Tris-acryl gelatin microspheres versus gelatin sponge particles in uterine artery embolization for leiomyoma

Abstract

Background

Tris-acryl gelatin microspheres (TAGM) and gelatin sponge particles (GS) have been used in uterine artery embolization (UAE) for leiomyoma. No direct comparisons of both embolic agents have been reported.

Purpose

To compare the outcomes of UAE with TAGM with those of UAE with GS for uterine leiomyoma.

Material and Methods

This was a non-randomized, single-institute, non-inferiority study. Between July 2008 and August 2015, 67 consecutive patients with symptomatic leiomyoma underwent UAE. GS was used for the first 49 patients and TAGM was used for the following 18 patients. The primary endpoint was tumor infarction on contrast-enhanced magnetic resonance imaging (MRI) 1 week after UAE. The secondary endpoints were changes in symptoms and quality-of-life scores with UFS-QOL questionnaires at 4 months, and adverse events (AEs) in the 4 months after UAE.

Results

The baseline characteristics of both groups were similar. Complete or nearly complete tumor infarction (≥90%) was achieved in 94.4% (17/18) of the TAGM group and 93.6% (44/47) of the GS group. This difference (0.8%; 95% CI, –11.9% to 13.5%) indicated the non-inferiority of the TAGM group to the GS group, with a pre-specified non-inferiority margin of 20%. No significant differences were observed in improvements in symptoms or quality-of-life scores at 4 months (P = 0.56 and P = 0.19) or in 4-month AEs (P = 0.29).

Conclusion

The outcomes of UAE with TAGM were comparable to those of UAE with GS, suggesting that both embolic agents are acceptable for the treatment of leiomyoma.

Keywords

Uterine artery embolization leiomyoma tris-acryl gelatin microspheres gelatin sponge magnetic resonance imaging (MRI)fibroid

Introduction

Embolic agents influence the success of uterine artery embolization (UAE) for uterine leiomyoma (1,2). Historically, non-spherical polyvinyl alcohol was introduced (3). Thereafter, several calibrated spherical microspheres, such as tris-acryl gelatin microspheres (TAGM; Embosphere®, Nippon Kayaku, Tokyo, Japan), have been used worldwide (4 –12). Gelatin sponge particles (GS), absorbable embolic agents also have been used in several countries (13 –17).

In Japan, GS was mainly used because no other embolic agents were commercially available (13 –16). Several single-arm studies on UAE with GS demonstrated that tumor infarction on magnetic resonance imaging (MRI) and the clinical success of UAE with GS were comparable to those achieved with other embolic agents (13 –16). In January 2014, TAGM became available as an approved embolic agent in Japan. Therefore, it is essential to assess and understand differences between UAE with TAGM and UAE with GS. However, no direct comparisons of the both treatments have been reported (17).

Therefore, the purpose of the present study was to compare the outcomes of UAE with TAGM with those of UAE with GS for symptomatic uterine leiomyoma.

Material and Methods

Study design

This was a non-randomized, single-institute, non-inferiority study to compare the effects of UAE with TAGM on imaging and clinical outcomes with those of UAE with GS among patients with symptomatic uterine leiomyoma. We obtained written informed consent for the study procedures including embolic agents and subsequent follow-up assessments, and opt-out consent for the use of retrospective clinical data. The procedures in this study (including the informed consent process) were approved by the Institutional Review Board. The present study did not have any funding from any sponsor.

Between July 2008 and May 2014, we performed UAE with porous GS (Gelpart®, Nippon Kayaku), a roughly calibrated embolic agent made of gelatin sponge, which was an off-label embolic agent in UAE in Japan (18). In January 2014, TAGM was approved by the Japanese Health, Labor, and Welfare Ministry as an embolic agent in UAE for leiomyoma. As a result, we changed to TAGM at our institution in June 2014. Thereafter, we designed the present study to evaluate the non-inferiority of UAE with TAGM (the study group) to UAE with GS (the control group). The sample size of UAE with TAGM required for the present study was estimated, and after the specific sample size had been obtained, the enrollment of patients was then completed.

