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High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results
Ultrasonics Sonochemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry journal homepage: www.elsevier.com/locate/ultson
High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results Lian Shui a,1, Shihua Mao b,1, Qingrong Wu c,1, Guohua Huang a,d, Jian Wang a,b, Ruitao Zhang a,c, Kequan Li a,d, Jia He e,⇑, Lian Zhang a,⇑ a State Key Laboratory of Ultrasound Engineering in Medicine Co-founded by Chongqing and the Ministry of Science and Technology, Chongqing Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, PR China b Department of Obstetrics and Gynecology, Three Gorges Central Hospital, Chongqing 404000, PR China c Department of Obstetrics and Gynecology, Fuling Central Hospital, Chongqing 408099, PR China d Department of Obstetrics and Gynecology, Chongqing Haifu Hospital, Chongqing 401121, PR China e Department of Obstetrics and Gynecology, Suining Central Hospital, Sichuan 629000, PR China
a r t i c l e
i n f o
Article history: Received 30 April 2015 Accepted 13 May 2015 Available online xxxx Keywords: Ultrasound-guided high-intensity focused ultrasound Adenomyosis Long-term follow-up Adverse effect
a b s t r a c t Objective: To evaluate the long-term improvement of clinical symptoms of adenomyosis after treatment with ultrasound-guided high intensity focused ultrasound (USgHIFU). Methods: From January 2010 to December 2011, 350 patients with adenomyosis were treated with USgHIFU. Among the 350 patients, 224 of them completed the two years follow-up. The patients were followed up at 3 months, 1 year, and 2 years after HIFU treatment. Adverse effects and complications were recorded. Results: All patients completed HIFU ablation without severe postoperative complications. 203 of the 224 patients who showed varying degrees of dysmenorrhea before treatment had the symptom scores decreased significantly after treatment (P < 0.001). The relief rate was 84.7%, 84.7%, and 82.3%, respectively at 3 months, 1 year, and 2 years after treatment. The menstrual volume in 109 patients with menorrhagia was significantly improved after treatment (P < 0.001) with a relief rate of 79.8%, 80.7%, and 78.9%, respectively at 3 months, 1 year, and 2 years after HIFU treatment. Conclusion: With its ability to sustain long-term clinical improvements, HIFU is a safe and effective treatment for adenomyosis. Ó 2015 Published by Elsevier B.V.
1. Introduction Adenomyosis is the endometrial ectopic growth in myometrium caused by a variety of factors. It is a common gynecological disease often found in women of childbearing age and its incidence is steadily increasing. The main manifestations of the disease include periodic dysmenorrhea, menorrhagia, and uterine enlargement [1,2]. Surgery and medications are the state-of-art treatments for this disease [3,4]. Radical cure can only be achieved via hysterectomy, which, however, is not applicable for patients with fertility desires or those who are reluctant to have their uterus resected. Additionally, hysterectomy is causatively related to a series of physiological and psychological problems, significantly ⇑ Corresponding authors. E-mail addresses: [email protected] (J. He), [email protected] (L. Zhang). 1 Shui Lian, Mao Shihua, and Wu Qingrong are joint first authors who all contributed equally to this research.
reducing patients’ quality of life. While less-invasive treatment such as myomectomy can conserve the uterus, the ill-defined borderlines of the disease often leads to incomplete removal of the lesions with this procedure and consequently results in a high rate of relapse. The long-term efficacy of drug therapy is also poor and is associated with many side effects. Thus, there is a urgent clinical need to explore new therapies for the treatment and management of this condition [5]. With its broad application in the management of uterine fibroids, liver cancer, osteosarcoma, and other solid tumors, high intensity focused ultrasound (HIFU) is gaining momentum and interests from patients and physicians for the treatment of adenomyosis [6–10]. However, most of the existing clinical studies have focused on assessing the short-term efficacy of HIFU treatment for adenomyosis, the long-term efficacy of HIFU for adenomyosis has not been investigated. This retrospective two-year follow-up study evaluated the long-term efficacy of HIFU in alleviating or improving the symptoms of adenomyosis.
http://dx.doi.org/10.1016/j.ultsonch.2015.05.024 1350-4177/Ó 2015 Published by Elsevier B.V.
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
2
L. Shui et al. / Ultrasonics Sonochemistry xxx (2015) xxx–xxx
2. Matherials and methods
2.5. Adverse effects
2.1. Materials
Adverse effect assessment was conducted according to SIR classification including the following variables: abdominal pain, coccydynia, abnormal vaginal secretions, fever, sensorimotor abnormalities of lower limbs, and skin burns.
From 2010 January to 2011 December, 350 patients, diagnosed with adenomyosis at Suining Central Hospital, Fuling Central Hospital, and Three Gorges Central Hospital, voluntarily underwent ultrasound-guided high-intensity focused ultrasound (HIFU) ablation treatment. Of 350 patients, 224 patients, with a mean age of 41.6 ± 4.6 (26–53) years, were followed up for 2 years, among which 203 patients presented persistent dysmenorrhea, and 109 presented menorrhagia before treatment.
2.6. Statistical analysis Statistical analysis was conducted using SPSS 17.0 software, and the results are expressed as mean ± SD. Scores of dysmenorrhea and menstrual volume after treatment at different follow-up period were compared with those at baseline with paired t test, and P < 0.05 was defined as statistically significant.
