(pdf-Datei, 612 KB)

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 2014.1
Osteooncology and Bone
Health
Osteooncology and Bone Health
© AGO
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1

Versions 2002-2013:
Bischoff / Böhme / Brunnert / Dall / Diel /
Fehm / Fersis / Friedrich/ Friedrichs /
Huober / Jackisch / Janni / Lux / Maas /
Oberhoff / Schaller / Scharl / Schütz /
Seegenschmiedt / Solomayer / Souchon

Version 2014:
Diel / Nitz
www.ago-online.de
Bisphosphonates in Breast Cancer
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1






www.ago-online.de

Hypercalcemia
Reduction of skeletal events (complications)
Reduction of bone pain
Treatment beyond progression of bone met‘s
In combination with neoadjuvant chemotherapy
Prevention of bone metastases/ survival advantage
 Adjuvant in postmenopausal patients
 Advanced breast cancer
Prevention of breast cancer with oral BPs
(in women receiving BP for low BMD)
1a
1a
1a
5
2b
A
A
A
D
C
++
++
++
++
+/-
1a
2b
3b
A
C
C
+
+/+/-
Denosumab in Breast Cancer
© AGO
e. V.
Oxford / AGO
LoE / GR
in der DGGG e.V.
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Guidelines Breast
Version 2014.1

Reduction of hypercalcemia
2a A
++

Reduction of skeletal complications
1a A
++

Reduction of bone pain
1b B
++
1b A
++
5
D
+
4
C
+/-
www.ago-online.de


Increasing bone pain-free survival
Treatment beyond progression

Progression under bisphosphonates
Bone Modifying Agents for the Therapy
of Bone Metastases
© AGO

Clodronate PO 1600 mg daily
Oxford / AGO
LoE / GR
1a
A ++

Clodronate IV 1500 mg q3w / q4w
1a
A ++

Pamidronate IV 90 mg q3w / q4w
1a
A ++

Ibandronate IV 6 mg q3w / q4w
1a
A ++

Ibandronate PO 50 mg daily
1a
A ++

Zoledronate IV 4 mg q4w
1a
A ++

Denosumab 120 mg s.c. q4w
1a
A ++

Other doses or schedules, e.g. derived
from studies of adjuvant therapy or
therapy of osteoporosis
5
D --
e. V.
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Guidelines Breast
Version 2014.1
www.ago-online.de
Skeletal Metastasis
Treatment with Radionuclids
© AGO
e. V.
Oxford / AGO
LoE / GR
in der DGGG e.V.
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Guidelines Breast
Version 2014.1

Tumor progression after standard treatment
of multiple / disseminated metastases
and intolerable bone pain
1b
B
+
diphosphonat (e.g. 186Re-HEDP)
2b
B
+
153
1b
B
+
1b
B
+
1b
C
+
(prerequisit: hot spots in the bone scintigraphy)
186Rhenium-hydroxyethylidene-

www.ago-online.de
89
Samarium
Strontium (e.g. Sr89)
 223
Radium
Cave: Myelosuppression with risks of pancytopenia has to balance
potential benefits.
Metastatic Bone Disease
of the Spine
© AGO
Indications for surgery
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Guidelines Breast
Version 2014.1
Oxford LoE: 2b
Spinal
www.ago-online.de
GR: C
AGO: ++
cord compression

With progressive neurological symptoms

With pathological fractures

Instability of the spine

Lesions in pre-irradiated parts of the spine
Bone Metastases
Acute Spinal Cord Compression /
Paraplegia
© AGO
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Guidelines Breast
Version 2014.1

Decompression surgery, reduction of
tumor volume, stabilisation surgery
(< 24 h) and irradiation of the spine (RT)
2b
C
++

Irradiation of the spine (< 24 h) +/- steroids
3b
C
++

Immediate start of treatment
1c
D
++
www.ago-online.de
Clinical trials have included patients with different tumor entities!
Surgery for Bone Metastases
© AGO
Spine and limbs
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Oxford LoE: 3b
GR: C
AGO: +
Guidelines Breast
Version 2014.1
www.ago-online.de

Marrow splints

Osteosynthesis

Bone replacement by PMMA or titanspacer

Tumor-Endoprothesis

Vertebroplasty / Kyphoplasty

Kypho-IORT (only in studies)*

Resection of involved bone in oligometastatic disease
(sternum, ribs, vertebrectomy and replacement with
spondylodesis)
*Study participation recommended
Metastatic Bone Disease:
Radiotherapy
© AGO
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Guidelines Breast
Version 2014.1
Bone metastases
Oxford / AGO
LoE / GR

With fracture risk
1a
B ++

With functional impairment
1a
B ++

With bone pain
1a
B ++
2a
B ++

Single RT = fractionated RT
www.ago-online.de

With neuropathic bone pain
1b
B ++

Asymptomatic isolated bone metastases
5
D +/-
Only few studies included breast cancer patients!
Metastatic Bone Disease
Recurrent Bone Pain
© AGO
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Oxford / AGO
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in der DGGG e.V.
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Guidelines Breast
Version 2014.1
Recurrent bone pain in pre-irradiated
parts of the skeleton

Single RT (1 x 8 Gy)
3b C
++

Fractionated RT (6 x 4 Gy)
3b C
+

Radionuclid therapy
3b C
+
www.ago-online.de
Side-Effects and Toxicity –
Bisphosphonates (BP) and Denosumab (Db)
© AGO
Oxford
LoE
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Guidelines Breast
Version 2014.1


