seminar 15-01-2009 - bisfosfonaten en kanker
TRANSCRIPT
Bisfosfonaten in de Oncologie
Dr. H.P. Sleeboom
Hagaziekenhuis Den Haag
Botmetastasen
Trabecular Bone Destroyed by Osteoclasts Due to Tumor Osteolysis
Figure fromL Mosekilde
Disease prevalence, Bone mets. MedianU.S. (in thousands) incidence (%) survival (mo)
Myeloma 75 - 100 70 - 95 24
Renal 198 20 - 25 12
Melanoma 467 14 - 45 6
Bladder 582 40 6 - 9
Thyroid 207 60 48
Lung 386 30 - 40 7
Breast 1,993 65 - 75 24
Prostate 984 65 - 75 36
Clinical Importance and Prognosis of Bone Metastases
NCI, 1997; International Myeloma Foundation, 2001.
Osteolysis in Multiple Myeloma
Osteoblastic Vertebral Metastases
Increasedbone
resorption
Hypercalcaemia
Fracture
Bone pain
Clinical Consequences of Increased Bone Resorption
Bone
The Burden of Skeletal Complications in Metastatic Bone Disease
% of patients affected in placebo arms of bisphosphonate trials
Disease Breast Myeloma Prostate OthersObservation time 12 months 9 months 15 months 9 months
Radiation to bone 33 22 29 32
Fractures 41 30 22 21
Hypercalcaemiaof malignancy 9 6 1 3
Surgery to bone 8 5 3 4
Spinal cordcompression 2 3 7 4
Treatment of Bone Metastases
Traditional treatments
Radiotherapy/radionuclides
Endocrine treatment
Chemotherapy
Orthopaedic intervention
Analgesics
Complementary approach
Osteoclast inhibition
“ Skeletal Related Events”
(dreigende) fracturen: chirurgie, radiotherapie
myelumcompressie
hypercalciëmie
pijnscore, kwaliteit van leven
nieuwe botmetastasen
Meeste studies: systemische therapie +/- bisfosfonaat
Weinig grote vergelijkende studies tussen amino – en niet - aminobisfosfonaten
Hypercalciëmie behandeling: snelheid normaliseren serumcalcium en duur response
Werking
Bisfosfonaten
Impact of Changes in Bone Remodelling
Coupled andbalanced
Bone
Uncoupled butbalanced
Bone
Coupled butimbalanced
Bone
Uncoupled andimbalanced
Bone
Gemetastaseerde maligniteiten
Niet – gemetastaseerde maligniteiten
Prostaatcarcinoom
(–HCM) at 6 months—Protocols 032 and INT05
Total N = 378
0
0.1
0.2
0.3
0.4
Total
24% 24%
P = 1.0
Pro
po
rtio
n w
ith
SR
E (
–HC
M)
SRE SMR
Mea
n S
MR
(–H
CM
)
0
0.2
0.4
0.6
0.8
Total
Pam 90 mgPlacebo
P = .942
0.30 0.29
Pamidronate in Prostate CancerNo Effect on Proportion of Patients With SRE and Mean SMR
Lipton A, et al. Cancer Invest. 2001;20:45-47.
Placebo q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Zoledronic acid 4 mg* q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Prostate Cancer Trial Design
0 15 monthsCore analysis
24 monthsFinal analysis
RRAANNDDOOMMIIZZEEDD
N = 214N = 214
N = 208
• Stratification based on presence or absence of any distant metastases at initial diagnosis of cancer• 221 patients were randomized to receive zoledronic acid 8 mg and then reduced to 4 mg; no efficacy conclusions drawn from 8/4 mg group
Prostate CancerPercentage of Patients With an SRE
38
49
0
10
20
30
40
50
60
Zoledr acid 4mg (N = 214) Placebo (N = 208)
Per
cen
t o
f p
atie
nts
P = .028
Significantly fewer patients (22% relative reduction) experienced an SRE
Zoledronic acid 4 mg versus placebo remained significant when asymptomatic fractures were excluded
Prostate CancerPercentage of Patients With Each SRE
26
17
46
20
33
25
8 74
1
0
5
10
15
20
25
30
35
Radiation tobone
Fractures Spinal cordcompression
Antineoplastictherapy
Surgery tobone
Hypercalcemia
Pe
rce
nt
of
pa
tie
nts
Zoledr acid 4 mg (N = 214) Placebo (N = 208)
Zoledronic acid consistently reduces all types of SREs
Prostate CancerTime to First SRE
Significant delay onset of skeletal complications by > 5 months
*After start of study drug.
