Dr.ssa Tiziana Falbo Oncologia Medica L OSTEOONCOLOGIA NELL APPROCCIO CON NEOPLASIA POLMONARE METASTATICA

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1 Dr.ssa Tiziana Falbo Oncologia Medica INI - Grottaferrata L OSTEOONCOLOGIA NELL APPROCCIO STRATEGICO AL PAZIENTE CON NEOPLASIA POLMONARE METASTATICA

2 BONE DESEASE :EPIDEMIOLOGY ~20% of patientswith t ith metastatic t ti disease develop bone metastases BONE represents the third most common site of metastasis, preceded by lung and liver. L INCIDENZA ANNUALE DI METASTASI OSSEE IN ITALIA E DI CIRCA NUOVI CASI ANNO Improvement in cancer diagnosis and treatment has led to increased patients estimated life. 80% OF BONE METASTASES BREAST, PROSTATE AND LUNG CANCER

3 SKELETAL RELATED EVENTS (SRES) Consequences to functional independence and QOL 75% sintomatiche Surgery to bone Loss of autonomy Bone pain Pathologic Spinal cord Radiotherapy to fracture compression bone Anxiety and depression Hypercalcemia 25% asintomatiche Page 3

4 SRES ARE PREVALENT IN PATIENTS WITH CANCER ASSOCIATED BONE DISEASE ents % of patie event, % ortion o th an e Propo wit * * Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Breast 1 Prostate 2 Multiple NSCLC and other 24 mo 24 mo myeloma* 3 solid tumors 4 21 mo 21 mo Cancer type 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. 1. Lipton A, et al. Cancer. 2000;88: ; 2. Saad F, et al. Am Urol Assoc Abstract 1472; 3. Berenson JR, et al. J Clin Oncol. 1998;16: ; 4. Rosen LS, et al. Cancer. 2004;100:

5 MALIGNANT BONE DISEASE IS PREVALENT LUNG CANCER COMMONLY METASTASIZES TO BONE approximately 30% to 65% of patients with metastatic lung cancer will develop bone metastases median survival lfrom the time patients develop bone metastases is less than 7 months Bone metastases cause significant morbidity Pain, fractures, loss of mobility, surgery etc Poorer quality of life and survival Parkin DM, et al. CA Cancer J Clin. 2005;55(2): Image courtesy Dr. David Cameron.

6 BONE METASTASES OBIETTIVI TERAPEUTICI O U C BONE METASTASES LIFE EXPECTANCY

7 L OSTEOONCOLOGIA è una disciplina che studia le alterazioni dell osso nel paziente oncologico: Tumori primitivi TUMORI SECONDARI CTIBL

8 TREATMENT OPTIONS IN METASTATIC BONE DISEASE LOCOREGIONAL THERAPY Radiation therapy Surgery Interventional procedures (vertebroplastic) tb ti) SYSTEMIC THERAPY Chemotherapy Target Therapy Radiometabolic Therapy Biphosphonates Denosumab

9 BISPHOSPHONATES

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11 THE GOAL OF BISPHOSPHONATE THERAPY 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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13 BISPHOSPHONATE INDICATIONS Indication Prevention of SREs HCM Multiple myeloma Breast cancer Prostate cancer a Other solid tumors Clodronate (oral) 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: and Further information for clodronate and ibandronate is available at and

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

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23 NTX LEVELS ARE OFTEN ELEVATED IN PATIENTS WITH BONE LESIONS Patients with each cancer type were categorised as low NTX, moderate NTX, or high NTX Proportio on of pat tients, % NTX (nmol/mmol CR) High ( 100) Moderate (50 99) Low (< 50) 0 Prostate Breast cancer cancer Multiple myeloma NSCLC Other solid tumours Adapted from Coleman R, et al. J Clin Oncol. 2005;23(22):

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29 NEW EVIDENCES: DENOSUMAB IN PATIENTS WITH ADVANCED LUNG CANCER

30 RANKL / RANK / OPG AND BONE osteoblast/stromal cell RANK RANKL OC precursor osteoblast/stromal cell differentiation, fusion, activation and survival of osteoclasts OPG OC precursor

31 PHARMACOLOGIC PROPERTIES OF DENOSUMAB Fully human monoclonal antibody IgG 2 isotype High affinity for human RANK Ligand High specificity for RANK Ligand No detectable binding to TNFα, TNFβ, TRAIL, or CD40L No neutralizing antibodies detected in clinical trials to date Model of Denosumab Bekker PJ, et al. J Bone Miner Res. 2004;19: 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: TNF = tumor necrosis factor; TRAIL = TNFα related apoptosisinducing Ligand

