Bisphosphonate treatment of metastatic bone disease in breast cancer NEW DATA

1
Bisphosphonate treatment of metastatic bone
disease in breast cancer- NEW DATA -
EIS on Supportive Care Brussels, November 2006
J.J. Body, MD, PhD Univ. Libre de
Bruxelles Brussels Belgium
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OUTLINE

• Decrease in skeletal morbidity
• Analgesic effects
• Safety issues
• Individualization of therapy ?
• Points for discussion

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Decrease in skeletal morbidity
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Prevalence of Skeletal-Related Events in Clinical
Trials
JJ Body
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Pamidronate vs Zoledronic acid Breast Cancer and
Multiple Myeloma
R A N DO M I Z E D
Zoledr. 4 mg q 3 to 4 wk
n 564
Zoledr. 8 mg q 3 to 4 wk
n 526
n 558
Pamidronate 90 mg q 3 to 4 wk daily oral
vitamin D 400 IU and calcium 500 mg
0
13 monthsCore analysis
25 months Final analysis

• Double-blind, double-dummy study designed to
  demonstrate noninferiority of Zoledronic acid
  compared with Pamidronate

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Proportion of Patients With SRE (HCM) at Month
13 by Stratum and Treatment (Intent-to-Treat)
Adapt. from Rosen et al., Cancer J 2001
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Multiple Event Analysis (adapted from Rosen et
al., Cancer 2003)
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Intravenous ibandronate significantly reduces
skeletal morbidity
2.0 1.5 1.0 0.5 0
SMPR 1.48 vs 1.19, p0.004
p0.004
Mean SMPR
p0.011
p0.396
p0.023
p0.075
Need forsurgery
Vertebralfractures
All newbone events
Need forradiotherapy
Non-vertebralfractures
Body JJ, et al. Ann Oncol 2003
Trial not powered for individual composite
endpoints
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BPs in Prostate Cancer - Multiple Event Analysis
-
Zoledronic acid significantly decreases the risk
of developing skeletal complications by 36
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Analgesic effects
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Pilot study of intravenous ibandronate in
patients with opioid-resistant metastatic bone
pain

• Design
• Open-label pilot study conducted in 18 patients
  with moderate-to-severe opioid-resistant bone
  pain
• 12 women, 6 men (breast cancer n10, other tumor
  types n8)
• Received non-standard, intensive ibandronate
  therapy 4mg given as a 2-hour infusion for 4
  consecutive days (16mg total dose)
• Efficacy assessed on days 0, 7, 21, and 42 (or
  until death)
• Adverse events monitored over 6-week study period

Mancini I, Body JJ JCO 2004
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Effects on pain (VAS) and MEDD(mean SEM)
MEDD (mg)
600 500 400 300 200 100 0
0 7 21 42
Days
Mancini I, Body JJ JCO 2004
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Safety Issues
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Renal toxicity of bisphosphonates

• Renal toxicity of bisphosphonates is rare
• zoledronic acid acute tubular necrosis
• Reports of acute tubular necrosis after 4 mg of
  zoledronic acid infused in 15 min (more after
  previous pamidronate therapy?)
• (Markowitz et al., Kidney Int 2003 Chang,
  NEJM 2003)
• Certainly exceptional but it is currently
  recommended to control serum creatinine before
  each infusion
• pamidronate collapsing glomerulonephritis
• clodronate, ibandronate
• none at clinically recommended dosages

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Osteonecrosis of the jaws associated with the use
of bisphosphonates a review of 63 cases
Ruggiero et al., J Oral Maxillofac. Surg 2004
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Systematic review bisphosphonates and
osteonecrosis of the jaws
Woo et al., Ann Intern Med 2006
368 reported cases

• 60 occurred after a dental surgical procedure
• primary diagnosis
• 171 (46.5) multiple myeloma
• 143 (38.8) breast cancer
• 15 (4.1) OPosis 14 alen.

• 94 were treated with iv BPs (124 Zole, 110 Pam,
  100 both)

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• median duration of BP use 22-39 m.
• cumulative hazard 1st yr 1 for Zole, 0 for
  Pam
• at 3 yrs 21 for Zole, 4 for Pam

•  oversuppression of bone T-O is probably
• the primary mechanism 

•  no published evidence to support or oppose
• discontinuation of BP therapy 
• interest of alternative dosing schedules ?

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Individualization of therapy ?? Role of bone
markers ?
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Bisphosphonates for metastatic breast cancer- ?
WHEN TO START? -
(from Hillner et al., ASCO 2003 update, JCO 2003)

• evidence of bone destruction on plain x-rays
• abnormal bone scan and an abnormal CT or MRI
  scan
• showing bone destruction  reasonable 
• only abnormal bone scan  not recommended 

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? WHEN TO STOP ?
Probably never (? antineoplastic treatment
!!) continued until evidence of substantial
decline in a patients general performance
status (ASCO guidelines) But lack of adequate
prospective cost-effectiveness studies risk
of excessive treatment (cf early trt) ?
gt Adjust our treatment to the individual
patient according to the response to systemic
therapy and/or to bone markers?? intermittent
treatments ?? decrease infusion frequency ?
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Predictive value of bone resorption and formation
markers in cancer patients with bone metastases
receiving the bisphosphonate zoledronic acid
Coleman et al., JCO 2005
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Analysis limited to breast cancer patients
JJ Body
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Zoledronic Acid Reduced Ntx Levels at Month 3 in
Patients With Elevated Baseline Ntx
n 137
Patients,
n 26
Elevated baseline Ntx
7/170 (4.1) patients with elevated baseline Ntx
levels died before month 3.Lipton A, et al.
Presented at 2005 ASCO Annual Meeting May
13-17, 2005 Orlando, FL. Abstract 532.
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Relative Risk of Clinical Events in BC Patients
With Persistently Elevated NTX Versus Normalized
NTX
P value
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.5
3.0
3.5
Risk ratio and 95 CI
Lipton A, et al. Presented at SABCS, 2005.
Abstract 3015.
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Use of Bone Resorption Markers to Direct
Zoledronic Acid TherapyBISMARK

• 1,400 patients with bone metastases from breast
  cancer treated with zoledronic acid
• Primary endpoint skeletal events

Recruitment ongoing (planned enrollment 1,400
patients) Results expected 2011
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Bisphosphonates for breast cancer metastatic to
bone
POINTS FOR DISCUSSION (1)

• Decrease in  event rate  by a maximum of 40
  even when BPs are started at diagnosis of BM
• osteoclasts still active?
• bone resorption by cancer cells?
• target the osteoblast??
• Have we reached the maximal therapeutic benefit
  of BPs using current schemes?
• need for other therapeutic schemes?
• need for other compounds?

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POINTS FOR DISCUSSION (2)

• When to start? When to stop?
• cf ASCO guidelines still OK ?
• Avoid  excessive  treatment (cf role in ONJ ?)
• gt Tailor our treatment to the individual
  patient
• cf. markers of bone T-O
• but also take into account
• severity of the bone disease
• response to antineoplastic therapy

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Thank you for your attention !
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Mortality Is Increased in BC Patients with
Persistently Elevated NTx
Persistentently elevated NTX
Normalized NTX
Normal baseline NTX
Lipton A, et al. Presented at SABCS, 2005.
Abstract 3015.
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Comparative effects of oral ibandronate and
zoledronic acid on bone turnover markers
Body JJ, et al. Presented at Skeletal
Complications of Malignancy IV, 2005