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Comparing imaging changes and pain response in patients with intra- or extra-osseous bone metastases treated palliatively with magnetic resonance guided high intensity focused ultrasound (MRgHIFU)
Sharon L Giles1, Matthew RD Brown2,3, Ian Rivens4, Martin Deppe5, Merel Huisman6, Young-Sun Kim7, Gail R ter Haar4, and Nandita M deSouza1

1CRUK Cancer Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom, 2Targeted Approaches to Cancer Pain, The Institute of Cancer Research, London, United Kingdom, 3Pain Medicine Department, Royal Marsden Hospital, London, United Kingdom, 4Therapeutic Ultrasound, The Institute of Cancer Research, London, United Kingdom, 5Philips MR Therapy, Vantaa, Finland, 6University Medical Center Utrecht, Utrecht, Netherlands, 7Samsung Medical Center, Seoul, Korea, Republic of

Synopsis

Imaging changes and pain relief were compared in 21 patients with intra- versus extra-osseous bone metastases treated palliatively with magnetic resonance guided high intensity focused ultrasound (MRgHIFU). Thermal dose volumes measured on proton resonance frequency shift (PRFS) thermometry were significantly larger in the extra-osseous group. Intra-osseous lesions showed focal non-enhancement by Day 30, and patients had better pain response to MRgHIFU than those with extra-osseous lesions. By Day 30, 67% (6/9) patients with intra-osseous lesions were responders, compared with 33% (4/12) of patients with extra-osseous lesions. In neither group was pain response indicated by non-enhancement on Gd-T1W imaging.

Background

Magnetic resonance guided high intensity focused ultrasound (MRgHIFU) can palliate painful bone metastases1,2. Targeting the bone cortex is thought to cause periosteal denervation3, so may be ineffective for extra-osseous tumors, where cortical bone is absent. During treatment, proton resonance frequency shift (PRFS) thermometry4,5 in adjacent aqueous soft tissues regions is used to indicate ablative temperatures6. After treatment, Gadolinium enhanced T1-weighted (Gd-T1W) imaging can show non-perfused regions indicative of tissue ablation7, but the significance of the non-perfused volume (NPV) in relation to treatment response is unclear8,9.

Purpose

To compare imaging changes and pain response after MRgHIFU in patients with painful intra- versus extra-osseous bone metastases, and determine whether imaging changes during and after treatment are indicative of response.

Methods

Patients: 21 patients with a dominant painful bone metastasis (13 pelvis, 3 ribs, 2 humerii, 2 femurs, 1 sacrum) were treated using a Sonalleve HIFU device (Profound Medical, Ontario, Canada) at 3 centers.

Treatments: MRgHIFU treatments were delivered using volumetric ‘cells’10. For intra-osseous lesions, cells were centred on the cortical surface; for extra-osseous lesions, additional cells were positioned within tumors.

Intra-procedural imaging: 3D T1W imaging was used to confirm patient positioning and plan treatments. PRFS data obtained during exposures were used to evaluate temperature change. After treatments, Gd-T1W images were obtained.

Post treatment assessments: Follow-up imaging was obtained at Days 30/60/90 after treatment, and pain scores were recorded for comparison with baseline values. Treatment response was classified from Brief Pain Inventory11 worst pain scores and change in analgesic intake using established criteria12.

Data analysis: Thermal changes measured on PRFS were summarised by estimating thermal dose volume (V240EM) (Figure 1), and by calculating the mean maximum temperature (TM) recorded in the target region.

Maximum lesion diameters at baseline were compared with measurements made at Days 30/60/90. NPV was measured on Gd-T1W images, by drawing regions-of-interest on the immediate post-treatment and Day 30/60/90 images. Where NPVs were not measurable, images were scored as: Unchanged, Grade 1 change (ill-defined expansion of NPV) or Grade 2 change (definite focal increase in NPV).


Results

Patients: Nine patients had intra-osseous lesions (Group 1), 12 had extra-osseous lesions (Group 2). There was no age difference between Group 1 and 2 patients (52.6±9.6 vs. 58.1±11.3 years, p=0.25) but the former were predominantly female (6/9) and the latter predominantly male (8/12). Intra-osseous lesions were smaller at baseline than extra-osseous ones (maximum diameter: 38.9±12.8 vs. 55.7±14.9 mm, p=0.01).

Treatments: Fewer sonications were delivered to intra-osseous than extra-osseous lesions (15±5, 29±15, p=0.022). Although treatment volumes were smaller, and treatment times shorter in Group 1 (12.1±13.3 ml, 70.6±28.2 minutes) compared to Group 2 (16.4±12.0 ml, 89.4±42.0 minutes), differences were not significant (p=0.21, p=0.25).

Thermal changes: V240EM was significantly smaller for Group 1 (5.4±9.9 ml, range: 0.29-31.2 ml) compared to Group 2 (13.9±19.1 ml, range: 2.4-62.7 ml, p=0.04), but there was no significant difference in TM between the groups (62.2±5.9 vs. 60.6±4.7oC respectively, p=0.51).