2.2. Preoperative preparations 3. Results All patients took ECG, blood routine test, and other relevant examinations following the MRI to determine lesion range, location, and blood supply; and signed the written informed consent for HIFU treatment. Patients were given clear instructions about bowel preparation three days prior to the treatment. To avoid gas or feces present in the bowel during HIFU procedure, these patients were requested to take liquid food for two days, without meat, popcorn, beans, vegetables, or fruits; enema was performed in the morning of the treatment day following 12-h fasting. Skin preparation, degassing, and degreasing were performed right before treatment to reduce the risk of skin burns. Urinary catheter was inserted to control the bladder volume with saline injection to optimize the therapeutic acoustic pathway.
3.1. Baseline information of the patients In this study, 350 patients diagnosed with adenomyosis underwent USgHIFU therapy and were followed-up for two years. The follow-up rates for 3 months, 1 year, and 2 years were 82.5% (289/350), 82.0% (287/350), and 64.0% (224/350), respectively. We thus analyzed treatment and follow-up data for the 224 patients who completed the 2 years follow-ups. Among the 224 patients included in our study, 109 had menorrhagia and 203 had persistent dysmenorrhea before the treatment. The mean age of this cohort was 41.6 ± 4.6 (26–53) years, and the mean volume of adenomyosis was 66.2 ± 48.6 (4.2–373.3) cm3 (see Table 1). 3.2. Evaluation of the treatment effectiveness
2.3. HIFU ablation The adenomyotic lesion was treated by ultrasound-guided high-intensity focused ultrasound tumor therapeutic system JC200 (Chongqing Haifu Medical Co. Ltd.). Patients were preoperatively administered Fentanyl and Midazolam for sedation and analgesia, and lying prone to enable their skin to be in full contact with degassed water. A balloon was used to push away the intestines to avoid intestinal damage during treatment. After ultrasound localization of the lesions, HIFU ablation began from the center of the lesion, covering the entire lesion point by point and layer by layer. The power and sonication energy were adjusted according to real-time changes on the gray-scale. Close attention was paid to protecting the skin of the patients and to monitoring adverse effects during treatment.
2.4. Evaluation of clinical symptom after HIFU treatment The scoring systems for dysmenorrheal and menstrual volumes: (1) Dysmenorrhea scores: dysmenorrhea was scored before and after treatment in accordance with the standards of Visual Analogue Scale (VAS): mild pain (1–3 points), moderate pain (4– 6 points), and severe pain (7–10 points). (2) Menstrual volumes were scored according to patients’ description on a 5-point scale: small (1 point), moderately large (2 points), large (3 points), very large (4 points), and extremely large (5 points). The scores of dysmenorrhea and menstrual volume before and after treatment were compared to determine whether the symptoms were alleviated using the following criteria: (1) obvious relief: the difference is over 2 points; (2) partial relief: the difference is 1 point; (3) complete relief: symptoms are completely relieved; (4) aggravation: post-operative scores increase. Clinical relief included obvious relief, partial relief, and complete relief.
All the patients successfully completed ultrasound-guided HIFU ablation. The contrast-enhanced ultrasonography was done immediately after the treatment or dynamic enhanced MRI examination was done on the next day of the treatment. Areas of non-perfusion were detected in all ablated lesions (Fig. 1). The average treatment time lasted 103.8 ± 59.4 (range: 11.0–247.0) min, the non-perfused volume (NPV) was 49.4 ± 37.5 (range: 2.4–187.3) cm3, and the NPV ratio reached approximately 72.7 ± 18.0 (range: 5.0–99.0)% (see Table 2). 3.3. Adverse effects The adverse effects are summarized in Table 3. No serious adverse effects occurred, and no patients underwent prolonged
Table 1 Baseline characteristics of patients before HIFU treatment. Variables
Value
Age (year) Diameter of adenomyotic lesion (cm) Volume of adenomyotic lesion (cm3) Diameter of the uterus (cm) Volume of the uterus (cm3)
41.6 ± 4.6 (26–53) 5.1 ± 1.4 (1.1–10.2) 66.2 ± 48.6 (4.2–373.3) 9.8 ± 1.5 (6.5–15.0) 253.1 ± 109.3 (100.4–708.2)
Menstruation pain score 0 point 1–3 points 4–6 points 7–10 points
21 64 91 48
Menstruation volume score 1 point 2 points 3 points 4 points 5 points
115 31 55 21 2
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
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L. Shui et al. / Ultrasonics Sonochemistry xxx (2015) xxx–xxx
Fig. 1. Preoperative and postoperative enhanced MRI. (A) Enhanced MRI image of adenomyosis before treatment, which shows the myometrium in fundus of uterus was thickening and rich in blood supply. (B) Enhanced MRI image obtained from a patient with adenomyosis 1 day after HIFU treatment, which shows non-perfused area in the lesion.
Table 5 Scores of dysmenorrhea at different follow-up time periods.
Table 2 HIFU ablation parameters. Parameters Treatment time (min) Sonication time (s) Treatment intensity (s/h) Average power (W) Non-perfused volume (cm3) NPV ratio (%)
Value
Time points of evaluation
Scores
103.8 ± 59.4 (11.0–247.0) 1197.3 ± 744.2 (114–4000) 689.5 ± 146.8 (305.0–1144.0) 379.2 ± 30.8 (218.0–400.0) 49.4 ± 37.5 (2.4–187.3) 72.7 ± 18.0 (5.0–99.0)
Before treatment 3 months 1 year 2 years
5.0 ± 2.2 1.9 ± 1.7 1.8 ± 1.7 2.2 ± 2.0
Table 3 The incidence and SIR classification of adverse effects. SIR classification
Adverse effects
Cases
Pain or discomfort in treated region Mild sacral pain Abnormal vaginal discharge Fever Leg pain Superficial I°–II° skin burns
115 107 23 27 1 1 3
A
B
*
P (1–10) (0–7)* (0–7)* (0–8)*
N/A 0.00 0.00 0.00
P < 0.05 was considered as significant different.
