thromboprophylaxis for the ambulant ‘medical’ cancer patient anthony maraveyas frcp, phd dpt....

Thromboprophylaxis For The Ambulant ‘Medical’ Cancer

Patient

Anthony Maraveyas FRCP, PhD Dpt. Academic Oncology (PGMI)

Silver Silver In: In: The Hematologist - modified from Blom et. al. The Hematologist - modified from Blom et. al. JAMAJAMA 2005;293:715 2005;293:715

• Population-based case-control (MEGA) study

• N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects

• CA patients = 7x OR for VTE vs. non-CA patients

Effect of Malignancy on Risk of Effect of Malignancy on Risk of Venous Thromboembolism (VTE)Venous Thromboembolism (VTE)

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Type of cancer Time since cancer diagnosis

2828

22.222.220.320.3

4.94.9

19.819.8

53.553.5

14.314.3

2.62.61.11.13.63.6

Thromboprevention in the Ambulant Cancer Patient :

Warfarin

• Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (*INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer

• 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy

• Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo

• 1 VTE in warfarin group vs 7 in placebo arm • 85% risk reduction, P = .03, with no increased bleeding

Levine M, et al. Lancet. 1994;343:886-889.*INR=international normalized ratio

n=59Twilley C. H. 2002

n=59

CapecitabineTamoxifenSorafenibSunitinib

Twilley C. H. 2002

5

10

15

20

2 4 6 8 10 12

%

Months

Cumulative Incidence Of Major Bleeding On Warfarin

Prandoni P, et al. Prandoni P, et al. Blood. Blood. 2002;100:3484-3488. 2002;100:3484-3488.

Warfarin to maintain INR 2Warfarin to maintain INR 2––33Major bleeding 12.4% vs 4.9%; HR 2.2Major bleeding 12.4% vs 4.9%; HR 2.2

P = 0.019

Cancer

Non-Cancer

Recurrent thrombosis while on WarfarinRecurrent thrombosis while on Warfarin

20

0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 1212

Time (months)Time (months)

30

00

10

Cum

ulat

ive

prop

ortio

n C

umul

ativ

e pr

opor

tion

recu

rren

t VT

E (

%)

recu

rren

t VT

E (

%)

Cancer

No cancer

20.7% vs 6.8%; HR 3.2 at 1 year

Number ofNumber ofpatientspatientsCancer Cancer 181 181 160 160 129 129 92 92 73 73 6464No cancer No cancer 661 661 631 631 602 602 161 161 120 120 115115

Prandoni P, et al. Prandoni P, et al. Blood. Blood. 2002;100:3484-3488. 2002;100:3484-3488.

RCTs Kakkar et al

Sideras et al

Altimbas et al

Freund et al Gatzemeier et al

Perry et al

ACRONYM FAMOUS - - TOPIC-1 TOPIC-2 PRODIGE

LMWH dose

Agent

5,000 UContinuous

Dalteparin

5,000 UContinuous

Dalteparin

5,000U for 18 /52

Dalteparin

3,000 uFor 6 /12

Certoparin

3,000 uFor 6 /12

Certoparin

5,000 uFor 6/12 (12 /12 option)

Dalteparin

Cancer Type All Cancers All Cancers SCLC Breast Cancer NSCLC Glioma

Clinical VTE (C vs E) %

3 Vs 2 7 Vs 6 2.4 Vs 0 4 vs 3.9 8.3 vs 4.5 17 vs 11

LMWHs- Thromboprevention RCTs in Cancer

● Large trials but with little attention paid to – Anatomical site– Time from diagnosis– Accurate staging– Grade of Histology– Performance status– Line of treatment– Previous response

● 1PROTECHT– 1166 patients- 3800 units Nadroparine sc-od

• The first significant difference • VTE incidence from 3.9% reduced to 2.0%• Risk reduction 49%

Strategy 1 : Treat ‘Cancer’ as a generic diagnosis

1Agnelli et al (2009) Lancet Oncol 2009; 10: 943-949.

Thromboprophylaxis in ambulatory cancer patients receiving chemotherapy- Agnelli

PROTECHT study

● Patients with solid tumours receiving chemotherapy randomised (2:1) to nadroparin 3800 IU od or placebo for up to 4 months

Nadroparin Placebo p value, RRR, NNT

Overall VTE 2.0% (15/769) 3.9% (15/381) Single-sided p=0.024, RRR 49.6%, NNT 50.5

VTE rates in cancer subgroups

Lung 3.5% (7/199) 8.8% (7/80) RRR 61.2%, NNT 18.9

Gastrointestinal 1.5% (4/272) 2.7% (4/148) –

Pancreas 8.3% (3/36) 5.9% (1/17) –

Other 0.4% (1/262) 2.2% (3/136) –

1. Agnelli G et al. Lancet Oncol 2009; 10: 943-949.2. Agnelli G et al. Debate presentation at ICTHIC 2010.

Thromboprophylaxis in ambulatory cancer patients receiving chemotherapy

● PROTECHT (lung cancer patients; nadroparin vs placebo)1 and TOPIC-2 (lung cancer patients; certoparin vs placebo)2 ad hoc combined analysis

