1 year after the embolization. Sirolimus therapy was therefore reinitiated at the family’s request. Currently, the patient has been receiving sirolimus for more than 2 years and tolerating the maintenance treatment well (with a target trough level of 5-6 ng/mL to minimize adverse effects). Subsequent magnetic resonance imaging approximately 6 months after sirolimus therapy was restarted revealed a notable reduction in volume, and the patient has no clinical evidence of regrowth to date.
The most common adverse effect reported in the patients was mouth sores secondary to sirolimus use. In all cases, treatment with “magic mouthwash” (compounded with diphenhydramine, viscous lidocaine, antacid, mystatin, and corticosteroids) resolved the mouth sores. In patient 1, sirolimus was discontinued 1 month after embolization owing to subsequent skin ulceration, which responded to systemic antibiotics, surgical debridement, and a small skin graft to the antihelix. After recovery, the patient reported complete resolution of pain and bleeding from the AVM. The postoperative course of patient 4 was complicated by hemoptysis and pleuritic chest pain owing to glue microemboli to the lung that developed 10 days after the third embolization. He was treated with a brief course of prednisone and antibiotics with no additional sequelae. He continued sirolimus therapy for 2 additional months before discontinuing therapy. After a more than 80% reduction of the AVM after embolization, patient 6 underwent resection of soft tissue overgrowth on the forehead to ensure a good cosmetic outcome (Figure, A). He continued sirolimus therapy for 9 months, with marked improvement. Subsequent magnetic resonance imaging 18 months after surgery revealed minimal residual AVM.
Figure. Forehead Arteriovenous Malformation (AVM) of a 13-Year-Old Boy (Patient 6).
A, Clinical photograph of patient at presentation with soft tissue asymmetry and swelling of the forehead due to underlying AVM. B, Clinical photograph of patient 9 months after treatment.
Discussion
Extracranial HNAVMs are the least common and most challenging type of vascular malformation to manage. Even when standard treatment options are feasible, a complete cure of HNAVMs is rare. Review of a large series of AVMs in 272 patients by Liu et al4 showed an approximately 57% recurrence rate within 1 year after surgical resection (with or without embolization) and an 86% 1-year recurrence rate with embolization alone. One hypothesis for the rapid recurrence is elevated levels of vascular endothelial growth factor and angiopoietin 2 and activation of mTOR signaling in affected tissues.5,6,7
Inactivating mutation in RAS p21 protein activator 1 (RASA1) causes capillary malformation–arteriovenous malformation characterized by randomly distributed capillary malformations and predisposition for cerebral and noncerebral AVMs.8 Somatic MAP2K1 mutations have recently been associated with extracranial AVMs as well9; this mutation was also found in patient 3. Phosphatase and tensin homologue (PTEN) mutation associated with PTEN-tumor hamartoma syndrome is also associated with increased high-flow vascular malformations, including AVM. Both RASA1 and PTEN are known regulators of the mTOR pathway, suggesting a potential therapeutic role for mTOR inhibition in AVMs.
Sirolimus, an inhibitor of the mTOR pathway, has demonstrated safety and efficacy in the treatment of various vascular tumors and malformations.1,10,11,12 In vivo animal models showed that sirolimus inhibits angiogenesis via downregulating the PI3K/AKT signaling pathway and the expression of vascular endothelial growth factor.12 However, published studies to date have shown limited response of HNAVMs to sirolimus alone.13
Limitations
The limitations of our study include a small number of patients in the treatment cohort and the lack of a control group. The optimal perioperative dosing and duration of sirolimus treatment still need to be investigated. Nonetheless, the combination treatment appears to be superior compared with the reported rates of embolization alone. Only 1 patient in our cohort had partial recurrence after discontinuation of sirolimus therapy, and disease progression was halted soon after sirolimus therapy was resumed.
Conclusions
We report the first case series, to our knowledge, on the successful combination use of sirolimus and endovascular embolization for complicated HNAVMs. The optimal perioperative dosing and duration of sirolimus treatment still need to be investigated. We hypothesized that concurrent use of antiangiogenic therapy before, during, and after surgical intervention may provide increased clinical benefits and a more sustained clinical response. The patients that we have treated to date using this protocol have had favorable outcomes with few complications and were pleased with their therapeutic outcomes and improvement in overall quality of life. Our results therefore suggest that sirolimus can be used as a safe and effective adjuvant therapy with endovascular embolization in the management of complicated, unresectable HNAVMs. Well-controlled, larger-scale multicenter studies are needed to validate this approach.
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