TY - JOUR
AU - Douek, M
AB - Abstract Background A systematic review was undertaken to assess the clinical efficacy of non-invasive high-intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer. Methods MEDLINE/PubMed library databases were used to identify all studies published up to December 2013 that evaluated the role of HIFU ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least one clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. Results Nine studies fulfilled the inclusion criteria. The absence of tumour or residual tumour after treatment was reported for 95·8 per cent of patients (160 of 167). No residual tumour was found in 46·2 per cent (55 of 119; range 17–100 per cent), less than 10 per cent residual tumour in 29·4 per cent (35 of 119; range 0–53 per cent), and between 10 and 90 per cent residual tumour in 22·7 per cent (27 of 119; range 0–60 per cent). The most common complication associated with HIFU ablation was pain (40·1 per cent) and less frequently oedema (16·8 per cent), skin burn (4·2 per cent) and pectoralis major injury (3·6 per cent). MRI showed an absence of contrast enhancement after treatment in 82 per cent of patients (31 of 38; range 50–100 per cent), indicative of coagulative necrosis. Correlation of contrast enhancement on pretreatment and post-treatment MRI successfully predicted the presence of residual disease. Conclusion HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no imaging modality has been able confidently to predict the percentage of complete ablation. Consistent tumour and margin necrosis with reliable follow-up imaging are required before HIFU ablation can be evaluated within large, prospective clinical trials. Introduction Breast cancer is the most common cancer in the UK. In 2010, just under 50 000 women were diagnosed with invasive breast cancer, with 11 684 deaths in 2011, making it the second most common cause of death from cancer in women after lung cancer1. With the wider use of mammographic screening, breast cancers are being diagnosed at an increasingly earlier stage. Surgery in the form of either breast conservation or mastectomy followed by adjuvant therapy constitutes the mainstay of treatment2–4. Breast conservation is dependent on clear margins, defined as no tumour cells visible on ink on the resected specimen according to American Society for Radiation Oncology (ASTRO) guidelines5. However, during surgery the surgeon is unable to visualize the tumour to aid in determining clear margins. This lack of intraoperative target definition results in high rates of reoperation to excise residual tumour. There is a clinical need to develop minimally invasive ablative techniques to define better the target and tumour margins during treatment. These techniques potentially benefit from the absence of general anaesthesia, a reduced recovery time and absence of scarring, and consequently also have economic benefits6. High-intensity focused ultrasound (HIFU) ablation is a non-invasive technique that has been used for the treatment of liver, kidney, prostate, brain, bone and breast cancers7,8. During HIFU treatment, an ultrasound beam generated by a piezoelectric ultrasound transducer propagates through tissue as a high-frequency pressure wave8. The beam is focused on to the targeted tissue, and each treatment volume is approximately 0·8 × 0·2 × 0·2 cm3. The energy from the beam raises the temperature of the focused area to 60–95°C within a few seconds without causing damage to the adjacent tissues, thereby leading to very localized protein denaturation and coagulative necrosis8,9. Depending on the type of application and penetration depth, ultrasound beams with a frequency between 0·5 and 4 MHz are used7,8. The available HIFU devices are generally integrated with either MRI or ultrasound imaging in order to plan treatment and monitor response in real time. MRI has the advantage of excellent anatomical resolution, high sensitivity for lesion detection and temperature mapping; ultrasonography offers real-time visualization of the targeted volume, thereby detecting patient movement, and guidance of energy deposition within the treated area through a hyperechogenic cross visible during pulse application. In addition, ultrasonography provides a rapid real-time assessment of the volume of coagulative necrosis during treatment by visualization of a hyperechogenic spot on the screen7,8. Temperature imaging with MRI, on the other hand, is challenging owing to the large amount of fat and lack of reliability of water proton phase-shift-based measurements within fat10. HIFU ablation provides a completely non-invasive therapy, thus avoiding potential complications associated with general anaesthesia and surgery11. It has been evaluated for treatment of fibroadenomas in a single clinical trial12. For breast cancer, HIFU treatment has the potential to improve cosmetic outcomes as scarring is prevented, and earlier administration of systemic therapies is possible as postoperative recovery times are shorter11. This systematic review evaluates the current evidence for HIFU ablation in the management of breast cancer, with a focus on residual disease, establishing treatment response through imaging and cosmetic outcome. Methods Study selection A systematic review of the literature was performed using MEDLINE/PubMed library databases to identify all studies published up to December 2013 that evaluated the role of HIFU in the treatment of breast cancer. The medical subject heading (MeSH) search terms used were: ‘High Intensity Focused Ultrasound’, ‘HIFU’, ‘focused ultrasound ablation’ and ‘FUS’, all in combination with ‘breast’. The search was restricted to reports in the English language and human subjects; there were no further restrictions. The related articles function was used to broaden the