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ScienceDirect EJSO 41 (2015) 967e974

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Interventional Radiologist’s perspective on the management of bone metastatic disease R.L. Cazzato a,*, X. Buy b, R.F. Grasso a, G. Luppi a, E. Faiella a, C.C. Quattrocchi a, F. Pantano c, B. Beomonte Zobel a, G. Tonini c, D. Santini c, J. Palussiere b a

Department of Radiology, Universita “Campus Bio-Medico di Roma”, Via Alvaro del Portillo 200, 00128, Rome, Italy b Department of Radiology, Institut Bergonie, 229 Cours de l’Argonne, 33000, Bordeaux, France c Department of Medical Oncology, Universita “Campus Bio-Medico di Roma”, Via Alvaro del Portillo 200, 00128, Rome, Italy Accepted 14 May 2015 Available online 3 June 2015

Abstract Bone metastases can be treated by interventional radiologists with a minimally invasive approach. Such treatments are performed percutaneously under radiological imaging guidance. Different interventional techniques can be applied with curative or palliative intent depending on lesions and patients’ status. In the whole, available interventional techniques are distinguished into “ablative” and “consolidative”. Ablative techniques achieve bone tumor necrosis by dramatically increasing or decreasing intra-tumoral temperature. This option can be performed in order to alleviate pain or to eradicate the lesion. On the other hand, consolidative techniques aim at obtaining bone defect reinforcement mainly to alleviate pain and prevent pathological fractures. We herein present evidence supporting the application of each different interventional technique, as well as common strategies followed by interventional radiologists while approaching bone metastases. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Interventional radiology; Bone; Metastasis; Ablation; Cementoplasty

Introduction Different image-guided techniques can be used for curative or palliative treatment of bone metastases. Commonly applied techniques are distinguished into “ablative” or “consolidative”. Ablative techniques are applied to achieve partial or complete necrosis of the * Corresponding author. Tel.: þ39 380 7377000. E-mail addresses: [email protected] (R.L. Cazzato), x.buy@ bordeaux.unicancer.fr (X. Buy), [email protected] (R.F. Grasso), [email protected] (G. Luppi), [email protected] (E. Faiella), [email protected] (C.C. Quattrocchi), [email protected] (F. Pantano), [email protected] (B. Beomonte Zobel), g.tonini@ unicampus.it (G. Tonini), [email protected] (D. Santini), [email protected] (J. Palussiere). http://dx.doi.org/10.1016/j.ejso.2015.05.010 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.

neoplastic tissue by a dramatic increase (50  C) or decrease (around 40  C) of intra-tumoral temperature.1 Consolidative treatments aim at obtaining bone defect reinforcement through percutaneous injection of polymethylmethacrylate (PMMA) cement (i.e. cementoplasty or osteoplasty). Surgical or non-surgical bone reinforcement (e.g. endomedullary nailing) may be combined with percutaneous cementoplasty.2 Most evidence on interventional radiology (IR) management of secondary bone malignancies is restricted to osteolytic bone disease, and experience with sclerotic metastases is limited to a few sporadic cases.3 The aim of the present paper is to present IR strategies and techniques applied to treat osteolytic bone metastases. We will additionally cover the evidence supporting its application which is mainly

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derived from single center experiences given the lack of randomized controlled trials (RCTs). The quality of the presented evidence is reported according to the Scottish Intercollagiate Guidelines Network (SIGN ).4 Evidence and strategies for interventional radiology (IR) management of bone metastases According to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Quality Improvement guidelines for bone tumor management,5 from an strategic standpoint it should be clear whether: 1) the goal of treatment is “curative” or “palliative”; 2) the target lesion is at risk of fracture.