14 days. Low-grade fever (<38 °C) was found in 1 patient and the temperature automatically returned to normal at 3 days after treatment. Sensory motor abnormalities of the lower limbs were observed in one patient and the symptom was gradually relieved within one month after treatment. Surgical scar on the abdominal skin was found in 3 patients with SIR Type B. One patient had superficial II° burns and small vesicles adjacent to the scar. Necrotic tissue was removed along the previous surgical scar, and the burns healed two weeks after the treatment. The other two patients who had I° burns were treated with only local dressing, and the burns healed one month after the treatment. 3.4. Improvement of dysmenorrheal
hospitalization or readmission due to complications. According to SIR classification, 97.5% (115/118) recorded adverse effects belonged to SIR Type A category and did not need clinical intervention. Coccydynia, pain or discomfort in the treated area disappeared one day after the treatment in most patients, and the rest of the patients had the pain disappeared within 7 days after the treatment. Vaginal discharge disappeared in 27 patients after 7–
The clinical effectiveness of HIFU in alleviating dysmenorrhea in 203 patients who had completed the two-year follow-up reached 84.7%, 86.2%, and 82.3%, respectively at 3 months, 1 year, and 2 years after treatment. According to VAS standards for dysmenorrhea, patients with dysmenorrhea were scored before treatment and 3 months, 1 year, and 2 years after treatment, respectively. Compared with the scores before ablation, the symptoms after treatment were significantly alleviated (Table 5, P < 0.001).
Table 4 Evaluation of treatment efficacy in 203 patient with dysmenorrhea after HIFU treatment. Follow-up time
Complete relief
Obvious relief
Partial relief
No response
Aggravation
Clinical effective rate
3 months 1 year 2 years
64 (31.5%) 63 (31.0%) 44 (21.7%)
87 (42.9%) 89 (43.8%) 92 (45.3%)
21 (10.3%) 23 (11.3%) 31 (15.3%)
24 (11.8%) 20 (9.9%) 20 (9.9%)
7 (3.4%) 8 (3.9%) 16 (7.9%)
172 (84.7%) 175 (86.2%) 178 (82.3%)
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
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L. Shui et al. / Ultrasonics Sonochemistry xxx (2015) xxx–xxx
Table 6 Evaluation of treatment efficacy in 109 patients with menorrhagia after HIFU treatment. Follow-up time
Complete relief
Obvious relief
Partial relief
No response
Aggravation
Clinical effective rate
3 months 1 year 2 years
75 (68.8%) 74 (67.9%) 68 (62.4%)
1 (0.9%) 3 (2.8%) 4 (3.7%)
11 (10.1%) 11 (10.1%) 14 (12.8%)
12 (11.0%) 15 (13.8%) 18 (16.5%)
10 (9.2%) 6 (5.5%) 5 (4.6%)
87 (79.8%) 88 (80.7%) 86 (78.9%)
Table 7 Menstruation volume scores before and after HIFU treatment in 109 adenomyosis patients presenting with menorrhagia.
*
Evaluation time
Menstrual volume scores
P
Before treatment 3 months 1 year 2 years
2.9 ± 0.8 1.6 ± 0.9 1.5 ± 0.9 1.6 ± 1.0
N/A 0.00 0.00 0.00
(2–5) (1–5)* (1–5)* (1–5)*
P < 0.05 was considered as significant different.
3.5. Improvement of menstrual volume Among the 224 patients who had completed the two-year follow-up, 109 had varying degrees of menorrhagia before treatment. Compared with the menstrual volume before treatment, the relief rates were 79.8% (87/109), 80.7% (88/109), and 78.9% (86/109) respectively at 3 months, 1 year, and 2 years after treatment, which showed significant improvement of this symptom (Tables 6 and 7, P < 0.001).
