Dr.ssa Tiziana Falbo Oncologia Medica I NI - Grottaferrata I NI - - - PowerPoint PPT Presentation

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Dr.ssa Tiziana Falbo Oncologia Medica I NI - Grottaferrata I NI - Grottaferrata LOSTEOONCOLOGI A NELLAPPROCCI O STRATEGI CO AL PAZI ENTE STRATEGI CO AL PAZI ENTE CON NEOPLASI A POLMONARE METASTATI CA BONE DESEASE :EPIDEMIOLOGY ~ 20%

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Dr.ssa Tiziana Falbo Oncologia Medica I NI - Grottaferrata I NI - Grottaferrata L’OSTEOONCOLOGI A NELL’APPROCCI O STRATEGI CO AL PAZI ENTE STRATEGI CO AL PAZI ENTE CON NEOPLASI A POLMONARE METASTATI CA

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BONE DESEASE :EPIDEMIOLOGY

20% f ti t ith t t ti di

~ 20% of patients with metastatic disease

develop bone metastases BONE represents the third most common site of metastasis, preceded by lung l and liver.

L’INCIDENZA ANNUALE DI METASTASI OSSEE IN ITALIA E’ DI CIRCA 35.000 NUOVI CASI ANNO

80% OF BONE METASTASES Improvement in cancer diagnosis and treatment has led to increased patients’ estimated life BREAST, PROSTATE AND LUNG CANCER patients estimated life.

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SKELETAL RELATED EVENTS (SRES)

Consequences to functional independence and QOL

Loss of autonomy

Bone pain

Anxiety and depression

Pathologic Spinal cord Radiotherapy to 75% sintomatiche

QOL

Surgery to bone Pathologic fracture Spinal cord compression py bone Hypercalcemia

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25% asintomatiche

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SRES ARE PREVALENT IN PATIENTS WITH CANCER‐ASSOCIATED

Pathologic Pathologic fracture racture

BONE DISEASE

52

50 60

Pathologic Pathologic fractur fracture Radiation t Radiation therapy herapy Surgical in rgical intervent ention

  • n

Spi Spinal cord cord comp compressi ssion

ents %

37 34 34 33 43

30 40

  • f patie

event, %

25 22 8 11

20 30

  • rtion o

th an e

4 5 5 3 8 3 4

10

Breast1 Prostate2 NSCLC and other Multiple

Propo wit * *

Breast 24 mo Prostate 24 mo NSCLC and other solid tumors4 21 mo Multiple myeloma*3 21 mo

Data results from placebo arm of clinical trials.

Cancer type

  • 1. Lipton A, et al. Cancer. 2000;88:1082-1090; 2. Saad F, et al. Am Urol Assoc. 2003. Abstract 1472; 3. Berenson JR, et al.

J Clin Oncol. 1998;16:593-602; 4. Rosen LS, et al. Cancer. 2004;100:2613-2621. Data results from placebo arm of clinical trials. NSCLC = Non-small cell lung cancer. * Only 9-month data are available for surgical intervention and spinal cord compression in myeloma.

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MALIGNANT BONE DISEASE IS PREVALENT

LUNG CANCER COMMONLY METASTASIZES TO BONE

appro imatel 30% to 65% of patients ith

‐ approximately 30% to 65% of patients with

metastatic lung cancer will develop bone metastases di i l f h i i ‐median survival from the time patients develop bone metastases is less than 7 months Bone metastases cause significant morbidity – Pain, fractures, loss of mobility, surgery y g y etc – Poorer quality of life and survival

Parkin DM, et al. CA Cancer J Clin. 2005;55(2):74‐108. Image courtesy Dr. David Cameron.

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OBI ETTI VI TERAPEUTI CI OBI ETTI VI TERAPEUTI CI

BONE METASTASES

OBI ETTI VI TERAPEUTI CI OBI ETTI VI TERAPEUTI CI

BONE METASTASES

O U C O U C

BONE METASTASES

O U C O U C

LI FE EXPECTANCY

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L’OSTEOONCOLOGIA

è una disciplina che studia le alterazioni è una disciplina che studia le alterazioni dell’osso nel paziente oncologico:

  • Tumori primitivi
  • Tumori primitivi
  • TUMORI SECONDARI
  • TUMORI SECONDARI

CTIBL

  • CTIBL
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TREATMENT OPTIONS IN METASTATIC BONE DISEASE

SYSTEMIC THERAPY LOCOREGIONAL THERAPY SYSTEMIC THERAPY

  • Chemotherapy
  • Radiation therapy
  • Surgery
  • Target Therapy
  • Radiometabolic Therapy
  • Surgery
  • Interventional procedures

( t b l ti )

py

  • Biphosphonates
  • Denosumab

(vertebroplastic)

