Bone Metastases. Sukanda Denjanta, M.Sc., BCOP Pharmacy Department, Chiangrai Prachanukroh Hospital

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1 Bone Metastases Sukanda Denjanta, M.Sc., BCOP Pharmacy Department, Chiangrai Prachanukroh Hospital 1

2 Outline Pathophysiology Signs & Symptoms Diagnosis Treatment Spinal Cord Compression 2

3 General Information Bone is the 3 rd most common organ affected by metastases, after lungs & liver. Bone metastases Primary bone cancer Usually incurable, but able to shrink, slow, or stop cancer growth. Occurring in: 70-95% in Multiple Myeloma (MM) 65-75% in advanced breast or prostate cancer 20-35% in lung, colon, bladder, stomach, uterus, rectum, thyroid, or kidney N Engl J Med 2004;350:

4 Common Metastatic Sites of Bones Metastases can occur in any bone in the body. Most often found in bones near the center of the body. The spine is the most common site of bone metastases. Humerus Spine Pelvis Femur 4

5 Why Bone is The Preferred Site of Metastases? High blood flow in red marrow area. Tumor cells produce adhesive molecules that bind them to marrow stromal cells and bone matrix. Bone is the source of various growth factors. N Engl J Med 2004;350:

Normal Bone Remodeling Cycle http://www.endotext.

6 Normal Bone Remodeling Cycle 6

7 Regulation of Bone Resorption & Bone Formation Bone Resorption Bone Formation N Engl J Med 2004;350:

8 Vicious Cycle in Bone Metastasis OPG 8

9 Abnormal Bone Lesions 1. Osteolytic (lytic) lesions Most predominate in breast cancer Pure lytic lesions in multiple myeloma 2. Osteoblastic (blastic, sclerosis) lesions Most predominate in prostate cancer 3. Mixed lesions (lytic/blastic) 9

10 Signs & Symptoms Bone pain Bone fractures Spinal cord compression Hypercalcemia Skeletal-Related Events (SREs) 1. Pathologic fractures 2. Radiation therapy to bone 3. Surgery to bone 4. Spinal cord compression + Hypercalcemia of malignancy Usually not include bone pain 10

11 Diagnostic Tests Imaging techniques X-Ray, bone scan, CT scan, MRI, PET scan Biochemical markers Biopsies o Tumor markers e.g. CEA, PSA, CA19-9 o Serum calcium, alkaline phosphatase o Marker of bone formation & bone resorption e.g. N-terminal propeptide of type I collagen (NTX) Needle biopsy, surgical bone biopsy 11

12 Diagnosis: X-Rays 12

13 Diagnosis: Bone Scan

14 Diagnosis: CT Scan 14

Diagnosis: MRI www.google.co.th/imgres?q=bone+metastasis+mri&um=1&hl=th&tbo=d&biw=1069&bih=517&tbm=isch&tbnid=woa_egvyopem:&imgrefurl=http://www.wmicmeeting.

15 Diagnosis: MRI docid=rw9vecrahqzam&imgurl= vh=201&hovw=251&tx=173&ty=179&sig= &page=1&tbnh=137&tbnw=174&start=0&ndsp=21&ved=1t:429,r:11,s:0,i:111 15

16 Diagnosis: PET Scan 16

17 Diagnosis: PET-CT Scan 17

18 Prevention Treat the cancer before it has spread. There are several investigations in prevention by using bisphosphonates (clodronate, zoledronic acid) in various type of cancers. Need more results to confirm the benefits and target patients. 18 Cancer Control 2012;19(2):92-101

19 Treatment Goals Maximize pain control Achieve functional preservation & restoration Stabilize the skeletons Control the tumor locally Reduce morbidity & mortality Increase quality of life 19 Cancer Control 2012;19(2):84-91.

