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Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities of molecularly targeted agents in combination with chemotherapy.

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Presentazione sul tema: "Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities of molecularly targeted agents in combination with chemotherapy."— Transcript della presentazione:

1 Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities of molecularly targeted agents in combination with chemotherapy

2 Tossicita dei nuovi agenti biologici Trastuzumab –Cardiotossicita Bevacizumab –ipertensione –Proteinuria –Malattia tromboembolica Cetuximab –Tossicita cutanea Sunitinib –Diarrea –astenia Imatinib –Astenia –diarrea

3 I farmaci biologici modificano o incrementano la tossicita dei chemioterapici ? Trastuzumab –Antracicline Bevacizumab –Oxaliplatino –irinotecan –Taxani –carboplatino Cetuximab –Irinotecan –taxani

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8 La differenza della incidenza degli eventi cardiaci (scompensi e morti) tra terapie con H e senza è inferiore al 4%. Analisi a 9 mesi: 500 pz per braccio con diminuzione della LVEF 15% dal basale (dopo AC) - 0,0% (95% CI, 0,0-0,7%) per il braccio di controllo - 2,2% (95% CI, %) per il controllo vs sequenziale - 3,3% (95% CI, %) per il controllo vs terapia concomitante con paclitaxel * * a 9 mesi questi pazienti hanno ricevuto ulteriori cicli di H rispetto al gruppo sequenziale. Perez et al ASCO 2005 NCCTG N9831 Effetti della introduzione di H sulla tollerabilità cardiaca

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10 SAFETY ANALYSIS POPULATION Cardiotoxicity 0.5% (95% CI: ) 0.5% (95% CI: ) 0 % (95% CI: ) 0 % (95% CI: ) Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist Cardiac death Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist Cardiac death 7.1 % 2.2 % Decrease by 10 EF points and LVEF < 50% Decrease by 10 EF points and LVEF < 50% 1 year trastuzumab N= year trastuzumab N=1677 Observation N=1736 Observation N= % 0% HERA TRIAL

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13 Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer. Buzdar et al JCO 2005 Event P>FEC alone n = 19 P>FEC +H n = 23 Grade 4 neutropenia 1121 Neutropenic fever 88 Neutropenic infections 35 Hospitalization 13 Chemotherapy dose reduction as a result of neutropenia 510 Cardiac safety data CHF 10% decrease in ejection fraction Decrease on P Decrease on FEC Improvement in ejection fraction on follow-up evaluation 23 Abnormal troponin-T 01

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16 Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: Results of a Randomized Phase II Trial by the M77001 Study Group Marty et al, JCO 2005 ToxicityTrastuzumab + Docetaxel (n=92) Docetaxel alone (n=94) Anemia11 Thrombocitopenia00 Leukopenia2015 Neutropenia3222 Febrile neutropenia / Neutropenic sepsis2317 Alopecia106 Astenia106

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19 I farmaci biologici modificano o incrementano la tossicita dei chemioterapici Trastuzumab –Antracicline Bevacizumab –Oxaliplatino –irinotecan –Taxani –carboplatino Cetuximab –Irinotecan –taxani

20 Unusual chemotherapy-related toxicity NB: not adjusted for different time on therapy *p<0.05 Hurwitz H, et al. N Engl J Med 2004;350:2335–42

21 Hypertension: incidence NR = not reported

22 Proteinuria: incidence

23 Thromboembolic events during first-line therapy (AVF2192) Novotny W, et al. J

24 Thromboembolic events during first-line therapy (AVF2107) Novotny W, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3529

25 Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer surgery Complication IFL/placebo (n=155) (%) IFL/bevacizumab (n=150) n (%) 5-FU/LV/bevacizumab (n=37) (%) Abscess000 Perforated large intestine 01 (0.67)0 Perforated stomach ulcer 01 (0.67)0 All types (total)02 (1.3)0 Wound healing complications

26 Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer surgery (contd) Haemorrhage IFL/placebo (n=155) n (%) IFL/bevacizumab (n=150) n (%) 5-FU/LV/bevacizumab (n=37) (%) GI1 (0.65)00 Rectal01 (0.67)0 All types1 (0.65)1 (0.67)0 Bleeding complications

27 Bleeding: incidence *Epistaxis + GI haemorrhage

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30 I farmaci biologici modificano o incrementano la tossicita dei chemioterapici Trastuzumab –Antracicline Bevacizumab –Oxaliplatino –irinotecan –Taxani –carboplatino EGFR inibitori (Cetuximab/TKI) –Irinotecan –gemcitabina –taxani

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33 CRYSTAL trial: Safety: Grade 3/4 AE FOLFIRI n=602, % Cetuximab + FOLFIRI n=600, % Any Neutropenia Febrile neutropenia Diarrhea Vomiting Fatigue Skin reactions a Hypomagnesemia b Infusion-related reactions a There were no grade 4 skin reactions b Available only from a subset of patients (at least one measurement in 20% of population)

34 Tossicita dei nuovi agenti biologici Trastuzumab –Cardiotossicita Bevacizumab –ipertensione –Proteinuria –Malattia tromboembolica Cetuximab –Tossicita cutanea Sunitinib –Diarrea –astenia Imatinib –Astenia –diarrea


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