Staff-Lecture-SREs-copy.skeletal related event

Skeletal related event

1. Bone Health in Cancer Patients Skeletal Related Events (SREs)
SaniataLuarngjindarat, MD
Orthopedics departmentRajavithiHospital

2. Outline
Introduction : what is SREs? 1
How to prevent SREs?2
What are treatment for SREs?3
Bone Health in Cancer Patients Skeletal Related Events (SREs)

6. Pink Ribbon
(Breast cancer awarenessmonth)

8. Bone metastasis
85%70%
40%40%
1 Prevalence and Survival Patterns of Patients with Bone Metastasis from Common Cancers in Thailand, 2016
Thailand 1

9. Primary tumor to metastasis “Seed & Soil”

10. Why is it important?
Bone metastasis
Skeletal Related Events
2. Pathological fracture
Increase cancer burden
3. Spinal cord compression
4. Pain that need surgery or RT
1. Hypercalcemia
Decrease quality
of life (QoL)
Shortened survival
Increased health
resource utilization

11. Why is it important?
Bone metastasisSkeletalRelatedEvents
2. Pathological fracture
Increase cancer burden
3. Spinal cord compression
4. Pain that need surgery or RT
1. HypercalcemiaDecrease quality of life (QoL)Shortened survivalIncreased health resource utilization
Treatment Goals
Prevention SREsRelief pain & improve QoL

12. Principles of multidisciplinarymanagement
Treatment decisions depend on•The nature of the underlying malignancy•The bone disease is localized or widespread•The presence or absence of extra skeletal metastases
Oncologist Medicine
Orthopedic surgeons
Interventional radiologists
nuclear medicine physicians
palliative medicine

13. PRIMARY CARCINOMALAB INVESTIGATIONSTAGINGPre-op embolizationGet Rid 1stcarcinomaOption treatment
Thyroid cancer
•Thyroid function test (TFT)•USG thyroid/ FNA
•Skeletal survey•Total body scan with I-131•PET-CT•MRI whole body
O
•Total or subtotal thyroidectomy
•Surgery•I-131•Thyroid suppressing hormone
Renal cancer•Skeletal survey•PET-CT•MRI whole body•Nephrectomy•Surgery•RT (Radioresistance)•CMT
Hepatocellular•Liver function test (LFT)
Routine staging
•Hepatectomy•Transarterial chemoembolization (TACE)•Radiofrequency ablation (RFA)•Liver transplantation•Surgery•RT
Colorectal
X
•Colectomy•CCRT
Prostate cancer•Orchidectomy•Surgery•Hormonal therapy (ADT)•Radium-223
Breast cancer
•Breast-conservative surgery/ mastectomy•Sentinel LN Bx (SLNB)/ Axillary LN Dissection (ALND)
•Surgery•Hormonal therapy (ER/PR +ve)•Targeted therapy (HER-2 +ve)•CCRT

14. PRIMARY CARCINOMALAB INVESTIGATIONSTAGINGPre-op embolizationGet Rid 1stcarcinomaOption treatment
Lung carcinoma•SCLC•NSCLCRoutine staging
X
•Lobectomy•Thoracotomy with wedge resection•Mediastinal LND
•Surgery•RT•CMT•Targeted therapy (EGFR, ALK +ve)
Multiple myeloma•immunofixation
•Skeletal survey•Low-dose CT whole body (Gold standard1)•Bone marrow biopsy/ aspiration
Non-stem cell transplantation•VMP•Rd
Stem cell transplantation•VTD•VCD•Surgery•CMT•RT
LymphomaBone marrow biopsy/ aspirationR-CHOP
1.Multiple myeloma ESMO Clinical Practice Guideline2.Bone health in cancer: ESMO Clinical Practice Guideline, 2020
VMP(Bortezomib, Melphalan, and Prednisone)Rd(Lenalidomide and low-dose dexamethasone)VTD(Bortezomib, thalidomide, and dexamethasone)VCD(Bortezomib, cyclophosphamide and dexamethasone)R-CHOP(Rituximab, Cyclophosphamide, Vincristine, Doxorubicin, Prednisolone)

15. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

16. Early detection
of bone metastasis

17. Radionuclide bone scan (Tc-99, I-131)
18F-fluorodeoxyglucose (FDG)-PET-CT/MRI
Plain radiographs (Bone survey)
Whole body MRI
Whole body CT
Early detection of bone metastasis
Structural imagingMetabolic & molecular imaging
-Insensitive test-Lesion must be >1cm, loss >50% of bone mineral content
-Detect bony destruction and sclerosis-Difficult to differentiation : metabolically active VS inactive bone lesions
-Detect marrow signal change, soft tissue extension-Useful for evaluating in bone scan +vebut normal Xray-Spinal metastases : better than bone scan for decision-making in spinal cord compression
-Detect osteoblastic activity-False negative : MM, RCC, CA thyroid-False positive : after CMT 3-6 mo. (Flare phenomenon)
-Detect aerobic glycolysis-Superior to bone scan-Differentiation osteosclerosis (CT) : tumor progression VS response to therapy
Low-dose whole-body CT FDG-PET-CT imaging >> preferred imaging modalities in MM

18. Evaluate Risk
of pathologic fracture

19. ProphylaxisVS Fixation
pathologic fracture
Early functional recoveryDecreased morbidity
Shorter hospital stayDecreased total cost
Better surgical control Lesser op timeLesser blood loss

20. ProphylaxisVS Fixation
pathologic fracture
Early functional recoveryDecreased morbidity
Shorter hospital stayDecreased total cost
Better surgical control Lesser op timeLesser blood loss

21. ProphylaxisVS Fixation
pathologic fracture
More difficult to reductionLonger operation timeMore blood perfusion
Delayed functional recovery Increase morbidity
Longer hospital stayIncrease total cost of treatment

22. Harrington’s Criteria
1. Lytic lesion > 2.5 cm in proximal femur
2. Cortical bone destruction > 50%
3. Lesser trochanter involvement
4. Persistent stress pain despite radiation
Evaluate Risk
of pathologic Fracture
Modality of choice !Plain radiograph!CT-based!MRI-based
Limitation : This classification accounts only for the proximal femur

23. Point of mirelsscoreRisk of pathologic fracture %
≤ 74
8 15
9 33
1082
1196
12100
Controversy
Conservative
Surgery
Evaluate Risk
of pathologic Fracture
Mirels, H. CORR, 1989.
Mirel’sscore

24. Patients with femoral metastatic lesions
2004-2008
Mirelsscoreby orthopaediconcologist
Sensitivity, Specificity, PPV, NPV ROC curve
underwentCT scans
6 study centers CTRA(125 pts)
78 (62%) No prophylactic fixation1.Fracturethrough the lesion within 12 months of CTRA2.Deathwithin 12 months of CTRA3.12-month survivalafter CTRA without fracture
Evaluate Risk
of pathologic Fracture
Definition of an impending fracture based on CTRA : reduction > 35% in axial, bending or torsional rigidities at the lesion.

25. ROC analysis: CTRAto be superior to Mirelsscoring regardless of what Mirelsscore cutoff was used
Suggest that Mirelsscore of >= 10 is a better screening tool

26. •CT-based structural rigidity analysis is better thanMirelsscore in predicting femoral impending pathologic fracture.
•CTRA appears to provide a substantial advance in the accuracy of predicting pathological femur fractureover currently used clinical and radiographic criteria.
Conclusion

27. 157 pts with metastatic tumors of femurs
March 2013 –March 2017
Retrospective study
Group I: Pathological fracture (57)Group II: High risk fracture (100)
Group I: Pathological fracture (5)Group II: High risk fracture (45)
Complete CT scan data
Mirels score
No Surgery (11)

29. Calculated the median tensile or compressive principal strain at 4 regions of the disease free femurs
The strain fold ratioabsolute maximum principal strain of the tumor typical median strain of the disease-free femur

30. •Absolute increases of > 48%in tumor associated
strains compared to typical strains at the same region in disease free femurs.
•The typical strain fold ratios: 1.48 -2.41
Gr.I: Pathologic fracture
5 pts
Gr.II: High risk fracture (Mirels score)
45 pts
20 pts
25 pts
low risk of fracture (44.4%)
high risk of fracture (55.6%)
7 pts
No Surgery & None fracture in 5 mo F/U
4 pts
Specificity of 63%

31. •CTFEA may be superior to the current standard methods used to evaluate the need for prophylactic surgery in patients with femoral metastases.