4. Discussion The uterus-conserving treatment of adenomyosis is a clinical challenge. Unlike uterine myomas, the margin of adenomyotic lesion is often ill-defined, posing difficulties for surgical resection. Even worse, surgical removal often results in large trauma and high incidence of recurrence. A new treatment, therefore, has been highly sought after in clinical practice. As an emerging non-invasive treatment technology in recent years, HIFU, featuring good tissue penetration, can induce coagulation necrosis of the targeted lesion through thermal and other biological effects caused by the instant temperature rise due to focused energy generated by ultrasound waves focusing onto the target inside the body. Although it is difficult to ablate the adenomyotic lesion completely by means of HIFU, this treatment is non-invasive with minimal or no injuries to the surrounding normal tissues. Thus it can be repeated many times. A number of studies in recent years have shown the safety and effectiveness of HIFU ablation in the treatment of adenomyosis [11–13]. This retrospective study has demonstrated the safety and effectiveness of HIFU ablation in the treatment of adenomyosis. In 224 patients with adenomyosis who were followed up for 2 years after receiving HIFU treatment, The average NPV ratio was 72.7 ± 18% (range, 5.0–99.0%). During two years of follow-up, no serious complications related to HIFU therapy were identified. Although varying degrees of adverse effects during the treatment were observed in 118 patients, 115 of whom were of SIR Type A. 90.7% of the patients experienced pain or discomfort in the region of treatment. The sacral discomfort some patients complained of may be a manifestation of paresthesia of sacral nerve resulting from thermal diffusion. This diffusion of energy is attributable to the fact that their lesions were located in the posterior wall of the uterus or distributed diffusely. Pain disappeared immediately after treatment. The complication of varying degrees of skin burns in three patients was mainly related to their prior abdominal surgical scars. In the treatment, the scar tissue along the acoustic path affected
ultrasound penetration, resulting in energy deposition adjacent to the scar, resulting in the observed skin burn in three cases. By decreasing the duration of consecutive sonication and increasing the intervals of treatment, and reducing the power intensity, skin burns could be avoided. Therefore, HIFU is safe for treating adenomyosis, which is consistent with the findings in the literature [12,13]. Periodic dysmenorrhea is one of the most common symptoms of adenomyosis. In this study, 203 of the 224 patients followed up for 2 years presented with the symptoms of periodic dysmenorrhea before treatment, and the severity of the symptom scored over 4 in majority the patients, and the average pain score was 5.0 ± 2.2 points. After HIFU treatment, the scores of periodic dysmenorrhea decreased significantly. Clinical effectiveness, measured by alleviation of this symptom reached over 80% during the two-year follow-up. These findings indicate that ablation of 70% or higher of the volume of adenomyotic lesions is sufficient to alleviate dysmenorrhea in over 80% of the patients (Tables 4 and 5). Menorrhagia is another common symptom in patients with adenomyosis. In the 224 patients completing 2 years of follow-up, 109 had menorrhagia before HIFU treatment. According to the 5-point scoring standard, the mean score of menstrual volume was 2.9 ± 0.8 cm3, and it decreased significantly after HIFU treatment. During the 2 years of follow-up, the clinical effective rate was near 80% (Tables 6 and 7). These findings also demonstrate the effectiveness of HIFU in the treatment of adenomyosis. The above results were consistent with the reports of Zhang, et al. [13]. In this study, only few patients had no relief of symptoms and even fewer of them had aggravated symptoms, which may be a result of insufficient ablation or the comorbidity of pelvic endometriosis. A more rigorous screening of patients and higher NPV ratio may enhance the clinical efficacy of HIFU in the management of adenomyosis. This is the first study to demonstrate the safety and efficacy of HIFU for treating adenomyosis through short-term to long-term follow up in a large clinical cohort. However, one of the limitations of this study is that the retrospective study had a high incidence of loosing patients during the second year of follow-up, which may lead to the underestimation of the long-term efficacy of HIFU. Therefore, future study needs to intensify follow-up and reduce loss to follow-up, so as to obtain more complete, reliable, and high quality clinical follow-up results. 5. Conclusions Based on the above analyses, we believe that HIFU is a safe, effective, non-invasive, and uterus-conserving local treatment for adenomyosis, which can significantly improve patients’ quality of life owing to its ability to alleviate the major symptoms of adenomyosis without compromising the integrity of the uterus. Disclosure Lian Zhang is a senior consultant to Chongqing haifu company. The other authors have no potential conflicts of interest to disclose.
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
L. Shui et al. / Ultrasonics Sonochemistry xxx (2015) xxx–xxx
Acknowledgements This study was supported by the State Key Program of National Natural Science of China (Grant No. 30830040), National Key Technology R&D Program in the 11th Five year Plan of China (Grant No. 2006BAI03A02) and Chongqing Science and Technology Key Project (Grant Nos. [2007] 11CSTC, 2007AA502). References [1] C. Bergeron, F. Amant, A. Ferenczy, Pathology and physiopathology of adenomyosis, Best Pract. Res. Clin. Obstet. Gynecol. 20 (4) (2006) 511–521. [2] P. Vercellini, P. Vigan‘o, E. Somigliana, R. Daguati, A. Abbiati, L. Fedele, Adenomyosis: epidemiological factors, Best Pract. Res. Clin. Obstet. Gynecol. (2006) 20(4):465–77. [3] C. Farquhar, I. Brosens, Medical and surgical management of adenomyosis, Best Pract. Res. Clin. Obstet. Gynecol. 20 (4) (2006) 603–616. [4] C. Wood, Surgical and medical treatment of adenomyosis, Human Reprod. Update 4 (4) (1998) 323–336. [5] A. Shrestha, R. Shrestha, L.B. Sedhai, et al., Adenomyosis at hysterectomy: prevalence, patient characteristics, clinical profile and histopatholgical findings, Kathmandu Univ. Med. J. 10 (1) (2012) 44–47.
