Managing Skeletal Metastases

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Phebe Adams
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1 School of Breast Oncology 2012 Managing Skeletal Metastases Cathy Van Poznak, MD Assistant Professor University of Michigan Comprehensive Cancer Center Saturday, November 3, 2012

2 Learning Objectives: Define skeletal related events (SREs) & SRE incidence Review therapeutic interventions for patients with metastatic breast cancer (MBC) involving bone Integrate multidisciplinary palliative care strategies for metastatic bone disease (MBD)

3 Importance of Bone Integrity Structural framework Mineral homeostasis Hematopoietic homeostasis Bone metastases: morbidity & mortality: Pain Anemia Compromised mobility Skeletal Related Events Bone matrix elaborates growth factors that may promote cancer growth

4 Fracture Vertebral Compression Fracture

5 Bone Metastases & SREs Skeletal Related Events (SREs) Fracture Need for radiation to bone Need for surgery to bone Spinal cord compression Hypercalcemia of malignancy Oncologic Emergency

6 Bone Metastases in Breast Cancer Prevalence ~100,000 women living in the USA with metastatic breast cancer (MBC) (Hillner 2000) Bone metastases & Skeletal Related Events (SREs) 65-75% of pts w/ MBC have bone lesions (Coleman 1987) 50-70% of pts experience SREs (Domcheck 2000, Coleman 2004) Mean number of SREs/year in MBC 3.7 (Lipton 2000) SREs account for 63% of UK hospital costs in metastatic breast cancer (Coleman 1997) Median Survival MBC with Metastatic Bone Disease: 2-4 years, with 20% having 5 y survival (Coleman 1997, Giordano 2004, Van Poznak 2005)

7 Metastatic Process Metastatic process Disseminated tumor cells Bone as the First site of metastases Most common site of metastases Norton Nature Medicine 2006

8 Vicious Cycle PTHrP IL-6 IL-8 PGE 2 TNF- CSF-1 BMP PDGF FGFs IGFs TGFβ Roodman NEJM 2004

9 Breaking the Vicious Cycle X Anti-cancer therapy X Adjunctive Bone directed therapy

10 Adjuvant Osteoclast Inhibition (Anticancer Effects?) Bone metastases free survival Diel NEJM 1998: clodronate (+) Saarto JCO 2001: clodronate (-) Powles: JCO 2002: clodronate (+) Disease free survival ABCSG-12: Gnant NEJM 2009: zoledronic acid (+) AZURE: Coleman NEJM 2011: zoledronic acid (-) GAIN: Mobus SABCS 2011: ibandronate (-) NSABP B-34: Paterson Lancet Onc 2012: clodronate (-) Ongoing adjuvant studies are investigating Bisphosphonates Denosumab (+) positive study result (-) negative study result

11 Bone Modifying Agents (Osteoclast Inhibitors) Metastatic Bone Disease (MBD) Approved throughout the world for reduction in SREs in patients with Metastatic Bone Disease Denosumab Pamidronate (IV) Zoledronic acid (IV) Clodronate (IV, oral) Ibandronate (IV, oral) Approved in USA & outside of USA for MBD Approved for MBD Outside USA Osteoclast inhibition the risk of SREs ~ 30% Denosumab > zoledronic acid for SRE Stopeck JCO 2010 Zoledronic acid > pamidronate for Hypercalcemia of Malignancy Major JCO 2001

12 Bone Modifying Agents in Clinical Practice Pivotal Trials in MBC: Endpoint SREs Pamidronate vs Placebo (both + Chemotherapy) Hortobagyi NEJM 1996 Pamidronate vs Placebo (both + Endocrine therapy) Theriault JCO 1999 Pamidronate vs. Zoledronic acid Rosen Cancer J 2001 Zoledronic acid vs Placebo Kohno JCO 2005 Denosumab vs Zoledronic Acid Stopeck JCO 2010 ASCO: Update on the Role of Bone Modifying Agents in Metastatic Breast Cancer Van Poznak, JCO 2011