32. Harrington’s criteria 01
Sensitivity & Specificity: 67% and 48% Mirelscore 02
04
Accuracy 80-90%Sensitivity & Specificity: 100 and 60%
CT-based structural rigidity analysis (CTRA)03
Evaluate Risk
of pathologic Fracture
CT-based finite element

33. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

34. Early prophylaxis forSREs

35. Early prophylaxis forSREs
!Bone-targeted agents (BTAs) are used to reduce the risk of SREsas well as to treat hypercalcemiaof malignancy>> improve survival in some patient
!Factors for consideration selecting type of BTA: •Efficacy •Route of administration•Convenience•Renal status•Side effects •Health economic issue

36. Early prophylaxis Bone-Targeted Agent (BTA)

37. •Inhibitosteoclast activity>> Apoptosis
Dose regimen
•Pamidronate 90 mg + 5%DW 500 ml IV in 2 hr(q 4 wk)
•Zolendronate4 mg + 5%DW 1000 ml IV in 15 min (q 4 wk)
•Monoclonal antibody that binds to RANKL
(Inhibit RANKL)
•Causing rapid suppression of bone resorption
Dose regimen
•Denosumab 120 mg SC (q 4 wk)
BisphosphonatesDenosumab

38. Denosumab 120 mg SC q 4 wk
VS
Zolendronate4 mg IV q 4 wk
Management of bone health in solid tumors: From bisphosphonates to a T monoclonal antibody
Roger von Moosa,⁎, Luis Costab, Eva Gonzalez-Suarezc, EvangelosTerposd, Daniela Niepele
In breast cancer, denosumabwas
statistically superior to zoledronatein term of delaying time to first SRE, subsequence SREs and progressive pain.
Efficacyof BTAs

39. Dosing frequencyof BTAs
•Survival time increase >>> concerning issues •cumulative risks for AEs•treatment costs •inconvenience for patients with prolonged use
•There are no prospective data on the validity of intermittent
treatments or ‘drug holidays’, but extended dosing intervals of
zoledronate have been tested in several randomized trials.
4 WksVS 12 Wks????

40. Management of bone metastasis with intravenous bisphosphonates in breast cancer: a systematic review and meta-analysis of dosing frequency
MEDLINE, PubMed, Embase Cochrane libraryFrom 1947 -present 4 WksVS12 Wks
Comparing the efficacy BPs
Complication-SREs-ONJ-Renal function
Dosing frequencyof BTAs
Received IV bisphosphates before enrollment >> Lesser skeletal-related events

41. Dosing frequencyof BTAsResults
•Administration of bisphosphate
every 12 weeks wasnon-inferiorto standard every 4 weeks.
•No significant difference in SREs, renal dysfunction, and ONJ.
•Patients will benefit from fewer clinic visits, lower costs, and reduced medical toxicity
•NCCN guideline "standard bisphosphonatefor 12 months before de-escalation.

42. Rebound osteolysis after Denosumab
•Rapid decrease in bone mineral density (BMD) after discontinuation of denosumaband increase risk of vertebral fracture.
•After stopping denosumab, bisphosphonatetherapy should be considered to reduce or prevent the rebound.
•The optimal bisphosphonate regimen post-denosumab is unknown but many osteoporosis clinicians use a single 4-or 5-mg treatment of zoledronate.
Safetyof BTAs
•AEs after IV bisphosphonatesare infrequent >> infused at the recommended dose and duration
>> acute phase response : fever and myalgia
•Renal toxicity of bisphosphonates, especially in MM patient•dose reductions when CrCis 30-60 ml/min•If CrC< 30 ml/min "use Denosumab
Denosumab compared with zoledronicacid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010 Dec 10;28(35):5132-9.

