Effects of High-Intensity-Focused Ultrasound Treatment on Benign Uterine Tumor

High-Intensity-Focused Ultrasound; Benign Uterine Tumor; Treatment Effects Jaeyoon Park,1,4 Jae Seong Lee,2 Jae-Hwan Cho,3 and Sungchul Kim4 1Department of Radiology, Incheon Christian Hospital, Incheon, Korea; 2Department of Obstetrics and Gynaecology, Aegis Womanmed Clinic, Seoul, Korea; 3Department of Radiological Technology, Ansan College, Ansan, Korea; 4Department of Radiological Science, Gachon University Medical Campus, Incheon, Korea Received: 18 January 2016 Accepted: 11 May 2016 Address for Correspondence: Sungchul Kim, PhD Department of Radiological Science, Gachon University Medical Campus, 191 Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Korea E-mail: [email protected] http://dx.doi.org/10.3346/jkms.2016.31.8.1279 • J Korean Med Sci 2016; 31: 1279-1283

The uterus, which is associated with sex and childbirth, has been socioculturally recognized as a symbolic organ of mature wom- en (1). According to the 2011 in-depth analysis of the results of a patient survey in South Korea, 329.6 in every 100,000 women had undergone hysterectomy, the highest rate among the OECD countries (2). Fibroids and adenomyosis are the most common indications of hysterectomy, accounting for approximately 30% and 20% of the total, respectively (3). According to the National Health Insurance Service of South Korea, 237,000 patients were diagnosed with fibroids in 2009, and the number increased to 293,000 in 2013 for a mean annual increase of 5.5%. The num- ber increased in all age groups except the 20s or younger (4). The fundamental method of benign uterine tumor treatment is hysterectomy or myomectomy, but it requires general anes- thesia, hospitalization, and a long recovery period. Furthermore, women who want pregnancies or want to preserve their uterus require non-invasive treatments (5). High-intensity-focused ul- trasound (HIFU) is a non-invasive and non-hazardous method of preserving organs. It can be used repeatedly and is not affect- ed by the lesion size. The treatment process can be monitored in real time for evaluation of its performance. Physical trauma can be minimal because no incision or resection of tumors is performed. The normal functions of the uterus could be main- tained (6,7). However, few fundamental studies on HIFU treat- ments have been conducted in South Korea. In this study, the effects of HIFU on fibroids and adenomyo- sis patients treated in a Hospital in South Korea were analyzed.

Study subjects Of the 1,168 patients diagnosed with fibroid or adenomyosis (546 fibroids patients and 622 adenomyosis patients) 333 pa- tients (141 fibroid patients and 192 adenomyosis patients) who underwent HIFU treatment between February 4, 2010 and De- cember 29, 2014, and followed for three- and six-month follow- ups were selected for this study. To enhance the accuracy of the volume measurements, the subjects were followed up for up to six months. HIFU treatments and the tumor volume measurement

Before HIFU treatment, the size and location of the fibroids and adenomyosis were confirmed using transvaginal ultrasound, and the feasibility of the HIFU procedure was assessed through simulation. The strength of the ultrasound was adjusted from ORIGINAL ARTICLE Urology Park J, et al. • Ultrasound Treatment on Benign Uterine Tumor 1280 http://jkms.org http://dx.doi.org/10.3346/jkms.2016.31.8.1279 300 W to 400 W considering the subject’s pain level and the trans- mutation level of the fibroid and adenomyosis shown in the ul- trasound. The clinician determined the treatment duration. The median room time was 102 minutes, and mean time for sonica- tion was 20 minutes 11 seconds. ACCUVIX V10 (Samsung Medison, Seoul, Korea) was used to measure the tumor volume. A single gynecologist measured the horizontal, vertical, and longitudinal lengths of the fibroids and adenomyosis using the transvaginal ultrasound method before the HIFU procedure was performed, and the process was repeated three and six months later (Fig. 1). In patients with two or more fibroids or adenomyosis, the largest one was mea- sured, and their volume was calculated using the following el- lipsoid volume equation. Volume = π/6 × H × V × L -------------------------- Equation 1 H: Horizontal Length, V: Vertical Length, L: Longitudinal Length SPSS ver. 18.0 was used for the statistical analyses. ANOVA was used for the analyses according to the subject’s age, fertility, and treatment duration, and the independent t-test was used for the analysis by disease. The significance test was used to ver- ify the significance of the volume reduction and the reduction rate of the fibroids and adenomyosis. Statistical significance was accepted at P < 0.05. Ethics statement The study protocol was approved by the institutional review board of Inchon Christian Hospital (2015-01), and written in- formed consent was provided by all subjects.