Inclusion and exclusion criteria

Premenopausal patients aged ≥ 20 years were eligible for this study if they had definite symptoms related to uterine leiomyoma (i.e. menorrhagia, pain, and bulk-related symptoms). We did not place upper limits on the volume of leiomyoma or the uterus. We included pedunculated subserosal leiomyoma and co-existing adenomyosis unlikely to be associated with symptoms.

Exclusion criteria included acute pelvic infection, gynecological malignancy, an undiagnosed pelvic mass, coagulopathy, pregnancy, menopause, contraindications for MRI, being allergic to iodinated contrast medium or gadolinium, dominant adenomyosis mainly causing symptoms, dominant infarcted leiomyoma, and a history of UAE.

Study population

Between July 2008 and August 2015, 120 patients were referred to the Department of Radiology at our hospital as candidates for UAE for uterine leiomyoma (Fig. 1). Of the 120 patients, 76 consecutively underwent UAE for symptomatic leiomyoma. Of these patients, nine with a history of UAE were excluded based on exclusion criteria. As a result, the remaining 67 patients who fulfilled the inclusion and exclusion criteria were included in the present study. Between July 2008 and May 2014, GS was used for the first 49 patients, whereas TAGM was used for the following 18 patients between June 2014 and August 2015. Both groups consisted of consecutive patients, starting with the first patient to be treated with the embolic agent at our institution. Patient selection, procedures, and background care were provided based on the same protocol.

Fig. 1.

Flowchart of patients. *CE-MRI, contrast-enhanced MRI. **This patient was considered to be censored due to transvaginal myomectomy to treat infertility within the first 4 months after UAE.

Embolization technique

All procedures were performed by a single experienced operator with a unilateral femoral approach. A 5-Fr catheter was advanced near to the orifice of the uterine artery or inserted into the orifice. A microcatheter was then advanced coaxially into the transverse segment of the uterine artery.

When GS was used, the suspension with GS labeled as 1 mm in size was administered into uterine arteries under fluoroscopy. Thereafter, GS labeled as 2 mm in size were added. No other embolic agents were used. The angiographic endpoint of embolization was near-stasis of the ascending uterine artery (16). After the endpoint was reached, we immediately embolized the contralateral uterine artery, and the procedure was completed.

When TAGM was used, a suspension with 500–700-µm particles was administered. However, if the desired endpoint had not been reached after the use of approximately 3–5 syringes (6–10 mL) per side, the particle size was increased to 700–900 µm. The endpoint was defined as sluggish flow in the ascending uterine arteries with visualization of the administered contrast material for ≥ 5 cardiac beats on fluoroscopy (4 –6). After the initial endpoint, a 5-min waiting period was employed to assess early recanalization (9 –12). If increases in blood flow were observed, embolization was continued until the desired endpoint (9 –12). No additional embolization using other embolic agents was performed.

A two-night period of hospitalization was scheduled.

Pain management

Post-procedural pain was managed in both groups with the same protocol as follows: (i) the administration of diclofenac sodium (50 mg) before the procedure; (ii) the intramuscular and intravenous infusions of morphine hydrochloride hydrate (≥10 mg) and the intravenous infusion of droperidol (1.25–2.5 mg) during the procedure; (iii) the intravenous administration of morphine hydrochloride hydrate using a patient-controlled pump after the procedure; (iv) the oral administration of naproxen (600 mg) for 5–10 days; (v) the administration of loxoprofen sodium (60 mg) and/or diclofenac sodium (50 mg) as necessary.

MRI

All patients underwent MRI before and 1 week and 4 months after UAE using a 1.5 T system (Gyroscan Intera, Philips Medical Systems, Best, The Netherlands). T1-weighted (T1W) images before and after the administration of contrast material and T2-weighted (T2W) images were obtained by turbo spin-echo. Contrast-enhanced MRI was scanned with 0.2 mL/kg of Meglumine Gadopentetate (Magnevist; Bayer Schering Pharma, Berlin, Germany). The MRI protocol was the same in each group.

