117 PROFESSIONAL ARTICLE Metastatic disease of the spine Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Metastatic disease of the spine Metastatska bolezen hrbtenice David Mernik,1 Janez Ravnik,2 Tamara Petrun3 Abstract Tumours of the spine are either primary or secondary. The spine is the most common site where we find bone metastases. Up to 70% of patients with cancer develop a metastasis in the spine. Up to 10% of patients with cancer suffer from meta- static spinal cord compression. Metastases in the spine are 20 times more common then primary tumours. Very often they are the first sign of a systemic cancer disease that we find. The symptoms of metastatic spine disease are very varied. There are many different approaches to treatment, and there has been tremendous advancement in recent years, especially with the development of stereotactic radiotherapy. The tretment of metastatic spine disease is a very complex and important field of medicine. It takes an interdisciplinary and decisive approach to save the patient’s critical spinal function. Not rec- ognizing metastatic spinal disease or its inappropriate treatment usually has irreversible consequences. Izvleček Tumorji hrbtenice so primarni in sekundarni. Hrbtenica je najpogostejše mesto, kjer odkrijemo kostne metastaze. Do kar 70 % bolnikov z neoplazmo razvije metastazo v hrbtenici. Do 10 % bolnikov z neoplazmo utrpi metastatsko kompresijo hrbtenjače. Metastaze so kar 20-krat pogostejša neoplazma hrbtenice kot primarna neoplazma. Zelo pogosto je metastaza v hrbtenici prvi znak bolezni. Klinična slika je pestra in obstajajo različni pristopi k zdravljenju, ki so se precej spremenili v zadnjih letih. Revolucionarni uspeh je zdravljenje z uporabo stereotaktične radioterapije. Zdravljenje metastaz v hrbtenici je zelo pomembno in kompleksno področje, v katerem se prekriva veliko medicinskih strok in zahteva široko znanje in hitro ukrepanje. Pravilno diagnosticiranje in zdravljenje je ključnega pomena za bolnikovo kakovost življenja. Če se le ta bolezen ne prepozna in se nepravilno ali nepravočasno ukrepa, pa so posledice običajno nepopravljive. 1 Division of Surgery, University Medical Centre Maribor, Maribor, Slovenia 2 Department of Neurosurgery, Division of Surgery, University Medical Centre Maribor, Maribor, Slovenia 3 Department of Haematology and Hematologic Oncology, Division of Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia Correspondence / Korespondenca: David Mernik, e: dr.david.mernik@gmail.com Key words: cancer; spine; metastasis; surgery; oncology; radiotherapy; spinal instability; spinal cord compression Ključne besede: rak; hrbtenica; metastaza; kirurgija; onkologija; radioterapija; hrbtenična nestabilnost; kompresija hrbtenjače Received / Prispelo: 29. 7. 2020 | Accepted / Sprejeto: 23. 6. 2021 Cite as / Citirajte kot: Mernik D, Ravnik J, Petrun T. Metastatic disease of the spine. Zdrav Vestn. 2022;91(3–4):117–27. DOI: https://doi. org/10.6016/ZdravVestn.3141 eng slo element en article-lang 10.6016/ZdravVestn.3141 doi 29.7.2020 date-received 23.6.2021 date-accepted Cytology, oncology, cancerology Citologija, onkologija, kancerologija discipline Professional article Strokovni članek article-type Metastatic disease of the spine Metastatska bolezen hrbtenice article-title Metastatic disease of the spine Metastatska bolezen hrbtenice alt-title cancer, spine, metastasis, surgery, oncology, radiotherapy, spinal instability, spinal cord compression rak, hrbtenica, metastaza, kirurgija, onkologija, radioterapija, hrbtenična nestabilnost, kompresija hrbtenjače kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2022 91 3 4 117 127 name surname aff email David Mernik 1 dr.david.mernik@gmail.com name surname aff Janez Ravnik 2 Tamara Petrun 3 eng slo aff-id Division of Surgery, University Medical Centre Maribor, Maribor, Slovenia Klinika za kirurgijo, Univerzitetni klinični center Maribor, Maribor, Slovenija 1 Department of Neurosurgery, Division of Surgery, University Medical Centre Maribor, Maribor, Slovenia Oddelek za nevrokirurgijo, Klinika za kirurgijo, Univerzitetni klinični center Maribor, Maribor, Slovenija 2 Department of Haematology and Hematologic Oncology, Division of Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia Oddelek za hematologijo in hematološko onkologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor, Maribor, Slovenija 3 Slovenian Medical Journallovenian Medical Journal 118 CYTOLOGY, ONCOLOGY, CANCEROLOGY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3141 1 Introduction Spinal tumours are either primary or secondary (metastases). Primary tumours originate from the spine or associated structures. Secondary tumours originate from distal organs and spread through the bloodstream and involve the spine (1). Rarely, metastasis can occur by direct invasion, through the lymphatic system or ce- rebrospinal fluid (i.e. drop metastasis) (2). Metastases contain cells that are similar to the primary tumour (1). The spine is the most common site of bone metastases (3,4). Up to 70% of patients with cancer develop spinal metastases (1,3-6). Up to 10% of patients with cancer develop metastatic spinal cord compression (3-10). Spi- nal metastases are 20 times more common than prima- ry tumours (6). Most tumours are located in the extradural space (6). Most commonly, the thoracic spine is affected (70%), followed by the lumbar spine (20%) (4). The ini- tial anatomical site of spinal metastasis is the posteri- or part of the vertebral body. The pedicle is never the primary site of metastasis; even though the first sign of metastasis, visible on a plain radiograph, is pedicle destruction, it is only involved in the metastasis process after involvement of the vertebral