search, and all abstracts, studies and citations obtained were reviewed. References of the articles acquired were also searched by hand. The last search was conducted on 20 December 2013. Inclusion criteria Studies were considered eligible for the systematic review if they were performed on patients with breast cancer, and objectively recorded at least one clinical outcome measure of response (cosmetic, imaging and/or histopathology) to HIFU treatment. Exclusion criteria Studies that failed to fulfil the inclusion criteria, and those in which the outcomes of interest were not reported or could not be analysed from published reports, were excluded. Conference abstracts, letters, editorials and case reports were also excluded. Data extraction Each study was evaluated initially for either inclusion or exclusion. The data extracted from included studies were: first author, year of publication, study design, number of patients included, mean patient age, lesion type, lesion size, type of guided imaging, frequency, dose, treatment margin used, total treatment time, whether resection was carried out, follow-up, cosmetic outcome, imaging outcome, histopathology staining, histopathological outcome, complications, retreatment of lesions and recurrence. One reviewer extracted data for all selected studies, and a second reviewer verified the accuracy of the extracted data. Risk of bias in individual studies The risk of bias tool in the Cochrane Handbook13 was used to determine the suitability of randomized clinical trials (RCTs) selected for inclusion in the quantitative analysis. The quality of cohort studies was assessed according to the recommendations of the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement14. Seven items of the STROBE statement were considered relevant for quality evaluation. Studies with a score of less than 4 were excluded. Two reviewers did the assessment independently. In the event of disagreement, a consensual decision was made. Statistical analysis All extracted data were tabulated and presented as means with percentages. Numerators and denominators were provided to address outcomes of included studies. The mean proportion of patients with no residual tumour left after HIFU treatment was evaluated by calculating the pooled inverse-variance weighted proportion. Studies with a standard deviation of 0 (where there was 100 per cent ablation) were excluded from the analysis. A random-effects analysis was performed in view of the suspected high degree of heterogeneity among the included studies. All statistical analyses were carried out in Stata® version 12.0 (StataCorp LP, College Station, Texas, USA). Results Selected studies A total of 140 articles published up to December 2013 were identified from the literature search (Fig. 1). After reviewing the abstracts, 101 non-relevant articles were excluded and 39 articles underwent full-text examination. A total of nine studies matched the selection criteria, of which six6,15–19 were feasibility studies, one20 was a prospective cohort study and one9 was a retrospective cohort study. A single RCT7 was identified in which HIFU ablation followed by mastectomy was compared with mastectomy alone. Fig. 1 Open in new tabDownload slide PRISMA flow diagram showing selection of studies for systematic review Study characteristics In total, nine studies with 167 patients (mean age 58·5 years) and 169 breast lesions were included in the review. In three studies9,17–18 the breast cancer types were not specified. In the remaining studies6–7,15–16,19–20 the included breast cancer types were: invasive ductal carcinoma (83·5 per cent, 106 of 127 patients), ductal carcinoma in situ (5·5 per cent, 7 of 127 patients), adenocarcinoma (2·4 per cent, 3 of 127), invasive lobular carcinoma (2·4 per cent, 3 of 127), invasive mucinous adenocarcinoma (0·8 per cent, 1 of 127 patients) and unknown breast carcinoma (5·5 per cent, 7 of 127 patients). The characteristics of the studies are summarized in Table 1. Six studies6,15–19 (116 patients) used MRI as the mode of guided imaging for HIFU ablation, and the remaining three7,9,20 (51 patients) used ultrasonography. After HIFU treatment, resection of the lesion was performed in six studies6–7,15–16,18–19, follow-up with biopsies in two17,20, and follow-up by both surgery and biopsy in one study9. The cosmetic outcome was described in two studies18,20, histopathology results were discussed in all nine papers6–7,9,15–20, and imaging results were reported for six series7,9,16–17,19–20. The outcomes are described in Tables S1 and 2. Table 1 Patient and treatment characteristics of studies using HIFU in breast cancer Reference . n . Age (years) . Tumour size . Ablation margin (cm) . Image guiding modality . Maximum power/pulse (W)‡ . Treatment time (min) . Complications and cosmetic results . Gianfelice et al.15 (2003) 12 60 2·77 (0·11–8·80) cm3 0·5 MRI 400 80 (35–133) Pain/discomfort: slight (4), moderate (8) Tenderness: mild (1), moderate (2) Second-degree burn (2) Gianfelice et al.17 (2003) 24 74·2 1·51 (0·6–2·5) cm – MRI 60 – Pain: moderate (14), mild (10) Second-degree skin burn (1) Gianfelice et al.16 (2003) 17 61·2 2·49 (0·11–8·80) cm3 – MRI – – – Wu et al.7 (2003) 23 46·5 3·1(0·79) (2·0–4·7) cm* 1·5–2·0 US 545 78 (45–210)† Minimal skin burn (1), mild local pain, warmth and sensation of heaviness in breast (14), oedema (unknown) Wu et al.20 (2005) 22 48·6 3·4 (2·0–4·8) cm 1·5–2·0 US 545 132 (60–180)† Local oedema (all patients), mild local pain (14; oral analgesics 6) Cosmesis: good–excellent (16 of 17), acceptable (1 of 17) Zippel and Papa18 (2005) 10 56  2·2 cm 0·5 MRI – Maximum 240 Second-degree burn (2), pain during procedure Cosmesis: good–excellent (9), acceptable (1) Furusawa et al.6 (2006) 28 56·9 1·3 (0·5–2·5) cm 0·5 MRI 400 140 (76–231) Third-degree