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

www.ago-online.de
Association with anti-angiogenetic therapies
3b

Severe hypocalcemia (Dmab>BPs)
1b

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.
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Guidelines Breast
Version 2014.1
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)
www.ago-online.de
 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 rare
*Osteonecrosis of the jaw
Adjuvant Bisphosphonates for Reduction of
Bone Metastases and Survival Advantage
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1


www.ago-online.de
Clodronate (oral)
 Postmenopausal patients
 Premenopausal patients
1a A
1a B
+
+/-
Aminobisphosphonates (iv or oral)
 Postmenopausal patients
 Premenopausal patients
1a
1a
+
+/-
A
B
Adjuvant Bisphosphonates for Reduction of
Bone Metastases and Survival Advantage
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2014.1





www.ago-online.de




Coleman R, Gnant M, Paterson A et al. Effects of bisphosphonate treatment on
recurrence and cause-specific mortality in women with early breast cancer. A metaanalysis of individual patients data from randomized trials. SABCS 2013, abstract S4-07
Winter MC, Coleman RE. Bisphosphonates in the adjuvant treatment of breast cancer:
an Overview. Clin Oncol 2013;25:135-45
Zhu J, Zheng Y, Zhou Z. Oral adjuvant clodronate therapy could improve overall survival
in early breast cancer. Results from an updated systematic review and meta-analysis.
Eur J Cancer 2013 ;49:2086-92
He M, Fan W, Zhang X. Adjuvant zoledronic acid therapy for patients with early stage
breast cancer: an updated systematic review and meta-analysis. J Hematol Oncol 2013,
6:80: http://www.jhoonline.org/content/6/1/80
Valachis A, Polyzos NP, Coleman RE et al. Adjuvant therapy with zoledronic acid in
patients with breast cancer. A systematic review and meta-analysis. The Oncologist
2013;18:353-61
Figueroa-Magalhães, Miller RS. Bone-Modifying Agents as Adjuvant Therapy for earlystage breast cancer. Oncology 2012;26:
http://www.http://www.cancernetwork.com/breast-cancer/content/article/10165/2107660
Yan T, Yin W, Zhou Q et al. The efficacy of zoledronic acid in breast cancer adjuvant
therapy: A meta-analysis of randomised controlled trials. Eur J Cancer 2012; 48:187-95
Chlebowski RT, Col N. Bisphosphonates and breast cancer, incidence and recurrence.
Breast Disease 2011;33:83-101
Dosage of Adjuvant Bisphosphonates
for Improvement of Survival
© AGO
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1
www.ago-online.de

Non-Aminobisphosphonates:

Clodronate PO 1600mg/d (Bonefos/ Clodronic acid)

Clodronate PO 1040mg/d (Ostac)

Aminobisphosphonates:

Zoledronate IV 4mg/6m (Zometa/ Zoledronic acid)

Ibandronate PO 50mg/d (Bondronat/ Ibandronic acid)

Pamidronate PO (orally not available in most countries)

Risedronate PO 35mg/w*(Actonel/ Risedronic acid)

Alendronate PO 70mg/w (Fosamax/ Alendronic acid)
Aminobisphosphonates include:
Zoledronic acid (65%), Oral ibandronate (24%), Oral pamidronate (8%),
Oral residronate (2%), Oral alendronate (1%) (data from EBCTCG-metaanalysis)
Therapy and Prevention of Tumor TherapyInduced Bone Loss / Osteoporosis
© AGO
Oxford / AGO
LoE / GR
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1

Bisphosphonates
Therapy
 Prevention
Denosumab
 Therapy
 Prevention
www.ago-online.de
1b B
1b A
++
+
1b B
1b A
++
+
5

HRT (independent from ER-status of BC)
D
-

Regular BMD-measurement recommended 2b B
(Intervals depending from previous T-values)
+
Therapy and Prevention of Tumor TherapyInduced Bone Loss / Osteoporosis
© AGO
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1
Further recommendations (based on
DVO-guidelines for treatment, diagnosis
and prevention of osteoporosis)*
Oxford / AGO
LoE / GR
Physical activity
4
C ++
 Avoiding immobilisation
4
C ++
 Calcium (1000–1500 mg/d. Nutrit./Suppl.)** 4
C ++
 Vitamine D suppl. (800–2000 U/d)
4
C ++
 Reduction of smoking
4
C ++
 Avoiding BMI < 20 mg/m2
3b C ++
 Drugs approved for the treatment of osteoporosis in
adults (see next slide)

www.ago-online.de
*http://www.dv-osteologie.org/dvo_leitlinien/dvo-leitlinie-2009
New DVO-guidelines will be presented soon in 2014
**if intestinal uptake is reduced (in combination with Vit D only)
Medical Treatment of Osteoporosis
© AGO

