“Bone Health” della paziente con carcinoma della mammella: approccio multidisciplinare F. Bertoldo, P. Pronzato
“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