Efficacy of MR-guided High Intensity Focused Ultrasound (MRgHIFU) in the treatment of painful bone metastases from prostate cancer
Efficacy of MR-guided High Intensity Focused Ultrasound (MRgHIFU) in the treatment of painful bone metastases from prostate cancer
Authors Valerio D’Agostino*, V.D. (1), Bianca Vanzi, B.V.(1), Mariada Perrone, M.P.(1), Maria Pilar Aparisi Gomez, MPA.G(2), Alberto Bazzocchi, A.B. (1). Affiliations (1) IRCCS Istituto Ortopedico Rizzoli- Bologna, Italy (2) Auckland District Health Board – Auckland, New Zealand *lead presenter
Pain management of bone metastases is performed with systemic and local therapies. Even though stereotactic radiotherapy is nowadays the gold standard for painful metastasis, other interventional radiology (IR) applications could be used, like CT-guided thermoablations. Even in the relatively novel IR field, innovations regarding minimally invasive treatments have been developed for non-responder patients. Among thermotherapy, MRgHIFU is a new non-invasive weapon for bone pain palliation. MRgHIFU uses a beam of focused ultrasound instead of radiofrequency to treat the pathological tissue, thus allowing complete ablation of deep lesions with minimal invasiveness (no need for needles). This therapy is performed under the continuous guidance of magnetic resonance imaging (MRI) which allows for the targeted use of high-intensity focused ultrasound (MRgHIFU). In recent years, MRgHIFU has expanded the number of approved indications, including its role as a new non-invasive weapon for the palliation of bone pain. In a recent study involving 31 patients undergoing MRgHIFU, the authors observed a 69% post-treatment pain reduction at 3-month follow-up with no recording of serious therapy-related adverse events. Scientific literature suggests that this technique may be effective and safe in controlling pain related to bone metastases. According to Naples et al., MRgHIFU may play a role in local tumor control and even curative treatment in case of single metastasis or a few repetitive lesions. Other researchers are exploring the possibility of employing minimally invasive curative treatments in oligometastases. The term oligometastatic disease refers to cases with a limited number of metastatic lesions due both to the poor biological capacity of the tumor to spread and to its good response to systemic chemotherapy. In these cases, since the tumor has a low metastatic capacity, local treatments could be curative. Also, since there is no exposure to ionizing radiation, it can be repeated if necessary. This is a very important aspect to take into consideration when choosing the type of treatment, especially when dealing with young patients. Finally, this treatment has the added benefit of providing a rapid response with a prompt reduction in patient-reported pain (typically within 1 week), much faster than the 5-6 weeks required to achieve a response with stereotactic radiotherapy. Given that currently subjects undergoing MRgHIFU often have a low life expectancy, the speed of the palliative response is a crucial factor to consider in choosing the most appropriate treatment for the individual patient. An easy approach and a proper acoustic window are more predictable in osteolytic than osteoblastic lesions (Fig.1). A distance greater than 1 cm between the target lesion and sensitive structures is highly recommended in MRgHIFU treatments of bone lesions. Thus, the primary aim of this work is to evaluate the efficacy and safety of MRgHIFU treatment in pain palliation of bone metastases from prostate cancer located in close proximity (<1cm) of sensitive structures.
This retrospective study was approved by our local committee and performed following the statement of the Declaration of Helsinki. Given its retrospective nature, informed consent collection was waived. We retrospectively reviewed all the MRgHIFU treatments performed at our institution from January 2021 to March 2022. Inclusion criteria were treatment of painful metastases from prostate cancer, age>18 yo, adequate quality of imaging, clinical data, and previous imaging to assess the characteristics of the lesion treated. Exclusion criteria were: treatment performed for other reasons (mostly osteoid osteomas and metastases from other tumors), incomplete treatment due to lack of patient compliance, and scarce image quality. The selected patients were divided into two groups according to the type of metastases (Group A: Osteoblastic, Group 2: Osteolytic). The close proximity between the site of treatment and sensitive structures was measured on pre-treatment MR exams by two radiologists with almost 5 years of experience in musculoskeletal imaging (mean of 9 years). NRS pain score at baseline, 3 and 6 months after treatment was assessed in all patients. A significative palliative response was defined as a reduction of at least 4 points on the NRS pain scale from the baseline. MR/CT imaging was performed before and 3-6 months after treatment. The primary endpoint of this study was the assessment of pain palliation according to the “International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases” criteria. Secondary endpoints were local tumor control (according to MD Anderson criteria), to assess major and minor complications involving sensitive structures and differences in outcome between the osteoblastic and osteolytic lesions. Shapiro-Wilk test was used to assess the distribution of the data, and chi-squared or Fisher’s exact test was used when adequate. Statistical analysis was performed using SPSS statistics. Significance was set at p<0.05.
