Hypercalcaemia and Bone Metabolism in the Cancer Patient

1
Hypercalcaemia and Bone Metabolism in the Cancer
Patient

• Prof. Robert Coleman
• University of Sheffield

2
Calcium Balance and Bone Remodeling
3
The 'Vicious Cycle' Hypothesis of Osteolytic
Metastases
Tumour Cell
Mundy Nature Reviews 2002
4
Patients With Bone Metastases Are at High Risk
for Developing Skeletal Morbidity (SREs)
Proportion experiencing an event
SREs
Any
Pathologic fracture
Radiation therapy
Surgical intervention
Spinal cord compression
Hypercalcaemia
Patients with SRE,
Breast1 24 months
Prostate2 24 months
Cancer type
Placebo arms of large randomized studies
SRE Skeletal-related event
.1. Lipton A, et al. Cancer. 2000881082-1090
2. Saad F, et al. Eur Urol Suppl. 20076(Issue
11)683-688.
5
Aims of Bone Targeted Therapies

• Reducing clinical burden of metastatic bone
  disease
• Treatment of hypercalcaemia
• Reduction in the number severity of skeletal
  complications
• Relief of bone pain
• Maintenance of quality of life and physical
  function
• Improvement in survival
• Preserving the normal skeleton
• Preventing bone loss
• Normalising bone turnover
• Prevention of metastasis

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Pathogenesis of Hypercalcaemia

• Accelerated osteolysis
• Bone metastases
• PTHrP
• Inappropriate tubular reabsorption of calcium
• PTHrP
• Fluid depletion
• Diuretic effect of calcium
• Tubular damage
• Bence-Jones protein deposition

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Management of Hypercalcaemia

• Rehydration
• Bisphosphonates
• Zoledronic acid, pamidronate, ibandronate
• Glucocorticoids
• Lymphoma and myeloma
• Calcitonin
• Effective anticancer treatment

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Pamidronate (APD) for Hypercalcaemia
N27
N27
Coleman et al Br J Cancer 1987
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Efficacy of Zoledronic Acid or Pamidronate in
Hypercalcaemia of Malignancy
normalised
88 P .002
83.3 P .010
N 275
87 P .015
82.6 P .005
56 P .021
70
64
Complete responders ()
45
33
Complete response rate return of corrected serum
calcium to ? 2.7 mmol/L.
Denotes statistical significance versus
pamidronate.
Major P, et al. J Clin Oncol 2001
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Bone Targeted Therapy With Zoledronic Acid
Reduces Skeletal Morbidity
Breast1
Prostate2
Lung cancer3
Renal4
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Relative risk of Skeletal Related Event (SRE)
In favour of Zoledronic acid
In favour of placebo
RCC Renal cell carcinoma ZOL Zoledronic acid.
1. Kohno N, et al. J Clin Oncol.
2005233314-332 2. Saad F, et al. J Natl Cancer
Inst. 200496879-882 3. Rosen LS, et al.
Cancer.20041002613-2621 4. Lipton A, et al.
Cancer. 200398962-969.
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Unanswered Questions

• BUT
• What are the prognostic factors in metastatic
  bone disease?
• Who is most likely to experience a skeletal
  event?
• Are there patients who will rarely (never)
  experience an SRE?
• Who benefits most from bone targeted treatments?
• What is the most cost effective treatment
  strategy?
• Can we personalise the treatment schedule?

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Biochemical Markers of Bone Turnover
Corrected for creatinine concentration
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Baseline NTX Levels by Primary Cancer

• Patients with each cancer type were categorized
  as low NTX (lt50), moderate NTX (50-99), or high
  NTX (100)
• nmol BCE/mmol creatinine

Coleman et al. J Clin Oncol. 2005234925-4935.
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Increased Bone Turnover Predicts Clinical
Outcomes (n438)
Bone Resorption (Urinary NTX)
Prostate Cancer
Lung and Others
NTX gt 100 v lt 100 nmol/mmol creatinine
NTX gt 100 v lt 100 nmol/mmol creatinine
RR
95 C.I.
P value
RR
95 C.I.
P value
in the absence of bisphosphonates
Brown JE, et al. J Natl Cancer Inst. 20059759-69
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Increased Bone Turnover Predicts Clinical
Outcomes (n1462)
Plt.001 in all analyses
2.35
All SREs
2.32
Time to 1st SRE
2.21
Progression in bone
4.80
Death
5.91
Ntx gt100 vs lt50
Hazard Ratio
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
in the presence of bisphosphonates
Coleman et al - J Clin Oncol 2005
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Meta-analysis of Placebo Controlled Zoledronic
Acid Studies and Overall Survival
0.880-1.469
(n 351vs 180)
0.696-0.985
(n 518 vs 286)
All patients (1071 vs 571) 0.939
0.828-1.064 0.3229
Coleman et al. Cancer Treatment Reviews. 2008,
34 (suppl 1) abstract 81, s86.
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Meta-analysis of Placebo Controlled Zoledronic
Acid Studies and Overall Survival
All patients (1071 vs 571) 0.939
0.828-1.064 0.3229
Coleman et al. Cancer Treatment Reviews. 2008,
34 (suppl 1) abstract 81, s86.
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Schedule of Bisphosphonate Treatment

