Management of bone metastasis with stereotactic body radiation therapy for pain control and spinal cord compression: a systematic review

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Management of bone metastasis with stereotactic body radiation therapy for pain control and spinal cord

compression: a systematic review

Isabel Cristina Usuga Public health

University of Eastern Finland Faculty of Health Sciences School of Medicine

May 2021

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University of Eastern Finland, Faculty of Health Sciences School of Medicine

Public health

Usuga, Isabel: Management of bone metastasis with stereotactic body radiation therapy for pain control and spinal cord compression: a systematic review.

Master's thesis, 70 pages, 4 appendices (9 pages).

Thesis instructors: Professor of epidemiology Tomi-Pekka Tuomainen, Adjunct Professor, Medical physicist Tuomas Virén and Radiation oncologist Kristiina Vuolukka

May 2021

Keywords: Bone metastases, Radiation therapy, Stereotactic body radiotherapy, Pain control, Spinal cord compression

Stereotactic body radiation (SBRT) has allowed the application of higher doses per fraction with greater sparing of healthy tissue. The main aim of this research was to evaluate the use of SBRT for treatment of pain and spinal cord compression (SCC) in cancer patients with bone

metastasis. A literature search was conducted in PubMed, Medline, and Cochrane library from 2000 to February 2021. Selected studies comparing conventional radiotherapy and SBRT were grouped in a subcategory for meta-analysis for both variables pain response and SCC. Forest plots based on each study’s odd ratios were computed using a random effects model and the Mantel–Haenszel statistic. A total of 15 studies were included in this review. Pain response and SCC variables measures varied significantly in the studies. However, pain response measures were congruent for meta-analysis. Meta-analysis presents a significant improvement of 38 % in pain response in SBRT compared to conventional radiotherapy (RT) after 3 months.

Heterogeneity on SCC measures made it difficult to compare outcomes across trials. In

conclusion, SBRT is effective for pain control in a significant proportion of patients three months after the treatment. This is comparable to conventional radiotherapy pain response rates. In addition, evidence suggest that the use of SBRT could be feasible for epidural tumor reduction and low rate of pathologic fractures compare to conventional radiotherapy notwithstanding there still a need of optimization in balanced dose/toxicity regimes for SBRT.

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Abbreviations and Acronyms

2D Two dimensional

3D-CRT Three dimensional conformal

4DCT Four-dimensional computed tomography

ASTRO American society for therapeutic radiology and oncology

BED Biological equivalent dose

CR Complete response

CSF Cerebrospinal fluid

CT Computed tomography

CTCAE Common Terminology Criteria for Adverse Events

CTV Clinical target volume

DFI Disease-free interval

DFS Disease-free survival

DVH Dose- volume histogram

EBRT External beam radiotherapy

ESTRO European society of therapeutic radiation oncology

FDG 18F-fluorodeoxyglucose

Fx Fraction

GTV Gross target volume

Gy Gray

HCC Hepatocellular carcinomas

IAEA International atomic energy agency

ICRU International commission on radiation units & measurements

IGRT Image guided radiotherapy

IMRT Intensity modulated radiotherapy

IR Indeterminate response

ITV Internal target volume

JASTRO Japanese Society for Radiation Oncology

kV Kilo voltage

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LC Local control

LINAC Linear accelerator

MDT Metastasis directed therapies

MED Morphine-equivalent doses

MFRT Multiple fraction radiation therapy

MLC Multi leaf collimator

MM Multiple myeloma

MRI Magnetic resonance imaging

MV Mega-electron-volt

NRS Numerical rating scale

OAR Organs at risk

OM Oligometastatic

OMD Oligometastatic disease

OMED Oral morphine equivalent dose

OS Overall survival

PAP Prostatic acid phosphatase

Pca Prostate cancer

PERCIST PET response criteria in solid tumors

PET Positron emission tomography

PFS Progression-free survival

PMMA Poly(methyl methacrylate)

PP Pain progression

PR Partial response

PRV Planning organ at risk volumes

PSA Prostate specific antigen

PSMA Prostate-specific membrane antigen PTHrP Parathyroid hormone-related protein

PTV Planning target volume

QA Quality assurance

QOL Quality-of-life

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RCC Renal cell carcinoma

RECIST Response evaluation criteria in solid tumors RT Radiotherapy

RTOG Radiation therapy oncology group SBRT Stereotactic body radiation therapy

SCC Spinal cord compression

SRE Skeletal related event

TFI Treatment-free interval

VAS Visual analogue scale

VCF Vertebral compression fractures

VMAT Volumetric modulated arc therapy

WHO World Health Organization

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1 Introduction

The interest in stereotactic body radiation therapy (SBRT) has grown during in the last two decades. This technique allows to deliver high radiation dose per fraction by combining image guidance, accurate dose delivery techniques, and modern treatment planning techniques to treat intra and extracranial tumors (Ishigaki et al. 2019). The use of SBRT have develop from an exclusive treatment for lung, liver, and spinal tumors to more complex and different applications such as treatments for pancreatic cancer, primary liver cancer, prostate cancer, renal cell cancer, head and neck cancer, gynecologic cancer, and non-spine bone metastases (Ishigaki et al. 2019).

Interest to SBRT is also increasing as an alternative to some well establish treatments performed with conventional external beam radiotherapy (EBRT). Some of the existing data regarding the treatment of bone metastases suggest that radiosurgery is safe and can provide durable symptomatic response, local control and prevent pathologic fractures as well as spinal cord compression (Gerszten et al. 2009). As a result of multiple studies performed in treatment centers around the world some indicators, prescription dose and treatment technique

recommendations have been established. However, further research is still needed to obtain comprehensive treatment guidelines for different indications (Lo et al. 2015).

One of recent trends is to use SBRT for bone metastases which is one of the most common cause of cancer-related pain (Popovic et al. 2015). Guidelines for SBRT to treat bone metastases are not fully established. However, some trends for spine and oligometastases disease have started to emerge. Literature providing standardization or consensus about SBRT still growing internationally and “Technical Specifications of Radiotherapy Equipment for Cancer Treatment”

and “Bone health in cancer: ESMO Clinical Practice Guidelines” are some examples (World Health Organization & International Atomic Energy Agency 2021, Coleman et al. 2020). Nevertheless, there still a need to establish more robust evidence about SBRT clinical recommendations. The main aim of this research is to evaluate the use of SBRT for treatment of pain and spinal cord compression in cancer patients with bone metastasis.

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2 Bone metastasis and stereotactic body radiation therapy

2.1 Bone metastasis

Metastasis is a systematic process where cells from a primary tumor detach, migrate and invade a nearby or distant tissue. This process is highly complex and seems to start even before the arrival of the circulating tumor cells to the host tissue. It can be described in to two stages according to Ingangi et al. (2019).

1. Pre-metastatic niche formation. The pre-metastatic niche formation stage consists of the active participation of the primary tumor by preparing the microenvironment at the host tissue that will allow the colonization of future disseminated tumor cells. Different factors have been identified to be involved in this process include soluble and

inflammatory factors, cytokines and chemokines, exomes and oncosomes.

2. Metastatic niche formation. The metastatic niche formation stage facilitates the

colonization and the establishment of the disseminated tumor cells. The metastatic niche provides signals that regulate processes like epithelial mesenchymal transition and proliferation which determine the dormancy or activation of the disseminated tumor cells.

