Sirolimus experience in adult patients with vascular malformations

Abstract

Aim

Sirolimus, a mammalian target of rapamycin inhibitor, inhibits cell growth and proliferation by controlling ribosome biogenesis and protein synthesis in vascular anomalies and cancers. However, most sirolimus studies on vascular anomalies were conducted in the pediatric population, with limited data in adults. In this study, we assessed the effectiveness and safety of sirolimus in adult patients with vascular malformation, a subtype of vascular anomaly.

Methods

We conducted a retrospective analysis of adult vascular malformation patients aged over 16, treated at Hacettepe University Cancer Institute from January 2013 to September 2022. Patient demographics and clinical characteristics were recorded. The primary outcome was the efficacy of sirolimus evaluated by response and disease control rates. The disease control rate was defined as the cumulative percentage of complete or partial responses, along with stable disease. The secondary endpoint was toxicity and safety.

Results

38 patients with a median age of 21 (IQR: 18–33) were recruited. Prior to sirolimus treatment, 57.9% of patients had undergone other therapeutic interventions, predominantly sclerotherapy and surgery. The median follow-up time during sirolimus treatment was 18.5 (IQR: 11.3–74.5) months. The disease control rate was 92.1% (35/38). Head-neck localization was associated with better response rates (p = .001). Sirolimus was generally well tolerated and grade 1 or 2 oral mucositis (n = 4) and skin rash (n = 3) were the most common side effects.

Conclusion

In this study, we found sirolimus was efficacious and well tolerated in adult patients with vascular malformation.

Keywords

Vascular anomaly vascular malformation mammalian target of rapamycin inhibitors sirolimus adults

Introduction

Vascular anomalies are classified as vascular tumors and vascular malformations by the International Society for the Study of Vascular Anomalies.¹ Simple malformations include arteriovenous malformations, congenital arteriovenous fistulas, venous malformations, lymphatic malformations, and capillary malformations. These anomalies are quite common, with a frequency of about 5%.² Vascular tumors are characterized by proliferation of endothelial cells, whereas malformations grow due to expansion of a developmental anomaly without concomitant proliferation.³ Although there are inherited forms of vascular malformation, more than 90% of cases are sporadic. Patients with vascular malformation experience progressively increasing clinical symptoms. Vascular malformations are typically treated by a multidisciplinary team when they are symptomatic or complicated. There are few treatment options available, and their efficacy has not been confirmed in prospective clinical trials. In the past, interventional or surgical procedures were mainly used to manage symptoms. But treatment for these patients recently has concentrated on cellular pathways involved in abnormal vascular growth and proliferation.

Several kinases are required for cell cycle regulation, proliferation, invasion, and angiogenesis in cancer cells and vascular malformation.⁴ Mammalian target of rapamycin (mTOR) has antiproliferative activity in a variety of cancers.⁵ mTOR was discovered to be a crucial kinase working downstream of phosphatidylinositol 3 kinase activation (PI3K). The PI3K/AKT signaling pathway is essential for cell growth and angiogenesis. The mTOR inhibitor, sirolimus, controls ribosome biogenesis and protein synthesis to modulate cell growth and proliferation.⁶ Tissue overgrowth and vascular anomalies have both been linked to disorders characterized by abnormal activation of the PI3K/AKT/mTOR pathway. The first animal model of vascular malformation was recently generated by injecting tyrosine kinase receptor-mutated human umbilical vein endothelial cells subcutaneously into nude mice.⁷ In this animal model, the treatment of sirolimus was successful in inhibiting the growth of vascular malformation lesions. Besides this study, there is scientific support for the use of oral sirolimus to treat vascular malformations, consisting primarily of case reports and brief retrospective studies.^8,9 However, most of these studies were in the pediatric population, and the experience with sirolimus in adult patients is limited.

The purpose of this study was to share our clinical experience with sirolimus in treating adult patients with vascular malformation, including data on dosage, efficacy, and safety. To the best of our knowledge, this is the first sirolimus study for vascular malformation treatment conducted solely in adult patients.

Methods

We retrospectively evaluated the patients with vascular malformation over the age of 16 years who were treated with sirolimus in our clinic from January 2013 to September 2022. We gathered information on patient characteristics, type of vascular anomaly, location and width of lesions, symptoms, associated complications, dosage, length of treatment, efficacy, and adverse effects. All patients were diagnosed at birth or later in life by physical examination, or imaging studies, especially magnetic resonance imaging and computed tomography scanning.