Alendronate 70 mg po/w*
Oxford / AGO
LoE / GR
1b
B ++

Denosumab 60 mg sc/6m*
1b
B
++

Ibandronate 150 mg po/m*
1b
B
++

Ibandronate 3 mg iv/3m
1b
B
+

Parathyroid hormone (1-84) 100 µg sc/d
1b
B
+

Raloxifene 60 mg po/d
1b
B
+

Risedronate 35 mg po/w*
1b
B
++

Strontium ranelate 2 g po/d
1b
B
+

Teriparatide (1-34) 20 µg sc/d
1b
B
+

Zoledronate 5 mg iv/12 m*
1b
B
++
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1
www.ago-online.de
* Drugs testet in clinical studies with breast cancer patients and tumor therapy-induced
osteoporosis
© AGO
e. V.
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Guidelines Breast
Version 2014.1
www.ago-online.de
Therapieempfehlung für Personen ohne
spezifische Risiken und/oder Frakturen
© AGO
e. V.
in der DGGG e.V.
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Guidelines Breast
Version 2014.1
Schwellenwerte der T-Werte der Knochendichte für eine medikamentöse
Therapie in Abhängigkeit vom Geschlecht und dem Lebensalter für Personen ohne prävalente Frakturen oder andere spezifische Frakturrisiken
Lebensalter in Jahren T-Wert
www.ago-online.de
Frau
<50
50–60
60–65
65–70
70–75
>75
Mann
<60
60–70
70–75
75–80
80–85
>85
T-Wert
–4,0
–4,0
–3,5
–3,0
–2,5
–2,0
http://www.dv-osteologie.org/dvo_leitlinien/dvo-leitlinie-2009
Neue DVO-Leitlinie erscheint voraussichtlich 2014
Therapieempfehlung für Personen mit
spezifische Risiken und/oder Frakturen
© AGO
e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Guidelines Breast
Version 2014.1
www.ago-online.de
Risikofaktoren, die die Therapieschwelle mitbestimmen (auszugsweise*)
1. Allgemeine Risiken
periphere Fraktur nach dem 50. Lebensjahr
multiple Stürze
Immobilität
fortgesetzter Nikotinkonsum
Abnahme der DXA-Knochendichte am Gesamtfemur
um 5% und mehr in 2 Jahren
Hypogonadimus
2. Krankheiten
Diabetes mellitus Typ 1
rheumatoide Arthritis
3. Medikamente
Antiandrogene/ Antiöstrogene Therapie
Aromatasehemmer-Therapie
orale Glukokortikoide < 7,5 mg für mehr als 3 Monate
*http://www.dv-osteologie.org/dvo_leitlinien/dvo-leitlinie-2009
Neue DVO-Leitlinie erscheint vermutlich 2014
B
B
B
B
B
B
B
D
B
D
B
Osteooncology and Bone Health (2/22)
No further information
No references
Bisphosphonates in Breast Cancer (3/22)
No further information
References:
Chlebowski RT, Col N. Bisphosphonates and breast cancer, incidence and recurrence. Breast Disease 2011;33:83-101
Coleman R, Gnant M, Paterson A et al. Effects of bisphosphonate treatment on recurrence and cause-specific mortality in
women with early breast cancer. A meta-analysis of individual patients data from randomized trials. SABCS 2013, abstract
S4-07
Figueroa-Magalhães, Miller RS. Bone-Modifying Agents as Adjuvant Therapy for early-stage breast cancer. Oncology
2012;26: http://www.http://www.cancernetwork.com/breast-cancer/content/article/10165/2107660
He M, Fan W, Zhang X. Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated
systematic review and meta-analysis. J Hematol Oncol 2013, 6:80: http://www.jhoonline.org/content/6/1/80
Valachis A, Polyzos NP, Coleman RE et al. Adjuvant therapy with zoledronic acid in patients with breast cancer. A
systematic review and meta-analysis. The Oncologist 2013;18:353-61
Winter MC, Coleman RE. Bisphosphonates in the adjuvant treatment of breast cancer: an Overview. Clin Oncol
2013;25:135-45
Zhu J, Zheng Y, Zhou Z. Oral adjuvant clodronate therapy could improve overall survival in early breast cancer. Results
from an updated systematic review and meta-analysis. Eur J Cancer 2013 ;49:2086-92
Yan T, Yin W, Zhou Q et al. The efficacy of zoledronic acid in breast cancer adjuvant therapy: A meta-analysis of
randomised controlled trials. Eur J Cancer 2012; 48:187-95
Denosumab in Breast Cancer (4/22)
No further information
No references
Bone Modifying Agents for the Therapy of Bone Metastases (5/22)
No further information
No references
Skeletal Metastasis Treatment with Radionuclids (6/22)
Further information:
Bei multilokaler Schmerzsymptomatik aufgrund einer kleinherdigen disseminierten ossären Metastasierung stellt die
Therapie mit osteotropen Radionukliden eine zusätzliche Option im multimodalen analgetischen Therapiekonzept dar. Sie
kann angewendet werden, wenn durch eine zuvor erforderliche diagnostische Skelettszintigraphie mit 99Technetium (Tc)
eine ausreichend hohe Affinität in befallenen Knochenabschnitten dokumentiert ist, keine pathologische Fraktur vorliegt
und die Hämatopoese nicht (z.B. durch eine Karzinose oder myelotoxische Chemotherapie) eingeschränkt ist. Der Effekt
der Radionuklidtherapie ist dabei weniger von der Histologie, sondern vor allem vom pathologisch gesteigerten
Knochenstoffwechsel abhängig. Verwendet werden heutzutage vor allem die Radiopharmaka 153Samarium (Sm-EDTMP),
89
Strontium (Sr-Chlorid) und 186Rhenium (Re-HEDP). Sie unterscheiden sich in ihrer Reichweite, physikalischen
Halbwertzeit und Energiedosisleistung, die maßgeblich sind für deren therapieassoziierte Nebenwirkungen. Die
Ansprechraten liegen zwischen 70 und 90 % mit kompletter Schmerzfreiheit bei 20-30%. Die Anzahl der in Studien zur
Schmerzbeeinflussung ossärer Metastasen von Mammakarzinomen mit Radionukliden untersuchten Patientinnen ist
