Download (CVC-related VTE) in cancer patients

Epidemiologia e fattori di rischio della
trombosi CVR-relata
Giuseppe Curigliano
Divisione di Oncologia Medica,
Istituto Europeo di Oncologia
Milano
Epidemiologia
• 66,106 pazienti neoplastici adulti ricoverati per neutropenia
postchemioterapia
• 115 centri medici USA
• TE V e A in 5,272 pazienti (7.98%)
• TEV 4,255 paz (6.44%)
• 3,828 (5.79%) trombosi venosa
• 711 (1.08%) embolia polmonare
• Ca pancreas (12.1%)
• Cerebrali (9.5%)
• Ca endometrio (8.9%)
• Ca gastroenterico (7.64%)
• Ca polmone (7%)
Khorana A.A. et al. Journal of Clinical Oncology 2006; 24: 484-490
Fattori di Rischio
Modello per la predizione del rischio di tromboembolismo associate a
chemioterapia
Caratteristiche del paziente
Score
Sede del cancro: stomaco, pancreas
2
Sede del cancro: polmone, linfoma, vescica, testicolo, vie ginecologiche 1
Conta piastrinica ³ 350,000/mm3
1
Emoglobina < 10 g/dL o uso di eritropoietina
1
Conta leucocitaria > 11,000/ mm3
1
Body mass index ³ 35
1
Score: 0 = basso rischio; 1-2 = rischio intermedio; > 2 = rischio elevato
Epidemiology of catheter related Venous Thromboembolism
(CVC-related VTE) in cancer patients
 The reported incidence of symptomatic CVC-related VTE varies from 0.3 to 28.3%,
with a rate of 12% in pediatric patients
 The incidence of CVC-related VTE assessed by venography has been reported to
vary from 27 to 66%. Most of the thrombi in these studies were asymptomatic.
 There is no conclusive evidence that a particular type of CVC is more or less
thrombogenic than others
 Time course analysis of CVC-related VTE indicates the first 6 weeks after CVC
insertion at higher risk of thromboembolic complication
M. Verso and G. Agnelli. Venous Thromboembolism Associated With Long-Term Use of Central Venous Catheters
in Cancer Patients. J Clin Oncol 21:3665-3675, 2003.
Gli accessi venosi centrali: utilizzo
• Somministrazione della chemioterapia con
schedula infusionale
• Terapia parenterale
• Terapia di supporto
• Monitoraggio della tossicità da chemioterapia
Fattori di rischio per tromboembolismo
venoso
PERSISTENTI
• Cancro
• Deficit Proteina C
• Deficit Proteina S
• Deficit AT-III
• Resistenza alla Proteina C attivata Fattore VLeiden
• Mutazione protrombina
• Sindrome da Anticorpi
Antifosfolipidi
• Iperomocisteinemia
TRANSITORI-REMOVIBILI
• Trauma
• Frattura
• Chirurgia
• Prolungata immobilità
• Gravidanza, puerperio, aborto
• Contraccetivi orali
• Accessi Venosi Centrali (CVC)
Fattori di rischio per tromboembolismo venoso nei
pazienti con CVC
• Tipo di catetere (materiali e disegno)
(Monreal M et al, Thromb Haemost 1994;72:548)
•
•
•
•
•
Numero di venipunture (una vs >2)
Manutenzione, complicanze settiche
Paziente (tipo di neoplasia, condizioni generali)
Problemi di posizionamento
Farmaci infusi (tipo e modalità di somministrazione)
Conseguenze della trombosi venosa
da CVC
• Embolia polmonare
• Infezioni
• Rimozione dell’AVC
Incidence of clinically overt CVC-related VTE in cancer patients
Authors
Study
No. Patients
CVC-related
VTE (%)
Smith, 1983
Retrospective
Adults
2800
0.3
Soto-Velasco, 1984
Retrospective
Adults
1611
0.7
Cassidy, 1987
Prospective
Adults
416
2.6
Gould, 1993
Prospective
Adults
255
14.5
Eastridge, 1995
Prospective
Adults
322
10
Kock, 1996
Retrospective
Adults
1500
2.5
Schwarz, 2000
Prospective
Adults
923
3.1
Biffi, 2001
Prospective
Adults
304
6.6
Kurtakose, 2002
Prospective
Adults
422
7.1
Incidence of venographic CVC-related VTE in cancer patients
Authors
Study
No. Patients
CVC-related
VTE (%)
Stoney, 1976
Prospective
Adults
203
31
Ladefoged, 1978
Retrospective
Adults
48
27.1
Brismar, 1982
Prospective
Adults
53
35.8
Bern, 1990
Retrospective
Adults
42
37.5
Monreal, 1996
Retrospective
Adults
26
62
De Cicco, 1997
Prospective
Adults
127
