Download BSH 2007 - Edge Medical Communications

BSH 2007
Dr Peter Rose
How many patients with VTE have
cancer in the UK?
VERITY (Venous Thromboembolism Registry 2005)
No of patients
Proven VTE
5719
Counterpart group
19459
Cancer(no/ %)
808/ 14
643/ 4.2
What is the age distribution of
VTE with cancer?
Cancer rates broken down by age and gender for patients
with VTE (n=11,557)
Which cancers are more
commonly associated with VTE?
Cancer rates broken down by age for the most frequently occuring cancers in
VERITY amongst patients with VTE (n=11,558)
Are some cancers more
thrombogenic?
What is the prognosis of patients
with VTE and cancer?
What is the prognosis for
different cancers in association
with VTE?
The adverse impact on survival
by different cancers
Cancer Site
VTE
Median survival
(Months)
Bowel
+ (89 cases)
- (30 cases)
9
36
Prostate
+ (61 cases)
- (41 cases)
31
33
Breast
+ (56 cases)
- (62 cases)
34
47
Lung
+ (29 cases)
- (17 cases)
5
4
Gynaecological
+ (41 cases)
- (22 cases)
17
50
Paneesha, et al; BSH 2007
Is the outcome related to the
D-dimer level at presentation?
D-dimer levels in VTE patients with or
without malignancy
47.5
45.0
42.5
40.0
1. VTE with no cancer
2. VTE with Ca Breast
3. VTE with Ca Bowel
4. VTE with Ca Prostate
5. VTE with Ca Lung
6. VTE with Miscellaneous Ca
7. VTE with Gynaecological Ca
8. VTE with subsequent Ca
37.5
35.0
32.5
30.0
D-dimer level
27.5
25.0
22.5
20.0
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
1
2
3
4
5
6
7
8
Median D-dimer levels (ng FEU/ ml) in patients with
& without VTE in different clinical settings
Patients with VTE
Patients without VTE
No cancer
2200
1000
Ca Breast
3780
1250
Ca Bowel
4000
1200
Ca Prostate
2850
1100
Gynae Ca
3140
1150
Miscellaneous Ca
3180
900
Ca Lung
3400
1800
Do high D-dimer levels predict
survival?
Overall survival in VTE patients according to presentation D-dimer level
p value: <0.001
Paneesha, et al. BJH, 2006
Do high D-dimer levels predict
survival?
Overall survival in VTE patients with no malignancy according to presentation D-dimer
p value: 0.282
Paneesha, et al. BJH, 2006
Do high D-dimer levels predict
survival?
Overall survival in VTE patients with malignancy according to presentation D-dimer
p value:<0.001
Paneesha, et al. BJH, 2006
How many patients with VTE go
on to be diagnosed with cancer?
How can unnecessary investigations
for underlying cancer be avoided in
VTE patients?
A predictive model to identify patients
with venous thromboembolism (VTE) at
minimal risk of malignancy
S Paneesha1, W Zhang2, N Parsons2, K. French3 ,E. Cheyne3, S. Bacchu3,
A. Borg1, P. Rose1,3



Department of Haematology, Warwick Hospital, UK
Department ofStatistics, University of Warwick, Coventry, UK
Department of Haematology, UniversityHospitals of Coventry and
Warwickshire NHS Trust, Coventry, UK
Aims of the study

To create a predictive model to identify patients with
VTE at minimal risk of malignancy with prior
identified prognostic variables age, quantitative Ddimer and site of thrombosis at presentation with
VTE.

