Trattamento integrato delle metastasi ossee Dott. Rossi Luigi Oncologia Università Sapienza Polo Pontino

MTSO: Epidemiologia Causa maggiore morbilità nel paziente oncologico Scheletro: terza sede più comune di MTS dopo polmone e fegato In Italia incidenza circa 35.000 nuovi casi/anno 25% dei pz con MTSO rimane asintomatico 75% MTSO sono responsabili di complicanze

Incidence of Skeletal-Related Events Breast Cancer* 68 Multiple Myeloma† 51 Prostate Cancer* 49 SREs, skeletal-related events.   The natural history of SREs associated with cancer as determined from the placebo arms of randomized clinical pamidronate and zoledronic acid trials revealed that approximately one half of the patients will have an SRE. Therefore, only some patients with bone metastases will experience SREs in the short term, and it is not clear how to differentiate these patients from those who will not experience SREs. Lung Cancer/Others† 48 20 40 60 80 *24 mos. †21 mos. ‡Placebo arm of pamidronate or zoledronic acid randomized trials. Patients With SREs (%)‡ Coleman RE. The Oncologist. 2004;9(suppl 4):14-27 References: 1. Coleman RE. Bisphosphonates: clinical experience. The Oncologist. 2004;9(suppl 4):14-27. 2. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88:1082-1090. 3. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol. 1998;16:593-602. 4. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882. 5. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 2004;100:2613-2621.

Metastasi ossee Complicanze Dolore osseo severo Impotenza funzionale Fratture patologiche Compressione midollo spinale o radici nervose Alterazione ematopoiesi da infiltrazione midollo osseo Ipercalcemia

IL DOLORE Il dolore osseo è presente nel 28-45% dei pazienti affetti da cancro e nel 70% di quelli con malattia in fase avanzata. La presenza di dolore non sempre è correlata con la sede, il numero e l’entità delle metastasi e l’età dei pazienti

LE FRATTURE PATOLOGICHE Spontanee, avvengono anche in assenza di trauma Compaiono nel 8-30% dei pazienti Le sedi più frequenti: Rachide Bacino Femore prossimale Omero prossimale

COMPRESSIONE MIDOLLARE La compressione midollare è una seria complicanza, talvolta anche potenzialmente mortale L’esordio è subdolo con vaghi dolori, debolezza agli arti e parestesie

COMPRESSIONE MIDOLLARE Rischio di morte per paralisi respiratoria A quadro conclamato possono comparire disturbi sfinterici, perdita della sensibilità, sino a paraplegia e tetraplegia L’esordio può essere: - Acuto (<48 ore) nel 22% dei casi - Nel 60% dei casi progredisce in 7-10 giorni verso la paraplegia o tetraplegia Rischio di morte per paralisi respiratoria

IPERCALCEMIA In piccola parte è causata dal riassorbimento del calcio dall’osso per azione litica diretta delle cellule metastatiche Per la maggior parte dei casi è mediata dai fattori attivanti gli osteoclasti (in primis il paratormone) da parte delle cellule neoplastiche Si manifesta nel 20 - 30 % dei pazienti

SINTOMI DELL’ IPERCALCEMIA Generali Gastrointestinali Renali Neuromuscolari Cardiaci Disidratazione, perdita di peso, anoressia, prurito, polidipsia Nausea, vomito, stipsi, ileo paralitico Poliuria, insufficienza renale Affaticabilità, letargia, debolezza muscolare, iporeflessia,stato confusionale, psicosi, convulsioni, coma Bradicardia, allungamento dell’intervallo PR, accorciamento dell’intervallo QT, aritmie atriali o ventricolari

Terapia locoregionale OPZIONI TERAPEUTICHE Terapia locoregionale Terapia sistemica Radioterapia Chirurgia Interventistica (vertebroplastica)) Ormonoterapia Chemioterapia Terapia biologica Terapia radiometabolica Terapia con bifosfonati Terapia antalgica

