Different approaches to target volume definition and boost delivery in surgery de-escalation clinical trial in breast cancer patients with pathological complete response.

PURPOSE: We evaluate various approaches to target volume definition and boost delivery in patients with complete response to neoadjuvant systemic therapy (NST) who were treated by radiotherapy without a surgery. MATERIALS AND METHODS: A pathological complete response (pCR) was diagnosed in 21 of 27 patients included in "surgery de-escalation" prospective observation study. Clips were placed in the primary tumor volume (PrTV) before NST and during the vacuum aspiration biopsy. Twenty patients with pCR underwent the whole breast irradiation and a boost to the PrTV. High-dose rate brachytherapy (HDRB) was the basic technique for boost delivery. Finally, we identified the value of fused images (computed tomography [CT] before NST with simulation CT), clips and their combination for an accurate boost delivery. RESULTS: A complete overlap between PrTV on pre-treatment CT with the localization of the clips on simulation CT was mentioned in 10, partial mismatch in three patients. In 12 of these 13 women, HDRB was successfully used for the boost delivery. In five cases we mentioned a marked discrepancy between the PrTV on fused images and the topography of the clips. In other two women we did not find clips on simulation CT. The fused images in five of these seven patients showed anatomical landmarks (scar, fibrosis) used for identification of the gross tumor volume. In all 20 women with pCR (average follow-up of 16.6 months), there were no locoregional recurrences. CONCLUSION: Combination of the clips with fusion of pre-NST and simulation CTs is important for an accurate boost delivery.

A comparison between high dose rate brachytherapy and stereotactic body radiotherapy boost after elective pelvic irradiation for high and very high-risk prostate cancer.

PURPOSE: To compare biochemical recurrence-free survival (BRFS) and toxicity outcomes of high dose rate brachytherapy (HDRB) and stereotactic body radiotherapy (SBRT) boost after elective nodal irradiation for high/very high-risk prostate cancer. MATERIALS AND METHODS: a retrospective analysis was performed in 149 male. In 98 patients, the boost to the prostate was delivered by HDRB as 2 fractions of 10 Gy (EQD2 for α/ß = 1.5; 66 Gy) or 1 fraction of 15 Gy (EQD2 for α/ß = 1.5; 71 Gy). In 51 male, SBRT was used for the boost delivery (3 fractions of 7 Gy; EQD2Gy for α/ß = 1.5; 51 Gy) because brachytherapy equipment was out of order. RESULTS: In 98 patients that received HDRB boost, 3- and 5-year BRFS were 74.6% and 66.8%. Late grade-II genitourinary toxicity was detected in 27, grade-III in 1 case. Grade-II (maximum) rectal toxicity was diagnosed in nine patients. For 51 male patients that received SBRT boost, 3- and 5-year BRFS was 76.5% and 67.7%. Late grade-II (maximum) genitourinary toxicity was detected in five cases, late grade-II rectal toxicity in four cases. Other three patients developed late grade-III-IV rectal toxicity that required diverting colostomy. SBRT boost was associated with higher maximum dose to 2 cm3 of anterior rectal wall (D2cm³rectum) compared to HDRB: 92% versus 55% of dose to prostate. Severe rectal toxicity was negligible at EQD2 D2cm³rectum <85 Gy and EQD2 D5cm³ rectum <75 Gy. CONCLUSION: Our results indicate similar 3- and 5-year BRFS in patients with high/very high-risk prostate cancer who received HDRB or SBRT boost, but SBRT boost is associated with higher rate of severe late rectal toxicity.

Single photon emission computed tomography-computed tomography visualization of sentinel lymph nodes for lymph flow guided nodal irradiation in oral tongue cancer.

