CLINICAL-APPLICATION BACKGROUND
Bone is one of the most frequently involved sites for many common cancers such as breast, prostate, lung and kidney cancers and multiple myeloma. Bone metastases are preferentially located in areas of red marrow where blood flow is higher, which accounts for two-thirds of the lesions to be extraspinal ( 1 , 2 ). Current methods for treatment of painful extraspinal metastases combine systemic and local therapies, including surgery, radiotherapy, chemotherapy, and narcotic sedatives. When a localized painful lesion is identified, surgery is rarely a satisfactory therapeutic option because it is often too invasive for a fragile patient. Radiotherapy is a good solution but has some limitations, such as delayed effect and tissue tolerance ( 3 ). Bisphosphonates, hormone therapy, and chemotherapy (especially phosphonic acid) are effective in breast cancer, multiple myeloma, and metastatic carcinoma, but their clinical efficiency is not particularly obvious because of the delayed effect and short survival time ( 4 ). It is estimated that at least 45% of patients with bone metastases suffer from intractable pain due to not receiving adequate treatment ( 5 ). This has prompted the search for new therapies to relieve pain, such as radiofrequency ablation (RFA), cryoablation, microwave ablation (MWA), POP, and magnetic resonance–guided ultrasound (6-8). RFA treatment can significantly reduce the use of opioids, and an ongoing preliminary study shows that MWA is also very promising ( 7 ). However, early research suggests that ablation has obviously delayed effects and cannot strengthen bones; therefore, it is not the best choice for preventing impending pathological fracture lesions. Figure 1 Percutaneous osteoplasty. Figure 1.
As an extension of PVP, POP was first put forth by Zhou et al. ( 9 ) and has proven highly effective in relieving pain from extraspinal metastases, alone or in combination with other techniques. It can reduce the risk of a pathological fracture, achieve pain regression and improve mobility ( 8 , 10 ).
MECHANISM
The principle of pain relief in POP is based on the consolidation of the weakened and pathological cancerous bone and on the combined chemical and thermal cytotoxic effect produced during cement polymerization. Due to strong stress resistance and high hardness, the injection of bone cement into the lesion site can increase bone strength and prevent microfractures. Therefore, POP is more suitable for treatment of weight-bearing bone damage and most impending pathological fractures. Meanwhile, polymerization of bone cement can necrotize peripheral nerve endings and tumor cells, thus alleviating pain. The toxicity of the bone cement monomer may also play a role in POP’s anti-tumor effect and shrinking of tumor volume (11-13).
INDICATIONS
Inclusion criteria are normally as follows: patients with intense and focal pain associated with evidence from plain X-ray films and computed tomography (CT) or magnetic resonance imaging (MRI) of osteolytic bone lesion with or without impending bone fractures; unsatisfactory response to conventional pain therapy; life expectancy of > 3 months; age > 18 years and sound mental condition; and provision of informed consent.
Exclusion criteria are as follows: non-correctable coagulation disorders (platelets 90,000, international normalized ratio 1.50); systemic or local infection; and distance between the lesion and vessels or vital organ < 10 mm. Lost integrity of the cortical bone is not an exclusion parameter.
OSTEOPLASTY TECHNIQUES
The Biochemical index and coagulation function should be detected before POP. The surgery must be carried out under strict aseptic conditions and under local anesthesia, and vital signs should be monitored during the operation. Broad-spectrum antibiotics can be used for patients with insufficient immune function. POP can be divided into 2 equally important components: needle placement and cement injection. Well-chosen imaging guidance is of utmost importance for precise lesion targeting, uncomplicated needle placement, accurate visualization of cement distribution, and early detection of leaks. Biplane fluoroscopy or dual guidance with a mobile C-arm placed in front of the computed-tomography (CT) gantry is suggested, with the latter being required in cases of difficult-to-access extraspinal lesions.