Treatment effects according to the subject’s age In all age groups of the subjects who underwent the HIFU pro- cedure, decreases in the benign tumor volume were measured. The 30s group showed the greatest reduction of 158.36 cm3, but the differences among all age groups were statistically insignifi- cant. In terms of the reduction rate of the benign uterine tumor volume, all age groups showed changes three and six months after HIFU treatment. The 20s groups showed the highest re- duction rate of 64.9% six months later, but the difference was statistically insignificant (Table 1). Treatment effects according to the subject’s disease The adenomyosis volume decreased by 164.83 cm3 six months later, which was the most statistically significant treatment ef- fect. The myoma showed a statistically significant 68.5% volume reduction rate (Table 2). Fig. 1. Measurement of the adenomyosis by ultrasound scanning. (A) Horizontal & vertical length. (B) Longitudinal length. (C) Horizontal and vertical length. (D) Longitudinal length. A C B D Park J, et al. • Ultrasound Treatment on Benign Uterine Tumor http://jkms.org 1281http://dx.doi.org/10.3346/jkms.2016.31.8.1279 Treatment effects according to the subject’s fertility The reduction of the benign uterine tumor volume was statisti- cally significant up to six months after treatment in all fertilities. The volume reduction rates were sustained for up to six months after treatment, but the difference was statistically insignificant (Table 3). Benign uterine tumor change according to the treatment duration In all treatment durations, the benign uterine tumor volume decreased with statistical significance up to six months post- operatively. The volume reduction rate were unchanged up to six months after treatment, so the difference was statistically in- significant (Table 4).

