LA GESTIONE DEL PAZIENTE CON

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1 LA GESTIONE DEL PAZIENTE CON COMORBIDITÀ Sacco Cosimo Dipartimento di Oncologia Udine

2 LA GESTIONE DEL PAZIENTE CON COMORBIDITÀ Paziente con comorbidità Malattie cardiovascolari Malattie dismetaboliche Pregresse neoplasie Pazienti anziani Comorbidita indotta dal trattamento Tossicità acuta dei farmaci Complicanze a lungo termine

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4 FRAGILITA E ETA

5 Oncologia geriatrica: piramide di Fratino No comorbidità No disabilità Pazienti anziani selezionati per gli studi clinici di fase II/III Candidato per ogni forma di terapia standard Tutti gli altri Richiede un approccio individualizzato Età > 85 anni > 3 comorbidità >1 disabilità > 1 Sdr Geriatrica Candidato solo per terapie palliative

6 Oncologia geriatrica: rombo di Sacco No comorbidità No disabilità Pazienti anziani selezionati per gli studi clinici di fase II/III Candidato per ogni forma di terapia standard Tutti gli altri Richiede un approccio individualizzato Età > 85 anni > 3 comorbidità >1 disabilità > 1 Sdr Geriatrica Candidato solo per terapie palliative

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9 LH-RH ANALOGHI E ANTAGONISTI

10 Androgen deprivation therapy,used in the treatment of prostate cancer, can induce alterations similar to those of metabolic syndrome, including increased obesity, decreased insulin sensitivity and altered lipid profiles

11 Sexual effects Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density Metabolic changes include lipid changes, anemia and diabetes mellitus. Mental changes Decrease in physical activity Cardiovascular diseases

12 OBESITY IS ASSOCIATED WITH CASTRATION-RESISTANT DISEASE AND METASTASIS IN MEN TREATED WITH ANDROGEN DEPRIVATION THERAPY AFTER RADICAL PROSTATECTOMY: RESULTS FROM THE SEARCH DATABASE CONCLUSIONS: Among men treated with early ADT, our results suggest that obese men may have increased risk of PC progression. These data support the general hypothesis that obesity is associated with aggressive PC, although validation of these findings and further study of the mechanisms linking obesity and poor PC outcomes are required.

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15 Population: men who received between 1997 & 2007 primary endocrine therapy, curative treatment, and surveillance men developed a thromboembolic disease All men with prostate cancer were at higher risk of thromboembolic diseases, with the highest risk for those on endocrine therapy. Lancet Oncol 2010; 11:

16 ADT and cardiovascular events D'Amico, A. V. et al. J Clin Oncol; 25:

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18 ANTIANDROGENS: SIDE EFFECTS Gynecomastia (50% of cases) Breast pain Hot flushes Hepatotoxicity

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22 RECOMMENDATIONS from American Heart Association, American Cancer Society, American Urological Association and American Society for Therapeutic Radiation Oncology (2010) Statin therapy to lower low-density lipoprotein cholesterol levels to <70 to 100 mg/dl (based on baseline cardiovascular history and risk) Anti-hypertensive therapies to lower blood pressure Glucose-lowering therapies to recommended levels in patients with a history of diabetes mellitus Aspirin for patients with known cardiovascular disease Smoking cessation programs for men who continue to smoke (which remains a relevant recommendation for all prostate cancer survivors)

23 DOCETAXEL

24 Docetaxel - TAX 327 Study design (N=1006): the past Metastatic HRPC Stratify Pain level PPI 2 or AS 10 vs PPI < 2 or AS < 10 KPS 70 vs 80 R A N D O M I Z E 1:1 Docetaxel 75 mg/m 2 q3 wks + Prednisone 5 mg bid Docetaxel 30 mg/m 2 wkly 5 of 6 wks + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wks + Prednisone 5 mg bid Treatment duration in all 3 arms = 30 wks Tannock et al, N Engl J Med 2004; 351:

25 Docetaxel: TAX 327 Safety data Grade 3-4 Hematologic Toxicity (%) Docetaxel Q 3 wk Docetaxel wkly Mitoxantrone Treated (N) Anemia Neutropenia Neutropenic infection Febrile neutropenia Septic death Non hematological Toxicity (%) All Grades 3/4 All Grades 3/4 All Grades Alopecia 65 NA 50 NA 13 NA Fatigue Nausea Diarrhea Neuro-Sensory Nail Change 30 NA 37 NA 7 NA Constipation /4 Tannock IF et al. N Engl J Med 2004;351:

26 26 patients aged treated at Cleveland Clinic (median age 76) PSA response in 11/22 assessable men 9 men (34%) hospitalized for toxicity (neutropenic fever, diarrhea, dehydration)

27 CABAZITAXEL

28 NON HEMATOLOGICAL ADVERSE EVENTS All grades (%) MP (n=371) Grade 3/4 (%) All grades (%) CBZP (n=371) Grade 3/4 (%) Any adverse event Febrile neutropenia Diarrhea 11 < Fatigue Back pain Nausea 23 < Vomiting Hematuria Abdominal pain

29 HEMATOLOGICAL ADVERSE EVENTS MP (n=371) All grades (%) Grade 3 (%) CBZP (n=371) All grades (%) Grade 3 (%) Anemia Leukopenia Neutropenia* Thrombocytopenia

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31 Cabazitaxel: EAP Italia - Analisi conclusive I risultati di questa analisi ad interim dell EAP italiano dimostrano che il trattamento con cabazitaxel è ben tollerato, soprattutto per quanto riguarda l'incidenza di neutropenia, neutropenia febbrile e diarrea di grado 3 o 4. Eventi avversi correlati al trattamento nella popolazione in studio (n = 218) TEAE Pazienti; n (%) TEAE di grado 3 o 4 con una prevalenza >2% Overall 129 (59,2) TEAE ematologici di grado 3 o 4 con una prevalenza >2% Neutropenia 74 (33,9) Leucopenia 34 (15,6) Anemia 13 (6,0) Neutropenia febbrile 11 (5,0) TEAE non ematologici di grado 3 o 4 con una prevalenza >2% Astenia 13 (6,0) Fatigue 8 (3,7) Diarrea 6 (2,8) TEAE di qualsiasi grado correlati a cabazitaxel che hanno portato al termine del trattamento con una prevalenza >1% Anemia 7 (3,2) Neutropenia 3 (1,4) Insufficienza epatica 3 (1,4) Fatigue 3 (1,4) Astenia 3 (1,4) TEAE: Treatment-emergent adverse event. Bracarda S, et al. Future Oncol. (Epub ahead of print). doi: /fon CABA- 031

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33 Incidenza delle tossicità incrementa con l età

34 FACTORS ASSOCIATED WITH COMPLICATED CLINICAL COURSE IN FEBRILE NEUTROPENIA Age Inpatient status Prolonged and severe aplasia Comorbidities (bleeding, dehydratation, liver and kidney failure) and chronic conditions Shock, hemodynamic instability, hypotension, sensory loss Presence of a localized infection (pneumonia, enteritis, catheter infection...)

35 POSSIBLE SIDE EFFECTS ASSOCIATED WITH DOCETAXEL AND CABAZITAXEL Neutropenia Leukopenia Anemia Diarrhea Febrile neutropenia Fatigue Asthenia Back pain Nausea Vomiting Hematuria Abdominal pain Peripheral neuropathy Nail changes De Bono JS et al. Lancet 2010;376(9747):

36 ABIRATERONE

37 Abiraterone: analisi dei risultati - Safety Il trattamento con Abiraterone non sembra aumentare il rischio di alterazioni metaboliche o sintomi associati alla deprivazione androgenica cronica. Tuttavia, è opportuno mantenere un follow-up costante per valutare l eventuale tossicità nel lungo periodo. ABI-037 *I disturbi cardiaci associati al trattamento con Abiraterone, identificati seguendo le definizioni del Medical Dictionary for Regulatory Activities (versione 11.0) comprendevano: cardiopatia ischemica, infarto del miocardio, tachiaritmie sopraventricolari, tachiaritmie ventricolari, insufficienza cardiaca, aritmie ed eventuali analisi, segni e sintomi. De Bono JS, et al. N Engl J Med. 2011; 364(21):

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39 Efficacy and Safety of Abiraterone Acetate in Elderly ( 75 Years) Chemotherapy- Naïve Patients With Metastatic Castration-Resistant Prostate Cancer Smith M et al. ECC 2013; Abstract 2932 (Poster Presentation)

40 Impact on Functional Status FACT-P Total Score Prostate Cancer Subscale E.Basch Lancet Oncol 2013; 14:

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42 ENZALUTAMIDE

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44 Enzalutamide: AFFIRM : analisi dei risultati - Safety ENZA- 044 Scher HI, et al. N Engl J Med 2012;367:

45 Enzalutamide: PREVAIL- Safety ENZA- 045 Beer TM, et al. J Clin Oncol 32, 2014 (suppl 4; abstr LBA1^)

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48 POSSIBLE SIDE EFFECTS ASSOCIATED WITH ENZALUTAMIDE: SEIZURES CASE Time on study On study drug? 2 months 10 months 2 months 5 months 10 months Yes Yes Yes Seizure type Focal onset Generalized g Complex partial status Off trial drug for 26 days Focal onset Yes Unknown, fall not witnessed Recurrence No No No No No Large 5 x 4-cm temporal lobe brain IV lidocaine inadverten tly administer Atrophy and leukoaraio sis on Multiple CNS metastases : Eye, meninges, Potential confounding factors metastase ed just brain MRI; De Bono JS et al. Proc ASCO s 2012;Abstract before nil else cerebellar Scher HI for the AFFIRM Investigators. seizure N Engl J Med 2012;367(13): Alcohol excess; started on haloperido l 7 days prior

49 DENOSUMAB HAS BEEN DEVELOPED AS TWO PRODUCTS WITH DIFFERENT DOSING REGIMENS AND THERAPEUTIC INDICATIONS Denosumab is a fully human monoclonal antibody that binds human RANK Ligand with high affinity and specificity 1 Prolia (denosumab) 2 XGEVA (denosumab) 3 Dose 60 mg SC 120 mg SC Regimen Every 6 months Every 4 weeks Indication(s) Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures Treatment of osteoporosis in postmenopausal women at increased risk of fractures Prevention of SREs in adults with bone metastases from solid tumours 1. McClung MR et al. N Engl J Med 354: , Prolia (denosumab) Summary of Product Characteristics, Amgen. 3. XGEVA (denosumab) Summary of Product Characteristics, Amgen.

50 SAFETY RESULTS OF INTEREST Adverse event, n (%) Zoledronic acid (n = 945) Denosumab (n = 943) Infectious AEs 375 (40) 402 (43) Acute phase reactions (first 3 days)* 168 (18) 79 (8) Cumulative osteonecrosis of the jaw (total) 12 (1) 22 (2) Hypocalcaemia 55 (6) 121 (13) New primary malignancy 10 (1) 18 (2) *Flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias, and myalgias; P = P < Adapted from: Fizazi K et al. Lancet 377: , 2011.

51 ONJ: CLINICAL AND RADIOLOGICAL FINDINGS

52 PHASE III ALSYMPCA TRIAL Eligibility (n = 921) Confirmed symptomatic CRPC 2 bone metastases No visceral metastases Post docetaxel/unfit for docetaxel 2:1 R Radium Best supportive care (n = 614) Placebo + Best supportive care (n = 307) Median overall survival: 14.9 versus 11.3 months Time to first skeletal-related event: 15.6 versus 9.8 months Bone pain Grade >3: 18% versus 23% Parker C et al. Proc ESMO 2012;Abstract 898PD.

53 POSSIBLE SIDE EFFECTS ASSOCIATED WITH RADIUM-223 Bone pain Diarrhea Nausea Vomiting Constipation Anemia Neutropenia Thrombocytopenia Parker C et al. Proc ESMO 2012;Abstract 898PD.

54 SIDE-EFFECT PROFILE OF RADIUM-223 VERSUS OTHER RADIOPHARMACEUTICALS Radiopharmaceutical Radium-223 (clinical) Strontium-89 (clinical) Samarium-153 (clinical) Side effects Minor GI toxicities; mild neutropenia/thrombocytopenia 1 Increased but tolerable hematologic toxicity 2 Significant leukopenia and thrombocytopenia 3 1 Harrison MR et al. Cancer Manag Res 2013;5:1-14; 2 Porter AT et al. Int J Radiat Biol Phys 1993;25(5):805-13; 3 Harrison MR et al. Cancer Manag Res 2013;5:1-14.

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56 MIE PERSONALI CONCLUSIONI La neoplasia prostatica coinvolge in tutti le sue fasi pazienti che possono presentare diverse comorbidita La valutazione complessiva della malattia e del paziente (VGM) devono guidare la scelta terapeutica Nei pazienti anziani la formazione anche del care-giver e la collaborazione con il medico curante e fondamentale