body (11). However, there are exceptions. An example of a solitary metasta- sis in the spinous process has been described (12). The highest incidence of metastatic spine disease (MSD) is between 40 and 65 years of age, which reflects the overall incidence of cancer (6). Prostate cancer, breast cancer and lung cancer are the source in half of all cases of spinal metastases. These are followed by kid- ney cancer, gastrointestinal cancer, thyroid cancer and haematological cancers (multiple myeloma, lympho- mas) (4). The origin of the metastasis can usually be de- termined by the medical history, but in some patients, spinal metastasis is the first disease sign (13). Metasta- sis of unknown origin is the first disease sign in up to 7% of cancer patients (14). In a series of 201 patients in the tertiary neurosurgical unit in Austria, spinal metas- tasis was the first disease finding in as many as 40.3% of patients (15). Metastases can occur several years after successful completion of cancer treatment (1). If vertebral body destruction is extensive enough, malignant spinal cord compression (MSCC) occurs (9,16,17). The term MSCC refers to the spinal cord as well as cauda equina (16). Spinal cord compression can be categorized into two phases. The early stage is curable and reflects the short duration of spinal cord compression caused by the tumour and is characterized by spinal oedema, venous congestion and demyelin- ation. However, with prolonged spinal cord compres- sion, an irreversible second phase occurs. The reason for this is a spinal cord infarction. Malignant compres- sion requires immediate surgical intervention or im- mediate radiotherapy in highly radiosensitive tumours (myeloma, lymphoma) (8). 2 Clinical presentation Spinal pain is the first and most common symptom (1,2,6). Pain in the thoracic spine is particularly suspi- cious, where degenerative pain is less common than in the lumbar or cervical spine (2). Initially, the cause of the pain is pressure on the periosteum (1). Palpation or percussion of the affected part can elicit pain (2,6). Typ- ical pain due to a tumour begins gradually, intensifies over time and persists at night and at rest. Acute pain without known trauma is a symptom of a pathological fracture (1). When pain worsens with movement of the affected segment, we speak of mechanical pain (or axial pain). It is suspicious for mechanical instability of the spine. This pain does not normally respond to conservative treat- ment (2,6). The Spine Oncology Study Group defined mechanical instability as the loss of spinal integrity as a result of a neoplastic process that is associated with movement-related pain, symptomatic or progressive deformity and/or neural compromise under physiolog- ical loads (18). If the metastasis causes compression of a spinal nerve, radicular pain occurs. Radicular pain can also be caused by a pathological fracture (1,2,6). In a patient with known cancer and new-onset back pain, the diagnosis is always MSD until it is excluded (6). The second most common symptom is a neuro- logical deficit. Muscle weakness, numbness and au- tonomic dysfunction occur (most commonly urinary incontinence) (2,6). Neurological deficit occurs due to metastatic pressure on the spinal cord, severe spinal de- formity or fracture with retropulsion of tissue into the spinal canal (19). Brown-Sequard syndrome may occur with intradural and intramedullary metastases (6). Malignant spinal cord compression (MSCC) is an urgent condition that requires immediate treatment (9). Studies have shown that MSCC is recognized very late in the course of the disease. The ability to walk after 119 PROFESSIONAL ARTICLE Metastatic disease of the spine Figure 1: Computed tomography (CT) of breast cancer metastasis at the C6 level in a 50-year-old patient. treatment is directly associated with the ability to walk at the time of diagnosis. When the patient is no lon- ger ambulatory, the likelihood of regaining function is minimal, and most will consequently need continuous care (16). Patients with paresis (but not plegia) become paraplegic within 24 hours in 28% of cases, which in- dicates the urgency of the condition (19). In a series of 248 patients with a radiographically confirmed diag- nosis, 94% complained of back pain and/or radicular pain. Radicular pain was reported by 79% of patients (196/248). The mean pain intensity described by the vi- sual analogue scale was 8/10; 29% reported 10/10 pain. The pain was described as sharp, shooting, deep and burning. The compression level did not correlate with the site of pain. Only 18% of patients were still ambu- latory at the time of diagnosis. 85% of patients expe- rienced weakness or difficulty walking. The mean du- ration of weakness was 20 days (range 7–120). There was no correlation between pain and walking ability (although physicians in clinical practice often attribute walking difficulty to pain). 68% noticed impaired sen- sation. 56% reported problems with urination (at least one occasion of an inability to urinate; a quarter report- ed urinary retention and 15% incontinence). Weakness on clinical examination was detected in 84% and sen- sory dysfunction in 58%. Clinically established levels of compression did not correlate with findings in imaging studies (16). Delayed referral of a patient with spinal metastases with symptoms to a spinal surgeon is the strongest pre- dictor of poor treatment outcome. Patients with MSD who underwent elective surgery had significantly bet- ter outcomes compared to patients who required acute treatment due to the development of alarming MSD symptoms (neurological deficit, mechanical instabil- ity). The elective group had less invasive procedures (52.9% vs. 13.3%), less blood loss (200 ml vs. 450 ml), shorter hospital stays (7 days vs. 13 days) and fewer complications (26.2% vs. 48%). This strongly empha- sizes the importance of timely referral to a specialist (17). Several studies have noted a worrying trend of dis- proportionately frequent urgent referrals on weekends (especially on Fridays), indicating poor health system organization and poor recognition of the problem (15). At an Oncology Orthopaedics Department in Po- land, 854 patients were hospitalized for spinal metasta- ses. The mean duration of primary disease before me- tastasis was 13 months (range 4–43 months); 81% of patients had a pathological fracture on admission and only 19% had metastasis without fracture (5). 