66
Martin, 1999
Prospective
Adults
60
58.3
Lee A, 2006
Prospective
444
4.3
Thromboembolism in breast cancer
Study
Population
Treatment
Rate
NSABP P1
Prevention
Tamoxifen
0.2% per year
Placebo
0.1% per year
Tamoxifen
0.9%
Placebo
0.2%
NSABP B14
Node negative
Thromboembolism in breast cancer
Study
Population
NSABP 16
Node positive†
NSABP B20
NCIC MA4
SWOG
Node positive*
Node positive†
Node positive†
† Postmenopausal patients
* Pre and postmenopausal patients
Treatment
Rate
T
1.6%
AC + T
3.1%
T
1.8%
CMF + T
7.0%
MF + T
6.5%
T
1.4%
CMF + T
9.6%
T
0
CMFVP
1.3%
CMFVP + T
3.6%
Risk factors for developement of CVC-related DVT in cancer
patients
CVC features
Patients features
Chemical structure
High platelet counts
Catheter diameter
Cancer related activation of
coagulation
Number of lumens
CVC-related activation of
coagulation
Side of insertion
Chemotherapy-related
activation of coagulation
CVC-related infection
Thrombofilic molecular
abnormalities
Insertion techniques
Risk factors for developement of CVC-related DVT in cancer
patients
CVC features
Two or more vs one
insertion attempt
Patients features
Ovarian Cancer
Pancreatic cancer
Previous CVC
Anticoagulant therapy
Venous thromboembolism (VTE) during chemotherapy
Chemotherapy itself can increase the risk of thromboembolic disease:
 Acute damage on vessel walls (bleomycin, carmustine, vinca alkaloids,
adriamycin)
 Decrease of natural coagulation inhibitors (reduced levels of protein C and
S with cyclophosphamide, methotrexate and fluorouracil and reduced
levels of antithrombin III with L-aspariginase)
Risk of Venous Thromboembolism in Patients With Cancer
Treated With Cisplatin: A Systematic Review and MetaAnalysis
J Clin Oncol 30. © 2012 by American Society of Clinical Oncology
Methods
• PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies
included prospective randomized phase II and III trials evaluating cisplatin-based versus non–cisplatinbased chemotherapy in patients with solid tumors.
• Data on all-grade VTEs were extracted.
• Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model.
Results
• A total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were
included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based
chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non–cisplatin-based regimens.
• Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95%
CI, 1.25 to 2.23; P .01).
• Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent
cisplatin dose 30 mg/m2 (2.71; 95% CI, 1.17 to 6.30; P .02) and in trials reported during 2000 to 2010
(1.72; 95% CI, 1.27 to 2.34; P .01).
Conclusion
• Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors
when compared with non–cisplatin-based chemotherapy.
VTE in solid tumors-haemapoetic
growth factors
Study
Agent(s)
Tumour type
Number of pts
VTE (%)
Wun
cisplatin, rads, epo
cervix
75
22.6
Wun
cisplatin, rads
cervix
72
2.7
Lavey
cisplatin, rads, epo
cervix
53
13.0
VTE in cancer patients: the role of chemotherapy
179 consecutive germ cell cancer patients
Cisplatin containing regimens
15 patients (8.4%) developed 18 major VTE between the start of chemotherapy
and 6 weeks after administration of the last cycle in first line treatment
Of these 18 events, 3 (16.7%) were arterial events, including 2 cerebral ischemic
strokes and 15 (83.3%) were VTE including 11 pulmonary embolism. One
(5.6%) of the 18 events was fatal.
Weijl et al.Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the
literature. J Clin Oncol 2000, 18: 2169-78
VTE in cancer patients: the role of hormone therapy and chemo-
endocrine therapy
Authors observed one or more thromboembolic events in 48 of 353 women
(13.6%) randomized to receive tamoxifen plus CMF compared to 5 of 352
women (2.6%) randomized to receive tamoxifen alone (p=0.001).
