Management of Bone Metastases

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1 Management of Bone Metastases Mustafa Ozdogan, MD Medical Oncologist Akdeniz University Antalya/TURKEY

2 Bone Metastases: Scope of the Problem Bone metastases affect more than 500,000 patients in the United States Myeloma: > 90% of patients Breast: 2/3 of patients Prostate: 2/3 of patients Lung: 1/3 of patients

3 Bone Metastases Can Lead to SREs Patients (%) Patients who will likely develop an SRE without treatment 74 Renal Cell Carcinoma (n = 74) Multiple Myeloma (n = 179) Breast (n = 114) Prostate (n = 208) NSCLC (n = 250) Up to 74% of patients with bone metastases may experience an SRE despite standard anticancer treatments Data are from placebo-controlled arms of bisphosphonate trials. Lipton A, et al. Cancer. 2003;98: Berenson JR, et al. J Clin Oncol. 1998;16: Kohno N, et al. J Clin Oncol. 2005;23: Saad F, et al. J Natl Cancer Inst. 2004;96: Rosen LS, et al. Cancer. 2004;100:

4 Distribution of Metastases in Bone Weight bearing bones at risk for fracture Skull: 46% Cervical spine: 40% Scapula and clavicle: 20% Proximal humerus: 17% Ribs: 53% Thoracal spine: 68% Lumbar spine: 65% Pelvis: 70% Proximal femur: 52%

Normal Bone Biology Bone is always in an active state of remodeling

bone, creating a cavity Reversal: bone surface is prepared for

resorbed bone and fill the cavity with new bone Resting: bone

5 Normal Bone Biology Bone is always in an active state of remodeling (build up/break down) Resorption: stimulated osteoclasts erode bone, creating a cavity Reversal: bone surface is prepared for osteoblasts to begin forming bone Formation: osteoblasts replace resorbed bone and fill the cavity with new bone Resting: bone surface rests until a new remodeling cycle begins Adapted from Novert's Pharmaceuticals

6 Bone Metastases: General Mechanism seed and soil Primary cancer Angiogenesis Invasion Embolism Response to microenvironment Multicell aggregates (lymphocytes, platelets) Transport Extravasation Adherence Arrest in distant capillary bed in bone Tumor cell proliferation Bone metastases Adapted from Guise and Mundy. Endocr Rev. 1998;19:18. -Osteolytic -Osteoblastic -Mixt

7 The Vicious Cycle of Bone Destruction Growth factors and cytokines released by tumor cells PTHrP IL-6 IL-8 PGE 2 TNF-a CSF-1 BMP PDGF FGFs IGFs TGF-β Osteoclastic resorption stimulated Peptides (eg, TGF-β) released by bone resorption Tumor cell production of factors increased More bone resorption Tumor cell proliferation Adapted from Mundy GR, et al. N Engl J Med. 1998;339:

8 Effect of Bisphosphonates on Vicious Cycle of Bone Destruction Decrease activity of osteoclasts PTHrP IL-6 IL-8 PGE 2 TNF-a CSF-1 BMP PDGF FGFs IGFs TGF-β Reduction in release of peptides Slowed tumor-cell growth Reduced production of PTHrP and other factors Decrease in bone resorption Adapted from Mundy GR, et al. N Engl J Med. 1998;339:

Bisphosphonates: Mechanism of Action Bisphosphonates have a strong affinity for calcium phosphate Bind to resorption sites Bisphosphonates inhibit bone resorption Direct effects on osteoclasts

9 Bisphosphonates: Mechanism of Action Bisphosphonates have a strong affinity for calcium phosphate Bind to resorption sites Bisphosphonates inhibit bone resorption Direct effects on osteoclasts Indirect effects via other cells Bisphosphonates decrease 4 parameters of osteoclast function Recruitment of cells Adhesion to bone Lifespan of cells (increasing rates of apoptosis) Cellular activity

$density and strength; high risk for fracture Most common in multiple myeloma and breast cancer Osteolytic bone$

10 Osteolytic metastases Tumor cells produce growth factors that stimulate bone destruction i.e. RANK ligand Osteoclasts are activated and break down bone Osteoblasts cannot build bone back fast enough Decreased bone density and strength; high risk for fracture Most common in multiple myeloma and breast cancer Osteolytic bone metastasis is due to an imbalance in the RANKL/OPG ratio. Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.