3 Diagnosis Early diagnosis of MSD should be the goal, and not waiting for unequivocal clinical signs of severe impair- ment. Establishing a diagnosis before the patient los- es the ability to walk is crucial (16). Elective surgery should be pursued to avoid urgent referrals, so the di- agnostic process should be rapid (17). In addition to the medical history and clinical ex- amination, imaging studies are a key part of diagnosis (19). The plain radiography is normally the first imag- ing study performed due to ease of access, use and an extremely low cost (2). In a study of 248 patients with MSCC, a plain radiograph correctly predicted com- pression levels in only 21% of patients (16). Radio- graphic changes are noticeable only when at least 50% of the cancellous bone in vertebrae is destroyed (1). The (absent) pedicle sign, also called the winking owl sign, is the first sign of metastasis on a plain radiograph (6). Bone scintigraphy is a procedure in which a radio- isotope is used to detect regions with increased bone remodelling, which can be used to detect metastases (1,2). It has a high sensitivity, but low specificity (a pos- itive result occurs also in cases of infection or spondy- losis) (1,6). In a series of 139 scintigraphs performed in patients with MSCC, it accurately predicted the level of compression in only 19% of cases (16). 120 CYTOLOGY, ONCOLOGY, CANCEROLOGY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3141 Figure 2: Magnetic resonance imaging of breast cancer metastasis at the C6 level in a 50-year-old patient. Figure 3: Magnetic resonance imaging of lung cancer metastasis at the L4 level in a 56-year-old patient. Computed tomography (CT) is an imaging study that is suitable for showing bone structures and allows for dif- ferentiation of lytic and blastic lesions (2), as shown by Figure 1. Positron emission tomography (PET) detects increased fluorodeoxyglucose metabolism in cancer cells. It is used in combination with computed tomogra- phy (PET/CT). As it is expensive and has a high radiation burden, it should only be used if other imaging studies have been performed first (2). Its advantage is early de- tection of metastatic disease and high sensitivity (2,20). Magnetic resonance imaging (MRI) is the gold stan- dard for diagnosing MSD (1,2,6,16,20). This method al- lows for the best assessment of the bone marrow, spinal canal and the relationship of metastases to surrounding structures (1), as shown by Figures 2 and 3. Compared to other imaging methods (plain radiograph, CT, nuclear imaging) it is superior in accuracy, sensitivity and spec- ificity (2). MRI is 98% sensitive and specific for the de- tection of vertebral metastases (21). T2 images obtained by MRI are useful for determining spinal cord compres- sion. T1 and STIR images are effective in fracture de- tection. The addition of gadolinium (a contrast agent) allows for better recognition of vascular structures and tumour infiltration (2). Post-contrast fat suppression al- lows for differentiation of metastasis from bone marrow in borderline cases (6). Due to MRI clearly being the best diagnostic option, opting for a plain radiograph or scintigraphy before MRI is not indicated and only leads to delayed diagnosis (16). CT is used as an alternative to MRI when the patient has inserted osteosynthetic mate- rial that would cause metal-induced artifacts in MRI (2). A patient with myelopathy (muscle weakness, sen- sory deficit, urinary incontinence) and a known diag- nosis of cancer (or highly suspected cancer) should be admitted to hospital immediately. A patient with cancer and suspicious pain should have an urgent MRI when available (6). In the case of a known history of cancer, the number of metastases is a fundamental issue. In case of metasta- sis of unknown origin, biopsy is crucial for histological confirmation of the diagnosis. Biopsy is also performed in case of differential diagnostic ambiguity (e.g. the pa- tient has two primary cancers or non-cancerous disease is suspected) (22). This can be done in several ways: as fine needle aspiration, Tru-Cut biopsy, incisional or ex- cisional biopsy. Due to the possibility of tumour seed- ing in the biopsy tract, biopsies must be performed far from neurovascular structures by using small incisions which could then be removed along with the tumour mass during the definitive surgical procedure (1). In the case of metastasis of unknown origin, in addition to routine laboratory tests, testing for tumour markers, PSA, thyroid function tests and protein electrophoresis is performed. Whole-body MRI, chest-abdomen-pelvis CT and PET/CT are useful imaging tests for locating the primary tumour. The biopsy should be the last in a series of tests as it weakens the affected bone and can lead to a pathological fracture (22,23). 121 PROFESSIONAL ARTICLE Metastatic disease of the spine 4 Treatment The remarkable development of MSD treatment techniques has made it very difficult to decide on the right treatment regimen. Treating a patient with MSD requires a multidisciplinary approach and the combined knowledge of an oncologist, spinal surgeon, radiologist and pain specialist (24). 