Significantly more women developed severe VTE in the T plus CMF arm than
in the T arm (34 vs 5: p=0.0001).
Most thromboembolic events occurred while women were actually receiving
chemotherapy ( 39 of 54, p<0.0001).
Pritchard K. Et al. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a
randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol, 1996: 14: 2731-2737
New agents in medical oncology and the risk of venous
thromboembolism
Bevacizumab
Combined treatment with bevacizumab and chemotherapy, compared with
chemotherapy alone, was associated with increased risk for an arterial
thromboembolic event but not for a venous thromboembolic event.
Combination treatment with bevacizumab and chemotherapy, compared with
chemotherapy alone, was associated with an increased risk of arterial
thromboembolism but not venous thromboembolism.
Frank A. Scappaticci et al , Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with
Chemotherapy and Bevacizumab, JNCI, August 8 2007
VTE with Novel Agents
Study
Tumor
Agent
VTE(%)
All Gr 3/4
Bleeding(%)
All
Gr 3/4
Kabbinavar
metastatic colon
(n=104)
5FU/LV vs
5FU/LV+
bevacizumab
9
19.4
2.8
10.4
11
59.7
0
6
Hurwitz
metastatic colon
(n=813)
IFL/PL vs
IFL +
bevacizumab
16.1
19.3
-
-
2.5
3.1
Miller
metastatic breast
(n=462)
capecitabine vs.
capecit +
bevacizumab
5.6
7.4
3.7
5.7
11.2
28.8
0.5
0.4
JR Skillings ASCO 2005
• Analyzed 5 trials of chemotherapy versus
chemotherapy plus bevacizumab (BV)
• 1745 solid tumor patients (breast, colon, lung)
• Arterial thrombosis increased with BV, 3.8%
versus 1.7%
• Risk factors for thrombosis were age > 65, and
prior history of atherosclerosis
New agents in medical oncology and the risk of venous
thromboembolism
Trastuzumab
Thrombosis not common.
Thomas M. Suter et al , Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial, JCO,
Vol 25, No 25 (September 1), 2007: pp. 3859-3865
New agents in medical oncology and the risk of venous
thromboembolism
Sorafenib and Sunitinib
No reported event.
New agents in medical oncology and the risk of venous
thromboembolism
Lenalidomide and Thalidomide
Ten patients (8%) developed deep vein thrombosis, including 4 who were not
receiving any thromboprophylaxis at the time of the event. The rate of
thromboembolic events was not different between patients who received
concomitant erythropoietin therapy and those who did not, 4.8% and 8.6%,
respectively (P = .54). A higher number of venous thrombotic episodes
occurred in the high-dose corticosteroid group compared with the lowdose corticosteroid therapy group (12% vs 6%), but the difference was not
statistically significant (P = .3).
VTE in cancer patients
European Institute of Oncology Policy
Influence of Factor V Leiden and the G20210A prothrombin mutation on the
development of deep vein thrombosis in cancer patients treated with
chemotherapy
Controls
(n. 50)
Age
Cases
(n. 25)
p values
50
43-54
51
46-55
0.4
Pre
24
49%
11
44%
0.8
Post
25
51%
14
56%
Locally advanced
29
59%
15
60%
Metastatic
20
41%
10
40%
Number of cycles
6
4-6
3
2-5
0.9
Prothrombin
0
0%
1
4%
0.3
Factor V Leiden
2
4%
5
20%
0.04
Menopausal status
Tumor stage
0.9
Mutations
Frequency
1-14%
9-39&
Venous thrombosis in cancer patients
The pathogenesis of DVT in patients with CVC is probably multifactorial.
Early thromboembolic events are essentially related to the loss of vessel
integrity caused by CVC placement.
Late thromboembolic events are probably related to CVC features, insertion
technique, catheter tip position, and occurrence of catheter infection.
The role of thrombophilic molecular abnormalities is less clear.
Venous thrombosis in cancer patients
CVC-related DVT in cancer patients complicates the management
of the disease contributing to the morbidity and mortality of cancer patients.
Recognition of risk factors associated with CVC-related DVT may help to
reduce the rate of this complication.
This objective is more likely to be achieved by pharmacologic prophylaxis
during long-term CVC dwell.