Post-treatment Imaging: Lesion diameter post-treatment was unchanged in both groups (p>0.1). For Group 1, a NPV was recognizable in 8/9 patients immediately post-treatment, and in 7/9 at Day 30 (Figure 2). NPV immediately after treatment (5.5±9.9 ml, range: 0.1-27.3 ml) correlated with V240EM (r=0.87, p=0.01), and was unchanged by Day 30, (5.7±8.8 ml, range: 1.0-25.3 ml, p=0.25). In comparison, all Group 2 patients had heterogeneous Gd-T1W appearances before treatment: unchanged after treatment in n=7, Grade 1 change in n=2, Grade 2 change in n=3. Grade 2 change was maintained in 2 cases at Day 30.

Pain Response: Reductions in pain scores from baseline at Days 30/60/90 were only significant for Group 1 (Figure 3) (p=0.01, p=0.03, p=0.04 respectively). Onset of pain relief occurred earlier for Group 1 than Group 2 (>2-point improvement 1 day after treatment for Group 1, but not until Day 22 for Group 2). 6/9 Group 1 patients (67%) were responders at Day 30, compared to 4/12 (33%) in Group 2. On follow-up imaging, Gd-T1W changes did not differ between responders and non-responders in either Group.

Discussion and Conclusion

Response rates for patients with intra-osseous lesions were considerably better than for those with extra-osseous ones, despite the larger thermal dose volume in the latter. Imaging changes of intra-osseous lesions post-treatment correlated with thermal dose volume. The pattern of imaging changes differed between intra- and extra-osseous lesions, but in neither group did immediate post-treatment or follow-up imaging indicate response. Whilst MR guidance is crucial for the safe planning and delivery of treatments, follow-up scanning after MRgHIFU treatment of painful bone metastases might only be required for assessing disease progression or adverse events.

Acknowledgements

CRUK and EPSRC support to the Cancer Imaging Centre at ICR and RMH in association with MRC and Department of Health C1060/A10334, C1060/A16464 and NHS funding to the NIHR Biomedical Research Centre and the Clinical Research Facility in Imaging. We would also like to acknowledge the support of Philips Healthcare and the Focused Ultrasound Foundation.

References

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2. Brown MR, Farquhar-Smith P, Williams JE, Ter Haar G, deSouza NM. The use of high-intensity focused ultrasound as a novel treatment for painful conditions-a description and narrative review of the literature. Br J Anaesth. 2015;115(4):520-30.

3. Maloney E, Hwang JH. Emerging HIFU applications in cancer therapy. Int J Hyperthermia. 2015;31(3):302-9.

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5. Rieke V, Butts Pauly K. MR thermometry. J Magn Reson Imaging. 2008;27(2):376-90.

6. Jenne JW, Preusser T, Gunther M. High-intensity focused ultrasound: principles, therapy guidance, simulations and applications. Z Med Phys. 2012;22(4):311-22.

7. Jolesz FA. MRI-guided focused ultrasound surgery. Annu Rev Med. 2009;60:417-30.

8. Anzidei M, Napoli A, Sacconi B, Boni F, Noce V, Di Martino M, et al. Magnetic resonance-guided focused ultrasound for the treatment of painful bone metastases: role of apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) MRI in the assessment of clinical outcome. Radiol Med. 2016.

9. Napoli A, Anzidei M, Marincola BC, Brachetti G, Ciolina F, Cartocci G, et al. Primary pain palliation and local tumor control in bone metastases treated with magnetic resonance-guided focused ultrasound. Invest Radiol. 2013;48(6):351-8.

10. Kohler MO, Mougenot C, Quesson B, Enholm J, Le Bail B, Laurent C, et al. Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry. Med Phys. 2009;36(8):3521-35.

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13. Giles SL, Winfield JM, Collins DJ, Rivens I, Civale J, ter Haar GR, et al. Value of diffusion-weighted imaging for monitoring tissue change during magnetic resonance-guided high-intensity focused ultrasound therapy in bone applications: an ex-vivo study. European Radiology Experimental. 2018;2(1).

Figures

Figure 1: V240EM estimates. The white line represents the 240EM at 43oC thermal dose contour in (a) the axial, and (b) the coronal planes, overlaid on T1W imaging acquired for treatment planning. The product of the 3 largest orthogonal dimensions of this contour was used to estimate the thermal dose volume of each sonication. This method of measuring thermal dose volumes has been reported previously13. The total of these volumes was recorded as the total thermal dose volume (V240EM) for each patient.

Figure 2: Example Gd-T1W image appearances 30 days after treatment. A clear focal region of non-enhancement (arrowed) was seen either side of the bony cortex for intra-osseous lesions, shown in (a) a 36 year old male with metastatic lung cancer, and (b) a 45 year old female with metastatic breast cancer. In both cases, a thin rim of enhancing tissue was also seen at the proximal border of the region of non-enhancement.

Figure 3: Pain scores recorded for (a) 9 Group 1 patients and (b) 12 Group 2 patients. In each graphic, the horizontal lines show the mean±SD scores, and a discrete marker shape is used to show the individual score for each patient at each time-point. At Days 30, 60 and 90 after treatment, scores were significantly lower than pre-treatment (Pre Tx) for Group 1, but not for Group 2. The displayed p-values have been corrected for multiple comparisons; p>1* indicates that the uncorrected p-value was already >0.34.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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