4.1 The NOMS framework To help with the choice of therapy, the NOMS frame- work, a modern, sophisticated and reliable model for the treatment of patients with MSD, has been devel- oped. (25,26). The NOMS decision framework consists of the neurologic, oncologic, mechanical, and systemic considerations (24). It can be applied in practice and enables a multidisciplinary approach and continuous development by introducing novel treatment methods (26). 4.1.1 Systemic disease Patients with metastases are usually considered in- curable with very different but limited survival times (18). There is currently no proven effective cure for MSD, so treatment is aimed at maintaining function (27). Patients need to be in good general condition so they can tolerate the planned procedures (26). The ben- efits of any treatment must be weighed against the bur- den of the underlying disease, and the potential bene- fits of treatment must be weighed against the risks. The patient may have such a short survival time that they would not gain any benefit from the procedure. Realis- tic treatment options should be presented to the patient, along with a discussion about treatment goals (18). The presence of symptomatic systemic disease in key organs (brain, lungs, liver) reduces the need for urgent interventions for minimally affected patients with spi- nal metastases. If the patient is in poor general condi- tion (Karnofsky score ≤ 40) and is expected to survive ≤ two months, we opt for external radiation therapy and palliative care to minimize the side effects of treatment (18). Surgery is usually acceptable if survival is estimat- ed at three months or more (2,3). As decisions on sur- gery are made by surgeons, they should be well aware of the prognostic factors that determine survival (3). The histologic type of primary tumour has the greatest impact on survival (22). The median survival at diag- nosis of spinal metastasis varies greatly depending on the primary tumour origin. Lung cancer has the worst median survival at 3.9 months. Prostate cancer has a median survival of 18.8–24 months, and kidney cancer 24.5 months. Breast cancer has the best prognosis at a median survival of 24–80 months (27). We need to be aware that there is tremendous variability in survival even within individual histological types of cancer. If the patient’s lung cancer has mutations that allow mod- ern targeted therapy, their survival is extended from a few months to several years (24). The ability to walk be- fore surgery has a statistically significant effect on sur- vival. The presence of multiple metastases, pathological fractures and cervical metastases do not affect survival (27). There are a number of predictive scoring systems that are supposed to allow survival assessment. The Tokuhashi and Tomita scores are the most commonly used, although there is no consensus on the best scoring system. There are studies that favour other scoring sys- tems (2). A comparison of six scoring systems (Tomita, Tokuhashi, Van der Linden, Bauer, Rades, Bollen) esti- mated that the Bollen system was the most accurate with an estimated four month accuracy of 75% (28). Due to the constant and significant progress in primary dis- ease treatment (development of new forms of systemic treatment), we must be sceptical about the use of scor- ing systems or even abandon them altogether (2,27,29). There are no grade 1 evidence to support these systems. When the usefulness of these systems was evaluated in retrospective studies, they proved to be unreliable (27). 4.1.2 Mechanical instability The pain that accompanies spinal metastasis is ei- ther due to the effect of the tumour (the pressure of the tumour on the periosteum) or mechanical in nature (pain is present during movement, but absent at rest). Mechanical pain is a sign of possible spinal instability. It is important the patient is seated when assessing me- chanical pain. It is a common mistake for physicians to examine the patient in the supine position and assume they are without pain as the patient does not report pain in the supine position (8). The Spinal Instability Neo- plastic Score (SINS) is used to assess mechanical insta- bility of the spine. This is the first evidence-based and easy-to-use spine instability assessment system (22). SINS allows easy communication between different clinical specialists and spinal surgeons (30). The sensi- tivity of SINS for the determination of unstable lesions and potentially unstable lesions is 96%, while the spec- ificity is 80% (2). Recognition of instability is crucial, 122 CYTOLOGY, ONCOLOGY, CANCEROLOGY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3141 as it significantly affects the choice of treatment meth- od (22). Patients with a high SINS score (13-18) have a clear indication for surgical stabilization and their con- dition significantly improves after surgery (24). 4.1.3 Neurologic assessment The neurologic assessment includes a clinical neuro- logical examination (signs and symptoms of myelopa- thy, radiculopathy, motor and sensory deficits) and as- sessment of the spinal cord compression risk on MRI (18). Bilsky et al developed a scale that allows the defini- tion of spinal cord compression based on MRI imaging (31). The Bilsky scale has become commonplace among spinal oncologists (18). A patient who develops a motor neurological deficit due to solid cancer metastasis needs immediate surgical decompression (32). Exceptions are the completely radiosensitive cancer types (18). 