jedoch relativ klein. Der maximale analgetische Effekt wird nach etwa 10 Tagen erreicht und hält – abhängig vom
eingesetzten Radiopharmakon – im Mittel 5 bis 8 Wochen an.
Vorteile gegenüber der lokalen perkutanen Radiotherapie bestehen in der Möglichkeit von Wiederholungsbehandlungen
und der Beeinflussung bereits anreichernder, aber noch nicht symptomatischer Metastasen. Einschränkungen der
Radionuklidtherapie sind begründet in deren z.T. ausgeprägter, jedoch zumeist reversiblen Myelosuppression bei 20-60%
der Patientinnen und die Beschränkung der Therapie auf kleinherdige Knochenmetastasen aufgrund der begrenzten
Reichweite der hierbei emittierten ß-Strahlung. Sie ist nicht geeignet bei größeren Knochenmetastasen oder begleitenden
Weichteiltumoren.
References:
Hoskin PJ: Radioisotopes for metastatic bone pain. Lancet Oncol. 2005 Jun;6(6):353-4
Mertens WC, Filipczak LA, Ben-Josef E, Davis LP, Porter AT. Systemic bone-seeking radionuclides for palliation of
painful osseous metastases: current concepts. CA Cancer J Clin 1998;48:361-74, 321
Übersicht:
Bauman G, Chrrette M, Reid R, Sathya J. Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic
review. Radioth Oncol 2005; 75: 258-70
Roque M, Martinez MJ, Alonso-Coello P et al (2004) Radioisotopes for metastatic bone pain (Cochrane Review). In: The
Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, Ltd. (Cochrane Database Syst Rev 2003:CD003347)
Fischer M. Leitlinie für die Radionuklidtherapie bei schmerzhaften Knochenmetastasen. Nuklearmedizin 1999;38:270272.
89
Strontium (89Sr-Chlorid)
Baziotis N, Yakoumakis E, Zissimopoulos A, Geronicola-Trapali X, Malamitsi J, Proukakis C. Strontium-89 chloride in
the treatment of bone metastases from breast cancer. Oncology 1998;55:377-81
Fuster D, Herranz D, Vidal-Sicart S, Munoz M, Conill C, Mateos JJ, Martin F, Pons F. Usefulness of strontium-89 for
bone pain palliation in metastatic breast cancer patients. Nucl Med Commun 2000;21:623-26
Kasalicky J, Krajska V. The effect of repeated strontium-89 chloride therapy on bone pain palliation in patients with
skeletal cancer metastases. Eur J Nucl Med 1998;25:1362-67
Sciuto R, Festa A, Pasqualoni R, Semprebene A, Rea S, Bergomi S, Maini CL. Metastatic bone pain palliation with 89-Sr
and 186-Re-HEDP in breast cancer patients. Breast Cancer Res Treat 2001;66:101-19
186
Rhenium (186Re-HEDP)
de Klerk JM, van het Schip AD, Zonnenberg BA, van Dijk A, Quirijnen JM, Blijham GH, van Rijk PP. Phase 1 study of
rhenium-186-HEDP in patients with bone metastases originating from breast cancer. J Nucl Med 1996;37:244-49
Han SH, Zonneberg BA, de Klerk JM, Quirijnen JM, van het Schip AD, van Dijk A, Blijham GH, van Rijk PP. 186Reetidronate in breast cancer patients with metastatic bone pain. J Nucl Med 1999;40:639-42
Kolesnikov-Gauthier H, Carpentier P, Depreux P, Vennin P, Caty A, Sulman C. Evaluation of toxicity and efficacy of
186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer. J Nucl Med
2000;41:1689-94
Limouris GS, Shukla SK, Condi-Paphiti A, Gennatas C, Kouvaris I, Vitoratos N, Manetou A, Dardoufas C, Rigas V,
Vlahos L. Palliative therapy using rhenium-186-HEDP in painful breast osseous metastases. Anticancer Res
1997;17:1767-72
153
Samarium (153Sm-EDTMP)
Anderson PM, Wiseman GA, Dispenzieri A, Arndt CA, Hartmann LC, Smithson WA, Mullan BP, Bruland OS. High-dose
samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with
osteosarcoma and bone metastases. J Clin Oncol 2002;20:189-96
Serafini AN. Systemic metabolic radiotherapy with samarium-153 EDTMP for the treatment of painful bone metastasis. Q
J Nucl Med. 2001;45:91-9
Kolesnikov-Gauthier H et al., J Nucl Med 2000; 41: 1689-1694
Zonneberg H et al., J Nucl Med 1999; 40: 639-642
Limouris GS et al., Anticancer Res 1997; 17: 1767-1772
de Klerk JM et al., J Nucl Med 1996 37: 244-249
Palmedo H et al., Nuklearmedizin 1996 35: 63-67
Metastatic Bone Disease of the Spine (7/22)
Further information:
Bei Wirbelsäuleninstabilität, ossärer Kompression und/oder Paraplegie stellt die operative Intervention mit anschließender
Radiotherapie das mit hoher Evidenz belegte geeignetste Vorgehen dar. Bei subklinischer Rückenmarkkompression, d.h.
bei nicht paraplegischen und ambulant zu behandelnden Patientinnen ohne Anhalt für Instabilität, ist die Radiotherapie als
Therapie der Wahl gut validiert. In dieser Situation kann auf eine begleitende Kortisontherapie verzichtet werden.
Wenn bei ossären Wirbelsäulenmetastasen mit konsekutiver Spinalkanalbeteiligung Kortikoide eingesetzt werden, ist der
Nutzen nur für eine hochdosierte Dexamethason-Medikation (96 mg/d) gut belegt.
References:
Rades D, Veninga T, Stalpers LJ, Schulte R, Hoskin PJ, Poortmans P, Schild SE, Rudat V. Prognostic factors predicting
functional outcomes, recurrence-free survival, and overall survival after radiotherapy for metastatic spinal cord
compression in breast cancer patients. Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):182-8. Epub 2005 Sep 28.
Rades D, Stalpers LJA, Veninga T, Schulte R, Hoskin PJ, Alberti W . Effectiveness and toxicity of reirradiation (Re-RT)
for metastatic spinal cord compression (MSCC) Strahlenther Onkol 2005;181:595-600
