- Top of page
Uterine fibroids (myomas) are the most widespread type of benign tumor afflicting women of childbearing age1–3. The range of symptoms, such as menorrhagia, dysmenorrhea, pelvic pain and bulk-related symptoms, depends on the size and location of the fibroid within the uterus4. Uterine fibroids can also interfere with fertility5. Hysterectomy, the most common treatment for uterine fibroids, may be associated with lengthy hospitalization and complications6, which has resulted in a demand for less invasive treatment modalities. Various myomectomy procedures, uterine artery embolization and magnetic resonance-guided focused ultrasound surgery (MRgFUS) are viable treatment options for uterine fibroids. The advantages of the conservative modalities over open surgical procedures are lower morbidity and shorter recovery times compared with hysterectomy7–10.
MRgFUS is a non-invasive treatment that uses focused ultrasound to thermally coagulate targeted areas while sparing surrounding tissue. The combination of therapeutic ultrasound energy with magnetic resonance imaging (MRI) enables anatomical visualization and three-dimensional planning11, 12. Moreover, real-time thermal monitoring of the treated region, during the course of the ultrasound pulses (termed sonications), is performed using the temperature dependence of the proton-resonant frequency (PRF). The evaluation of these PRF images allows physicians to control the levels of thermal energy delivered to each specific target13. The US Food and Drug Administration approved the method for the treatment of uterine fibroids in 200414. Several published clinical studies and case reports have demonstrated that MRgFUS offers considerable symptomatic relief and fibroid shrinkage along with a good safety profile15–23.
MRgFUS was introduced into four clinical centers in Japan, none of which had any experience with this treatment modality. Partial and preliminary outcomes of the population described here have already been published20–22, 24. These previous reports have focused on the clinical effects of MRgFUS, particularly the relationship between treatment results and pretreatment signal intensity of the fibroids, and the correlation between the extent of treatment and fibroid shrinkage. The objective of this study was to describe the learning curve effect in the use of MRgFUS for the treatment of uterine fibroids in Japan.
- Top of page
A total of 287 Japanese patients with symptomatic uterine fibroids diagnosed by clinical examination, ultrasound imaging and MRI were treated with MRgFUS at Iseikai Hospital, Osaka (109 patients), Itabashi Chuo Medical Center, Tokyo (84 patients), Shinsuma General Hospital, Kobe (74 patients) and Aizu Chuo Hospital, Aizuwakamatsu (20 patients), between April 2003 and May 2006. Pregnant women, women wishing for future pregnancy and those with a contraindication to MRI were excluded. In addition, patients with scars, bowel in the path of the ultrasound beam or fibroids located close to the sacral surface were excluded to ensure a clear ultrasound beam path16.
The ExAblate 2000 (InSightec, Haifa, Israel) is integrated with a 1.5-T MRI system (GE Medical Systems, Milwaukee, WI, USA), which supplies the images used for planning the treatment and delivers real-time thermal measurements during sonications. On the treatment day, patients were provided with conscious sedation to relieve anxiety, provide more comfortable positioning and alleviate pain. Conscious sedation was chosen in order to allow the patient to communicate their feelings and sensations to the treating physician throughout the treatment. Patients were also given a ‘stop button’, which they could use to stop the sonication immediately in case of pain or discomfort.
Treatment planning was done using T2-weighted magnetic resonance images in three orientations, on which the physician outlined the targeted fibroid volume. In addition, sensitive areas that should be avoided (bowel, pubic bone, sacral nerves) were also identified and marked, in order to limit the energy passage in their vicinity. A low-energy test sonication was performed to confirm accuracy of the thermal spot location23. When preparations were complete, multiple high-energy sonications were used to thermally ablate the targeted volume. After treatment, contrast-enhanced T1-weighted images were acquired to measure non-enhanced regions. The non-enhanced areas represent the non-perfused volume (NPV) to which the blood supply has been interrupted by the procedure. Slice-by-slice measurements of these areas were then summed and transformed into volumetric results. The therapeutic effect of the procedure was assessed by comparing the NPV with pretreatment total fibroid volume. This ratio has become a useful tool by which clinical treatment effects can be measured20–23, 25 and it allows comparison of the results from various clinical studies.
Adverse effects were recorded and followed until resolution. Previously reported side effects include localized pain in the abdomen, lower back or legs, vaginal discharge, fever and localized skin burns23. More significant previously reported adverse effects of MRgFUS, while rare, include nerve damage and skin burns resulting in ulceration and scar formation16, 26.
A coordinator nurse followed patients for 12 months after MRgFUS and additional therapy for symptomatic fibroids was recorded. Minimally invasive treatment modalities often evaluate treatment success by counting the number of patients who underwent additional forms of intervention for their recurrent symptoms within a specified period27, 28. Alternative treatments were defined as myomectomy, hysterectomy, uterine artery embolization or any type of hormonal therapy.
