“Bone Health” della paziente con carcinoma della mammella: approccio multidisciplinare

F. Bertoldo, P. Pronzato

Balancing cost & benefit of maintaining bone health by

bisphosphonates

• Bisphosphonates prevent bone complications in patients with osseous metastases and represent the treatment of osteoporosis

• Pts receiving bisphosphonates may be at risk of ONJ

Balancing cost & benefit of maintaining bone health by

bisphosphonates

• Bisphosphonates prevent bone complications in patients with osseous metastases and represent the treatment of osteoporosis

• Pts receiving bisphosphonates may be at risk of ONJ

Bisphosphonates in breast cancer – Pts with bone metastases

• Reduction in skeletal events with pamidronate, zolendronate or ibandronate in trials of long-term treatment

• Risk of ONJ in this context is not negligible

Annual estimatenew cases - US,

x1000

Incidence of bone metastases,

%

Median survival, months

Myeloma 16 70 - 95 50 - 67Renal 36 20 - 25 8 - 21Melanoma 60 14 - 45 5 - 31Bladder 63 40 9 - 20Thyroid 26 60 49Lung 173 30 - 40 17 - 33Breast 213 65 - 75 18 - 24Prostate 232 65 - 75 16 - 24

Metastatic Bone Disease is an Important Clinical Problem in Cancer

Patients

52

22

37

22

43

29

34 34

11

3 4 537

2 4

19

7,5 7,5 7,5

0

10

20

30

40

50

60

breast c. prostate c. multiple myeloma NSCLC and othersolid tumor

pathologic fractureradiotherapysurgery to bonespinal cord compressionhypercalcemia

Incidence of Skeletal Related Events in Incidence of Skeletal Related Events in Patients with Bone MetastasesPatients with Bone Metastases

52

22

37

22

43

29

34 34

11

3 4 537

2 4

19

7,5 7,5 7,5

0

10

20

30

40

50

60

breast c. prostate c. multiple myeloma NSCLC and othersolid tumor

pathologic fractureradiotherapysurgery to bonespinal cord compressionhypercalcemia

Incidence of Skeletal Related Events in Incidence of Skeletal Related Events in Patients with Bone MetastasesPatients with Bone Metastases

FractureFracture FractureFracture

HypercalcemiaHypercalcemiaHypercalcemiaHypercalcemia

Bone Metastases Have Debilitating ConsequencesBone Metastases Have Debilitating Consequences

Surgery to boneSurgery to boneSurgery to boneSurgery to bone

Rx therapy Rx therapy to boneto bone Rx therapy Rx therapy to boneto bone

Disease Skeletal-related events

Loss of Loss of autonomyautonomyLoss of Loss of autonomyautonomy

Bone painBone painBone painBone pain

Consequences to functional independence and QOL

Bone Bone metastasesmetastasesBone Bone metastasesmetastases

Spinal cord Spinal cord compressioncompressionSpinal cord Spinal cord compressioncompression

QOL = Quality of life.

9

Impact on Survival: Fractures Negatively Affect Survival

Pathologic fractures correlate with a significantly increased relative risk of death1,2

– Breast Cancer 1.32 (1.10, 1.59) P=0.003– Multiple Myeloma 1.44 (1.06, 1.95)

P=0.02– Prostate Cancer 1.29 (1.01, 1.65) P=0.04– Lung Cancer / other 1.08 (0.87, 1.34) P=0.49

1 Saad F, et al. ECCO, 2005. Abstract 1265; 2 Hei Y et al. Presented at SABCS 2005, Abstract 6036

Riduzione del rischio calcolato di eventi scheletrici nel tumore metastatico della mammella

1.Body JJ et al. ASCO 2003; 2. Estimated from Coleman et al. SABCS 2002;3. Lipton A et al. Cancer 2000; 88: 1082-90; 4. Pavlakis N, Stockler M. The Cochrane Library 2002

16

33

37

38

40

0 10 20 30 40 50

Clodronato4

Pamidronato3

Zoledronato2

Ibandronato os 50 mg1

Ibandronato ev 6 mg1

Riduzione degli eventi scheletrici (%)

11Zoledronic Acid Randomized Phase III Trials in Patients With Bone Metastases

Trial N

Zoledronic acidversus:

Patientpopulation

Treatmentduration, mo

036/0371 287 PamidronateHypercalcemia of

malignancy1 infusion

0102 1,648 PamidronateBreast cancer

Multiple myeloma 24

15013 227 Placebo Breast cancer 12

0394 643 Placebo Prostate cancer 24

0115 773 PlaceboNSCLC and other

solid tumors21

1. Major P, et al. J Clin Oncol. 2001;19:558-567. 2. Rosen LS, et al. Cancer. 2003;98:1735-1744. 3. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 4. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882. 5. Rosen LS, et al. Cancer. 2004;100:2613-2621.

12

Zoledronic Acid in Metastatic Breast Cancer:Continuing Reduction in SRE Risk (subset analysis)

Zheng M et al. St. Gallen 2005. Poster 104

During the second year on zoledronic acid, the relative risk of experiencing an SRE remains lower than with pamidronate.

13

Continuing Reduction in the Risk of a Second SRE (Breast ca., 2nd event subset analysis; multiple event analysis)

Zheng M et al. St. Gallen 2005. Poster 104

Compared with pamidronate, zoledronic acid in breast cancer reduced the risk of experiencing a second SRE by about one-third.

Bisphosphonates in breast cancer – Pts without bone metastases

• Pts with breast cancer, mainly because of chemotherapy or endocrine-therapy induced suppression of estrogen action are at higher risk of osteoporosis and bone fracture

• The risk of ONJ in this context is very low! (understimated?)