The migration of circulating tumor cells is not always successful as some of these cells do not survive immune system or vascular barriers. However, bone and its continuous dynamics to maintain the integrity and skeletal support - specifically its vascular system with large

intercellular spaces - lack of venous valves, hematopoietic stem cell and osteoblastic microenvironments seems to highly favour the disseminated tumor cells and metastasis processes (Ingangi et al 2019).

The incidence of bone metastases is surpassed only by lung and liver metastases and the incidence varies according to type of primary tumor. It is estimated that at least 80 % of bone metastases are developed by breast, prostate, lung and kidney cancers as well as by multiple myeloma (MM) (Heymann 2015, Coleman, R. et al. 2020). There is also variation in how the

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tumor cell phenotype compromise the balance of the dynamics of bone remodelling and formation during metastasis: bone metastases are classified as osteolytic when lesion intervenes in bone reabsorption. When osteoblasts overrule in bone formation the bone metastases are classified as sclerotic. Both kinds of lesions can present also at the same time (mixed lesions) (Heymann 2015). In general, the incidence of bone metastases has increased due to increase in survival time and rise in the use of diagnostic imaging (Kim et al. 2008)

2.1.1 Bone metastases and primary tumor Breast cancer

Bone metastases due to metastatic breast cancer is most frequently seen in spine, pelvis, ribs, skull, femur, humerus, and scapula. Approximately 65 % of the lesions are lytic followed by 25 % of mixed lesions. Only 10 % of the bone metastases of the breast cancer represent as sclerotic lesions. On average metastases develop within 30 months after treatment of the primary tumor.

However, there appear to be a mechanism that allows tumor cells to remain dormant and, in some cases, bone metastases do not manifest itself until 10 to 20 years after initial treatment.

Some of the immunohistochemical markers used to identify the bone metastases to be due to breast cancer are estrogen receptor, mammoglobin, GCDPF-15 and GATA-3. (Heymann 2015)

Prostate cancer

Between 80-100 % of the patients with metastatic prostate cancer (Pca) develop bone

metastases and it is the main cause of death among these patients . It is estimated that the time between the diagnosis of bone metastases and death is about three to five years. Bone

metastases of Pca present mainly as sclerotic lesions (approx. 75 %) followed by mixed 15 % and lytic lesions 10 %. However, at the initial stage of diagnosis bone involvement is not common.

Some of the immunohistochemical markers used to identify the bone metastases to be due to Pca are PAP and PAS (Heymann 2015).

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Lung cancer

Bone metastases of lung cancer can manifest itself as acral metastases affecting distal areas such as elbow and knee. Most of the bone lesions of the metastatic lung cancer (approx. 80 %) are lytic. Only a small proportion of 5 % of the lung cancer bone metastases are present as sclerotic lesions and they are associated to adenocarcinomas and small cell lung cancer. The rest (15 %) of these bone metastases present as mixed ones. Some of the immunohistochemical markers used to identify the bone metastases to be due to lung cancer are TTF-1 and Napsin A (Heymann 2015).

Kidney cancer

Along with thyroid cancer, metastatic kidney cancer usually develops solitary bone metastasis. A vast majority (approx. 90 %) of the bone lesions of renal cell carcinoma (RCC) are lytic and they are characterized by triggering a large bone reabsorption. Bone metastases of RCC are often very painful and they can also represent as hemorrhagic. Some of the immunohistochemical markers used to identify the bone metastases to be due to kidney cancer are RCC, PAX 8 and CD10 (Heymann 2015).

Thyroid cancer

Approximately 8% of patients with metastatic thyroid cancer develop bone metastasis and the lesions are most often located in spine, pelvis, and ribs. The bone metastases may represent a decrease in the survival of patients from ten years without metastases to only five years with bone metastases. The bone lesions are often lytic and one of the most severe characteristics of the bone lesions of thyroid cancer is that they can be hemorrhagic. Some of the

immunohistochemical markers used to identify the bone metastases to be due to kidney cancer are Thyroglobulin and TTF-1 (Muresan et al. 2008, Heymann 2015).

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Other primary tumors

In addition to the solid tumors mentioned above, also other solid tumors such as hepatocellular carcinomas (HCC), melanomas and neuroblastomas can lead to bone metastases although with lower incidences (Heymann 2015). In HCC the most common site of metastasis are spine and pelvis. Melanoma concentrates most of its bone lesions in the axial skeleton and

neuroblastomas usually appear in the skull and long bones (Heymann 2015)

Unknown primary tumor

In case of metastaic bone lesions, the identification of the primary tumor is not always possible, although it is an atypical condition. Among the patients with unknown primary tumor, the initial histopathology reveals undifferentiated tumors and the examinations and medical history do not provide clarity to the origin of the adenocarcinoma or carcinoma. However, different

techniques involving the morphology or imaging could help to suggest the origin. In some cases, the diagnosis of metastases can even be the first sign to identify the disease (Heymann 2015).

2.1.2 Classification

The implementation of metastasis directed therapies (MDT) has evolved in parallel with the availability of new diagnostic and therapeutic tools. However, MDT is still experimental and prospective studies regarding its clinical benefits are awaited and its role in guidelines is still to be determined. Also, the terminology such as oligometastatic state and others derived from it are still evolving and needs to be determined in definitive way (Lievens et al. 2020).

During the last decade, the use of the term oligometastatic (OM) has become widely used to define an intermediate state between localized disease and systemic metastatic disease.

However, its definition varies between the different reports. In 1995 (Hellman & Weichselbaum) defined oligometastatic disease as “tumor stages intermediate between purely localized lesions and those widely metastatic”. Therefore, international organizations such as European Society of

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Therapeutic radiation Oncology (ESTRO) and American Society for Therapeutic Radiology and Oncology (ASTRO) have developed a consensus document to define oligometastatic disease from the perspective of radiation oncology. The results of this review document can be defined in 16 statements presented in Table 1. (Lievens et al. 2020).

Table 1. ESTRO and ASTRO consensus defining oligometastatic disease (Lievens et al. 2020).

Statement 1 The concept of oligometastatic disease (OMD) is independent of primary tumor type and histology.

Statement 2 The concept of OMD is independent of the metastatic site or sites.

Statement 3 There are currently no validated biomarkers that differentiate between the oligometastatic and the polymetastatic state.

Statement 4 Diagnostic imaging should be performed using whichever modalities are most adequate to image sites of common metastases and to detect small lesions for that histology.

Statement 5 The ability to safely treat all oligometastases with radiotherapy does not mean that one should treat every patient irrespective of other prognostic factors.

Statement 6 Regardless of the number of metastases, the risks and benefits of metastasis- directed radiotherapy should be balanced carefully in all oligometastatic patients.

Statement 7 OMD is differentiated into synchronous versus metachronous states, defined by the interval between primary cancer diagnosis and development of OMD.

Statement 8 Different states of systemic therapy induced OMD are reported in the literature, with inconsistent nomenclature and definition.

Statement 9 A disease-free interval (DFI) is not mandatory to define OMD.

Statement 10 A treatment-free interval (TFI) is not mandatory to define OMD.

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Statement 11 There was no consensus on the criteria for a maximum number of metastases or organs for systemic therapy induced OMD.