As the initial treatments in our four centers began when worldwide experience with the procedure was limited and the available data were obtained from volume-restricted treatments (owing to regulatory requirements), we retrospectively analyzed the effect of ‘learning curves’, examining the improvement in treatment results over time. The patients were divided into two equal groups according to the chronological treatment time. NPV ratios, and the proportion of patients who suffered skin burns and who underwent alternative treatments were compared between the groups. Significance was measured using Mann–Whitney U-test and Chi-square analysis. Within each subgroup, differences between patients who were lost and those who continued the follow-up visits were assessed in order to verify that the lack of follow-up in the missing patients did not bias the results.
In addition, we compared our results with those from previous clinical trials in the USA and Europe. The NPV ratio distributions of the two groups were compared, with the median NPV ratios being compared using the Wilcoxon rank-sum test. The data were obtained following personal communication with the author of the published report (E.A. Stewart)25.
Statistical analyses were performed using R Statistical Package (The R Foundation, Vienna, Austria)29. P < 0.05 was considered statistically significant.
- Top of page
The mean ± SD age and mean total fibroid load of the 287 patients who were treated at the four participating sites were 42.5 ± 5.3 (range, 24–60) years and 326 ± 221 (range, 17–1480) mL. Table 1 describes the number of patients by follow-up appointment. Two hundred and twenty-eight patients completed their 6- and 12-month post-treatment period, with 59 lost to follow-up.
Table 1. Comparison between patients in each of the chronological treatment groups
|Variable||Group I (treated April 2003 to April 2005)||Group II (treated April 2005 to May 2006)||P|
|Number of patients treated||144||143|| |
|Postprocedure adverse events|| || || |
| Abdominal pain||17 (12)||16 (11)||0.9|
| Lower back or leg pain||9 (6)||11 (8)||0.8|
| Vaginal discharge or bleeding||12 (8)||11 (8)||1|
| Fever||7 (5)||9 (6)||0.8|
| Skin burns*||10 (7)||2 (1)||0.04|
|Patients evaluable for NPV analysis||140||139|| |
|NPV ratio (%)||39.3 ± 23.6 (0–91.3)||54.0 ± 18.7 (0–100)||< 0.001|
|Patients reaching 6-month follow-up||105||123||0.006|
|Alternative treatments by 6-month follow-up||5 (5)||3 (2)||0.34|
|Patients reaching 12-month follow-up||105||123||0.006|
|Alternative treatments by 12-month follow-up||13 (12)||6 (5)||0.04|
During the 6-month follow-up period, 4% of the patients (8/228) underwent additional treatments for their fibroids. An additional 5% of the patients underwent alternative treatment in the 6–12-month follow-up period, resulting in a total of 8.3% (19/228) undergoing alternative treatment for their fibroids over the course of the 12-month follow-up period (Table 1).
The mean ± SD NPV ratio was 46.6 ± 22.5% (n = 279; median, 48.6%; range 1–96%). Post-treatment contrast-enhanced imaging was not performed on eight patients owing to reported allergic reaction to the contrast agent. These patients are not included in the NPV analysis.
Directly following the procedure, adverse events data were collected from all treated patients; these are summarized in Table 1. All adverse events were managed conservatively, did not require surgical intervention and resolved at follow-up. None of the 12 patients with skin burns had ulceration; however, in three patients a small scar formed.
The effect of the learning curve is shown in Table 1. Over time, there was a significant improvement in the NPV ratio, from 39.3 ± 23.6% to 54.0 ± 18.7% (P < 0.001). In addition, there was a noticeable improvement with regard to skin burns, as the majority of the skin burns (n = 10) occurred in the first chronological group, compared with only two cases in the second chronological group (P = 0.04). The number of patients undergoing an alternative treatment by their 12-month post-treatment follow-up was also reduced significantly, from 13 (12%) in the early group to six (5%) in the latter one (P = 0.04).
Baseline data (age and fibroid volume) and immediate treatment outcomes (NPV ratios) were compared within each of the two groups between patients with complete follow-up and those lost to follow-up (Table 2). All comparisons yielded statistically insignificant differences. The number of patients who were lost to follow-up was reduced from 39 (27%) in the first period to 20 (14%) in the second.