4.1.4 Oncologic assessment The oncologic assessment considers the best possi- ble treatment according to the type of tumour. Different histological types of tumours are treated very different- ly, with systemic therapy, surgery or radiation (8). There are three crucial properties of a tumour: radiosensitivity, radioresponsiveness, and vascularity. Radiosensitivity is the sensitivity of cancer cells to the destructive effect of ionizing radiation, thus achieving better local control of the tumour. It affects the choice of radiation dose. Ra- dioresponsiveness is a reflection of the rate at which a tumour shrinks in response to radiation. This property is important in tumours that cause spinal cord compres- sion and influences the decision whether to perform de- compression by radiation or surgery. Vascularity is the amount of blood vessels contained in a tumour and is especially important in the surgical approach (18). 4.2 Corticosteroids Corticosteroids are well established in spinal metas- tases treatment. They are thought to help reduce oedema and inflammation, which is supposed to help with spinal cord compression. It is also thought to have a direct cy- totoxic effect on certain haematogenous types of cancer (lymphoma, myeloma) and occasionally even on breast cancer. Dosing and guidelines for use are still unclear and vary widely in practice (33). When prescribing cor- ticosteroids exclusively for MSCC, a review of the liter- ature conducted by Cochrane found that there were no significant beneficial effects of corticosteroid treatment compared to placebo. This does not apply to the general treatment of spinal metastases. It is clear that high doses (96 mg dexamethasone per day) are associated with se- rious side effects that were not observed at lower doses (16-32 mg dexamethasone) (34). Although there is no quality literature on corticosteroid therapy in case of compression, Kumar et al, after a review of the literature, suggest treating MSD with an initial intravenous bolus of 10 mg dexamethasone, followed by 16 mg dexameth- asone orally daily. After definitive treatment, corticoste- roids should be tapered off (35). 4.3 Supportive therapy with bisphosphonates and denosumab Bisphosphonates are a group of drugs that inhibit os- teoclast activity and thus reduce osteolysis stimulated by spinal metastases. They reduce the risk of pathological fracture, relieve lytic pain and prevent hypercalcaemia (2). Bisphosphonates reduce mortality, associated with bone metastases, and also improve quality of life. They are also cost effective. Denosumab has been shown to be slightly more effective compared to zoledronic acid (36). 4.4 Systemic therapy Systemic treatment is an integral part of long-term management of spinal metastases. Therapy varies ac- cording to the histological type of the tumour (2). It is rarely used as a stand-alone treatment, except in the case of highly chemosensitive tumours such as lympho- ma, seminoma and neuroblastoma (33). Oncology has advanced tremendously in the treatment of cancer, and genetic analysis with targeted therapy represents a revo- lution in the treatment of certain types of cancer and has significantly extended the expected survival of patients (24,25,29,30,37). Due to the extensive clinical applica- tions of systemic therapy, it is important that spinal sur- geons are aware of new findings in the field of systemic cancer treatment (30). 4.5 Radiotherapy Radiotherapy is the basic treatment for patients with spinal metastases. It achieves pain relief and local con- trol of tumour growth or its reduction (2,18,33). It can be a stand-alone treatment or treatment in combination with surgery or other treatment. Almost all cases are treated with radiotherapy in various forms: radiothera- py with external radiation, stereotactic radiotherapy and stereotactic radiosurgery (18). 123 PROFESSIONAL ARTICLE Metastatic disease of the spine Figure 4: Radiographic image after surgery (posterior approach, spinal canal decompression, multilevel fixation and vertebroplasty of the affected vertebral body) due to lung cancer metastasis at the L4 level in a 56-year-old patient. External radiation therapy is most commonly used (18,33). An area of the body, which also includes healthy tissue, is irradiated. As the spinal cord is highly sensi- tive to radiation, the dose is limited (21). External radi- ation therapy is fractionated. Single fraction radiother- apy is three times more likely to require re-irradiation than multiple fraction radiotherapy. There is evidence that multiple fraction radiotherapy provides better local control than single fraction radiotherapy (18). Patients with estimated good survival should receive more frac- tions and should be offered long-term follow-up (34). Knowledge of the tumour’s radiosensitivity is crucial for the implementation of external radiation therapy (18). Tumours that respond well to external radiation therapy are haematological neoplasms and certain solid tumours (breast cancer, prostate cancer and germinomas). In radioresistant tumours (kidney cancer, colorectal can- cer, melanoma, sarcoma, thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer), local control is achieved in less than 50% (24,30,33). In radiosensi- tive tumours, external radiation therapy is an excellent stand-alone therapy for MSCC; it is less successful in other histological types of cancer (24). Stereotactic radiosurgery and stereotactic radiother- apy are terms that can be used interchangeably in the context of the spinal metastasis treatment (2). Stereotac- tic surgery was developed in Sweden to treat central ner- vous system metastases. When the same principle was used 20 years later to treat pathology outside the central nervous system, this technique was called stereotactic radiotherapy (38). High radiation doses are precisely fo- cused on the tumour under imaging guidance. Normally, one to five fractions are used (2). Compared to conven- tional radiotherapy, three times the bioeffective dose of radiation can be applied without damaging vital struc- tures near the metastasis (18). These novel radiotherapy techniques allow permanent control of all metastases re- gardless of histological type and have thus virtually erad- icated the concept of radioresistant tumours. Statistical analyses report up to 98% successful local control four years after treatment (39). Currently, the danger of neu- rological damage is too great (due to the proximity of vi- tal structures) to use stereotactic radiotherapy in MSCC (24). In the absence of MSCC, stereotactic radiation can be used as definitive treatment (25). 