20 Treatment Modalities Pharmacologic treatment Chemotherapy Hormonal therapy, Immunotherapy Bone Modifying Agents (BMA) Non - pharmacologic treatment Radiation Radiopharmaceuticals, Radionuclides Surgery Ablation techniques Vertebroplasty / Kyphoplasty 20

21 Bone Modifying Agents (BMAs) In 2011, ASCO changed term Bisphosphonates to Bone Modifying Agents due to including of denosumab to the management guideline in breast cancer with bone metastases. BMAs = Bisphosphonates + Denosumab 21 J Clin Oncol 2011;29(9):

22 Bisphosphonates Approved indication for bone metastases: USA Pamidronate Zoledronic acid Thailand Pamidronate Zoledronic acid Clodronate (PO) Other countries Pamidronate Zoledronic acid Clodronate Ibandronate 22 Cancer Control 2012;19(2):92-101

23 Bisphosphonates Mechanism of Action Inhibit osteoclast activity Induce osteoclast apoptosis Inhibit tumor cell adhesion to bone 23

24 Denosumab Mechanism of Action Binds to RANKL and neutralizes its activity Reduces osteoclast activity and bone resorption 24

25 BMAs Products Denosumab Zoledronic acid Pamidronate Sterile sol for inj 120 mg/1.7 ml (Xgeva ) Sterile sol for inj 4 mg/5 ml (Zometa ) Sterile powder for inj 30 mg + Diluent 10 ml (Aredia ) 25

26 Approved Indication in Oncology Indication Denosumab Zoledronic acid Pamidronate Prevention of SREs in Solid Tumors Yes Yes Yes (only in breast cancer) Prevention of SREs in Multiple Myeloma Hypercalcemia of Malignancy No Yes Yes No Yes Yes Dosage Regimen for Prevention of SREs 120 mg SC q 4 wk at the upper arm, upper thigh, or abdomen 4 mg IV infusion > 15 min q 3-4 wk 90 mg IV infusion > 2 hr q 3-4 wk 26

27 Dosage Adjustment in Renal Impairment Denosumab Zoledronic acid Pamidronate No need for dosage adjustment Patients with Clcr < 30 ml/min or receiving dialysis are at risk for hypocalcemia. Adequately supplement with calcium and vitamin D Clcr (ml/min) Dose (mg) < 30 Avoid use In multiple myeloma with albuminuria > 500 mg/24 hr: Withheld until renal function returns to baseline, and increase infusion time > 30 min Avoid use in severe renal impairment In multiple myeloma: Scr > 3 mg/dl or Clcr < 30 ml/min with extensive bone disease: 90 mg IV > 4-6 hr Albuminuria > 500 mg/24 hr: Withheld until renal function returns to baseline, and give mg IV > 4 hr q 4 wk

28 Duration of Treatment Denosumab Zoledronic acid Pamidronate Not yet defined. Should be continued as long as: It is well tolerates. Until there is a significant decrease in performance status of patients. Same as denosumab Same as denosumab Thai ED condition 2012: Multiple myeloma: Not more than 2 years Breast cancer: Not more than 1 year Discontinue if patients have more aggressive disease. Coadminister oral calcium supplements of 500 mg and 400 IU of Vitamin D daily. 28 (Not use in patients with history of hypercalcemia)

29 Monitoring Monitoring Denosumab Zoledronic acid Pamidronate Oral & Dental Examinations Prior to drug initiation and periodic examination during therapy Serum Creatinine Periodically Prior to each treatment Serum electrolytes (Calcium, Phosphate, Magnesium, Potassium) and CBC with differential After initiation of treatment and periodically throughout the treatment (not specify the exact interval) Urine albumin Not specify Every 3 to 6 months in multiple myeloma 29

30 Clodronate (Bonefos ) Treatment of osteolytic bone metastases due to carcinoma of the breast and osteolytic lesions of multiple myeloma. Dose: 1,600 mg (2 tab) daily single dose or divided into two doses. Taken in the morning on an empty stomach together with a glass of plain water. 30

31 Clinical Application of BMAs in Breast Cancer Patients must have the evidence of bone destruction (lytic or mixed lytic/blastic lesions). One BMAs is not recommended over another. No BMAs have effects on overall survival compared with placebo. A randomized phase III trial by Stopeck, et al: Denosumab was superior to zoledronic acid in delaying or preventing SREs in breast cancer with bone metastases. J Clin Oncol 2011;29(9): J Clin Oncol 2010;28:

32 Clinical Application of BMAs in Prostate Cancer Patients with prostate cancer who have progressed after treatment with at least one hormonal therapy will obtain benefit from bisphosphonates. Zoledronic acid is the only bisphosphonate that has a benefit compared to placebo. Denosumab was superior to zoledronic acid for preventing SREs in castrate-resistant prostate cancer with bone metastases (but overall survival was not difference). Lancet 2011;377: Cancer Control 2012;19(2):