Efficacia dei Bifosfonati I BP sono in grado di ridurre il rischio di SRE e di ritardarne significativamente il tempo di comparsa I BP hanno una documentato effetto sul dolore e migliorano la qualità della vita. Tuttavia non devono sostituire la terapia antalgica e non costituiscono la prima scelta nella terapia del dolore da metastasi scheletriche E’ considerata preferibile la somministrazione endovenosa rispetto a quella orale, tranne in particolari condizioni di trasportabilità o mobilità del paziente AIOM 2013

Riduzione del rischio calcolato di SRE 16 33 37 38 40 10 20 30 50 Clodronato4 Pamidronato3 Zoledronato2 Ibandronato os 50 mg1 Ibandronato ev 6 mg1 Riduzione degli eventi scheletrici (%) 1. Body JJ et al. ASCO 2003; 2. Estimated from Coleman et al. SABCS 2002; 3. Lipton A et al. Cancer 2000; 88: 1082-90; 4. Pavlakis N, Stockler M. The Cochrane Library 2002

Zoledronic Acid Reduces the Risk of SREs Across All Tumor Types Reduction, % P Value Breast 41 . 019 Prostate 36 . 002 Solid Tumors 31 .003 32 .016 Lung Cancer RCC, renal cell carcinoma; SREs, skeletal-related events; ZOL, zoledronic acid.   What has been accomplished with bisphosphonates in the last 20 years? This slide lists trials of zoledronic acid vs placebo in multiple tumor types. On average, the rate of SREs was decreased by approximately one third. Skeletal-related events are still occurring but at a much slower rate. 58 .010 RCC 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Relative Risk of SRE In favor of ZOL In favor of placebo Kohno N, et al. J Clin Oncol. 2005;23:3314-332. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882. Rosen LS, et al. Cancer. 2004;100:2613-2621. Lipton A, et al. Cancer. 2003;98:962-969. References 1. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96: 879-882. 2. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in treatment of skeletal metastases in patients with non-small cell lung cancer and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 2004;100:2613-2621. 3. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98:962-969.

Growth Factors (TGF-β, IGFs, FGFs, PDGFs, BMPs) RANK Ligand Is a Key Mediator in the “Vicious Cycle” of Bone Destruction Cancer Cells in Bone Direct Effects on Tumor? Cytokines and Growth Factors (IL-6, IL-8, IL-1, PGE-2, TNF-, CSF-1, PTHrP) Growth Factors (TGF-β, IGFs, FGFs, PDGFs, BMPs) RANKL Osteoclast RANKL BMP, bone morphogenetic protein; CSF-1, colony-stimulating factor-1; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; PGE-2, prostaglandin E2; PTHrP, parathyroid hormone–related protein; RANK, receptor activator of nuclear factor-κB; RANKL, RANK ligand; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha.   The key role of RANKL in promoting the vicious cycle by stimulating osteoclasts was discussed earlier in this presentation. This slide incorporates the additional possibility that RANKL can directly stimulate tumor cells in the bone marrow microenvironment. Bone Resorption Osteoblast Lineage RANKL Bone RANK Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Mechanism of Action of Denosumab Osteoclast Formation, Function, and Survival Inhibited by Denosumab Y Denosumab CFU-M OPG Y Prefusion osteoclast RANKL RANK Y Growth factors Hormones Cytokines Multinucleated osteoclast RANKL Y CFU-M, colony-forming unit macrophage; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-κB; RANKL, RANK ligand.   Denosumab is a monoclonal antibody targeting the RANKL that holds great promise as an inhibitor of osteoclast formation, function, and survival. This molecule is now in development for the treatment of osteoporosis and for the prevention and treatment of treatment-induced bone loss and bone metastases. Denosumab has been shown to inhibit treatment-induced bone loss in both prostate and breast cancer. A study conducted by Ellis and colleagues demonstrated that denosumab stabilized bone health relative to placebo in patients receiving endocrine treatment for breast cancer. Mature osteoclast Osteoblast Bone Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.