All patients included in this study received peroral sirolimus therapy. Sirolimus was initially given orally at 2 mg twice daily. Pharmacokinetically-guided dosing kept sirolimus levels between 5 and 15 ng/mL. Dose modifications were made for patients who were not in the appropriate range according to the sirolimus level. The primary outcome was the efficacy of sirolimus, defined by complete or partial response and stable disease. It has not yet been determined which method of disease assessment is more appropriate for patients who have vascular anomalies. Therefore, efficacy of sirolimus was determined by clinical symptoms, physical examination, as well as imaging in all patients. Since clinical examination will be insufficient to evaluate deep invasion and internal organs, radiological imaging (ultrasound or magnetic resonance imaging) was used in each patient. Response rates were assessed according to “Response Evaluation Criteria In Solid Tumors” (RECIST) 1.1.¹⁰ All patients were evaluated for disease control rate, which was defined as the absence of progression.

The secondary endpoints were toxicity and safety. Patients were initially assessed 2 weeks after the start of the treatment, then monthly for the 3 months, then every 3 months until the first year, then every 6 months. At each visit, complete blood count, liver and kidney functions, and cholesterol levels were tested, as well as clinical examination and serum sirolimus level. The treatment was continued until progression or toxicity.

All approaches utilized in this study were compatible with the 1964 Helsinki Declaration and any later amendments. The study was authorized by the local ethics committee, and all of the study subjects or their relatives provided written informed consent.

Statistical analyses

IBM SPSS Statistics Version 28 (IBM Inc., Armonk, NY) software was used for statistical analyses. Descriptive statistics were presented with frequency (%) and median (interquartile range, IQR). We compared baseline characteristics with Chi-square and Fischer exact tests. We used the Kruskal-Wallis test to compare more than two nonparametric groups. Statistical significance was defined as a p value 0.05.

Results

Baseline characteristics

A total of 38 (24 women and 14 men) patients with a median age of 21 (IQR: 18–33) years were included. The median age at diagnosis was 5 (IQR: 0–15) years. Twenty-two (57.9%) patients had venous malformations, 7 (18.4%) had venolymphatic malformations, 2 (5.3%) had lymphatic malformations, and 7 (18.4%) patients had vascular malformation associated with specific syndromes (2 Klippel-Trenaunay syndrome, 1 Gorham Disease, 1 Bannayan-Riley-Ruvalcaba syndrome, 1 Mafucci Syndrome, 1 Wyburn-Mason Syndrome, 1 Proteus Syndrome). The most common locations were head and neck (34.2%) and upper extremities (21.1%). Most patients (57.9%) had previously been treated with several sequences of sclerotherapies and/or surgical resection or other treatment strategies before sirolimus treatment. The median duration of sirolimus treatment was 14.4 (IQR: 9.7–66.3) months. In 78.9% of patients, 1 mg BID was sufficient to achieve the pharmacokinetic-guided target serum levels. The baseline characteristics of the patients are shown in Table 1.

Table 1.

Baseline characteristics of patients.

Characteristics		Frequency (%), n = 38
Age, median (IQR), years		21 (18–33)
Age at diagnosis, median (IQR), years		5 (0–15)
Sex	Women	24 (63.2)
Sex	Men	14 (36.8)
Location	Head and neck	13 (34.2)
	Upper limb	8 (21.1)
	Thorax	6 (15.8)
	Lower limb	5 (13.2)
	Pelvis	4 (10.5)
	Abdomen	2 (5.3)
Types of vascular anomalies	Venous malformations	22 (57.9)
	Venolymphatic malformations	7 (18.4)
	VM with a syndrome	7 (18.4)
	Lymphatic malformations	2 (5.3)
Previous therapies	None	16 (42.1)
	Sclerotherapy	8 (21.1)
	Surgery	5 (13.2)
	Embolization	2 (5.3)
	Intralesional bleomycin	2 (5.3)
	IFN alpha 2b	1 (2.6)
	Radiation therapy	1 (2.6)
	IFN alpha, propranolol, surgery, and embolization together	3 (7.9)
Sirolimus doses	1+ 1mg	30 (78.9)
	1,5+ 1mg	4 (10.5)
	1,5 + 1.5 mg	2 (5.3)
	1 + 0.5 mg	2 (5.3)

IFN: interferon, IQR: interquartile range, VM: vascular malformations.