0
20
40
60
80
100
0 120 240 360 480 600 720
Days*
Pe
rce
nt
wit
ho
ut
ev
en
t
Median,days P value
Zoledr acid 4 mg 488 .009Placebo 321
Prostate CancerTime to First Pathologic Fracture
Significant delay onset of fractures by > 6 months
0
20
40
60
80
100
0 120 240 360 480 600 720
Days*
Pe
rce
nt
wit
ho
ut
ev
en
t
Median,days P value
Zoledr acid 4 mg NR .020Placebo NR
*After start of study drug.NR = not reached
Prostate Cancer Survival
0
20
40
60
80
100
0 120 240 360 480 600 720 840 960
Days*
Per
cen
t su
rviv
ing
Median, days P value
Zoledr acid 4 mg 546 .103Placebo 469
*Time after start of study drug.
Mammacarcinoom
Oral ibandronate study MF 4434
Randomized, double-blind,placebo-controlled phase III study
Treatment group (one tablet per day before breakfast)– placebo – 20mg ibandronate– 50mg ibandronate
Duration: up to 96 weeks
Companion study of similar design completed and under analysis
Patient disposition
Entered study443 patients*
Number evaluable435 patients
Placebo143 patients
20mg ibandronate144 patients
50mg ibandronate148 patients
Completed54 patients
Withdrawn89 patients
Completed55 patients
Withdrawn89 patients
Completed63 patients
Withdrawn85 patients
PWFU dataadditional69 patients
PWFU dataadditional56 patients
PWFU dataadditional56 patients
*Australia/New Zealand, Russia, South Africa, USA
Primary endpoint events
All new bone events
Placebo(n=143)
20mgibandronate
(n=144)
50mgibandronate
(n=148) p-value
Mean number of eventsper patient
2.23 1.36p=0.001
1.43p=0.014
0.017
Mean number ofmeasurement periodswith events per patient
1.27 0.79p=0.002
0.84p=0.014
0.017
Total number of periodswith events
182 114p=0.002
125p=0.014
0.017
Percentage of patientswith events
61.5 46.5p=0.011
52.0p=0.102
0.036
Breast Cancer and Multiple Myeloma Strata*
zoledronic acid pamidronate4 mg
90 mgN = 561 N = 555
Breast cancer 378 388 Chemotherapy 178 181 Hormonal therapy 200 207
Multiple myeloma 183 167
*ITT population.
Breast Cancer and Multiple Myeloma Trial Design
0 13 monthsCore analysis
25 monthsFinal analysis
RANDOMIZED
Zoledronic acid 4 mg* q 3 to 4 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Zoledronic acid 4 mg* q 3 to 4 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Pamidronate q 3 to 4 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
Pamidronate q 3 to 4 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
N = 564N = 564
N = 558N = 558
• Stratification based on multiple myeloma, breast cancer patients receiving chemotherapy, and breast cancer patients receiving hormonal therapy
• 526 patients were randomized to receive zoledronic acid 8 mg and thenreduced to 4 mg; no efficacy conclusions drawn from 8/4 mg group
Zoledronic acid in Patients With Breast Cancer and Osteolytic Lesion(s)Time to First Skeletal Complication
0102030405060708090
100
0 50 100 150 200 250 300
Days*
Pe
rce
nt
wit
ho
ut
ev
en
t
Zole 4 mg 310 .013Pam 90 mg 174
Median time,days P value
Zoledronic acid delays the onset of skeletal complications by 4.5 months in patients with osteolytic lesions
*After start of study drug.
Zoledronic acid in Patients With Breast Cancer and Osteolytic Lesion(s)Multiple-Event Analysis
Zoledronic acid significantly reduces the risk of developing a skeletal complication in patients with osteolytic lesions
Relative risk (zole 4 mg versus pam)
In favor of zole In favor of pamidronate
P value
Osteolyticlesions .010
All patients
.037
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 20
Noosteolyticlesions
.760
OverviewMultiple-Event Analysis
Relative risk (zole 4 mg versus placebo)
P value
.010
.028
.151
Other solidtumors
NSCLC
Other
In favor of zole In favor of placebo
Prostate cancer .002
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
P value
Relative risk (zole 4 mg versus pam)
Total
In favor of zole In favor of pam
Multiple myeloma
0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 20
Zoledronic acid decreases the risk of a skeletal complication
Breastcancer
.059
.731
.042
Bijwerkingen
Osteonecrosis of the jaw
Preventie Botmetastasen
Randomized, placebo controlled trial of Clodronate in patients with primary
operable breastcancer
Powles T et al. J.Clin. Oncology. 2002 : 3219 - 3224
Clodronaat 1600 mg per dag oraal – versus placebo gedurende 2 jaar.
Mediane follow up 2007 dagen
Powles T et al. J.Clin. Oncology. 2002 : 3219 - 3224
Clodronaat
N = 530 %
Placebo
N = 539 % P
patiënt met botmeta.
