Supplementary File B -Descriptive data of the included studies
Author year / Study design / Primary site / Key exclusion criteria / Treated site(s) / Treatment/ intervention groups / Number of patients (number of lesions) / Extracted outcome parametersANIMALS
Arrington, 2008[29] / Controlled trial (mice) / Injected cells: F10 breast carcinoma / n/a / Distal femur / A) No treatment (0 Gy)
B) RT (20 Gy)
C) RT (20Gy) + BP (ZA)
D) Control (non-metastatic limbs of A and B) / A) 12 (12)
B) 9 (9)
C) 9 (9)
D) 9 (-)
/ Bone density
Micro-architecture
Strength / BMD [g/cm2] using DEXA
Fractional trabecular bone volume [-] using μCT
Strength [Nmm] using whole limb torsional testing
Arrington, 2010[30] / Controlled trial
(mice) / Injected cells: F10 breast carcinoma / n/a / Distal femur / A) No treatment (0 Gy)
B) RT (20 Gy)
C) RT (20 Gy) + BP (ZA)
D) Control (non-metastatic limbs of B) / A) 14 (14)
B) 14 (14)
C) 14 (14)
D) 14 (-)
/ Bone density
Micro-architecture
Strength / BMD [g/cm2] using DEXA
Fractional trabecular bone volume [-] using μCT
Strength [Nmm] using whole limb torsional testing
Krempien, 2003[31] / Controlled trial
(rats) / Injected cells: Walker carcinosarcoma 256B / n/a / Proximal tibia / A) RT (17 Gy)
B) RT (17 Gy) + early BP (CL)
C) RT (17 Gy) + simultaneous BP (CL) / A) 17 (34)
B) 17 (34)
C) 17 (34) / Bone density
Micro-architecture / BMD [n.s.] using X-ray
BAr [%] using stereo microscopy
HUMANS
Atahan, 2010 [32] / Randomized controlled trial / Breast / Pathological fracture in target region(s), previous RT of target lesion, previous treatment with BPs / Axial skeleton, extremities / A) RT (5 x 3 Gy) + BP (ZA)
B) RT (10 x 3 Gy + BP (ZA) / A) 51 (n.s.)
B) 49 (n.s.) / Pathological fracture / Vertebral or non-vertebral pathological fracture
Balagamwala, 2012 [33] / Retrospective cohort study / Kidney / ≥ 2 fractions of SBRT, spinal instability / Spine / SBRT (1 x 8-16 Gy) / 57 (88) / Pathological fracture / Infield or adjacent (within 1 VB) failure on MRI
Chang, 2014 [34] / Retrospective cohort study / Liver / Overt spinal instability / Spine / A) RT (10 x 3 Gy or 13 x 3 Gy)
B) SRS (mean 28.7 Gy in 1-5 fractions) / A) 32 (n.s.)
B) ? (39) / Pathological fracture / Vertebral compression fracture: newly developed fracture or progression of an existing fracture
Cheng, 1980 [35] / Retrospective cohort study / Breast / Femur, acetabulum, humerus / Femur/ acetabulum: RT (± 30 Gy in 10 fractions or 40 Gy in 12 fractions)
Humerus: RT (20 Gy in 5 fractions) / 59 (97) / Pathological fracture / n.s.
Chow, 2004 [36] / Cohort study / Breast / Pathological fractures, previous RT to target lesion, recent change (within 4 weeks of delivery of RT) of BPs / Trunk, extremities / A) RT (1 x 8 Gy)
B) RT (5 x 4 Gy)
C) RT (10 x 3 Gy) / 25 pt completed the study / Bone density / CT density [HU] using CT
Crone-Munzebrock, 1988 [37] / ? / Various / Use of drugs affecting bone metabolism, change in vertebral height during treatment / Vertebrae / RT (40-50 Gy in fractions of 2.5 Gy) / 19 (n.s.) / Bone density / Mineral salt content [mg/ml] using CT and calibration phantom
El-Shenshawy, 2006 [38] / Controlled clinical trial / Various / Prior RT to target lesion, pathological fractures except compression fractures of the vertebral spinal column, new current treatment during RT which might mask the therapeutic response / Spine, ribs, pelvis, hip, femur, humerus / A) RT (1 x 8 Gy)
B) RT (5 x 4 Gy or 10 x 3 Gy)¥ / A) 50 (n.s.)