Study Design (20050136) Key Inclusion: advanced breast cancer and confirmed bone metastases Key Exclusion: current or prior intravenous BP administration Stratified by previous SRE, prior oral BP, current chemotherapy, and geographic region (Japan vs others) N = 1020 Zoledronic acid 4 mg IV* and SC placebo every 4 weeks N = 1026 Denosumab 120 mg SC and Placebo IV* every 4 weeks Supplemental Calcium and Vitamin D Criteri esclusione vi era la terapia in corso o precedente con NBPS IV Studio in doppio cieco pz randomizzati a ricevere …… A total of 2046 eligible adult subjects who were naïve to intravenous bisphosphonates were randomized in a double-blind, double-dummy design to receive subcutaneous denosumab 120 mg or intravenous zoledronic acid (ZA) 4 mg adjusted for creatinine clearance every 4 weeks The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphonate use for osteoporosis was allowed Zoledronic acid was administered per Zometa® prescribing information. IV product dose that was either zoledronic acid or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstituted once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa® label. Subjects with creatinine clearance < 30 mL/min were excluded per the Zometa® label There was no modification of the subcutaneous product, which included denosumab or placebo either at baseline or on study Subjects were stratified by previous SRE, prior oral bisphosphonate, current chemotherapy, and geographic region (Japan vs others) All subjects were strongly recommended to take daily supplemental calcium (500 mg) and vitamin D (400 IU) No crossover was allowed during the treatment phase The median time on study was 17 months for both treatment arms The median time on treatment was 16.5 months for both treatment arms The study duration was 34 months The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression. Secondary endpoints included a superiority test for time to first and time to first-and-subsequent on-study SRE. Subject Disposition 46% of subjects in the denosumab arm and 45% of subjects in the zoledronic arm remained on study through the primary data analysis cut-off date The main reasons for study discontinuation were deaths, disease progression, and consent withdrawn Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. 1° Endpoint 2° Endpoints Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label) Stopeck A, et al. JCO, 2010 17

Primary endpoint: Time to First On-Study SRE Reduced risk: 18% HR 0.82 (95% CI: 0.71, 0.95) P < 0.0001 (Non-inferiority) P = 0.01 (Superiority)* 1.00 * Adjusted for multiplicity 0.75 Proportion of Subjects Without SRE 0.50 KM Estimate of Median Months 0.25 per qunto rigurda il tempo alla I sre durante lo studio il denosumab ha dimostrato di essere superiore alZa e di ridurre il rischio del 18 di SRE si nei test di non inferiorità che superiorità. Il tempo medio no raggiunto x denosum er a26. 5 x Za The primary endpoint is represented on a Kaplan Meier curve Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to 0.95. The P value was less than 0.0001 for noninferiority and equal to 0.01 for superiority The median time to first on-study SRE was not reached for denosumab and was 26.5 months for zoledronic acid The 2 most common components of SREs were fractures and radiation to bone Approximately 30-37% of subjects experienced an on-study SRE Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. Denosumab Not reached Zoledronic acid 26.5 3 6 9 12 15 18 21 24 27 30 Months Subjects at risk Zoledronic Acid 1020 829 676 584 498 427 296 191 94 29 Denosumab 1026 839 697 602 514 437 306 189 99 26 Stopeck A, et al. JCO, 2010 18

Secondary endpoint: Time to First and Subsequent On-Study SRE Secondary endpoint: Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) * Events that occurred at least 21 days apart 1.5 Total # of Events Denosumab 474 Zoledronic acid 608 1.0 Cumulative Mean Number of SRE Successive For the secondary endpoint of time to first and subsequent SRE, otherwise known as the multiple event analysis, denosumab was also superior to zoledronic acid and reduced the risk of multiple events by 23% (rate ratio: 0.77; 95% CI: 0.66–0.89; P=0.001) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. 0.5 Reduced risk: 23% Rate Ratio 0.77 (95% CI: 0.66, 0.89) P = 0.001† 3 6 9 12 15 18 21 24 27 30 Months † Adjusted for multiplicity Stopeck A, et al. JCO, 2010 19

