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 ScoreSede del cancro: stomaco, pancreas 2Sede del cancro: polmone, linfoma, vescica, testicolo, vie ginecologiche 1Conta piastrinica ³ 350,000/mm3 1Emoglobina < 10 g/dL o uso di eritropoietina 1Conta leucocitaria > 11,000/ mm3 1Body mass index ³ 35 1

Score: 0 = basso rischio; 1-2 = rischio intermedio; > 2 = rischio elevato

M. Verso and G. Agnelli. Venous Thromboembolism Associated With Long-Term Use of Central Venous Cathetersin Cancer Patients. J Clin Oncol 21:3665-3675, 2003.

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

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

Authors Study No. Patients CVC-related VTE (%)

Smith, 1983 RetrospectiveAdults

2800 0.3

Soto-Velasco, 1984

RetrospectiveAdults

1611 0.7

Cassidy, 1987 ProspectiveAdults

416 2.6

Gould, 1993 ProspectiveAdults

255 14.5

Eastridge, 1995

ProspectiveAdults

322 10

Kock, 1996 RetrospectiveAdults

1500 2.5

Schwarz, 2000 ProspectiveAdults

923 3.1

Biffi, 2001

Kurtakose, 2002

ProspectiveAdults

ProspectiveAdults

304

422

6.6

7.1

Incidence of clinically overt CVC-related VTE in cancer patients

Authors Study No. Patients CVC-related VTE (%)

Stoney, 1976 ProspectiveAdults

203 31

Ladefoged, 1978

RetrospectiveAdults

48 27.1

Brismar, 1982 ProspectiveAdults

53 35.8

Bern, 1990 RetrospectiveAdults

42 37.5

Monreal, 1996 RetrospectiveAdults

26 62

De Cicco, 1997 ProspectiveAdults

127 66

Martin, 1999 ProspectiveAdults

60 58.3

Lee A, 2006 Prospective 444 4.3

Incidence of venographic CVC-related VTE in cancer patients

Thromboembolism in breast cancer

Study Population Treatment Rate

NSABP P1 Prevention Tamoxifen 0.2% per year

Placebo 0.1% per year

NSABP B14 Node negative Tamoxifen 0.9%

Placebo 0.2%

Thromboembolism in breast cancer

Study Population Treatment RateNSABP 16 Node positive† T 1.6%

AC + T 3.1%

NSABP B20 Node positive* T 1.8%

CMF + T 7.0%

MF + T 6.5%

NCIC MA4 Node positive† T 1.4%

CMF + T 9.6%

SWOG Node positive† T 0

CMFVP 1.3%

CMFVP + T 3.6%

† Postmenopausal patients

* Pre and postmenopausal patients

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 Patients features

Two or more vs one insertion attempt

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 CancerTreated With Cisplatin: A Systematic Review and Meta-

AnalysisJ 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–cisplatin-based 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

BevacizumabCombined 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 AgentsStudy Tumor Agent VTE(%)

All Gr 3/4

Bleeding(%)

All Gr 3/4

Kabbinavar metastatic colon (n=104)

5FU/LV vs

5FU/LV+ bevacizumab

9 2.8

19.4 10.4

11 0

59.7 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 3.7

7.4 5.7

11.2 0.5

28.8 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 low-dose 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)

Cases (n. 25)

p values

Age 50 43-54 51 46-55 0.4

Menopausal status

Pre 24 49% 11 44% 0.8

Post 25 51% 14 56%

Tumor stage

Locally advanced 29 59% 15 60% 0.9

Metastatic 20 41% 10 40%

Number of cycles

6 4-6 3 2-5 0.9

Mutations

Prothrombin 0 0% 1 4% 0.3

Factor V Leiden 2 4% 5 20% 0.04

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 managementof 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.