Galasko CS, Norris HE, Crank S. Spinal instability secondary to metastatic cancer. J Bone Joint Surg Am 2000;82:570594
Loblaw DA, Laperriere NJ. Emergency treatment of malignant extradural spinal cord compression: an evidence-based
guideline. J Clin Oncol. 1998;16:1613-24
Maranzano E, Latini P. Effectiveness of radiation therapy without surgery in metastatic spinal compression: Final results
from a prospective trial. Int J Radiat Oncol Biol Phys 1995;32:959-967
Regine WF, Tibbs PA, Young A, Payne R, Saris S, Kryscio RJ, Patchell RA. Metastatic spinal cord compression: a
randomized trial of direct decompressive surgical resection plus radiotherapy vs. radiotherapy alone. Int J Radiat Oncol
Biol Phys 2003:57(Suppl.):S125. abstract #3
Walker MP, Yaszemski MJ, Kim CW, Talac R, Currier BL. Metastatic disease of the spine: evaluation and treatment. Clin
Orthop 2003;415 Suppl:S165-75
Bone Metastases Acute Spinal Cord Compression / Paraplegia (8/22)
Further information:
Metastatic spinal cord compression (MSCC) as well as bone metastases should be managed in an interdisciplinary
approach mostly as combined modality treatment according to the specific clinical situation. Best results are achieved by
close interdisciplinary cooperation minimizing the interval between diagnosis and onset of treatment. Most important
criteria for prognosis and choice of treatment (mostly combined multimodal therapy) are neurological status at diagnosis of
MSCC, time course of duration and progression of the neurological symptoms. RT is effective and regarded as treatment
of choice for MSCC with or without motor deficits and / or bone metastases, which do not need immediate surgical
intervention. It may be used either postoperatively or as primary treatment in case of inoperability. An optimal dosefractionation schedule or optimal standard dose for treatment of bone metastases has not been established. With regard to
different therapeutic goals, different dose concepts and fractionation schedules, single versus multifraction palliative RT (1
x 8, 5 x 4, 10 x 3, 15 x 2.5, 20 x 2 Gy), should be adapted individually.
The role of radiotherapy is well established in the case of MSCC without neurological deficits. Additionally, primary
radiotherapy is indicated in the case of beginning paraplegia with complete response to steroids and lack of necessity to
operate. Radiotherapy is the method of choice in inoperable cases due to low rate of side effects,
short hospitalisation / outpatient procedure and – a key factor – the radiosensitivity of breast cancer. These advantages are
also relevant in patients with a dismal overall prognosis, short life expectancy and severe co-morbidity, especially because
radiotherapy is equivalent to simple laminectomy with respect to the functional outcome. Local radiotherapy is indicated
postoperatively to achieve local tumour control and should be initiated as soon as possible (LoE IIa, grade of
recommendation A).
3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) allows concave shaping of isodose distributions
with at least partial sparing of critical structures adjacent to the target volume (14, 25, 65). Thus, the maximal and mean
doses to the spinal cord can be kept below 20% and 50% respectively of the dose given to the vertebral body.
In case of in-field recurrence of MSCC, re-irradiation can be performed in selected cases, again considering individual
factors and therapeutic aims (LoE III). In these situations all technical efforts should be used to limit the dose to the spinal
cord.
References:
New
Souchon R, Feyer P, Thomssen C, Fehm T, Diel I, Nitz U, Janni W, Bischoff J, Sauer R. Clinical recommendations of
DEGRO and AGO on preferred standard palliative radiotherapy (RT) of bone and cerebral metastases, metastatic spinal
cord compression, and leptomeningeal carcinomatosis in breast cancer. Breast Care 2010;5:401-7
Souchon R, Wenz F, Sedlmayer F, Budach W, Dunst J, Feyer P, Haase W, Harms W, Sautter-Bihl ML, Sauer R. DEGRO
practice guidelines for palliative radiotherapy of metastatic breast cancer: Bone metastases and metastatic spinal cord
compression (MSCC). Strahlenther Onkol 2009;185:417-424
Further references
Rades D, Heidenreich E, Karstens JH. Final results of a prospective study of the prognostic value of the time to develop
motor deficits before irradiation in metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2002;53:975-9
Rades D, Karstens JH, Hoskin PJ, et al. Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal
cord compression. Int J Radiat Oncol Biol Phys 2007;67:525-31
Rades D, Fehlauer F, Veninga T, et al. Functional outcome and survival after radiotherapy of metastatic spinal cord
compression in patients with cancer of unknown primary. Int J Radiat Oncol Biol Phys 2007;67:532-7
Rades D, Veninga T, Stalpers LJ, et al. Improved posttreatment functional outcome is associated with better survival in
patients irradiated for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2007;67:1506-9
Rades D, Veninga T, Stalpers LJ, et al. Outcome after radiotherapy alone for metastatic spinal cord compression in patients
with oligometastases. J Clin Oncol 2007;25:50-6