Efficiency

The median follow-up time from the start of sirolimus was 18.5 (IQR: 11.3–74.5) months. Based on assessment with both clinical examination and radiological imaging, 3 (7.9%) patients had progressive disease. Stable disease and partial response were obtained in 29 (76.3%) and 6 (15.8%) patients, respectively. Disease control rate was 92.1% (35/38) and no patients had complete response (Table 2). There was no significant relationship between treatment response with age (p = .221), age at diagnosis (p = .255), and sex (p = .361); while the head and neck location had higher partial response rates than other locations (p = .001) (Table 3).

Table 2.

Best responses with sirolimus.

Response	Frequency (%), n = 38
Complete response	0 (0)
Partial response	6 (15.8)
Stable disease	29 (76.3)
Progressive disease	3 (7.9)
Disease control rate (CR+PR+SD)	35 (92.1)

CR: complete response, PR: partial response, SD: stable disease.

Table 3.

The comparison of the PR/SD/PD rate of the two groups according to the presence of lymphatic anomaly and location.

Characteristics, n		PR	SD	PD	p value
Age, median, years		22.3	22.2	17	0.221
Age at diagnosis, median, years		1.7	7	0	0.255
Sex	Women	4	17	3	0.361
Sex	Men	2	12	0
Location	Head and neck	6	6	1	0.001
Location	Others	0	23	2
Type of VM	Venous only	4	17	1	0.626
Type of VM	Others	2	12	2
Previous therapy	Present	4	16	2	0.830
Previous therapy	Absent	2	13	1

PD: progressive disease, PR: partial response, SD: stable disease, VM: vascular malformations. Bold text indicates statistical significance at p < 0.05 level.

Vascular malformation types were not associated with the efficiency of sirolimus (venous only vs others, p = .626). In patients with venous malformation (n = 22), 1 patient had progressive disease, 17 patients had stable disease, and 4 patients had partial response. While the lesion progressed in one of the two patients with lymphatic malformation, the other had stable disease. In the venolymphatic malformation group (n = 7), one, five, and one patient had progressive disease, stable disease, and partial response, respectively. In one patient with Wyburn-Mason syndrome, partial response was obtained in the lesions of the left eye, palate and left cheek, and the treatment was continued for 119.1 months. Stable disease was observed in the remainder of the patients with the syndrome (n = 7) (Figure 1).

Figure 1.

Sirolimus efficacy according to vascular malformation types.

No significant relationship was found between the presence of prior treatment and the efficiency of sirolimus (p = .83). Similarly, there was no difference in treatment response between previous sclerotherapy and no treatment (p = .769) or other treatment modalities (p = .418) (Figure 2).

Figure 2.

Sirolimus efficacy relative to treatment strategies prior to sirolimus.

Safety

Sirolimus was generally well tolerated and no grade 3 or 4 side effects were encountered. Grade 1 or 2 side effects consisted of mouth ulcers or oral mucositis (n = 4), skin rash (n = 3), fatigue (n = 2), headache (n = 2), acne (n = 1), and diarrhea (n = 1). All were managed with symptomatic therapy or short-term cessation. Due to grade 2 headache and grade 2 mucositis, two patients discontinued sirolimus for a few days. One patient developed lymphopenia and another patient developed anemia, both of them not needing to stop the treatment, and treatment was continued with dose reduction. Adverse effects are summarized in Table 4.

Table 4.

Adverse effects with sirolimus.

Grade 1–2 adverse effects	Frequency (%), n = 38
Oral mucositis	4 (10.5)
Skin rash	3 (7.8)
Fatigue	2 (5.2)
Headache	2 (5.2)
Acne	1 (2.6)
Diarrhea	1 (2.6)
Lymphopenia	1 (2.6)
Anemia	1 (2.6)

Discussion

In this study, we reported our experiences using sirolimus in patients with vascular malformation. Only 7.9% of our patients under sirolimus exhibited progression, whereas 92.1% of patients had disease control (stable disease or partial response).

