Multimodal locoregional procedures for cancer pain management: a literature review

Abstract

Pain is the most common and fearsome symptom in cancer patients, particularly in the advanced stage of disease. In cancer pain management, the first option is represented by analgesic drugs, whereas surgery is rarely used. Prior to considering surgical intervention, less invasive locoregional procedures are available from the wide pain management arsenal. In this review article, comprehensive information about the most commonly used locoregional options available for treating cancer pain focusing on interventional radiology (neurolysis, augmentation techniques, and embolization) and interventional radiotherapy were provided, also highlighting the potential ways to increase the effectiveness of treatments.

Introduction

Pain is the most common symptom experienced by cancer patients, particularly in the advanced stage of the disease¹ where 80% of patients have moderate to severe pain,² with an estimated prevalence of pain of more than 50% in all cancer type and all disease stages.³ While untreated pain leads to physical⁴ and emotional sufferings,⁵ decreased quality of life,⁶ unnecessary hospital admissions and Emergency Departments visits,⁷ and increased costs^8,9 ; and despite numerous developed guidelines from worldwide organizations^10–12 ; cancer pain remains poorly managed with 30–50% of patients receiving inadequate treatment for their pain.^13,14 Pharmacological treatments are reliant on cancer pain management, the use of opioid analgesics for moderate and severe cancer pain is essential¹⁰ and must be adequately adjusted to reach a balance between optimal pain relief and minimum side effects.¹⁵ Refractory cancer pain has been defined as pain related to cancer or its treatment, of at least 3 months duration, that has not responded to standard treatment with opioids and analgesics.¹⁶ In this scenario, each additional medication has a reduced likelihood of controlling pain and an increased potential for added toxicity.¹⁷ Nowadays, surgery is rarely used for the treatment of cancer pain and less invasive locoregional procedures are available in the wide pain management arsenal.^18–21

In this review article, we attempt to provide comprehensive information about the most commonly used locoregional available options for cancer pain treatment, focusing on interventional radiology and interventional radiotherapy, also highlighting the potential methods to optimize the effectiveness of treatments.

Interventional radiology

Interventional radiology techniques for pain management and mobility improvement in cancer patients include percutaneous techniques such as neurolysis, bone augmentation, as well as transarterial embolization (TAE).

Percutaneous neurolysis

Technique

Percutaneous neurolysis (PN) as second-line therapy is a valuable option to achieve the palliative task of controlling the pain induced either by tumoral tissue growth and/or infiltration or by post-operative insult of surrounding structures belonging to the sensory pathway of pain, breaking off the locoregional nervous fibers network without significantly affecting patients’ survival.^22,23

Percutaneous neurolysis can be effected using chemical or thermal means. The two most commonly used agents in chemical neurolysis are phenol (injected at a concentration of 3–20%) and absolute alcohol (95–100%) which result in Wallerian degeneration, protein denaturation and coagulative necrosis of neural tissue²⁴ (Figure 1).

Figure 1.

A 59-year-old male affected by pancreatic cancer and suffering chronic drug-uncontrollable pain due to perivascular celiac infiltration (a, thin arrow). Percutaneous alcoholization of the celiac trunk (b–e) is performed with the patient prone and a posterior approach. After the localization scan (b) performed with cutaneous markers (white circles), (c) local anesthesia is performed and (d) 20-Gauge needles are inserted in the proximity of the celiac trunk. (e) Final CT control shows the mixture of 95% ethanol and contrast medium being correctly distributed.

Phenol is adsorbed by the axonal and perineural blood vessels causing protein denaturation and has an immediate local anesthetic effect which reduces intraprocedural pain; on the other hand, ethanol favors lipoprotein and mucoprotein precipitation with cellular membrane weakening sustained by cholesterol, phospholipid, and cerebroside extraction, has a lower viscosity which improves the mixture process with contrast medium and has a more durable effect.²⁵

Thermal neurolysis can be effected by means of heat (radiofrequency and microwave)²⁶ or cold (cryoablation).²⁷ When a tumor engulfs the neural target, these methods effect tumor ablation resulting in additional pain alleviation.