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[6] K. Komura, T. Inamoto, H. Masuda, et al., Experience with high-intensity focused ultrasound therapy for management of organ-confined prostate cancer: critical evaluation of oncologic outcomes, Acta bio-med. Atenei Parmensis. 83 (3) (2012) 189–196. [7] L. Zhang, Z.B. Wang, High-intensity focused ultrasound tumor ablation: review of ten years of clinical experience, Front. Med. Chin. 4 (3) (2010) 294–302. [8] W. Chen, H. Zhu, L. Zhang, et al., Primary bone malignancy: effective treatment with high-intensity focused ultrasound ablation, Radiology 255 (3) (2010) 967. [9] T.T. Cheung, S.T. Fan, S.C. Chan, et al., High-intensity focused ultrasound ablation: an effective bridging therapy for hepatocellular carcinoma patients, World J. Gastroenterol. 19 (20) (2013) 3083. [10] S. Peng, Y. Xiong, K. Li, et al., Clinical utility of a microbubble-enhancing contrast (‘‘SonoVue’’) in treatment of uterine fibroids with high intensity focused ultrasound: a retrospective study, Eur. J. Radiol. 81 (12) (2012) 3832– 3838. [11] T.Y. Fan, L. Zhang, W. Chen, et al., Feasibility of MRI-guided high intensity focused ultrasound treatment for adenomyosis, Eur. J. Radiol. 81 (11) (2012) 3624–3630. [12] M. Zhou, J.Y. Chen, L.D. Tang, et al., Ultrasound-guided high-intensity focused ultrasound ablation for adenomyosis: the clinical experience of a single center, Fertil. Steril. 95 (3) (2011) 900–905. [13] X. Zhang, K. Li, B. Xie, et al., Effective ablation therapy of adenomyosis with ultrasound-guided high-intensity focused ultrasound, Int. J. Gynecol. Obstet. 124 (3) (2014) 207–211.
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry journal homepage: www.elsevier.com/locate/ultson
High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results Lian Shui a,1, Shihua Mao b,1, Qingrong Wu c,1, Guohua Huang a,d, Jian Wang a,b, Ruitao Zhang a,c, Kequan Li a,d, Jia He e,⇑, Lian Zhang a,⇑ a State Key Laboratory of Ultrasound Engineering in Medicine Co-founded by Chongqing and the Ministry of Science and Technology, Chongqing Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, PR China b Department of Obstetrics and Gynecology, Three Gorges Central Hospital, Chongqing 404000, PR China c Department of Obstetrics and Gynecology, Fuling Central Hospital, Chongqing 408099, PR China d Department of Obstetrics and Gynecology, Chongqing Haifu Hospital, Chongqing 401121, PR China e Department of Obstetrics and Gynecology, Suining Central Hospital, Sichuan 629000, PR China
a r t i c l e
i n f o
Article history: Received 30 April 2015 Accepted 13 May 2015 Available online xxxx Keywords: Ultrasound-guided high-intensity focused ultrasound Adenomyosis Long-term follow-up Adverse effect
a b s t r a c t Objective: To evaluate the long-term improvement of clinical symptoms of adenomyosis after treatment with ultrasound-guided high intensity focused ultrasound (USgHIFU). Methods: From January 2010 to December 2011, 350 patients with adenomyosis were treated with USgHIFU. Among the 350 patients, 224 of them completed the two years follow-up. The patients were followed up at 3 months, 1 year, and 2 years after HIFU treatment. Adverse effects and complications were recorded. Results: All patients completed HIFU ablation without severe postoperative complications. 203 of the 224 patients who showed varying degrees of dysmenorrhea before treatment had the symptom scores decreased significantly after treatment (P < 0.001). The relief rate was 84.7%, 84.7%, and 82.3%, respectively at 3 months, 1 year, and 2 years after treatment. The menstrual volume in 109 patients with menorrhagia was significantly improved after treatment (P < 0.001) with a relief rate of 79.8%, 80.7%, and 78.9%, respectively at 3 months, 1 year, and 2 years after HIFU treatment. Conclusion: With its ability to sustain long-term clinical improvements, HIFU is a safe and effective treatment for adenomyosis. Ó 2015 Published by Elsevier B.V.
1. Introduction Adenomyosis is the endometrial ectopic growth in myometrium caused by a variety of factors. It is a common gynecological disease often found in women of childbearing age and its incidence is steadily increasing. The main manifestations of the disease include periodic dysmenorrhea, menorrhagia, and uterine enlargement [1,2]. Surgery and medications are the state-of-art treatments for this disease [3,4]. Radical cure can only be achieved via hysterectomy, which, however, is not applicable for patients with fertility desires or those who are reluctant to have their uterus resected. Additionally, hysterectomy is causatively related to a series of physiological and psychological problems, significantly ⇑ Corresponding authors. E-mail addresses: [email protected] (J. He), [email protected] (L. Zhang). 1 Shui Lian, Mao Shihua, and Wu Qingrong are joint first authors who all contributed equally to this research.
reducing patients’ quality of life. While less-invasive treatment such as myomectomy can conserve the uterus, the ill-defined borderlines of the disease often leads to incomplete removal of the lesions with this procedure and consequently results in a high rate of relapse. The long-term efficacy of drug therapy is also poor and is associated with many side effects. Thus, there is a urgent clinical need to explore new therapies for the treatment and management of this condition [5]. With its broad application in the management of uterine fibroids, liver cancer, osteosarcoma, and other solid tumors, high intensity focused ultrasound (HIFU) is gaining momentum and interests from patients and physicians for the treatment of adenomyosis [6–10]. However, most of the existing clinical studies have focused on assessing the short-term efficacy of HIFU treatment for adenomyosis, the long-term efficacy of HIFU for adenomyosis has not been investigated. This retrospective two-year follow-up study evaluated the long-term efficacy of HIFU in alleviating or improving the symptoms of adenomyosis.
http://dx.doi.org/10.1016/j.ultsonch.2015.05.024 1350-4177/Ó 2015 Published by Elsevier B.V.
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
2
L. Shui et al. / Ultrasonics Sonochemistry xxx (2015) xxx–xxx
2. Matherials and methods
2.5. Adverse effects
2.1. Materials
Adverse effect assessment was conducted according to SIR classification including the following variables: abdominal pain, coccydynia, abnormal vaginal secretions, fever, sensorimotor abnormalities of lower limbs, and skin burns.