Curative treatment Indications The goal of curative treatment is to completely and definitively destroy the tumoral tissue. This therapeutic option should be reserved to selected patients presenting limited bone disease (2 weeks before ablation and restarted >2 weeks after ablation. Target intra-tumoral temperature >60  C was considered as an indicator of adequate ablation. Mean tumor size was 5.2 cm. Lesions were located in the pelvis, chest wall, spine, and extremities. Three grade 3 toxicities (according to the NCI CTC-AE v4.0 classification) were reported and were consistent with refractory pain and neural damage. “Pain relief”, “patients’ mood” and “pain intensity” were analyzed at 1- and 3-month follow-up based on a 0e100 point-scale. Pain severity was evaluated at the same intervals on a dedicated 1e8 scale (1 ¼ no pain; 8 ¼ excruciating pain). The average increase in pain relief from pre-to post-ablation was 26.3 (p < 0.0001) and 16.4 (p ¼ 0.02) at 1- and 3-month follow-up, respectively. The average increase in patients’ mood from pre-to postablation was 19.9 (p < 0.0001) and 14.9 (p ¼ 0.005) at 1- and 3-months follow-up, respectively. The average decrease in pain intensity from pre-to post-ablation was 26.9 (p < 0.0001) and 14.2 (p ¼ 0.02) at 1- and 3-months follow-up, respectively. In the end, the odds of experiencing lower pain at 1 month were 14.0 (p < 0.0001) times higher than at pre-ablation and 8.0 (p < 0.001) at 3 months. None of the outcomes correlated

Figure 2. CT scan shows an aggressive sternal metastatic disease from breast cancer in a young lady (A): the most aggressive and destructive part of the lesion is seen (arrow). The lesion was painful (8 points on 0e10 VAS) and resistant to analgesic medications including morphine. Due to the particular anatomical conformation of the sternum, two oblique sagittal applications of the RFA probe were done in order to cover the most aggressive part of the tumor (arrows B, C).

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with the volume of ablation. Previous radiotherapy to the site of the specific RFA treatment did not correlate with a reduction in pain intensity, improvement in mood, and increase in pain relief. Callstrom et al. carried out a single-arm observational multicenter trial9 proving that percutaneous CA is a safe therapeutic option to achieve pain palliation in patients with bone metastases. They treated 61 patients with 1 or 2 painful (4 on a 0e10 point scale over 24 h) bone metastases. Chemotherapy or radiation therapy were stopped >3 weeks prior to the enrollment in the study. Patients with tumors within 0.5 cm of the spinal cord or brain, and patients with impending pathologic fractures were not eligible for the study. Response to ablation was mainly evaluated with the Brief Pain Inventory-short form. Evaluation of analgesic drug consumption was also recorded. On a whole, 69 tumors (mean size 4.8 cm) were treated. The mean score for worst pain in a 24-h period decreased from 7.1/10 before ablation to 5.1/10, 4.0/10, 3.6/10, and 1.4/10 at 1-, 4-, 8-, and 24-week follow-up, respectively. Eighty-three percent of the patients reporting opioid use before CA reduced their intake during follow-up. One major complication (grade 3 according to the NCI CTC-AE V4) consistent with an infection of the treated area was noted. Early experience with palliation of bone metastases achieved with HIFU was obtained by Gianfelice et al.10 They treated 11 patients affected by localized painful bone metastases with MR-guided HIFU, under conscious sedation. Most of the treated lesions were osteolytic (n ¼ 8); mixed (n ¼ 1) and osteoblastic (n ¼ 2) lesions were also treated. Lesions located into weight-bearing bones or spinal lesions were not treated to comply with safety and effectiveness requirements. Average VAS score before treatment was 6.0 (range 4e9). It decreased to a mean score of 1.3 and 0.5 at 1- and 3-months follow-up, respectively. All patients diminished their intake of analgesic drugs; 7 patients no longer needed any pain medication at 3-months follow-up and the remaining 4 patients decreased the dose of analgesic by at least 50%. No particular complications were noted during the entire follow-up (3 months). The majority of patients affected by osteolytic metastases showed a certain extent of necrosis in the enhancing medullary component of the lesion at 1- and