32 DENOSUMAB BINDS RANK LIGAND AND INHIBITS OSTEOCLAST MEDIATED BONE DESTRUCTION Pre Fusion P F i Osteoclast CFU M RANKL RANK Denosumab 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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37 PHASE III STUDY DENOSUMAB VS ZOLEDRONIC ACID: ANALYSIS OF THE LUNG CANCER SUBGROUP ANALYSIS OF THE LUNG CANCER SUBGROUP Patients with advanced lung cancer and confirmed bone metastases, with no previous bisphosphonate exposure Denosumab 120 mg SC and Placebo IV* q4w (n = 411) Supplemental calcium (500 mg) and vitamin D (400 IU) recommended Zoledronic Acid 4 mg IV*and Placebo SC q4w (n = 400) Lung Cancer Type, n (%) Zoledronic Acid Denosumab NSCLC 352 (88) 350 (85) Adenocarcinoma 211 (60) 189 (54) Squamous cell 75 (21) 88 (25) Other 66 (19) 73 (21) SCLC 48 (12) 61 (15) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label)

38 DENOSUMAB VS ZOLEDRONIC ACID: OS IN LUNG CANCER Pro oportion of Patients Remaining Alive KM Estimate of Median OS, Mos Denosumab Zoledronic acid HR: 0.80 (95% CI: ; P =.01) Patients at Risk, n Study Mo Zoledronic acid Denosumab

39 DENOSUMAB VS ZOLEDRONIC ACID: OS IN NSCLC 1.0 KM Estimate of Median OS, Mos Pro oportion of Patients Remaining Alive Denosumab Zoledronic acid HR: 0.78 (95% CI: ; P =.0104) Patients at Risk, n Study Mo Zoledronic acid Denosumab

40 DENOSUMAB VS ZOLEDRONIC ACID: OS IN SMALL CELL LUNG CANCER Pro oportion of Patients Remaining Alive KM Estimate of Median OS, Mos Denosumab Zoledronic acid HR: 0.81 (95% CI: ; P =.3580) Patients at Risk, n Study Mo Zoledronic acid Denosumab

41 DENOSUMAB VS ZOLEDRONIC ACID: OS IN NSCLC BY HISTOLOGIC TYPE Adenocarcinoma Squamous Cell Carcinoma Pr roportion of Pa atients Remaining Al live Denosumab Zoledronic acid HR: 0.80 (95% CI: ; P =.0751) KM Estimate of Median OS, Mos Pr roportion of Pa atients Remaining Al live Denosumab Zoledronic acid HR: 0.68 (95% CI: ; P =.0350) KM Estimate of Median OS, Mos Patients at Risk, n Study Mo Patients at Risk, n Study Mo Zoledronic acid Zoledronic acid Denosumab Denosumab

42 DENOSUMAB VS ZOLEDRONIC ACID IN LUNG 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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44 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.

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46 LINEE GUIDA AIOM NEOPLASIA POLMONARE METASTATICA

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49 BONE METASTASES: RADIOTHERAPY AND ORTHOPEDIC SURGERY

50 Linee Guida AIOM La radioterapia e controllo del dolore

51 Linee Guida AIOM La compressione midollare

52 LINEE GUIDA AIOM Lacompressione spinale: Chirurgia ortopedica La chirurgia i va riservata a casi molto selezionati i 1. Chirurgia seguita da radioterapia: 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 controindicata.

53 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 operato.

54 PROGETTO NAZIONALE: APPROCCIO MULTIDISCIPLINARE AI PAZIENTI CON METASTASI OSSEE RIVOLUZIONE CULTURALE

55 PROGETTO NAZIONALE: APPROCCIO MULTIDISCIPLINARE AI PAZIENTI CON METASTASI OSSEE (D. Amadori O. Bertetto S. Cascinu PF. Conte) Corsi di formazione nazionale 2002 Bologna, Roma Napoli, Bologna Napoli, Firenze Pubblicazioni: 3 libri Corsi di formazione teorico-pratici in Osteoncologia (Modena Forlì) Corsi di Osteoncologia Master di II livello Modena Forlì Bologna) Dottorato di Ricerca (campus Biomedico Roma) Masters/Dott. Ricerca in Osteoncologia Centri di Osteoncologia Torino,Meldola, Modena, Reggio Calabria, Grottaferrata, Roma Campus Società Italiana di Osteoncologia (2008)

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57 LINEE GUIDA AIOM MULTIDISCIPLINARIETÀ E CENTRI DI OSTEONCOLOGIA 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 mediconucleare, ilradiologo diagnosta e interventista, ilfisiatra,ilpatologo 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 (UniversitàCampus 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)

58 FUTURE DIRECTIONS 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 of metastatic t ti disease, thoughh whether hth this is adirect 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 will establish tblihwhether hth BPs given early in the courseof cancer will be able to prevent the formation of metastases, bone or otherwise.

59 GRAZIE PER LA VOSTRA ATTENZIONE e buon lavoro a tutti noi!!!