11 Osteoblastic Metastasis Osteoblasts are stimulated by tumors to lay down new bone Bone becomes abnormally dense and stiff, Paradoxically bones are also at risk of breaking Most common in prostatic carcinoma

12 Radiology: How to Evaluate Imaging tests X-ray Bone scan Sensitive, not specific. False positives: trauma, arthritis, infection CT ( CAT scan) PET scan MRI scan Bone biopsy for confirmation Blood tests Calcium, alkaline phosphatase Bone Scan

13 MRI imaging T1 T2 Sensitive for detection of fluid signal (e.g edema)

14 FDG PET/CT imaging (before and after the cancer treatment) T11 49 years old, female patient; breast cancer, after 18 months chemo-hormanal-bp therapy. Sclerotic changes of the bone methastases and hepatic response. Tateishi U et al. Radiology 2008;247:

15 Bone methastases and treatment response by PET/CT

16 False negativity by PET/CT Clin Nucl Med 2009;34: )

17 Negative Impact of Bone Complications Increased medical costs [1] Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases Impaired mobility [6] Hip fracture associated with a 50% disability rate; 25% of these require nursing home care Skeletal Complications Diminished quality of life [2-4] History of a skeletal complication is associated with lower QOL in breast and prostate cancer Negative impact on survival [5] Men with prostate cancer without skeletal fracture survived 39 months longer than those with a fracture 1. Groot MT, et al. Eur Urol. 2003;43: Weinfurt KP, et al. Ann Oncol. 2002;13(suppl 5): Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: Riggs BL, et al. Bone. 1995;17:505S-511S.

18 Clinical Consequences of Cancer-Induced Bone Lesions Pathological fractures Nonvertebral Vertebral compression Spinal cord compression/collapse Radiation therapy Surgery to bone Hypercalcemia Skeletal-related events Bone pain Use of analgesics Quality-of-life effects Survival

19 Management of Bone Disease in Cancer Requires a Multidisciplinary Approach Oncologist Surgeons Orthopedist Neurosurgeon Radiation therapist Nuclear medicine specialist Pain specialist Rehabilitation/physical medicine Physician Physical therapist

20 Structure of Bisphosphonates: Amino Versus Non-aminobisphosphonates O OH R 1 OH P C P O OH R 2 OH Inhibitors of bone loss Potency varies greatly depending on R1 & R2 side chains Relative R 1 R 2 Potency Etidronate OH CH 3 1 Clodronate Cl Cl no N 10 Tiludronate H S Cl 10 Pamidronate OH (CH 2 ) 2 NH Alendronate OH (CH 2 ) 3 NH Risedronate H CH 2 N 5000 Ibandronate OH (CH 2 ) 2 -N-(CH 2 ) 4 -CH 3 N 10,000 Zoledronic acid OH N CH 3 N 100,000

21 Available IV bisphosphonates Pamidronate In placebo-controlled trials significantly reduced fracture, radiation, pain Zoledronic Acid More potent agent; equally effective in trials Shorter infusion time (15 min vs 3 hours) Theriault, R. L. et al. J Clin Oncol; 17:

22 Newest Bisphosphonate: Ibandronate Both oral and IV forms Prevents bone events (fractures, radiation, surgery ) compared with placebo Can relieve bone pain when given with a loading dose (but takes up to 12 weeks) May have less kidney toxicity Ongoing comparisons to zoledronic acid are underway Cameron et al, The Oncologist, 2006

23 Rate of renal toxicity

24 52 pts, 6 months follow up, clinical response and safety were tested breast, prostate, lung, urogenital or colon cancer pts; received IV ibandronic acid 6 mg infused or oral IB 50 mg/day Both formulations improved pain, physical and functioning scores

25 Meta-analysis: SRE Risk Reduction in MBC With Bone Mets BPs vs Placebo Adapted from Pavlakis N, et al. Cochrane Database Syst Rev. 2005:CDC

26 18 RKÇ 18 RCT Morbidity Mortality

28 Germany UK

29 Bisphosphonates: Structure-related Safety Profiles Bisphosphonates Nonnitrogen Nitrogencontaining Oral Oral IV Esophagitis Diarrhea Acute phase response 3,4 Uveitis/scleritis 5, Renal impairment de Groen PC, et al. N Engl J Med. 1996;335: Powles T, et al. J Clin Oncol. 2002;20: Adami S, et al. Calcif Tissue Int. 1987;41: Singer FR, Minoofar PN. Adv Endocrinol Metab. 1995;6: Fraunfelter FW, Fraunfelder FT. N Engl J Med. 2003;348: Scrip report. April Markowitz GS, et al. Kidney Int. 2003;64:

30 Zoledronic Acid Adjustment of Starting Dose for Renal Insufficiency Baseline CrCl, ml/min Recommended Zoledronic Acid Dose, mg > < 30 Not recommended

31 Indication of the BPs expected survival; more than 6 months proven osteolytic metastases, bone pain due to metastases, hypercalcemia 11 : Highest priority 7-11: Moderate priority <7 : Low priority

32 Biochemical Response and Survival Baseline NTx stratification 3-mo NTx status Group Elevated ZA 4 mg/3-4 wks Elevated E E E group ( 64 nmol/mmolcreatinine) Normal Normal E N N group (< 64 nmol/mmol creatinine) Lipton A, et al. Oncologist. 2007;12:

33 Biochemical Response Correlates With Improved Outcome Skeletal Complications Survival 1.0 E-E group (n = 36) E-N group (n = 160) N group (n = 132) Persistently elevated NTx 1.0 E-E group (n = 36) E-N group (n = 160) N group (n = 132) Proportion With SRE or Death E-N vs E-E risk reduction: 49% Normalized NTx Normalized baseline NTx P = Time on Study (Mos) Proportion Died Persistently elevated NTx Normalized NTx Normalized baseline NTx E-N vs E-E risk reduction: 48% P = Time on Study (Mos) Lipton A, et al. Oncologist. 2007;12: Reprinted with permission.

35 Bisphosphonate-associated osteonecrosis of the Jaws Bamias et al. JCO 2005

36 Possible Mecanism of Bisphosphonate-associated Osteonecrosis of the Jaws reduced bone remodeling proapoptotic effect on keratinocytes avascular bone necrosis

37 Bisphosphonate-associated osteonecrosis of the Jaws Kohno et al. İnt. J Clin Oncol. 2008

38 Relative Risk Factors for ONJ Cancer Radiation therapy Corticosteroids Poor dental hygiene Poor diet Ethanol or tobacco use Coagulopathy Chemotherapy Infection Bisphosphonates Dental work Trauma

2009 by American Society of Clinical Oncology 1,621 pts, 29,006 IV BP, monthly administration The rate of osteonecrosis; Multpl myeloma 8.5 %, Breast cancer 3.1 % Prostatic carcinoma 4.

39 2009 by American Society of Clinical Oncology 1,621 pts, 29,006 IV BP, monthly administration The rate of osteonecrosis; Multpl myeloma 8.5 %, Breast cancer 3.1 % Prostatic carcinoma 4.9 % Multivariate analysis; Use of detures, Dental extraction, Usage of zolendronat; statistically significant. Smoking, periodonditis, age, root canal treatment; statistically insignificant

40 Staging and treatment strategy of osteonecrosis of the jaw Exposed/necrotic bone; Stage 1; asymptomatic and have no evidence of infection Antibacterial mouth rinse, Clinical follow-up, Patient education and review of indications for continued bisphosphonate therapy Discontinuation of bisphosphonates therapy until osteonecrosis heals. Stage 2 ; associated with infection (pain and erythema with or without purulent drainage) Oral antibacterial mouth rinse and broad-spectrum oral antibiotics Pain control Only superficial debridements to relieve soft-tissue irritation Stage 3 ; pain, infection, and 1 of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border. Antibacterial mouth rinse, antibiotic therapy and pain control Surgical debridement/resection for longer-term palliation of infection and pain Regardless of the disease stage, mobile segments of bony sequestrum should removed without exposing uninvolved bone. be American Academy of Oral and Maxillofacial surgeons. The American Journal of Medicine (2009) 122, S33 S45

41 Stage III osteonecrosis of the mandible and surgical exposure of the left hemi-mandible after segmental resection Goytia et all. Orthop Clin N Am 40 (2009)

42 Minimizing the Risk of ONJ Excellent oral hygiene is the best prophylaxis Limit EtOH and tobacco use Patients should have a dental assessment prior to starting IV BPs Dental procedures (extensive) should be done prior to starting IV BPs if possible Avoid dental procedures once IV BPs started

43 Rarely observed side effects Oculary inflamation, posterior skleritis, retinal pigment ephelitis were rarely observed. Gupta S et al. Ind J Cancer 2009

New Systemic Therapy: Denosumab Denosumab: antibody against RANK ligand, the stimulator for osteoclasts IgG 2, fully human monoclonal antibody to RANKL Once-a-month subcutaneous injection Promising