13 Skeletal Complication Risk: Incremental Benefits in Breast Cancer No bisphosphonate 64% 2 yrs Pamidronate ~ 20% risk reduction Zoledronic acid ~ 20% risk reduction Denosumab 18% risk reduction 64% 51% 34% 27% Lipton Cancer. 2000, Rosen Cancer J 2003; Stopeck J Clin Oncol 2010

14 Phase III Denosumab vs Zoledronic Acid Stopeck JCO 2010 Time to 1 st SRE ( 18%) Time to 1 st & Subsequent SREs ( 23%) Overall Survival: No Change Time to Progression: No Change Renal Toxicity: 4.9% (Dmab) vs 8.5% (ZA) ONJ: 2.0% (Dmab) vs 1.4% (ZA)

15 Osteoclast Inhibitors & Side Effects Oral administration (bisphosphonates): GI tract Osteonecrosis of the jaw (ONJ) [rare] Atypical fracture [rare] IV administration (bisphosphonates): Acute phase reactions Hypocalcemia Renal insufficiency Osteonecrosis of the jaw (ONJ) [uncommon] Atypical fracture [rare] Subcutaneous administration (denosumab) Hypocalcemia Osteonecrosis of the jaw (ONJ) [uncommon] Coleman Ann Onc 2005; Conte Oncologist 2004; Ross BMJ 2003; Stopeck JCO 2010

16 Uncommon Adverse Events Associated with Osteoclast Inhibition, but Etiology Unknown Atypical Fractures Osteonecrosis of the Jaw (ONJ) Bisphosphonates Bisphosphonates & Denosumab

17 Markers of Bone Turnover and Relative Risk Ratios in Breast Cancer NTX: N-Telopeptide of Type I Collagen Coleman JCO 2005

18 Dosing of IV Bisphosphonate by Markers of Bone Turnover Coleman ASCO 2012 BISMARK Met Breast Cancer to bone R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Dosed by Markers of Bone Resorption Follow For SREs Planned N= 1500 Study closed early due to poor accrual with N <300

19 BISMARK: untx Directed Therapy Time to First SRE Coleman ASCO 2012 Larger number of SREs in M-Zol 150 vs 109 in S-Zol More patients on M-Zol experienced multiple SREs NTX levels were higher in M-Zol group at all time points

20 Study of Dosing Intervals in Prolonged Zoledronic Acid Use: ZOOM Ripamonti ASCO 2012 ZOOM Metastatic Breast Cancer to bone 9-12 prior doses of zoledronic acid R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Every 12 weeks No Statistical Difference in Skeletal Morbidity Rate OPEN LABEL Approx 300 patients Variable Intervals for: Clinical Assessments Imaging Assessments Ripamonti ASCO 2012 abs #9005

21 Study of Dosing Intervals in Prolonged Zoledronic Acid Use: Optimize 2 Optimize 2 Metastatic Breast Cancer to bone > 9 doses of bisphosphonate R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Every 12 weeks Follow For SREs Placebo Controlled Await Results ClinicalTrials.gov # NCT

22 Study of the Interval of Zoledronic Acid Dosing: New Start of Therapy CALGB Bone Metastases Breast Prostate Multiple Myeloma No prior treatment with IV BP R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Every 12 weeks Follow For SREs & Toxicity Open Label N= approx 1500 Await Results ClinicalTrials.gov # NCT

23 Radiation Therapy External Beam (EBRT) Rapid & long lasting pain relief Targeted to site of symptoms Radiopharmaceutical 3 FDA approved agents Systemic treatment Shorter efficacy retreat Marrow suppressing & with 32 P there is a risk of leukemia Clinical Trials To Note: Radium-223 (223Ra) alpha particle emission (Alpharadin ) Breast NCT Prostate Phase III, ALSYMPCA: NCT (placebo controlled) IV q4w x6 OS Parker ASCO 2012 #4512