MRI was prospectively reviewed by radiologists with ≥ 10 years of experience of MRI and interventions. The volumes of the largest tumor and the uterus were measured on MRI using the formula for a prolate ellipse (length × depth × width × 0.5233). Leiomyoma of ≥ 1 cm in size was regarded as leiomyoma tissue. We prospectively calculated the infarction rate of all leiomyoma tissue on contrast-enhanced MRI 1 week after UAE (range, 0–100%; interval, 10%). The infarction rate was estimated visually by two experienced radiologists by comparing the non-perfusion volume to that of all leiomyoma tissue. They independently interpreted all images and subsequently estimated the subjective impression of infarction rates of all leiomyoma tissue. If there were any differences between the radiologists’ interpretations, they were resolved by a consensus in a subsequent discussion. The volumes of the largest tumor and the uterus, and the rates of reductions in the volumes of the largest tumor and the uterus, were measured 4 months after UAE.

Clinical evaluation

We obtained information on baseline characteristics such as age, weight, reproductive history, previous treatment, leiomyoma-related symptoms, etc. with medical records. Baseline symptoms and quality-of-life scores were obtained with the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire (19). Information on technical and peri-procedural outcomes, such as technical success (20), procedure time, fluoroscopy time, visual analog scale (VAS) scores at each time, duration of post-procedural pain, and time until a full recovery, was obtained with medical records.

Patients were routinely followed up 1 week, 4 months, and 1 year after UAE and annually thereafter. At the 1-week follow-up, we asked each patient about VAS scores and their subjective feelings about the extent of their recovery (in percentage terms) after UAE. Each patient completed the UFS-QOL and original written questionnaires 4 months after UAE. Symptom control and patient satisfaction with the outcomes achieved were assessed with the original written questionnaire 4 months after UAE.

Adverse events (AEs) were evaluated according to the Society of Interventional Radiology guidelines (21,22). Amenorrhea was investigated using the questionnaires 4 months after UAE. We did not evaluate whether amenorrhea was permanent or transient because it was assessed 4 months after UAE. The onset age of amenorrhea was recorded.

Study outcomes

The primary outcome measure was defined as the complete or nearly complete infarction (≥90%) of all leiomyoma tissue on contrast-enhanced MRI 1 week after UAE (9 –12,23). Secondary outcome measures included short-term clinical outcomes; i.e. changes in symptoms and quality-of-life scores according to the UFS-QOL questionnaires 4 months after UAE, and the frequency and severity of AEs during the 4 months after UAE (9 –12,23). Outcomes other than the primary and secondary outcomes were considered to be tertiary outcome measures.

Statistical analysis

Based on the results of the GS group, the sample size of the TAGM group was calculated a priori. The complete or nearly complete infarction (≥90%) of all leiomyoma tissue (according to contrast-enhanced MRI after UAE) was achieved in 93.6% (44/47) of the GS group in the present study and that in the TAGM group was expected to be 93.3% based on a previous study (12). A non-inferiority margin of 20%, which we consider to be the minimal clinically important difference in the rate of complete or nearly complete infarction, was set in the present study. A sample size of 18 in the TAGM group, together with 47 in the GS group, was estimated to provide 80% power (one-sided type І error of 2.5 %) to achieve the non-inferiority setting assuming a 10% drop-out rate.

Statistical analyses were performed with R version 3.0.3 (R Core Team 2014) or Dr. SPSS II (11.0 J; SPSS Japan Inc., Tokyo, Japan). The Student’s t-test was used for comparisons of continuous variables, and Fisher’s exact test was used for comparisons of discrete variables. P values of < 0.05 were considered to be significant.

We compared the following results between groups: (i) baseline characteristics; (ii) technical and peri-procedural outcomes; (iii) MRI outcomes; (iv) 4-month AEs; and (v) clinical outcomes 4 months after UAE.

Results

The enrollment of patients for the present study was completed in August 2015; the date of the last follow-up evaluation was November 2015. No significant differences were observed in baseline characteristics including MRI findings of leiomyoma and the uterus between the two groups (Table 1).