From 2010 January to 2011 December, 350 patients, diagnosed with adenomyosis at Suining Central Hospital, Fuling Central Hospital, and Three Gorges Central Hospital, voluntarily underwent ultrasound-guided high-intensity focused ultrasound (HIFU) ablation treatment. Of 350 patients, 224 patients, with a mean age of 41.6 ± 4.6 (26–53) years, were followed up for 2 years, among which 203 patients presented persistent dysmenorrhea, and 109 presented menorrhagia before treatment.
2.6. Statistical analysis Statistical analysis was conducted using SPSS 17.0 software, and the results are expressed as mean ± SD. Scores of dysmenorrhea and menstrual volume after treatment at different follow-up period were compared with those at baseline with paired t test, and P < 0.05 was defined as statistically significant.
2.2. Preoperative preparations 3. Results All patients took ECG, blood routine test, and other relevant examinations following the MRI to determine lesion range, location, and blood supply; and signed the written informed consent for HIFU treatment. Patients were given clear instructions about bowel preparation three days prior to the treatment. To avoid gas or feces present in the bowel during HIFU procedure, these patients were requested to take liquid food for two days, without meat, popcorn, beans, vegetables, or fruits; enema was performed in the morning of the treatment day following 12-h fasting. Skin preparation, degassing, and degreasing were performed right before treatment to reduce the risk of skin burns. Urinary catheter was inserted to control the bladder volume with saline injection to optimize the therapeutic acoustic pathway.
3.1. Baseline information of the patients In this study, 350 patients diagnosed with adenomyosis underwent USgHIFU therapy and were followed-up for two years. The follow-up rates for 3 months, 1 year, and 2 years were 82.5% (289/350), 82.0% (287/350), and 64.0% (224/350), respectively. We thus analyzed treatment and follow-up data for the 224 patients who completed the 2 years follow-ups. Among the 224 patients included in our study, 109 had menorrhagia and 203 had persistent dysmenorrhea before the treatment. The mean age of this cohort was 41.6 ± 4.6 (26–53) years, and the mean volume of adenomyosis was 66.2 ± 48.6 (4.2–373.3) cm3 (see Table 1). 3.2. Evaluation of the treatment effectiveness
2.3. HIFU ablation The adenomyotic lesion was treated by ultrasound-guided high-intensity focused ultrasound tumor therapeutic system JC200 (Chongqing Haifu Medical Co. Ltd.). Patients were preoperatively administered Fentanyl and Midazolam for sedation and analgesia, and lying prone to enable their skin to be in full contact with degassed water. A balloon was used to push away the intestines to avoid intestinal damage during treatment. After ultrasound localization of the lesions, HIFU ablation began from the center of the lesion, covering the entire lesion point by point and layer by layer. The power and sonication energy were adjusted according to real-time changes on the gray-scale. Close attention was paid to protecting the skin of the patients and to monitoring adverse effects during treatment.
2.4. Evaluation of clinical symptom after HIFU treatment The scoring systems for dysmenorrheal and menstrual volumes: (1) Dysmenorrhea scores: dysmenorrhea was scored before and after treatment in accordance with the standards of Visual Analogue Scale (VAS): mild pain (1–3 points), moderate pain (4– 6 points), and severe pain (7–10 points). (2) Menstrual volumes were scored according to patients’ description on a 5-point scale: small (1 point), moderately large (2 points), large (3 points), very large (4 points), and extremely large (5 points). The scores of dysmenorrhea and menstrual volume before and after treatment were compared to determine whether the symptoms were alleviated using the following criteria: (1) obvious relief: the difference is over 2 points; (2) partial relief: the difference is 1 point; (3) complete relief: symptoms are completely relieved; (4) aggravation: post-operative scores increase. Clinical relief included obvious relief, partial relief, and complete relief.
All the patients successfully completed ultrasound-guided HIFU ablation. The contrast-enhanced ultrasonography was done immediately after the treatment or dynamic enhanced MRI examination was done on the next day of the treatment. Areas of non-perfusion were detected in all ablated lesions (Fig. 1). The average treatment time lasted 103.8 ± 59.4 (range: 11.0–247.0) min, the non-perfused volume (NPV) was 49.4 ± 37.5 (range: 2.4–187.3) cm3, and the NPV ratio reached approximately 72.7 ± 18.0 (range: 5.0–99.0)% (see Table 2). 3.3. Adverse effects The adverse effects are summarized in Table 3. No serious adverse effects occurred, and no patients underwent prolonged
Table 1 Baseline characteristics of patients before HIFU treatment. Variables
Value
Age (year) Diameter of adenomyotic lesion (cm) Volume of adenomyotic lesion (cm3) Diameter of the uterus (cm) Volume of the uterus (cm3)
41.6 ± 4.6 (26–53) 5.1 ± 1.4 (1.1–10.2) 66.2 ± 48.6 (4.2–373.3) 9.8 ± 1.5 (6.5–15.0) 253.1 ± 109.3 (100.4–708.2)
Menstruation pain score 0 point 1–3 points 4–6 points 7–10 points
21 64 91 48
Menstruation volume score 1 point 2 points 3 points 4 points 5 points
115 31 55 21 2
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
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Fig. 1. Preoperative and postoperative enhanced MRI. (A) Enhanced MRI image of adenomyosis before treatment, which shows the myometrium in fundus of uterus was thickening and rich in blood supply. (B) Enhanced MRI image obtained from a patient with adenomyosis 1 day after HIFU treatment, which shows non-perfused area in the lesion.