$5 cm Lesion: 50% bone diameter Lesion is a Lesser trochanter avulsion Patient has 6 weeks life expectancy Lesion At risk For Fracture Scoring system to predict pathologic fractures: clinically not$

24 To Operate, Most Surgeons Consider: Consider surgery: Size of lesion: 2.5 cm Lesion: 50% bone diameter Lesion is a Lesser trochanter avulsion Patient has 6 weeks life expectancy Lesion At risk For Fracture Scoring system to predict pathologic fractures: clinically not used Limited outcomes data: surgery for impending fracture vs. surgery for completed fracture (favors pre-fracture tx) Shorter hospital stays (7 vs. 11 days) Greater likelihood of discharge home (vs. extended care) (79% vs 56%) Greater likelihood of support-free ambulation (35% vs. 12%) Mirels Clin Ortho 2003 Ward CORR 2003

25 Spinal Cord Compression: Clinical Trial Randomized: multi-institutional, non-blinded trial Patients: 101 pts with cord compression due to cancer mets (displacement of the spinal cord by epidural mass, symptoms <48h, must be within 1 surgical field, good medical status, etc) Treatment: Randomized to Surgery & Radiation Therapy vs Radiation Therapy alone Corticosteroids and Radiation Therapy dose (10 x 3 Gy) constant in both arms Primary endpoint was the ability to walk. Interim Analysis: Stopped early due to early-stopping rules & better outcome for combination therapy Patchell, Lancet 2005

26 Spinal Cord Compression: Randomized Trial: Radiation +/- Surgery Able to walk after treatment: Surgical & RT: 42/50, (84%) Radiation: 29/51, (57%) OR 6 2 [95% CI ] p=0 001 Surgery + RT RT Duration of ability to walk: Surgical & RT: 122 D Radiation: 13 D p=0.003 Continence & functionally better with surgery & RT Patchell, Lancet 2005

VCF (sham procedures) Kallmers NEJM 2009 Buchbinder NEJM 2009 Kyphoplasty VCF in Cancer:

27 Vertebroplasty & Kyphoplasty NOT indicated for spinal cord compression Vertebroplasty Needle + Cement/PMMA Kyphoplasty Balloon + Cement/PMMA Vertebroplasty: RCT x2 (-) in osteoporotic VCF (sham procedures) Kallmers NEJM 2009 Buchbinder NEJM 2009 Kyphoplasty VCF in Cancer: Procedure vs. not Procedure improved pain at 1m Berenson Lancet Onc 2011 polymethylmethacrylate (PMMA)

28 Bone Metastases Systemic Treatment Considerations Osteoclast inhibitors Bisphosphonates Denosumab Gallium nitrate Calcitonin Src inhibitors (TKIs) in study now Established practice of IVBP: When to initiate therapy? Optimal dose? Optimal schedule? Duration of tx? Other targets CXCR4 antagonists Anti-CCR2 Antibody MLN1202 (SWOG 0916) HDAC inhibitors Α v β 3 (L ) TGF-b inhibitors Endothelin A antagonist MTOR SOST/Sclerostin Endothelial cells: PDGFR And more.

29 Take Home Points Metastatic Bone Disease interdisciplinary approach Pain control RX: NSAIDs, Opiates External beam radiation & Radiopharmaceuticals Osteoclast inhibition (supportive therapy) Reduce fracture risk Surgery and/or radiation Osteoclast inhibition Quality of Life & Survival SREs carry significant morbidity & mortality Osteclast inhibition has not been associated with increased survival Problems/questions remain Design & participate in trials

30 Thank you

Norton L et al. Nature Med 2006

Norton L et al. Nature Med 2006 New Bone Targeting Agents Ana Maria Gonzalez-Angulo, M.D. Associate Professor Section Chief, Clinical Research and Drug Development Breast Medical Oncology Systems Biology Padua, Italy 11/2012 Outline