Radiofrequency ablation procedure is usually performed under conscious sedation and consists in the placement of a small (20–22 Gauge) electrode with a 5–15 mm active tip, next to the target structure under CT, cone-beam CT or magnetic resonance guidance. Subsequent treatment is performed with different ablation protocols at variable temperatures (75–100°C) and procedural time (60–100 s), usually obtaining an adequate thermocoagulation volume. Some trials also described a pulsed radiofrequency treatment at lower temperatures and prolonged procedural time with encouraging results aiming instead of neurolysis to neuromodulation.²⁸

At present, microwave ablation due to its high power has been rarely used for percutaneous neurolysis.

Cryoablation is considered a promising tool for PN applications for at least two main reasons: first, the procedure requires less sedation and is more tolerable for the patient due to lower intraprocedural pain when compared to radiofrequency ablation; second, the ablation volume (ice ball) is clearly distinguishable on the intraprocedural imaging, assisting interventionist in the final technical success evaluation immediately after the procedure.²⁷ In addition, in a recent retrospective series by Behbahani et al, the procedure seemed to minimize gastrointestinal disorders such as diarrhea and fewer gastrointestinal side effects in respect to chemical ablation techniques.²⁹ There is no agreement in the recent PN literature about treatment protocols for cryoablation. In general, a single application with one or two probes per side, at very low temperatures (<−70°C) is considered adequate to obtain functional denervation and obtain durable pain control.²² However, despite the good results produced by cryoablation, its application in PN is currently limited by its high costs and is reserved for patients with very high preprocedural anesthesiologic risk, in those in which there is high risk of alcohol non-target diffusion, and in those in which cancer mass ablation is also required.³⁰

Indications

In particular, this therapeutic approach is indicated for patients with advanced progressive cancer and short-moderate life expectancy of 6–12 months in which pain control is unsatisfactory and/or requires high doses of opioids. In addition, the association of PN with opioid drugs administration increases treatment effects minimizing both drug addiction and collateral effects, improves patient quality of life, and promotes the reduction of drug doses required to achieve pain control.^22,31,32

PN application has been described for the ablation of stellate ganglion, thoracic plexus, celiac plexus and splanchnic nerves, lumbar and sacral plexus, as well as superior hypogastric plexus in the setting of cancer patients, but it can be potentially used for any peripheral nervous structure that mediates pain signals.^26,33,34

Complications

The risk of intraprocedural hemorrhage due to underlying coagulopathy and/or the potential crossing of vascular structures in particularly challenging settings should be carefully investigated such as the risk of ongoing infections in order to obtain an adequate cost–benefit balance before the procedure.¹⁹

Contraindications

For all of these techniques, the relative contraindications are coagulopathy, thrombocytopenia, or anticoagulant therapy.¹⁹

Outcomes

Several studies reported a success rate of 70–80% and a mean complication rate of 0.5%.^{19,26,30,33,34}

Musculoskeletal and spine augmentation techniques

Advantages of these techniques are related to their minimally invasive nature and include short hospitalization, low complication rates, little to no interruption of systemic chemotherapy agents and ability to combine with other palliative treatment options. A patient and lesion tailored approach should be provided in order to maximize efficacy.

Technique

Percutaneous techniques for the spine metastatic disease include vertebroplasty and balloon augmentation both of which apply cement injection without or with cavity creation respectively; recently implant-based technologies have been applied in the spine as a medium for structural support of the vertebral body.^35,36 Most commonly used implants include jacks, stents and metallic or peek cages (Figure 2).^36–38 Percutaneous techniques for augmentation and structural support in the peripheral skeleton include cementoplasty (using cement injection as a stand-alone treatment) or augmented osteoplasty (during which cement injection is combined to placement of cannulated screws, peak or metallic constructs).³⁹ All these techniques aim for pain palliation, functional restoration and life quality improvement.

Figure 2.

A 54-year-old female multiple myeloma patient with an extensive lytic L4 lesion treated with spinal augmentation using a PEEK polymer cage (KIVA system). (A) Cone beam CT sagittal reconstruction illustrating the working cannula and the PEEK polymer cage deployed inside L4 vertebral body. (B) Cone beam CT coronal reconstruction post-polymer injection.