Statement 12 Patients with prior polymetastatic disease can become OM based on response to systemic therapy.

Statement 13 The risk of treatment related toxicity impacts treatment indications for oligometastatic disease.

Statement 14 Several clinical outcome measures are considered as important endpoints.

They include measures such as overall survival (OS), disease-free survival (DFS) or progression-free survival (PFS), quality-of-life (QOL) or local control (LC), patient-reported outcome measures, cost, delay or deferral of systemic therapy and ability to stay on the same line of systemic therapy.

Statement 15 Although technology per se does not impact the indications, adequate technology and/or techniques (e.g., SBRT or hypofractionated image-guided radiotherapy) are a minimum requirement to treat OMD when pursuing curative intent.

Statement 16 Although there is a broad variation in the delivered doses being reported, the goal is control of the targeted metastasis for which the current data support a higher biological equivalent dose (BED >100 Gy), when it can be safely

delivered.

According to Lievens et al (2020) the definitions of the various new terms and endpoints vary between the different publications but are often referred as the following:

• Oligometastatic disease (OMD): “An intermediate state between local and systemic disease, where radical local treatment of the primary cancer and all metastatic lesions might have a curative potential. Usually considered as up to 3-5 separate lesions.”

• Synchronous OMD: “OMD at the time of initial diagnosis; primary tumor and limited number of metastases detected simultaneously.”

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• Metachronous OMD (often used interchangeably with oligo-recurrence):

“Oligometastatic recurrence during the course of disease at least three months after the initial diagnosis (‘metachronous’), as a state of metachronous limited recurrence. Many refer to the original definition of Niibe and Hayakwa: Metastases detected while the primary tumor is controlled and that can be treated with local therapy.”

• Oligo-Progression: “Few oligometastatic lesions progress on a background of widespread but stable systemic disease”

• Oligo Persistence: “Persistent oligometastatic lesions after systemic therapy”

2.1.3 Symptoms Pain

Pain is a characteristic symptom of skeletal metastases. The pain associated with metastasis involves tissue damage resulting from the interaction of bone mechanisms and tumor cells.

Tissue damage activates inflammatory processes, neurotransmitters, cytokines, and other factors that provide stimulus to active the receptors in the primary afferent fibers of adjacent tissue. Pain can be constant or intermittent. Continuous pain is insidious, difficult to locate, with constant presence and has a progression parallel to the disease. Intermittent pain is not

constant but has greater acuity which is known as incidental pain. Depending on the location of the lesion, metastases can limit joint movements and have localized inflammation (Heymann 2015, Coleman, Robert E. 2006).

The location of the metastases has an impact on the spectrum of symptoms. For example, when bone metastases appear at the base of the skull, they may present with headaches, cranial nerve palsies and neuralgia. In the weight bearing bones, such as the pelvis, lower limbs and back metastases can cause incident pain and mechanical instability. Metastases located in the vertebrae may manifest as pain in the neck and they may result into neurological implications (Coleman 2006).

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Hypercalcemia

The increase of calcium in the blood, hypercalcemia, results from the imbalance in bone remodeling due to the destruction of bone tissue by osteolytic metastases. Associated

symptoms are fatigue, anorexia, and constipation. The increase in serum calcium level may lead to mental deterioration and serious alterations in kidney function and, if not intervened, could result in death due to kidney failure and cardiac arrhythmias. Hypercalcemia is frequently seen in several types of tumors such as metastatic breast, lung, and kidney cancer as well as in hematological malignant tumors such as myeloma and lymphoma (Coleman 2006).

Tumor cells seems to stimulate the proliferation and activity of osteoclasts, increasing bone remodeling markers through humoral and paracrine factors. Parathyroid hormone-related protein (PTHrP) is a hormone associated with cancer cells. PTHrP levels are elevated in most patients with humoral hypercalcemia. The kidneys also intervene in malignant hypercalcemia increasing serum calcium levels even more due to an increase of renal calcium reabsorption mediated by PTHrP (Coleman 2006).

Pathological fractures

Damages of bone tissue caused by pathological fractures change the shape and the weight- bearing capacity of bones, particularly in large lytic lesions. In principle, pathological fractures manifest as microfractures and pain, progressing to clinical fractures later on. Fractures located in long bones and spine are associated with higher health risks and hence may significantly effect on the QOL of the patient. An example of the complications that occur due to pathological fractures is a tumor that surpasses the epidural space and reaches the spinal cord. See figure 1.

Pathological fracture can also manifest itself in ribs and extremities (Coleman 2006).

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Figure 1. Compromised vertebra by metastatic tumor involving cord compression. Source:

(Highsmith 2019)

Compression of the spinal cord or cauda equina

Compression of the spinal cord (SCC) or compression of the cauda equina are considered as medical emergencies that require urgent attention. SCC presents itself with muscle weakness or paralysis. Late manifestations are numbness and distal anesthesia at the intervened level and incontinence. In lesions that involve the medullary cone, autonomic dysfunction of the bladder, rectum and genitals may present early. These patients also present with localized pain in the area peripheral to the tumor and the pain gets worse when performing activities that cause more intradural pressure such as coughing. SCC and compression of cauda equina may cause radiating pain and the recurrence pattern is at night, which is the opposite of a degenerative disease. SCC can occur weeks or months before some neurological signs is noticed (Coleman 2006).

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Spinal instability

An abnormal movement between spine segments due to bone metastases may cause spinal instability. That compromises the anatomical stability and alignment of the spine presenting in severe back pain. In some patients, surgery must be performed to stabilize the segments involved in the lesion (Coleman 2006).

Skeletal related events (SREs)

Symptoms and other complications associated to bone metastases are grouped under the term SREs. SREs include i.e., pathological fractures, radiotherapy to the bone, surgery to the bone, SCC, and hypercalcemia. They have an impact on QOL and lead to increased healthcare costs and poor survival (Grávalos et al. 2016, Coleman et al. 2020).

2.1.4 Diagnosis Imaging

X-ray is an option for simplified diagnose of bone metastases. However, its sensitivity is low, and it is estimated that it is necessary to have 30 to 70 % of the vertebra involved to identify lytic injury in simple X-rays (Witt et al. 2020) Computed tomography (CT) is an alternative to locate lesions. It provides good contrast and tissue recognition also for biopsies. CT also allows

visualization of bone destruction and sclerosis. Magnetic resonance imaging (MRI) is an imaging method used widely for diagnosis and monitoring bone metastases located in the spine and bone marrow. MRI allows the identification of size, number, position and, SCC in spinal lesions, and the possible invasion of the bone metastases to the surrounding tissues (Coleman et al.

2020).