LMWH Placebo RR (95% CI), NNT/H

Symptomatic thromboembolic events

PROTECHT 3.5% (7/199) 8.8% (7/80)

TOPIC-2 3.0% (8/268) 5.7% (15/264)

Total 3.2% (15/467) 6.4% (22/344) RR 0.50 (0.26–0.95) NNT 31

Major bleeding

PROTECHT 1.0% (2/199) 0 (0/80)

TOPIC-2 3.7% (10/273) 2.2% (6/273)

Total 2.5% (12/472) 1.7% (6/353) RR 1.50 (0.57–3.95) NNH 125

Agnelli G et al. Debate presentation at ICTHIC 2010.Adapted from 1. Agnelli G et al. Lancet Oncol 2009; 10: 943-949. And 2. Haas S et al. J Thromb Haemost 2005; 3 (suppl 1): OR059.

Characteristic OR P value

Site of Cancer

Upper GI

Lung

Lymphoma

3.88

1.86

1.5

0.03

0.0076

0.05

0.32

Pre-chemotherapy platelet count > 350,000/mm3 2.81 0.0002

Hgb < 10g/dL or use of red cell growth factor

1.83 0.03

Use of white cell growth factor in high-risk sites

2.09 0.008

Khorana, Cancer, 2005Khorana, Cancer, 2005

Strategy 2 : ‘Cancer’ remains a generic diagnosis but select ‘High Risk’ groups

Predictive Model

Patient Characteristic Score

Site of CancerVery high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, GU excluding prostate)

2

1

Platelet count > 350,000/mm3 1

Hgb < 10g/dL or use of ESA 1

Leukocyte count > 11,000/mm3 1

BMI > 35 1

Khorana AA et al. Khorana AA et al. JTH JTH Suppl Abs O-T-002Suppl Abs O-T-002

Risk Score 0 1 2 3 4N 1,352 974 476 160 33

VTE(%) /2.4 mo.s 0.8 1.8 2.7 6.3 13.2

Inci

denc

e of

VT

E O

ver

2.4

Mon

ths

Inci

denc

e of

VT

E O

ver

2.4

Mon

ths

0%0%

2%2%

4%4%

6%6%

8%8%

10%10%

12%12%

14%14%

16%16%

18%18%

00 11 22 33 44

Actual IncidenceActual IncidenceEstimated IncidenceEstimated Incidence95 % Confidence Limits95 % Confidence Limits

Predictive ModelPredictive Model

Predicting VTE risk in cancer patients

● Biomarkers predictive of VTE have been identified, which could be added to the risk score:– Tissue factor: pancreatic cancer patients with high TF

expression (in the tumour) had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low TF expression (p=0.04) 1

– Thrombin generation: patients with high peak thrombin generation (>75th percentile) had a significantly greater risk of VTE than other patients in the Vienna CATS study [HR 2.0 (95% CI 1.3–3.2), p=0.003) 2

– sP-selectin and d-dimer: adding these to the Khorana risk score allowed the identification of patients with a very high risk of VTE (30.3% for those with a score of >5) 3

1. Khorana AA et al. Clin Cancer Res 2007; 13: 2870-2875.2. Ay C et al. Thromb Res 2010; 125: S166-S191 (abstract PO-32).3. Ay C et al. J Thromb Haemost 2009; 7 (Suppl 2): OC-TU-016.

Strategy 3: Study the anti-coagulant as an anti-cancer agent

● Imagine you are not studying a –rin but you are studying a –nib

● Single malignancy- Stage- Line

- Identical ‘Cancer’ treatment- Accurately described (e.g dose intensity)

- Performance Status- Survival risk modelling

- E.g. Motzer, Childs Pugh etc- Previous surgery to primary- Histological parameters

16

Gemcitabine with or without prophylactic weight-adjusted dalteparin (WAD) in patients

with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised

phase IIB trial.

The UK FRAGEM study

A. Maraveyas, J. Waters, R. Roy, D Fyfe, D. Propper, F. Lofts, E.

Gardiner, J. Sgouros K.R. Wedgwood.

The Queen’s Oncology & Hematology Centre, The Queen’s Oncology & Hematology Centre, Hull. Hull. Kent Oncology Centre, MaidstoneKent Oncology Centre, MaidstoneDiana Princess of Wales, Grimsby Diana Princess of Wales, Grimsby Lancaster Royal Infirmary, LancasterLancaster Royal Infirmary, LancasterSt Bartholomew’s Hospital, LondonSt Bartholomew’s Hospital, LondonSt George’s Hospital Medical School LondonSt George’s Hospital Medical School London

With regional-stage disease With metastatic disease

Adapted from Chew et al, Arch Intern Med 2006.