skin burn (1), minor adverse events (claustrophobia 1, abdominal and breast skin redness 1, pain 2, shoulder pain 1) Khiat et al.19 (2006) 25 61·3 3·29 (0·11–11·2) cm3 – MRI – – – Kim et al.9 (2010) 6 62·1 2·56 (1·2–3·7) cm 1·0 US 240 171 (80–285) Mammary oedema (6), pectoralis major muscle injury (6), skin and trabecular thickening Reference . n . Age (years) . Tumour size . Ablation margin (cm) . Image guiding modality . Maximum power/pulse (W)‡ . Treatment time (min) . Complications and cosmetic results . Gianfelice et al.15 (2003) 12 60 2·77 (0·11–8·80) cm3 0·5 MRI 400 80 (35–133) Pain/discomfort: slight (4), moderate (8) Tenderness: mild (1), moderate (2) Second-degree burn (2) Gianfelice et al.17 (2003) 24 74·2 1·51 (0·6–2·5) cm – MRI 60 – Pain: moderate (14), mild (10) Second-degree skin burn (1) Gianfelice et al.16 (2003) 17 61·2 2·49 (0·11–8·80) cm3 – MRI – – – Wu et al.7 (2003) 23 46·5 3·1(0·79) (2·0–4·7) cm* 1·5–2·0 US 545 78 (45–210)† Minimal skin burn (1), mild local pain, warmth and sensation of heaviness in breast (14), oedema (unknown) Wu et al.20 (2005) 22 48·6 3·4 (2·0–4·8) cm 1·5–2·0 US 545 132 (60–180)† Local oedema (all patients), mild local pain (14; oral analgesics 6) Cosmesis: good–excellent (16 of 17), acceptable (1 of 17) Zippel and Papa18 (2005) 10 56  2·2 cm 0·5 MRI – Maximum 240 Second-degree burn (2), pain during procedure Cosmesis: good–excellent (9), acceptable (1) Furusawa et al.6 (2006) 28 56·9 1·3 (0·5–2·5) cm 0·5 MRI 400 140 (76–231) Third-degree skin burn (1), minor adverse events (claustrophobia 1, abdominal and breast skin redness 1, pain 2, shoulder pain 1) Khiat et al.19 (2006) 25 61·3 3·29 (0·11–11·2) cm3 – MRI – – – Kim et al.9 (2010) 6 62·1 2·56 (1·2–3·7) cm 1·0 US 240 171 (80–285) Mammary oedema (6), pectoralis major muscle injury (6), skin and trabecular thickening Values are mean (range) unless indicated otherwise; * values are mean(s.d.) (range) and † median (range). ‡ Defined before surgery. US, ultrasonography. All ablations were performed by ExAblate® 2000 (InSightec, Haifa, Israel), with the exception of references 7,9 and 20 where Haifu Model JC (Chongqing Haifu Medical Technology, Chongqing, China) was used. Open in new tab Table 1 Patient and treatment characteristics of studies using HIFU in breast cancer Reference . n . Age (years) . Tumour size . Ablation margin (cm) . Image guiding modality . Maximum power/pulse (W)‡ . Treatment time (min) . Complications and cosmetic results . Gianfelice et al.15 (2003) 12 60 2·77 (0·11–8·80) cm3 0·5 MRI 400 80 (35–133) Pain/discomfort: slight (4), moderate (8) Tenderness: mild (1), moderate (2) Second-degree burn (2) Gianfelice et al.17 (2003) 24 74·2 1·51 (0·6–2·5) cm – MRI 60 – Pain: moderate (14), mild (10) Second-degree skin burn (1) Gianfelice et al.16 (2003) 17 61·2 2·49 (0·11–8·80) cm3 – MRI – – – Wu et al.7 (2003) 23 46·5 3·1(0·79) (2·0–4·7) cm* 1·5–2·0 US 545 78 (45–210)† Minimal skin burn (1), mild local pain, warmth and sensation of heaviness in breast (14), oedema (unknown) Wu et al.20 (2005) 22 48·6 3·4 (2·0–4·8) cm 1·5–2·0 US 545 132 (60–180)† Local oedema (all patients), mild local pain (14; oral analgesics 6) Cosmesis: good–excellent (16 of 17), acceptable (1 of 17) Zippel and Papa18 (2005) 10 56  2·2 cm 0·5 MRI – Maximum 240 Second-degree burn (2), pain during procedure Cosmesis: good–excellent (9), acceptable (1) Furusawa et al.6 (2006) 28 56·9 1·3 (0·5–2·5) cm 0·5 MRI 400 140 (76–231) Third-degree skin burn (1), minor adverse events (claustrophobia 1, abdominal and breast skin redness 1, pain 2, shoulder pain 1) Khiat et al.19 (2006) 25 61·3 3·29 (0·11–11·2) cm3 – MRI – – – Kim et al.9 (2010) 6 62·1 2·56 (1·2–3·7) cm 1·0 US 240 171 (80–285) Mammary oedema (6), pectoralis major muscle injury (6), skin and trabecular thickening Reference . n . Age (years) . Tumour size . Ablation margin (cm) . Image guiding modality . Maximum power/pulse (W)‡ . Treatment time (min) . Complications and cosmetic results . Gianfelice et al.15 (2003) 12 60 2·77 (0·11–8·80) cm3 0·5 MRI 400 80 (35–133) Pain/discomfort: slight (4), moderate (8) Tenderness: mild (1), moderate (2) Second-degree burn (2) Gianfelice et al.17 (2003) 24 74·2 1·51 (0·6–2·5) cm – MRI 60 – Pain: moderate (14), mild (10) Second-degree skin burn (1) Gianfelice et al.16 (2003) 17 61·2 2·49 (0·11–8·80) cm3 – MRI – – – Wu et al.7 (2003) 23 46·5 3·1(0·79) (2·0–4·7) cm* 1·5–2·0 US 545 78 (45–210)† Minimal skin burn (1), mild local pain, warmth and sensation of heaviness in breast (14), oedema (unknown) Wu et al.20 (2005) 22 48·6 3·4 (2·0–4·8) cm 1·5–2·0 US 545 132 (60–180)† Local oedema (all patients), mild local pain (14; oral analgesics 6) Cosmesis: good–excellent (16 of 17), acceptable (1 of 17) Zippel and Papa18 (2005) 10 56  2·2 cm 0·5 MRI – Maximum 240 Second-degree burn (2), pain during procedure Cosmesis: good–excellent (9), acceptable (1) Furusawa et al.6 (2006) 28 56·9 1·3 (0·5–2·5) cm 0·5 MRI 400 140 (76–231) Third-degree skin burn (1), minor adverse events (claustrophobia 1, abdominal and breast skin redness 1, pain 2, shoulder pain 1) Khiat et al.19 (2006) 25 61·3 3·29 (0·11–11·2) cm3 – MRI – – – Kim et al.9 (2010) 6 62·1 2·56 (1·2–3·7) cm 1·0 US 240 171 (80–285) Mammary oedema (6), pectoralis major muscle injury (6), skin and trabecular thickening Values are mean (range) unless indicated otherwise; * values are mean(s.d.) (range) and † median (range). ‡ Defined before surgery. US, ultrasonography. All ablations were performed by ExAblate® 2000 (InSightec, Haifa, Israel), with the exception of references 7,9 and 20 where Haifu Model JC (Chongqing Haifu Medical Technology, Chongqing, China) was used. Open in new tab Table 2 Histopathology outcomes of studies Reference . Type of specimen collected . Time of specimen collection . Complete histopathological response (% of patients) . < 1 month . 