Table 5 Scores of dysmenorrhea at different follow-up time periods.
Table 2 HIFU ablation parameters. Parameters Treatment time (min) Sonication time (s) Treatment intensity (s/h) Average power (W) Non-perfused volume (cm3) NPV ratio (%)
Value
Time points of evaluation
Scores
103.8 ± 59.4 (11.0–247.0) 1197.3 ± 744.2 (114–4000) 689.5 ± 146.8 (305.0–1144.0) 379.2 ± 30.8 (218.0–400.0) 49.4 ± 37.5 (2.4–187.3) 72.7 ± 18.0 (5.0–99.0)
Before treatment 3 months 1 year 2 years
5.0 ± 2.2 1.9 ± 1.7 1.8 ± 1.7 2.2 ± 2.0
Table 3 The incidence and SIR classification of adverse effects. SIR classification
Adverse effects
Cases
Pain or discomfort in treated region Mild sacral pain Abnormal vaginal discharge Fever Leg pain Superficial I°–II° skin burns
115 107 23 27 1 1 3
A
B
*
P (1–10) (0–7)* (0–7)* (0–8)*
N/A 0.00 0.00 0.00
P < 0.05 was considered as significant different.
14 days. Low-grade fever (<38 °C) was found in 1 patient and the temperature automatically returned to normal at 3 days after treatment. Sensory motor abnormalities of the lower limbs were observed in one patient and the symptom was gradually relieved within one month after treatment. Surgical scar on the abdominal skin was found in 3 patients with SIR Type B. One patient had superficial II° burns and small vesicles adjacent to the scar. Necrotic tissue was removed along the previous surgical scar, and the burns healed two weeks after the treatment. The other two patients who had I° burns were treated with only local dressing, and the burns healed one month after the treatment. 3.4. Improvement of dysmenorrheal
hospitalization or readmission due to complications. According to SIR classification, 97.5% (115/118) recorded adverse effects belonged to SIR Type A category and did not need clinical intervention. Coccydynia, pain or discomfort in the treated area disappeared one day after the treatment in most patients, and the rest of the patients had the pain disappeared within 7 days after the treatment. Vaginal discharge disappeared in 27 patients after 7–
The clinical effectiveness of HIFU in alleviating dysmenorrhea in 203 patients who had completed the two-year follow-up reached 84.7%, 86.2%, and 82.3%, respectively at 3 months, 1 year, and 2 years after treatment. According to VAS standards for dysmenorrhea, patients with dysmenorrhea were scored before treatment and 3 months, 1 year, and 2 years after treatment, respectively. Compared with the scores before ablation, the symptoms after treatment were significantly alleviated (Table 5, P < 0.001).
Table 4 Evaluation of treatment efficacy in 203 patient with dysmenorrhea after HIFU treatment. Follow-up time
Complete relief
Obvious relief
Partial relief
No response
Aggravation
Clinical effective rate
3 months 1 year 2 years
64 (31.5%) 63 (31.0%) 44 (21.7%)
87 (42.9%) 89 (43.8%) 92 (45.3%)
21 (10.3%) 23 (11.3%) 31 (15.3%)
24 (11.8%) 20 (9.9%) 20 (9.9%)
7 (3.4%) 8 (3.9%) 16 (7.9%)
172 (84.7%) 175 (86.2%) 178 (82.3%)
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
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Table 6 Evaluation of treatment efficacy in 109 patients with menorrhagia after HIFU treatment. Follow-up time
Complete relief
Obvious relief
Partial relief
No response
Aggravation
Clinical effective rate
3 months 1 year 2 years
75 (68.8%) 74 (67.9%) 68 (62.4%)
1 (0.9%) 3 (2.8%) 4 (3.7%)
11 (10.1%) 11 (10.1%) 14 (12.8%)
12 (11.0%) 15 (13.8%) 18 (16.5%)
10 (9.2%) 6 (5.5%) 5 (4.6%)
87 (79.8%) 88 (80.7%) 86 (78.9%)
Table 7 Menstruation volume scores before and after HIFU treatment in 109 adenomyosis patients presenting with menorrhagia.
*
Evaluation time
Menstrual volume scores
P
Before treatment 3 months 1 year 2 years
2.9 ± 0.8 1.6 ± 0.9 1.5 ± 0.9 1.6 ± 1.0
N/A 0.00 0.00 0.00
(2–5) (1–5)* (1–5)* (1–5)*
P < 0.05 was considered as significant different.
3.5. Improvement of menstrual volume Among the 224 patients who had completed the two-year follow-up, 109 had varying degrees of menorrhagia before treatment. Compared with the menstrual volume before treatment, the relief rates were 79.8% (87/109), 80.7% (88/109), and 78.9% (86/109) respectively at 3 months, 1 year, and 2 years after treatment, which showed significant improvement of this symptom (Tables 6 and 7, P < 0.001).
