Clinical Benefit of Bisphosphonates for Cancer Patients with Metastatic Bone Disease

1
Clinical Benefit of Bisphosphonates for Cancer
Patients with Metastatic Bone Disease

• James R. Berenson, MD
• Medical Scientific Director
• Institute for Myeloma Bone Cancer Research
• Los Angeles, California

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Metastatic Bone Disease Scope of the Problem

• Extremely common - gt 500,000 patients in USA
• Myeloma - gt 90
• Breast - two thirds of patients
• Prostate - two thirds of patients
• Lung - one third of patients
• Median survival measured in years, not weeks or
  months
• Major clinical consequences for patients,
  families, and society

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Clinical Consequences of Metastatic Bone
Disease
of patients/yr

• Pathologic fractures 10 - 25
• Spinal cord compression/collapse 3 - 5
• Radiation therapy 15 - 20
• Surgery to bone 5 - 10
• Hypercalcemia 2 - 10
• Bone pain 50
• Use of analgesics 40
• Quality-of-life effects
• Survival

SREs

• SREs Skeletal-related events.
• From PLAC arms of randomized clinical trials
  with Aredia or Zometa.

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IV BisphosphonatesMajor Impact in Reducing
Skeletal Complications for Cancer Patients With
Metastatic Bone Disease
with SRE with SRE with SRE SREs per yr SREs per yr SREs per yr
Placebo BP ? Placebo BP ?
Prostate(Saad et al.) 49 Z-38 22 1.5 0.7 47
Breast (Hortobagyi et al.) (Kohno et al.) 64 50 A-51 Z-30 20 40 3.7 1.42 2.4 0.7 35 50
Myeloma (Berenson et al.) 51 A-38 26 2.0 1.0 50
Others(Rosen et al.) 46 Z-39 15 2.7 1.7 37
SRE Skeletal-related event Pbo Placebo BP
Bisphosphonate Z Zometa A Aredia P lt
0.05 Relative decrease
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Breast Cancer and Multiple Myeloma Efficacy
Summary
Proportionwith SRE, Time to first SRE (median) Mean skeletal morbidity rate Multiple event analysis Hazard ratio
Zometa 4 mg 47 376 1.04 0.841
Aredia 90 mg 51 356 1.39
P value .243 .151 .084 .030
Rosen LS, et al. Cancer. 20039817351744.
Hypercalcemia of malignancy (included as a
skeletal-related event).
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Benefits of IV Bisphosphonates in Metastatic Bone
Disease

• Reduce skeletal complications
• Aredia
• Breast cancer and myeloma with lytic lesions
• Ineffective in prostate cancer
• Not tested in other tumor types
• Zometa
• Breast cancer, myeloma, and prostate cancer
• Tested and effective in other tumor types
• Decrease pain and analgesic use
• Prevent deterioration of quality of life

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ONJ in Myeloma PatientsThe IMBCR Experience

• 6 cases of ONJ
• Range of severity
• 3 patients required intermittent antibiotics
  (Aredia Zometa, Zometa only in 2) - remain on
  bisphosphonate treatment
• 1 patient recently diagnosed with minor temporary
  discomfort (Aredia only) - remains on treatment
• Largely resolved with clarithromycin PO
• 2 patients (Aredia Zometa, Zometa only)
  discontinued bisphosphonate secondary to
  significant effect on mastication
• Status of myeloma
• 3 in long-term complete remission (auto-PSCT,
  VAD, thalidomide)
• 1 in near complete remission (on steroids)
• 2 with long-term indolent myeloma requiring no
  other therapy
• 1 patient with 40 reduction in M-protein for gt 4
  yr

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PerspectiveIV Bisphosphonates in Cancer Patients
with Bone Involvement

• Skeletal complications have profound effects on
  the lives of patients with metastatic bone
  disease
• IV bisphosphonate (Zometa and Aredia)
• Reduce bony complications
• Number of events/yr one third to one half
• Percent of patients with events by 15 to 40
• Decrease bone pain, reduce pain meds, and prevent
  deterioration in QOL

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PerspectiveIV Bisphosphonates in Cancer Patients
with Bone Involvement

• Patients receiving IV bisphosphonates (Zometa
  and Aredia)
• Infrequently develop any form of ONJ (0.1 to
  2/yr)
• Severity varies most patients improve while
  continuing bisphosphonate therapy
• ONJ risk minor - rarely clinically significant
  compared with major problems that frequently
  occur without Aredia or Zometa treatment (eg,
  fractures, spinal cord compression, radiation
  therapy, or surgery)

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IV Bisphosphonates for Patients With Metastatic
Bone DiseaseBenefits vs Risks
Benefits Risks
Fractures Radiotherapy Bone pain
ONJ ? Renal (infrequent)
Humeral fracture in a myeloma patient