43. Safetyof BTAs Osteonecrosis of jaw (ONJ)
Definition : Painful bone destruction, secondary infection and delayed healing in the mandible and/or maxilla.
Incidence2% (similarinzoledronate and denosumab)
Before BTA therapy "Recommended oral examinationand appropriate
preventive dentistry
Maintain good oral hygiene and ensure regular dental review
Patients should avoid invasive dental procedures (extractions and implants)during therapy if possible
When tooth extraction cannot be avoided-prophylactic antibiotics -BTA should be suspended until healing of the tooth socket appears complete
Denosumab compared with zoledronicacid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010 Dec 10;28(35):5132-9.

44. Safetyof BTAs Atypical femoral fracture (AFF)
Incidence of atypical femoral fractures in the treatment of bone metastasis: An alert report. Takumi Kaku, Journal of bone oncology, 2020.
•Oncologic use of BTA has been increasing."Long-term use : risk for atypical femoral fracture (AFF).
•721 patients with bone metastasis in a Japanese university hospital."incidence of AFF was 0.9% (n=5) among 529 BTA-exposed patients
•Higher incidence of AFF in patients with breast or prostate cancer(6.6%) due to have longer life expectancy >> more prolonged exposure to BTAs, than those with lung cancer.

45. Safetyof BTAs Atypical femoral fracture (AFF)
Incidence of atypical femoral fractures in the treatment of bone metastasis: An alert report. Takumi Kaku, Journal of bone oncology, 2020.
Routine radiographic screening for the development of AFF should be considered in patients with long-term exposure to BTAs (>2-3 years) for bone metastasis, even if asymptomatic.
Mean use 5.5 years Bone union mean 7.8 Mo

46. Safetyof BTAs Calcium balance
•Hypocalcaemia"muscle spasms, tetany, paraesthesias, seizures, and cardiac arrhythmias.-Corrected total blood calcium < 8.5 mg/dL
•Hypocalcaemia occurs more common in prostate cancer 30%-Osteoblasticbone metastases "excessive uptake of calcium by bone-forming metastases
•BTA use for prevention of SREs "hypocalcaemia more common in Denosumabuse
•Risk factors : vit-D def, renal insuff., osteoblasticmetastases and low baseline blood calcium levels"educated symptoms of hypoCa
Hypercalcemiais common in osteolyticbone metastasis
-LAB W/U & monitor -Supplement calcium 1000 mg/day-Vitamin D3 800-2000 IU per day

47. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

48. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

49. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

50. HYPERCALCEMIA

51. 30%
H Y P E R C A L C E M I A
Most common
Lung CABreast CAMultiple myelomaRenal cell CASCCAof Head, neck
S
E
V
E
R
I
T
Y
O
V
E
R
V
I
E
W
Mild
Moderate
Severe
10.5 -11.9 mg/dL
12 -13.9 mg/dL
> 14 mg/dL
Cancer-Associated Hypercalcemia, NEJM 2022
Clinically Presentation depend on degree of hypercalcemia

52. Pathophysiology
4 subtypes : 1.Humoral hypercalcemia of malignancy -Most common 75-80%-Caused by tumor secretion of PTH-related Peptide-Patients typically have few or no bone metastasis
2.Local osteolytic -Extensive bone metastasis "Cytokines "increase osteoclast acitivity
3.1,25-dihydroxyvitamin D–mediated-Increase intestinal uptake of Ca, PO
4.Ectopic hyperparathyroidism (PTH)

53. ApproachHypercalcemia

54. HYPERCALCEMIA IN MALIGNANCY
1.Decrease calcium intake
2.Discontinuing medications and supplements
Non-Medical TxMedical Tx
1.Isotonic NSS 1-2 L IV bolus then rate 150-300 ml/hr2. Lasix 20-40 mg IV (Adequate hydration)
Bisphosphonate-Zoledronic acid 4 mg IV in 15 min or -Pamidronate 60-90 mg IVin 2 hr
Calcitonin 4 to 8 IU/kg subcutaneously or IM
Failure
F/U Lab q 1 d
Dialysis
Baseline Creatinine Clearance (ml/min)Dose recommend (mg)
> 604
50-603.5
40-493.3
30-393
OptionCreatinine or GFR
GFR > 30GFR < 30
Denosumab 120 mg SC
> 1 wkPrevious dose
HYPERCALCEMIA
Mild10.5 -11.9 mg/dL
Moderate12 -13.9 mg/dL
Severe> 14 mg/dL
Mostly better in 4 days