Indications

According to CIRSE guidelines on percutaneous vertebral augmentation, indications for cancer patients include painful vertebrae with extensive osteolysis due to malignant infiltration by multiple myeloma, lymphoma and metastasis.⁴⁰ Pain relief in malignant fractures is related to a success rate of 60–85% with complication rate being <11.5%.⁴⁰

Pathologic or impeding fractures constitute indications for percutaneous structural support techniques in the peripheral skeleton aiming for pain palliation and functional restoration.⁴¹ Selection of treatment of choice depends upon factors including presence of mechanical pain, location, size and type of the lesion, associated destruction of bony cortex, previous local therapies (including radiation therapy) and presence or not of a pathologic fracture.⁴² Polymethyl-methacrylate (PMMA) is a great material for the spine and locations of peripheral skeleton where only axial forces apply; in weight-bearing locations where other forces apply as well (including torsion, bending and shearing forces) PMMA should be combined to some kind of hardware aiming for improved stability.⁴³ Image-guided percutaneous Fixation with Internal Cemented Screws (FICS) is the most commonly applied and biomechanically evaluated technique; other alternatives include combination of cement with metallic micro-needles (rebar concept), rods or PEEK constructs.^43–46

Combining ablation to the aforementioned techniques in a single session therapy aims to provide local tumor control, decreased rates of tract seeding and improved structural support with pain palliation effect (Figure 3). Percutaneous ablation can be performed applying any kind of available energy including radiofrequency, microwave or cryoablation whilst MR-guided HIFU (high intensity focused ultrasound) is a non-invasive alternative; combining HIFU with ancillary techniques for protection and structural support could increase the number of patients eligible for this treatment.^43,46,47 In the spine, cement injection can be combined to ablation in case of asymptomatic or uncomplicated painful spinal metastasis as well as upon stable pathologic vertebral compression fractures.⁴⁸

Figure 3.

A 68-year-old male HCC patient with a lytic metastatic lesion in the left acetabulum treated with percutaneous microwave ablation and cementoplasty. (A) Anteroposterior fluoroscopy view illustrating the microwave antenna inside the lesion. (B) Anteroposterior fluoroscopy view post ablation illustrating a bone trocar for polymer injection. (C) Anteroposterior fluoroscopy view illustrating filling of the lytic lesion with polymer. HCC, hepatocellular carcinoma.

Spine and peripheral skeleton augmentation techniques are feasible, safe and efficacious treatments aiming for pain palliation and functional restoration.

Complications

Most common complications for percutaneous vertebral augmentation procedure include cement leakage (asymptomatic in the vast majority of cases) and infection (<1%); the suggested threshold for all symptomatic complications post-vertebral augmentation techniques in cancer patients should be 10%.⁴⁰ Complications are related to needle access (including direct traumatic injury to artery, nerve, or muscular tendon), periosteal cement extrusion and leakage (with symptoms resulting from direct compression on adjacent nerves or muscle) and cardiopulmonary adverse events (including cement emboli, fat embolism, transient hypotension or bradycardia); other complications include infection and screws migration.⁴⁷ Related to the technique’s minimally invasive character, the complication rate is low and usually related to self-limiting hematomas.^46,47

Contraindications

• Significant spinal stenosis or compressive myelopathy caused by fracture retropulsion or epidural tumor extension.⁴⁷

• The index vertebral body is very small either from marked loss of body height or because the index level is above T5.

• Severe osteopenia resulting in poor visualization of osseous structures on fluoroscopy

• Disruption of the posterior cortex

Outcomes

CAFÉ trial included 134 patients randomly assigned to balloon augmentation and conservative therapy groups reporting significant reductions in analgesic use, days of bed rest, improvement in the quality of life and Karnofsky performance status in the balloon group compared to conservative therapy.⁴⁹ These improvements in pain, overall functional status, and quality of life continued for the 12 months of the study period.

Transarterial embolization

TAE has been primarily applied for pre-operative embolization of hypervascular tumors to minimize intraoperative blood loss (Figure 4).⁵⁰ Additionally, it has also emerged as an important palliative tool in cancer pain management, mainly from musculoskeletal tumors (either metastatic or primary) as it achieves reduction of the tumor volume and alleviates the pressure of the periosteum and surrounding structures.⁵¹ Moreover, in case of spinal tumors TAE controls the expansion of the tumor to the spinal cord, thus preventing compression and neurological compromise, improving the quality of life.⁵²

Figure 4.

A 43-year-old male sarcoma patient treated with pre-operative embolization in order to decrease vascularity. Pre- (A) and post-embolization (B) images.

