Current Management of Vertebral Metastases: Teamwork

Abstract

Metastatic spinal disease is common in patients with advanced cancer, and leads to complications inherent in its progression, such as pathological vertebral fracture and metastatic neural compression. A review of the current therapeutic aspects regarding the progression and complications of metastatic spinal disease was performed, highlighting its systemic, personalized approach. Our aim is to provide information about the current treatment of this condition and the usefulness of its systemic and multidisciplinary management.

Keywords

spinal metastases - spinal radiosurgery - separation surgery - review

Basic Concepts

During their disease, 40% of cancer patients present with vertebral metastases, 80% of which originate from breast tumors, prostate tumors, and lung neoplasms. The main dissemination route is hematogenous: arterial flow for the vertebral endplates; venous return via the Batson's plexuses for the vertebral body; tissue-specific intravertebral dissemination mechanisms; and via intravertebral circulation.[1] In total, 75% of vertebral metastases are located at the thoracolumbar spine; 80% of metastases occur in the vertebrae, mainly at the junction of the pedicle and the vertebral body; 15% are located in perivertebral tissues; and only 5% of metastasis are within the epidural space. Vertebral metastases generally present multiple locations, with only 10% of isolated lesions.[2]

In postmortem studies, 30% to 70% of the cancer patients present metastases. Approximately 25% of cancer patients have symptoms. In these subjects, the most frequent symptom is pain, with a rate of 75%, followed by pathological vertebral fracture in 10%, hypercalcemia in 10%, and spinal or root injury in 5% of the patients.[3]

In the vast majority of patients, the goal of the treatment of vertebral metastases is palliative, focused on the symptoms resulting from the invasion of the vertebra and epidural space by the tumor, and it includes management of the pain, improvement or preservation of the neurological function, prevention or treatment of the pathological fracture, and control of the local disease. The ultimate goal is to improve the quality of life in the last days of the patient, always taking care to minimize the adverse effects or complications of the therapy.[4]

The present paper aims to review the literature and discuss our conduct in the treatment of vertebral metastases from a comprehensive point of view, regarding the oncologist, the radiotherapist, and the spine surgeon.

The therapeutic tools available for the treatment of local complications of vertebral metastases include medication (corticosteroids, chemotherapy, hormonal therapy, immunotherapy, and osteoclast inhibitors), radiotherapy, and surgery.

Medical Treatment: Increased Survival and Control of the Metastases

The development of screening techniques significantly decreased the incidence of the main tumors that affect the population worlwide, such as breast, lung, and prostate.[5]

The evolution and progress of pharmacological and biological therapies have enabled a sustained advancement in the cure of cancer and, above all, in the prolongation of the life expectancy of patients with advanced tumors.

Regarding breast cancer, the recognition of different molecular subtypes with distinct clinical behavior,[6],[7] and the discovery, in the 1980s, of a transmembranic protein called human epidermal growth factor receptor 2 (HER2)[8] led to the revolutionary development of biotechnology, which enabled the clinical application of monoclonal antibodies such as trastuzumab, which has favorably impacted both early and late-stage diseases and increased the cure and survival rates.[9] [10] Next, the introduction of other anti-HER-2 drugs, such as pertuzumab,[11] trastuzumab emtansine (TDM-1)[12] and lapatinib, has contributed to the care of patients with advanced cancer.[13] The application of different types of hormone therapy in patients expressing hormone receptors has expanded the possibility of cure in early stages[14] and a prolonged survival in advanced stages.[15] More recently, the incorporation of cyclin-dependent kinase inhibitors, such as palbociclib, improved the rates of response and progression-free survival.[16]

Lung tumor is the leading cause of cancer mortality in the world,[17] so efforts have been made to improve cytotoxic chemotherapy combinations.[18] A new drug class, referred to as tyrosine kinase inhibitors, interferes with the signaling pathways at a specific point, improving progression-free survival in patients with specific mutations.[19] The most recent innovation in this area has been the development of immunotherapy, which improved the survival of lung cancer patients, including those with primary tumors and metastases.[20] [21] [22] [23]

Prostate cancer is a common tumor. In advanced stages, it is associated with a high frequency of bone metastases, which can be controlled with hormone therapy and chemotherapy. Historically, the first hormonal intervention consisted of surgical castration.[24] Subsequently, chemical castration with luteinizing hormone-releasing hormone (LH-RH) analogs was implemented;[25] next, these drugs were combined with antiandrogen agents for complete androgen blockade.[26] More recently, new antiandrogen agents, such as enzalutamide[27] or abiraterone,[28] were introduced. Other new available tools, such as chemotherapy with docetaxel and cabazitaxel, have significantly improved overall survival.[29] [30] [31] [32]

These new oncological therapies significantly prolonged the survival of the patients, and enable subjects with advanced cancer to live in good general conditions. However, they also resulted in a greater opportunity for the development of vertebral metastases and related complications, such as pain, vertebral fracture, and/or neurological compromise.[33]