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Castration-Resistant Prostate Cancer Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Supplemental Calcium and Vitamin D Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) This was a head-to-head comparison vs. active comparator, resulting in much higher sample size per arm (almost 1000) as compared to the historic zoledronic acid registration trial, which was placebo-controlled (about 220 per arm). The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI. The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphosphonate use for osteoporosis was allowed. Zoledronic acid (ZA) was administered per Zometa® prescribing information. IV product dose that was either zoledronic acid or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstituted once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa® label. Subjects with creatinine clearance <30 mL/min were excluded per the Zometa® label. There was no modification of the subcutaneous product, which included denosumab or placebo either at baseline or on study. Subjects were stratified by previous SRE (YES/NO), current chemotherapy (within 6 weeks prior to randomization) (YES/NO), Baseline PSA (<10 vs. ≥10 ng/mL). All subjects were strongly recommended to take daily supplemental calcium (500 mg) and vitamin D (400 IU). 1° Endpoint 2° Endpoints Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) Fizazi K et al. LANCET, 2011 20 20

Time to First On-Study SRE 1.00 Proportion of Subjects Without SRE 3 6 9 12 15 18 21 24 27 0.25 0.50 0.75 KM Estimate of Median Months Denosumab Zoledronic acid 20.7 17.1 HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) 18% Risk Reduction Efficacy analyses are vs. the most potent bisphosphonate used in clinical practice, and the only one approved for use in prostate cancer bone metastasis. This is NOT a comparison vs. placebo, as has been done in Novartis registration trial The primary endpoint is represented on a Kaplan Meier curve. Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to 0.95. The P value was equal to 0.0002 for noninferiority and equal to 0.008 for superiority. The median time to first on-study SRE was 20.7 months for denosumab and was 17.1 months for zoledronic acid, a 3.6 mo difference. The 2 most common components of SREs were fractures and radiation to bone. 727 subjects experienced a first on-study SRE; subject incidence was 341 (35.9%) in the denosumab arm and 386 (40.6%) in the zoledronic acid arm. Study Month Subjects at risk: Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 Fizazi K et al. LANCET, 2011 21

Time to First and Subsequent On-Study SRE (Multiple Event Analysis) 2.0 Rate Ratio = 0.82 (95% CI: 0.71, 0.94) Risk Reduction 18% 1.8 P = 0.008 1.6 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 For the secondary endpoint of time to first and subsequent SRE (multiple event analysis) denosumab was also superior to zoledronic acid and reduced the risk of multiple events by 18% (rate ratio: 0.82; 95% CI: 0.71–0.94; P=0.004). Only events which were at least 21 days apart from each other were counted, matching a similar analysis reported for zoledronic acid in its registration trial (Saad et. al., JNCI 2004) Events 0.4 Denosumab 494 0.2 Zoledronic acid 584 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Study Month Fizazi K et al. LANCET, 2011 22

Study Design (20050244) N = 886 Denosumab 120 mg SC and Placebo IV* every 4 weeks Key Inclusion Adults with solid tumors and bone metastases (excluding breast and prostate) or multiple myeloma Key Exclusion Current or prior intravenous bisphosphonate administration Supplemental Calcium and Vitamin D N = 890 Zoledronic acid 4 mg IV* and SC placebo every 4 weeks A total of 1776 eligible adult subjects who were naïve to intravenous bisphosphonates were randomized in a double-blind, double-dummy design to receive subcutaneous denosumab 120 mg or intravenous zoledronic acid (ZA) 4 mg adjusted for creatinine clearance every 4 weeks The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphonate use for osteoporosis was allowed Zoledronic acid was administered per Zometa® prescribing information. IV product dose which was either Zometa or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstated once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa label. Subjects with creatinine clearance < 30 mL/min were excluded per the Zometa label There was no modification of the SQ product which included denosumab or placebo either at baseline or on study Subjects were stratified by tumor type, previous SRE, and systemic anti-cancer therapy All subjects were strongly recommended to take daily supplemental calcium ( 500 mg) and vitamin D ( 400 IU) No crossover was allowed during the treatment phase The median time on study was 7.3 months for both treatment arms The median time on treatment was 6.7 months for both treatment arms The study duration was approximately 34 months The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression. Secondary endpoints included a superiority test for time to first and time to first-and-subsequent on-study SRE Subject Disposition Approximately 20% of subjects in the denosumab arm and 20% of subjects in the zoledronic arm remained on study through the primary data analysis cut-off date The main reasons for study discontinuation were deaths, disease progression, and consent withdrawn Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. 1° Endpoint 2° Endpoints Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label) Henry D, et al. JCO, 2011 23