Most recently, HIFU has been widely applied in clinical cases, and an increasing number of hospitals are using HIFU equip- ment. HIFU is recognized as a more conservative and safe meth- od with a faster recovery time than surgical methods, thereby drawing the attention of patients with benign uterine disease. However, its treatment effects and safety have not yet been ade- quately studied. In previous studies, only the reduction rates of fibroids and adenomyosis--no other factor of the benign uterine tumor size- Table 1. Changes in the benign uterine tumor volume according to the subject’s age Period Age group, yr No. Volume (cm3) Mean ± SD P value Reduction rate (%) Mean ± SD P value Before treatment 20-29 30-39 40-49 50-59 22 134 154 23 249.35 ± 211.45 277.91 ± 188.05 256.59 ± 159.93 260.54 ± 144.57 0.733 3 months after 20-29 30-39 40-49 50-59 22 134 154 23 114.95 ± 107.57 136.16 ± 94.28 124.81 ± 83.44 123.13 ± 74.60 0.606 57.02 ± 10.73 50.40 ± 14.83 51.67 ± 13.68 53.90 ± 16.72 0.194 6 months after 20-29 30-39 40-49 50-59 22 134 154 23 103.25 ± 113.32 119.55 ± 86.36 104.44 ± 78.05 104.33 ± 63.00 0.443 64.86 ± 14.47 57.98 ± 15.73 60.52 ± 15.19 61.39 ± 15.85 0.188 SD, standard deviation. Table 2. Changes in the reduction rate of the benign uterine tumor volume according to the subject’s disease Period Disease No. Volume (cm3) Mean ± SD P value Reduction rate (%) Mean ± SD P value Before treatment Myoma Adenomyosis 141 192 218.23 ± 175.50 299.28 ± 165.12 < 0.001 3 months after Myoma Adenomyosis 141 192 97.77 ± 91.85 151.25 ± 79.73 < 0.001 57.35 ± 13.39 47.50 ± 13.43 < 0.001 6 months after Myoma Adenomyosis 141 192 77.74 ± 81.90 134.45 ± 75.86 < 0.001 68.54 ± 13.50 53.45 ± 13.58 < 0.001 SD, standard deviation. Table 3. Changes in the reduction rate of the benign uterine tumor volume according to the subject’s fertility Period Fertility No. Volume (cm3) Mean ± SD P value Reduction rate (%) Mean ± SD P value Before treatment 0 1 2 3 147 49 124 13 295.85 ± 201.77 253.21 ± 141.72 222.60 ± 130.49 364.15 ± 216.05 0.001 3 months after 0 1 2 3 147 49 124 13 140.33 ± 98.89 128.29 ± 82.31 110.89 ± 70.19 166.24 ± 130.66 0.036 53.08 ± 12.42 49.14 ± 12.82 50.65 ± 16.67 55.02 ± 11.89 0.176 6 months after 0 1 2 3 147 49 124 12 126.36 ± 97.61 105.30 ± 65.88 90.47 ± 60.83 140.14 ± 114.03 0.005 59.56 ± 16.45 58.69 ± 14.39 60.55 ± 14.81 60.63 ± 14.96 0.811 SD, standard deviation. Park J, et al. • Ultrasound Treatment on Benign Uterine Tumor 1282 http://jkms.org http://dx.doi.org/10.3346/jkms.2016.31.8.1279 -were investigated (8,9). In addition, the factors of the treatment effects according to the patient’s age, disease, fertility, and HIFU treatment duration were not investigated. In this study, the ef- fects of HIFU treatments according to the patient’s age, disease, fertility, and treatment duration were examined. During HIFU treatment, the necrotized benign tumor is ab- sorbed via the nearby micro-blood flow. Thus, this study was conducted to prove the hypothesis that younger patients with an active blood flow experience better treatment effects. In our results, the treatment effects in the 20s age group were the great- est, and those in the 30s age group were the lowest, but the be- nign uterine tumor volume reduction and its reduction rates did not show a statistically significant difference among the age groups. In this study, the volume reduction and the volume reduc- tion rate of fibroids and adenomyosis were statistically signifi- cant. In a previous study on the changes in fibroids and three, six, and 12 months after completion of HIFU treatment, the volume was reduced by 58.1%, 66.2%, and 77.6%, respectively. Regarding adenomyosis, reduction rates of 44.0%, 47.0%, and 54.0% were observed, respectively (10). Ren et al. (11) reported the reduction rates of 27.2%, 47.9%, and 50.3% at 3, 6, and 12 months, respectively (11), and Wang et al. (8) showed 46.7%, 68.2%, 78.9%, and 90.1% at 3, 6, 12, and 24 months, respectively. Since pregnancy and childbirth cause hormonal changes, fertility was thought to have affected the changes in the fibroid and adenomyosis. In this study, the subjects who had given birth three times experienced the greatest treatment effects, and those who had given birth only once experienced the least treatment effects. The volume reductions according to fertility were statis- tically significant, but no statistically significant reduction rate