Table 1.

Baseline characteristics.

	TAGM (n = 18)	GS (n = 49)	P value
Age (years)	43.3 ± 6.6	44.0 ± 5.2	0.66
Weight (kg)	58.3 ± 9.5	56.2 ± 8.9	0.40
Height (cm)	157.8 ± 4.3	159.0 ± 5.5	0.38
BMI	23.5 ± 4.1	22.2 ± 3.4	0.22
Reproductive history
Nulliparous	9	20	0.58
Pregnancy plan
Preservation of fertility	4	2	0.04
Hope to retain the uterus	15	40	0.99
Previous treatment for leiomyoma
Myomectomy	2	13	0.32
Gn-RHa	3	20	0.09
Birth control pills	1	3	0.99
Symptoms
Menorrhagia	14	38	0.99
Dysmenorrhea	9	34	0.16
Genital bleeding	4	18	0.38
Pelvic pressure	11	36	0.37
Bloating	14	44	0.24
Constant urination	11	34	0.57
Anemia (number)	9	32	0.27
UFS-QOL symptom score	55.9 ± 16.5	52.6 ± 16.0	0.46
UFS-QOL total score	52.9 ± 16.7	58.3 ± 19.4	0.30
FSH*	10.7 ± 12.2	7.4 ± 8.8	0.24
Uterine volume (mL)	1057 ± 529	1007 ± 597	0.76
Largest tumor
Submucosal	2	8	0.91
Intramural	14	35
Subserosal	2	6
Max diameter (cm)	9.3 ± 3.1	9.6 ± 8.9	0.89
Volume (mL)	392 ± 321	299 ± 305	0.28
Co-existing adenomyosis	0	4	0.57

Data were presented as the mean ± SD for continuous variables and frequencies for categorical variables.

The FSH level was measured in a manner that did not take account of menstrual cycles.

FSH, follicle stimulating hormone; Gn-RHa, gonadotropin-releasing hormone agonists.

Technical outcomes

The technical success rate was 100% in both groups. The procedure time was significantly longer in the TAGM group than in the GS group (71.1 min versus 56.5 min, P < 0.001), although no significant differences were observed in the fluoroscopy time (P = 0.33, Table 2).

Table 2.

Technical and peri-procedural outcomes.

	TAGM (n = 18)	GS (n = 49)	Difference (95%CI)	P value
Technical success rate (%)
Embolization of the uterine artery	100 (18/18)	100 (49/49)	0 (0.01–19.5)	0.99
Ovarian artery embolization (%)	0 (0/18)	2 (1/49)	0 (0.04–29.4)	0.99
Procedure time (min)	71.1 ± 10.9	56.5 ± 14.6	14.6 (7.0–22.1)	< 0.001
Fluoroscopy time (min)	18.4 ± 4.2	16.8 ± 6.5	1.6 (–1.7 – 4.9)	0.33
Syringes/vials used (n)	6.4 ± 3.3	4.2 ± 1.6
AEs during the procedure	0	0
Morphine used (mg)	14.0 ± 3.6	15.6 ± 3.0	–1.6 (–3.3 – 0.2)	0.09
Maximum VAS scores
<24 h	4.9 ± 2.8	5.9 ± 2.1	–1.0 (–2.2 – 0.3)	0.13
24 h to 1 week	3.4 ± 2.3	3.2 ± 2.0	0.24 (–0.90 – 1.4)	0.44
1 week	0.1 ± 0.24	0.4 ± 0.6	–0.36 (–0.66 – 0.05)	0.001
Maximum body temperature (℃)
<24 h	37.6 ± 0.27	37.5 ± 0.34	0.08 (–0.10 – 0.26)	0.40
1 week	36.9 ± 0.3	36.7 ± 0.3	0.13 (–0.05 – 0.31)	0.14
Length of hospital stay (days)	2.9 ± 0.2	3 ± 0	–0.06 (–0.17 – 0.06)	0.33
Subjective recovery rate at 1 week (%)	83.4 ± 9.4	79.4 ± 14.0	4.0 (–3.5 – 11.6)	0.29
Blood data at 1 week
WBC	6233 ± 1456	5914 ± 1634	319 (–556 – 1194)	0.47
CRP	1.5 ± 2.2	1.2 ± 1.3	0.29 (–0.58 – 1.16)	0.51
Time required for the complete disappearance of post-procedural (days)	5.1 ± 3.5	11.1 ± 14.1	–6.1 (–10.5 – 1.6)	0.01
Time required for a full recovery (days)	11.5 ± 10.0	22.5 ± 22.5	–11.0 (–19.2 – 2.7)	0.01