Table 2. Statistical comparison of treatment-day assessments between patients with complete follow-up and those lost to follow-up, according to chronological treatment group
|Variable||Group I (treated April 2003 to April 2005)||Group II (treated April 2005 to May 2006)|
|All||Complete follow-up||Lost to follow-up||P||All||Complete follow-up||Lost to follow-up||P|
| Number of patients||144||105 (73)||39 (27)|| ||143||123 (86)||20 (14)|| |
| Age (years)||42.5 ± 5.3||42.3 ± 5.4||43.3 ± 6.0||0.34||42.3 ± 5.0||42.5 ± 5.1||41.5 ± 4.2||0.29|
| ||(24–60)||(24–54)||(30–60)|| ||(26–51)||(26–51)||(32–47)|| |
| Total fibroid load (mL)||354 ± 232||358 ± 303||338 ± 202||0.84||298 ± 207||298 ± 210||297 ± 179||0.77|
| ||(47–1480)||(47–1480)||(47–847)|| ||(17–1318)||(17–1318)||(63–673)|| |
| n for NPV analysis||140||105 (75)||35 (25)|| ||139||123 (88)||16 (12)|| |
| NPV ratio||39 ± 24||40 ± 24||37 ± 22||0.50||54 ± 19||54 ± 19||51 ± 15||0.46|
| ||(1–91)||(1–91)||(1–90)|| ||(4–100)||(4–100)||(22–78)|| |
The comparison of the NPV ratio distribution between our Japanese data and the data from clinical trials in the USA and Europe is shown in Figure 125. The mean NPV ratio reported here (mean ± SD, 46.6 ± 22.5%; median, 48.4%; range, 1–96%) is over double that obtained in the previous clinical trials (mean ± SD, 21.9 ± 18.7%; median, 22.3%; range, 0–100%)25 (P < 0.001). In addition, the percentage of patients in the Japanese cohort seeking alternative treatment after 12 months (8%) was significantly smaller than that reported previously by Stewart et al. (28%; P = 0.001)19.
Figure 1. Comparison of the non-perfused volume (NPV) ratio distribution observed in this study (□) and that found in previously reported clinical trials ()25.
Download figure to PowerPoint
- Top of page
In this retrospective analysis, we have shown that treatment outcomes, measured by the immediate NPVs and the proportion of patients who had undergone alternative treatments at 1-year follow-up, were significantly improved over time. In addition, the accumulated experience reduced the number of post-treatment skin burns. Physicians understand today that they should strive to obtain larger NPVs in order to achieve long-term treatment efficacy25.
In order to achieve large NPVs, MRgFUS treatment should be optimized using several techniques. First, the ultrasound beam targeting the fibroid should be angled in order to reach as much fibroid volume as possible, while avoiding obstacles such as the bowel or pubic bone. Second, the amount of energy, along with the method of energy distribution within the sonication spot, should be optimized based on the thermal images in order to achieve high therapeutic temperatures within the target tissue. For example, if the temperature is too low, energy should be increased and the energy distribution should be changed to a more focused pattern. Third, treatment sonications should be planned to cover the entire fibroid volume, up to its edges, leaving minimal margins. Fourth, the spatial distribution of the sonications should be closely packed to leave minimal distance between the spots. In addition, the treatment should be terminated only when the entire device-accessible fibroid region is ablated.
Furthermore, an important aspect of MRgFUS treatment that we have developed over time is patient selection; physicians should screen out patients for whom this technology cannot obtain optimal NPV results. These patients include those with hyperintense fibroids that are difficult to heat20 and patients in whom there are technical limitations, such as the ultrasonic beam being obstructed by bowel loops or bone30.
The skin burn profile has also improved as part of the learning curve, with the majority of skin burns observed in the first period. Although the importance of acoustic coupling between the patient and the transducer system was well known at the beginning of the study, we learned how to better implement and control acoustic coupling. Pretreatment procedures were implemented (such as shaving and cleaning the patient's abdomen before treatment23 and the addition of sufficient water to avoid air bubbles22). In addition, we utilized magnetic resonance images in order to find air bubbles on the skin, and to look for indications in the real-time thermal images for heat in the vicinity of the skin. In such cases, improved acoustic coupling may be achieved by repositioning the patient.
Over the past few years, physicians with increasing expertise in using MRgFUS in the treatment of uterine fibroids have helped to refine the technique, resulting in improved safety as well as improved short- and mid-term outcomes15–19, 23 We compared our results with previously published results from clinical trials in the USA and Europe, and found that the NPV ratios described here were significantly larger than those reported previously. This may be explained by the technical restrictions imposed during those initial clinical trials23. The limitations initially included a time constraint on the treatment duration, as well as a volume restriction (enabling only 33% of the fibroid to be treated). Furthermore, precautionary measures limited the treatment distance from the serosa as well as from the endometrium. Our experience, gained over the course of this study, has taught us that, in order to achieve better results, the treated volume should be as large as possible, while adhering to strict safety rules.
In accordance with other reports15–23, the information presented here appears to show that the risk of suffering from an adverse event as a result of being treated with MRgFUS is not high.
A weakness of this report is the fact that 21% of the patients (59/287) were lost to follow-up during the 12-month follow-up period. However, when we compared the group of patients with complete follow-up with those who were lost to follow-up, we found no significant differences in age, pretreatment fibroid volume or NPV ratios. Thus, the possibility of this group affecting the final results is limited. In addition, the number of patients who were lost to follow-up was reduced from 39 (27%) in the first period to 20 (14%) in the second.
It is encouraging to see that the results obtained after treating uterine fibroids with MRgFUS are long lasting and comparable to those of existing modalities10, 31, 32. Further studies should be performed to investigate ways in which the NPV ratio for treated patients can be increased.