To validate the predictive model with an
independent data of patients with proven VTE.
Patient characteristics
No of patients
Female/ Male
Age at diagnosis (median/ range)
Age>60yrs
D-dimer (ng FEU/ ml) (median/range)
D-dimer >8000ng FEU/ ml
Site of thrombosis
Above knee VTE
Below knee VTE
Upper limb
Presence of Malignancy
Subsequent malignancy
Time for subsequent malignancy (median / range)
Recurrence of VTE
Follow up (median/ range)
696
358 / 338
65 (16 - 96 yrs.)
438 patients (59.3%)
2300 (100-46300)
115 (17.2%)
412 (55.9%)
308 (41.8%)
17 (2.3%)
188 (25.4%)
29 (4.15%)
1.6 (0 - 18mths)
36 (5.2%)
23.2 (0 - 59 mths)
Multivariate logistics regression
model
exp(β0+β1.loge(D-dimeri)=βsite i=β2.Agei=β3.Agei2)
pi =
1+exp(β0+β1.loge(D-dimeri)=βsite i=β2.Agei=β3.Agei2)
Parameter and estimates and standard errors for the model of equation
Model
Term
Estimate
se
t(*)
exp(estimate)
β0
Constant
-11.00
1.93
-5.69
0.00001674
β1
Loge (D-dimer)
0.329
0.103
3.19
1.390
0
0.456
2.612
0.2756
*
*
β2
Site: Below knee
Site: Above knee
Site: Upper limb
Age
1.000
1.577
13.63
13.17
β3
Age2
-0.001984
0.000470 -4.22
βsite
0.229
0.696
0.0609
1.99
3.76
4.53
0.9980
Performance of model in predicting
absence of malignancy
Predicted
No
No
Yes Total
473 7
480
Correct(%)
98.5%
Performance of model in predicting
absence of malignancy in the
validation dataset
Predicted
No
No
Yes Total
Correct(%)
72
1
98.6%
73
Results

The model correctly identified the VTE patients without
malignancy in 473 out of 480 cases (98.5% accuracy)

Model showed that below a predicted probability of 0.10 <
5% of the patients actually developed cancer (9/190)
whereas for a predicted probability of 0.19 <10% of
patients actually developed cancer (27/276)

