Seminar 15-01-2009 - bisfosfonaten en kanker

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


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





PWFU dataadditional69 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


Zoledronic acid 4 mg* q 3 to 4 wk


Pamidronate q 3 to 4 wk


Pamidronate q 3 to 4 wk


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

Health & Medicine

Seminar 15-01-2009 - bisfosfonaten en kanker