33 Clinical Application of BMAs in Multiple Myeloma (MM) MM patients with lytic lesions or osteopenia should receive bisphosphonates. MM patients without lytic lesions & MGUS stage should not use bisphosphonates. Pamidronate was noninferior to zoledronic acid in development of SREs. Denosumab was noninferior to zoledronic acid in delaying the time to first SREs (but still not approved to use in MM) J Clin Oncol 2007;25: Cancer J 2001;7(5): J Clin Oncol 2011;29(9):

34 Clinical Application of BMAs in Other Tumors Zoledronic acid is the only bisphosphonate that is approved for this indication. Denosumab was noninferior to zoledronic acid in delaying the time to first and subsequent SREs. Still need more the results to specify which patients should receive bisphosphonates or denosumab. 34 J Clin Oncol 2011;29(9):

35 ADRs: Bisphosphonates Renal dysfunctions Electrolyte disturbances (hypocalcemia, hypophosphatemia, hypomagnesemia) Acute phase reactions (Flu-like symptoms), Tumor flare reaction Anemia Constipation Anorexia Edema (lower limb) Osteonecrosis of the jaw (ONJ) 35 The Oncologist 2005;10:52-62.

36 Osteonecrosis of The Jaw (ONJ) 36 Oncology 2006;20(9):

37 ADRs: Denosumab Most common ADRs (> 25%): fatigue / asthenia, hypophosphatemia, and nausea Most common serious ADRs: dyspnea Most common ADRs resulting in drug discontinuation: osteonecrosis, hypocalcemia No major concerns about renal dysfunction, but need for close monitoring about hypocalcemia in patients who have Clcr < 30 ml/min. ONJ, hypocalcemia, hypophosphatemia is similar to bisphosphonates. Xgeva prescribing information, Revised 01,

of vertebral collapse or instability by metastatic spread or direct

38 Malignant Spinal Cord Compression NICE clinical guideline 2008: Spinal cord or cauda equina compression by direct pressure and/or induction of vertebral collapse or instability by metastatic spread or direct extension of malignancy that threatens or causes neurological disability 38

39 Malignant Spinal Cord Compression Oncologic emergencies S&S: Severe back pain (95%), weakness of limbs (85%), sensory loss (50%), unexplained bowel or bladder disturbance Diagnostic tools: MRI (preferred) within 24 hr Goals of treatment: o Relieve pain o Preserve or improve neurologic function o Provide local tumor control o Stabilize the spine 39 NICE clinical guideline 2008

40 Malignant Spinal Cord Compression Treatment 1. Corticosteroids Immediate administer in strongly suspected or confirmed MSCC Decrease spinal cord edema to prevent further neurological deterioration Dexamethasone 4-10 mg PO or IV q 6 hr 2. Radiation therapy 3. Surgery 40 NICE clinical guideline 2008

41 Non Vertebral Bone Metastases 41 Cancer Control 2012;19(2):84-91.

42 Vertebral Bone Metastases 42 Cancer Control 2012;19(2):84-91.

43 Role of Pharmacists Checking of indication, dosage and administration of bisphosphonates according to the evidence based literature. Planning to monitor laboratory parameters related to drug use e.g. Scr, electrolytes. Monitoring of clinical symptoms in both efficacy and safety of treatment. Communicating the important information to patients e.g. ADRs observation & prevention. Taking care of other complications esp. bone pain. 43

44 Conclusions Bone metastases cause significant morbidity affected patients survival and QOL. There are various therapeutic options in order to prevent and manage SREs. Drug treatment with bisphophonates is commonly used to prevent SREs. Many clinical studies are ongoing to support new drugs and new indications. Pharmacists have the crucial roles in the multidisciplinary team for the treatment of bone metastases. 44

45 Q & A 45

Current Management of Metastatic Bone Disease

Current Management of Metastatic Bone Disease Evaluation and Medical Management Dr. Sara Rask Head, Medical Oncology Simcoe Muskoka Regional Cancer Centre www.rvh.on.ca Objectives 1. Outline an initial