B) 50 (n.s.) and 50 (n.s.) / Bone density
Pathological fracture / Hounsfield Units [HU] of delineated metastatic lesions using CT
n.s.
Foerster, 2015 [39] / Retrospective cohort study / Breast / Spine / RT (median 30 Gy in fractions of 3.0 Gy) / 115 (135) / Bone density / Bone density [HU] within bone metastases and irradiated uninvolved bone using CT
Garmatis, 1978 [40] / ? / Breast / Skull, spine, pelvis, hips, ribs, extremities / RT (20-25 Gy in 8-10 fractions) / 75 (158) / Radiologic response / Objective response using X-rays:
a) marked improvement (considerable decrease in the size of the metastatic lesion and evidence of re-calcification);
b) stable condition (unchanged status with no evidence of further growth of the lesion);
c) progression (continuous increase in the size of the metastatic disease)
Hartsell, 2005 [41] / Controlled clinical trial / Breast or prostate / Prior RT or palliative surgery, pathologic or impending fracture of target lesion, planned surgical fixation of the bone, introduction BPs within the 30 days before entry into the study / n.s. / A) RT (1 x 8 Gy)
B) RT (10 x 3 Gy) / A) 455 (n.s.)
B) 443 (n.s.) / Pathological fracture / Pathologic fractures within or within plus adjacent to treatment field
Huber, 2002 [42] / Retrospective cohort study / Breast / Various / Main schedules¤:
1) Conventional RT (40-60 Gy in 20-23 fractions)
2) Short-course RT: (30-36 Gy in 10-12 fractions)
3) Fast course RT: (8-28 Gy in 1-4 fractions) / 44 (n.s.)§ / Radiologic response / Either:
Re-calcification of osseous involvement, development of marginal sclerosis, reduction of sclerosis in case of blastic lesions, decrease in lesion size, disappearance of lesions and arrest of previously progressive disease, or progression of osseous disease
Kijima, 2008 [43] / Retrospective cohort study / Kidney / Previous complete surgical resection of target lesion. For RT group: no BP during treatment course / Mostly vertebrae and pelvis / A) RT (20-45 Gy)
B) RT (20-45 Gy) + BP (ZA) / A) 13 (n.s.)
B) 10 (n.s.) / Radiologic response
Pathological fracture / Objective response of bone metastatic lesions using CT:
a) Complete remission (disappearance of osteolyticbone lesions);
b) Partial response (>50% calcification of osteolytic bone lesions and/or shrinkage of bone lesions)
N.S.
Koswig, 1999 [17] / Controlled clinical trial / Breast, lung, prostate, kidney / Previous RT to target lesion, start of new systemic treatment in two weeks before start RT / Spine, extremities, pelvis / A) RT (1 x 8 Gy)
B) RT (10 x 3 Gy) / A) 52 (52)
B) 55 (52) / Bone density / CT density [HU] using CT
Kouloulias, 2003 [44] / Intervention study / Breast / Previous use of BPs or calcitonin; no previous RT in target lesion; pathologic fracture / Femur, humerus, iliac bone / RT (total dose ≤ 30 Gy in 10 fractions) + BP (DP) / 33 (33) / Bone density / Mean value of gray-level histogram (MVGLH) using X ray
Lee, 2013 [45] / Retrospective cohort study / Various / Spine / High dose RT using HT
Median total dose and dose per fraction:
A) Primary HT:
27 Gy and 8 Gy, resp.
B) Boost-treatment: 12 Gy and 3 Gy, resp.