1–3 months . 3–6 months . > 6 months . Gianfelice et al.15 (2003) Resection Unknown – – – – Gianfelice et al.17 (2003) Biopsy 6 months – – Complete necrosis (58%) Second treatment: total complete necrosis (79%) Gianfelice et al.16 (2003) Resection 3–21 days Complete necrosis (24%), residual tumour < 10% (53%), residual tumour 30–75% (24%) – – – Wu et al.7 (2003) Resection 1–2 weeks Complete necrosis of tumour (100%) and margin of mean(s.d.) 1·80(0·58) cm – – – Wu et al.20 (2005) Biopsy 2 weeks, 3, 6, 12 months Complete necrosis of tumour and adjacent margin (100%) Partial fibrosis (100%, n = 18) Complete fibrosis (100%, n = 14) Complete fibrosis (100%, n = 14) Zippel and Papa18 (2005) Resection 7–10 days Complete necrosis (20%), microscopic foci of residual tumour (20%), 10% residual tumour (30%), 10–30% residual tumour (30%) – – – Furusawa et al.6 (2006) Resection 5–23 days Complete necrosis (54%), < 10% residual disease (36%), 10–15% residual disease (10%) – – – Khiat et al.19 (2006) Resection 3–21 days Complete necrosis (31%), residual tumour < 10% (42%), residual tumour 20–90% (27%) – – – Kim et al.9 (2010) Resection and biopsy 2–20 months – Viable tumour (50%) No viable tumour (67%) No viable tumour (67%) Reference . Type of specimen collected . Time of specimen collection . Complete histopathological response (% of patients) . < 1 month . 1–3 months . 3–6 months . > 6 months . Gianfelice et al.15 (2003) Resection Unknown – – – – Gianfelice et al.17 (2003) Biopsy 6 months – – Complete necrosis (58%) Second treatment: total complete necrosis (79%) Gianfelice et al.16 (2003) Resection 3–21 days Complete necrosis (24%), residual tumour < 10% (53%), residual tumour 30–75% (24%) – – – Wu et al.7 (2003) Resection 1–2 weeks Complete necrosis of tumour (100%) and margin of mean(s.d.) 1·80(0·58) cm – – – Wu et al.20 (2005) Biopsy 2 weeks, 3, 6, 12 months Complete necrosis of tumour and adjacent margin (100%) Partial fibrosis (100%, n = 18) Complete fibrosis (100%, n = 14) Complete fibrosis (100%, n = 14) Zippel and Papa18 (2005) Resection 7–10 days Complete necrosis (20%), microscopic foci of residual tumour (20%), 10% residual tumour (30%), 10–30% residual tumour (30%) – – – Furusawa et al.6 (2006) Resection 5–23 days Complete necrosis (54%), < 10% residual disease (36%), 10–15% residual disease (10%) – – – Khiat et al.19 (2006) Resection 3–21 days Complete necrosis (31%), residual tumour < 10% (42%), residual tumour 20–90% (27%) – – – Kim et al.9 (2010) Resection and biopsy 2–20 months – Viable tumour (50%) No viable tumour (67%) No viable tumour (67%) Open in new tab Table 2 Histopathology outcomes of studies Reference . Type of specimen collected . Time of specimen collection . Complete histopathological response (% of patients) . < 1 month . 1–3 months . 3–6 months . > 6 months . Gianfelice et al.15 (2003) Resection Unknown – – – – Gianfelice et al.17 (2003) Biopsy 6 months – – Complete necrosis (58%) Second treatment: total complete necrosis (79%) Gianfelice et al.16 (2003) Resection 3–21 days Complete necrosis (24%), residual tumour < 10% (53%), residual tumour 30–75% (24%) – – – Wu et al.7 (2003) Resection 1–2 weeks Complete necrosis of tumour (100%) and margin of mean(s.d.) 1·80(0·58) cm – – – Wu et al.20 (2005) Biopsy 2 weeks, 3, 6, 12 months Complete necrosis of tumour and adjacent margin (100%) Partial fibrosis (100%, n = 18) Complete fibrosis (100%, n = 14) Complete fibrosis (100%, n = 14) Zippel and Papa18 (2005) Resection 7–10 days Complete necrosis (20%), microscopic foci of residual tumour (20%), 10% residual tumour (30%), 10–30% residual tumour (30%) – – – Furusawa et al.6 (2006) Resection 5–23 days Complete necrosis (54%), < 10% residual disease (36%), 10–15% residual disease (10%) – – – Khiat et al.19 (2006) Resection 3–21 days Complete necrosis (31%), residual tumour < 10% (42%), residual tumour 20–90% (27%) – – – Kim et al.9 (2010) Resection and biopsy 2–20 months – Viable tumour (50%) No viable tumour (67%) No viable tumour (67%) Reference . Type of specimen collected . Time of specimen collection . Complete histopathological response (% of patients) . < 1 month . 1–3 months . 3–6 months . > 6 months . Gianfelice et al.15 (2003) Resection Unknown – – – – Gianfelice et al.17 (2003) Biopsy 6 months – – Complete necrosis (58%) Second treatment: total complete necrosis (79%) Gianfelice et al.16 (2003) Resection 3–21 days Complete necrosis (24%), residual tumour < 10% (53%), residual tumour 30–75% (24%) – – – Wu et al.7 (2003) Resection 1–2 weeks Complete necrosis of tumour (100%) and margin of mean(s.d.) 1·80(0·58) cm – – – Wu et al.20 (2005) Biopsy 2 weeks, 3, 6, 12 months Complete necrosis of tumour and adjacent margin (100%) Partial fibrosis (100%, n = 18) Complete fibrosis (100%, n = 14) Complete fibrosis (100%, n = 14) Zippel and Papa18 (2005) Resection 7–10 days Complete necrosis (20%), microscopic foci of residual tumour (20%), 10% residual tumour (30%), 10–30% residual tumour (30%) – – – Furusawa et al.6 (2006) Resection 5–23 days Complete necrosis (54%), < 10% residual disease (36%), 10–15% residual disease (10%) – – – Khiat et al.19 (2006) Resection 3–21 days Complete necrosis (31%), residual tumour < 10% (42%), residual tumour 20–90% (27%) – – – Kim et al.9 (2010) Resection and biopsy 2–20 months – Viable tumour (50%) No viable tumour (67%) No viable tumour (67%) Open in new tab Quality assessment Seven items of the STROBE statement14 were used for quality assessment of the included cohort studies (Table 3). One study with of quality score below 4 was excluded. All studies included specified study objectives and all had clear inclusion criteria and used standard imaging. A standard technique was used in six studies and five reported standard histopathology. Patient follow-up was undertaken until surgery