3-months follow-up obtained by means of contrastenhanced MR imaging. Interestingly, at 3-months CT follow-up, 56% of the osteolytic lesions showed an increased bone density, suggesting a potential consolidative role of HIFU. However, this hypothesis needs to be confirmed. A further and larger study conducted in 31 patients supported the use of HIFU for the treatment of bone metastases.11 Twenty-five patients completed the 3-month follow-up with a mean VAS score of 1.8 (vs 5.9 before treatment). Reduction of opioid intake was reported in 67% of the patients. No adverse events were noted in this study population. Although promising, palliative results obtained with MWA are still limited.12,13 Therefore, larger prospective studies are needed to confirm the safety and effective profile of MWA in the palliative setting. Evidences obtained from single-arm prospective multicenter studies support ablatative techniques (RFA, CA or HIFU) applied to alleviate pain caused by bone metastases (SIGN2þ). Further prospective studies are needed to investigate the performance of MWA. Nowadays, it seems appropriate to think about prospective randomized trials comparing the palliative performance of interventional treatments to that of the gold-standard (i.e. external beam radiation therapy). Percutaneous cementoplasty and risk of fracture management Indications All bone metastases should be evaluated in order to find out impending pathological fractures especially in weight bearing bones. For lesions of the limbs (i.e. long bones), a practical system applied to quantify the risk of fracture is the Mirels’ score14 (Table 1). Patients reporting a Mirels’ score 9 should be considered at high risk of fracture, and therefore, should be offered dedicated consolidative therapies. Consolidative options differ according to the bone site involved by the metastatic disease. In particular, it is crucial to establish whether compressive or torsional forces are predominant in the involved bone. In bones where compressive forces are more likely to act (i.e. spine, acetabulum, femoral condyles, tibial ends, talus and calcaneus), percutaneous injection of PMMA cement

Table 1 Mirels’ score. Adapted from Mirels’ et al.14

Site Pain Lesion radiological aspect Cortical bone involvementa

Score 1

Score 2

Score 3

Upper limb Mild ( 10 to receive percutaneous kyphoplasty or conservative non-surgical management.19 Kyphoplasty was performed in 65 patients and conservative treatment in 52 patients. Clinical followup was obtained at 1, 3, 6, and 12months. The primary end-point was RDQ assessment at 1-month. The secondary outcome included the analysis of several different tests along with the evaluation of the VAS and RDQ scores at 1-, 3-, 6-, and 12-months. Due to the high primarydisease related mortality, only 74 patients completed the 12-month follow-up. The primary outcome (RDQ score at 1-month), was improved by 8.4 points in the kyphoplasty group vs 0.1 points in the group of patients receiving conservative treatment (p < 0.0001). Such RDQ improvement for the kyphoplasty group was still evident at 6 months but not at 12 months. The VAS score was significantly better for the kyphoplasty group at 1-month but not at later follow-ups. In the whole, all tested outcomes favored kyphoplasty over conservative treatment at all-time points, but statistical significance vanished as time passed by probably due to the relative few patients remaining in the conservative treatment group. Two major procedure-related

Figure 3. CT scan shows a wide, painful and lytic (7 points on 0e10 VAS) lesion in the right acetabulum (arrows, A, B) carrying a high risk of secondary fracture. The patient underwent percutaneous cementoplasty (C) to guarantee bone consolidation, prevent pathologic fractures and control pain.

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Figure 4. CT scan shows a lytic metastasis of the rib (arrow) from kidney cancer in a 80-years old lady (A). The patient underwent percutaneous cementoplasty (arrow, B) in order to control pain. The same patient received also a vertebroplasty of a dorsal vertebra due to the same neoplastic disease (arrow head, B).

complications were reported in the kyphoplasty group (one intra-operative myocardial infarction and one new fracture in the adjacent-level of treatment 1 day following the procedure). Several case series prospectively and retrospectively analysed the performance of percutaneous cementoplasty applied in “extra-spinal” bone lesions.20e27 All papers proved percutaneous cementoplasty to be safe and effective in providing rapid pain relief in all bone districts other than spine. Mechanisms by which pain relief is achieved are thought to be the same as for spinal lesions. However, the consolidation achieved with percutaneous cementoplasty in districts other than spine is considered optimal if compressive forces are involved (i.e. acetabulum, femoral condyles, tibial ends, talus and calcaneus) and sub-optimal in longbones, where torsional forces are more likely to act. A large retrospective study26 collecting the 10-year experience of an oncologic tertiary centre in 51 consecutive patients affected by painful long-bone metastatic lesions, reported a secondary PMMA stress fracture rate of 9.1% (six fractures out of 66 treated lesions) within a mean delay of 3.2 months (range 0.5e11). All the lesions reporting a fracture had high pre-operative Mirels’ score (mean 9). Four of the six fractures needed surgical interventions consistent with external fixation, which was considered less demanding from a technical point of view considering that previous PMMA injection into osteolytic bone lesions helped the orthopedic surgeon in screws fixation. Although limited, some studies have shown that combined singlesession percutaneous stabilization and percutaneous cementoplasty of long bone lesions can significantly cut down the risk of secondary fractures within a mean follow-up of 9.9e14.8 months.2,23,28 Percutaneous cementoplasty performed in spinal and extra-spinal lesions may be complicated by PMMA cement leakage. This inconvenience is limited if PMMA injection is performed under continuous fluoroscopic guidance allowing the immediate stop of the injection in cases of sudden leakage. Moreover, if the cement is injected during the “tooth-paste” phase of its polymerization rather than in the