Regine WF, Tibbs PA, Young A, et al. Metastatic spinal cord compression: a randomized trial of direct decompressive
surgical resection plus radiotherapy vs. radiotherapy alone. Int J Radiat Oncol Biol Phys 2003:57(Suppl.):S125. abstract #3
Bei beginnender Querschnittsymptomatik infolge metastatischer Rückenmarkkompression ist eine operative Entlastung
(z.B. Laminektomie) so früh als möglich anzustreben, um notfallmäßig durch die operativ-mechanische Dekompression
eine spinale Entlastung zu erreichen. Die operative Entlastung sollte innerhalb kürzester Zeit (Stunden!) erfolgen, was ggf.
auch für die Radiotherapie gilt: Notfallbehandlung innerhalb von 24 Stunden! In allen operierten Fällen ist eine lokale
Nachbestrahlung erforderlich, um eine lokale Tumor- und Metastasenkontrolle zu erreichen. Das Ausmaß der Rückbildung
von spinalen Symptomen ist maßgeblich vom Zeitintervall zwischen dem Einsetzen der Symptome und dem Beginn der
Radiotherapie sowie vom prätherpeutisch bestehendem Mobilitätsgrad der Patientin abhängig.
Hill ME, Richards MA, Gregory WM, Smith P, Rubens RD. Spinal cord compression in breast cancer: a review of 70
cases. Br J Cancer 1993;68:969-73
Hoskin PJ, Grover A, Bhana R. Metastatic spinal cord compression: radiotherapy outcome and dose fractionation.
Radiother Oncol 2003;68:175-180 (Nb:28% des Kollektivs hatten Mammakarzinom! )
Loblaw DA, Laperriere NJ. Emergency treatment of malignant extradural spinal cord compression: an evidence-based
guideline. J Clin Oncol 1998;16:1613-24
Maranzano E, Latini P. Effectiveness of radiation therapy without surgery in metastatic spinal compression: Final results
from a prospective trial. Int J Radiat Oncol Biol Phys 1995;32:959-967
Maranzano E, Frattegiani A, Rossi R, Bagnoli R, Mignogna M, Bellavista R, Perruci E, Lupatelli M, Ponticelli P, Latini P.
Randomised trial of two different hypofractionated radiotherapy schedules (8 Gy x 2 vs 5 Gy x 3; 3 Gy x 5) in metastatic
spinal cord compression (MSCCC). Radiother Oncol 2002;64(Suppl 1): S82. abstract # 245
Regine WF, Tibbs PA, Young A, Payne R, Saris S, Kryscio RJ, Patchell RA. Metastatic spinal cord compression: a
randomized trial of direct decompressive surgical resection plus radiotherapy vs. radiotherapy alone. Int J Radiat Oncol
Biol Phys 2003:57(Suppl.):S125. abstract #3
Walker MP, Yaszemski MJ, Kim CW, Talac R, Currier BL. Metastatic disease of the spine: evaluation and treatment. Clin
Orthop 2003;415 Suppl:S165-75
Galasko CS, Norris HE, Crank S. Spinal instability secondary to metastatic cancer. J Bone Joint Surg Am 2000; 82: 570–
594
Walker MP, Yaszemski MJ, Kim CW et al. Metastatic disease of the spine: evaluation and treatment. Clin Orthop
2003;415 Suppl: S 165–175
Loblaw DA, Laperriere NJ. Emergency treatment of malignant extradural spinal cord compression: an evidence-based
guideline. J Clin Oncol 1998;16: 1613–1624
Helweg-Larsen S, Sorensen PS, Kreiner S. Prognostic factors in metastatic spinal cord compression: a prospective study
using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys
2000;46: 1163–1169
Surgery for Bone Metastases (9/22)
Further information:
Osteosynthesen und/oder Einbringung von Polymethylmethacrylat (PMMA; Knochenzement) sind operative
Standardverfahren zur Behandlung metastatisch bedingter pathologischer Frakturen. Mit diesen können eine rasche
Wiederherstellung bzw. Verbesserung frakturbedingter Funktionsstörungen und Schmerzlinderungen erreicht werden.
Eine prophylaktische operative Fixierung von drohenden Frakturen infolge einer Metastasierung ist an statisch belasteten
langen Röhrenknochen zu erwägen, wenn keine Konsolidierung durch Radio-, systemische antineoplastische oder
Bisphosphonattherapie erreicht wird. Zur Abschätzung des individuellen Risikos von Frakturen und somit zur
Entscheidung über eine prophylaktische operative Intervention können unterschiedliche Risikoscores hilfreich sein.
References:
Hipp JA, Springfield DS, Hayes WC. Predicting pathologic fracture risk in the management of metastatic bone defects.
Clin Orthop 1995;312:120-35
Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures.
Clin Orthop 1989;249:256-64
Mirels H. Metastatic disease in long bones: A proposed scoring system for diagnosing impending pathologic fractures.
1989. Clin Orthop 2003;415 Suppl:S4-13
Patel B, DeGroot H 3rd. Evaluation of the risk of pathologic fractures secondary to metastatic bone disease. Orthopedics
2001;24:612-7
Thompson RC Jr. Impending fracture associated with bone destruction. Orthopedics 1992;15:547-50
Ali SM, Harvey HA, Lipton A (2003) Metastatic breast cancer: overview of treatment. Clin Orthop Rel Res 1 (415S)
(Suppl): 132–137
British Association of Surgical Oncology Guidelines (1999) The management of metastatic bone disease in the United
Kingdom. Eur J Surg Oncol 25: 3–23
Ewerbeck V, Friedl W. Chirurgische Therapie von Skelettmetastasen. Springer, Berlin, Heidelberg, New York, 1992.
Fourney DR, Gokaslan ZL (2003) Thoracolumbar spine: surgical treatment of metastatic disease. Curr Opin Orthop 14 (3):
144–152
Fourney DR, Schomer DF, Nader R et al (2003) Percutaneous and kyphoplasty for painful vertebral body fractures in
cancer patients. J Neurosurg 98 (Suppl): 21–30