4.6 Surgery The surgical approach to MSD treatment has changed dramatically in recent decades. The established surgical practice before the end of the 20th century was posterior decompression (laminectomy), but this led to poor treatment results. Because metastatic spinal cord com- pression is anterior to the spinal cord, such an interven- tion did not eliminate the cause of the problem at all, but caused additional spinal instability. Later, decompres- sion by ventral resection of the tumour was developed (2,7,8,27,29). The basis of surgical treatment of spinal metastases is the removal/debulking of the tumour to alleviate the pressure on surrounding neural tissue, fol- lowed by instrumented fusion (40), as shown in Figure 4. In 2005, Patchell et al published a ground-breaking study in which they demonstrated markedly better out- comes in MSCC treatment in the group treated with de- compressive surgery followed by radiotherapy compared with the group treated with radiotherapy alone. In par- ticular, the neurological outcome was markedly better (the ability to walk was 62% in the group that was treated with surgery and radiotherapy vs. 19% in the group that was treated with radiotherapy alone). Radiosensitive tu- mours were excluded from the study (33). 124 CYTOLOGY, ONCOLOGY, CANCEROLOGY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3141 Figure 5: Algorithm for spinal metastasis treatment. palliative external radiation therapy and palliative care SPINAL METASTASIS mechanical instability > 3 monthsestimated survival <3 months stable spine spinal cord compression the spinal cord is not compromised surgical decompression MANAGEMENT BY ONCOLOGIST surgical stabilization MECHANICAL ASSESSMENT SYSTEMIC ASSESSMENT NEUROLOGIC ASSESSMENT Surgical treatment is not in its essence oncological, which means that surgery alone is not locally curative. The recurrence rate in one series of patients was ex- tremely high (96% at four years) (42). Kaloostian et al published an analysis of various surgical procedures for MSD treatment: laminectomy with or without radio- therapy achieved neurological improvement in 46%, laminectomy with radiotherapy and posterior stabili- zation in 62%, and anterior decompression with stabili- zation was most successful with neurological improve- ment in 68% of cases (19). Patients with good systemic disease control and a solitary metastasis are suitable candidates for en bloc resection. In the case of thyroid and kidney cancer, such an approach is even more appropriate due to the rich vascularity of the metastases, making it risky to di- rectly involve the metastasis during surgery. In the case of pheochromocytoma, en bloc resection is also more appropriate because of the risk of a sympathomimetic effect (8). Kwon et al showed that patients who respond- ed to adjuvant therapy had significantly better survival with gross total resection compared with patients who underwent subtotal resection. In case of non-response to adjuvant therapy, the extent of resection does not af- fect survival (43). Separation surgery is a procedure used to treat MSD in which tumour resection is limited to removing only the part of the tumour that is in contact with neural elements, creating a 2–3 mm space between the tumour and the spinal cord. This allows for safe stereotactic ra- diotherapy 2–4 weeks after surgery (2). The goal is to achieve 360˚ decompression, which allows complete expansion of the dura and nerve roots. Incomplete sep- aration is more frequently associated with disease re- currence (18,24). The transpedicular approach is opti- mal (33). Due to the destabilization of the spine during surgery, the spine must be surgically stabilized at the same time (18). When using separation surgery with hypofractionated radiotherapy, local tumour progres- sion was observed in only 4.1% after one year (44). Clear indications for surgery are mechanical insta- bility, MSCC due to a radioresistant tumour, prepara- tion for stereotactic radiotherapy (separation surgery) and local tumour management in case radiotherapy cannot be used (18). Complications and the need for repeat surgery are an obvious problem of surgical treat- ment, which we must take into account when deciding on surgery (33). Vertebroplasty and kyphoplasty are minimally in- vasive procedures used to treat pathological fractures, 125 PROFESSIONAL ARTICLE Metastatic disease of the spine Started immediately DEXAMETHASONE 8 mg i.v. bolus followed by DEXAMETHASONE 8 mg/12 hours i.v./i.m. SYMPTOMS: paresis, sensory deficit, loss of bowel and bladder control, plegia Urgent imaging: whole spine MRI with contrast (CT myelography in case of contraindications for MRI) Assessment of spinal cord compression and spinal instability Consultation with a spinal surgeon MALIGNANT SPINAL CORD COMPRESSION Indications for surgery: EMERGENCY SURGERY No indications for surgery: EMERGENCY RADIOTHERAPY Consultation with an oncologist Postoperative radiotherapy Figure 6: Algorithm for malignant spinal cord compression management. provided that the spine is stable (2,7,18). Kaloostian et al state in their meta-analysis that vertebroplasty achieves an improvement in mobility in 62% and an improvement in pain in 91%. In the same analysis, they reported that kyphoplasty improves mobility in 69% and pain in 93% (19). Itshayek et al reviewed the literature on the topic of timing of surgery and radiotherapy. They found that the use of radiotherapy was safe for at least a week be- fore the procedure or afterwards (45). 