Extraspinal-osteoplasty patients may be positioned prone, supine or lateral decubitus, depending on the exact anatomic location of the lesion. The adequate access point, puncture angle and distance from skin to lesion can be determined beforehand via CT and/or magnetic resonance imaging (MRI). In order to avoid critical nerves and blood vessels, the shortest puncture distance is recommended. In cases of acetabuloplasty, the anterior lateral approach can avoid injury to the femoral nerve, while the posterior approach can avoid injury to the sciatic nerve. A small incision is made at the puncture site after anesthesia using 2% lidocaine. A dedicated beveled vertebroplasty needle, 18–10 gauges in diameter, is advanced into the bone lesion. A bevel tip is preferable, as this feature allows easy repositioning and precise steering of the needle. In most cases, the simple pressure of the operator’s hands on the needle is sufficient to correctly place it into the lesion; it can be assisted by surgical hammer when a hard bone is encountered.
Polymethyl methacrylate (PMMA) can be successfully used for bone metastases, whereas a biological osteoconductive calcium phosphate bone cement is preferable for benign lesions. A sterile 2, 5 or 10 mL Luer Lock polypropylene syringe, or a dedicated pressure injector, can be used to inject the cement into the bone lesion. The cement can be slowly injected under real-time surveillance; the injection must be stopped immediately if any leakage occurs. Post-operative CT scan is performed to observe the distribution of bone cement and leakage. More than 1 lesion can be treated in the same session, depending on the doctor’s experience and the patient’s physical condition. For hypervascular bone metastases, it is recommended that bony angiography be used to predict the flow and distribution of bone cement and help prevent the occurrence of leakage.
There have been some recent improvements in bone cement injection techniques. Kawai describes POP using a cement-filled catheter for a pathological fracture of the humerus, after which the patient experienced immediate pain relief and improved limb mobility ( 14 ). Sun reported that for patients with multiple osteolytic metastases in the same humerus, the POP technique of a cement-filled catheter with multiple side holes is feasible and may be advantageous over regular POP ( 10 , 15 ).
As for metastases located in the long bones, it has been argued that POP alone should be contraindicated because osteoplasty alone provides inadequate consolidation during weight bearing ( 16 , 17 ). To improve mechanical consolidation of osteoplasty, several authors have proposed combining osteoplasty with the insertion of different types of devices in the femur, such as pins, nails, or cannulated screws (18-25). Tian et al. reported that a modified trocar needle was implanted into the proximal femur through a bone puncture needle sheath parallel to the vertical and horizontal axis of the femoral neck and the vertical axis of the thighbone respectively before PMMA injection ( 18 ). In 2012, Deschamps et al. reported 100% technical success for osteoplasty combined with the insertion of 3 cannulated screws along the inferior cortical femoral neck and against the upper cortical femoral neck. PMMA was then injected around the screws ( 25 ).
CLINICAL OUTCOMES
POP has proven to be highly effective for relieving pain in case of extraspinal metastases, alone or in combination with other techniques such as ablation ( 8 , 26 - 33 ).
Iannessi et al. demonstrated that 17 patients with painful extraspinal bone lesions who were treated with POP experienced a significant, rapid, and long-lasting decrease in their pain (4.1 points; P < 0.1; 7.75 months of follow-up on average) ( 29 ). Sun et al. performed POP for 51 consecutive patients with painful bone metastases outside the spine; all patients experienced a satisfying resolution of painful symptoms at 3 months follow-up ( 27 ). In Masala et al.’s study, 39 patients with painful extraspinal bone lesions from multiple myeloma underwent POP, which provided long-lasting pain relief with frequent tumor control and a significant reduction in the use of analgesic drugs ( 30 ). Anselmetti et al. reported that POP with PMMA achieved significant pain relief in 50 patients with painful extravertebral lytic bone metastases that were nonresponsive to conventional therapy ( 8 ). Cazzato et al. systematically reviewed the current evidence for POP of long bones and reported that it is safe, offering good pain relief and recovery of impaired limb function ( 31 ). Tian et al. combined POP with RFA for painful extraspinal bone metastases in 38 patients and achieved immediate pain relief and function improvement ( 32 ). Pusceddu et al. applied MWA and osteoplasty in patients with painful bone metastases of the femur and acetabulum and achieved promising results, which suggests that the combination is safe and effective in treating painful bone metastases which are at a high risk of fracture ( 33 ).
COMPLICATIONS
Cement leakage, pathological fracture, infection, allergy, and bleeding are the common events with POP ( 16 , 34 ). There are more likely to be complications when there is cortical destruction, soft-tissue invasion or hypervascular bone metastasis.