PURPOSE: To evaluate correlation of single photon emission computed tomography-computed tomography (SPECT-CT) data on lymph flow (LF) from oral tongue cancer (OC) and the topography of lymph nodes (LN) metastases; to determine the clinical value of lymph flow guided radiotherapy (LFGRT). MATERIALS AND METHODS: SPECT-CT visualization of LF from the OC lesions was performed after peritumoral injection of 99mTc-phytate in 26 primary patients with clinical stage cT1-2N0M0 disease. We determined the individual drainage (unilateral/bilateral) from the tumor, and localization of sentinel LNs according to the neck levels. Metastases in LNs were verified with histology and a 2-year follow-up. RESULTS: SPECT-CT detected bilateral LF in 10 (38.5%) of 26 patients; in 16 (61.5%) cases the drainage was unilateral. Histology revealed LNs metastases in three cases; regional recurrences were diagnosed in other four patients. In all seven observations metastases were located at the same site and level as the sentinel LNs. In eight (30.8%) of 26 patients sentinel LNs were visualized unilaterally at levels Ib-IIa; in five cases, unilaterally at levels I-IIa-III. In these patients, LFGRT demonstrated 59%-70% reduction of irradiated volume, and 26%-42% and 51%-70% decrease of the mean dose to the spinal cord and the contralateral parotid gland. In patients with a bilateral drainage the reduction of doses absorbed by the spinal cord and contralateral parotid gland was 19% and 6%, respectively. CONCLUSION: Localization of sentinel LNs determined by SPECT-CT corresponds to the localization of metastatic LNs in terms of side and levels.

Atlas of sentinel lymph nodes in early breast cancer using single-photon emission computed tomography: implication for lymphatic contouring.

PURPOSE: to determine the localization of sentinel lymph nodes (SLNs) in a large cohort of patients with breast cancer and validate the European Society for Therapeutic Radiology and Oncology (ESTRO), Radiation Therapy Oncology Group (RTOG), and Radiotherapy Comparative Effectiveness (RADCOMP) guidelines on regional lymph node clinical target volume (CTV-LN) delineation. MATERIALS AND METHODS: A total of 254 women with cT1-3N0-1M0 breast cancer underwent single-photon emission computed tomography (SPECT-CT) visualization of SLNs after intra- and peritumoral injection of 99mTc-radiocolloids. All SPECT-CT images were fused with reference simulation computed tomography. A 3D atlas of SLNs was created and used for evaluation of CTV-LN defined by contouring guidelines. RESULTS: SPECT-CT visualized 532 SLNs that were localized in axillary level I in 67.5%, level II in 15.4%, level III in 7.3%, internal mammary in 8.5%, and supraclavicular in 1.3% cases. The majority of level II-IV and internal mammary SLNs were inside the recommended CTV-LN. Axillary level I SLNs were covered by ESTRO and RTOG contours in 85% and 85% cases, respectively. "Out of contours" SLNs were mostly detected in lateral subgroup of level I LN (18.5%), while 98%-99% of anterior pectoral and central axillary SLNs were covered by CTV-LN. Internal mammary SLNs were visualized in 33 cases and were outside ESTRO and RTOG contours in 3 and 6 observations, respectively. CONCLUSION: SPECT-CT atlas of SLNs demonstrated that in most cases ESTRO and RTOG guidelines correctly represented CTV-LNs with the exception of lateral subgroup of SLNs.

SPECT-CT visualization and biopsy of sentinel lymph nodes in patients with stage IAB-IIA cervical cancer.

OBJECTIVE: To evaluate the diagnostic accuracy of sentinel lymph node (SLN) biopsy and to determine clinical significance of preoperative single-photon emission computed tomography/computed tomography (SPECT-CT). METHODS: We retrospectively evaluate data and images of 55 women with stage IAB-IIA cervical cancer that underwent sentinel lymph node biopsy and subsequent lymph node dissection. 99mTc-phytate (300 MBq) was injected submucosally in 4 points and SPECT-CT started 2 h after the injection. All lymph nodes (LN) that accumulated radiocolloids were regarded as sentinel. Next day after the mapping radical hysterectomy with complete pelvic and parametrial LN dissection and SLN biopsy were performed according to the institute protocol. RESULTS: SPECT-CT identified SLNs in 51 of 55 patients. All SLNs were successfully detected during the surgery. The SLN mapping efficacy was 92.7%. LN metastases were diagnosed in 6/51 (11.8%) cases, including 2 patients with positive SLNs. Sensitivity, negative predictive value (NPV) and false-negative rate for SLN biopsy were as follows: 33.4%, 91.8% and 66.6%. In patients with unilateral SPECT-CT localization of SLNs, LN metastases were identified in 4 (20%) of 20 patients but SLN biopsy was false negative in all cases. In 31 women, SPECT-CT detected SLNs on both sides of the pelvis. In this group, regional LN metastases were diagnosed in 2 patients, and in both cases metastases were detected only in SLNs. CONCLUSIONS: In women with SPECT-CT visualization of SLNs on both sides of the pelvis, SLN biopsy had high sensitivity and NPV. In patients with unilateral SLN localization, SLN biopsy cannot be used for the prediction of regional LN status.