Technique

Endovascular embolization is a minimally invasive angiographic intervention consisting in the injection of embolic agents in the arteries supplying the tumor in order to achieve necrosis due to loss of vascular supply. Hypervascularity of the musculoskeletal tumors renders them ideal target for embolization. The choice of embolic material varies in literature and remains a field of controversy. Each embolic material has its own speed, reliability of delivery, duration of occlusive effect and preservation of but also upon operator’s experience.^52–55 The commonest embolic agents used include onyx, gelfoam, poly-vinyl-alcohol (PVA) particles, N-butyl cyanoacrylate (NBCA) and coils. Liquid agents (NBCA, Onyx) seem to achieve more tumor necrosis than particulates.⁵⁴ However, there is an increased risk of non-target embolization and non-target necrosis when compared with particulate emboli.^52–56

Indications

It may be utilized as an operative adjuvant aiming to diminish the potential hazard of hemorrhage, better delineation of tumor margins and thereby, simplification of surgery especially in highly vascularized lesions. Also, it could be employed in pain palliation, relief of fever and hypercalcemia are considered valuable indications of TAE in the setting of bone tumor management.

Complications

Potential complications of TAE include post-embolization syndrome, non-target embolization and infection.^50,53 Post-embolization syndrome is the commonest complication of TAE characterized by development of low-grade fever, pain and malaise usually presented the first 32 h from embolization. Non-target embolization can result in normal tissue loss and may be associated with nerve palsy, skin breakdown and subcutaneous or muscle necrosis. In case of embolization of spinal tumors, it is of greatest importance to recognize and avoid the artery of Adamkiewicz and the possible connections with the tumor-feeding vessels.⁵⁷

Controindications

Although there are no absolute transarterial embolization exclusion criteria, recognized relative contraindications include inability to undergo arteriography (owing to uncorrectable thrombocytopenia, coagulopathy, renal insufficiency, or severe allergic reaction to iodinated contrast medium), decompensated liver disease or liver insufficiency, poor performance status, large tumor burden, active systemic infection, life expectancy <3 months.⁵⁸

Outcomes

Superselective catheterization and embolization of the pathological feeding arteries of the involved bone lesion with the most appropriate embolic agent can achieve significant success rates of 50–100% as far as pain palliation is concerned (Table 1).^54,55,59,60 Although survival rates are not affected by TAE the vast majority of patients experience reduction of pain and life quality improvement whilst subsequent imaging after embolization shows tumor necrosis and variable ossification.^51,55,56 Forauer et al achieved a clinical response in 36 out of 39 treated sites of TAE in bony metastasis from renal cell carcinoma, with a mean duration of 5.5 months.⁵⁴ In the study by De Vries et al regarding TAE of metastatic bone disease from thyroid carcinoma, 17 patients (out of 31) reported improvement of their symptoms, including pain and neurological impairment.⁵⁷ Koike et al included bony metastasis from several primary sites achieving pain relief in 83% of the cases, with significant decrease of the visual analog scale score (p < 0.001) whilst the devascularization grade during embolization was significantly related with pain relief.⁶¹ Similarly, in the large study of Rossi et al including 243 patients with bone metastases from variable primary cancers, 97% of the patients reported a decrease of pain symptoms, with a mean duration of pain relief of 8.1 months.⁵⁵ According to current literature, the onset of pain relief after TAE of musculoskeletal metastasis ranges from a few hours to 15 days and lasts for a mean of 8.3 months.⁶⁰ Jiang et al performed transarterial chemoembolization in 39 patients with bone and soft tissue sarcomas, reporting lower pain in patients’ VAS scores.⁶² Combined therapies including TAE along with radioiodine or external irradiation seem to prolong the duration of the results.^63,64 A large Italian study evaluated 164 cancer patients treated with embolization for spinal metastases from variable primary cancers; pain score and need for analgesics was reduced by 50% after treatment and mean duration of pain relief was 9.2 months.⁵² In the same study, authors also stated that the addition of chemotherapeutic drugs in the embolization procedure seemed to provide longer pain relief than embolization alone. Similarly combining vertebroplasty and embolization seems to achieve more promising outcomes.⁶⁵

Table 1.