C) Re-irradiation:
30 Gy and 3 Gy, resp. / 36 (51)
A) n.s. (37)
B) n.s. (4)
C) n.s. (10) / Pathological fracture / Symptomatic compression fracture
Lee, 2015 [46] / Retrospective cohort study / Liver / Prior RT or surgery to target region, receiving concurrent systemic treatment / Spine / A) SBRT (18-40 Gy in 1-4 fractions)
B) SBRT (10 x 5 Gy) / A) 11 (15)
B) 12 (21) / Pathological fracture / Compression fracture: new endplate fracture or new collapse deformity compared with pre-treatment imaging
McDonald, 2015 [47] / Retrospective cohort study / Various / Nonspine / SBRT (most common: 5 x 7 Gy (47.5%), 5 x 6 Gy (22.5%), 2 x 12 Gy (12.5%)) / 31 (40) / Bone density / Bone density [HU] using CT
Rasmusson, 1995 [48] / Controlled clinical trial / Breast / Fractures in bone metastases prior to RT, except vertebral compression fractures / Spine, sternum, pelvis, extremities / A) RT (10 x 3 Gy)
B) RT (3 x 5 Gy) / 217 (n.s.)
A) n.s. (n.s.)
B) n.s. (n.s.) / Radiological response / Radiological response on X-ray: a) complete response (complete disappearance of lesions with reconstruction of normal bone tissue;
b) partial response (decreased size of the osteolytic focus or appearance of osteosclerosis in the border or diffusely in the lesion (primarily osteolytic and mixed metastases) and decreased size or number of the sclerotic lesions without signs of osteolysis in the radiation field (primarily sclerotic metastases));
c) mixed response (both an increase in size and/or number of metastases and appearance of sclerosis in previous osteolytic foci (primarily osteolytic and mixed metastases));
d) progressive response (increased size of osteolytic foci already present or appearance of new osteolytic foci within the radiated field (primarily osteolytic and mixed metastases) and appearance of osteolytic foci or new osteosclerotic metastases (primarily sclerotic metastases))
Reichel, 2007 [49] / Retrospective cohort study / Kidney / Spine, ribs, hip, extremities, shoulder, pelvis / RT (total dose median 30 Gy, range 15.50 -42.50) / 28 (36) / Pathological fracture / n.s.
Rhee, 2014 [50] / Retrospective cohort study / Colon / Use of BP, prior surgery, SBRT, or procedure related to vertebral stability / Spine / RT (total dose median 30 Gy in fractions of median 3 Gy) / 16 (68),
of whom n.s. (42) metastatically affected / Pathological fracture / New and progressive (>20% reduction in vertebral height) compression fracture
Rieden, 1989a [51] / Cohort study / Breast, lung, kidney, prostate / Extremities, ribs, pelvis, acetabulum / RT (9 x 3 Gy) / 34 (60) / Radiologic response / Objective response:
a) re-calcification (enabling loading of pre-RT fracture prone sites);
b) status idem (stabilization of previously progressive destruction);
c) progression
Rieden, 1989b [52] / Retrospective cohort study / Breast, lung, kidney, prostate / Spine, pelvis, extremities, skull, sternum, ribs / RT (total dose 30-50 Gy in fractions of 2-3 Gy) / 239 (578) / Radiologic response / Objective response
a) re-calcification
b) status idem
c) progression
Rief, 2013 [53] / Retrospective cohort study / Lung / Spine / RT (median 30 Gy in fractions of 3 Gy) / 338 (981) / Pathological fracture / Pathological fractures in vertebral bodies in which no fracture could be detected prior to the start of therapy using CT
Schlampp, 2014 [54] / Retrospective cohort study / Breast / Spine / RT (most common: 10 x 3 Gy) / 115 (157) / Pathological fracture / Pathological fractures in vertebral bodies in which no fracture could be detected prior to the start of therapy using CT
Sellin, 2015 [55] / Retrospective cohort study / Kidney / Spinal instability / Spine / SRS (5 x 6 Gy (n = 4); 3 x 9 Gy (n = 9), 1 x to 24 Gy (n = 24)) / 37 (40) / Pathological fracture / Compression fracture
Sohn, 2014 [56] / Retrospective matched-pair study / Kidney / Previous surgery / Spine / A) SRS (mean 38.0 Gy in median 4 fractions)
B) RT (mean 29.4 Gy in median 11 fractions) / A) 13 (n.s.)
