Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities...
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Transcript of Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona Toxicities...
Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche
Ancona
Toxicities of molecularly targeted agents in combination with chemotherapy
Tossicita’ dei nuovi agenti biologici
Trastuzumab– Cardiotossicita’
Bevacizumab– ipertensione– Proteinuria– Malattia tromboembolica
Cetuximab– Tossicita’ cutanea
Sunitinib– Diarrea– astenia
Imatinib– Astenia– diarrea
I farmaci biologici modificano o incrementano la tossicita’ dei chemioterapici ?
Trastuzumab– Antracicline
Bevacizumab– Oxaliplatino– irinotecan– Taxani– carboplatino
Cetuximab– Irinotecan– taxani
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, 2.0-5.1%) per il controllo vs sequenziale - 3,3% (95% CI, 2.0-5.1%) 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 N9831Effetti della introduzione di H
sulla tollerabilità cardiaca
SAFETY ANALYSIS POPULATIONSAFETY ANALYSIS POPULATIONCardiotoxicityCardiotoxicity
0.5%0.5%
(95% CI: 0.25(95% CI: 0.25 --1.02)1.02)0.5%0.5%
(95% CI: 0.25(95% CI: 0.25 --1.02)1.02)
0 %0 %
(95% CI: 0.00(95% CI: 0.00 --0.21)0.21)
0 %0 %
(95% CI: 0.00(95% CI: 0.00 --0.21)0.21)
Same LVEF criteriaSame LVEF criteriaandandsymptomatic symptomatic CHF NYHA class CHF NYHA class III/IV, confirmed III/IV, confirmed
by cardiologist by cardiologist
Cardiac deathCardiac death
Same LVEF criteriaSame LVEF criteriaandandsymptomatic symptomatic CHF NYHA class CHF NYHA class III/IV, confirmed III/IV, confirmed
by cardiologist by cardiologist
Cardiac deathCardiac death
7.1 %7.1 %7.1 %7.1 %2.2 %2.2 %2.2 %2.2 %Decrease by Decrease by 10 EF points 10 EF points
and LVEF < 50% and LVEF < 50%
Decrease by Decrease by 10 EF points 10 EF points
and LVEF < 50% and LVEF < 50%
1 year trastuzumab1 year trastuzumab
N=1677N=16771 year trastuzumab1 year trastuzumab
N=1677N=1677ObservationObservation
N=1736N=1736ObservationObservation
N=1736N=1736
0.1% 0%
HERA TRIAL
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 2005Event P>FEC alone
n = 19
P>FEC +H
n = 23
Grade 4 neutropenia 11 21
Neutropenic fever 8 8
Neutropenic infections 3 5
Hospitalization 1 3
Chemotherapy dose reduction as a result of neutropenia
5 10
Cardiac safety dataCHF10% decrease in ejection fractionDecrease on PDecrease on FEC
0505
0743
Improvement in ejection fraction on follow-up evaluation
2 3
Abnormal troponin-T 0 1
LVEF Declines by NYHA Class
1181Grade 3/4 CHF
4256>15%, <LLN
7349>10%, <LLN
TCHAC- THAC- T
1181Grade 3/4 CHF
4256>15%, <LLN
7349>10%, <LLN
TCHAC- THAC- T
I mplication: Trastuzumab per se is not cardiotoxic; it becomes so when it keeps company with DOX
CAN DOXORUBI CI N BE ELI MI NATED?