  • Denosumab
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BISPHOSPHONATES BISPHOSPHONATES

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THE GOAL OF BISPHOSPHONATE THERAPY THE GOAL OF BISPHOSPHONATE THERAPY

  • Bisphosphonates proven benefits
  • Bisphosphonates proven benefits

– Prevent skeletal‐related events (SREs)

  • Prevent first and subsequent SREs
  • Delay the onset of the first SRE

– Palliate and control bone pain

  • Reduce the need for analgesics and palliative radiotherapy

⇒ Bisphosphonates improve patient’s quality of life

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BISPHOSPHONATE INDICATIONS

Indication Prevention of SREs HCM Multiple myeloma Breast cancer Prostate cancera Other solid tumors Clodronate (oral)

  • P

id t (IV)

  • Pamidronate (IV)
  • Zoledronic acid (IV)
  • Ibandronate

(oral and IV)

  • = European Registration

= Worldwide Registration

BC, breast cancer; HCM, hypercalcemia of malignancy; IV, intravenous; SRE, skeletal‐related event.

a In the United States, prostate cancer must have progressed despite hormone therapy.

Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.

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BONE MARKERS AND OUTCOME IN BONE MARKERS AND OUTCOME IN METASTATIC BONE DESEASE

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NTX LEVELS ARE OFTEN ELEVATED IN PATIENTS WITH BONE LESIONS PATIENTS WITH BONE LESIONS

Patients with each cancer type were categorised as low NTX moderate NTX or high NTX low NTX, moderate NTX, or high NTX

% 100 NTX

/

High (≥ 100) tients, % 75 NTX (nmol/mmol CR) Low (< 50) Moderate (50‐99)

  • n of pat

50 Low (< 50) Proportio 25 P

Prostate cancer Breast cancer Multiple myeloma NSCLC Other solid tumours

Adapted from Coleman R, et al. J Clin Oncol. 2005;23(22):4925‐4935.

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NEW EVIDENCES: DENOSUMAB IN PATIENTS WITH ADVANCED LUNG CANCER ADVANCED LUNG CANCER

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RANKL / RANK / OPG AND BONE RANKL / RANK / OPG AND BONE

RANK

  • steoblast/ stromal cell

RANKL RANK

differentiation,

RANKL

OC precursor

fusion, activation and survival of

  • steoblast/ stromal cell
  • steoclasts

OPG OPG

OC OC precursor precursor

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PHARMACOLOGIC PROPERTIES OF DENOSUMAB

  • Fully human monoclonal antibody

M d l f D b

  • IgG2 isotype
  • High affinity for human RANK Ligand
  • High specificity for RANK Ligand

Model of Denosumab

High specificity for RANK Ligand

– No detectable binding to TNFα, TNFβ, TRAIL, or CD40L

  • No neutralizing antibodies detected in clinical

trials to date

TNF = tumor necrosis factor; TRAIL = TNFα‐related apoptosis‐ inducing Ligand Bekker PJ, et al. J Bone Miner Res. 2004;19:1059‐1066. Data on file, Amgen. Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354:821‐31. duc g ga d

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DENOSUMAB BINDS RANK LIGAND AND INHIBITS OSTEOCLAST‐MEDIATED BONE DESTRUCTION

P F i RANKL RANK Denosumab CFU‐M Pre‐Fusion Osteoclast

Hormones Growth factors Cytokines Osteoclast Formation, Function, and Survival Inhibited

Osteoblasts

Bone Formation Bone Resorption Inhibited

Provided as an educational resource. Do not copy or distribute.

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PHASE III STUDY DENOSUMAB VS ZOLEDRONIC ACID: ANALYSIS OF THE LUNG CANCER SUBGROUP ANALYSIS OF THE LUNG CANCER SUBGROUP

Denosumab 120 mg SC and Placebo IV* q4w (n = 411) Patients with advanced lung cancer Zoledronic Acid 4 mg IV* and Placebo SC q4w Patients with advanced lung cancer and confirmed bone metastases, with no previous bisphosphonate exposure Supplemental calcium (500 mg) and vitamin D (400 IU) recommended

Lung Cancer Type, n (%) Zoledronic Acid Denosumab

Zoledronic Acid 4 mg IV* and Placebo SC q4w (n = 400)

NSCLC 352 (88) 350 (85)

Adenocarcinoma

211 (60) 189 (54) S ll 75 (21) 88 (25)

Squamous cell

75 (21) 88 (25)

Other

66 (19) 73 (21) SCLC SCLC 48 (12) 48 (12) 61 (15) 61 (15)

*IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label)

( ) ( ) ( ) ( )

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DENOSUMAB VS ZOLEDRONIC ACID: OS IN LUNG CANCER OS IN LUNG CANCER

KM Estimate of Median OS, Mos D b 8 9 1.0 Denosumab Zoledronic acid 8.9 7.7 0.6 0.8 Patients g Alive