• Schedule of intravenous bisphosphonates largely
  empirical
• 6 - 12 X more intensive than for treatment of
  osteoporosis
• Ignores the impact of underlying anticancer
  treatment
• Response slows bone resorption rate
• Expensive, inconvenient, with greater potential
  for toxicity
• Role of bone marker directed therapy under
  evaluation

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Treatment Example - Fixed Schedule
Zoledronic Acid treatments
NTX level
26 treatments Over 112 weeks 1 SRE
Durable endocrine response ? over-treated
SRE
Weeks
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Treatment Example - Marker Directed
Zoledronic Acid treatments
NTX level
15 treatments Over 112 weeks 3 SRE
Sequential response and progression
Docetaxel
Exemestane
SRE
Letrozole
Weeks
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BISMARK Ongoing NCRN Bone Marker Directed
Therapy Trial

• Primary Endpoint Frequency and timing of SREs
• Secondary Endpoints Pain/QOL, clinical burden of
  SREs, disease progression, overall survival,
  health economics, changes in bone markers

measured every 16 weeks
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Bone Loss With Cancer Therapies
10
Naturally occurring bone loss
CTIBL
7.7
8
7.0
6
Bone loss at I year
4.6
4
2.6
2.0
2
1.0
0.5
0
Premature menopause secondary to chemotherapy5
Normal men1
ADT3
Menopausal Women lt551
AI therapy in postmenopausal women2
AI therapy plus GnRH agonist in premenopausal
women4
Postmenopausal Women gt551

• Kanis JA. Osteoporosis.199722-55.
• Eastell R et al. J Bone Mineral Res. 2002.
• Maillefert JF et al. J. Urol. 19991611219-1222.
  
• Gnant M. San Antonio Breast Cancer Symposium,
  2002.
• Shapiro CL et al. J Clin Oncol. 2001193306-3311.

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ABCSG-12 Trial Design

• 1,803 premenopausal breast cancer patients
• Endocrine-responsive (ER and/or PR positive)
• Good/intermediate prognosis
• No adjuvant chemotherapy
• Treatment duration 3 years

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6 Monthly Zoledronic Acid Reduces Bone Loss From
Goserelin Tamoxifen or Anastrazole
END OF TREATMENT
Ana ZA plt0.0001
Tam ZA p0.049
Tamoxifen alone plt0.0001
Anastrozole alone plt0.0001
ABCSG-12 Austrian Breast and Colorectal Cancer
Study Group Trial 12.
Gnant MF, et al. Lancet Oncology 2008
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First DFS Events (ITT Population) ZOL vs No ZOL
Death without prior recurrence
Secondary malignancy
Contralateral breast cancer
90
Distant recurrence
2
Locoregional recurrence
80
First event per patient, n
10
70
10
60
0
50
9
6
41
40
30
29
20
20
10
10
0
No ZOL
ZOL
(n 904)
(n 899)
Gnant M, et al. Presented at ASCO 2008.
Chicago, IL, USA. Abstract LBA4 and New Engl J
Med in press.
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RANKL Inhibition May Interrupt The Vicious
Cycle of Cancer-Induced Bone Destruction
RANKL RANKDenosumab
Tumor Cell
FormationInhibited
PDGF, BMPs TGF-ß, IGFs FGFs, Ca2
PTHrP, BMP,TGF-ß, IGF, FGF,VEGF, ET1, WNT
Apoptotic Osteoclast
Osteoblasts
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Denosumab vs Placebo For Aromatase Inhibitor Bone
Loss in Breast Cancer
Ellis G, et al. J Clinical Oncology 2008
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Conclusions

• Fundamental interactions between normal bone
  cells and cancer cells in the bone
  microenvironment
• Bone targeted therapies prevent skeletal
  complications, relieve pain and treat
  hypercalcaemia
• Important effects of cancer treatments on bone
• Targeting the microenvironment may diminsh risks
  of cancer metastasis