early liquid phase, the risk of leakage is reduced. Leakage is predicted by cortical bone disruption and extra-bone extension of disease.26 Corcos et al. retrospectively analysed factors predicting leakage during vertebroplasty procedures performed to treat spinal metastases.29 They found that history of prior treatment was an independent protective factor against leakage, which they distinguished into vascular (occurring in the venous peri-vertebral plexus and being responsible of PMMA pulmonary embolism) and cortical (occurring outside the cortical bone). In particular, in their experience, vascular leakage was decreased when lung was the primary tumor, in cases of osteolytic vertebrae or when there was a vertebral collapse. On the other hand, cortical leakage correlated with the operator’s experience and vertebral collapse. In the end, leakage occurring into inter-vertebral discs was not of clinical relevance and was predicted only by endplate cortical destruction. Although predictable, it should be noted that PMMA leakage is usually asymptomatic without any relevant consequence.18,20,26 However, some particular situations need careful attention to avoid leakage-related complications such as spinal lesions showing posterior wall disruption and bone lesions abutting the articular surfaces in long bones. For patients presenting with painful spinal malignancies extending into the epidural space, the palliative strategy consists of: 1) tumor debulking achieved by means of plasma-mediated RFA and then 2) cementoplasty. The rationale for such strategy is to create a definite and precise cavity within the neoplastic mass not crossing the posterior boundary,30 which is then filled with PMMA in order to reduce the risk of fracture. Although valuable, experience with this technique is still limited.31 Robust evidence obtained from large, prospective multicenter series and from prospective randomized trials support the palliative application of percutaneous vertebroplasty in assuring rapid pain relief and long-lasting bone consolidation in patients with malignant spinal disease (SIGN 1þþ). Less robust evidence obtained from prospective and retrospective case-series proved that percutaneous

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cementoplasty may be applied to obtain rapid pain relief in “extra-spinal”bone metastatic lesions (SIGN 2þþ). General requirements needing careful analysis before IR procedures Despite the goal of treatment, metastatic bone disease does not require biopsy before interventional sessions, unless: - the primary cancer is unknown; - more than two primary tumors are suspected; - specimen analysis is crucial to adjust systemic therapy. Before undergoing IR procedures, each patient should have normal recent laboratory tests including blood cells count, coagulation tests (prothrombin time, activated partial prothrombin time and international normalized ratio) and normal kidney function. In case of known or suspected local or systemic infection, any type of IR procedure should be postponed until the infection is over. In fact, any kind of IR bone procedure needs a strict sterile environment and prophylactic intra-operative antibiotic coverage (1 g cefazolin i.v.).25 Careful anesthesiological evaluation is advised before IR procedures. In fact, bone procedures are usually painful25 thus requiring some kind of intra-operative anesthesiological assistance ranging from mild conscious sedation to general anesthesia. Other frequently applied anesthesiological strategies are nerve root block or spinal anesthesia. Any kind of known allergy especially to anesthetic or antibiotic drugs should be known in advance. Following a careful review of the radiological exams available, the interventional radiologist performing the procedure should carefully report any anatomical structure (spinal cord, nerve roots, blood vessels or viscera) being close (

Interventional Radiologist's perspective on the management of bone metastatic disease.

Bone metastases can be treated by interventional radiologists with a minimally invasive approach. Such treatments are performed percutaneously under r...
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