There is evidence that sirolimus may be useful in the treatment of different types of vascular anomalies.^11–14 It is effective in both venous and accompanying lymphatic anomalies.¹⁵ The majority of the literature, however, deals with pediatric patient populations.^9,15 Diversely, in our study, the median age was 21 (IQR: 18-33) years. Despite the fact that there is no obvious gender preference in vascular anomalies, infantile hemangiomas are more common in females than males.^3,16,17 A female preponderance of 1.4:1 was identified in a series of 41 patients with vascular anomaly (6 had vascular tumors and 35 had vascular malformation) presented by Triana P et al.⁹ There was also female dominance in our study (63.2% vs 36.8%).

Due to its nature, complete response is not common in vascular anomalies. In 2015, Lackner H et al reported 50% complete response and 50% partial response rates with oral sirolimus in 6 children with various vascular anomalies.¹⁴ In another study, 82.5% partial response, 5.2% stable disease, and 12.3% progressive disease were observed after 6 courses of oral sirolimus in patients aged 0-29 years with complicated vascular anomalies. Although the partial response and stable disease rates obtained in this study were different from our cohort, the overall disease control rate was similar (87.7% vs 92.1%).⁸ Similarly, in 2017, Triana P et al reported an overall response rate of 80.4% in 41 vascular anomaly patients with a median age of 12.8 (0.16–47) years.⁹ One of the largest systematic reviews on the safety and efficacy of sirolimus in treating vascular anomalies was conducted by Freixo C et al.¹⁸ They concluded that sirolimus may enhance the prognosis of vascular tumors associated with life-threatening coagulopathy and venous and lymphatic malformations.

There is no data in the literature on the relationship between vascular anomaly localization and sirolimus response. In our analysis, head and neck location was found to be associated with increased partial response rate (p = .001). There are insufficient data on which cells to better inhibit mTOR signaling with sirolimus. Prospective trials with larger numbers of patients are needed to support a variety of treatment responses based on vascular anomaly localization.

Sirolimus was well tolerated, both in females and in males. The majority of adverse events were classified as grade 1 or 2 and were easily treatable with symptomatic medication. Oral mucositis and skin rashes are the most common side effects in our study. Mucositis, headaches, lethargy, gastrointestinal side effects, peripheral oedema, hypertension, and poor healing are the most commonly documented side effects of sirolimus in the literature.¹⁹ Sirolimus has also been linked to hematological adverse events.²⁰ Two patients in our cohort who experienced lymphopenia and anemia recovered after dose reduction. However, the reported adverse events were benign and manageable in most case series, such as in our study.

The main experience with the long-term use of mTOR inhibitors comes from transplant patients. These patients are closely monitored in terms of serum drug levels and organ toxicities after drug initiation. The risk of secondary lymphoma and skin cancer associated with long-term use of mTOR inhibitors is also increased. Therefore, patients are advised to limit exposure to the sun or ultraviolet light and to use appropriate sunscreen. However, when patients realize that their lesions are not growing, they prefer to use the drug for a long time because their quality of life and mood improves. Sirolimus may offer an effective solution for vascular malformations that persist in progressing despite surgical or endovascular interventions. Furthermore, sirolimus may serve as a successful first-line option for lesions that are not amenable to local treatments due to their anatomical location or size, as well as for patients who are unwilling to undergo invasive procedures.

The retrospective design and the relatively small sample size was the main limitations of our study. Nevertheless, our study was the first to demonstrate the experience of sirolimus in adult patients with vascular malformation. If confirmed by prospective evidence, our results could support the sirolimus as the standard of care for adult patients with vascular malformation similar to pediatric patients. It is worth noting that, alongside traditional response evaluation criteria, assessing changes in quality of life may also hold significance for these patients.

Conclusion

Our research confirms that sirolimus is an effective therapeutic option for adult patients with vascular malformation. Unfortunately, there are still no answers to important questions, such as what problems may arise from long-term use and how long the patient should be treated.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

Presenting in a congress

This study was accepted as a poster presentation to the ESMO Sarcoma and Rare Cancers Congress (20 – 22 March 2023, Lugano, Switzerland).

ORCID iDs

Rashad Ismayilov

Omer Denizhan Tatar

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