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Metabolic and molecular imaging

Nuclear medicine identifies metabolic alterations on bone tissue and metastasis by

incorporating markers that according to composition and level of radiation can be captured by different visualization methods. Markers can be classified as osteotropic (active bone affinity) or oncotropic (malignant cells affinity). One example of nuclear medicine, scintigraphy, in combined with osteotropic marker as i.e., technetium-99 (⁹⁹Tc). Scintigraphy visualizes reactive bone as well as new bone production and hence reveals the areas where metastases develop even before being identified with X-ray. With positron emission tomography (PET) systems and osteotropic markers like 18F labelled sodium fluoride (NaF), image acquisition takes less time at higher resolution and accuracy compared to scintigraphy. To achieve specificity for the location of the bone metastases PET is often complemented with a CT (Coleman et al. 2020)

PET-CT in combination with oncotropic marker 18F-fluorodeoxyglucose (FDG)-PET-CT reveals tissues with high glucose consumption i.e., tissues with cell proliferation and growth. This phenomenon is increased in intermediate and advanced stages of cancer and metastases identification can be achieved. FDG is not a specific marker for skeletal metastases but it is sensitive to them and thus used widely. However, FDG-PET-CT has a low sensitivity for proliferation and a better assimilation with lytic lesions. Specific markers, such as gallium-68 (68Ga) and prostate-specific membrane antigen (PSMA), are used for staging and evaluation of biochemical relapse in intermediate and high-risk Pca (Coleman et al. 2020).

Biopsies

Most specific information regarding the characteristics of a metastatic lesion is achieved with biopsies. The location of the bone metastases, physical examination and available diagnostic images all have an impact when perform a biopsy for a bone lesion. According to (Łukaszewski et al. 2017). the techniques used for biopsy include:

• Fine-needle aspiration biopsy is a percutaneous puncture used for diagnosing osteolytic and mixed metastasis in different areas.

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• Core-needle biopsy is performed with a stylet needle and facilitates more analyses and accurate diagnoses. However, it is invasive and compromise more tissue than with fine needle biopsy.

• Open biopsy is a surgical procedure where fragments of the tumor are removed to be analyzed, and at the discretion of the specialist, tissue could be completely removed.

• Image guided biopsy utilizes CT or MRI to confirm the position of the needle for the procedure, hence increasing the accuracy of acquiring samples of the growing tumor tissue and decreasing the probability of extracting necrotic tissue from the tumor.

Response assessment

Generally, the evaluation of the tumor response is carried out by a follow-up imaging and by utilizing anatomical response assessing methods like response evaluation criteria in solid tumors (RECIST) in aaddition to tumor volume control, bone metastasis can be monitored by different variables to evaluate tissue response. Bone behavior is considered in terms of bone repair and destruction to carry out an evaluation during the care stages. Metabolic response by PET for example favor an early detection of disease progression since the metabolic effects are evident before the changes in anatomy. (Grávalos et al. 2016, Coleman et al. 2020)

However, RECIST criteria has limitations in evaluation of the response of bone metastases due to their anatomical location. Plain radiographs cannot differentiate osteoblastic from osteolytic activity and scintigraphy could have limitations in some cases due to slow progression and presence of confounders such as sclerosis and osteoarthritis (Grávalos et al. 2016). To overcome limitations especially in the most metabolically active metastases, assessing a combination of different diagnosis tools like FDG-PET and CT, it is possible to use alternative evaluation criteria.

The PET response criteria in solid tumors (PERCIST) have been established as a widely accepted tools for evaluating tumor response, allowing to carry out the evaluation including the metabolic activity when the anatomical changes are not significant or possible to assess (Costelloe et al.

2010, Coleman et al. 2020).

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2.1.5 Treatment

The development of the treatments for bone metastases has been achieved by multidisciplinary teamwork. A careful control and mitigation of the disease is arranged and planned according to the characteristics such location, quantity, histology, and extension of the primary disease and the metastases. The aim of the MDT is to manage the symptoms, improve the QOL and, at best, to increase the overall survival. To reach this goal, guidelines are needed. Current options - individually or in combination - for treating bone metastases include pharmaceuticals, radiotherapy, and surgery (Coleman 2006). The decision to start an intervention considers individual characteristics like concurrent treatment, histology, and clinical resources. However, not all asymptomatic patients with bone metastases need an intervention immediately and follow-up can sometimes be sufficient (Coleman et al. 2020).

Bisphosphonates

Bisphosphonates act as inhibitors of bone resorption inducing apoptosis in osteoclasts either by cytotoxic effects process through non-nitrogen-containing bisphosphonates or through direct apoptosis as nitrogen-containing bisphosphonates. This drug is indicated for pain relief, for reducing the risk of skeletal events (SREs) and to treat hypercalcemia. When selecting the optimal bisphosphonate (clodronate, pamidronate, ibandronate or zoledronate) for a patient, individual characteristics such as the general condition and the risk of SREs are considered. Some studies have related bisphosphonates with antitumor and antiangiogenic properties, but the effect is consensual among researchers (Coleman et al. 2020).

Denosumab

Denosumab is a monoclonal antibody that adheres to a molecule involved in bone metabolism called receptor activator for nuclear factor κ b ligand (RANKL). The denosumab prevent its adhesion to the cell receptor inhibiting the osteoclast and causing the suppression of bone absorption. Among the associated side effects of denosumab some of the most frequent are osteonecrosis of the jaw and hypocalcemia. In contrast denosumab treatments could be more

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beneficial for kidney health compared with bisphosphonates, renal failure events and acute phase reactions are less frequent with denosumab and do not require dose adjustments. However, its cost is high and when treatment is discontinued, a rebound effect of osteolysis can be observed (Coleman et al. 2020, Grávalos et al. 2016)

External radiotherapy

EBRT treatment uses high-energy beams directed at the tumor location. This causes damage to cancer cells through direct DNA breakdown or indirectly through free radicals produced after radiation interaction with water molecules. This damage occurs in cancer cells and healthy cells indistinctly. Both cell types have the ability to repair DNA damage, however cancer cells have a lesser capacity to carry out the repair process leading to a higher cell death in cancer cells (Heymann 2015).

EBRT is one of the first-line treatments for the palliative treatment of painful metastases. It is highly effective and overall response rates of 70 % to 80 % have been reported. However, some patients may present flares of pain usually one to two days after the treatment and dexamethasone is prescribed in these cases (Coleman et al. 2020).

Radionuclide therapy

Radionuclide therapy is applied to control and mitigated bone metastasis using radiopharmaceuticals for irradiating specific metastasis avoiding healthy tissue. Its specificity for tumoral tissue is achieved through radionuclides transported by molecules with high affinity to receptors or antigens of the tumor allowing targeting multiple tumor site. The radiation will depend on the radionuclides used and the radiation and dose emitted by it. For radionuclide therapy alpha and beta ionizing radiation are preferred, because of its low range of penetration (International Atomic Energy Agency, (IAEA) 2021).

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Some of the current radiopharmaceuticals used for bone metastases are iodine-131 for thyroid carcinoma metastasis and strontium chloride-89. Samarium-153 has been used to treat bone metastases of Pca. In recent clinical trials like ALSYMPCA, radium-223 showed improvements of 3.6 and 5.8 months in survival and delay in the appearance of SREs respectively for castration- resistant bone metastases from Pca (Coleman et al. 2020).

SBRT

SBRT technique was developed to precisely deliver high doses of radiation in one or few fractions in a short period of time, to a carefully define location. SBRT uses multimodality and motion imaging to treatment planning, target localization and treatment delivery (Haridass 2018). This treatment will be explained in more detail in the chapter “Radiotherapy” in this master thesis.

Surgery

In general surgery and specifically orthopaedical surgery is indicated to prevent fractures caused by bone metastases. Surgery is often necessary also to stabilize imminent fractures or fractures that can involve nerve compression. The most frequent anatomic sites that are surgically intervened are long bones, hip, joins and spine (Agarwal & Nayak 2015).

