Cancer Associated thrombosis (CAT) (bsh 2024, ITAC 2022, ASH 2021)

 

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 occurrence may delay urgent cancer treatment (surgery, chemotherapy, radiotherapy)

High risk group of patients, esp in the first 4 weeks post VTE

—> Mortality 3-fold higher in cancer patients with VTE, compared to those without (JAMA 2006)

 

Thromboprophylaxis

 

Inpatients

  • BHS recommends:

    • LMWH prophylaxis throughout medical & surgical admissions unless contraindicated

    • Extended (4 weeks) prophylaxis after abdominopelvic surgery, either LMWH throughout or initial LMWH followed by a switch to DOAC.

  • Example trials

    • Thromboprophylaxis reduces risk of VTE in medical cancer inpatients (e.g. MEDENOX 1999)

    • Thromboprophylaxis reduces risk of VTE in surgical cancer inpatients (e.g. Cochrane 2018)

Outpatients

  • BSH recommends (does not specify DOAC vs LMWH):

    • Use of a myeloma-specific risk assessment score —> prophylaxis if intermediate or high score

    • Pancreatic cancer patients receiving SACT should be offered prophylaxis

    • Consider assessing other ambulatory patients with a risk assessment score

    • Consider omitting prophylaxis when platelet count <50

  • Above similar to the NICE guidelines 2018

  • ITAC 2022 & ASH 2021 both also recommend either LMWH or DOAC

  • DOAC vs placebo trials have shown 2x rate of major bleeding with mixed success in reducing VTE (CASSINI 2018, AVERT 2022)

  • 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.

    • Myeloma scores include SAVED, PRISM and IMPEDE-VTE. All yet to be prospectively validated and none clearly superior to the others (as of 2024)

    • 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

Principles

  • Risk of recurrent VTE 2-fold higher with cancer VTE

  • Weighed against increased risk of bleeding on anticoagulants in cancer

  • —> Estimated mortality with VTE recurrence outweighs that of major bleeding (Thromb&Haem 2020)

 

Initial Six Months

  • Minimum 6 months AC recommended for CAT (BSH and ITAC)

  • DOAC or LMWH can be used first line

    • Multiple trials have shown non-inferiority of DOACs vs LMWH (see below)

    • No head to head trials of different DOACs. Possibly lower bleeding rates with apixaban.

  • Shared decision with patient about AC choice. Issues to consider:

    • Tumour site - intraluminal/intracranial tumours,

    • GI tract impairment (oral absorption)

    • Renal impairment / body weight

    • Drug interactions

    • Quality of Life

    • Patient choice

Beyond 6 months / Long-term AC

  • BSH recommends continued AC in patients with ongoing active cancer diagnosis / other persisting risk factors but consider patient’s prognosis and quality of life and discuss with patient.

  • Risk of VTE recurrence persists beyond 6 months (JTH 2022)

  • ?Reduce AC dose after six months like in non-cancer VTE. Data currently lack, trial of low dose apixaban is ongoing (as of 2024)

  • Stop if cancer eradicated and no other persisting risk factors

  • N.B. Definitions of ‘Active Cancer’ include:

    • Diagnosis within last 6 months, recurrent, regionally advanced or metastatic, treatment administered within the last 6 months or haematological cancers not in complete remission.

Recurrence during treatment

Lower recurrence rate with DOAC vs LMWH (?LMWH compliance important factor) (JHO 2022)

Options:

  • If on DOAC, consider switch to LMWH

  • If on LMWH, consider increasing 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

Some relevant trials for treatment of cancer-associated VTE

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

Epidemiology

Accounts for up to 50% of CAT. Lower risk of recurrence / fatal PE than other VTE sites (ISTH 2018)

Approx. 4% of cancer patients with CVC develop symptomatic line-associated thrombosis (JCO 2006)

DVT Risk higher with PICC, with approx. 7% developing upper limb DVT (Lancet 2013), but PE risk lower.

BSH 2024 recommends:

  • Minimum 3 months and then for as long as line remain in place

  • LMWH or DOAC (there is no comparative data)

Aim to keep line in, provided:

  • Still functioning

  • Still required for treatment

  • 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. This is expert opinion only. Other 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 (BSH 2024 + ISTH 2018)

There is no randomised trial evidence to direct treatment for CAT occurring with thrombocytopenia

BSH 2024 recommends:

  • High risk - consider transfusing platelets to a plt count >40-50 and give full dose AC

  • Low risk - consider a reduced dose AC using 50-75% or prophyl. dose LMWH for plt count 25-50

  • If it is not possible to maintain plt count >25, AC should be avoided

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)

  • Consider IVC filter only in patients with absolute contraindication to anticoagulation.

High Risk? Low Risk?

  • (High risk = includes, but not limited to, symptomatic PE, proximal DVT, previous VTE)

  • (Low risk = line-associated VTE, asymptomatic subsegmental PE, distal DVT)

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 highly variable practice.

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

 

SOMIT study 2004

  • 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