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
BONE DESEASE :EPIDEMIOLOGY ~ 20% of patients with metastatic disease 20% f ti t ith t t ti di develop bone metastases BONE represents the third most common site of metastasis, preceded by lung and liver. l L’INCIDENZA ANNUALE DI METASTASI OSSEE IN ITALIA E’ DI CIRCA 35.000 NUOVI CASI ANNO Improvement in cancer diagnosis and treatment has led to increased 80% OF BONE METASTASES patients’ estimated life patients estimated life. BREAST, PROSTATE AND LUNG CANCER
SKELETAL RELATED EVENTS (SRES) Loss of Anxiety and Consequences Bone pain autonomy depression to functional independence and QOL QOL 75% sintomatiche Radiotherapy to py Pathologic Pathologic Spinal cord Spinal cord Hypercalcemia bone Surgery to bone fracture compression 25% asintomatiche Page � 3
SRES ARE PREVALENT IN PATIENTS WITH CANCER ‐ ASSOCIATED BONE DISEASE Pathologic fractur Pathologic Pathologic fracture Pathologic fracture racture Radiation t Radiation therapy herapy 60 ents Surgical in rgical intervent ention on 52 Spinal cord Spi cord comp compressi ssion 50 event, % % of patie 43 40 37 34 34 33 ortion o 30 30 th an e 25 22 20 11 Propo wit * 8 8 * 10 5 5 4 4 3 3 0 Breast 1 Prostate 2 Breast Prostate Multiple Multiple NSCLC and other 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. 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;88:1082-1090; 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.
MALIGNANT BONE DISEASE IS PREVALENT LUNG CANCER COMMONLY METASTASIZES TO BONE ‐ approximately 30% to 65% of patients with appro imatel 30% to 65% of patients ith metastatic lung cancer will develop bone metastases ‐ median survival from the time patients di i l f h i i 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.
BONE METASTASES BONE METASTASES BONE METASTASES OBI ETTI VI TERAPEUTI CI O OBI ETTI VI TERAPEUTI CI OBI ETTI VI TERAPEUTI CI O O O OBI ETTI VI TERAPEUTI CI U U U U C C C C LI FE EXPECTANCY
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
TREATMENT OPTIONS IN METASTATIC BONE DISEASE SYSTEMIC THERAPY SYSTEMIC THERAPY LOCOREGIONAL THERAPY • Chemotherapy • Target Therapy • Radiation therapy • Radiometabolic Therapy py • Surgery • Surgery • Biphosphonates • Interventional procedures • Denosumab • Denosumab ( (vertebroplastic) t b l ti )
BISPHOSPHONATES BISPHOSPHONATES
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
BISPHOSPHONATE INDICATIONS Indication Prevention of SREs Multiple Prostate Other solid HCM myeloma Breast cancer cancer a tumors � � � Clodronate (oral) � � � � � � P Pamidronate (IV) id t (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.
BONE MARKERS AND OUTCOME IN BONE MARKERS AND OUTCOME IN METASTATIC BONE DESEASE
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 % tients, % NTX NTX (nmol/mmol CR) / High ( ≥ 100) 75 on of pat Moderate (50 ‐ 99) 50 Low (< 50) Low (< 50) Proportio 25 P 0 Multiple Breast Prostate NSCLC Other myeloma cancer cancer solid tumours Adapted from Coleman R, et al. J Clin Oncol. 2005;23(22):4925 ‐ 4935.
NEW EVIDENCES: DENOSUMAB IN PATIENTS WITH ADVANCED LUNG CANCER ADVANCED LUNG CANCER
RANKL / RANK / OPG AND BONE RANKL / RANK / OPG AND BONE osteoblast/ stromal cell RANK RANK differentiation, RANKL RANKL fusion, activation OC precursor and survival of osteoclasts osteoblast/ stromal cell OPG OPG OC OC precursor precursor
PHARMACOLOGIC PROPERTIES OF DENOSUMAB • Fully human monoclonal antibody M d l f D Model of Denosumab b IgG 2 isotype • High affinity for human RANK Ligand • • High specificity for RANK Ligand High specificity for RANK Ligand – No detectable binding to TNF α , TNF β , TRAIL, or CD40L • No neutralizing antibodies detected in clinical trials to date TNF = tumor necrosis factor; TRAIL = TNF α‐ related apoptosis ‐ inducing Ligand duc g ga d 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.
DENOSUMAB BINDS RANK LIGAND AND INHIBITS OSTEOCLAST ‐ MEDIATED BONE DESTRUCTION P Pre ‐ Fusion F i CFU ‐ M RANKL Osteoclast RANK Denosumab Hormones Growth factors Osteoclast Formation, Function, Cytokines and Survival Inhibited Osteoblasts Bone Formation Bone Resorption Inhibited Provided as an educational resource. Do not copy or distribute.
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 Patients with advanced lung cancer Supplemental calcium (500 mg) and and confirmed bone metastases, vitamin D (400 IU) recommended with no previous bisphosphonate exposure Zoledronic Acid 4 mg IV* and Placebo SC q4w 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 S ll 75 (21) 75 (21) 88 (25) 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)
DENOSUMAB VS ZOLEDRONIC ACID: OS IN LUNG CANCER OS IN LUNG CANCER 1.0 KM Estimate of Median OS, Mos D Denosumab b 8 9 8.9 0.8 Patients Zoledronic acid 7.7 g Alive 0.6 oportion of Remaining 0.4 R Pro 0.2 HR: 0.80 (95% CI: 0.67-0.95; P = .01) 0 0 3 6 9 12 15 18 21 Study Mo Patients at Risk, n Zoledronic acid Zoledronic acid 400 400 309 309 207 207 135 135 98 98 43 43 24 24 13 13 Denosumab 411 323 233 164 120 71 43 26
DENOSUMAB VS ZOLEDRONIC ACID: OS IN NSCLC OS IN NSCLC 1.0 KM Estimate of Median OS, Mos D Denosumab b 9 5 9.5 0.8 Patients Zoledronic acid 8.1 g Alive 0.6 oportion of Remaining 0.4 R Pro 0.2 HR: 0.78 (95% CI: 0.65-0.94; P = .0104) 0 0 3 6 9 12 15 18 21 Study Mo Patients at Risk, n Zoledronic acid Zoledronic acid 352 352 275 275 185 185 123 123 91 91 40 40 23 23 12 12 Denosumab 350 278 203 148 110 66 39 24
DENOSUMAB VS ZOLEDRONIC ACID: OS IN SMALL CELL LUNG CANCER OS IN SMALL ‐ CELL LUNG CANCER 1.0 KM Estimate of Median OS, Mos D Denosumab b 7 6 7.6 0.8 Patients Zoledronic acid 5.1 g Alive 0.6 oportion of Remaining 0.4 R Pro 0.2 HR: 0.81 (95% CI: 0.52-1.26; P = .3580) 0 0 3 6 9 12 15 18 21 Study Mo Patients at Risk, n Zoledronic acid Zoledronic acid 48 48 34 34 22 22 12 12 7 7 3 3 1 1 1 1 Denosumab 61 45 30 16 10 5 4 2
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