Bisphosphonates and RANKL-Antibody Denosumab

Bisphosphonates and RANKL-Antibody Denosumab

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
Bisphosphonates and
RANKL-Antibody
Denosumab
Bisphosphonates and
RANKL-Antibody Denosumab
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
www.ago-online.de
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Versions until 2011:
Diel / Fehm / Friedrich/ Jackisch /
Schaller/ Scharl / Schütz / Solomayer
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Version 2012:
Lux / Solomayer
Bisphosphonates in Breast Cancer
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
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in der DKG e.V.
Guidelines Breast
Version 2012.1
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www.ago-online.de
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Hypercalcemia
Reduction of skeletal events (complications)
Reduction of bone pain
Treatment beyond progression of bone met‘s
In combination with neoadjuvant chemotherapy
Prevention of metastases
 Primary breast cancer in subgroups
 Advanced breast cancer
Tumor therapy-induced bone loss
 Prevention
 Therapy
Prevention of breast cancer with oral BPs
(in women receiving BP for low BMD)
1a
1a
1a
5
2b
A
A
A
D
C
++
++
++
++
+/-
1b
2b
B
C
+
+/-
1b
1b
3b
B
B
C
+
++
+/-
Bisphosphonate Use And Breast Cancer
Incidence
© AGO
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in der DGGG e.V.
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in der DKG e.V.
Guidelines Breast
Version 2012.1
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Chlebowski RT et al. Oral Bisphosphonate Use and Breast Cancer Incidence in
Postmenopausal Women. J Clin Oncol 28:3582-3590
RANKL-Antibody Denosumab in
Breast Cancer
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford / AGO
LoE / GR
Guidelines Breast
Version 2012.1
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Reduction of hypercalcemia
Reduction of skeletal complications
Reduction of bone pain
Treatment beyond progression
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www.ago-online.de
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Progression while therapy with
bisphosphonates
Prevention of tumor therapy-induced
osteoporosis
Therapy of tumor therapy induced
osteoporosis
2a
1a
1b
5
A
A
B
D
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++
++
+
4
C
+/-
1b B
+
1b A
++
Therapy and Prevention of Tumor TherapyInduced Bone Loss / Osteoporosis
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
www.ago-online.de
Regular BMD-measurement recommended 2b
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Bisphosphonates
1b
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RANK-ligand antibody
Therapy
1b
 Prevention
1b
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HRT (independent from ER-status of BC)
5
Further recommendations (based on the guidelines
for osteoporosis)*
 Physical activity
4
 Calcium (≥ 500–1,200 mg/d)
4
 Vitamine D suppl. (800–2,000 U/d)
4
 Reduction of smoking
4
 Avoiding BMI < 20 mg/m2
3b
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*http://www.dv-osteologie.org/dvo_leitlinien/dvo-leitlinie-2009
B
B
+
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A
B
D
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+
-
C
C
C
C
C
++
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++
++
++
Bisphosphonates and Denosumab for
the Therapy of Bone Metastases
© AGO
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Clodronate PO 1600 mg daily
Oxford / AGO
LoE / GR
1a
A ++
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Clodronate IV 1500 mg q3w / q4w
1a
A ++
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Pamidronate IV 90 mg q3w / q4w
1a
A ++
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Ibandronate IV 6 mg q3w / q4w
1a
A ++
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Ibandronate PO 50 mg daily
1a
A ++
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Zoledronate IV 4 mg q4w
1a
A ++
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Denosumab 120 mg s.c. q4w
1a
A ++
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Other doses or schedules, e.g. derived
from studies of adjuvant therapy or
therapy of osteoporosis
5
D --
e. V.
in der DGGG e.V.
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in der DKG e.V.
Guidelines Breast
Version 2012.1
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Denosumab vs. Zoledronat
to Reduce Skeletal Events
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
www.ago-online.de
Stopeck AT et al. Denosumab Compared With Zoledronic
Acid for the Treatment of Bone Metastases in Patients With
Advanced Breast Cancer: A Randomized, Double-Blind
Study, J Clin Oncol 28:5132-5139
Adjuvant Bisphosphonate Treatment
in Primary Breast Cancer
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
www.ago-online.de
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Clodronate PO 1600 mg daily for 2 y
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Zoledronate IV 4 mg every 6 months for 3–5 y
 Postmenopausal patients
 HR+ premenopausal patients
 Adjuvant endocrine therapy only
 Adjuvant chemotherapy
 HR- premenopausal patients
1b B
+
2b B
+
1b B
5
D
1b C
+
+/+/-
AZURE-trial –
Postmenopausal Women
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
www.ago-online.de
Coleman RE et al. Breast-cancer adjuvant therapy with
zoledronic acid. N Engl J Med. 2011;365(15):1396-405
Zoledronic Acid in
Premenopausal Women the ABCSG12-trial
© AGO
e. V.
in der DGGG e.V.
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in der DKG e.V.
Guidelines Breast
Version 2012.1
Gnant M, Endocrine therapy plus zoledronic acid in
premenopausal breast cancer. N Engl J Med. 2009;360(7):679-91
Reduction of risk for event (DFS) by 36%
No. of
Hazard ratio (95% CI)
events/ # at risk vs. No ZOL
P -value
ZOL
54/ 899
0.643 (0.46; 0.91)
0.011
No ZOL 83/ 904
www.ago-online.de
Zoledronic Acid in
Premenopausal Women Update of the ABCSG12-trial
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
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Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al. Long-term
follow-up in ABCSG-12: Significantly improvedoverall survival with
adjuvant zoledronic acid in premenopausal patients with
endocrine-receptor–positive early breast cancer.
Cancer Res. 2011; 71(24 Suppl.):95s-96s
Side-Effects and Toxicity –
Bisphosphonates (BP) and Denosumab (Db)
© AGO
Oxford
LoE
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Guidelines Breast
Version 2012.1
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Renal function deterioration due to
IV-aminobisphosphonates
1b
Osteonecrosis of the jaw (ONJ) mostly
under IV-BP and denosumab therapy
(1.8%/ 1.8%)
1b
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Association with anti-angiogenetic therapies
3b
Acute phase reaction
(IV Amino-BPs, Db) 10-30%
1b
Gastrointestinal side effects
(oral BPs) 2-10%
1b
In adjuvant bisphosphonate therapy,
major side effects were rarely observed (except APR).
Recommendations for Precautions to
Prevent ONJ*
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2012.1
Oxford LoE: 4
GR: C
AGO: +
 During bisphosphonate or denosumab treatment, avoid any
elective dental procedures, which involve jaw bone
manipulations – if interventions are inevitable, prophylactic
antibiotics are recommended (LoE 2b)
 Optimize dental status before start of bisphosphonate or
denosumab treatment, if feasible (LoE 2b)
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 Inform patients about ONJ risk and educate about early
symptom reporting
 In case of high risk for ONJ, use oral bisphosphonate
In adjuvant bisphosphonate therapy,
ONJ was extremely rare
*Osteonecrosis of the jaw