Primary end point: Time to First On-Study SRE Reduced risk: 16% 1° - HR: 0.84 (95% CI: 0.71–0.98) P = 0.0007 Non inferiority 2° - Unadjusted P = 0.03 Superiority* Adjusted P = 0.06 1.00 0.75 Proportion of Subjects Without Skeletal Related Event 0.50 KM Estimate of 0.25 Median Months Denosumab 20.6 This is the primary endpoint represented on a Kaplan Meier curve Denosumab reduced the risk of first on-study SRE by 16% compared with Zometa, with a confidence interval from 0.71 to 0.98 This was significant for noninferiority with a P=0.0007. The median time to first on-study SRE was 20.6 months for denosumab and 16.3 months for zoledronic acid Although directionally favorable, the time to first on-study SRE did not meet statistical superiority for denosumab over zoledronic acid due to adjustments for multiplicity (adjusted P=0.06) The 2 most common components of SREs were fractures and radiation to bone Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. Zoledronic Acid 16.3 3 6 9 12 15 18 21 24 Study Month Subjects at Risk Zoledronic Acid 890 578 376 261 194 126 86 47 Denosumab 886 582 387 266 202 134 96 55 *Due to multiplicity adjustment Henry D, et al. JCO, 2011 24

Integrated analysis – Study Design A Lipton Eur J Canc 2012

Time to First On-Study SRE A Lipton Eur J Canc 2012

Eventi Avversi Subject incidence, n (%) Zoledronic Acid (N = 945) Denosumab (N = 943) Infectious AEs 375 (39.7) 402 (42.6) Infectious serious AEs 108 (11.4) 130 (13.8) Acute phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal AEs* 153 (16.2) 139 (14.7) Cumulative rate of osteonecrosis of the jaw (ONJ)† 12 (1.3) 22 (2.3) Year 1 5 (0.5) 10 (1.1) Year 2 8 (0.8) Hypocalcemia 55 (5.8) 121 (12.8) New primary malignancy 18 (1.9) *Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatininemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. †P = 0.09 Fizazi K et al. LANCET, 2011

Supporto vitaminico A tutti i pazienti che effettuano bisfosfonati per via endovenosa o orale e denosumab per via sottocutanea è raccomandata una supplementazione di calcio e vitamina D E’ consigliabile somministrare una dose di 1000 UI/die di vitamina D e di 500 mg/die di calcio Utile monitoraggio di calcemia durante il trattamento con bisfosfonati o denosumab al fine di correggere valori ipocalcemici severi AIOM 2013

Terapia Radiometabolica Indicazioni: Dolore nella malattia ossea multifocale Modalità primaria Su una progressione sintomatica già irradiata In associazione alla RT con fasci esterni Obiettivi: Importante riduzione del dolore Rallentamento progressione metastatica ossea Riduzione delle complicanze AIOM 2013

Il ruolo della RT nel trattamento delle MTSO Controllo Dolore: Immediato: ↓ citochine che agiscono su recettori del dolore Prolungato: ↓ effetti meccanici di compressione / infiltrazione per azione citocida sulle cellule neoplastiche - Effetto antalgico nel 75-85% dei casi 50% dei pz beneficio superiore ai 6 mesi AIOM 2013

RADIOTERAPIA Prevenzione delle fratture patologiche: Incidenza fratture patologiche dopo RT: 2-10% Terapia fratture patologiche: Consolidamento post-chirurgico Sindrome da compressione midollare: Emergenza Oncologica Terapia standard: radioterapia+corticosteroidi AIOM 2013