2.2 Radiotherapy

Once biological systems are exposed to ionizing radiation, charged particles interact with atoms of the irradiated cells ionizing and exciting them. Ionization and excitation trigger chemical reactions that ends with broken molecules and breakage of chemical bonds. These molecules or free radicals seek to establish an electronic charge equilibrium and subsequently generates changes in biologically important molecules like DNA. Most of the generated damages will be

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repaired and those injuries that cannot be repaired will result in cell death during interphase, mitosis or even after several cell divisions after exposure to radiation (Joiner & Kogel 2019).

In radiotherapy, high radiation dose is delivered to well define target volume in order to kill tumor cells and cure the patient (curative intent) or to manage the symptoms caused by the tumor (palliative intent). Radiotherapy treatments use different types of radiation: Charged particles (electrons, protons and carbon ions), photons (high energy X-rays, gamma rays) and neutrons. Radiation modalities differ from each other on penetration and energy transfer properties. Furthermore, costs and availability of the radiation modalities differs significantly.

High energy X-rays and electrons are most commonly used on radiotherapy (Sibtain et al. 2012, Rodrigues et al. 2013).

Radiation dose is typically given in multiple daily fractions to take advantage of reoxygenation and reassortment of tumor cells. Also, fractionation enables the normal tissue repair and repopulation and thus, increase the normal tissue tolerance to radiation. (Sibtain et al. 2012, Rodrigues et al. 2013). Typical fraction dose is 2 Gy / day. If more than 2 Gy delivered on a fraction treatment is called hypofractionation and if fraction dose is less than 2 Gy treatment is called hyperfractionation (Joiner & Kogel 2019).

Radiotherapy can be divided in two main categories: One defined as external beam radiotherapy (EBRT) if radiation is delivered from an external source to the patient using, for example, Linear accelerators. And a second defined as brachytherapy if radiation is delivery from a source that is transferred inside the patient (World Health Organization & International Atomic Energy Agency 2021). In the present review, all evaluated radiotherapy treatments were given using EBRT, high energy X-rays and hypofracionation.

Goals of cancer therapy include survival-based endpoints, tumor control endpoints, health related QOL, and various palliative or symptom control endpoints. In bone metastases main goals are decrease pain and prevention of the morbidity associated to it. General considerations

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for radiotherapy are patient immobilization, simulation, treatment planning and treatment.

(Rodrigues et al. 2013).

2.2.1 Radiotherapy techniques

As described by WHO and IAEA (2021) radiotherapy techniques can be two-dimensional (2D), three dimensional conformal (3D-CRT), intensity–modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT) or stereotactic radiotherapy:

• 2D: Based on 2D imaging as radiographs and anatomical references. Dose calculation are simple performed manually or computerized. Organs at risk (OAR) sparing is difficult. See figure 2.

• 3D-CRT: Based on 3D imaging as CT. Treatment planning is computerized. One or multiple radiation fields are delivered from different gantry angles. Radiation fields are shaped according to target volume using multi leaf collimator (MLC). More conformal treatment plans than with 2D some OAR sparing can be achieved.

• IMRT: Based on 3D imaging. Inverse treatment planning is used to create complex dose distributions allowing effective OAR sparing while high coverage to target volume is maintained. IMRT can be delivered using fixed gantry angle beams or during continuous arc. If arc is used technique is commonly referred as Volumetric modulated arc therapy (VMAT)

• IGRT: To improve the accuracy of the treatments several on-board imaging systems have been introduced for targeting radiotherapy treatments. Cone beam computed

tomography, 2D kV imaging, MRI and optical systems are currently used for image guidance in radiotherapy. Using daily imaging uncertainty margins of treatment volume could be decreased. To take into account breathing motion optical systems can be used to track chest wall movement and treatment can be delivered during a triggered part of breathing cycle or more commonly during deep inspiratory breath hold. For some systems online treatment adaptation to breathing motion is possible.

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Figure 2. CT Planning comparison of (a) conventional radiotherapy (2D RT); (b) 3D-CRT;

and (c) IMRT plan for head-neck cancer. Source: (Gupta et al. 2010)

• SBRT Development of accurate modern radiotherapy techniques and sophisticated image guidance systems have made stereotactic radiotherapy widely available for treatment of extra cranial targets. In SBRT treatment, highly conformal dose distribution is delivered in submillimetre accuracy to well defined target volume. Additionally, modern image

guidance system is used to ensure the patient position and location of the target volume before and/or during the treatment delivery. Typically, SBRT treatments are delivered in high fraction doses using small number of fractions (Sahgal et al. 2012, World Health Organization & International Atomic Energy Agency 2021).

2.2.2 Stereotactic body radiation therapy and bone metastases

Bone metastases are frequent in cancer patients. Symptoms related to bone metastases are localized pain, SREs or deficits from compression of the spinal cord, nerve roots or peripheral nerves. With pain as the most common symptom requiring intervention. SBRT shows promise in the treatment of these patients. (Vassiliou et al. 2014). General consideration for SBRT treatment path for bone metastases are:

• Therapeutic considerations: Concurrent treatments as bisphosphonates, radionuclides, kyphoplasty, vertebroplasty, surgical decompression or stabilization (Rodrigues et al.

2013).

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• Patient immobilization: Immobilization is required for effective simulation and

treatment. In order to minimize movement during radiotherapy fraction and improve the position reproducibility between the fractions. Typical devices for immobilization are vacuum systems, head and foot rests, thermoplastic masks, or motion management techniques (Garcia 2019, Rodrigues et al. 2013).

• Simulation: Obtain information for treatment planning. Includes the definition and localization of targets, normal tissues and patient anatomy including the external contour of the patient. MRI or PET-CT registered to treatment planning CT can be used to guide the delineation of target and normal tissues. Four-dimensional computed tomography (4DCT) can be used to evaluate margins needed to take into a count the respiratory movement (Garcia 2019, Rodrigues et al. 2013).

• Treatment planning: Modern inverse planning techniques are typically used with SBRT.

To delivered high fraction dose to target tissue highly conformal dose distribution is created and dose to normal tissues surrounding the target is minimized. Regular quality assurance measurement is warranted to verify that dose distribution calculated with treatment planning software is in line with dose delivered to patients (Garcia 2019, Rodrigues et al. 2013).

• Treatment: Accurate image guidance is required for verification of patient positioning and monitoring the patient movements during the treatment fraction when frameless treatment delivery is used. For stereotactic treatments localization accuracy under 1 mm is recommended. Regular quality assurance measurements are warranted to evaluate the end-to-end accuracy of the treatment system (Garcia 2019, Rodrigues et al. 2013).

SBRT can be delivered in multiple equipment including gantry based linear accelerators (LINAC) (for example, Infinity, Elekta AB, Stockholm, Sweden, figure 3.), Robotic LINAC (Cyber knife, Accuray, CA,USA), Bore based LINAC (Halcyon Varian, CA, USA), or Cobalt system (Gamma Knife, Elekta AB, Stockholm, Sweden).

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Figure 3. Gantry based LINAC in Kuopio university hospital (KUH) (Infinity, Elekta). Image;

radiotherapy unit of KUH.