5 Proposed treatment algorithm by the authors It is clear that prompt and appropriate treatment of a patient with MSD is extremely important. A pa- tient with a history of cancer and suspicious spinal pain should have an MRI performed as soon as possible. A patient with myelopathy (muscle weakness, sensory deficit, loss of bowel or bladder control) with known cancer should be admitted to hospital immediately and whole spine MRI with contrast should be performed immediately (to exclude multilevel spinal cord com- pression). If MSCC is suspected, the patient should receive anti-oedematous therapy with corticosteroids (dexamethasone 8 mg i.v. bolus, followed by dexameth- asone 8 mg/12 hours i.v./i.m./p.o.). On the basis of im- aging studies, predicted outcome and consultation with a spinal surgeon, further treatment follows. Appropri- ate management in patients with spinal metastasis is explained by an algorithm, as shown in Figure 5. Man- agement of MSCC is shown in Figure 6. Conflict of interest None declared. 126 CYTOLOGY, ONCOLOGY, CANCEROLOGY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3141 References 1. Ciftdemir M, Kaya M, Selcuk E, Yalniz E. Tumors of the spine. World J Orthop. 2016;7(2):109-16. DOI: 10.5312/wjo.v7.i2.109 PMID: 26925382 2. Yurter AJ, Sciubba DM. Management of Metastatic Spine Disease. JSM Neurosurg Spine. 2014;2(2):1020. 3. Choi D, Crockard A, Bunger C, Harms J, Kawahara N, Mazel C, et al.; Global Spine Tumor Study Group. Review of metastatic spine tumour classification and indications for surgery: the consensus statement of the Global Spine Tumour Study Group. Eur Spine J. 2010;19(2):215-22. DOI: 10.1007/s00586-009-1252-x PMID: 20039084 4. Klimo P, Schmidt MH. Surgical management of spinal metastases. Oncologist. 2004;9(2):188-96. DOI: 10.1634/theoncologist.9-2-188 PMID: 15047923 5. Guzik G. Current Incidence of Different Morphological Types of Malignant Metastases to the Spine Based on Magnetic Resonance Imaging. Ortop Traumatol Rehabil. 2017;19(2):137-44. DOI: 10.5604/15093492.1238001 PMID: 28508764 6. Perrin RG, Laxton AW. Metastatic spine disease: epidemiology, pathophysiology, and evaluation of patients. Neurosurg Clin N Am. 2004;15(4):365-73. DOI: 10.1016/j.nec.2004.04.018 PMID: 15450871 7. Fridley JS, Hepel JT, Oyelese AA. Current Treatment of Metastatic Spine Tumors - Surgery and Stereotactic Radiosurgery. R I Med J (2013). 2017;100(6):18-20. PMID: 28564663 8. Galgano M, Fridley J, Oyelese A, Telfian A, Kosztowski T, Choi D, et al. Surgical management of spinal metastases. Expert Rev Anticancer Ther. 2018;18(5):463-72. DOI: 10.1080/14737140.2018.1453359 PMID: 29560739 9. L’espérance S, Vincent F, Gaudreault M, Ouellet JA, Li M, Tosikyan A, et al.; Comité de l’évolution des pratiques en oncologie. Treatment of metastatic spinal cord compression: cepo review and clinical recommendations. Curr Oncol. 2012;19(6):e478-90. DOI: 10.3747/co.19.1128 PMID: 23300371 10. Maccauro G, Spinelli MS, Mauro S, Perisano C, Graci C, Rosa MA. Physiopathology of spine metastasis. Int J Surg Oncol. 2011;2011:107969. DOI: 10.1155/2011/107969 PMID: 22312491 11. Algra PR, Heimans JJ, Valk J, Nauta JJ, Lachniet M, Van Kooten B. Do metastases in vertebrae begin in the body or the pedicles? Imaging study in 45 patients. AJR Am J Roentgenol. 1992;158(6):1275-9. DOI: 10.2214/ ajr.158.6.1590123 PMID: 1590123 12. Demirçay E, Civelek E, Demiralay E. Solitary spinous process metastasis: a case report. Eklem Hastalik Cerrahisi. 2013;24(1):58-61. DOI: 10.5606/ ehc.2013.14 PMID: 23441745 13. Iizuka Y, Iizuka H, Tsutsumi S, Nakagawa Y, Nakajima T, Sorimachi Y, et al. Diagnosis of a previously unidentified primary site in patients with spinal metastasis: diagnostic usefulness of laboratory analysis, CT scanning and CT-guided biopsy. Eur Spine J. 2009;18(10):1431-5. DOI: 10.1007/ s00586-009-1061-2 PMID: 19533181 14. Buyukbebeci O, Karakurum G, Tutar E, Gulec A, Arpacioglu O. Biopsy of vertebral tumour metastasis for diagnosing unknown primaries. J Orthop Surg (Hong Kong). 2010;18(3):361-3. DOI: 10.1177/230949901001800321 PMID: 21187552 15. Debono B, Braticevic C, Sabatier P, Dutertre G, Latorzeff I, Hamel O. The “Friday peak” in surgical referrals for spinal metastases: lessons not learned. A retrospective analysis of 201 consecutive cases at a tertiary center. Acta Neurochir (Wien). 2019;161(6):1069-76. DOI: 10.1007/s00701- 019-03919-z PMID: 31037499 16. Levack P, Graham J, Collie D, Grant R, Kidd J, Kunkler I, et al.; Scottish Cord Compression Study Group. Don’t wait for a sensory level—listen to the symptoms: a prospective audit of the delays in diagnosis of malignant cord compression. Clin Oncol (R Coll Radiol). 2002;14(6):472- 80. DOI: 10.1053/clon.2002.0098 PMID: 12512970 17. van Tol FR, Choi D, Verkooijen HM, Oner FC, Verlaan JJ. Delayed presentation to a spine surgeon is the strongest predictor of poor postoperative outcome in patients surgically treated for symptomatic spinal metastases. Spine J. 2019;19(9):1540-7. DOI: 10.1016/j. spinee.2019.04.011 PMID: 31005624 18. Spratt DE, Beeler WH, de Moraes FY, Rhines LD, Gemmete JJ, Chaudhary N, et al. An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report. Lancet Oncol. 