44 New Systemic Therapy: Denosumab Denosumab: antibody against RANK ligand, the stimulator for osteoclasts IgG 2, fully human monoclonal antibody to RANKL Once-a-month subcutaneous injection Promising results as osteoporosis treatment in clinical trials Emerging role in the treatment of bone metastases Ellis SABCS 2007; Lipton ASCO breast 2008; McClung et al, NEJM 2006 Control Treated Morony et al. Cancer Res. 2001;61:4432. Blocking RANK ligand in a mouse can fill in a mouse bone metastases

The RANKL/RANK/OPG Axis: Receptor-Ligand Interactions RANKL; secreted from osteoblasts and other stromal cells, interacts with the RANK receptor on osteoclast precursors and

45 The RANKL/RANK/OPG Axis: Receptor-Ligand Interactions RANKL; secreted from osteoblasts and other stromal cells, interacts with the RANK receptor on osteoclast precursors and other cells Osteoprotegerin; natural decoy receptor that competes for binding with RANK and slows bone turnover. This important pathway is the basis of a new therapeutic target.

Critical Role for NFκB Ligand (RANKL), RANK, M-CSF in Osteoclastogenesis Op/op

However this deficiency can be resolved with: VEGF [1] or Flt3 ligand [2] Normal

inability to inhibit bone resorption and the development of severe osteopenia.

activaty) and the development of significant osteopetrosis.

46 Critical Role for NFκB Ligand (RANKL), RANK, M-CSF in Osteoclastogenesis Op/op (M-CSF deficient) mouse also has significant osteopetrosis. However this deficiency can be resolved with: VEGF [1] or Flt3 ligand [2] Normal 4 wks of age RANKL KO 4 wks of age Knocking out osteoprotegrin leads to an inability to inhibit bone resorption and the development of severe osteopenia. Knocking out RANKL leads to an inability to bone resorbtion (no osteclast activaty) and the development of significant osteopetrosis. OPG KO 8 wks of age RANK KO 4 wks of age 1. Niida S, et al. J Exp Med. 1999;190: Lean JM, et al. Blood. 2001;98:

Denosumab: Potential Mechanism of Action RANKL RANK

Growth Factors (IL-6, IL-8, IL-1ß, PGE 2, TNF-α,

Growth Factors (TGF-ß, IGFs, FGFs, PDGFs, BMPs) Bone

47 Denosumab: Potential Mechanism of Action RANKL RANK Denosumab RANK-Expressing Tumor Cells Cytokines and Growth Factors (IL-6, IL-8, IL-1ß, PGE 2, TNF-α, CSF-1, PTHrP) Direct Effects on Tumor? Growth Factors (TGF-ß, IGFs, FGFs, PDGFs, BMPs) Bone Resorption Ca 2+ Adapted from Roodman GD. N Engl J Med. 2004;350:

48 111 patients enrolled, Among patients with elevated untx despite ongoing IV BP therapy, Denosumab reduced markers of bone breakdown. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs

49 San Antonio Breast Cancer Symposium 2009

52 Denosumab and prostat cancer Castrate resistant, bone metastases, no previous BP (N = ~ 1900) Denosumab monthly Zoledronic acid monthly Primary endpoint: SREs Accrual complete 2008 Q4 Final analyses 2009 ClinicalTrials.gov identifier: NCT

53 Systemic Agents in Development Cathepsin K inhibitors Cathepsin K degrades the bone An oral inhibitor reduced bone turnover from breast cancer bone metastases (ASCO 2009 poster) SRC kinase inhibitors (dasatinib) SRC necessary for osteoclast bone breakdown Dasatinib is oral, approved for chronic leukemia, may have activity against breast cancer as well Ongoing trials are using these drugs after, with, or instead of zoledronic acid

54 Bone-Seeking Radiopharmaceuticals Composition Radioactivity: samarium-153, strontium-89 Targets bone especially areas of increased activity EDTMP with samarium-153 Strontium (acts like calcium) Radiopharmaceuticals are proven to relieve pain in patients with osteoblastic bone lesions that enhance under radionuclide bone scans. Major toxicity is hematologic Proximity to bone marrow

55 Samarium-153 Lexidronam Change in AUPC-VAS at Wk 4 Among Primary Tumor Subgroups All Prostate Breast Lung and Patients Cancer Cancer Other Cancers (n = 118) (n = 78) (n = 21) (n = 19) Placebo 0.5 mci/kg 1.0 mci/kg -20 AUPC-VAS, area under the pain curve-visual analogue scale. Serafini et al. J Clin Oncol. 1998;16: Reprinted with permission American Society of Oncology. All rights reserved.