Kelly CM, Wilkins RM, Eckardt JJ, Ward WG (2003) Treatment of metastatic disease of the tibia. Clin Orthop Rel Res 1
(415S) (Suppl): 219–229
Koizumi M, Yoshimoto M, Kasumi F, Ogata E (2003) Comparison between solitary and multiple skeletal metastatic
lesions of breast cancer patients. Ann Oncol 14 (8): 1234–1240
Martin JB, Wetzel SG, Seium Y et al (2003) Percutaneous vertebroplasty in metastatic disease: transpedicular access and
treatment of lysed pedicles – initial experience. Radiology 229(2): 593–597
Walker MP, Yaszemski MJ, Kim CW, Talac R, Currier BL (2003) Metastatic disease of the spine. Evaluation and
treatment. Clin Orthop Rel Res 1 (415S) (Suppl): 165–175
Wunder JS, Ferguson PC, Griffin AM, Pressman A, Bell RS (2003) Acetabular metastases: planning for reconstruction
and review of results. Clin Orthop Rel Res 1 (415S) (Suppl): 187–197
Metastatic Bone Disease: Radiotherapy (10/22)
Further information:
Bone metastases in breast cancer have a high clinical relevance and are commonly seen by the radiation oncologist.
Different therapeutic goals (pain relief, local tumour control, prevention or improvement of motor deficits, stabilization of
the spine or other bones) require complex approaches considering individual factors (i.e. life expectancy, tumour
progression at other sites). Best results are achieved by close interdisciplinary cooperation minimizing the interval between
diagnosis and onset of treatment. Most important criteria for prognosis and choice of treatment (mostly combined
multimodal therapy) are neurological status at diagnosis of MSCC, time course of duration and progression of the
neurological symptoms. RT is effective and regarded as treatment of choice for MSCC with or without motor deficits and /
or bone metastases, which do not need immediate surgical intervention. It may be used either postoperatively or as primary
treatment in case of inoperability. An optimal dose-fractionation schedule or optimal standard dose for treatment of bone
metastases has not been established. With regard to different therapeutic goals, different dose concepts and fractionation
schedules, single versus multifraction palliative RT (1 x 8, 5 x 4, 10 x 3, 15 x 2.5, 20 x 2 Gy), should be adapted
individually.
The principles of therapy and the guidelines for palliative radiotherapy of bone metastases in patients with breast cancer
might be summarized regarding different therapeutic goals:
Therapeutic goal: pain reduction: Single dose RT 1 x 8 Gy (cave: >8 Gy to the myelon may cause paresis) (LoE III)
Therapeutic goal: stabilisation, good prognosis: Fractionated regimen preferable e.g. 10-12 x 3 Gy (LoE IIb)
Oligometastases: Full dose fractionated regimen recommended, e.g.. 20-25 x 2 Gy to 40-50 Gy (LoE IIb, III)
References:
New:
Souchon R, Feyer P, Thomssen C, Fehm T, Diel I, Nitz U, Janni W, Bischoff J, Sauer R. Clinical recommendations of
DEGRO and AGO on preferred standard palliative radiotherapy (RT) of bone and cerebral metastases, metastatic spinal
cord compression, and leptomeningeal carcinomatosis in breast cancer. Breast Care 2010;5:401-7
Souchon R, Wenz F, Sedlmayer F, Budach W, Dunst J, Feyer P, Haase W, Harms W, Sautter-Bihl ML, Sauer R. DEGRO
practice guidelines for palliative radiotherapy of metastatic breast cancer: Bone metastases and metastatic spinal cord
compression (MSCC). Strahlenther Onkol 2009;185:417-424
Bates T, Yarnold JR, Blitzer P, Nelson OS, Rubin P, Maher J. Bone metastasis consensus statement. Int J Radiat Oncol
Biol Phys 1992;23:215-216
Bates T. A review of local radiotherapy in the treatment of bone metastases and cord compression. Int J Radiat Oncol Biol
Phys 1992;23:217-221
Galasko CS, Norris HE, Crank S. Spinal instability secondary to metastatic cancer. J Bone Joint Surg Am 2000;82:570594
Haddad P, Wong R, Wilson P, McLean M, Levin W, Bezjak A. Factors influencing the use of single versus multiple
fractions of palliative radiotherapy for bone metastases: a 5-year review and comparison to a survey. Int J Radiat Oncol
Biol Phys 2003:57(Suppl.):S278. abstract #1029
Hartsell WF, Scott C, Bruner DW, Scarantino CW, Ivker R, Roach M, Suh J, Demas W, Movsas B. Phase III randomised
trial of 8 Gy in 1 fraction vs. 30 Gy in 10 fractions for palliation of painful bone metastases: preliminary results of RTOG
97-14. Int J Radiat Oncol Biol Phys 2003:57(Suppl.):S124. abstract #1
Hoskin PJ, Yarnold JR, Roos DR, Bentzen S. Second Workshop on Palliative Radiotherapy and Symptom Control:
Radiotherapy for bone metastases. Clin Oncol (R Coll Radiol) 2001;13:88-90
McQuay HJ, Collins SL, Carroll D, Moore RA. Radiotherapy for the palliation of painful bone metastases. Cochrane
Database Syst Rev 2000;2:CD001793
Roos DE, O'Brien PC, Smith JG, Spry NA, Hoskin PJ, Burmeister BH, Turner SL, Bernshaw DM. A role for radiotherapy
in neuropathic bone pain: preliminary response rates from a prospective trial (Transtasman Radiation Oncology Group,
TROG 96.05). Int J Radiat Oncol Biol Phys 2000;46:975-981
Steenland E, Leer J, van Houwelingen H, Post WJ, van den Hout WB, Kievit J, de Haes H, Martijn H, Oei B, Vonk E, van