Incidence of VTE Within 2 Years of Diagnosis of 5 Different Types of Cancer (235,149 cases)

Eligibility Criteria:Inoperable Advanced Pancreatic Cancer

Stratification factorsPS (90-100 vs 60-80) Metastatic vs Locally Advanced

FRAGEM Study Design

Gemcitabine + Dalteparin

1:1

RANDOMIZATION

Gemcitabine

Primary endpoint : Reduction of all-type VTESecondary endpoints: Toxicity, effect on EDB, PFS,TTTF,OS.

Dose-Schedule:

Dalteparin12 weeks sc od 200 IU/kg week 1-4 and 150 IU/kg week 5-12 (CLOT investigator’s WAD)

Gemcitabine1000 mg/m2 weekly (Burris schedule)

Maraveyas A et al. Thromb Res 2010; 125: S166-S191 (abstract OC-02).


FRAGEM study

● Patients with inoperable or metastatic advanced pancreatic cancer randomised to gemcitabine + weight-adjusted dalteparin (CLOT schedule) or gemcitabine alone for 12 weeks

Gemcitabine (n=63)

Gemcitabine + dalteparin (n=60)

RR, (95% CI), p value

‘All-type’ VTE overall

31% 12% RR 0.380 (0.172, 0.840) p<0.02

Clinical VTE overall

24.2% 8.5% RR 0.350 (0.136, 0.903) p=0.038

‘All-type’ VTE <100D

25% 3.5% RR 0.138 (0.033, 0.578) p<0.002

Clinical VTE <100D

17.7% 0% RR 0.046 (0.003, 0.758) p<0.001

Fatal VTE <100D

9% 0% RR 0.083 (0.005, 1.447) p=0.028)



Conclusions

● WA-dalteparin in APC was well tolerated

● During the WA-dalteparin period there was almost total prevention of VTE and total prevention of the clinical impact of VTE

– Prevention of fatal VTE

● Significant reduction in all-type VTE throughout the patients’ lifetime was also found

● WA-LMWH thromboprophylaxis with first-line gemcitabine in APC should now be considered a standard of care, with WA dalteparin for 3 months being an option

FRAGEM studySecondary endpoints● Low SAE (3% major bleed n.d)

● No difference in overall survival

● No difference in time to treatment failure

● No difference in response rate



Study (agent) Criteria for inclusion* N Endpoints

SAVE-ONCO (semuloparin up to 4 mos)

Lung, bladder, GI, ovary

Metastatic or locally advanced

3200 DVT, PE, VTE-related death

PHACS (dalteparin x 12 weeks)

Risk score >3 404 Asymptomatic and symptomatic VTE

MicroTEC (enoxaparin x 6 mos)

Lung, colon, pancreas

Metastatic or unresectable

Elevated TF-MPs

227 VTE

Ongoing studies

Connolly GC & Khorana AA. Thromb Res 2010; 125: S1-S7.

*All studies enrol patients initiating a new chemotherapy regimen

BEST Strategy● Combination of all three Strategies?

– Cancer drug approach in Model Malignancy• Pancreatic Cancer

– Biggest bang for buck?» If you can’t prove efficacy and cost

effectiveness in this model what chances elsewhere?

• Correct dose and duration of anticoagulant– Risk Modelling

• Within the malignancy setting chosen– Previous DVT– Diabetes?– High platelets-WBC– Caucasians ( Western diet –lifestyle -risk factors)

– Power• Power appropriately for SURVIVAL advantage

Maraveyas WJGO 2009

FRAGMATIC

● Cancer drug approach– Lung Cancer– Cost effective? –Dose 5000 so will at least get data of

quality on this dosing schedule

● Risk modelling?– Large trial allowing subgroup analyses (e.g SCLC)

● Power– 2200 patients!

Griffiths GO et al. BMC Cancer 2009; 9: 355.

LMWH therapy to prolong survival in cancer patients – FRAGMATIC study

● Primary outcome measure: overall survival

● Secondary outcome measures include:– VTE-free survival– Metastasis-free survival– Quality of life– Breathlessness– Anxiety and depression– Cost effectiveness– Cost utility – Serious adverse events/toxicity

● Expected primary completion date: August 2012

Ongoing open-label, randomised, multicentre study to assess the impact of long-term dalteparin on overall survival in patients with lung cancer

2200 (target enrolment) patients with histopathological or cytological diagnosis of primary bronchial carcinoma aged 18 years or over

Griffiths GO et al. BMC Cancer 2009; 9: 355.

R

Anticancer treatment according to local practice + dalteparin 5000 IU SC

OD (n=1100)

Anticancer treatment according to local practice + no dalteparin

(n=1100)

Primary outcome

assessment

Day 1 24 weeks

R

Anticancer treatment according to local practice + dalteparin 5000 IU SC

OD (n=1100)

Anticancer treatment according to local practice + no dalteparin

(n=1100)

Primary outcome

assessment

Day 1 24 weeks

Thank you

[email protected]

thromboprophylaxis for the ambulant ‘medical’ cancer patient anthony maraveyas frcp, phd dpt....

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