  • portion of

Remaining 0.4 Pro R HR: 0.80 (95% CI: 0.67-0.95; P = .01) 0.2 3 9 12 21 Study Mo Patients at Risk, n Zoledronic acid 400 309 98 13 135 6 207 15 43 18 24 Zoledronic acid Denosumab 400 411 309 323 98 120 13 26 135 164 207 233 43 71 24 43

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DENOSUMAB VS ZOLEDRONIC ACID: OS IN NSCLC OS IN NSCLC

KM Estimate of Median OS, Mos D b 9 5 1.0 Denosumab Zoledronic acid 9.5 8.1 0.6 0.8 Patients g Alive

  • portion of

Remaining 0.4 Pro R HR: 0.78 (95% CI: 0.65-0.94; P = .0104) 0.2 3 9 12 21 Patients at Risk, n Zoledronic acid 352 275 91 12 123 6 185 15 40 18 23 Study Mo Zoledronic acid Denosumab 352 350 275 278 91 110 12 24 123 148 185 203 40 66 23 39

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DENOSUMAB VS ZOLEDRONIC ACID: OS IN SMALL CELL LUNG CANCER OS IN SMALL‐CELL LUNG CANCER

KM Estimate of Median OS, Mos D b 7 6 1.0 Denosumab Zoledronic acid 7.6 5.1 0.6 0.8 Patients g Alive

  • portion of

Remaining 0.4 Pro R HR: 0.81 (95% CI: 0.52-1.26; P = .3580) 0.2 3 9 12 21 Patients at Risk, n Zoledronic acid 48 34 7 1 12 6 22 15 3 18 1 Study Mo Zoledronic acid Denosumab 48 61 34 45 7 10 1 2 12 16 22 30 3 5 1 4

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DENOSUMAB VS ZOLEDRONIC ACID: OS IN NSCLC BY HISTOLOGIC TYPE OS IN NSCLC BY HISTOLOGIC TYPE

Adenocarcinoma Squamous Cell Carcinoma

KM Estimate of Median OS, Mos Denosumab Zoledronic acid 9.6 8.2 0.8 1.0 atients live KM Estimate of Median OS, Mos Denosumab Zoledronic acid 8.6 6.4 0.8 1.0 atients live 0.6 roportion of Pa Remaining Al 0.4 0 2 0.6 roportion of Pa Remaining Al 0.4 0 2 3 9 12 21 Pr HR: 0.80 (95% CI: 0.62-1.02; P = .0751) Study Mo 0.2 Patients at Risk n 6 15 18 3 9 12 21 Pr HR: 0.68 (95% CI: 0.47-0.97; P = .0350) Study Mo 0.2 Patients at Risk n 6 15 18 Patients at Risk, n Zoledronic acid Denosumab 211 189 169 154 55 59 8 16 71 83 113 114 21 40 14 22 Patients at Risk, n Zoledronic acid Denosumab 75 88 56 66 17 25 2 3 28 34 38 47 7 13 4 10

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DENOSUMAB VS ZOLEDRONIC ACID IN LUNG CANCER: ADVERSE EVENTS CANCER: ADVERSE EVENTS

Event, n (%) Denosumab (n = 406) Zoledronic Acid (n = 395) All adverse events 393 (96.8) 377 (95.4) Serious adverse events 268 (66.0) 288 (72.9) Fatal adverse events 183 (45.1) 189 (47.8) Adverse events of interest

Hypocalcemia

35 (8.6) 15 (3.8)

ONJ

3 (0.7) 3 (0.8)

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LINEE GUIDA AIOM NEOPLASIA POLMONARE METASTATICA

“Occorre tuttavia considerare come la cattiva prognosi di questi pazienti possa rendere non strettamente necessario il loro impiego in tutti i pazienti e quindi occorre fare una attenta selezione di costi e benefici “ attenta selezione di costi e benefici.

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LINEE GUIDA AIOM NEOPLASIA POLMONARE METASTATICA

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LINEE GUIDA AIOM NEOPLASIA POLMONARE METASTATICA

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BONE METASTASES: RADIOTHERAPY AND ORTHOPEDIC SURGERY

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Linee Guida AIOM

La radioterapia e controllo del dolore

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Linee Guida AIOM La compressione midollare

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LINEE GUIDA AIOM

La compressione spinale: Chirurgia ortopedica La compressione spinale: Chirurgia ortopedica

L hi i i i l l i i La chirurgia va riservata a casi molto selezionati

  • 1. Chirurgia seguita da radioterapia:

g g p

  • Instabilità della colonna.
  • Presenza di frammenti ossei causa di compressione midollare o radicolare.
  • In caso di dubbi diagnostici
  • Paziente in buone condizioni generali con compressione in sede singola e aggredibile chirurgicamente e lunga

aspettativa di vita.