HER2 +FISH
4 x AC60/ 600 mg/ m2
4 x Docetaxel100 mg/ m2
6 x Docetaxel and Platinum salts75 mg/ m2 75 mg/ m2 or AUC 6
1 Year Trastuzumab
N=31501 Year Trastuzumab
ACT
ACTH
TCH
BCI RG 006
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
Toxicity Trastuzumab + Docetaxel
(n=92)
Docetaxel alone (n=94)
Anemia 1 1
Thrombocitopenia 0 0
Leukopenia 20 15
Neutropenia 32 22
Febrile neutropenia / Neutropenic sepsis 23 17
Alopecia 10 6
Astenia 10 6
I farmaci biologici modificano o incrementano la tossicita’ dei chemioterapici
Trastuzumab– Antracicline
Bevacizumab– Oxaliplatino– irinotecan– Taxani– carboplatino
Cetuximab– Irinotecan– taxani
Patients (%)
IFL + placebo (n=397)
IFL + bevacizumab (n=393)
Bleeding Grade 3/4
2.5
3.1
Any thromboembolic event Arterial Venous
16.2 1.0
15.2
19.4 3.3
16.1 Deep thrombophlebitis Grade 3
6.3
8.9
Pulmonary embolus Grade 4
5.1
3.6
Any hypertension Grade 3
8.3 2.3
22.4* 11.0*
Any proteinuria Grade 2 Grade 3
21.7 5.8 0.8
26.5 3.1 0.8
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
Hypertension: incidence
Trial
Regimen
All grades
Grade 3/ 4
Grade 3
Grade 4
E32001 FOLFOX NR NR 2 <1
FOLFOX + bevacizumab (10mg/ kg)
NR NR 5 1
Bevacizumab (10mg/ kg) NR NR 6 0
AVF07802 5-FU/ LV 3 0 NR NR
5-FU/ LV + bevacizumab (5mg/ kg)
11 8.6 NR NR
5-FU/ LV + bevacizumab (10mg/ kg)
28 25 NR NR
AVF21073 IFL 8.3 NR 2.3 0
IFL + bevacizumab (5mg/ kg) 22.4 NR 11 0
AVF21924 5-FU/ LV 4.8 NR 2.9 0
5-FU/ LV + bevacizumab (5mg/ kg)
32.0 NR 16.0 0
NR = not reported
Proteinuria: incidence Trial
Regimen
All grades
Grade 3/4
Grade 3
Grade 4
E32001 FOLFOX NR NR 0 0
FOLFOX + bevacizumab (10mg/kg)
NR NR <1 0
Bevacizumab (10mg/kg) NR NR <1 0
AVF07802 5-FU/LV 11.4 NR NR NR
5-FU/LV + bevacizumab (5mg/kg)
22.8 NR NR NR
5-FU/LV + bevacizumab (10mg/kg)
28.1 NR NR NR
AVF21073 IFL 21.7 NR 0.8 0
IFL + bevacizumab (5mg/kg) 26.5 NR 0.8 0
AVF21924 5-FU/LV 19.2 NR 0 0
5-FU/LV + bevacizumab (5mg/kg)
38.0 NR 1.0 0
Thromboembolic events during first-line therapy (AVF2192)
No. of patients (%)
5-FU/LV + placebo (n=104) 5-FU/LV + bevacizumab (n=100)
All Grades
Grade 3
Grade 4
All
Grades
Grade 3
Grade 4
Total venous and arterial events
19 (18.3)
14 (13.5)
5 (4.8)
18 (18.0)
10 (10.0)
6 (6.0)
All venous events 14 (13.5) 12 (11.5) 2 (1.9) 9 (9.0) 5 (5.0) 3 (3.0)
Select venous events Pulmonary embolism Deep thrombophlebitis
9 (8.7) 2 (1.9)
9 (8.7)
0
0
2 (1.9)
6 (6.0) 3 (3.0)
6 (6.0)
0
0
3 (3.0)
All arterial events 5 (4.8) 2 (1.9) 3 (2.9) 10 (10.0) 5 (5.0) 4 (4.0)
Select arterial events Myocardial infarction Arterial thrombosis Cerebrovascular accident Cerebral infarction Cerebral ischaemia
2 (1.9) 1 (1.0) 1 (1.0)
0 1 (1.0)
0
1 (1.0) 0 0
1 (1.0)
2 (1.9)
0 1 (1.0)
0 0
2 (2.0) 1 (1.0) 2 (2.0) 2 (2.0) 3 (3.0)
0
1 (1.0) 0 0
3 (3.0)
2 (2.0)
0 2 (2.0) 1 (1.0)
0
Novotny W, et al. J