Contemporary TAE outcomes for pain palliation in cancer patients

Study	Primary cancer site	Site of embolization	Number of sites treated	Number of patients	Follow-up time	Duration of the results	Pain decrease	Complications
Facchini41	Various	Spine	178	164	15m	9.2 m	50%	56.7% (minor)
Nagata42	Bone and soft tissue sarcomas + metastatic	Thoracic & Lumbar spine,Ilium, Pubis, Sacrum, SI joint, Ischium, Rib, Scapula, Paravertebra L2-L4	50	41	n/a	n/a	79%	One major (gluteal muscle necrosis)
Forauer44	RCC	Spine, Pelvis, Upper + Lower limb	39	21	n/a	5.5 m	36/39 (92%)	2 Major
Rossi46	Various	Spine, Pelvis, Upper + Lower limb, Thoracic cage	309	243	4y	8.1m	97%	86/243 minor + 1 major (gluteal muscle necrosis)
Chen47	Various (TACE)	Spine	12	11	n/a	n/a	90.9%	None
De Vries48	Thyroid carcinoma	Spine, pelvis, scapula, rib, upper +lower limb, skull	65	13	n/a	8.1 m	55%	11.6% (minor)
Koike49	Various	Spine, Pelvis, Lower limb, Sternum	40	18	7.5m	7.5m	83%	Local pain in three sessions
Jiang50	Bone and soft tissue sarcomas	Upper & lower extremities, Pelvis, Chest, Retroperitoneal	85	39	three y	n/a	Decrease cancer pain VAS score	100% (minor)
Eustatia-Rutten51	Thyroid carcinoma	Spine, Pelvis, Sternum	41	16	2m- 8.6y	6.5m	26/41 (63%)	1 out of 16 post-embolization
Uemura52	HCC	Spine, pelvis, scapula, rib, upper limb, skull	n/a	11	182d	n/a	67% partial relief, 22% complete relief	ten out of 11 (minor)
Wible 59	HCC (TACE)	Liver	n/a	73	n/a	n/a	Significant change in pain body scores (p < 0.047, n = 21)	None
Yilmaz60	RCC	Pelvis, Upper limb	6	2	n/a	2m	100%	None

HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; TACE, transarterial chemoembolization; TAE, transarterial embolization.

Overall, TAE has been proven an efficient technique in palliative care of metastatic and primary skeletal disease. Thus, TAE is an attractive option in the treatment of cancer pain, especially if other treatment modalities have failed or cannot be used. Duration of the results remains short, but TAE offers the advantage of multiple sessions as well as the combination with other treatment modalities (Table 1).^66,67

Radiation therapy

Radiation therapy is primary treatment with palliative intention, via a single/multiple fraction external beam radiation, a half-body treatment, or a systemic radiopharmaceutical, which can provide effective pain relief with minimal side effects.^68–70 Brachytherapy, also known as interventional radiotherapy (IRT) is a feasible and effective treatment method for the palliation of malignant bone lesions.^71–75 However, IRT is not yet included in any guideline or scientific society treatment recommendation,^68–70 although both low- and high-dose rate brachytherapy offer the best compromise between target irradiation and surrounding healthy tissue sparing.^71,76

External beam radiotherapy (EBRT)

Indications

EBRT represents the mainstay for the treatment of painful, uncomplicated bone metastases. The functions of radiotherapy are pain control and durable local control to improve or prevent neurological compromise.

Technique

Depending on the intent of treatment and other case-specific circumstances, radiotherapy can be delivered as three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT), stereotactic spine radiosurgery (SRS)/spine stereotactic body radiotherapy (SBRT) and volumetric modulated arc therapy (VMAT).

3D-CRT

The likelihood of durable local control depends on tumor histology, radiosensitivity, and dose. Radiosensitive histologies (lymphoma, multiple myeloma, germinoma) have favorable long-term local control.⁷⁷ For more radioresistant tumors, such as sarcomas and renal carcinoma, long-term local control rates are consistently less than 50%.^78,79 Numerous prospective randomized trials have shown that 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction can provide excellent pain control and minimal side effects. The longer course has the advantage of a lower incidence of repeat treatment to the same site, and the single fraction has proved more convenient for patients and caregivers.