Preventive Treatment of the Complications of Vertebral Metastases

The administration of osteoclast inhibitors, such as bisphosphonates, or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, such as denosumab, has shown a significant role in the reduction of metastasis-related bone events, including pathological vertebral fracture, the need for surgery on metastatic bone, or myeloradicular compression. Its benefits far outweigh its potential complications, such as mandibular bone necrosis and atypical fractures. Pamidronate was one of the first intravenous bisphosphonates to show a significant reduction in skeletal events and a delay in the first bone event compared to a placebo.[34] Subsequently, zoledronic acid demonstrated its superiority in comparison to pamidronate.[35] A new therapeutic family, the so-called RANKL inhibitors (denosumab), demonstrated a superiority of up to 18% over zoledronic acid.[36]

The selection of the antiresorptive treatment to prevent metastatic events is based on clinical aspects, including bone extension and renal function. Patients with normal renal function are treated with zoledronic acid, whereas those with impaired renal function or very extensive bone involvement receive denosumab.

Preventive therapies are limited by symptomatic vertebral metastases featuring pain or pathological fracture. Osteoclast inhibitors have not been shown to reduce pain and the compression of neural structures at this stage. Although they should continue to be used to lower the risk of other bone lesions in minor stages, complicated, symptomatic vertebral metastases require specific treatment, with radiotherapy and/or surgery.[37]

Categorization of Patients with Vertebral Metastases

We have incorporated the neurologic, oncologic, mechanical, and systemic (NOMS)[33] decision framework to assess, categorize and define the treatment of patients with vertebral metastases ([Table 1]). This system considers a comprehensive evaluation of the patient with vertebral metastases, taking into account the neurological (N) status, that is, the degree of epidural compression of the neural structures by the tumor and the resulting neurological compromise[38] ([Figure 1]); oncological (O) aspects, that is, tumor biology and radiosensitivity ([Table 2]); spinal mechanical (M) stability in the presence of a vertebral metastasis per the Spine Instability Neoplastic Score (SINS)[39] ([Table 3]) and the resulting risk of fracture, pain and/or neural compression; and the systemic (S) general medical status of the patient, that is, their potential survival.

Table 1

N	Neurological status
O	Oncological considerations
M	Mechanical stability
S	Systemic diseasea

Fig. 1 Six-degree scale of Spinal Cord Epidural Compression.[38] 0: lesion confined to the vertebral body; 1a: invasion of the epidural space with no dural sac deformation; 1b: dural sac deformation with no spinal cord impingement; 1c: spinal cord impingement with no cord compression; 2: cord compression with visualization of the cerebrospinal fluid; and 3: spinal cord impingement with no visualization of the cerebrospinal fluid.

Table 2

Radiosensitivea	Radioresistanta
Lymphoma	Renal
Multiple myeloma	Thyroid
Seminoma	Hepatocellular
Breast	Gastrointestinal
Prostate	Lung (non-small cells)
Ovary	Sarcoma
Neuroendocrine carcinoma	Melanoma

Table 3

SINS elements	Scorea
Location
Joint (occipital-C2, C7-T2, T11-L1, L5-S1)	3
Mobile spine (C3-C6, L2-L4)	2
Semirigid spine (T3-T10)	1
Rigid spine (S2-S5)	0
Pain
Mechanical	3
Occasional and not mechanical	1
No pain	0
Type of bone lesion
Lytic lesion	2
Mixed (lytic and sclerotic) lesion	1
Sclerotic lesion	0
Radiographic alignment of the spine
Subdislocation/Translation	4
Kyphosis/Scoliosis (de novo)	2
Normal alignment	0
Collapse or compromise of the vertebral body
> 50%	3
< 50%	2
No collapse, but body compromise > 50%	1
None of the above	0
Compromise of posterolateral elementsb (fracture or tumoral lesion)
Bilateral	3
Unilateral	1
None of the above	0

Using this evaluation system, we can classify each patient with a symptomatic vertebral metastasis and indicate a tailored treatment.

Radiation Therapy

The ideal indication for radiotherapy as a sole treatment is for cases of vertebral metastasis causing pain at rest but with sustained mechanical stability of the spine despite tumor invasion.

Several external radiation therapy techniques are currently available. Different dose-fractionation schemes can be defined based on the therapeutic goal, and on the volume and origin of the tumor. A single fraction of 8 Gy can be administered for pain relief in highly-symptomatic patients with a short life expectancy. Subjects with better life expectancies can receive conventional radiotherapy, such as 30 Gy divided into 10 sessions. These treatments enable total or partial control of pain in 80% of the patients, occasionally for many years.

High-dose regimens in few fractions can be used depending on the proximity to especially sensitive organs, for re-irradiation or in radioresistant tumors. Image-guided stereotactic radiotherapy techniques (IGRTs) are ideal for these cases, because they minimize the irradiation margins required between the tumor tissue and the surrounding healthy tissues, especially at the spinal cord, thus reducing complications such as radiation myelopathy.

The availability of these new techniques resulted in a significant increase in the total dose administered in some special cases, reducing “radioresistance” in selected tumors, such as those of renal origin.[40] However, it is important to remember that these techniques considerably increase the costs of the treatment; as such, their use must be rational.