Data were presented as the mean ± SD for continuous variables and frequencies for categorical variables.

Peri-procedural outcomes

The mean maximum VAS scores obtained < 24 h and from 24 h to 1 week after UAE did not differ significantly; however, the mean maximum VAS score at 1 week was significantly lower in the TAGM group than in the GS group (0.1 versus 0.4, P = 0.001; Table 2). The subjective feelings of patients about the extent of their recovery 1 week were not significantly different (TAGM, 83.4%; GS, 79.4%; P = 0.29). The time until the complete disappearance of post-procedural pain and the time until a full recovery were significantly shorter in the TAGM group than in the GS group (5.1 versus 11.1 days, P = 0.009; 11.5 versus 22.5 days, P = 0.01) (Table 2).

MRI outcomes

The complete or nearly complete infarction (≥90%) of all leiomyoma tissue was achieved in 94.4% (17/18) of patients in the TAGM group and 93.6% (44/47) of patients in the GS group (Supplementary Table 1, Fig. 1). The difference between these values was 0.8%, and the 95% CI was–11.9% to 13.5%, which indicated that UAE with TAGM was non-inferior to UAE with GS because the lower limit of –11.9% was larger than the pre-specified non-inferiority margin of –20% (Supplementary Table 1).

No significant differences were observed in the extent of reductions in the volumes of the largest tumor and the uterus 4 months after UAE (Supplementary Table 1).

Clinical outcomes

No significant differences were observed in improvements in UFS-QOL symptoms or quality-of-life scores 4 months after UAE between the two groups (P = 0.56, P = 0.19, Table 3). Symptom control and patient satisfaction were not significantly different 4 months after UAE (Table 3).

Table 3.

Clinical outcomes.

	TAGM (n = 18)	GS (n = 49)	P value
Four-month follow-up (%)*	89 (16/18)	96 (47/49)	0.29
UFS-QOL symptom score
4 months	28.7 ± 16.4	26.7 ± 11.8	0.66
Reduction from baseline	28.5 ± 22.0	25.6 ± 15.0	0.56
UFS-QOL total score
4 months	83.0 ± 7.7	82.1 ± 11.2	0.75
Increase from baseline	30.8 ± 17.5	23.8 ± 18.4	0.19
Symptom improvement at 4 months (%)^†
Menorrhagia	85 (11/13)	81 (30/37)	0.99
Dysmenorrhea	50 (4/8)	79 (26/33)	0.18
Genital bleeding	100 (4/4)	83 (15/18)	0.99
Pelvic pressure	78 (7/9)	94 (34/36)	0.17
Bloating	83 (10/12)	98 (43/44)	0.11
Constant urination	78 (7/9)	82 (28/34)	0.67
Patient satisfaction at 4 months (%)^†	94(15/16)	78 (36/46)	0.26
FSH
4 months after UAE	12.1 ± 14.6	13.5 ± 18.1	0.79
Increase from baseline	1.1 ± 18.7	5.9 ± 16.7	0.36
Amenorrhea during the first 4 months (%)^‡	18.8 (3/16)	21.3 (10/47)	0.99

Data were presented as the mean ± S.D. for continuous variables and frequencies for categorical variables.

Two patients in the TAGM group were lost to the follow-up due to no hospital visits, and two patients in the GS group were lost to the follow-up due to missing data and transvaginal myomectomy to treat infertility during the first 4 months, respectively.