Bone cement leakage is the most common complication of POP, including leakage into blood vessels, joints, and soft tissues. The risk of leakage can be problematic when intra-articular, in contact with a nerve trunk or on a support zone. In any case of osteolysis adjacent to the joint, injection must be administered with extreme care to avoid the risk of rapid chondrolysis in the event of intra-articular leakage ( 35 ). In Weill et al.’s study, the incidence of leakage into the surrounding soft tissue was 28% and that into the hip joint was 11%, but only 1 case showed symptoms ( 26 ). Kelekis et al. observed that the incidence of leakage into the hip joint was 28% and reported that a leakage in the obturator foramen resulted in continued pain, which was treated by RFA of the pudendal nerve ( 28 ). Intraosseous venography before injection of bone cement has been advocated as a way to identify sites of potential venous leakage during the procedure. Note that the anatomical configuration of extraspinal lesions needs a 3-dimensional imaging. Therefore, we believe that a combination of CT and fluoroscopic guidance makes the procedure safer.
The risk of bleeding is greater during needle insertion and in hypervascular metastases (thyroid, kidney and melanoma) ( 34 ). In these cases, it is recommended that the surgeon maintain compression for 5 minutes or implement trans-catheter arterial embolization (TAE) to effectively reduce bleeding ( 36 , 37 ). The overall rate of infectious complications reported is < 1%. Fat embolism is also a matter of concern. Bone cement injection can cause bone marrow fat to be squeezed into the blood, leading to fatal pulmonary embolism. Bone cement injection can cause bone marrow fat to be squeezed into the blood, leading to fatal pulmonary embolism or to hypotension and arrhythmias. The entry of bone cement into the circulatory system may also result from secondary fat embolism after bone marrow replacement ( 11 ). Patients may have transient fever and local pain after POP, and the degree of pain is positively correlated with the amount of bone cement injected. However, total pain relief occurs after 24 hours. Few patients are allergic to bone cement, and fatal allergies are extremely rare.
The biomechanical properties of cement are perfectly adapted to withstand compression fractures that occur in the flat bones and weight-bearing joints such as the acetabulum or the femoral condyle. POP alone cannot provide adequate consolidation during weight bearing for metastases that are located in the long bones and that often cause pathological fractures. Therefore, the rate of fractures despite osteoplasty is very high in the literature. In a retrospective analysis of 21 consecutive patients, fractures occurred in one-third of patients and were significantly more frequent if associated with a > 30 mm cortical rupture ( 8 , 16 , 38 ).
OUTLOOK
At present, there are 2 main research hotspots in POP: the development of new bone cement and the combination therapy mode with POP.
PMMA is the most widely used cement, with several decades of application in orthopedic surgery. Older-generation PMMA cements had to be mixed with barium sulfate, tungsten, or tantalum powder because of their inherently low radiopacity ( 39 ). The high temperature during PMMA polymerization results in thermocoagulation of tumor cells locally, but may also damage healthy adjacent tissues, such as neural roots and the spinal cord itself, in cases of severe leakage. Moreover, PMMA is nonreactive to new bone formation. Newer filler materials for POP are composite cements and calcium phosphate cements (CPCs) (40-42). CPCs are the most expensive bone cements on the market but have the best compatibility and osteogenic induction ( 43 ). Some experts add a variety of osteogenesis-inducing growth factors and antitumor drugs into the cement, making it a carrier of antitumor treatment (44-46). However, these studies remain in the experimental stage, a long distance from clinical application. Future development will focus on improving the cure rate with good bone conduction, bone inducement and tumor filling materials; and restoring the anatomical structure and physiological characteristics of bone to a greater extent.