63 11.9 80 14.8 0.127
medicatie
periode
12 2.3 28 5.2 0.016
follow up
periode
51 9.6 52 9.7 0.732
Clodronaat
N = 530 %
Placebo
N = 539 % P
patiënt met extra ossale
metastasen
112 21.1 128 23.7 0.257
medicatie
periode
38 7.2 39 7.2 1.0
follow up
periode
74 14.0 89 16.5 0.139
metastasen 139 26.2 145 26.9
overleden 98 18.5 129 23.9 0.047
Conclusie:
Significante reductie botmetastasen tijdens behandeling
Significante reductie mortaliteit
Asco 2008
Adjuvant ovarian suppression combined with tamoxifen
or anastrozole, alone or in combination with zoledronic
acid, in premenopausal women with hormone
responsive, stage I and II breast cancer: First efficacy
results from ABGSG-12
M.Gnant et al.
Studie Gnant
1801 vrouwen
Gosereline
Anastrozole versus Tamoxifen
+/- Zoledroninezuur: 4 mg iv/ 6 maanden
Studie Gnant
60 maanden mediane follow-up
Disease free survival:
* Zoledroninezuur behandelde groep
reductie van 36 %
H R 0.64 95 % C I 0.46 – 0.91
p = 0.01
Studie Gnant
Relapse free survival
* zoledroninezuur behandelde groep
reductie van 35 %
H R 0.65 95 % CI 0.46 – 0.92
p = 0.015
Studie Gnant
Geen verschil overall survival
* H R 0.60 95% C I 0.60 - 1.11
p= 0.10
Bisfosfonaten bij aromataseremmers
14
Tumor cellTumor cell
NucleusNucleus
AndrostenedioneAndrostenedioneAndrostenedione
Intracellular Aromatase
AndrostenedioneAndrostenedioneAndrostenedione
Human BreastAdipose
Fibroblasts
Human BreastHuman BreastAdipose Adipose
FibroblastsFibroblasts
AROMATASE
AARROOMMAATTAASSEE
AROMATASE
AARROOMMAATTAASSEE
LetrozoleAnastrozoleLetrozoleLetrozole
AnastrozoleAnastrozole
Hamster OvarianTissue
Hamster Hamster OvarianOvarianTissueTissue
Endocrine cellEndocrine cell
Normal Bone Osteoporosis
A skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.
National Institutes of Health (USA)Consensus Development Panel on Osteoporosis Prevention,
Diagnosis, and Therapy, 2001.
Osteoporosis
Therapy-Induced Bone Loss May Increase Fracture Risk in Breast Cancer Patients
1. Coleman RE, et al. J Clin Oncol. 2006;24(18S):5s. Abstract 511. 2. Baum M, et al. Cancer. 2003;98:1802-1810.
3. Howell A, et al. Lancet. 2005;365:60-62.
37 Months2 68 Months3
Anastrozole
Tamoxifen
Δ Lumbar Spine
BMD, %1
Year
Δ Total Hip
BMD, %1
Year
4
0
-4
-8
4
0
-4
-8
1 2 5
0
3
6
9
12
Fractures, %
1 2 5
Data from the Arimidex®, Tamoxifen, Alone or in Combination (ATAC) study. N = 9366 postmenopausal women with localized breast cancer.
P < .001
P < .0001 P < .0001
Zofast studie
Zoledroninezuur bij letrozole
upfront of delayed
bij adjuvante behandeling
mammacarcinoom
Zofast studie
BMD after 12 month
upfront delayed
L2 – L4 + 4.39 % - 4.9 %
Hip + 1.89 % - 3.52 %
p= < 0.0001
Proposed Trt Algorithm for AI-induced bone loss
T-score < -2.0
Monitor BMDevery 2 years
Bisphosphonate therapy
(e.g.zoledronic acid 4 mg/6 months)
plus calcium and Vit. D supplements
Calcium and Vitamin DExercise?
Monitor risk statusand BMD
every 1-2 years
T-score ≥ -2.0No additionalRisk factors
Any 2 of the following risk factors:-T-score < -1.5- age > 65 years- low BMI- Family history of hip fracture- Personal history of fragility fracture after age 50- Oral corticosteroid use of > 6 months- Smoking (current and history of)
Patient with breast cancer initiating AI therapy
Hadji, Body, Aapro et al.; Ann Oncol 2008
Tenslotte….
Adapted from Roodman D. N Engl J Med. 2004;350:1655.
Osteoblasts
Activated Osteoclast
RANKL
RANK
Cytokines and Growth Factors
Growth Factors
Cancer Cells in Bone Metastasis
RANK Ligand is a Key Mediator in the ‘Vicious Cycle’ of Bone Destruction in Metastatic Cancer
Bone Resorption
Osteolytic Lesions
RANK Ligand is Implicated in Bone Loss Across a Broad Range of Conditions
Post-Menopausal
Osteoporosis
Male Osteoporosis
Rheumatoid Arthritis
Pathological Bone Loss
Glucocorticoid-Induced
Osteoporosis
Therapy-Related Bone
Loss
Treatment-Induced Bone Loss
Gluco-corticoids
Aromatase Inhibitors
AndrogenDeprivationTherapy
Bone Metastases/
Multiple Myeloma
Cancer-Related Bone Destruction