  • 2. Chirurgia esclusiva:
  • Peggioramento dello status neurologico durante o dopo la radioterapia
  • Compressione midollare recidiva in una sede precedentemente irradiata e/o dove una reirradiazione sia
  • Compressione midollare recidiva in una sede precedentemente irradiata e/o dove una reirradiazione sia

controindicata.

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Linee Guida AIOM

La chirurgia ortopedica delle metastasi ossee ‐ Indicazioni ‐

Metastasi solitarie da tumore primitivo a buona prognosi Il trattamento chirurgico in questi casi deve comprendere l’asportazione della lesione metastatica con margini i più ampi possibile, e la ricostruzione stabile del segmento

  • perato.
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PROGETTO NAZI ONALE: APPROCCI O MULTI DI SCI PLI NARE AI PAZI ENTI CON METASTASI OSSEE OSSEE

2000 2010 2000 2010

RI VOLUZI ONE CULTURALE RI VOLUZI ONE CULTURALE

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PROGETTO NAZIONALE: APPROCCIO MULTIDISCIPLINARE AI PAZIENTI CON METASTASI OSSEE

(D Amadori‐ O Bertetto‐ S Cascinu‐ PF Conte) (D. Amadori‐ O. Bertetto‐ S. Cascinu‐ PF. Conte)

2000 2000 2010 2010

Corsi di formazione nazionale

Pubblicazioni: 3 libri

Corsi di formazione nazionale

2002 Bologna, Roma - 2003 Napoli, Bologna - 2004 Napoli, Firenze

Corsi di Osteoncologia

2003 – 2009

Corsi di formazione teorico-pratici in Osteoncologia (Modena Forlì)

g

Masters/Dott. Ricerca i O t l i (Modena – Forlì)

2003 – 2005

Master di II livello

2008 – 2010

Dottorato di Ricerca in Osteoncologia

Centri di Osteoncologia

Società Società Italiana Italiana di di

Master di II livello Modena – Forlì – Bologna) Dottorato di Ricerca (campus Biomedico – Roma)

Centri di Osteoncologia

Torino, Torino,Meldola Meldola, Modena, Reggio C , Modena, Reggio Calabria,

alabria,

Grottaferrata Grottaferrata, Roma Campus , Roma Campus

Società Società Italiana Italiana di di Osteoncologia Osteoncologia (2008) (2008)

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LINEE GUIDA AIOM

MULTIDISCIPLINARIETÀ E CENTRI DI OSTEONCOLOGIA

  • Negli ultimi anni è nato in Italia un nuovo modello organizzativo per l’approccio

Negli ultimi anni è nato in Italia un nuovo modello organizzativo per l approccio multidisciplinare al paziente con metastasi ossee, che prevede il coinvolgimento di diverse figure professionali: l’oncologo, il palliativista , il radioterapista, l’ortopedico, il medico nucleare, il radiologo diagnosta e interventista, il fisiatra, il patologo clinico , medico nucleare, il radiologo diagnosta e interventista, il fisiatra, il patologo clinico , l’anatomo‐patologo, il biologo, l’infermiere professionale e il data manager.

  • Dal 2003 sono iniziate esperienze multidisciplinari a Torino, Forlì, Reggio Calabria,

Modena Genova Roma (Università Campus Bio‐Medico) e Grottaferrata I primi Modena, Genova, Roma (Università Campus Bio Medico) e Grottaferrata. I primi risultati sul loro effetto positivo comincia a essere segnalato da parte dei pazienti (livello di soddisfazione alto, molto utile questo approccio e no disagio dalla presenza di diverse figure) g )

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FUTURE DIRECTIONS FUTURE DIRECTIONS

  • New directions in metastatic bone disease include personalised BP

New directions in metastatic bone disease include personalised BP therapy, such as using bone markers to guide frequency of BP administration and bone targeting agents such as denosumab

  • Early data suggest that zoledronic acid might have a role in the prevention

f t t ti di th h h th thi i di t ff t

  • f metastatic disease, though whether this is a direct effect on cancer

cells, or indirect via the bone marrow micro‐environment, or both, is as yet undiscovered.

  • Over 20,000 patients with breast, prostate or lung cancer are currently

participating in adjuvant Bisphosphonates randomised trials.

  • The results of these trials should be available in the next few years, and this

ill t bli h h th BP i l i th f ill b bl t will establish whether BPs given early in the course of cancer will be able to prevent the formation of metastases, bone or otherwise.

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…GRAZI E

GRAZI E PER LA VOSTRA ATTENZI ONE…… PER LA VOSTRA ATTENZI ONE……

…e buon lavoro a tutti noi!!!