SPECT-CT localization of axillary sentinel lymph nodes for radiotherapy of early breast cancer.

PURPOSE: To evaluate the opportunities of single photon emission tomography/computerized tomography (SPECT-CT) for localization of axillary sentinel lymph nodes (ASLNs) and subsequent radiotherapy planning in women with early breast cancer. MATERIAL AND METHODS: Individual topography of ASLN was determined in 151 women with clinical T1-2N0M0 breast cancer. SPECT-CT visualization of ASLNs was initiated 120 min after intra-peritumoral injection of 99mTc-radiocolloids. Doses absorbed by virtual ASLNs after the whole breast irradiation with standard and extended tangential fields were calculated on a treatment planning station. RESULTS: SPECT-CT demonstrated a large variability of ASLN localization. They were detected in the central subgroup in 94 (61%) patients, in pectoral - in 77 (51%), and in interpectoral - in 4 (3%) patients. Sentinel lymph nodes "lying on the chest" were revealed in 35 (23%) cases.We found that with standard tangential fields coverage of ASLNs was obtained only in 20% of evaluated women. Extended tangential fields can effectively irradiate ASLNs localized in all axillary sub-regions with the exception of ASLNs "lying on the chest". CONCLUSION: SPECT-CT mapping of ASLNs in women with cT1-2N0M0 breast cancer reveals their variable localization. This information can be important for planning of radiation treatment in women that underwent breast conserving surgery without an axillary surgery.

99mTc-MIBI scintimammography and digital mammography in the diagnosis of multicentric breast cancer.

OBJECTIVE: To compare diagnostic accuracy of scintimammography (SMG) and digital mammography (DS) in the diagnosis of multicentric breast cancer. SUBJECTS AND METHODS: Three hundred and sixty seven women with histologically confirmed breast cancer were included in this analysis. All patients were candidates for conservative breast surgery and had cT1-3N0-1 stage of disease. Scintimammography was performed in prone position 5-10min after intravenous injection of 740MBq of technetium-99m-methoxy-isobtyl-isonitrile (99mTc-MIBI) with acquisition time of 10min for every lateral and anterior projection. Digital mammography was done in all women according to a standard clinical protocol. Final diagnosis was established by histopathology. Multicentric breast cancer was defined as 2 or more distinct invasive tumors located in more than one quadrant or additional lesions from the primary tumor of more than 4cm in size. RESULTS: According to histopathological examinations multicentric breast cancer was diagnosed in 47 of 367 (12.8%) patients. Scintimammography was more effective than mammography in detecting multicentric breast cancer: sensitivity: 83.0% vs 40.4% (P<0.001), specificity: 97.8% vs 95.3% (P=0.4), accuracy: 95.9% vs 88.3% (P<0.001), positive and negative predictive values: 84.8% vs 55.9% (P=0.004) and 97.5% vs 91.6% (P<0.001), respectively. Combination of DM and SMG was characterized by increased sensitivity (93.6%), worse specificity (93.4%), accuracy (93.4%) and worse predictive value (67.7%) as compared to only SMG. CONCLUSION: Scintimammography was significantly much better by all statistical parameters than DM in the detection of multicentric breast cancer. High positive predictive value of scintimammography (84.8%) advocates it as a tool for surgery and radiotherapy planning.

The use of single-photon emission computed tomography-computed tomography in detecting multiple metastatic lymph nodes in patients with breast cancer.