SRS and SBRT

In patients with oligometastatic disease, SRS and SBRT are effective alternative to 3D-EBRT. Its important to identify patients with favorable prognoses who may derive benefit from bone SBRT. Age, performance status, comorbidities, and functional capacity can help in the patient’s selection. Bone SRS and SBRT delivers high doses of radiation to tumors and spares adjacent healthy tissues. The high amounts of DNA damage elicited by spine SRS and SBRT appear to obviate the histological dependence that exists for 3D EBRT to achieve local control, and multiple studies have demonstrated 12 month local control rates of over 85% for even the most classically radioresistant histologies.^80–84 Usually, bone SRS is delivered in a single fraction, whereas bone SBRT is delivered as two to five treatments.

Complications

Bone SBRT or SRS is generally well tolerated, and the risk of serious adverse events is <5%. Potential complications are pain flare, vertebral compression fracture and myelopathy.

Contraindications

Although there are no absolute EBBRT exclusion criteria, recognized relative contraindications include genetic syndromes of hyper-radiosensitivity and impossibility of maintaining the position necessary for the delivery of treatment. When substantial epidural or intramedullary disease is present, SBRT or SRS is not recommended as first-line treatment.

Outcomes

EBRT can provide significant palliation of painful bone metastases in 50–80% of patients, with up to one-third of patients achieving complete pain relief at the treated site. After conventional EBRT, about 25% of patients report complete resolution in pain, typically for a duration of 3–4 months, depending on histology.⁸⁵ SBRT has been shown to improve outcomes in patients with spinal metastases, with up to 80% of patients achieving local tumor control and reporting pain relief. SBRT have a potentially better outcomes than traditionally 3D EBRT techniques. Patients receiving SBRT achieved pain relief more quickly during the 4  weeks after treatment and had more durable pain relief assessed at 6  months compared with those receiving standard 3D EBRT.⁸⁶

Interventional radiotherapy (IRT)

Technique

IRT use sealed radioactive sources which are placed in the immediate vicinity of a tumor with the help of afterloading device.

Indications

IRT is not yet included in any guideline or scientific society treatment recommendation for bone metastases. Main indications are palliation of metastatic bone lesions refractory to EBRT and/or chemotherapy, and/or analgesic medications.

Complications

Most common complications are subcutaneous hemorrhage, fever, myelosuppression, local skin reaction, de novo vertebral compression fractures and implant displacement.

Contraindications

Main contraindications are low Karnofsky Performance Scale (KPS), coagulopathy, genetic syndromes of hyper-radiosensitivity and patients unfit for sedation/anesthesia.

Outcomes

Li et al demonstrated good outcomes combining percutaneous vertebroplasty (PVP) plus interstitial implantation of 125-I seeds in osteoblastic central and peripheral vertebral metastases with better results in terms of clinical benefit, VAS and disease control rate when using a multineedle approach; multiple case series suggest to perform this approach in case of failure of EBRT.⁷³ Although 125-I seeds and RFA have similar effects in terms of pain control, their association was proven to be significantly better than 125-I seeds alone (Table 2).^87,88

Table 2.

Summary of bone lesions treated with radiation therapy

	Yang Zu. et al.65	Li et al.66	Feng et al.67	Yao et al.68	Jiao et al.70	Zhang et al.71	Xie et al.73	Yang Zu et al.74	Wang C et al.75	Wang W et al.76	Lu et al.77	Chen et al.78	Yang Ze et al.79	Xiang et al.81
#	50	29	26	24	38	33	161	40	22	133	49	11	14	96
PELVIC	+	-	-	-	+	n.d	-	-	+	+	-	-	-	+
RIB	+	-	-	-	+	n.d	-	-	-	+	-	-	+	+
VERTEBRA, C -T	+	+	+	+	+	n.d	+	+	-	+	+	+	-	+
VERTEBRA, L-S	+	+	+	+	+	n.d	+	+	-	+	+	+	-	+
SCAPULA	+	-		-	+	n.d	-	-	-	+	+	-	-	+
CLAVICULA	+	-		-	+	n.d	-	-	-	+	-	-	-	+
EXTREMITY	+	-		-	+	n.d	-	-	-	+	-	-	-	+
SACRUM	-	+		-	+	n.d	-	-	-	+	-	-	+	+
STERNUM	-	-		-	+	n.d	-	-	-	-	-	-	+	-
SKULL	-	-		-	-	n.d	-	-	-	+	-	-	-	-
OSTEOLYTIC	-	29		n.d	27	n.d	-	n.d	n.d	n.d	n.d	n.d	n.d	49
OSTEOPLASTIC	50	-	n.d	n.d	6	n.d	-	n.d	n.d	n.d	n.d	n.d	n.d	15
MIXED	-	-	n.d	n.d	5	n.d	-	n.d	n.d	n.d	n.d	n.d	n.d	12
RADIATION SOURCE	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds	I-125 seeds
RESULTS	125I + PVP significant better	Multineedle is better than single needle	effective after EBRT failure	125I reirradiation is feasible in vertebral mets	RFA better at 1 month No diff. at 3 months	RFA+125I better than RFA alone	125I+ PVP significant better	PVP+125I significant better	2 yrs OS 45,5% 2 yrs LC 36,4%	Safe and effective	PVP + 125I Is better as PVP + RFA	Pre-plan differ from final applied dose	125I + chemoem-bolisation effective and feasible	PVP + 125I better than PVP+ EBRT