In addition, since up to 38% of patients submitted to radiotherapy can present collapse, pain and/or neural compression 8 to 10 weeks postirradiation, radiological and clinical follow-ups are recommended to investigate these complications.[41]

With the exception of vertebral lymphomas or myelomas, both of which are highly-sensitive to corticosteroids and radiotherapy, the exclusive use of irradiation as a treatment for neurological compromise due to epidural tumor invasion has a significantly lower yield of neurological recovery and an increased risk of local complications. Therefore, the literature recommends that these patients are submitted to tumor decompression surgery and surgical stabilization before radiotherapy, if allowed by their medical condition.[42]

Surgical Treatment

Surgery is the last tool in the treatment of symptomatic spinal metastases. The indication for surgery is limited to the treatment of mechanical pain resulting from a pathological fracture and compression of neural structures.

Patients with mechanical pain due to pathological fracture but no neurological compromise and with an intermediate score on the SINS, potentially indicating mechanically-unstable injuries, are submitted to vertebral augmentation techniques, such as vertebroplasty or kyphoplasty. These are little aggressive, percutaneous surgical procedures with a proven efficacy for pain control in pathological vertebral fractures. They consist of an intravertebral injection of acrylic cement (polymethylmethacrylate), which is distributed within the vertebra for fracture stabilization, preventing further vertebral collapse. Fortunately, severe complications from these procedures, such as cement leakage into the spinal canal or pulmonary embolism caused by the cement, are rare.[43] These techniques can be combined with radiotherapy for local metastasis control with no reduction in the efficacy of the irradiation.[44]

In patients with a pathological fracture or a mechanically-unstable vertebral metastatic lesion (high SINS score) but no neurological compromise, we perform percutaneous vertebral fixation techniques. These little aggressive techniques enable the effective stabilization of the compromised spinal segment; in addition, they significantly reduce the risks of infection when compared to conventional open spinal fixation surgery. After percutaneous stabilization, the patients can undergo early adjuvant radiotherapy with no increased risk of surgical wound-related complications.[45] [46] [47]

In patients with neurologically-compromised vertebral metastasis, either due to vertebral collapse or epidural tumor invasion, and resistance to conventional radiotherapy, the literature recommends epidural decompression, surgical stabilization, and postoperative high-intensity radiotherapy.[33],[48] Conventional epidural decompression and open fixation surgery, although effective in the improvement of the neurological status, have high complication rates, ranging from 25% to 40%. In spite of improving the neurological function, this treatment can drastically worsen the quality of life during the last months of the patient.[45] Following the trend of less aggressive techniques, these patients are submitted to vertebral fixation and minimally-invasive epidural decompression. Neural decompression is performed transmuscularly, away from the midline, along with an intralesional resection. This procedure reduces the tumoral mass around neural structures, and it is referred to as “tumor separation surgery.” It creates a space between the tumor and the dural sac, so that postoperative stereotactic radiotherapy can be effectively applied to the remaining tumor with a safety margin that avoids damage to the neural structures. The association of minimally-invasive techniques, properly applied to avoid insufficient decompression, to postoperative stereotactic radiotherapy combines the advantages of vertebral fixation and neural decompression of lower surgical risk with high-concentration radiotherapy, achieving effective local control, with recurrence rates lower than 5% per year[48] [49] [50] ([Figure 2]). In our opinion, minimally-invasive surgery for vertebral metastases may benefit patients with a limited life expectancy or a higher risk of complications.

Fig. 2 Tumor separation surgery and postoperative stereotactic radiotherapy. A 74-year-old man with prostate cancer. After eight years of treatment with hormonal blockers, the patient started to present progressive mechanical back pain and paraparesis. (A-D) Magnetic resonance imaging (MRI) scans of the spine, showing T10 vertebral metastasis with grade-3 cord compression. (E) Percutaneous fixation surgery by posterior approach to T8-T12. (F) Decompression of the spinal canal, with resection of the epidural tumor mass. (G-H) Postoperative spinal radiography showing correct implant positioning and spinal alignment. (I) Postoperative computed tomography image showing spinal decompression. (J) Planning of the image-guided stereotactic radiotherapy techniques (IGRTs). (K-L) Postradiotherapy spinal MRI. Patient with updated survival of 20 months and recovery from the paraparesis.

Conclusions

For patients with spinal metastases, the treatment is mainly palliative. Advances in oncological and adjuvant therapies, in addition to the technological development of implants and less invasive surgical techniques, resulted in increased survival with a lower rate of complications. This enables us to meet the main therapeutic goal, which is to improve the patients' quality of life during their last days.

The NOMS decision framework provides a broad view of the patient and of their spinal metastatic disease, so treatment can be tailored according to neurological status, tumor biology, spinal stability, and general health condition.

Fluent communication among oncologists, radiotherapists and spine surgeons consolidates this therapeutic framework, offering patients with advanced cancer personalized, timely, and effective solutions, with minimal morbidity.

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Publikationsverlauf

Eingereicht: 05. Juli 2020

Angenommen: 31. März 2021

Artikel online veröffentlicht:
30. September 2021