Cancer Associated thrombosis (CAT) (ITAC 2022, ASH 2021, bsh 2015)
Dalteparin (CLOT 2003) & (CATCH 2015)
Edoxaban (Hokusai VTE 2017)
Rivaroxaban (SELECT-D 2018, CASTA-DIVA 2022)
Apixaban (Caravaggio 2020) & (ADAM 2020)
Any DOAC (CANVAS meta-analysis 2022)
intro
Pathophysiology
Expression of tissue factor on tumour cells
Pro-thrombotic properties of mucin
Risk Factors
Tumour type - highest risk cancers (adjusted for prevalence) are pancreas, ovary and brain (Circulation 2003)
Age, Immobilisation, Surgery, CVC lines, infection, chemotherapy, radiotherapy
Risk remains elevated longterm even after remission - ?smoking ?increased weight
Effects of Cancer on VTE
VTE risk 4-fold greater in cancer than general population. 6.5-fold if on chemotherapy (Circulation 2003)
Outcomes worse compared to non-cancer VTE (COPE 2021, Circulation 2003)
Recurrence is higher compared to non-cancer VTE (20% vs 7% at 6 months) (Blood 2002)
Major bleeding is higher compared to non-cancer VTE (12% vs 5% at 6 months) (Blood 2002)
Effects of VTE on Cancer
VTE occurence may delay urgent cancer treatment (surgery, chemotherapy, radiotherapy)
High risk group of patients, esp in the first 4 weeks post VTE
These delays contribute to the poor outcomes described above
Thromboprophylaxis
Inpatients
All routinely assessed since 2007 DoH guidelines
Extended (4 weeks) prophylaxis is recommended following abdomino-pelvic surgery
Outpatients
If used, ITAC & ASH both recommend either LMWH or DOAC
NICE guidelines 2018 recommend ambulatory thromboprophylaxis for:
Pancreatic cancer on chemotherapy
Myeloma on IMiD (Trials used LMWH/Aspirin but current practice has largely moved to DOACs)
Any other patient where additional VTE risk factors are present in addition to the cancer.
Risk scores for making thromboprophylaxis decisions:
Khorana Score - commonly used, scored prior to start of chemotherapy, score of 2+ recommends prophylaxis. BUT only 25% of patients who go to develop VTE would have scored 2+ at the outset.
Other scores available but all with the same problem of missing majority of patients.
Thromboprophylaxis not indicated in:
Prevention of CVC thrombosis
Adjuvant hormonal therapies
Solely as a measure to increase life expectancy
Treatment of VTE
Initial Six Months
Minimum 6 months AC recommended for CAT (ITAC 2022)
DOAC or LMWH can be used first line
LMWH - consider the QoL implications
DOAC - consider intraluminal tumours, drug interactions, body weight, creatinine clearance.
CLOT trial 2003 = recurrence rates of 8% LMWH > 15% Warfarin
Multiple trials since then have shown non-inferiority of DOACs vs LMWH (see top of page)
No head to head trials of different DOACs. Possibly lower bleeding rates with apixaban.
Beyond 6 months / Long-term AC
Risk of VTE recurrence persists beyond 6 months (JTH 2022)
Offer continued AC (?reduced dose) in patients with ongoing active cancer diagnosis / other persisting risk factors. But consider patient’s prognosis and quality of life and discuss with patient.
As of 2023, a trial of low dose apixaban is in process
Stop if cancer eradicated and no other persisting risk factors
Recurrence during treatment
If on DOAC, consider switch to LMWH
If on LMWH, increase dose by 20-25% or consider switch to DOAC
If further VTE on increased LMWH dose, increase dose to aim anti-Xa 1.6 – 2.0 if OD (0.8 – 1.0 if BD) or consider switch to DOAC
IVC filters not indicated
Bleeding Risk
GI/GU cancers - high risk of bleeding it there is luminal disruption by cancer. This risk returns to baseline if damaged lumen resected/resolved
Primary brain cancers - high baseline risk which is elevated further by AC (Blood Advances 2022)
Brain metastasis - high baseline risk but only minimally increased by AC (Blood Advances 2022)
No good scoring system to predict bleeding risk. CAT-BLEED shows some promise (T&H 2022)
Line-Associated CAT
Accounts for up to 50% of CAT. Lower risk of recurrence / fatal PE than other VTE sites (ISTH 2018)
Up to 7% of cancer patients with PICC develop upper limb DVT (Lancet 2013)
ITAC 2022 recommends:
Minimum 3 months and then for as long as line remain in place
LMWH preferred (as direct comparison with DOACs not been made). QoL considerations may trump this.