AIM: The aim of the present study was to determine the accuracy of single-photon emission computed tomography-computed tomography (SPECT-CT) with technetium-99m-sestamibi (Tc-MIBI) for detecting multiple (>2 nodes) axillary lymph node involvement in patients with breast cancer (BC). PATIENTS AND METHODS: A total of 184 women with BC were examined. Clinically, axillary lymph nodes were classified as N0 in all cases. Patients underwent SPECT-CT breast and axillary region imaging 10-15 min after a 740 mBq intravenous injection of Tc-MIBI. SPECT-CT data were then verified by definitive histopathological examination (sentinel-node biopsy and/or axillary lymph node dissection were used as reference standard). Diagnostic values of different CT and SPECT signs of multiple (>2) lymph node involvement were evaluated. RESULTS: Histological examination of excised lymph nodes showed metastatic involvement in 62 (33.7%) out of 184 patients. In fact, 25 (13.6%) patients had more than two lymph node involvements. In another 37 (20.1%) cases the metastasis was revealed in one or two sentinel lymph nodes only. The main SPECT-CT criteria of multiple (>2) lymph node involvement were as follows: the maximum size of the primary tumor (>20 mm), lymph node dimensions (>12 mm along the long axis and >10 mm along the short axis), nodal cortical thickness (>4 mm), round shape, solid structure, quantity of identified abnormal lymph nodes (>1), and intensity of tracer uptake. The developed integrated model offers the possibility to exclude multiple lymph node metastasis (>2) in BC patients with a probability of 99%. CONCLUSION: This single-center study showed that in patients with BC, a combination of functional and anatomical data that were obtained by using SPECT-CT with Tc-MIBI can significantly improve detectability of multiple (>2) axillary metastases.

Lymph flow guided irradiation of regional lymph nodes in patients with cervical cancer: Preliminary analysis of scintigraphic data.

PURPOSE: To evaluate patterns of lymph flow from primary lesions in patients with cervical cancer and to determine how useful for radiotherapy planning this information can be. MATERIALS AND METHODS: SPECT-CT visualization of sentinel (SLN) lymph nodes (LNs) was performed in 36 primary patients with IB-IIB cervical cancer. The acquisition started 120-240 min after 4 peritumoral injections of 99mTc-radiocolloids (150-300 MBq in 0.4-1 ml). We determined localization of LN with uptake of radiocolloids, type of lymph flow (mono-, bi-lateral) and lymph flow patterns (supraureteral paracervical, infraureteral paracervical and directly to para-aortic LNs). RESULTS: SLNs were visualized in 31 of 36 women. Bilateral lymph-flow was detected in 22 (71%), monolateral - in the other 9 (29%) cases. The distribution of SLNs was as follows: external iliac - 64.5%, internal iliac - 54.8%, obturator - 32.2%, common iliac - 35.5% and pre-sacral 3.2%. Para-aortic LNs were visualized in 5 (16.1%) patients. The supraureteral paracervical pattern of lymph flow was identified in 22, infraureteral paracervical - in 4 and their combination - in the other 5 women. CONCLUSION: Visualization of an individual pattern of lymph flow from primary cervical cancer can be considered as a promising tool for optimization of the volume of irradiated regional LNs.

Why do we need irradiation of internal mammary lymph nodes in patients with breast cancer: Analysis of lymph flow and radiotherapy studies.

AIM: Using clinical data and results of lymphoscintigraphy to calculate probability of internal mammary lymph node (IMLN) invasion by breast cancer (BC). To evaluate clinical value of lymphoscintigraphy as the guide for irradiation of IMLN. METHODS: Using the data of eight published studies that analyzed lymph flow from primary BC (4541pts) after intra-peri-tumoral injection of nanosized 99mTc-colloids we determined probability of lymph-flow from internal-central and external BC to IMLN. In 7 studies (4359pts) axillary staging was accompanied by IMLN biopsy (911pts) that helped us to estimate probability of IMLN metastatic invasion in relation to the status of axillary LN. Finally, we estimated probability of IMLN invasion by BC in five randomized and observation studies that analyzed effect of IMLN irradiation on overall survival (OS). We calculated possible gain in survival if they would be treated according to lymph-flow guided radiotherapy to IMLN. RESULTS: Lymph-flow from internal/central BC to IMLN was mentioned in 35% from external lesions - in 16% cases. In women with negative axillary LN metastases in IMLN were revealed in 7.8%pts, in the case of positive axillary nodes average risk of IMLN invasion increased to 38.1%. Calculated probability of IMLN metastatic invasion in pts included in evaluated trials did not exceed 10%. If lymphoscintigraphy would drive decision about irradiation of IMLN than 72-78% of pts included in these studies would escape radiotherapy to IMLN. In the remaining 21-28%pts with lymph-flow to IMLN their irradiation probably would increase gain in OS from 1.0-3.3% to 4.3-16.8%. CONCLUSION: Lymphoscintigraphy can be used to optimize the strategy of IMLN irradiation.