in six studies and further follow-up carried out in two. In three studies, patients withdrew during the course of treatment. The overall STROBE score ranged from 4 to 6 (mean(s.d.) 5·3(0·71)). The Cochrane checklist13 was used to assess the quality of the single RCT7 (Table 4). The study was randomized, and contained complete outcome data with no short-term outcome data missing; it was free from selective reporting and other biases. It did not, however, contain a power analysis, or blind patients, participants or results. Table 3 Study quality assessment of included cohort studies Reference . Study objectives . Clear inclusion criteria . Standard technique . Standard histopathology . Standard imaging . Patient follow-up . Withdrawals from study . Gianfelice et al.15 Yes Yes No Yes Yes No* No Gianfelice et al.17 Yes Yes No Unknown Yes No* No Gianfelice et al.16 Yes Yes Yes Yes Yes No* No Wu et al.20 Yes Yes Yes Yes Yes Yes Yes Zippel and Papa18 Yes Yes Yes Unknown Yes No* No Furusawa et al.6 Yes Yes Yes Yes Yes No* Yes Khiat et al.19 Yes Yes Yes Yes Yes No* No Kim et al.9 Yes Yes Yes No Yes Yes Yes Reference . Study objectives . Clear inclusion criteria . Standard technique . Standard histopathology . Standard imaging . Patient follow-up . Withdrawals from study . Gianfelice et al.15 Yes Yes No Yes Yes No* No Gianfelice et al.17 Yes Yes No Unknown Yes No* No Gianfelice et al.16 Yes Yes Yes Yes Yes No* No Wu et al.20 Yes Yes Yes Yes Yes Yes Yes Zippel and Papa18 Yes Yes Yes Unknown Yes No* No Furusawa et al.6 Yes Yes Yes Yes Yes No* Yes Khiat et al.19 Yes Yes Yes Yes Yes No* No Kim et al.9 Yes Yes Yes No Yes Yes Yes Assessed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. * Studies in which the lesion was resected and follow-up was until surgery. Open in new tab Table 3 Study quality assessment of included cohort studies Reference . Study objectives . Clear inclusion criteria . Standard technique . Standard histopathology . Standard imaging . Patient follow-up . Withdrawals from study . Gianfelice et al.15 Yes Yes No Yes Yes No* No Gianfelice et al.17 Yes Yes No Unknown Yes No* No Gianfelice et al.16 Yes Yes Yes Yes Yes No* No Wu et al.20 Yes Yes Yes Yes Yes Yes Yes Zippel and Papa18 Yes Yes Yes Unknown Yes No* No Furusawa et al.6 Yes Yes Yes Yes Yes No* Yes Khiat et al.19 Yes Yes Yes Yes Yes No* No Kim et al.9 Yes Yes Yes No Yes Yes Yes Reference . Study objectives . Clear inclusion criteria . Standard technique . Standard histopathology . Standard imaging . Patient follow-up . Withdrawals from study . Gianfelice et al.15 Yes Yes No Yes Yes No* No Gianfelice et al.17 Yes Yes No Unknown Yes No* No Gianfelice et al.16 Yes Yes Yes Yes Yes No* No Wu et al.20 Yes Yes Yes Yes Yes Yes Yes Zippel and Papa18 Yes Yes Yes Unknown Yes No* No Furusawa et al.6 Yes Yes Yes Yes Yes No* Yes Khiat et al.19 Yes Yes Yes Yes Yes No* No Kim et al.9 Yes Yes Yes No Yes Yes Yes Assessed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. * Studies in which the lesion was resected and follow-up was until surgery. Open in new tab Table 4 Study quality assessment of included randomized clinical trial Reference . Adequate sequence generation . Power analysis . Concealed allocation . Blinding . Incomplete data addressed . Free from other bias . Free from selective reporting . Wu et al.7 Yes No Unknown No No Yes Yes Reference . Adequate sequence generation . Power analysis . Concealed allocation . Blinding . Incomplete data addressed . Free from other bias . Free from selective reporting . Wu et al.7 Yes No Unknown No No Yes Yes Assessed according to the risk of bias tool in the Cochrane Handbook. Open in new tab Table 4 Study quality assessment of included randomized clinical trial Reference . Adequate sequence generation . Power analysis . Concealed allocation . Blinding . Incomplete data addressed . Free from other bias . Free from selective reporting . Wu et al.7 Yes No Unknown No No Yes Yes Reference . Adequate sequence generation . Power analysis . Concealed allocation . Blinding . Incomplete data addressed . Free from other bias . Free from selective reporting . Wu et al.7 Yes No Unknown No No Yes Yes Assessed according to the risk of bias tool in the Cochrane Handbook. Open in new tab Types of imaging used to assess response to high-intensity focused ultrasound ablation Different imaging modalities have been used to determine the response to HIFU ablation (Table S1). In all studies both pretreatment and post-treatment imaging was performed. In two studies7,20 (26·9 per cent, 45 of 167 patients) ultrasonography with colour Doppler imaging was performed before the treatment and in one study20 after treatment to determine perfusion of the lesion. In one study20 single-photon emission CT was carried out both before and after treatment (3·6 per cent, 6 of 167 patients). MRI was undertaken before and after treatment in 77·8 per cent of all patients (130 of 167)6–7,9,15–20. Although all nine studies used MRI before and after treatment, different MRI systems and sequences were used. The systems used were the 1·5-T Signa® Excite® (GE Medical Systems, Milwaukee, Wisconsin, USA) in four studies9,15–16,19, a non-specified 1·5-T system (GE Medical Systems) in two6,17 and the 1·0-T Impact® (Siemens, Erlangen, Germany) in two7,20; in one report18 the MRI system was not specified. MRI-based assessment of high-intensity focused ultrasound treatment Of the 130 patients (77·8 per cent of 167) who underwent post-treatment MRI, the results were not reported in one study (12 patients)15. In four studies6,16,18–19 (80 patients), general descriptive findings were reported without quantitative findings. Contrast enhancement was seen on pretreatment scans and no enhancement was observed after treatment. In four studies7,9,17,20, 82 per cent of patients (31 of 38; range 50–100 per