†

These figures were calculated based on the answers available to the original questionnaire.

‡

Amenorrhea was defined when it occurred after UAE and continued for ≥ 2 months.

No major AEs occurred in either group. Minor AEs were observed in two patients in the TAGM group and two patients in the GS group, with no significant difference (P = 0.29). There was no significant difference in onset of amenorrhea during the first 4 months between the groups (P = 0.99, Table 3). The onset age of amenorrhea was ≥ 45 years in 2/3 patients in the TAGM group and in 9/10 patients in the GS group.

Discussion

Our results suggest that UAE with TAGM was non-inferior to UAE with GS in terms of the ability to achieve tumor infarction on contrast-enhanced MRI after UAE. Moreover, complete or nearly complete tumor infarction (≥90%) was achieved in most cases in each group. These results are consistent with previous findings on UAE with TAGM (9,10,12) and UAE with GS (14,16). Additionally, no significant differences were observed in improvements in symptoms and quality-of-life scores after UAE or in the frequency and severity of AEs between the groups. Therefore, we consider TAGM and GS to both be acceptable embolic agents in UAE for leiomyoma.

This is the first study to compare the effects of UAE with TAGM on imaging and clinical outcomes with those of UAE with GS among patients with symptomatic leiomyoma. We consider our results to contribute to treatment strategies, i.e. choice of embolic agents in UAE for leiomyoma.

Tumor infarction on contrast-enhanced MRI after UAE has been recognized as a good indicator of embolic effects and a useful predictor of long-term outcomes (24 –26). Kroencke et al. reported that the complete or nearly complete infarction (≥90%) of all leiomyoma tissue was associated with improvements in clinical symptoms and a low likelihood of re-interventions in the long term (26). Tumor infarction on contrast-enhanced MRI has been used as an important measure in most studies on comparisons of embolic agents (9 –12). Therefore, we defined it as a primary outcome measure.

No significant differences were observed in terms of most tertiary outcomes, except for the procedure time and recovery time after UAE. The procedure time was significantly longer in the TAGM group. A possible explanation for this is that several 5-min waiting periods were employed in the TAGM group during the procedure, which increased the procedure time, whereas no such waiting periods were employed in the GS group. However, since the fluoroscopy time did not differ significantly, we considered the difference in the procedure time to not be of critical importance clinically.

UAE with TAGM resulted in quicker recovery in the present study. However, maximum VAS scores in both groups 1 week after UAE were minimal, and the subjective feelings of patients about the extent of their recovery in both groups 1 week after UAE were equally sufficient (Table 2). Therefore, the difference in the duration required for the complete disappearance of pain and a full recovery does not appear to be important clinically.

It was difficult to conduct a study to assess the superiority of UAE with TAGM over UAE with GS because the MRI outcomes of pilot studies for each treatment were similar. Thus, we hypothesized that UAE with TAGM was non-inferior to UAE with GS.

The present study had some limitations. This was a non-randomized, comparative study. A randomized controlled trial is warranted (23). However, in our study, despite non-randomization, patient selection was consistently the same and no significant differences were observed in baseline characteristics or technical outcomes between the both groups. Additionally, a single experienced operator consistently performed the procedure and post-procedural management and follow-up were equal. Therefore, we consider the bias in both groups to be small. Another limitation is that the present study was designed after some of the data had already been obtained. This may have induced a potential bias. Furthermore, we only compared short-term outcomes between the groups. Thus, comparisons of long-term outcomes are required. However, tumor infarction on contrast-enhanced MRI is known to be associated with long-term clinical outcomes (24 –26). Since imaging outcomes did not significantly differ, we presume that the long-term outcomes of both groups are similar.

In conclusion, the present study demonstrated that the effects of UAE with TAGM on imaging and clinical outcomes were comparable to those of UAE with GS, suggesting that both embolic agents are acceptable in UAE for uterine leiomyoma.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TK received payments for lectures and writing a manuscript in a journal from Nippon Kayaku. These payments are not related to the present manuscript. The other authors have 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.

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