One sampe binomial tests revealed there was no
significant difference in the number VTE patients with
cancer between the model and the validation dataset for
the predicted probabilities of 0.10 an 0.19 (p-values of
0.650 and 0.246 respectively
Patient with VTE at minimal risk
of harboring malignancy
Age
D-dimer
Site
Probability
43
1
Below
0.056
Patient with VTE at high risk of
harboring malignancy
Age
D-dimer
Site
Probability
65
8
Above
0.419
Patient with VTE at high risk of
harboring malignancy
Age
D-dimer
Site
Probability
65
8
Upper
0.862
Which cancer patients require
thromboprophylaxis?
Surgery and VTE
Multicentre Trial 4,121 patients
General Surgery
UFH
vs
No Prophylaxis
DVT
7.7%
24.6%
Autopsy PE
3%
22%
P<0.005
Lancet 1975; 2:45-51
A systematic review of DVT prophylaxis
in cancer patients undergoing surgery
26 randomised control studies (7,639 cancer patients)
DVT Rate
Pharmaceutical Prophylaxis
Control
12.7%
35.2%
High-dose LMWH
Low-dose LMWH
7.9%
14.5% (P< 0.01)
3% Bleeding complications
Leonardi MJ et al. Ann Surg Oncol 2007; 14(2):929-36
Surgery in cancer patients
Rates of VTE reduced in Enoxacin II Study with
extended prophylaxis
4 weeks
1 week
4.8%
12%
Bergqvist D et al. N. Engl J Med 2002; 346: 975-80
Cancer breast surgery
Mechanical anti-embolism devices/ early mobilisation
3,898 patients, 4,416 procedures
7 post operative DVTs - with 60-days
No relation between stage / type
2 Neo adjuvant Treatment
Andtbacka et al, Ann Surg 2006; 243 (1): 96 - 101
VTE as a Complication in
Breast Cancer
Stage of disease
Thrombosis Rate%
Treatment
I
0.1
1.0
4.5
Nil
Tamoxifen
Tam + Chemo
II
0 - 1.6
1.3 - 10
31. - 9.6
Tamoxifen
Chemotherapy
Tam + Chemo
III / IV
15 - 17
Chemotherapy
Current breast surgery
thromboprophylaxis in the UK
None
ES/PC
HEP
Both
35yr excision biopsy
fibroadenoma
44.6
45.4
2.9
5.8
55yr fit breast
conserving surgery + nodes
5.8
22
5.4
65.8
4.2
11.7
4.2
79.6
70yr ISD mastectomy + clearance
Partial response to neo adjuvant
chemotherapy
Kirwan et al BJ Surg 2006
Healthy women at risk of breast
cancer
Breast cancer prevention trial
Tamoxifen
vs
Placebo
DVT rate per year
0.13%
0.084%
PE rate per year
0.069%
0.023%
Fisher et al, J Natl Cancer Inst 1998; 90: 1371-88
Retrospective analysis colorectal cancer patients
and VTE (California study)
6,814 colorectal cancer patients
70% surgery
5% events within 6 months
1.4% events within 6-12 months
0.6% events within 12-24 months
Risk factors metastatic disease
3 or more co-morbid conditions
Risk
Asian / Pacific Islanders
Abdominal surgery
HR 3.2
HR 2.0
HR 0.4
HR 0.4
Alcalay et al, J Clin Oncol 2006; 24(7); 1112-8
Lung Cancer & VTE
537 Patients (Leiden)
Thrombotic risk
20-fold higher than general population (SMR)
Squamous Cell (21.2 per 1,000 years)
Adenocarcinoma (66.7 per 1,000 years)
Risk Higher
-
Metastases
Radiotherapy
Chemotherapy
Blom J et al
J Thromb Haemost. 2004; 2 (10): 1760-5
Clinically overt VTE after
Urologic Cancer Surgery (Ristos
Study)
685 cases (61% endoscopic surgery)
Incidence of VTE 0.87%
3 fatal / 3 non-fatal VTE’s
New treatments may be thrombogenic
Estramustine (Meta-analysis)
Taxanes ?
Lubiniecki Cancer 2004; 101 (12): 2755-9
Tester Cancer J 2006: 12 (4) 299-304
Incidence of thromboembolic phenomenon
observed in various myeloma trials
REFERENCE n
CHEMOTHERAPY
STAGE OF MYELOMA
VTE
PERCENTAGE
Cavo
Zangari
Zangari
Minnema
Osman
Osman
Zangari
Camba
Rajkumar
Urbauer
Moehler
Rodeghiero
TD
D-PACE
CDEP
TC
TD
TD
VAD
TC
TD
CDEP + T
CTED
Thalidomide
Newly diagnosed
Relapsed myeloma
Relapsed myeloma
Relapsed myeloma
Newly diagnosed
Newly diagnosed
Newly diagnosed
Relapsed myeloma
New diagnosed
Refractory myeloma
Refractory myeloma
Relapsed myeloma
5
31
1
7
5
4
14
5
6
3
4
8
26
16
3
35
11
27
28
27.8
12
21
4.2
13.8
19
192
40
20
45
15
50
18
50
14
95
58
Thromboprophylaxis for Cancer
Patients
Assess all patients
- Predisposing factors for VTE
- Thrombotic risk of tumour
- Tumour spread
- Prognosis
Treatment Plan






Surgery extended prophylaxis?
Indwelling catheter
Chemotherapy
Hormone therapy
Anti-angiogenic therapy
Other medication
Should patients with cancer and
indwelling catheters have
thromboprophylaxis?
Catheter related thrombosis in
cancer patients
2-4%
clinically overt
18%
venography (absence of A/C’s)
15-25%
UL-DVT+cancer clinically overt PE
50%
autopsy proven PE
Agnelli et al, Nat Clin Pract Oncol 2006; 3 (4): 214-22
Systematic Reviews of
thromboprophylaxis for indwelling
venous catheters
No benefit for low-dose Warfarin
No benefit for LMWH’s
Cunningham MS BJ Cancer 2006; 94 (2) 189-94
How should patients with VTE and
cancer be managed?
Cancer and VTE (Clot Trial)

6 months Dalteparin 200iu/kg per day for 4
weeks
150iu/kg for 5 months vs
Warfarin INR 2-3

Dalteparin significantly less (recurrence
rate)
(8 vs 16%)
Bick N, et al, Eng J Med 2003; 349: 109
Cancer patients with venous
thrombosis
Assess prognosis

Palliative care - symptomatic treatment - LMWH

Active treatment of cancer - long-term - LMWH