55. TREATMENT

56. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

58. #Overall response rates70 -80% are reported
•Complete relief of pain in1/3 of patients
•40%of responders showing benefit within 10 days1
#Guidelines recommend single-fraction RT in patients with painful uncomplicated bone metastases due to convenience for patients and caregivers2
•Meta-analyses show no differencein pain control between fractionated treatment and a single fraction1
#Side-effects: depend on the body area treated
•Initial flare in bone pain is common >> prophylactic with dexamethasone + analgesics
1.Rich SE, Chow R, Raman S, et al. Update of the systematic review of palliative radiation therapy fractionation for bone metastases RadiotherOncol. 2018;126:547e557.2.Bone health in cancer: ESMO Clinical Practice Guideline
Palliative RT

59. #In patients with good performance status, pathological or impending fractures
•prefer surgery to fix or prevent fracture
•Postoperative RT is recommended >> prevent prosthesis failure and reduce the need for subsequent surgery
#In patients who have extremely short life expectancies, RT alone may be considered for pain relief, although it does not restore bone stability.
.1.Bone health in cancer: ESMO Clinical Practice Guideline
Palliative RT

60. #Spinal Cord Compression is a medical emergency
•Require urgent MRI to confirm the diagnosis
•Patients should start 16-24 mg dexamethasone per day without delay and, if possible, steadily reduce over 2 weeks.
#In patients with good performance status, limited disease and a single area of compression >> palliative decompression and spinal instrumentation to restore stability followed by RT are generally recommended.
•In patients who are not suitable for surgery, RT alone is sufficientfor those with a poor prognosis.
•Local tumor control and pain relief >80%
•Vertebral body fractures can also be treated by percutaneous cement augmentation (vertebroplasty or kyphoplasty).
.1.Bone health in cancer: ESMO Clinical Practice Guideline
Palliative RT

61. Radionuclide therapy
Targeted RT: specific delivery of the radiation dose to multiple tumor
sites with relative sparing of normal tissues compared with EBRT.
•Thyroid follicular carcinoma:
•Iodine-131 (131I)
•Castration-resistant prostate cancer (mCRPC)
•Radium-223 (223Ra)
•improved overall survival (OS) by 3.6 months and delayed new
symptomatic skeletal events (SSEs) by 5.8 months1
•improvement in patient QoL and fewer hospitalizations than placebo.
1. Parker C, Lewington V, Shore N, et al. Targeted alpha therapy, an emerging class of cancer agents: a review. JAMA Oncol. 2018;4:1765e 1772.

63. Principle management
For pathologic fracture
Fixation
•Immediate weight bearing stability•Whole bone fixation•+/-Debulking tumor & Augmentation with PMMA•Lifelong implant•Post op RT
Preop embolization
•Renal cell carcinoma•Thyroid carcinoma
Choice of implant
•IM Nail +/-cement•Plate + cement•Arthoplasty•Endoprosthesis
Solitary / Oligometastatic
Enbloc resection solitary lesion for increase survival•Renal cell carcinoma•Thyroid carcinoma•Breast carcinoma
M.Koizukiet al. Comparison between solitary and multiple skeletal metastasis lesion of breast cancer patient. Annual of oncology 2003Szendroiet al. Prognostic factor and survival of renal clear cell carcinoma patients with bone metastasis. Patrol.Oncol.Res2010M.Ratasvuoriet al. Prognostic role of enbloc resection and late bone metastasis.L.Surg.Oncol. 2014

70. Prevention SREsTreatment SREs
-Structural imaging-Metabolic & molecular imaging
Early Detection
-Bone-Targeted Agent Early Prophylaxis
-Palliative RT-Radioisotopes-Medication treatment for hypercalcemia
Non-surgical
-Fixation pathologic fracture-Nerve decompression
Surgical
2. Pathological fracture 1. Hypercalcemia3. Spinal cord compression
4. Pain that need surgery or RT
Skeletal Related Events

71. Outline
Introduction : what is SREs? 1
How to prevent SREs?2
What are treatment for SREs?3
Bone Health in Cancer Patients Skeletal Related Events (SREs)

72. Thank you
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