Stereotactic body radiotherapy followed by surgical stabilization for patients with painful unstable spinal metastases: First-in-man study according to the IDEAL recommendations

Bone metastases are a frequent distant manifestation from different types of
malignant tumors, especially in patients with breast or prostate cancer. Bone
metastases affect 60-75% of these patients, and 30-40% of patients with lung or
kidney cancer (Coleman 2006, Hage 2000, Nguyen 2011). The spinal column is the
most common location among osseous sites for metastatic deposits: between 30 to
70% of the patients with cancer have evidence of spinal metastases at autopsy
(Falicov 2006). The exact incidence of bone metastases is unknown, but is has
been estimated that 16,000 to 22,000 people in the Netherlands die from bone
metastases each year (Nguyen 2011).

Pain is a common and devastating consequence of bone metastases. It strongly
interferes with quality of life and daily functioning and often requires
hospitalization. While similar to other bone metastases in terms of bone
involvement and pain relief after external beam radiation therapy (Howell
2013), spinal metastases have a unique clinical consideration. Spinal
metastases can present with epidural compression caused by a soft tissue mass
at the paraspinal area, a compression or a burst fracture. Therefore, patients
with spinal metastases can have severe back pain with (impending) associated
neurological problems. When neurological problems occur, the performance status
of these patients can further compromise.

Survival prospects vary greatly and range from several months in patients with
multiple organs involved, to more than 5 years for patients with exclusively
skeletal metastases. The survival of patients with bone metastases has
substantially improved as a result of effective systemic chemotherapy,
immunotherapy and radiotherapy (Fisher 2010, Nguyen 2011). With prolongation in
survival, the main challenge is to maintain the quality of the patient*s
remaining life.

Spinal instability

The concept of spinal instability is critical in the management of spinal
metastases. Spinal instability as the result of a neoplastic process differs
considerably from high-energy traumatic injuries in the pattern of bony and
ligamentous involvement, potential for healing, and bone quality. Therefore,
spinal metastases require a specific and different set of criteria for
stability assessment. The Spinal Oncology Study Group (SOSG), which consists of
spine oncology experts, defined spinal instability due to metastatic disease as
**loss of spinal integrity as a result of a neo-plastic process that is
associated with movement-related pain, symptomatic or progressive deformity
and/or neural compromise under physiological loads* (Fisher 2010).

To assess spinal instability due to metastatic disease the SOSG developed the
Spinal Instability Neoplastic Score (SINS) (Fisher 2010, Fourney 2011), to
provide a tool to guideline referrals to appropriate oncology specialists (e.g.
surgeons or radiation oncologists). The SINS is the sum of six easily assigned
radiographical and clinical parameters, resulting in a score ranging from 0 to
18 (Fisher 2010). The total score is divided in three categories of stability;
stable (0 to 6 points), potentially unstable (7 to 12 points), and unstable (13
to 18 points). Surgical consultation is recommended for patients with a score
of * 7.

The cervical spine is unique from other regions of the spine because of the
generous mobility in all planes, stability role for the head, neighboring
anatomy and a spectrum of anatomic and biomechanical variability throughout the
region (specifically O-C1, C1-C2, C3 *C7 and finally C7-T1) compared to the
thoracic, lumbar and sacral spine. In the current study, we therefore focus on
thoracic and lumbar metastases only.

Current treatment of thoracic and lumbar metastases

A major goal in the treatment of metastatic disease is the preservation or
restoration of spinal stability, since spinal instability increases the risk on
neurological compromise (Falicov 2006, Weber 2011). When patients are closely
evaluated, loss of neurological function and ambulatory status due to spinal
instability is preventable. This is important since loss of neurological
function and ambulatory status before treatment is correlated with a poor
prognosis (Rades 2008, Harel 2010). Early identification of these lesions is
necessary, as prompt referral and early surgical intervention can improve
outcomes and survival for patients with spinal metastases (Weber 2011).
Surgical decompression and stabilization in patients with spinal metastatic
disease is now feasible and is supported by strong evidence, due to advances in
biomaterials, imaging and surgical techniques (Weber 2011, Falicov 2006, Thomas
2006).

Another major goal in the treatment of spinal metastases is to achieve pain
relief. Regardless of localization, primary loco-regional treatment for most
patients is low dose single-fraction external beam radiation therapy (EBRT)
(Gerszten 2000, Lutz 2011). Although radiotherapy is effective in achieving
pain relief in most patients, 30-40% of patients do not obtain any pain relief
and complete response even occurs in only 30% of responders (Sze 2004, Chow
2012). It is not completely understood why some patients respond well to
radiotherapy and others do not. We hypothesize that metastatic bone pain, if
predominantly caused by mechanical instability of the spine, responds less well
to radiotherapy than metastatic bone pain caused by local tumor activity. Local
tumor activity may consist of direct invasion of tumor cells, periosteal
stretching, or the release of inflammatory mediators (Coleman 2006, Mercadante
1997; Nguyen 2011) On the other hand, disruption of the homeostasis between
osteoclasts and osteoblasts can cause loss of mechanical integrity leading to
painful (micro-) motion within the vertebrae. As affected vertebrae weaken and
become compressed, adjacent muscles may spasm attempting to maintain stability
(Nguyen 2011; Tomita 2001; Vakaet 2004). Besides these compression fractures,
metastases may also cause burst fractures. Tumors are more likely to cause
burst fractures if they are located in the posterior portion of the centrum,
the region most sensitive to changes in centrum pressurization, due to the
*bean* shape of the vertebra (Weber 2011). Probably, both generators of pain
(local tumor-related and mechanical) are present simultaneously in spinal
metastases although their relative contribution to pain may vary.

Therefore, painful unstable spinal metastases may benefit from surgical
stabilization prior to EBRT. Ghogawala et al (2001) demonstrated a relation
between pre-operative conventional radiotherapy and the rate of wound
complications. Therefore, a minimum two-week interval between surgery and
irradiation is currently considered necessary to avoid wound complications in
the postoperative phase. Yet, this study was a retrospective chart review
involving patients from 1970 till 1996 who underwent surgery for spinal cord
compression. The systematic review of Itshayek et al (2010) reported a range of
11% to 50% for major wound complications in patients who had radiotherapy
before surgical intervention. Yet, this included three retrospective studies
and two very small prospective studies. In a recently conducted prospective
study on adverse events in patients who underwent emergent spinal surgery for
spinal metastatic disease, did not show a significant relation between
conventional radiation therapy and wound complication rate (Dea 2013).
Advancements in radiation treatments, surgical techniques and post-operative
care may account for these differences in influence on wound complications.

Advantages of combining two effective treatments

When more advanced radiotherapy planning and delivering techniques are employed
(for example, stereotactic body radiotherapy (SBRT)), exposure of the
vulnerable surgical site to radiation can largely be avoided. Therefore, the
interval between surgical stabilization and radiotherapy may be shortened or
even eliminated. As a result, the patient may experience the analgesic effect
from irradiation two weeks earlier and both interventions can be planned and
performed in a single, shorter hospital admission period. Both irradiation and
surgical techniques have been proven to be safe and effective in isolation and
are commonly practiced in our hospital. To date, no information on feasibility
or safety is available when the two modalities are combined in a 48-hour window.

In 2009, the IDEAL recommendations were introduced (McCulloch 2009). These
recommendations provide direction for reporting and evaluation of innovative
surgical procedures which are being undertaken for the first time, and for
adoption of new procedures in other centers and by other teams. IDEAL is an
acronym for the five stages that complex interventions go through, namely
Innovation, Development, Evaluation, Assessment and Long term evaluation.
In stage 1 (Innovation or Idea), the new procedure is used in humans for the
first time. The initial patients are usually highly selected on an individual
basis. Feasibility, duration and complication are reported for a small number
of patients. These reports should contain clear anonymous details of the
patient, their condition, the rationale and background for use of the
procedure, exactly what was done, and adequate details of relevant outcomes.
Progression to stage 2a (Development) is justified by successful implementation
of the new procedure in several consecutive patients without serious adverse
events. With practitioners maintaining confidence, the new approach becomes a
practical alternative to the standard procedure. Reporting during this stage
needs to include: selection criteria and proportion of eligible patients
selected; a clear description of the procedure and each modification, with
timing; and relevant outcomes, with recognized standard definitions of
important categories, such as specific complications.
Transition to stage 2b (Evaluation or Exploration) is justified by improvements
in procedure times and the avoidance of adverse events, with major refinements
of the method completed. This stage consists of a larger series of consecutive
patients. Stage 3 (Assessment) aims to answer the essential question: Is the
clinical efficacy of this intervention better than the standard treatment?
Comparative studies, preferably with a randomized component, are favored. Stage
4 (Long term evaluation) starts when the effectiveness of new intervention has
been demonstrated and the intervention is implemented in daily clinical
practice. The current study is a combination of stage 1 (Idea) and stage 2a
(Development).

