The management and treatment options for secondary bone disease. Omi Parikh July 2013

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1 The management and treatment options for secondary bone disease Omi Parikh July 2013

2 Learning Objectives: The assessment and diagnostic process of patients with suspected bone metastases e.g bone scan, MRI, ALP etc. Specific concerns such as pathological fracture, MSCC. Criteria for selection of patients for surgical treatments of bone metastases as prevention or treatment of skeletal related events The medical treatments of bone metastases as prevention or treatment of skeletal related events e.g. bisphosphonates, Denosumab, radiation, New emerging and treatments of bone metastases

3 Anatomy-Bone 1

4 Abnormal Bone Formation: Seed and Soil Analogy Seed: certain cancer cells have incredible affinity for growth in bones Soil: bone provides a fertile environment for cancer cell growth Hence, the vicious cycle of seed and soil

5 1) Assessment and diagnosis: Bone scan Alk phos Uncertainty: MRI CT Plain films Restage after hormones?bone turnover markers.

6 Diagnosis of Skeletal Complications of Malignancies Signs and symptoms Bone Pain Pathological Fractures Hypercalcaemia Spinal Cord Compression Blood tests Calcium levels (corrected Calcium levels) Bone resorption markers Radiology Plain-film radiography Radioisotope bone scan Computed tomography scan Magnetic resonance imaging

10 Timing: When does bone disease need managing? Hormone sensitive Hormone refractory Systemic control

11 Hormone sensitive: Palliative radiotherapy Calcium and vitamin d3 supplements? Zoledronic acid? denosumab

12 2: Complications: Specific concerns such as pathological fracture, MSCC.

13 Bone metastases may result in clinically significant and serious consequences of skeletal-related events (SREs) SREs are defined as 1,2 : Radiation to bone Pathological fracture Spinal cord compression Surgery to bone 1. Saad F, et al. J Natl Cancer Inst 2004;96:879 82; 2. Ibrahim A, et al. Clin Cancer Res 2003;9:

14 SREs have associated down-stream implications SRE Pathological fracture Radiation to bone Surgery to bone Spinal cord compression Potential complications Extended healing time Reduced survival 1,2 Loss of mobility Need for care/ nursing home residence (especially hip fracture) 3 Potential for pain flare after therapy 4 Myelosuppression 5 Repeat visits for treating spinal cord compression 6 Hospital stay In-hospital mortality rate ~8% 7 High rate of surgical complications 7,8 High failure rate; inability to restore function 7 Excruciating pain 8 Need for steroidal medications 8 Repeat visits for radiotherapy 6 Irreversible paraparesis or paraplegia 8 Loss of continence 8 1. Gainor, Buchert. Clin Orthopaed Rel Res 1983;178: ; 2. Saad F et al. Cancer 2007;110:1860 7; 3. Poor et al. Osteoporos Int 1995;5:419 26; 4. Loblaw et al. Supp Care Cancer 2007;15:451 5; 5. Hellman, Krasnow. J Palliat Med 1998;1:277 83; 6. Maranzano et al. Tumori 2003;89:469 75; 7. Katzer et al. Arch Orthopaed Trauma Surg 2002;122:251 8; 8. Loblaw et al. J Clin Oncol 2005;23:

15 Advanced solid tumours commonly metastasise to bone Cancer Incidence of bone metastases * Breast cancer 65 75% Prostate cancer 65 75% Lung cancer 30 40% *Based on post-mortem examinations. Coleman RE. Cancer Treat Rev 2001;27:

16 Bone metastasis/bone lesions lead to skeletal-related events (SRE) Breast cancer (24 months) Prostate cancer (24 months) Lung/other solid tumours (21 months) Pathological fractures 52% 25% 22% Hypercalcaemia of malignancy 13% 1% 4% Spinal cord compression 3% 8% 4% Radiation to bone* 43% 33% 34% Surgery to bone** 11% 4% 5% * Usually given for pain ** Usually a result of fracture Lipton A, et al. Clin Adv Hematol Oncol 2009;7(5 Suppl 11):1-30. Reprinted with permission from Clinical Advances in Hematology and Oncology.