EBRT, external beam radiotherapy; HDR, high-dose-rate interventional radiotherapy(brachytherapy); LC, local control; OS, overall survival; PVP, percutaneous vertebroplasty; RFA, radiofrequency ablation.

# number of implanted targets; n.d. = no data; *femur intramedullary metastasis of melanoma.

In a 2021 meta-analysis by Sharma et al, 14 studies (7 prospective) were evaluated, for a total of 689 patients, analyzing the efficacy, safety and tumor control of 125-I seed brachytherapy for the management of bone metastasis, showing that 125-I seed IRT alone or in combination with PVP could be a good salvage strategy.⁸⁹

Space for future research is in defining the dose of IRT, giving the best balance between radiation myelopathy and tumoricidal effects (because of non-anchored seeds within the target).⁸⁹ The forced use of the stepping source technology with the personalized and secure dose distribution potential could probably improve the results.⁹⁰

IRT also showed superior outcomes in lung cancer metastases following one cycle chemotherapy than conventional EBRT—with a statistically significant cost advantage of IRT treatments.^91,92

Surgery

The aim of surgical intervention in bone metastases is to maintain patient functionality and mobility, prevent impending fractures or stabilize a pathological fracture, manage spinal cord compression and improve quality of life by alleviating pain. Patient selection for surgery is critical, particularly in the setting of fracture prevention.⁹³

In patients with spinal cord compression, surgery does not obviate the need for post-operative EBRT for patients. The choice of surgical decompression should be made by an interdisciplinary team that includes a neurosurgeon, with the performance status, primary tumor site, extent and distribution of metastases, and expected survival taken into account.⁹³

Technique

The most common surgery procedures are external bracing, vertebroplasty, kyphoplasty, pedicle screw placement, decompression alone or in combination with stabilization.

Indications

• Solitary site of tumor progression

• Absence of visceral or brain metastases

• Spinal instability

• Age <65 years.

• KPS ≥70.

• Survival of >3 months

• Slow progression of neurologic symptoms

• Maintained ambulation

• Relatively radioresistant tumor histologic type (i.e. melanoma).

• Site of origin suggesting relatively indolent course (i.e. prostate, breast, kidney).

Complications

Complications may be bleeding, dura and neurological damage, infections wound and soft tissue, systemic—cardiac, renal, respiratory injury and hypercoagulable state.⁹³

Controindications

Multiple metastases, age >65 year and KPS <70 are the main contraindications to surgery.

The surgical treatment of metastatic disease cannot be considered curative, meaning that surgery alone is unlikely to eradicate the disease with durable local control.⁹³

Outcomes

The local recurrence rate is 96% at 4 years and there was no difference in overall survival between patients who received complete vs incomplete surgical resections.⁹⁴

Conclusions

Mini-invasive multimodal locoregional treatments, such as percutaneous neurolysis with radiofrequency ablation and/or cryoablation, vertebral augmentation techniques, endovascular treatments as TAE, as well as brachytherapy, represent a great tool to achieve good and satisfactory pain control in cancer patients, improving symptoms and, therefore, their quality of life. In this scenario, a multidisciplinary approach by the mean of spinal, oncological and pain boards can be an additional tool to improve the management of these patients.