cent) showed an absence of enhancement at the index tumour and a thin rim of enhancement at the periphery. In 18 per cent of patients (7 of 38) nodular enhancement was seen at the periphery of the tumour, consistent with residual disease. Two studies9,20 recorded a reduction in tumour size by post-treatment MRI. A mean(s.d.) reduction of 26·7(12·2) per cent was reported after 6 months, 45·2(22·1) per cent after 12 months, 72·3(32·1) per cent after 24 months20, and a reduction of 46·3 per cent between 11 and 24 months9. MRI within the first 2 weeks after treatment showed transient oedema surrounding the target volume7. Any change in lesion size as a result of oedema was not documented. MRI was carried out immediately after HIFU treatment in three studies6,18–19, within the first 2 weeks in eight6–7,9,15–19 and at an unknown subsequent time in one study20. MRI immediately after HIFU treatment showed decreased enhancement, although not sufficient to determine treatment response. Two studies16,19 showed a good correlation between the increase in signal intensity (ISI) (r = 0·897 and r = 0·749 respectively), maximum difference function (MDF) (r = 0·789)16, positive enhancement integral (PEI) (r = 0·859 and r = 0·778 respectively) and the percentage of residual tumour. In one of these studies16 a stronger correlation was seen (r = 0·932 for ISI and r = 0·964 for PEI) when only MRI performed 7 days after HIFU treatment was included. One study17 with 24 patients, 18 of 19 patients who were considered to have had successful treatment based on biopsy results, demonstrated a lack of enhancement on MRI; three of five patients whose treatment was deemed to have failed, because residual tumour was found on biopsy, demonstrated persistent enhancement on MRI after two HIFU sessions. Histopathological outcome after high-intensity focused ultrasound treatment Histopathology was discussed in all nine studies (Table 2). The absence of tumour or residual tumour after treatment was reported for 95·8 per cent of patients (160 of 167). In six studies6–7,15–16,18–19 (68·9 per cent, 115 of 167 patients) the histopathology results were based on specimens from surgical removal of the tumour by lumpectomy or mastectomy after HIFU. Core needle biopsies were obtained in two studies17,20 (27·5 per cent, 46 of 167 patients), and a combination of core needle biopsies and surgical removal was used in the remaining study9 (3·6 per cent, 6 of 167 patients). In five6–7,16,18–19 of seven studies, patients underwent surgery 1–3 weeks after the HIFU treatment and in one study9 patients underwent surgery after 3–11 months; the final study15 did not specify the time of surgery after HIFU treatment. In five studies6–7,15–16,20 haematoxylin and eosin was used for histopathological staining, whereas the other four9,17–19 did not report the type of staining used. To get a clear view of the percentage of complete ablation and residual tumour, histopathology findings were divided into three groups: complete ablation, less than 10 per cent residual tumour, and residual tumour between 10 and 90 per cent. Complete ablation is a primary outcome and therefore reported as a separate group. Thus an incomplete ablation indicates an incomplete treatment. The threshold of 10 per cent residual tumour was used in four studies6,16,18–19. One study7 recorded complete necrosis of the tumours in all patients. In total, complete ablation or no residual tumour was found in 46·2 per cent (55 of 119; range 17–100 per cent) of all patients who underwent surgical excision after HIFU treatment. Weighted summary proportion analysis showed that an estimated 30 (95 per cent c.i. 18 to 43) per cent of patients had no residual disease after HIFU treatment (Fig. 2). The I2 statistic of 47·2 per cent confirms the heterogeneity among studies. The study7 that reported 100 per cent ablation was excluded from this analysis. Fig. 2 Open in new tabDownload slide Forest plot showing random-effects analysis of patients with residual disease after high-intensity focused ultrasound ablation. Effect sizes are shown with 95 per cent c.i. Residual tumour of less than 10 per cent was found in 29·4 per cent of patients (35 of 119; range 0–53 per cent)6,15–16,18–19. These histopathology results were obtained within the first 3 weeks after HIFU treatment. Residual tumour between 10 and 90 per cent was found in 22·7 per cent (27 of 119; range 0–60 per cent)6,15–16,18–19. Surgical resection of the tumour was performed between 1 and 3 weeks after surgery, and in one study15 no time of resection was mentioned. One study9 reported the number of patients with complete ablation, but the percentage of residual tumour in the remaining patients (2 of 119; 1·7 per cent, 0–33 per cent) was not mentioned. In the three studies9,17,20 that used core needle biopsies, no residual disease was found in 90 per cent of patients (43 of 48; 79–100 per cent). Residual disease was found in the other five patients, but no quantitative statements were made. The core biopsies were performed after 2 weeks20, 6 months17 and 2–20 months9. One study20 reported partial fibrosis in the core biopsies of all 18 patients after 3 months; complete fibrosis was visible in all biopsies from 14 patients after 6 and 12 months. Two studies6,16 determined the percentage of tumour located in the treated area. The whole tumour was located in the treated area in 83 per cent of patients (33 of 40; range 58–93 per cent), between 90 and 99 per cent of the tumour was located in the treated area in 10 per cent (4 of 40; range 7–17 per cent), and less than 70 per cent of the tumour was located in the treated area in 8 per cent (3 of 40; range 0–25 per cent). One study7 measured the ablated margin around the tumour, which was mean(s.d.) 1·80(0·58) cm. The ablated margin around the tumour was