4. Discussion The uterus-conserving treatment of adenomyosis is a clinical challenge. Unlike uterine myomas, the margin of adenomyotic lesion is often ill-defined, posing difficulties for surgical resection. Even worse, surgical removal often results in large trauma and high incidence of recurrence. A new treatment, therefore, has been highly sought after in clinical practice. As an emerging non-invasive treatment technology in recent years, HIFU, featuring good tissue penetration, can induce coagulation necrosis of the targeted lesion through thermal and other biological effects caused by the instant temperature rise due to focused energy generated by ultrasound waves focusing onto the target inside the body. Although it is difficult to ablate the adenomyotic lesion completely by means of HIFU, this treatment is non-invasive with minimal or no injuries to the surrounding normal tissues. Thus it can be repeated many times. A number of studies in recent years have shown the safety and effectiveness of HIFU ablation in the treatment of adenomyosis [11–13]. This retrospective study has demonstrated the safety and effectiveness of HIFU ablation in the treatment of adenomyosis. In 224 patients with adenomyosis who were followed up for 2 years after receiving HIFU treatment, The average NPV ratio was 72.7 ± 18% (range, 5.0–99.0%). During two years of follow-up, no serious complications related to HIFU therapy were identified. Although varying degrees of adverse effects during the treatment were observed in 118 patients, 115 of whom were of SIR Type A. 90.7% of the patients experienced pain or discomfort in the region of treatment. The sacral discomfort some patients complained of may be a manifestation of paresthesia of sacral nerve resulting from thermal diffusion. This diffusion of energy is attributable to the fact that their lesions were located in the posterior wall of the uterus or distributed diffusely. Pain disappeared immediately after treatment. The complication of varying degrees of skin burns in three patients was mainly related to their prior abdominal surgical scars. In the treatment, the scar tissue along the acoustic path affected
ultrasound penetration, resulting in energy deposition adjacent to the scar, resulting in the observed skin burn in three cases. By decreasing the duration of consecutive sonication and increasing the intervals of treatment, and reducing the power intensity, skin burns could be avoided. Therefore, HIFU is safe for treating adenomyosis, which is consistent with the findings in the literature [12,13]. Periodic dysmenorrhea is one of the most common symptoms of adenomyosis. In this study, 203 of the 224 patients followed up for 2 years presented with the symptoms of periodic dysmenorrhea before treatment, and the severity of the symptom scored over 4 in majority the patients, and the average pain score was 5.0 ± 2.2 points. After HIFU treatment, the scores of periodic dysmenorrhea decreased significantly. Clinical effectiveness, measured by alleviation of this symptom reached over 80% during the two-year follow-up. These findings indicate that ablation of 70% or higher of the volume of adenomyotic lesions is sufficient to alleviate dysmenorrhea in over 80% of the patients (Tables 4 and 5). Menorrhagia is another common symptom in patients with adenomyosis. In the 224 patients completing 2 years of follow-up, 109 had menorrhagia before HIFU treatment. According to the 5-point scoring standard, the mean score of menstrual volume was 2.9 ± 0.8 cm3, and it decreased significantly after HIFU treatment. During the 2 years of follow-up, the clinical effective rate was near 80% (Tables 6 and 7). These findings also demonstrate the effectiveness of HIFU in the treatment of adenomyosis. The above results were consistent with the reports of Zhang, et al. [13]. In this study, only few patients had no relief of symptoms and even fewer of them had aggravated symptoms, which may be a result of insufficient ablation or the comorbidity of pelvic endometriosis. A more rigorous screening of patients and higher NPV ratio may enhance the clinical efficacy of HIFU in the management of adenomyosis. This is the first study to demonstrate the safety and efficacy of HIFU for treating adenomyosis through short-term to long-term follow up in a large clinical cohort. However, one of the limitations of this study is that the retrospective study had a high incidence of loosing patients during the second year of follow-up, which may lead to the underestimation of the long-term efficacy of HIFU. Therefore, future study needs to intensify follow-up and reduce loss to follow-up, so as to obtain more complete, reliable, and high quality clinical follow-up results. 5. Conclusions Based on the above analyses, we believe that HIFU is a safe, effective, non-invasive, and uterus-conserving local treatment for adenomyosis, which can significantly improve patients’ quality of life owing to its ability to alleviate the major symptoms of adenomyosis without compromising the integrity of the uterus. Disclosure Lian Zhang is a senior consultant to Chongqing haifu company. The other authors have no potential conflicts of interest to disclose.
Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024
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Acknowledgements This study was supported by the State Key Program of National Natural Science of China (Grant No. 30830040), National Key Technology R&D Program in the 11th Five year Plan of China (Grant No. 2006BAI03A02) and Chongqing Science and Technology Key Project (Grant Nos. [2007] 11CSTC, 2007AA502). References [1] C. Bergeron, F. Amant, A. Ferenczy, Pathology and physiopathology of adenomyosis, Best Pract. Res. Clin. Obstet. Gynecol. 20 (4) (2006) 511–521. [2] P. Vercellini, P. Vigan‘o, E. Somigliana, R. Daguati, A. Abbiati, L. Fedele, Adenomyosis: epidemiological factors, Best Pract. Res. Clin. Obstet. Gynecol. (2006) 20(4):465–77. [3] C. Farquhar, I. Brosens, Medical and surgical management of adenomyosis, Best Pract. Res. Clin. Obstet. Gynecol. 20 (4) (2006) 603–616. [4] C. Wood, Surgical and medical treatment of adenomyosis, Human Reprod. Update 4 (4) (1998) 323–336. [5] A. Shrestha, R. Shrestha, L.B. Sedhai, et al., Adenomyosis at hysterectomy: prevalence, patient characteristics, clinical profile and histopatholgical findings, Kathmandu Univ. Med. J. 10 (1) (2012) 44–47.
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Please cite this article in press as: L. Shui et al., High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Ultrason. Sonochem. (2015), http://dx.doi.org/10.1016/j.ultsonch.2015.05.024