B) 13 (n.s.) / Pathological fracture / Vertebral compression fracture: de novo fracture (i.e. a new endplate fracture or collapse deformity as compared with before treatment) or fracture progression of an existing fracture
Steenland, 1999 [57] / Controlled clinical trial / Breast, prostate, lung, other / Previous RT to target lesions, pathological fractures needing surgical fixation / Various / A) RT (1 x 8 Gy)
B) RT (6 x 4 Gy) / A) 585 (n.s.)
B) 586 (n.s.) / Pathological fractures / n.s.
Switlyk, 2014 [58] / Retrospective study / Breast / Prior RT for spinal metastases from breast cancer / Spine / RT (10 x 3 Gy) / 32 (32) / Pathological fracture / New and progressive (≥2 mm difference between the pre- and post-treatment vertebral height) fracture established using MRI
Tabata, 2012 [59] / Retrospective cohort study / Prostate / Spine, femur, pelvis, hip, sternum, ribs / A) RT (<40 Gy)
B) RT (≥40 Gy) / A) 14 (n.s.)
B) 21 (n.s.) / Pathological fracture / n.s.
Takeda, 2012 [60] / Retrospective cohort study / Kidney / ZA more than twice / Various / A) RT (25-51 Gy in 5-30 fractions)
B) RT (25-36 Gy in 5-16 fractions) + BP (ZA) / A) 12 (18)
B) 15 (16) / Pathological fracture / n.s.
Thibault, 2014 [61] / Retrospective cohort study / Kidney / Spine / SBRT (18-30 Gy in 1-5 fractions) / 37 (71), of whom n.s. (61) non postoperative / Pathological fracture / New and progressive compression fracture
Ursino, 2015 [62] / Retrospective cohort study / Various / Previous surgery or RT to target lesion, chemotherapy ≤ 3 before or after SBRT / Pelvis, scapula, vertebra, rib, humerus, tibia / SBRT (1 x 24 Gy or 3 x 9 Gy) / 40 (n.s.) / Pathological fracture / n.s.
Vassiliou, 2007a [63] / Cohort study / Various / Previous BP, previous RT to target lesion, pathological fracture / Various / RT (total dose 30-40 Gy in fractions of 1.8-2.0 Gy) + BP (IB) / 45 (n.s.) / Bone density / Hounsfield Units [HU] of delineated metastatic lesions using CT
Vassiliou, 2007b [64] / Cohort study / Various / Previous BP, previous RT to target lesion, pathological fracture / n.s. / RT (total dose 30-40 Gy in fractions of 1.8-2.0 Gy) + BP (IB) / 70 (n.s.) / Bone density
Pathological fracture / Hounsfield Units [HU] of delineated metastatic lesions using CT
n.s.
Wachenfeld 1996, [65] / ? / Breast / Spine / RT (18 x 2 Gy) / 14 (50) / Bone density / BMD [mg/ml calciumhydroxylapatite] using CT and calibration phantom
Wagner 1991, [66] / Retrospective cohort study / Breast / Various / RT (total dose 15-30 Gy in 86.3% of the patients) / 167 (n.s.) / Radiologic response / Recalcification
¥: patients were randomized to receive either of the three fractionation schedules; ¤: All patients were analyzed as one group; §: Only the patients receiving RT were included in this systematic review;n.s.: not stated; ?: unclear; n/a: not applicable; BAr = 100% x (bone area / tissue area);BMD = Bone Mineral Density; BP = Bisphosphonate; CL: Clodronate; CT: Computed Tomography; DEXA: Dual Energy X-ray Absorptiometry; DP: Disodium Pamidronate; Gy: Gray; HT = Helical Tomotherapy; HU: Hounsfield Units; IB = Ibandronate; MRI: Magnetic Resonance Imaging; RT = Radiotherapy; SBRT = Stereotactic Body Radiation Therapy; SRS = Stereotactic Radiosurgery; VB = Vertebral Body; ZA: Zoledronic Acid