stated as 0·5 cm in three studies6,15,18, 1·0 cm in one study9, and 1·5–2·0 cm in two reports7,20. Complications after high-intensity focused ultrasound treatment Complications were described in seven studies (Table 1, Fig. 3)6–7,9,15,17–18,20. Pain was reported in 40·1 per cent of patients (67 of 167), and was slight in 6 per cent, moderate in 33 per cent, mild in 57 per cent and unknown in 4 per cent of these 67 patients. Skin burns occurred in 4·2 per cent (7 of 167), with one superficial, five second-degree and one third-degree burns. Oedema of the lump was noted in three studies7,9,20 and occurred in at least 16·8 per cent of patients (28 of 167). In one study7 oedema was noted, but the number of patients was not reported. The oedema disappeared within 2 weeks of treatment. Pectoralis major injuries were reported in one study9 and occurred in six patients (6 of 167, 3·6 per cent). Other complications were claustrophobia (1 of 167, 0·6 per cent), redness of the skin (1 of 167, 0·6 per cent) and tenderness of the breast (1 of 167, 0·6 per cent). Fig. 3 Open in new tabDownload slide Complications after high-intensity focused ultrasound ablation Breast cancer recurrence after high-intensity focused ultrasound treatment Recurrence of the tumour was found in two patients in one study20 (2 of 167 patients overall, 1·2 per cent; 2 of 28 with follow-up, 7 per cent). Both had modified radical mastectomy followed by chemotherapy; one patient died from metastatic disease 44 months after HIFU ablation. Cosmetic outcome after high-intensity focused ultrasound treatment In two studies18,20 a cosmetic outcome analysis was performed after HIFU treatment. A good to excellent cosmetic result was achieved in 25 of 27 patients and an acceptable result in two patients. High-intensity focused ultrasound treatment time Five studies6–7,9,15,20 reported the treatment times for HIFU; the median duration ranged between 78 and 171 min for a lesion between 1·3 and 3·4 cm in size. Discussion The studies included in this systematic review demonstrate that HIFU treatment has been shown in small series to induce coagulative necrosis in breast cancers. No residual tumour was found at histopathology in 46·2 per cent of patients. However, residual tumour of less than 10 per cent was found in 29·4 per cent, and between 10 and 90 per cent in 22·7 per cent. The volume of residual tumour was not mentioned in 1·7 per cent of patients6,15–16,18–19. Recurrence was reported in two patients, in whom an increase in tumour size was seen after an initial reduction on ultrasonography. The percentage of residual tumour after HIFU treatment varied between the studies. In previous studies21,22 tumour cells that showed normal cellular structure after staining with haematoxylin and eosin were found not to be viable on subsequent reduced nicotinamide adenine dinucleotide staining and electron microscopy. Therefore, the percentage of residual tumour might be lower than reported here. Failure to achieve complete ablation of the lesion may be related to accuracy of targeting the treatment area or to failure of the technique. Problems in targeting can be due to problems in the imaging process itself, or to movement of the patient during HIFU treatment. In many of the reviewed studies, it is unclear whether the whole tumour was actually located within the treated field, whether complete necrosis was achieved, and subsequently what part any difficulties in targeting may have played in the failure to achieve full ablation. Such data were reported in only two6,16 of the nine studies. The remaining studies recorded only the percentage of patients in whom complete ablation of the tumour was achieved. It is therefore not evident whether this represents a failure of the HIFU treatment itself or in actually locating the lesion. It is possible that, with improved targeting of the lesion, the efficacy of HIFU treatment could potentially be higher than described here. Surprisingly, ultrasound-guided HIFU treatment7,9,20 gave better results than MRI-guided ablation6,15–19. Although only three studies described HIFU performed under ultrasound guidance, two7,20 of these had an efficacy of 100 per cent and the third9 an efficacy of 67 per cent; however, the latter investigation included only six patients. It is likely that patients are selected for ultrasound treatment and so patient selection may partially be responsible for this observation. The extra margin of normal tissue ablated around the target tumour in the included studies varied from 0·5 to 1·5–2·0 cm. The two studies7,20 with a margin of between 1·5 and 2·0 cm are the only two to report complete necrosis of the lesion in all patients, and both used ultrasound-guided HIFU therapy. The only other ultrasound-guided study9 applied a margin of 1·0 cm and achieved complete ablation in four of six patients. In the MRI-based studies6,15–19, the margins treated around the lesion were between 0 and 1·0 cm, and complete ablation was obtained in fewer instances. This wider treated margin of surrounding tissue could explain the high rates of complete ablation achieved in studies that used ultrasound guidance. Post-treatment MRI images showed an absence of contrast enhancement and a thin rim enhancement at the periphery of the treated area in 31 of 38 patients, indicative of coagulative necrosis7,9,17,20. A positive correlation between the percentage of residual tumour and the ISI, MDF and PEI was observed on MRI after HIFU treatment16,19, and this could be used to determine the extent of residual lesion. A positive correlation was found between the ISI on MRI after HIFU treatment and the percentage of residual tumour tissue after HIFU treatment16,19. Before the HIFU treatment, strong enhancement of the whole tumour lesion was observed on dynamic contrast-enhanced