Template guided transperineal saturation biopsy of the prostate: lessons for focal and urethra-sparing high-dose-rate brachytherapy for localized prostate cancer.

PURPOSE: The aim of this work is to evaluate results of prostate transperineal saturation biopsy as a guide for focal high-dose-rate brachytherapy in patients with prostate cancer (PCa). MATERIAL AND METHODS: Template guided saturation biopsy was performed in 67 primary patients with suspicion for prostate cancer. Biopsy was performed under ultrasonography (US) control with the help of brachytherapy grid and 5 mm distance between samples. We put special attention for accurate sampling of prostate in periurethral region. The number of cores varied from 17 to 81 (average 36 cores). Finally, in 40 patients with confirmed prostate cancer results of biopsy were used for brachytherapy planning. RESULTS: Saturation biopsy revealed prostate cancer in 40 of 67 evaluated patients. The extent of biopsy core involvement varied from 5% to 100% (average: 57%). Focal nature of PCa (single unilateral tumor nodule) was diagnosed in 10 (25%), multifocal - in another 30 (75%) patients. Hemigland invasion was mentioned in 12 (30%) cases. Saturation biopsy detected PCa in periurethral cores in 27 (67.5%) of 40 evaluated patients. In 10 patients, the extent of involvement in periurethral cores varied between 10% and 50%; in another, 17 observations exceeded 50%. According to results obtained on saturation biopsy, we performed HDR brachytherapy with "urethra low dose tunnel" (D10ur ≤ 80-90%) in 13 patients with noninvolved periurethral cores. Theoretically, hemigland brachytherapy was possible in 12 of 40 evaluated patients with PCa. CONCLUSIONS: In low risk patients with PCa results of template guided saturation biopsy indicates high frequency (75%) of multifocal disease and high probability (67.5%) of periurethral invasion. Suitable candidates for focal HDR brachytherapy or irradiation with additional sparing of urethra can be effectively determined with the help of saturation biopsy.

Technetium-99m methoxyisobutylisonitrile scintimammography for monitoring and early prediction of breast cancer response to neoadjuvant chemotherapy.

PURPOSE: The aim of the study was to evaluate the clinical value of scintimammography (SMG) with technetium-99m methoxyisobutylisonitrile (Tc-MIBI) for evaluating the efficacy of neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: A total of 65 patients with advanced breast cancer (BC) were included in the study. Planar SMG with 740 MBq of Tc-MIBI was performed before the start and after two to three and four to six cycles of NAC. NAC efficacy was estimated as progression (grade I), stabilization (grade II), partial effect (grade III), prominent efficacy (grade IV), and complete response (grade V). In 59 women, histopathologic verification of BC response to NAC was performed according to the Miller-Payne classification with the same scores as were used in the evaluation of scintigraphic response. RESULTS: After two to three cycles of NAC, disease progression was detected in five of 65 (7.7%) patients. In 27 (41.5%) patients SMG detected early stabilization of BC. Only one of these patients achieved prominent (grade IV) response after the end of NAC. Partial (grade III) response after two to three cycles of NAC was seen in 24 (36.9%) patients. One-third of them had grades IV-V response at the end of treatment. The most promising was the group of nine (13.8%) patients with early-grades IV-V response, all of which transformed to complete response at the end of NAC. As per histopathologic verification, early SMG had 85.7% sensitivity, 94.2% specificity, and 93.2% accuracy in predicting complete pathologic response to four to six cycles of NAC. CONCLUSION: After two to three cycles of NAC, SMG with Tc-MIBI can determine patients with low, intermediate, and high probability of complete response to five to six cycles of NAC Video Abstract: http://links.lww.com/NMC/A43.