Example of CT appearance of a blastic and a lytic metastasis from prostate cancer
18 patients (mean age 65±12,4) with 18 bone metastases (Fig. 2 shows the metastatic sites) were treated with MRgHIFU and enrolled in our study. Group A consisted of 10 patients with 11 metastases treated, Group B of 8 patients with 8 metastases treated, with a total number of 19 lesions (Flowchart in Fig. 3) Group characteristics are reviewed in Tab. 1 Overall NRS at baseline was 5±1,7, with a significant reduction at 3 months (1,57±1.5, p <0.0001) and at 6 months (0,8±0,7, p <0.0001). NRS for osteoblastic lesions at baseline was 4±2,7, with a significant reduction at 3 months (1,27±2.5, p <0.0001) and at 6 months (1,5±1,2, p <0.0001). NRS for osteoblastic lesions at baseline was 6±1,2, with a significant reduction at 3 months (2,23±0.5, p <0.0001) and at 6 months (1,8±2,1, p <0.0001). The comparison of NRS trends is shown in Fig. 4. No adverse events over grade 2 were documented. Follow-ups at 3 and 6 months from treatment were available for 17 patients: • Complete response was seen in 3 cases (2 Group B, 1 Group A) • Partial response in 6 (3 Group B, 3 Group A) • Stability in 6 (3 Group B, 3 Group A) • Progression in 2 (1 Group B, 1 Group A) No statistically significant differences were found between the two groups in terms of pain response (p=0,3348) and tumor control (p=0,4582).
Pictorial representation of the sites of metastatic lesions, being the hip the most affected skeletal region, according to epidemiologic data.
Flowchart of patient selection and division in two groups (Group A: Osteoblastic; Group B: Osteolytic).
Clinical and radiological characteristics of the groups of this study (Group A: Osteoblastic; Group B: Osteolytic).
MRgHIFU is a promising minimally invasive technique offering new opportunities for the treatment of patients affected by bone metastasis from prostate cancer. A distance <1 cm from sensitive structures of the target lesion is currently considered an exclusion criterion for MRgHIFU treatment. Since the targeted bone metastases may be in different areas of the patient’s body, positioning of the patient on the table should be optimized by centering the treatment target area over the water bath containing the transducer, which creates a normal incidence angle with as much of the bone surface as possible. Some technical precautions can be performed to prevent the excessive proximity to sensitive structures, such as a different positioning of the patient (that ie exert a minor gravity compression of subcutaneous soft tissues), a different approach and course of the ultrasound beam to avoid them and different positioning system, probe and MRI systems. Other cooling systems like those used in RFA (water/air cooling systems) are not viable with MRgHIFU, because air could cause susceptivity artifacts (making thermometry sequences less reliable and post-treatment evaluation more difficult) and refract/reflect the ultrasound (with a reduction in ablation’s effectiveness and precision). Even if a cooling system using different materials without the above issues is concocted, it would be necessary to inject the material on site, losing MRgHIFU's advantage of being a needless treatment. Nevertheless, these adjustments have limits and isn’t always possible to fit the recommended proximity threshold limit, thus a proper study addressing this issue was deemed necessary and of paramount importance. The results of this study show that MRgHIFU can be safely and effectively performed on lesions located at <1 cm from sensitive structures. Moreover, our study suggests the need for revision of nowadays MRgHIFU exclusion criteria in clinical practice and research, thus improving the range of applications and allowing a higher number of patients to benefit from its optimal results in terms of local control and pain palliation. Regarding the efficacy of the treatment in different kinds of metastases, this study did not find statistically significant differences between osteolytic and osteoblastic lesions. This could be explained by the relative compensation of the better FUS penetration in osteolytic lesions with the higher acoustic adsorption rate of the osteoblastic lesions. However, our results should be interpreted with caution and only serve as a framework around which to design future large-scale clinical trials. Nevertheless, modern ongoing developments in the technology used to deliver treatment and an expansion in the clinical research supporting its adoption make it likely that MRgHIFU will have a role in pain management in the future.
Graph showing the NRS score trend through the 3 and six months follow-up, where a statistically significative pain reduction was observed. (Group A: Osteoblastic; Group B: Osteolytic).