MRI. After treatment, no enhancement was seen when complete necrosis was achieved. When residual tumour was left behind, post-treatment MRI scans showed nodular enhancement at the periphery of the treated area. However, some benign processes such as oedema, fibrosis, necrosis and inflammation can mimic malignant contrast enhancement, and so the time interval between treatment and the imaging procedure, as well as the shape of the enhancement curves, must be taken into account. Malignant tissues continue to show an irregular border, rapid enhancement and an early distinct washout phase after HIFU ablation19. The histopathology and MRI results after HIFU treatment were compared directly in three studies7,17,20. Two studies7,20 with complete ablation demonstrated on histopathology also showed complete ablation on MRI. However, in the other study17, MRI gave one false-positive and two-false negative results when compared with histology. This suggests that MRI is a fairly accurate predictor of complete ablation following HIFU treatment. To treat breast cancer with HIFU ablation, histopathology of the tumours must be established before therapy for definitive diagnosis. Surgical resection after HIFU treatment may not provide definitive diagnostic or prognostic factors for the determination of adjuvant systemic therapies. Some prognostic factors (such as presence or absence of lymphovascular invasion) cannot be assessed reliably on the limited sampling of a core biopsy sample. This may potentially limit the value of this technique in the setting of breast cancer treatment until improvements in imaging and genomic evaluations allow collection of prognostic factors comparable to those identified by histopathology. When only limited examination with small biopsies is performed, it is not possible to conclude whether complete or incomplete ablation has been achieved after HIFU therapy. The most common complications during and after treatment are pain (40·1 per cent), skin burns (4·2 per cent), oedema (at least 16·8 per cent) and pectoralis major injury (3·6 per cent). These are relatively mild problems compared with the possible complications of breast surgery (infection, bleeding, incomplete wound healing). The most significant concern regarding HIFU treatment of malignant lesions is inadequate treatment of the breast cancer, although recurrence was described in only two patients20. However, follow-up was reported in only two studies9,20, so this number is likely to be higher overall among all patients with HIFU-treated breast cancer. The cosmetic result after HIFU treatment was good to excellent in 25 of 27 patients asked and acceptable in the other two18,20. However, the cosmetic outcome of HIFU could not be assessed in the majority of the studies because HIFU treatment was mostly followed by surgical resection. Lesion resorption is a long process and can take 6 months after HIFU treatment17,20. This could prove a challenge during follow-up and may also have a psychological impact on patients, who might believe that they still have a lesion or even recurrence7. Therefore, it is important to inform patients that lumps may remain palpable for some time. Furthermore, HIFU treatment might also prove challenging for interpretation of breast imaging, if radiologists are not made aware that this treatment has been carried out. The treatment times for HIFU therapy are a major disadvantage of the technique. The mean duration for a lesion with dimensions between 1·3 and 3·4 cm ranged from 78 to 171 min. To make this treatment a viable alternative not only for patients clinically unfit for surgery, it is imperative that treatment times be reduced. All cohort studies reviewed were performed in different ways, and varied in outcome measures and consistency of reporting of results; the results could not, therefore, be compared directly in a quantitative analysis. There are significant variations in, for example, the times of further imaging and subsequent biopsies as well as the lesions included in the studies, the mode of HIFU treatment, different MRI devices and MRI sequences. Heterogeneity was also found in the width of the surrounding tissue treated, the ablation dose and the frequency of treatment. Inclusion criteria differed in terms of the distance between the lesion and the skin, chest wall and nipple. Finally, the median number of patients per study was 16·7, and two studies9,18 included ten or fewer patients. Strict standardization within the setting of clinical trials is needed to compare HIFU with breast surgery, and to compare MRI-guided versus ultrasound-guided HIFU. Acknowledgements The authors thank Theraclion Ltd (Malakoff, France) for an unrestricted grant to evaluate HIFU treatment for breast fibroadenomas. Disclosure: The authors declare no conflict of interest. Supporting information Additional supporting information may be found in the online version of this article: Table S1 Imaging findings and outcomes (PDF document) Editor's comments Open in new tabDownload slide References 1 Cancer Research UK . Breast Cancer 2013 . http://publications.cancerresearchuk.org/downloads/Product/CS_KF_BREAST.pdf [accessed 5 February 2014]. 2 Fisher B , Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer . N Engl J Med 2002 ; 347 : 1233 – 1241 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Early Breast Cancer Trialists' Collaborative Group . 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TI - Systematic review of high-intensity focused ultrasound ablation in the treatment of breast cancer
JF - British Journal of Surgery
DO - 10.1002/bjs.9793
DA - 2015-06-10
UR - https://www.deepdyve.com/lp/oxford-university-press/systematic-review-of-high-intensity-focused-ultrasound-ablation-in-the-GUU7IqfAg9
SP - 873
EP - 882
VL - 102
IS - 8
DP - DeepDyve
ER -