56 Local Therapies Local therapies treat a limited number of locations; do not treat the whole body Types: Radiotherapy Interventional Radiology Surgery Goals: Relieve pain Prevent fracture Enhance mobility and function Preserve quality of life

57 Radiation Therapy Radiation therapy can be used to treat painful bone metastases refractory to systemic therapies % of breast cancer patients experience relief of symptoms 40-46% experience full relief 70% never have pain in that region again May take months before full pain relief is realized Tong et al, Cancer 1982

58 Radiation Therapy: Specifics Can take 1-4 weeks; 2 weeks is most common Chemotherapy is usually on hold during RT Side effects: nausea, diarrhea, low blood counts, fatigue Typically radiation is not used again in the same place

59 Interventional Radiology What is it? Minimally invasive procedures performed by specialized radiologists to treat symptoms from bone metastases Indications: To treat bone pain refractory to other conservative pain control measures Specialized technique for metastatic cancer to spine bones Stabilize broken bone

60 Interventional Radiology: Techniques Vertebroplasty: Injection of bone cement to support weakened bones Provides immediate and substantial pain relief Kyphoplasty: Balloon inflation of compressed spine bone is performed before cement injection Used for compression fractures

61 Positioning in Interventional Radiology

62 Example: Vertebroplasty

63 Example: Vertebroplasty

64 Concept of kyphoplasty

65 Concept of kyphoplasty

Other Local Techniques Radiofrequency Ablation (RFA) and cryoablation Minimally invasive procedures to burn or freeze a tumor Desensitizes by killing

66 Other Local Techniques Radiofrequency Ablation (RFA) and cryoablation Minimally invasive procedures to burn or freeze a tumor Desensitizes by killing nerve endings near the metastasis Most commonly used for cancer in the spine Techniques can achieve excellent pain control Use may expand with further data

67 Surgical Joint Stabilization Indications for surgery for bone metastases: Prevention of bone fracture ( prophylactic ) Risk depends on location of metastasis, type, size, and presence of symptoms Alleviation of pain Maintain ability to walk (for hip metastases) Stabilize broken bone after pathologic fracture Beals et al, Cancer 1971

68 Surgical Joint Stabilization Benefits of surgery Procedures designed for rapid recovery Simple pin placement to full hip replacement Most are walking again soon after hip surgery Most have good to excellent pain relief Can dramatically improve healing after fracture Typically performed in combination with radiotherapy Ryan et al. J Bone Joint Surg Am, 1976

69 Ongoing Trials Randomized phase III metastasis-prevention studies of bisphosphonates Bisphosphonates; may enhance the antitumour activity of cytotoxic drugs, increase tumour cell apoptosis, inhibit tumour cell adhesion, invasion and proliferation and angiogenesis by modifying the bone microenvironment Matthew C et all Curr Opin Oncol 21:

70 Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases 317 patients with initial bone metastasis; 87 patients (27.4%) had HR negative. HR negative and ZA received group had better survival (1.7 vs 1.3 years). Jungsil R et all. BMC Cancer 2009; The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. NSCLC patients with bone metastases; Group A: 87 pts received ZOL, 4 mg i.v. every 21 days Group B: 57 patients received no ZOL Docetaxel-Cisplatin-Zolendronat vs DC PFS and OS (578 vs 384 days) Zaragoulidis K. Et all. Int J Cancer 2009;125:

71 The antitumoral effectiveness of the BP Studies from Turkey Cell Biol Int Feb;33(2): Epub 2008 Dec 11. Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic Bcl-2 protein level in hormone-refractory prostate cancer cells. Karabulut B, Erten C, Gul MK, Cengiz E, Karaca B, Kucukzeybek Y, Gorumlu G, Atmaca H, Uzunoglu S, Sanli UA, Baran Y, Uslu R. Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey. Cell Biol Int Sep;31(9): Epub 2007 Feb 25. Cisplatin cytotoxicity is enhanced with zoledronic acid in A549 lung cancer cell line: preliminary results of an in vitro study. Ozturk OH, Bozcuk H, Burgucu D, Ekinci D, Ozdogan M, Akca S, Yildiz M. Akdeniz University, Department of Biochemistry, Antalya, Turkey.

72 Thanks

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