2.2.3 Global context

In 2021 World health Organization (WHO) and International Atomic Energy Agency (IAEA) published “Technical specifications of radiotherapy equipment for cancer treatment”. A report aimed to provide technical specifications for radiotherapy equipment commonly used in the treatment of cancer and referred SBRT as an emerging technique. This report addresses the lack of robust evidence to support SBRT. However, reinforce the current results that favor SBRT in terms of reducing the overall treatment time by reducing the number of fractions been possible to increase the number of patients to be treated by the oncology department (World Health Organization & International Atomic Energy Agency 2021)

Literature providing standardization or consensus still growing, some examples are

“International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases”, “RTOG 0631 phase 2/3 study of image guided stereotactic radiosurgery for localized (1-3) spine metastases: phase 2 results” and “Defining oligometastatic disease from a radiation

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oncology perspective: An ESTRO-ASTRO consensus document” (Chow et al. 2002, Lievens et al.

2020, Ryu, S. et al. 2014). The international commission on radiation units & measurements (ICRU) recently publish ICRU report 91adressing aspects on small field dosimetry, accuracy requirements for volume definition and planning algorithms, and the precise application of treatment by means of image guidance. Also, recommendations for prescribing, recording, and reporting (Wilke et al. 2019).

Other standard recommendations and nomenclature relevant for SBRT are ICRU reports number 50, 62 and 83. These reports provide information as definition of concepts for gross target volume (GTV), clinical target volume (CTV), internal target volume (ITV) and planning target volume (PTV) as well as OAR and planning organ at risk volumes (PRV) (Wilke et al. 2019).

Associations like ESMO, JASTRO and ASTRO constituted an international reference to identified dose regimes, imaging protocols, consensus, and definitions. Also, suitable research end points, multiple guidelines, and standards for SBRT.

Patterns of SBRT for OM disease are still not fully consensual. In a profound review by Lewis et al. (2017) a total of 1007 completed surveys were reported from radiation oncologists in 43 countries reveling the most common SBRT regimes, dose (Gy) and fraction (Fx) used for oligometastases by region:

• Western Europe 20 Gy / 1 Fx, 54 Gy / 3 Fx and 60 Gy / 8 Fx

• United States 48 Gy / 4 Fx, 50 Gy / 5 Fx and 30 Gy / 5 Fx

• Japan 48 Gy / 4 Fx, 50 Gy / 5 Fx, 60 Gy / 8 Fx and 45 Gy / 15 Fx

• Canada 60 Gy / 5 Fx, 48 Gy / 4 Fx, 35 Gy / 5 Fx, 30 Gy / 5 Fx and 20 Gy / 5 Fx

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2.3 Summary of literature

The incidence of bone metastases is surpassed only by lung and liver metastases and the Incidence varies according to type of primary tumor. It is estimated that at least 80 % of bone metastases are developed by breast, prostate, lung and kidney cancers as well as by MM (Heymann 2015, Coleman et al. 2020). In general, the incidence of bone metastases has increased due to increase in survival time and rise in the use of diagnostic imaging (Kim et al.

2008). Patients with bone metastases experience symptoms like pain and SREs (Coleman 2006).

Imaging techniques like PET- CT are one of the major tools to diagnose and follow bone metastases patients (Coleman et al. 2020). Patients with bone metastases are traditionally treated with conventional RT. The average duration of palliation is approximately four months.

(Spencer et al. 2019).

In 2021 World health Organization (WHO) and International Atomic Energy Agency (IAEA) published “Technical specifications of radiotherapy equipment for cancer treatment”. A report aimed to provide technical specifications for radiotherapy equipment commonly used in the treatment of cancer and referred SBRT as an emerging technique. SBRT has allowed the

application of higher doses with greater precision and care of healthy tissue. There are already some indications that SBRT can improve pain response and its duration along with local control.

However, there is still need for more clinically relevant evidence. (Spencer et al. 2019).

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3 Aims

The primary aim of this research is to evaluate the use of SBRT for treatment of pain and spinal cord compression in cancer patients with bone metastasis.

A secondary aim it is synthesize the information about the use of SBRT for pain response and spinal cord compression in cancer patients with bone metastasis as a point of reference from a public health perspective.

4 Methodology

4.1 Search process

This systematic review was carried out in line with the guidelines of the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2009 statement (Moher et al. 2009), later reviewed and modified under the updated version PRISMA 2020 guidelines (Page et al.

2021). Publication search was conducted with PubMed from 2000 to February 2021, using the search terms on Appendix 3. Another search was done using Medline, and the Cochrane Library to identify trials published during the same period.

Seven articles were previously identified in related sources from the research proposal process.

Language restricts to Spanish and English in the three searches. Non-randomized studies and systematic reviews were included. Publication reference were collected and process for duplicated using RefWorks. Published reports with both full and abstract publications, from studies using SBRT and studies comparing conventional external beam radiation therapy and SBRT were included. Trials from SBRT technical evaluations like contouring and movement tracing were excluded from the analysis. Full-text articles selected for further sorting were reviewed independently by the author.

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4.2 Data management

Outcomes of interest were pain response and spinal cord compression. Due to the

heterogeneity of SCC definitions, these were collected as reported and defined by the respective studies. Other variables extracted were sample size, primary cancer site, follow up, SBRT dose and conventional RT dose (if available), location of treatment, concurrent treatment, bias, general outcome. Studies were excluded if no information could be obtained regarding the outcomes of interest from full text of at supplements.

Studies were excluded re-irradiation of same site was performed, addressing the difficulty to estimate the response rates from the initial radiation. This recommendation was reported in the international consensus on palliative RT end points for future clinical trials in bone metastases (Chow et al. 2002). Selected studies comparing conventional RT and SBRT were grouped in a subcategory for meta-analysis for both variables pain response and SREs.

After a further evaluation on selected studies, a methodological variation on control group definition in for SREs was found in (Wardak et al. 2019). Resulting in an unfeasible meta-analysis for SREs variable. Additional description is provided on result section under the title “Meta- analysis outcome for SREs”. Pain response meta-analysis was assessed and reported.

Tabulation and management of variables for systematic review was performed on IBM SPSS statistic 27 and tabulation and management of meta-analysis subgroup result were presented as a summary of the articles and forest plots created using a random effects model and the

Mantel–Haenszel statistic on Review Manager (RevMan 5.4) by Cochrane IMS.

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5 Results

Literature search outcome is summarized in figure 4. 526 references were identified in the literature search and 7 references in related sources. Duplicate references were removed, and 469 reference were screened. Based on screening 50 articles were selected for further full text review including two systematic reviews by Spencer et al. (2019) and Faruqui et al. (2018). After full text review a total of 15 articles were found to have relevant data and were included for review. From these 15 articles 2 articles (Sprave et al. 2018ba) and (Sprave et al. 2018ab) reported different outcomes from same study trial ending with a total of 14 studies with 5 studies including pain response, 3 studies including SREs, and 7 including both outcomes. For meta-analysis subgroup comparing SBRT and conventional radiotherapy 5 studies were included with 3 studies including pain response and 2 including pain response and SREs outcomes.

A total of 746 patients were reported in 12 studies and 3,886 patients from 2 systematic reviews (Spencer et al. 2019, Faruqi et al. 2018). 120 for both variables, 2,602 for pain response and 1,910 for SREs. For meta-analysis subgroup a total of 459 patients were included, 35 for both variables, 368 for pain response and 56 for SREs.