der Steen-Banasik E, Wiggenraad RG, Hoogenhout J, Warlam-Rodenhuis C, van Tienhoven G, Wanders R, Pomp J, van
Reijn M, van Mierlo I, Rutten E, Leer J, van Mierlo T. The effect of a single fraction compared to multiple fractions on
painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999;52:101-109
Van der Linden Y, Lok J, Steenland E, Martijn H, Marijnen C, Leer J. Re-irradiation of painful bone metastases: a further
analysis of the Dutch Bone Metastasis Study. Int J Radiat Oncol Biol Phys 2003:57(Suppl.):S222. abstract #163
Schnabel K, Adamietz IA, Haase W et al.: Leitlinien in der Radioonkologie „Strahlentherapie von Knochenmetastasen“ In:
Haase W et al. (Hrsg.) Leitlinien in der Radioonkologie, DEGRO Eigenverlag 1998.
Hoskin PJ, Yarnold JR, Roos DR, Bentzen S (2001) Second Workshop on Palliative Radiotherapy and Symptom Control:
Radiotherapy for bone metastases. Clin Oncol (R Coll Radiol) 13: 88–90
McQuay HJ, Collins SL, Carroll D, Moore RA (2004) Radiotherapy for the palliation of painful bone metastases
(Cochrane Review). In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, Ltd. (Cochrane Database Syst
Rev 2000; 2: CD001793)
Roos DE, Fisher RJ (2003) Radiotherapy for painful bone metastases: an overview of the overviews. Clin Oncol (R Coll
Radiol) 15: 342–344
Wu J, Bezjak A, Chow E et al (2003) A consensus development approach to define national research priorities in bone
metastases: proceedings from NCIC CTG workshop. Clin Oncol (R Coll Radiol) 15: 496–499
Saarto T, Janes R, Tenhunen M, Kouri M (2003) Palliative radiotherapy in the treatment of skeletal metastases. Eur J Pain
6: 323–330
Chow E, Harris K,Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin
Oncol 2007;25:1423-36
Metastatic Bone Disease Recurrent Bone Pain (11/22)
Further information:
Indication and dosage of an optional re-irradiation depend on the previously applied dose, the initial response, the interval
to the preceding radiation therapy, and the dose per fraction to critical organs. A re-irradiation of metastases in the
extremities or the peripheral parts of the trunk is usually possible. In most cases one may again apply full doses, e.g. 10 x 3
Gy or 20 x 2 Gy, favouring the use of small single doses.
Prior to re-irradiation of the base of skull, the vertebral column and the pelvic bones overall radiation tolerance of the
critical organs like brain stem, spinal cord, bowel and bladder has to be considered. Following a typical first course of 10 x
3 Gy without hot spots in the brain stem or the spinal cord, a partial recovery after about 6 months may be assumed.
Therefore, a second course of radiotherapy can be performed in urgent cases with an increased but acceptable risk by
applying doses of up to 15 x 2 Gy, provided that tolerance doses of the critical organs are respected.
References:
Souchon R, Wenz F, Sedlmayer F, Budach W, Dunst J, Feyer P, Haase W, Harms W, Sautter-Bihl ML, Sauer R. DEGRO
practice guidelines for palliative radiotherapy of metastatic breast cancer: Bone metastases and metastatic spinal cord
compression (MSCC). Strahlenther Onkol 2009;185:417-424
Souchon R, Feyer P, Thomssen C, Fehm T, Diel I, Nitz U, Janni W, Bischoff J, Sauer R. Clinical recommendations of
DEGRO and AGO on preferred standard palliative radiotherapy (RT) of bone and cerebral metastases, metastatic spinal
cord compression, and leptomeningeal carcinomatosis in breast cancer. Breast Care 2010;5:401-7
Galasko CS, Norris HE, Crank S. Spinal instability secondary to metastatic cancer. J Bone Joint Surg Am 2000;82:570594
Haddad P, Wong R, Wilson P, McLean M, Levin W, Bezjak A. Factors influencing the use of single versus multiple
fractions of palliative radiotherapy for bone metastases: a 5-year review and comparison to a survey. Int J Radiat Oncol
Biol Phys 2003:57(Suppl.):S278. abstract #1029
Van der Linden Y, Lok J, Steenland E, Martijn H, Marijnen C, Leer J. Re-irradiation of painful bone metastases: a further
analysis of the Dutch Bone Metastasis Study. Int J Radiat Oncol Biol Phys 2003:57(Suppl.):S222. abstract #163
Side-Effects and Toxicity – Bisphosphonates (BP) and Denosumab (Db) (12/22)
No further information
No references
Recommendations for Precautions to Prevent ONJ* (13/22)
No further information
No references
Adjuvant Bisphosphonates for Reduction of Bone Metastases and Survival Advantage (14/22)
No further information
No references
Adjuvant Bisphosphonates for Reduction of Bone Metastases and Survival Advantage (15/22)
No further information
No references
Dosage of Adjuvant Bisphosphonates for Improvement of Survival (16/22)
No further information
No references
Therapy and Prevention of Tumor Therapy-Induced Bone Loss / Osteoporosis (17/22)
No further information
No references
Therapy and Prevention of Tumor Therapy-Induced Bone Loss / Osteoporosis (18/22)
No further information
No references
Medical Treatment of Osteoporosis (19/22)
No further information
No references
(20/22)
No further information
No references
Therapieempfehlungen für Personen ohne spezifische Risiken und/oder Frakturen (21/22)
No further information
No references
Therapieempfehlungen für Personen mit spezifischen Risiken und/oder Frakturen (22/22)
No further information
No references