Patients have increased chances of developing SREs as survival times improve Median time to first SRE vs median overall survival Breast 1,2 7.0 25.2 Prostate 3,4 10.7 21.7 Lung 5,6 5.2 12.

17 Patients have increased chances of developing SREs as survival times improve Median time to first SRE vs median overall survival Breast 1, Prostate 3, Lung 5, Median time to first SRE Median overall survival Months 1. Lipton A, et al. Cancer 2000;88: ; 2. Miller K, et al. N Engl J Med 2007;357: ; 3. Saad F, et al. J Natl Cancer Inst 2002;94: ; 4. Kantoff PW, et al. N Engl J Med 2010;363;411 22; 5. Rosen LS, et al. Cancer 2004;100: ; 6. Sandler A, et al. N Engl J Med 2006;355:

% of patients with on-study SREs Prior SRE increases the risk for subsequent SREs 70 Breast cancer 1 Prostate cancer 2 Lung cancer and other solid tumors 3 60 50 58% 51% 52% 47% 40 30 32% 40% 20 10 0

18 % of patients with on-study SREs Prior SRE increases the risk for subsequent SREs 70 Breast cancer 1 Prostate cancer 2 Lung cancer and other solid tumors % 51% 52% 47% % 40% Prior SRE No Prior SRE 1. Kaminski M, et al. Poster presented at: ASCO Annual Meeting. June 5-8, 2004; New Orleans, LA. Abstract 857; 2. Saad F, et al. Clin Genitourin Cancer 2007;5:390 6; 3. Hirsh V, et al. Clin Lung Cancer 2004;6:170 4.

19 The impact of skeletal complications treatment costs burden carers Skeletal complications quality of life HSE resource survival rates

20 Probability SREs increase risk of death in men with prostate cancer Survival at day 360 No SRE: 49.7% 1 SRE: 28.2% P = 0.02, n = Survival (days) depuy V et al. Support Care Cancer 2007;15:

21 3: Surgical intervention: Criteria for selection of patients for surgical treatments of bone metastases as prevention or treatment of skeletal related events

25 Indications for surgical intervention: Pathological fracture? Impending Pain / mobility Cord compression

26 Pathological Fracture: The primary treatment of pathologic fracture is surgery where possible Radiotherapy has a major role in postoperative treatment treatment of fractures that are inoperable site such as a rib or pelvis, general poor condition of the patient.

$likely to cause pain; somewhat less likely to cause fracture compared to typical lytic lesion Studies of bone markers show patients with prostate cancer have as much evidence of bone resorption as$

27 Prostate Cancer X-rays show new blastic lesions from prostate cancer Bone metastases frequently involve spine Characteristic x-ray findings suggest enhanced osteoblastic activity Bone lesions more likely to cause pain; somewhat less likely to cause fracture compared to typical lytic lesion Studies of bone markers show patients with prostate cancer have as much evidence of bone resorption as patients with breast cancer

28 Prophylactic pinning: Impending vs non-pending fractures Non-impending fractures can be treated with primary radiotherapy Impending fractures:? > 30% risk of fracture within 6 months.

29 Mirels Scoring system:

30 Mirels conclusions: Score 7 or less prophylactic pinning not indicated Score 9 or more prophylactic pinning indicated Score 8: dilemma Rare for prostate cancer to be referred for prophylactic pinning.