was obtained. The volume reductions according to the Table 4. Changes in the reduction rate of the benign uterine tumor volume according to the subject’s treatment duration Period Minute No. Volume (cm3) Mean ± SD P value Reduction rate (%) Mean ± SD P value Before treatment 0-30 31-60 61-90 91-120 121-150 151- 7 71 127 79 37 12 78.55 ± 40.10 150.55 ± 87.66 229.37 ± 121.51 330.24 ± 165.33 382.91 ± 178.35 633.99 ± 223.60 < 0.001 3 months after 0-30 31-60 61-90 91-120 121-150 151- 7 71 127 79 37 12 37.96 ± 26.40 81.10 ± 55.45 108.19 ± 65.13 156.44 ± 83.36 190.46 ± 96.32 304.67 ± 117.69 < 0.001 59.27 ± 19.64 48.47 ± 18.33 53.10 ± 13.44 52.46 ± 11.44 49.99 ± 12.61 51.06 ± 11.07 0.178 6 months after 0-30 31-60 61-90 91-120 121-150 151- 7 71 127 79 37 12 34.90 ± 24.94 69.39 ± 56.85 94.19 ± 60.79 136.63 ± 84.13 148.79 ± 89.76 278.67 ± 104.65 < 0.001 62.96 ± 20.86 59.23 ± 20.23 59.85 ± 15.01 59.53 ± 11.81 62.50 ± 14.44 55.41 ± 7.42 0.778 SD, standard deviation. treatment duration were statistically insignificant; but as a re- sult of ANOVA on the volume reduction rate, statistically signifi- cant results were obtained. What was unique about the treatment duration was that the subjects with 31-60 minutes and 121-150 minutes experienced lesser treatment effects three months lat- er, but at six months post-operatively, they showed a greater re- duction than the subjects with any other treatment duration. This study had the following limitations. Although some pa- tients were followed up to 12 months after HIFU treatment, this study contains only short-term treatment (6 months) effect. The discrimination based on the contrast-enhancement ultrasound using microbubbles might be more meaningful than the meth- od used in this study. In the case of two or more fibroid or ade- nomyosis, only the largest one was used for the analysis of treat- ment effect. In addition, patients who underwent HIFU treat- ment only at a Hospital were targeted. In future studies, patients from various hospitals may be targeted. Considering the size of the benign uterine tumor, would be decreased up to 24 months after completion of HIFU treatment, a longer follow-up period might be needed. Next, HIFU can also cause complications but data related to HIFU complications were not collected in this study. For HIFU treatment, however, it is known that the gener- al complications are as follows: subcutaneous edema can occur on the patient’s skin. In addition, pain similar to that experienced due to a slight burn can occur. Although HIFU treatment does not cause bleeding because it is an extracorporeal treatment, it can cause damage to the surrounding organs (i.e., heart, stom- ach, and intestine). In cases of liver cancer, there is a low possi- bility of nerve damage. However, if nerves exist in adjacent re- gions like uterine myoma, some transitional disabilities have been reported. There is also the possibility of infection in the tissues with coagulation necrosis (12). In cases of uterine myo- Park J, et al. • Ultrasound Treatment on Benign Uterine Tumor http://jkms.org 1283http://dx.doi.org/10.3346/jkms.2016.31.8.1279 ma, the follow-up observation of 7 pregnant women who expe- rienced unplanned pregnancies showed that all women had a full term delivery and did not have any specific complications related to the pregnancy within 1 year (range: 5-32 weeks, aver- age: 20 ± 8.85 weeks) after receiving HIFU treatment. Although it is considered safe for women to get pregnant 1 year after HIFU treatment, the need for a large-scale study on the topic has been mentioned (13). However, Bohlmann et al. (14) mentioned that there has yet to be any prospective research on the effects of HIFU treatment on pregnancy; therefore, they recommend that HIFU treatment be conducted selectively only for the following types of patients: patients at high risk of undergoing surgery, patients who refuse surgery, or infertile patients. Complications observed have been predominantly of Society of Interventional Radiology class A (no medical intervention required), with a small number of Society of Interventional Radiology class B (nominal therapy, no consequence). Class A adverse effects have included abdominal pain, mild sciatic/buttock pain, geni- tal bleeding/increased discharge, and a prolonged next period (15). Zhang et al. (9) reported a slightly increased frequency of abdominal pain (64% vs. 71%) and skin reaction (0.8/2.4%) in patients with diffuse adenomyosis compared with those with focal disease. In their recent large analysis of 346 cases, Lee et al. (10) reported a range of more unusual complications, includ- ing foot drop (one case), transient unilateral leg weakness (one case), tumor lysis syndrome with transient acute prerenal fail- ure (one case), sleep apnea due to a sedative agent (one case), first degree skin burn (five cases), second degree skin burn (three cases), and transient hematuria (ten cases) (10). Research on HIFU complications is planned in the future. HIFU is a relatively effective method of treating benign uter- ine tumors. It can be used for patients who cannot undergo the conventional surgical methods due to their poor medical con- dition. In conclusion, HIFU might replace existing methods of treating benign uterine tumors. DISCLOSURE The authors have no potential conflicts of interest to disclose. AUTHOR CONTRIBUTION Concept and design: Park J, Lee JS, Cho JH, Kim S. Data collec- tion and analysis: Park J, Lee JS, Cho JH. Interpretation of the data and critical review: Park J, Lee JS, Cho JH, Kim S. Revision: Park J, Lee JS, Cho JH, Kim S. Approval of final manuscript and agreement of submission: all authors. ORCID Jaeyoon Park http://orcid.org/0000-0001-7212-7391 Jae Seong Lee http://orcid.org/0000-0002-3988-1496 Jae-Hwan Cho http://orcid.org/0000-0001-7112-3866 Sungchul Kim http://orcid.org/0000-0002-4195-1297

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