ONJ

Osteonecrosis of the Jaw

• Few literature reports before 20031-3

– Most often reported: osteoradionecrosis (ORN) following head and neck radiation (reported incidence from 0.4% to 8.2%4)

• Since 2003, a growing number of cases of ONJ have been reported in patients who had not been treated with H&N radiation therapy

• A common finding among these patients was the active treatment with bisphosphonates (BPs) an association between BPs exposure and ONJ has been described

1. Winer et al. J Am Dent Assoc. (1972)2. Schwartz. Head Neck Surg. (1982)3. Sung et al. Spec Care Dent. (2002)4. Reuther et al. Oral Max Surgery. (2003)

• Reduced osteoclastic activity in an area where bone remodeling is critical for bone healing and survival

• Alteration of vascular supply resulting in ischemia and necrosis of the bone

• Direct antiangiogenic effect of bisphosphonates:– Significant decrease in circulating levels of VEGF in MBC (pamidronate) *

– Inhibition of endotelial cell function in vitro and in vivo (clodronate, risedronate, ibandronate, and zoledronic acid) °– Inhibition of vessel sprouting in chick embryo model (zoledronic acid) ^

• ONJ has been described almost exclusively after exposure to nitrogen-containing bisphosphonates (more potent)

• A few cases have been described in patients taking alendronate for osteoporosis

ONJ: Pathogenesis

* Santini et al: Clin Cancer Res 2002; ° Fournier et al, Cancer Res 2002; ^ Wood et al J Pharmacol Exp Ther, 2002

ONJ in Cancer Patients Treated With BPs

Frequency EstimatesSource Frequency estimate

Spontaneous reports

Aredia

Zometa

Both

(estimated total # pts exposed)

305 of 1.9 million (0.016%)

1335 of 1.15 million (0.12%)

587 of 3.05 million (0.019%)

Retrospective review of Zometa clinical trials*

16 of 16,900 (0.10%)

Web-based survey (Durie)

75 of 1203 (6.2%) of respondents reported ONJ

MDACC 33 cases of 4029 charts (0.8%)

MSKCC 6 cases of 934 charts (0.6%)

* Observation period typically 12 months

Prospective assessment of ONJ in cancer patients receiving

bisphosphonates

• Prospective assessment of ONJ since 2003• 1st BPS administration among ONJ pts: 1997• 252 pts treated since 01/97 were included in this

analysis (MBC: 70; MM: 111; PC: 46; other: 25)• To ensure adequate exposure to BPS: exclusion of

pts who received < 6 doses • All pts with dental problems were referred to

maxillofacial surgeon to confirm diagnosis• Review of medical records to exclude sign/symptoms

of ONJBamias A, J Clin Oncol 2005

Prospective assessment of ONJ in cancer patients receiving

bisphosphonates

• 17 pts (6.7%) were diagnosed with ONJ– MM: 11/111(9.9%)

– BC: 2/70 (2.9%)

– PC: 3/46 (6.5%)

– Other: 1/25 (4%)

• Type of bisphosphonate– 8 Zoledronic acid

– 9 Zoledronic acid after pamidronate

Bamias A, J Clin Oncol 2005

Cumulative hazard of developing osteonecrosis of the jaw from the date of initiation of treatment

Wilkinson, G. S. et al. J. Natl. Cancer Inst. 2007 99:1016-1024

Indipendent from other risk factors considered: diabetes, alcoholism, smoking, obesity, hyperlipidemia, pancreatitis, CT with L-asparaginase

Wilkinson, G. S. et al. J. Natl. Cancer Inst. 2007 99:1016-1024

Copyright restrictions may apply.

Wilkinson, G. S. et al. J. Natl. Cancer Inst. 2007 99:1016-1024; doi:10.1093/jnci/djm025

Kaplan-Meier estimates for adverse bone outcomes for matched cancer patients who did or did not receive intravenous bisphosphonates

Absolute Risk at 6 years was 5.48 events/100 pts

Bisphosphonate-associated ONJ in pts with osteoporosis or Paget’s Disease

Study n disease BP

Ruggiero 7 Osteop (7) A (6); A+Z(1)

Cheng 8 Osteop(3); Paget (5) A(5); P(2); A+P(2)

Marx 3 Osteop (3) A (3)

Marunick 2 Osteop (2) A(2)

Migliorati 1 Osteop (1) A(1)

Purcell 1 Osteop (1) A (1)

Farruggia 5 Osteop (4); Paget (1) A (5)

Chang 11 Osteop (11) A(11)

Mavrokokki 32 Osteop (26); Paget (6) A (25); P (2); R (2); A+R (2); A+P (1)

Starck 1 Osteop (1) E

Hoefert 3 Osteop (3)

Najm 3 Osteop (3) A(2); P+Z (1)

Carter 3 Paget (3) A(1); P(2)

Pozzi 1 Osteop (1)

TOTAL (excl overlapping)

64 Osteop (57); Paget(7)

Facing the problem of ONJ risk in pts with bone metastases receiving BPs

• Applying the least “bone-toxic” drugs• Applying prevention tools• Avoiding BPs?• Limiting duration of treatment?• Selecting a certain BP?• Estimating risk and benefit

Application of BPs in pts without metastases

• Waiting for definitive results of clinical trials• Applying the least “bone-toxic” drugs• Applying prevention tools• Avoiding BPs?• Limiting duration of treatment?• Selecting a certain BP?• Estimating risk and benefit