Aim to keep line in, provided:
Still functioning
Correctly positioned
No evidence of infection
Symptoms from the VTE resolve
Minimum AC prior to line removal?
If must be removed, ISTH 2014 guidance statement recommends 3-5 days AC prior to removal, if clinically practical. There is expert opinion only. Othe guidelines make no recommendations.
Since then, Blood Advances 2021 —> retrospective review of >600 pts. Early removal of CVC, with or without AC, was not associated with an increased risk of PE. Will this change future recomendations?
Thrombocytopenia + CAT (ISTH 2018)
There is no randomised trial evidecne to direct treatment for CAT occurring with thrombocytopenia
ISTH 2018 Guidance for first 30 days of CAT with platelet count <50:
High risk - transfuse platelets to a plt count >40-50 and give full dose AC
Low risk - adapt AC dose to platelet count (e.g. 50% dose if plt 25-50, omit <25)
(High risk = includes, but not limited to, symptomatic PE, proximal DVT, previous VTE)
(Low risk = line-associated VTE, asymptomatic subsegmental PE), distal DVT)
Consider IVC filter only in patients with absolute contraindication to anticoagulation.
Blood 2022 - post hoc analysis of Hokusai trial. Review 100 pts with plt <100. 2x increased risk of bleeding complications from anticoagulation. (only 14 pts had plt count <50)
CAVEaT 2022 - UK audit found variable adherence to ISTH guideline.
Incidental finding of VTE
3-4% of CT Chest performed of reasons other than ?PE find a PE in cancer patients
6-month mortality is increased in cancer patients with VTE whether incidental or symptomatic
Indicative of a general pro-thrombotic state
—> Therefore, treat fully as for symptomatic VTE
Future therapies?
Abelacimab - FXI monoclonal antibody. Data so far is for post-op prophylaxis in orhtopaedic patients (NEJM 2021). Aster and Magnolia trials recruiting as of 2023.
Screening for Cancer in seemingly unprovoked VTE
6% undiagnosed cancer in unprovoked VTE patients
Screening reduced time to diagnosis but no survival benefit, which may be due to VTE being associated with advanced stage cancer.
Extensive screening (CT AP + mammogram + sputum cytology) causes anxiety
NEJM 2015 Screening for Occult Cancer in unprovoked VTE
4% cancer diagnosis within 1 year of VTE
Missed cancers: 29% limited screening vs 26% extensive screening
Time to cancer diagnosis: 4.2 months limited screening vs 4 months extensive screening
Annals of Internal Medicine 2017 Systematic Review and Meta-analysis
5.2% cancer diagnosis within 1 year of VTE
7-fold higher prevalence if >50 y.o.
Unclear that screening translates into survival benefit
Limited screening plus age/sex related Ix as good as extensive screening
(Limited = Hx, Ex, FBC, U&E, LFT, CXR. Extensive = limited + CT AP)
Consider screening in >40 y.o. with unprovoked VTE
Hokusai Trial 2017
Open label, non-inferiority study of edoxaban vs dalteparin
1050 patients
Edoxaban 60mg OD (30mg if CrCl 30-50, body weight <60kg or taking P-glycoprotein inhib)
Dalteparin 200 U/Kg for 30 days, thereafter 150 U/Kg. Dose reduced if plt count <100!
Primary outcome = composite of recurrent VTE or major bleeding = Edox 12.8%, Dal 13.5%
Edoxaban = 7.9% recurrent VTE, 6.9% major bleeding
Dalteparin = 11.3% recurrent VTE, 4.0% dalteparin