The combination of POP and multiple other methods in the treatment of benign and malignant extraspinal tumors is another hotspot in the current research; it has had a better clinical effect, with a pain relief rate of 95–100% ( 5 ). Tian et al. evaluated a combination of RFA and POP in 38 patients with 54 painful extraspinal bone metastases and achieved inspiring results ( 32 ). RFA before cement injection has the advantage of decreasing tumor cell spread, either mechanically through the formation of an ablation shell barrier or via embolization of necrotic tumor cells. In addition, RFA may result in thrombosis of the venous plexus, which should decrease the risk of cement extravasation. Pusceddu et al. demonstrated the effectiveness of CT-guided percutaneous MWA and POP in patients with painful bone metastases at high risk of fracture. In their study, mean reduction of VAS score and improvement in surviving patients’ walking ability were 90% and 100%, respectively ( 33 ). Masala et al. ( 47 ). reported mean VAS score reductions of 79%, 6 months post-treatment in patients treated with radiofrequency and osteoplasty and 71% in those treated with cryoablation and POP.
Various factors should be considered in the management of extraspinal metastases: tumor histological characteristics, the patient’s physical condition, disease progress, the degree of bone destruction, and the purpose of treatment (radical or palliative). For metastases resistant to conventional therapy (radiation, chemotherapy or a combination), POP provides a new and promising method that can effectively relieve pain, strengthen bones, and inactivate some tumors so as to improve the patients’ quality of life.
Conflict of interest:
The authors declare that they have no conflict of interest.
Funding:
This work was sponsored by grant National Natural Scientific Fund of China [grant number 81701798], Natural Fund from Shanghai Science And Technology Commission [grant number 18ZR1429400], Shanghai Sailing Program [grant number 17YF1414600], and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital East Campus [grant number 2016014], China.
Ethical approval: Not applicable.
Informed consent: Written informed consent was obtained from each patient or his/her immediate family.
REFERENCES
1 Callstrom MR Charboneau JW Image-guided palliation of painful metastases using percutaneous ablation Tech Vasc Interv Radiol 10 2007 120 131 18070690 10.1053/j.tvir.2007.09.003
2 Yin JJ Pollock CB Kelly K Mechanisms of cancer metastasis to the bone Cell Res 15 2005 57 62 15686629 10.1038/sj.cr.7290266
3 Chow E Harris K Fan G Palliative radiotherapy trials for bone metastases: A systematic review J Clin Oncol 25 2007 1423 1436 17416863 10.1200/JCO.2006.09.5281
4 Ross JR Saunders Y Edmonds PM Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer BMJ 327 2003 469 12946966 10.1136/bmj.327.7413.469 PMC188427
5 Meuser T Pietruck C Radbruch L Symptoms during cancer pain treatment following WHO-guidelines: A longitudinal follow-up study of symptom prevalence, severity and etiology Pain 93 2001 247 257 11514084 10.1016/S0304-3959(01)00324-4
6 Liberman B Gianfelice D Inbar Y Pain palliation in patients with bone metastases using mr-guided focused ultrasound surgery: A multicenter study Ann Surg Oncol 16 2009 140 146 19002530 10.1245/s10434-008-0011-2
7 Goetz MP Callstrom MR Charboneau JW Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: A multicenter study J Clin Oncol 22 2004 300 306 14722039 10.1200/JCO.2004.03.097
8 Anselmetti GC Manca A Ortega C Treatment of extraspinal painful bone metastases with percutaneous cementoplasty: A prospective study of 50 patients Cardiovasc Intervent Radiol 31 2008 1165 1173 18704572 10.1007/s00270-008-9396-3
9 Zhou B Wu CG Cheng YD Effect analysis of percutaneous osteoplasty for the treatment of malignant osteolytic lesions outside the vertebrae J Intervent Radiol 18 2009 29 33