All studies report multiple primary tumors. The systematic review by (Spencer et al. 2019) reported 73 % of various tumors and 27 % from individual diagnosis group. The systematic review by (Faruqi et al. 2018) did not report specifically primary tumor, but only lytic tumor as a risk factor. The spine is the most common site reported with 83 % of 12 studies. The most frequent dose for SBRT was 20 Gy (range 9-30) and number of fractions 1 (range 1-5). The most frequent dose for conventional RT from reported data was 30 Gy (range 8-30) and number of fractions 6 (range 1-10). The mean follow-up period was 5 months (range 0.5 – 24).

Treatment paths were consistent in the use of CT and MRI for planning and also immobilization system but varied in contouring , CTV and PTV definitions, and in used radiotherapy equipment.

A summary of the treatment paths from individual studies can be found on Appendix 4. A reference image of an SBRT planning treatment can be seen in figure 5.

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Figure 4. Prisma workflow.

Records identified from:

PubMed (n =174) Cochrane (n =159) MEDLINE (n =193)

Records removed before screening:

Duplicate records removed (n =57)

Records screened

(n = 462) Records excluded

(n =380)

Reports sought for retrieval

(n = 82) Reports not retrieved

(n = 32)

Reports assessed for eligibility (n =50)

Reports excluded:

Re-irradiation (n =6) Pain as toxicity (n =7) Technical evaluation (n =7) In systematic reviews included (n=15)

Records identified from:

Organisations (n =2) Citation searching (n =5)

Reports assessed for eligibility

(n = 3) Reports excluded:

Not pain or SCC assessed (n =1)

Re-irradiation (n =1)

Studies included in review (n = 15)

Studies includes for meta-analysis (n = 5)

Identification of studies via databases and registers Identification of studies via other methods

Reports sought for retrieval

(n =7) Reports not retrieved

(n = 4)

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Figure 5. An SBRT treatment plan of CyberKnife® device created with MultiPlan® planning programme. The target is the corpus of the vertebra Th 11 and the treatment is delivered with fractionation of 24 Gy / 3 Fx and two fractions per week.

5.1 Pain response

Summary of pain response outcomes from individual studies is listed in Table 2. The arms treated with SBRT report pain response of 70 % immediately after treatment (Sakr et al. 2020);

After one month of SBRT Pichon et al. (2016) report a significant decrease in VAS score from 2,40 to 1,35. After one month pain response rates varied from 44 % to 85 % (Nguyen et al. 2019, Jin et al. 2007); Three months after SBRT pain response varied from 33% to 95 % (Nguyen et al. 2019, Wardak et al. 2019); Six months after SBRT pain response rates varied from 69% to 83 % (Ito et al. 2019, van de Ven et al. 2020).

Overall pain response rate after SBRT reported by Van de Ven et al. (2020) was 84 % with a median duration of six months (range 0 – 12.5). The difference was not statistically significant compared to conventional RT with overall pain response rate of 81% and a median duration of

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5.75 months (range 0.25 – 14.5) (van de Ven et al. 2020). From the systematic review by Spencer et al. (2019) the range of pain response outcomes of SBRT treatment varied from 27 % to 98 % (Spencer et al. 2019). In a study by Sprave et al. (2018b), no significant differences were reported at three months, but significant lower VAS scores were found at six months in SBRT group

compared with conventional RT (Sprave et al. 2018b).

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Table 2. Pain response outcome summary Author

year

N Site Mean SBRT

Dose/Fractionation (range)

Mean Conv-RT Dose/Fractionation (range)

Outcome pain response

Ito et al.

2019

20 Spine 24 Gy / 2 N/A The pain response rate at six months were 83 %.

Jin et al.

2007

49 Spine 12 Gy / 1 Fx (10-16 Gy)

N/A At four weeks after SBRT overall pain relief was seen in 85 % of the patients treated. Complete pain relief was achieved in 38 % of patients. Partial pain relief was achieved in 47 % of patients.

Nguyen et al. 2019

160 Multiple Lesions >4cm 12 Gy / 1Fx Lesions <4cm 16 Gy / 1 Fx

30 Gy / 10 The response rates (CR + PR) at one month were 44 % for the SBRT group vs 30 % for the conventional RT group (P = .18), and the corresponding rates at three months were 38 % vs 21 % (P = .05)

Pichon et al. 2016

30 Spine 9 Gy / 3 Fx N/A The mean pain scores diminished significantly in one month (1.35; P=.0125) and 3 months (0.77; P<.0001) after treatment compared with pain scores at study entry (2.49).

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Author year

Redmond et al. 2020

35 Spine 30 Gy / 5 Fx N/A In comparison to the baseline, VAS score at the time of last recorded follow-up was reduced in 54.2 %, stable in 12.5 %, increased by one point in 8.3 % and

increased by two or more points in 25 %; 20.8 % of patients reported no pain in any part of their body at the time of last follow-up.

Sakr et al.

2020

22 Multiple 27 Gy / 3 Fx 20 Gy / 5 Fx Complete pain relief was not documented in any patient in both groups. Partial pain relief after three months was comparable with a p-value of 0.6.

Immediate partial pain relief was seen in seven patients (70 %) of 27Gy/3fr schedule versus only one patient (8 %) in 20Gy/5fr schedule with a p-value of 0.06. The increase in immediate pain relief in the 27Gy arm was numerically but not statistically significant.

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Author year

Spencer et al. 2019 (Systematic review)

38 articles

Multiple sites

(6 - 52.5 Gy) / (1 - 6 Fx)

N/A Studies included report higher rates of pain response following SBRT than have previously been reported following conventional RT. However, these outcomes may very well be the result of study methodology and, most importantly selection bias.

Sprave et al. 2018b

55 Spine 24 Gy / 1 Fx 30 Gy / 10 Fx At three months after SBRT no significant differences for VAS score between groups (p = 0.13). At six months significantly lower VAS values were reported in the SBRT group (p = 0.002). There were no differences in OMED consumption at three (p = 0.761) and six months (p = 0.174). There was a trend toward improved pain response in the SBRT arm at three months (p = 0.057), but significantly so after six months (p = 0.003).

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Author year

Van de Ven et al. 2020

131 Multiple sites

18 Gy / 1 Fx 30 Gy / 3 Fx

8 Gy /1 Fx 30 Gy / 10 Fx

At a median follow-up of 23 weeks (range 1-58) and 24 weeks (range 0-50), pain response was achieved in 81% and 84% among the patients treated with conventional RT and SBRT, respectively.

Wardak et al. 2019

35 Spine 20 Gy / 1 GTV and 14 Gy / 1 Fx for bone marrow

Historical control The three-month pain response was significantly improved compared to RTOG 9714: 95 % versus 51 % (P < .0001). The local control with a median follow-up of 9.6 months was 92 %.

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Meta-analysis outcome for pain response

Five studies fulfilled the criteria for meta-analysis for pain response. See Table 5. Pain response categorization was based on patient reported VAS or NRS ranged (0-10) and analgesic

consumption (MEDs or OMED) (Sprave et al. 2018b, Nguyen et al. 2019, Wardak et al. 2019, Sakr et al. 2020, van de Ven et al. 2020). Definition was as follow:

• Complete response (CR): was defined as VAS = 0 without an increase in analgesic use.