2017;18(12):e720-30. DOI: 10.1016/S1470-2045(17)30612-5 PMID: 29208438 19. Kaloostian PE, Yurter A, Zadnik PL, Sciubba DM, Gokaslan ZL. Current paradigms for metastatic spinal disease: an evidence-based review. Ann Surg Oncol. 2014;21(1):248-62. DOI: 10.1245/s10434-013-3324-8 PMID: 24145995 20. Andreula C, Murrone M. Metastatic disease of the spine. Eur Radiol. 2005;15(3):627-32. DOI: 10.1007/s00330-004-2627-3 PMID: 15696290 21. Mossa-Basha M, Gerszten PC, Myrehaug S, Mayr NA, Yuh WT, Jabehdar Maralani P, et al. Spinal metastasis: diagnosis, management and follow- up. Br J Radiol. 2019;92(1103):20190211. DOI: 10.1259/bjr.20190211 PMID: 31322920 22. Szendrői M, Antal I, Szendrői A, Lazáry Á, Varga PP. Diagnostic algorithm, prognostic factors and surgical treatment of metastatic cancer diseases of the long bones and spine. EFORT Open Rev. 2017;2(9):372-81. DOI: 10.1302/2058-5241.2.170006 PMID: 29071122 23. Hanc M, Ravnik J, Movrin I, Kavalar R, Rečnik G. Prikaz bolnika z zasevkom v telesu vretenca L1 nejasnega izvora. Onkologija. 2013;17(2):149-52. 24. Laufer I, Bilsky MH. Advances in the treatment of metastatic spine tumors: the future is not what it used to be. J Neurosurg Spine. 2019;30(3):299- 307. DOI: 10.3171/2018.11.SPINE18709 PMID: 30835704 25. Barzilai O, Fisher CG, Bilsky MH. State of the Art Treatment of Spinal Metastatic Disease. Neurosurgery. 2018;82(6):757-69. DOI: 10.1093/ neuros/nyx567 PMID: 29481645 26. Laufer I, Rubin DG, Lis E, Cox BW, Stubblefield MD, Yamada Y, et al. The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist. 2013;18(6):744-51. DOI: 10.1634/theoncologist.2012-0293 PMID: 23709750 27. Yao A, Sarkiss CA, Ladner TR, Jenkins AL. Contemporary spinal oncology treatment paradigms and outcomes for metastatic tumors to the spine: A systematic review of breast, prostate, renal, and lung metastases. J Clin Neurosci. 2017;41:11-23. DOI: 10.1016/j.jocn.2017.04.004 PMID: 28462790 28. Bollen L, Wibmer C, Van der Linden YM, Pondaag W, Fiocco M, Peul WC, et al. Predictive Value of Six Prognostic Scoring Systems for Spinal Bone Metastases: An Analysis Based on 1379 Patients. Spine. 2016;41(3):E155- 62. DOI: 10.1097/BRS.0000000000001192 PMID: 26866742 29. Fridley J, Gokaslan ZL. The evolution of surgical management for vertebral column tumors. J Neurosurg Spine. 2019;30(4):417-23. DOI: 10.3171/2018.12.SPINE18708 PMID: 30933909 30. Barzilai O, Boriani S, Fisher CG, Sahgal A, Verlaan JJ, Gokaslan ZL, et al. Essential Concepts for the Management of Metastatic Spine Disease: What the Surgeon Should Know and Practice. Global Spine J. 2019;9(1):98S-107S. DOI: 10.1177/2192568219830323 PMID: 31157152 31. Bilsky MH, Laufer I, Fourney DR, Groff M, Schmidt MH, Varga PP, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13(3):324-8. DOI: 10.3171/2010.3.SPINE09459 PMID: 20809724 32. Laufer I, Zuckerman SL, Bird JE, Bilsky MH, Lazáry Á, Quraishi NA, et al. Predicting neurologic recovery after surgery in patients with deficits secondary to MESCC: systematic review. Spine. 2016;41:S224-30. DOI: 10.1097/BRS.0000000000001827 PMID: 27488300 33. Yahanda AT, Buchowski JM, Wegner AM. Treatment, complications, and outcomes of metastatic disease of the spine: from Patchell to PROMIS. Ann Transl Med. 2019;7(10):216. DOI: 10.21037/atm.2019.04.83 PMID: 31297381 34. George R, Jeba J, Ramkumar G, Chacko AG, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev. 2015(9). DOI: 10.1002/14651858.CD006716. pub3 PMID: 26337716 127 PROFESSIONAL ARTICLE Metastatic disease of the spine 35. Kumar A, Weber MH, Gokaslan Z, Wolinsky JP, Schmidt M, Rhines L, et al. Metastatic Spinal Cord Compression and Steroid Treatment: A Systematic Review. Clin Spine Surg. 2017;30(4):156-63. DOI: 10.1097/ BSD.0000000000000528 PMID: 28437329 36. Andronis L, Goranitis I, Bayliss S, Duarte R. Cost-Effectiveness of Treatments for the Management of Bone Metastases: A Systematic Literature Review. PharmacoEconomics. 2018;36(3):301-22. DOI: 10.1007/s40273-017-0595-0 PMID: 29224174 37. Choi D, Bilsky M, Fehlings M, Fisher C, Gokaslan Z. Spine Oncology- Metastatic Spine Tumors. Neurosurgery. 2017;80(3S):S131-7. DOI: 10.1093/neuros/nyw084 PMID: 28350950 38. Bijlani A, Aguzzi G, Schaal DW, Romanelli P. Stereotactic radiosurgery and stereotactic body radiation therapy cost-effectiveness results. Front Oncol. 2013;3:77. DOI: 10.3389/fonc.2013.00077 PMID: 23580234 39. Yamada Y, Katsoulakis E, Laufer I, Lovelock M, Barzilai O, McLaughlin LA, et al. The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery. Neurosurg Focus. 2017;42(1):E6. DOI: 10.3171/2016.9.FOCUS16369 PMID: 28041329 40. Ahangar P, Aziz M, Rosenzweig DH, Weber MH. Advances in personalized treatment of metastatic spine disease. Ann Transl Med. 2019;7(10):223. DOI: 10.21037/atm.2019.04.41 PMID: 31297388 41. Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-8. DOI: 10.1016/S0140-6736(05)66954-1 PMID: 16112300 42. Klekamp J, Samii H. Surgical results for spinal metastases. Acta Neurochir (Wien). 1998;140(9):957-67. DOI: 10.1007/s007010050199 PMID: 9842434 43. Kwon YM, Kim KS, Kuh SU, Chin DK, Jin BH, Cho YE. Survival rate and neurological outcome after operation for advanced spinal metastasis (Tomita’s classification > or = type 4). Yonsei Med J. 2009;50(5):689-96. DOI: 10.3349/ymj.2009.50.5.689 PMID: 19881974 44. Laufer I, Iorgulescu JB, Chapman T, Lis E, Shi W, Zhang Z, et al. Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18(3):207-14. DOI: 10.3171/2012.11.SPINE12111 PMID: 23339593 45. Itshayek E, Yamada J, Bilsky M, Schmidt M, Shaffrey C, Gerszten P, et al. Timing of surgery and radiotherapy in the management of metastatic spine disease: a systematic review. Int J Oncol. 2010;36(3):533-44. PMID: 20126972