Axillary lymph node staging in breast cancer: clinical value of single photon emission computed tomography-computed tomography (SPECT-CT) with 99mTc-methoxyisobutylisonitrile.

OBJECTIVE: To determine diagnostic accuracy of SPECT, CT and SPECT-CT in axillary lymph node (LN) staging in breast cancer (BC). METHODS: Sixty consecutive patients with primary operable T1-3NxM0 BC were included in this study. All patients underwent SPECT-CT examination on Symbia-T16 scanner which consists of dual-head gamma camera combined with 16 slices diagnostic CT. SPECT-CT acquisition started 10-15 min after i/v injection of 740-1,000 MBq of 99mTc-MIBI. On CT images of axillary LN we analyzed following diagnostic signs: size (short axis more or less than 10 mm), shape (round or oval), cortical thickness and fat content (solid or with fat gate). Intensity of tracer uptake in axillary LN was classified as follows: grade (Gr) I-background, Gr II-slightly above background, Gr III-intense but below uptake in muscles, Gr IV-as high as in muscles. Histological examination of dissected LN was used as gold standard. RESULTS: Various combinations of CT signs of axillary LN involvement demonstrated moderate diagnostic value with best results characterized by low (55 %) sensitivity (SEN), 97 % specificity (SP) and 83 % accuracy (AC). Intensive (Gr IV) uptake of 99mTc-MIBI in axillary LN characterized by low (55 %) SEN, high (100 %) SP and moderate (84 %) AC. Combination of CT and SPECT signs looks most promising especially when LN metastases were diagnosed in patients with enlarged solid LN or normal sized LN with Gr III-IV 99Tc-MIBI uptake. In these cases, SEN was equal to 75 %, SP-90 %, AC-85 %, only one of 5 patients with false negative results had metastases in more than 2 LN. CONCLUSIONS: By combination of SPECT and CT data we can more accurately diagnose axillary LN invasion by breast cancer.

Comparison of two treatment strategies for irradiation of regional lymph nodes in patients with breast cancer: Lymph flow guided portals versus standard radiation fields.

AIM AND BACKGROUND: Radiotherapy being an essential part of breast cancer treatment, we evaluate various radiotherapy strategies in patients with breast cancer. MATERIALS AND METHODS: Lymph node (LN) scintigraphy was performed in 172 primary patients with BC. LN visualization started 30-360 min after intratumoral injection of 75-150 MBq of 99mTc-nanocolloids. Our standard recommendation for postoperative radiotherapy in patients with LN invasion by BC were as follows: for patients with external localization of tumour - breast + axillary (Ax) + sub-supraclavicular (SSCL) regions; with internal localization - all above + internal mammary nodes (IM). Proposed strategy of lymph flow guided radiotherapy is based on the assumption that only regions that contain 'hot' LNs must be included in a treatment volume. RESULTS: Among 110 patients with external localization of BC, Ax LNs were visualized in all cases and in 62 patients it was the only region with 'hot' LN. Twenty-three patients (20.9%) had drainage to Ax + SSCL, 12 (10.9%) - Ax + IM, 13 (11.8%) - Ax + SSCL + IM regions. After the visualization of lymph flow patterns, standard treatment volume was changed in 87/110 cases (79.1%): in 56.4%, reduced, in 22.7%, enlarged or changed. In 62 patients with tumours in internal quadrants, we revealed the following patterns of lymph-flow: only to the Ax region in 23 (37.1%); Ax + IM, 13 (21%); Ax + SSCL, 15 (24.2%); Ax + IM + ISSCL, 11 (17.7%) cases. After lymph-flow visualization, the standard irradiation volume was reduced in 53/62 (85.5%) cases. CONCLUSION: Visualization of an individual lymph flow pattern from BC can be used for the optimization of standard fields used for irradiation of regional LNs.

Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results.

BACKGROUND: Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases. METHODS: Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher's exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. RESULTS: One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day. CONCLUSIONS: This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments.