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Prophylactic surgery of impending fractures in long bone metastasis :…
Prophylactic surgery of impending fractures in long bone metastasis : towards new decision-making tools - A short review
Mirels score
(Mirels et al 2003)
4 criteria : lesion size, Radiological appearance, anatomical site, related pain
cut-off : score ≥ 9/12
pb : moderate risk of Mirels' score = 8 (15% facture risk, FP 6%) => undertreatment
lack of specificity for score ≥ 9/12 : overtreatment
(Van der linden et al 2004)
Unnecessary preventing surgeries in 2/3 of the patients
(Damron et al 2003)
Missing permeative cortical lesions diagnosis on standard X ray,
(Shinoyama et al 2017)
Permeative lesions are frequent (57%) leading to unmeasurable critical diameter neither specific percent involvement of the bone
54% of the 26 pathologic fractures occured through these unmeasurable lesions (
(Keene et al 1986)
low total score inter and intra observer concordance (kappa=0,294 and kappa=0,323)
(El-Husseiny et Coleman 2010, Howard et al 2018)
Pain : highest inter-observer discordance
(Damron et al 2003)
even if moderate to severe bone pain was experienced by the patients, only 11% of them sustained fractures. Radiotherapy relieved bone pain but did not prevent from sustaining fractures => pain, alone, is not a reliable indicator of impending fractures
(Keene et al 1986)
The use of single stance body weight can be a useful in conjunction with the Mirels score to predict pathological fracture. If less than 85% of total body weight can be put through the affected limb, the risk of fracture increases, and consideration of treatment is suggested.
(Howard et al 2019)
Context
Bone metastasis = turning point in patient's oncologic history
(Roodman et al 2004, Coleman et al 2006, Body et al 2013)
SRE
: hyperCa2+ / medullar compression / pain / fractures
50%
fractures
following the first 2 years after ∆g
(Carter et al 2013)
Impairs autonomy and quality of life
(Carter et al 2013)
Increasing mortality
(Coleman et al 1987, Hirsh et al 2009, Ofelein et al 2002, Saad et al 2007, Howard et al 2016, Howard et al 2016, Saad et al 2017, Cella et al 1993, Weinfurt et al 2005, Perisano et al 2015)
surgical management : additional cost (compared to preventive stabilization)
(Bland et al 2016, Antczak et al 2014, Carter et al 2013)
Impending fractures ∆g : a matter of necessity
(Piccioli et al 2014, Benca et al 2016, Howard et al 2018, Anract et al 2017)
Prophylactic surgery
better survical rates
(Mavrogenis et al 2012, Ratasvuori et al 2013)
arthroplasty, intramedullary nailing, plating with bone cement injections
(Errani et al 2017)
Not always a solution : complications
(Swanson et al 2000, Ratasvuori et al 2013)
1989 Mirels
(Mirels et al 2003)
lack of specificity
(Howard et al 2018, Damron et al 2003, Crenn et al 2020)
ACI, CTFEA, CTRA
(Van der Linden et al 2004, Anez Bustillos et al 2014)
History (Before Mirels) Fractures are predictable
(Van der Linden 2004, Beals et al 1971, Fidler et al 1981)
Radiotherapy
Single and multiple fraction regimens provided equal
pain relief
; however, significantly higher retreatment rates occurred in those receiving single fractions.
(Chow et al 2012)
effectiveness in neuropathic bone pain also
(Roos 2015)
RT along with immunotherapy target tumor stroma and helps to
restrain tumor proliferation
(Menon et al 2019)
attention, pas dans les bone metastasis
Bone recalcification
after RT in multiple myeloma
(Matuschek et al 2015)
single vs multi-fraction RT
: equally pain relief, but more re-irradiation for recurrent bone pain with single-fraction RT
(Rades et al 2010)
, and controversial data regarding the pathological fracture rates after RT (seems to be less if multi-fraction RT)
(Sze et al 2003, Chow et al 2007)
Moreover, a recent in vivo animal study illustrated that a 20 Gy radiation is associated with an increased risk for late-onset fragility fractures within the irradiated area, as it decreases the elastic modulus of bone organic matrix and energy to failure, diminishing fatigue strength
(Bartlow et al 2021)
.
Single fraction
stereotactic
body radiotherapy (12 Gy if ≤ 4 cm lesion, 16 Gy if ≥ 4 cm) is more effective concerning pain response than 30 Gy multi fraction conventional external radiotherapy
(Nguyen et al 2019)
with a 1,2% rate of associated pathological fracture
In conventional external beam radiotherapy, various fraction regimens have been de-scribed, ranging from single-fraction (maximum 8 Gy) to short (maximum 22,5 Gy) or long-course multi-fraction radiotherapy (maximum 30 Gy)
(Rades et al 2010)
efficacy of zolendronic acid (bisphosphonates) in preventing SRE
(Santini et al 2006)
along with Denosumab which decreases bone resorption by inhibiting RANKL
(Body et al 2010)
radionuclide / theranostics
Combined with computed tomography (CT), 68Ga PSMA-11 PET/CT outperformed CT alone to detect osseous metastases, with a sensitivity of 99% and specificity of 88% while a CT scan shown a sensitivity and specificity of 87% and 61% respectively
(Pyka et al 2016)
Relying on substitution of β+ by β- or α-particle emitters, the PET tracer is switched for a therapeutic radionuclide, exploiting the same specific molecular target for imaging and therapy
(Notni et Wester 2018)
In particular, prostate specific membrane antigen (PSMA) has become an attractive target for radionuclide-chelating ligands
(Barrio et al 2016)
predictive biomarker to confirm target expression for endoradiotherapy, which can be achieved with 177Lu PSMA-617 β− emitters
(Rahbar et al 2016)
bisphophonates / radionuclides : , 68Ga-/177Lu-DOTA-ZOL seemed to be an effective palliative MBD treatment
(Meckel et al 2017, Fernandez et al 2021)
ACI > 30 mm
(Van der Linden et al 2003, Van der Linden et al 2004)
reduced the unecessary procedures from 87 to 42%
relatively low sensitivity 86% with only 58% Specificity : under treatment
(Van der Wal et al 2020)
recommended in Netherlands for managing long bone metastastic lesions
CCI ≥ 30%
(CT-scan)
(Tatar et al 2019)
Biomechanical models based on QCT
(Nazarian et al 2015, Sternheim et al 2018)
CTRA
X ray attenuation (HU) are converted to equivalent bone mineral ash density (HAP phantom)
(Snyder et al 2009)
Ex-Vivo studies
load bearing capacity of the simulated lytic lesion # to the rigidity at the weakest cross section
(Hong et al 2004)
CTRA correlated well with yield loads of failure
(Whealan et al 2000)
Reduction in axial / bending / torsional rigidities > 35% => high risk for fracrture
(Leong et al 2010, Snyder et al 2006)
In-vivo studies
Sn 100%, Sp 60,6%, VPP 17,6%, VPN 100% compared to Mirels ≥ 9 (66,7%, 47,9%, 9,8%, 94,4%)
(Damron et al 2006)
After providing CTRA results, physicians changed their plan for 36 over 124 patients, but 7 who did not undergo fixation resulted in actual fractures
(Nazarian et al 2015)
curved beam CTRA
- Ex-vivo study
(Oftadeh et al 2016)
=> useful to approximate intertrochanteric region : cf intrinsic boner curvatture influence
intertrochanteric region = curvature (cf wolff's law : mechanical loads affect bone arthitectature)
(Hammer et al 2014)
mechanical stresses and loading forces in vivo are not restricted to a single plane
(Mourtada et al 1995)
1/5 lesion occurs in this intertrochanteric parrticular region
(Feng et al 2016)
specific procedure
(Sterinheim et al 2020)
: phantom + controlateral femora free of tumor, without any arthroplasty) Manual procedure 30 minutes duration performed by an experiences biomedical engineer
(Anez Bustillos et al 2014)
CT-FEA
Extracting elastic modulus / strength / post-failure behaviour data
(Keyak et al 2005)
take in account patient's weight along with bone anatomy
(Sas et al 2020)
End of the 80's : FE as a tool to predict fracture risk in MBD
(Mc Broom et al 1988, Cheal et al 1993)
Non-linear FE models provide good correlations in predicting failure load
(Damron et Mann 2020)
Ex-vivo studies
Model-experiment correlation varied from r^2=0,77 to r^2=0,98
(Benca et al, 2019, Keyak et al 2005, Tanck et al 2009, Dericks et al 2012)
CTFEA > CTRA and curved beam CTRA
(Oftadeh et al 2016)
In-vivo studies
SFR > 1,48 Sn 100, FEA 67% AUC 0,905
(Sternheim et al 2020)
failure load < 7,5 BW Sn 100% Sp 74% PPV 39%, NPV 100%
(Eggermont et al 2020)
Inner cortex lesions
Inner cortex lesions are more susceptible to loss of strength
(Cheal et al 1993, Tanck et al 2009)
Cut-off value : thickness of the inner cortex < 3,67 as a prredictor of pathological fracture (Sn 100%, Sp 75,1%) ex-vivo study population containing aneurysmal cysts, infectious along with MBD,
(Kawabata et al 2017)
air artefact causing a shading on the calibration phantom
(Eggermont et al 2020)
arthroplasty implants may create artefacts that affect HU and corrupt the material characterization in CT FEA models
(Sternheim et al 2020, Eggermont et al 2018)
8h per sample, complex biomechanics analysis requirements, specific software
(Anez Bustillos et al 2014, Oftadeh et al 2016, Yosibash et al 2014)
, vs automatic process of 1 h
(Sternheim et al 2020)
Muscle loads
However, designing the whole muscle insertion significantly complicates the modelling and requires specific anatomical knowledge
(Polgar et al 2003) (Rohlmann et al 1982, Lee et al 2007)
Discussion
What do we need ?
Multidisciplinary approach
(Cumming et al 2009)
standardized protocol for CT-FEA
- loading conditions differ between studies / more complex models than just a compressive axial force to simulate loading / be careful : too complex => too long
implement
anisotropic
material properties
(Keyak et al 2005, Kazembakhshi et Luo 2014)
Accuracy of the models are limited by the use of isotropic material properties.Yet, trabecular bone is orthotropic. (Keyak et al 2004). integrating anisotropic mechanical properties have proved to to enhance bone strength and siffness prediction in pooled stance and side-fall configurations.
(Kazembakhshi et al 2014, Panyasantisuk et al 2018)
Image reconstruction algorithm - linear vs non linear FE models
(Keyak et al 2001 => non linear, Yosibash et al 2014=> linear)
Linear models generallu used, Non-linear models FE models were found better to improve fracture prediction in single-limb stance.
BW controversy
: 7,5BW ?
(Eggermont et al 2020)
2,5 BW ? Goodheart suggest to combine FE LW + mirels > 8, providing Sn 80 and Sp 100
Goodheart et al 2015)
the average hip joint load while walking is about 238% BW. When climbing stairs, the load raises up to 251% BW.
(Bergmann et al 2001)
including
blastic lesions
? overestimation of femoral bone strength
(Eggermont et al, Biomaterials 2018)
Sterinheim et al 2020)
Hipp et al 1992, Kaneko et al 2004 Goodheart et al 2015
inter TDM differences
(Carpenter et al 2014, Eggermont et al J Orthop research 2018, Dragomir et al 2015, Paul et al 2012)
Statistically significant differences in gray scale values were found depending on scan parameters : slice thickness, power, anthropomorphic or water phantom. (Paul et al 2012) strength and stiffness estimated from high resolution scans were larger than those obtained from low resolution scans, except for strength of normal and osteopenic femora which are smaller. (Dragomir-Daescu et al 2015).
determine a
threshold
in FE models (Strain fold ratio ? inner cortex thickness ? failure load < 7,5x BW ?)
How do we get there ?
machine learning
life expectancy after surgical management of bone metastases machine-learned BBN
(Forsberg et al 2011)
Machine learned decision-tree based to predict SRE in MBD
(Wang et al 2016)
pathfx : on-line available tool providing good accuracy in predicting life expectancy after surgical management of BMD
(Anderson et al 2020)
Only 5 on 28 oncologists routinely used a fracture predictive score => multidisciplinary approach
(Cumming et al 2009)
ANN > BBN in accuracy for prediction of life expectancy after surgery of MBD
(Forsberg et al 2012)
, but BBN deals with missing data inputs
(Rubin et al 1991)
FRAX tool : machine learned score to predict fracture in osteoporotic bones (clinical + Rx data)
(Kanis et al 2017, Kong et al 2020)
Machine learning + FE in osteoporotic patients
(Galassi et al 2020)
FE + ML : time gain from 1800 minutes to 1000 ms
(Hambli et al 2011, Phellan et al 2021)
Net benefits analysis
(Vickers et al 2019)
Useful only if each patient has the same expected benefit and cost of intervention : disease specific score
(Toci et al 2021)
cf CT/RT delays ?
(Kerr et al 2016)
Where are we now ?
Mirels : Dependent on the practioner, given tthe high inter and intra-observer discordances,
nuclear medecine imaging techniques
PET-CT (
Ulaner et al, 2017)
SPECT-CT
(Riaz et al, 2018)
: Mirels combined with ACI, without X-Ray but SPECT-CT
hybrid imaging technics
Hybrid imaging technics combine anatomic data, from computed tomography (CT) or magnetic resonance imaging (MRI), with cross sectional details of functional informations from radiotracers tumoral avidity (
O'Sullivan et al 2015)
.
PET-CT < PET-MRI in evaluation of osseous metastases of cancer breast patients
(Catalano et al 2015, Ming et al 2020)
Conclusion
Even if CTRA might have an influence on perceived fracture risk, it did not increase the interobserver agreeement.
Increased exposure of clinicians to this tool may establish it as a uniform guideline to assess fracture risk
(Nazarian et al 2016)
Most of the actual risk-threshold value for pathologic fracture focus on femoral fractures (even if it is the most vulnerable site to pathologic fracture) with direct clinical impact as any practiian could advise the patient to avoid full wieght bearing
Mirels has never been evaluated prospectively ¨(Damron et al 2003)*
multidisciplinary approach (cf multifactorial problem)
Disease specific rating system (cf differences concerning life expectancy, responses to RT or CT)
Better define the contribution of mechanical and non mechanical factores to fracture risk
Other significant fracture predictors (biological parameters, age, WHO status)
(Eriksson et al 2014, Mun et al 2021)
trabecular ≠ cortical bone behaviour
(Morgan et al 2003, Niebur et al 2000, Kaneko et al 2003)