Primary Objective

To assess the feasibility and safety of combining stereotactic body
radiotherapy and pedicle screw fixation in a 48-hour window for the treatment
of painful unstable metastases of the thoracic and/or lumbar spine.

Secondary Objectives

The secondary objectives of this study are:

* Measurement of pain response to combined therapy
* Measurement of duration of pain relief
* Measurement of rapidity of pain relief
* Length of stay in the hospital
* 30-days mortality
* Neurological detoriation
* Evaluation of quality of life
* Overall survival

This study will be a prospective development study (IDEAL stage 1 and 2a)
(McCulloh 2009) performed at the University Medical Center Utrecht (UMCU). A
group of 13 patients with (impending) spinal instability requiring radiation
therapy and surgical intervention will be studied to assess the safety and
feasibility of combining stereotactic body radiotherapy ensued by surgical
stabilization within a 48-hours window. Patients will be recruited from the
outpatient clinics of Oncology; Radiation Oncology; Neurology; Neurosurgery and
Orthopedic Surgery. Adverse events will be scored using the SAVES [Street 2012]
form (appendix) and according to CTC-AE 4.0

Shortened time window
Stereotactic body radiotherapy and surgical stabilization will be performed
within a 48-hour time window instead of today*s standard of care of two weeks
between surgical stabilization and external beam radiotherapy.

Stereotactic Body Radiotherapy
Stereotactic body radiotherapy will be used to irradiate the spinal metastases
instead of today*s standard of care of external beam radiotherapy. Stereotactic
body radiotherapy (SBRT) is a radiation technique that delivers high-dose
radiation precisely to the spinal metastases in a single or a few fractions. It
does so using a combination of image-guidance, to remediate the inter- and
intra-fraction motion, and advanced inverse treatment planning algorithms to
achieve highly conformal dose distributions (Sahgal 2008, Sahgal 2013).

In a first step, patients will undergo SBRT on a priority base within 48 hours
before surgery. Patients undergo a planning CT scan and MRI scan in treatment
position. Patients will receive high dose, single fraction radiotherapy
consisting of 18 Gy to the metastases exclusively. However, adjacent
physiologic appearing bone marrow spaces may harbor subclinical disease and
could potentially serve as a source for a local recurrence as reported from
prospective data (Cox et al 2012). Therefore, the bony compartment will receive
the conventional low dose of 8 Gy * in order to treat subclinical disease *
whereas the metastasis will receive 18 Gy. To deliver this high dose safely,
accurate treatment planning and positioning is needed. Treatment planning is
performed on the pre-treatment CT and MRI data that are mutually registered to
yield information on all relevant structures for planning assessing dose
distribution using volumetric modulated arc therapy. MRI is used to delineate
the gross tumor volume (GTV), clinical target volume (CTV), planned target
volume (PTV) and the organs at risk (OAR). With the aid of T1 weighted, T2
weighted and diffusion weighted imaging sequences, it is possible to delineate
the GTV accurately. Dose constraints are set for the OAR and other anatomical
constraints based on institution specific guidelines. These constraints are of
primary concern. So, if necessary, dose delivery to the GTV will therefore by
limited in order to meet these criteria.

For all patients, online cone beam CT (CBCT) data will be acquired with the
patient in treatment position on the treatment table just before start of the
treatment. The CBCT data yields the exact position of the bony anatomy and is
also registered to the pre-treatment CT and MRI data. Given the fact that the
target volume is bony anatomy, the actual re-positioning data is determined for
all the pre-treatment defined relevant structures for safe dose delivery.
Alignment of the patient or, more specifically, the tumor volume, with
pre-treatment plan will be performed. After correction, a second CBCT will be
performed. A third CBCT will be taken post-treatment to document stability of
the target during treatment.