• Partial response (PR): Reduction of two or more in pain score from baseline site without increasing analgesic intake, or analgesic reduction of 25 % or more from baseline without an increase in pain.

• Pain progression (PP): Increase in pain score of two or more above baseline or an increase of 25 % or more in analgesic intake compared with baseline.

• Indeterminate response (IR): Any response that is not categorized as CR, PR, or PP.

• Responders (CR + PR)

• No responders (PP + IR)

Scores provided by the authors had equivalency and were all assessed by the patients.

Categorization and analgesic used were also comparable allowing to perform a second

categorization into dichotomous data as responders and no responders. Using the “Per-protocol analysis data” instead of “Intent to treat data” form the studies the results from the meta-

analysis for month three and month six are presented in figures 6 and 7, respectively. Results present a significant improvement of 38 % in pain response in SBRT treatment compared to conventional RT after three months with a 95 % confidence interval of [1.08, 1.71]. See figure 6.

Heterogeneity among studies is moderated. At six months the was difference towards

improvement of 27 % in SBRT treatment compared to conventional RT but not significant with a 95 % confidence interval [0.92, 1.76].

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Figure 6. SBRT vs. Conventional RT pain response at three moths forest plot.

Figure 7. SBRT vs. Conventional RT pain response at six months forest plot.

5.2 Skeletal related events

Summary of SREs outcomes from individual studies is listed in Table 3 and 4. Spinal cord compression variable was compiled in a broader variable of SREs because of the heterogeneity of the measurement for this outcome. Variables reported:

• According to Ryu et al. (2010), Metastatic epidural compression (MEC) defined radiographically, ranging from minimal canal compromise and thecal indentation to actual displacement of the spinal cord.

• According to Pichon et al. (2016), a spinal cord adverse event was defined as grade 2 or greater event according to the Common terminology criteria for adverse events (CTCAE)

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Version 4.0 (2021) and a bone event was defined as pathologic fracture, cord compression, or surgical procedure on a bone segment.

• According to Ghia et al. (2018), metastatic epidural spinal cord compression (MESCC) scale described by Bilsky was used to grade the degree of epidural extent. 0 Bone only disease, 1a Epidural impingement without deformation of the thecal sac, 1b Deformation of the thecal sac without spinal cord abutment, 1c Deformation of the thecal sac with spinal cord abutment but without cord compression, 2 Spinal cord compression but with cerebrospinal fluid (CSF) visible around the cord, 3 Spinal cord compression, no CSF visible around the cord (Bilsky et al. 2010).

• VCF definition varied between studies by Chang et al. (2017), Sprave et al. (2018), Ito et al.

(2019) and Wardak et al. (2019); According to Sprave et al. (2018a) and Wardak et al.

(2019) VCF was defined as the reduction of the vertebral body height by more than 20 %.

While in studies by Chang et al. and Ito et al. (2018) VCF was defined as an adverse event using the CTCAE Version 4.0 (2021).

In a study by Ryu et al. (2010) a mean epidural tumor volume reduction of 65 ± 14 % at two months after SBRT were reported and an overall neurological function improved in 81 % also after SBRT. Downstaging of the MESCC scores compare to base line is reported in 60 % of patients after SBRT (Ghia et al. 2018). New VCFs rate of 8.7 % were reported at three months after SBRT and higher rates of 27.8 % were evidence after six months. However, no VCF required salvage surgical intervention and there was a trend towards higher baseline pathologic fractures in the SBRT cohort (Sprave et al. 2018a). A crude rate of VCF reported in a study by Chang et al.

(2017) was 6.7% and a median time until VCF was 15.4 months (range 1.1 - 24.6 months). From the systematic review by Faruqi et al. (2018) reported VCF rates ranged from 5.7 % to 39 %. The median clinical and imaging follow-up ranged between 7.3 and 21.2 months and 7.4 and 14.9 months respectively.

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Table 3. Skeletal related events (MEC, MESCC and spinal cord event) outcome summary.

Author year

N Site Mean SBRT

Outcome SREs (MEC, MESCC and spinal cord event)

Ghia et al.

2018

32 Spine GTV 18Gy 24 Gy

N/A 17 from 28 evaluable patients had downstaging of their MESCC grade, including 7 of 9 patients with MESCC grade 2 disease at the time of treatment.

Pichon et al. 2016

30 Spine 9 Gy / 3 Fx N/A No radiation-induced spinal cord adverse reactions were observed at 12 months or in patients who survived longer than this. One patient presented with a grade 1 brachiocervical neuralgia at 3 months, with bilateral paresthesia in the upper limbs, after irradiation of the C7 vertebra. This required no treatment and resolved spontaneously.

Redmond et al. 2020

35 Spine 30 Gy / 5 Fx N/A The change in MESCC grade was statistically significant between the base line and after SBRT imaging (P < .001) and from the base line imaging to the three months after SBRT imaging (P

=.034).

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Author year

N Site Mean SBRT

Outcome SREs (MEC, MESCC and spinal cord event)

Ryu et al.

2010

62 Spine 16 Gy / 1 Fx (12-20 Gy)

N/A The mean epidural tumor volume reduction was 65 ± 14 % at two months after SBRT. The epidural tumor area at the level of the most severe SCC was 0.82 ± 0.08 cm² before SBRT and 0.41

± 0.06 cm² after SBRT (P < .001). Thecal sac patency improved from 55 ± 4 % to 76 ± 3 % (P < .001). Overall, neurological function improved in 81 %.

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Table 4. Skeletal related events (VCF) outcome summary.

Author year

Outcome SREs (VCF)

Chang et al.

2017

60 Spine 24 Gy / 2 Fx (16-52.5 Gy) (1-3 Fx)

N/A There were four cases (6.7 %) of vertebral compression fracture and no cases of radiation myelopathy.

Faruqui et al. 2018 (Systematic review)

11 articles

Spine (18 - 27 Gy) (1 – 3 Fx)

N/A A total of 2911 spinal segments were treated with a crude VCF rate of 13.9 %.

Ito et al.

2019

20 Spine 24 Gy / 2 Fx N/A VCFs were observed in two patients (14 and 16 months after SBRT).

Pichon et al. 2016

30 Spine 9 Gy / 3 Fx N/A Vertebral collapse in the irradiated zone occurred in one (2 %) treated vertebra.

Sprave et al. 2018a

55 Spine 24 Gy / 1 Fx 30 Gy / 10 Fx The three-month incidence of new pathological fractures was 8.7 % in the SBRT arm vs. 4.3 % in the 3DCRT arm. At six months after SBRT 27.8 % and 5 % in 3DCRT. No pathological fractures in either group

required salvage surgical intervention.

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Author year

Outcome SREs (VCF)

Wardak et al. 2019

35 Spine 20 Gy / 1 Fx GTV 14 Gy / 1 Fx to bone marrow

N/A The freedom from VCF was 90 % at 1 year. Spine SABR was well tolerated with no grade 2 or higher toxicities.

A single patient with disease extending from the vertebral body into the spinal canal developed vertebroplasty-related myelopathy, which was corrected with surgery.

Management of bone metastasis with stereotactic body radiation therapy for pain control and spinal cord compression: a systematic review