10 Liu XW Jin P Liu K Comparison of percutaneous long bone cementoplasty with or without embedding a cement-filled catheter for painful long bone metastases with impending fracture Eur Radiol 27 2017 120 127 27097791 10.1007/s00330-016-4347-x
11 Tran Thang NN Abdo G Martin JB Percutaneous cementoplasty in multiple myeloma: A valuable adjunct for pain control and ambulation maintenance Support Care Cancer 16 2008 891 896 17960432 10.1007/s00520-007-0344-6
12 Stephenson MB Glaenzer B Malamis A Percutaneous minimally invasive techniques in the treatment of spinal metastases Curr Treat Options Oncol 17 2016 56 27627999 10.1007/s11864-016-0433-1
13 Deramond H Wright NT Belkoff SM Temperature elevation caused by bone cement polymerization during vertebroplasty Bone 25 1999 17S 21S 10458268 10.1016/s8756-3282(99)00127-1
14 Kawai N Sato M Iwamoto T Percutaneous osteoplasty with use of a cement-filled catheter for a pathologic fracture of the humerus J Vasc Interv Radiol 18 2007 805 809 17538148 10.1016/j.jvir.2007.03.002
15 Sun G Jin P Li M Percutaneous cementoplasty for painful osteolytic humeral metastases: initial experience with an innovative technique Skeletal Radiol 40 2011 1345 1348 21491154 10.1007/s00256-011-1170-y
16 Dayer R Peter R Percutaneous cementoplasty complicating the treatment of a pathologic subtrochanteric fracture: A case report Injury 39 2008 801 804 18539281 10.1016/j.injury.2008.01.009
17 Chang SW Murphy KPJ Percutaneous CT-guided cementoplasty for stabilization of a femoral neck lesion J Vasc Interv Radiol 16 2005 889 890 15947056 10.1016/s1051-0443(07)60698-8
18 Tian QH He CJ Wu CG Comparison of percutaneous cementoplasty with and without interventional internal fixation for impending malignant pathological fracture of the proximal femur Cardiovasc Intervent Radiol 39 2016 81 89 26044668 10.1007/s00270-015-1133-0
19 Kim JH Kang HG Kim JR Minimally invasive surgery of humeral metastasis using flexible nails and cement in high-risk patients with advanced cancer Surg Oncol 20 2011 e32 e37 20870403 10.1016/j.suronc.2010.09.001
20 Kim YI Kang HG Kim TS Palliative percutaneous stabilization of lower extremity for bone metastasis using flexible nails and bone cement Surg Oncol 23 2014 192 198 25306259 10.1016/j.suronc.2014.03.006
21 Kelekis A Filippiadis D Anselmetti G Percutaneous augmented peripheral osteoplasty in long bones of oncologic patients for pain reduction and prevention of impeding pathologic fracture: The rebar concept Cardiovasc Intervent Radiol 39 2016 90 96 26048014 10.1007/s00270-015-1138-8
22 Cornelis FH Tselikas L Carteret T Percutaneous internal fixation with Y-STRUT® device to prevent both osteoporotic and pathological hip fractures: a prospective pilot study J Orthop Surg Res 12 2017 27 28183325 10.1186/s13018-017-0514-2 PMC5301413
23 Deschamps F de Baere T Hakime A Percutaneous osteosynthesis in the pelvis in cancer patients Eur Radiol 26 2016 1631 1639 26318372 10.1007/s00330-015-3971-1
24 Deschamps F Farouil G Hakime A Percutaneous stabilization of impending pathological fracture of the proximal femur Cardiovasc Intervent Radiol 35 2012 1428 1432 22203060 10.1007/s00270-011-0330-8
25 Cornelis FH Tselikas L Carteret T A novel implant for the prophylactic treatment of impending pathological fractures of the proximal femur: Results from a prospective, first-in-man study Cardiovasc Intervent Radiol 40 2017 1070 1076 28233056 10.1007/s00270-017-1613-5
26 Weill A Kobaiter H Chiras J Acetabulum malignancies: Technique and impact on pain of percutaneous injection of acrylic surgical cement Eur Radiol 8 1998 123 129 9442143 10.1007/s003300050351
27 Sun G Jin P Liu Xw Cementoplasty for managing painful bone metastases outside the spine Eur Radiol 24 2014 731 737 24272227 10.1007/s00330-013-3071-z
28 Kelekis A Lovblad KO Mehdizade A Pelvic osteoplasty in osteolytic metastases: Technical approach under fluoroscopic guidance and early clinical results J Vasc Interv Radiol 16 2005 81 88 15640414 10.1097/01.RVI.0000141717.84515.92