31 Cord compression: MRI proven surgery followed by radiotherapy is better than radiotherapy alone Selected group of patients Isolated bone mets Fit for surgery Neurological symptoms Good prognosis (6 months)

32 Surgery vs Surgery +RT Sx+ RT RT Retained ability 126 days 35 days P=0.006 to walk Regained ability 56% 19% P=0.03 to walk Morphine/ day 0.4mg 4.8mg P=0.002 Dex / day 1.6mg 4.2mg P=0.009 OS 129 days 100 days P=0.08 Non sig

33 4) Medical management: Bisphosphonates, Denosumab, radiation

34 Current Therapeutic Approaches for Skeletal Complications of Malignancies Radiotherapy Endocrine therapy Chemotherapy Orthopaedic interventions Analgesia Bisphosphonates 1 Treatment of choice in hypercalcaemia of malignancy (HCM or TIH) Potent inhibitors of pathologic bone resorption Effective therapy for skeletal complications of bone metastases Denosumab 1. Body JJ, et al. J Clin Oncol

35 Zoledronic acid: Standard of care for symptomatic HRPC with bone mets STAMPEDE trial Usage varies

36 Denosumab: Novel mechanism of action Patient request it NICE approved for all solid malignancies apart from prostate cancer. bisphosphontes aren t indicated so neither should an alternative

37 Normal bone remodelling is tightly regulated RANK Ligand is an important mediator of bone resorption Osteoblasts release RANK Ligand RANK Ligand RANK Ligand binds to RANK on osteoclast precursor cells, which then develop into osteoclasts and become active Osteoblasts Osteoclast The resultant bone lost needs to be replaced by osteoblasts (formation) Active osteoclasts remove bone tissue (resorption) Adapted from Boyle WJ et al. Nature 2003;423: RANK, receptor activator of nuclear factor κ B

40 Denosumab targets RANK Ligand to break the vicious cycle Denosumab precisely binds to RANK Ligand, preventing activation of the RANK receptor on osteoclasts RANK Ligand By binding to RANK Ligand denosumab inhibits osteoclast formation, function and survival Denosumab Osteoblasts Tumour Osteoclast Denosumab prevents the maturation of osteoclasts, decreasing bone resorption and breaking the vicious cycle of bone destruction Adapted from Roodman GD. N Engl J Med 2004;350: ; Mundy GR. Nat Rev Cancer 2002;2:

41 Denosumab: Key Inclusion Criteria Castration-resistant prostate cancer and 1 bone metastases Key Exclusion Criteria Current or prior IV bisphosphonate treatment N = 950 denosumab 120 mg SC and placebo IV Q4W Supplemental calcium and vitamin D strongly recommended N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W Primary Endpoint Secondary Endpoints Time to first on-study skeletal-related event (SRE) (noninferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE(s) (superiority) *Per protocol and IV zoledronic acid label, product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine. Fizazi K, et al. Lancet. 2011;377:

42 Baseline Characteristics IQR = interquartile range. ECOG = Eastern Cooperative Oncology Group. PSA = prostate-specific antigen. Fizazi K, et al. Lancet. 2011;377: Characteristic Denosumab (N = 950) Zoledronic Acid (N = 951) Median age, years (IQR) 71 (64 77) 71 (66 77) ECOG performance status of 0 or 1, n (%) 882 (93) 886 (93) Stratification Factors PSA at randomisation 10 g/l, n (%) 805 (85) 806 (85) Recent chemotherapy ( 6 weeks before randomisation), n (%) 132 (14) 132 (14) Previous SRE, n (%) 232 (24) 231 (24) Median time from diagnosis of bone metastasis to randomisation, months (IQR) 3.94 ( ) 5.19 ( )

43 Proportion of Subjects Without SRE Primary Endpoint: Time to First On-Study SRE 1.00 HR = 0.82 (95% CI, ) P (noninferiority) P = (superiority) Denosumab Zoledronic acid Kaplan-Meier Estimate of Median Months Patients at Risk: Study Month Zoledronic acid Denosumab Fizazi K, et al. Lancet. 2011;377:

44 5: New Treatments: Alpharadin

46 Alpharadin: Radiopharmaceutical Alpha radiation from radium-223 decay has an effect over a range of 2-10 cells less damage to surrounding healthy tissues half life of 11.4 days FDA approved May On CDF when licensed,? Given through nuclear medicine

51 Thank you Questions?

Elderly men with prostate cancer + ADT

Elderly men with prostate cancer + ADT Background and Rationale ADT and Osteoporosis Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis 21 18 +6.8%; P