Pedicle Screw fixation
Pedicle screw fixation is a commonly performed procedure to achieve spinal
fusion or stabilization for the treatment of spinal trauma, spinal deformity,
degenerative disease and spinal neoplastic processes. It has gained widespread
acceptance and its safety is has been well studied (Lonstein 1999, Jutte 2001,
Gautschi 2011). Pedicle screw associated complications are rare, with 2.4%
overall complication rate reported in a study of 875 patients with 4790 screw
placements (Lonstein 1999). A recent systematic literature review of 35 630
pedicle screws showed a complication rate of 0.18% per pedicle screw for dural
tears, 0.19% per pedicle screw for nerve root irritation, 0.2% per pedicle
screw for pedicle fracture, one case of pneumothorax, one case of pleural
effusion and no cases of vascular injuries (Gautschi 2011). These
complications are mostly associated with the insertion of the pedicle screws,
this recent literature study reported 92.2% screw placement accuracy. Yet, not
all-inaccurate placed screws are symptomatic or clinically relevant.

Stereotactic body radiotherapy
Stereotactic body radiotherapy has evolved as an innovative treatment for the
treatment of spinal metastases. Treatment of spinal metastases with SBRT is
associated with risks for the patient [Lutz 2011]. In contrast with the risk
low risk on late toxicities with external beam radiotherapy, ten cases of
radiation myelopathy have been described associated with SBRT, 5 without prior
radiotherapy and 5 cases after re-irradiation [Sahgal 2009A, Sahgal 2009B].
Furthermore, SBRT has been associated with new or progression of vertebral
compression fractures, with a study from Memorial Sloan Kettering reporting a
fracture progression in 38% [Rose 2009]. As a consequence patient may require
additional intervention such as surgical stabilization [Lutz 2011]. Yet, in our
study the decision for surgical stabilization is already made based on the
imaging and clinical parameters.
Finally, pulmonary and esophageal side effects may occur with external beam
radiation therapy although they are rare. One case of fatal esophageal necrosis
and one case bronchial stenosis has been described after SBRT in a series of
119 patients [Gomez 2009]. Lack of knowledge about the radiation tolerance of
normal tissue has highly contributed to these toxicities. The incidence of
radiation myelopathy after SBRT has already decreased due to different research
projects, which have resulted in guidelines for the maximum radiation dose for
the spinal cord[Lutz 2011].

Radiation therapy and Surgery
Ghogawala et al (2001) demonstrated a relation between pre-operative
conventional radiotherapy and the rate of wound complications. Therefore, a
minimum two-week interval between surgery and irradiation is currently
considered necessary to avoid wound complications in the postoperative phase.
Yet, this study was a retrospective chart review involving patients from 1970
till 1996 who underwent surgery for spinal cord compression.The systematic
review of Itshayek et al (2010) reported a range of 11% to 50% for major wound
complications in patients who had radiotherapy before surgical intervention.
Yet, this included three retrospective studies and two very small prospective
studies. In a recently conducted prospective study on adverse events in
patients who underwent emergent spinal surgery for spinal metastatic disease,
did not show a significant relation between conventional radiation therapy and
wound complication rate (Dea 2013). Advancements in radiation treatments,
surgical techniques and post-operative care may account for these differences
in influence on wound complications. To our knowledge no studies describe the
relationship between pre-operative stereotactic body radiotherapy and
complications.

SBRT and Surgery
Being a first-in-man evaluation, there is no data available about the possible
complications and risk on these complications for the combination of SBRT and
surgical intervention within 48 hours. By performing preoperative high-dose
irradiation (SBRT), we may experience problems in the irradiated and operated
field (delayed wound healing, infection of implants). However, SBRT allows high
precision irradiation, with sparing of the surrounding tissues, reducing the
risk of postoperative problems in the irradiated area. Also, both treatments
separately have proven to be safe. Given the huge potential benefit for the
patient, we feel the experiment is justified.