Thromboembolic events during first-line therapy (AVF2107)
No. of patients (%)
IFL + placebo (n=396) IFL + bevacizumab (n=392)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Total venous and arterial events
64 (16.2)
34 (8.6)
23 (5.8)
76 (19.4)
47 (12.0)
22 (5.6)
All venous events 60 (15.2) 34 (8.6) 20 (5.1) 65 (16.6) 45 (115) 14 (3.6)
Select venous events Pulmonary embolism Deep thrombophlebitis
25 (6.3) 20 (5.1)
25 (6.3)
0
0
20 (5.1)
35 (8.9) 14 (3.6)
35 (8.9)
0
0
14 (3.6)
All arterial events 4 (1.0) 0 3 (0.8) 13 (3.3) 3 (0.8) 9 (2.3)
Select arterial events Myocardial infarction Arterial thrombosis Cerebrovascular accident Cerebral ischaemia
3 (0.8) 1 (0.3)
0 0
0 0 0 0
3 (0.8)
0 0 0
6 (1.5) 3 (0.8) 2 (0.5) 1 (0.3)
0
2 (0.5) 0
1 (0.3)
6 (1.5)
0 2 (0.5)
0
Novotny W, et al. J Clin Oncol 2004;22(July 15 Suppl.): Abstract 3529
Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer
surgery
ComplicationIFL/placebo(n=155) (%)
IFL/bevacizumab (n=150) n (%)
5-FU/LV/bevacizumab
(n=37) (%)
Abscess 0 0 0
Perforatedlarge intestine 0 1 (0.67) 0
Perforated stomach ulcer 0 1 (0.67) 0
All types (total) 0 2 (1.3) 0
Wound healing complications
Bevacizumab does not increase wound healing/bleeding complications when given 28–60 days following cancer
surgery (cont’d)
Haemorrhage
IFL/placebo
(n=155)
n (%)
IFL/bevacizumab
(n=150)
n (%)
5-FU/LV/bevacizumab
(n=37) (%)
GI 1 (0.65) 0 0
Rectal 0 1 (0.67) 0
All types 1 (0.65) 1 (0.67) 0
Bleeding complications
Bleeding: incidence
Trial Regimen All grades Grade 3/4 Grade 3 Grade 4
E32001 FOLFOX NR NR 0 0
FOLFOX + bevacizumab (10mg/kg)
NR NR 2.0 0
Bevacizumab (10mg/kg) NR NR 2.0 0
AVF07802 5-FU/LV 11* 0* NR NR
5-FU/LV + bevacizumab (5mg/kg)
52* 0* NR NR
5-FU/LV + bevacizumab (10mg/kg)
69* 9.4* NR NR
AVF21073 IFL NR 2.5 NR NR
IFL + bevacizumab (5mg/kg) NR 3.1 NR NR
AVF21924 5-FU/LV NR 2.9 1.9 1.0
5-FU/LV + bevacizumab (5mg/kg)
NR 5.0 3.0 2.0
*Epistaxis + GI haemorrhage
I farmaci biologici modificano o incrementano la tossicita’ dei chemioterapici
Trastuzumab– Antracicline
Bevacizumab– Oxaliplatino– irinotecan– Taxani– carboplatino
EGFR inibitori (Cetuximab/TKI)– Irinotecan– gemcitabina– taxani
CRYSTAL trial:Safety: Grade 3/4 AE
FOLFIRI
n=602, %
Cetuximab + FOLFIRI
n=600, %
Any 59.5 78.0
Neutropenia 23.3 26.7
- Febrile neutropenia 2.2 2.7
Diarrhea 10.5 15.2
Vomiting 5.0 4.5
Fatigue 4.5 5.0
Skin reactionsa 0.2 18.7
Hypomagnesemiab 0.2 1.8
Infusion-related reactions 0 2.3
aThere were no grade 4 skin reactions
bAvailable only from a subset of patients (at least one measurement in 20% of population)
Tossicita’ dei nuovi agenti biologici
Trastuzumab– Cardiotossicita’
Bevacizumab– ipertensione– Proteinuria– Malattia tromboembolica
Cetuximab– Tossicita’ cutanea
Sunitinib– Diarrea– astenia
Imatinib– Astenia– diarrea