Chirurgia ortopedica delle MTSO Obiettivi principali: prevenzione/cura fratture patologiche prevenzione/cura compressione midollare spinale controllo del dolore garantire QoL il più possibile adeguata preservare/ripristinare funzione articolare preservare/ripristinare stabilità segmentaria controllo locale MTSO In considerazione della mancanza di trials randomizzati, i livelli di evidenza esposti nelle linee guida per determinati trattamenti chirurgici sono relativamente bassi indicazioni all’intervento standardizzate tecniche chirurgiche sono più difficilmente standardizzabili richiedendo un’elettività chirurgica capace di utilizzare le tecniche e dei mezzi di sintesi e le protesi in funzione delle lesioni In pazienti lungosopravviventi o a buona prognosi, il trattamento chirurgico deve comprendere l’asportazione della lesione metastatica con margini i più ampi possibile, e la ricostruzione stabile del segmento operato Una resezione articolare o intercalare in questi casi viene ricostruita con sistemi protesici modulari cementati e spaziatori intercalari Le lesioni metastatiche solitarie delle ossa spendibili (perone, coste, clavicola, ulna distale) possono essere facilmente resecate senza alcun residuo funzionale La colonna vertebrale rappresenta la localizzazione più frequente di MTS ossee Le lesioni classicamente tendono ad interessare la porzione posteriore del corpo vertebrale, ed in un secondo momento si possono estendere alla porzione anteriore del corpo vertebrale ed alle strutture posteriori Obiettivi del trattamento chirurgico sono il trattamento di dolore, instabilità segmentaria e/o compressioni sulle strutture neurologiche Le indicazioni chirurgiche devono essere limitate in quanto solo pz selezionati possono beneficiare dal trattamento chirurgico, mentre altri possono necessitare di RT ed ortesi o RT adiuvante postoperatoria La chirurgia deve esser “curativa” nei pazienti ad ottima prognosi e stato generale e con lesione metastatica isolata In questi casi la lesione viene trattata come un tumore primitivo dello scheletro con exeresi en bloc (Livello di evidenza: IV: Forza raccomandazione: B) Compressione spinale Il paziente con MTS spinali deve essere considerato per l’intervento una volta che insorge un deficit neurologico Genericamente infatti, nei pazienti in cui non sia presente un danno neurologico in atto è ragionevole pensare ad un trattamento conservativo con ortesi e RT ± CHT Unica eccezione è rappresentata da pz con lesione singola a buona prognosi, in cui è ragionevole pensare ad un trattamento chirurgico anche in caso di assenza di deficit neurologici evidenti (Livello di evidenza IV: Forza raccomandazione: B) AIOM 2013

Vertebroplastica/Cifoplastica: dolore intrattabile e non responsivo da MTS spinale fratture patologiche in pz il cui stato clinico non permette di eseguire interventi chirurgici tradizionali  Iniezione percutanea TC guidata di cemento acrilico nel corpo vertebrale Mc Graw JK et al, J Vasc Interv Radiol 2003

Approccio integrato Coinvolgimento di figure ad alta specialità: Oncologo Palliativista Radioterapista Ortopedico Neurochirurgo Medico Nucleare Radiologo Diagnosta ed Interventista Fisiatra Infermiere professionale, fisioterapista

Uno studio prospettico ha esaminato l'utilizzo di risorse sanitarie e i costi associati agli SRE in una coorte europea (Germania, Italia, Spagna e Regno Unito) di pazienti con tumori solidi 478 pazienti con ECOG 0-2 e aspettativa di vita ≥ 6 mesi, che avevano manifestato un SRE anche 97 giorni prima dell'arruolamento 893 SRE. L'irradiazione ossea era l'evento più comune (66%), la compressione del midollo spinale (7%) e la chirurgia ossea (10%) erano gli eventi meno frequenti, ma che più spesso richiedevano ospedalizzazione SRE più costosi erano la compressione del midollare (media tra i Paesi esaminati: 4884 - 12082 Euro) e la chirurgia ossea (3348 - 9407 Euro). I ricoveri ospedalieri erano la principale forza motrice dei costi COSTI G Hechmati J Med Econ 2013