29 Iannessi A Amoretti N Marcy PY Percutaneous cementoplasty for the treatment of extraspinal painful bone lesion, a prospective study Diagn Interv Imaging 93 2012 859 870 23026130 10.1016/j.diii.2012.08.001
30 Masala S Volpi T Fucci FPM Percutaneus osteoplasty in the treatment of extraspinal painful multiple myeloma lesions Support Care Cancer 19 2011 957 962 20505957 10.1007/s00520-010-0910-1
31 Cazzato RL Palussière J Buy X Percutaneous long bone cementoplasty for palliation of malignant lesions of the limbs: A systematic review Cardiovasc Intervent Radiol 38 2015 1563 1572 25799950 10.1007/s00270-015-1082-7
32 Tian QH Wu CG Gu YF Combination radiofrequency ablation and percutaneous osteoplasty for palliative treatment of painful extraspinal bone metastasis: A single-center experience J Vasc Interv Radiol 25 2014 1094 1100 24801500 10.1016/j.jvir.2014.03.018
33 Pusceddu C Sotgia B Fele RM Combined microwave ablation and cementoplasty in patients with painful bone metastases at high risk of fracture Cardiovasc Intervent Radiol 39 2016 74 80 26071108 10.1007/s00270-015-1151-y
34 Shinoto M Hasuo K Aibe H Percutaneous osteoplasty for hypervascular bone metastasis Radiat Med 26 2008 603 608 19132491 10.1007/s11604-008-0277-0
35 Leclair A Gangi A Lacaze F Rapid chondrolysis after an intra-articular leak of bone cement in treatment of a benign acetabular subchondral cyst: an unusual complication of percutaneous injection of acrylic cement Skeletal Radiol 29 2000 275 278 10883447 10.1007/s002560050607
36 Gangi A Sabharwal T Irani FG Quality assurance guidelines for percutaneous vertebroplasty Cardiovasc Intervent Radiol 29 2006 173 178 16362467 10.1007/s00270-005-0146-5
37 Manke C Bretschneider T Lenhart M Spinal metastases from renal cell carcinoma: Effect of preoperative particle embolization on intraoperative blood loss Am J Neuroradiol 22 2001 997 1003 11337348 PMC8174929
38 Basile A Giuliano G Scuderi V Cementoplasty in the management of painful extraspinal bone metastases: our experience Radiol Med 113 2008 1018 1028 18779931 10.1007/s11547-008-0314-1
39 Gangi A Guth S Imbert JP Percutaneous vertebroplasty: Indications, technique, and results Radiographics 23 2003 e10 12889460 10.1148/rg.e10
40 Gao CX Liu HL Luo ZP Modification of calcium phosphate cement with poly (γ-glutamic acid) and its strontium salt for kyphoplasty application Mater Sci Eng, C 80 2017 352 361 10.1016/j.msec.2017.05.070 28866174
41 Klein R Tetzlaff R Weiss C Osteointegration and resorption of intravertebral and extravertebral calcium phosphate cement Clin Spine Surg 30 2017 e291 e296 28323714 10.1097/BSD.0b013e3182aab2df
42 Lieberman IH Togawa D Kayanja MM Vertebroplasty and kyphoplasty: Filler materials Spine J 5 2005 S305 S316 10.1016/j.spinee.2005.02.020 16291128
43 Eliaz N Metoki N Calcium phosphate bioceramics: A review of their history, structure, properties, coating technologies and biomedical applications Materials 10 2017 334 10.3390/ma10040334 PMC5506916 28772697
44 Qi YY Niu L Zhao TF Combining mesenchymal stem cell sheets with platelet-rich plasma gel/calcium phosphate particles: a novel strategy to promote bone regeneration Stem Cell Res Ther 6 2015 256 26689714 10.1186/s13287-015-0256-1 PMC4687276
45 Sprio S Dapporto M Montesi M Novel osteointegrative sr-substituted apatitic cements enriched with alginate Materials 9 2016 763 10.3390/ma9090763 PMC5457115 28773884
46 Luo GM Huang YL Gu FF RhBMP2-loaded calcium phosphate cements combined with allogenic bone marrow mesenchymal stem cells for bone formation Biomed Pharmacother 92 2017 536 543 28577492 10.1016/j.biopha.2017.05.083
47 Carrafiello G Laganà D Mangini M Microwave tumors ablation: Principles, clinical applications and review of preliminary experiences Int J Surg 6 2008 S65 S69 19186116 10.1016/j.ijsu.2008.12.028